{"text": "Wild sheep and many primitive domesticated breeds have two coats: coarse hairs covering shorter, finer fibres. Both are shed annually. Exploitation of wool for apparel in the Bronze Age encouraged breeding for denser fleeces and continuously growing white fibres. The Merino is regarded as the culmination of this process. Archaeological discoveries, ancient images and parchment records portray this as an evolutionary progression, spanning millennia. However, examination of the fleeces from feral, two-coated and woolled sheep has revealed a ready facility of the follicle population to change from shedding to continuous growth and to revert from domesticated to primitive states. Modifications to coat structure, colour and composition have occurred in timeframes and to sheep population sizes that exclude the likelihood of variations arising from mutations and natural selection. The features are characteristic of the domestication phenotype: an assemblage of developmental, physiological, skeletal and hormonal modifications common to a wide variety of species under human control. The phenotypic similarities appeared to result from an accumulation of cryptic genetic changes early during vertebrate evolution. Because they did not affect fitness in the wild, the mutations were protected from adverse selection, becoming apparent only after exposure to a domestic environment. The neural crest, a transient embryonic cell population unique to vertebrates, has been implicated in the manifestations of the domesticated phenotype. This hypothesis is discussed with reference to the development of the wool follicle population and the particular roles of Notch pathway genes, culminating in the specific cell interactions that typify follicle initiation. The changes in fleece traits are consistent with the observations of Darwin , who not8.et al., One aspect of the evolution of the fleece not previously addressed has been the effect of the domestication process itself, beginning at the capture of animals from the wild and introducing them to an environment created by humans. The pioneering work of the Soviet scientist Dmitry Belayev, using wild silver foxes, demonstrated that by selecting individuals for a single behavioural trait (tameness), an array of seemingly unrelated developmental, physiological, hormonal and skeletal modifications were induced Belayev, , 1979. Iet al., et al., et al.  in which the only common denominator was that of being brought under human control (Trut , et al.  to descr9.The genetic and developmental mechanisms underlying domestication have been widely canvassed. The observations suggested that mutations with equivalent effects were present in the same genes. The phenotypic similarities in such a range of species seemed likely to result from a gradual accumulation of cryptic genetic changes early during vertebrate evolution. The implications are that the mutations, because they did not affect fitness in the wild, were not exposed to adverse selection. Their frequencies were therefore inherited unchanged, becoming increasingly buffered against alterations as species diverged. Their accumulated effects only became apparent following exposure to a human environment.et al. (et al., et al., Wilkins et al.  postulat et al., . Differe et al., , NCCs miet al., et al., et al., et al., It was proposed that the domesticated phenotype developed as a consequence of deficits in proliferation or migratory capacities of the NCCs, resulting in lower densities at their final destinations (Wilkins 10.et al., et al., et al., et al., et al., We propose that, in the sheep, rather than failing to migrate, NCCs are redirected to fates that include an increased commitment to hair follicle morphogenesis. There is evidence to support this view. NCCs are found in epidermal and dermal compartments of the skin and hair follicles, together with NC-derived cells (Fernandes et al., et al., et al., et al., et al., et al., et al., et al., Previously, we have shown that both follicle density and fibre diameter in the sheep are determined at follicle initiation (Moore 11.Primitive sheep and the modern Merino are generally regarded as occupying either end of a range of fibre-producing breeds. However, examination of the nature of the fleece and its ready adaptability suggest that the differences are less striking than their similarities. The development and types of follicles initiated are essentially identical, and similar growth cycles are present, albeit to varying degrees. The rapidity and apparent facility with which a follicle population may convert from shedding to continuous growth and revert from domesticated to feral states argue that the apparent differences are simply stages in a spectrum of types, ranging from coarse fibres and two coats to fine and continuously growing. The random appearance of primitive traits in modern flocks then becomes a not unexpected occurrence. A labile process appears to be in play.Domestication has emerged as a dynamic feature of the evolution of sheep breeds. Within this environment, modifications to the coat structure and composition have occurred in timeframes and to sheep population sizes that exclude evolutionary variations arising from random mutations and natural selection. The fact that these changes occur so consistently and, from available evidence, rapidly, points to an accumulation of a suite of genetic changes that only achieved phenotypic expression through exposure to an environment managed by humans. The involvement of NCCs in follicle morphogenesis is a working hypothesis that provides a single, coherent and essentially consistent rationale for the appearance of changes in coat structure, characteristics and composition associated with a domesticated phenotype.Seemingly, the Merino has access to an extensive wardrobe. What it is wearing at any particular time is a consequence of two competing and unrelenting environmental forces: one natural, the other human."}
{"text": "Bioelectric signals provide an extraordinary opportunity to discover and quantify a wealth of phenomena associated with the organs that generate them. In addition, they provide extensive potentially valuable information for medical doctors (MDs), physiotherapists (PTs), occupational therapists (OTs), and movement scientists (MSs), for functional diagnosis, patient path management, evaluation of patient recovery and progress, and to document or quantify the effectiveness of treatments/trainings.Clinical researchers and engineers have expected that such information would be highly welcomed by clinicians because of the evidence that such information would add to their rehabilitative activity. This has not been the case for surface EMG (sEMG), a fact that motivated this Frontiers project, as well as the publication of a number of tutorials and consensus papers \u20135, and sCampanini, Disselhorst-Klug et al., while results of interviews are presented in Manca et al., Feldner et al., and Cappellini et al. as well as the situation in specific countries , and teaching/communication experiences . Specific clinical applications concerning neurorehabilitation, gait analysis, sport, kinesiology, exoskeletons, occupational medicine, and ergonomics, are discussed in Cappellini et al., Agostini et al., Felici and Del Vecchio, Goffredo et al., Medved et al., Steele et al., Pilkar et al., Campanini, Cosma et al., Ranavolo et al., and Disselhorst-Klug and Williams.This Frontiers Project presents 18 contributions from 7 countries and 80 authors  who are highly respected experts in the many fields of sEMG. The general problem is addressed in Ranavolo et al.; Martin and Acosta-Sojo). These \u201cquantities\u201d are not easy to measure. The focus on the clinical impact of quantitative assessments of movement and of the so called \u201chard sciences\u201d to the rehabilitation field is relatively recent . Proper interpretation of sEMG requires both technical and clinical competencies. Should these two different types of expertise be merged into a single professional expert, or in two distinct professional figures?Manca et al. indicate that, in reply to their questionnaire, \u201c\u2026 the professional figure of \u2018human motion analyst\u2019 was put forward by some respondents as a possible reference to manage sEMG assessments in the clinical setting.\u201d Some interviewees in the work of Cappellini et al. made similar propositions.Some universities . Other authors propose that practical experience working with sEMG should be embedded into education in the form of workshops or course placements to effectively promote its use, and outline a basic tutorial which could be used as a tool for teaching or self-guided learning . A new medical degree addressing technological issues,The alternative option of integrating technical knowledge into the training of PTs, OTs, MSs, and other health operators, finds approval but few implementation efforts. A research group integrating clinicians from Brazil and Chile promoted a Winter School to integrate knowledge about sEMG into the background of clinical operators . Lack of time seems to be one of the main reasons behind this barrier (see the section below).Some contradictions are linked to the fact that (as opposed to ECG) visual analysis and interpretation of sEMG is not easy. However, improper muscle coordination and timing  can be readily detected visually. Nonetheless, the interpretation of this information requires a thorough comprehension of biomechanics, of the existing boundaries to movement consequent to pathology and, more generally, several years of expertise  as well as insufficient education/practice during refresher courses (reported by 20/28), and inadequate education and training of PTs and MDs on sEMG (reported by 17/28). This is another vicious cycle since adequate education, in turn, reduces time for learning and clinical application.Difficult interpretation of sEMG without specific education/training was reported by 21 out of 28 interviewees .Most clinical research studies involving sEMG have been carried out by engineers and life-scientists in research centers, on small groups of 10\u201350 subjects. Larger clinical trials are few because they must be carried out within health institutions where engineers are rarely present and clinical operators may lack the competence, the support, and the time to carry them out , but the initial effort of the SENIAM project  and its Disselhorst-Klug and Williams) along with the contribution to clinical decision-making . Scientific societies should address this issue.On another related issue, the number of publications about methodologies for sEMG analysis is overwhelming and confusing. Twenty-four years ago Hodges and Bui  tested 2Feldner et al.; Martin and Acosta-Sojo). The application and connection of electrodes is indicated as time-consuming. This is no longer true with the use of wireless systems but knowledge about proper electrode positioning is required to promote time saving .Only a few insurance companies reimburse basic sEMG examinations. Institutional stakeholders should outline the fact that muscle assessment for proper treatment selection would likely generate savings, rather than cost increases  would reduce the weight of ineffective therapies, increase insurance profits, and reduce costs for national health systems.Furthermore, in stroke patients \u201csurface EMG would supply information for better assessment of deficits as well as rehabilitation progress and/or efficacy\u201d . In theSeveral negative factors, inconsistencies, and contradictions are outlined in the project. On the one hand, rehabilitation clinicians; (a) recognize the value and need for formal education to enable more rigorous and clear evidence highlighting the benefits of sEMG; and (b) assert that the opportunities to pursue it are inadequate due to administrative and time resource limitations. On the other hand, many textbooks  and the Removing administrative obstacles is equally important to lighten the workload of clinical operators, leaving time for applying and investigating more recent and well-documented techniques. Doing so would promote experience-based technical improvements, prime virtuous cycles incrementing knowledge, applications, market, and reducing the commercial prices of devices.Introducing new professional figures such as rehabilitation engineers or clinical technologists (see text footnote 1), alongside clinical operators, would substantially reduce (but would not eliminate) the need for technical training of the latter. As rehabilitation technology is rapidly developing, such figures will become necessary very shortly and early training of these operators is certainly appropriate. The clinical responsibilities of these two professional figures should be defined soon. Finally, a common language for proper communication must be available on both sides to understand the information carried by sEMG.All authors contributed equally to the preparation of the Editorial.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Mental imagery is a multimodal cognitive simulation process that enables us to represent perceptual information in our minds in the absence of actual sensory input  and MIP? Thirdly, how do cognitive representations of covertly rehearsed skills change during MIP? Finally, what aspects of MI skills change over time as a function of MIP? Before addressing these issues, however, we must consider how MIP effects are typically explained.Motor simulation theory (MST; Jeannerod, In the traditional MIP paradigm, participants in the cognitive rehearsal condition receive a scripted sequence of instructions designed to help them to see and feel the target skill in their imagination. Surprisingly, little is known about how people translate such verbal or written instructions into procedural skill representations. Nevertheless, sport psychology researchers like Holmes and Collins  and WillWM is a cognitive system that stores and manipulates currently relevant information for short periods of time (D'Esposito and Postle, In sport, expert performers are adept at prioritizing specific contextual and motor-relevant information in order to anticipate opponents' offensive plays (e.g., see Murphy et al., A key tenet of modern cognitive psychology is the assumption that human behavior is causally related to \u201cmental representations\u201d\u2014knowledge structures in memory that correspond to objects of thought. Accordingly, Schack and Ritter  cognitivWhat effect does MIP have on mental representation development in skill learners? Frank et al.  investigThere is evidence to suggest that MIP can improve MI ability (Rodgers et al., Although at first glance, thinking and action appear to lie at opposite ends of the behavioral spectrum, cognition and action are elaborately interconnected (Rosenbaum et al., All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "As the authors of the article \u201cViewpoint: WHO World Mental Health Surveys International College Student Initiative: Implementation issues in low\u2010 and middle\u2010income countries\u201d (LMICs) have pointed out, the university system and the number of students are rapidly growing and changing in LMICs (Evans\u2010Lacko & Thornicroft, Although racism is known to have a causal link with morbidity, disability, and mortality, this issue is not commonly addressed in public health or mental health agendas (Bailey et al., Likewise, South Africa has an ongoing challenge to reconcile a society strongly harmed by racism. At the end of the apartheid system, the early 1990s started a process of liberation; however, in what is known as the Soudien Report, a Ministerial Committee on Transformation and Social Cohesion and the Elimination of Discrimination in Public Higher Education still found discrimination based on gender and race to be endemic in public higher education institutions (Soudien et al., We support Evans\u2010Lacko and Thornicraft's  contentiHigher education systems in Brazil and South Africa leave black students and academics with experiences of alienation, limiting a healthy experience of belonging for black students within their campuses. Nonetheless, racist experiences among students have also been acknowledged as an issue in other large LMICs (Laruelle,"}
{"text": "The effect of long\u2010term chemical fertilization on plant\u2010microorganisms and microbe\u2010microbe interactions. In fact, in order to feed the growing world population, current estimates indicate that our global agricultural output will need to be increased by at least 50% by 2050 (Muller et al., et al., et al., et al., et al., et al., et al., et al., The interactions between plants and non\u2010pathogenic bacteria have been largely studied, and the advantages that both partners obtain from such association have been explored in different model systems (Berg and Koskella, et al., et al., et al., et al., et al., et al., et al. (et al., (in silico analysis revealed that long\u2010term fertilization not only reduced the interactions between soil microbes but also the complexity of the networks between plants and functional microbial communities. Thus, while five plant species showed an association with microbial functional genes in unfertilized soils, only one plant species showed a connection with microbial functional groups in long\u2010term fertilized soils. Finally, the authors showed that carbon and nitrogen contents in soil were the main parameters that modulate plant and microbe networks. They further highlighted that functional microbial communities play an important role in plant diversity (Huang et al., The emergence of the above\u2010mentioned next\u2010generation green revolution aimed at developing sustainable alternatives to improve crop production is also reflected in the increasing number of articles that are focused on investigating the composition of soil microbiota and how soil treatments alter bacterial soil communities. Among them, there is a remarkable number of studies that investigate the impact of long\u2010term fertilization, chemical or organic, on the diversity of plants and microorganisms. In general, these studies reveal that chemical fertilization reduces the diversity of plants and microorganisms as well as negatively impacts plant\u2013microbe interactions and the soil microbiome\u2019s capacity to contribute to soil nutrient cycling (Pierik , et al.  recently(et al.,  found thet al., et al., et al., et al., et al. (Anthropogenic changes in natural ecosystems are dramatically affecting global diversity. In particular, the soil microbiome plays a key role in modulating plant diversity as well as nutrient retention and recycling (Geisen , et al. . ConsequNone declared."}
{"text": "Dear Editor,As the evidence base for the efficacy of physical exercise for cognition in older adults is mounting, efforts to detect the most efficacious exercise settings are critical for clinical translation and guidelines development. Chen et al.  conducten\u2009=\u20093008 (Table 2) to 7023 in the overall model, (b) underestimation of standard error and thus overestimation of precision, and (c) assigning excessive weight to studies that reported multiple outcomes regardless of their actual sample size, which bias not only the pooled effect estimates but also investigations of small-study effect (\u2018publication bias\u2019). Although Chen et al.    are unliThird, it is not clear to us why the authors chose to include only studies published since 2003, i.e., after the publication of Colcombe and Kramer\u2019s seminal meta-analysis in this area . In theiLike many in the exercise science and sports medicine community, we were encouraged by Chen et al.\u2019s  positive"}
{"text": "Blood flow restriction (BFR) training is a bourgeoning exercise modality which promotes increases in skeletal muscle mass and strength during resistance exercise Sato, . In pracSpranger et al.  offered Several studies in young, healthy individuals have shown that BFR-RE exacerbates cardiovascular responses. Downs et al.  reportedWhile caution is warranted even in healthy individuals, the primary concern of Spranger et al.  specificA few studies have employed BFR-RE in populations with cardiovascular disease with generally favorable conclusions. However, these conclusions were drawn despite the fact that either hemodynamics were not assessed in the study (Madarame et al., Patterson et al. , profferPatterson et al.  intend fThe author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Telomere attrition is increased in various disorders and is therefore a potential biomarker for diagnosis and/or prognosis of these disorders. The contribution of telomere attrition in the pathogenesis of neurodegenerative disorders is yet to be fully elucidated. We are reviewing the current knowledge regarding the telomere biology in two common neurodegenerative disorders, Alzheimer\u2019s disease (AD), and Parkinson\u2019s disease (PD). Furthermore, we are discussing future prospective of telomere research in these disorders. The majority of studies reported consistent evidence of the accelerated telomere attrition in AD patients, possibly in association with elevated oxidative stress levels. On the other hand in PD, various studies reported contradictory evidence regarding telomere attrition. Consequently, due to the low specificity and sensitivity, the clinical benefit of telomere length as a biomarker of neurodegenerative disease development and progression is not yet recognized. Nevertheless, longitudinal studies in large carefully selected cohorts might provide further elucidation of the complex involvement of the telomeres in the pathogenesis of neurodegenerative diseases. Telomere length maintenance is a complex process characterized by environmental, genetic, and epigenetic determinants. Thus, in addition to the selection of the study cohort, also the selection of analytical methods and types of biological samples for evaluation of the telomere attrition is of utmost importance. Telomeres are tandemly repeated nucleotide sequences at the end of the linear chromosomes. Their main function is maintaining genomic stability by protecting chromosomal ends from degradation and end-to-end fusion  is considered as a surrogate marker for other cells as well. In elderly patients, TL in leukocytes is significantly shorter compared to skin, synovial tissue  method enables measurement of all individual telomeres per metaphase , type and amount of sample required, accuracy, reproducibility, robustness, throughput, and technical skills required. Terminal Restriction Fragment (TRF) analysis using Southern blot (Harley et al., The selection of a method should be made with consideration of their advantages and disadvantages. For larger epidemiology and population studies qPCR is the most practical choice while q-FISH and STELA are more appropriate for studies with fewer samples or when more accurate and specific measurements are required (Aubert et al., During embryonic brain development, most cells express telomerase, while after birth, the activity in most cells quickly declines to undetectable levels (Wright et al., Studies of the relationship between TL and cognitive performance have led to inconsistent results. While TL was reported in cognitive decline in elderly people and suggested to be a possible biomarker of cognitive aging (Kljajevic, post-mortem study in neuropsychiatric disorders reported a highly significant difference in TL in different brain regions, where telomere were the longest in substantia nigra and the shortest in the dorsolateral prefrontal cortex (Mamdani et al., LTL has been proposed as a surrogate marker for the central nervous system TL (Daniali et al., Telomere attrition has been investigated in many neurodegenerative disorders (Eitan et al., AD is a slowly progressing neurodegenerative disease and a common cause of dementia in the elderly worldwide (Prince et al., Amyloid-beta deposition and advanced age are the major risk factors for AD development, and both have been associated with the activation of microglia (Flanary et al., Oxidative stress can trigger chronic inflammation and contribute to neuronal dysfunction and cell death in AD (Mhatrea et al., Studies of TL in patients with AD are inconsistent. Their major observations along with the characteristics of the study cohorts and methods are summarized in Guan et al.  publisheLukens et al., 2009, reported a direct correlation between TL in leukocytes and cerebellum, but cerebellum TLs were not significantly different in AD patients (Lukens et al., A few studies investigated TLs in brain tissue. The data regarding the involvement of telomere attrition in AD progression is contradictory and needs further elucidation. The common characteristic of all these studies but one (Honig et al., Parkinson\u2019s disease is characterized by both motor and non-motor features (Kalia and Lang, substantia nigra were also reported in PD patients (Hudson et al., Studies of TLs in patients with PD showed contradictory results and are summarized in The majority of the studies reported no significant telomere attrition in PD . A SwediReported studies evaluating TL in PD are very heterogeneous regarding the study population, sample type, TL detection method, and the cohort size. Even though telomere attrition was observed in only two studies with 30 or fewer participants and different sample types (Maeda et al., Studies of telomere dynamics in AD and PD have provided inconclusive results. Currently, the telomere attrition is believed to be associated with AD (Forero et al., Smith et al., using an umbrella review approach where findings were derived by examining the epidemiological credibility of the evidence, pointed out several weaknesses in reporting relationship between TL and different disorders (Smith et al., The clinical benefit of TLs as a biomarker of neurodegenerative diseases is questionable due to its low specificity and sensitivity. Telomere shortening is not present only in neurodegenerative diseases, but also in a vast amount of other diseases and different demographic factors may contribute to telomere attrition. A recent study by Different study designs, methods for TL measurement, and tissues in which TLs are investigated may contribute to the variability between studies. Moreover, although qPCR is the most commonly used method in TL measurement, there are still inconsistencies in recent reports. Recently, Lin et al. carefully evaluated all critical steps in qPCR telomere length assay and provided guidance and recommendations for each step based on current knowledge (Lin et al., post mortem studies of TLs in different brain cells are needed to fully evaluate the LTL as the appropriate surrogate marker for the central nervous system.One of the most important aspects is the selection of the representative tissue that corresponds to the pathological processes in the affected tissue, such as the brain in neurodegenerative diseases. The discrepancy in TL in different brain regions (Mamdani et al., The number of subjects to show statistical significance between two groups is a crucial factor and must be calculated taking into account high inter- and intra-variability in TLs. In most reported studies, the sample size was relatively small, which may be the cause for statistical insignificance. Furthermore, classification of the patients into subgroups, such as progression rate, disease stage, etc. may be beneficial to show statistical significance, but it requires an even larger total sample size. In this view, the longitudinal studies in carefully selected cohorts may provide more reliable results since a smaller sample size is needed (Aviv et al., To conclude, longitudinal studies in carefully selected cohorts and sample types are required to elucidate the complex role the telomeres may have in the pathogenesis of neurodegenerative diseases and possible targets for intervention with a final goal to possibly prevent or delay neurodegenerative diseases. Furthermore, the integration of various experimental and clinical data might improve the strength of such studies. Additionally, standardized protocols for TL measurements addressing sample types and methods might be beneficial since and would enable a more relevant comparison of results from different laboratories.TL and EK wrote the manuscript. VD revised the manuscript. KT conceptualized, wrote, and revised the manuscript. All authors reviewed and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "People suffering from neurological conditions such as Parkinson's disease, stroke, and brain injury encounter and endure numerous situations in their daily lives that cause excess disability and restrict full participation in their meaningful activities.Neuroscience and rehabilitation science are complementary disciplines, engaged in the exploration of the human Central Nervous System (CNS) and the amelioration of functional disability. There is often, however, a lack of discourse between these disciplines, which precludes opportunities for meaningful exchange and synergistic collaboration to improve the lives of people who suffer from a disability.The goal of this current theme issue was to foster original research papers in neuroscience and rehabilitation science that may serve to address the existing disconnect between disciplines. This platform offered an opportunity for a meaningful exchange of ideas, findings, and practices toward ultimately promoting knowledge, improving clinical practice, and reducing performance deficits and participation restrictions for people with neurological ailments and diseases. This broader, biopsychosocial approach to understanding rehabilitation and recovery from neurological deficits, embraces the concept that true understanding of recovery and living with a chronic condition, goes beyond knowledge of disease mechanisms. Social determinants and secondary disease sequelae may have a significant impact on functional performance and participation.The initial call for papers invited researchers and practitioners to submit research papers on the topic of \u201cPerformance and Participation Outcomes for Individuals with Neurological Conditions.\u201d This focused topic recognized the need for a more comprehensive and integrative perspective in research and practice to address this disconnect between neuroscience and rehabilitation. This perspective should thus reveal neglected key domains, as well as incorporate a range of components intricately involved in human performance, such as motor, sensory, cognitive, and emotional components. Such integration may serve to significantly enhance the functional outcomes for persons suffering from any of the range of neurological conditions.The theme call aimed at addressing these respective issues by soliciting original research papers, review articles, or meta-analyses, covering topics ranging from basic research to translational studies anchored in neuroscience or rehabilitation.Schliep et al.;Val\u00e8 et al.;Wang, Wang et al.; and Sul et al. addressed the need for greater understanding of prognostic indicators of recovery such as lesion location, behavioral characteristics, EMG assessment in motor disorders, and the initiation of swallowing in disorders of consciousness. Performance outcomes and their contributors was the focus of Fasoli and Adans-Dester, Ranford et al., Yael et al., and McCambridge et al.. The vast majority of the papers included in this special issue cluster around the multifactorial outcome of participation: Rotenberg et al., Malone et al., Yosef et al., Wang, Chan et al., Toglia et al., Erler et al., Nicholas et al., and Cattaneo et al..The encouraging response to our call yielded 22 submitted papers that underwent a peer-review process. Ultimately, 16 papers were adjudged to favorably meet the theme call objectives and scientific standards. As this special issue was designed to organize our thinking around outcome, rather than disease, we provide a classification of the articles by their primary outcome focus. We categorized the papers as addressing prognostic indicators of recovery (4 articles), performance (4 articles), or participation (8 articles). The breadth of neurological conditions and methodological approaches in this issue is astounding. Although broad in scope, our focus on the larger outcomes of people with neurological conditions, we believe, enables us to glean principles for maximizing performance and participation at the highest conceptual level. One of the most striking themes that emerged from this collection, for example, is that cognitive and emotional factors are of utmost importance for the performance of motor-intensive activities and participation in life activities that are motorically-demanding in diseases classically thought of as diseases of the motor system. Moreover, social support is a major predictor of resumption of pre-disease activities.Of course, putting the focus on outcome introduces factors that are outside the purview of neurological science and will not replace studies focused on disease mechanisms that foster new treatment approaches aimed at treating or curing disease. The vast majority of the patients living with these neurological conditions will be doing just that\u2014living with their chronic conditions. Our hope is that a more holistic scientific treatment of factors predicting outcome will advance our rehabilitation attempts to promote better living for people with neurological conditions.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Mitochondria are indispensable for energy metabolism and are essential for the regulation of many cellular processes in healthy as well as in transformed cells. Mitochondria in malignant cells differ structurally and functionally from those in normal cells, which make them a promising target for anticancer therapy. Mitochondria in cancer cells are characterized by reactive oxygen species (ROS) overproduction, which promotes cancer development by inducing genomic instability, modifying gene expression and participating in signaling pathways. Additionally, the pleiotropic roles of mitochondrial ROS in the regulation of anticancer immunity are now coming to light. The involvement of mitochondria in cancer cell metabolic reprogramming as well as in the anticancer immune response has been utilized for designing novel mitochondria-targeted anticancer agents. However, we are still far from an in depth understanding of the role played by mitochondria in cancer development. Therefore, the main aim of this Special Issue was to collect novel findings and ideas from scientists involved in basic research as well as in translational studies in the field of mitochondria and cancer. Hguen and Pandey  discusseAnother interesting point in gender-related anticancer treatment is the topic of the review of Stakisaitis et al.: \u201cThe Importance of Gender-Related Anticancer Research on Mitochondrial regulator Sodium Dichloroacetate in Preclinical Studies In Vivo\u201d . The revJeena et al.  hypothesAutophagy is a key node for the regulation of ROS levels as well as for the ROS-dependent cellular regulation. Therefore, such regulation could be a potential target mechanism for cancer treatment. Based on this idea, Sanches-\u00c1varez et al.  recognizThe drug resistance, without question, is a huge barrier in the struggle against cancer. As previously mentioned, it is important to know the structural differences between normal and cancer cells. Moscheni et al.  also conFinally, Meng et al.  in theirSummarizing, a small but high quality spectrum of reviews and original papers from this issue provides an insight into new research directions linked to an extremely important topic \u201cMitochondria and Cancer\u201d. I hope all readers of this Special Issue enjoy taking a closer look into a subject of this compendium."}
{"text": "Figure 1 legend and should read:In the original article Albert et al. Figure 1. Previously published sets of transcriptomic data (Florio et al., The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
{"text": "Biological invasions are a global consequence of an increasingly connected world and the rise in human population size. The numbers of invasive alien species \u2013 the subset of alien species that spread widely in areas where they are not native, affecting the environment or human livelihoods \u2013 are increasing. Synergies with other global changes are exacerbating current invasions and facilitating new ones, thereby escalating the extent and impacts of invaders. Invasions have complex and often immense long\u2010term direct and indirect impacts. In many cases, such impacts become apparent or problematic only when invaders are well established and have large ranges. Invasive alien species break down biogeographic realms, affect native species richness and abundance, increase the risk of native species extinction, affect the genetic composition of native populations, change native animal behaviour, alter phylogenetic diversity across communities, and modify trophic networks. Many invasive alien species also change ecosystem functioning and the delivery of ecosystem services by altering nutrient and contaminant cycling, hydrology, habitat structure, and disturbance regimes. These biodiversity and ecosystem impacts are accelerating and will increase further in the future. Scientific evidence has identified policy strategies to reduce future invasions, but these strategies are often insufficiently implemented. For some nations, notably Australia and New Zealand, biosecurity has become a national priority. There have been long\u2010term successes, such as eradication of rats and cats on increasingly large islands and biological control of weeds across continental areas. However, in many countries, invasions receive little attention. Improved international cooperation is crucial to reduce the impacts of invasive alien species on biodiversity, ecosystem services, and human livelihoods. Countries can strengthen their biosecurity regulations to implement and enforce more effective management strategies that should also address other global changes that interact with invasions. I.(1)et al. . However, in the second call, besides stressing the need to respond to indirect drivers of biodiversity loss , Ripple et al.  addresseet al. . IAS are et al., . The rec(2)et al., et al., et al., et al., et al., et al., Alien species (as opposed to native species) are those whose presence in a region is attributable to human actions, deliberate or inadvertent, that enabled them to overcome biogeographical barriers (Richardson (3)i) appraise the current state of biological invasions in marine, freshwater, and terrestrial ecosystems; (ii) show that current societal responses are insufficient to address impacts of IAS on ecosystems, biodiversity, and human well\u2010being and to mitigate future risks; and (iii) argue that a warning to humanity regarding the threats posed by IAS is both timely and relevant to complement other focused papers pointing to current threats to nature and the importance of nature for humans  Where do we stand? (ii) Why should we care? (iii) What tools are available to deal with these problems? (iv) What comes next? We treat these questions separately and then provide recommendations for policy, management, and research.To support global initiatives addressing the loss of biodiversity and ecosystem services, this paper presents a comprehensive global overview of a major environmental change \u2013 invasion by alien species. We (II.(1)et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., www.iucngisd.org), which contains profiles of key IAS, and the Global Register of Introduced and Invasive Alien Species , and NEMESIS (https://invasions.si.edu/nemesis) exemplify cross\u2010taxonomic initiatives that have produced such databases for particular regions , and the aliens also reach much higher abundances  have led to established alien populations  as a well\u2010known reptile example et al., via anthropogenic corridors ; or unaided spread from other invaded regions. The intentional pathways \u2018escape\u2019 and \u2018release\u2019 are most important for plants and vertebrates, whereas for invertebrates, algae, fungi, and microorganisms, unintentional \u2018contaminant\u2019 and \u2018stowaway\u2019 transport pathways prevail; representation of these pathways differs only slightly among marine, freshwater, and terrestrial environments  of the CBD calls for urgent action by the Parties (i.e. signatory States) to identify and prioritize alien species pathways and to implement measures to manage pathways to prevent alien species introduction and establishment CBD, . Six broet al., Bufo marinus; Shanmuganathan et al., Historically, many species were deliberately released for economic, recreational, or aesthetic benefits Lever, . Althouget al., et al., et al., Ornamental plants have escaped from gardens for centuries  between the Atlantic and Pacific Oceans. As with ocean plastic rafting, we have yet to fully grasp the short\u2010 and long\u2010term consequences of the disappearance of the ice\u2010bound Arctic, which has long formed an impassable barrier between oceans and continents  migrating from the UK to Spain, or the currant\u2010lettuce aphid (Nasonovia ribisnigri), dispersing on wind currents from New Zealand to Tasmania and subsequently throughout Australia. This unaided pathway poses major challenges for international regulation as well as biosecurity measures within individual countries et al., et al., et al., et al., et al., et al., et al., et al., 2017) or indirectly through other variables, such as the movement of particular commodities, eutrophication, or the intensity of anthropogenic disturbance et al., et al., et al., et al., The acceleration of alien species introductions and invasions has been highlighted for several regions et al., www.protectedplanet.net); they are a key component of the societal response to environmental degradation et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Given the many pressing environmental issues, one must ask how prominently biological invasions should feature in political and public agendas? The magnitude and variety of impacts of IAS provide an unambiguous reason for much more urgent attention to be given to invasions. Research on invasion impacts has developed rapidly over the past decade , four mammals , one crayfish (Procambarus clarkii), the varroa mite (Varroa destructor), and four plants   and insects . One must also consider that native species, even if not yet driven to local or global extinction, often suffer from population declines attributable to IAS, and many now exist only as remnant populations et al., et al., et al., Mnemiopsis leidyi, which led to the abandonment of anchovy fisheries in parts of the Black Sea because clogging of nets by this species made fishing impractical  injuring fishermen in the eastern Mediterranean  threatening outdoor activities and causing costs associated with the nuisance of large colonies near homes in parts of Australia et al., et al., Invasion biologists and policy\u2010makers generally agree that efficient responses to biological invasions require prioritizing measures to prevent the arrival of potentially invasive alien species, the timely management of incursions, and effective management of those already established  by 2050 . The ongoing process of maintaining the list relies on collaboration between scientists and policymakers. The European example highlights the key components required to establish robust and sustainable policies for dealing with biological invasions et al., et al., et al., https://www.ippc.int) of the UN Food and Agriculture Organization as the international standard\u2010setting body for border biosecurity. Because import quarantines can be cited as unfair barriers to free trade, the IPPC provides rules by which national plant protection organizations can implement biosecurity practices. The IPPC also sets standards that are harmonized among countries to limit the spread of invasive alien species while promoting free trade. Under IPPC guidelines, each country is able to select a level of predetermined risk when implementing biosecurity practices, but this selection must be justified based on the best available science and uniformly applied .The term \u2018biosecurity\u2019 refers to measures to prevent and manage biological invasions Hulme, a. A clo(3)et al., et al., et al., et al., Petromyzon marinus) with an eye towards control in the Laurentian Great Lakes  when the insect attacks the plant   of the bee to express dsRNA sequences of varroa mite genes, thus entraining the mite's RNAi (ribonucleid acid interference) mechanism, killing the mite. Gene\u2010silencing for control of invasive populations is also under study for plants  into cells to destabilize messenger RNA, has been studied especially for applications to human health and agriculture, but with much research also aimed at getting targeted invasive species to eat substances including dsRNA . Other invasive animals targeted by current projects entailing use of transgenes include the Channel catfish , common carp (Cyprinus carpio), and Pacific oyster (Crassostrea gigas)  and GBIRd for invasive rodents (www.geneticbiocontrol.org).Recognition that CRISPR\u2010Cas9  gene\u2010editing technology, usually together with transgenes, could aid in management or eradication of invasive alien species (Esvelt (4)et al., et al., et al., et al., et al., The importance of early\u2010warning and rapid\u2010response initiatives, and concurrently the need for surveillance to inform such approaches, is widely recognized. Most countries do not implement integrated national invasive alien species surveillance programs. Also, many IAS that can affect biodiversity and ecosystems adversely do not fulfil the criteria for inclusion under government\u2010funded schemes. Engaging volunteers in surveillance and monitoring is a low\u2010cost, large\u2010scale, and long\u2010term option , but also through non\u2010linearities and synergisms with other components of global change. Unlike some other components of global change, biological invasions can be effectively managed and mitigated. We suggest the following priorities to ensure progress in dealing effectively with the many dimensions of biological invasions.(1)et al., et al., et al., et al., Acacia). The forthcoming assessment of IAS as part of IPBES will play a crucial role in this endeavour. This first comprehensive assessment will address past and future trends in the spread, pathways, evolutionary change, and distribution of invasive alien species, and gaps in existing knowledge; direct and indirect drivers responsible for their introduction, spread, abundance, and dynamics; global environmental, economic, and social impacts of invasive alien species; the effectiveness of past and current programmes and tools for the global, national, and local prevention and management and future options for the prevention and management of invasive alien species; and analysis of possible support tools for decision makers. A number of overarching themes are also being developed to guide the assessment including interactions of IAS with climate change. The IPBES assessment will bring together more than 70 experts spanning diverse disciplines. The completed assessment is expected to be presented in 2023 to the 10th session of the IPBES Plenary composed of representatives from 132 member states.National capacities to respond to invasions differ among countries (Early (2)et al., et al., i) high\u2010risk pathways, activities, and/or societal sectors that use alien species  to prevent introduction, (ii) newly arrived species for removal to prevent further spread, and (iii) vulnerable habitats/native species to monitor and impede invasions from impacting them. Managing invasions is difficult and often expensive, but emerging evidence shows that even expensive interventions, especially related to prevention, generally result in net benefits et al., et al., Protected areas are an important part of global efforts to conserve biodiversity. Nevertheless, integrated efforts involving science, management, and policy for dealing with IAS in protected areas are insufficient. The extent and overall impact of invasive species in protected areas is increasing worldwide, especially for invasive plants, despite some notable successes in dealing with such invasions (Shackleton (4)et al., et al., conditio sine qua non in the quest for comprehensive solutions to deal with biological invasions. Overcoming knowing\u2013doing gaps et al., et al., et al., et al., Despite numerous correlative bioclimatic models predicting that many alien species will likely become more widespread as a result of climate change, there is a dearth of empirical data that clearly link shifts in alien species distributions with changes in temperature or precipitation. Analysis of long\u2010term and large\u2010scale spatial data on alien species distributions is urgently needed to disentangle how they correlate with climate variables and other aspects of global change, such as intensified land use and transformation, pollution, and propagule pressure (Bellard VII.(1) Biological invasions are a major driver of ecosystem degradation. The number of invasive alien species is increasing rapidly with no evidence that either the rate of species introduction or the emergence of new invasive species is slowing down.(2) Islands and coastal mainland areas are hotspots of invasions, but ecosystems in all biomes throughout the world are increasingly affected. Although boundaries of protected areas provide some resistance to invasions, even the most isolated and well\u2010managed reserves are experiencing pressure from invasive alien species.(3) The global escalation in biological invasions is attributed to the increase in the number of pathways of introduction and spread of species, and particularly the volume of traffic (and therefore species) along these pathways. Emerging pathways are creating new categories of invasions, such as plastics providing rafts for transport of organisms across oceans.(4) Interactions with other drivers of global change are exacerbating current biological invasions and facilitating new ones, thereby greatly escalating the extent and impacts of invaders. Although biological invasions are sometimes symptoms (or \u2018passengers\u2019) of other human\u2010mediated change, they are themselves often key drivers of change.(5) Invasions have complex and often immense long\u2010term direct and indirect impacts, many of which manifest decades or more after invasions commence, when the invaders are established and extend across large geographic ranges. Invasive alien species break down biogeographic realms, affect native species richness and abundance, increase the risk of native species extinction, affect the genetic composition of native populations, change native animal behaviour, alter phylogenetic diversity across communities, and modify trophic networks. Many invasions alter ecosystem functioning and the delivery of ecosystem services, thereby adversely impacting human livelihoods. All these types of impacts are accelerating and predicted to increase in the future, often following non\u2010linear trajectories. Despite advances in understanding impacts of biological invasions, little is known about the impacts of alien pathogens  and associated emerging infectious diseases on biodiversity and ecosystems.(6) Strategies to reduce future invasions are in place in many countries but are often implemented ineffectively. Unlike some other facets of global environmental change, with sufficient foresight and resources many biological invasions can be managed and mitigated. There is increasing evidence of successful long\u2010term and large\u2010scale management of established invaders, such as the eradication of mammals on increasingly large islands and biological control of weeds across continental areas. In many countries, however, invasions receive inadequate attention. Management approaches must be objectively prioritized by accounting for feasibility and considering invasion debt . Engaging people from diverse stakeholder groups is essential to enhance understanding of biological invasions and inform decision\u2010making including effective implementation of biosecurity.(7) Multidisciplinary collaborations and integrated approaches through international cooperation are critical to reduce the impacts of invasive alien species, including alien pathogens, on biodiversity, ecosystem services, and human livelihoods. Countries must strengthen their biosecurity regulations to implement and enforce effective management strategies that address invasions in tandem with other facets of global change.VIII.P.P., J.P. and L.C.F. were supported by EXPRO grant no. 19\u201028807X (Czech Science Foundation) and long\u2010term research development project RVO 67985939 (Czech Academy of Sciences). S.B. was supported through the 2017\u20102018 Belmont Forum and joint call for research proposals, under the BiodivScen ERA\u2010Net COFUND programme, and by the Swiss National Science Foundation . F.E. was supported by a grant from the Austrian Science Foundation FWF (grant I 3757\u2010B29). L.C.F. acknowledges South African National Parks, the DSI\u2010NRF Centre of Excellence for Invasion Biology, Stellenbosch University, and the National Research Foundation of South Africa (Grant Numbers IFR2010041400019 and IFR160215158271). P.E.H. was supported through grant C09X1611 \u201cWinning against Wildings\u201d from the New Zealand Ministry of Business, Innovation and Employment. J.M.J. was supported by the Deutsche Forschungsgemeinschaft  and the Belmont Forum\u2010BiodivERsA projects InvasiBES and AlienScenarios with the national funder German Federal Ministry of Education and Research . A.M.L. was supported by EVA4.0, No. CZ.02.1.01/0.0/0.0/16_019/0000803 financed by OP RDE and by the USDA Forest Service. A.P. was funded by CONICYT AFB\u2010170008 and Fondecyt 1180205. D.M.R. acknowledges support from the DSI\u2010NRF Centre of Excellence for Invasion Biology and the Oppenheimer Memorial Trust (grant 18576/03). H.E.R. was supported by the Natural Environment Research Council award number NE/R016429/1 as part of the UK\u2010SCAPE programme Delivering National Capability. M.v.K. was supported by the Deutsche Forschungsgemeinschaft (DFG: grant 264740629). M.V. was supported by the Belmont Forum\u2010BiodivERsA project InvasiBES (PCI2018\u2010092939) funded by the Spanish Ministerio de Ciencia, Innovaci\u00f3n y Universidades. H.S. was supported by Belmont Forum\u2010BiodivERsA with the national funder German Federal Ministry of Education and Research . D.S. was supported by the Nancy Gore Hunger Professorship in Environmental Studies at the University of Tennessee."}
{"text": "We are very glad to hear from Maertens and Blot , and theIn the study reported by Mahmoodpoor et al. in 2013 [In another study published by Monsel et al. in 2016 , in ordeIn most of the studies included by us, the polyvinylchloride (PVC) cuffs were used, and many other studies suggested that polyurethane- (PU-) tapered cuffs showed no benefits on microaspiration reduction. Thus, only PVC cuffs in Philippart's study reported in 2014  were incIn Mahmoodpoor's study reported in 2017 , the tapOur study only included the published studies but not the unpublished studies.Finally, we believe that we share with Maertens and Blot  the opin"}
{"text": "Increasing rates of male infertility have led to a greater need for relevant model systems to gain further insight into male fertility and its failings. Spermatogenesis and hormone production occur within distinct regions of the testis. Defined by specialized architecture and a diverse population of cell types, it is no surprise that disruption of this highly organized microenvironment can lead to infertility. To date, no robust in vitro system has facilitated full spermatogenesis resulting in the production of fertilization\u2010competent human spermatozoa. Here, we review a selection of current in vitro systems available for modelling the human testis microenvironment with focus on the progression of spermatogenesis and recapitulation of the testis microenvironment. Additionally, CSF\u20101, produced by Leydig cells, has been demonstrated to promote self\u2010renewal of SSCs which is perhaps unsurprising given their proximity to the SSC niche  supplementation  to generate rat testicular organoids in vitro (Alves\u2010Lopes et al., et al., et al., et al., et al., Alternative dynamic culture approaches have been described in an attempt to promote germ cell differentiation in vitro. Using a bioreactor system, Perrard and colleagues report differentiation of morphologically mature spermatozoa from spermatogonia in human seminiferous tubule fragments enclosed in porous chitosan hydrogel tubes immersed in culture medium (Perrard A functioning somatic microenvironment is crucial for the process of spermatogenesis. When considering in vitro modelling of the human testis with the intent of generating mature spermatozoa, this must be a primary consideration. Studies that have made the most progress have either exploited the intrinsic microenvironment using testis tissue fragments or encapsulated dissociated cells within a supportive matrix to generate a 3D structure. In the effort to replicate human spermatogenesis in vitro, future focus should be on maintaining the functional niche or, in the case of immature tissue, maturation of the niche to support spontaneous spermatogenesis."}
{"text": "Lancet Psychiatry position paper on multidisciplinary research priorities for the coronavirus disease 2019 (COVID-19) pandemic (Holmes et al., et al., et al., Older adults have been identified as a \u201cpopulation of interest\u201d by the recent et al., et al., Learning from history is a helpful starting point. Even as far back as the 1918\u20131919 \u201cSpanish\u201d influenza pandemic, there has been discussion of an increase in rate of psychosis and suicide at that time Harris, . The impet al., et al., The very recent history of providing mental health services to older adults in China during the COVID-19 pandemic has been challenging, with the \u201cdigital divide,\u201d quarantines, and restrictions on movement having significant impact (Yang Older adults living with dementia in the COVID-19 world have experienced reduced access to support and activities. These changes have caused distress and exacerbated behavioral and psychological symptoms of dementia. We have seen community-dwelling older adults with dementia referred due to inability to understand and retain information about social distancing, with relatives fearing they will be at risk of contracting COVID-19 or receiving penalties from law enforcement agencies. A concerning development is the increasing media discussion about the relative worth of human lives based on age and remaining life expectancy which could divide generations and challenge established ethical values.et al., et al., Our response to COVID-19 for older adults can borrow general mental health recommendations from historic pandemic influenza preparedness initiatives including a focus on strengthening social networks and community support, communication networks, directive leadership and stress management (Douglas Lancet Psychiatry, It is heartening to see the relative increase in attention being paid to mental health by governments, researchers, and clinicians for those affected by COVID-19, when compared to previous pandemics ("}
{"text": "The discovery that a considerable fraction of the eukaryotic proteins lacks a well-defined three-dimensional structure in their native state has revolutionised our general understanding of proteins. In fact, the dogma sequence determines structure determines function constituted, until recently, the foundations of our description of the protein universe. Consequently, it is not surprising that the early years of the intrinsically disordered proteins (IDPs) field have seen some scepticism. In fact, the experimental finding that some proteins did not display a well-ordered structure in isolation was merely considered as an artefact, assuming that the crowded environment of the cell could in fact reshape the native state. Thus, disorder was very far from being considered as a key player in orchestrating some of the molecular events controlling cell biology.Life, a collection of articles is presented with the specific focus of describing the \u201cFunctions, Regulation and Dysfunction of Intrinsically Disordered Proteins\u201d. Lermyte et al [The recent collaborative efforts between experimentalists and theoreticians, however, have contributed in catalysing a revolution in the protein universe and protein disorder has gradually acquired a central role in molecular biology. In this issue of te et al  providedte et al  review ate et al  used kinIn the study of IDPs, molecular dynamics simulations (MD) have made fundamental contributions. In this issue, Sullivan and Weinzierl  used MD In the context of \u03b1S interactions, Burmann and co-workers  reviewedThe onset and development of neurodegenerative diseases such as Parkinson\u2019s and Alzheimer\u2019s are inherently associated to the insurgence of oxidative stress in the neurons. The excessive production of free radicals and reactive oxygen species (ROS) have been associated to the mechanisms leading to neuronal death, review by Abramov et al.  IntracelThe main conformational transition of IDPs involved in neurodegenerative diseases involves the formation of fibrillar aggregates with common structural topologies (cross-\u03b2 spine) and showing peculiar mechanical properties at a microscopic level that make them stronger than steel. Scollo and La Rosa  reviewedIn summary, we have assembled a collection of articles that study and discuss different aspects of this intriguing class of proteins. More remains to be discovered in the IDP universe, and this elusive state poses the challenges for the next decades to overcome the limitations of current techniques in vitro and in vivo that have mostly been tailored to study structurally defined systems."}
{"text": "The Food and Agriculture Organization of the United Nations has recently estimated that the world equid population exceeds 110 million (FAOSTAT 2017). Working equids  remain essential to ensure the livelihood of poor communities around the world. In many developed countries, the equine industry has a significant economical weight, with around 7 million horses in Europe alone. The close relationship between humans and equids, and the fact that the athlete horse is the terrestrial mammal that travels the most worldwide after humans, are important elements to consider in the transmission of pathogens and diseases, amongst equids and to other species. The potential effect of climate change on vector ecology and vector-borne diseases is also of concern for both human and animal health.With this Special Issue, which assembles a collection of communications, research articles, and reviews, we intend to explore our understanding of a panel of equine viruses, looking at their pathogenicity, their importance in terms of welfare and potential association with diseases, their economic importance and impact on performance, and how their identification can be helped by new technologies and methods. Beyond their potential risk to other species, including humans, equine viruses may also represent an interesting model for reproducing virus infection in the host species.orbivirus AHS virus (AHSV), induces a very high mortality rate that can exceed 95% in its most severe form. This disease mostly occurs in southern African countries, but its transmission by Culicoides biting midges is of great concern in the current context of global warming and its consequence on displacement of vector populations. In the absence of treatment, prevention is essential, and Dennis et al. also provide a comprehensive review of the different vaccine strategies and technologies available and in current development against AHSV. While live attenuated and inactivated AHSV vaccines have played a role to reduce the impact and occurrence of AHS in affected areas, the number of AHSV serotypes in circulation and their lack of DIVA markers  is a drawback that leads to the development of a new generation of vaccines, such as poxvirus-vectored or reverse genetics vaccines. Lecollinet et al. [Flaviridae family , Saint Louis encephalitis virus (SLEV), and Murray Valley encephalitis virus (MVEV)) or the alphaviruses from the Togaviridae family . In relation to VEEV, Rusnak et al. [Dennis et al.  contribut et al.  reviewedt et al. . A commut et al.  and an at et al. ). The MLt et al. . Lecollik et al.  presenteEqcopivirus by the authors, with no specific and/or statistical association with disease. Equine parvovirus-hepatitis was also the subject of the article from Meister et al. [Altan et al.  have user et al. , which rr et al.  identifir et al. , who repr et al.  developer et al.  shed somFinally, Fatima et al.  investigWe hope this Special Issue helps to highlight the diversity of equine viruses and their importance, in terms of welfare and/or economic impact, to equids and humans."}
{"text": "To develop a diabetes education model based on individual beliefs, knowledge and risk awareness, aimed at migrants with type 2 diabetes, living in Sweden.Type 2 diabetes is rapidly increasing globally, particularly affecting migrants living in developed countries. There is ongoing debate about what kind of teaching method gives the best result, but few studies have evaluated different methods for teaching migrants. Previous studies lack a theoretical base and do not proceed from the individuals\u2019 own beliefs about health and illness, underpinned by their knowledge, guiding their health-related behaviour.A diabetes education model was developed to increase knowledge about diabetes and to influence self-care among migrants with type 2 diabetes. The model was based on literature review, on results from a previous study investigating knowledge about diabetes, on experience from studies of beliefs about health and illness, and on collaboration between researchers in diabetes care and migration and health and staff working in a multi-professional diabetes team.This is a culturally appropriate diabetes education model proceeding from individual beliefs about health and illness and knowledge, conducted in focus-group discussions in five sessions, led by a diabetes specialist nurse in collaboration with a multi-professional team, and completed within three months. The focus groups should include 4\u20135 persons and last for about 90 min, in the presence of an interpreter. A thematic interview guide should be used, with broad open-ended questions and descriptions of critical situations/health problems. Discussions of individual beliefs based on knowledge are encouraged. When needed, healthcare staff present at the session answer questions, add information and ensure that basic principles for diabetes care are covered. The diabetes education model is tailored to both individual and cultural aspects and can improve knowledge about type 2 diabetes, among migrants and thus increase self-care behaviour and improve health. A physician should also attend this session. At the third session the participants discuss their individual beliefs about why diabetes-related short- and long-term complications occur, how they affect the body and particularly how they can be prevented. A podiatrist should also attend this session, with whom the participants have the opportunity to discuss daily foot care and how to prevent \u2018the diabetic foot\u2019. During the fourth session, diet and eating habits are discussed, and the participants discuss their individual beliefs about how they should eat in relation to type 2 diabetes, thus, principles for dietary adjustment. A dietician should also attend the session. The fifth and last session is planned to summarise beliefs about how to achieve good glycaemic control and the complex relation between diet, exercise, medication and awareness/knowledge. Thus the effects of exercise, diet and medication are also discussed, and how to assess blood glucose control. At this session, the whole diabetes team is present, in order to contribute to a holistic picture of the management and to answer any of the participants\u2019 questions. In addition, during the sessions, booklets are handed out in the participants\u2019 native language, concerning diabetes-related complications and self-care.The content of this article is unique since it describes a culturally appropriate health diabetes education model based on individual beliefs about health and illness and knowledge conducted in focus-group discussions guided by a semi-structured interview guide in five sessions, led by a diabetes specialist nurse in collaboration with a multi-professional team, and completed in three months.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Despite a previously expressed need, culturally tailored diabetes education models for migrants are lacking  (Krueger and Casey, et al., et al., This education model is led by a nurse specialised in diabetes care who acts as a moderator, promoting interaction and discussions between the participants in the group. The diabetes specialist nurse provides support with new knowledge when knowledge gaps are found. This means that, by focussing on the participants\u2019 individual beliefs and knowledge about health and illness, that is, internal resources, the diabetes specialist nurse will use the educative and supportive nursing system in facilitating learning about diabetes and self-management, and thereby improve a person\u2019s self-agency Orem, . Furtheret al., et al., et al., 2003; 2005; The education model described here has been developed to achieve the goal of a culturally appropriate programme, which is to develop culturally and linguistically appropriate services that function within the context of the cultural beliefs, behaviour and needs presented by an ethnic group (Attridge It has been found that migrants have difficulties assimilating knowledge about diabetes in existing education models offered by health care. Therefore a culturally appropriate diabetes education model has been developed, conducted in a focus-group discussion based on the participants\u2019 individual beliefs about health and illness and their knowledge about diabetes and diabetes care and experiences of self-care. The education model is therefore both individually and culturally tailored and intended to improve knowledge about type 2 diabetes among migrants and thus increase self-care behaviour and improve health.It is a strength that many aspects, from both a scientific and clinical perspective, and a theoretical base were considered when this education model was developed in collaboration with a multi-professional diabetes team. Further, this education model ought to be appropriate for several population groups considering that it is based on the participants\u2019 individual beliefs about health and illness and can be implemented at different phases during the illness trajectory and thus be delivered at various times. However, one limitation might be that the model is not tested yet, which is the next step in the research process. Then an evaluation from the users\u2019 perspective will also be included to further revise the model."}
{"text": "We recently completed the Special Issue on \u2018Plant Virus Epidemiology and Control\u2019. As editors, we decided not to offer vouchers to scientists that submit to this issue. This action had an effect on the number of papers received and accepted. We received a total of 19 papers and we accepted four. The study of Kinoti et al.  providesThe study of Tahzima et al.  focuses The study of Dall et al.  deals wiThe fourth paper, the study of Alazem et al. , exploreViruses.Overall, the three editors are very satisfied with the quality of the published papers and we are looking forward to additional high-impact plant virus epidemiology and control papers being submitted to"}
{"text": "Enemy\u2010risk effects, often referred to as non\u2010consumptive effects (NCEs), are an important feature of predator\u2013prey ecology, but their significance has had little impact on the conceptual underpinning or practice of biological control. We provide an overview of enemy\u2010risk effects in predator\u2013prey interactions, discuss ways in which risk effects may impact biocontrol programs and suggest avenues for further integration of natural enemy ecology and integrated pest management. Enemy\u2010risk effects can have important influences on different stages of biological control programs, including natural enemy selection, efficacy testing and quantification of non\u2010target impacts. Enemy\u2010risk effects can also shape the interactions of biological control with other pest management practices. Biocontrol systems also provide community ecologists with some of the richest examples of behaviourally mediated trophic cascades and demonstrations of how enemy\u2010risk effects play out among species with no shared evolutionary history, important topics for invasion biology and conservation. We conclude that the longstanding use of ecological theory by biocontrol practitioners should be expanded to incorporate enemy\u2010risk effects, and that community ecologists will find many opportunities to study enemy\u2010risk effects in biocontrol settings. We provide a synthetic review of enemy\u2010risk effects in biological control of arthropod pests. We provide a conceptual overview of enemy\u2010risk effects, review the current body of literature documenting risk effects in biocontrol systems and describe in detail ways in which risk effects may impact the implementation of biocontrol programs. Pseudacteon spp. parasitoids lay eggs in adult worker ants, the resulting parasitoid larvae completing their development in the heads of their host ants, which fall off as the larvae develop (hence their common name: decapitating flies).The red imported fire ant, Pseudacteon spp. in the native ranges of the fire ants concluded, however, that they were poor candidates for effective biological control, because they achieved very low rates of parasitism , including within\u2010generation changes in behaviour , the consequences for the individual prey/host (e.g. reduced growth rate) or the consequences at the prey/host population level (e.g. increased emigration). Referring to all three levels as NCEs reduces the important distinctions between them, we advocate for a more explicit framework Fig.\u00a0, and cleBehavioural shifts are a commonly studied trait responses in arthropods, and are generally the most rapid and reversible. Examples include changes in time spent feeding  is often a result of reduced foraging effort . This can make physiological shifts difficult to categorise within the framework shown in Fig.\u00a0et al., et al., Morphological shifts are generally slower to appear and more difficult to reverse than behavioural or even physiological shifts. They have been less described in terrestrial arthropods, but thoroughly studied in systems such as Daphnia pulex, where predator cues trigger production of carapace protrusions that decrease vulnerability to predation  with the effect of constrained predators  or predator cues (NCEs only) on prey. A meta\u2010analysis of these experiments found that the importance of NCEs was highly variable, but on average roughly the same magnitude as CEs  and the perception of risk upon detection (e.g. perceived risk may be lower if a refuge is nearby). Response to risk can be highly state dependent; a starving organism may be more likely to accept higher risk to avoid starvation, and a larger, faster individual may assess risk differently than a smaller, more vulnerable organism. In some cases, it can take a combination of multiple cues to trigger a response  if prey are energy stressed (hungry), resources or mates are abundant but more accessible only if prey show little anti\u2010predator response, or if prey have high reproductive value  increases mortality from another enemy  history with enemies (or specific enemies) often exhibit much weaker anti\u2010enemy responses and thus suffer heavy mortality (strong CEs) when novel enemies appear  separating NCEs and CEs to improve predictions of pest population dynamics see Box\u00a0, (2) conBox 4et al., A central difference between CEs and NCEs is their consequences for natural enemy reproduction  for mass\u2010rearing and release. Finally, after classical biocontrol agents are released and established, it is important to evaluate efficacy, including effects on targets and non\u2010targets. The methods used in each of these stages of assessment are overlapping, and different methods can be complementary  population density as the primary response variables Table\u00a0, therebyet al., et al., et al., Recent research on prey responses to exotic enemies emphasises the importance of prey\u2019s eco\u2010evolutionary experience (EEE) with enemies , are often used to predict pest movement and abundance within a patchy habitat, but the inclusion of mobile enemies and prey perception of enemies can drastically alter those predictions  and heterozygotes (RS) are killed on Bt plants. Only the rare resistant homozygotes (RR) can survive. The \u2018refuge\u2019 refers to a planted block of non\u2010Bt plants, which are expected to produce relatively large numbers of SS individuals. The rare RR homozygotes surviving on Bt plants are then expected to mate with one of the abundant SS individuals developing in the refuge, and the offspring (genotype RS) are subsequently killed on the Bt crops, removing R alleles from the population. In this way, the models suggest, resistance can be dramatically delayed  additive, independent effects; (2) greater than additive, or synergistic effects; or (3) less than additive, or disruptive effects , then total predation may be less than expected when both predators are present (Vance\u2010Chalcraft and Soluk, et al.  showed tet al., et al., et al., Insect herbivores face the dual challenge of well\u2010defended host plants and natural enemies Polis, . It has et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Natural enemies express a broad array of responses to their own predators. A common response is to move away from areas where predator risk is perceived; this may be measured experimentally as shorter patch residency times (Nakashima and Senoo, et al., et al., et al., et al., et al., per capita reproductive output, perhaps as a consequence of reduced expression of costly anti\u2010predator defences (Van Veen et al. et al. What influence these responses have on the overall success of biological control is uncertain. Much of the literature is framed around the idea that anti\u2010enemy behaviour of intraguild prey ameliorate the impact of IGP, potentially facilitating the coexistence of multiple natural enemies, and presumably enhancing the suppression of pest populations. In the short\u2010term, however, anti\u2010predator responses that reduce potential IGP or cannibalism often results in reduced overall consumption of prey (Sih et al., et al., et al., Interactions between top\u2010down and bottom\u2010up pressures have received much attention in broader natural enemy ecology, but specific breakdown of CEs and NCEs has been less common (but see Kaplan and Thaler, et al., et al., Bottom\u2010up effects do not always affect anti\u2010enemy behaviours simply by changing the cost\u2010benefit ratio of those behaviours. Additive effects may be possible if pests respond to plant defences and enemy risk in qualitatively different ways. For example, phytohormones have been shown to reduce aphid population growth, while natural enemies induce the production of winged morphs (Kaplan and Thaler, per capita consumptive rates and NCEs. The interactions between plant defences and natural enemies are numerous, including risk effect pathways and others not discussed here, which have been more thoroughly reviewed elsewhere (Pappas et al., Finally, many biocontrol agents are omnivorous, meaning plant defences may affect their fitness directly. If high\u2010quality plants increase omnivorous enemy populations, consumption of prey may increase. However, high\u2010quality plants may also reduce the omnivore\u2019s need to forage for prey, reducing The study of enemy\u2010risk effects has advanced greatly in the past two decades, developing into a more fully realised field, incorporating theoretical frameworks, many experimental methods and even predictive models. However, the field of biological control is still catching up to broader natural enemy ecology, and the incorporation of enemy\u2010risk effects into the biocontrol framework is still in its infancy. There is a significant body of research documenting the importance of risk effects in biocontrol systems, but there is much room to grow beyond this. We have outlined several areas in which risk effect literature may provide insight into biocontrol practice, and hope that further studies will investigate specific interactions between enemy\u2010risk effects and IPM programs more thoroughly.Community ecologists likewise can find, in biological control systems, rich examples where the consequences of risk effects play out in well\u2010characterised predator\u2013prey systems, including both coevolved versus novel predator\u2013prey associations. Agricultural systems provide ideal settings for examining both the shorter\u2010 and the longer term consequences of risk effects, on both smaller and larger spatial scales. Opportunities exist to examine how risk effects shape trophic cascades, the distributions of prey populations in space and even microevolutionary responses to plant defensive traits.One of the most crucial aspects of the merging of the fields will be broadly considering biocontrol of arthropods as an inherently behavioural issue. A focus on preventing unwanted and damaging pest behaviour, whether through killing pests or changing their behaviour, broadens the scope of interactions that may be utilised in biological control. The historical focus on population density is no longer sufficient in light of research demonstrating the importance of enemy\u2010risk effects and how they can cascade to the level of plants.Studies of risk effects in biocontrol systems should also include more holistic studies of the numerous interactions, either synergistic or antagonistic, between pest behaviour and broader IPM practices. Studies in this area can simultaneously investigate core ecological concepts and provide more concrete suggestions for biocontrol practitioners.Finally, we recognise that it may not be feasible to investigate all possible enemy\u2010risk effects in a given agroecosystem when attempting to predict the effects of a biocontrol agent, which is why we propose the incorporation of theory and predictive models from risk effect research into biocontrol decision\u2010making processes. By considering the evolutionary history of the pest, bottom\u2010up effects of the crop and spatiotemporal dynamics of the agroecosystem, pest management programs may be able to predict the relative importance of various types of risk effects and how they may interact with management practices. Just as other detailed aspects of pest and agent biology are incorporated into management decisions, we advocate for the inclusion of enemy\u2010risk effect knowledge as well.All the authors discussed ideas and structure, wrote sections of the manuscript, reviewed literature and contributed substantially to revisions.https://publons.com/publon/10.1111/ele.13601.The peer review history for this article is available at Supplementary MaterialClick here for additional data file."}
{"text": "In Amazonia, human activities that occurred hundreds of years ago in the pre\u2010European era can leave long\u2010lasting effects on the forests \u2013 termed ecological legacies. These legacies include the intentional or nonintentional enrichment or depletion of certain species. The persistence of these legacies through time varies by species, and creates complex long\u2010term trajectories of post\u2010disturbance succession that affect ecosystem processes for hundreds of years. Most of our knowledge of Amazonian biodiversity and carbon storage comes from a series of several hundred forest plots, and we only know the disturbance history of four of them. More empirical data are needed to determine the degree to which past human activities and their ecological legacies affect our current understanding of Amazonian forest ecology. The type and intensity of human disturbance (e.g. clear cut versus forest burning) affect the trajectory of the ecological legacy in Amazonian systems on decadal timescales (e.g. Mesquita 3Bertholettia excelsa (Brazil Nut), Bactris gasipaes  and other edible plants were enriched in the pre\u2010European era, and their abundances have remained artificially high ever since (i.e. for hundreds of years) (Fig.\u00a0et al., et al., et al., c.\u00a01100 forest plots in Amazonia, there were higher richnesses and abundances of domesticated tree species in locations that were closest to known pre\u2010European archaeological sites (Levis et al., et al., Most studies of ecological legacies on Amazonian forest composition have focused on the enrichment and long\u2010term persistence of useful species. It has been suggested that Cecropia or Trema (Fig.\u00a0Ficus and Pilea, have longer life spans and can persist for centuries, but eventually decrease in abundance (\u00c5kesson et al., et al., et al., Ecological legacies following disturbances may not always be persistent, as is the case with early successional taxa, such as ema Fig.\u00a0. Mid\u2010 toIriartea deltoidea, which occurs in higher abundances where there is little to no evidence of human activity compared with areas containing past fire and cultivation (Bush & McMichael, et al., Iriartea deltoidea usually recovers c.\u00a0100\u00a0yr after site abandonment and often reaches abundances higher than before the disturbance (Fig.\u00a0Iriartea deltoidea is currently the sixth most common tree species in Amazonia (ter Steege et al., et al., Ecological legacies in Amazonia can also include the depletion of species by people Fig.\u00a0. The mosnce Fig.\u00a0. IriarteWettinia is a genus of mid\u2010successional palms that has a similar, nonpersistent, negative response to human disturbance like I. deltoidea. Wettinia, however, does not seem to have the recovery overshoot that has been documented in Iriartea (Fig.\u00a0et al., Euterpe includes the first and seventh most common tree species in Amazonia (ter Steege et al., Euterpe species are useful for their fruit, but their abundances do not seem to shift drastically in response to low levels of human disturbance (Fig.\u00a0et al., Palms are disproportionately abundant in Amazonia compared with other tree families, and have varying degrees of responses to human disturbances. 4et al., et al., et al., Amazonia provides a significant input to global carbon and climate models, and is believed to sequester more carbon than it releases (i.e. is a carbon sink; e.g. Aragao et al., c. 60\u00a0yr after abandonment, and this process can happen for over 100\u00a0yr (Fig.\u00a0et al., et al., Old growth forests typically contain high amounts of biomass, but have relatively low productivity and mortality rates Fig.\u00a0. Landscaet al., et al., Bertholettia excelsa in southwestern Amazonia, which may be related to past human enrichment (Fig.\u00a0et al., et al., It is possible that the decline of the Amazonian carbon sink and slowing down of productivity observed in the last 30\u00a0yr (Brienen ent Fig.\u00a0, play a 5et al., et al., et al., There are several knowledge gaps and debatable aspects regarding ecological legacies in Amazonian forests. The first concerns the timing and intensity of the disturbance that created the ecological legacy. Most research has focused on linking pre\u2010European human activities with modern vegetation, but the impacts of the last 400\u00a0yr of postcolonial activities are also beginning to be considered (McMichael et al., et al., The time since the last major disturbance is almost unknown in the forest plots used to study biodiversity and carbon dynamics. The time since the last fire has been published in only four out of the hundreds of surveyed forest plots (Fig.\u00a02 concentrations (Koch et al., et al., et al., 14C dating (Heijink et al., et al., The spatial extent of these past human activities and ecological legacies into less well\u2010studied and less accessible regions of the forest also remains unknown and is highly debated. Some have argued that the extent of site abandonment and subsequent forest regrowth after European arrival was so great that it caused a global decrease in COet al., et al., The integration of ecological, palaeoecological, and archaeological data are crucial to understanding the long\u2010term ecology and ecological legacies in Amazonian forests. Archaeologists and palaeoecologists are beginning to collect complementary datasets (Mayle & Iriarte, et al., et al., et al., Advancements in techniques of looking into the past are pushing the boundaries of what can be learned from ecological, palaeoecological and archaeological datasets. One example is by extracting dendrochronological, isotopic and genetic information from living trees, and using that information as time capsules of past human and climatic change (Caetano\u2010Andrade"}
{"text": "Health-related fear is a normal and common response in the face of the global pandemic of COVID-19. Children and young people are frequently being exposed to messages about the threat to health, including from the media and authorities. Whilst for most, their anxiety will be proportionate to the threat, for some, existing pre-occupation with physical symptoms and illness will become more problematic. There is a growing body of evidence that health anxiety may occur in childhood, however much of the literature is taken from research using adult samples. This practitioner review aims to give an overview of the assessment and treatment of health-related worries in children and young people in the context of the COVID-19 pandemic. This review is based on the limited existing evidence in this population and the more substantial evidence base for treating health anxiety in adults. We consider the adaptations needed to ensure such interventions are developmentally appropriate. For most, anxiety will be a proportionate and adaptive response to the threat posed by the virus, motivating individuals to engage in sensible, precautionary health behaviours Taylor, . HoweverThere are both individual and systematic factors that may render children and young people particularly vulnerable to health-related worries in the context of COVID-19. It is important to acknowledge that there are key differences in the presentation of anxiety between children and adolescents  and multi-informant  approach to assessment is recommended  or health threat information . As children and young people are less likely to scrutinise the quality and relevance of incoming information, a threat response may be triggered at a lower threshold than adults. Cognitions might typically centre on the risk and likelihood of becoming ill with COVID-19, alongside thoughts of how catastrophic this could be (i.e. ultimately death of self/parent). Behaviours resulting from these health-related fears would be strategically aimed at reducing both distress and risk of contracting COVID-19, with the unintended consequence of increasing anxiety through prevention of disconfirmation, e.g. symptom checking, overly restrictive practices, excessive handwashing. This process also serves to increase the perception of worrying physical sensations, through symptom hypervigilance for example, or interoceptive experience of physiological arousal associated with anxiety. This further acts as a health-related stimulus, elevating anxiety and perceived health risk, and so the cycle continues. This is particularly problematic due to the limited ability that children may have to understand and express their own emotions, therefore the experience of emotions themselves may be perceived as threatening.Within this adapted formulation we also present key mechanisms between the parent and child that may contribute to the maintenance of distress, albeit inadvertently. Illness beliefs in the anxious parent trigger safety-seeking strategies that are designed to keep both themselves, and the child, emotionally and physically safe. However, parental safety-seeking behaviours, and the anxieties that underpin them, are likely to raise salience of the health threat to the child. This in turn drives the child\u2019s own safety-seeking behaviours, which also seek to reduce distress and threat to physical health. Parental safety-seeking behaviours are also likely to influence the child\u2019s behaviours without an explicit cognitive route, e.g. parent repeatedly checks for signs of illness, this behaviour is repeated by the child, learned via modelling and reinforced by the absence of negative consequences. This, within a societal context of public health messages that everyone must stay home in order to be safe and keep others safe, and with schools and workplaces closed, may lead to intensifying difficult dynamics within the family home.et al., et al., et al.  to high-intensity interventions (nine to 20 face-to-face sessions: Creswell , et al.  conducte (et al.  conducteet al., et al., et al., et al., et al., et al., CBT is effective in treating HA in adults (Cooper et al. (We propose that formulation-driven CBT for health-related worries and HA is probably the best treatment available for children and young people with HA. This will be most effective if adapted to be developmentally appropriate. Creswell et al.  suggest et al., The aim of CBT for HA is to reduce distress, reduce unhelpful safety-seeking behaviours and enable consideration of alternative explanations of physical sensations that are being misinterpreted as signs of disease (Daniels and Loades, et al., As with adult HA interventions and good practice in CBT for children and young people (Fuggle There is a qualitative difference to a child\u2019s thinking processes compared with an adult, and they will have a different understanding of illness and disease.Reassurance seeking will often be directed to adults in the child\u2019s life such as parents, caregivers and teachers rather than health professionals.Maintaining factors will be inextricably linked to the beliefs and psychosocial functioning of parents.While there are differences between HA in adults and in those aged under 18, it is also important to consider that there are also likely to be developmental differences between children and young people (Waite and Creswell, et al., et al., et al., et al., Rask  outlineset al., et al., Creswell and colleagues  suggest et al. (et al., et al., et al., et al., et al., et al., Dalton et al.  indicateIn the absence of online HA-specific interventions for children and young people, adapting existing online evidence-based programmes for anxiety to address health-related worries relevant to COVID-19 specifically may hold promise. The adaptations needed would include specific content about coronaviruses and COVID-19, and about concerns children and young people may have about the health threat to adults as well as to themselves. This would need to acknowledge the ongoing uncertainty about COVID-19 and to include a focus on coping with this uncertainty, as well as uncertainty about how long disease containment measures will be in place and how they will be lifted. Content and techniques, including practical exercises, would need to consider physical distancing and disease containment measures. Specific suggestions about how to seek social support and to maintain social contact within these limitations may also be helpful. Further research is needed to establish if existing transdiagnostic programmes, delivered online, are effective in the pandemic context at reducing health-related worries.In the context of a global pandemic, some degree of health-related fear is normal and adaptive. However, for a minority of children and young people, this health-related fear may become particularly distressing. It may interfere substantially with their functioning and persist over time, in a way that we recognise in HA. For these children and young people, adopting a multi-informant approach to assessment, including using existing HA scales to complement clinical interview, could help to establish the extent of their HA. An individualised formulation of the problem, including the cognitive, behavioural and emotional components, based on the CBT model, should be developed. Consideration of developmental factors such as cognitive ability, emotional literacy, intergenerational transmission of beliefs and parental modelling or reinforcement of behaviours, is an important part of the formulation. Adapting existing evidence-based HA treatments for adults and offering these to children and young people may be most helpful. More research is needed to establish age-appropriate diagnostic criteria and standardised tools for assessment of HA in younger children, and to evaluate developmentally appropriate treatment intervention/programmes."}
{"text": "Among the constituents of food, volatile compounds are a particularly intriguing group of molecules, because they give rise to odour and aroma. Indeed, olfaction is one of the main aspects influencing the appreciation or dislike of particular food items. Volatile compounds are perceived through the smelling sensory organs of the nasal cavity, and evoke numerous associations and emotions, even before the food is tasted. Such a reaction occurs because the information from these receptors is directed to the hippocampus and amygdala, the key regions of the brain involved in learning and memory.In addition to identifying the odour-active compounds, the analysis of the volatile compounds in food is also applied for detecting the ripening, senescence, and decay in fruit and vegetables, as well as monitoring and controlling the changes during food processing and storage . Nineteen research papers and two review papers cover the topics of this Special Issue. The majority of the papers investigated volatile compounds from vegetable origin products (16) and four papers reported volatile compounds from animal origin products (dairy products).Six of the research papers were mainly focused on the sensory aspects related to volatile compounds ,3,4,5,6,Mu\u00f1oz-Gonz\u00e1lez et al.  studied Endrizzi et al.  studied Deuscher et al.  used gasLiberto et al.  exploredIn the work of Genovese et al.,  it was sYan et al.  used fasFatty acids and their derived volatile compounds were studied in \u201cThompson Seedless\u201d Raisins during air-drying and sun-drying processes by Wang et al. . The stuThe work of Ma et al.  evaluateVidal et al.  in theirChitarrini et al.  combinedIn a further work, Chitarrini and co-workers  used theSmith and Peterson  combinedIanni et al.  studied A further study on the effect of animal feeding on volatile compounds in dairy products was undertaken by Bennato and co-workers . These aSlaghenaufi et al.  studied Yang et al.  studied Lobo-Prieto et al.  tracked In the paper of Coelho and co-workers , a liquiIn the work of Capozzi et al.  two compTanaka and co-workers , in theiIanni et al.,  in theirIn conclusion, volatile compounds are responsible for the aroma of food and may be influenced by processing, storage, harvesting or animal feeding, and they require a dedicated analytical approach for the identification and the monitoring All these aspects were covered by the manuscripts submitted and published in the Special Issue \u201cVolatile Compounds and Smell Chemicals (Odor and Aroma) of Food\u201d. These manuscripts contributed\u2014with their topics and their quality\u2014to the success of this Special Issue."}
{"text": "As cancer continues to pose a major health risk and the global incidence rate is expected to almost double in the next two decades, the importance of radiation therapy will continue to grow. Radiation oncology will be shaped by oncoming advances in medicine, including early and lower\u2010cost detection methods, integrated multidisciplinary approaches, personalized medical strategies, and cancer prevention. In addition, radiation oncology will be influenced by future societal changes, including the establishment of more efficient, value\u2010based healthcare systems, and, importantly, extended European and global cooperation in research and care for the fight against disease.et al., The establishment of a radiotherapy department needs considerable upfront investment in state\u2010of\u2010the\u2010art diagnostic and therapeutic technologies and devices. Nevertheless, as these devices can be used for many years, radiotherapy enables cost\u2010efficient treatment of thousands of patients.Radiotherapy needs to be administered by well\u2010trained personnel and by multiprofessional teams. But, Europe does not have enough well\u2010trained staff and will need national overarching efforts to train a sufficient number of experts in the coming years. These expert teams should consist at least of radiation oncologists, medical physicists, and radiation therapy technologists. In addition, radiation biologists, data scientists, engineers, and experts from many other fields are of fundamental importance for the further development of radiation oncology.Radiotherapy requires a certain degree of centralization to ensure that a critical mass of equipment and personell are available for delivering all of radiotherapy required by current and future cancer treatment regiments. Consequently, radiotherapy departments cannot be established in all medical centers and sites within a country. This can cause problems for decision\u2010makers as to selecting locations for radiotherapy centers.Radiotherapy is only one component of cancer treatment, as it is always combined with other diagnostic and therapeutic disciplines in a multidisciplinary framework. Radiotherapy departments are therefore best located within multidisciplinary cancer treatment units, such as comprehensive cancer centers.If decentralized radiotherapy units are needed to provide access for all citizens nationwide, these units can, for example, be connected to larger network centers. In general, decentralized services closer to the patients\u2019 homes are more beneficial and practical for palliative care, or if tumors require well\u2010defined and frequently applied standard treatments. More specialized treatment should ideally be provided by larger departments. Last but not least, modern telemedicine connectivity and reliable and ubiquitous patient referral systems are needed to ensure that even patients living in more remote areas have access to all treatments offered.The importance of a common European mission is evident in view of the current enormous disparity regarding patient access to state\u2010of\u2010the\u2010art radiotherapy from one European country to the other (Lievens Finally, going beyond patient care, Europe also needs innovation. Europe has a strong track record not only in biological research and drug development, but particularly also in medical engineering and medical technologies that form the backbone of modern radiotherapy. As the driving ideas behind new generations of technology often stem from close interactions among the clinical care sector, academic research, and industry, investment into radiation oncology will also boost European research and economies.Molecular Oncology discusses central questions of the future direction and development of radiotherapy in Europe. The cancer mission must take into account the needs of tomorrow\u2019s aging population, as well as the nationwide diversity of systems in Europe. This is only possible if all research areas are brought together in a symbiotic approach to cure and slow down tumor growth and combat comorbidities.This thematic issue in et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., We would like to thank the authors of this special issue for providing the data and for laying the foundation for further developments in radiation oncology, covering a broad range of topics from innovative, technology\u2010, and data\u2010driven approaches to translational medicine and personalized strategies to cancer prevention and patient care in radiation oncology (Lievens"}
{"text": "Ever since it was first discussed in evolutionary terms by Haldane , MedawarStead et al., with special emphasis on ways that modulation of autophagy can be beneficial for healthy aging. A specific focus on lessons learned from Drosophila on the functional connection between autophagy and aging is provided by Marusz et al. However, what is less clear from the data available so far is whether enhanced autophagy on its own is necessary and sufficient to extend life span. Some studies strongly support the idea that this is the case  material in cells as a function of age. Such material can be dysfunctional mitochondria, accumulated lipids and, in the case of neurons, aggregated proteins potentially causing neurodegeneration (Gatica et al., Kounakis et al. Finally, it is important to remember that aging is a very complex process that affects with different severity and timing the various bodily tissues. Along those lines, the relation between autophagy and aging of specific cells and tissues is also addressed in this collection. Macian reviews the role of autophagy in T cell function and immunosenescence, a very interesting phenomenon in immune cells, whereas Eckhart et al. discuss how the various cells of the skin activate autophagy and the connection of this process to skin aging.How does autophagy engage with the aging process? At one level this is related to caloric restriction, one of the most reliable ways to extend life span in model organisms (L\u00f3pez-Ot\u00edn et al., Schmeisser and Parker. Of note, several genes whose downregulation enhances lifespan are also shown to be important for early development (Kenyon, The developmental theory of aging proposes that the optimization of developmental programs necessary for reproductive fitness has the unwanted consequence of also causing aging when these programs continue to operate past reproductive age (de Magalh\u00e3es and Church,  Kenyon, . AutophaWe hope that the articles collected in this volume will stimulate further hypothesis-driven experimental work detailing the role of autophagy in the aging process.TP-C and NK wrote and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "We read with great interest the article by Posma et al. who reported that early lactate levels were strongly associated with mortality and, irrespective of the degree of hyperlactatemia, similar lactate levels were associated with a lower mortality rate in metformin (MET) users compared with MET non-users . We woul"}
{"text": "The lung epithelium is a cellular barrier that protects the lung from environmental exposure to pathogens and chemical insults that could otherwise compromise its physiological role in gas exchange during respiration. In the distal lung, the exchange of oxygen and carbon dioxide occurs within the alveoli, facilitated by type I alveolar epithelial cells (AECs). In addition to their important role in gas exchange, mucus and surfactant secreted by AECs contain a range of host\u2010defence proteins which aid epithelial barrier function and protection from invading pathogens. The lung epithelium is supported by a network of mesenchymal cells including fibroblasts that form the basement membrane that acts as a further layer of protection to prevent access of microbes to the underlying tissue.Clinical & Translational Immunology, the reviews include a broad range of topics examining the clinical challenges associated with the diagnosis of ILDs and the nature of the innate and adaptive immune responses elicited following tissue damage in ILDs and in lung regeneration. This series of articles explores how the immune response is modulated during lung cancer and how novel immunotherapeutic approaches are being explored to treat this disease. The use of animal models to study the pathobiology of ILDs is discussed and highlights how these models may inform novel therapeutic strategies to treat ILDs or lung cancer in humans.Many interstitial lung diseases (ILDs) share similar clinical symptoms and findings on radiographic or pathologic assessment often making diagnosis difficult. The accurate diagnosis of an ILD is critical for the long\u2010term management of the disease and can inform the choice of treatment a patient receives and their prognosis. We are beginning to appreciate the importance that immune status has on disease progression and clinical outcome. In this Special Feature of MUC5B, SPC , TOLLIP (innate immune cells) or PARN, TERT (telomere genes),The review by McLean\u2010Tooke and colleagues examines the challenges associated with the accurate diagnosis of ILDs in patients.et al.et al.et al.et al.The reviews by Warheit\u2010Niemi et al.et al. describe a range of preclinical mouse studies using various anti\u2010cytokine therapy approaches and cytokine gene knockout models. Although some of these approaches have shown promise, this success has not yet been translated to human patients. Collectively, the three reviews by Warheit\u2010Niemi et al., Denneney et al. and Lucas et al. highlight the important role of innate and adaptive immune responses in tissue damage and repair mechanisms.Lucas et al.Miles et al.+ cytotoxic T cells is critical for eliminating cancer cells and reducing tumor burden. However, it is now known that tumor cells can subvert the immune system by expressing checkpoint ligands which bind to inhibitory receptors on T cells, rendering them ineffective for tumor surveillance and eradication. A range of checkpoint inhibitory receptors and ligands have been defined and are being evaluated in a range of clinical trials in cancer. Checkpoint therapy has revolutionised cancer therapy for melanoma, and it is being evaluated for the treatment of lung cancer and other cancer types. Early indications are that monotherapies of checkpoint inhibitors in lung cancer may not be effective in all tumors, thus prompting the use of combination therapies.The final review by Neeve Chronic diseases of the lung, such as pulmonary fibrosis or lung cancer, can disrupt the delicate tissue architecture and compromise gas exchange across alveoli. If disease pathology is not arrested, it can severely impact the quality of life and long\u2010term survival of the patient. We need to better understand the complex relationship between host genetics, the environment, and the host immune response, and how this shapes disease pathogenesis within the lung. Improved diagnostics will be developed with integration of new emerging technologies such as immune cell phenotyping, transcriptomics and metabolomics that may help to better stratify patients into appropriate clinical subgroups. This may have the benefit of improving the outcome of clinical trials of novel interventions that may be targeted to a specific response pathway.The authors declare no conflict of interest.Cecilia Pr\u00eale: Conceptualization; Writing\u2010original draft; Writing\u2010review & editing. Gerard Hoyne: Conceptualization; Writing\u2010original draft; Writing\u2010review & editing."}
{"text": "The number of oncology, surgery and anaesthesia procedures in older patients has greatly increased in recent years due to ageing populations. Older patients are typically characterised by physical changes such as comorbidities, decline in physiological activities and cognitive impairment. All these factors, together with polypharmacological therapies, may substantially impact perioperative outcome, quality of recovery and, more in general, quality of life. A comprehensive multidisciplinary approach to perioperative care is thus needed. The assessment of frailty has a central role in the pre-operative evaluation of older patients and, with a multidisciplinary approach. The best surgical procedures and oncologic therapies can be accurately discussed in the pre- and post-operative periods. All clinicians involved in this scenario should be proactive in multidisciplinary care to achieve better outcomes. It is well known that cancer is typically an age-related disease with approximately 60% of all newly diagnosed malignant tumours and 70% of all cancer deaths occurring in persons aged 65 years or older . This olet al [et al [et al [et al [et al [et al [The constant and progressive ageing of the population in recent years has led to an increase in the number of surgeries in older cancer patients and consequently also the risk of mortality and morbidity after such operations . In the et al  recruiteet al , but recl [et al  developel [et al  evaluatel [et al  assessedl [et al  evaluatel [et al  proposedl [et al . The tril [et al .Older patients are at an increased risk of surgical complications, and this makes pre-operative evaluation by an anaesthesiologist more difficult . As mentet al [et al [et al [et al [The definition of frailty in geriatric oncology is very difficult, and still, there is no universal consensus about the right definition. Frailty in oncology could be defined as an impairment of at least one of the four geriatric domains evaluated with CGA , 39. Theet al  validateet al . Furtheret al  and a poet al . VES-13 et al . VES-13 l [et al  in a stul [et al . VES-13 l [et al . Even mol [et al  and consl [et al . CARG scl [et al  developel [et al ), cognitl [et al ) and ECOl [et al  were thel [et al  is recoml [et al . Falls al [et al . AssessiThis review was intended to highlight the current oncological, surgical and anaesthesiological knowledge concerning the elderly population. With the review of the literature, it is clear that the multidimensional geriatric evaluation represents an extremely useful and important tool in everyday clinical practice for all older patients undergoing surgery or oncologic treatments. Their careful pre-surgical evaluation and precautions even during surgery could avoid many complications during surgery and during post-operative stay in hospital, but, unfortunately, we have seen that, in real-life, there are few surgeons and surgical centres that apply this evaluation model. We hope that, in the future, older patients will gain attention from the medical class because, given the constant increase in the average age, the number of these patients will increase more and more, and willingly or not, all health professionals will have to interface with this population.The authors declare that they have no conflicts of interest.No funding was received."}
{"text": "In an interesting study, Wu et al.  exploredper se, or whether the effect of EFT on DD is temporally invariant. Recently, reduced DD could be observed not only in participants who had imagined future events, but also in those who had remembered past events or imagined, vividly, present events alternative to the current experience, as compared to merely describing the current situation, before making intertemporal choices (Ciaramelli et al., Wu et al.  also remIt is well-established that EFT and DD rely on a common neural network that encompasses fronto-medial regions, and lesional studies have clearly shown that disruption of such areas results in both increased DD (Frost and Mcnaughton, Wu et al.  showed tFinally, it is worth noting that Wu et al.  tested EThe author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Trends in Digital Medicine provided a series of contributed papers covering a variety of aspects currently defining the digital paradigm  and the effect of advancing translational medicine toward the identification of new principles useful to define healthy vs. diseased individuals and predict their profiles and health/disease trajectories.We asked to refer to a few basic questions, following widely debated topics \u20135 such aAssale et al. who examined the relevance of the notes produced in clinical practice whose unstructured nature prevents a profitable secondary use but whose potential is increasingly relevant in digitized facilities for improving data quality and thus enabling predictive inference models to be designed and implemented. Other examples were provided by Cazzaniga et al., who discussed cancer registries as main resources for real world data research, and by Geldof et al. who discussed sector-specific challenges in exploratory and hypothesis-driven studies aimed at assessing treatment effectiveness.The first question about digitalization was addressed by a few contributed papers, such as Riba et al., who reviewed current issues related to data integration and governance in the medical field, by Silverio et al., who discussed of CVD and the importance of harmonizing large data sets to build algorithms for targeting and personalizing treatments, and then by Pala et al., who examined in urban contexts the role of both environmental and socioeconomic factors influencing common pathological outcomes such as asthma. The study has introduced spatial methodologies cross-linking data from hospitalized patients and pollution plus other factors and then enabling stratifications based on conditions such as poverty and health insurance together with well-studied race and obesity.The second question on EHR was addressed by Gialluisi et al. have discussed of healthy aging and in particular of biological age, a sort of latent feature of every organism that can be derived from the combination of various biomarkers . Of relevance to screening and risk profiling practices, the concept has been applied to the Moli-sani, a prospective population-based cohort study of 24,325 subjects (35\u201399 years). In such context, the analysis of brain age via neuroimaging combined with epidemiological, environmental and genetic variables may be very useful to advancing knowledge on common age-related diseases such as Alzheimer.The third question on the relationships between Big Data and Big Killers has been elaborated by three studies. Franchini et al. introduced a model called Individual Profile of Pathology (IPP) designed to stratify populations affected by chronic diseases. When such conditions are considered dynamically driven by evolving multifactorial processes, then IPP offers advantages in assessing surveillance programs and guiding public health policy makers.Finally, EC wrote the article. All authors shared and approved the contents.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Histopathology.As the wave of COVID\u201019 disease has spread across the globe, so medical publications have followed as part of scientific efforts to characterise, manage and hopefully prevent this disease. Papers pertaining to pathology have, by their very nature, lagged slightly behind those describing clinical and imaging cohorts, but we are now seeing increasing numbers of publications that give us insight into how human tissues are infected and damaged by the virus, three in this particular issue of et al. report a cohort of 21 patients dying of COVID\u201019 infection. Acute lung injury was the main pathology at autopsy, primarily showing the exudative phase of diffuse alveolar damage (DAD), with a minority displaying the organising (or proliferative) phase.Menter The identification of vascular lung pathology in some, but not all, patients is also consistent with clinical and imaging data in relation to pro\u2010thrombotic states,et al. describe a patient operated on for a benign lung lesion before developing symptoms of COVID 19 infection.In the second paper, Zeng et al. is also interesting for its description of a moderately intense lymphoid infiltrate within the interstitium, focally cuffing the pulmonary vasculature. This is also seen in other reports,et al., whereas a relative dearth of lymphoid infiltrate is reported in other cases.et al. report a relative lack of CD8+ lymphocytes in the alveolar interstitium, also reported in the haematological literature.+ lymphocytes outnumbering CD4+ lymphocytes.+ lymphocytes were, however, present in the paper by Zeng et al., the latter again reported by others in bronchoalveolar lavageThe paper by Zeng et al. in 2002,As data amass on COVID\u201019\u2010related lung pathology, it is worth taking a step back and reviewing the variety of patterns of interstitial lung disease that have been reported since the beginning of the pandemic, ranging from interstitial lymphoid infiltrates, oedematous exudates, acute fibrinous and organising pneumonia (AFOP)Therefore, it is important that a balance is maintained between splitting COVID\u201019 into a multitude of histological patterns for research into pathogenesis and merging them all together as \u2018COVID\u2010lung\u2019 for the purposes of management, as is the case with other interstitial lung diseases.et al., reporting an individual suffered erosive gastrointestinal injury following intentional repetitive sublethal ingestion of ethanol\u2010based hand cleaner.et al.et al. has wonderful direct links to whole slide images. Our approach to all forms of education will surely change.The COVID\u201019 pandemic also has seen many indirect consequences, as shown in the third paper by Binder However, the basics still apply. The autopsy remains a valuable source of information which, whether it be a full autopsy or minimally invasive, if coupled with thorough sampling and retention of tissue for research and taken with appropriate consent, is key to understanding diseases and helping in their prevention.None.All authors contributed to the writing and editing of the manuscript."}
{"text": "The employment of directed acyclic graphs to advance the tracking, control and appraisal of crystallographic phasing strategies is discussed. Phasertng, which uses directed acyclic graphs natively for input/output, has been initiated. In Phasertng, the codebase of Phaser has been rebuilt, with an emphasis on modularity, on scripting, on speed and on continuing algorithm development. As a first application of phasertng, its advantages are demonstrated in the context of phasertng.xtricorder, a tool to analyse and triage merged data in preparation for molecular replacement or experimental phasing. The description of the phasing strategy with directed acyclic graphs is a generalization that extends beyond the functionality of Phasertng, as it can incorporate results from bioinformatics and other crystallographic tools, and will facilitate multifaceted search strategies, dynamic ranking of alternative search pathways and the exploitation of machine learning to further improve phasing strategies.Crystallographic phasing strategies increasingly require the exploration and ranking of many hypotheses about the number, types and positions of atoms, molecules and/or molecular fragments in the unit cell, each with only a small chance of being correct. Accelerating this move has been improvements in phasing methods, which are now able to extract phase information from the placement of very small fragments of structure, from weak experimental phasing signal or from combinations of molecular replacement and experimental phasing information. Describing phasing in terms of a directed acyclic graph allows graph-management software to track and manage the path to structure solution. The crystallographic software supporting the graph data structure must be strictly modular so that nodes in the graph are efficiently generated by the encapsulated functionality. To this end, the development of new software,  All entries are found in the PDB-REDO database  with optimization level 3. Differences between runtimes for 4.3.Phasertng over Phaser . Average speed improvements are shown in Table\u00a02Phasertng code without threading runs between threefold and eightfold faster than the broadly equivalent Phaser code. With threading, the total runtime  runs between fivefold and 30-fold faster when using five threads. The dependence of runtime on the number of threads is shown for one case each of no TNCS, TNCS of order 2 and TNCS of order greater than 2 ; in the ARCIMBOLDO suite there are ARCIMBOLDO, ARCIMBOLDO_LITE, ARCIMBOLDO_BORGES and ARCIMBOLDO_SHREDDER (Rodr\u00edguez et al., 2009et al., 2013et al., 2018Auto-Rickshaw (Panjikar et al., 2005Phaser. Phaser is also used as the engine behind the UCLA Diffraction Anisotropy Server (Strong et al., 2006SBGrid wide-search MR server (Stokes-Rees & Sliz, 2010Phaser-dependent difference-map pipeline DIMPLE for ligand screening (Wojdyr, 2018Phaser for specific purposes in laboratory and synchrotron settings of which we are not aware.We hope that shifting to the phenix.MRage pipeline processes many MR models in parallel and if a solution is found with one model then all models are superimposed on the solution and rescored, so that the best model can be used to phase the map put forward for model building (Bunk\u00f3czi et al., 2013ARCIMBOLBO software makes high-level use of persistence of solutions while the model is systematically varied (Rodr\u00edguez et al., 2009et al., 2013et al., 2018et al., 2016ab initio phasing using molecular averaging (Tsao et al., 1992et al., 2004et al., 2000et al., 2005et al., 2010et al., 1999Phasertng.A simplistic approach to phasing is best described as a disjoint union of DAGs: every MR or SAD phasing trial is treated independently. More sophisticated search strategies simultaneously consider results from searches with different MR models or SAD substructures or both, as in MR-SAD. The Phasertng is central to the development of phaser.voyager, which will leverage the solution-tracking capabilities of the DAG in sophisticated and exhaustive phasing pathways. The DAG, paired with a formal database architecture for efficient model storage and retrieval, will streamline the termination and restarting of phasing pathways in order to simplify user intervention in search strategies. Wrapping Phasertng and the DAG data structure in phaser.voyager enables us to make optimal use of the maximum-likelihood and multivariate statistics for the preparation and selection of the data, the choice of SAD or MR as the primary phasing strategy, the generation of ensemble models customized to both the data and the hypothesis of the contents of the unit cell, tracking the persistence of solutions, managing coordinate editing and refinement. By applying graph analysis and data-mining methods to databases of phaser.voyager-generated DAGs, we aim to improve the efficiency of phasing and discover unexpected dependencies between DAG node data elements. Details of the phaser.voyager pipeline will be published elsewhere.Phasertng, phasertng.xtricorder and phaser.voyager will be made available through the Phenix (Liebschner et al., 2019CCP4 (Winn et al., 2011"}
{"text": "Many of us work from home, at least partially. Traveling, especially in an international context, is restricted. Performing research and providing education is challenging. Although we aim for On the other hand, a crisis like the COVID-19 pandemic, also opens new chances. For example, the digital transformation of our societies gets a real push and might help us to develop a more sustainable behaviour. Videoconferences are now fully accepted, beneficial effects of remote teaching become visible, and thus in the future we will be better able to evaluate if travels are really needed.The digital transformation also affects our glass research \u2013 and this will definitely continue: Digital image processing is used in the paper of Dix et al. for the evaluation of anisotropy effects in pre-stressed glass; Drass et al. use semantic segmentation with deep learning for the detection of cracks at cut edges of flat glass, Hayez et al. give design rules for silicone joints in cold bent glass based on numerical simulations.The other papers in the current issue focus on the glass itself and material combinations with glass. Pauli et al. perform experimental and numerical investigations on glass fragments to derive a material model which in the future might be used to enhance post-fracture models for laminated glass, Brokmann et al. revisit the well-known problem of subcritical crack growth as a function of the environmental conditions, Joachim et al. perform testing of a novel combination of materials in composite panels made of glass and fibre-reinforced plastics and finally G\u00f6tzinger et al. show first results of a new type of glass laminates adding paper as an interlayer.Stay healthy and keep reading our journal - especially if you are trapped at home!"}
{"text": "Frontiers in Phytolith Research Topic includes high quality work across this whole range of phytolith research.Interest in phytoliths has grown significantly in recent years. The Research Topic is unusual in its highly interdisciplinary nature, and in the huge range of scales covered: from cellular and molecular studies of phytolith formation to investigations focussing on the role of phytoliths in biogeochemical cycling. This Bokor et al. paper in our issue reports a Si transporter in date palm for the first time. Two papers in our collection  investigate the effects of Si fertilization on phytolith accumulation in rice, and in both cases showed significant increases in deposition. Whether Si transporters are directly involved in the formation of phytoliths remains to be studied.For phytoliths to form, plants need to absorb silicon (Si) from their environment. Since Ma et al.  first deVolkov et al.) in our collection. The authors investigate silica and its carbohydrate matrix in the elaters of Equisetum arvense, using Raman and scanning electron microscopy, assisted by density functional theory. Phytolith chemistry has usually been analyzed in bulk samples, but Zancajo et al. investigate individual phytoliths in the leaves of Sorghum bicolor using Raman and synchrotron FTIR microspectroscopies. They show that bilobate silica cells have a different silica molecular structure and type of occluded organic matter compared with prickles and long cells.Plant internal processes and structure also impact on phytoliths. Phytoliths not only vary in shape and size, but also in their chemistry, and this is influenced by the environment in which they form Hodson, . Carole Ge et al. and Bhat et al. worked on members of the Panicoideae. Ge et al. consider morphological variation in the phytoliths from the inflorescence bracts of 38 weed and crop species in China, while Bhat et al. work on the leaf and synflorescence phytoliths of three Setaria species. In both cases the authors report that it is possible to distinguish fairly closely related taxa using phytolith morphological and morphometric traits. Two papers take very different approaches to the study of palm phytoliths . Bokor et al. work on the phytoliths found in stegmata cells present in roots, stems and leaves. The stegmata are located on the outer surface of sclerenchyma bundles or associated with the vascular bundles. Huisman et al. study the phytoliths of 12 palm species from mid-elevation Andean forests and identify a number of distinctive morphotypes that are characteristic of a particular species. But phytoliths do not always distinguish between related taxa. Wang et al. show that bulliform phytolith size could not be reliably used to distinguish between cultivated rice and three wild rice species, and moreover hydrothermal factors  led to increased size.One of the areas of phytolith research where we have seen major advances in the last 20 years is morphometrics. This work was further advanced by the publication of the International Code for Phytolith Nomenclature (ICPN) 2.0, while we were in the midst of compiling our collection [International Committee for Phytolith Taxonomy (ICPT), Mir et al. added to this body of literature, showing that Si fertilization of rescuegrass decreases herbivory by a grasshopper. They went on to show that the increased silica content of the plants caused greater mandibular wear of the grasshoppers.Plants deposit phytoliths for many reasons. It has been known for many years that plant silica acts as a physical defense against grazing and pathogens. Liu et al. study the translocation of phytoliths in soil profiles in Northeast China. They find that 22% of phytoliths are translocated beneath the surface, and that translocation depends on phytolith size and aspect ratio. The authors suggest that phytolith translocation should be considered in investigations concerning palaeoclimate and palaeovegetation reconstructions. Str\u00f6mberg et al.  investigate the effects of fertilization on carbon sequestration in phytoliths from rice. In both cases fertilization has no effect on the carbon content of phytoliths, but it did increase the mass of phytoliths in the plants, and hence the total amounts of carbon sequestered. A further two papers  emphasize the importance of bamboo in carbon sequestration. Chen et al. work on the belowground biomass of monopodial bamboo species in China, and find that this represents an important and overlooked PhytOC stock. Zhang et al. carry out a wider scale investigation of carbon sequestration in phytoliths in the forests of China. They find that sequestration is particularly high in bamboo, and that the litter layer beneath bamboo plants is very high in PhytOC. This could make a very significant contribution to the long term global biogeochemical carbon sink.Parr and Sullivan  first suHodson assesses this whole controversy, and attempts to find a way forward. He suggests that cell wall phytoliths are much richer in PhytOC than lumen phytoliths, as demonstrated by Zancajo et al., and that they may be highly significant in global carbon sequestration. Two hypotheses are advanced, one to explain what happens to phytoliths when they are prepared in the laboratory for analysis, and the other what happens in the soil. Hodson concludes that phytoliths probably are an important global carbon store.In recent years the whole topic of carbon sequestration in phytoliths has become mired in controversy. Some (e.g., Song et al., Zuo and Lu provide a comprehensive review of this topic. They are critical of the \u201cold carbon hypothesis\u201d and suggest that dating of phytoliths often gives consistent results.The carbon dating of phytoliths has become another controversial area in phytolith research. Discrepancies in dating have been suggested to indicate that it is not a reliable technique, and some workers have suggested the \u201cold carbon hypothesis\u201d to explain these problems (Reyerson et al., Zancajo et al. which suggests that bilobate silica cells in sorghum leaves have a different type of occluded organic matter compared with prickles and long cells may yet prove important when we consider carbon sequestration and dating. Therefore, phytolith researchers need to be aware of work that is some way from their immediate field of research. If this does not happen then we will all miss out. In his opinion article, Katz suggests that we need to break down the disciplinary barriers within phytolith research to produce a superdiscipline. He ends by stating, \u201cHence, embedding superdisciplinary thinking in plant silicon and phytolith research can not only advance our field, but increase its impact in the merger of Earth and life sciences into a single superdiscipline. Working toward this goal is a true new frontier for plant silicon and phytolith research, for Earth-life sciences and for science in general.\u201d There is much to be said in favor of this idea. We hope that Frontiers in Phytolith Research has, in some way, contributed to advancing the superdiscipline.Phytolith research is multidisciplinary and undertaken at many different scales. Often work in one area of research throws light on a topic at a different scale. So it is quite possible that the work of MH wrote the first draft of the editorial. ZS, TB, RE, and ES all commented on the draft. All authors agreed with the final draft.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Dear Editor,I read with interest the meta\u2010analysis of patient clinical characteristics and fatality rates in COVID\u201019 from Chinese samples by Li et al.Li et al do not include Guan et al in their meta\u2010analysis of fatality rates and no reason is given for its omission. This is a concern, as the study by Guan et al is twice as large as all the other studies reporting fatality rates combined, and would significantly reduce the overall pooled fatality rate."}
{"text": "People residing in care homes may not be able to see visitors due to social distancing and other measures to restrict movement and contact outside the \u201chousehold.\u201d In addition, people who are at very high risk from COVID-19 because of severe preexisting health conditions may be required to \u201cshield\u201d  orders, and ceiling of care and treatments such as avoiding hospitalization and declining antibiotic use at the end of life. End-of-life care discussions are encouraged with the aim to maximize comfort and avoid potentially futile and burdensome interventions at the end of life, increasing the quality of the dying experience for all.et al., et al., Having discussions about end-of-life care can have multiple benefits. Significantly, it provides an opportunity for older persons to express their preferences for end-of-life care or to indicate who they would like to be involved in the decision-making process. This is important as they may be unable or lack capacity to contribute to these discussions when closer to end of life. There are also benefits for healthcare professionals, given that their confidence to discuss end-of-life care improves when they are equipped with knowledge of patient and family wishes (Poppe et al., et al., Guidelines generally recommend that these discussions take place during the early stages of a disease trajectory, in particular, in conditions where mental capacity may become compromised such as dementia (van der Steen et al., et al., et al., During the pandemic, however, as death and dying become the focus of our day-to-day lives, the impetus for having these discussions and considering our end-of-life care preferences may be brought to the fore. Previous barriers, such as not perceiving death as imminent or difficulties anticipating the future (Dening et al., et al., et al., Families may be struggling to recall what they previously discussed with the individual, considering their previous wishes, and balancing that with would their wishes be the same in the current situation. However, for many where conversations have not occurred, they will be faced with uncertainty and trying to anticipate what they think the individual would want (Lamahewa et al., The substituted interests model is an approach that may help reduce the stress on family in end-of-life decision-making (Sulmasy and Snyder, et al., During the pandemic, there has been a public rhetoric around DNACPR plans and hospitalization which may not be helpful. It is important to understand that this is not a binary decision but a conversation that opens up alternative and just as important types of care. Adopting a palliative approach is not denying care but means a person receives a more holistic and person-centered approach that is in keeping with their previous wishes and may maintain comfort, quality of life, and ensure a good death. Society as a whole has their part to play with this; supportive social networks and communities can help to desensitize these conversations and ensure conversations are discussed before acute events, better preparing everyone involved (Sawyer et al., et al., et al., Carers may benefit from support with making decisions (Mathew et al., et al., et al., COVID-19 will bring forward death for many older people. While grief is a normal part of life and death, circumstances around death can impact the grief process. Having discussions and being involved in decision-making are important elements for helping families and carers prepare for end of life. Feeling unprepared for death is associated with higher levels of complicated grief after death (Hebert et al., et al., et al., The three-tiered public health approach to bereavement suggests that most people will manage grief with support through their social network (Aoun \u201cAll societies have a death system with the basic functions of warning and prediction, prevention, caring for the dying, disposing of the dead, social consolidation after death, making sense of death, and killing\u201d (Kastenbaum, The COVID-19 pandemic may help stimulate discussions regarding people\u2019s end-of-life care preferences and break down some of the stigma associated with these discussions. However, within this context, there are also new challenges and obstacles to overcome. Greater pressures on healthcare systems will mean access to scarce intensive care resources may not be available to all, particularly those who may be considered less likely to recover from a severe case of COVID-19. Discussions about end of life usually benefit from relationship building between healthcare professionals, patients, and families, but current circumstances may limit communication between all parties. Technology may offer alternative forms for communicating where social distancing is in place, but these options may be challenging or not possible for many frail older people and people with moderate to advanced dementia. Decision aids may offer a practical tool to help carers make difficult decisions as proxies for the family members.As the death toll from COVID-19 rises, particularly among older people, the opportunities for social support and rituals around death have become limited. This will impact on how people process their grief and may have lasting consequences after the worst of the pandemic has passed. Community acknowledgement and support for grief will require new approaches within the context of the COVID-19 era."}
{"text": "Increasing numbers of young adults need continued support for their attention deficit hyperactivity disorder (ADHD) beyond the age-boundary for children's services. The sparse literature on transition in general suggests patchy provision and huge gaps in transitional care, but also that young people with ADHD and other neurodevelopmental disorders fair particularly badly. Transition in health care coincides with many other important life-transitions while the difficulties associated with ADHD may make these challenges particularly hard to cope with. Parents or other advocates therefore often need to be involved, which can present problems in adult mental health services given that they tend to be less family oriented than children's services. Importantly, young people need help negotiating the transition from passive recipient of care to active self-management, and in building relationships with the adult team.In addition to patchy provision of adult ADHD services, transition is currently hampered by poor understanding of ADHD as a long term condition and uncertain knowledge of what services are available among young people and parents as well as the clinicians working with them. Guidelines recommend, and more importantly young people want, access to psycho-social interventions as well as medication. However, available evidence suggests poor quality transitional care and adult services that are highly focused on medication.v. generic adult mental health services, for young adults with ADHD the training, experience and availability of professionals are more important than their qualifications or setting.Adult ADHD services need to undergo similar development to that experienced by Child and Adolescent Mental Health Services and community paediatrics over the last few decades. While we debate the relative merits of dedicated or specialist  Prospective reports by consultant paediatricians and child psychiatrists across the United Kingdom and Southern Ireland suggest that between 270 and 599 per 100\u00a0000 17\u201319 year olds per year needed transition (Eke et al., et al., et al., et al., The focus on medication to the exclusion of other types of intervention is problematic (Janssens et al., et al., et al., et al., et al., et al., et al., et al., The difference in culture between child centred services, where parental involvement is assumed, to adult oriented services where parents were not necessarily included, causes problems for young people in transition and their carers (Singh et al., et al., et al., et al., Provision is strongly influenced by the historical development and funding processes (Crowley and Wolfe, et al., et al., et al., There have been a flurry of concerns about the provision of mental health care for young people, as well as for adolescents with long term conditions across high income countries (Crowley and Wolfe, et al., A systematic review identified three distinct but not mutually exclusive models of transitional care, all originating from the United States of America, as well as a lack of evidence to support their application (Nguyen generic adult mental health services or whether dedicated specialist services are preferable. There is also debate about what constitutes a specialist service? A Delphi study conducted about this issue in relation to eating disorders that concluded specialist services provide evidence-based interventions, must be multi-disciplinary, and staff working within the service must have a clear focus on, and expertise in, the focus condition (Petkova et al., v. generic eating disorder services for young people suggested that specialist services did not produce better outcomes but as they worked with young people who had more severe difficulties, they were cost-effective depending on willingness to pay (Byford et al., Despite the lack of evidence to support particular models of care in ADHD (Cortese and Barbui, transitional care, assessment and diagnostic services, drug titration, monitoring and review, and psychoeducation (Nutt et al., et al., et al., et al., et al., Adult ADHD services need to undergo similar development to that experienced by CAMHS and community paediatrics over the last three decades Coghill, . Clinicaet al., et al., et al., increase in the number of young adults who should transition. Service providers and commissioners should plan accordingly. As Professor Coghill argues, the training, experience and availability of professionals are more important than their qualifications or setting, but given how complex and variable the manifestations of ADHD can be, management by primary care without the support of specialist services may miss important comorbidities, even in \u2018uncomplicated cases\u2019 (Coghill, et al., We should be reassured that the epidemiological evidence points to continued under-recognition and under-treatment of children and young people in many countries (Ford Coghill, . What is"}
{"text": "Perioperative neurocognitive disorder (PND) is a common phenomenon associated with anesthesia and surgery and has been frequently described in the elderly and susceptible individuals. Microglia, which are the brain\u2019s major resident immune cells, play critical roles in maintaining neuronal homeostasis and synaptic plasticity. Accumulating evidence suggests microglial dysfunction occurring after anesthesia and surgery might perturb neuronal function and induce PND. This review aims to provide an overview of the involvement of microglia in PND to date. Possible cellular and molecular mechanisms regarding the connection between microglial activation and PND are discussed. Microglia are a type of neuroglia occurring in the central nervous system (CNS) and can be defined as tissue-resident macrophages  and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months , fractalkine receptor CX3CR1, Csf-1R and CD68  and other inflammatory mediators (Buvanendran et al., Systemic inflammation can induce neuroinflammation and cognitive dysfunction in aged animals (Yamanaka et al., in vivo two-photon microscopy (Sun et al., in vitro studies show propofol has neuroprotective effects by attenuating inflammatory response in microglia (Gui et al., in vivo imaging in awake and anesthetized animals could help study microglia-neuron interactions (Liu Y. U. et al., The target organ of general anesthesia is the brain, but whether it is the main culprit causing cognitive decline by microglia remains controversial. The isoflurane or ketamine anesthesia causes morphological changes of microglia in rodents by using A recent study showed that peripheral surgery-induced CNS mast cell degranulation, which could trigger microglial activation and neuronal damage, contributing to PND (Zhang et al., via neuronal TNF receptors (Stellwagen and Malenka, Microglia mediate the inflammatory response in the hippocampus, resulting in the alteration of glutamatergic synaptic transmission and plasticity, which may underlie the behavioral comorbidities seen in patients (Riazi et al., As mentioned above, microglia play an important role in PND associated with neuroinflammation. PND is mainly seen in the elderly, and experimental studies also showed that it occurs frequently in old animals. Anesthesia and/or surgery did not cause a change in cognitive function in young adult mice (Zhao et al., PND is a widespread phenomenon following the surgery and anesthesia and can have detrimental effects on an individual\u2019s quality of life and well-being. The pathogenesis of PND is not fully understood. Activation of microglia and neuro-glial interactions seem to be key mechanisms in PND . The preWF designed and drafted the manuscript and figure. LM and XZ analyzed the data. FH and HH revised the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The giant panda is one of the most endangered mammals in the world, and many studies have revealed their evolutionary adaptation to the local environment  on the evidences from population genetics and their gut microbiome. Here, based on the results of our analysis of the giant panda gut microbiome, we concluded that instability and resilience are the two primary characteristics of the giant panda gut microbiome. This basic information may have an impact on giant panda conservation, as well the management of other animal species. Additionally, increasing the connectivity among fragmented and isolated populations can increase gene flow and genetic diversity, which can mitigate negative effects due to inbreeding (Epps et al., 2.3Based on our previous research, we found some differences in the gut microbiome between wild Xiaoxiangling population and Minshan populations (Yao, Xu, Hu, et al., 2.4Antibiotic\u2010resistant pathogens can have a profound effect on animal and human health (Allen et al., None declared.All authors contributed to the manuscript writing. ZZ and TH contributed equally to this work."}
{"text": "Dogs and cats have gained a special position in human society by becoming our principal companion animals. In this context, efforts to ensure their health and well\u2010fare have increased exponentially, with in recent times a growing interest in assessing the impact of the gut microbiota on canine and feline health. Recent technological advances have generated new tools to not only examine the intestinal microbial composition of dogs and cats, but also to scrutinize the genetic repertoire and associated metabolic functions of this microbial community, revealing that the taxonomic composition and the metabolic repertoire of the intestinal microbial population of dogs and cats may be influenced by several factors, including diet, age and anthropogenic aspects, as well as intestinal dysbiosis. Dogs and cats have gained a special position in human society by becoming our principal companion animals. In this context, efforts to ensure their health and welfare have increased exponentially, with in recent times a growing interest in assessing the impact of the gut microbiota on canine and feline health. Recent technological advances have generated new tools to not only examine the intestinal microbial composition of dogs and cats, but also to scrutinize the genetic repertoire and associated metabolic functions of this microbial community. The application of high\u2010throughput sequencing techniques to canine and feline faecal samples revealed similarities in their bacterial composition, with Fusobacteria, Firmicutes and Bacteroidetes as the most prevalent and abundant phyla, followed by Proteobacteria and Actinobacteria. Although key bacterial members were consistently present in their gut microbiota, the taxonomic composition and the metabolic repertoire of the intestinal microbial population may be influenced by several factors, including diet, age and anthropogenic aspects, as well as intestinal dysbiosis. The current review aims to provide a comprehensive overview of the multitude of factors which play a role in the modulation of the canine and feline gut microbiota and that of their human owners with whom they share the same environment. Indeed, in addition to taxonomic composition, WMS offers in\u2010depth insights into the genomic content and compositional arrangement of bacterial consortia, also allowing predictions of their functional features  per gram of luminal content , XI (Peptostreptococcaceae family) and XIVa (Lachnospiraceae family and Blautia), while the Erysipelotrichi is mainly represented by Turicibacter, Catenibacterium and Coprobacillus genera . Furthermore, the total concentration of SCFAs was higher in faecal samples of treated cats when compared to the cellulose control , instead of the more conventional commercial dry food , while a negative correlation was observed with faecal output, indicating that the increased abundance of Clostridiaceae taxa in the faecal microbiota of dogs fed on a BARF diet is not detrimental for canine health, but, rather, is associated with protein degradation  is, indeed, generally accompanied by an increase in the biodiversity of the pups' gut microbiota  responsible for enhancing glucose\u2010dependent insulin secretion by pancreatic \u03b2\u2010cells , osteoarthritis or cardiovascular diseases that undermine canine and feline health  typical of an inflammatory status   and acute haemorrhagic diarrhoea syndrome  refers to a heterogeneous group of intestinal disorders that are generally classified in accordance to their response to treatment, encompassing diet\u2010responsive enteropathy (FRE), antibiotic\u2010responsive enteropathy (ARE) and immunosuppressant\u2010responsive enteropathy (IRE) better known as idiopathic inflammatory bowel diseases , highlighted that cats with CE generally show a decrease in the relative abundance of the Bifidobacterium genus, a trend that had not been documented for dogs suffering from CE  have been employed as therapeutic treatments  that promote proliferation of beneficial bacteria residing in the GIT of the host  and the method of faecal supplementation .et al., et al., et al., et al., et al., et al., et al., et al., et al., Alistipes, Pseudomonas, Slackia, Subdoligranulum, Eubacterium coprostanoligenes and Barnesiella, have apparently been lost by the domesticated canine core gut microbiota, the latter have acquired five other microbial taxa, including Dorea, Parabacteroides, Streptococcus, U. m. of Bacteroidales order and U. m. of Clostridiales order, which are typical components of the human core intestinal microbiota (Alessandri et al., Streptococcus genus was absent in the intestinal community of wolves, it was detected in the canine one (Wu et al., et al., et al., Ruminococcaceae, Desulfuromusa, Lactobacillus, Carnobacillus and Faecalibacterium, showed a significantly higher relative abundance in dogs, thus indicating that the composition of the canine gut microbiota has been influenced by dietary changes imposed by humans (Lyu et al., et al., Humans have been identified as major players in driving several evolutionary events, encompassing extinction or speciation through domestication, relocation and creation of novel ecosystems (Bull and Maron, et al., et al., et al., et al., Ruminococcus and Oscillospira genera, in the infant intestinal microbial community (Tun et al., Oscillospira is associated with leanness and lower body mass index in both adults and infants, Ruminococcus is linked to the maintenance of the intestinal barrier integrity (Tun et al., Ruminococcus and Oscillospira have been negatively related to the development of infant atopy and obesity, respectively, suggesting that pet\u2010associated microbiota may have a role in modulating the infant gut microbiota (Tun et al., et al., Escherichia coli, Salmonella and Campylobacter that may be transmitted horizontally, and may thus cause zoonotic enteric diseases to humans (Morato et al., et al., et al., et al., However, cohabitation and the resulting close relationship between humans and their pets have not only significantly influenced the animal microbiota, but also the human\u2010associated microbial community (Song During the course of evolution, dogs and cats have become the main companion animals for humans. Being an integral part of human life, interest for pet health and well\u2010being has rapidly increased during recent decades and has consequently promoted many studies concerning the canine and feline gut microbiota, which are known to influence the health status of the host. In this perspective, it has been demonstrated that diet, age, anthropogenic influences and several other environmental factors play a role in modulating both the taxonomical composition and the functional activities of the intestinal microbial community of dogs and cats. Furthermore, alterations of the intestinal homeostasis are generally associated with a dysbiotic gut microbiota and the onset of inflammatory bowel diseases that may be treated with different therapies, including prebiotics, probiotics, synbiotics, antibiotics or FMT as for humans IBD. Nevertheless, further research is necessary to deepen our understanding of the role of this microbial community and to better appreciate how it interacts with dogs and cats.The authors declare that they have no competing interests."}
{"text": "As the first case\u2013control study of malignant mesothelioma of the pericardium and the tunica vaginalis testis (mTVT), the paper by Marinaccio et al  is potencontrols by year of birth are distinctly different (P<0.002), whereas the birth-year distributions of cases of mesothelioma by site and gender are not (P\u22480.8).Any case\u2013control study can be viewed as being nested within a conceptual cohort, with controls being sampled from the at-risk cohort as cases arise over time. This view of case\u2013control studies leads to the concept of incidence-density sampling of controls . For Marinaccio et al  this wouIn the Marinaccio et al  sensitivThe second major issue of concern has to do with ascertainment of asbestos exposure. Information on exposure for the cases was presumably obtained at the time of registration. The two sets of controls, obtained from previously unpublished case-control studies, were interviewed during 2014\u20132015 and 2014\u20132016; that is, many years after the exposure for most cases was ascertained 1993\u20132015). Few other details of the control groups are provided, except that participation by one set of controls was <50%, raising additional concerns about selection bias. For details on the second set of controls, Marinaccio et al  would be helpful. Marinaccio et al  remarkedThe fact that few, if any, cases of mTVT and pericardial mesothelioma occurred in industries traditionally associated with high asbestos exposure raises the possibility that the results of Marinaccio et al  are attrThis research has received no outside funding. All authors are employees of Exponent, Inc., an international scientific and engineering consulting company. All authors have worked as both consulting and testifying experts in litigation matters related to asbestos exposure and asbestos-related disease."}
{"text": "Despite the progress made in HIV treatment and prevention, HIV remains a major cause of adolescent morbidity and mortality in sub-Saharan Africa. As perinatally infected children increasingly survive into adulthood, the quality of life and mental health of this population has increased in importance. This review provides a synthesis of the prevalence of mental health problems in this population and explores associated factors. A systematic database search  with an additional hand search was conducted. Peer-reviewed studies on adolescents (aged 10\u201319), published between 2008 and 2019, assessing mental health symptoms or psychiatric disorders, either by standardized questionnaires or by diagnostic interviews, were included. The search identified 1461 articles, of which 301 were eligible for full-text analysis. Fourteen of these, concerning HIV-positive adolescents, met the inclusion criteria and were critically appraised. Mental health problems were highly prevalent among this group, with around 25% scoring positive for any psychiatric disorder and 30\u201350% showing emotional or behavioral difficulties or significant psychological distress. Associated factors found by regression analysis were older age, not being in school, impaired family functioning, HIV-related stigma and bullying, and poverty. Social support and parental competence were protective factors. Mental health problems among HIV-positive adolescents are highly prevalent and should be addressed as part of regular HIV care. Of the 1.6 million adolescents living with HIV globally, around 1.1 million reside in Eastern and Southern Africa and another 430 000 in West and Central Africa UNICEF, . Approxiet al., et al., et al., et al., et al., et al., et al. . The systematic review aims at updating the findings from the review of Cortina et al.  on childet al., The systematic review was undertaken by the MEGA project team. MEGA is an international collaborative project for mental health promotion among adolescents in South Africa and Zambia ;\u2212 lack of prevalence data;\u2212 non-standardized or incomplete instruments, not regularly used in mental health research;\u2212 reviews, validation studies, or qualitative studies.Exclusion criteria were:The following search terms were used: child*, youth, adolesc*; sub-Saharan, Africa, South Africa, Zambia; prevalence, incidence, epidemiol*; psychiat*, mental, depress*, ADHD, anxiety . The database search revealed 1374 articles. In total, 65 additional articles were found through Google Scholar, further 22 through reference lists, citations, and contact with other researchers. After the removal of duplicates, 1070 records were left for the screening of title and abstract. After exclusion of articles on clinical psychiatric populations or youth beyond the age range of 10\u201319 and articles with a wrong publication type or date, 301 articles were eligible for full-text assessment.The exclusion of articles was done according to the PICO-based taxonomy  Critical Appraisal Checklist for Studies Reporting Prevalence Data . In eight of the studies, screening scales were used to assess mental health symptoms or behavior . Four stet al., et al., et al., et al., et al., and Menon et al., who focused on younger adolescents and Okawa et al., who focused on older adolescents   enrolled in a disclosure intervention trial in Kenya  and Namibia , reported a prevalence of 28.5% and 29.1% for emotional and behavioral problems   reported on the percentage that scored in the clinical range (29.2%)  to a sample of school children (n\u00a0=\u00a0420) . Three studies also reported results for the different subscales of the SDQ  from Uganda and reported a prevalence of 51%.Musisi and Kinyanda  made useSymptoms of depression were assessed in five of the studies , 25.3% of adolescents had high scores of depressive symptoms, according to the short form of the Center for Epidemiologic Studies Depression Scale (CES-D)  that used the Center for Epidemiologic Studies Depression Scale for Children (CES-DC) , 19% of adolescents scored positive for depression, according to the Patient Health Questionnaire (PHQ-9). However, 15% showed minimal, 3% minor, and 2% moderate or severe symptoms  showed symptoms of depression, according to the Child Depression Inventory (CDI)  were only reported from the South African sample , 21% of HIV-positive adolescents reported suicidal behavior (including self-harm) during the previous 6 months, compared to 13% of unaffected adolescents. Kemigisha et al. . In total, 69.2% of adolescents reporting suicidal ideation were female and 30.8% were male. Furthermore, 81% of adolescents reporting suicidality also scored positive for depression.Three studies assessed g et al.  reporteda et al.  reportedet al., et al., et al., et al., The prevalence of mental disorders was assessed by structured or semi-structured diagnostic interviews  in three studies   and anxiety disorders were the most prevalent type of emotional disorders (14.7%). The prevalence of major depressive disorder was 5.2%. Prevalence according to self-report alone were much lower .An overall prevalence of depressive disorder was 18.9% in a large sample  from Malawi  , 41.9% were diagnosed with depression, with the highest prevalence (83.3%) found in the 14\u201316 years age group  found a depression prevalence of 40.8% . Furthermore, 19.5% reported ever having made a suicide attempt and 17.1% had attempted suicide within the past 12 months.In a sample from Nigeria  and the experience of violence or abuse were associated with poor mental health. Social support through community, family, or friends, and good parenting were associated with better mental health outcomes in several studies. Individual-level factors such as feeling able to control the future and having dreams for the future were likewise associated with better mental health.Factors identified by logistic regression are shown in et al., et al., et al., found a significant association between conduct problems and non-adherence and also, though weaker, between self-reported depression and non-adherence. Okawa et al., did not find a significant association between depressive symptoms and non-adherence.Two other studies explored the factors associated with non-adherence, using mental health as an independent variable in logistic regression  who had to figure out their HIV status on their own were more likely to show mental health symptoms and internal stigma, compared to youth who were disclosed to (Ramos et al., The disclosure of HIV was not identified as a predictive factor for mental health in regression models. The bivariate analysis suggested no adverse effects of disclosure, but associations between mental health problems and disclosure of HIV status to others. WHO strongly recommends timely disclosure WHO, . Studieset al., et al., et al., et al., et al., et al., et al., suggests that the mode of infection might be an important factor for both mental health outcomes and retention in care and that it also has an influence on how adolescents are treated by health care workers.Findings on mental health as an independent factor for ART adherence were contradictory (Smith Fawzi et al., et al., et al., et al., et al., Given the high prevalence of mental health problems among HIV-positive adolescents, identifying and addressing these problems is crucial. Screening for mental health problems and integrating mental health care into regular HIV services is highly recommended (Musisi and Kinyanda, et al., et al., et al., Lyambai and Mwape  conducteet al., et al., et al., et al., et al., et al., et al., There are multiple approaches for improving the mental health of HIV-positive adolescents, e.g. enhancement of self-regulation skills and coping strategies (Bhana et al., et al., et al., et al., As different samples are exposed to a different set of risk and protective factors, differences in prevalence are comprehensible (Fisher et al., et al., et al., Two studies on younger adolescents reported a low prevalence of emotional and behavioral problems, almost comparable to the general adolescent population (Menon et al., et al. (et al., and only found a modest correlation between the two. A low inter-informant agreement was also reported by Doku and Minnis (Differences between self- and caregiver-report were described in two of the studies (Lyambai and Mwape, , et al.  exploredd Minnis  from a set al., et al., et al., Reviews on child and adolescent mental health found that studies that used screening instruments reported higher rates of mental health problems, compared to studies that used diagnostic interviews (Fisher et al., Most of the studies used self-reporting screening instruments. As screening instruments can merely identify symptomatic people or people with a probable psychiatric disorder, results from screening instruments are not equivalent to disorder prevalence. Using screening instruments can result in an overestimation of disorder prevalence, as could be shown for depression screening among people living with HIV in sub-Saharan Africa Tsai, . ParticuSelf-reported results are prone to reporting bias and may be influenced by social desirability, so results have to be interpreted with caution. Where sensitive issues are concerned, there is a considerable risk of underreporting. Most studies used convenience sampling which has an impact on the representativeness of the data. As the vast majority of studies were cross-sectional, no causal relationships can be derived from the results. Most of the studies did not use control groups, which makes it difficult to differentiate between HIV-related mental health risks and risks that adolescents share with their peers from the same community.et al., et al., et al., et al., et al., et al., et al., et al., et al. (The majority of standardized screening instruments and diagnostic interviews in use in the field of child and adolescent mental health today were developed in high-income settings. Questions developed and tested in high-income settings may be inappropriate when used in a low-resource setting, which can lead to an over- or underestimation of prevalence (Sweetland , et al.  have shoThe number of databases that were searched was limited due to time and capacity restrictions, though the most important ones were included. Because we focused on peer-reviewed articles only, EMBASE and conference websites were not searched. The inclusion of studies in other languages than English may have led to additional findings. Because of our focus on adolescents aged 10\u201319, publications employing a broader age than 10\u201319, reporting prevalence data for children and adolescents or for adolescents and young people up to the age of 24 may have been missed. Due to publication bias, studies that found a high prevalence of mental health problems may be overrepresented. As the review was conducted within an adolescent mental health promotion project in South Africa and Zambia, both countries were included in the search terms which might have led to an overrepresentation of studies from these two countries. Furthermore, the results presented here are a subsection of a larger systematic review and the comparability of the findings to the general sub-Saharan adolescent population, as well as other high-risk groups, can only be commented on once the other sections of the review have been published. Lastly, the review was limited to the period 2008 and 2019 and so studies published before and after this period, which may be informative, were excluded.This review updates and synthesizes evidence on the prevalence of mental health problems among HIV-positive adolescent populations in sub-Saharan Africa. Mental health problems are highly prevalent in this population and need to be addressed within regular HIV care settings. Poor mental health can be associated with non-adherence to ART and with other risk behaviors, leading to poorer physical outcomes and a higher risk of HIV transmission. Health care professionals working with HIV-positive adolescents should be enabled to recognize mental health problems and respond to them in an appropriate, non-discriminatory way to ensure the best possible outcomes."}
{"text": "Swift medically led scientifically informed responses to the Covid-19 epidemic nationally have been demonstrably superior to other, non-scientific approaches. In forensic psychiatry and across all psychiatric services, urgent and clinically led responses have underlined redundancies and confusions in the governance of mental health services and a vacuum in policy makers. For the future, a greater emphasis on services for patients with schizophrenia and other severe, enduring mental disorders must aim at reducing standardised mortality ratios, managing risk of violence and improving hard outcomes such as symptomatic remission, functional recovery and forensic recovery of autonomy. This will require more use of information technology at service level and at national level where Scandinavian-style population-based data linkage research must now become legally sanctioned and necessary. A national research and development centre for medical excellence in forensic psychiatry is urgently required and is complimentary to and different from quality management. The aim of forensic psychiatrists is to manage the COVID-19 crisis in secure hospitals and prisons to prevent clusters where possible, to provide effective medical assessment and treatment where necessary, whilst continuing to manage the mental health and violence risk posed by the vulnerable and stigmatised patients we serve. It is essential to evaluate and research organisational and service responses to this crisis and to continue to develop research in this field to improve \u2018hard\u2019 outcomes, mortality and functional recovery (Kennedy et al. et al.Forensic psychiatry occupies the interface between psychiatry and the law. It is a subspecialty within psychiatry, which provides specialist treatment to the most severely mentally ill. Like other tertiary referral services aiming to reduce mortality and manage risk such as oncology or obstetrics, forensic psychiatry is a national service because it requires a critical mass and minimum level of activity to maintain both effectiveness and efficiency (Amato et al. et al. et al. et al. et al. et al. et al. et al. In recent years, driven by new population needs, forensic psychiatry services have begun to develop new subspecialties within forensic psychiatry including forensic psychiatry for those with intellectual and developmental disabilities (Gulati et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. Forensic psychiatry in Ireland and Europe is at a turning point. At the beginning of 2020, the National Forensic Mental Health Service was in the advanced stages of preparing to move to the new forensic hospital in Portrane, Dublin (Kennedy, et al. et al. et al. Forensic psychiatrists are trained to give expert evidence and to be cross-examined on their evidence rationally and rigorously in the formal setting of a court of law Kenny, . The difCountries such as Ireland which have relatively low Covid-19 death rates are generally those with leaders who have quickly acted on expert advice \u2013 complex, imperfect, tolerant of diversity and capable of compromise. Ireland has done very well in this crisis, so far. This contrasts with populist leaderships who had \u2018enough of experts; and promised simple solutions to complex questions, perfect solutions, winner take all deals and an inability to make pragmatic compromises, with an intolerance of other points of view. Ireland has performed well by following expert advice concerning how to manage the Covid-19 epidemic so far. For the next steps in the COVID-19 crisis, as well as any future pandemics, success will depend on accepting the necessity of expertise, recognising scientific facts about epidemiology, and distinguishing experts from pundits (Collins & Evans, The Irish Government appointed a stellar list of academic and professional leaders to produce the Fitzgerald report to examine the needs for acute hospital beds (Department of Health, et al. et al. et al. et al. et al. The teaching hospitals benefit from their boards, ensuring governance that is medically responsible, patient centred and able to maintain an arms-length protection from cyclical austerity policies and the consequences of confusion about the nature of expertise. These teaching hospitals have world class research-driven programmes for translational medicine with traditions of excellence and patient-centred values that are still intact. Psychiatry, however, has been almost entirely subsumed by the directly managed public sector and this sector (Department of Health, How has the Covid-19 crisis tested our services and our preparedness? The spread of the Covid-19 pandemic to Ireland impacted everyone including patients detained in confined places such as prisons and secure psychiatric wards. The onset of the national emergency was sharp, as was governmental and public recognition. During the initial weeks, fire fighting became the order of the day. Clinicians had to rapidly reassess how to practice safely and effectively from day to day. The switch to remote working by phone and video improved efficiencies and generated new risks. There have been many outstanding examples of nimble and adaptable behaviour. Telemedicine has been implemented almost everywhere including the courts. Meetings are leaner, more driven by the agenda and the need to reach practical decisions quickly. Triage has become rigorous and effective.et al. et al. et al. et al. The chronic shortage of acute and intensive care beds in general medicine was solved in Ireland by taking the large number of private hospital beds into the public system, a political act that exposed our collective tolerance of \u2018normal\u2019 trolley queues. This has not yet benefitted forensic psychiatry where severely mentally ill people in prison have prolonged waiting times for admission to hospital. Triage was already invented and rigorously applied by necessity (Flynn In forensic psychiatry, court appearances by patients transferred overnight to telepresence (Day & Cleary, et al. et al. et al. et al. et al. et al. et al. Forensic psychiatrists have long since established that the busiest acute psychiatric units are remand prisons (Lenihan To meet the needs of this vulnerable prisoner group, the National Forensic Mental Health Service and Irish Prison Service worked together to develop a system of telemedicine to provide video-link mental health clinics for the prisons service, to support prisoners and the prison primary healthcare teams. Triage is completed by forensic psychiatry nurses and psychiatrists in cooperation with IPS nurses. When a prisoner requires an in-person review, this is now conducted in a closed, screened visitor area of the prison to prevent transmission of Covid-19 from either the hospital team to the prison or vice versa. These arrangements are safe, efficient, prompt and will likely continue.et al. Older prisoners are a uniquely vulnerable group. Older prisoners have a health age similar to elders in the community that are 10 years their senior (Davoren et al. et al. The National Forensic Mental Health Service is working very closely with colleagues in the Irish Prison Service to deliver the best possible service, whilst acknowledging the challenge of providing safe and effective care to such a vulnerable unwell group at this time. It has never been more pressing to provide humane drug-free prisons and enough acute, sub-acute, medium-term and long-term secure forensic hospital places, with decant wards and surge capacity (McManus et al. et al. et al. 2018, et al. et al. et al. et al. et al. et al. et al. The Covid-19 emergency has led to rapid changes in working practices in psychiatry (European Centre for Disease Control and Prevention, This is an idea that has at last found its moment. As with every other employer, the National Forensic Mental Health service must pay greater attention to promoting employee safety. Public health information is made available to increase awareness of the new risks associated with Covid-19. Training in the donning and removal of PPE and hand washing is the new normal. Support must also be made available for impacted employees. For the future, there should be a return to investing in career development \u2013 every trainee should be able to register for a higher degree relevant to their practice. This would be a real stimulus to the knowledge culture and economy of medicine and health professions.et al. et al. et al. et al. There will be no return to the old normality. It may take longer than expected to achieve sufficient population immunity through vaccination or exposure. There will likely be further, lesser epidemics and there may be more deadly ones. The universal recognition of medical need and medical leadership in the face of deadly illnesses needs to be kept in the forefront of policy and practice when the increased and increasing mortality of the severely mentally ill has been missed by lay policy makers until now (Crump Shared office space is already a thing of the past. Telemedicine may replace most but not all prison in-reach and outpatient clinics, and hospital practice will benefit from leaner, more focused patient reviews. Training for psychiatrists will likely revert to the model of valuing preliminary years of training in general medicine or general practice. Out-patient and hospital work will be far more efficient through the liberation of clinicians from administrative burdens and a greater task orientation towards achieving clinical goals. Formal productivity monitoring through the use of electronic clinical management systems will drive further reform of the deployment of all health professionals. Waiting lists will be managed through the deployment of senior clinicians to this key decision-making function, with re-medicalisation of assessment and neuropharmacological management.et al. Forensic psychiatry needs a governance structure in which medical leaders (Ham, et al.et al. et al. et al. et al. Prior to the Covid-19 pandemic, there was tolerance for a homeless, mentally ill and substance misusing population who cycle between psychiatric and addiction services, prisons and street services Maxmen, . They reet al. et al. et al. The future can be bright for patients in forensic psychiatry services. A new hospital will replace the 1850s Dundrum buildings in 2020. New teaching and research programmes will be an intrinsic part of the new hospital (Kennedy"}
{"text": "Current human-induced climate warming poses a threat to many organisms Somero, . SpeciesIn recent decades there has been a boom in studies that use genome-wide sequencing (Savolainen et al., Logan and Cox suggest that there is moderate heritability for upper thermal tolerance and, hence, the potential for heat tolerance to evolve. However, this may also be constrained by unfavorable genetic correlations with other thermal performance traits. They also suggest that the plastic response of the transcriptome depends on the magnitude of thermal shifts. Rodrigues and Beldade also study genomics and transcriptomics of plasticity, which are usually assumed to have the potential to enhance thermal adaptation. However, more research is needed because high phenotypic plasticity may be maladaptive in warmer and more variable future climates (Kreyling et al., Drosophila Genetic Reference Panel (DGRP, Mackay et al., Lecheta et al. found that heat tolerance is less variable than cold tolerance, with ~50% more identified genes affecting the latter. These results reinforce that heat tolerance is more constrained than cold tolerance (Ara\u00fajo et al., S\u00f8rensen et al. studied D. simulans populations after 20 generations of experimental evolution under predictable or unpredictable thermal fluctuations. The strongest response involved unpredictable fluctuations, and the genes under selection were distinct from the genes that are important for the adaptive plastic response under predictive thermal fluctuations. Other studies have shown that constant and fluctuating temperatures induce different plastic and evolutionary responses (Botero et al., Using a genome-wide association study and transcriptomic profiling in lines from the Zwoinska et al. found that males are more affected than females when flies were exposed at high sublethal temperatures. At the same time, they did not find additive genetic variance for reproductive performance at these temperatures. Similar results were obtained for the egg-to-adult viability assessed at different temperatures in D. melanogaster (Kristensen et al., Zwoinska et al. the power to map the genetic variants of relatively small effects may be reduced due to the low line number. Thus more studies, using several populations or more DGRP lines are needed.A potential limitation of studies on the evolution of heat tolerance is that most ignore the possible negative impacts of sublethal temperatures on oogenesis and spermatogenesis. This could lead to a higher vulnerability to climate warming in many organisms than is currently thought (David et al., Drosophila subobscura are remarkably consistent worldwide and highly correlated with environmental temperature, respond to seasonal changes and frequency shifts shortly after a heatwave (Balany\u00e0 et al., Karageorgiou et al. focused on the breakpoints of a particular inversion that shows cyclic seasonal changes and speculate that this might be partly due to antagonistic pleiotropic effects on reproduction and immunity resulting from a position effect affecting the expression of functional genes located at the breakpoints.Few studies have demonstrated that adaptive evolution is occurring as a consequence of climate change. Latitudinal and long-term trends in the frequency of inversions in Mazzucco et al. focussed on the endosymbiont Wolbachia infecting D. melanogaster lines evolved in cold and hot environments, and found that these dynamics cannot be straightforwardly linked to temperature, making it difficult to predict the impact of climate change.An important ingredient in a warming world is the ecological and evolutionary implications of parasite-host dynamics and prevalence. Cort\u00e9s et al. summarize some of the tools available to reveal the genetic consequences of climate change, but there are some shortcomings to linking fitness relevant genes with environmental factors; e.g., those related to data reporting as highlighted by Waldvogel et al. This is important, as genotype-environment associations can be a key ingredient in forecasting the response of natural populations to climatic variation.A goal of genome-wide analyses is to detect and understand the signatures left by natural selection on the genome. Alcorta et al. shed light on the genomic features and taxonomy of thermophilic cyanobacteria living in hot springs. These features included genome reduction, changes in GC content, coding density, and size of biosynthetic gene clusters.Relevant insights into the genetic basis of thermal evolution can come from studying the adaptations of organisms that live in extreme natural environments. Using a metagenomics approach, The contributions to this Research Topic add to our understanding of thermal adaptation and its multifactorial nature, and highlight the challenges that are still ahead of us in striving for a deeper understanding of adaptation to expected higher and more variable future temperatures. As shown in this Research Topic, increased knowledge should be brought about by complementary approaches comprising different levels of biological organization and their interaction, using a variety of methodologies and study organisms.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. All authors contributed to the writing of the editorial.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Large benthic Foraminifera (LBF) are major carbonate producers on coral reefs, and are hosts to a diverse symbiotic microbial community. During warm episodes in the geological past, these reef\u2010building organisms expanded their geographical ranges as subtropical and tropical belts moved into higher latitudes. During these range\u2010expansion periods, LBF were the most prolific carbonate producers on reefs, dominating shallow carbonate platforms over reef\u2010building corals. Even though the fossil and modern distributions of groups of species that harbour different types of symbionts are known, the nature, mechanisms, and factors that influence their occurrence remain elusive. Furthermore, the presence of a diverse and persistent bacterial community has only recently gained attention. We examined recent advances in molecular identification of prokaryotic (i.e. bacteria) and eukaryotic  associates, and palaeoecology, and place the partnership with bacteria and algae in the context of climate change. In critically reviewing the available fossil and modern data on symbiosis, we reveal a crucial role of microalgae in the response of LBF to ocean warming, and their capacity to colonise a variety of habitats, across both latitudes and broad depth ranges. Symbiont identity is a key factor enabling LBF to expand their geographic ranges when the sea\u2010surface temperature increases. Our analyses showed that over the past 66\u00a0million\u00a0years (My), diatom\u2010bearing species were dominant in reef environments. The modern record shows that these species display a stable, persistent eukaryotic assemblage across their geographic distribution range, and are less dependent on symbiotic photosynthesis for survival. By contrast, dinoflagellate and chlorophytic species, which show a provincial distribution, tend to have a more flexible eukaryotic community throughout their range. This group is more dependent on their symbionts, and flexibility in their symbiosis is likely to be the driving force behind their evolutionary history, as they form a monophyletic group originating from a rhodophyte\u2010bearing ancestor. The study of bacterial assemblages, while still in its infancy, is a promising field of study. Bacterial communities are likely to be shaped by the local environment, although a core bacterial microbiome is found in species with global distributions. Cryptic speciation is also an important factor that must be taken into consideration. As global warming intensifies, genetic divergence in hosts in addition to the range of flexibility/specificity within host\u2013symbiont associations will be important elements in the continued evolutionary success of LBF species in a wide range of environments. Based on fossil and modern data, we conclude that the microbiome, which includes both algal and bacterial partners, is a key factor influencing the evolution of LBF. As a result, the microbiome assists LBF in colonising a wide range of habitats, and allowed them to become the most important calcifiers on shallow platforms worldwide during periods of ocean warming in the geologic past. Since LBF are crucial ecosystem engineers and prolific carbonate producers, the microbiome is a critical component that will play a central role in the responses of LBF to a changing ocean, and ultimately in shaping the future of coral reefs. I.et al.,et al.,et al.,et al.,et al.,Across the globe, coral reefs are experiencing rapid declines due to deteriorating environmental conditions mainly driven by ocean warming  overlooked unicellular eukaryotic large benthic Foraminifera (LBF). Symbiosis with eukaryotic taxa  is essential for the health of reef ecosystems, and LBF are responsible for a significant proportion of the carbonate sediment across reef environments worldwide Langer, . From a et al.,et al.,et al.,et al.,et al.,It is becoming increasingly apparent that other microorganisms such as bacteria and Archaea (henceforth referred to as prokaryotic associates), fungi, and viruses, play a significant and complex role in maintaining the host's health  by persistent eukaryotic and prokaryotic microbial associations across the distribution of LBF species, which have been reported to be highly species\u2010specific and to determine ecological niches in LBF; (ii) the presence of a variable microbiome responsive to environmental gradients; (iii) the presence of a stable, persistent algal symbiont community coupled with flexible bacterial associations; and (iv) adaptable algal symbiosis with a persistent bacterial community, which could assist species in crossing biogeographical barriers and adapting to changing environmental conditions. The composition of the microbiome benefits the host in different ways, and different species are likely to utilise different strategies to maintain the holobiont system. Therefore, it is crucial to understand and disentangle how the host and symbiont compartments are likely to interact with, and respond to environmental change.We discuss how the microbiome could benefit and drive LBF evolution across species distribution ranges:  the acquisition of energy through photosynthesis, which is particularly favourable in oligotrophic environments  enhanced calcification rates, because the energy acquired through photosynthesis is orders of magnitude higher than in heterotrophy alone  agamonts, which are diploid, multinucleate, and microspheric ; (ii) schizonts that are diploid, multinucleate, and megalospheric ; and (iii) gamonts, which are haploid, mononucleate and megalospheric et al.,et al.,Four independently evolved families of LBF  host endosymbiotic diatoms Hallock, . It is wet al.,et al.,Nitzschia, Nanofrustulum, Amphora, and Navicula were the most commonly observed diatom symbionts in Amphistegina spp., whereas Achnanthes is a diatom genus commonly associated with Heterostegina  their ability to host multiple species and strains of diatom symbionts  their remarkable morphological plasticity Parasorites, which hosts chlorophytes  in marginal habitats characterised by high seasonal fluctuations in environmental parameters Parasorites. Most of these species are endemic to the Western Atlantic. A few species, including Parasorites orbitolitoides and Laevipeneroplis malayensis, have been reported from the Indo\u2010Pacific Peneroplis, Dendritina, Spirolina, and Monalysidium et al.,et al.,2 concentrations were at least twice present levels, and sea\u2010surface carbonate saturation was significantly lower  and Belgium (51\u00b0N) , the Middle Eocene climatic optimum (MECO), and the Middle Miocene climatic optimum (MMCO) et al.,i) in south\u2010west Europe during the Paleocene\u2013Middle Eocene, (ii) in the Middle East from the Late Eocene to Early Miocene, and (iii) the present\u2010day Indo West\u2010Pacific biodiversity hotspot (a)et al.,Amphistegina gibbosa (an Atlantic species) is continuous across its geographic range, but significantly different from the symbionts of the two Pacific species in the same genus, A. lessonii and A. lobifera, from Oahu, Hawaii, which also differ from each other  host eukaryotic symbiont communities similar to the Hawaiian population et al.,et al.,In contrast to globally distributed LBF hosts, species with a more restricted distribution tend to show a more diverse and variable eukaryotic community across their distribution range , and Caribbean/Atlantic regions et al.,et al.,et al.,It is predicted that conserved algal symbiont communities are particularly advantageous to LBF species living at the edge of species' geographical distribution, whereas variability in environmental conditions is accommodated by variable bacterial associations. For example, LBF and reef\u2010building corals living in tropical\u2013subtropical transition zones exhibit low diversity, and a dominant symbiont type  by maintaining consistent, beneficial algal symbionts, and (ii) by acquiring local bacterial taxa, stabilising host\u2013symbiont associations, and providing further capacity for local acclimation/adaptation et al.,et al.,et al.,Symbiodinium community et al.,In addition to selective pressures acting through bacterial and algal associates, the genetic diversity of the host can also provide mechanisms for responding to changes in environmental conditions. Genetic diversity within populations of LBF and their symbionts is poorly known, making it impossible to assess how genetic lineages within species (i.e. cryptic diversity) is distributed in space, and to test whether it is associated with different microbial associates. Speciation is not always accompanied by morphological change  by depending on the presence of a pre\u2010adaptive microbiome; or (ii) by re\u2010shaping the symbiont community. Given the relationship between LBF and their microbial associates, and the role that eukaryotic symbionts are known to play in LBF evolution  re\u2010assessment of eukaryotic symbiont diversity using molecular techniques in addition to morphology, specifically in the context of environmental gradients. Even though the identities of major algal groups hosted by LBF families are relatively well known, there are few studies on the intra\u2010 and interspecific distribution of eukaryotic symbionts, biogeographical breaks, and biotic and abiotic factors that influence the flexibility/specificity and diversity of these associations. (ii) Assessment of the diversity of bacterial communities associated with LBF, utilising next\u2010generation sequencing, across gradients of depth, latitude, and longitude. Quantifying functional shifts in bacterial communities, and how bacteria contribute to the energy budget and other physiological pathways will also represent important advances in LBF biology. The scarcity of data on the role of prokaryotes in LBF is a significant knowledge gap, and should be a high priority for future research. (iii) Identification of bacteria using imaging techniques such as fluorescent in situ hybridisation and electron scanning microscopy, which should help decipher the potential roles of bacteria in LBF intracellular space. (iv) Further research on neglected eukaryotic symbiont groups such as rhodophytes, chlorophytes, and chrysophytes. Rhodophyte\u2010bearing LBF are a particularly tantalising model, as not only do they show a peculiar relationship with their symbionts, but most species that host red algae are cosmopolitan and occupies a wide range of environments. (v) Study the presence of cryptic diversity and phylogeography of species that have been previously described based on morphological characteristics. Genetic differences are not necessarily accompanied by the development of morphologically divergent traits  Geological and modern records of LBF distributions show that diatom\u2010bearing taxa are the most common, abundant, and dominant taxa across wide environmental gradients, whereas dinoflagellate and chlorophytic species tend to be more restricted in their distribution, and less tolerant to nutrients and terrestrial influences.(2) Modern, cosmopolitan diatom\u2010bearing species depend less on their eukaryotic microbes for meeting their energetic requirements and show stable diatom symbiont communities in the core of their distribution. By contrast, dinoflagellate\u2010bearing taxa, are more reliant on their symbiont for survival, and tend to have a flexible association responsive to environmental conditions across their range of occurrence.(3) The occurrence of cryptic speciation in many LBF species can hide host\u2013symbiont specialisation and adaptation capacity of the host to different environments. The capacity of species to adapt to their new environment is a critical component for understanding the role of evolutionary processes in the assembly and dynamics of natural communities.(4) Abiotic factors , and eukaryotic symbionts had an important synergistic contribution to the expansion and contraction of LBF distribution during warming\u2013cooling cycles during the Cenozoic.(5) Interactions between the host, the eukaryotic symbionts, and the prokaryotic endobionts is key to understanding the plasticity, adaptive potential, and resilience of LBF to environmental change. Additionally, the physiological state of both the host and the associates is likely to influence the identity and diversity of the eukaryotic and prokaryotic community.(6) In recent years, we have seen major advances in describing and understanding the role of microbial assemblages in reef fauna, including reef\u2010building corals, sponges, and benthic Foraminifera, and the role that bacteria and other microorganisms play in maintaining the health of the reefs. LBF are essential ecosystem engineers and prolific carbonate producers, and the study of their microbiome should provide important information on their ability to respond to climate change.(7) Identifying host\u2013prokaryote\u2013eukaryote associations and genetic structure within LBF host populations is crucial to a better understanding of the capacities of LBF species to adapt to their new environment or to shift their distribution range. These are critical components for understanding the role of evolutionary processes in shaping the assembly and dynamics of natural communities."}
{"text": "The purpose of this study was to provide appropriate preoperative supportive conditions to improve anxiety and vital signs for patients undergoing Coronary Artery Bypass Grafting -CABG- surgery. n=30), intervention1 (n=30), and intervention2 (n=30). The control group received only the routine preoperative counseling of ward and admitted to the operating room as usual; the intervention1 and intervention2 groups in addition received another two counseling sessions, then the intervention1 group was admitted in the operating room as usual, but the intervention2 group was admitted by the counselor in the operating room. Data were collected using a three-part questionnaire including demographic characteristics, vital signs chart, and the Spielberger's State-Trait Anxiety Inventory.  This clinical trial study was performed on 90 patients undergoing CABG surgery in Farshchian Hospital of Hamadan, Iran in 2019. Sample was selected by convenience and were randomly divided into three groups: control  and also there was a significant difference between the mean systolic blood pressure, heart rate and respiratory rate of the three groups (p<0.001) but the mean of the variables of temperature and diastolic blood pressure in the three groups were not significantly different .  The results showed that there was a significant difference in the mean anxiety of the three groups after admission in the operating room (intervention2 was lower than intervention1 and control groups,  Our results revealed preoperative consultation and admission in the operating room by the consultant can reduce the level of anxiety and stability of vital signs of patients undergoing CABG. Cardiovascular disease has become a major worldwide problem and is a serious health threat that causes numerous biological, psychological and social problems and is one of the leading causes of death and disability. These diActually Cardiac surgery is often associated with anxiety and fear in patients undergoing it. Anxiety Given that the receptionist in the operating room is one of the last people the patient will be in contact with the patient before surgery, The researcher speculates that if this is a relationship with the patient who was already in touch with the patient, a positive interaction and Having a friendship between them will affect the patient's anxiety and vital signs. According to the researcher, no study has been conducted in this area, so the present study will be conducted to determine the interactive effect of preoperative consultation and patient admission in the operating room by counselor on the level of anxiety and vital signs in coronary artery bypass graft surgery (CABG).The present study was a clinical trial study performed at Farshchian Hospital of Hamadan, Iran in April 2019. Using convenience sampling, 90 patients were selected for CABG surgery and were randomly divided into three groups  using random sampling and weekly block method. The inclusion criteria were include the at least 18 years of age; fully conscious and knowledgeable regarding the time, place, and person; having the ability to communicate, not having a history of heart surgery, lacking physical and cognitive disorders; lacking medical education or what was related to it; not having a drug addiction; no prior medical diagnosis of anxiety and depression and not taking tranquilizer, anti-depressants, or anti-anxiety drugs at one month before surgery. The exclusion criteria were the unwillingness of patients to continue the participation in the study and their condition worsening during the study period.et al.  and most of the subjects were illiterate (55.6%) and the results of Chi-square test showed no significant difference between the three groups in terms of gender and education .p-values in the pre-test of the variables of heart rate, respiratory rate, systolic blood pressure and positional anxiety showed no significant difference between the three groups. But for the variables of temperature and diastolic blood pressure were significant at the 0.05 level . There was also a significant difference in the level of anxiety between intervention group 1 and intervention 2 (p<0.001). accordingly, the mean of anxiety in intervention 2 was lower than the control group and intervention 1 and the mean of anxiety in intervention 1 group was lower than control group (p=0.004), between the mean of heart rate in the control group with intervention 2 (p=0.001) and between the mean of heart rate in the intervention 1 group with intervention 2 (p=0.002) there was a significant difference that mean of heart rate in intervention 2 was lower than the control group and intervention 1 and the mean of heart rate in intervention 1 group was lower than control group  and also between the mean of respiratory rate in the intervention group 1 and intervention 2 group (p<0.001) there was a significant difference. It\u2019s that the mean of respiratory rate in intervention 2 was lower than the control group and intervention 1. The mean of respiratory rate in intervention 1 group was lower than control group (p=0.018), between the mean of systolic blood pressure in the control group with intervention 2 (p<0.001) and between the mean of systolic blood pressure in the intervention 1 group with intervention 2 (p=0.008) there was a significant difference that the mean of systolic blood pressure in intervention 2 was lower than the control group and intervention 1 and the mean of systolic blood pressure in intervention 1 group was lower than control group ( Between the mean of respiratory rate in the control group with intervention 1 and 2 groups (ol group . Betweenol group .et al.(et al.(et al.,(et al.(et al.(et al.,(et al.(et al.(The results of this study show that there is no significant difference between the pre-test anxiety scores of the three groups, which is in agreement with the results of studies such as Fazlollahpour et al., Amiri etet al. and Abbal.(et al. It has a.(et al., Abbasi e.,(et al. and Hemml.(et al. However,l.(et al.,26 The r.(et al., Rosiek e.,(et al. and TimuThe results also show that there is a significant difference between the post-test scores of the two groups of intervention 1 and intervention 2, which indicates the effectiveness of consultant admission in the operating room which no relevant article has been found in relation to this finding to compare the results that this indicating the novelty and importance of this study.et al.,(et al.,(et al.,(et al.(et al.(et al.,(et al. (This study showed that there is a significant difference between the three variables of heart rate, respiration and systolic blood pressure in the control group with the intervention group 1 and intervention group 2, which indicates the effectiveness of preoperative counseling on these variables. This is consistent with the findings of the study by Amiri et al., Hasan Ge,(et al., Degirmen,(et al., but is i.,(et al. The resul.(et al. and is i.(et al., and Degi,(et al.  studies.Based on the findings, it can be concluded that preoperative consultation and admission in operating room by counselor can reduce the level of anxiety and stability of vital signs in patients. According to the data it can be decided that the admission in operating room by counselor will increase the effectiveness of the surgical consultation, reduce the level of anxiety and stabilize the vital signs of the patients. This approach can be considered as a strength and superiority of the present study than previous studies which suggest that cardiac surgery centers should adopt these results in order to reduce the anxiety and stability of the vital symptoms of patients."}
{"text": "We thank Hassing et al. for their interest in our publication (Majeed et al., Second, Hassing et al. pointed out a lack of adjustment for liver cirrhosis in our association of bilirubin with QT interval. We agree that liver cirrhosis has been associated with a prolonged QT interval (Tsiompanidis et al., In their letter to the editor, Hassing et al. also report results of association of bilirubin with Fridericia's heart rate corrected QT interval in a sample of healthy participants aged 18\u201330\u00a0years. They observed a negative association of bilirubin with QT interval as opposed to the results of our study. Perhaps the authors should read the AHA/ACC/HRS recommendations for QT correction (Rautaharju et al.,"}
{"text": "Biological control is widely successful at controlling pests, but effective biocontrol agents are now more difficult to import from countries of origin due to more restrictive international trade laws (the Nagoya Protocol). Coupled with increasing demand, the efficacy of existing and new biocontrol agents needs to be improved with genetic and genomic approaches. Although they have been underutilised in the past, application of genetic and genomic techniques is becoming more feasible from both technological and economic perspectives. We review current methods and provide a framework for using them. First, it is necessary to identify which biocontrol trait to select and in what direction. Next, the genes or markers linked to these traits need be determined, including how to implement this information into a selective breeding program. Choosing a trait can be assisted by modelling to account for the proper agro\u2010ecological context, and by knowing which traits have sufficiently high heritability values. We provide guidelines for designing genomic strategies in biocontrol programs, which depend on the organism, budget, and desired objective. Genomic approaches start with genome sequencing and assembly. We provide a guide for deciding the most successful sequencing strategy for biocontrol agents. Gene discovery involves quantitative trait loci analyses, transcriptomic and proteomic studies, and gene editing. Improving biocontrol practices includes marker\u2010assisted selection, genomic selection and microbiome manipulation of biocontrol agents, and monitoring for genetic variation during rearing and post\u2010release. We conclude by identifying the most promising applications of genetic and genomic methods to improve biological control efficacy. I.Biological control , is arguably the best solution for phasing out large\u2010scale pesticide use . Next, we present the current state and future prospects of using genetic and genomic methods towards that aim. We consider these methods from evolutionary and ecological contexts, that is how these methods can realistically operate in long\u2010term breeding programs and in the field Fig. . BecauseII.et al. , which allows a trait to be improved by  selection. The amount of standing genetic variation depends on the type of trait and its genetic architecture, which can be defined as the number and location of the loci involved, and their interactions . Traits closely associated with fitness that are important for biocontrol, such as life\u2010history and behavioural traits et al., et al., et al., et al., et al., et al., Assembling a genome for a biocontrol agent of interest vastly expands the possibilities for generating new knowledge on the genetic architecture of biocontrol traits. A reference genome facilitates studies that focus on gene expression analyses, targeted gene editing, and marker\u2010informed selection. Although producing a high\u2010quality genome  is often portrayed as an essential goal Bentley, , a high\u2010et al., et al., 2010; Geib et al., 2017; Ferguson et al., 2020) but can be more challenging for species that are difficult to inbreed et al., et al., et al., Nasonia parasitoid wasp sex ratio  [e.g. maize height , and antennal perception of different olfactory cues, i.e. male mate\u2010searching versus female host\u2010searching in the parasitoids Cotesia vestalis   were identified by analysing RNA sequencing (RNAseq) data versus a complete ban in the EU et al., et al., et al., et al., et al., Currently, there is much interest in the role of the microbiome in organismal functioning. In a biocontrol context, it is known that microbes can generate chemical signals that attract parasitoids to their host, and that bacteria can have a defensive role against parasitoids, such as in aphids et al., Phytoseiulus persimilis Athias\u2010Henriot   For complex traits with highly polygenic bases or genes with complicated epigenetic effects, direct and linkage equilibrium MAS may not be possible. In such cases, it is possible to use markers that are linked to a total breeding value instead of any specific phenotype The availability of genetic markers allows for population genetic analyses, either at a coarse scale such as in the case of microsatellite panels, or at a fine scale such as dense SNP panels based on assembled genomes. A powerful application of population genetics in biocontrol is monitoring of agents released into the field Fig. , allowinet al.  for ongoing monitoring of a biocontrol programme in southern France via a breeding regime or by genetic manipulation  was fed bacterial supplements , as can feeding on factitious hosts or prey with a specific microbiome indirectly.Microbiomes may constitute an important target for modifying biocontrol agent performance. The composition of the microbial community of an organism can be altered through rearing conditions (e.g. a probiotic diet), et al., et al., It is also possible for host specimens to transmit their microbes to released biocontrol agents and influence their physiology and ecology  in numerous insect species, such as the Drosophila parasitoids Asobara and Leptopilina  are already being implemented Fig. . Others Novel methodology to uncover the genetic architecture of life\u2010history traits, in combination with increasing investment in research and development by biocontrol companies, will rapidly expand the knowledge base of the biocontrol field. Gene\u2010editing techniques are a useful research tool for delineating this genetic architecture, but as the current biocontrol market depends on a reputation of using more traditional genetics methods, now is not the time to use gene\u2010edited organisms in the field.et al., et al., et al., Knowledge about genetic variation can be used to design artificial selection programs, either by traditional selective breeding (White versus unpredicted host shifts in the field; Follett et al., A caveat is that these approaches do have their limitations; for example, a founding population may lack sufficient genetic variation to select upon (Mackauer, The aim of this review is to stimulate the application of genetic and genomic methodology in next\u2010generation biological control. We hope that it will lead to an increasing awareness of the potential of biocontrol agent breeding among scientists, the biocontrol industry, growers, and the general public."}
{"text": "Back in the mid-2000s, when Facebook was new and smartphones had still not become a major part of our everyday lives, researchers started to explore the use of Machine Learning in biomechanics. The road ahead appeared uncertain and people asked whether it was a new dawn or false hope?  data with less expert knowledge and without expensive equipment. As they state, motion capture systems are going to \u201cincrease the availability of motion analysis to a wider range of people.\u201d In other words, access to such systems enables a move toward pervasive healthcare systems  and Gaussian Mixture Model or Linear Discriminant Analysis. Another contribution by Remedios et al. describes an alternative way to objectively identify movement phenotypes without the need to a-priori prescribe movement features. Ross et al. discriminate \u00e9lite from novice athletes, devising inertial features that capture motion details related to competition level. The recognition of movement patterns was also a key focus in the study by Suda et al., which used ground reaction forces to recognize foot-ankle movement strategies in long-distance runners.The automatic classification of athletic tasks based on motion data gathered in real-world conditions with inertial sensors is another expanding area of investigation, as evidenced in papers by Guerra et al. propose an interesting application of automatic pose recognition  and classification to trigger an alarm in frail individuals. The study by Gregori et al. focused on rehabilitation by developing a deep-learning method to automatically evaluate grasping actions in people with upper limb prostheses. Background segmentation and shape classification allowed Monezi et al. to automatically detect the three-dimensional location of multiple players in a basketball court.Computer Vision represents a parallel trend, involving a combination of deep neural networks and simpler classification algorithms. Rethwilm et al. gained insights on trunk lean control in patients with Cerebral Palsy, combining PCA to binary logistic regression. In their technical paper, Burdack et al. explained how data filtering and unsupervised data reduction impacted gait classification based on ground reaction force data. Principal Component analysis is also the framework of analysis explored by Promsri and Federolf, who crafted a methodological paper explaining how to gain information about the coordinative structure of complex whole-body movements during balancing. In addition, De Roeck et al. focus on lower limb kinematics during deep squatting and in the forward lunge, devising a statistical model that predicts lower limb kinetics therein.Gait analysis is undoubtedly a collector of the data revolution. Instrumented gait assessment is routinely used to evaluate an individual's quality of life, morbidity, and/or mortality. Here, data science is a powerful complement to traditional approaches when handling large, heterogeneous, and sometimes noisy data sets  neural networks. LSTM was also combined with convolutional neural networks by Yu et al. to predict pre-impact fall for older people. Notably, this approach was also implemented in a microcontroller unit featuring a working device. The practical translation of these techniques constitutes a crucial step that has not yet been undertaken that requires further exploration in future studies.Cerveri et al.. de Ara\u00fajo et al. showed how hand resting tremors could be used in the diagnosis of Parkinson's Disease. For patients in a similar condition, Lebel et al. worked on the prediction of motor performance based on visible symptomatology. A crucial issue is discussed in the work by Chia et al., which developed a decision support system based on gait kinematics, anthropometric characteristics, and physical examination and trained a system to learn the recommendations formulated by clinicians.Many papers in the Research Topic propose research-grade applications, and the effective combination of technology and data science will be topical in the near future. The seed of this trend is already visible. For instance, statistical shape modeling supported by logistic regression has clinical applications in automating the identification of surgically-relevant landmarks, as demonstrated by C\u00f4t\u00e9-Allard et al.). Furthermore, as anticipated by many experts  \u201cidolatry of data,\u201d we believe that the road is paved for rapid and inevitable (re)volutions. Assisting human decisions is among the most impactful advancements that data science and human movement science together can provide to medicine in the next decade (Jones et al., The constant growth of computational power and wearable sensor miniaturization will also open pathways to pervasive real-time applications, exploiting the wealth of data available \u201cout in the wild,\u201d from marker-less motion capture to exercise monitoring and training assistance. To date, artificial intelligence does not simply provide new tools to study human motion. Rather, the way we study human motion is evolving thanks to artificial intelligence. By \u201cfollowing the data\u201d (Halevy et al., MZ, AK, and PF contributed equally to the writing of this editorial. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "In this study, the authors designed a visual stimulus with two overlapping random dot patterns, differing in their color (red vs. green) and motion direction (upward vs. downward) and with their left and right panels combining the color and motion inversely compared to the central panel  of the There are a multitude of mechanistic roles that are associated with alpha oscillations and low frequencies (<20 Hz) in general. These oscillatory activities have been proposed to act as a metronome for processing audio-visual stimuli . Whether these two findings could be attributed to attention levels should be studied in the future by examining the potential inter-individual correlation between alpha frequency and power and whether subjects with a weaker alpha power allocate higher levels of attention.Furthermore, changing levels of attention are associated with changes in the power of high frequency oscillations  (Fries et al., In summary, Zhang et al. documented a novel association between alpha frequencies and perceptual feature binding. We propose a more central role of attention as a causal factor for changes in alpha power and frequency of alternations between binding states. Zhang et al. showed in a previous study with controlled levels of attention that physical and active binding may happen at equal attention levels (Zhang et al., MC, PY, ST, and ME conceived the ideas. MC and ME wrote the manuscript. ST critically revised the manuscript. All authors approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Person-centred care is at the core of a value-based health system. Its transformative potential is to enable and support key policy, planning and service developments across the system even when these go against the self-interest of individual major players. It offers a potent test for decision makers at all levels. It demands responses that are multi-level, empirically grounded, expert-informed and data-driven that must converge on the singularity of individuals in the places that they live. This requires different approaches that recognise, respect and reconcile two necessary but constitutionally disparate perspectives: the bureaucratic, overtly decontextualised, top-down, policy and planning objectives of central governments and the formally complex, dynamic and contextualised experience of individuals in the system. Conflating the latter with the former can lead unwittingly to a pervasive and reductive form of quasi-Taylorism that nearly always creates waste at the expense of value. This has parallel application in the treatment domain where outcomes are non-randomly clustered and partitioned by socioeconomic status, amplifying unwarranted variation by place that is striking in its magnitude and heterogeneity. In this paper, we propose that a combination of (1) relevant, local and sophisticated data planning, collection and analysis systems, (2) more detailed person-centred service planning and delivery and (3) system accountability through co-design and transparent public reporting of health system performance in a manner that is understandable, relevant, and locally applicable are all essential in ensuring planned and provided care is most appropriate to more than merely the \u2018average\u2019 person for whom the current system is built. We argue that only through a greater appreciation of healthcare as a complex adaptive (eco)system, where context is everything, and then utilising planning, analysis and management methodologies that reflect this reality is the way to achieve genuine person-centred care. A consistent recommendation arising from countless reviews into the mental health system both within Australia , et al., et al., et al., et al., et al., et al., et al., et al., While not exactly a new concept  and downplay or dismiss empiricism and tacit knowledge (clinicians and patients). They are applied top-down in the manner of Soviet-style central planning without consideration of scale or context, with the result they are given lip-service by those responsible for planning, commissioning and managing regional and sub-regional services. The fundamental problem is not \u2018should be\u2019 models themselves: there are manifest advantages to be had in the use of such frameworks to estimate and plan resource allocations at the population-level, for example , Recognising also that a significant proportion of the population do not have access to the personal resources required to enable them to engage with care effectively is essential. Knowing this, it is the responsibility of system managers, not by-default the individual, to build facilitators into the structure of the intervention set itself if we are to develop truly responsive systems of care, not just for some notional average person with average personal resources. The current planning, implementation and service delivery models for mental health treatment in Australia objectively do not adequately meet the breath of needs of individuals or communities.et al., et al., et al., et al., Access to psychological therapies offers a case in point. Medicare in Australia provides for universal subsidised access to focused psychological therapy via GP referral , In addressing  these issues, we do not suggest that what we offer is a panacea. Instead, we frame a set of priority issues that we face, and in doing so offer tentative recommendations for improvement towards a person-centred mental health service system.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., in situ  individuals to a marked greater extent  that increase their risk of poor health outcomes for themselves, and create a toxic legacy for future generations, amplifying rather than attenuating enduring disadvantage (Wilkinson and Pickett, It is not good enough to design service systems or provide interventions without due consideration to the context in which these services are to be delivered (Robert and Fulop, et al., et al., et al., et al., et al., et al., Individuals have a valuable role to play in service planning and healthcare policy-making through meaningful and supported engagement and co-design in all levels and at all points of decision-making Groves, . Accountet al., This extends to the use of personal data. Measuring what is valued by patients and whether it is achieved, and reincorporating this into service development decisions is essential. Non-disclosive data on the planning and performance of health services funded through the public purse should be available for open scrutiny, reported at consistently meaningful aggregations \u2013 regional and sub-regional \u2013 and presented in a manner that is easily understood and relatable to the real-world, avoiding the use of obscurant metrics, or the bureaucratic tendency, well-meaning and benevolent as it may be, to confuse and conflate privacy and secrecy. As a result of this extractive rather than inclusive mentality to the use of personal data, most people have little if any idea whether their local health services are performing as they would wish or how they compare it to other localities in terms of value and cost Chen, . There aThe relative impotence of planning when unsupported by clear change processes underpinned by implementation science means demand will continue to outpace supply as provision is constrained within an artificially constructed organic healthcare economy. This inhibits innovation under the guise of protection and governance and places a premium and priority on the providers return on investment and in doing so demotes value from the user's perspective to a secondary benefit. Unless altered, we will continue to invest in the wrong things, believing them to the right things, often plausible, but nearly always they create waste, not value. We apply the evidence-based dictum partially, choosing not to apply the same test to service planning and implementation that we do to treatments. Governance processes formalise the latter as a therapeutic good, and rightly so. Perhaps it is time to consider the application of a similarly constituted standard to the former that enables us to co-design, test and implement promising new models using local data, taking a person-centred and whole-of-community contextual approach, understanding healthcare is formally complex and ultimately recognise that it is the people who determine the value of services, not the funders. Without this, we will continue to build in demand failure and suffer the consequences."}
{"text": "Litton et al. noted that many of the risk factors for iron deficiency are also risk factors for developing a critical illness, and consequently, iron deficiency is likely to be over-represented in critically ill patients . Hepcidi"}
{"text": "Femoral neck anteversion (FNA) is the angle between the femoral neck and femoral shaft, indicating the degree of torsion of the femur. Differences in FNA affect the biomechanics of the hip, through alterations in factors such as moment arm lengths and joint loading. Altered gait associated with differences in FNA may also contribute to the development of a wide range of skeletal disorders including osteoarthritis. FNA varies by up to 30\u00b0 within apparently healthy adults. FNA increases substantially during gestation and thereafter decreases steadily until maturity. There is some evidence of a further decrease at a much lower rate during adulthood into old age, but the mechanisms behind it have never been studied. Development of FNA appears to be strongly influenced by mechanical forces experienced during everyday movements. This is evidenced by large differences in FNA in groups where movement is impaired, such as children born breech or individuals with neuromuscular conditions such as cerebral palsy. Several methods can be used to assess FNA, which may yield different values by up to 20\u00b0 in the same participant. While MRI and CT are used clinically, limitations such as their cost, scanning time and exposure to ionising radiation limit their applicability in longitudinal and population studies, particularly in children. More broadly, applicable measures such as ultrasound and functional tests exist, but they are limited by poor reliability and validity. These issues highlight the need for a valid and reliable universally accepted method. Treatment for clinically problematic FNA is usually de\u2010rotational osteotomy; passive, non\u2010operative methods do not have any effect. Despite observational evidence for the effects of physical activity on FNA development, the efficacy of targeted physical activity remains unexplored. The aim of this review is to describe the biomechanical and clinical consequences of FNA, factors influencing FNA and the strengths and weaknesses of different methods used to assess FNA. Femoral neck anteversion (FNA) is the angle between the femoral neck and femoral shaft, which affects the biomechanics of the hip. FNA changes substantially throughout growth, which may relate to motor development, and varies by up to 30\u00b0 within adults. Several methods can be used to assess FNA, which may yield different values by up to 20\u00b0 in the same participant. Treatment for clinically problematic FNA is usually de\u2010rotational osteotomy; passive, non\u2010operative methods do not have any effect.  Even within each imaging method, there are variations in how anatomical landmarks are identified. Differences in cost, time, availability, repeatability and radiation exposure mean that certain methods are not applicable, e.g. for clinical studies or those involving children.The aim of this review is to discuss the implications of altered FNA, in terms of both its effects on movement and its clinical consequences. In addition, we describe normal variation and factors affecting FNA in healthy and clinical populations of different ages. Finally, we will outline the different methods and landmarks used to assess FNA and evaluate their strengths and weaknesses with regard to a defined study setting.2et al.,et al.,et al.,et al.,et al.,et al.,et al.,et al.,et al., et al., A change in FNA affects the position of the trochanter and therefore the line of action of the muscles surrounding that region. Regional torsional changes along the femur also result in a change of lever arms .The distal femoral axis Figure\u00a0 has been77.1et al.,Computed tomography can be used to acquire images of single cross\u2010sections or volumes of bone. Because the X\u2010ray attenuation is very different between bone and soft tissue, CT provides a sharp contrast between bone and soft tissue and is therefore good in depicting mature, well\u2010ossified bones. CT scanning times per slice are lower than 2\u00a0s and for 3D\u2010rendering of hip structures, which requires multiple slices, this can go up to 40\u00a0s . CT is considered cheap compared with MRI due to shorter scanning time. CT results in ionising radiation exposure of 0.3\u20130.5\u00a0mSv for six slices in adults  bones. On the other hand, the imaging of whole cross\u2010sections is possible in neonates and young infants where the bone is not yet mineralised and remains permeable by sound waves. US is free of ionising radiation, cheap compared with other imaging techniques, and fast in terms of image acquisition, with the whole protocol lasting up to 10\u00a0min , biplanar radiography allowing two different projections  of the hip joint in the axial plane. FNA can be assessed using the ratio of internal rotation over external rotation, with greater internal rotation associated with greater FNA  with differences in mean values between methods of up to 10\u00b0   with other imaging techniques  (Dunlap et al.,et al.,et al.,et al.,We can find a total average difference for biplanar radiography compared with dried femoral measurements of 2.6\u00b0\u20133.6\u00b0 with good correlation (et al. (et al.,et al.,et al.,et al.,et al.,et al.,et al.,et al.,et al.,et al.,et al.,Davids et al.  have sho8Abnormal FNA changes the biomechanics of the hip, altering muscular lever arms, hip contact forces and femoral neck shear forces, which may contribute to development of a wide range of skeletal disorders, such as osteoarthritis and alter the kinematics of the lower limbs. FNA grows in line with the growth plate, which seems to adjust according to mechanical forces acting on the proximal femur during movement, increasing the FNA during gestation to more than 30\u00b0 and thereafter decreasing steadily until completion of growth. This decrease is less pronounced or absent in individuals with conditions causing neuromuscular and movement impairment such as cerebral palsy. Interestingly, FNA in older adults is consistently lower than in younger adults, raising the question of mechanisms behind the modelling of the femur at a mature age following growth plate closure. Treatment for altered FNA is usually de\u2010rotational osteotomy, suggested only in the case of disabling conditions; passive, non\u2010operative methods such as braces or wearable cables do not have any effect. Despite observational evidence for the effects of muscular activity on FNA development during growth, the efficacy of targeted physical activity remains unexplored. Large variations between methods evaluating the FNA limit the ability to synthesise the large number of studies on the topic, as normative values must be set, relative to the method. It is not possible to draw conclusions on the choice of which femoral axis to utilise, and further studies are needed to determine the relevant forces shaping it. However, the authors endorse identification of landmarks which consider the femoral head and trochanter part of the femoral neck axis. Further studies are needed to explore the distal axis and whether the usual posterior condylar axis is the most relevant one. As for the imaging technique, it is situation\u2010driven, with MRI and CT giving the best images and measurement precision; MRI is superior to CT in terms of radiation hazard and CT is quicker and cheaper. The biplanar radiography EOS system seems to be a quick, low\u2010radiation option but it is not as reliable as the aforementioned approaches. However, both within clinical and basic science research, limitations of these methods prevent their broader application in healthy children and population studies. New US techniques already permit a 3D depiction of the femur with systems of probe localisation. Further improvements in US imaging and data analysis could provide a cheap, quick, non\u2010invasive and more broadly applicable alternative to MRI and CT.Matteo Scorcelletti, Neil Reeves, J\u00f6rn Rittweger and Alex Ireland declare that they have no conflict of interest.Conception or design of the work: Matteo Scorcelletti and Alex Ireland. Drafting the article: Matteo Scorcelletti. Critical revision of the article: all authors. Final approval of the version to be published: all authors."}
{"text": "This editorial of the Special Issue \u201cECG Monitoring System\u201d provides a short overview of the 13 contributed articles published in this issue.In the first paper, Bae and collaborators  propose In the second paper, Lackner and colleagues  provide In the third paper, Holmes and colleagues  explore In another manuscript, Satti et al.  introducTang and colleagues  discuss Klum and collaborators  employedAnother manuscript from Wang et al.  exploresBaty and colleagues  developeWang and collaborators  propose Nie and co-workers  discuss The review of Serhani and colleagues  presentsOhmuta et al.  developeFinally, Al-Karadi and collaborators  discuss"}
{"text": "However, the impact of the virus on these sexual and gender minority populations was masked for decades by the perception of HIV as a \u201cgeneralized\u201d epidemic in the African context . While tIncreasingly, MSM outreach, engagement and research participation have been recognized as vital to HIV prevention and control efforts in sub\u2010Saharan Africa. This has been evidenced by a proliferation of observational and interventional studies engaging African MSM as one of several key populations affected by the HIV pandemic . The suc2Sibanye Methods for Prevention Packages Project in Cape Town and Port Elizabeth, South Africa. Sullivan et al. [Two manuscripts in this supplement focus on MSM and TGW who enrolled in a one\u2010year prospective cohort study called the n et al.  describeet al. [Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and syphilis among South African MSM and TGW. While acceptance of screening for syphilis and urethral NG/CT was near universal, only about two\u2010thirds of participants accepted clinician\u2010assisted screening for rectal NG/CT. This discrepancy may reflect participant unfamiliarity with the possibility of anorectal sexually transmitted infections (STIs) [In their accompanying paper, Jones et al.  describes (STIs) , concerns (STIs)  and psycs (STIs) . Consists (STIs) , 36, 37,3et al. [et al. [et al. [Four manuscripts in this supplement focus on retention of MSM and TGW who enrolled in cohort studies. Wahome et al.  report l [et al.  also rep [et al.  also repTogether, these three studies highlight tremendous challenges in the retention of MSM and TGW in HIV\u2010related observational studies. Common themes include the need for early intervention with strategies to encourage continued research participation, as loss to follow\u2010up disproportionately occurred early in studies and among participants who had newly arrived in their communities. These studies also suggest the importance of identifying and addressing direct medical needs as a motivator of continued research engagement, such as treatment for alcohol dependence or STIs. For MSM and TGW who are otherwise healthy and without urgent medical needs \u2013 such as those who would be recruited for many HIV prevention studies \u2013 there may be limited incentives to risk the discrimination or human rights violations that can accompany disclosure of same\u2010sex sexual practices in order to participate in a research study, so researchers must work especially closely with community stakeholders to identify strategies to recruit and retain these participants.et al. [In contrast to the other retention\u2010focused studies included in this supplement, Sandfort et al.  report r4et al. [Two manuscripts in this supplement focus on identifying opportunities for improving MSM and TGW engagement in the HIV prevention and care cascade. Ramadhani et al.  describeet al. [Rwema et al.  also des5et al. [Two manuscripts in this supplement focus on strategies for improving engagement in the HIV prevention and care cascade. Fearon et al.  also fouet al. [Deficiencies in HIV testing uptake and frequency MSM in sub\u2010Saharan Africa mean that HIV is often diagnosed late in the disease course. Palmer et al.  conducteet al. . Given t6et al. [In their commentary, Makofane et al.  call foret al. [Lastly, van der Elst et al.  present 7The manuscripts included in this supplement illustrate that, as for other populations, we need to tailor care delivery to individual needs of African MSM and TGW. Young people, in particular, require differentiated services that facilitate continued engagement in care, such as access to a variety of dosing regimens to fit their diverse lifestyles, maintenance of contact through novel platforms such as social media, and creation of friendly and sensitive clinical care spaces. Given very high HIV incidence rates in MSM and TGW, participants should be targeted for acute and early HIV evaluation using NAAT\u2010based HIV\u2010testing algorithms \u2013 preferably point\u2010of\u2010care testing \u2013 and onwards linkage to prevention and care . In addiDevelopment of effective biomedical prevention strategies such as PrEP has changed the landscape of HIV prevention, but PrEP is only effective if people at risk are able and willing to adhere to it. Differentiated models are needed for delivering daily PrEP and future generations of biomedical prevention interventions to MSM in ways that yield the necessary uptake and adherence. Further engagement of end users of these interventions is needed in order to understand the factors that motivate uptake and adherence in order to tailor prevention interventions to the unique needs of African MSM and other key populations.Well\u2010laid out multi\u2010country and multicentre cohort studies similar to MACS, although costly, will bring tremendous progress to understanding HIV prevention and care uptake among MSM and TGW in sub\u2010Saharan Africa. Such efforts should be planned in collaboration with MSM and TGW stakeholders via community organizations, key opinion leaders and community advisory boards. Cross\u2010learning between countries may be useful to establish best practices for participant engagement and promotion of African investigators as leaders of research in their own communities. Future research must also move on from past conflation of MSM with other sexual and gender minorities through the design of service delivery and research studies that acknowledge and address the unique needs of transgender and non\u2010binary individuals. Tremendous progress has been made over the last 15\u00a0years in engaging African MSM in HIV research. However, much more must be done.The authors report no competing interests.TAC, PEF, LGB and EJS were\u00a0involved in conceptualization and writing of the manuscript."}
{"text": "Among which, biofilm engineering refers to harnessing the beneficial uses of microbial communities by understanding the fundamentals of biofilm developmental process. This definition is more specific and narrows the focus of biofilm engineering down to the beneficial uses of biofilms.Bacteria in natural and engineered habitats often live as multicellular aggregates embedded in a self\u2010produced matrix of extracellular polymeric substances (EPS), known as biofilms \u2010cyclic\u2010dimeric guanosine monophosphate (c\u2010di\u2010GMP) is also part of the regulatory networks orchestrating biofilm development. A decreased concentration of c\u2010di\u2010GMP reduces biofilm formation and a high level of c\u2010di\u2010GMP promotes the formation of biofilm Hengge, . Becauseet al.  engineere et al.  engineeret al., et al.  also play an important role in biofilm formation , regulates metabolism and biofilm formation in several bacteria by activating cAMP receptor protein (CRP) (Ritzert , et al.  overexpret al. (E. coli (Botyanszki et al., The hallmark of a biofilm is the self\u2010produced EPS matrix, which imparts numerous beneficial attributes to biofilms that are lacking in their planktonic counterparts (Flemming and Wingender, et al.  decorateet al., et al., et al., Chromobacterium violaceum, facilitated the biorecovery of gold from electronic waste (Liow et al., One of the major limitations that hampers the application of biofilm\u2010mediated bioprocesses lies in the uncontrollable dynamics of biofilm development, resulting in unpredictable and/or diminished performance (Hu Synthetic gene circuits impart programmable functionalities in microorganisms that can be implemented in various biotechnological applications. However, an important factor influencing the performance of synthetic gene circuits is the interference from the host\u2019s endogenous regulatory network. Therefore, it is desirable that the host itself should possess a low level of native signalling messengers/molecules to achieve an enhanced performance of the introduced gene circuit. Development of bacterial chassis by downregulating the gene expression of native signalling pathways, such as reduction of background c\u2010di\u2010GMP levels and QS signals, would improve the performance of gene circuits controlling biofilm development through mediating c\u2010di\u2010GMP and QS. CRISPR\u2010mediated gene silencing approach may offer an effective platform for systematically exploring the functions of genes involved in signalling pathways and facilitate genome\u2010scale manipulation to enhance the synthetic gene circuit activity for biofilm control.et al., et al., et al., Synthetic biology tools are widely used to design and control microbial communities by manipulating regulatory networks, regulating gene expression and engineering cell to cell interactions. By programming cellular behaviour of biofilms, synthetic biology approaches may enable broad applications ranging from understanding biofilm biology to engineering controllable biofilms for biocatalysis, energy generation and bioremediation. To achieve complex synthetic systems with high programmability and controllability, programmed gene circuits could be fine\u2010tuned by altering various input signals to generate desirable output/performance. Chemical inducers are often used to control the expression of programmed gene circuits; however, the potential toxicity, irreversibility and lack of spatial control limit their applications (Liu et al., Another approach to engineering biofilms is to alter the activities of key regulatory proteins and/or enzymes that control biofilm development.\u00a0In a previous study, an evolved variant of SdiA protein was generated through random mutagenesis and the variant led to higher biofilm formation in the presence of QS signals (Lee et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Biofilms in natural and engineered environments are generally composed of highly diverse microbial communities (Tan et al., et al., et al., et al., et al., et al., et al., Division of labour across different individuals in a consortium enhances a specialized function by reducing the metabolic burden of each population (Tsoi"}
{"text": "In this commentary, we reply to their comments attempting to critically discuss the evidence base needed to obtain regulatory approval.Maju  Even when an underpowered study detects a true effect, the estimate of the effect magnitude may be exaggerated   or to a detrimental potential of esketamine discontinuation. As a matter of fact, it cannot be excluded that withdrawal symptoms biased the outcome assessment (Turner, Another point raised in our commentary, as well as in other similar comments (Cristea and Naudet,  Turner, . In part Turner, .et al. commented that the safety profile of esketamine is well known from phase 1 and 2 studies and that the drug is safe (Maju et al., et al., et al., et al., et al., Maju et al. claimed that the SUSTAIN-1 trial (Daly et al., et al., Maju In conclusion, considering the notable uncertainty on tolerability and efficacy, both in the short- and in long-term, we argue that regulatory authorities should have to be more cautious in evaluating the approval of this drug (Cristea and Naudet,"}
{"text": "We read with interest the article titled \u201cThe Implications of an Ab Interno Versus Ab Externo Surgical Approach on Outflow Resistance of a Subconjunctival Drainage Device for Intraocular Pressure Control\u201d by Lee et al.,Allergan R&D would like to correct the assertion in the response from the authors that the origin of the pressure drop variability between the findings of Sheybani et al. and Lee et al. are due to manufacturing variability of the internal diameter of the XEN implant, as stated by Lee et al.XEN products are designed to provide safe, effective pressure drop to treat glaucoma. The manufacturing process yields far tighter control over pressure drop than the assertion implies. Furthermore, the XEN numerical product designation is not meant to be a product specification nor indication of manufacturing tolerance. Therefore, calculating expected pressure drop from the product name will not result in a meaningful value.Additionally, we would greatly appreciate it if you could ensure that this explanation travel with the manuscript as is customary."}
{"text": "Psychological Medicine published two articles that criticise these services and suggest that they should be dismantled or restructured. One paper also provides recommendations on how ARMS services should be operate.In the 1990s criteria were developed to detect individuals at high and imminent risk of developing a psychotic disorder. These are known as the at risk mental state, ultra high risk or clinical high risk criteria. Individuals meeting these criteria are symptomatic and help-seeking. Services for such individuals are now found worldwide. Recently In this paper we draw on the existing literature in the field and present the perspective of some ARMS clinicians and researchers.et al. paper are already occurring.Many of the critics' arguments are refuted. Most of the recommendations included in the Moritz ARMS services provide management of current problems, treatment to reduce risk of onset of psychotic disorder and monitoring of mental state, including attenuated psychotic symptoms. These symptoms are associated with a range of poor outcomes. It is important to assess them and track their trajectory over time. A new approach to detection of ARMS individuals can be considered that harnesses broad youth mental health services, such as headspace in Australia, Jigsaw in Ireland and ACCESS Open Minds in Canada. Attention should also be paid to the physical health of ARMS individuals. Far from needing to be dismantled we feel that the ARMS approach has much to offer to improve the health of young people. Instead services should provide needs-based care.Moritz et al.  provide et al. ((5)Individuals accessing these services are not representative of all the people at risk of psychotic disorder.(6)Sub-threshold psychotic symptoms, the hallmark of the ARMS criteria, are found in disorders such as anxiety and depression. Therefore the presence of these sub-threshold psychotic symptoms should not indicate that a person is at risk of psychotic disorder.(7)People meeting ARMS criteria have already started the process of developing psychotic disorder and therefore intervention at this stage is too late.(8)A public health approach to prevent psychosis would be more effective than ARMS services.In addition to argument 3 above, Ajnakina et al.  also staet al. present little evidence to support this contention. They cite Corcoran et al. , clinicians convey that \u2018risk\u2019 is not \u2018disorder\u2019, that symptoms can improve, and that recovery is possible   Clinic, was established in a generic adolescent health service and later moved into a shopping mall  will meet ARMS criteria. Such individuals may develop a psychotic disorder, persistent or recurrent mood or anxiety disorder, impaired psychosocial functioning, persistent attenuated psychotic experiences or a combination of these. They may also not develop any disorder and symptoms and functioning might resolve over time . This position is contrary to decades of research that ARMS criteria do predict onset of psychotic disorder and research that shows that anxiety and depression are frequently present in the prodromal phase before a first psychotic episode , is at odds with numerous intervention trials and meta-analyses, and the data from the South London service in relation to ethnic minorities (see above). These statements indicate that both critic groups believe that the ARMS criteria are indicative of impending psychotic disorder. This belief is also reflected in both group's use of the term \u2018prodromal\u2019, which suggests inevitable progression to psychotic disorder .et al. who believe that the time for ARMS clinics has \u2018gone\u2019, Moritz et al. believe that they should be renamed, that they should provide only needs-based care, that antipsychotics should not be prescribed, that a categorical view of mental illness be avoided and a staged approach be used. They call for a \u2018hope-oriented\u2019 service, which is ironic given they believe that no treatment can justify hope. In response to their recommendations:In contrast to Ajnakina et al., et al.'s  opinion that ARMS services are stigmatising despite empirical evidence to the contrary when ARMS individuals themselves are asked (see above).We agree that calling such services \u2018Prodromal Clinics\u2019 and using the term \u2018prodromal\u2019 should be avoided, for reasons described above. However a recent study found that the terms ARMS, UHR or \u2018Attenuated Psychotic Symptoms\u2019 were not thought to be stigmatising by ARMS individuals and only a minority thought these names should be changed  possibility of schizophrenia\u2019 (p. 3) and that patients are told that \u2018schizophrenia is looming over them\u2019 (p. 1). Ajnakina et al. state that the ARMS criteria are \u2018schizophrenia-light\u2019. First episode psychosis is not the same as schizophrenia and not all individuals with a first episode of psychosis will develop the functional difficulties associated with this clinical syndrome, especially if early detection and comprehensive care is provided (Correll et al., et al., incorrectly cite papers about Early Intervention for Psychosis services (Birchwood and Macmillan, et al., et al., et al., et al., et al., Both Moritz et al., et al., et al., et al., First, the assessment of attenuated psychotic symptoms is important. These symptoms are often distressing, can lead to maladaptive behaviours and their presence indicates risk for psychotic disorder and other poor outcomes. Cognitive behaviour therapy approaches have been developed specifically for such symptoms and have been found to be effective and non-stigmatising (Morrison"}
{"text": "Traditionally investigated in philosophy, body ownership and agency\u2014two main components of the minimal self\u2014have recently gained attention from other disciplines, such as brain, cognitive and behavioral sciences, and even robotics and artificial intelligence. In robotics, intuitive human interaction in natural and dynamic environments becomes more and more important, and requires skills such as self-other distinction and an understanding of agency effects. In a previous review article, we investigated studies on mechanisms for the development of motor and cognitive skills in robots (Schillaci et al.,  As has been shown in various experiments, for example in the rubber hand illusion  and ego-noise representation and imitation (AP).PL was employed by SoftBank Robotics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "For thousands of years, human beings have used natural products for the treatment of various types of pathologies. Even today, in many developing countries where modern medicines are still not available, many diseases are treated following the indications of traditional local medicine, using plant and algae extracts. Traditional remedies have the advantage of being well tolerated by people but have often shown little effectiveness, mainly because the natural extracts contain a limited dose of the required active molecule, or contain compounds acting as antagonists to it. Therefore, despite the evidence that traditional medicine represents an important resource for the treatment of human diseases, the availability of new potent, targeted and safe drugs represents one of the most important objectives in combating both acute and chronic diseases.In recent decades, technological progress and the development of artificial intelligence have led many researchers to believe in the possibility of generating new drugs using only an in silico approach. However, this strategy proved to be unsuccessful in most cases. One of the main reasons for this failure is the limited human ability to imagine new scaffold molecules in comparison to the natural ones that world can offer. Plants, algae and microorganisms synthesize thousands of structurally different molecules, most of which are often not reproducible in modern organic chemistry laboratories. This evidence suggests that in the coming years, despite strong technological progress, drug discovery will still be highly dependent on the identification of new natural bioactive molecules that exhibit drug-like activity.The purpose of this Special Issue is to confirm the enormous potential of the natural world in providing new molecules that exhibit different types of pharmacological activity. Thanks to the precious support of numerous researchers, this Special Issue has been enriched with fourteen original studies and two reviews.The study of Phi Hung Nguyen et al.  aimed toThe article by Ali S. Alqahtani et al.  exploredNajeeb Ur Rehman et al.  demonstrAuriane Dudoit et al.  and collWith their study, Poonam Kalhotra et al.  exploredThe results of a study conducted by F. Balestri et al.  showed tThe aim of the study conducted by Nabeelah Bibi Sadeer et al.  was to dThe study conducted by Umar M. Badeggi et al.  aimed toThe study conducted by Victor Marin et al.  demonstrThe scope of the study performed by Ericsson Coy-Barrera  was to iThe study of Thanh-Diep Ly et al.  aimed toGabriel Zazeri et al.  presenteBehzad Shahin-Kaleybar et al.  focused The purpose of the study conducted by Xi Chen et al.  was to iAndrea Baier and Ryszard Szyszka  focused The study presented by Renata Tisi et al.  offers aIn conclusion, taken together the studies reported in this Special Issue confirmed that the natural world still represents an irreplaceable source of inspiration for all researchers that aim to identify new scaffold molecules for the synthesis of a new generation of drugs."}
{"text": "Oncorhynchus gorbuscha) in 2019. Eighty\u2010four pink salmon were reported from 22 locations across Greenland. This comprised 76 specimens from 2019 and 8 specimens from 2013 to 2018. Of these, 12 were caught in fresh water, and a single pink salmon was from the bottom of the Nuuk Fjord near the Kapisillit River \u2013 the only known river in Greenland where the Atlantic salmon  spawn. It is unknown if pink salmon have reproduced in Greenland waters.Using social media, the Greenland Institute of Natural Resources collected data on the occurrence of pink salmon ( No accurate length measurements were obtained from the survey, but from fishermen's estimates as well as available photographs, it is estimated that all specimens measured approximately 50\u201360\u2009cm in total length. At least two females were reported to have ripe eggs and three males to have freely flowing sperm  received five reports of five pink salmon in the coastal waters of Greenland , Denmark, Ireland and Scotland (ICES, et al. (et al., et al., The establishment of pink salmon in Atlantic rivers is associated with the possibility of negative effects on local salmonids because of potential competition, infectious diseases and parasites, as presented in Hindar et al. . In Greeet al. . Higher  et al., . Therefo et al., , and theJ.N. coordinated this work and prepared the manuscript. All authors equally conceived the idea; contributed to scientific discussions; and revised, reviewed and finally approved the work."}
{"text": "This review focuses on these supercomplexes of vascular plants, which at the moment cannot be \u2018seen\u2019 but that represent functional units in vivo.Photosystems I and II are the central components of the solar energy conversion machinery in oxygenic photosynthesis. They are large functional units embedded in the photosynthetic membranes, where they harvest light and use its energy to drive electrons from water to NADPH. Their composition and organization change in response to different environmental conditions, making these complexes dynamic units. Some of the interactions between subunits survive purification, resulting in the well\u2010defined structures that were recently resolved by cryo\u2010electron microscopy. Other interactions instead are weak, preventing the possibility of isolating and thus studying these complexes  I.et al., Photosystem I (PSI) and Photosystem II (PSII) are large assemblies of many pigment\u2013protein complexes and can be divided into two functional parts: the core and the antenna. The cores are highly conserved in all organisms performing oxygenic photosynthesis and contain the reaction center (RC), where photochemistry occurs. The role of the antenna is to collect light and transfer the excitation energy to the RC. The antenna varies in composition and organization between organisms, and in plants it is composed of members of the light\u2010harvesting complex (LHC) multigenic family complexes, suggesting that the antenna size of the photosystems is larger II.et al., et al., 2S2 supercomplex; Wei et al., 2S2M2; Su et al., et al., et al., et al., et al., Chlamydomonas\u00a0reinhardtii in a 1 : 1 stoichiometry. This complex is very stable and its structure was resolved in 2003 by X\u2010ray crystallography , might give the impression that LHCII moves to PSI only in particular conditions, while usually it is associated with PSII, to which it \u2018moves back\u2019 during the state\u20102\u2010to\u2010state\u20101 transition. However, it was shown that part of the mobile LHCII pool is associated with PSI in most light conditions (Wientjes et al., et al., et al., et al., in vivo. Knowing that PSI\u2010LHCI contains 158 Chls and one trimer of LHCII 42 (Pan et al., State transitions are a short\u2010term response to changes in light color, while the long\u2010term response to the same effects is an adjustment of the PSI : PSII ratio (Chow et al., et al., et al., in vivo? Benson et al. concluded that in addition to the LHCII associated with PSI on the K side of the core, LHCII trimers in state 2 dock to PSI via the Lhca (Benson et al., et al., et al., in vivo varies between 72\u00a0ps in tobacco and 147\u00a0ps in maize, but it is always longer than that of the PSI\u2010LHCI complexes purified from the same plant (Chukhutsina et al., in vivo were also observed for spinach (Farooq et al., in vivo.Recent results show that more than one LHCII trimer can be associated with PSI. Patches of membranes with up to five LHCII trimers were purified from spinach using styrene\u2013maleic acid copolymer (Bell IV.et al., et al., et al., et al., The crowdedness of the membrane also favors the interactions between photosystems (Haferkamp in vivo? From the seminal work of Jan Anderson, it is well established that PSI and PSII are located in two distinct regions of the thylakoid membranes, the stroma lamellae and the grana, respectively (Andersson & Anderson, et al., et al., et al., et al., in vivo and represent functional units. Electron tomography data on cells of the alga C. reinhardtii revealed a random organization of the photosystems and a clear separation between appressed membranes, hosting PSII, and nonappressed membranes, hosting PSI (Wietrzynski et al., in vivo in physiologically relevant conditions.Do PSI and PSII interact V.in vivo in the thylakoid membrane in their functional state are larger than the purified forms in vitro. Whereas this was expected for PSII, it was somewhat surprising for PSI, the composition of which has been considered well defined for a long time. Now that this has been established, it would be very interesting to \u2018see\u2019 the photosystems in vivo and to relate their change in function in different environmental conditions to changes in their composition and organization. It is expected that, thanks to recent advances, a detailed description of the membrane can be obtained by integrating cryo\u2010electron tomography data with the high\u2010resolution structures of the photosystems. The structural information combined with spectroscopic data and modeling should then provide a comprehensive picture of the thylakoid membrane in action.Photosystems I and II, when present"}
{"text": "Muscle atrophy is an unfortunate effect of aging and many diseases and can compromise physical function and impair vital metabolic processes  as the first defining characteristic  appears to be a potential adjunct to prevent muscle atrophy and loss of muscle strength  similar to what is reported in young men (D'Souza et al., per se is of primary importance when it comes to improving muscle mass and strength, as well as functional capacity, as a substantial part of the older population does benefit from a resistance-type exercise training intervention (Churchward-Venne et al., In addition, the supplementation of essential amino acids and vitamin D can further augment protein anabolism and has been shown to improve muscle composition in mobility-limited older adults (Englund et al., Although testosterone supplementation in older men has been shown to improve body composition, yet the effects on muscular strength or physical function are still conflicting (Endo et al., It is essential to maintain good muscular fitness over the long-term to improve health outcomes. In this regard, it is important to incorporate physical performance assessment and promotion into healthcare in a manner that engages both clinicians and patients (Brannan et al., The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Both low intelligence and low emotional control have previously been linked to a higher risk of suicide, but it is unknown whether the associations apply consistently over the life course.The study was based on data on intelligence and emotional control, collected from 48 738 Swedish men conscripted in 1969\u20131970, at ages 18\u201320 years. The data were linked to national registers giving information on subsequent suicidal behavior (completed and attempted suicide) up to the age of 59 years. The associations were investigated using logistic regression and Cox proportional hazards regression models, with adjustment for childhood socioeconomic status.Intelligence and emotional control assessed in late adolescence both showed robust inverse associations with suicidal behavior over the 38-year follow-up. However, while the association between lower intelligence and higher rate of suicidal behavior remained the same throughout , the association between lower emotional control and suicidal behavior was substantially stronger in early adulthood (~100% increased hazard per unit) than in late middle age (~30% increased hazard per unit).The study adds to previous research by showing that the association between poor emotional control and subsequent suicide risk in men becomes weaker over the life course, while the association between low intelligence and suicide risk seems to be constant. The particularly high suicide risk of young men with poor emotional control may motivate targeted prevention efforts. About 97\u201398% of all Swedish men were conscripted at that time; the remaining 2\u20133% were in most cases exempted due to severe disability or congenital disorders. The cohort consisted of 49\u00a0321 men born 1949\u20131951 (aged 18\u201320). Approximately 2% of all the men who were conscripted during those years were born prior to 1949, and were excluded from the data set in order to obtain as homogeneous a cohort as possible. All information was anonymized before it was made available for research to protect the integrity of the individuals. The research has been approved by the ethical committee at Karolinska Institutet (numbers 2004/5:9\u2013639/5 and 2010/604:32).n\u00a0=\u00a075) and/or emotional control (n\u00a0=\u00a0396), and/or death or emigration prior to the start of follow-up (n\u00a0=\u00a0175), which left 48\u00a0738 men (98.8%) for analysis.From the original cohort, 583 men were excluded due to missing data on intelligence  distribution on a nine-level scale. The test battery was designed to measure general intelligence, and used primarily to find a position with appropriate learning demands and predict the conscript's ability to profit from education within the military Ross, . A detaiet al., Assessment of emotional control was made through a semi-structured interview administered by a trained psychologist. The interview took about 20\u201330\u00a0min, and a summary of the interview process is provided elsewhere  codes for suicide and suicide attempt , and for events of undetermined intent . The latter was included since previous research has shown that most deaths from events of undetermined intent are likely to be suicides  unskilled workers, (2) skilled workers, (3) assistant non-manual employees, (4) non-manual employees at intermediate or higher level, (5) farmers, and (6) others or those with no occupation reported.The associations between intelligence and emotional control at conscription and subsequent suicidal behavior were first estimated for the full follow-up period using Cox proportional hazard models, yielding hazard ratios (HRs) with 95% confidence intervals (CIs). The conscripts were followed until emigration, death, or the first event of suicidal behavior, or until the end of 2008, whichever came first.The follow-up period was then divided into four approximate decades . Thereafter, logistic regressions yielding odds ratios (ORs) were used to investigate the associations of intelligence and emotional control with suicidal behavior for each decade separately in the men who were alive and had not emigrated at the start of each period. Tests of interaction with time were performed to test formally whether the associations remained stable over time. The independent variables, intelligence and emotional control, were modeled as continuous variables, with HRs and ORs given for each step decrease on the scales of intelligence and emotional control, and also as categorical variables to obtain HRs and ORs for each level, with the highest levels as the reference categories. All analyses were adjusted for childhood SES. We then repeated the analyses with mutual adjustment for intelligence and emotional control to separate their associations with suicidal behavior from each other.Additionally, we performed sensitivity analyses by excluding completed suicide from the dependent variable, and also by excluding events with undetermined intent. These analyses were performed to check whether the results were robust to any differences between attempted and completed suicide and between undetermined and certain suicidal intent. All analyses were performed using SAS 9.4 .During the total follow-up period (1973\u20132008), 1725 of the men (3.5%) had a suicidal-behavior event (493 completed and 1232 attempted suicides as their first event). The numbers of men with a suicidal-behavior event across the levels of intelligence and emotional control are shown in The associations of intelligence and emotional control with suicidal behavior followed dose-response patterns, as shown in When modeling intelligence and emotional control as continuous variables (parts b and d in p\u00a0<\u00a00.0001 for interaction with time). In the models with mutual adjustments for intelligence and emotional control, the associations were weakly to moderately attenuated but the difference between them over the total follow-up period remained, see When analyzed over the separate follow-up periods, the association between intelligence and suicidal behavior remained fairly stable over the life course, whereas the association between emotional control and suicidal behavior gradually weakened, see In sum, our analyses showed that the association between low intelligence and suicidal behavior was fairly constant over the follow-up period to age 59 in this cohort of Swedish men, whereas the association between low emotional control and suicidal behavior weakened with increasing age. Mutual adjustment for intelligence and emotional control attenuated the associations somewhat but did not attenuate the difference between them. Adjustment for socioeconomic status during childhood had only marginal effects on the results.et al., et al., et al., et al., et al., et al., et al., Suicidal behavior has been linked to lower intelligence and higher neuroticism  in some previous studies (Brezo et al., et al., We are not aware of any previous studies focusing on changes in these associations over the life course, but a previous study using the same cohort showed that lower intelligence and a higher risk of hospitalization for major depression had a weakening association over the 38-year follow-up (Lager et al., et al., et al., et al., et al., Although the associations of both intelligence and emotional control with suicidal behavior remained after adjustment, it is not necessarily the case that low intelligence and low emotional control are immediate causes of suicidal behavior. To some extent, these psychological differences between individuals may also predict suicidal behavior along indirect pathways. Several potential mechanisms underlying the associations of intelligence and neuroticism with suicidal behavior have been presented in previous research. For example, Gottfredson and Deary  stress tOne of the main findings of this study was that the association between intelligence and suicidal behavior remained constant over the entire follow-up period, while the association between emotional control and suicidal behavior was particularly strong in young adulthood and then weakened across the four periods. Largely, the two characteristics were associated with suicidal behavior independently of each other, as shown in the mutually adjusted models. Each, however, accounted for some of the other characteristic's association with suicidal behavior: for emotional control to a greater extent in the first follow-up periods, and for intelligence to an increasing extent in the later periods. Thus, mutual adjustment did not reduce the difference in time trends between intelligence and emotional control.et al., et al., et al., et al., The gradual weakening of the association between emotional control and suicidal behavior may have some different potential explanations. One is that emotional control is more variable than intelligence from a life-course perspective. This idea is supported by previous research showing that there is a decrease in the population mean of neuroticism during late adolescence while intelligence seems to be more stable (Roberts et al., et al., et al., et al., et al., Our results highlight the possibility that low intelligence and \u2013 less surprisingly \u2013 poor emotional control influence the risk of suicide. The importance of this for suicide-preventive work may be worth investigating further. Other studies have discussed how low intelligence and poor emotional control also increase the likelihood of ending up in difficult circumstances, e.g. with low education or problematic social relations (Roberts et al., et al., et al., et al., et al., et al., et al., On the other hand, one possible reason for the long-term association between intelligence and suicidal behavior is that intelligence is robustly associated with attained education and socioeconomic position in adulthood (Plomin and Deary, There are several strengths to this study. The study population is strongly representative of the Swedish population of men who were born in 1950 and 1951, since nearly all men participated in compulsory conscription at that time. The exposure variables were measured using standardized test batteries and semi-structured interviews following manuals, and the outcome variables are based on national records with high reliability (Lilieblad and St\u00e5hlberg, et al., et al., et al., et al., There are, however, two aspects of this study that limits its generalizability. First, we cannot generalize the results to women since only men were obliged to participate in conscription. Second, the results cannot be directly extrapolated to other settings partly because suicidal behavior differs between cultures (Nock In line with previous research, this study confirms that low intelligence and low emotional control are both associated with a higher risk of suicidal behavior among men. Further, this study adds to previous research by showing that the association between intelligence and suicidal behavior seems constant over the life course, whereas the association between emotional control and suicidal behavior may become considerably weaker over time. The particularly high suicide risk of young men with poor emotional control may motivate targeted prevention efforts."}
{"text": "To the Editor,Journal of Medical Virology, Chen et al report clinical features and outcomes of pregnant patients with COVID\u201019 in the Maternal and Child Hospital of Hubei Province, China.The outbreak of coronavirus disease 2019 (COVID\u201019) is a major public health concern and increasing cases of infection are being reported during pregnancy. In the Although none of the patients in the study by Chen et alIn Chen's et alWhilst the neonates in Chen's et alDespite acknowledging its possibility, Chen et alOverall, we thank Chen et alThe authors declare that there are no conflicts\u00a0of interest."}
{"text": "Dear editor,We read with great interest the article by Nakamura et al.  discussiFor these reasons, rehabilitation appears as a key component of these patients\u2019 care. More specifically, international experts highlighted that early rehabilitation (with active involvement by a physiotherapist) can drastically improve activities of daily living, exercise function, length of hospital stay, and mechanical ventilation  and woulAlthough the method presented by Nakamura et al.  is interTherefore, although we truly think that the method described by Nakamura et al.  might be"}
{"text": "The best way to quantify antimicrobial use (AMU) in animals is still an elusive question, it probably does not have a unique answer. This collection of 15 articles describes different metrics, methodologies, data sources, animal scenarios, study designs, and levels of study about AMU quantification in animals. The diversity of approaches highlights a strong need for international collaboration, sharing of experiences, and more discussion about methods to improve uptake of harmonized standards (where harmonization might be suitable).The less controversial aspect of this topic is that there was consensus among these articles that a relative measure is needed, dividing amounts of antimicrobials (numerator) by a denominator summarizing the animal population at risk of being treated. However, both the numerator and denominator have their specific challenges. In addition, a period of time for data collection must be fixed or considered. In the human arena, a standardized population approach based on established defined daily doses (DDDs) and census data is utilized around the world, delivering information on the number of DDDs per population and year (or days) . NeverthG\u00f3chez et al.). However, Brault et al. demonstrated that dose-based metrics were more accurate than weight-based metrics when there was variation in the type  of antimicrobials used by the populations being compared. The studies by Agunos et al., Brault et al., and Van Cuong et al., where weight-based and dose-based metrics were applied to the same AMU data, all demonstrated a significant impact of those metrics on the study results, that could even lead to different conclusions . Agunos et al. stressed the added value of using multiple AMU indicators for monitoring the impact of stewardship activities and interventions. Nonetheless, weight-based and dose-based metrics are not mutually exclusive, and it is possible to convert one into another .The use of weight-based  vs. dose-based  metrics in the numerator was discussed in several papers of this collection. A main advantage of weight-based metrics is their higher availability , that make them a more accessible option for worldwide AMU monitoring  and poultry , as a tool for the calculation of the number of DDDs per animal population and year (a proxy of the number of treatments-day), at the country or region-level. This indicator is also discussed and used in the article of Brault et al. In addition, national vet defined course doses (DCDs) for pigs have been proposed in Switzerland in the article of Echtermann et al. to calculate the number of DCDs per population and year . A similar exercise for calculation of the number of treated animals in pigs and calves in Switzerland is presented in the article of Stebler et al. National DDDs lists proposed by Bosman et al. and DDDs and DCDs lists proposed by Echtermann et al. differed from those proposed by the European Medicines Agency for certain antimicrobial classes  DDDs for pigs , Brault et al. (beef feedlot), and Waret-Szkuta et al. (pigs). All three papers highlighted that the choice of DDD vs. UDD had an impact on the results. Interestingly, Kasabova et al. recommended using UDD-based calculations to run monitoring systems with a benchmark mission. Should DDD be preferred to compare AMU between populations, additional considerations should be made to adjust for discrepancies between DDD and UDD.Both the number of DDDs and the number of DCDs are indicators based on standardized measurements that do not necessarily reflect the real or actual AMU. For a more real AMU estimation in a given population with detailed data available, the used daily dose (UDD) may be a better choice to reflect what is happening in that specific population in terms of selection pressure. This is explored in the articles of Brault et al. addressed this question in beef cattle, where the use of estimated vs. actual weights notably influenced the results obtained. Similar observations were made in pigs by Waret-Szkuta et al. Equally, the use of weight at treatment vs. the weight at slaughter  or the weight sold  had a strong impact on calculations, especially for larger livestock species like cattle and pig.The third parameter having a huge effect on AMU indicators is the animal weight. The article of G\u00f3chez et al.; Stebler et al.). Nevertheless, prescriptions because they have more detailed information closer to the end-users, may be a more accurate source of possible selection pressure; prescriptions were used in the articles of Hommerich et al. and Hopman et al. to calculate AMU in German cattle and Dutch companion animals, respectively.Sales of veterinary medical products containing antimicrobials are a classical source of raw data for AMU consumption calculations , all of them using the above mentioned DDD approach. Data on AMU from pets were presented in three articles , using different approaches. Hopman et al. used DDD per clinic and year, whereas Singleton et al. and G\u00f3mez-Poveda and Moreno focused on the percentages of prescriptions. Specific scenarios regarding indications for AMU, such as bovine respiratory disease  and canine acute diarrhea  were also presented in this collection, as well as an article exploring drivers for AMU in the pig sector presented by Coyne et al..Although most of the literature on AMU in this collection focused on pigs and cattle , four articles considered AMU in poultry  were the ideal data for calculating and reporting AMU. Nevertheless, all these data are rarely available simultaneously, hence standard values are the pragmatic alternate choice for calculations. Consequently, transparency about the methods and data used to calculate AMU indicators is needed . This waMM produced the first draft of the editorial. All authors edited and approved the editorial.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer JD declared a past co-authorship with one of the author LC to the handling editor."}
{"text": "Dear Editor,I was searching for new modalities to prevent propofol injection pain (PIP) and I encountered and read with interest an article written by Akbari et al. in your journal . First o"}
{"text": "Integrating data on the architecture, kinetics, and transcriptional input\u2013output function is a promising approach to uncovering the underlying dynamic mechanism. For eukaryotes, distinct bursting features described by the multi\u2010scale and continuum models coincide with those predicted by four theoretically derived principles that govern how the transcription apparatus operates dynamically. This consistency suggests a unified framework for comprehending bursting dynamics at the level of the structural and kinetic basis of transcription. Moreover, the existing models can be unified by a generic model. Remarkably, transcriptional bursting enables regulatory information to be transmitted in a digital manner, with the burst frequency representing the strength of regulatory signals. Such a mode guarantees high fidelity for precise transcriptional regulation and also provides sufficient randomness for realizing cellular heterogeneity.There is accumulating evidence that, from bacteria to mammalian cells, messenger RNAs (mRNAs) are produced in intermittent bursts \u2013 a much \u2018noisier\u2019 process than traditionally thought. Based on quantitative measurements at individual promoters, diverse phenomenological models have been proposed for transcriptional bursting. Nevertheless, the underlying molecular mechanisms and significance for cellular signalling remain elusive. Here, we review recent progress, address the above issues and illuminate our viewpoints with simulation results. Despite being widely used in modelling and in interpreting experimental data, the traditional two\u2010state model is far from adequate to describe or infer the molecular basis and stochastic principles of transcription. In bacteria, DNA supercoiling contributes to the bursting of those genes that express at high levels and are topologically constrained in short loops; moreover, low\u2010affinity  I.et al., et al., et al., et al., et al., et al., et al., et al., Like a coin with two opposite sides, gene transcription exhibits duality. On the one hand, it is an accurate process. When and at what rate to transcribe a gene is subject to precise regulation, and accuracy is essential for cell fitness and development  was believed to fluctuate slightly around an average , it was observed that a number of mRNAs from a gene emerge suddenly and then disappear gradually during a short time window , inactivation rate koff (reaction rate from ON to OFF), and mRNA synthesis rate from the ON state km. kon is positively related to the concentration of transcriptional activators. Both koff and km are constant, i.e. the duration of the ON state is exponentially distributed and mRNA synthesis is a Poisson process.Intuitively, transcriptional bursting can be characterized with a simple two\u2010state model Fig. A, where et al., The original two\u2010state model was proposed to explain cell heterogeneity 25 years ago Ko, . It is wIII.et al., via tracing the time series of transcription initiation events or changes in MS2/PP7\u2010labelled mRNAs. While this is realizable, it has not been done sufficiently. Nevertheless, it was confirmed that mRNA production is not a Poisson process but can be well fitted by the two\u2010state model , the bursting was revealed to be primarily caused by DNA supercoiling . In contrast with the traditional view that transcription initiation is stimulated by an NtrC hexamer simultaneously bound to the two enhancers, Wang et al. . With the DNA bridging, the NtrC hexamer at the distal enhancer is in the vicinity of the TTS and thus immediately stimulates the polymerases one by one, leading to a burst. This work stresses the importance of low\u2010affinity sites, unstable protein complexes, and transient molecular interactions in orchestrating transcription.Upstream of the g et al.  revealedg et al. . MoreoveIV.et al., In higher eukaryotes, DNA is packaged by nucleosomes that consist of histones; both the DNA and histones are epigenetically modified , then the open complex (OPC), and the elongation complex, which synthesises a transcript  round of cycling and T is the total time corresponding to n rounds of cycling. As the activator concentration rises, n becomes larger in probability for fixed T, and so does RTOR. In this way, RTOR robustly encodes the activator concentration \u2019 between the enhancer and the Mediator Fig. A, which ion Fig. B. Note tThe Mediator transfers information from the settled activator to Pol II through allostery. The entry of an activator into the C\u2010space induces allostery in the Mediator, facilitating Pol II to assemble and initiate transcription. Without the activator, transcription initiation rarely occurs.RTOR is converted to the number of transcripts.With an activator in the C\u2010space, a convoy of Pol IIs is launched, leading to a burst of transcripts. The time interval between two successive initiation events is far shorter than the activator's residence time. Typically, the interval is of seconds. Such intensive initiations together with the Mediator's allostery guarantee that the basic unit of Based on the general structural organization and conformational changes of the TA, the ensemble and probability theories were exploited to probe how the TA dynamically operates  model Fig. E, with wres Fig. . AdditioVI.et al., et al., et al., et al., RTOR is exploited by the TA to encode activator concentration and guide transcription initiation  Genes are transcribed in episodic bursts. This feature is ubiquitous from bacteria to mammalian cells, regardless of whether they are constitutive or inducible genes.(2) Transcriptional bursts in eukaryotes take place with multiple timescales, and the transcription initiation rate is continuous during each ON period. Such features are consistent with those dictated by four theoretically derived principles that govern how the TA operates dynamically. This in turn suggests that eukaryotic genes likely share similar dynamic principles for TA operation, as they share the same set of general transcription factors.(3) The ratchet, multi\u2010scale, and continuum models emphasize different profiles of transcriptional dynamics. These models are applicable to genes of specific categories and can be unified by the WLW model, which depicts the core steps of regulated transcription and can be accommodated to characterize gene specificity. Additionally, conclusions derived from the traditional two\u2010state model should be treated cautiously.(4) Transcriptional bursting in eukaryotes allows digital information conversion, by which regulatory signals modulate the burst frequency rather than burst size. For a given TA, the burst size obeys a specific distribution; experimentally, the burst size might be mistaken as subject to modulation since it is hard to differentiate a burst from a burst cluster.RTOR code, which represents an accurate encoding of time\u2010varying activator concentration; moreover, bursting\u2010induced fluctuations in mRNA number can be smoothed by nuclear retention of mRNAs. On the other hand, such fluctuations can also be enlarged to achieve sufficient heterogeneity.(5) Transcriptional bursting fulfills the accuracy and stochasticity requirements for the transcriptional response. The modulation of burst frequency is an embodiment of the et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., (6) Low\u2010affinity DNA binding sites, unstable protein complexes, and DNA supercoiling can play crucial roles in regulating transcription. Investigating transcriptional dynamics necessitates both live imaging methods with high resolution  The significance of various bursting patterns from different promoters remains to be addressed. Firstly, unscrambling the bursting patterns paves the way to reveal the dynamics of both the chromatin and the TA. By statistically analysing the Mediator\u2010 and TBP\u2010dependent bursting dynamics , for example, it can be inferred that the Mediator interacts with the DNA much more transiently than the TBP (Tantale VIII.This work was supported by the Ministry of Science and Technology of the People's Republic of China [2013CB834104], National Natural Science Foundation of China , and Fundamental Research Funds for the Central Universities [JUSRP11838]."}
{"text": "Dear editor, \u201cLateral approach versus combined lateral and anteromedial approach for surgical treatment of terrible triad of the elbow: A meta-analysis\u201d by Meena et al., [We read with great interest the article et al., . They caet al., [et al., [et al., [p=0.03) and fewer number of complications (p=0.02). So, the conclusion of the meta-analysis is questionable. The new conclusion that can be drawn is that majority of TTIE can be operated by the lateral only approach due to shorter time duration and fewer complications with no difference in the functional outcomes between the two approaches.Our first observation is that authors included four studies for this meta-analysis, of which study by Li et al.,  is serie[et al.,  and Liu [et al., , both coNone declared."}
{"text": "Strizova et al.'s  recent rBorrelia burgdorferi has been shown to manipulate both the innate and adaptive immunity of its mammalian hosts in a variety of ways (Tracy and Baumgarth Borrelia burgdorferi. The organism abrogates the development of highly specific long-term immunity to persist in the host (Elsner et al. In short, the persistence of IgM antibodies in Lyme disease may represent chronicity, not a false positive. The classical pattern of B cell maturation and the IgM to IgG transition are lacking in chronic infection by"}
{"text": "P. falciparum erythrocyte invasion. This review summarizes the current understanding of the molecular interactions that lead to rosette formation, with a particular focus on host uninfected erythrocyte receptors including the A and B blood group trisaccharides, complement receptor one, heparan sulphate, glycophorin A and glycophorin C. There is strong evidence supporting blood group A trisaccharides as rosetting receptors, but evidence for other molecules is incomplete and requires further study. It is likely that additional host erythrocyte rosetting receptors remain to be discovered. A rosette-disrupting low anti-coagulant heparin derivative is being investigated as an adjunctive therapy for severe malaria, and further research into the receptor\u2013ligand interactions underlying rosetting may reveal additional therapeutic approaches to reduce the unacceptably high mortality rate of severe malaria.Malaria remains a major cause of mortality in African children, with no adjunctive treatments currently available to ameliorate the severe clinical forms of the disease. Rosetting, the adhesion of infected erythrocytes (IEs) to uninfected erythrocytes, is a parasite phenotype strongly associated with severe malaria, and hence is a potential therapeutic target. However, the molecular mechanisms of rosetting are complex and involve multiple distinct receptor\u2013ligand interactions, with some similarities to the diverse pathways involved in  Plasmodium falciparum infected erythrocyte (IE) adhesion phenotype that is associated with severe malaria in sub-Saharan Africa  as rosette-mediating adhesion molecules  results in smaller, weaker rosettes, equivalent to those seen in group O erythrocytes  that map to the C3b binding site on CR1 being effective inhibitors  are found on cell surfaces and in the extracellular matrix of many tissues, and have a role in multiple aspects of the et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Fluorescently-labelled heparin does bind to the surface of erythrocytes infected with rosetting parasites more than non-rosetting lines   was partially inhibited by a GYPC mAb (clone Ret40f) and by soluble recombinant GYPC , and was based on a single count for each isolate with no replication . Plasmodium falciparum isolates were not tested with the GYPC knockdown erythrocytes.For et al., P. falciparum culture-adapted parasite lines, Rowe et al. . Gerbich-negative erythrocytes formed rosettes normally with the five parasite lines tested. Goel et al. also report normal rosetting of Gerbich-negative erythrocytes from two donors (Goel et al., If GYPC is a rosetting receptor, it is possible that the \u2018Gerbich-negative\u2019 blood group type, which is common in Melanesian populations (Patel e et al.  tested tP. falciparum and P. vivax rosetting.Taking into account all existing evidence, further investigation of a wider range of parasite lines is needed to determine whether GYPC is an important host receptor for both P. falciparum erythrocyte invasion (Sim et al., et al., et al., GYPA is a highly-expressed erythrocyte surface glycoprotein that carries the MNS blood group antigens. It is known to be a receptor for et al., et al., There is some limited evidence to suggest that GYPA may have a role in rosetting. Parasites of the strain FCR3S1.2 transfected with a specific RIFIN gene formed rosettes that were largely dependent on blood group A (Goel P. falciparum and 11 P. vivax clinical isolates (Lee et al., et al., P. falciparum lines (Rowe et al., Despite the above positive evidence, there are no other data supporting a role for GYPA in rosetting. GYPA mAb fragments had no inhibitory effect on rosetting in ten et al., et al., None of the receptors described above fully account for the adhesion interactions between infected and uninfected erythrocytes, and it is likely that other host rosetting receptors remain to be identified. There is evidence to suggest that these unknown host receptors are carbohydrates or protease-resistant proteins, because uninfected group O erythrocytes treated with trypsin and other proteases are still able to form rosettes (Udomsangpetch et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., In order to progress rosetting research, alternative methods are needed. Rosetting experiments with GYPC and CR1 knockdown cultured human red cells derived from CD34+ haematopoetic stem cells have been performed (Lee Of the rosetting receptors described over the past 30 years, only the blood group A trisaccharide has been authenticated by a variety of methodological approaches from a range of different investigators. For all other potential rosetting receptors, the evidence remains fragmentary  and furt"}
{"text": "The application of engineering principles such as standardisation, together with several key technical advances, enabled a revolution in the speed and accuracy of genetic manipulation. Combined with mathematical and statistical modelling, this has improved the predictability of engineering biological systems of which nonlinearity and stochasticity are intrinsic features leading to remarkable achievements in biotechnology as well as novel insights into biological function. In the past decade, there has been slow but steady progress in establishing foundations for synthetic biology in plant systems. Recently, this has enabled model\u2010informed rational design to be successfully applied to the engineering of plant gene regulation and metabolism. Synthetic biology is now poised to transform the potential of plant biotechnology. However, reaching full potential will require conscious adjustments to the skillsets and mind sets of plant scientists.Powered by developments that enabled genome\u2010scale investigations, systems biology emerged as a field aiming to understand how phenotypes emerge from network functions. These advances fuelled a new engineering discipline focussed on synthetic reconstructions of complex biological systems with the goal of predictable rational design and control. Initially, progress in the nascent field of synthetic biology was slow due to the  Perhaps the most visible aspects have been impactful tools and techniques such as large\u2010scale DNA assembly, genome engineering and cell\u2010free protein expression. Thus, there has been a tendency for biologists to perceive synthetic biology as a field focussed on the development and application of novel technologies, while the media typically report it as \u2018advanced biotechnology\u2019. However, synthetic biology self\u2010defines as an emerging discipline of engineering. At its core is the central theory that applying engineering principles and approaches improves the predictability and increases the ease and efficiency with which biological systems can be designed, constructed, and characterised . These approaches are applied in iterative cycles of design\u2013build\u2013test\u2013learn, where quantitative data on performance are fed into predictive models to improve later design cycles Fig.\u00a0. The appet al., It should be noted, however, that there is not total acceptance that synthetic biology is able to operate as a field of engineering Kwok, . Engineest century .Plant synthetic biology encompasses diverse research areas, each focussed on improving the predictability of a particular approach to reprogramming biological systems through the application of engineering principles Fig.\u00a0. These aife Fig.\u00a0. These ret al., et al., Recent reviews have examined how crop\u2010improvement or the production of biofuels and plant natural products might be advanced by applying synthetic biology approaches  improved efficiency and flexibility. However, the recombinase\u2010enabled reaction did not allow for complex or precision design. Further, the proprietary nature was undesirable in the emerging synthetic biology community, which, inspired by progress in electronic and software engineering, prescribed that standards, infrastructure and enabling technologies should be \u2018open\u2019 in order to accelerate progress and provide an ecosystem encouraging of innovation and entrepreneurship  play an important role in natural gene regulatory circuits and artificial miRNAs (amiRNA) are widely used for silencing target genes  have been engineered into bacterial, yeast and mammalian cells , those beyond the canonical 20 used by the majority of organisms, have been used to control post\u2010transcriptional modifications and to enable site specific labelling for visualisation in living cells, as well for the production of antibody drug\u2010conjugates  are used to investigate intracellular metabolic reactions and to study biological behaviours (Miller & Gulbis, et al., The engineering of biologically derived materials into useful products sits at the cusp of synthetic biology and biomaterials. As synthetic biology approaches are being used to engineer biomolecules and materials, convergence could lead to new developments in the control of tissue organisation, the understanding of which is a major goal in fundamental biology and essential for progress in regenerative biology (Keating & Young, et al., et al., et al., et al., Mycoplasma\u00a0genitalium genome with 52 fewer genes (Hutchison et al., E.\u00a0coli genome that uses just 59 codons to encode 20 amino acids (Fredens et al., et al., Synthetic genomics, the bottom\u2010up redesign of genomes, is often considered as the ultimate exemplification of synthetic biology. The first genome\u2010scale DNA assembly project was completed in 2008 (Gibson These emerging research areas are developing exciting opportunities for plant science. Alongside advances in knowledge and novel technologies, these projects also provide the potential of new roles for plants in human life and society.VII.Marchantia polymorpha, offer advantages for the systems\u2010scale experiments that aid synthetic biology. Able to complete its lifecycle within a Petri dish, it is possible to track physiological and morphogenetic changes through the entire life cycle. Comparatively low gene numbers mean that functional studies of gene families, reconstruction of transcriptional networks, and the development of genome\u2010scale models are simplified (Boehm et al., et al., et al., et al., et al., The ability to engineer predictably is hampered by the unknown. Iterative progressions of design\u2013build\u2013test\u2013learn cycles are useful not only for optimising the performance of synthetic systems but also for improving models of biology. Synthetic biology approaches are therefore as relevant to fundamental plant biology as they are to plant biotechnology. However, many of the approaches discussed above remain challenging in long\u2010lived plant species with low transformation efficiencies. The use of modelling and streamlining experiments through, for example, the application of DoE, can be used to focus engineering efforts. However, more tractable species are better suited for complex manipulations. The numerous genome\u2010scale datasets and resources available for Arabidopsis underpin its importance in plant science, but simpler species such as the liverwort, et al., et al., et al., et al., et al., et al., et al., Synthetic biology approaches are being applied to numerous applications of plant biotechnology. In this review there are examples of how synthetic biology is being applied to increase crop yields (South et al., et al., The strength of synthetic biology lies in its intellectual diversity. While the majority of presenters at a typical plant science meeting will have trained as biologists, at synthetic biology meetings mathematicians, computer scientists, engineers, biologists, chemists and physicists will all be present in varying proportions. Arguably, the most thrilling achievements have been made at the overlaps of traditional disciplines (Cameron"}
{"text": "Secondary fracture healing is a complex multi\u2010stage process in which the mechanical environment plays a key role. The use of an appropriate mechanical stimulation such as strain is conducive to tissue formation between fracture ends, thus aiding the healing process. However, if the strain is too large or too small, the biological behavior of the cells involved in bone healing will be affected, resulting in non\u2010union or delayed healing. In this review, we summarize the current state of knowledge regarding the effect of strain on cells that play a role in the fracture\u2010healing process. Overall, the related literature suggests that selection of an adequate strain promotes fracture healing through the stimulation of angiogenesis and osteogenesis, along with inhibition of osteoclast differentiation and bone resorption. However, standardized methods for the application of mechanical stimulation are lacking, and a unified consensus on the mechanism by which strain promotes cell differentiation has not yet been reached. These issues, therefore, deserve further investigation. This article summarizes the state of knowledge regarding the effect of strain on cells involved in the fracture\u2010healing process. In fact, mechanical stimulation regulates the process of osteogenic differentiation. Osteoblasts are mainly derived from MSCs; they can continue to differentiate into bone cells and are embedded in the bone mineralized matrix. Osteoclasts are derived from hematopoietic stem cells under the influence of mechanical factors; they differentiate from monocytes into multinucleated cells and perform the function of bone resorption. Importantly, different types of strain will have different effects on these cellsFracture healing is a complex process that can be divided into the following stages: hematoma, granulation tissue formation, callus formation, and bone remodeling. The healing process is carried out by specific key cells including inflammatory cells, endothelial cells, fibroblasts, mesenchymal stem cells (MSCs), osteoblasts, and osteoclasts; not only the cells but also their secreted substances are importantvia external skeletal fixation to establish a fracture model. Importantly, the healing process was compared between a control group in which rigid fixation was maintained, and an experimental group in which mechanical stimulation  was applied daily. The authors found that the level of bone callus formation and the stiffness of the fracture site measured both in vivo and in vitro were higher in the experimental group than in the control group. Using the same model of tibial fracture, Kenwright et al.Goodship and KenwrightThis article reviews the available literature on the effect of applied strain in the proliferation, differentiation, and activity of different types of cells involved in fracture healing. This review aims to deepen the understanding of the fracture healing process and provide a reference for appropriate fracture treatments.et al.et al.et al.MSCs migrate to the fracture site from the surrounding tissues and blood circulationet al.When a fracture occurs, activated platelets release a variety of products including fibronectin (FN), platelet\u2010derived growth factor (PDGF), and transforming growth factor\u2010\u03b2 (TGF\u2010\u03b2). These substances trigger an inflammatory response, allowing inflammatory cells including fibroblasts and endothelial cells to enter the fracture gap and form new blood vessels and granulation tissueet al.Blood vessel formation after a fracture can be induced by a variety of cytokines, among which vascular endothelial growth factor (VEGF) plays the most critical roleTherefore, mechanical stimulation can enhance the angiogenesis of early hematomas, and VEGFR2 seems to play an important role in this process, which can persist even after removal of the mechanical stimulation.et al.et al.et al.The fibroblasts involved in fracture healing are mainly derived from the endosteum and periosteumet al.Yamamoto In addition, fibroblast growth factor (FGF) can promote the osteogenic differentiation of fibroblastsDifferent mechanical environments have different effects on MSC differentiation. Chen and Jacobset al.et al.et al.et al.Haasper et al.Sox9 and Col2 showed a gradual upward trend with increasing time of mechanical stimulation, and both markers were significantly higher than those in the control group without mechanical stimulation. Angele et al.Xie Collectively, these studies indicate that appropriate mechanical stimulation can promote chondrogenic MSC differentiation, which may be related to the RhoA/ROCK\u20101 signaling pathwayet al.et al.et al.et al.Proliferation and differentiation of osteoblasts are regulated by various factors such as hormones, growth factors, and mechanical stimuliet al.In addition, Weyts Osteoclasts are cells with bone matrix resorption functionet al.et al.RANK, whereas high\u2010strain conditions produced the opposite result. Rubin et al.Odf mRNA in the experimental group was only 59%\u2009\u00b1\u20093% that in the control group. In summary, proper mechanical stimulation can inhibit osteoclast differentiation and bone resorption.Studies have shown that the development and activity of osteoclasts are regulated by osteoblastsIn conclusion, recent studies have confirmed that most cells involved in fracture healing can respond directly or indirectly to mechanical stimulation and that the use of adequate mechanical stimulation is conducive to proper fracture healing. First, mechanical stimulation promotes the migration of MSCs and angiogenesis of early hematomas. Second, mechanical stimulation can promote the osteogenic differentiation of fibroblasts to aid the process of fracture healing. Third, adequate mechanical stimulation inhibits osteoclast differentiation and bone resorption, thus promoting bone reconstruction.However, the effect of mechanical stimulation still depends on the loading method used. Thus, similar mechanical stimulations may cause different or even opposite cell responses. The reason may be that the same mechanical transduction pathway may share different mechanical stimuli and that different signal pathways may interact with each otherAll authors listed meet the authorship criteria according to the latest guidelines of the International Committee of Medical Journal Editors, and all authors are in agreement with the manuscript."}
{"text": "Dear editor,We would like to thanks the readers of the Bulletin of Emergency And Trauma (BEAT) for their valuable comments regarding our recently published article. We appreciate their interest in our article . We ackn\u201cThere was no difference in Mayo elbow performance score (MEPS) between LA and CML groups \u201d.Another concern by the reader was the exclusion of two studies from the meta-analysis , 3. We det al., [1. The study by Pierrart et al.,  was not et al., [2. The study by Liu et al.,  was not We assume that further high quality randomized controlled trials (RCTs) are required to support our conclusion.None declared."}
{"text": "We thank Noud van Helmond and colleagues  for the In a number of studies, we have recently evaluated the possible value of a handy device (Viatom\u2019s Checkme) for measuring multiple vital parameters, including cuffless blood pressure (BP) determination.The Checkme device entered the medical domain after it was originally designed for the consumer market. This makes it very interesting and necessary to scientifically investigate its use in patients.After a comparison with a common BP monitor  and an eWe are aware of the questions about validity and certification raised by van Helmond et al , and we With regard to the interpretation of the accuracy of the absolute BP values in our home measurement study, we disagree with van Helmond et al . The cliFinally, we agree with van Helmond et al  that a mWe hope that our joint effort to scientifically examine these new devices leads to optimization of self-monitoring technology and eventually to improved patient care."}
{"text": "Natural product research continues to be a productive source of unusual chemistry, producing novel compounds for biomedical applications and, increasingly, sustainably providing commercially useful compounds. Despite its long history, the technologies used in natural products research are still amenable to improvements and the introduction of novel methods, materials and reagents. This special issue highlights several recent developments and improvements in the technology for natural products research.In recent years, laboratory culture of microbes has expanded the ability of natural products researchers to examine a wider variety of organisms and facilitated the isolation and identification of rare compounds. Gurusinghe et al.  comparedRhus genus. They report that not only did the method used affect the metabolic content, but that the impact of the methods was species-dependent as well.Biological material for natural products research is often collected in remote areas with limited access to sample storage or processing technology. Collection and sample processing methods can thus impact what can be identified or isolated from the material in a laboratory setting. Ju\u00e1rez-Arag\u00f3n et al.  quantifi2 extraction to obtain commercially useful compounds from microalgae was evaluated by Molino et al. [Radix physochlainae. Their protocol was quicker and more efficient than traditional methods.Solvent extraction is another step that greatly influences the outcome of a natural products program and for this reason alternatives to traditional organic solvents have been examined. The use of supercritical COo et al.  and Mehao et al. . Both gro et al.  used ionIn order for traditional medicines and herbal extracts to be safely introduced to the market, methods for verifying the provenance, composition and quality of the material are needed. Lee et al.  present Tsang et al.  present Biological activity can be modified dramatically by stereochemistry; thus, its determination is a critical component of natural product structure elucidation. Pearce et al.  present As the papers in this special issue show, many different facets of technology for natural product research continue to be explored. The processes impacting compound identification and discovery are being probed so that they may be better controlled, and the desired outcomes obtained. Methods to enhance quality control of herbal materials and traditional medicines, and to facilitate characterization of novel metabolites are being developed. We hope these reports will spur further developments and enable natural products research to continue to expand chemical space for the benefit of humanity."}
{"text": "Pure (single) cultures of microorganisms and mixed microbial communities (microbiomes) have been important for centuries in providing renewable energy, clean water and food products to human society and will continue to play a crucial role to pursue the Sustainable Development Goals. To use microorganisms effectively, microbial engineered processes require adequate control. Microbial communities are shaped by manageable deterministic processes, but also by stochastic processes, which can promote unforeseeable variations and adaptations. Here, we highlight the impact of stochasticity in single culture and microbiome engineering. First, we discuss the concepts and mechanisms of stochasticity in relation to microbial ecology of single cultures and microbiomes. Second, we discuss the consequences of stochasticity in relation to process performance and human health, which are reflected in key disadvantages and important opportunities. Third, we propose a suitable decision tool to deal with stochasticity in which monitoring of stochasticity and setting the boundaries of stochasticity by regulators are central aspects. Stochasticity may give rise to some risks, such as the presence of pathogens in microbiomes. We argue here that by taking the necessary precautions and through clever monitoring and interpretation, these risks can be mitigated. In this review paper, we highlight the impact of stochasticity in single culture and microbiome engineering. Stochasticity may give rise to some risks, such as the presence of pathogens in microbiomes. We argue here that by taking the necessary precautions and through clever monitoring and interpretation, these risks can be mitigated. AxenicA closed ecosystem maintaining a single monoclonal populationDeterministicThe absence of randomness in the development of the microbial community structure and composition, which is mainly influenced by manipulatable niche\u2010based factorsDriftThe random fluctuation in the number of gene variations within a population over a certain period of timeDynamicsThe change in microbial community composition in function of timeImmigrationThe addition of a specific taxon to a resident community from the species pool of the metacommunityInvasionThe establishment of an immigrant taxon within a certain niche or ecosystemSpeciationGenetic divergence within clonal populations as a result of lateral gene transfer and incorporation of foreign DNA through recombination, mutational divergence and natural selectionStochasticRandom processes that influence the development of the microbial community structure and composition, which cannot be steered or controlledet al., et al., For thousands of years, humans have been relying on microbial processes to produce a plethora of food products, such as bread, beer, vinegar, cheese and other fermented products. The industrialization of our society accelerated the development of novel technologies that directly exploit microorganisms and their unique abilities. For example, the treatment of wastewater by means of activated sludge and renewable energy recovery through anaerobic digestion is both established technologies, now in existence for over a century  cultures and microbiomes will be considered. Next, the mechanisms underlying stochasticity and the consequences (issues and opportunities) for engineered systems will be examined. Finally, the concept of stochasticity will be approached from a regulatory point of view for (in)direct human applications.Fuelled by rapid developments in (meta)genomics, transcriptomics, proteomics and metabolomics techniques, greater attention has been paid to study microbial communities in their entirety and to identify the mechanisms that shape and influence microbial ecosystems of both single cultures and microbiomes. Mainly in the last decade, scientists started to acknowledge the importance of ecological stochasticity in shaping the microbial community  are more likely to become fixed when a bacterial lineage has to adapt to a novel lifestyle that reduces its long\u2010term population size, such as obligate symbiosis or a limited habitat range , is powered by a broad array of deterministic factors, i.e., pairwise interactions that occur between species, such as (i) syntrophy   digestive tract, imply that these are open to different stochastic processes. In that context, two features are of particular interest, which are (i) entry of outsiders in the microbial ecosystem and (ii) exit of insiders to the outside world. The potential downsides of such an open system are twofold.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Invasion of non\u2010desirable microorganisms could disturb process performance or compromise safety. Invasion can be defined as the establishment of an \u2018immigrant\u2019 species in a resident microbial community  engineered processes, the key advantages, especially towards microbiomes, are also twofold.et al., et al., Homeostasis is the result of a dynamic balance of interactions between microorganisms in the community and with their environment  and \u2018equipped to deal\u2019 with to disturbances (redundancy). These examples show that stochasticity should be embraced for microbiome engineering as a natural mechanism of sustaining adequate process performance.Stochasticity is part of life when dealing with both single cultures and microbiomes in biotechnological applications and process engineering. Thus, it requires a suitable framework for the regulatory authority to deal with stochasticity in an economically feasible and safe way. This is a twofold issue, as it requires (i) accurate monitoring of stochasticity and (ii) setting of boundaries on stochasticity, regarding the system in which it is considered. A proposal to solve both issues is formulated here.et al., et al., et al., To monitor stochasticity, methods to detect changes in both single and mixed genetic and phenotypic traits are needed. Single culture phenotypic changes can be monitored through flow cytometry  should be absent in microbiomes in biotechnological applications. However, given the open feature of these systems, the invasion of potentially pathogenic species cannot be avoided and requires accurate monitoring.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., A first monitoring approach concerns the \u2018fingerprinting\u2019 approach in which the degree of microbial community dynamics, i.e., the change in microbial community composition in function of time can be evaluated. Such a fingerprint and its evolution in function of time can be obtained on the genetic level through 16S rRNA gene amplicon sequencing  the initial status of the microbial community, (ii) the deterministic processes  influencing the microbial community and (iii) the (change in) input streams, e.g., the absence of pathogens and ARGs, for which the \u2018omics\u2019 or targeted methods are needed, as discussed above. Taking these three conditions into consideration, if fingerprinting methods do not indicate a deviation from the background variation, no additional analyses nor direct actions are needed. Deviations from the background dynamics profile warrant further investigation to pinpoint potential stochastic hazards and take necessary actions.et al., et al., et al., et al., et al., Even though these fingerprinting techniques provide an important overall view on the microbial community dynamics and distinguish background dynamics from strong deviations or sudden changes, they fail to detect the gradual potential influx of pathogens. Hence, identification at the lowest most precisely possible taxonomic level is mandatory to identify potential pathogens. For this, 16S rRNA gene amplicon sequencing falls short on two levels, i.e., (i) the limited depth of phylogenetic identification  can take place through basic fingerprinting methods, as mentioned earlier. The selection of the appropriate fingerprinting method depends on the system, as amplicon sequencing at the DNA level can be considered suitable for processes in which the outcome does not directly link to human consumption, such as anaerobic digestion and activated sludge systems.\u00ae) obtained by growing a single culture of Methylococcus capsulatus under semi\u2010sterile conditions was eventually characterized by the presence of heterotrophic bacterial strains, which fill a key functional niche necessary to maintain acceptable process performances, i.e., the degradation of the organic carbon produced by Methylococcus capsulatus  treatment, energy recovery, drinking water supply and food processing, and, therefore, cannot be eliminated from our present society. Complete elimination of all risks in microbiomes is impossible (tolerance), due to the stochastic nature of the microbiome. However, if the necessary precautions and above\u2010mentioned level of monitoring, e.g., on site via the MinION\u2122 device (Maestri None declared."}
{"text": "Metastasis is a major cause of morbidity and mortality in cancer patients. However, the molecular and cellular mechanisms underlying the ability of cancer cells to metastasize remain relatively poorly understood. Among all solid tumors, small cell lung cancer (SCLC) has remarkable metastatic proclivity, with a majority of patients diagnosed with metastatic disease. Our understanding of SCLC metastasis has been hampered for many years by the paucity of material from primary tumors and metastases, as well as the lack of faithful pre\u2010clinical models. Here, we review recent advances that are helping circumvent these limitations. These advances include methods that employ circulating tumor cells from the blood of SCLC patients and the development of diverse genetically engineered mouse models of metastatic SCLC. New insights into the cellular mechanisms of SCLC metastasis include observations of cell fate changes associated with increased metastatic ability. Ongoing studies on cell migration and organ tropism promise to expand our understanding of SCLC metastasis. Ultimately, a better molecular understanding of metastatic phenotypes may be translated into new therapeutic options to limit metastatic spread and treat metastatic SCLC. Small cell lung cancer (SCLC) is highly metastatic, but rare resections of SCLC tumors and metastases have hampered our understanding of SCLC progression. This review offers a comprehensive overview of recent advances on models and mechanisms of SCLC metastasis. Circulating tumor cells (CTCs)Cancer cells that have left a tumor and circulate in the bloodstream.Epithelial\u2010to\u2010mesenchymal transition (EMT)The process by which epithelial cells acquire mesenchymal features. EMT in cancer is often associated with increased metastatic potential.Immune checkpoint inhibitorsInhibitors of negative regulators of immune reactions. Upon inhibition of these immune checkpoints, the anti\u2010cancer activity of immune cells can be enhanced.Macro\u2010metastasisA metastasis that can be detected without a microscope, often exceeding 2\u00a0mm in diameter in a cancer patient.Metastatic cascadeThe series of steps by which cancer cells leave the primary tumor and form metastases.Micro\u2010metastasisA small metastasis that can be best detected microscopically.Neuroendocrine tumorsTumors in which cancer cells have traits similar to those of both nerve cells and hormone\u2010producing cells.Pleural effusionExcess fluid around the lung. The growth of lung cancer cells outside of the lungs often generates pleural effusions.Tumor organoidsin vivo characteristics of tumors.Cellular clusters derived from tumors that mimic the three\u2010dimensional Vasculogenic mimicry (VM)The process by which cancer cells acquire features of vascular cells and organize themselves into blood vessel\u2010like structures.et al, Cancer is a leading cause of death, resulting in close to 9 million deaths worldwide every year. Tissue destructive macro\u2010metastases disrupt organ function and are a major source of morbidity and lethality for almost all solid tumor types  cancer types necessitates the analysis of cancer type specific molecular and cellular programs that contribute to metastasis.Cells progressing through the metastatic cascade must employ a series of diverse cellular processes, from local invasion and intravasation into the bloodstream, survival in circulation, and extravasation, to colonization and growth in new organ environments. These different steps are associated with different molecular programs that regulate migration, survival, and proliferation of cancer cells  is a highly metastatic and recalcitrant carcinoma. While worldwide data for SCLC are not available, it is estimated that SCLC accounts for ~\u00a015% of lung cancers and causes more than 200,000 deaths per year . A seminal study found that SCLC patients have uniquely high numbers of CTCs  and p53 (Trp53) enable the homozygous inactivation of these genes in lung epithelial cells of adult mice using adenoviral vectors expressing Cre recombinase (Ad\u2010Cre)  tumor suppressors in the context of the RP model. Inactivation of these genes, which are each recurrently mutated in human SCLC  shows rapid growth of SCLC tumors that are highly metastatic and metastasize within weeks of initiation  (see below), metastatic programs of the Pten or Crebbp mutant SCLC\u2010A subtype or the RPM SCLC\u2010N subtype have not yet been described. As mouse models for specific SCLC subtypes and genotypes are developed, molecular and functional characterization of the programs that drive their metastatic ability will provide further insights into how metastases differ across this heterogeneous cancer. Investigating how the different genetic alterations that drive initiation and growth affect metastatic programs will eventually help identify specific metastatic programs that can be targeted in a more precise manner.In addition to the coincident inactivation of additional tumor suppressor genes, members of the MYC family of oncogenes are frequently amplified in human SCLC  that express the neuroendocrine marker CGRP (using Adeno\u2010CGRP\u2010Cre\u2010mediated deletion of Rb/p53/p130), the resulting metastatic SCLC did not upregulate NFIB  were transplanted subcutaneously, they engrafted and grew tumors, but did not generate metastases. However, subcutaneous tumors generated from a mixed population of NE and non\u2010NE SCLC cells were uniquely capable of generating metastasis from the NE cells  is a process through which cancer cells acquire features of endothelial cells, enabling et al, Another distinct population of non\u2010NE SCLC cells can be generated by activation of Notch signaling in the tumor microenvironment, and this population can promote the growth of NE SCLC cells, including following chemotherapy treatment  via \u03b21\u2010integrin could activate PI3K signaling and promote the survival of SCLC cells following DNA damage  has not yet been studied. Such interactions between SCLC cells could be particularly important for clusters of CTCs found in the blood of patients  is an atypical ligand for NOTCH receptors that is expressed on SCLC stem cells  is an evolutionarily conserved program that has been implicated in enhancing mobility, invasion, and resistance to cell death during metastasis (Chaffer et al, et al, et al, et al, et al, et al, et al, et al, in vivo in both mouse and human models, facilitate the migration of SCLC cells in culture in a manner similar to neuroblast migration (Yang et al, in vivo remains unknown. Knock\u2010down of several diverse genes associated with the formation of these protrusions in SCLC cell lines did not affect subcutaneous tumor growth, but decreased the number of liver metastases after intravenous transplantation (Yang et al, et al, It has long been recognized that SCLC cells can express neuronal markers (reviewed in (Onganer et al, et al, et al, et al, et al, et al, et al, et al, et al, Small cell lung cancer tumors commonly metastasize to the brain, liver, bones, and distant lymph nodes, but also metastasize at lower frequencies in many other organs (Froudarakis, RP model increased kidney and bone metastases (Semenova et al, et al, et al, Interestingly, the genetic alterations in SCLC may also influence the locations of metastases. Notably, overexpression of NFIB in the et al, et al, et al, et al, et al, et al, et al, et al, Brain metastases occur in around 15\u201320% of SCLC patients at the time of diagnosis (Nakazawa et al, et al, et al, et al, et al, RP mouse model with overexpression of NFIB (Semenova et al, Another common site for SCLC metastasis is the bone, with around 20% of SCLC patients developing bone metastases (Nakazawa et al, Small cell lung cancer is an aggressively metastatic cancer. While an increase in knowledge of the genetic drivers of lung adenocarcinoma has enabled the development of new treatments that have extended survival and decreased mortality, the decrease in mortality from SCLC has been strictly driven by decreased incidence (Howlader et al, et al, et al, et al, et al, Differences in treatment responses between different models of SCLC are becoming increasingly apparent (Ferone in vitro phenotypes associated with metastasis, in vivo metastases that form from xenograft transplants, and metastases that form in genetically engineered mouse models. While these models are informative, they each have limitations. For example, models of metastatic SCLC based on cell lines can potentially reflect phenotypes gained during propagation in culture, and existing genetically engineered mouse models do not yet reflect the full range and frequency of metastases in patients. While promising new models like CDXs address some of these limitations, including the development of brain metastases in some CDX models, there are still important gaps in our ability to model key aspects of SCLC metastasis. For example, studying SCLC metastases in xenograft and autochthonous mouse models is limited to metastatic tumors that develop before the mice succumb to their primary tumors. New models that overcome or circumvent these differences in frequency of metastases in specific organs will be important to address additional aspects of organ tropism of SCLC. For example, irradiating primary lung tumors at late stages in autochthonous mouse models, generating primary tumors in only one lobe followed by partial pneumonotomy, or surgically removal of subcutaneous xenografts before they grow too large may provide more time for metastases to grow in other organs.The development of additional models of SCLC remains critical to further deconvolute the cellular and molecular mechanisms that drive SCLC metastasis. Current experimental systems rely on et al, et al, et al, et al, et al, et al, Furthermore, many new therapies for SCLC are focused on the interactions between cancer cells and immune cells. Both adaptive and innate immune cells can play significant roles at different stages of cancer growth and the metastatic process. In other cancer types, immune responses have pro\u2010 and anti\u2010tumorigenic effects on primary tumor growth, influence dissemination, and regulate metastatic seeding and growth (Kitamura Despite decades of being understudied, SCLC may soon be leading our conceptual understanding of the determinants of metastatic ability. With a growing understanding of the impact of the cell type of origin and cancer genetics, we are poised to uncover the spectrum of cellular and molecular mechanisms that influence SCLC metastasis. The certain complexity of these mechanisms can now be embraced rather than viewed as insurmountable task. Understanding the cellular and molecular drivers of each step of SCLC development remains a formidable undertaking. While the identification of genetic and cellular heterogeneity adds multiple layers of complexity to this disease, new models are rapid enhancing our ability to study each cellular process in the metastatic cascade and connect molecular mechanisms to cellular phenotypes. Identification of cellular and molecular mechanisms that drive metastatic potential will ultimately provide targets for the development of therapies to block the development of metastatic SCLC, prevent the growth of additional metastatic tumors during and after treatment, and treat multi\u2010organ metastatic disease.J.S. receives research funding from Stemcentrx/Abbvie and Pfizer, and licensed a patent to Forty Seven Inc./Gilead on the use of CD47 blocking strategies in SCLC. M.M.W. has equity in, and is an advisor for, D2G Oncology Inc.https://www.cancer.org/cancer/lung\u2010cancer/if\u2010you\u2010have\u2010small\u2010cell\u2010lung\u2010cancer\u2010sclc.htmlA lay person description of small cell lung cancer and treatment options by the American Cancer Society.https://www.omim.org/entry/182280A resource page on SCLC from the Online Mendelian Inheritance in Man online catalog of human genes and genetic disorders.https://www.metastasis\u2010research.org/An international professional society that supports research on processes fundamental to metastasis in various cancer types.https://depmap.org/portal/A database that includes a number of human SCLC cell lines and the consequences of gene knock\u2010down or knock\u2010out.https://www.cbioportal.org/A portal for cancer genomics that includes human SCLC tumors.Develop new pre\u2010clinical models that faithfully recapitulate metastasis in SCLC patients, including organ tropism.Gain a better understanding of how the cell type of origin, specific genomic alterations, and cell\u2013cell interactions influence metastatic development and response to therapy.Identify therapeutic strategies that can inhibit metastatic spread in early\u2010stage SCLC patients and that can block metastatic growth in late\u2010stage SCLC patients."}
{"text": "As reports from McKinsey Global Institute . Therefore, there is an urgent need to protect machine learning models against potential attacks. Although there is an active research directions for addressing adversarial attacks in machine learning (e.g., Zhou et al., All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The conditions, timing, and setting for the origin of life on Earth and whether life exists elsewhere in our solar system and beyond represent some of the most fundamental scientific questions of our time. Although the bombardment of planets and satellites by asteroids and comets has long been viewed as a destructive process that would have presented a barrier to the emergence of life and frustrated or extinguished life, we provide a comprehensive synthesis of data and observations on the beneficial role of impacts in a wide range of prebiotic and biological processes. In the context of previously proposed environments for the origin of life on Earth, we discuss how meteorite impacts can generate both subaerial and submarine hydrothermal vents, abundant hydrothermal\u2013sedimentary settings, and impact analogues for volcanic pumice rafts and splash pools. Impact events can also deliver and/or generate many of the necessary chemical ingredients for life and catalytic substrates such as clays as well. The role that impact cratering plays in fracturing planetary crusts and its effects on deep subsurface habitats for life are also discussed. In summary, we propose that meteorite impact events are a fundamental geobiological process in planetary evolution that played an important role in the origin of life on Earth. We conclude with the recommendation that impact craters should be considered prime sites in the search for evidence of past life on Mars. Furthermore, unlike other geological processes such as volcanism or plate tectonics, impact cratering is ubiquitous on planetary bodies throughout the Universe and is independent of size, composition, and distance from the host star. Impact events thus provide a mechanism with the potential to generate habitable planets, moons, and asteroids throughout the Solar System and beyond.  But how did life on Earth begin? There is some consensus regarding the requisite conditions for the transition from prebiotic chemistry to living systems: a maintained excess of Gibbs free energy (-\u0394G), a solvent (water), a mode for the encapsulation and concentration of prebiotic molecules, a mechanism of information storage, and the presence of catalytic molecules such as enzymes , which 13C values within carbonaceous inclusions found in apatite grains , and synthesized with results from other studies. We review the beneficial effects for microbial life ranging from generating conditions conducive to the origin of life  to varied habitats for life that persist long after an impact event, including transient hydrothermal systems, endolithic habitats in impact glasses and impact shocked rocks, and impact crater lakes. The purpose of this contribution is not to repudiate or argue against any previously proposed environments for the origin of life, but to synthesize ideas and data on the potential importance of meteorite impact craters. While impact craters represent a standalone environment, we show that they can also provide an alternative mechanism or pathway by which to generate previously proposed prebiotic environments, such as submarine hydrothermal vents, subaerial hydrothermal fields, and even pumice rafts. Furthermore, unlike other geological processes such as volcanism or plate tectonics, impact cratering is ubiquitous on rocky and icy bodies in the Solar System , and the high strain rates involved (\u223c104 s\u22121 to 106 s\u22121) set the impact cratering process apart from any other geological process, such as volcanism and tectonism . From a [et al. : (1) con [et al.  suggesteet al. , there is a notable increase in porosity and permeability in target rocks , the transient cavity undergoes only minor modification, which results in the formation of a bowl-shaped simple crater  lined wiet al.,i.e., for most objects in the Universe), impact cratering will thus be the primary agent of resurfacing, and impact ejecta deposits and central uplifts will be the primary mechanism to exhume ultramafic rocks, such as peridotite and basalt, from the deep subsurface. Furthermore, it is thought that plate tectonic rates during the Hadean were slower than the present-day and that the Hadean oceanic crust was much thicker  of the original transient cavity and to an even smaller proportion of the final crater. Indeed, it has been shown that even within rocks that were highly shocked and encased in impact melt rocks, bioessential elements  involved. The three dominant groups of alteration minerals in terrestrial craters are clays, zeolites, and carbonates  of target rock and fluid sources  and habitats (see Section 4) necessary to support the origins and early evolution of life.et al.,et al.,et al.,et al.,Once the impact-generated heat has fully dissipated from a crater and hydrothermal circulation has ceased, ambient surface temperatures return to pre-impact values: we consider this as the beginning of the next and longest-lived phase of post-impact ecological succession  that wilet al.,et al.,et al.,et al. . On Earth, this process is significant, and it is primarily driven by plate tectonics and wind/hydrological erosion. Although atmospheric density leads to differences in impact dynamics on Earth and Mars, the characterization of 198 craters on Earth . Meteorites can be classified into three main groups  but new biologically relevant molecules, including threose, erythrose, and ethylene glycol, were formed.In an intriguing set of experiments, McCaffrey et al.  mixed thA synthetic view of the conditions at the site of impact craters leads to a number of conditions that could be conducive to an origin of life. Cockell  suggesteet al.  crae.g., Newsom, i.e., vugs and veins) to being completely pervasive. The difference in intensity of hydrothermal alteration of crater-fill impactites has been ascribed to the presence/absence of an overlying crater lake . The authors outlined a series of metabolic pathways whereby chemolithotrophic microorganisms could have been involved in the weathering of hydrothermal sulfides. Sulfides are ubiquitous in impact-generated hydrothermal systems , sulfid [et al. , charact Naumov,  and provet al.,et al.,et al.,et al.,et al.,et al.,Is there evidence that these impact-generated hydrothermal systems were colonized by microorganisms? The most conclusive evidence thus far is sulfur isotope data from the Haughton . Rapid cooling or \u201cquenching\u201d of silicate impact melt results in the production of glass  and often containing quench crystallites of minerals such as pyroxene and feldspar  for liquid water to exist. However, as discussed by Neish et al. , transiee.g., Gold, et al.,et al.,et al.,et al.,et al.,et al.,In recent years, there has been a growing recognition of the importance of the deep subsurface biosphere on Earth  than New Quebec likely owing to the increased area for littoral zone organisms , complexification , and plausibility . Westall et al.  in the acidic Hadean ocean, satisfying the requirement for a -\u0394G. Furthermore, the resulting pH gradient between the highly alkaline effluent and the acidic ocean could have driven the first primitive proton pumps across a hydrothermal mound. These initial processes would have allowed for increased complexity and the generation of pyrophosphate in ferrous hydroxide layers, acting as highly reactive and permeable \u201cmembranes,\u201d allowing for concentration of prebiotic constituents. Although these hydrothermal vent and hydrothermal-sedimentary environments are set in the context of submarine volcanism, we contend that these processes could also have occurred in impact-generated hydrothermal environments on Hadean Earth.In Section 3, we reviewed how meteorite impacts could have delivered and generated the necessary ingredients for life\u2014ranging from amino acids, HCN and CO, to clay minerals\u2014on Hadean Earth. In Section 4, we discussed how impact events can also create unique new habitats for life. In this section, we return to the question of the environment (or environments) in which life originated on Earth. We draw extensively from the work of Westall et al. , who pro  but for the primary potential impact-generated habitats and substrates that they could contain.e.g., gullies, subglacial environments). Exactly when the transition from a potentially habitable surface to an inhospitable one occurred is not known. However, in extreme locations on Earth, surface conditions render the interior and subsurface of rocks, and soils beneath them, as preferential refugia for the propagation of life. Regardless of either an early warm and wet or cold and dry Mars, by the time the earliest evidence for life on Earth was recorded in the rock record, due to loss of the magnetic field by \u223c3.9\u20134.1 Ga . In many subsurface environments, life is generally not limited by space but by energy and nutrients , to exoplanets, we suggest that the concept of habitable zones and what factors influence planetary habitability should be reconsidered with meteorite impacts in mind.Looking beyond Earth, as we have discussed in this review, we suggest that impact craters should be considered as prime sites in the search for evidence of past life on Mars and may have increased the habitability of the subsurface, with implications for the potential of extant life on Mars. While not within the scope of this review, we contend that impacts could increase the potential for any planetary body with the necessary ingredients for life\u2014which could also be impact-delivered\u2014to be at least transiently habitable. From large asteroids, such as Ceres, to satellites of the outer Solar System  where life originated on Earth. This is a hypothesis that could eventually be tested on Mars or other planetary bodies. Would it not be poetic that impacts, long seen as harbingers of death, turn out to have in fact been the cradle of life?"}
{"text": "We read with interest the article by Hung et al. \u201cLong-Term Outcomes of Sentinel Lymph Node Biopsy for Ductal Carcinoma in Situ\u201d . The autWe do not think that this conclusion can be drawn based on the data they had available and selected for their analysis. As stated by Hung et al. , they usGuidelines on the use of SLNB in patients with biopsy-proven DCIS are divergent and so is the interpretation of these guidelines, because there also is considerable variation in the actual use of SLNB in these patients ,6. To imDisclosures: The authors have no disclosures to declare.Not applicable."}
{"text": "Dedicated to the memory of Arren Bar\u2010Even (1980\u20102020), one of the most brilliant biochemists of our times.et al., et al., Living beings are the result of a cocktail made with unknown doses of chance and necessity. Consider a thought experiment, in which we could rewind the \u2018tape of life\u2019 starting from the same initial conditions, what biochemical traits and cellular features would finally be the same as those we observe today? It is clear that what is real in biology is a subset of what is possible, and this issue has been discussed at different scales. Thus, structural and dynamic developmental constraints limit the space of solutions for animal bodies Alberch, , whereasEscherichia coli K12  and well\u2010defined physiological processes . Describing chemical transformations in cell\u2010free systems and the use of inhibitors, mutants or isotope labelling helped to draw the first metabolic pathways Morange, . More reet al., 2. Experiments in prebiotic systems chemistry, exploring the origin of glycolytic intermediates, indicate an early emergence of this historically frozen transformation of C3 in C2 moieties  is an artificial pathway composed of natural enzymes from different phylogenetic origins and showing a complete carbon conservation without decarboxylation steps during the transformation of glucose in acetate (i.e. one mole of hexose delivers three moles of acetate without carbon loss). NOG functions in vitro and in vivo in E. coli, by the action of canonical glycolytic and the pentose phosphate pathway enzymes from the host in combination of an enzyme of the bifid shunt, namely a phosphoketolase from Bifidobacterium adolescentis, allowing a new rearrangement and recycling of carbon skeletons (Bogorad et al., et al. (2 emissions by cellular factories. There is still a long way from all those laboratory successes to their efficient industrial implementations.Motivated by the Nobel prize winner Frances H. Arnold, I would say that metabolism is amazing not only because what it does now, but for what it , et al. . The lonin vitro combinations of purified natural enzymes performing unnatural chemical processes. What is now certainly innovative are the approaches, the tools and the engineering ideology under current synthetic biology projects. Thus, Fessner (et al., et al., et al., et al., et al., The idea of designing new metabolic processes and catalysts adopting a non\u2010conformist attitude \u2013 going beyond the naturally evolved pathways and enzymes \u2013 is not completely new. For instance, Fessner and Walter  proposed Fessner  has intr"}
{"text": "The past decades have witnessed tremendous progress in the detailed structural knowledge of proteins as potential or validated drug targets and the discovery of new drugs based on this wealth of knowledge progressed in parallel.In this Special Issue, several papers deal with the structure-based investigation of targets useful for the discovery of novel anticancer drugs. Al-Warhi et al.  targetedTargets involved in both cancer and inflammatory diseases have been the focus of intense structure-based design campaigns and are well-represented in this Special Issue. Londhe et al.  analyzed3 receptor (H3R) ligand, bearing an isothiocyanate warhead, that behaved as an inverse agonist of this G protein-coupled receptor (GPCR). Scarpino et al. [Two papers of this Special Issue deal with covalent ligands and the challenges posed by in silico analysis of covalent inhibitors. Wagner et al.  designedo et al.  designedBased on the concept that the knowledge of interactions at either a molecular or high topological level are important for the design of effective ligands, Bojarska et al.  designedMycobacterium tuberculosis survival and virulence, Battah et al. [The design of anti-infective compounds and of pest control agents is another field in which structure-based design plays a critical role for both the discovery of new agents and for the control of drug-resistance issues. Tian et al.  analyzedh et al.  identifih et al.  provided"}
{"text": "Intracerebral hemorrhage (ICH) is a destructive form of stroke that often results in death or disability. However, the survivors usually experience sequelae of neurological impairments and psychiatric disorders, which affect their daily functionality and working capacity. The recent MISTIE III and STICH II trials have confirmed that early surgical clearance of hematomas does not improve the prognosis of survivors of ICH, so it is vital to find the intervention target of secondary brain injury (SBI) after ICH. Mitochondrial dysfunction, which may be induced by oxidative stress, neuroinflammation, and autophagy, among others, is considered to be a novel pathological mechanism of ICH. Moreover, mitochondria play an important role in promoting neuronal survival and improving neurological function after a hemorrhagic stroke. This review summarizes the mitochondrial mechanism involved in cell death, reactive oxygen species (ROS) production, inflammatory activation, blood\u2013brain barrier (BBB) disruption, and brain edema underlying ICH. We emphasize the potential of mitochondrial protection as a potential therapeutic target for SBI after stroke and provide valuable insight into clinical strategies. Hemorrhagic stroke, which is less common but far more likely to be fatal, makes up about 13% of stroke cases. Indeed, two-thirds of stroke survivors will experience moderate or severe disability  are the causes of SBI after ICH  oxidase and myeloperoxidase  is a dynamic interface between the peripheral circulation and the CNS that prevents toxic substances from the CNS and contributes to the maintenance of brain homeostasis  and intimal anion channels (IMACs), and activation of these channels leads to an imbalance of REDOX homeostasis in cells and mitochondria, inducing ROS release  and apoptosis induction factor (AIF), which play a central role in the survival or death of neurons , a membrane protein, which is recruited into the mitochondrial outer membrane and triggers mitochondrial division (Montessuit et al., Previous studies have shown that the Drp1 inhibitor mdivi-1 can attenuate oxidative stress and neuronal apoptosis after subarachnoid hemorrhage (Fan et al., Mitophagy was first described by Lemasters , who detIn various pathological environments, \u201calternative\u201d activation pathways of mitophagy are also involved in mitophagy (Ma et al., In general, it appears that the effect of mitophagy depends on its severity. Under physiological conditions, mitophagy prevents accelerated cellular senescence and programmed cell death Kang, . HoweverIn cells, the MMP is typically maintained between 80 and 140 mV (Cloonan et al., in vivo and in vitro, and some researchers have found that melatonin can significantly inhibit apoptosis and mitochondrial damage in vivo and in vitro (Wang et al., via the inhibition of mitochondrial depolarization (Zheng et al., The mitochondrial injury induced by ICH is the result of mPTP opening, whereby various proteins, such as CytoC, are released into the cytoplasm, constituting important events that lead to apoptosis (Tomasello et al., in vivo and in vitro (Li et al., In addition, Miro1 is a glutamate receptor-dependent calcium sensor that targets the mitochondria of neurons, connecting mitochondria with motor proteins (Macaskill et al., Hayakawa et al.  demonstrin vitro ischemia/reperfusion model (Han et al., Astrocytic release of extracellular mitochondria particles was mediated by a calcium-dependent mechanism involving CD38/cyclic ADP ribose signaling. Transient focal cerebral ischemia in mice induced astrocytic mitochondria entry to adjacent neurons that amplified cell survival signals (Hayakawa et al., Studies have shown that the main function of transferred mitochondria is to enhance the capacity of recipient cells to metabolize energy (Picca et al., Mitochondrial dysfunction is an early initiating event in the pathophysiology of ICH. Bioenergy genetic defects, structural abnormalities and mitochondrial morphology, and aberrant mitochondrial dynamics play an important role in the activation of neuronal death signaling pathways. In preclinical studies, interventions aimed at mitochondrial quality control and mitochondrial dynamics have been shown to have neuroprotective effects (Chimeh et al., Recent evidence of mitochondrial transfer has provided a new perspective for intercellular communication. The latest research suggests that mitochondria themselves can act as \u201chelp me\u201d signals to respond to different extracellular stimuli and recruit adjacent cells to rescue those injured in stroke and those affected by aging, and disease (Heyck et al., Here, The clinical trials using mitochondrial protectants or antioxidants have not been successful or fulfilled yet. ROS and mitochondrial damage are produced rapidly and have a cascade amplification effect (Qu et al., WC, CG, and YC drafted the manuscript and figures. HF and YC proofread and revised the manuscript. YC gave the final proof for this submission. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Dear Editor,With great interest we have read the recent systematic review on \u201cNonspecific Complaints (NSCs) in the Emergency Department\u201d  and woulHowever, NSCs were first defined by Nemec et al  This oriSurprisingly, the original publication by Nemec et al. , coiningTherefore, we suggest that further research should be based on a common definition of nonspecific complaints in emergency presentations, in order to reduce heterogeneity of studies."}
{"text": "Cancer cachexia has been recognized as a major, life\u2010limiting complication in the treatment of cancer patients and is composed of distinctive stages: pre\u2010cachexia, cachexia, and refractory cachexia.Journal of Cachexia, Sarcopenia and Muscle, Morigny et al. have addressed the alterations in bioactive lipids associated with cancer cachexia in pre\u2010clinical mouse models  and complemented the results with the analysis of cancer patients with or without cachexia. The lipidome analysis performed by the authors included 1100 lipid species, and the results show that several bioactive lipids were regulated in cachexia. Sphingolipids (for comprehensive description of the sphingolipid metabolism, see Gault et al.et al.In the current issue of the The authors have no conflict of interest."}
{"text": "Understanding temperature\u2010induced variations in body size is therefore of fundamental and applied interest, yet thermal responses of body size remain poorly understood. Temperature\u2013size (T\u2013S) responses tend to be negative , which has been termed the temperature\u2013size rule (TSR). Explanations emphasize either physiological mechanisms  or the adaptive value of either a large body size (e.g. to increase fecundity) or a short development time . Oxygen limitation could act as a proximate factor, but we suggest it more likely constitutes a selective pressure to reduce body size in the warm: risks of oxygen limitation will be reduced as a consequence of evolution eliminating genotypes more prone to oxygen limitation. Thus, T\u2013S responses can be explained by the \u2018Ghost of Oxygen\u2010limitation Past\u2019, whereby the resulting (evolved) T\u2013S responses safeguard sufficient oxygen provisioning under warmer conditions, reflecting the balance between oxygen supply and demands experienced by ancestors. T\u2013S responses vary considerably across species, but some of this variation is predictable. Body\u2010size reductions with warming are stronger in aquatic taxa than in terrestrial taxa. We discuss whether larger aquatic taxa may especially face greater risks of oxygen limitation as they grow, which may be manifested at the cellular level, the level of the gills and the whole\u2010organism level. In contrast to aquatic species, terrestrial ectotherms may be less prone to oxygen limitation and prioritize early maturity over large size, likely because overwintering is more challenging, with concomitant stronger end\u2010of season time constraints. Mechanisms related to time constraints and oxygen limitation are not mutually exclusive explanations for the TSR. Rather, these and other mechanisms may operate in tandem. But their relative importance may vary depending on the ecology and physiology of the species in question, explaining not only the general tendency of negative T\u2013S responses but also variation in T\u2013S responses among animals differing in mode of respiration (e.g. water breathers  I.Body size is central to ecology at multiple scales, from organismal fecundity to the functioning of communities and ecosystems , that is they mature at a smaller size when reared in warmer conditions, despite initially growing faster , has in itself been used to argue that the TSR is adaptive , when reared under warmer conditions. Size\u2010at\u2010stage results from the interplay between the rate of growth and the length of the period spent growing, and therefore a faster growth to a smaller size in the warm (i.e. the TSR) arises logically from warming stimulating development rate more than growth rate. Body size responses to temperature vary both in strength and sign (i.e. increases or decreases) across species. Consequently, the field has moved to a more quantitative approach examining the magnitude and direction of size responses to temperature et al. , we will also describe the substantial variation in responses across different taxa and environments . Taking a meta\u2010analytical perspective, Horne et al.  extended et al. et al., et al., Differences in thermal sensitivity of growth and development rates give rise to T\u2013S responses et al., et al., Debates continue on whether or not growth rate is increasingly constrained during ontogeny, and if so, whether or not warmer temperature increases these constraints, leading to smaller size at maturity or final size  increase surface area for resource uptake during growth, such as by changing body shape  increase rates at which they obtain and distribute resources  reduce rates of demand for resources . These adjustments to the rate of resource uptake and demand reduce the likelihood that the constraints will be observed directly in controlled laboratory studies of the TSR, which provide abundant food, levels of oxygen availability typical for the species, non\u2010extreme  temperatures and an absence of predators and disease. Even in the field, such constraints may be observed only occasionally. On the other hand, overcoming or avoiding these physical constraints is unlikely to be cost\u2010free. Thus, organisms may have adapted so that they are not \u2018panting for breath\u2019 during normal growth, but could nonetheless experience resource limitation under more demanding conditions (e.g. when pursued by predators or encountering pathogens). Although such demanding conditions may be rare, they are also disproportionately detrimental. Organisms should therefore maintain a safety margin (e.g. aerobic scope) to prevent resource limitation of growth and reduction in fitness, exemplified by the maintain aerobic scope and regulate oxygen supply (MASROS) model, in which size is adjusted to maintain sufficient oxygen supply relative to demand et al., et al., et al., et al., et al., et al., et al., In order to grow, organisms need resources such as food and oxygen, which together shape the energy budget of an organism. Changes in the energy budgets and energy allocation with temperature have been used to explain the TSR  was highest in the youngest instars which lack air sacs and rely more on diffusive gas exchange  for metabolism to be independent of adult body size across a range of insect species. Larger species likely prevent progressive oxygen limitation with increasing body size by having greatly increased tracheal dimensions and these do appear to set upper limits to the size that insects may attain et al., et al., et al., et al., et al., et al., Fish have been documented to adhere to the TSR Manduca sexta, the decision to moult or pupate is size and oxygen dependent. As animals increase their body mass, their demand for oxygen also increases, but since the tracheal system can only be enlarged upon moulting they cannot correspondingly increase the capacity for oxygen supply. Such low capacity for oxygen supply relative to demand triggers the endocrine cascade that advances development  developed into smaller adults when reared under hypoxia, but more than doubled the number of moults to get there compared to normoxia. Under hyperoxia there were fewer moults, supporting the idea that oxygen availability directly influences developmental processes.Effects of oxygen and food are not limited to growth rate, but may also act on development Table . Callieret al., et al., et al., et al., et al., via basking. This could select for a reduced development rate, or a lower thermal sensitivity of development which avoids leaving insufficient time for completing growth in terms of mass, thus explaining converse TSR in heliotherms A notable exception to the near\u2010universal pattern of size reductions with warming are the grasshoppers. Grasshoppers could be less inclined to follow the TSR for several reasons.First, oxygen may be less limiting in larger terrestrial arthropods such as grasshoppers, because gas exchange in their tracheal network relies more on convection et al., et al., via changing cell size  resulted in a 50% increase in cell size, resembling the 50% increase in genome size  and mTOR  regulatory pathways  of 4 pg or 3.91 \u00d7\u2009109 base pairs], and the weakest T\u2013S responses were observed in the species with the smallest genome (T. crassus: ~\u20090.8 pg). Horne et al.  risks of oxygen limitation are more likely to arise in tissues made up of large cells, animals with larger cells may be more likely to reduce cell size plastically to improve oxygen provisioning. If variation in cell number is small, such changes in cell size will be reflected in stronger T\u2013S responses in body size. Triploid tadpoles of the frog , et al.  reportede et al.  report det al., et al., et al., et al., Genome size is also linked to development rate, with large genomes being associated with slower development in fruit flies  were reared for multiple generations, the smallest size was observed in fish reared under temperatures that were warmer than they had previously experienced ad libitum, growth rates could be adaptively modulated as a result of warming exacerbating resource limitation during the species\u2019 evolutionary history  the TSR, while the TSR is strengthened if development rates increase with temperature more than do growth rates. We have seen why warming\u2010induced acceleration is more likely curtailed for growth: although limited oxygen or food is unlikely to constrain growth rates directly when provided V.et al., vice versa via increased competition, predation or resource scarcity (food or oxygen). Such increased mortality risks may be associated with thermal acceleration of physiological rates , whose resultant energetic costs are known to impair immune function per capita resource demand and both their aerobic scope and their ability to obtain sufficient food or oxygen may be less capable of matching warming\u2010enhanced demand compared with that of smaller individuals Lecane inermis, gains in fecundity with body size were dependent not only on temperature, but also on oxygen levels  populations, the reproductive advantage of larger body size decreased with increasing site temperature within 100\u2009years sensu Blanckenhorn & Demont, Lycaena hippothoe than in multivoltine populations. Similarly, perceived time available can alter T\u2013S responses (see Section Lestes sponsa (i.e. a converse James\u2019 cline). Grasshoppers have a diapause at the egg stage, enforcing univoltism, which may explain why grasshoppers generally exhibit converse T\u2013S responses . The benefits of early breeding or even completion of an extra generation may be substantial Cole, , and canet al., et al. et al., et al., et al., et al., et al., et al., et al., i) the voltinism of the population from which the individuals originated; (ii) the physiological state of the individual; and (iii) the temperature and light regime of its environment  et al., et al., et al., et al., et al., et al., et al., The proximate mechanisms by which a shortage of oxygen puts large individuals in the warm at a disadvantage, especially in aquatic environments (see Section (4)via behavioural thermoregulation, reducing the information content of air temperature. Hypoxia is also more common in aquatic environments, especially during warm periods. The \u2018Ghost of Oxygen\u2010limitation Past\u2019 is therefore more likely to operate in aquatic ectotherms, favouring genotypes that grow to a smaller size in warm water, and consequently avoiding oxygen constraints on growth. This prediction is consistent with the stronger TSR in aquatic than in terrestrial species  and food conditions? How do T\u2013S responses affect community assembly by affecting geographic range shifts, predator\u2013prey relationships and phenology?Extend the scope of data on T\u2013S responses. How does developmental temperature affect body size in larger\u2010bodied species, both aquatic and terrestrial? How does size in aquatic species change across altitudinal clines? How do T\u2013S responses change over multiple generations when long\u2010term adaptation also starts to play a role? Do multiple\u2010generation T\u2013S responses differ if temperature is decoupled from proposed selective factors ?Create a database for T\u2013S responses, facilitating future (meta) analyses.Explain the adaptive nature of T\u2013S responses by integrating growth trajectories of juveniles to fitness consequences of adults  are decoupled from temperature. Are larger individuals more susceptible to oxygen limitation under warmer conditions and does such (incipient) oxygen limitation proximately or ultimately limit growth?We are beginning to understand the distinct patterns in T\u2013S responses across animal groups. Still, many important questions remain, and here we propose some questions and directions for future research:VIII.The many explanations proposed Table  for obseEffects of temperature are pervasive, affecting biological levels of organization ranging from whole\u2010organism growth performance down to activities of individual proteins, which makes it unlikely that a single proximate mechanism underlies the TSR. An oxygen perspective may help to explain the effects of temperature on size, especially in large aquatic ectotherms, which are arguably most susceptible to risks of oxygen limitation.Warming may exacerbate risks of oxygen limitation or reduce the safety margin of aerobic scope. For air breathers such as terrestrial insects, problems with insufficient oxygen may be less likely and time constraints take centre stage. Season length may constrain developmental period, forcing them to prioritize time over size as overwintering is more challenging. Day length and temperature may together provide information on how long conditions will remain favourable for development, explaining why thermal responses are modulated by photoperiod.via oxygen provisioning) and for safeguarding completion of development (via time sensing). As such, oxygen supply can be both a proximate mechanism and an ultimate driver (the \u2018Ghost of Oxygen\u2010limitation Past\u2019).Time constraints, mortality risks, and resource limitation are not mutually exclusive explanations for the TSR. Rather, they may operate in tandem but their relative importance may vary depending on the ecology and physiology of the species in question Fig. . At the"}
{"text": "Ecosystem monitoring is fundamental to our understanding of how ecosystem change is impacting our natural resources and is vital for developing evidence\u2010based policy and management. However, the different types of ecosystem monitoring, along with their recommended applications, are often poorly understood and contentious. Varying definitions and strict adherence to a specific monitoring type can inhibit effective ecosystem monitoring, leading to poor program development, implementation and outcomes. In an effort to develop a more consistent and clear understanding of ecosystem monitoring programs, we here review the main types of monitoring and recommend the widespread adoption of three classifications of monitoring, namely, targeted, surveillance and landscape monitoring. Landscape monitoring is conducted over large areas, provides spatial data, and enables questions relating to where and when ecosystem change is occurring to be addressed. Surveillance monitoring uses standardised field methods to inform on what is changing in our environments and the direction and magnitude of that change, whilst targeted monitoring is designed around testable hypotheses over defined areas and is the best approach for determining the causes of ecosystem change. The classification system is flexible and can incorporate different interests, objectives, targets and characteristics as well as different spatial scales and temporal frequencies, while also providing valuable structure and consistency across distinct ecosystem monitoring programs. To support our argument, we examine the ability of each monitoring type to inform on six key types of questions that are routinely posed for ecosystem monitoring programs, such as where and when change is occurring, what is the magnitude of change, and how can the change be managed? As we demonstrate, each type of ecosystem monitoring has its own strengths and weaknesses, which should be carefully considered relative to the desired results. Using this scheme, scientists and land managers can design programs best suited to their needs. Finally, we assert that for our most serious environmental challenges, it is essential that we include information from each of these monitoring scales to inform on all facets of ecosystem change, and this is best achieved through close collaboration between the scales. With a renewed understanding of the importance of each monitoring type, along with greater commitment to monitor cooperatively, we will be well placed to address some of our greatest environmental challenges. I.et al., et al., et al., et al., et al., Our natural and managed ecosystems are changing more dramatically than at any other time in human history. Habitat destruction, soil erosion, pollution, climate change and species extinction (together with and loss of genetic resources) are just some of the most serious environmental problems facing our planet , mandated (data collected as a legislative requirement) or question driven   what elements within the environment are changing? (ii) What is the direction and magnitude of that change? (iii) Where is environmental change occurring in the landscape? (iv) When is environmental change occurring and is the rate of change increasing or decreasing? (v) What is the cause of the environmental change we are observing? (vi) What action can be taken to ameliorate deleterious change and/or encourage positive change?Each year we expect ecosystem monitoring programs to answer a great number of questions and/or test and evaluate a range of hypotheses. Whilst specific questions embedded within monitoring programs may be taxon, environment and location specific, we argue that there are six fundamental categories of questions that scientists and managers routinely consider, and that ecosystem monitoring data must be capable of answering. These are: et al., et al., et al., et al., et al., et al.  and paired sites to assess the effect of fires and grazing by including control plots.Targeted monitoring programs focus on discreet areas  and are generally designed to address a specific hypothesis et al., et al., et al., et al., et al., et al., et al., Surveillance monitoring is primarily concerned with identifying what is changing in the environment and detecting the magnitude and direction of that environmental and ecosystem change through time  of Australia's Terrestrial Ecosystem Research Network (TERN)  data et al., et al., et al., et al., et al., et al., et al., Landscape monitoring is primarily concerned with where and when change is occurring at very large spatial scales , and is principally focussed on analysis of vegetation communities or biomes  over large geographic areas at scales where ground\u2010based data collection is simply not plausible , NASA and other similar groups.Relationships developed between reflectance and variables of interest need to be validated using information that was not used to create these models along with accuracy assessments of resultant mapping As we have demonstrated, all monitoring types provide useful data for the scale and focus for which they are implemented, but none can address all questions required of a comprehensive monitoring system. This is because of the fundamental trade off between space, time and information content that exists across the targeted\u2013surveillance\u2013landscape spectrum. Recognition of this necessitates the integration of different types of monitoring.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al. The different types of ecosystem monitoring do have different strengths and some are better than others at addressing our key environmental change questions  change is usually only measured for a narrow range of variables; and (ii) the measured change will only be relevant to a restricted spatial area. Surveillance monitoring is also well\u2010equipped to determine \u201cWhat is the direction and magnitude of that change?\u201d across broad areas, including land types and jurisdictional boundaries. Both landscape and targeted monitoring programs can inform on magnitude and direction questions, however, as discussed above, targeted monitoring can only provide information for a restricted area, and landscape monitoring is limited to phenomena with a spectral response (or some surrogate thereof).By monitoring a broad suite of critical variables across regions, countries, and continents, surveillance monitoring programs are well placed to inform on \u201cWhat is the cause of the environmental change we are observing?\u201d. By focusing on a particular process\u2010based question, these programs can incorporate sufficient replication and power to inform on the causes of change. In addition, targeted programs can be used to compare areas with different land management or conservation strategies. As a result, they are the gold standard for informing on causation. Once a causal relationship is identified, the results of targeted monitoring can be integrated with other types of monitoring. For example, landscape\u2010monitoring data can be used to extrapolate process\u2010based mechanisms over similar areas, outside the original study site. Targeted monitoring is also uniquely positioned to inform on \u201cWhat action can be taken to ameliorate deleterious change and/or encourage positive change?\u201d. With careful program and experimental design, hypotheses about the impact of different management actions on known causes of change can be tested. Therefore, targeted programs are able to provide objective information on the most appropriate management technique from a range of options. Neither surveillance nor landscape\u2010based programs are able to determine the appropriateness of management actions in meeting diversity goals directly, and can only do so via a correlation between specific management interventions and measured responses.Given their hypothesis\u2010driven design, specific methods, and frequent sampling, targeted monitoring programs excel at determining \u201c(3)et al., et al., It is worth clarifying that we are not arguing that all monitoring programs can or should be the same, rather, we argue that comprehensive monitoring programs rely on exploiting the strengths and complementary nature of multiple monitoring schemes. Individual programs might prefer one form more than another, but to monitor and manage regional to global areas we need to capitalise on the inherent strengths of each form of monitoring in a holistic system. Only then can monitoring programs help answer the six key environmental change questions we so often ask in ecological research. Whilst seemingly self\u2010evident, we reiterate that all types of monitoring benefit from clear objectives or direction setting  that occur between an organism and its habitat. Similar to landscape monitoring, results of surveillance and targeted monitoring schemes are presented and published in venues not particularly accessible to spatial scientists. Ultimately, to realise a comprehensive three\u2010tiered monitoring program will require all conservation practitioners, policy officers, and researchers to combine their skills and provide clear avenues for effective communication whilst always valuing the contribution of their peers working under other monitoring paradigms.Clearly, all three forms of monitoring are needed effectively to address all six questions we defined (see Table et al., et al., et al., et al., et al., All forms of ecosystem monitoring are relatively costly to implement and require sustained investment over long periods for maximum benefit (Lovett V.Maintaining ecosystem services is currently one of society's greatest challenges. To do that effectively we need ecosystem monitoring programs that can inform on different aspects of environmental change. Information from these monitoring programs is essential to successful land management actions. However, traditionally there has been little agreement about how to define different forms of ecosystem monitoring or how they can contribute to various management and research goals.Herein we have provided clarity around a framework that can be used succinctly to articulate types of monitoring and their value in observing different forms of ecological change. We have identified three types of monitoring, namely landscape, surveillance and targeted monitoring, and explored each of their applications. We recommend this framework to assess current monitoring programs and to discuss and design effective future programs. This system is broad, clear, flexible, and can be used to investigate a wide range of changes in the environment at a variety of scales.We have also detailed six key questions that ecosystem monitoring is expected to inform. Ecosystem monitoring questions relate to where and when change is occurring, what elements of the environment are changing, and the direction and magnitude of that change. Questions of why change is occurring, and how to ameliorate undesirable change are also critical to our understanding of environments. We have documented how each form of ecosystem monitoring contributes to our ability to inform on these questions. In this context, we identified the strengths and weaknesses of each type of monitoring.We have established it is essential that all three types of monitoring be implemented together in order for all forms of ecological questions to be addressed. With well\u2010designed surveillance monitoring complementing both targeted and landscape\u2010wide programs, we can arm ourselves with the information necessary to address some of our greatest environmental challenges.Finally, we advocate for renewed cooperation and collaboration between practitioners of each form of monitoring, and for them to work together to provide society with this crucial information. We encourage them to articulate their value, and the value of all types of ecosystem monitoring in a holistic rather than competing manner. Only when that happens will it be possible for society to realise the essential value of ecosystem monitoring programs.B.D.S. developed the idea, B.D.S. conducted the literature review, all authors contributed ideas, B.D.S. wrote the initial draft, and all authors provided assistance and substantial revisions."}
{"text": "Micromachines is devoted to optical trapping, and the enormous range of uses the method has found in the decades since its first demonstration. The papers published here include both novel research articles and in-depth reviews, innovative optical trapping schemes and notable new applications. This diversity of the research field is reflected in the breadth of papers contained in this Special Issue. This Special Issue of Two papers are concerned with the investigation of mechanical interactions of red blood cells (RBCs). Zhu et al. have investigated the disaggregation of RBCs by using optical tweezers to quantify the force required to separate aggregated cells, showing that a short irradiation from a pulsed helium-neon laser may reduce the aggregation force . AvsieviVivek et al. have used optical tweezers to study biomembranes, by inducing the controlled fusion of giant unilamellar vesicles (GUVs) . The manOptical tweezers also find application in single-molecule biophysics, such as the work reported by Kretzer et al.  By combiA novel optical trapping scheme utilizing a micro-ring resonator is reported by Ho et al., who used the evanescent field of the device to trap microscopic particles . The sysIn their communication, Shishkin et al. reported on the development of microscopic optomechanical tools for use with optical tweezers . They deMicroscopic optically trapped and actuated machines are considered in depth in the review article by Andrew et al. . The autFinally, Zhao et al. have provided an in-depth review of an alternative optical trapping scheme, namely optical fibre tweezers . They haWe would like to thank all the authors who have contributed their work to this Special Issue, and all the referees who have dedicated their time to the rigorous reviewing process.Optical Trapping and Manipulation: from Fundamentals to Applications is accepting contributions until 31 January 2021, for publication later that year.In closing this editorial, we would like to remind readers that a second volume of"}
{"text": "The extracellular matrix (ECM) is a specialized, highly organized and dynamic three-dimensional network composed of a complex mixture of proteins and other molecules forming the physical scaffolding of a cell and determining the tissue architecture of organs  entitled \u201cCCNs and other extracellular matrix proteins\u201d contains a comprehensive editorial, 7 reviews, and 4 original research articles reporting novel concepts and major advances in our understanding of basic and clinical aspects on CCN biology. The collection of these articles demonstrates the eminent progress made in the CCN field during the last years and supports the hope that this knowledge will help establishing novel therapies for various pathologies associated with imbalance or de-regulation of CCN proteins and pathways modulated by this multifaceted protein family.This Special Issue of 22. Finally, functional interaction of different CCNs, occurrence of biological active modules, and many other factors further increase the complexity of the CCN network. Undoubtedly, this contribution stimulates reflection and in-depth discussion and shows that individual CCNs are not lone wolves, but a pack of wolves acting together in an orchestrated, finely tuned manner, in which their interplay set the final biological opportunities of their activities.The first contribution in this Special Issue is a profound Editorial by Perbal et al.  in whichIn retinal neuronal and vascular development and function, various CCN proteins play essential function. The review by Chaqour  highlighAnother example of the complexity of CCN function is described by Muromachi et al. . In theiLi and Li  systematIn the original article presented by Qin et al. , the autccn gene knockout mice demonstrate that each CCN member also has specialized functions that cannot be compensated by other members.The brief review by Xega et al.  providesBorkham-Kamphorst et al.  analyzedThe review by Barkin et al.  summarizThe personal perspective of Yeger  providesCCN3 promoter region. Elevated CCN3 then reduce cell proliferation and assist cellular survival by reducing energy expenditure, while maintaining the quiescence and stemness of chrondrocytes. Consequently, CCN3 is a kind of biological guard that prevents \u201coverwork\u201d by chondrocytes, while CCN2 stimulates chondrocyte proliferation in articular, auricular and growth-plate cartilage.In focus of the review by Kubota et al.  is CCN3 Modified expression of CCNs can also be induced by physical shear stress. In general, the cell microenvironment is formed by physical (shear stress), biochemical (cell interactions), and physicochemical . In their review, Wang et al.  compreheFinally, the review by Monsen and Attramadal  criticalTo sum up, this Special Issue provides a unique compilation of contemporary findings and new concepts on CCN biology from leading laboratories originating from 9 countries and working in this research area. Although the individual contributions demonstrate the relentless progress in field of this versatile protein family, there is still a gap in translating basic laboratory findings into human applications and potential treatments. However, there is hope that the new findings, ideas and concepts presented in this Special Issue will help to foster the process of clinical translation into therapies and development of new diagnostic tests."}
{"text": "The United Nations Convention on the Rights of the Child  recognizDing et al. showed that short sleep periods and low sleep quality were associated with suboptimal self-reported health among medical students in China. Qin et al. reported an association between weight and physical fitness in Chinese high school students thus showing an association between physical activity and obesity in younger age groups. Physical activity has direct and indirect benefits for health. In this Research Topic, Zeng et al. showed that physical activity mitigated the negative impact of prolonged use of screens on visual acuity among Chinese children during the COVID-19 pandemic, thus, providing evidence to guide parenting practices. Despite this health promoting effect of physical activity, Deng and Fan presented data from a national US survey of adolescents showing that sports participation has declined in the last decade with differences among ethnic subgroups and subsequent negative health effects to be expected among this young population. Obesity (The Research Topic sheds light on risk factors that may impact young people's health like they impact the health of adults such as use of tobacco, obesity, inadequate sleep and limited physical activity in addition to risk factors that are more relevant to younger age groups such as longer screen use time and use of e-cigarettes. The quality of sleep and physical activity affect perceived and actual health. In this Research Topic,  Obesity  and sede Obesity  are modeDai et al., showed that exposure to second-hand smoking and multiple sales sources, as well as having parents and friends who use e-cigarettes were all associated with greater likelihood of Chinese adolescents' expressing an intention to use e-cigarettes. Mai et al. also confirmed the association between friends' using e-cigarettes and Chinese adolescents' use of e-cigarettes although they showed that some personality traits, like agreeableness, may be associated with lower odds of e-cigarettes' use. Ribera-Osca et al. also confirmed the impact of having parents who are smokers on secondary school students' tobacco use in Spain.Tobacco use is another global health problem with statistics showing that although cigarette smoking has decreased among adolescents, the use of other tobacco products has increased or remained the same over the last two decades . This ReGasoyan et al. described a program to improve oral health and reduce caries among Armenian schoolchildren in rural areas where fluoridation is not possible. Nagy-P\u00e9nzes et al. reported on a school-based program that improved health-related knowledge, reduced unhealthy eating and alcohol consumption and improved physical activity among Hungarian secondary school students. Gross et al. used quality improvement and participatory approach to design a health education curriculum to improve American adolescents' health behaviors. These various interventions demonstrate the usefulness of school-based interventions to modify and instill positive health behaviors thus benefiting from the social environment in which children and adolescents live and turning perceived norms and role modeling into an opportunity rather than a threat.The Research Topic offers an insight into health intervention opportunities that are of special importance to children and adolescents by describing several school-based health interventions. School health programs offer a good chance to integrate health promotion activities into school activities and to reduce workforce needs by utilizing schoolteachers to supervise program activities. The health of children and adolescents is at a critical stage. New challenges specific to this age group and risks that are characteristic of older age groups but apply to younger populations require innovative solutions that build on the specific attributes of young people and their vulnerability to the impact of peers and role models. Involving members of the target group in designing health behavior modification interventions is key to promoting the health of children and adolescents.ME: Writing\u2014original draft, Writing\u2014review and editing."}
{"text": "In this Research Topic, we recognize the work of future leaders in the field of Aquatic Microbiology by presenting a collection of articles that showcases the high-quality work of \u201crising stars\u201d that are in the early stages of their careers and on a trajectory to potentially becoming internationally recognized leaders in their field. We aim to highlight research by these upcoming leading scientists of the future across the entire breadth of Aquatic Microbiology, with advances in theory, experimental design, and methodology with applications for compelling problems. We trust that this Research Topic will give a hint of who to follow in the coming years.Chen et al. investigates the seasonal patterns, ecological function, and assembly processes of bacterioplankton communities in the Danjiangkou Reservoir (DJR), China. Using high-throughput sequencing, PICRUSt2, and other methods, this study reveals the composition, function, interaction, and assembly of bacterioplankton communities in the DJR, providing a reference for the protection of water quality and the ecological functions of DJR bacterioplankton. In the article by Summers et al., the authors assess how different stone materials that are used in seawall construction  affect biofilm formation in tropical marine waters. Their results show bacterial biofilm colonization and succession are similar across different types of stone materials, suggesting that marine biofilms converged over time to a generic marine biofilm, rather than the underlying stone substrata type playing a significant role in driving community composition. The article by Brenes-Guill\u00e9n et al. reports new insights into the prokaryotic diversity and community structure, in conjunction with physicochemistry along vertical gradients, during stratification and mixing periods in Lake Cote, Costa Rica, and provides an example of lake hydrodynamic impacts on microbial communities and their function in Central American lakes with implications for other shallow, upland, and oligotrophic lake systems. Zhao et al. report on the biogeographical patterns and assembly processes of the abundant and rare bacteria from river sediment at high altitudes  and their potential association with antibiotic resistance genes (ARGs). Their results reveal that abundant bacteria shaped by deterministic processes have a high abundance of potential ARGs in the plateau river sediment. The article by Puigcorb\u00e9 et al. shows how the vertical connectivity of the prokaryotic assemblages associated with particles of three different sizes at two East Antarctic polynyas with different surface productivity is linked to the magnitude of the particle export fluxes measured using thorium-234 (234Th) as particle tracer. Whilst the results support recent studies evidencing links between surface productivity and deep prokaryotic communities, this study provides the first evidence of sinking particles acting as vectors of microbial diversity to depth in Antarctic polynyas and highlights the direct influence of particle export in shaping the prokaryotic communities of mesopelagic waters.In this Research Topic, five articles highlight new findings on the functions and seasonal and ecosystem effects of microbial communities in aquatic systems. To begin, the article by Tian et al.; Singh et al.) focus on the microbiology of wastewater treatment plants (WWTPs). The article by Tian et al. presents a critical overview of the existing knowledge of bioaerosol emissions from WWTPs, including their nature, magnitude, and size distribution, and highlights shortcomings associated with existing sampling and analysis methods. The mini-review by Singh et al. provides an appraisal of the different types and sources of coliphage and their fate and behavior in source waters and engineered drinking water treatment systems, and provides exciting future prospects for the use of coliphages in aquatic microbiology based on current scientific evidence and practical needs.A couplet of review articles , 3\u201320 (nano-), and 20\u2013200 mm (micro-size), and their findings suggest that the cell size of microbial eukaryotes is a phylogenetically conserved trait which is tightly associated with biogeographic patterns.Body size is an important ecological trait, but it has been poorly explored in microbial communities. The article by Xia et al., comparative genomics was used to reveal a new strain of flavobacteria, Tamlana sp. S12, which can potentially degrade complex algal polysaccharides, thus expanding our knowledge on how marine Flavobacteriaceae adapt to marine algal polysaccharide environments.In the study by In summary, these articles provide a snapshot of what is to come with respect to more high-quality work from these \u201crising stars\u201d across the wide breadth of Aquatic Microbiology. We hope that this Research Topic will also inspire the younger \u201cclan\u201d of early career researchers to what may be possible in uncovering more about our enigmatic and incredibly profound world of microbes.TG: Conceptualization, Funding acquisition, Validation, Writing\u2014original draft, Writing\u2014review and editing. HL: Validation, Writing\u2014review and editing."}
{"text": "This issue brings together a collection of papers about e-cigarettes using a range of study designs and data sources, in a range of geographic locations and addressing a range of policy domains.et al find that Instagram is a global unregulated marketplace for electronic nicotine delivery systems (ENDS), with little age verification for flavoured products.et al also focus on Instagram, and report that in 2020 there was an interconnected network of e-cigarette influencers worldwide, with most not restricting youth access to their promotional content.et al, finds that the vast majority used recruitment or trial-based appeals including smoking cessation and product sampling and programmes, and almost three-quarters used reinforcement or addiction-related appeals such as loyalty programmes.et al asked people from 22 countries to engage in live webchat communications on the IQOS website, which they conclude can be another opportunity for companies to make claims about their products that may not be warranted.Eleven papers address marketing. Shah et al conducted an experiment with UK youth aged 13\u201317, finding that among those who visit retail stores regularly (and who passed the study\u2019s attention checks), seeing e-cigarette retail displays was associated with increased susceptibility to smoking and decreased harm perceptions of smoking.et al reports on an unintended consequence of a New Zealand law whereby specialist \u2018stores-within-a-store\u2019 emerged to sell e-cigarettes; we have come to learn well that the tobacco industry exploits any loopholes to skirt the spirit of a law, but papers such as this one allow jurisdictions to learn from others and build upon their experiences.et al describe a troubling access channel they observed in Guatemala City\u2014vending machines selling disposable e-cigarettes with no age verification.et al finds that Philip Morris International is using similar marketing tactics as they have used for cigarettes, including direct promotional activities.Keeping with the marketing theme but moving to country-specific studies, Blackwell et al recounts a success story in thwarting an industry marketing initiative. The Cheyenne River Sioux Tribe used its sovereign power to redirect JUUL from achieving a proposed \u2018partnership\u2019.et al report on the high prevalence of IQOS marketing within retail stores in Atlanta.et al used Google search queries and sales data in the USA, finding that JUUL\u2019s removal of their sweet and fruit-flavoured products resulted in increases in Puff Bar search queries and sales until the House passed a flavoured e-cigarette ban bill; after a steep decline in Puff Bar sales when they suspended sales, the decline slowed after Puff Bar relaunched their products as containing \u2018synthetic nicotine\u2019.From the USA, an Industry Watch by O\u2019Leary et al describe how they generated a public database of US state and local standardised e-cigarette tax data.et al report on ENDS excise tax incidence for US jurisdictions and examine how tax incidence varies by whether a specific or ad valorem tax base is used, finding that the relationship is moderated by product type ; they discuss the trade-offs between the different types of taxes, along with the added complications of the wide range of design features across the ENDS market.et al among US adults who smoke but have a low interest in quitting found that neither a proposed menthol ban nor cigarette taxes encouraged much self-reported intention to switch from cigarettes to e-cigarettes.et al present an analysis of the US Population Assessment of Tobacco and Health survey data from 2017 to 2019 which suggested that those using e-cigarettes to help with their quit attempt were less likely to quit than those using no quit aid or a pharmaceutical aid, though the authors point out that the high-nicotine e-cigarettes that are popular today were not used by many participants at the time of their analysis.This issue also contains papers addressing policy domains other than marketing. Cotti et al found that health warning labels on e-cigarette liquids attracted less attention than other parts of the liquid vial and did not increase perceptions of addictiveness, indicating that more work needs to be conducted to develop appropriate and effective health warning labels for e-cigarettes.et al report on a public opinion survey in Australia where parents supported restrictions on the use of e-cigarettes.et al find that prevalence and intensity of e-cigarette use among high school students was lower in states that spent more on tobacco control.et al conducted an online survey of US adolescents to evaluate a range of e-cigarette prevention ads and make recommendations for messages that seem to be more effective for preventing youth use of e-cigarettes.An experimental online survey among 18\u201325 year-olds in Columbia by Gantiva et al used sales scanner data, finding a decrease in e-cigarette sales in response to news about EVALI and state policies banning the sale of some or all e-cigarettes; cigarette sales were mostly unaffected, however, except in Massachusetts where sales of cigarettes had a temporary increase, primarily of brands used by young people.et al, indicates that after a year following the peak in EVALI deaths, there remained misperceptions about the cause of the outbreak and half of respondents indicated that EVALI reduced their interest in using e-cigarettes in the future.This issue contains two papers related to e-cigarette, or vaping product, use-associated lung injury (EVALI), a serious medical condition that damaged the lungs of people who had used vaping products. Liber et al conducted a survey of low-income adults in the US state of California, finding that using e-cigarettes was a risk factor for food insecurity and that using both e-cigarettes and cigarettes was associated with greater risk of food insecurity than using cigarettes alone.et al computed nicotine flux\u2014the rate of nicotine emission per second\u2014for a range of tobacco products; they report a wide range of nicotine flux across products, that the upper limit of nicotine flux has been increasing for ENDS since 2015, and suggest that nicotine flux could be a useful regulatory target.et al evaluate the ethical arguments put forward to maximise ENDS\u2019 potential to reduce harm, conclude that the reasoning in these arguments is flawed and recommend further assessment of ENDS from an ethical perspective to help inform policy.There are additional contributions included in this issue that increase our understanding of e-cigarettes. Gu The papers in this issue provide further insight into e-cigarettes and can inform what might be done to maximise their benefits and reduce their harms. Clearly, the heterogeneity of the e-cigarette\u2014for example, the range of design features of the devices and liquids that influence their appeal, the variation in use patterns and the extent to which they deliver nicotine and other chemicals to users\u2014poses many challenges for research as well as for regulation. The continued rapid change in the products that are available and how they are marketed does not help. From a policy perspective, we need to remain open-minded about the interventions that could achieve our policy goals, evaluate their impacts and unintended consequences and remember that policies that address a very circumscribed target may result in a \u2018whack-a-mole\u2019 state where our \u2018solution\u2019 yields another problem popping up elsewhere."}
{"text": "Mitochondrial dysfunction is a vital aspect of copious neurological ailments ranging from neuromuscular to neurodegenerative diseases. Mitochondrial dysfunction in the form of oxidative stress, disturbed calcium ions homeostasis, altered redox signaling, mutations in mitochondrial DNA as well as apoptosis are responsible for the pathogenesis of many common neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, as well as many neuropsychiatric disorders. Furthermore, abnormalities at different complexes of the electron transport chain by either genetic or exogenous factors, have been reported in many neurological disorders. In recent years, targeting mitochondria for the attenuation of neurological disorders has been attracting great attention. This special issue aimed to collect articles that highlight the current progress in the development of effective mitochondrial therapies against neurological disorders.et al., [In this article, Sehgal et al.,  reviewedet al., [In this article, Khan et al.,  exploredet al., [In this article, Dhasmana et al.,  summarizet al., [In this article, Rahman et al.,  reviewedet al., [In this article, Gareev et al.,  providedet al., [In this article, Nabi et al.,  aimed toIn this article, Kundu and Singh  exploredet al., [In this article, Almikhlafi et al.,  presenteet al., [In this article, Shaito et al.,  presente"}
{"text": "Nanomaterials. This Special Issue highlights recent advances in the mechanisms of nanomaterial toxicity as well as approaches for risk assessment, linking nanoparticle characteristics and in vitro toxicity to in vivo observations for advanced risk assessment. Here, the availability of data and the development of databases are important.The increasing use of nanomaterials in almost every area of our daily life renders toxicological risk assessment a major requirement for their safe handling. Thus, risk assessment strategies ensuring the health of individuals exposed to these types of materials must be adopted and continuously reviewed. Major challenges include the enormous amount of engineered nanomaterials (ENMs) used in workplaces , the limSafe-by-Design concept that is expected to foster the development of safe ENMs before they enter the market.With three original articles by Murugadoss, M\u00fclhopt et al., Elje et al., and Meindl et al., addressing various aspects, the respiratory tract toxicities of titanium dioxide, carbon nanotubes, and nanosilver have been described and some assays can be further validated. A link between in vitro screening and results from in vivo testing for lung effects is provided by Creutzenberg et al., describing results from the PLATOX project. Focusing on the aspect of data availability and reproducibility, Krug describes the development of the CoCoN-Database, while Elberskirch et al. describe the results of a round-robin test that includes data science tools to increase comparability among different labs. Another relevant and important aspect is addressed by de Souza Castro et al., comparing 2D and 3D cell culture models of bone mineralization. Here, the 3D model showed improved induction of bone osteointegration by nanoparticles. Mechanisms related to the possible genotoxicity of ENM are described in the papers by Schumacher et al., May et al., and Murugadoss, with Godderis et al. also addressing the crucial aspect of realistic exposure scenarios in vitro. These papers are also relevant to the key issue of dosimetry, as described by Petersen et al. . The pap"}
{"text": "Thank you for drawing our attention to the correspondence article by Taxiarchi et al. . Our oriTaxiarchi et al.\u2019s  work looThese studies are looking at different outcomes for different populations in different datasets, but both highlight the importance of accurate and accessible recording of healthcare contacts in order to describe and quantify healthcare utilisation. In response to the commentary article published at the time , we high"}
{"text": "To the Editor,Liang et al.Anisocytosis, which is indicated by higher RDW values, might cause the progression of heart failure and incremental mortality due to erythrocyte deformability and impaired oxygen\u2010carrying capacity.Heart failure itself also has a considerable impact on the increase in RDW levels.The author declares no conflict of interest."}
{"text": "Brewster et al. have raised an important point that the current hypertension guidelines reviewed by Meinert et al.  overlookWe appreciate the comments by Brewster et al. on this topic and agree that current hypertension guidelines should address sex and gender-specific differences in more detail including aspects suggested by these authors. Whether or not different thresholds for initiation and targets of blood pressure lowering treatment in women with hypertension could be considered is also an important question. However, the latter depends on the available evidence to do so as supported by dedicated clinical trials. The higher risk of cardiovascular events in normotensive women with uterine fibroids is another interesting point that could be included in risk stratification representing an additional sex-specific difference in the management of individuals with hypertension."}
{"text": "Dear Colleagues,We thank the authors for their thoughts on our article \u2018Once after a full moon: acute type A aortic dissection (ATAAD) and lunar phases\u2019 . The relHypertension is the strongest risk factor for ATAAD  and we bper se. For instance, Cajochen et al. [et al. [We agree that the finding of an increased incidence of ATAAD after full moon could be both fortuitous and unexplainable and therefore sought to find an explanation beyond the lunar phases n et al.  demonstr [et al.  showed tFinally, the nature and strength of our findings limits the clinical relevance of the study, and the results should not be regarded as definite but as an inspiration to think beyond the obvious pathophysiological mechanisms of disease. We now realize that our curiosity is shared by others."}
{"text": "The study of plant metabolome and the role of cellular pathway end products has gained increased attention. Analytical techniques coupled with statistical methods are successfully employed in plant functional genomics for biological and crop physiology applications. Significant research papers and reviews, collected in the Special Issue of CIMB \u201cAdvanced research in plant metabolomics\u201d, focused on the plant metabolome, genome and transcriptome characterization after environmental stress, for possible plant crop yield and quality improvement and for phytochemicals characterization aimed at medical purpose.Among external stresses, Low temperature with Low light [LL] are known to induce photosynthesis inhibition and oxidative stress in pepper plants, affecting crop production. Ding et al.  describeRehmannia glutinosa, was analyzed focusing on its regulatory mechanism by Li et al. [Omics technologies was also used in relevant research papers and review aimed to crops quality and yield increase. In particular: the effect of naphthylacetic acid (NAA), commonly used to improve the tuberous root production of i et al. . Due to Expression of gene was also investigated by Chen et al. . in a reAmong plants of commercial values, tree species with important role in ecological environment construction and sustainable forestry production were investigated. Xiao et al.  reportedOn overview of various metabolomic applications for crop quality was presented by Ncube et al  In this Daphne odora, was studied by Eom et al. [Daphne odora extract was in vitro tested focusing on its inhibitory effect on the melanin biosynthesis pathway suggesting a potential use of this molecule as a depigmenting agent.Furthermore, identification and characterization of phytochemical compounds was the topic of two research papers collected in the present special issue. The cardio-protective activity of a phenolic compound from the black walnut tree was investigated . In partm et al. , focusinThe interesting researches of this Special Issue reveal as the study of plant metabolome, performed with \u201comics\u201d platform together with traditional technologies could provide deep insight into plant cellular pathway. The identification and the characterization molecular components with specific activity could be usefully employed in plant functional genomics with important application for both quality and yield crop increase and for medical purpose."}
{"text": "Ten years ago, The Cancer Genome Atlas (TGCA) Research Network classified endometrial cancer into four molecular categories with prognostic significance, suggesting sensitivity to postsurgical treatments. This molecular classification is not used in clinical practice due to its high cost and the requirement of using fresh or frozen tissue . TherefoSantoro et al.  conducteFavier et al.  focused Assuming that women with both endometrial cancer and LS are typically younger than women with endometrial cancer but without LS, Pasanen et al.  tested wHenry et al conducted research to verify whether the classification proposed by the PORTEC group was also applicable to the population of Aotearoa, a contemporary Maori-language name for New Zealand . The autWhile exploring new immunohistochemical markers that may contribute to the prognostic characterization of endometrial cancer, Hojnik et al.  investigEritja et al.  investigThis series of valuable papers by researchers worldwide aims to provide useful information to clinicians and researchers. Indeed, clinicians must increasingly address the complexity of the realm of endometrial cancer to not only provide modern patient care but also design targeted therapeutic research protocols considering all diagnostic updates. Researchers should follow the insights offered by immunohistochemistry to identify new markers that will, hopefully soon, progressively reduce the percentage of carcinomas, which are currently defined as NSMP due to the absence of a specific molecular profile for this group."}
{"text": "Functional lateralization of the brain , is a research field that has progressed immensely before and after the turn of the Millennium, incorporating inputs from many aspects of biology  and psychology , not doing full justice to the understanding of how the complexity of behavioral asymmetries is linked to genetic and epigenetic causation. Because behavioral lateralization involves a much more articulate pattern, especially when looked through the lens of social interaction, their proposal to expand the laterality phenotype spectrum assessed in GWAS and EWAS studies  as one of the earliest socio-environmental factors epigenetically canalizing neurodevelopment  also might represent a convenient model for social laterality (intended as positional side-bias observation during social interactions; Karenina et al., Comparative research is also under the Loconsole et al., who discuss the influence of asymmetrical spatial numerical association on numerical discrimination in chicks by recoding behavioral data from a previous study (Rugani et al., Another comparative study is that of Tonello and Vallortigara address the issue of the simulation models which so far have been proposed to account for population-level brain and behavioral asymmetries. According to one of these (Ghirlanda et al., Finally, All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
{"text": "One of the most important aspects of engineering assessment of the technical condition of structures and materials is the ability to assess the fatigue behavior of materials and structures. On the other hand, an important topic is the design of materials or structures to resist fatigue and fracture. Modern science provides us with an increasing number of new materials, from superalloys of metals manufactured conventionally and by additive manufacturing to functionally advanced composites. Against this background, the fundamental knowledge of the fatigue behavior and fracture mechanics of different material groups provides a convenient platform for communication between different interested groups and fields, from material scientists, numerical engineers and mathematical modeling to hybrid methods for fatigue life prediction. This Special Issue provides such an exchange of ideas on recent developments in the field of fatigue and fracture and is especially focused on fatigue crack growth analysis, the description of fatigue damage in metals and composites, probabilistic approaches, fracture mechanics analysis, fatigue failure analysis and lifetime prediction. A summary of the articles is given in this editorial. This Special Issue contains thirteen original research papers on fatigue and cracking in materials. The presented articles mainly concern experimental research and numerical calculations. In the paper by Volodymyr Hutsaylyuk et al. , an analBased on the twin bridge shear specimen, Xinna Liu et al.  performeThe study by Maria Letizia Raffa et al.  applies Furthermore, Krzysztof Junik et al.  present In the article by Antonin Bermond et al. , the infII, the crack inclination asymmetry caused by curvature, and the effects of the friction coefficient on the stress intensity factors of the pipe with an inclined inner surface crack under axial compression load and external pressure were explored. To be suitable for defect assessment, the solutions for stress intensity factors KII and KIII were derived, and new correction factors, f\u03b8 and f\u03bc, were proposed in the empirical solutions to accommodate the crack inclination asymmetry and the friction coefficient, respectively. Xi-Ming Yao et al. , based oThe study by \u017divil\u0117 Decker et al.  concernsTakayuki Shiraiwar et al.  proposedThe research by Micha\u0142 B\u00f6hm et al.  presenteFaezeh Hatami and Ahmad Varvani-Farahani  evaluateIn the paper by Branko Ne\u010demer et al. , a comprSimilar to , \u017divil\u0117 Tong Li et al.  studied Materials Editorial Office, especially Felix Guo, Assistant Editor, who managed and facilitated the publication process.We would like to thank all of the reviewers for their contributions and efforts in producing this Special Issue, as well as the authors for preparing the papers. We would also like to thank all the staff at the"}
{"text": "In the original publication by Khan et al., 2022 , there wThe authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."}
{"text": "The Special Issue \u201cMetabolic Regulation in the Development of Cardiovascular Disease and Heart Failure\u201d focused on how metabolic diseases could cause a predisposition to cardiovascular diseases and, in particular, heart failure due to systolic or diastolic dysfunction or a combination thereof. Among metabolic disorders, impaired glucose metabolism is the metabolic condition most commonly associated with a greater incidence of both coronary artery disease and heart failure. However, there are also other very relevant aspects deserving of investigation related to the complex role of metabolic regulation in the different pre-clinical and clinical stages of heart failure. Moreover, the study of metabolic therapeutic approaches to treat patients with heart failure at different stages is a challenging field of research. Novel classes of hypoglycemic drugs, such as type 2 sodium-glucose cotransporter inhibitors (SGLT2i), have been shown to exert both cardio- and nephroprotection in patients with HF independently of the presence of diabetes.In this complex scenario, the original article of Stratmann et al.  providesA complete picture of pathophysiological mechanisms in patients affected by type 2 diabetes mellitus is reported in detail in the review of Andreadi et al. [The beneficial effects of this class of drugs may be better understood by consulting the review of Gronda et al. , which hIf Gronda et al.\u2019s review focuses on SGLT2 inhibitors, the review of Belli et al.  discusseThe review of Kruszewska et al.  further The prediction of atrial fibrillation in patients receiving extracorporeal circulation after cardiac surgery is the subject of the original article of Altieri et al. . PostopeThe Special Issue also includes two interesting papers highlighting the possible role of new biomarkers. The original article of Szab\u00f3 et al.  evaluateThe review of Sygitowicz and Sitkiewicz  focuses Finally, the original article by Chang et al.  focuses"}
{"text": "The production of lime plaster is especially important as a technological development in human prehistory as it requires advanced knowledge and skills to transform rocks to a plastic yet durable material. The large-scale production of lime plaster is considered a development of farming societies during the Neolithic period around 10,000 years ago. To date, the archaeological evidence from the Middle and Late Epipalaeolithic in the southern Levant  indicates that only initial production of partially carbonated lime plaster was performed by Palaeolithic foragers. Our study analysed lime plaster covering burials at a Natufian cemetery in Nahal Ein Gev II, dating to 12,000 years ago. Using infrared spectroscopy and soil micromorphology we show how this lime plaster is of an unprecedented high quality and we reconstruct its production. The results exhibit a technological leap forward at the end of the Palaeolithic. We provide a new model for understanding the evolutionary paths of lime plaster technology during the Palaeolithic\u2013Neolithic transition. Social media summary: Lime plaster covering burials 12,000 years ago presents a technological leap forward at the end of the PalaeolithicThe knowledge and skill to produce synthetic materials using fire is one of several important trajectories in the technological evolution of human history. Fire can be used as a tool to transform materials into new materials with new properties . The production of lime plaster involves different stages of preparation that must be carried out carefully in order to produce a high-quality product. First, quicklime powder is produced by burning rocks  at very high temperatures (>700\u00b0C). The lime is then mixed with water to form a plastic putty that can be applied and shaped. Upon drying, the plaster retains durable properties and exhibits a hard surface. Technological developments in the making of lime plaster included the addition of different materials to give the plaster different properties, for example better binding properties or resistance to water Boynton . Thus, tet al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.This kind of material manipulation on a massive scale and the widespread production of lime plaster are considered a development of farming societies during the Pre-Pottery Neolithic B (PPNB), which took place in the Levant beginning about 10,000 years ago , located at the Upper Jordan Valley , a cemet3 \u2013 usually found in the form of calcite mineral) which if burnt at very high temperatures (>700\u00b0C) for a prolonged time, usually using kilns, transform into calcium oxide . Quicklime is slaked with water, forming a putty of calcium hydroxide (Ca[OH2]) to obtain plasticity. At this stage a wide range of materials can be added to the slaked lime to obtain various characteristics . The slaked lime putty is then shaped and applied, and as the material dries and reacts with the air in the atmosphere it transforms back to calcium carbonate    and natural deposits. The mixed nature of the matrix suggested the presence of partly carbonated lime plaster, slaked with archaeological sediment and the local loess .Finally, both phases were sealed with a layer of small stones.The top of the burial ground was reached 1\u00a0m below the base of a five-course wall which was sealed by a distinct surface of small stones . The extRecent excavation defined the boundaries of the plaster layer that marks the extent of the burial area that reaches a monumental wall to the North of the original trench , but then\u00a0=\u00a017) were collected from Area A according to sediment colour, texture and hardness. Samples were collected from: the massive white layer covering the burials (n\u00a0=\u00a07); mixed sediments from the white layer and above it, ranging from grey to brown in colour (n\u00a0=\u00a04); sediments infilling the later pits dug into the massive white layer (n\u00a0=\u00a05 sediments and n\u00a0=\u00a01 stone found inside the sediments); and control rock samples (n\u00a0=\u00a011) from the vicinity of the site including limestone, chalk, marl and dolomite ranging from the Middle Eocene to Miocene   spectroscopy in order to identify the major mineral components for each sample Weiner , p. 275..et al. , we also  for micromorphological analysis were prepared from impregnated undisturbed monolithic sediment blocks (n\u00a0=\u00a03) sampling the sedimentary sequence from above the white layer (sample 14-2) to its bottom (sample 14-3). In addition, a thin section was made from off-site sediments (sample 14-6) and used as a control sample.Petrographic thin sections  the extent of calcite atomic disorder ; (2) theet al.The first step in the production of the lime plaster involved the acquisition of raw material in the form of local rocks rich in calcite. The area around the site presents access to several geological formations ranging from the Middle Eocene to the Miocene (Michelson The next step would have been to burn the raw material in order to produce quicklime. Based on the extent of the calcite atomic disorder  and the in situ while hot and in many cases also with sediment. Thus, \u2018hot mixing\u2019 commonly results in heterogeneous slaking of the quicklime, leaving lumps and unreacted areas (Karkanas It has been argued that many Neolithic lime plasters in the Near East were produced by \u2018hot mixing\u2019 Karkanas . As oppoKarkanas . The micKarkanas . Thus, wKarkanas  and in uKarkanas .In the absence of pottery, the question of how exactly people transferred quicklime \u2013 known as an extremely hazardous material causing irritation to the skin, eyes and respiratory system \u2013 from the kilns or hearths onto the burial ground, remains an open question. It is possible that they used either skin, wood or rock containers that simply did not preserve in the archaeological record, but to date, no evidence has been found to support any of these possibilities.During later phases in the activity at NEG II, pits were dug into the lime plaster for more burials to be placed within the thick lime plaster layer. Mineralogical analysis of the materials infilling the pits showed that the sediments in the pits display geogenic calcite  and unalLastly, the sharp boundary between the lime plaster and the local sediment overlaying it  suggestset al.et al.et al.et al.Recent geoarchaeological studies have demonstrated that mineralogical analysis, and in particular evaluation of calcite atomic disorder, integrated with micromorphological observations is the best method to evaluate lime plaster technology and quality (Goshen et al.et al.In terms of production technique, early experiments with burning lime are evident during the Middle Epipalaeolithic, when pure lime was produced in very small quantities for hafting lithics as an adhesive material (Bar-Yosef and Goring-Morris et al.et al.et al.et al.et al.et al.et al.et al.During the Early Natufian period, lime plaster was produced in small scales for plastering surfaces and in burials, as evident from Eynan (Kingery et al.et al.et al.In many aspects, the lime plaster from NEG II seems to continue earlier Natufian technology, not only in its use in mortuary context but also in its production technique. The presence of half-burnt limestone in NEG II plaster suggests that burning of the raw material did not take place in a closed kiln for several hours or even days. Rather, it was probably burnt using an open hearth, such as the one found in the Natufian layers of Hayonim Cave dating to c. 14 k cal BP (Chu et al.et al.et al.et al.The lime plaster in NEG II shows mixing of quicklime with the local sediment containing anthropogenic activity residues, similar to the reports from Natufian plasters (Goring-Morris et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.When compared with PPNB lime plasters, NEG II presents a higher extent of calcite atomic disorder even from most PPNB plasters (Chu To the best of our knowledge, so far no evidence has been reported for the presence of lime plaster in PPNA sites in the southern Levant. It is therefore uncertain how exactly the evidence from NEG II relates to PPNB lime plaster technology more than 1000 years later. While, from a technological aspect there seems to be successive steps in lime plaster technological evolution, it is nevertheless possible that lime plaster technology was lost during the PPNA and reinvented during the PPNB. We hope that future studies of PPNA sites will help to clarify this question.Lastly, although it is not within the scope of this article, the technology and production technique behind NEG II lime plaster may help, when integrated with other lines of evidence, to illuminate new aspects about how technological innovation during the end of the Epipalaeolithic was associated with communal effort, ritual activity and the rise of more complex forms of society. In addition, the increase in the scale of exploitation of natural resources, for instance the use of rocks required to produce lime plaster, could mark an important transition in the perception of the environment as part of a broader process of \u2018domestication\u2019 \u2013 one that goes beyond the mere domestication of plants and animals \u2013 the \u2018domestication\u2019 of the landscape. To conclude, the development of lime plaster technology forms an important aspect of human cultural evolution and deserves more attention when discussing the transformations in human society and culture during the Palaeolithic\u2013Neolithic transition."}
{"text": "The true integration between different ecological levels  of mental health practice evidence remains an ongoing task and there remains an implementation gap between mental health policy and practice , that promotes a framework of understanding of mental health and social inclusion that pays particular attention to the socio-political and cultural context of people with lived experience of mental health difficulties. The concept of Citizenship (Rowe et al., Citizenship-based programmes involving people with different psychosocial needs have been developed internationally in different sociocultural contexts (Pelletier et al., Drivenes et al. illustrated the struggle in mental health care to establish a common understanding between service users and therapists in decisional processes regarding treatments.Regarding our Research Topic, we have included seven works that focus their efforts at different ecological levels. Regarding analyses at the micro level, Cases et al., who recount the creation and validation of a method to examine discrepancies between guidelines relating to persons diagnosed with borderline personality disorder and current clinical practices in psychiatric emergencies. In a more practical vein, Havsteen-Franklin et al. developed a program logic model for arts-based psychosocial practice within South African rural communities.Works framed at the meso-level include the work of Su et al. report the methodology of a large-scale mental health survey carried out in the 85 million-inhabitants Chinese Sichuan province. Guo et al. conducted a meta-analysis of the mental health literacy levels of medical staff in China finding lower literacy rates in developing regions. Li and Zhang used a large data sample of insurance reimbursement settlements to estimate the effect of a payment reform on the quality of public healthcare. Finally, Li et al. also analyzed the impact of family doctor contracting on medical expenses.At the macro level, We believe that the works included in this Research Topic contribute to promoting critical thinking in public health at different levels of the complex system of healthcare, from daily practice to public policies, thereby embodying a citizenship focused approach to mental health. Perhaps the difficulties encountered by humanity in recent years have also prevented us from collecting a broader set of works with similar perspectives on mental health. However, we hope that these works provide alternative views to their readers, helping to promote an integrated view of mental health care.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
{"text": "International Journal of Epidemiology came to different conclusions about the association between parental income and offspring\u2019s mental health diagnoses. Using panel data analysed with logistic regression and adjustment for observed confounders, Kinge et al.et al.et al.Two articles recently published in the To investigate if the diverging results are due to different study populations, study designs, statistical approaches or definitions of exposure and outcome, we analysed data from Norwegian children with Scandinavian parents born between 1997 and 2012. We implemented the analytical approaches used in the two articles and a conditional logistic regression modelet al., higher parental income is associated with lower risk for mental health diagnoses. This association is stronger among children whose parents do not have a mental health diagnosis. The middle panel shows that accounting for unit-level fixed effects with a conditional logistic model substantially weakens the income-mental health associations. The third panel shows that, replicating the results of Sariaslan et al., employing a sibling design results mostly in associations that no longer reach statistical significance. These findings show that, using the same dataset and exposure definition, different assumptions and resulting analytical approaches lead to results that do or do not support a causal association between parental income and child mental health.The left panel in et al., some prefer estimates from sibling or panel design studies as estimates of a causal effect. However, such studies use only a small, specific subset of the target population, in which the variation of the exposure is substantially smaller than in the population (compare Ledberg et al.Given the more obvious problem of unobserved confounding in the analysis of Kinge ,,In addition to previously described biases specific to sibling design studies,et al. and Sariaslan et al. provide valuable insight into the relationship between parental income and children\u2019s mental health, and at the same time highlight the strong dependency of study results on implicit and explicit assumptions. Study designs that reduce one type of bias can simultaneously increase risk for another bias, and choosing between designs can mean trading off one type of bias for another. In a triangulation approach, similar results from studies with different biases can provide evidence supporting a causal effect of the exposure on the outcome.The articles of Kinge The research was approved by the Regional Comittees for Medical Research Ethics South East, project number 26684. The study was conducted in compliance with international standards such as the Declaration of Helsinki."}
{"text": "In the published article Manning et al.  and Mann3 providing a framework with systematic data management capacity that enables user input support and EA. The online APP also includes a new heterogeneous component (which we describe and test here), that reveals and measures variations across social groups informing justice reform investment decisions that best manage and mitigate social group specific grievances while maximising economic consequence to society. We refer to this APP hereon as the \u201cenhanced CBA APP\u201d.\u201cMore recent developments have been undertaken by the authors of this paper . A full discussion of the six modules included in the enhanced CBA APP is provided by Manning et al. (\u201cg et al. .\u201dA correction has also been made to The benefits of the described CBA APP modules and next steps, Paragraph 1. The corrected paragraph appears below:Modules 1 to 3 of the enhanced CBA APP. The data driven capacity within the current version of the enhanced CBA APP can identify which justice processes and societal factors are most significant for the costs and benefits of processes specific to context. The current APP, therefore, is capable of accounting for macro variables like inflation, provision of best and worst-case scenarios, identification and accounting of data bias, proportion of costs borne per year, and effects on outcome, including outcomes specific to social groups, to context and to specific intervention elements. Manning et al. (Presented above was a clear outline and test of g et al.  provide A correction has also been made to Footnote 3. The corrected footnote appears below:\u201cThe current version of Smart CBA, with crime-related data as examples, can be found at: Manning et al. . New exaThe authors apologize for these errors and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
{"text": "In the last few years, the attention regarding the health of the lungs and heart of equine patients has been continuously growing. Indeed, if we search for studies categorized in the PubMed database on the topic \u201cequine respiratory medicine\u201d, we can find that 980 articles have been published in the last decade . InteresThe content of this Special Issue aims to reflect the current direction of research, dealing with a wider understanding of the pathophysiological mechanisms underlying respiratory and cardiac diseases of horses, as well as the development of novel diagnostic and therapeutic approaches that are essential to improve their management.For instance, the review by Kozlowska et al.  highlighAnother key theme in the current literature is represented by the complex immunological pathways involved in equine asthma (EA). The review by Sim\u00f5es et al.  widely eThis Special Issue also investigates the different respiratory diseases commonly observed in racehorses, such as dynamic upper airway obstructions (DUAOs), exercise-induced pulmonary hemorrhage (EIPH), and mild\u2013moderate equine asthma (MEA). In the first of their two retrospective studies, Lo Feudo et al.  identifiLastly, the focus of the paper of Marzok et al.  is a speIn conclusion, we believe that the papers published in this Special Issue could enrich the current knowledge of equine cardio-respiratory medicine with innovative, interesting, and useful data, and we hope that readers will be positively impressed."}
{"text": "As suggested by the title of this Research Topic, this is a broad and diverse group of articles encompassing themes that expand beyond movement disorders into subjects pertinent to neurodegenerative diseases generally. As the second most common neurodegenerative disease, Parkinson's disease is especially important. One of the major challenges in the treatment of neurodegenerative disease is its early diagnosis. There are several challenges surrounding the early diagnosis of Parkinson's disease (Tolosa et al., Yi et al. explored the effect of sleep on the progression of Parkinson's disease, addressing both motor and non-motor symptoms. Both categories were found to be negatively impacted by poor sleep hygiene. A separate study by Zhou et al. examined oculomotor function and found that it is an early indicator of Parkinson's disease and can be used to monitor disease progression. An important observation provided by Kang et al. revolves around the association of gait disturbance and cognitive impairment. The results of this study emphasize the importance of evaluating specific aspects of gait disturbance in Parkinson's patients with mild cognitive impairment. Finally, Liu et al. investigated task-generated subjective fatigue in Parkinson's patients associated with regional blood flow changes; fatigue, while one of the most common non-motor symptoms, is underdiagnosed and may in fact be one of the earliest symptoms.As is the case with neurodegenerative disease generally, identifying modifiable risk factors and markers of disease progression is essential. Sleep has emerged as an important factor in neurodegeneration (Musiek and Holtzman, Silvian presented a mini-review on targeting the PINK/Parkin pathway in mitochondrial quality control as a potential treatment for Parkinson's disease. Chen et al. looked specifically at medium spiny neurons and found that a deficiency of Pitx3 resulted in many of the pathological features of Parkinson's disease, suggesting that enhancing Pitx3 may prevent disease and provide a marker for disease diagnosis. Chiu et al. addressed the increased subjective pain sensitivity associated with Parkinson's disease in a rat model. Using fetal tissue allografts, they showed that rats exhibited increased nociceptive thresholds and improved motor function. This study also showed the promise of using fMRI to analyze efficacy. Another major problem associated with movement disorders is fall risk, which can lead to a variety of sequelae including hip fracture. Oddsson et al. demonstrated that a prosthesis provided significant improvement in gait and balance during extended use and suggested that the long-term effect indicates that this is not simply a placebo effect.Targeting and treating movement disorders are also crucial efforts. Mitochondria have been implicated in the development of neurodegenerative diseases, and this is true of movement disorders as well. Zhang et al. provided an extensive epidemiological analysis in China that suggests that farmers are at increased risk for ALS. This provides a basis for searching for broader links between pesticide exposure and neurodegenerative conditions beyond PD.While it is well-known that agricultural work is a risk factor for PD, Zeng et al. examined the hypothesis that Parkinson's disease may be derived from the gut, with a focus on whether gastrointestinal diseases are a factor. An interesting observation is that Parkinson's disease and gastrointestinal diseases may have bi-directional correlations, i.e., Parkinson's may predispose to gastrointestinal disease, and gastrointestinal disease may predispose to Parkinson's disease.The importance of the gut microbiome to brain health/function is increasingly apparent. In their review, It is hoped that this diverse collection of articles will provide focus for future research into Parkinson's disease and age-related movement disorders. Thanks are extended to the authors, editors, and reviewers for helping to assemble and clarify this diverse collection of contributions.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
{"text": "The title of the current Special Issue, \u201cFeature Papers in Materials Simulation and Design\u201d, has identified the aims of this collection since its opening: the gathering of research works and comprehensive review papers that advance the understanding and prediction of material behavior at different scales, from atomistic to macroscopic, through innovative modeling and simulation.In this context, interdisciplinary researches that tackled challenging and complex material problems where the governing phenomena might span different scales of material behavior, with an emphasis on the development of quantitative approaches to explain and predict experimental observations, have been collected. Likewise, peculiar attention has been given to homogenization techniques for the evaluation of the mechanical properties of new materials and multi-phase composites. Innovative numerical approaches for the mechanical analysis, highlighting their accuracy, reliability, and stability features, have been also welcomed. Significant space has been also given to advanced and sustainable technologies. From the aforementioned topics, it is evident that this Special Issue has represented the ideal forum for disseminating excellent research findings, as well as sharing innovative ideas in this significant field.Throughout the several months of activity, this Special Issues has been able to attract many interesting researches. Its success is proven by the sixteen papers collected and published, which have passed through the rigorous review process carried out by experts in the field, who should be gratefully acknowledged for their efforts. An heartfelt thanks should be also given to all the authors, coming from many different countries of the world, who contributed to the success of the collection. This important achievement could be barely reached without the constant and kind support given by the Section Managing Editor, Ms. Fay Liu, who should be gratefully thanked for her dedication and commitment. Finally, the Editors-in-Chief of Materials should be also mentioned for the fantastic opportunity of managing this successful Special Issue.A brief review of the papers published in the collection is now presented as a proof of the advancements and innovations achieved in the field of materials simulation and design. Nurek et al.  investigLarix decidua Mill.) during a four-step seed extraction process and to determine optimum process time on that basis, describing also the microscopic cellular structure of scales in cones for different values of moisture content. Their results have highlighted the conditions for the automation of this process.The paper by Tulska et al.  has beenDe Schryver et al.  proved tThe paper by Chen et al.  aimed atOn the other hand, the paper by Ursini and Collini  has beenBragov et al.  have disA fully autonomous computational workflow to identify light-harvesting materials for water splitting devices based on properties has been presented by Ludvigsen et al. . In partChomka et al.  investigVahed et al.  highlighThe topic of green composites has been discussed in the paper by Jiao-Wang et al. , developCivalek et al.  developeA beam model for thermal buckling analysis of a bimetallic box beam has been developed by Simonetti et al. , consideThe results presented in the paper by Esencan T\u00fcrkaslan et al.  proved tA series of experimental and numerical studies concerning the influence of temperature on mode II fracture of a T800/epoxy unidirectional laminates has been presented by Gong et al. . The faiDastjerdi et al.  developeThe last paper by Cheng and Vescovini  presenteThe Guest Editors would like to congratulate all the authors for the remarkable results presented in these papers."}
{"text": "COVID-19, the first documented coronavirus pandemic in history has been considered a human catastrophe unseen in the past century . Excess The pandemic has had a direct impact on the physical aspects of health, and impinges on the mental health, of our worldwide population. As people are exposed to traumatic events, frontline medical and health professionals have been the group that crops the hardest hit . It has This Research Topic aims to report the work of a group of researchers who have been investigating the issue of the psychological status and mental health problems of healthcare workers during the pandemic from diverse disciplinary and methodological backgrounds.El Sharif et al.; Li et al.; Liu et al.; Mei et al.; Ning et al.; Peng J. et al.; Peng P. et al.; Pahrol et al.; de Vroege and van den Broek; Zhao et al.). Four studies employed a qualitative approach with semi-structured interviews with participants . Banse et al. reported a case study and Xu et al. followed a cohort of hospital staff who had been involved in the Employee Assistance Program (EAP).This series consists of 16 articles of different study designs reporting on the different ways the pandemic impinged the mental health of frontline healthcare workers, including medical, nursing, and allied health professionals. Of these, ten were cross-sectional surveys using self-reported questionnaires . Four studies were conducted in Europe, including the UK , the Netherlands (de Vroege and van den Broek), Belgium , and Spain . Two reported findings are from the Middle East with one from Palestine  and a recent one from Kuwait .  Pahrol et al. investigated the topic in Malaysia.For geographical distribution of these studies, since the first outbreak of the COVID-19 pandemic occurred in China, it is not surprising to find that more than half of these studies were conducted in China, including Hong Kong the Special Administrative Region  perceived the outbreak has a low impact on their life and work.In terms of the prevalence of mental health problems exhibited during the pandemic period between early 2020 and the end of 2022, various studies provided slightly different estimates. Li et al. among dentists in China found that various situational variables, such as the impact of COVID on daily life and work, exposure to the virus, and lack of awareness of the preventive and control measures, were associated with mental health problems. Ning et al. also identified that the perceived risk of exposure was associated with both depression and anxiety. The UK study by Peng J et al. discovered that married women had lower mental well-being than married men and the well-being of single women was significantly lower than that of married women and men. On the other hand, environmental and organizational factors would be protective of healthcare workers' mental health. El Sharif et al.'s study in Palestine found that better mental health was associated with confidence in the system's ability to manage the pandemic. Furthermore, training in IPC procedures and sufficient provision of PPE increased the trust of staff.Some risk and protective factors were identified in these studies. For example, the study by Alsaeed et al. among Keratinase healthcare workers, three main themes emerged on the readiness of healthcare workers for future crises. These included the enhancement of self-resilience, a better-equipped workforce and healthcare environment, mitigation of stigma, and increased public awareness of preventive measures. Banse et al. also showcased a multiple-approach intervention program implemented in a Belgium hospital to support workers during COVID and the process of reinforcing the impact of the program in preparation for future similar crises. Xu et al. reported the results of an intervention program using the EAP as a means to provide support to hospital staff. Results indicated significant reductions in mental health problems, including depression and anxiety, among staff after they completed the EPA program.For the intervention and prevention of mental health problems among healthcare workers during and beyond the pandemic period, some information and examples have been provided from a few studies. In the study by We hope this series of articles can draw attention to the issue of mental health and mental well-being of all personnel, particularly frontline healthcare workers, after being exposed to traumatic events and global health crises, such as the COVID-19 pandemic. The experience of these trauma exposures could be long-lasting and affected individuals may require lengthy rehabilitation. More thorough research into effective preventive intervention strategies is needed to enhance the readiness and preparedness of all walks of life to face up the challenges of similar global crises in the future.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
{"text": "The development and optimization of materials is critical to several contemporary scientific and technological challenges, including renewable energy technologies, novel catalytic routes to sustainable fuels and chemicals and electronic technologies. Computational modelling now plays an essential role in materials science and is used in an increasingly predictive manner. Simulations typically explore the multi-dimensional energy landscape, initially seeking low-energy minima, then the local ergodic region about these minima and the saddle points, or energy barriers, between them. The landscape is typically a function of atomic positions, and, as can be seen in 15) to exascale (1018 floating-point operations per second) and investigating the possibility of exploiting quantum computers. For example, the UK government has just confirmed around \u00a3900 million investment into exascale supercomputers and a dedicated AI research resource [The power of modelling techniques continues to grow with the expansion of the capabilities of the computational hardware and the developments in algorithms and software. The growth of artificial intelligence (AI) and machine learning (ML) tools is also having a rapidly increasing impact on the field. In terms of hardware, nations are striving to upgrade their supercomputers from peta 10015 to exresource  as largeresource  and softresource .In view of the rapid advances in materials modelling using high-performance computing, the Royal Society organized a Discussion Meeting in 2022 to review and discuss recent developments in the field, with a satellite meeting focusing on software solutions. The articles in this volume are based on a selection of\u00a0the presentations at these meetings.et al. [The topics discussed in the volume are wide ranging. Sch\u00f6n addresses the key area of structure prediction focusing on low-dimensional systems . Two-dimet al.  who modeet al. . Christiet al. . The artet al. describe the modelling of the effect of stress on the recrystallization and dissolution of apatite\u2014key processes in bone mineralization\u2014while Rogal et al. describe how liquid structure and dynamics can provide information on crystal nucleation mechanisms. The breadth of the field is illustrated by the articles of Ahmad et al. [et al. [et al. [et al. [et al. [et al. [Modelling has for many years played an important role in understanding the processes of crystallization, which are the focus of two contributions \u201310: Deymd et al.  who desc [et al.  who empl [et al.  discuss  [et al.  present  [et al.  describe [et al.  report nWe hope that the articles in the volume illustrate both the achievements and challenges in the field of materials modelling using high-performance computing, and that they convey the excitement of the field and the pace at which it is evolving.Finally, we would like to thank both the Royal Society Scientific Meetings and Publishing staff for their help and support in the organization of both the Discussion and Satellite meeting and the preparation of this volume."}
{"text": "The COVID-19 pandemic forced colleges and universities to send students home, and to offer courses remotely. It is well established that many students are in chronobiological conflict with the schedules of courses, being required to get up earlier than desired for courses, and or staying up to finish work. The result is that college students tend on average to be sleep-deprived and socially jet-lagged , which iRice et al.,  analyzedConsistent with this finding, the usual differences between sleep timing on weekdays and weekends went away, suggesting that students had less sleep dept and or were experiencing less weekday-imposed social jetlag when allowed more freedom in determining their sleep schedule. A final ray of light from Rice et al.,  was thatThe study by Rice et al., was not large\u201460 people cannot represent all students in all situations, even if this group was fairly diverse. And the results, while encouraging about sleep and light exposure, did not directly measure the outcomes that better sleep and daily rhythms might improve. So while the findings support the hypothesis that some version of remote learning might promote better performance and well-being, future work is needed to confirm that those effects really do follow from the observed changes.As ambient data sources become more common, more studies like this may be possible over broader populations without substantial additional material costs. Experimenting with college schedules is not usually possible. The approach taken by Rice et al.,  to mine"}
{"text": "After this incident, Georgi Markov developed high temperature and died within 4\u00a0days  was first described in 1888 by Stillmark at the University of Dorpat , an important centre of pharmacology in the late nineteenth century  are an important class of protein toxins that consist of A and B chains linked by an inter-chain disulfide bond. It has been recognized since long that isolated A and B chains are not toxic (Creppy et al Techniques for the detection of ricin A have been reviewed in detail (Bozza et al Currently no antidote, vaccine, or other specific effective treatment is available for ricin poisoning or prevention. Treatment with supportive care is still the only means to limit morbidity and mortality (Abbes et al Thus, although being known as drug and toxicant since ancient times, ricin is a matter of active and highly interesting contemporary research."}
{"text": "A recent paper in this journal by Mozaffari et al.  reportedThe authors correctly argue that LCSA is an integrated approach to cover the three aspects of sustainability: environmental, economic and social  at a location (Bardaskan). That is valuable. But an activity is not a life cycle (Heijungs & Cucurachi,"}
{"text": "Editorial on the Research TopicWomen in science: strengthening rehabilitation in health systemsFrontiers in Rehabilitation Sciences underline their concern on gender gap in science and offered a platform to promote the work of women scientists. While less than 30% of researchers worldwide are women according to Unesco Institute of Statistics, 82% of the authors who published in this topic are women (27 authors: 22 women and 5 men).Global Report on Health Equity for Persons with Disabilities (2022) of the WHO \u201capproximately 1.3 billion people (16% of the population) have significant disability\u201d  clinical point of view, to a team approach and to qualitative research.Yuan et al.From a PRM clinical point of view, a clinical approach focused on the importance of PMR diagnosis: Ultrasound evaluation, by Defi et al.From a team approach, the case report of an elderly woman with tetraplegia and sarcopenia due to spinal tuberculosis focused on the importance of functional outcomes and QoL, by Lampart et al.Hale et al.Feldner et al.): the goal setting process in acute SCI emphasized the importance of strong collaboration between different professionals, communication abilities to educate patients with acute traumatic or non-traumatic SCI as well as planning therapies within a true patient-centered perspective by Lampart et al.From qualitative research in other articles .Finally, \u0399t is impressive that significant supply and demand gaps were found even in high-income and not just lower-income countries where rehabilitation services are presumed to be lacking. These discrepancies were enlarged during COVID-19 pandemic. There is an urgent need to promote and further develop the rehabilitation services in every level of health care from the primary care level to the tertiary care levels ."}
{"text": "We applaud Bressler et al  for theiWhile this study successfully characterizes opportunities for dermatologists to interact on social media , the gravity of these findings was not explored, as dermatologists are a significant minority of contributors to social media information. For example, Wells et al  found thP<.001) [An additional, unique aspect of Bressler et al\u2019s  study isP<.001) , for exaBressler et al  also higWhile dermatologists are minor contributors in the scheme of social media, it is more important than ever for this group to advocate for their patients and profession. While there are potential negatives with social media use, it is important that we recognize and face these barriers as a means to provide clear, accurate information to our patients while simultaneously providing greater access to high-quality care."}
{"text": "We have read the article titled \u2018Clinical Outcome of Coronavirus Disease 2019 in Patients with Primary Antibody Deficiencies\u2019 by Milota et al. with great interest [First, the interpretation of the literature by the authors is confusing for the readers. In the abstract, the authors say that there are poorer outcomes in primary antibody deficiencies (PADs) compared to other inborn errors of immunities . HoweverSecond, the authors cited Milota et al.\u2019s study reporting the largest proportion of infections occurred in patients with CVID, hereditary angioedema (HAE), and unclassified PADs . HoweverThird, the authors also mentioned a meta-analysis by Sunjaya et al. concluding that the risk of severe COVID-19 in patients with bronchial asthma was lower compared to non-asthmatic ones . This al"}
{"text": "Peritoneal dialysis (PD) is a widely used treatment for patients with kidney failure/end-stage kidney disease, and a suitable alternative to hemodialysis (HD). Existing for over 40\u00a0years , the adoPD has several advantages over HD, including better preservation of residual kidney function, better blood pressure control, and a more flexible and independent treatment schedule that provides greater patient autonomy . PD can Jak\u0161i\u0107 et al.; Yamashita et.), and three evaluated risk factors for catheter failure Chang et al.; Zhao et al.; Hangai et al. Two of these manuscripts add an interesting discussion to the literature about the impact of unplanned PD on outcomes Zhao et al.; Hangai et al.Some topics were more common in this Research Topic, and we\u2019d like to highlight them here. The leading theme was related to problems with catheter insertion, which accounted for almost one out of every four papers published in this Research Topic. PD catheter insertion is a mandatory step in initiating and maintaining chronic PD, and the rates of catheter dysfunction can reach upward to 30% . Given tDo et al.; Roth-Stefanski et al.; Verger et al.; Guedes et al. Nutrition is a critical aspect of care for patients on PD, as it can affect both short-term and long-term outcomes. These manuscripts shed light on several important aspects related to nutrition in PD including the risk factors for sarcopenia, the diagnosis of protein-energy-wasting, impact of PD prescription on body composition, and an interesting discussion involving inflammation, nutrition, and protein loss.In second comes manuscripts involving nutrition, totalling four articles Maggiani-Aguilera et al.; Song et al.; Zhang et al.), two papers that investigated ways to improve detection and prevention cardiovascular disease in the PD population , as well as two papers that investigated risk factors for peritonitis and associated technique failure events . Finally, but not less important, other articles of this series investigated associations in CKD-MBD biomarkers and survival , the use of PD for patients with chronic liver failure and acute kidney injury , periodontal disease and alveolar bone loss in PD , a method to increase physical activity and quality of life in a controlled trial , and a review detailing the pathophysiology of peritoneal membrane aging (Krediet).Other themes included three papers that explored ways to try to optimize ultrafiltration and prevent volume overload in PD (In summary, all the excellent articles published in this Research Topic reinforce the huge variety of needs in the provision care in PD patients, advancements by the scientific community, and the numerous research opportunities to be addressed within the field of PD. Ongoing efforts are needed to improve the quality of care for patients on PD and to increase the availability and utilization of the modality worldwide."}
{"text": "This special topic presents experimental work on the effects of alcohol (ethanol) on the brain, and how these effects impact behavior across multiple domains. The World Health Organization (WHO) estimates that 2.3 billion people regularly consume alcohol, making alcohol one of the most widely used drugs in human society WHO, . AlcoholHaaranen et al. used a chemogenetic approach to alter neuronal activity in these individual brain regions, and in the specific insula outputs to the nucleus accumbens and basolateral and central subregions of the amygdala, to determine the functional role of this network on alcohol consumption in alcohol preferring Alko Alcohol (AA) rats. This type of sophisticated circuit-level analyses is necessary to understand how neural networks function to control alcohol consumption, in order to design targeted treatment strategies aimed at altering network function. The previous study found that activating the insula projections to amygdala or nucleus accumbens increased alcohol consumption, consistent with prior work demonstrating the insula is a critical driver of alcohol relapse (Campbell et al., Eren-Yazicioglu et al. in this special edition.Animal models play a crucial role in understanding the effects of alcohol on the brain and behavior (Mineur et al., Deal et al. found that both social and non-social stressors enhance the release of catecholamines in the basolateral amygdala, and acute alcohol blunts this stress response, perhaps providing a brain-based rationale for the self-medication hypothesis (Ayer et al., Buhr et al. suggests that it does not alter alcohol's effects on serotonin and dopamine-related turnover in the striatum and brain stem. However, alcohol drinking altered neurochemical correlates of exercise in the hypothalamus, a key component of brain networks responsible for maintaining physiological homeostasis. As demonstrated in the study by Starski et al., repeated and prolonged alcohol use can lead to allostasis and further exacerbate behavioral engagement with alcohol. Furthermore, the behavioral and brain response to stress is sexually dimorphic, and the brain response to stress and drug cues predicts subsequent relapse (Smith et al., Alcohol use can be triggered by numerous factors, and stress is one of the most potent triggers for craving and relapse (Wemm et al., Corongiu et al. demonstrates that adolescents typically drink more alcohol than adults, but that this precise phenotype interacts with genetic background. Moreover, sex can influence alcohol use and behavior, with AUD being diagnosed more often in men than women. In line with this, Bryant et al. found that male mice were more sensitive to the motivating effects of alcohol, and Landin and Chandler report that male rats exposed to alcohol during adolescence were more prone to have greater behavioral responses to threat in adulthood, although females were already predisposed to this phenotype, regardless of alcohol history. To make matters more complex, the neurobiological hallmarks of adolescent alcohol exposure may be sexually dimorphic. For example, Asarch et al. found that in male rats, mesolimbic dopamine peaks during adolescence then declines and stabilizes in adulthood, but adolescent alcohol exposure prolongs the elevated dopamine levels into adulthood, an \u201carrested development\u201d phenotype not observed in female rats, whose dopamine levels are stable throughout adolescence and adulthood. On a more positive note, Rodd et al. report that negative allosteric modulators of the nicotinic \u03b17 receptors may hold promise as prophylactics against the deleterious effects of binge alcohol use during adolescence.Genetic factors, as well as age and sex, can influence alcohol use and behavioral phenotypes associated with alcohol use. Alcohol drinking often begins in adolescence (Abela et al., Overall, the contributions to this special topic have broadened our understanding of how, where, and when alcohol acts in the brain to promote continued alcohol use, which in some individuals can lead to full blown AUD. The extensive comorbid use of alcohol with other drugs is also of growing concern and calls for novel preclinical models of polydrug use to determine the neurobiological consequences of comorbid alcohol use with other substances and to effectively screen emerging therapeutics. Continued research in this area is needed in order to develop novel treatment interventions, including prophylactics, medications, and natural remedies.JP wrote the original editorial draft. All authors edited and revised the editorial."}
{"text": "Editorial on the Research TopicCurrent and future role of artificial intelligence in cardiac imaging, volume IIHeart imaging without the need for invasive procedures plays a crucial role in various aspects of cardiology, including diagnosis, risk evaluation, treatment decisions, medical and invasive therapies, prognosis, and ongoing monitoring. As a key component in the pursuit of precision medicine, cardiac imaging enables a personalized approach to healthcare. Cardiac imaging is essential for a comprehensive understanding of cardiovascular conditions, intricate physiology, and the implications of imaging results for managing cardiovascular health and disease. Consequently, the demand for cardiac imaging continues to grow.Artificial Intelligence (AI) methods are increasingly needed for improving imaging exams, to optimize workflow, reduce waiting times, improve accuracy and precision, reduce costs and benefit patient outcomes. The special issue on \u201cCurrent and Future Role of Artificial Intelligence in Cardiac Imaging\u201d in 2020 provided 10 comprehensive reviews of a wide range of AI applications in cardiovascular imaging, from efficient image acquisition and fast reconstruction, to structure and function analysis, to statistical atlases and imaging-genetics synergies. In the meantime the field has been advancing rapidly. The second volume of this topic focuses on original research articles which showcase new methods and applications. Applications were invited for all topics and forms of cardiac imaging, and the resulting published papers reflect a range of modalities and applications which have a common goal of improving patient outcomes through extraction of more detailed and precise information than has previously been possible.Abdulkareem et al., Alabed et al., Beetz et al., Campello et al., Chen et al., Hampe et al., Li et al., Lin et al., Lin et al., Puyol-Ant\u00f3n et al., Suinesiaputra et al., Szabo et al., Zhai et al., Zhao et al. and Zhao et al.). The special issue attracted a greater number of submissions than the first edition, with 15 papers eventually published , followed closely by CT  and echocardiography . One paper provided a guide to trustworthy and responsible AI in all imaging modalities . Although not an imaging method, ECG processing is an important topic in cardiovascular disease, and can give anatomical information such as hypertrophy, which was the focus of one paper . In terms of application area, the most common was structural analysis  , followed by image motion analysis [in echo  and CT ]. These reflect the ongoing development of methods for quantifying anatomy and function in cardiac images, which are extremely important for diagnosis and prognosis. Two papers were concerned with synthesis of images or anatomy, using generative adversarial networks  and variational auto encoders  respectively. This is an exciting area of research with the promise to synthesise large numbers of datasets with different pathology and characteristics, which can be used to understand the influence of disease processes on structure and function. Two papers discussed learning contrast-enhanced information from non-contrast scans, applied to late gadolinium enhancement CMR  and calcium scoring CT  respectively. These highlight the ability of AI methods to leverage information present in standard scans to provide additional information, which would normally require an extra scan and administration of a contrast agent. The papers on AI fairness , and trustworthiness , illustrate another promising area of research into methods for improving AI methods, mitigating bias in the training data and explaining how inferences are made in complex networks. These were identified in the first special issue as topics of high importance. Another important topic highlighted by the first special issue is the reporting of AI methods to foster reproducibility and generalization, and this is the focus of the review article .Imaging modality was varied with CMR being the most common (AI methods are becoming ubiquitous in all areas of cardiac imaging. This is driven by the increasing role of imaging in guidelines for patient treatment, as well as the wealth of data generated by large cohort imaging studies such as the UK Biobank and the Multi-Ethnic Study of Atherosclerosis. The recent advent of widely available large language models which link imaging and videos with text such as GPT-4 highlight the rapidly advancing technology which will transform medical imaging in general and cardiovascular imaging in particular. The ability to generate reports from images and to combine images and reports into structured datasets will enable large amounts of data already residing in hospital databases to be reused for new applications. Generative models will enable new understanding of the ways in which longitudinal changes between imaging exams can be more precisely quantified, by comparing predicted follow-up images with the actual scans and highlighting any anomalies. Physics-based networks and neural implicit functions are also on the horizon which will enable super-resolution in fluid flow imaging, and computation of physical entities such as pressure and stiffness from imaging data. The linking of digital twins with imaging methods will enable surrogate AI-based methods to simulate growth and remodeling in health and disease, to estimate physiological parameters from non-invasive imaging. In summary, this second issue on AI in cardiac imaging illustrates important areas which are rapidly developing. However the next advances in this area are only limited by the imaginations of the researchers in the community. At present, there is no AI solution for this!"}
{"text": "Ren et al. contribute to this Research Topic by identifying a novel sulfur dioxide probe that inhibits high glucose-induced senescence in umbilical vascular endothelial cells by inducing the degradation of lipid droplets . Senescence is also induced after adjuvant therapy (chemotherapy and radiotherapy) by inducing DNA damage. In their study, Jiang et al. demonstrated that the small GTPases RagC and Rheb are required for the activation of mTOR to promote chemoresistance in chemotherapy-induced senescence in HepG2 cells . Moreover, the regulatory role of E3 ubiquitin ligases is discussed in response to DNA damage, as reviewed by Lu et al..This Research Topic of Frontiers in Physiology includes important studies on senescence and some of the various physiopathological events that play an important role in the process. The article by Zhang et al. points out that polo-like kinase 1 activity delays senescence formation of nucleus pulposus cells and mediates the reduction of intervertebral disc degeneration and thus the prevention of back pain . Apart fIn conclusion, recent reports of this Research Topic fill an important gap in the physiopathological events in which senescent takes place."}
{"text": "The loss of muscle mass is a common adaptation to some physiological situations , but also to many diseases , which is due to an imbalance between protein synthesis and protein degradation . Muscle Depending on the catabolic situation, different signaling pathways controlling the main proteolytic pathways and protein synthesis can be implicated in the development of muscle atrophy, which implies a large panel of potential therapeutical targets for fighting against muscle atrophy . NumerouInternational Journal of Molecular Sciences entitled \u201cMuscle atrophy: from bench to bedside\u201d includes a total of six contributions  providing new information in the field of skeletal muscle atrophy, with a special focus on key actors controlling muscle proteostasis.The Special Issue of the Cussonneau et al.  addresseDowling et al.  addresseValdebenito-Maturana et al.  addresseVan de Haterd et al.  reviewedWinzer et al.  addresseYoshihara et al.  provide"}
{"text": "Cerebral small vessel disease (CSVD) is a common chronic and progressive disease that can lead to mental and cognitive impairment. Damage to brain structure and function may play an important role in the neuropsychiatric disorders of patients with CSVD. Increasing evidence suggests that functional changes are accompanied by structural changes in corresponding brain regions. Thus, normal structure\u2013function coupling is essential for optimal brain performance, and disrupted structure\u2013function coupling can be found in many neurological and psychiatric disorders. To date, most studies on patients with CSVD have focused on separate structures or functions, including reductions in white matter volume and blood flow, which lead to cognitive dysfunction. However, there are few studies on brain structure\u2013function coupling in patients with CSVD. In recent years, with the rapid development of multilevel  brain structure\u2013functional coupling analysis methods based on multimodal magnetic resonance imaging (MRI), new evidence has been provided to reveal the correlation between brain function and structural abnormalities and cognitive impairment. Therefore, studying brain structure\u2013function coupling has a potential significance in the exploration and elucidation of the neurobiological mechanism of cognitive impairment in patients with CSVD. This article mainly describes the currently popular brain structure\u2013function coupling analysis technology based on multimodal MRI and the important research progress of these coupling technologies on CSVD and cognitive impairment to provide a perspective for the study of the pathogenesis and early diagnosis of CSVD. Cerebral small vessel disease (CSVD) is a general term for intracranial vascular  diseases based on a variety of pathological and neurological processes and refers to syndromes with different clinical manifestations and neuroimaging features caused by structural changes in blood vessels and brain parenchyma  is a tight regional and temporal coupling in the brain, which means that brain regions with stronger connectivity tend to have more frequent neuronal activity and more energy expenditure, resulting in increased cerebral blood flow (CBF)  parameters and gray matter (GM) morphological parameters, and the other is the coupling of rs-fMRI parameters and diffusion tensor imaging (DTI)-based white matter (WM) microstructural parameters.In the first approach, Kang et al.  combinedIn the second approach, Tan et al. combined DTI and rs-fMRI and found that patients with classical trigeminal neuralgia had high fractional anisotropy (FA) and low ReHo in the right hippocampus, and the ReHo and FA values were positively correlated with the Montreal Cognitive Assessment scale score. This indicated that there is a clear correlation between cognitive dysfunction and hippocampal functional and structural dysfunction in classical trigeminal neuralgia patients. Strong evidence has been provided showing that pain depends on the activation of mechanisms in higher brain centers that control emotions and generate emotional recognition   or functional connectivity (FC) (Shah et al., Studies have shown significantly altered SC and FC between hippocampal cognitive and emotional subregions and cortical areas in patients with cognitive impairment, which is manifested as an increase in the early stage of the disease, possibly due to compensatory mechanisms (Liang et al., The tight coupling between neuronal activity and CBF is called NVC (Li L. et al., There is increasing evidence that impaired NVC is present in many patients with CSVD. Increased microvascular damage and a decrease in the number of microvessels in the hippocampus and neocortex can cause a decrease in vasodilator reserve, leading to impaired NVC function, which is associated with cognitive decline (Phillips et al., As an important anatomical structure, the hippocampus is of great significance in the pathogenesis of neuropsychiatric diseases. Neuropsychiatric disorders caused by CSVD can lead to structural and functional damage to the hippocampus in many ways. Indeed, hippocampal neuronal loss and atrophy, regional cerebral blood volume reduction, and hippocampal microinfarction have been observed in patients with CSVD (Perosa et al., At present, structure\u2013function coupling analysis methods and research specific to the hippocampal region are developing continuously. Recently, Bayrak et al. isolated the hippocampus and investigated its structure\u2013function coupling using the twin setup of the Human Connectome Project with multimodal neuroimaging (Bayrak et al., In summary, the above structure\u2013function coupling methods, including voxel-wise structure\u2013function coupling, SC-FC coupling, and NVC, are of great significance for CSVD, but the current research is not perfect, and most of them only focus on independent structural or functional aspects. In addition, although multimodal MRI has been widely used in studies of CSVD, some issues remain. For instance, the mechanisms leading to cognitive impairment are complex and may be the result of a combination of factors other than CSVD alone (Lawrence et al., In addition, advances in machine learning have led to the development of artificial intelligence algorithms that can aid in the diagnosis of diseases based on MRI for detection at the preclinical stage. Using machine learning techniques, Uysal and Ozturk, successfully differentiated patients with cognitive impairment, patients with Alzheimer's disease, and normal subjects by hippocampal volume information (Uysal and Ozturk, Therefore, with the continuous development of multimodal MRI fusion analysis technology, brain structure\u2013function coupling will become a hot spot in the study of CSVD in the future.NW and CL wrote the main manuscript text. XZ, CS, and YG prepared the imaging data. LG and HW revised the main manuscript text. All authors reviewed the manuscript. All authors contributed to the article and approved the submitted version."}
{"text": "No man is an island, entire of itself;Every man is a piece of the continent, a part of the main\u2026\u2026!\u2014John Donne's (1572\u20131631) in Devotions upon Emergent Occasions.Those lines penned by John in 1624 succinctly captured the challenges and opportunities facing not only mental health (MH) professionals but also other health experts worldwide. Like other horrifying pandemics of the past, the COVID-19 was a wake-up call that reminded all health professionals to seriously think of humanity as \u201ca whole greater than the sum of its parts,\u201d borrowing from the wisdom and research work of Gestalt psychologists who followed his steps. As clinicians who tirelessly work to ease the suffering of people with mental and physical disorders, we are often plagued by the nagging question at the back of our minds/psyche, \u201cis this all I can do?\u201d given the interconnected and multisectoral web of challenging predisposing, precipitating, and perpetuating factors in terms of biopsychosocial, epigenetic, and spiritual spanning the entire macrocosm often beyond our reach, as also evident in World Health Organization report , \u201cHope. It is the quintessential human delusion, simultaneously the source of (y) our greatest strength, and greatest weakness.\u201d Born of this delusional\u2014like hope, this Research Topic on \u201cTian et al., on the effort-reward imbalance in ER physicians, the review on MH interventions at the workplace by Pandya et al. and the impact of welfare schemes and programs offering fringe benefits to urban and rural employees by Luo et al. span the multiple areas of occupational MH.The research by Hu J et al., in their study on MH literacy, sleep and depressive symptoms. A worldwide online survey of 65 countries on stigma of medical students toward psychiatric patients by Babicki et al., shows that more needs and efforts to be done and address this pernicious attitude.The MH of students and young adults is captured by Tang et al., and the MH of Trans women and its association with sexual myths by Uyar et al., explore issues in marginalized and minority populations.The MH of female domestic workers and their relation to social networks by Wu J et al., in their study of mindfulness exercise guided by a Smartphone application. Gatto et al., have presented positive results concerning an online brief emotional training program for emerging adults, and Kim et al., have developed an online-coaching blended couple-oriented intervention for adults. At the same time, the negative effects of technology on MH have been explored by Zhang et al., on smartphone addiction, sleep, academic stress, and depression.Technology-driven MH promotion is presented with positive results by Sun et al., investigated the factors influencing the attitudes of patients living in the community toward long-acting depot antipsychotics, while the risk factors of violent behavior in schizophrenic psychosis is presented by Huang et al., in a 2-year follow-up study. Interestingly, wisdom as a protective factor for psychotic-like experiences in the general population are reported by Wu Z et al. Sexuality in people with ultra-high risk such as late adolescents and early adulthood, genetic vulnerability and attenuated psychotic symptoms and first-episode psychosis is systematically reviewed by Ciocca et al..Promoting the adherence to treatment in chronic and severe mental disorders, Li W et al.; chronic low back pain and depression by Hu Y et al.; body image concerns in hemodialysis by Nia et al.; social support and quality of life in female systemic lupus erythromatosis sufferers by Gao et al.; the impact of maternal depression on neonatal outcomes by Li H et al.; psychological factors affecting treatment adherence in patients with tuberculosis by Pradhan et al.; and finally a review of the impact of MH on outcome in tuberculosis by Agbeko et al., are presented in this issue.In the area of liaison psychiatry, depression, type 2 diabetes mellitus, and coronary atherosclerotic heart disease by Chen et al., on the restorative effect of rooftop gardens in urban settings needs special mention. Similarly, Zhou et al., have demonstrated that childhood neighborhood cohesion has a significant impact on neurocognitive functions in later life. Also a protocol for assessing the feasibility of psychological or MH first aid training of front-line healthcare workers in the provision of MH care during emergencies is presented by Wang L et al..Novel studies including the research by Yang et al., in their study on the impact of volunteering services in older adults and Wang J et al., in their research paper related to social participation in community activities in middle age and elderly residents.The role of community services on positive MH is highlighted by Moro et al., and the review of telemental health use during COVID-19 pandemic by Abraham et al., find place in this Research Topic.Finally, the impact of the COVID-19 pandemic on the MH of healthcare workers in Italy during the reopening phase after lockdown by To summarize, we are sure this issue does justice to MH Promotion and Protection, as we coordinate our resources, influence policy makers, engage with the community, and strive to make this World a better place for our future generations. We tentatively suggest the next topic of greatest interest: \u201cTraumatic events in infants and adolescents and its psychiatric trajectories in future life.\u201dAll authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
{"text": "With a growing aging population around the world , frailtyThis Special Issue contains fourteen papers. Three studies were conducted in Japan. The study by Tsujishita et al.  aimed to\u201cHow to Make Primary Healthcare More Popular\u201d is the title of the study by Fu et al. . These rTasioudi et al.  identifiThis Special Issue also includes a systematic review and meta-analysis by To et al.  who aimeTwo papers describe studies conducted in the Netherlands. One of these studies examined the opinions of nurses on frailty  . The nurThe deterioration of cognitive and psychophysical ability associated with aging has an effect on road safety, especially in the driving of vehicles. Mirabet et al.  evaluateIn conclusion, this Special Issue offers a wide range of papers that all contribute to our knowledge about frailty in older people. This knowledge is much needed given the increasing global number of frail community-dwelling older people and helps ensure that their quality of life is not diminished."}
{"text": "Editorial on the Research TopicInsights in orthopedic surgery: 2021Zhou et al. all topics that constituted background noise at the turn of the 21st century. In this context, we thought it would be informative to open up a topic with an open editorial agenda; we asked our thinkers to provide us with a glimpse of orthopaedics today.When we opened up this topic in just past 2020, orthopaedic surgery was moving at a pace and in ways that we could not have predicted even a few decades ago. Certainly, the way we examine, evaluate and investigate our thoughts, behaviors and results continues to change year to year, even month to months. Some of our most spirated debates now incorporate psychosocial nuances of care, honest solutions around preventing opioid-induced deaths and\u2026artificial intelligence Wan et al. shoulder dysfunction from rotator cuff tears Zhou et al. and Jin et al. hip fractures and frailty of our older family members Yu et al. and our never ending dance with our microbial co-habitants Kankilic et al. But besides the new knowledge and skills gained over time, the way we analyze what we have done continues to make progress in ways difficult to predict. In addtion to the standard clinical study methodologies, systematic review and meta-analyses, our compendium now includes modalities such as the aforementioned artificial intelligence and modern ways of conceptualizing our research trends and attention through bibliometric analysis, be it for ankle fractures, patellar instability or rotator cuff disease Zeng et al., Zheng et al. and Jin et al.What we found was that some issues that have plagued our patients continue to do so although some of the ways we evaluate and treat them have changed dramatically over the years: back pain and symptoms from lumbar disc herniation As we progress through this decade and beyond, what will we see? AI assembled meta-analyses and registry reports? A dashboard that provides live bibliometric data on-demand? A decision aid phone app that is up-to-the-second current on the literature? Wiil the lines between \u201cresearch\u201d and data-driven patient care blur? What kind of \u201cknowledge\u201d will we be reporting on in 2050? Bone glue that supports weight-bearing, adaptive surgical implants that guide tissue healing, a cell-programming biologic that requires no surgery at all? I am excited to not only find out but to participate and contribute; and hope that you are too."}
{"text": "To critically appraise the literature to determine availability and identify the cultural responsiveness of infant resuscitation education for Aboriginal and Torres Strait Islander populations.Despite overall reductions in infant mortality in the last two decades, Aboriginal people have some of the highest rates of infant mortality of any developed nation. One of the key factors that has attributed to improvements in infant mortality rates is parent and carer education around risk factors and actions of first responders. Identifying gaps in the current basic first-aid initiatives available to Aboriginal communities may contribute to developing resources to contribute to reductions in Aboriginal neonatal mortality rates.The review used key terms and Boolean operators across an 11-month time frame searching for research articles utilising the databases of CINAHL, Scopus, Ovid Emcare, Informit, Pubmed and Proquest. After review, 39 articles met the inclusion criteria, 25 articles were discarded due to irrelevant material and 14 articles were included in the structured literature review. The search process was developed using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Articles were assessed for validity and inclusion using the Critical Appraisal Skills Program checklist.Research literature relating to First Nation community-based CPR and first-aid education programmes in Canada, USA, India, UK and Europe, Asia and Africa were identified; however, none pertaining specifically to CPR and first-aid education in Australian Aboriginal communities were found.Despite the lack of research evidence relating to infant cardiopulmonary resuscitation (CPR) education for Australian Aboriginal populations, the reviewed studies noted the importance of culturally responsive education designed in collaboration with First Nation peoples, using novel ways of teaching CPR, that align with the language, culture and needs of the communities it is intended for.Further research is required to create a framework for the delivery of culturally responsive infant resuscitation education for Australian Aboriginal parents and communities. The importance of providing culturally responsive education to Aboriginal communities, which are co-designed and community-specific.Review of novel ways for infant resuscitation education for parents.What does this paper add to the wider global clinical community?Note: for conciseness the term Aboriginal will be used to refer to both Aboriginal and Torres Strait Islander peoples with no disrespect intended.et al., et al., Aboriginal and Torres Strait Islander people have some of the highest rates of infant death in Australia, including sudden unexpected death in infancy (SUDI) and sudden infant death syndrome (SIDS). In 2018, data from the Australian Mothers and Babies Report  guidelines, the review was conducted between the end of November 2020 and the end of September 2021 utilising the databases CINAHL, Scopus, Ovid Emcare, Informit, Pubmed and Proquest. The search strategy involved the use of the following Boolean operators \u2018Resus* OR CPR * OR Cardiopulmonary Resuscitation* OR Infant resus* OR first aid OR basic life support\u2019 AND \u2018Infant* OR baby OR Neonate* OR Newborn\u2019 AND \u2018education OR training OR cultural programs\u2019 AND \u2018Aboriginal parents OR Aboriginal mothers OR Indigenous Parents OR Indigenous Mothers OR Aboriginal carers or Indigenous carers OR Aboriginal communities OR Indigenous communities\u2019. Boolean operators were used to make the search more precise whilst still remaining broad enough to capture the required data.A total of 550 articles were initially found using the search strategy criteria, and 18 others were found from additional sources during sequel searches. After an initial review and the removal of duplicates, a total of 160 articles remained. These first pool articles were reviewed, and a further 121 articles were further excluded for not meeting criteria  checklists. Specific CASP study design checklists were used for the differing study designs, and the results against the appraisal criterion are presented in Table\u00a0A total of 14 studies were included in the review. Several study types were noted which included one retrospective case study (7%), one retrospective observational analysis (10%), five surveys/questionnaires 35%), two prospective cohort studies (15%) and three community-based participatory research methods (22%), one randomised trial (7%) and one focus group (7%). The studies were conducted in Australia (7%), Ireland (14%), Singapore (7%), America (36%), Canada (22%), Sweden (7%) and South Sudan (7%). Outcomes ranged from the diagnosis and need for high-dependency transport (7%) to knowledge and attitudes to learning infant CPR (36%), teaching high-risk populations first aid (14%), rural medical issues (21%) and native language training (21%). In those studies that utilised an infant CPR education kit, outcomes ranged from knowledge levels pre- and post-kit use and satisfaction with the kit (50%) to confidence in skills and ability to perform resuscitation skills (17%). Of the four studies that reviewed infant CPR education kits, 75% used the CPR Anytime\u2122 training Kit and 25% used the pillow CPR kit and e-learning programme. Further information, including aims and limitations of the studies, are included in Table\u00a05%, two pet al., et al., A retrospective study conducted in Australia reviewing the need for aeromedical high-dependency transport described the cohort of 789 cases as being predominantly Aboriginal . The most common causes of transport were respiratory, with bronchiolitis and pneumonia at 31%, and the mean age range for transportation with bronchiolitis was 0.7 years (0.1\u20136.8) . The researchers noted that the majority of transport cases were newborns, which included preterm infants occurring in higher rates amongst the Aboriginal population. The increased risks and needs for high-dependency intervention amongst Aboriginal infants suggest a need for education for Aboriginal caregivers surrounding infant CPR. Another study was conducted in the USA  also looked at the specific challenges faced by First Nation peoples living a traditional life in the remote wilderness. Using a community-based participatory research approach, 20 Sachigo Lake First Nation people were involved in the SLWEREI training course mentioned previously. The irrelevance of generic first-aid courses in remote settings which focus on patient stabalisation while awaiting almost immediate assistance and transporation were highlighted. The findings identified the need for relevant remote medical emergency training to increase the community\u2019s confidence to provide care that could lead to improved outcomes for remote populations. Similar issues were identified in a study conducted with 10 Nishnawbe Aski Nation health leaders and 33 other stakeholders, to review their emergency response systems  explored the management of medical emeregencies in remote First Nation communities. The findings identified that remote communities often lacked an established coordinated response system, and that there was a need to create education that was culturally specific and sustainable for the individual community and the region it was to be used in  in the USA. One study conducted by Yip et al.  in Seatt et al., . The stuTo determine parent\u2019s knowledge, attitudes and perceptions of infant basic life support, Chia and Lian  recruiteet al.  enrolled 311 participants including 238 parents of premature infants and 73 parents of infants with congenital heart disease and aimed to assess the usefulness and parent comfort associated with the infant CPR Anytime\u2122 kit. This is a particularly high-risk group of infants more likely to need infant CPR. It was noted that 75% of participants had received prior CPR education before receiving the kit (Pierick et al., et al., et al., et al., Pierick et al.  enrolledet al.  enrolledet al.  enrolledet al.  enrolledet al., et al., et al., et al., Knight, Wintch, Nichols, Arnolde and Schroeder provided the infant CPR Anytime\u2122 kit to 117 parents of high-risk infants prior to discharge from the hospital, who were then contacted at one, three and six months to assess retention of knowledge and skills and comfort with using the kit (Knight Barry  enrolledet al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., The main purpose of this structured review was to critically appraise the literature to determine availability and identify the cultural responsiveness of infant resuscitation education for Australian Aboriginal populations. Despite an extensive literature search, only one non-research focused case study was found addressing a community-based first-aid programme in an Australian Aboriginal community (Anderson, et al., et al., et al., et al., et al., et al., et al., et al., et al., Many of the reported OHCAs that occurred in homes involved infants, and bystander CPR has been shown to increase the odds of survival two to three times, supporting the idea that teaching parents CPR could save lives (Knight Providing infant CPR education to parents will likely lead to the development of appropriate skills, improved confidence and decreased levels of anxiety to act as first responders. Bystander CPR is a critical step to ensure survival with good neurological outcomes, and there can be a delay in commencing CPR if bystanders need to be instructed by dispatchers. The use of self-instructional infant CPR kits provide education at a time that is beneficial to parents. The paucity in the literature regarding Aboriginal parents\u2019 perceptions of infant CPR and the lack of availability of culturally specific infant CPR training programmes in Australia supports the need for collaborative and consultative research into these areas. Utilising these methods and engaging and collaborating with Australian Aboriginal communities to develop a framework for infant resuscitation education that is culturally responsive to Aboriginal parents\u2019 needs and adaptable to a variety of settings could save lives and provide parents, carers and communities with important skills. Evaluation should also be conducted on the provision of such culturally sensitive infant CPR education to determine its effectiveness and if such education impacts on infant mortality and morbidity rates, particularly in remote communities."}
{"text": "Journal of Medical Internet Research titled, \u201cAddiction Symptom Network of Young Internet Users: Network Analysis\u201d by Lu et al [We read with great interest the article published in the Lu et al . With thLu et al  used theThe study stated that participants were recruited from 2 universities in Jiangsu, China, via advertisement. We do not know the exact environment of the 2 universities that the participants were recruited from. Environmental factors are known to play a great role in the development of IA . It may The authors should clarify the process and describe the implications of using advertisements as the method of recruitment. Participants in studies are often motivated by different factors, which could result in biases . It shouIn conclusion, we believe addressing the above points can help clarify the interpretation of the results. Lu et al  touch up"}
{"text": "The ocular surface is a unique sensory ecosystem consisting of the cornea, conjunctiva, and adnexal elements, which are coated by a thin layer of the pre-ocular tear film . There iSingh et al.; Ramos et al.; Chen et al.; Li et al.). Recent developments in regenerative medicine have opened the door to the use of novel therapeutics with encouraging outcomes. This includes ocular surface regeneration using limbal tissues, cultured cells, and biomaterials. The approach of stem cell-based therapy has been spectacularly successful in the management of blinding chronic sequelae of chemical injuries . Once c et al.; . Besides et al.; .Now the horizon for application of cell therapy is being expanded to corneal opacification due to scarring using mesenchymal stem cells . This isChen et al.; (Singh et al.; (There is also great interest in regenerative approaches for the lacrimal and meibomian glands, that are important adnexal elements and critical to the health of the ocular surface . Damage et al.; . Three m et al.; . These g et al.; ].The ocular surface is exceptional in terms of the range of research that is being done for developing regenerative approaches for each individual element be it the cornea, the conjunctiva, or the lacrimal glands. These developments are exciting and could pave the way for disruptive new therapies in the future. Once of the challenges would be to achieve the right balance between efficacy, safety, and affordability. As researchers we must not lose sight of those who are most desperately in need of these new therapies. Therefore, an equal emphasis must be placed on developing low-cost products that are easy to deliver . DespiteThe author confirms being the sole contributor of this work and has approved it for publication."}
{"text": "Editorial on the Research TopicAnticoagulation in cardiovascular diseases: evolving role, unmet needs and grey areasThrombosis is a key pathophysiological mechanism for many serious cardiovascular diseases, including deep vein thrombosis (DVT), pulmonary embolism (PE), acute coronary syndrome (ACS), and ischemic stroke.Thrombi consist of aggregated platelets, fibrin, and trapped cells, with the distribution of these components differing substantially between arterial and venous thrombi . The maiFor several decades, vitamin K antagonists (VKAs) have been the treatment of choice for long-term oral anticoagulation. Unfortunately, VKAs have many disadvantages that limit their use in the real world. Almost all the limitations of VKAs have been overcome by DOACs, which are at least as effective as VKAs in preventing thrombotic events in patients with non-valvular atrial fibrillation (NVAF) and venous thromboembolism (VTE), with the advantage of being safer in terms of bleeding risk  and easier to use . This haHard to believe until a while ago, DOACs\u2014which have been called \u201cnovel anticoagulants\u201d for many years\u2014might become \u201colder\u201d very soon. This is because strategies that target coagulation factors XI and XII (FXI and FXII) might soon hit the market. These newer medications promise to have the ability to limit thrombosis growth with an impact on hemostasis that is lower than that of DOACs . Very rePastori et al. on the use of DOACs in patients with antiphospholipid syndrome (APS). This is indeed a delicate issue, with controversial recommendations among the different international guidelines. For instance, the European Society of Cardiology (ESC) recommends against the use of DOACs in APS patients. However, the authors correctly argue that these recommendations do not make any distinction between single-, double-, and triple-positive APS patients, between patients who only had venous thrombotic events and those who had arterial events, nor between different DOACs. This is despite the fact that these recommendations are exclusively based on the results of the Trial on Rivaroxaban in AntiPhospholipid Syndrome (TRAPS)  , which h (TRAPS) \u201315. AccoFu et al., which compared the relative risk of embolism and major bleeding between apixaban and warfarin in patients with NVAF and compromised kidney function, was also highly viewed. The use of DOACs in subjects with severe chronic kidney disease (CKD), i.e., hemodialysis patients, was the focus of a meta-analysis by Elfar et al. This contribution is of interest because hemodialysis patients have been excluded from clinical trials on DOACs, and therefore, the evidence of their efficacy and safety is weak in this cohort.The research paper by Parsi et al., Liu et al., Zeng et al., Gao et al. These articles are important because they reflect the need for physicians to better understand how to treat frail older adults in real life.Many contributions to our Research Topic consisted of articles on anticoagulation in frail subjects, including those with cancer, dementia, and increased risk of falling Gotts\u00e4ter, which focused on the rationale for recommendations on dual antiplatelet and anticoagulant treatment in subjects with peripheral artery disease (PAD), the original cross-sectional study by Suo et al. on the evolution of antithrombotic treatments for patients with AF and coronary syndromes in China, and the mini-review by Hardy et al. on the possible importance of DOAC level for an uninterrupted DOAC approach for catheter ablation in AF.Other contributions that merit mention are the review by Wu et al. on the association between the use of anticoagulants and bone fractures, Mirijello et al. on pulmonary artery stump thrombosis, Prouse et al. on the possibility of using the SOFA Score to identify subjects at high risk for VTE among those affected by SARS-CoV-2, Li et al. on a nomogram to predict left atrial thrombus in patients with AF, Liu et al. on the reappraisal of DOACs in AF patients, Lin et al. on the differences in the presentation of arterial thrombotic events between patients with a history of VTE or AF, Liu et al. on intraocular bleeding in patients with AF treated with different anticoagulants, Meihandoest et al. on a heparin-calibrated anti-Xa assay, Liu et al. on the evidence available on DOACs vs. VKA in Latin American patients with AF, Liu et al. on the risk of diabetes in patients with AF treated with DOACs compared to VKA, Cao et al. on anticoagulation in AF patients who have bioprosthetic heart valves, Li ei al. on the clinical characteristics and prognosis of patients with left ventricular thrombus in China, and Gao et al. on the use of sodium alginate hydrogel coatings on extracorporeal membrane oxygenation for anticoagulation.In this Research Topic, there were also contributions on anticoagulation during cardiac surgery. Other contributions were from"}
{"text": "A number of previous reviews of the literature have shown the prevalence of mental disorders in prisons is considerably higher than in the general population \u20133. This In regard to the treatment of prisoners with mental disorders, a policy document from the WHO \u201cGood governance for prison health in the twenty first century\u201d  recommenWhere studies have been undertaken they have indicated the needs for treatment of prisoners for mental health disorders have often not been identified and treatment needs have not been met , 11. FewSimpson et al. conducted a systematic review of publications investigating mental health services in the correctional framework. In regard to those passing through the correctional system, they found no evidence for standardized assessment approaches, some evidence to support specific psychosocial interventions and relatively weak evidence to support reintegration methods back into the community.Yesuf et al. looked at the prevalence of mental illness among inmates in north-western Ethiopia. They found around 75% of inmates had some form of mental disorder with symptoms including feeling unhappy and finding it difficult to play an important role in life. However, those that took part in rehabilitation activities had an improved outcome. The authors concluded that this was an area for further research and development that could lead to better outcomes for those with symptoms of mental disorder.Other contributors to our topic have added to what is known. Linked to the theme of the effectiveness of interventions for those passing through the criminal justice system, Stawinska-Witoszynska et al. found a high level of generalized anxiety disorders (GAD) in the population of inmates detained in one of the largest penitentiary units in north-eastern Poland. They found a three times higher prevalence of GAD among inmates detained in a closed type prison compared with those in an open prison. They made the case for increased availability of psychological therapies for prisoners.McIntosh et al. conducted a mental health needs assessment for Scotland's prison population. They concluded that existing provision to support the mental health needs of people in prison in Scotland was inadequate. This was partly due to a lack of integrated care between the justice, health and social work systems resulting in prisoners not receiving the support they needed both during and following imprisonment.Another theme of this topic is whether care is sufficiently integrated between the criminal justice system and community based services. Sekiguchi et al. looked at treatment options for persistent methamphetamine associated psychosis and how this should be distinguished from schizophrenia spectrum disorder. They found benefits from using a lower dose antipsychotic to treat methamphetamine associated psychosis. Naidoo et al. in a study based on a women's correctional center in South Africa emphasized the need to educate, support and manage those infected with HIV which has a high prevalence in South Africa. In Canadian based studies, Moghimi, Knyahnytska, Zhu et al. explored the mental health needs of correctional workers and found, Moghimi, Knyahnytska, Omrani et al. digital mental health care interventions could help meet these needs. Shafti, Steeg et al. and Shafti, Taylor et al. explored the relationship between aggressive behaviors and self-harm and implications for managing such behavior in correctional settings.In line with another topic theme some research has been undertaken on treatment options for different mental health conditions seen in prisons in various countries. Skipworth et al. a study in New Zealand indicated that there has been an increasingly poor outcome in terms of imprisonment following discharge from a mental health unit over a ten-year period and concluded that models of community based mental health care may be increasingly reliant on the criminal justice system to manage aggressive and dangerous behavior among those with mental illness. There have been reports of similar trends in other countries including the UK.In terms of other themes of this Research Topic such as whether an individual's needs for treatment and care are successfully handed over to community-based services and the impact of the quality of care on the likelihood of recidivism more research is needed. As noted by NM: Writing\u2014original draft. AF: Writing\u2014review and editing."}
{"text": "Karystianis et al.; Popovic et al.; Yu et al.) and a systematic review .Machine learning (ML) as a modern form of statistical analysis is becoming more and more common in psychiatric research. The possibilities of ML to analyze complex relationships and potentially build predictive models seem particularly appealing regarding multifactorial yet poorly understood phenomena like violence and offending. This Research Topic aimed to gather evidence in this area to further promote the application of ML in forensic psychiatry. The contributing works comprise three original articles , data analysis, and creation of predictive models to anticipate events relevant to forensic psychiatry. With ML becoming more widespread, an increase in studies with similar methodology can be well-expected. However, it is essential to ensure that the application and evaluation of the calculated models would be done on different patient populations\u2014ideally international ones. Only then, generally valid predictors can be identified, and a robust generalizable model can be built and applied in clinical practice.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
{"text": "Michael James is remembered. Michael James12, and the first protein structures having recently been determined in Cambridge. Michael\u2019s thesis project was to determine structures of antibiotic peptides. While there, he was exposed to protein crystallography through the work going on at the same time to determine the 3D structure of insulin.Michael James was born in Vancouver and grew up in Winnipeg, Manitoba on the Canadian prairies. After high school, he studied chemistry at the local University of Manitoba, where he was excited to learn that it was possible to see the 3D structures of molecules using X-ray crystallography. Aiming to get the best possible background for a future working in this area, he applied to do a DPhil at Oxford with Dorothy Hodgkin in 1963. It was a time of great advances in crystallography, with Dorothy about to win the Nobel Prize for her ground-breaking structures of penicillin and vitamin BStreptomyces griseus protease B, a serine protease) in 1974 (Delbaere et al., 1975After completing his DPhil in 1966, Michael took a postdoctoral position determining small-molecule structures in the Department of Chemistry at the University of Alberta in Edmonton, Canada. He remained at the University of Alberta for the rest of his life. However, his career took a quick turn when he learned that the Biochemistry Department was seeking to set up a protein crystallography laboratory. With his move to Biochemistry he became the first protein crystallographer in Canada, determining the first 3D protein structure (that of et al., 1979In his research, Michael brought the same expectations of high precision to proteins that he had learned in small-molecule crystallography, and his group became known for the quality of the structures it produced, becoming early adopters of least-squares refinement (Sielecki et al., 1979et al., 1982et al., 1977et al., 1989Initially, Michael concentrated his group\u2019s efforts on understanding the structure and function of proteases, an area that remained important to him through the rest of his career. The group worked on a variety of serine proteases and their complexes with both small molecules (Brayer et al., 1994et al., 1997et al., 1999Eventually, the James laboratory turned its interest to the proteolytic enzymes from picornaviruses. Members of the laboratory determined the structures of the 3C proteinases from hepatitis A virus (Allaire et al., 2004Prior to 2004, five families of proteolytic enzymes were known. A sixth family, the glutamic peptidases, was discovered in a collaboration between the James laboratory and Professor Kohei Oda of Kyoto, Japan (Fujinaga et al., 1994et al., 1996et al., 2003et al., 2006et al., 2013Branching out into other areas, Michael\u2019s group carried out structural studies of a variety of biochemically and medically important proteins. The structure of troponin-C (Herzberg & James, 1985et al., 2003In collaboration with the Canadian company ViroChem Pharma, members of the James laboratory determined the structures of allosteric inhibitors of NS5B, the RNA-dependent RNA polymerase from hepatitis C virus (Wang et al., 2022His last published paper, on a protease from a virus that causes porcine epidemic diarrhoea, was special in having his daughter Michelle as a coauthor (Shamsi Michael received many honours during his long and distinguished career. He was elected as a Fellow of the Royal Society of Canada in 1985 and as a Fellow of the Royal Society of London in 1989. He was presented the Martin Buerger Award of the American Crystallographic Association in 2009. In 2010, he received an honorary doctorate of science from his undergraduate alma mater, the University of Manitoba. In June of 2023, the month before he died, he was appointed an Officer of the Order of Canada, one of Canada\u2019s highest honours.In his approach to science, Michael\u2019s passion was always to move closer to the truth. As a consequence, he took as much pleasure in the scientific advances of others in the MRC Group and the Department of Biochemistry as he did in his own group\u2019s breakthroughs. He wanted to contribute and to understand, but was always unassuming; he could laugh at himself and never dominated or inflated his ego at the expense of others. Beloved by members of his laboratory, Michael was an inspirational friend and mentor to his students, postdoctoral associates and colleagues, and a joyous companion to those lucky enough to know him.Michael James died on the 24 July 2023 after a short admission to the University of Alberta Hospital. He is survived by his three children, Daphne and Marcus from his first marriage to Pat, and Michelle from his third marriage to Deborah."}
{"text": "Mixed-species groups of birds, fishes and mammals have traditionally been described in taxa-specific journals. However, mixed-species systems are actually more widely found when one includes aggregative (non-moving) systems, such as those common in amphibians and invertebrates. The objective of this special issue is to dispel the idea that mixed-species phenomena are a \u2018niche topic\u2019 to ecology and instead explore how taking a mixed-species perspective can change our conception of important ecological patterns and processes. A mixed-species perspective starts by understanding the relative abundance and positioning of individuals of different species and their behavioural synchrony; it is enriched by understanding differences between species in their vulnerability/attractiveness to predators, their potential for competing with other group participants and their use as a source of public information. Contributions to the special issue show how the mixed-species perspective can change our ideas about invasion ecology, island biogeography, keystone species, mimicry, predator eavesdropping and more. Rather than seeking synthesis, the special issue celebrates the taxonomic and conceptual breadth of the field of mixed-species groups, with detailed descriptions of many distinctive systems.This article is part of the theme issue \u2018Mixed-species groups and aggregations: shaping ecological and behavioural patterns and processes\u2019. These groups and aggregations include flocks of birds that can reach up to 60 species and 100 individuals , and groMixed-species group phenomena have historically been described separately within taxonomic boundaries, with little cross-talk between these streams of research. Reports about moving groups have traditionally been in three clusters: birds , social Philosophical Transactions of the Royal Society, B, entitled \u2018Collective behaviour through time\u2019 (edited by Christos Ioannou and Kate Laskowski) will also cover some exciting mixed-species systems.Our special issue is representative of the historical development of the field, as we include a large range of bird flock studies , two mammal studies, one fish study and two papers that aim to be applicable to multiple taxa. We also include aggregation systems: one each for amphibians, birds, insects, and a system of fishes and pelagic mammals. In bringing the studies on aggregations into the fold with moving systems, our hope is to show that a range of \u2018mixed-species\u2019 questions\u2014shown perhaps best in the bird literature\u2014can be applied to a much wider range of other taxa. Indeed, some of the issues of how groups of species in close proximity interact might be relevant to the burgeoning research field focused on plant communication and behaviour ,20. We w (i)how many and which species are present in a group, how do they differ in their relative abundance, and how stable are these characteristics over time and space? (ii)what is the spatial organization of individuals in these groups? How far are individuals typically apart from each other? Is the spacing between individuals different for conspecifics and heterospecifics? (iii)if the whole system moves together, which species lead and which species follow? Is this consistent across different contexts and different group compositions? If the whole system is stationary, which species initiate aggregation at a location and which arrive subsequently? (iv)how synchronous or asynchronous is individual behaviour, for both conspecifics and heterospecifics? This could include movements, foraging activities or communicative signals; (v)how does information flow through the group? Is it unidirectional or multidirectional? Is it mutualistic or does it typically include aspects of eavesdropping/parasitism? (vi)how does predation influence these groups? Does predation pressure increase group formation? Do group participants share the same level of vulnerability to the same predators or does this vary across species? Are some species in these groups preferred by predators and therefore each species benefits differently in both degree and type of benefits they receive in the group? (vii)how does competition influence group structure (composition and organization) and how does this relate to an individual's proximity to resources? How do dominance hierarchies influence group structure? (viii)how does a specific species composition affect a group's functioning, and how can we effectively experimentally remove or add individuals of different species or simulate their absence/presence to investigate this question? (ix)how does the environment (e.g. gradients and habitat structure) affect, or even dictate, local group structure? (x)how does the grouping phenomenon itself affect the composition of the whole community, as well as how that community uses resources? and (xi)how does the grouping phenomenon affect the participants' responses to human disturbance and how can this information be used to improve conservation approaches?What then are the common themes across all this diversity? First, we are talking about groups of animals (and possibly microorganisms) in mobile life stages that are of the same trophic level. Basic \u2018mixed-species\u2019 questions that can be asked of these groups include:With the inclusion of aggregations, it is clear that mixed-species phenomena are ubiquitous. Further, the breadth of these kinds of questions, from those that focus on the behaviour of individuals, to those that probe questions of community assembly, suggest that mixed-species issues are not a niche, but rather a core topic of ecological study. Below we argue further that thinking about the differences among participants in mixed-species groups can fundamentally alter the way we think about ecological patterns and processes.. 2et al. [et al. [et al. [et al. [et al. [In the last section of Goodale et al.  the authet al.  review t [et al.  examine  [et al.  explore  [et al.  revisit  [et al.  study pret al. [et al. [et al. [et al. [et al. [et al. [The second section is behavioural in focus, with the unifying concept being the comparison between intraspecific and interspecific sociality. We start with several papers that chronicle in depth the proximity of species to each other and their behavioural synchrony in a fascinating set of different contexts: captive South American monkeys by Daoudi-Simison et al. , groups et al. , and pel [et al. . This se [et al.  provide  [et al.  describe [et al.  use a la [et al.  use a miet al. [et al. [et al. [et al. [The third section asks what effects mixed-species systems have at the community level. Here the unifying concept is exploring how behavioural interactions between species influence species distributions and community composition across abiotic or biotic gradients. Charabidze & Aubernon  chroniclet al.  examine  [et al.  review t [et al.  examine  [et al.  investig [et al.  use an i [et al.  describe. 3One final storyline for this special issue is also social in nature, but focused on human sociality, for this special issue developed out of an online symposium in June 2021. For Kathryn Sieving and Eben Goodale, this was the third such mixed-species group symposium in a decade, after a 2011 meeting sponsored by the Field Ornithology Group of Sri Lanka, and one in 2015 at Ecosummit in Montpellier, France, that was the first to attempt to mix researchers who work on different animal taxa. The topic of bird sociality and interspecific information flow has also been the focus of symposia before . Anne passed away unexpectedly towards the end of the preparation of this special issue. She was an active member of our team, handling five of these manuscripts, and we are deeply grateful for her contribution, as well as saddened by losing her. Her passion for mixed-species systems and her beloved fish shoals shines forth in these pages."}
{"text": "R2 value (0.9680) and small root mean square error (RMSE) value (2.6409) compared to APCS-MLR model. Meanwhile from the sensitivity analysis, fertilizer waste acts as the dominant pollutant contributor (59.82%) to the basin studied followed by anthropogenic input (22.48%), surface runoff (13.42%), erosion (2.33%) and lastly chemical and mineral changes (1.95%). Thus, this study concluded that receptor modeling of APCS-ANN can be used to solve various constraints in environmental problem that exist between water distribution variables toward appropriate water quality management.Recent techniques in the management of surface river water have been expanding the demand on the method that can provide more representative of multivariate data set. A proper technique of the architecture of artificial neural network (ANN) model and multiple linear regression (MLR) provides an advance tool for surface water modeling and forecasting. The development of receptor model was applied in order to determine the major sources of pollutants at Kuantan River Basin, Malaysia. Thirteen water quality parameters were used in principal component analysis (PCA) and new variables of fertilizer waste, surface runoff, anthropogenic input, chemical and mineral changes and erosion are successfully developed for modeling purposes. Two models were compared in terms of efficiency and goodness-of-fit for water quality index (WQI) prediction. The results show that APCS-ANN model gives better performance with high  In addition, surface waters are most susceptible due to easy accessibility for wastewater  and antet al.,); sewageet al.,) and urbMonitoring programs often worked out with frequent water samplings at many sampling sites all over the world and determination of physiochemical parameters can provide a representative and dependable estimation of the surface water quality. In Malaysia, Department of Environment (DOE) has been conducting unstoppable monitoring activities since 1978 resulting to large data matrix collection and desperately requires remarkable statistical tools such as multivariate and artificial intelligent for exceptional data illustration.in-situ measurements of the river water quality. According to the DOE\u2019s Environmental Quality Report in 2007, 158 river basins are involved in this program to monitor river quality changes on a continuous basis . Even tWater quality is referring to the characteristics of water whether in its physical, chemical or biological character. Based on the water quality data, the water quality index (WQI) was developed to evaluate the water quality status and river classification in Malaysia. WQI provides a useful way to predict changes and trends in the water quality by considering multiple parameters. WQI is formed by six selected water quality variables, namely dissolved oxygen (DO), BOD, chemical oxygen demand (COD), SS, AN and pH . WQI vaet al., [et al., [et al., [Continuous monitoring of river water quality reveals the chemical and physico-chemical parameters for the interpretation of large data set with many variables; therefore environmetric approach need to be constructed to comprehend the variation on the data since it is not entirely convincing. In this study, the large data matrix obtained from monitoring programme conducted by DOE, Malaysia from year 2003 to 2007 was introduced to receptor models techniques that involved varimax factor from principal components analysis (PCA) with two different data based on multiple linear regression (MLR) and artificial neural network (ANN) models. These approaches were conducted in many fields such as prediction of ozone concentrations , foreca[et al., ), predic[et al., ), predic[et al., ) howeveret al., [Source apportionment techniques were applied in the data set by combining PCA with MLR and PCA with ANN. The aim of this study is to discover the major pollution sources that significantly change the WQI values in Kuantan River Basin from the varimax factors produced for MLR and ANN models. The uncorrelated new variables that account much of the original data will be used as input variables for the models; other than combining statistical and an artificial intelligent techniques which has been received great spotlight in environmental pattern recognition study . Moreovet al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., [Generally, MLR may lead to incorrect identification of most the predictor due to collinearity between the input variables . Many s[et al., ; Chaloul[et al., ; Bandyop[et al., ; Sousa e[et al., ; Jahandi[et al., ; Gutierr[et al., ; Rossel [et al., ; Wu et a[et al., ). ANNs a[et al., ) and hav[et al., . MLR als[et al., ). Althou[et al., ).The objectives of this study are to predict WQI values as well as to estimate the main contributor using MLR and ANN model from the varimax factors generated by PCA. This study will provide comprehensive understanding on goodness and weakness for both models and consequently finalised the correct model for WQI prediction in the Kuantan River Basin.2 catchment area which started from forest reserved area in Mukim Ulu Kuantan through agricultural areas, Kuantan town  towards the South China Sea. Kuantan River Basin consists of several important tributaries and these rivers drain the major rural, agricultural, urban and industrial areas of Kuantan District and discharge into South China Sea.Kuantan River Basin is in the district of Kuantan at the north eastern end of Pahang State in Peninsular Malaysia Figure . It is oKuantan River basin which is in Kuantan District area has six administrative mukims . In terms of land use, the main types of land use in this district are forest and agriculture that cover approximately 56% and 32% respectively, from the whole area of Kuantan District. Majority of the forested areas are at the west of Kuantan District or in upstream of the basin. Besides that, there is an ex-tin mining land in Sungai Lembing or at upstream or low sub basin area. The mining activities was started in 1906 and stopped in 1986 due to economic recession in our country.In term of land use utilisation, agriculture is considered to be one of the main economic activities in this river basin where it covers about 70,128 hectares of the area . Accordet al., [There are three palm oil mills which are the major agro-based industries in the middle of the basin and might be contributed to deterioration of Kuantan river water quality . Recentet al., ). Since et al., ).3), chloride (Cl-), phosphate (PO4-), Escherichia coli (E. coli) and coliform. According to DOE [The water quality data were collected in 2003 to 2007 from eleven monitoring stations provided by DOE. However, some of the stations are inconsistently sampling thus leading to the missing data. Thirty water quality parameters are selected by DOE in order to represent the water quality in the river. Unfortunately only 13 parameters are consistently sampled along 2003 to 2007 therefore a total of 275 observations were used for source apportionment and modeling techniques. The thirteen water quality parameters are selected for analysis in this study are: pH, dissolve oxygen (DO), biological oxygen demand (BOD), chemical oxygen demand (COD), suspended solid (SS), ammoniacal nitrogen (AN), dissolved solids (DS), total solids (TS), nitrate .et al., [et al., [et al., [et al., [The data were initially arranged according to the stations and year of monitoring. Variables that are not have been detected (below detection limit) were set to half of its detection limit in order to ensure that there is no missing data in the dataset. Normality test were performed using the Anderson-Darling test since the multivariate statistical techniques requires the variables to be normally distributed . Data t[et al., ). Log sc[et al., ). Statis[et al., ).et al., [et al., [et al., [et al., [et al., [The most powerful technique for pattern recognition that attempts to explain the variance of a large set of inter-correlated variables and transforming it into smaller set of independent (uncorrelated) variables . PCA aims to uncover a more underlying set of factors that accounts for the major pattern across all the original variables . Moreov[et al., ). This t[et al., ; Helena [et al., ; Wunderl[et al., ). PCA is[et al., ). Hence,z is the component loading, y is the component score, x is the measured value of a variable, a is the component number, b is the sample number, and m is the total number of variables. PCA was performed on correlation matrix of rearranged data which explains the structure of the underlying dataset. The correlation coefficient matrix measures the variance of each constituent explained by relationship with each others. PCA of the normalized variables were then performed to extract the significant PCs and reduce the variables with minor significance. These PCs were subjected to varimax rotation (raw) generating VFs as it sometimes not readily interpreted thus performing varimax rotation is recommended to reduce the dimensionality of the data and identify most significant new variables. Varimax factor (VF) coefficient having a correlation >0.75 are regarded as strong significant factor loading . Meanwhet al., [et al., [Receptor modeling application based on APCS-MLR is a commonly apply statistical technique for source apportionment of environmental contaminants in air pollution studies . It hasZbc is the normalized concentration of contaminant (variable), Qab refers to the factor loadings, the coefficient matrix of the components relates with pollution sources and their elemental concentrations; and Rbc the factors cores in Eq. (2). Qab is dimensionless. Since, Zbc in Eq. (2) is normalized value of variables, it cannot be used directly for computation of quantitative source contributions, the normalized factor scores determined in Eq. (2) were converted to unnormalized APCS following the method reported elsewhere . The coMbc is the contaminant\u2019s concentration; da0 is the average contribution of the bth contaminant from sources not determined by PCA/FA, Dab is the linear regression coefficient for the ath contaminant and the bth factor, and (APCS)bc the absolute factor score for the bth factor with the cth measurement. The values for Mbc, da0 and Dab have the dimensions of the original concentration measurements. After determining the number and identity of possible sources influencing the river water quality by PCA/FA, source contributions were computed through APCS-MLR technique. Quantitative contributions from each source for individual parameter or contaminant were compared with their measured values.Where et al., [Several studies on water quality model have been developed in order to manage and protect the water quality in many countries. Most of the models demand many inputs for model development and eventually lead to time consuming and high priced. ANN models are defined by topology, node characteristics and training or learning rules. It is an inter-related set of weights that composed of the knowledge generated by the model. An ANN contains large number of simple processing units, each interconnecting with others via excitatory or inhibitory connections. The most unique features of ANN model is the non-linear modeling capability, ability dealing with large sets amount of data and robustness to noisy data . The di3, Cl-, PO4, E. coli and coliform).(i) An input layer which is connecting the input information to the network. In this assessment thirteen input nodes representing the thirteen water quality parameters were applied  Hidden layer which is acting as the intermediate computational layer. Multi-layer feed forward network formed by only one hidden layer. ANN models consist of the following set of equations: P represents the scaled input vector and M is output vector of the neurons contain in the hidden layer. The bias is set equal to 1.(iii) Output layer is producing the desired output which is in this case the WQI following this equation: Pab and Pbc in the summation, which are usually referred as the weights, are the fitting coefficients of the neural model.The coefficients Many studies already emphasized the use of linear regression in apportionment of sources toward the dependable variables in their studies. Nonetheless, ANN application was yet to be explored. The aim of this method is to minimize the effect of multicollinearity and achieve better prediction model with minimum residual errors. The small number of input variables from APCS was combined with the ANN model to obtain high interpretability as the irrelevant and superfluous variables were excluded Figure .The PCA showed that the two main PCs accounted for 45.13% of the total variance  for the overall observations. The larger variability graph for factor loading 1 and factor loading 2 were plotted to explain the variance. The 13 variables were well represented on the plane.et al., [The five VFs were generated after varimax rotation based on eigenvalues >1 , Figur. Eigenvaet al., ). PCA afet al., [PCA aims to exclude redundant information from the original raw dataset by obtaining a small number of variables. This is comprehensible especially for detailed analysis such as modeling. Source apportioning are well known especially for air pollution and water quality data as it integrated with WQI although it is less documented in tropical regions. In air pollution studies, PCA and environmetric techniques are used extensively to determine possible natural and anthropogenic contributions in the determination of total mass and concentration . Therefet al., [et al., [et al., [R2) is commonly used to evaluate model performance . Therefet al., ). Other [et al., ). MLR ar[et al., ). SourcePearson, ); howeve et al., ). Table Figure Figure Figure et al., [et al., [et al., [APCS-ANN is a comparatively new concept driven in river water quality modeling to allow non-linear relationships between variables to be \u2018learnt\u2019 through repeated presentation of input\u2013output data sets. The use of numerical models such as ANN provides powerful tools to stimulate complex natural resources management problems . Curren[et al., ). Althou[et al., ).Figure Figure et al., [et al., [Classical process-based modeling approaches can provide good evaluations of water quality variables however the approach is too common to be applied directly without a lengthy data calibration process . Since [et al., ).R2 values .et al., [3-NL, DS, TS, NO3, Cl-, PO4, E.coli, coliform) with 275 observations to identify the pollution sources. PCA is able to describe the relationship between analytical variables than single analytical variable alone. VF1  represents 21.40% of the total variability in one axis (VF1) comprising DO, AN and PO4. VF1 represents moderate loading matrix of coliform and E. coli. while DO was negatively correlated to AN and PO4 owing to the decrease of DO values in the increasing AN and PO4 inputs in the water body at Kuantan River. VF2 explain DS, TS and Cl in new variable with strong factor loadings.Based on Figure et al., ). PCA wa4 were strongly correlated to VF1 (32.409% of variance) and a new variable termed as fertilizer waste which explains that NH4 likely to comes from the vicinity of animal farm and agricultural nonpoint source . Modera-. While for VF3 (9.605% of variance)  Figure  was stro et al., ). VF4 . MoreovR2 value for APCS-MLR model in this study is 0.87 and the model indicates that 87% variability of WQI explained by the five independent variables used in the model. While for adjusted R2 it is always less than R2 and increases only if the new term improve the model . Mean SR2 and adjusted R2 values closet to unity  and Schwarz Bayesian Criteria (SBC) values and  et al., ). In genBased on Figure R2 value, 0.9680 (Table APCS-ANN (WQI) was developed to investigate which pollution patterns contribute most to the Kuantan River Basin. Previously five VFs were generated from PCA after varimax rotation and the VFs were used as input parameter for ANN model. The five input parameters were fertilizer waste, surface runoff, and anthropogenic input, chemical and mineral changes and erosion and WQI as output. Based on Figure R2 is (0.9680) and low RMSE (2.6409) as compared to other models. From the sensitivity analysis, the highest pollutant that contributed to Kuantan River Basin (WQI variation) was identified. Fertilizer waste (L-FW) accounted as the main pollution contributor  due to the exclusion of the parameters results in reduction of R2 (0.8115) and high RMSE (6.9275) which signify the model. Anthropogenic input (L-AI) was identified as the second pollution contributor , R2 (0.9092) and RMSE (4.549) followed by surface runoff (L-SR), erosion (L-E) and lastly chemical and mineral changes (L-CMC) which were the least contributors as the inputs influencing the APCS-ANN model performance.As shown in Figure et al., [APCS-MLR in apportionment of sources affecting water quality reveals that industrial discharge contributed the highest pollutant of ammonia observed . Howeve4 inputs that reflects to DO reading from year 2003\u20132007, were due to the oil palm, rubber and forestry areas along the river. This also leads to chemical mineral changes to the field areas. From the results stated above, it is shown that ANN gives better accuracy as compared to MLR technique for WQI forecasting. Moreover ANN also capable to stimulate the complex relationship between the data set and consequently is able to justify the water quality puzzles. By using PCA, main pollution contributors to the basin were justified without eliminating any data and parameters. Moreover due to non-linearities of dependent variables in this study and the intricate associations between water quality parameters and WQI values, APCS-ANN model is able to justify and predict the WQI values at Kuantan River Basin. In this sense, APCS methods proved constitute recommended tools for more comprehensible of large volume data sets especially in environmental monitoring studies. Thus, the prediction of WQI values using APCS-ANN model can be used for environmental monitoring agencies in Malaysia to reduce the monitoring and chemical analysis cost as only significant parameters  will further used for monitoring purposes. The model gives efficient computational judgments.As a conclusion, agricultural practices and minimum contribution of anthropogenic human activities were among the responsible sources for surface water pollution in Kuantan River Basin, Malaysia. A main AN and POThe authors declare that they have no competing interests.Nasir MFM, carried out the environmental modeling studies, assisting in the writing, data analyzing, drafted and submission of the manuscript. Zali AM, carried out the environmental modeling studies, assisting in the writing, data analyzing and drafted the manuscript. Juahir H, carried out the environmental modeling studies, participated in sequence alignment and reviewing the manuscript. Hussain H, contributed in the data and landuse map of the manuscript. Zain SM, participated in the reviewing of the manuscript. Ramli N., contributed in the water quality data for the manuscript. All authors read and approved the final manuscript."}
{"text": "In Response: We welcome the critiques of Nasci, et al. (The underlying data were obtained with an ELISA specific to severe fever with thrombocytopenia syndrome virus (SFTSV). The conclusion was based on our knowledge, at the time our manuscript was submitted, that in North America no other known phleboviruses of this expanded Uukuniemi group that contains SFTSV and HLV were reported to be cross-reactive with SFTSV. When tested by using our reagent, SFTSV was not cross-reactive with Rift Valley fever virus. Related phleboviruses of this group  have not been reported in North America  are distantly related and have \u224811% amino acid sequence homology to SFTSV. The recently characterized Lone Star virus appears to be the closest relative to SFTSV and HLV and may cross-react with SFTSV and HLV, as also suggested by Nasci et al., but this virus is apparently known only from 1 isolate obtained in 1967 ("}
{"text": "As one of the phylogenetically and ontogenetically oldest neurotransmitters, the monoamine serotonin (5-HT) is derived from tryptophan in neurons within the raphe nuclei, and innervates various parts of the nervous system (Jacobs and Azmitia, Although the serotonergic system has been studied for many years, an integrative account of its underlying functions remains elusive. This could be partly attributed to the high variability and heterogeneity in terms of neuronal properties and receptor subtypes, and its extensive connections with other brain regions. Indeed, it has been claimed that serotonin is in involved \u201cin virtually everything, but responsible for nothing\u201d (Jacobs and Fornal, in vitro and in vivo conditions.At the receptor and cellular levels, Maejima et al.  discusseAt the neuronal circuit level, Celada et al., Besides the cortex, serotonin is also known to modulate important subcortical brain regions. Using a mathematical model of multiple brain regions, Reed et al.  demonstrIt has been proposed that reinforcement learning models can be used as a platform for studying neurological and neuropsychiatric disorders (Maia and Frank, We hope that this issue will provide a comprehensive review of the diverse and complex functions and computations of serotonergic and related systems at multiple scales of investigation. We wish that this will motivate and inspire a more integrative research approach from cellular to systems level toward understanding neuromodulatory systems."}
{"text": "Anxiety is arguably an emotion that predates the evolution of man. Its ubiquity in humans, and its presence in a range of anxiety disorders, makes it an important clinical focus. Developments in nosology, epidemiology and psychobiology have led to significant advancement in our understanding of the anxiety disorders in recent years. Advances in pharmacotherapy and psychotherapy of these disorders have brought realistic hope for relief of symptoms and improvement in functioning to patients. Neurotic disorders are basically related to stress, reaction to stress  and individual proneness to anxiety. Interestingly, both stress and coping have a close association with socio-cultural factors. Culture can effect symptom presentation, explanation of the illness and help-seeking. Importance given to the symptoms and meaning assigned by the physician according to their cultural background also differs across culture. In this way culture can effect epidemiology, phenomenology as well as treatment outcome of psychiatric illness especially anxiety disorders. In this review an attempt has been made to discuss such differences, as well as to reflect the important areas in which Indian studies are lacking. An attempt has been made to include most Indian studies, especially those published in Indian Journal of Psychiatry. Anxiety is arguably an emotion that predates the evolution of man. Its ubiquity in humans, and its presence in a range of anxiety disorders, makes it an important clinical focus. Developments in nosology, epidemiology and psychobiology have significantly advanced our understanding of the anxiety disorders in recent years. Advances in pharmacotherapy and psychotherapy of these disorders have brought realistic hope for relief of symptoms and improvement in functioning to patients.The word anxiety is derived from the Latin \u201canxietas\u201d  and encompasses behavioral, affective and cognitive responses to the perception of danger. Anxiety is a normal human emotion. In moderation, anxiety stimulates an anticipatory and adaptive response to challenging or stressful events. In excess, anxiety destabilizes the individual and dysfunctional state results. Anxiety is considered excessive or pathological when it arises in the absence of challenge or stress, when it is out of proportion to the challenge or stress in duration or severity, when it results in significant distress, and when it results in psychological, social, occupational, biological, and other impairment.The DSM-IV (American Psychiatric Association) includesNeurotic disorders are basically related to stress, reaction to stress  and individual proneness to anxiety. Interestingly, both stress and coping have close association with socio-cultural factors. Culture can affect symptom presentation, explanation of the illness and help-seeking. Importance given to the symptoms and meaning assigned by the physician according to their cultural background also differ across culture. In this way culture can affect epidemiology, phenomenology as well as treatment outcome of psychiatric illness especially anxiety disorders. In this review an attempt has been made to highlight on any such difference if there, as well as this review will also reflect the important areas, in which Indian studies are lacking.This review will summarize most Indian studies pertaining to anxiety disorders published in Indian Journal of Psychiatry as well as found in other journals too.P < 0.5) were significantly higher  in urban communities than rural, and all neurotic disorders were significantly high among females . Though meta-analysis has its own limitations, this was the first attempt to analyze the epidemiological studies.To the author\u2019s knowledge there are three meta-analyses of Indian epidemiological studies of psychiatric disorders. A meta-analysis of 13 psychiatric epidemiological studies (Reddy and Chandrashekhara) with a tIt has been seen that rural epidemiological studies are more difficult to conduct as compared to urban ones, due to ignorance, stigma and lack of resources. Disorders like obsessive compulsive disorder often go unaccounted due to ignorance and attribution of such issues to personality factors. This canGanguli analyzedMadhav, in an anDelineation of the sample and initial contact with subjects including collection of background demographic data.Identification of suspected cases, usually on the basis of interviews and questionnaire by non-psychiatric personnel like social workers and sometimes by psychological tests. Physical examination of suspected cases by medical personnel was part of this phase.Psychiatric examination and clinical diagnosis and classification of suspected cases were the third stage.Epidemiological data of anxiety disorder in special population like pediatric and elderly are scant. To the best of the author\u2019s knowledge, one population-based study on geriatric population was reported by Tiwari and Srivastava. These auet al.)[et al.[et al.[A prevalence rate of psychiatric morbidity among pediatric population has been reported since very early 9 but theet al.) observed.)[et al. found nel.[et al. found thl.[et al. reportedIn an another epidemiological study conducted by Manchanda and Manchanda, a total et al.)[In another epidemiological study of possession syndrome  conducteet al.)[Recently a community-based study was conducted by ICMR in Lucknow  and Banget al.) in childet al.).[Most of the epidemiological studies done in India neglected anxiety disorders. The use of poor sensitive screening instruments, single informant and systematic under- reporting has added to the discrepancy in the prevalence rate. The prevalence of mental disorders reported in epidemiological surveys can be considered lower estimates rather than accurate reflections of the true prevalence in the population .et al.).[Most of the Indian epidemiological studies analyzed here have surveyed a population less than 6000. This raises a query whether the findings can be generalized to even one State of India. Mental health care priorities need to be shifted from psychotic disorders to common mental disorders like depression, anxiety disorders, somatoform disorder, etc., which are also associated with high disability in all measures .In children and adolescents, review of literature shows that common disorders seen are dissociative convulsions and stupor.\u201329 Sympt30262628The phenomenology of panic disorder has been studied widely in the West but rarely in India. Srinivasan and Neerakal studied Social Anxiety Disorder (SAD) is a chronic, disabling and treatable disorder with common onset in adolescence. There is only one study conducted by Mehtalia and Vanker to find PTSD has a global significance, and its impact in countries that have been experiencing repeated disaster and social unrest for many years could be a large public health problem. Despite having a global significance, its prevalence has been best studied in industrialized societies only particularly in USA. It is unThe very first paper published in Indian Journal of Psychiatry, in 1951, was authored by Dr. P.K. Ray, titled \u201cCommon Obsession \u2013compulsive symptoms in India\u201d. In this et al.[Akthar et al.54 tried et al.[et al.),[Khanna et al. tried toet al. and compet al. which ha[et al.), T hey de[et al.),.Understanding the biology of various psychiatric disorders has taken the front seat in psychiatric research. Indian studies particularly on this area of anxiety disorders are very less .et al.[et al.[Only a few studies have assessed neuro-cognitive domains in anxiety disorders. A study by Tarafder et al. on 20 pal.[et al. on 30 paBhatti and Channabasavanna studied Sharma and Ram carried et al.),[et al.)[Studies based on treatment of anxiety states or disorders are being published in Indian Journal of Psychiatry since 1959. The initial few published studies have been - Effect on anxiety states of carbon dioxide Jetley, and Guaiet al.), Trial ofet al.), double bet al.), clinicalet al.), and stud,[et al.)et al.[The first Indian study on the effect of Benzodiazepines in anxiety disorders was conducted by Master and Kajaria. This douet al. and lateet al.et al.[Khanna et al. studied et al.[Shah et al. conducteet al.81 More pet al.[Shah et al. evaluateet al.[et al.,[Sahasi et al. ascertai.[et al., found siet al.[Vahia et al. conducteet al.[et al.).[Andrade et al. conducte[et al.). India isStatus of anxiety disorder research from India in relation to epidemiology, phenomenology, course, outcome and management are lacking. Research areas like family studies, genetics, and neurobiology are not touched adequately. Most of the studies have tried to replicate the findings from the West. Despite rapid advancement in the field of psychopharmacology, the researches in the field of anti-anxiety and antidepressant drugs are dismally low from India. Furthermore research is lacking in the areas of non-pharmacological management like relaxation therapies, yoga, other meditation techniques and psychotherapies despite India being the birth place of many such techniques. Most of the research is done by tertiary centers involving limited sample which may not provide the real picture."}
{"text": "Antipsychotic as a class of medications became available for treatment of various psychiatric disorders in the early 1950\u2019s. Over the last 60 years many antipsychotics have become available. In line with the west, Indian researchers have evaluated the efficacy of antipsychotics in various conditions. Additionally, researchers have also evaluated the important safety and tolerability issues. Here, we review data originating from India in the form of drug trials, effectiveness, usefulness, safety and tolerability of antipsychotics. Additionally, data with respect to other important treatment related issues is discussed. When one looks at the history of psychiatric treatments, prior to availability of electroconvulsive therapy (ECT), measures like magic, restraints, blood letting, emetics, purgatives, surgical operations on various organs, removal of foci of infections, vaccines and endocrines were tried as treatment options for schizophrenia. Therapies like insulin coma and electroconvulsive therapy became available. However,India, as a country was not isolated from all these developments. Over the years many classes of antipsychotics have become available in India, some of which have stood the test of time and are still in use and some are no more marketed or are no more favorite of the clinicians. Research focusing on the usefulness of psychotics in India has more or less followed the trends in the West; however, some of the newer antipsychotic drugs which are currently marketed have not been evaluated as thoroughly as others. The pharmaceutical industry and the policy of the government have ensured that these medications are available at a reasonable price.This review focuses on research done on various anti psychotics in India. For this a thorough internet search was done using key words like India, antipsychotics, name of each antipsychotic, efficacy, effectiveness, usefulness, tolerability, side effects, metabolic syndrome, weight gain, prescription, cost in various combinations. Various search engines like PUBMED, GOOGLE SCHOLAR, SCIENCEDIRECT, SEARCH MEDICA, SCOPUS, and MEDKNOW were used. In addition, a through search of all the issues of Indian Journal of Psychiatry available online was done. Hand search of some of the missing issues was also attempted and this yielded a few more articles. We have excluded review articles which we felt did not reflect the Indian scenario to a large extent or did not cover the available Indian data. Data from the animal studies that originated in the form of case reports and studies published only as abstract have not been included.Twenty eight studies which have evaluated the efficacy of first generation oral antipsychotics in schizophrenia have been published.\u201329 Of thExcept for some of the trials in the 1960s and early 1970s, the efficacy and side effects were measured on some rating scales. All these trials have not used the dropouts in their final analysis of data. Data from all these trials can be summarized as: Typical antipsychotics are useful for treatment of schizophrenia, typical antipsychotics are more efficacious than placebo in the treatment of schizophrenia, improvement is seen more in paranoid and catatonic symptoms, aggression and less so in depressive symptoms; addition of trihexyphenidyl doesn\u2019t reduce the efficacy of antipsychotic like trifluperazine and extrapyramidal symptoms are common with typical antipsychotics.et al.[Nine trials have evaluated the efficacy of depot antipsychotics in schizophrenia.\u201338 Some et al. that comThirteen studies have compared typical antipsychotics with either electroconvulsive therapy (ECT) alone or a combination of ECT and typical antipsychotic medication.39\u201350 AllCentbutindole was developed by Central Drug Research Institute, Lucknow; it has been evaluated in four trials and has been compared with trifluperazine, haloperidol and risperidone . Another multicentric trial, which included subjects from India too, showed that both risperidone and haloperidol were better than placebo; however, there was no difference in the efficacy of risperidone and haloperidol.[P < 0.01). At 12 weeks, the response rate was maintained in almost all subjects who responded at three weeks and additionally more than 80% of the subjects who did not respond  to risperidone or haloperidol at three weeks but continued the medications responded at 12 weeks.However, in the recent trials, atypical antipsychotics have been evaluated in large samples in double blind placebo control trials and the outcomes have been measured using standard instruments. In the study by Khanna et al. risperidoperidol. At threeet al.[Four studies have reported the efficacy of antipsychotics in the management of acute psychosis, of which three have specified that the trials included subjects with acute and transient psychosis,7477 whil74Studies in 1970s and 1980s evaluated the efficacy of low dose haloperidol, flupenthet al.[et al.[Two studies have evaluated the role of antipsychotic in violent and agitated subjects attending the psychiatry emergency settings. In a randomized controlled trial, Alexander et al. comparedl.[et al. comparedOnly a small case series of seven cases reported that risperidone is effective in the management of delirium and it is well tolerated by these subjects.et al.[Good response to antipsychotics like trifluperazine, haloperidol and chlorpromazine was reported in cases of delusional parasitosis. In theiret al. found thSeven studies have evaluated the efficacy of various antipsychotics in childhood disorders or childhood/adolescent onset disorders. Studies done in 1960s and early 70s evaluated the role of antipsychotics primarily in the behavioral problems in children with epilepsy/epilepsy and mental retardation and have shown that trifluperazine, prothipendyl and trifluperidol are useful but fluphenazine is ineffective. One small study evaluated the usefulness of clozapine in childhood onset schizophrenia. A study et al.[P = 0.03) and schizophrenia (P = 0.04), but the association was rendered insignificant after corrections for multiple comparisons. Vijayan et al.(2007)[et al.[et al.[With increasing interest in the role of genetic factors in treatment response and side effects of medications, studies from India have tried to address the genetic links of tardive dyskinesia, treatment response and severity of psychopathology.\u201396 Howevet al. evaluateal.(2007) studied 7)[et al. reportedA study reported that subjects, who showed initial dysphoric response to a test dose of neuroleptic, later respond poorly to the neuroleptics.et al.[et al.[et al.[et al.[A few studies have evaluated the antipsychotic prescription patterns from India. In one of the early studies, Khanna et al. evaluatel.[et al. reportedl.[et al. evaluatel.[et al. evaluateIn a recently conducted survey, Grover and Avasthi found thet al.[et al.[et al.[et al.[et al.[Khanna et al. reportedl.[et al. reportedl.[et al. studied l.[et al. evaluatel.[et al. reportedl.[et al. reportedA recently published study, which compared three groups of community dwelling subjects with schizophrenia, showed that mean disability scores remain virtually unchanged in those who remained untreated, but showed a significant decline (indicating decrement in disability) in those who continued to receive antipsychotics and in those in whom antipsychotic treatment was initiated. The proportion of patients classified as \u2018disabled\u2019 declined significantly in the treated group, but remained the same in the untreated group.et al.[et al.[A few studies have evaluated the cost of antipsychotics per se and cost of management of schizophrenia. Girish et al. found thet al. showed tl.[et al. found thl.[et al. In anothl.[et al. reportedet al.[Besides the efficacy or usefulness studies, some studies have specifically evaluated the side effects and tolerability issues with antipsychotics.\u2013136 In o118124et al.\u2013133 wheret al.130 Studiet al. and amonet al.Reasonably good amount of data on the efficacy of antipsychotics in schizophrenia is available from India. In addition, studies also suggest usefulness of antipsychotics in mania, acute and transient psychosis, delusional disorders and agitation and violence. Older studies also suggest that typical antipsychotics have usefulness in anxiety states. Many of the recent studies followed double blind randomized controlled design and had a reasonable sample size. Further, many studies have been carried out at multiple sites throughout the country. To some extent, data is also available with regards to the tolerability of antipsychotics and it shows that extrapyramidal symptoms and NMS are more common with typical antipsychotics and weight gain is more common with antipsychotics like olanzapine and risperidone.However, the major limitation of the research is that there are not many studies on the treatment of schizophrenia in elderly, in subjects with comorbid physical illnesses and in cases with comorbid substance abuse. Data on long term efficacy of antipsychotics is also meager. There is still a need to conduct long term comparative multicentric studies to evaluate the efficacy, effectiveness, tolerability and side effects of antipsychotics."}
{"text": "Listening to a lecture on \u201citching\u2014what's behind it?\u201d can induce observable scratching behavior and self-reported itchiness in the audience . That is, both the quality of itchiness (self-reported) and the action of scratching (as observed) is vicariously shared\u2014as already noted by Holle et al. . Similarly, we coded the part of the body that was scratched. Although the visual stimuli depicted scratching only to the arms and chest (and with cropping at the neck), the vast majority of the participants' own scratches were directed toward their face and hair  vs. conceptually induced itch . A more recent behavioral study by Lloyd et al.  used sta"}
{"text": "A biological and socio-cognitive framework may enhance our understanding of the security process, as the two perspectives collectively acknowledge that (i) competition for resources is/was an important factor in human social behavior and evolution  based on uncertain outcomes. Error management theory proposes that cognition has evolved so that when faced with two alternate strategies, we pick the strategy that would result in the least-costly errors  given their own personality or immediate environment? These issues are clearly very current, as commentators debate the \u201ctrade off\u201d between security and civil liberties. Indeed, the extent to which human error accounts for the false conviction of suspects  and losers are more likely to withdraw from future confrontation [reviewed in Hsu et al. ]. Recentintent on causing harm to others (their perceived trustworthiness) and the extent to which an individual appears capable of causing harm to others [their perceived dominance; (Oosterhof and Todorov, Information provided by the face plays an important role in social interaction (Bruce and Young, Perceptions of dominance and trust appear to have an underlying biological basis and are of obvious relevance to security scientists. Although the relationship between hormones and facial appearance is complex (see Pound et al., Other aspects of facial appearance may predict trusting behavior in the exchange of resources. While attractive individuals are more likely to be trusted in economic exchanges (Solnick and Schweitzer, immediate costs on others during face-to-face competition. Future research could explore the relationship between personality and hacking behavior using a behavioral measure of \u201cpersistence\u201d in \u201ccode-cracking\u201d tasks.If visible cues play an important role in trusting behavior and the exchange of resources, the context in which we interact with others may be important for security-related outcomes. For example, while direct face-to-face combat could be described as the \u201ctraditional method\u201d of resource competition, online theft presents an evolutionary-novel challenge that strategists might only just be coming to terms with (see Anderson et al., Understanding how individual and environmental differences predict security outcomes could generate practical solutions to problems. The extent to which personality and appearance influence social judgments and behavior at key \u201cbarriers\u201d to entry may enhance the overall quality of professional recruitment and training. For example, work has already demonstrated that self-rated attention to detail is predictive of security screening performance (Rusconi et al., Competition for resources could be investigated at the neural level by exploring the neural basis of individual differences in morality and risk-taking in contexts related to resource acquisition and defence. Testosterone is associated with both financial risk-taking (Apicella et al., Biology provides a unifying framework with which to understand human behavior in light of differences between individuals and their surrounding environment. An understanding of the biological basis of strategic \u201cbiases\u201d in social judgments can potentially increase the quality of security decision-making in light of greater awareness of the contexts and environments that might mitigate or exacerbate the risk of lost resources."}
{"text": "In a recent article in Frontiers in Evolutionary Psychology, Krupp et al.  propose Krupp et al.  state, \u201cnepotistic assistance to highly psychopathic individuals by less psychopathic kin. Psychopathy may persist in human populations in part because of kin support to (not from) psychopathic individuals.We applaud these authors for raising the issue of the treatment of relatives by psychopathic individuals as it is commonly asserted that offenders do better when they have supportive family ties .integrated emotions systems (IES) model .\u201d We disagree, as there is significant co-morbidity between paranoid personality disorder and psychopathy  (Johnson et al., Rather than being \u201can adaptation\u201d psychopathy may represent a spandrel\u2014a syndrome that arises as a consequence of other features (Buss et al., We strongly dispute the assertion that psychopathy is not a disorder. Psychopathy is a mental disorder according to both the Wakefield definition cited in this study and American Psychiatric Association criteria (American Psychiatric Association,"}
{"text": "This thematic series presents theoretical and empirical papers focused on understanding autism from the perspective of reward processing deficits. Although the core symptoms of autism have not traditionally been conceptualized with respect to altered reward-based processes, it is clear that brain reward circuitry plays a critical role in guiding social and nonsocial learning and behavior throughout development. Additionally, brain reward circuitry may respond to social sources of information in ways that are similar to responses to primary rewards, and recent clinical data consistently suggest abnormal behavioral and neurobiologic responses to rewards in autism. This thematic series presents empirical data and review papers that highlight the utility of considering autism from the perspective of reward processing deficits. Our hope is that this novel framework may further elucidate autism pathophysiology, with the ultimate goal of yielding novel insights with potential therapeutic implications. This thematic series presents theoretical and empirical papers focused on understanding autism from the perspective of reward processing deficits. This framework suggests that the well-known deficits in social functioning that characterize individuals with autism may reflect or may even be caused by decreased motivation to interact with the social world and decreased feelings of pleasures during social exchanges . Likehttp://www.nimh.nih.gov/research-funding/rdoc.shtml), we feel that understanding autism through the lens of reward systems has the potential to both improve etiologic understanding of autism and to suggest novel approaches for diagnosis and intervention.Although the core symptoms of autism have not traditionally been conceptualized with respect to altered reward-based processes, it is clear that brain reward circuitry plays a critical role in guiding social and nonsocial learning and behavior throughout development . Additioet al.[Research on reward processing in autism is in a nascent stage, and there is a pressing need for empirical studies to define the boundary conditions of reward processing deficits in this disorder. This thematic series contains six empirical papers spanning a number of measurement methods. Cascio et al. extend tet al.,9). Thiset al.,11. By eet al.-16.et al.[McPartland et al. used eveet al.,19 by foet al.[Lin et al. examinedet al.[Damiano et al. used an et al.. These aet al.[This thematic series also includes a pupilometry study by Sepeta et al. that addet al.[This thematic series is complemented by a number of review papers as well. Kohls et al. evaluateDawson et al. ) review et al.[Dichter et al. take a bet al.[Kishida et al. describeet al.[Finally, Watson et al. provide This thematic series suggests a novel framework for understanding the core features of autism, and, perhaps most critically, includes reviews that suggest the utility of considering this framework for understanding variability in treatment response in autism. Articles contained within this thematic series introduce a new theoretical perspective, review vast literature across several disciplines, and suggest ways to leverage an established neurobiological framework and associated behavioral and neuroimaging tasks for understanding the core features of autism. Our hope with this thematic series is to encourage other researchers to consider this framework, and to complement existing research programs addressing social-communicative deficits and restricted and repetitive behaviors in autism.GD is an Assistant Professor of Psychiatry and Psychology and an investigator at the Carolina Institute for Developmental Disabilities at the University of North Carolina at Chapel Hill. RA is the Bren Professor of Psychology and Neuroscience and a Professor of Biology at the California Institute of Technology."}
{"text": "Sir,et al.[et al.[With reference to the article on honey treatment for burns by Baghel et al. and commet al. the folll.[et al. in theirl.[et al. about thHoney may contain botulinum, and hence it is necessary to sterilize honey by gamma irradiation, but majority of the clinical studies used raw honey and no adverse effects have been reported so far."}
{"text": "Sir,et al. with great interest. We applaud the authors for conducting such a study in Indian setup. However, the high cost of therapy with interferon and even glatiramer acetate is a matter of concern in treatment of patients with multiple sclerosis in Indian setup. A study by Singhal et al. has concluded that mitoxantrone, which is a cheap alternative to interferon, has shown promising results in Indian setup when given as an initial therapy for the patients with multiple sclerosis[et al.[We read the article \u201cBeta-interferons in multiple sclerosis: A single center experience in India\u201d by Guptasclerosis and coulsclerosis Mitoxantis[et al. Althoughis[et al.et al. reported reduced disability in patients treated with alemtuzumab.[et al. showed significant improvement in disability score with use of natalizumab.[The new emerging therapies for the treatment of multiple sclerosis include alemtuzumab, natalizumab, and autologous stem cell transplantation which have also shown promising results in trials with respect to disability improvement. A study done by Cole mtuzumab. A multicalizumab. Another alizumab. However,Nonetheless, the authors have done a commendable job in view of the patients who seriously impaired by multiple sclerosis and we appreciate their efforts."}
{"text": "Dear Editor,Attention should be drawn to the study by colleagues Saito O et al. published in the International journal of Endocrinology and Metabolism . The stu"}
{"text": "The role of these processes in recovery may be due to the multi-componential character of neglect syndrome (Milner and McIntosh, Remapping of space (Berti and Frassinetti, In such view, however, it is necessary to consider that the well-known dissociation far and near space is not exhaustive to explain treatment success. One may speculate further that the multisensory integration facilitated by the immediate feedback provided by seeing one owns upper limb reflected in the far space while reaching objects, might facilitate the spatial remapping between far and near space through the updating of the body schema, which is strongly dependent on multisensory integration (Aglioti et al., ad hoc to allow within group contrasts, aimed at verifying the suitability of paradigms across different neglect subtypes.As a final remark, effectiveness of VG based treatments on diverse subtypes of neglect should be explored. For instance, these techniques might not be suitable for all neglect patients, considering that additional impairments such as somatoparaphrenia or perseverations might be present (Bottini et al., wider and enriched scenario including meaningful actions, rather than abstract geometric targets as stimuli and movements that do not resemble reality, is more motivating, encouraging, and finally ecological for patients engaged in recovery programs (Laver et al., Appropriate rehabilitation techniques may influence cognitive functions even in the chronic phase (Teasell et al.,"}
{"text": "Elevated levels of stress and anxiety often accompany vestibular dysfunction, while conversely complaints of dizziness and loss of balance are common in patients with panic and other anxiety disorders. The interactions between stress and vestibular function have been investigated both in animal models and in clinical studies. Evidence from animal studies indicates that vestibular symptoms are effective in activating the stress axis, and that the acute stress response is important in promoting compensatory synaptic and neuronal plasticity in the vestibular system and cerebellum. The role of stress in human vestibular disorders is complex, and definitive evidence is lacking. This article reviews the evidence from animal and clinical studies with a focus on the effects of stress on the central vestibular pathways and their role in the pathogenesis and management of human vestibular disorders. Stress may influence central vestibular function in health and disease either directly through the actions of glucocorticoids (cortisol and corticosterone) on ion channels and neurotransmission in the brain, or indirectly through the effects of stress-related neuroactive substances  on these structures. In the periphery stress hormones also regulate the function of ion transporters and ionic homeostasis in the inner ear, while in some conditions the anti-inflammatory actions of glucocorticoids may also come into play  have been shown to activate the stress axis. Gliddon et al.  measuredTighilet et al.  quantifiBy contrast, Lindsay et al.  and ZhanIn contrast to the effects of UVD, following bilateral vestibular deafferentation (BVD) in rats serum corticosterone was not found to be elevated when compared with sham surgery at 3\u2009weeks , into the middle ear to induce a functional inactivation of the injected ear Figure . FollowiIn the frog, hypophysectomy delays compensation after UVL while ACTH (4\u201310) administered post-UVL restores it  and the cerebellum , Meniere\u2019s disease, or migrainous vertigo. If the process of vestibular compensation is inadequate, the underlying dysfunction may persist and eventually present as chronic dizziness (Bronstein et al., While animal studies (e.g., in Figure Human imaging and behavioral studies, particularly with reference to spatial memory in patients with loss of vestibular function, suggest the hippocampus may be an important center for vestibular compensation (Brandt et al., In addition, of particular relevance is that stress responsiveness is importantly influenced by various developmental and environmental factors including genetic and fetal programming and early life stressful events, as well as varying with age and gender (de Kloet et al., A number of clinical studies have suggested a beneficial role for steroids in the treatment of acute vestibular dysfunction. Ariyasu et al.  studied Kitahara et al.  comparedA systematic study on 141 patients with acute onset vestibular neuritis was conducted by Strupp et al. . PatientThe effects of prednisolone treatment in vestibular neuritis were investigated by Shupak et al.  in 30 paKarlberg and Magnusson  reportedTwo recent meta-analyses have reviewed the role of steroids in the treatment of acute vestibular dysfunction (Goudakos et al., Horii et al.  reportedIn patients with chronic bilateral vestibular loss, testing with virtual navigation tasks without self motion revealed significantly impaired spatial memory that was accompanied by a reduction in hippocampal volume on MRI imaging (Brandt et al., Eagger et al.  reportedArousal with aversion and a lack of control are behavioral hallmarks of the stress response (Kim and Diamond, In a cross-sectional study Eckhardt-Henn et al.  found thHowever, not all patients perceive or handle stress in the same way. Patients\u2019 ability to habituate or cope with repeated stress may be factors that determine outcomes. Tschan et al.  assessedThe causal relationships between balance dysfunction, anxiety, and stress need to be explored experimentally especially within the context of vestibular compensation. An acute stress response is known to be essential for learning and memory formation (Joels et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "In Response: We thank Davies et al. for their letter (S. aureus (MRSA) registry data were derived from swab specimens and clinical isolates; the distribution of anatomic sites differed between the cases and controls in our study. However, all study participants were proven MRSA carriers. As per their comment in their letter (Davies et al. correctly note that the original methicillin-resistant Davies et al. apparently pooled data from 3 studies and stated that there is negligible risk for livestock-associated\u2013MRSA among persons who do not have livestock or farm contact. Each of these studies was designed differently and had different comparison groups, and each report conceded that factors such as indirect human or environmental transmission could have exposed study participants who lacked known farm risk factors.In addition, Davies et al. state that our observed association of increased odds of livestock-associated\u2013MRSA compared with a typeable strain of MRSA in regions with higher livestock densities should be limited to hypothesis generation. We agree, as stated in the final sentence of our report (To clarify our statement comparing pig densities in the United States and the Netherlands ("}
{"text": "We thank Tsuda et al. for sharing their views. Along with their previous publications on Minamata disease, we find their comments useful as a complement to our brief historical review of the mass poisonings in Japan and associated events . However"}
{"text": "Research in oral and maxillofacial pathology has unlimited potential. We use every technology available to us for better and faster reliable diagnosis. But in most institutions, private laboratories and multispecialty hospitals, tissue processing takes considerable time, and therefore delays the diagnosis, which is required in urgent cases. We, in this institution, conducted a study to hasten the processing by using a simple kitchen microwave.To analyze tissue sections processed by microwave as compared to the gold standard of conventional processing.et al., in 2008. This is the second such study that used a sample size of 50 cases.Studies published from 1970 till 2008, used body tissues such as brain, liver, kidney, heart, and lungs, for microwave processing. Oral tissues were not processed in microwave till now, except one study by Dr Shivaparthasundaram A kitchen microwave was used for irradiation of the tissues. Conventional processing was carried out as per departmental protocol. A total of 50 microwave-coded slides were mixed with 50 conventional slides. All 100 slides were evaluated by four different pathologists.The result was subjected to statistical analysis using Chi-square test.It was found that to make a diagnosis, microwave-processed tissue were at par with the conventional technique. Thus, it is time to move on from conventional processing to microwave processing to yield faster and reliable results. Conventional tissue processing is as old as 100 years and still remains the gold standard against which all new technologies and methods need to be assessed. A laborious and tedious manual sequence, tissue processing is of paramount importance for having good thin sections without artifacts.Microwaves, which were invented by Percy Spencer in 1945, created a small buzz and soon became an integral part of our daily lives.[This study uses microwaves for the processing of oral tissues and Analysis the cellular and nuclear morphology as well as staining characteristics. Comparison is done with the conventional technique with the same parameters.To evaluate the quality of stained sections by both techniques.Microwave ovens can generate heat from within, and thereby warm tissues and reagents uniformly in a short time. The objective of this study is to process the tissues in a microwave oven and then compare the sections with the gold standard of conventional processing.National microwave oven ; Model no.: NN \u2013 5208; Serial no.: N 09130085; Input- 1180 W, 5.2 A, 240 V, 50 Hz; Output- 600 W, 2450 MHz.Jar- 600 ml; two jars of 200 ml each; seven glass vessels of 200 ml each10% Formalin; acetone; absolute alcohol; xylene; chloroform and paraffin waxSpecimens for this study were selected randomly from those received in the department of Oral and Maxillofacial Pathology, Bharati Vidyapeeth Dental College and Hospital, Pune, and from private hospitals and clinics in and around Pune.Only soft tissue was preferred for this studyThe sample size was 1 cm \u00d7 1 cm or greaterThe thickness of 5-8 mm was taken for microwave processingThe tissue was then divided into equal halves; one was processed in a microwave and the other was processed conventionally.10% formalin was used as a fixative.The processing was started at 8.30 am; the cassette was kept in water for 1 hour to remove formalin. Dehydration in acetone was done in four steps of 1 hour each, using graded acetone  from 9.30 to 1.30 pm. Tissue was cleared in xylene in three steps of 1 hour each , using 100% concentration of the solution. At the end of the college hours, the cassette was kept in paraffin wax bath I for impregnation, which had a preset temperature of 40\u00b0C. The subsequent morning at 9.00 am, the tissues were removed from paraffin wax bath I and placed in wax bath II for 1 hour (preset temperature of 40\u00b0C). This was done to allow proper impregnation of the wax into the tissues. At 10.00 am, tissue was removed from the wax bath II and embedded. This procedure was followed routinely.All processing was done at room temperature, except for impregnation and embedding.Xylene has a high boiling point and low microwavability, ie, it will take double the time for the same amount of reagent to get heated. Therefore, in this study, chloroform was used as a clearing agent for microwave tissue processing.A pilot study was done in which each reagent was microwaved for 5 and 10 minutes. The tissues microwaved for 5 minutes showed improper dehydration, clearing, and impregnation, while those microwaved for 10 minutes showed improper clearing and tissue breakage while cutting. The tissues and reagents were microwaved for 15 minutes. The dehydration, clearing, and impregnation of tissues were found to be satisfactory. Hence, this method was taken as a standard protocol for all tissues.et al., where the following steps were used:The time taken for dehydration, clearing, and impregnation was same as that of Klump et al., Absolute alcohol: 15 minutes (one step)Chloroform: 15 minutes (\u201c)Paraffin impregnation: 15 minutes (\u201c)The solutions are not covered with the lid because we had two jars: the first jar contained a 200 ml solution  along with the tissue inside, and the second one contained a water load of 500 ml and placed next to the first jar. In this way, We were able to control the excess heat, which was absorbed by the water.Due to very small size of the oral tissues, the temperature of the tissue cannot be measured. Thus, it was assumed to be similar to that reached in the solution, which was in the range of 45\u00b0C-58\u00b0C.The power of the microwave available for this model was warm, low, medium low, high. In this study, the power modes used were as follows:Power mode for each solution:First 5 min- low mode and next 10 min - warm modePower mode for paraffin wax:First 5 min- medium low mode and next 10 min - low modeThis was done to allow chloroform to effectively boil out of the tissue and replace it with paraffin.A total of 50 pairs of slides were obtained; one each for microwave and conventional tissue processing. All 100 slides were coded by an independent observer, in which 50 slides were coded with an alphabet (A) and the other 50 slides were coded (B). Four observers evaluated all 100 slides without the knowledge of the type of processing used.For cellular morphology evaluation, greater eosinophilia of cytoplasm producing enhancement of the nuclear-cytoplasmic contrast, good stroma, whether secretory products are appreciable, red cell lysis absent, whether differentiation can be made between inflammatory cells. If most Evaluation of slides for nuclear morphology was done on the basis of chromatin condensation, prominent nuclear membrane, and crisp staining of the nucleus and mitotic activity, if appreciable. It was dStaining of tissues was evaluated as poor, satisfactory, and good. Poor indicates that the tissue failed to take up stain adequately, stained unevenly or had artifacts in processing or staining. Satisfactory indicates that details were not visualized up to the mark, but slide was suitable to give diagnosis. Good means good contrast between the nucleus and cytoplasm, and visibility of details along with brilliance of staining.67 The ov6After evaluation by all four observers, the processing code was broken and results were subjected to statistical analysis.The reliability test was done to evaluate the interobserver variations. Similarly, The histological assessment was done by three independent observers and myself. The observers were as follows: observer no 1- Oral pathologist with 15 years of teaching experience; observer no 2- a General pathologist with a teaching experience of 7 years; and observer no 3- an Oral pathologist with a teaching experience of 2 years.et al.[The microscopic quality of the sections was comparable to, or slightly better than, conventionally processed tissue having the same formalin fixation time. The architecture in the sections was well preserved as in concordance with Kok et al.From these results, we believe that rapid microwave-assisted tissue processing is the optimal method for producing quality sections. Also, excellent microscopic sections obtained by this technique revealed no differences in the cellular and nuclear morphology in several types of tissues.The formula for diffusion states that: the average squared distance covered by a particle in solution is proportional to the diffusion time. This shows that the thickness of biopsies should be small: three times as thick means nine times as long for comparable effects. It should be noted that the length and breadth does not matter here.Proteins in the tissue are denatured by absolute alcohol to such a degree that subsequent heating does not have any additional influence on the light microscopic results. Alcohol is also used as a coagulant fixative that hardens the tissue, and this is needed for cutting of sections. This hardening effect is caused by coagulation of proteins.The literature on microwaves for histoprocessing comprises several papers that advocate the use of domestic microwave ovens. In the book by Kok and Boon, the total processing time was 111 minutes when 500-ml containers were used and 30 blocks were prepared. In all steps, the working temperature of 75\u00b0C was maintained.et al.,[et al.[In this study, the microwave processed tissue sections had better cytoplasmic  and nuclet al.,12 Mathai.,[et al.et al.,[et al.,[et al.,[et al.[Boon et al., Chaudhar,[et al., and Mora,[et al.,12 found ,[et al.,. No cris.,[et al.et al.[In this study, the effect of microwaves on the different types of tissue such as epithelium, fibrous, and glandular, showed no statistically significant variation, as also seen in studies by Panja et al.et al.[Boon et al. found thet al. and 5, aet al.et al.,[et al.[Red cells were not lysed  by microet al., Mayers,[et al., Leong,[4et al., the red et al.,, and thi.,[et al.et al.,[The microwave processed slides of malignancy cases such as angiosarcoma , verrucoet al., who acceThere was excellent staining of tumor cells as compared to similar sections processed with conventional technique Figures \u20139. Irreget al.,[Foci of dystrophic calcification were preserved as seen in cases of Hopewood et al., and exceThere was no significant difference between nuclear size and shapes, as seen in Figures  and 15 aet al.,[et al.,[et al.,[et al.,[et al.,[et al.,[et al.,[et al.,[et al.,[et al.[The staining of tissues in the microwave and conventionally processed slides did not show significant variation . This waet al., Chaudhar,[et al., Morales ,[et al.,12 Panja ,[et al., Zenobia ,[et al., Galvez e,[et al., Suri et ,[et al., Leong et,[et al.,21 Kok et,[et al., and Rohr.,[et al. Microwav.,[et al. and 17, et al., where cytoplasm stained moderately eosinophilic, with no deeper eosinophilia observed.[et al.[Similar findings were observed in the study carried out by Sivdas observed. Also, Hod.[et al. and Leond.[et al. noted eod.[et al.et al.[As the tissue that can be processed is very small, often the sample may not be representative of the site, and hence proper diagnosis could not be reached in few cases, which were in consonance with Suri et al. This disFew sections seen in conventional technique showed artifacts, such as uneven staining. This was due to inadequate dehydration and also due to faulty clearing techniques during the staining process.Moreover, residual paraffin in the tissue would have resulted in uneven staining.\u201325 CelluRight from pre-cancerous conditions and lesions to malignancy, reactive lesions to benign tumors, microwave technique has shown a remarkable difference without losing the architecture and morphology of the cells.The slides obtained by microwave processing did not in any way alter the cellular morphology, nuclear morphology, or staining characteristics. A comparison of the microwave processed slides with the conventionally processed slides shows that the results are statistically insignificant.In addition, the profitability of any diagnostic laboratory would be increased by using this technique, as this will enable handling a large batch of samples in a single day. Moreover, this will be a boon for the technical personnel whose work practices and lifestyles would change for the better, and this is something which defies statistical analysis."}
{"text": "Cannabis sativa is a plant containing over 70 active compounds called cannabinoids  in the left parahippocampal gyrus and decreased rCBF in the amygdala-hippocampus complex, including the posterior cingulate cortex (Crippa et al., Accordingly, it would be worthwhile to examine how the impact of CBD on ACC activity may extend to the domain of cognitive performance. Since modulation of ACC activity is assumed to be the mechanism through which CBD affects brain connectivity during emotional processing (Fusar-Poli et al., Taken together, research regarding the impact of CBD on ACC activity appears to be contradictory (see Table It is also interesting to consider the ACC-mediated impact of CBD on emotional processing. Animal research indicates that the anxiolytic effect of CBD depends on action of the compound on specific brain areas and that the effect could also, in some cases, be anxiogenic (Marco et al., In sum, existing research seems to undermine Schier's et al.  suggesti"}
{"text": "Dear Editor,I read with interest the article by Kashani et al, on the use of hydroxyurea (HU) in the treatment of chronic hepatitis B published in Hepatitis Monthly . In thei"}
{"text": "Traditional theories of motor skill learning . To illustrate, in a naturalistic investigation of the attentional foci adopted by elite golfers during competition, Bernier et al. (r et al.  found thr et al. . In anotr et al.  discoverr et al. , is \u201cselvice versa. This may happen, for example, when they relinquish spontaneity and use knowledge of facts to alter \u201cattenuated\u201d movement patterns in the practice context or when they are strategizing during competitive performance. Although Stanley and Krakauer (knowledge of what to do to initiate an action, the current paper provides evidence of how skill may be continually improved by proprioceptive knowledge of how to change/alter an action and how performance proficiency may be maintained by propositional knowledge of how best to plan an action during competition.The research literature on the cognitive psychology and neuroscience of skill has tended to present a dichotomized view of the role knowledge plays in guiding skilled performance. According to this body of work, skilled performers engage in intuitive or absorbed coping (see Dreyfus and Dreyfus, Krakauer  use an e"}
{"text": "Dear Editor,et al. Vocal cord position Vocal cord movement Coughing Movement of the limbs Intubating conditions are regarded as excellent , good , and poor   for tracheal intubation without neuromuscular blocking agents (NMBAs) with regard to the incidence of coughing.I read with keen interest the article by Imani et al.  in which  or not required to facilitate surgical access ."}
{"text": "Cataract is one of the earliest secondary complications of diabetes mellitus. The lens is a closed system with limited capability to repair or regenerate itself. Current evidence supports the view that cataractogenesis is a multifactorial process. Mechanisms related to glucose toxicity, namely oxidative stress, processes of non-enzymatic glycation and enhanced polyol pathway significantly contribute to the development of eye lens opacity under conditions of diabetes. There is an urgent need for inexpensive, non-surgical approaches to the treatment of cataract. Recently, considerable attention has been devoted to the search for phytochemical therapeutics. Several pharmacological actions of natural flavonoids may operate in the prevention of cataract since flavonoids are capable of affecting multiple mechanisms or etiological factors responsible for the development of diabetic cataract. In the present paper, natural flavonoids are reviewed as potential agents that could reduce the risk of cataract formation via affecting multiple pathways pertinent to eye lens opacification. In addition, the bioavailability of flavonoids for the lens is considered. Cataract, eye lens opacification, is one of the earliest secondary complications of diabetes mellitus , pyridazines  and carboxymethylated pyridoindoles , isolated as a bioactive flavonoid from the leaves of et al., 1997).The flavonoid venoruton, a mixture of mono-, di-, tri- and tetrahydroxyethylrutosides, significantly reduced the degree of opacification and the leakage of lactate dehydrogenase in rat lens organ culture simulating diabetic conditions . Analogically, in the same galactosemic rat model, Mohan et al.  recorded et al., . The reset al., et al., 2009; Kyselova, et al.  did not affect cataract formation. The flavonoid fraction from Emilia sonchifolia was reported  was reported . Grape seed extract rich in flavonoids reduced hydrogen-peroxide-induced apoptosis of human lens epithelial cells and depressed H2O2-induced activation and translocation of NF-kB . Flavonoid chelating activity for transition metal ions has been well documented . Flavonoids inhibit xanthine oxidase, the enzyme responsible for superoxide anion production . Interestingly, isorhamnetin (3-methylquercetin) was found to inhibit xanthine oxidase, even more efficiently than the aglycone form of quercetin  and spirohydantoins, with epalrestat and sorbinil being the most representative members of each respective family catechin>kaempferol  is not a substrate of lactase phlorizin hydrolase. The quercetin aglycone is released hydrolytically by bacterial \u03b1-rhamnosidases and \u03b2-glucosidases in the lower gastrointestinal tract. Thus absorption of quercetin from rutin is delayed, and quercetin bioavailability is much smaller in comparison with that of quercetin-glucosides. This example stresses the role of sugar type for bioavalability of natural flavonoid glycosides (Hollman et al., et al., et al., et al., et al., et al., et al., et al., Flavonoids occur in plants mainly in the form of O-glycoside conjugates linked to sugars like glucose, galactose, arabinose or rhamnose (Bravo, et al., et al., et al., et al., Excellent reviews covering broadly the topic of bioavalability of flavonoids were published (Scalbert & Williamson, ex vivo experiments reported by Cornish et al. (et al., et al., et al., To date, only a few studies have investigated delivery of flavonoids to the eye. Drug delivery to the ocular tissues depends on the physicochemical and biopharmaceutical characteristics of the selected flavonoids and very importantly on the route of administration. Topical application is the most favored mode for ocular conditions. The topical route is mainly used to deliver drugs to the anterior segment of the eye. Local administration may yield much higher and effective concentrations of the parent flavonoids in the ocular tissues and at much lower doses, than the oral route. In the anterior chamber of the eye, the aqueous humor bathes the anterior surface of the lens, providing all oxygen and nutrient requirements. It is therefore this route through which dietary flavonoids would reach the lens. For example, in the h et al. , quercet et al., , it was et al., et al., Presently, surgical extraction remains the only cataract cure. Cataract surgery has become the most frequent surgical procedure in people aged 65 years or older in the Western world, causing a considerable financial burden to the health care system (Head, In diabetic patients, tight control of hyperglycemia is the first prerequisite to attenuate the risk of cataract. In addition, adjunct therapy is needed to help preserve vision in diabetic patients, aimed at correcting biochemical and metabolic abnormalities in the hyperglycemic milieu of the diabetic individual.The current data on natural polyphenols in relation to cataract, along with epidemiological knowledge on diet and lens opacity, demonstrate that flavonoids may play a role in cataract prevention. Yet future clinical trials are needed to assess the benefits of flavonoids in lowering the risk of both age-related and diabetic eye complications."}
{"text": "An improved algorithm for the piecewise-smooth Mumford and Shah functional is presented. Compared to the previous work of Chan and Vese, and Choi et al., extensions of the key functions"}
{"text": "The role of the neuropeptide oxytocin in social cognition and prosocial behavior continues to fascinate the scientific community  of 18\u201390 year old African Americans with low-incomes: they found that individuals with the GG genotype on rs53576 who experienced severe childhood maltreatment were more likely to have disorganized attachment styles and higher levels of emotional dysregulation.In a study recently published in this journal, McQuaid et al.  examinedThus, in contrast to the majority of published studies focusing on rs53576, Bradley et al.  and McQuFindings from Bradley et al.  and McQu"}
{"text": "The integration of different stimulus properties as an object is the process of feature binding. The research topic \u201cInhibition in the process of feature binding\u201d aimed to debate which features bind together, why, and how; and what happens to features which are not integrated.The authors of the review articles took up the debate in earnest. Wyatte et al.  emphasizThe relevance of features is the key factor in the process of binding for Jaswal . She attHerzog et al.  also addMeier and Rey-Mermet  discuss Moving from features to objects, Dent et al.  review bThe four articles contributing original research extend the study of binding to novel avenues. As merits empirical investigations, all studies not only document details of current work in these new areas, they also indicate hypotheses for future investigations.Delogu et al.  enter thGiersch et al.  scale upThe two original research articles based on computational models conceptualize binding as part of other processes. Schrobsdorff et al.  propose The aim of this research topic was to consider the process of binding from various perspectives such that an integrated view emerged to guide future research and theory. Challenging the assumption that feature binding is an automatic \u201cevent\u201d driven by bottom up processes dependent on conjunctively coding neurons or synchrony, the collection of these articles yield the conclusion that the emergence of a bound object capable of further processing, is itself a sub-process, which is heavily contingent on re-entrant mechanisms and is probably resource demanding. Future investigations may explore feature binding as a basic process in myriad behavioral sequences of diverse populations."}
{"text": "Rice is a staple food for at least 50% of the world's population. Therefore, it is one of the most important crop plants on Earth  were identified, as transport proteins which only internalize Fe during germination, chelating molecules such as nicotianamine and deoximugineic acid, low levels of ferritin protein in the endosperm tissue and mostly high levels of phytic acid (Paul et al.,"}
{"text": "Different views have been expressed on the topic of \u2018combination therapy of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB): rational or irrational?\u2019 in the form of correspondences published in the Indian Journal of Pharmacology.\u20134et al.,[The discussion on this topic started with the editorial by Gautam and Aditya in which they had suggested that the combination of enalapril and losartan is irrational. Tandon, Sharma eet al., and Petret al., have arget al., categoriThe results of the ONTARGET study have been published in a recent issue of the New England Journal of Medicine; the study found that the combination of telmisartan (an ARB) and ramipril (an ACE inhibitor) was associated with more adverse events, without offering any increase in benefits. This particular combination showed higher rates of hypotensive symptoms, syncope, renal dysfunction, and hyperkalemia, with a trend toward an increased risk of renal dysfunction requiring dialysis. The VALI9To sum up, available evidence-based information indicates that the combination of an ARB and an ACE inhibitor is irrational."}
{"text": "Dear Sir,et al.,[We read the article \u201cMRI in T staging of rectal cancer: How effective is it?\" by Mulla et al., publisheet al.[However, it would be interesting to know the criterion used by the authors for predicting the involvement of the CRM. Beets et al. have shoet al. have als"}
{"text": "The suicide rate in India is 10.3. In the last three decades, the suicide rate has increased by 43% but the male female ratio has been stable at 1.4 : 1. Majority (71%) of suicide in India are by persons below the age of 44 years which imposes a huge social, emotional and economic burden. Fifty four articles on suicides have been published in IJP. Several studies reveal that suicidal behaviours are much more prevalent than what is officially reported. Poisoning, hanging and self immolation (particularly women) were the methods to commit suicide. Physical and mental illness, disturbed interpersonal relationships and economic difficulties were the major reasons for suicide. The vulnerable population was found to be women, students, farmers etc. A social and public health response in addition to a mental health response is crucial to prevent suicidal behaviour in India. More than one lakh lives are lost every year due to suicide in India. In the last three decades (from 1975 to 2005), the suicide rate increased by 43%. The rates were approximately the same in 1975 and 1985; from 1985 to 1995 there was an increase of 35% and from 1995 to 2005, the increase was 5%. However, the male-female ratio has been stable at around 1.4 to 1. There is a wide variation in suicide rates within the country. The southern states of Kerala, Karnataka, Andhra Pradesh and Tamil Nadu have a suicide rate of >15 while in the Northern States of Punjab, Uttar Pradesh, Bihar and Jammu and Kashmir, the suicide rate is <3. This variable pattern has been stable for the last 20 years. Higher literacy, a better reporting system, lower external aggression, higher socioeconomic status and higher expectations are the possible explanations for the higher suicide rates in the southern states .[Majority of the suicides (37.8%) in India are by those below the age of 30 years. The fact that 71% of suicides in India are by persons below the age of 44 years imposes a huge social, emotional and economic burden on society.The near equal suicide rates of young men and women and consistently narrow male:female ratio denotes that more Indian women die by suicide than their Western counterparts. Poisoning (34.8%), hanging (31.7%) and self-immolation (8.5%) were the common methods used to commit suicide .[Fifty four articles on \u201cSuicide\u201d have been published in the IJP from 1958 to 2009. The relative paucity in publications can be attributed to several factors but chiefly to the fact that it is an extremely difficult area to take up for research considering its sensitive nature, associated stigma and legal implications. It is interesting to note that the first article on attempted suicide appeared only in 1965. The articles ranged from references to suicide in ancient literature to psychobiological variables in suicide, epidemiological studies to prevention strategies.The publications have been categorized under (1) Incidence and prevalence studies (2) Profiling and identification of risk factors (3) Suicide and suicidal behavior in specific communities (4)Studies on Non Fatal Deliberate Self Harm (DSH) (5) Suicide prevention strategies (6) and other, suicide related publications. The segregation is for the sake of convenience alone and should not be seen as being exclusive to its allocated category.There have been four studies from abroad published in the IJP that have not been covered in the present review, these comprise of a study on women from Trinidad and Tobago, a study from US on adolescence, on teenage suicide attempters from UK and a Japanese study on pesticide suicides.There have been several studies reporting the incidence of suicide in India. Over the years the studies have reported incidence rates ranging from 2.36 to 42 per 100,000 populations. The majority of these have been hospital based studies along with a few community based samples.In one of the first article on attempted suicide published by the IJP, Venkoba Rao reportedet al.[Nandi et al. studied Hedge in his set al.[In contrast to these reports Shukla et al. in theiret al.[These findings were supported by Banarjee et al. who studMajority of the published studies on suicide have dealt with identifying the socio-demographic and psychosocial aspects of suicide attempters and those who have completed suicide. Some of these have also attempted to identify the characteristic differences between the two groups. Most of these were hospital based studies. The study methods used varied, from use of psychological autopsies to interviews to perusal of records.Venkoba Rao in his hIn another hospital based study Lal and Sethi reportedet al.[Nandi et al. investiget al.[et al.[Bagadia et al. attemptel.[et al. (2004) iet al.[In their study from Ludhiana, Narang et al. reportedet al.[Bagadia et al. conducteet al.[et al.[et al.[These findings were also confirmed by Gupta and Singh who repoet al. investigl.[et al. also foul.[et al. identifiBadrinarayana found a et al.[et al.[Anand, et al. in theirl.[et al. revealedIn his comparison study between suicide attempters and completers, Suresh Kumar, reportedVery few studies pertaining to the biology of suicides have been published in the IJP. The earliest article published was by Devi and Rao, who studet al.[Palaniappan, et al. exploredet al. in theirThere have been several studies which focus on vulnerable populations and high risk populations including students, the aged, women, armed forces, farmers, migrant populations and those with chronic physical and mental illness.Venkoba Rao, in his aet al.[et al.[In an another study on the psychosocial and clinical factors associated with adolescent suicidal attempts Kumar, Sudhir et al. comparedl.[et al. in theirRao Venkoba, studied et al.[In a study on 100 female burns cases admitted at the Madurai Medical college Venkoba Rao, et al. reportedet al.[Jacob, et al. in theirIn a study on terminally ill cancer patients Latha and Bhat examinedet al.[Satyavati investiget al. in theirSrivastava and Kumar in theirIn a study on the armed forces Goel argued tet al.[The need to focus on migrants as a specifically vulnerable group was brought out by the study of Chavan, et al. who usedOn a study on farmer suicides in the Vidarbha region, Behere and Behere employedet al.[Sethi, et al. studied et al.[Sarkar et al. attempteet al.[et al.[Das, et al. in theirl.[et al. who founet al.[In their study on non fatal deliberate self harm attempters, Chowdhury et al. identifiThere have been very few articles that have dealt exclusively with suicide preventive strategies or with a scientific and systematic evaluation of a strategy.Singh in his aVenkoba Rao in his aJena and Siddharta reviewedVijayakumar in an edet al.[Gupta, et al. publisheet al.[Somasundaram et al. in theirA social and public health response to suicide is crucial in India, and should complement a mental health response. Mental illness is a risk factor for suicide, in India, as it is in developed countries. However, additional risk factors are prominent in India. These tend to relate to societal structures and specific stressors. A social and public health approach acknowledges that suicide is preventable, and promotes a framework in integrated system of interventions across multiple levels within society including the individual, the family, the community, and the health care system. A key step in such an approach involves modifying attitudes toward suicide via educational efforts and legal levers ."}
{"text": "Environmental chemical exposure has been linked to numerous diseases in humans. These diseases include cancers; neurological and neurodegenerative diseases; metabolic disorders including type 2 diabetes, metabolic syndrome and obesity; reproductive and developmental disorders; and endocrine disorders. Many studies have associated the link between exposures to environmental chemicals and cardiovascular disease (CVD). These chemicals include persistent organic pollutants (POPs); the plastic exudates bisphenol A and phthalates; low molecular weight hydrocarbons (LMWHCs); and poly nuclear aromatic hydrocarbons (PAHs). Here it is reported that though the chemicals reported on differ widely in chemical properties and known points of attack in humans, a common link exists between them. All are lipophilic species that are found in serum. Environmentally induced CVD is related to total lipophilic chemical load in the blood. Lipophiles serve to promote the absorption of otherwise not absorbed toxic hydrophilic species that promote CVD. Lipophilic chemicals are routinely used to promote the permeation of hydrophilic species and are used in pharmaceutical delivery systems since most hydrophilic drugs do not penetrate epithelial barriers at rates necessary for clinical usefulness without lipophilic permeability enhancers . Kow is indicative of the relative lipophilic character of a given chemical. It is defined as the logarithm of the ratio of that quantity of chemical dissolved in the n-octanol phase to that dissolved in the water phase of an octanol-water mixture. Species with Kow of 2.00 or higher are considered lipophilic and those with Kow values of less than 2.00 are labeled as hydrophilic Zeliger, .As a general rule, hydrophilic chemicals are more acutely toxic than lipophilic chemicals as can be seen from their permissible exposure levels , permissible exposure levels (PEL), or maximum contamination level (MCL).It has been previously shown that mixtures of toxic chemicals containing at least one lipophile and one hydrophile produce effects that are not predicted from the known toxicology of the individual species. These effects include attack on organs and systems not known to be impacted by the individual species and low-level toxicity induced by exposures to concentrations far below those known to be toxic by the single chemicals in the mixtures Zeliger, . The corIn all the published studies, the levels of lipophiles in the blood are far lower than those known to be acutely toxic for the individual species.Total lipophilic load in serum is postulated as responsible for the induction of CVD. As used here, total lipophilic load refers to the total concentration of all exogenous lipophilic chemicals found in serum, without specification of individual chemical species.et al., et al., et al., et al., et al., Mechanisms by which environmental chemicals trigger cardiovascular diseases have been proposed. These include: include oxidative stress  have been found to be associated with CVDs. The POPs include PCBs, OCs, dioxins and furans, PBDEs and PFOEs. Plastic exudates include BPA and phthatlates. LMWHCs include benzene, toluene, ethyl benzene, xylenes, C3\u2013C8 aliphatics, gasoline, chlorinated methanes and ethanes and chlorinated ethylenes. PAHs include the following 17 compounds:Though most studies on PAHs have been carried out on benzo[a]pyrene, all 17 of these compounds have been associated with cardiovascular disease and all are environmental pollutant products of the combustion of fuel and tobacco smoke ATSDR, .Diethylhexyl phthalateDibutyl phthalateDi-n-pentyl phthalateDicyclohexylphthalateDiallyl phthalateDiethyl phthalateDiisodecyl phthalateDi-n-hexyl phthatateDiisobutyl phthalateDi-n-octyl phthalateDiisononyl phthalateDiheptyl phthalateMany different phthalates are used in the manufacturing of phthalates. These include the following 12 compounds ; triclosan, an antibacterial compound widely used in tooth paste, cleaners and other consumer products , phthalates, BPA and hydrocarbons. These chemicals come from a variety of chemical classes that include chlorinated and brominated hydrocarbons, esters, ethers, polynuclear aromatic hydrocarbons, mononuclear aromatic hydrocarbons and straight chain aliphatic hydrocarbons. These chemicals differ widely in chemical properties, reactivities and rates of metabolism and elimination from the body.et al., et al., et al., et al., POPs are long-lived and accumulate in white adipose tissue (WAT) from which they can transfer to the blood and be transported around the body , endocrine disruption , periodontal disease (Lee et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Support for this proposal comes from a consideration of other environmental diseases that have been attributed to exposures to these chemicals. POPs exposures have been associated with type 2 diabetes (Zeliger, et al., et al., As previously discussed, PAHs, emanating from the combustion of fossil fuels and tobacco, are considered to induce cardiovascular disease. Several of the studies cited have made the association with inhalation of fine particulates rather than with the PAHs (Costello, et. al., et al., et al., et al., et al., et al., et al., It is to be noted that although the literature relating CVD to other exogenous lipophilic chemicals is scanty, both triclosan (Cherednichenko Cardiovascular disease is rising rapidly throughout the world. It is proposed here that this increase is due in large part to increased exposure to exogenous lipophilic chemicals which, though varying widely in structure, toxicology and chemical reactivity, render the body susceptible to attack via subsequent exposure to low levels of hydrophilic toxins that would otherwise not be absorbed. The lipophilic chemicals can be POPs that are metabolized and eliminated slowly, or BPA, phthalates, PAHs, LMWHCs and other lipophilic species that are eliminated from the body more rapidly, but are constantly replenished in the body from polluted air and water and contaminated food. The accumulation of lipophilic chemicals in the body proceeds until a critical level is reached, at which point the body is vulnerable to attack by low levels of toxic hydrophilic chemicals that would otherwise not be toxic. Sequential absorption of lipophiles followed by hydrophiles provides a unified explanation of how low levels of far different environmental pollutants are responsible for the growing pandemic of cardiovascular disease and other environmental diseases. These findings suggest that allowable levels of exposure need to be dramatically lowered and that research be carried out to find ways to help the body eliminate even low levels of serum exogenous lipophilic chemicals."}
{"text": "Complete surgical resection is associated with improved outcomes in gallbladder cancer. Whether the extra-hepatic bile duct (EHBD) should be routinely excised for gallbladder cancer is unclear. Objective: To analyze literature concerning EHBD excision to determine if it is associated with survival advantage and hence can be routinely recommended.A systematic search using Medline, Embase, and Cochrane Central Register of Controlled Trials for the years 1988-2008.EHBD excision was reported to be performed routinely for T1-4 in some studies, while others reported resection to facilitate lymph node clearance or if the EHBD was grossly involved by disease that remained otherwise resectable. While one study demonstrated 100% survival in T1 disease, other reports do not demonstrate any survival benefit of EHBD excision in T1 disease. Four studies (level IV-V) demonstrated 60% to 90% five-year survival for routine excision in T2 disease, while three other studies demonstrated no survival advantage but increased morbidity due to the procedure. In T3/4 disease, one study (level IV-V) demonstrated a benefit in T4 disease only, and another study (level IV-V) reported a survival advantage in patients in whom the bile duct was not involved; five other studies showed no impact of routine EHBD excision on survival but reported morbidity following anastomotic leaks.Available evidence does not support routine resection of EHBD in gallbladder cancer. EHBD excision should be performed in the presence of specific indications, viz., to achieve an R0 resection of the primary tumor and/ or to aid complete lymph node dissection that would compromise the EHBD by devascularization. It is widely accepted that complete surgical resection offers the best chance of long-term survival in gallbladder cancer.\u201318 HowevWhile some surgeons routinely recommend the resection of the extra-hepatic bile duct (EHBD) for gallbladder cancer, the possibility of post-EHBD-resection complications and the lack of a survival advantage lead us to the question, \u201cDoes the EHBD need to be routinely resected in gallbladder cancer?\u201dWhile the patterns of spread of gallbladder cancer have been presented by various authors,1920 the 19How is the EHBD involved in gallbladder cancer?What is the justification of an EHBD resection?Should the bile duct be resected in all stages of gallbladder cancer?An extensive and systematic Medline and Embase search was performed to identify the existing literature on resection of the EHBD in gallbladder cancer. The search terms used included \u2018gallbladder cancer,\u2019 \u2018extra-hepatic bile duct,\u2019 \u2018resection,\u2019 \u2018hepatoduodenal ligament,\u2019 \u2018radical,\u2019 \u2018aggressive,\u2019 \u2018surgery,\u2019 \u2018anastomotic leak.\u2019 Using the above search terms yielded a total of 981 publications published in the last 30 years. These publications were then analyzed specifically looking at those papers which addressed the resection of the extra-hepatic bile duct in gallbladder cancer. Of the 51 papers thus retrieved and referenced in the current review, only 15 that actually looked at the impact of extra-hepatic bile duct resection on outcomes of gallbladder cancer were analyzed.While considering the development of gallbladder cancer, it is important to realize that there are differences in the pathophysiology of gallbladder cancer in different parts of the world. The basiet al.,29]et al.[et al.[et al.[et al.[et al.[et al.,[Suzuki et al. suggestel.[et al. supportel.[et al. found thl.[et al. were impl.[et al. They alsl.[et al. Shirai el.[et al.35 recomml.[et al. while thl.[et al. suggeste.[et al., too, advet al.[et al.[et al.[et al.[Todoroki et al. recommenl.[et al. Kosuge el.[et al. recommenl.[et al. This stul.[et al. did recoet al.[Kaneoka et al. routinelConsiderable data has accumulated over the last few years to substantiate the argument that routine excision of the EHBD is not warranted in gallbladder cancer . The two11311131Literature on the role of EHBD resection for gallbladder cancer is confusing and at times contradictory. This probably stems from a number of factors: the most likely being the low number of cases of gallbladder carcinoma and their uneven distribution around the world, the often delayed presentation by patients who attribute the early symptoms to other common benign diseases including gallstones, a possible difference in aggressiveness amongst surgeons while managing such patients, and the possibility of a varied pathogenesis (as highlighted above). Also, the management strategies employed in the treatment of gallbladder cancer center around the T stage. However, the inability to accurately predict this T stage preoperatively leads to further confusion, with some surgeons preferring to do more, rather than less, given the dismal prognosis associated with a non-curative resection. So, is there sufficient evidence to support the routine resection of the bile duct irrespective of the T stage of the disease?A closer analysis of the studies supporting the routine resection of EHBD for early stages seems to indicate that there have been instances where some groups have chosen to be conservative with regard to the EHBD, and it has not affected survival.et al.[et al.[et al.[et al.,[In the case of patients with T1 disease, Shimada et al. found thl.[et al. found nol.[et al. The auth.[et al., who founet al.[et al.[et al.,[Suzuki et al. noted thl.[et al. compared.[et al., the outcet al.[et al.[et al.[Further, the data supporting the role of routine EHBD resection in stages II-IV seems to be contradictory based on the conclusions of Chijiiwa et al. and Kosul.[et al. Studies l.[et al. that in Thus, for T2 cancers and even some T3 tumors, in the absence of gross nodal disease, a resection that includes a cholecystectomy with a wedge resection of the gallbladder bed/ segment IVB and V resection, along with a regional lymph nodal dissection, has been shown to constitute a curative surgery.4246\u20134942et al.[et al.,[39The role of EHBD resection in the presence of bile duct involvement is also very confounding. However, what seems to emerge is that the involvement of the bile duct in gallbladder cancer is itself a poor prognostic indicator of survival. Sikora et al. had prev.[et al., the over.[et al.,3940 BesiThe studies highlighted in Indications for the resection of the EHBD in all stages of disease include \u2014Tumors involving the EHBD - PreopeTumors/gross lymph nodal enlargement close to or involving the common hepatic duct or hilumInflamed or a fatty hepatoduodenal ligament rendering nodal dissection difficultPatients undergoing re-resection (since postoperative inflammation makes differentiation of tumor and scar difficult).50 This iPositive cystic duct margin on intraoperative frozen sectionCystic duct cancers43Patients with associated APBDJ /choledoIn case of need for associated vascular resection/ reconstructionWhile theoretically there is the possibility of involvement of the EHBD in gallbladder cancers, the synchronous existence of a malignancy in the EHBD and the gallbladder is uncommon. In the absence of convincing data to demonstrate a survival advantage for the routine excision of the EHBD in gallbladder cancer, the morbidity of the procedure needs to be taken into consideration. This is because the most important complication following bile duct resection and reconstruction, is the development of an anastomotic leak with its attendant short-term sequelae of sepsis and peri-operative mortality; also, there are long-term effects like stricture formation and repeated attacks of cholangitis, rendering the patient a \u201cbiliary cripple.\u201d Given the biases in different parts of the world with regard to the excision of the EHBD, it seems unlikely that a randomized controlled trial would be undertaken. In the absence of level 1 evidence to support the routine resection of the EHBD in gallbladder cancer, such a resection should be performed only in the presence of the specific indications, viz., to achieve an R0 resection of the primary tumor and/ or to aid the performance of a complete lymph node dissection that would compromise the EHBD due to devascularization."}
{"text": "A case of a female child born at full term after normal vaginal delivery with bilateral secondary complete cleft palate and vomerine hamartoma mimicking intra-oral midline encephalocoele. Radiologically the tumour was confined to the vomer without intra-cranial extension. The lesion was occupying the oral cavity causing feeding problem. Surgical excision of the tumour at the age of six months and two flaps palatoplasty at the age of twelve months were performed. On histopathology the lesion turned out to be a lipomatous hamartoma of a benign nature. The child was followed for 9 years with no evidence of recurrence and a satisfactory speech. To our knowledge this is the first report of cleft palate with vomerine hamartoma in the English literature. Congenital malformations may be the product of errors in embryogenesis or the result of intrauterine events disturbing embryonic and foetal growth. Hamartomas and teratomas presenting at birth are tumour-like malformations of anatomical developmental error.\u20134 Hamart12A female child, a product of a full term spontaneous normal vaginal delivery, with a birth weight of 3.500 kg and the Apgar at birth, 5, and 15 minutes was 9, 11, and 14, respectively had a positive parental consanguinity and positive family history of cleft palate. She presented to our clinic at the age of four days. Clinical examination revealed bilateral complete cleft palate and a midline palatal mass extending to the palatal shelves laterally and alveolar arch anteriorly measuring about 4cm \u00d7 3cm \u00d7 0.5cm . The lipAt the age of 6 months, under general anaesthesia and endotracheal intubation the tumour mass was excised leaving a sleeve of mucosal tissues on either side for closure . Histopaet al.[et al.,[et al.,[et al.,[et al.,[et al.,[et al.[Hamartoma of the oral cavity is a rare tumour.\u201310 The l.[et al., Piattell,[et al., De Biase,[et al., Liang et,[et al., and Zait.,[et al. made theet al.[et al.[et al.[Takeyama et al. describel.[et al. has repol.[et al. reportedHaving a cleft palate and a vomerine or palatal tumour would be preferably managed by starting with tumour excision at the age of 3\u20136 months. This would solve the problem of dysphagia or dyspnoea if present, give more time to study the lesion histologically, and to evaluate the risk of recurrence or the need for re-excision. Consequently, definitive treatment of the cleft can take place later at the age of 9\u201312 months. More reports of these rare tumours are needed to understand their nature and behaviour."}
{"text": "With the advent of new antiepileptic drugs comes the potential for significant advances in the emergent management of status epilepticus. Traditional antiepileptic drugs possess side effect profiles that may limit their clinical utility or lead to increased patient morbidity or mortality. The relatively recent development of levetiracetam shows promise for effective control of acute status epilepticus in adults, but current objective data of its use as a first-line agent for control of status is quite limited. This paper serves to examine existing literature while considering levetiracetam as a first-line therapy in status in the adult patient population. Although existing studies are narrow in their scope, the present data lay a substantial foundation for further investigation of levetiracetam as a primary therapy in acute status epilepticus. The emergent management of status epilepticus has been restricted to a small subset of antiepileptic drugs suitable for acute intravenous infusion. Of the three major traditional drugs used in first-line therapy for status, each carries a side effect profile that may ultimately lend to limited clinical utility in the critical patient. Lorazepam, phenytoin, and phenobarbital individually convey specific risks to the patient, among them respiratory depression, medication interaction due to cyp450 induction, and teratogenicity . Each ofGiven its minimal known side effect profile, limited drug interactions, and availability as a rapid delivery IV formulation, levetiracetam, a relatively new AED by comparison, may be a viable, and practical option in the first-line management of status epilepticus , 3. StatThe traditional approach taken in the emergent management of status was described by Riviello et al.  in theirThe reasoning behind the traditional management of status is perhaps most apparent in Brophy et al.\u2019s  discussiWhile levetiracetam is approved as an adjuvant agent for the management of status, data on its use as a first-line therapy is quite limited, as noted in the Neurocritical Care Society\u2019s Guidelines discussed previously. Review of available literature via PubMed search reveals fewer than 10 reports of levetiracetam used as a first-line agent in status, with only a single randomized pilot study and a limited number of case and retrospective reports available in current publication. Despite this, evaluating existing data as a whole opens the discussion for levetiracetam administration as a first-line approach in status epilepticus.A clinical pilot performed by Misra et al.  providesIn a review written by Zelano and Kumlien , levetirLevetiracetam\u2019s limited side effect profile makes it particularly appealing in older patient populations, where drug interaction and the potential for intubation leading to significant mortality is of great concern. Fattouch et al. explored this in a limited retrospective of nine patients, older than 65\u2009years old with video EEG confirmed status epilepticus who received loading doses of 1500\u2009mg IV levetiracetam as a first-line agent . Eight oAdditionally, Farooq et al.  reportedBerning et al.  addresseIt is the potential for limited increase in mortality that makes levetiracetam particularly appealing for first-line use in critically ill patients, which was explored by R\u00fcegg et al. . In theiSpencer et al.  pointed Nau et al.  served tLiu et al.  served tAiguabella et al.  set out While clinical studies of the use of levetiracetam are undoubtedly not yet sufficient to dictate large-scale changes to clinical practice, a substantial foundation for future clinical trials has been laid. Given multiple case reports of successful use of levetiracetam as an initial agent in the emergent treatment of status, there is certainly basis for the development of larger scale randomized controlled trials allowing for a direct, standardized comparison between traditional first-line agents and levetiracetam for emergent management of status epilepticus. The clinical utility of levetiracetam is most suggested by Misra et al.\u2019s  pilot stSuch a hypothesis exists that levetiracetam may well fit the description of an ideal agent as outlined by Reugg et al. . Lyseng Certainly no pharmacotherapy is without fault, and it remains both possible and likely that levetiracetam carries administration concerns not yet apparent to clinical practitioners. Just as our understanding of its clinical benefits are restricted by limited data, so too is our comprehension of its potential pitfalls. With the growing establishment of levetiracetam\u2019s clinical pedigree, as well as ever-increasing desire for an efficacious, accessible, and comparatively benign agent for the emergent treatment of status, levetiracetam may prove a worthy contender in the future of acute treatment of status epilepticus.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Maternity care providers, particularly midwives, have a window of opportunity to influence pregnant women about positive health choices. This aim of this paper is to identify evidence of effective public health interventions from good quality systematic reviews that could be conducted by midwives.Relevant databases including MEDLINE, Pubmed, EBSCO, CRD, MIDIRS, Web of Science, The Cochrane Library and Econlit were searched to identify systematic reviews in October 2010. Quality assessment of all reviews was conducted.Thirty-six good quality systematic reviews were identified which reported on effective interventions. The reviews were conducted on a diverse range of interventions across the reproductive continuum and were categorised under: screening; supplementation; support; education; mental health; birthing environment; clinical care in labour and breast feeding. The scope and strength of the review findings are discussed in relation to current practice. A logic model was developed to provide an overarching framework of midwifery public health roles to inform research policy and practice.This review provides a broad scope of high quality systematic review evidence and definitively highlights the challenge of knowledge transfer from research into practice. The review also identified gaps in knowledge around the impact of core midwifery practice on public health outcomes and the value of this contribution. This review provides evidence for researchers and funders as to the gaps in current knowledge and should be used to inform the strategic direction of the role of midwifery in public health in policy and practice. The reproductive period offers maternity care providers the opportunity to maximise the health and well-being of women and their families potentially impacting on public health outcomes, both short and long term. Although all maternity care providers who engage with pregnant women are presented with such opportunities, it is the midwife that could have the most significant impact from regular contact and building of relationships through continuity of care. There are interventions that could be implemented by midwives, which potentially would have a public health impact but it is important such interventions are evidence based. Recognition of the importance of the relationship between public health and midwifery was highlighted when a general review of midwifery in the UK, named phttp://www.midwifery2020.org. A systematic review of systematic reviews was selected as the methodology, given the breadth of this topic area and the timescale of the project. This paper outlines the review methodology and builds on the original review findings by providing new and updated information about effective high quality public health interventions which could be implemented by midwives or other health care providers for women during pregnancy and the postnatal period who have a similar role, for example, public health nurses, obstetric nurses, labour and delivery nurses or health visitors.This paper presents an update of a systematic review of systematic reviews conducted in 2009. The aim of the 2009 review was to evaluate the effectiveness of interventions relevant to the public health role of the midwife. The 2009 review was commissioned and conducted within the context of the Midwifery 2020 initiative. The final report of the Midwifery 2020 initiative (Delivering Expectations) and full report of the systematic review of reviews are avaiet al.[The Preferred Reporting Items of Systematic reviews Meta-Analyses (PRISMA) guidelines was adhered to when conducting this review. A systeet al..Databases searched included: MEDLINE, PubMed, EBSCO (CINAHL/British Nursing Index), MIDIRS Online Database, Web of Science, The Cochrane Library, CRD (NHS EED/DARE/HTA) and EconLit. Eligibility criterion included reviews published from 1999 onwards; English language publications and reviews originating from economically developed countries as indicated by membership of the Organisation for Economic Co-operation and Development (OECD). An additional search was conducted of the National Institute for Health and Clinical Excellence, UK (NICE) website to identify key publications or findings from systematic reviews within guidelines. Reference lists of identified reviews were manually searched for additional relevant reviews. The searches were initially conducted in November 2009 and updated in October 2010. The titles and abstracts were obtained and the decision process for eligibility was conducted by all members of the project team in collaboration . Full text was obtained of all eligible reviews and those whose eligibility could not be discerned from reading the abstract. Eligible systematic reviews also had to publish a clearly identified search strategy or detail the reference databases used.Data were extracted on: number of papers included in the review; methodological details; midwifery intervention; outcome measures and results. Data were systematically extracted using a data extraction form by individual project team members and verified by one other project team member. The project team subsequently met to discuss and achieve consensus regarding any contentious issues. A parallel process of developing a logic model to act as an overarching framework to inform forward planning was also conducted. Logic models are essentially a conceptual framework, which can be used for evidence\u2010based decision making and planning. The modet al.[et al.[any public health intervention relevant to midwifery. However for the purpose of this paper the focus was to report on public health interventions relating to midwifery that demonstrated a statistically significant effect in favour of the intervention (referred to subsequently as effective interventions for the sake of brevity). Reviews graded 1- or above and of high methodological quality which reported evidence of no effect, are not discussed in this paper. However, they have been summarised in TableIt is important to consider both the type of evidence included in reviews i.e. was the review restricted to randomised trials only or were other types of studies included and also assess how well the review was conducted methodologically. As such, a two stage process was employed: initially the level of evidence was graded and secondly, the methodological quality was assessed. Recognised frameworks were used to support this process,14. In tet al.. Reviewsl.[et al.. A diffeA narrative review is provided for each of the systematic reviews and in table format the number and date range of papers included, intervention(s), primary outcome or other public health outcomes of interest, results  are described and whether the review included a meta analysis or not. It was not expected that a quantitative analyses would be conducted given the diversity of interventions across the broad subject of public health.In total 214 systematic reviews were eligible of which 91 reported on effective interventions and 117 found no effect or were inconclusive. This paper only reports on high quality reviews with a level of evidence grading above 1-. Of the 91 systematic reviews which reported on effective interventions, 36 were identified which were graded as evidence level 1- or above and rated as high quality. The flow chart in FigureThere were no high quality reviews that reported on effective interventions in the pre conceptual period.The majority of reviews reporting effective interventions were relevant to the antenatal period (n=20). Included reviews have been grouped into screening, supplementation, support, education and mental health.et al.[et al.[et al.[et al.[et al.[et al.[Reviews (n=4) related to screening reported on interventions relating to ultrasound,27, loweet al. conductel.[et al. however,l.[et al. indicate.[et al.. The rev.[et al. conducteet al.[Eight reviews-37 consiet al. reviewedet al.[et al.[et al.[et al.[Calcium supplementation was the focus of three reviews-36. Hofmet al. reportedl.[et al. reportedl.[et al. on calcil.[et al. reviewedet al.[Three reviews-40 consiet al. reviewedet al. assessedet al.[et al.,[et al.[et al.[et al.[et al.[Educational interventions in the antenatal period were the focus of four systematic reviews-44 that et al. reviewed[et al., reviewed,[et al. and Lemol.[et al. reportedl.[et al..One review by Dennis & Creedy considerEligible systematic reviews relevant to the intranatal period yielded the smallest number in comparison to either the antenatal or postnatal periods. Five reviews-50 were et al.[Cluett & Burns reviewedet al. reviewedet al.. Althouget al.[et al.[et al.[The birth setting was the subject of four reviews although all were on different aspects. Hodnett et al. reviewedl.[et al.. The intl.[et al. concludeOne review considered interventions aimed at reducing caesarean section rates. ChailleEleven reviews-61 reporet al.[et al.[et al.[et al.[et al.[et al.[2 =55%; p= 0.006). The authors also highlighted an increased rate (22%) of any  and exclusive  short term breastfeeding with interventions that included a component of lay support. Sikorski et al.[et al.[2=53.4%). Early skin to skin contact was reviewed by Moore et al.[Reviews on this topic generally related to either support or promotion of breastfeeding. Britton et al. reviewedl.[et al. and Sikol.[et al.. Breastfl.[et al. and Chunl.[et al. involvedl.[et al. from a mki et al. reviewedl.[et al. focused re et al. reviewedOne review focused on improving maternal mental health and considered postnatal psychological and psychosocial interventions. Dennis et al.[One review considered support for women in relation to weight reduction in the post partum period focusinget al. demonstrThe parallel development of the logic model resulted in a summary model Figure providesThe focus of this paper is the development of the public health role of the midwife based on effective interventions and highlighting the short, medium and long term effects that these interventions could bring about. Any intervention must be considered within the context in which it is to be delivered as inequalities, resources, culture and vulnerable groups can influence the choice of intervention to best suit the population of women being served. The second column represents the inputs or activities; these are the interventions which are intended to bring about the change in outcomes. In relation to public health and midwifery these are interventions that may impact on public health primarily through education, screening and support. The outputs are the products or the targets of the service delivered and can been seen in the boxes entitled organisation of care under short and medium term outcomes. While the logic model provides a visual outline of midwifery public health roles, using this approach facilitates understanding of how public health programs can be planned and subsequently evaluated. Conducting the data synthesis in tandem with developing the logic model has also highlighted where the gaps in knowledge are and identified areas where midwives could potentially have a much greater role and subsequent impact on public health.This paper sought to report on systematic reviews providing high quality evidence of effective interventions, in essence the \u2018cream of the crop\u2019. Reviews reporting on effective interventions were those which presented a statistically significant meta analysis or where the intervention was supported by a generally positive trend of results when a meta analysis was not possible to ensure the recommendations of the paper are based on strong evidence of good quality. There were a number of reviews included which presented statistically significant positive findings. However, in some cases these were limited by small numbers of participants or small numbers of trials included in the review. As a result of conducting the review and analyzing eligible systematic review evidence, three key areas for future consideration were identified including: recommendation and implementation of effective evidence; gaps in knowledge and developing the role of the midwife in public health which are discussed further in the following sections.It is clear from this review of effective interventions, there are areas where evidence has been incorporated into guidelines and thus recommended for implementation into routine practice. However, it has also highlighted many areas where it has not. There has been extensive debate and commentary in the literature about knowledge transfer and translation of knowledge into practice, however, this paper confirms that despite the existence of good quality evidence, the gap remains. From this review, several effective interventions were identified, which are already recommended as routine practice, for example education about folic acid supplementation and pelvic floor muscle training to prevent or reduce the risk of urinary incontinence are advocated by current practice guidelines in the UK and furtThe review identified many gaps in systematic review literature relating to core midwifery practice, which potentially could impact on public health population goals. The UK Department of Health, Public Health Strategy emphasizIn order for midwives to utilise their potential in relation to public health it is important not only to consider the interventions that could be implemented but also take cognisance of wider strategies and policy relating to public health. The logic model Figure, which wet al.[There are a number of methodological challenges in using systematic review evidence which must be taken into account. It is difficult to summarise the evidence from systematic reviews as often there is significant diversity between interventions included in individual reviews or outcome measures used. In addition the results presented may be inconsistent between reviews or inconclusive, however, Smith et al. suggest et al. highlighet al.. HoweverThis paper has reported on high quality effective interventions identified from a larger systematic review on public health interventions that could be delivered primarily by midwives or maternity care providers. From the effective interventions identified it is clear that while some have been recommended for implementation into routine practice, others have not. This highlights the continuing gap between evidence and practice and the need for professionals and researchers to work better together to ensure specific interventions that are effective, are translated into practice and subsequently audited to provide evidence of knowledge translation. The public health role of the midwives has not been well researched or reviewed and the impact of everyday midwifery practice on longer term, holistic maternal and family well-being outcomes is poorly articulated in review literature. A shift in research, policy and practice is needed to fully articulate the public health role of the midwife. This systematic review of systematic reviews identifies a number of effective interventions that provide a useful starting point on which to build future practice. The logic model demonstrates the need to fill in major gaps in our knowledge on effective interventions to achieve both short and long term public health benefits for women and their families. Such benefits will remain elusive without investment in a collaborative, strategic approach to the role of public health in midwifery.The authors declare that they have no competing interest.Ms Liz Bannon, Senior Midwife, & Co Director of Maternity Services, Social Services, Family & Child Care Belfast Health and Social Care Trust, Belfast, Northern Ireland; Professor Debra Bick, Professor of Evidence Based Midwifery Practice, Kings College London, England; Dr Helen Cheyne, Nursing, Midwifery & Allied Professions Research Unit, University of Stirling, Scotland; Professor Mike Clarke, then Professor of Clinical Epidemiology & Director of UK Cochrane Centre, now Professor/Director of MRC Methodology Hub, Queen\u2019s University Belfast; Ms Joanne Gluck, Consumer Representative; Professor Billie Hunter, Professor of Midwifery, Swansea University, Wales; Dr Dermot O\u2019Riley, Centre of Excellence for Public Health Northern Ireland, Queen\u2019s University Belfast, Northern Ireland.JM extracted and interpreted data and wrote the first draft of the manuscript. FL conducted the searches of the literature, extracted and interpreted data and assisted with the manuscript. FA extracted and interpreted data and assisted with the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/12/955/prepub"}
{"text": "In a recent issue of Current Biology, Ventura and Worobey  reviewedAmong the numerous factors discussed by the authors the genetic influence seems to cover a key role.The review addressed this aspect by discussing the growing research about the genetic factors which are responsible of the individual differences in perceiving flavors. For example, the authors reported that the TAS2R38 gene polymorphism is predictive of the level of bitterness  perceived when tasting some particular compound . The opioids have a role in the regulation of mechanisms of the hedonic impact (food \u201cliking\u201d), although they are able to modulate the \u201cwaiting\u201d processes as well  and hyperphagia, which are characterized by two antithetic feeding behaviors, provide important evidence in support of the neuromodulator hypothesis.The core of the AN disorder is characterized by a marked disgust sensitivity for food and the human body (Troop et al., From a genetic point of view, there is evidence that the expression of the D2 dopamine receptor might play a role in the feeding behavior of AN. Bulik et al.  have shoSerotonin polymorphism has been also associated to AN. A recent meta-analysis (Calati et al., Hyperphagia is characterized by a strong desire to consume palatable, high calorie foods. Disgust seems to be reduced in these patients, which could, at least partly, explain their increased appetite (Houben and Havermans, 2 receptor in this region compared to lean individuals (Wang et al., It was already shown that a reduced serotonin 5-HT patter of neurotransmission may precipitate in compulsive eating behavior (Blundell, Even for this clinical condition, interesting insights are provided by the literature on the neuromodulators polymorphism. For example, a recent study (Dykens et al., There is also evidence of a relationship between dopaminergic polymorphism and hypherphagia. For example, a strong relationship was shown between a gene involved in the synthesis of dopamine, the A1 allele of the DRD2/ANKK1-TaqIA, and obesity (Felsted et al., Finally, it was shown (Davis et al., The evidence that the polymorphism of the above mentioned neuromodulators is able to affect the feeding behavior by influencing the hedonic experience and the motivational state of the individual, certainly provide intriguing elements of investigation for disclosing which factors might have an early influence on taste perception and preferences. In this framework of reference, it might be intriguing also to explore if the mentioned polymorphisms influence taste receptor function and the perceived palatability of food. This might be of particular relevance for serotonin, which is already known to participate within the bud (Kaya et al., However, we should keep in mind the study of de Araujo et al.  which reThis supports the suggestion that the inborn taste preference and avoidance might be founded on mechanisms of molecular polymorphism involving a central regulation; while the molecular polymorphism affecting the taste receptors might express its role by regulating the intensity of the hedonic/ disliking experience associated to a flavor."}
{"text": "Vasoactive stimuli can be released by neighbouring tubular epithelial, endothelial, red blood cells and neuronal cells in response to changes in NaCl transport and oxygen tension. The experimentally described sensitivity of pericytes to these stimuli strongly suggests their leading role in the phenomenon of MBF autoregulation. Because the debate on autoregulation of MBF fervently continues, we discuss the evidence favouring a physiological role for pericytes in the regulation of MBF and describe their potential role in tubulo-vascular cross-talk in this region of the kidney. Our review also considers current methods used to explore pericyte activity and function in the renal medulla.Regulation of medullary blood flow (MBF) is essential in maintaining normal kidney function. Blood flow to the medulla is supplied by the descending vasa recta (DVR), which arise from the efferent arterioles of juxtamedullary glomeruli. DVR are composed of a continuous endothelium, intercalated with smooth muscle-like cells called pericytes. Pericytes have been shown to alter the diameter of isolated and  An increase in net MBF would result in \u2018washout\u2019 of the cortico-medullary osmotic gradient Cowley  and impaet al. et al. et al. et al. It has been suggested previously that pericyte-mediated changes in DVR diameter can regulate MBF and alter its distribution in response to changes in active NaCl transport and the oxygen demands of renal tubular cells  velocity at two separate points on the same capillary], to determine blood flow, velocity and vasa recta diameter in the exposed rat papilla concluded that MBF is regulated within a limited arterial pressure range (125\u2013130 mmHg) and that regulation of MBF is governed upstream by renal arterial pressure  techniques to measure regional red blood cell flux  have also failed to provide any clear answers  , endothelin-1 (ET-1), nitric oxide (NO), adenosine and prostaglandin E Pallone .2, NO, adenosine, adenosine triphosphate (ATP),] as are interstitial cells (PGE2) and sympathetic nerves  , hydrogen peroxide (H2O2) or hydroxyl free radical (OH)  are also known to be potent regulators of MBF methyl]-L-ornithine, methyl ester, monohydrochloride (L-NAME), a NO inhibitor, have demonstrated that inhibition of endogenous NO in live kidney slices shows pericyte-mediated vasoconstriction of vasa recta capillaries  and collecting duct epithelial cells (Pallone 2-mediated vasodilation is thought to increase NaCl excretion (Silldorff et al. 2 itself may modulate solute absorption along the nephron through its direct action at pericytes. Crawford et al. (in situ vasa recta, specifically at pericyte sites (Crawford et al. et al. et al. et al. in situ vasa recta, which is direct evidence for tubulo-vascular cross-talk in the medulla (Crawford et al. Similarly, the constrictive effects of both ET-1 and Ang-II are subject to attenuation by vasodilatory PGE Pallone . The ensd et al.  have demet al. et al. In support of this key role for pericytes in the kidney, there are similar studies describing pericyte communication or interactions with adjacent cell types in other systems. For example, retinal and cerebellar pericytes respond to changes in the metabolic demands of the surrounding neurones and alter capillary diameter accordingly; however, the exact mechanism by which this occurs is still unclear (Wu et al. et al. et al. et al. et al. In the retina, it is well established that loss of pericyte function is an instrumental factor in the development of pathological conditions such as diabetic retinopathy (Sakagami et al. et al. et al. et al. in vivo is still heavily debated (Wada et al. et al. et al. et al. et al. in vivo or ex vivo using cell markers because alpha-SMA, a commonly used myofibroblast marker, is also expressed by pericytes (Park et al. et al. In the kidney, a role for pericytes in the pathogenesis of renal fibrosis and progression of chronic kidney disease has been proposed (Lin in vitro cell culture approaches to isolated vessel preparations and LDF have been employed to further our understanding of MBF regulation. To make significant advances, the technical problem of renal medulla inaccessibility must first be overcome. As already discussed, early approaches to the investigation of MBF regulation based on the LDF technique or the dual-slit imaging method have been inconclusive. To date, the best-established technique for studying pericyte-mediated regulation of vasa recta is the isolated perfused DVR method (Pallone et al. in vivo, and it is at least consistent with our proposal that pericytes may be key mediators. The in vitro blood-perfused juxtamedullary technique (Casellas & Navar et al. A variety of experimental techniques from  Pallone . Althougin vivo and in vitro experiments (Layton & Layton Mathematical modelling has also been applied to investigate the regulation of MBF (Zhang & Edwards in vitro experimental model in which medullary structures can be investigated in situ. As with most techniques, this model is not without its limitations. For example, it is not possible to simulate the osmotic and oxygen gradients present in vivo, and DVR in the live slice model are not perfused (Crawford et al. in situ environment, and data collected using this model have confirmed that in vitro observations regarding pericyte activity are reproducible, and new insights into pericyte activity and regulation are being described (Crawford et al. et al. per se is a well-established model for investigating brain function and has previously been used to investigate the role of pericytes in regulating the cerebellar microcirculation (Peppiatt et al. A recent development of a live kidney slice model provides an alternative In summary, there appears to be significant experimental evidence, which favours regulated blood flow in the medulla, and this complements the need for maintained homoeostasis in this region. We propose pericytes are key players in the regulation of renal medullary function, a proposal that is supported not only by their physical location on the vasa recta, but also by evidence describing their ability to respond to endogenous vasoactive agents originating from neighbouring tubular and interstitial cells. There is still much to understand about renal pericyte activity, particularly about their ability to communicate with neighbouring structures and the way in which they transcribe changes in tubular function to changes in blood flow. However, technical advances coupled with increased interest, particularly because of the implication of pericytes in renal disease, should rapidly lead to increased understanding of pericyte activity in renal physiology and pathophysiology."}
{"text": "Squamous cell carcinoma of the external auditory canal, middle ear and temporal bone is a rare and unusual malignancy. The lack of a unifying classification system in the past, along with the rarity of the disease has made the development of clear treatment guidelines difficult. In this report, we describe a clinical case of a patient with this rare malignancy, discuss the challenges associated with the diagnosis and treatment of the disease, and review the literature for trends while outlining the most beneficial treatment strategy for this patient population. The ear canal, middle ear and temporal bone are rare sites of malignancies among which squamous cell carcinoma is the most commonly occurring cancer type . The incWhile there is a lack of data for optimal tumor treatment, a convincing body of evidence has shown that early stage cancer is associated with a higher treatment success and survival rate, compared to late stage disease ,6. ThereIn light of these diagnostic and therapeutic challenges, the present report described a case of advanced squamous cell carcinoma of the external auditory canal in a patient whose cancer was initially diagnosed and treated as osteomyelitis, in the setting of chronic ear infections, at a non-US institution.A 73-year-old Hispanic female with a past medical history of diabetes and chronic left-sided suppurative otitis media that resulted in mastoidectomy in her mid-thirties, was admitted to our institution with left-sided otalgia. The pain was associated with a serosanguineous ear discharge, dizziness, headache, fever, sore throat, generalized weakness and a twenty-pound unintentional weight loss. Previously, the patient had been diagnosed and treated for chronic mastoiditis and later for temporomandibular joint osteomyelitits that extended to the temporal bone. She received several courses of antibiotics, without relief. At the time, cultures of the ear grew staphylococcus epidermidis and diphteroid species. Left ear canal biopsy revealed a small number of keratinizing atypical squamous cells and chronic inflammation, suspicious for neoplasia.6/\u03bcl, but otherwise normal laboratory parameters. Cultures of the blood and ear discharge were both negative. The chest roentgenogram was within normal limits. Computed tomography (CT) of the head with and without contrast, revealed a soft tissue mass invading the left middle cranial fossa with destruction of the adjacent sphenoid and temporal bones  or Union for International Cancer Control (UICC) staging system for this type of neoplasm. Arriaga et al suggeste al(et al in 2000  al(et al.Although the lack of a unifying classification, along with the rarity of the disease have made the development of clear treatment guidelines difficult, there have been uniform observations in the literature, that may help us outline the most beneficial treatment strategies for this patient population.Surgical resection is crucial as a treatment modality, and early surgical intervention is associated with increased survival \u201311. Addiet al(et al(Tumors that are limited to the external auditory canal with or without limited bone erosion and soft tissue involvement are classified as Pittsburgh stages T1 and T2 . In theset al found th al(et al suggest  al(et al.et al(et al(In Pittsburgh stage T3 disease, i.e., with middle ear extension, Kollert et al again reet al. Prasad  al(et al noted th al(et al. While s al(et al, other a al(et al.Involvement of the petrous apex, cochlea, carotid, jugular foramen, dura, temporomandibular joint or the styloid process as well as the presence of facial paresis signal Pittsburgh stage T4 disease . In caseet al(Irrespective of stage of the disease, Moffat et al emphasizet al,14\u201317. Het al(et al(There is conflicting data in the literature regarding the benefits of chemotherapy with or without radiation. While Ogawa et al did not  al(et al has suggIn a small study  that evaPredictors of poor survival in this patient population include extensive tumor involvement, neck node metastasis, facial nerve paralysis, pain, middle ear involvement, cervical or periparotid lymphadenopathy and concomitant chronic otitis media ,7,15,19.In conclusion, in this report, we describe a case of a rare and aggressive tumor type for which the most beneficial therapeutic approach remains to be determined. It is clear however, that, if diagnosed late, this disease exhibits poor outcomes, while it is associated with higher response rates and increased survival at early stages.Thus, emphasis should be placed on the importance of early detection, diagnosis and treatment of squamous cell carcinoma of the temporal bone and middle ear as the simplest and most effective measure to increase patient survival. We also urge the medical community for prompt diagnostic work-up in patients with chronic and treatment-resistant ear infections."}
{"text": "Throughout the developing world, the long-term consequences of insufficient amounts of essential micronutrients in the human diet can be more devastating than low energy intake. Micronutrients are involved in all aspects of development, growth, and physiology of the human body (including from early embryonic stage), and their deficiencies can cause birth defects, permanent physical and mental impairment, as well as an increased risk of death by infectious and chronic diseases. As plant scientists, we are now facing challenging and urgent goals: how to feed the world's increasing population and how to feed it better. In other words, we need to produce more plant food in sustainable ways and such food should be of the highest nutritional value.This e-Book aims to provide the most recent advances on plant biofortification for micronutrients as well as a comprehensive overview of the different approaches that can be pursued for producing micronutrient-rich staple plants. We list here some of the major points arising from these papers.1, B6, C, or D in edible parts of the plant are discussed, together with the possible effects of such increases on plant tolerance to stress.Vitamins are organic compounds that are required in limited amounts for normal human growth and activity and that cannot be synthesized by the human body. Various genetic engineering approaches for increasing the concentrations of vitamin B1 (thiamin) can result in fatal neurological and cardiovascular disorders. Pourcel et al. . Vanderschuren et al.  to such food crops.Vitamin Bn et al.  comment 3 biosynthesis requires UV-B rays for its photochemical conversion from pro-vitamin D3, a process occurring in the human body; therefore, depending on latitude or season, people may be at risk for vitamin D deficiency if sufficient vitamin D is not consumed through supplementation or through a vitamin D-rich diet. Fish are good sources of vitamin D, whereas only small amounts of vitamin D can be found in plants  for humans, for whom severe deficiency causes scurvy and can lead to death. Sub-optimal vitamin C intake, by leading to increased susceptibility to infections and diseases, can represent a health threat for both developing and developed world populations. In the review by Locato et al. , possiblIron (Fe) and zinc (Zn) are two essential metal micronutrients for human health; their deficiencies in the human diet contribute to high rates of mortality in developing countries. Manganese (Mn) deficiency, though less prevalent than Fe and Zn deficiency, can also lead to serious health problems, including birth defects (Bashir et al., Japonica rice variety were also achieved by stacking a set of Fe homeostasis genes (Masuda et al., Success in increasing Fe and Zn concentrations in polished seeds of a major rice variety in Myanmar, through a transgenic approach targeting metal transport and accumulation, is presented by Aung et al. . In anotPvZIP12, is proposed in Astudillo et al. (OsNAC5 gene in senescence and metal re-mobilization (Ricachenevsky et al., Three different gene families have been described in detail and proposed as possible targets for future Zn or Fe biofortification strategies: the NAC transcription factors (Ricachenevsky et al., o et al.  and a mo\u22123 to I\u2212 and that such reduction is dependent, at least in part, on external iodine conditions. Such results suggest the existence of an iodate reductase in plant roots (Kato et al., 3 during growth.Iodine is a non-metal micronutrient that is essential for human health and whose deficiency impairs thyroid functions. When severe deficiency occurs, fetal development can be affected with consequent irreversible brain damage and mental retardation. A possible approach to produce plants biofortified with iodine is to administer exogenous iodine salts to the soil during plant growth. Kato et al.  demonstrThe papers presented in this e-Book demonstrate how knowledge in plant metabolism, physiology, and molecular biology can provide approaches for increasing the nutritional value of plant derived foods. The contributions also draw attention to the need for multidisciplinary efforts to cope with the challenges of food security and micronutrient malnutrition. We believe that the information presented in this e-Book will provide several novel ideas and will stimulate new directions amongst researchers in the field of plant biofortification. We also hope that these contributions can serve as a good source of background knowledge to educate and bring new scientists into the field. We are indebted to the many authors who have contributed to this e-Book and for their continued work in this important field of science. We feel privileged to have had the opportunity to oversee and edit this fine group of papers."}
{"text": "Denollet et al. claim that high social inhibition and negative affectivity, termed type D personality, predict negative cardiovascular disease outcomes, and notably mortality . Our groWe provided data from our study to Grande et al. for inclusion in their meta-analyses . ConsistIn a further meta-analysis, Grande et al. combined multivariate analyses from Denollet et al. that consistently exceeded the number of allowable covariates, making spurious results likely. Problems in the credibility and generalizability of such overfit regression equations  are not Grande et al. found substantial heterogeneity and evidence of publication bias in their meta-analysis and should have further pursued that this was due to what they termed a striking rift between \u201cvery large effects in small studies and low or null effects from the largest studies,\u201d  which weOnly after presenting their analyses, do Grande et al. concede \u201cOur review cannot overcome some serious methodological shortcomings in Type D research,\u201d Grande et al. then cataloged many of the criticisms of this research that we  had prevOur assessment is that this literature is indeed ailing, but we believe that pulling the plug is better than keeping it on life support. There simply is no encouragement from adequately powered studies conducted outside the Tilburg group to continue this line of research. This would be apparent in a meta-analysis that used an appropriate statistical approach in calculating type D and accurately pointed to the source of the publication bias in studies sharing some characteristics: positive results from small samples, inappropriate statistics, and having been conducted by a single investigator group."}
{"text": "In part, this is because viruses so intimately associate with their hosts that decoupling host and virus biology is difficult, and virus-host interactions occur at multiple scales, from within cells to populations, each of which is intrinsically complex. As a consequence, ecologists, population biologists, evolutionary biologists, and researchers from quantitative fields, including mathematics, statistics, physics and computer science, make significant contributions to the field of virology. Our understanding of virus dynamics and evolution has substantially benefited from these multidisciplinary efforts. It is now common to see advanced phylogenetic reconstruction methods used to determine the origins of emergent viruses, to estimate the effect of natural selection on virus populations, and to assess virus population dynamics. Mathematical and statistical models that elucidate complex virus and host interactions in time and space at the molecular and population level are appearing more regularly in virology and biomedical journals. Massive quantities of data now available due to technological innovation in imaging, increased disease surveillance efforts, and novel approaches to determine social contact structure are changing approaches to study the dynamics and evolution of viral infections in heterogeneous environments. The next decade presents exciting new opportunities and challenges for the expanding field of researchers investigating dynamics of viral infections that will lead to innovation and new insight on virus interactions in both individual hosts and in populations. The compilation of articles in this 1.1.et al. [in vitro infection experiments. These investigators assess the dynamics of host innate defenses to two strains of Respiratory Syncytial Virus (RSV) that have distinct epidemiological patterns but can coinfect an individual. The authors used spatial statistical methods to evaluate how the resistance of na\u00efve cells to a challenge infection with one of the RSV strains changed as a function of proximity to a cell infected with a different RSV strain and the time between the primary and challenge infection. In this experimental setting, every infected cell is a data point. An important result of their study is that even in cell lines, asynchrony in growth and replication in a culture can change the susceptibility of cells to infection, which is presumably due to an intrinsic property of replicating or differentiating cells and not an innate immune response to virus infection. However, despite the background heterogeneity in cell susceptibility to infection, the authors demonstrate that one RSV strain, but not the other, can limit the ability of the heterologous strain to establish infection; an effect that would be obscured if the authors had used aggregate instead of point process analysis in their study. Further development of spatial statistical models will be imperative as data on responses of individual cells in population of cells become more widely available.Tissue culture is a mainstay for virologists studying cellular response to virus infection and efficacy of therapeutic interventions and treatment; response variables are typically aggregate counts of infected cells or production of a soluble factor. However, averaging values over cells, which are in different growth phases or stages of viral infection, can obscure or confound important responses to virus infection. Simenov et al.  report oSpecial Issue on \u201cVirus Dynamics and Evolution\u201d reveal important features of virus-host interactions by integrating detailed knowledge of viral life history strategy with viral sequence evolution over the course of infection of the natural host organisms. Virus evolutionary changes are determined by mutation rate and viral generation time and by selective pressures imposed by the host environment. These metrics inform variation in virus replication under changing host conditions. However, there are many features of virus life history strategy that can confound estimating these standard evolutionary parameters. For example, the efficacy of viral strategies to modulate host immunity is not constant over time. As the host environment changes, so does viral replication and this can complicate rate estimates that are based on viral sequence data. Harrison et al. [Three manuscripts in this n et al.  explain et al. [et al. [et al. [Carpenter et al.  address  [et al.  discuss  [et al.  for HBV.et al. [Viral infections, although complex on their own, rarely occur in isolation. Polymicrobial infections can exacerbate clinical consequences to the host but can also attenuate disease. Feline immunodeficiency virus (FIV) infection of its domestic cat host is an exemplary system to explore the mechanisms by which an avirulent FIV strain (PLV) attenuates CD4 cell loss induced by a virulent FIV in the absence of measurable antibody or cellular defenses [et al.  compared1.2.et al. [in vivo infection, virus cycling among host species does not unambiguously constrain virus fitness in either host or lead to a fitness trade off if specialization occurs. On the contrary, fitness can increase in sequential passage of virus between insects and vertebrates and, of significance, virus fitness in some vertebrate or mosquito species may be less constrained than in related host species. Thus, specialization or enhanced fitness in one environment does not necessitate trade-offs. These experimental studies highlight important areas for future research. Much of the work in this field relied on consensus sequencing and therefore failed to assess the full extent of virus diversity. Advances in sequencing technology will allow thorough exploration of sequence diversity from in vitro evolution experiments. However, our understanding of the significance of diversity in viral populations is also limited . DetailWhereas virus life history strategy is a key factor driving virus dynamics and evolution within a host, host life history, behavior, and social structure have profound effects on the patterns of virus transmission and consequently the dynamics of viruses in populations. For example, the number and type of contacts an individual has affects virus transmission in a specified population. Network science provides an intriguing approach to study virus spread in a population of known contact structure . The rel1.3.et al. [Virus infections affect the population structure of host organisms and can have a profound influence on the interaction among individuals and their environment. Hence, the consequences of virus and other pathogen infection are central to the interests of ecologists. Vandegrift et al.  discuss et al.  in this At cellular to population scales, our paradigms in virology are largely based on virus infections that have a detrimental affect on the host. However many\u2014and probably most\u2014viruses are not pathogens and some are beneficial to their host. Not surprisingly, the ecology and biology of apathogenic viruses have not been extensively investigated. The article by Roossinck  provides2.Special Issue reveal new information about virus host interaction at each of these scales and demonstrate the unique perspective that virus evolution provides into the complex environment of the host. New tools will continue to capture virus dynamics and evolutionary change at finer spatial and temporal scales, which will lead to new challenges and opportunities for researchers trained in a variety of disciplines to contribute to data analysis and interpretation. Collectively, these efforts will advance our knowledge of viral pathogenesis, elucidate innovation in evolving protein structures, provide specific targets for therapeutic intervention, and inform models of infection spread in heterogeneous populations.Virus infection is inherently a dynamic process from the protein to the population level. The articles in this"}
{"text": "Transcriptomes as assessed by either microarrays or next-generation sequencing have produced a hitherto unprecedented data flood regarding transcript identity and levels in plant systems. Microarray data has been extensively used over the last 15 years or so and evaluation of the data thus produced has progressed well beyond early statistically quality evaluation and descriptive lists to a mature science whereby gene networks and cascades have been able to provide mechanistic insight. The development of sensitive quantitative PCR for lowly expressed genes such as transcription factors has additionally allowed another layer of complexity to be accessed and the modeling of transcription factor expression with that of target genes has met considerable success. Yet more recently, data emanating from RNAseq studies have greatly improved the coverage of transcript profiling. That said, this technology further compounded transcriptome analysis by making it possible to identify differentially spliced transcripts etc. In this research topic we would like to provide an \u201con the fly\u201d portrait of the use of either microarray or RNAseq based datasets in contemporary Plant Systems Biology.Given the relative simplicity of doing so, much information has been gleaned from microarray datasets by assuming guilt-by-association. The success of this approach is summarized by articles of Provart  and TohgJunker et al.  follow ahttps://www.genevestigator.com/gv). But much information and potentially knowledge is untapped by adopting this approach. This leaves one wondering if aided by modern biostatistics and bioinformatics one shouldn't be able to do better. To improve this situation Klie et al. (However, when it comes to data analysis of whole genome expression datasets, particularly those obtained from complex temporally and/or spatially resolved experiments visualization helps in finding \u201cthe meaning within the noise.\u201d Thus, currently the researcher typically zooms in on a particular subset of the data which excites their biological curiosity, often obtaining such data from public repositories such as genevestigator (e et al.  present e et al.  is appliAs is evident from the multitude of manuscripts dealing with microarray data, there is still much to be learned from these data sets. However, time moves on and whilst it seems difficult to teach old dogs new omics tricks, RNAseq is slowly becoming more and more popular. Already machine learning techniques are trickling in to help separating noise from the data. Thus, Thieme et al.  try to fSuch analyses are assuming, however, that one actually knows which transcripts to deal with. But one of the perceived beauties of RNAseq is that one could learn about the transcriptome on the fly whilst analysing the data by assembling the reads into transcripts. This seems, however, an ambituous goal and thus in their article Schliesky et al.  address Rose et al.  then rouFinally, in his article Kliebenstein , tries t"}
{"text": "The major commercial NGS platforms available to researchers are the 454 Genome Sequencer (Roche), Illumina (formerly Solexa) Genome analyzer, the SOLiD system (Applied Biosystems/Life Technologies) and the Heliscope (Helicos Corporation). The techniques and different strategies utilized by these platforms are reviewed in a number of the papers in this special issue. These technologies are enabling new applications that take advantage of the massive data produced by this next generation of sequencing instruments.Next Generation Sequencing (NGS) refers to technologies that do not rely on traditional dideoxy-nucleotide (Sanger) sequencing where labeled DNA fragments are physically resolved by electrophoresis. These new technologies rely on different strategies, but essentially all of them make use of real-time data collection of a base level incorporation event across a massive number of reactions  reads produced by NGS Technologies. Another review article [In this special issue, nine papers review and demonstrate the utility and potential of next generation sequencing. One of the biggest consequences with NGS technologies is how to deal with all of the data produced by these platforms. Magi et al.  review tlleagues  introduc article  on bioinet al. [Another application that is particularly well-suited for the types of data produced using NGS is microRNA sequencing. MicroRNAs (miRNAs) and short interfering RNAs (siRNAs) are small RNA molecules of 17 to 24 bases that have been shown to play a critical role in gene regulation by mediating RNA interference. Motameny et al. ,6 in thiet al. [et al. [The subjects of metagenomics  and sequencing of ancient DNA samples are two additional areas where NGS platforms have provided unforeseen opportunities for generating previously unattainable levels of understanding from these samples. Rooks et al.  demonstr [et al.  utilized [et al.  review t [et al.  review dThe articles in this special issue represent a cross section of applications demonstrating the utility of NGS. New sequencing platforms are being introduced  by companies utilizing single molecule detection techniques to record individual DNA molecules during incorporation (Pacific Biosciences) or reading DNA directly by sieving it through nanopores. It is an exciting time in the field of genomics with rapidly changing and advancing technologies. The costs of sequence will surely continue to decrease and new applications of this technology will be introduced to address critical areas in academic and clinical research. I would like to thank all the authors and reviewers who contributed to this special issue and look forward to hearing about new sequencing technologies and application advances in the future."}
{"text": "Some of these actions probably occur through non-conductive mechanisms, such as intrinsic enzyme activity or conformational coupling with other membrane proteins , by an interaction mediated by PDZ domain.Following the lead of the seminal studies in lymphocytes  are homo- or heteropentamers of \u03b1 and \u03b2 subunits. These were originally identified in the nervous system, but are now increasingly recognized to be widely expressed outside the nervous system (Egleton et al., Another central aspect of the function of normal and neoplastic cells is the regulation of cell volume, as reviewed by Pedersen et al. . This ap+ to support cancer cell survival and invasiveness and is the only human CA isoform containing an extracellular proteoglycan domain (Monti et al., A key step of the neoplastic progression is the regulation of cell migration, whose derangement is implicated in the metastatic cascade (Becchetti and Arcangeli, Several of the above papers describe the potential therapeutic applications of targeting specific ion channels and transporters. Cancer treatment is however more specifically addressed by Huber et al. , who illBesides illustrating some of the hot topics in the field, the papers of the present Research Topic Issue constitute a most useful introduction to a literature that has already become too vast to be mastered by a single investigator."}
{"text": "Methanocaldococcus jannaschii in 1996 (Bult et al., The publication of the genome of This collection of 11 papers attempts to put this quiet maturation in archaeal molecular biology in context with a mix of overview articles (Atomi et al.,"}
{"text": "Dear Editor,et al.[We thank Rath et al. for the et al. and theiet al. is the same.They are correct in their supposition that the patient reported by us and Patil et al.[et al.[To quote from our article, \u201cWe are reporting this case because orbital involvement of actinomycetoma is very unusual. In our review of the literature, we did not come across any such case.\u201d We do not claim to be the first to report a case of orbital actinomycetoma. Our literature search did not bring up the articles by Pagliani et al. and Sulll.[et al. and we tet al.[At the time of submission of our article (September 2008), we were not aware that this article was to be submitted by the dermatology department . Our ar"}
{"text": "To the Editor,In our review article entitled \u201cMicroRNA dysregulation in multiple sclerosis\u201d published online on January 22nd, 2013, we have made an error that we would like to correct.We request to change the following sentences in the review article:\u201cExamination of Treg cells in MS (De Santis et al., To\u201cExamination of Treg cells in MS (De Santis et al., We would also like to apply this change in a revised figure Figure  that refFrontiers in Genetics and to the authors of the De Santis et al., manuscript, for this error that was not corrected during the review process of our manuscript.We apologize to the readers of"}
{"text": "The burden of post-malaria cognitive impairment is often overlooked. Given the large number of infections occurring worldwide, the magnitude of the problem is likely to be substantial. The objectives of this paper are; (i) to assess the evidence on post malarial cognitive impairment or impact on school education; (ii) to assess the possible positive impact of malaria drug prophylaxis on cognition; and (iii) to suggest recommendations on minimizing the burden of post-malarial cognitive impairmentPUBMED and SCOPUS were searched for all articles with the key word 'Malaria' in the title field and 'cognitive impairment' in any field. Google Scholar was searched for the same keywords anywhere in the article. The search was restricted to articles published in English within the last 15 years (1995-2010). After filtering of abstracts from the initial search, 44 papers had research evidence on this topic.Cognitive abilities and school performance were shown to be impaired in sub-groups of patients  when compared with healthy controls. Studies comparing cognitive functions before and after treatment for acute malarial illness continued to show significantly impaired school performance and cognitive abilities even after recovery. Malaria prophylaxis was shown to improve cognitive function and school performance in clinical trials when compared to placebo groups. The implications of these findings are discussed. Mortality and morbidity due to malaria is still substantial in many tropical countries. In 2006, 247 million cases of malaria were estimated, resulting in 881,000 deaths [There exists an important hidden burden of malaria, namely, that of cognitive impairment and effects on school performance resulting from malaria infection in children. This effect could be postulated to have a long-lasting impact on patients' lives preventing them from achieving their full potential. This impact is difficult to summarize in terms of DALYs or traditional cost evaluation methods of estimating direct losses due to illness. However, given the large number of infections occurring worldwide annually, and the potential impact on lives of patients and family, this hidden burden is likely to be considerable.et al in 2001 on the same topic concluded that malaria infections  have a lasting effect on cognition, behaviour and performance in children [et al (2006) on post malarial cognitive impairment conclude that a significant proportion of children with cerebral malaria and severe falciparum malaria are at risk of subsequent cognitive impairment. This impairment in cognitive abilities was seen in all cognitive spheres; language, attention, memory, visuospatial skills and executive functions [A review published by Holding children . Howeverunctions ,4.This paper reviews the current evidence on cognitive impairment due to malaria and aims: (i) to assess the evidence on post malarial cognitive impairment or impact on school education; (ii) to assess the possible positive impact of malaria drug prophylaxis on cognition; and (iii) to suggest recommendations on minimizing the burden of post-malarial cognitive impairment.PUBMED and SCOPUS were searched for all articles with the key word 'Malaria' in the title field and 'cognitive impairment' in any field. Google Scholar was searched for the same keywords anywhere in the article (both terms together). The keywords were kept less specific to collect all relevant articles in the first screening. The search was restricted to articles published in English within the last 15 years (1995-2010). There were 971 abstracts in the original search with these restrictions. The software Endnote X3  was used to filter articles. Bibliographies of cited literature were also searched. All abstracts were read independently by the three authors, and key articles were identified based on a consensus among all authors. Related or cited papers were also included. Sources were screened for relevance to the topic. These sources included review articles published in core clinical journals, cohort studies, interventional studies, case control studies, case series and cross sectional analyses related to malaria and post infection cognitive impairment. The epidemiological data were downloaded from the websites of international agencies, such as the World Health Organization (WHO). After filtering of abstracts from the initial search, only 44 papers had research evidence on this topic.et al [In the past, recovery from cerebral malaria has generally been thought to be complete. Early studies suggested that neurological sequelae were relatively uncommon ; howeveret al  who asseet al [Idro et al  reportedIt is interesting to note the high percentage of behavioural problems observed in this series which included behaviours closely resembling a formal diagnosis of attention deficit hyperactivity disorder (ADHD), conduct disorder and pervasive developmental disorder. While it may be questioned whether the behavioural disorders were causally linked to cerebral malaria, it should be noted that the behavioural problems had started after recovery from cerebral malaria. The changed behaviours were well noticeable and disruptive to daily functioning of the child and family. These changes could be attributed to an alternative explanation (side effects of phenobarbitone) in only one child.Another study of behavioural problems following a diagnosis of cerebral malaria (n = 64), has also reported effects such as withdrawn/depressed behaviour(15.6%), thought problems (12.5%), aggressive behaviour (9.4%) and oppositional defiant behaviour (9.4%).et al [Though cerebral malaria may have a causal role in cognitive impairment, some authors hold that seizures per se during a malarial episode may not be strongly associated with cognitive impairment. Kihara et al  assessedet al retrospectively assessed a cohort of children aged 6-9 years who had an episode of cerebral malaria [et al, Carter et al showed that persistent epilepsy after malaria has an impact on cognition. Abubakar et al [et al, the role of seizure prophylaxis during an acute phase is still open to discussion. The failure to see a benefit in the treatment arm may be due to the use of phenobarbitone in the initial study which itself can cause cognitive impairment.In addition to short-term ill effects, cerebral malaria may have a long-term impact on cognition as well. Carter  malaria -12. Agaiar et al  assessedet al [In another prospective study over two years, John et al ,15 asseset al -18.et al [Many authors have acknowledged the difficulty in applying formal neuropsychological testing adopted in western populations to rural African communities given the cultural, language and educational differences. Therefore Kihara et al  have recet al [et al [et al [et al [et al [et al [Reliable predictors for cognitive impairment following cerebral malaria are clearly of importance. Kihara et al  identifil [et al  in theirl [et al . Holdingl [et al  suggest l [et al  in a sepl [et al describe l [et al  in theirl [et al ,12.et al, have assessed the impact of malaria on cognitive performance in Sri Lanka where a majority of the malaria infections acquired by children are acute uncomplicated febrile episodes from which they make an apparent complete recovery when treated. Several studies were carried out taking into consideration that school performance is a reflection of the cognitive ability of a child and is dependent on a number of factors including facilities available at school, the quality of teaching and other social factors such as parental supervision. In the first study, Fernando et al [There are few studies assessing the impact of post-malarial cognitive impairment outside Africa. Fernando do et al  assessedIn order to confirm these findings, two other studies were carried out in Sri Lanka ,24. The A further investigation was carried out to determine the impact of an acute attack of malaria on short-term educational achievements and on school absenteeism . Six hunet al [th centile for class/grade) school performance (p=0.04). Interestingly, in a small scale study (n=97) Boivin et al [Al Serouri et al  in a caset al . The numin et al  have demMany of the studies carried out outside Africa have demonstrated that uncomplicated malaria per se was a significant predictor of cognitive function after controlling for potential confounding factors. This further strengthens the fact that malaria contributes significantly to loss of school time, ill health and poor performance.et al [et al [Many of the studies cited above had arms with children diagnosed as having cerebral malaria. How certainly a diagnosis of cerebral malaria can be made would also affect the interpretation of results. In an autopsy study of 31 children thought to have died from cerebral malaria, Taylor et al  demonstrl [et al  and overl [et al -32. The l [et al . It is net al [et al [Taking this factor into account, Birbeck et al  followedl [et al  in anothHowever, it needs to be appreciated that the studies cited above are not comparable to each other in their designs and results for many reasons. Some have followed up patients with severe malaria, some with cerebral malaria and some have compared these two entities with healthy community controls. Others are more different in that they have enrolled participants from communities who would have had a spectrum of malaria infections from asymptomatic parasitaemia to severe malaria. Similarly, the age range of children tested also varied significantly and this brings forth two issues; the inapplicability of formal cognitive testing to very young children and the differences of cognitive impairments that would be observed depending on the age. The developing brain is more vulnerable to insults but some authors suggest that it may recover from it also due to plasticity. Damage to neuronal circuitry during early childhood may cause obvious defects in memory, language and learning but more subtle changes involving social sensitivity, social integration and executive functions may appear later as the child ages and when such skills become important. On the same note, there are many other confounding factors that can affect the observations of cognitive impairment such as, home and family environment, nutrition, quality of teaching, cultural and language barriers in applicability of neurocognitive testing. In fact, malaria transmission itself is determined by prevalent socioecomonic conditions of the community which may render some children more vulnerable than others and some communities more at risk compared to others. Therefore when referring to cognitive and behavioural effects of the studies cited above, all these coviariates and confounding factors have to be acknowledged. The 'cognitive' impact itself is not a single entity but varies according to the severity of illness, age of the child and methods of measurement.et al [While there are many studies assessing the cognitive impairment of children after malaria, the impact on adults is not addressed by systematic research. In an earlier study, Dugbartey et al  have shoIt is of fundamental interest to establish whether malaria is causally related to cognitive impairment, poor school performance and other behavioural disturbances as reported in previous studies. Cognitive impairment can be hypothesized to be an end result of many confounding factors  and it is important to understand whether malaria itself can be demonstrated as an independent causative factor for cognitive impairment.et al [In the study by Idro et al  the neuret al [et al [et al [et al [In the study by Kihara et al  which shl [et al ,11 the rl [et al  also shol [et al  which deIn the other community based studies outside Africa, similar adjustments were made for confounding factors and still the results showed a significant association even between uncomplicated malaria and cognitive impairment or school performance -26.Overall, in summation, it is fair to assume from reported methodology that all the key studies had made adjustments for potential confounding factors and still found a significant association for post malarial cognitive impairment after complicated/cerebral malaria as well as after uncomplicated attacks. This strongly favours an argument for malaria as an independent causative factor for cognitive impairment. The studies on the impact of malarial prophylaxis on cognition quoted later under the subtopic 'malaria and cognitive impairment; strategies on prevention and rehabilitation' of this article (see below) provides further evidence regarding the causal role of malaria in cognitive impairment. Still, what is obscure is the exact pathology for this impairment. The following section summarizes the current knowledge base in this regard.et al assessed the levels of different cytokines in cerebrospinal fluid (CSF) in 76 children with cerebral malaria and compared it with eight controls [The pathology of cerebral malaria and its neurocognitive sequelae is still open to debate. It is assumed that parasitic sequestration within cerebral circulation with resultant hypoxia, host immune response and cytokine induced damage via nitric oxide production may contribute to neuronal cell death . Animal controls . Many cyet al [As certain cognitive domains  and higher functions (speech and language) are shown to be selectively affected in cerebral malaria, it is also plausible that imaging studies such as magnetic resonance imaging (MRI) and positron emission tomography (PET) may reveal the involvement of specific brain areas related to these functions to be affected by cerebral malaria. However there are no case series or systematic studies with MRI/PET evidence other than isolated case reports ,40. Potcet al  report aet al ,14,39.Plasmodium berghei strain ANKA do manifest many characteristics of infection similar to cerebral malaria in humans. Desruisseaux et al [Attempts are being made to model the impact of cerebral malaria in animal models in view of extrapolating the findings to humans. However, such comparisons may not be valid due to species differences of both the host and the parasite. Still, it is observed that mice strain C57BL/6 infected with ux et al  studied ux et al .Failure to understand the pathogenesis of cerebral malaria has significantly slowed the development of neuroprotective pharmacological measures during the acute stage of illness. Different agents are being assessed on animal models with promising results but human trials are not still under way. The B5 complex provitamin pantetheine and the immunomodulatory agent glatiramer acetate have both shown promise in animal studies by down regulating the immune response . High doet al[Cognitive impairment of children living in endemic areas and the impact of prophylaxis has been assessed by a limited number of studies ,47,46,47et al [et al [A study with a different experimental design  assessedet al . In the l [et al  when thel [et al .et al [A more recent trial by Clarke et al  assessedConsidering the outcome of this study, a follow up controlled randomized trial is now underway in Kenya that plans to assess the impact of improved health  on improved literacy skills. The randomized design has divided schools in the region to 4 groups (25 schools in each group) to receive malaria intervention alone, literacy intervention alone (skill development of teachers in teaching English and Swahili), both interventions and none (control). The study is expected to be completed by 2012 .Still, rather than concentrating on pharmacological prophylaxis alone, there are many other cost effective simple measures of preventing malaria such as residual insecticide spraying and insecticide impregnated bed nets . Simply Another avenue to explore is the prevention of identified adverse prognostic indicators for subsequent cognitive impairment by the studies cited above. These include; preventing hyperpyrexia, hypoglycaemia, malnutrition and seizures during acute illness. The place for such measures needs to be properly assessed by trials.et al [The 'rehabilitation' strategies for post malarial cognitive impairment are another area assessed by several recent trials. The effect of cognitive training on children affected by severe malaria has shown a positive impact in a study by Bangirana et al . Sixty fet al [Cognitive rehabilitation in cerebral malaria has still not been evaluated extensively by systematic studies. Much of the speculated benefit of cognitive training is extrapolated from the studies on cognitive training in traumatic brain injury. Though 'traditional' therapist centered or computer based cognitive retraining may indeed be beneficial, the feasibility of such interventions in resource limited settings  is questionable. In a recent review on cognitive rehabilitation of children with cerebral malaria, Bangirana et al  describeet al [The number of studies assessing the impact of malaria on cognitive functions were few and those assessing the impact of prophylaxis were even fewer. The number of patients enrolled in observational studies and case series were in the range of 20-200 except in the trial by Clarke et al . In addiHowever despite these limitations some common themes emerge in the analysis of observations in the previously mentioned studies:1. The cognitive abilities and school performance were impaired in the groups with malaria  in almost all the studies at a statistically significant level compared to healthy controls.2. Hypoglycaemia, seizures and coma during cerebral malaria have been shown to predict later cognitive impairment ,17,20.3. While observations are made regarding cognitive impairment based on neuropsychological test batteries that concentrate on clinical performance, these are not supported by biochemical or imaging studies which could help to elicit the underlying pathology.4. Studies comparing cognitive functions before and after treatment of acute illness continue to show significantly impaired school performance and cognitive abilities even after recovery compared to healthy controls ,25,26.5. However, the three studies on malarial prophylaxis all show improved cognitive function/school performance compared to placebo groups at the end of follow up which in two studies were more than one year ,47,49.Given the large number of infections in endemic areas, these findings carry much weight and needs to be highlighted. This 'hidden' burden of malaria is often unnoticed and overlooked but may place vulnerable populations  at a disadvantage by causing cognitive impairment resulting in poor school performance and non achievement of full potential in life. This burden of illness is difficult to quantify and is probably much larger than the already publicized tangible costs of malaria. It must also be highlighted that treating an established attack of malaria in a child and preventing malaria in the same child have different consequences. As suggested by the available evidence, the latter option is the better choice.Therefore it is recommended that:1. Countries where malaria is endemic should pay special attention to prevent malaria by appropriate prophylaxis for populations at risk.2. Such programmes must pay special attention to infants, toddlers and children as this is a crucial age in cognitive development and for schooling. However, cognitive impairment in adults may also be significant but unfortunately this has not yet been assessed properly.3. The impact of malaria on cognitive development must be highlighted and the public should be educated to ensure compliance in prophylaxis campaigns.4. Early identification and treatment of malarial fever should be given priority with providing necessary infrastructure and staff education on clinical and parasitological diagnosis.5. Attacks of cerebral malaria, coma, seizures and hypoglycaemia during an acute attack must be actively looked for and avoided to prevent later cognitive impairment and local guidelines should stress these facts.Areas for further research on this timely topic include;1. Establishing the effect of acute malarial infections and prophylaxis on cognitive functions of adults in endemic areas.2. Observational studies to identify the pathophysiology of post malarial cognitive impairment by correlating biochemical markers, serum and CSF cytokine levels and imaging studies with clinical findings.3. Assessment of long term cognitive impact of recurrent malarial attacks with a longer prospective follow up (more than one year) with intermittent cross sectional assessments.4. Development of methods to quantify the impact of post malarial cognitive impairment in terms of financial costs.The authors declare that they have no competing interests.All authors have participated in designing, article search, information coding and writing of the manuscript. All authors have read and approved the final manuscript"}
{"text": "Dear Editor,In recent article which is published in your journal Crisan D et al.  has beenNow in calculation of the severity of liver fibrosis, liver biopsy stayed the gold standard; however the acceptability of this method by patients is low. In addition this method has some major limitation and its limitations made it a non-favorable method . But it"}
{"text": "Attention is one of the oldest and most pivotal themes in cognitive science. A current and widely accepted theory holds that anatomically-distinct, hierarchically-organized networks, each responsible for specific components of the attention process , constitute the attention system (Posner and Petersen, Geva et al.  recentlyA first interesting aspect of Geva et al.'s paper relates to the investigation of the putative interaction among the different attention networks, and in particular between the alerting and orienting components, a somewhat controversial topic that has recently received great interest. In fact, while Callejas et al.  showed tper se as in earlier theories of LC\u2013NE activity (Aston-Jones et al., A second aspect of Geva et al.'s work that deserves particular attention is related to their attempt to extend the Aston-Jones and Cohen's  adaptiveIn summary, Geva et al.  provide"}
{"text": "The purpose was to develop a questionnaire, gathering the professionals\u2019 opinion, to measure the degree of collaboration between clinicians from different levels of care  in a given healthcare organisation. This questionnaire was originally developed to assess processes of care integration in the Basque Health System (Spain), but can also be used in other contexts.The questionnaire was based on the four-dimension model and 10 indicators of interprofessional collaboration in healthcare organisations proposed by D\u2019Amour et al. [The resulting questionnaire was pre-tested and its construct validity and homogeneity evaluated in three healthcare organisations of the Basque Health Service.A 10 items questionnaire has been developed. Each of its items corresponds to one of the indicators proposed by D\u2019Amour et al. ["}
{"text": "Acute appendicitis is the most common surgical abdominal emergency. Immidiate diagnosis of this disease is crucial, because this condition can lead to appendiceal perforation, potential peritonitis, and even death. We read with great interest the article \u2018The role of red cell distribution width (RDW) in the diagnosis of acute appendicitis: a retrospective case-controlled study\u2019 by Narci et al. and wanted to discuss whether RDW alone provide certain information about the inflammatory status of the patient with acute appendicitis. We read with great interest the article \u2018The role of red cell distribution width in the diagnosis of acute appendicitis: a retrospective case-controlled study\u2019 by Narci et al. . They aiRDW which is used in the differential diagnosis of anemia, is an automated measure of the variability of red blood cell size . PreviouIn a previous study, two novel biomarkers, calprotectin (CP) and serum amyloid A (SAA) were found to be related to acute appendicitis . Recent We are of the opinion that the findings of Narci et al.  will leaWe have no competing interests to declare."}
{"text": "Additional remote-sensing information and output from land surface models were used to identify that groundwater losses are the major source of this trend. The approach used in this study provides an example of \u201cbest current capabilities\u201d in regions like the Middle East, where data access can be severely limited. Results indicate that the region lost 17.3\u00b12.1 mm yr\u22121 equivalent water height of groundwater during the study period, or 91.3\u00b110.9 km3 in volume. Furthermore, results raise important issues regarding water use in transboundary river basins and aquifers, including the necessity of international water use treaties and resolving discrepancies in international water law, while amplifying the need for increased monitoring for core components of the water budget.In this study, we use observations from the Gravity Recovery and Climate Experiment (GRACE) satellite mission to evaluate freshwater storage trends in the north-central Middle East, including portions of the Tigris and Euphrates River Basins and western Iran, from January 2003 to December 2009. GRACE data show an alarming rate of decrease in total water storage of approximately \u221227.2\u00b10.6 mm yr Amery and Wolf, Wolf and Newton, Wolf, Integrated Regional Information Networks, U.S. Department of Agriculture (USDA), Michel et al., Sullivan, Water scarcity in the Middle East, and the high frequency of conflict that emerges over what few resources do exist, is well established [e.g., Solomon, Food and Agriculture Organization (FAO), Wolf and Newton, Bayazit and Avci, FAO, Water management in the Tigris-Euphrates River Basin has been historically challenging Solomon, . The TigUnited Nations, Weiss, Two major issues complicate water management in the region. First, there are no formal water allocation rights for both surface and groundwater. At the core of this dilemma are underlying differences in the interpretation of international water law [Chenoweth et al., Jones et al., Kavvas et al. [A second challenge is the paucity of hydrologic data for the region. Inconsistent monitoring combined with a lack of data transparency and accessibility is a problem that plagues water managers around the globe, and the Tigris-Euphrates region is no exception. Such data scarcity and inaccessibility result in an incomplete understanding of water availability and use in this area of the Middle East. Although there have been other studies in the region [s et al.  showed tTapley et al., Lettenmaier and Famiglietti, Rodell et al., Tiwari et al., Famiglietti et al., Rodell and Famiglietti, Wahr et al., Ramillien et al., Syed et al., Yeh et al., Rodell et al., Ramillien et al., Zaitchik et al., Rodell et al., Tiwari et al., Famiglietti et al., Reager and Famiglietti, Andersen et al., Yirdaw et al., Leblanc et al., Agboma et al., Chen et al., Swenson and Wahr, Wang et al., Satellite observations of time-variable gravity from the Gravity Recovery and Climate Experiment (GRACE) satellite mission [Wada et al. [Siebert and D\u00f6ll [In this study, we used 84 months of GRACE data (January 2003 to December 2009) to examine the behavior of water storage in the north-central region of the Middle East, an area that includes most of the Tigris and Euphrates River Basins and western Iran. Additional data sets, including precipitation, evapotranspiration, streamflow, reservoir levels, and soil moisture, were compiled to help characterize the causes of observed variations and emerging trends. As an area that is well known for water scarcity and tension over transboundary waters, the Tigris-Euphrates region offers a compelling example of the power of satellite observations to provide insight into critical water resource issues in regions where hydrological observations are otherwise difficult to obtain. a et al.  and Sieband D\u00f6ll  develope2. It includes most of the Tigris River Basin, the upper and middle section of the Euphrates River Basin, and western Iran. Consequently, we refer to the masked region in The specific study area within the Tigris-Euphrates region see  was seleGerman Federal Institute for Geosciences and Natural Resources (BRG) and United Nations Educational, Scientific, and Cultural Organization (UNESCO), The TEWI region spans the countries of Turkey, Syria, Iraq, and western Iran. Portions of Georgia and Azerbaijan, as well as all of Armenia, are also included in the study region, as are several large surface water bodies, namely, Lake Daryace, Lake Van, Lake Tharthar, the Asad Reservoir, and the Qadisiyah Reservoir. In addition to the area's surface water, a complex groundwater system [Siebert et al., Land use within the broader area surrounding the study region must also be considered. This broader area encompasses southeast Turkey, where most of the water management infrastructure\u2014dams, reservoirs, and canals\u2014of the GAP project is located. Additionally, there is extensive irrigation for agriculture in the study region and the broader surrounding [Chambers, Swenson and Wahr [Swenson and Wahr, Velicogna and Wahr, \u22121) was computed after removal of the annual signal. Note that the impact of contributions of the Caspian Sea, which abuts the TEWI region to the northeast, to variations in total water storage, were determined to be minor, accounting for less than 1.5% of the TEWI trend in total water storage.We used 84 months, from January 2003 to December 2009, of GRACE-derived variations in total terrestrial water storage computed at the Center for Space Research at the University of Texas at Austin [and Wahr , 2009 inRodell et al., Xie and Arkin, Derber et al., Pfaendtner et al., An extensive search for hydrological data in the region confirmed that in situ observations were publicly unavailable during the time period of interest. Consequently, to better understand the water balance dynamics in the study region, we used output from the NASA Global Land Data Assimilation System (GLDAS) [Liang et al., Chen et al., Koren et al., Dai et al., Kato et al., Koster et al., Syed et al., Zaitchik et al., In this study, we used the results of three land surface models from GLDAS\u2014VIC [Observed precipitation and model outputs for evapotranspiration and streamflow were combined in the water balanceP is precipitation, E is evapotranspiration, Q is streamflow, and all are expressed in mm mo\u22121. Model-derived\u22121) of the anomalies of total water storage described above. GLDAS outputs for soil moisture and snow water equivalent were combined with satellite altimetry measurements of lake and reservoir heights (described below) in order to understand the respective contributions of each to the total water storage variations from GRACE. Outputs were prepared as monthly anomalies with respect to the study mean (mm) and as trends (mm yr\u22121) after removal of the annual signal.where Laboratoire d'Etudes en G\u00e9ophysique et Oc\u00e9anographie Spatiales (LEGOS), Cr\u00e9taux et al., Remotely sensed altimetry data from the Hydroweb database at Laboratoire d'Etudes en G\u00e9ophysique et Oc\u00e9anographie Spatiales (LEGOS) were used to calculate variations in water storage from surface water bodies [\u22121) was also determined after the annual signal was removed. We used these data to ultimately infer the contribution of surface water variations to the total water storage variation observed by GRACE.Altimetry data for monthly water heights were converted to monthly changes in water volume using measurements of the mean surface area for the respective water bodies, as provided by LEGOS. We combined these values and divided by the total area of the region to calculate the anomaly of surface water storage (mm) with respect to the mean of the study period. The trend in surface water storage  and SW\u2032 (6.4 mm), respectively, onto the least-squares-estimated trends and are 0.6 mm yr\u22121 and 0.4 mm yr\u22121, respectively. Errors for soil moisture and snow water equivalent trends are the standard deviations of the trends computed from the three land models used in the GLDAS simulations , using the methods based on the study by Kato et al. [\u22121 and 0.5 mm yr\u22121, respectively.o et al. , which sG\u2032 is computed similarly to equation .Monthly error on equation  and plotGRACE observations of monthly terrestrial water storage anomalies were compared with the GLDAS-simulated anomalies for the study region, which were taken as the mean of the three land surface models . The comRodell and Famiglietti, Rodell et al., Rodell et al., Syed et al., Swenson and Wahr, Swenson et al., Yeh et al., Syed et al., Wahr et al., Swenson and Wahr, Swenson and Milly, Niu et al., Syed et al., Niu et al. [Lo et al. [First, numerous studies have demonstrated that the GRACE data capture natural water storage variations very well when compared with observations [u et al.  found tho et al.  used GRATiwari et al. [Famiglietti et al., Third, land surface model simulations of total water storage will deviate significantly from GRACE observations in areas where human water use and management  dominate the regional storage balance. For example, i et al.  subtractSwenson and Wahr, Wang et al., Famiglietti et al., Rodell et al., Syed et al., 2008; Yeh et al., Given the fact that the Tigris-Euphrates River Basin has extensive water infrastructure, the impacts of water management may significantly influence the trend in water storage anomalies in the TEWI region [\u22121 for the study region. This equates to a \u221220.5\u00b10.4 km3 volume loss of water each year, for a total volume loss of approximately \u2212143.6\u00b12.8 km3 during the study period. This rate of water loss is among the largest liquid freshwater losses on the continents [Rodell et al., 3 loss during the 7-year study period is nearly equivalent in volume to the entire Dead Sea, which has an average volume of 147 km3.\u22121, and the trend in snow water equivalent was \u22120.9\u00b10.5 mm yr\u22121, representing volumetric losses of \u22122.3\u00b11.4 km3 yr\u22121 and \u22120.7\u00b10.4 km3 yr\u22121, respectively. These negative trends are largely climate driven and reflect the regional drought mentioned above. Together they account for roughly one fifth of the observed water losses.\u22121 with an equivalent volume loss of \u22124.4\u00b10.3 km3 yr\u22121, or nearly 20% of the total volume of water lost during the 84 month period studied. It is likely that our surface water trend underestimates the actual trend as only five water bodies comprised the calculation, Lakes Daryace, Van, and Tharthar and the Asad and Qadisiyah Reservoirs, and changes in the respective surface areas are not taken into account. As mentioned above, the five water bodies for which altimetry data were available likely represent approximately two-thirds of the actual surface water storage changes within the boundaries of the study area . By assuming a constant surface area, our estimate of monthly surface water storage is overestimated; however, with this assumption of constant surface area, the rate of decrease, or trend, is actually underestimated. Thus, in both cases (missing reservoirs and neglecting surface area shrinkage), we underestimate the surface water storage trend. Consequently, our estimates in the residual groundwater storage component may be overestimated. As discussed above, we acknowledge the shortcomings and additional uncertainties that this contributes to the study; however, we suggest that this work offers an example of a \u201cbest available\u201d approach for regions where in situ data are inaccessible.Surface water storage anomalies are shown in \u22121 , a considerable loss that accounts for 63% of the total water storage change from 2003 to 2009. As seen in Following equation , groundw3 over the 7-year period studied. This loss is particularly alarming for regions such as the TEWI region, which is already facing severe water scarcity. The analyses presented here suggest that groundwater depletion is the largest single contributor to the observed negative trend, accounting for approximately 60% of the total volume of water lost, the majority of which occurred after the onset of drought in 2007. As we do not have in situ data to validate these conclusions, we acknowledge that there is uncertainty in this analysis, which we have attempted to quantify. However, we believe that this combination of remotely sensed and modeled data provides a very valuable alternative for understanding hydrologic changes occurring in data-scarce regions.The GRACE data indicate a total water volume loss of nearly 144 kmAlipour et al., Lashkaripour et al., Motagh et al., Michel et al., Although in situ hydrologic observations are nearly impossible to obtain, the results presented here are consistent with published reports from the region. Land subsidence due to overabstraction of groundwater near Tehran, Iran, is well documented [Famiglietti et al., Chulov [Chulov [Water use behavior in Iraq during the study period followed the typical pattern of increased groundwater abstraction in response to drought and declining surface water availability [, Chulov , by the  [Chulov  noted thSalman, UN Environmental Program (UNEP), Wolf and Newton, The water management response to the drought in the Tigris-Euphrates Basin portion of the study area, and the overall negative TEWI water storage trend, raises the critical issue of effective, science-informed transboundary water management strategies. Unfortunately, international water law fails to provide a guiding principle for transboundary management in the Tigris-Euphrates Basin as its application varies from nation to nation. Consequently, Turkey, Syria, and Iraq have foregone any legally binding water allocations or management practices for the two rivers. In the absence of binding agreements, downstream users\u2014Syria and Iraq\u2014are dependent on upstream water management decisions\u2014by Turkey\u2014which ultimately determine the downstream flows of the Tigris and Euphrates [Directorate of State Hydrolic Works (DSI), Harris, Ozdogan et al., FAO, Zawahri, Without an effective international water management strategy, each country is free to act unilaterally. Economically, each is dependent on Tigris and Euphrates water for agricultural irrigation, a core component of the national economies. In fact, the main purpose of the expansive GAP was to provide water resources for agriculture expansion in southeast Turkey [USDA, The consequences of this lack of transboundary management are clear from this study. The ultimate downstream user is left with little surface water availability and must deplete its nonrenewable reserves of groundwater. After the drought began in 2007, agricultural productivity declined for all three nations. Upstream, Turkey was least affected, with most crop yields slightly declining or remaining constant. However, downstream in Syria and Iraq, significant, larger declines occurred in all crops, particularly barley USDA, . The dec3 of water was lost in the TEWI region from 2003 to 2009. Using supplementary data sets from global hydrologic models and from satellite altimetry in a mass balance framework, we determined that the drivers of this trend were a combination of drought and corresponding increases in groundwater use. Approximately 91 km3 of the total amount of water lost during the study period came from groundwater.Our analysis highlights the role that the GRACE mission, and other recent and near future advances in hydrologic remote sensing, can play as important new tools for regional and transboundary environmental decision making. The study described here offers a valuable and unique opportunity to understand hydrologic trends in a data-inaccessible region such as the region of the Middle East studied here. Using GRACE data, we reported that nearly 144 kmOur analysis also placed this research in its regional economic and political context. Economically, this crisis resulted in the loss of agricultural yields, unemployment, emotional hardship, and mass migrations. Politically, the response to the drought represents a missed opportunity for cooperative transboundary water management.Swenson and Wahr, Tiwari et al., Rodell et al., Famiglietti et al., Famiglietti et al., Wood et al., Hopefully, we provided valuable insights for a region with little transparency in its water management decisions and few publicly available data sources. Although there is no substitute for ground-based observational data, GRACE and other emerging satellite water sensors will provide a unique tool for water management across the globe. Presented with a holistic picture of changing water availability, while confronted with the common problems of preserving and protecting this shared resource, nations and states may experience new incentives to collaborate on water management issues across political boundaries. Moreover, the synoptic view from space may ultimately render data denial and management opacity policies obsolete, as water management practices are being increasingly revealed from space [Emerging advances in hydrologic remote sensing and hydrological models, combined with enhanced access to observational data, suggest that the opportunity to construct the most accurate and holistic picture of freshwater availability, for a particular region or across the globe, is now on us. Such science-informed studies are essential for more effective, sustainable, and in transboundary regions, collaborative water management."}
{"text": "Laparoscopy was introduced more than 15 years ago into clinical practice. However, its role in colorectal surgery was not well established for want of better skills and technology. This coupled with high incidences of port site recurrences, prevented laparoscopic surgery from being incorporated into mainstream colorectal cancer surgery. A recent increase in the number of reports, retrospective analyses, randomized trials and multicentric trials has now provided sufficient data to support the role of laparoscopy in colorectal cancer surgery. We, thus, present a review of the published data on the feasibility, safety, short - and long-term outcomes following laparoscopic surgery for colorectal cancers. While the data available strongly favors the use of laparoscopic surgery in colonic cancer, larger well powered studies are required to prove or disprove its role in rectal cancer. The morbidity and mortality associated with surgical procedures performed on the colon and rectum have plagued surgeons since time immemorial. As surgeons began to perform open colorectal surgery with increasing confidence these very same problems assumed high significance until the principles of antisepsis and the refinements in surgical technique began to make a considerable dent in these negative outcomes. At this same time, surgeons had already explored the role of minimal invasiveness in treating colorectal problems, viz. the use of the sigmoidoscope to deflate a sigmoid volvulus, perineal procedures for prolapse in elderly persons, etc. The laparoscopic cholecystectomy in 1987 in France, performed by Philipe Mouret for the first time during a laparoscopic gynecologic surgery, rapidly established its role in place of open surgery.[Laparoscopy for colorectal cancers has not gained universal acceptance for a number of reasons3Questions on feasibility: Laparoscopic large bowel surgery is much more complicated than laparoscopic cholecystectomy with a steeper learning curve. It requires more advanced laparoscopic technique.Early reports of port-site recurrence / implantation in laparoscopic port sites.\u20138Presence of an anastomosis or stoma prevents rapid discharge from hospital.The efficacy of large bowel laparoscopic surgery for cancer with respect to factors like tumor clearance and the fear that laparoscopic surgery enhances tumor dissemination.Safety - this implies that laparoscopic surgery carries with it not only some of the general complications encountered with surgery on the bowel, but also a set of unique complications that can occur more or sometimes exclusively only in laparoscopic surgery, e.g., pneumothorax, gas embolism, port site hernias, etc.Advances in techniques of laparoscopy that have paved the way for a shift in the role of laparoscopic surgery in colorectal diseases from the initial intended role of an adjunct to open surgery, to an important operative modality have been, firstly, the realization of the benefit of such a procedure in elderly patients where the morbidity of the large incision of open surgery can be overcome by the reduction in pain and overall bacterial contamination. Videolaparoscopic techniques in colorectal surgery were used for the first time in 1990 by Moises Jacobs in Miami, Florida while performing a right hemicolectomy. The deveThe most important aspect if the feasibility of laparoscopy has to be assessed in case of colorectal malignancies is to unconditionally prove that the oncological resection, i.e., the margins of resection - proximal, distal and circumferential and the number of nodes harvested are comparable, if not better than in open surgery.et al also concluded that the distance of the tumor from resection margins and the number of lymph nodes harvested with the operative specimen did not vary from those obtained in open surgery.[et al, however, noted that the difference in distal resection margins (4.6 cm in the lap group versus 5.3 cm in the open group) were statistically significant in favor of open surgery. On the basis of correlation they concluded that laparoscopic surgery was as adequate as the conventional approach. Bretagnol et al, have shown that R0 resections could be achieved in 93% of patients undergoing laparoscopic low colorectal and coloanal surgeries.[Numerous studies313 in th3 surgery. A recent surgery. showed turgeries.et al[The introduction of laparoscopy into the armamentarium of surgery for colorectal cancer has brought, along with the novel idea of minimal access, a novel set of complications associated with the creation of pneumoperitoneum, port placement and diathermy use that require a considerable amount of skill as well as specialized training if they have to be prevented. et al concludeet al to 29%.[et al The concet alet al,[et al,[Braga et al, in theirl,[et al, have shol,[et al, on the sl,[et al, have beel,[et al, has concet al,[et al,[Laparoscopic colorectal surgeries have constantly been under scrutiny with respect to the long-term outcomes - survival data and recurrence rates. The data available\u201335 has s1836et al, have evel,[et al, have in l,[et al, has showl,[et al,40 have set al[et al,[et al,[After the first reported port site metastasis in 1978, numerouset al had stroal[et al, found noal[et al,44\u201346 foul,[et al, the incil,[et al, meticulol,[et al, wideningl,[et al,While the operative time for laparoscopic surgery is obviously more than that for open surgery, there are several beneficial outcomes resulting directly from the use of laparoscopy as compared with open surgery. As there is no large abdominal incision, the corresponding postoperative pain and the ensuing need for analgesia is reduced.23274748 23274729The incidence of small bowel related problems postoperatively including adhesive obstruction and the incidence of postoperative ventral hernias have also been seen to be on the lower side in the laparoscopically resected group of patients.The incidence of injuries to the pelvic autonomic nerves during dissection in rectal cancers has been associated with bladder and sexual dysfunction. An increased rate has been noted in some studies.\u201353 This Laparoscopy has been shown to have an important role in early colonic carcinomas viz, laparoscopic-assisted colonoscopic polypectomy, laparoscopic wedge resection and laparoscopic colostomies with a 67-100% success rate for avoiding a formal bowel resection. This can be achieved by preoperative colonoscopic tattooing for localization.According to the data available, laparoscopic surgery definitely appears to have a role in colonic malignancies. The short-term and long-term outcomes clearly favor this approach. It should be realized, though, that the benefits of laparoscopic surgery can be obtained only when performed by persons trained in the art of laparoscopy so as to avoid unnecessary morbidity and even the risk of mortality. As for rectal cancer, the present data on the role of laparoscopy is not mature enough, especially for anterior resections. At present, laparoscopic anterior resection should only be considered within the context of clinical trials."}
{"text": "In the Discussion of our paper, we mentioned that such abnormalities were not observed in an earlier study using long-term IUE of ChR2 under the same promoter (Huber et al., In our recent paper (Miyashita et al.,"}
{"text": "Science by Liu and Imlay (Escherichia coli act via the production of reactive oxygen species (ROS). This hypothesis contradicts the view, proposed by Kohanski and colleagues  dye fluorescence. Furthermore, the authors assumed that this quenching was due to the production of hydroxyl radicals. This belief in an ROS-mediated bactericidal mechanism has now been challenged  initially formed by the Fenton reaction rather than the hydroxyl radical decomposition product.Recent articles in nd Imlay , and Kernd Imlay  questionlleagues , that balleagues  came to Pseudomonas putida is resistant to the bactericidal activity of ampicillin and the bacteriostatic activity of chloramphenicol. This resistance is achieved via TtgABC efflux pump-mediated extrusion of the antibiotics (Godoy et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., 2+ formed in the presence of bactericidal compounds enhances killing in addition to the direct inhibition of cell wall assembly, protein synthesis or interference with DNA metabolism."}
{"text": "OccasioDuring evolution, DNA base mutations occurred intracellulaly and not in extracellular environments. The DNA polymerase components that are involved in DNA replication directly influence the base composition of the genome (Zhao et al.,"}
{"text": "In their valuable article, Knops et al.  challengWe take the liberty of adding own results in this commentary which further support these findings. We have also tested the OME in typically achieving children and a matched group with developmental dyscalculia (DD) Table . TypicalTogether with the findings of Knops et al., it seems that the left\u2013right associations underlying the OME are dependent on development and experience. One might hypothesize that a complex interaction between visuo-spatial and attentional processes together with number related skills influence its development whereupon an early predisposition to relate representations of non-symbolic numerical magnitude to spatial length builds a core system (De Hevia and Spelke, According to the assumption of such a hierarchical and interwoven model of OME, the impairment of one or several aspects may affect the development of the OME negatively.DD is a specific learning disability of number processing and calculation. In addition to profound problems in numerical understanding, abnormalities in visuo-spatial, and attentional processes have also been associated with DD.As expected, no OME was observed in our tested group of children with DD Figure . TherefoIt is important to note that an adult control group is missing in our study. However, since Pinhas and Fischer  demonstrKnops et al. argue that the lack of an OME during childhood speaks against a flawed compression-uncompression mechanism as the driving factor of the operational momentum bias, which implies that the OME is caused by a systematic bias during uncompression of a logarithmic representation of the MNL. Furthermore, number representations change from a logarithmic mapping to a linear mapping scheme during development and familiarity in a number range (Siegler and Opfer, In contrast to the cohort of Knops et al., children in our study were older and showed a linear function describing the MNL representation like in adults, but exhibited no OME. Moreover, our results indicated that even after the completion of a specific number line training (Kucian et al., Findings reported by Knops et al. and our study corroborate that the OME is not necessarily present in childhood and unlikely to be caused by flawed uncompression of the MNL. In addition, our results further point to a possible negative impact of DD on the development of the OME. In conclusion, the OME is probably dependent on development and a complex interaction of the maturity of numerical skills, visuo-spatial, and attentional processes as well as cultural conventions."}
{"text": "A recent review paper, published online on April 24 2012 in Frontiers in Psychology, argues that antidepressants interfere with the normal homeostatic response of the body and cause more harm than good  improve both mental and physical health outcomes (Katon et al., Finally, the argument that evidence from randomized control trials that show little difference between antidepressants and placebos proves that antidepressants are not effective is a simplistic interpretation of the data. Recent work has demonstrated that these trials show small mean differences between the two groups because they lump responders together with non-responders. When looking at subgroups of responders, there are large differences between antidepressants and placebo (Thase et al.,"}
{"text": "Chronic fatigue syndrome (CFS) is characterized by fatigue, sleep dysfunction, and cognitive deficits (Fukuda et al.,  Myalgic Encephalomyelitis/chronic fatigue syndrome (CFS) is an illness characterized by persistent excessive fatigue , post-exertional malaise, flu-like symptoms, and cognitive impairments  is a disease characterized by orthostatic tachycardia without orthostatic hypotension. In other words, patients with POTS often experience an excessive increase in heart rate when they stand up. POTS is known to be comorbid with CFS. In particular, POTS is often commonly found to be comorbid with adolescents with CFS  contributes to orthostatic intolerance (OI), a symptom of both CFS and POTS  (Demitrack et al., It is clear that understanding cognitive impairments and symptoms in CFS and POTS is not a simple task. However, the common theme suggests some sort of impairment within the central nervous system. Further research should focus on the central nervous system as a possible gateway of understanding the etiology of these disorders further.Patients with CFS and POTS suffer from cognitive impairments that could lead to difficulties with daily functioning. Although there are studies that question the presence of cognitive impairments in CFS (Altay et al., Patients with POTS experience a mental clouding known as \u201cbrain fog\u201d (Raj et al., Cognitive impairments in both CFS and POTS have the potential to create problems with daily functioning, including difficulties with school and employment. Cognitive impairment is a core symptom of CFS, and the presence of cognitive impairments is part of the definition of CFS (Fukuda et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Curiosity about the numerical abilities of non-human animals has been a topic in experimental psychology for about as long as such a science has existed. Some of the earliest comparative work looked at how well animals could use number as a cue in making different kinds of judgments. Early results were mixed, and in some cases were incredibly controversial . After the \u201cfall\u201d of behaviorism and the \u201crise\u201d of cognitive psychology, the question of numerical competence became one of the dominant research areas in the new field of comparative cognition. The present series of papers in this special topic represents the newest additions to that research area. This special topic also serves as an anniversary of sorts, as it comes 25 years after one of the most influential papers on the subject of numerical competence in animals . Subitizing remains an interesting phenomenon, sometimes evident in animal research but other times not evident (see Murofushi, Davis and Perusse  and the This special topic encompasses 16 novel studies, including mammals (e.g., Beran et al., The special topic also includes theoretical and research studies on human infants. In particular, attention has been focused on number-space interaction (de Hevia et al.,"}
{"text": "Crystal structures of a membrane protein transporter in three different conformational states provide insights into the transport mechanism. Microbacterium liquefaciens, has been determined in three conformational states; from this a mechanism is proposed for switching from the outward-facing open conformation through an occluded structure to the inward-facing open state.Secondary active transporters move molecules across cell membranes by coupling this process to the energetically favourable downhill movement of ions or protons along an electrochemical gradient. They function by the alternating access model of transport in which, through conformational changes, the substrate binding site alternately faces either side of the membrane. Owing to the difficulties in obtaining the crystal structure of a single transporter in different conformational states, relatively little structural information is known to explain how this process occurs. Here, the structure of the sodium-benzylhydantoin transporter, Mhp1, from  Many of these integral membrane proteins can be broadly categorized into two classes, primary and secondary transporters. Primary transporters are energized by the hydrolysis of ATP, redox reactions or light. Secondary transporters, on the other hand, harness the energy stored in electrochemical gradients across the membrane to the transport process (Crane et al., 2008et al., 2010Many transporters are thought to work by an alternating access mechanism. The principle of this mechanism, which was first proposed in 1966 (Jardetzky, 1966Microbacterium liquefaciens is a member of the nucleobase-cation symport-1 family of transporters (Suzuki & Henderson, 2006et al., 2010l-hydantoins into l-amino acids (Suzuki & Henderson, 2006Mhp1 from 2.et al., 2008et al., 2005et al., 2008et al., 2009et al., 2010et al., 2009et al., 2009et al., 2009The crystal structure of Mhp1 was solved initially at a resolution of 2.85\u2005\u00c5 (Weyand i.e. the structure was outward-open in the definition of the alternating access model (Fig. 3et al., 2005E. coli in defined media in the presence of selenomethionine (Shimamura et al., 2010In the initial structure of Mhp1 a large cavity was present extending from the extracellular face of the protein into the centre, el Fig. 3 and did 3.et al., 2010The conformational changes that take place as the protein goes from outward-open through the occluded to the inward-open state can be described best by considering the core ten TMs in three parts Fig. 4 (ShimamuIn going from the outward-open structure to the occluded structure the N-terminal half of TM\u200510 bends, closing over the substrate in its binding site. At this resolution there are no other significant movements that can be assigned unambiguously. However, there is a small but definite shift of the hash motif and C-terminus towards the bundle. To switch the substrate binding site from facing outward to facing inward a surprisingly simple rigid body rotation of 30\u00b0 of the hash motif relative to the bundle occurs around an axis roughly in line with TM\u20053. This simultaneously blocks further the substrate binding site from the outside and opens it to the inside. This rotation is accompanied by two other main changes to the protein. Firstly, TM\u20055, the N-terminal equivalent of TM\u200510, flexes in a similar manner to TM\u200510 to open the cavity further to the exterior. Secondly, a small extracellular helix moves to seal the extracellular face of the protein completely.4.et al., 2009The mechanism of converting between the different states of the protein has also been described in terms of two sets of gates: thick and thin (Krishnamurthy 5.et al., 2008et al., 2010The sodium and substrate binding sites are located at the interface of the bundle and the hash motif. In the outward-facing structures both are intact with the sodium ion interacting with residues on TM\u20051 and TM8 and the benzyl\u00adhydantoin fitting snugly between the indole rings of Trp 117 on TM\u20053 and Trp 220 in TM\u20056 Fig. 5. In the 6.et al., 2008et al., 2008et al., 2005et al., 2005et al., 2010The derivation of the mechanism above was enabled by our knowledge of the three structures of Mhp1. Since Mhp1 is part of the LeuT superfamily the question arises as to whether this mechanism is also relevant for the other members. This superfamily contains proteins with very different substrates that are regulated by sodium or by protons and both symporters and antiporters. For the sodium-coupled sym\u00adporters it seems likely that the switching between the outward- and inward-facing structures is based on the same principle. A similar mechanism of the switching between outward- and inward-facing conformations caused by a rigid-body movement of the four-helix bundle relative to the rest of the protein was, in fact, first proposed for LeuT based on the asymmetry of the crystal structure and investigated more thoroughly using a mutational analysis of the serotonin transporter (Forrest"}
{"text": "In a nomenclature proposal published in 2010 monocytes were subdivided into classical and non-classical cells and in addition an intermediate monocyte subset was proposed. Over the last couple of years many studies have analyzed these intermediate cells, their characteristics have been described, and their expansion has been documented in many clinical settings. While these cells appear to be in transition from classical to non-classical monocytes and hence may not form a distinct cell population in a strict sense, their separate analysis and enumeration is warranted in health and disease. Human monocyte subsets are typically analyzed in multi-color flow cytometry using antibodies to CD14 (the LPS receptor) and CD16  was not significantly increased in the intermediates but antibody staining showed a specific twofold higher expression for TIE2 protein.Zawada et al.  used SupThese data show that delineation of monocyte subsets cannot be restricted to the transcript level but will have to take on board all the other levels of gene expression including the proteome.TIE2-expressing monocytes strongly overlap with and may be identical to the intermediate cells.The Zawada findings of high TIE2 protein expression in the intermediates is in line with earlier work by Murdoch et al.  and receThere have been transcriptome studies into intermediate monocytes in non-human primates by Kim et al.  and theyMost functional studies into monocyte subsets have looked at two types of cells  with intermediate monocytes being excluded or allotted to one or the other of the two main monocyte types. However, a few studies specifically addressing functions of the intermediates have been published.Looking at cytokine production Skrzeczynska-Moncznik et al.  isolatedEarlier functional studies by Grage-Griebenow et al.  defined in vitro model revealed a selective cluster formation for the intermediate monocytes. Together with the selective increase of TIE2 protein expression and a similar increase of endoglin and VEGF receptor 2 by the intermediates (Zawada et al., TIE2-expressing monocytes in the mouse has shown that among blood mononuclear cells only these cells are capable of inducing a capillary network (De Palma et al., Also, studies in an angiogenesis in vitro culture they develop into non-classical monocytes or into a unique progeny, which is different from the progeny of classical or non-classical monocytes. If it can be demonstrated that intermediate monocytes give rise to a unique type of DC or macrophage then this would support the concept that they are a biologically meaningful monocyte subpopulation.Monocytes are precursors for dendritic cells and macrophages. For the non-classical monocytes a higher propensity to become DCs with a higher capacity to induce T-cell proliferation and IL-4 in CD4 T-cells has been reported (Randolph et al., In clinical settings the intermediate monocytes have been noted to increase in number in several diseases (for a detailed review, see Wong et al., For rheumatoid arthritis Cooper et al.  noted a In adult survivors of childhood acute lymphoblastic leukemia intermediate monocytes were found increased along with increases of several inflammatory markers (Sulicka et al., When testing M-CSF in preclinical trials Weiner et al.  have notIn a model of viral infection, injection of the TLR7/8 ligand R-848 into non-human primates was shown to lead to a strong increase in intermediate monocytes on day 1 followed by a peak of non-classical monocytes on day 2 (Kwissa et al., Whether or not the intermediate monocytes, induced by various stimuli, go on to develop into non-classical monocytes may be dependent on the type and on the strength of the stimulus.When comparing gene expression patterns in classical and non-classical monocytes for man versus mouse it was noted that a differential gene expression between the two subsets was reverse in man and mouse for a number of biologically relevant genes (Ingersoll et al., Since the discovery of the CD16-positive monocytes by flow cytometry this approach has been used to distinguish these cells from the major population of classical monocytes. A third population of intermediate monocytes initially had been overlooked because of its low number and transitional nature. Now clinical studies have demonstrated that these cells can strongly expand and laboratory analyses have shown intermediate but also unique features for these cells. Specific markers for the intermediate monocytes will be required in order to unequivocally identify and enumerate these cells.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "TO THE EDITOR: The recent article by Demir et al.  in your For instance, artemin enhances transcription of bcl2 \u2013 leading to it's up regulation and thereby augments tumor growth in human non-small cell lung carcinomas (Tang et al., Increased expression of artemin is also seen in esophageal carcinomas. Interestingly transfection with a mir-223 vector decreases expression of artemin and thereby suppresses tumor growth in esophageal carcinomas (Li et al., The above examples clearly illustrate the significant enhancement of oncogenicity secondary to artemin in tumors ranging from lung carcinomas to endometrial carcinomas. There is a clear and urgent need to identify inhibitors of artemin function in order to improve the prognosis in these tumors."}
{"text": "Diabetes is a major threat to global public health. According to the latest data from the International Diabetes Federation (IDF), at least 366 million people are living with diabetes and this number is projected to be 552 million by 2030. At least 50% of people with diabetes suffer from one or two major diabetic complications such as diabetic cardiomyopathy, nephropathy, neuropathy, retinopathy, and diabetic foot diseases. Development of an authentic model of each type of diabetes and their associated complications, which exactly mimic the human pathogenesis, is very crucial not only for a better understanding of the core causes of the diseases but also for the development and routine pharmacological screening of novel anti-diabetic drugs. A number of genetic and nongenetic animal models of the different types of diabetes and their associated complications have been developed in last three decades but none of them are without limitations.This special issue of the Journal of Diabetes Research has been designed to publish original and review articles with novel approaches of the development of animal model of diabetes and its associated complications. Almost all areas of the animal models of diabetes and its associated complications have been covered by this issue. Among the reviews: the animal models of diabetic retinopathy by A. K. W. Lai and A. Lo, animal models of diabetic neuropathy by M. S. Islam, murine models of diabetic neuropathy by L. L. Kong et al., methods and models for metabolic assessment by G. Pacini et al., and porcine models of accelerated coronary atherosclerosis by D. Hamamdzic et al. contributed significantly by summarizing the advantages, disadvantages, and suitability of animal models developed to study the above-mentioned diabetic complications. Many other original papers such as role of adrenomedulin in the renal NADPH oxidase and (pro)renin in diabetic mice by M. Hayashi et al., development of glomerulopathy in the KK.Cg-Ay/J mouse with the pathology of diabetic nephropathy by P. Stephen et al., and the role of ERK/MAPK and TGF-beta/Smad signaling pathways in the kidney fibrosis of diabetic mice by X. Cheng et al. contributed novel information in the pathogenesis of diabetic nephropathy, a major and common complications of diabetes mellitus. Finally, an exceptional paper has been contributed by E. Hillhouse et al. on the effect of nearby construction on the progress to overt autoimmune diabetes in NOD mice. As a whole, papers from almost every aspects of the animals models of diabetes and its associated complications have been published in this special issue so it can be a special interest of diabetes researchers particularly those who are working in the different areas of diabetic complications.Md.\u2009\u2009Shahidul\u2009\u2009IslamMd.\u2009\u2009Shahidul\u2009\u2009IslamDaisuke\u2009\u2009KoyaDaisuke\u2009\u2009KoyaBernard\u2009\u2009PorthaBernard\u2009\u2009Portha"}
{"text": "Pituitary adenylate cyclase activating polypeptide (PACAP) is a pleiotropic neuropeptide, first isolated from hypothalamic extracts, but later shown in peripheral organs, such as endocrine glands, gastrointestinal system, cardiovascular system, and reproductive organs. PACAP plays a role in fertility and reproduction. Numerous studies report on the gonadal regulatory effects of PACAP at hypothalamo-hypophyseal levels. However, the local effects of PACAP at gonadal levels are also important. The present review summarizes the effects of PACAP in the ovary. PACAP and its receptors are present in the ovary, and PACAP plays a role in germ cell migration, meiotic division, follicular development, and atresia. The autocrine-paracrine hormonal effects seem to play a regulatory role in ovulation, luteinization, and follicular atrophy. Altogether, PACAP belongs to the ovarian regulatory peptides. Pituitary adenylate cyclase activating polypeptide (PACAP) was originally isolated from the hypothalamus, and named after its cAMP increasing effect in pituitary cells  migrate from the wall of the yolk sac to the ovaries during early mammalian development. Ovarian germ cells then undergo mitosis and develop further into primary oocytes. Developing oocytes are surrounded by epithelial cells, which build the ovarian follicles. At first, follicular epithelial cells are flattened and surround the primary oocytes entering the first meiotic division. They subsequently are arrested during fetal development until the female reaches sexual maturity. The first meiotic division is only completed during the follicular development before ovulation in each cycle, and the second meiotic division is completed only at the time of fertilization, resulting in the haploid gamete Sadler, .A cohort of primordial follicles is activated at the beginning of the maturation process in cyclic manner. Follicular maturation involves changes in the oocyte, the follicular epithelial cells, and the surrounding ovarian stroma. Although significant inter-species differences exist in the follicular growth and its regulation, the major steps show basic similarities in mammalian species, and in most mammals, the vast majority of follicles undergo apoptosis similarly to humans (Matsuda et al., There is evidence for the involvement of PACAP in the proliferation of primordial germ cells (Pesce et al., In rat ovarian cells, PACAP positive cells were found in the preovulatory and ovulatory periods (Gras et al., Pituitary adenylate cyclase activating polypeptide expression in the corpus luteum of the rat was subsequently shown by Kotani et al. , 1998. PTransient expression of PACAP has also been observed in the mouse ovary within granulosa cells of preovulatory follicles after hCG treatment (Barberi et al., In situ hybridization has revealed that PACAP receptor mRNA is present mainly in the granulosa cells of the large preantral follicles, while atretic follicles and mural granulosa cells are devoid of the receptor. The authors have also demonstrated that the dominant splice variant of the PAC1 receptor was the short variant in the ovary (Park et al., Earlier studies examining binding sites for PACAP have already identified specific binding sites in the ovary (Gottschall et al., in vivo. Gras et al. (A more detailed analysis of the rat ovarian PACAP receptor expression has confirmed the expression of PAC1 receptors in the granulosa cells and, furthermore, the presence of VPAC2 receptors in these cells (Vaccari et al., s et al.  also dess et al. .All three receptors have also been identified in the mouse (Barberi et al., In all mammalian species, the early stages of folliculogenesis, including the initiation of primordial follicle growth, are independent from gonadotropins (Latini et al., Studies on the endocrine effects of PACAP revealed that PACAP can stimulate cAMP accumulation and steroidogenesis in the rat ovary (Zhong and Kasson, Interestingly, one intracerebroventricular PACAP treatment was shown to inhibit ovulation in adult animals (Koves et al., The effects of PACAP on ovarian steroidogenesis have been confirmed in human studies as well (Apa et al., PLC was activated by PACAP in granulosa but not theca cells (Vaccari et al., In addition to gonadotropins, factors secreted from granulosa cells, including steroids, growth factors, and cytokines, are essential for granulosa cell survival and follicular growth (Matsuda et al., One of the main effects of PACAP is its cell survival-promoting effects, which was first described in neuronal cells, and thus, PACAP was designated as an important neuroprotective peptide (Vaudry et al., Based on these data, it is expected that PACAP can also exert antiapoptotic effects in ovarian cells. Indeed, several studies have shown this in granulosa cells. In isolated granulosa cells, apoptosis can be induced by serum-free culturing. In accordance with the generally known antiapoptotic role of PACAP, the peptide could reduce the granulosa cell apoptosis in a dose-dependent manner, an effect that could be blocked by the PACAP antagonist PACAP6-38 (Vaccari et al., Expression of PACAP in both benign and malignant ovarian tumors has been shown (Odum and Fahrenkrug, Fully developed oocytes express PAC1 receptor and the addition of nanomolar concentrations of PACAP induces calcium release. However, this answer could not be observed in Met-I and II phase oocytes, supporting that finding that receptors are expressed stage-specifically (Vaccari et al., Xenopus oocytes, PACAP has been described to modulate membrane potential by eliciting hyperpolarization-activated chloride current, thereby affecting oocyte physiology (Kato et al., In Very interesting results have been described by Apa et al.  supportiRecently, mass spectrometric and radioimmunoassay analysis have shown that PACAP is present in human follicular fluid obtained from patients undergoing hyperstimulation treatment (Brubel et al., Recent reports point to the important roles of PACAP in fish reproduction, pointing to the fact that the effects of PACAP on the hypothalamo-pituitary axis, as well as in the gonads, are conserved and biologically ancient functions (Levy and Degani, Given the important functions of PACAP in reproduction outlined above, it would be expected that the lack of endogenous PACAP have major effects on fertility and reproduction. Indeed, PACAP deficient mice have been shown to have lower reproductive rates in several studies (Shintani et al., The present review summarized findings on the presence and effects of PACAP in the ovary. It has to be emphasized that this is only one role in the plethora of actions that PACAP plays in fertility and reproduction and that the detailed discussion of these is beyond the scope of the present review. Briefly, PACAP, at the hypothalamic level, influences receptive behavior in female rodents, in association with GnRH and steroids (Apostolakis et al., Pituitary adenylate cyclase activating polypeptide also plays a role in the muscle contraction of the vaginal wall as well as that of the uterus and uterine tube (Steenstrup et al., Effects of PACAP have also been shown in the placenta where PACAP and its receptors are present (Scaldaferri et al., In summary, PACAP is one of the peptides regulating germ cell development in the ovary and it has several other regulatory functions in reproduction. PACAP influences ovarian hormone production, affects meiosis, and is an important local regulator of follicular development. The exact physiological role and its possible clinical importance still awaits further investigation, but the current evidence points to a possible clinical diagnostic or therapeutic use of the peptide in both human and veterinary fertility.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "We apologize if our article  was unclContrary to the claims by Gochfeld et al., the Avon Longitudinal Study of Parents and Children (ALSPAC) study was designed to investigate the effects of various prenatal measures of the environment ; the initial aim was to determine the relationship of these measures to a variety of different outcomes.Gochfeld et al. state that \u201c< 2% of the ALSPAC subsample\u201d were women who ate fish frequently (> 3 portions a week). However, when consumers of both oily and white fish are combined, the frequent fish-eaters actually comprised 647 (18%) of our pregnant population.In our article , we repoIn their letter, Gochfeld et al. cite two references  to suppoThe categorical nature of our food frequency questionnaire successfully characterizes fish consumption in the study population; people do not eat the same type of fish regularly but typically consume different types of seafood. Internal validation of our fish exposure estimates shows that they are correlated with biological markers of fish consumption, such as omega-3 fatty acids . The meaIn response to the statement of Gochfeld et al. that our study \u201cdid not address the risk for the frequent fish-eater who has elevated blood mercury,\u201d we analyzed separately the group of frequent fish consumers (> 3 portions/week). We found that members of this group had a similar or lower contribution of blood mercury from seafood than the less-frequent consumers.Gochfeld et al. suggest that published benefits of fish consumption may generally be a result of healthy lifestyles in general. In a previous study , we perfAs we note in our paper , detaileWe were surprised that Gochfeld et al. did not highlight the important finding of contributions to mercury levels from foods that have no obvious nutrient value, such as herbal drinks, which we found to have an important association with blood mercury levels. Warning against such drinks may have greater net benefits to pregnant women than reduced fish consumption.Finally, we agree with Gochfeld et al. that pregnant women might benefit slightly by substituting fish species containing very high methylmercury with those having lower levels, but we do not recommend that women cut down their overall fish consumption."}
{"text": "Non-communicable causes of death and disability will dominate global health agenda for the foreseeable future. The progress in addressing their burden and achieving measurable reduction in low\u2013 and middle\u2013income countries (LMICs) will likely require similar steps that were effective in reducing maternal and child mortality globally: (i) defining the size of the burden and the main causes responsible for the majority of the burden; (ii) understanding the most important risk factors and their importance in different contexts; (iii) systematically assessing the effectiveness and cost of the interventions that are feasible and available in LMICs; and (iv) formulating evidence\u2013based health policies that will define appropriate health care and health research priorities to tackle the burden in the most cost\u2013effective way.Over the past year the pandemic of non\u2013communicable diseases (NCDs) has become a key focus of global political agenda. At the United Nations' high\u2013level meeting on the prevention and control of NCDs in September 2011, a general consensus has been reached that NCDs were already the leading causes of death in all world regions and that their burden is increasing rapidly . In LMICThe release of the new global burden of disease (GBD) estimates for the year 2010, by the Institute for Health Metrics and Evaluation (IHME) at the University of Washington in Seattle, is anticipated with great interest . The newThe first step in this process is to measure the burden of NCDs in LMICs. This is a challenging task given the scarcity of available data, inconsistency in case definitions of the measured diseases, differences in reporting of results  used by different investigators, lack of funding, research infrastructure and capacity for community\u2013based studies in LMICs, changing definitions of diseases over time, low transcultural adaptability of screening instruments, and many others -8. MethoJournal of Global Health, we are publishing several studies that attempt to summarise information on the burden of non\u2013communicable diseases and provide estimates for a region that has traditionally been considered \u201cinformation gaps\u201d: the African continent. The papers by George-Carey et al. [In the current issue of the y et al. , Paul ety et al. , Graham y et al.  and Dowmy et al.  provide y et al. , Moten ey et al. , Kolcic y et al. , while My et al. . In the"}
{"text": "We show that this claim is not supported by the data and analysis reported in Allen et al.\u2019s paper.There has been much recent debate in Australia over whether lethal control of dingoes incurs environmental costs, particularly by allowing increase of populations of mesopredators such as red foxes and feral cats. Allen  Canis dingo Meyer 1793). The usual approach to this problem is to attempt to suppress dingo populations by distributing meat baits laced with poison [Vulpes vulpes) and feral cat (Felis catus) [One of the most vexed issues in the management of Australian wildlife is how to protect livestock from predation by dingoes  ,6, whichet al.[Varanus sp.) was measured on each area . Then, they applied a differential poison-baiting regime in which the treatment area was baited twice per year for two to three years, and the control area was left unbaited.In a recent paper, Allen et al. report tet al. make two claims from the results of this experiment: (i) as a result of poison-baiting, activity of dingoes was \u201cdemonstrably less\u201d in baited areas; and (ii) increase of mesopredators did not occur in response to these reductions because those smaller predators were also suppressed by baiting, with the result that mesopredators were in \u201csimilar or greater abundance in unbaited areas relative to baited areas\u201d. Allen et al. conclude that poison baiting of dingoes does not lead to mesopredator release. The purpose of this comment is to make it clear that this conclusion is not supported by Allen et al.\u2019s data.Allen et al. tested for an effect of their baiting programs on dingo activity by averaging all estimates of activity through time and contrasting mean values on their treatment and control areas. They found significantly higher dingo activity in unbaited areas at four of the six experimental sites. On the face of it, this suggests that baiting tended to produce sustained reductions in dingo activity. However, at two of these sites (Mt Owen and Quinyambie), the activity of dingoes was already higher on the \u2018unbaited\u2019 areas before the differential baiting treatment was applied . These differences did not obviously change thereafter, and so cannot be attributed to baiting. Presumably, they were caused by other differences between those areas that were not considered in the analysis. These two sites happened to be the ones with the highest measures of dingo activity on the sites that were allocated to the \u2018unbaited\u2019 treatment, so they make a large contribution to the difference in mean activity on \u2018baited\u2019 versus \u2018unbaited\u2019 sites.Allen et al.\u2019s analysis of their data. Their experimental design should have allowed them to compare the difference in dingo activity on paired study areas before and after the imposition of the differential baiting treatment, and so attribute changes in mean activity to the effect of their baiting programs. But they did not make this before/after comparison: they compared activity on baited and unbaited sites after taking means of all measurements of activity, pooling samples from before and after application of their treatment. It remains unclear whether baiting did cause sustained reductions in dingo activity on their sites. We requested Allen et al.\u2019s raw data so that we could check for such an effect, but they were unwilling to provide it. Inspection of Allen et al.\u2019s plotted data  suggests that the effect of their baiting programs on mean dingo activity was in fact weak or absent in most cases.This observation points to a serious problem in Allen et al. tested whether individual episodes of bating caused short-term reductions in dingo activity. They did this by comparing activity of dingoes before and soon after individual episodes of baiting, and making the same comparison on paired unbaited areas surveyed at the same times. They conclude that baiting produced rapid reductions in dingo activity, but that dingo activity then recovered towards pre-baiting levels, presumably due to immigration. However, their own analysis of their data refutes this. A short-term effect of baiting would be revealed by a significant time-by-treatment interaction in the ANOVA that Allen et al. used to analyse these data. The interaction term in their ANOVA was weak and non-significant, showing that knockdowns due to baiting were either too small or too transient to be distinguished from background variation in activity.In a separate analysis, Allen et al.\u2019s analysis. Their data on activity of dingoes and other predators are highly skewed and contain many zero values. Data with such skewed distributions ought not be analysed by conventional parametric methods such as ANOVA unless normalised by appropriate data transformations. This was evidently not done. For this reason alone, all inferences that Allen et al. draw from their results should be regarded as unreliable.We note in passing a third problem with Allen et al. have little support for their inference that baiting affected dingo activity. There is even less support for their conclusion that smaller predators were affected by baiting, such that they showed higher activity on unbaited areas relative to baited areas. The problems here are similar to those detailed above. At only two of the six experimental sites (Cordillo and Quinyambie) was average fox activity significantly higher on unbaited than baited areas, but these differences were present before the differential baiting treatment was applied and so cannot be attributed to the effects of baiting. There are no indications of differences in activity with respect to baiting for feral cats and goannas at any of the study sites. The analysis testing for short-term responses also found no effects for foxes, cats or goannas.So, Allen et al. Foxes readily take poison baits laid for dingoes and, other things being equal, should have increased their activity in the absence of baiting. Instead, one of the strongest patterns in Allen et al.\u2019s data is that fox activity was consistently low at all of their sites, and at almost all times. Activity indices for foxes were typically about 5-10\u00a0% of those measured for dingoes, and many surveys returned zero values for fox activity. Other research using similar methods in the same region has shown that measures of fox activity varied over a similar range to that of dingoes . Why Allen et al. recorded such low fox activity is puzzling. One explanation could be that availability of prey for foxes was low at the times and in the places where Allen et al. worked, so foxes were unable to increase when released from the effects of baiting; alternatively, dingo activity might have remained sufficiently high to prevent foxes  from increasing in unbaited areas. Supporting this latter interpretation, Letnic et al.\u2019s (2009) surveys found that fox activity was greatest at levels of dingo activity lower than those recorded at any of the sites sampled by Allen et al.The lack of evidence for increased fox activity in unbaited areas should have been surprising to Allen et al. \u2013 sand-plot tracking \u2013 is relatively insensitive to changes in activity of cats and goannas [For feral cats and goannas, a direct impact of baiting on activity would be more surprising. Feral cats are much less likely than foxes to take meat baits, because they have a strong preference for hunting of live prey ,10. Goan goannas .et al. had produced large and sustained reductions in dingo activity? This question is an important one, because while baiting seems to have had little effect in this study, there is evidence that it can be effective in reducing dingo activity [et al.\u2019s results are not relevant to areas where broad-scale aerial baiting is employed, or where ground baiting is coordinated over large areas, or conducted in conjunction with exclusion fencing. These measures are likely to increase the efficacy of baiting in reducing dingo populations.The question this study cannot answer is: what would have happened if the poisoning programs implemented by Allen activity ,5. Otheractivity  or, if bactivity ,15. In aet al. for taking an experimental approach to this problem. Unfortunately, they have not conducted a rigorous analysis of their data. Especially, we find little or no support for their inference that the poison baiting programs reported in their paper had any effect on activity of wild predators, contrary to their view that baiting suppressed activity of all medium-sized and large vertebrate predators. We conclude that their study does not provide useful evidence on the environmental costs of lethal control of dingoes.The management of dingoes is a highly conflicted and frequently emotional issue in rural Australia. There is an urgent need to find approaches that can balance the needs of agricultural production with environmental conservation. Achieving this balance requires rigorous evaluation of evidence on the effectiveness of alternative strategies of dingo management and their environmental consequences. We commend Allen The authors declare that they have no competing interests.All authors contributed equally to the content of the paper; CNJ led the writing. All authors read and approved the final manuscript.CNJ is Professor of Wildlife Conservation at the School of Zoology, University of Tasmania; MSC is Senior Lecturer at the School of Biological Sciences, University of Sydney; CRD is Professor in Terrestrial Ecology at the School of Biological Sciences, University of Sydney; MIL is ARC Future Fellow at the Centre for Ecosystem Science, School of Biological Earth and Environmental Sciences, University of New South Wales; TMN is Postdoctoral Scholar at the Department of Forest Ecosystems and Society, Oregon State University; DGN is Postdoctoral Scholar at the Centre for Integrative Ecology and School of Life and Environmental Sciences, Deakin University; EGR is Senior Lecturer at the Centre for Integrative Ecology and School of Life and Environmental Sciences, Deakin University; ADW is Adjunct Lecturer at the School of Marine and Tropical Biology, James Cook University."}
{"text": "Obesity remains a prominent public health concern in the United States as well as many other countries, with 33% of adults worldwide overweight or obese in 2005 and an estimated 60% by 2030  (Davis et al.,"}
{"text": "A number of cellular stresses and cytotoxic agents trigger mitochondrial permeability transition (mPT), considered as a final common pathway of cell death  ratio warrants further analysis, particularly in view of the fact that the number of copies of subunit c is constant and appears to be independent of the metabolic state within all vertebrate animals and most invertebrate species  was able to almost completely block TNF/emetine-induced cell death, aurovertin B  had no effect on mPT in this cell death modality (Shchepina et al., Finally, these findings recall an old question about the pharmacology of mPT. Oligomycin, a potent inhibitor of the F1F0 ATP-synthase in mPT and cell death will soon follow.Altogether, as shown by the above list of outstanding questions, we anticipate that the findings by Bonora et al.  are only"}
{"text": "Publication of papers related to psycho-social interventions in general and Behavior Therapy, in particular, in Indian Journal of Psychiatry has been limited. Though the first paper related to Behavior Therapy was published in 1952, a manual search of all available issues of the journal from 1949 showed that only 42 papers related to Behavior Therapy have been published till 2009. Among them 10 are case reports. Methodological limitations abound even in the papers on larger groups of patients. Studies using operant conditioning have been very few. Aversion therapy and progressive muscle relaxation have been very frequently used. The published articles are reviewed under the various diagnostic categories. Publications in the recent years have been mostly on Cognitive Behavior Therapy. Even after 57 years of co-existence, the relationship between Behavior Therapy and Indian Psychiatry remains a tenuous one. One of the characteristics of psychiatry, as practised in India, is the extremely limited use of psycho-social methods of treatment. In 1973, when Varma and Ghosh[The above observation on psychological methods of treatment in general is also true with regard to Behavior Therapy (BT) or any of its variants. Most psychiatrists in India, I feel, will admit that these psychological methods are useful or even essential in some psychiatric disorders, but many of them do not have either the time or inclination to practice them. Often such patients are referred to psychologists or social workers who are interested in psycho-social methods of treatment. So it is likely that publications like Indian Journal of Clinical Psychology may have many more papers on BT than Indian Journal of Psychiatry. However, the present article is not an attempt to review the state of BT in India, but is a more restricted attempt to review articles published in Indian Journal of Psychiatry since it will more accurately reflect the Indian psychiatrists\u2019 attitude towards BT.Using the key words \u2018Behavior Therapy\u2019 on the IJP web site yielded a list of 42 articles related to the topic. However, when one went through the list only nine articles were found to have anything to do with BT and the rest were on totally unrelated topics ranging from \u2018ECT and clozapine\u2019 to \u2018psychotic symptoms in acromegaly\u2019!So a manual search was done through the contents of all available issues of Indian Journal of Neurology and Psychiatry (1949 to 1953) and Indian Journal of Psychiatry (1958 to 2008) in the DVD published by Indian Psychiatric Society. Contents of the three issues of the Journal published in 2009 were also searched. Articles which contain words like - Behavior therapy, behavior modification, behavioral intervention, cognitive therapy, and cognitive behavior therapy, biofeedback, relaxation training, which are related to BT, were searched. In addition, if the title of the articles suggested the possibility of BT use, for example \u2018Treatment of Trichotillomania,\u2019 then the articles were given a detailed look to see whether the authors have in fact used BT and those papers were also selected.The article which could be considered the first on this topic was authored by Ganguly in IndiaIt may come as a surprise to many readers, especially of the older generation, that Satyanand who has Skepticism about the newly emerging treatment method is evident in Neki\u2019s review oIn the early 1970s BT was still a new entrant in to the field of psychiatry in India. This is evident from the two articles by Chopra.6 In the All 11 patients improved (six markedly improved) with the treatment. On follow-up varying from one month to two years only one patient was found to have relapsed. Though published in IJP, the papers were based on the author\u2019s work in Australia. It is interesting to note that Chopra as well as other authors at that time, while talking about outcome on follow-up usually added \u201cthere was no symptom substitution,\u201d perhaps to counter the criticism of psychoanalytically oriented therapists who held that BT is only removing symptoms at a superficial level and since the deep seated conflicts are not dealt with, the patient will invariably present with some other symptoms at a later date.BT was the first psychological method of treatment which showed that its therapeutic efficacy can be established by rigorous scientific methods of evaluation like randomized, placebo-controlled, double blind studies, instead of merely relying on the subjective opinions of patients and therapists. It has shown that methodological issues like sample size, randomization, use of controls, masking of the assessor, valid outcome measures, determination of statistical as well as clinical significance of outcome etc. are important and feasible in evaluating efficacy of psychotherapeutic methods also. But when we go through the published studies in India it becomes obvious that we have not paid attention to such methodological issues.Out of the 42 articles related to BT till 2009, 10 are single case reports. In a newly emerging model of treatment single case reports have a place. BT papers by western workers have shown that efficacy of treatment technique can be more convincingly demonstrated, even in a single case by following an A-B-A-B design. But none of our case reports have included such a step.Main model of BT as practiced in India seems to be classical conditioning. Operant conditioning which has emerged as a more versatile and effective approach and has a greater degree of acceptance by patients, has few adherents here.Excessive reliance on aversive techniques is seen in many of the studies in a wide variety of disorders-hysteria, homosexuality, tremors, titubation etc. It is interesting to note that even in the 1970s, in the \u2018Instructions to Authors\u201d in the well known BT journal, \u2018Behavior Therapy and Experimental Psychiatry\u2019 (edited by Joseph Wolpe), it was stated that reports using aversion therapy techniques will not be accepted, unless no other proven method of treatment exists for that condition.Jacobson\u2019s Progressive Muscle Relaxation (JPMR) is used as a part of BT in almost all conditions ranging from nail-biting to schizophrenia! Justification for its use is not given in many of the papers, so much so, even in some of our academic institutions JPMR is considered to be synonymous with BT, even to the extent of postgraduate trainees in psychiatry who are posted in Behavior Therapy units getting trained only in JPMR.Many of the reports show that every behavioral technique described in a standard text book on the subject is used for every disorder, often without justifying such a multipronged approach, which reduces the cost effectiveness of the therapy and its application in settings with limited time and trained personnel.et al.[et al.[Agarwal\u2019s paper inet al. treated l.[et al. treated In an attempt to help unmarried men who present with ED, but were unable to go through the classical Masters and Johnson sex therapy, because of the lack of a partner, Kuruvilla introducThe above reviewed studies highlight some of the modifications introduced by Indian therapists to deal with certain special difficulties encountered in our country, in the treatment of sexual dysfunctions.et al.[et al.[et al.[In the 1970s and 80s, men with ego-dystonic homosexuality often came to Indian psychiatrists for help and behavioral techniques were used in treating such persons. Sakthivel et al. treated l.[et al. with elel.[et al. treated et al.[in-vivo for eliminating the avoidance behavior to social situations which produced anxiety in him because of frotteurism. Frotteurism itself was treated with exposure to situations of bodily contact with males in imagery and in-vivo and also aversion therapy. Symptoms were eliminated in 10 sessions. This patient was followed up for one year when he was found to have no anxiety in social situations and no indulgence in frotteurism. BT consisting of relaxation training, aversion therapy with aversion relief, modeling, orgasmic reconditioning, behavioral counseling and sex education, was used by Andrade et al.[A case of frotteurism was treated by Kuruvilla et al. with sysde et al. for a paet al.[et al.[et al.[Nammalvar et al. treated et al. suggest l.[et al. treated l.[et al. describeet al.[et al.[et al.[et al.[Fernandez reportedet al. paper pul.[et al. brought l.[et al. also repl.[et al. reportedet al.[Biofeedback, which is often considered a BT technique, was used in the treatment of anxiety neurosis by Sargunraj et al. Thirty set al.[et al.[Sahasi et al. comparedl.[et al. but thiset al.[Sethi et al. comparedFive executives with tension headache were treated by Mehta with JPMGada comparedet al.[Trivedi et al. reportedet al.[In a more recent paper, Kaur et al. reportedet al.[Seven females diagnosed with \u2018hysterical vomiting\u2019 were treated by Bhattacharya et al. with eleet al.[Vyas et al. reportedet al.[Nasirabadi et al. reportedet al.[Forty eight alcoholics were treated by Bagadia et al. with eleTen patients diagnosed to have \u2018neurotic depression\u2019 were given multi-modal BT by Kumariah. TreatmenThe earliest case report on the use of BT, published in IJP was by Ratan Singh who treaet al.[Nammalvar et al. treated et al.[A four-and-a-half year old child with an I.Q of 110, with encopresis for two and a half years, unable to even attend nursery school, was treated by Behre et al. Basal raReevar reportedThe emergence of Cognitive Therapy (CT) as an effective treatment approach for many conditions like depression and anxiety disorders and its subsequent merger with BT to form Cognitive Behavior Therapy (CBT) has had its impact on the Indian scene also. There are a few psychiatrists and many psychologists practicing it, but publications in this field in IJP have been few. An early paper by Kuruvilla on 17 paThe few original reports on the use of CBT which have appeared in IJP are reviewed below.et al.[in vitro, exposure and response prevention, stress inoculation, skills training and cognitive restructuring. Treatment led to improved adjustment scores in Bell\u2019s Adjustment Inventory, decrease in intensity of perceived symptoms and automatic thoughts. During follow-up, gradual decline in improvement with CBT happened, but at nine months the patients were still better than they were before CBT. The paper does not give information on concomitant anti-psychotic medication which also could have had an influence on the outcome. Description of the symptoms the patients in this study had suggest that at the time of CBT most of them were in a state of post psychotic depression and were not actively psychotic. It is also not clear how many patients have had each of the various interventions listed and their effect on specific problems. Clinical significance of the improvement seen on rating scales is not given either.Shriharsh et al. treated et al.[In a case report on a 31-year-old man with paranoid schizophrenia, who had the delusion of being controlled, being made to laugh, cry etc. through the internet, Dugal et al. report tet al.[in vivo exposure. The second group was treated by what the authors call \u2018behavioral intervention\u2019 (BI), which included only psycho-education and applied relaxation. BT group had 15 to 20 sessions in five weeks while the BI group had eight to 10 sessions in two weeks. Although both the groups showed improvement, the CBT group was superior in the reduction of panic symptoms, avoidance behavior, safety behaviors and negative cognitions. In a large percentage of CBT patients the magnitude of change was clinically significant. The therapist herself being the assessor of improvement, inequality in the time of contact with the therapist as well as total duration of treatment are some the methodological problems that could have influenced the outcome. The BI group had only psycho-education and applied relaxation as its components whereas standard BT of panic disorder also include interoceptive exposure and in vivo exposure while in this study they are part of CBT only.Thirty patients with panic disorder were treated by Manjula et al. in two gIn a survey of the current scene on the use of CBT, Kuruvilla evaluate"}
{"text": "BMC Medicine, several aspects of autoimmunity have been addressed, suggesting that we are now at the forefront of autoimmunity science. Within the environmental factors generating autoimmunity are now included unsuspected molecules such as vitamin D and aluminum. Some adjuvants such as aluminum are recognized as causal factors in the development of the autoimmune response. An entirely new syndrome, the autoimmune/inflammatory syndrome induced by adjuvants (ASIA), has been recently described. This is the new wind blowing within the branches of autoimmunity, adding knowledge to physicians for helping patients with autoimmune disease.Almost 25 years ago, the concept of the \u2018mosaic of autoimmunity\u2019 was introduced to the scientific community, and since then this concept has continuously evolved, with new pebbles being added regularly. We are now looking at an era in which the players of autoimmunity have changed names and roles. In this issue of  BMC Medicine, several aspects of autoimmunity have been addressed suggesting that we are now at the forefront of autoimmunity science.Almost 25 years ago the concept of the \u2018mosaic of autoimmunity\u2019 was intret al.[One of the mainstays of the mosaic concept is that autoimmune diseases (ADs) occur in genetically predisposed individuals. This coet al.. Physiciet al.[highFoxP3+ T-regulatory cells, is very characteristic in elderly people. It is possible that during aging, an imbalance between thymic and peripheral regulatory T-cell output occurs, with the ratio favoring the peripheral component, which possibly allows a pro-inflammatory response and increases the susceptibility to autoimmunity. Furthermore, in addition to this disruption of adaptive immunity, it has been shown that disruption of the autoimmune response also occurs in the innate immune system[et al.[Strengthening the theory of a genetic basis is the evidence that ADs occur more often in young people. Howeveret al. suggestee system. Pollard[et al. suggeste[et al.. By recr[et al.. By cont[et al..Nonetheless, environmental factors are still central to autoimmunity. Indeed,et al.[per se, or a result of the background therapy, or if it represents another causative factor of ADs[Ramagopalan et al. analyzedr of ADs.et al.[et al.[It has been shown that a link exists between the mycobacterium, ADs, and, surprisingly, another component of the puzzle, namely, vitamin D. Vitaminet al.. Moreove[et al., in thei[et al.,24. The [et al.. Finally[et al..Thus, it is evident that every day, people are exposed to several triggering factors for ADs. People can be exposed to such elements through diet , and other sources. For instance, another defendant, aluminum , is used as an adjuvant in vaccines, and its association with autoimmunity has recently been highlighted. Alum caet al.[Alum has a number of mechanisms by which it works as an adjuvant Table\u00a0. Moreoveet al. showed tThese various lines of evidence reinforce the idea that alum is neurotoxic, and that continuously escalating doses of this poorly biodegradable adjuvant in the population may become insidiously unsafe, especially in cases of over-immunization or immature/altered blood\u2013brain barrier or high constitutive CCL-2 production.It is possible that this is part of the explanation for the real new wave in autoimmunity, that of autoimmune/inflammatory syndrome induced by adjuvants (ASIA). This syet al.[et al.[Neuropsychiatric (NP)SLE is triggered by multiple mechanisms, including several autoantibodies. One of the leading pathogenic autoantibodies in NPSLE is anti-ribosomal P protein. Carmona-Fernandes et al. found thet al.,32. Like[et al. identifi[et al.. This po[et al., who higet al.[One of the autoimmune conditions more clearly associated with CNS involvement is anti-phospholipid syndrome (APS). Katzav et al. have shoet al.[The thrombophilic network is also involved in another autoimmune disorder, celiac disease. Lerner et al. showed tA further component in the mosaic of autoimmunity is the question of what stays in the renal pyramids. Renal involvement represents a major issue in autoimmune connective tissue diseases (CTDs). The main question is whether renal damage is caused by the underlying disease or by interventions, particularly by drug reactions as described by Kronbichler and Mayer. ConsequPhosphodiesterase-targeted therapies 4 are also a promising tool for treating patients with a variety of autoimmune diseases. Intriguingly, these inhibitors have been used to treat both diseases of the CNS (such as Parkinson\u2019s disease) and of the lung (such as chronic obstructive pulmonary disease), suggesting a common soil between the lung and the CNS.et al.[Finally, the revolutionary roads traced by biologic therapies continue to provide benefits for patients with ADs. Rosman et al., in theiIn conclusion, a new wind is blowing within the branches of autoimmunity, from the unexplored continent of ASIA syndrome, which iThe authors declare that they have no competing interests.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/11/101/prepub"}
{"text": "In this research topic, Herzallah et al.  have conThe findings reported in this paper (Herzallah et al., Several paradigms have been used to explore the processing capabilities of depressed patients in contexts of reward and/or punishment. Findings have not been entirely consistent, possibly due to heterogeneity of patient samples and differences in testing protocols, with different authors suggesting that patients with MDD have more significant deficits in reward learning (Henriques and Davidson, Others have compared neural responses to stimuli with positive and negative valence between depressed and non-depressed volunteers. McCabe et al.  comparedemotional blunting described by some patients during SSRI treatment (Price et al., per se and the effects of recovery from depression. Future work, with a longitudinal study design and/or including groups at different phases of treatment or treated with non-SSRI drugs or non-pharmacological alternatives, should address these questions.The findings now reported by Herzallah et al.  highligh"}
{"text": "Long non-coding RNAs are attracting the attention of researchers in many fields. These RNAs are longer than 200 nucleotides and do not encode any protein. A subset of them is reported to be strongly correlated with poor patient prognosis, suggesting a potential role in cancer progression , and Array Express Databases to analyze the expression level of most recent cited and noted lncRNAs in studies on cancer progression  between gastric cancer and normal tissues are brought in Table Student's MALAT-1 is not significantly different between gastric cancer and normal tissues in the datasets. MALAT-1 was originally identified to be up-regulated in patients at the high risk of metastasis of non-small cell lung tumors (NSCLC). It seems that MALAT-1 functions in the regulation of alternate splicing by modulating the activity of SR proteins (Ji et al., We found that the expression level of ANRIL plays an important role in the repression of P14ARF, P15INK4b, and P16INK4a. The proposed mechanism of ANRIL is an interaction with Polycomb complexes and silencing target genes. Although some relationships between the ANRIL gene and cancer progression have been reported (Yu et al., There are some reports indicating that CRNDE has been identified as an lncRNA whose expression is highly elevated in some tumors. It seems that CRNDE is associated with a \u201cstemness\u201d signature in some cancer types (Ellis et al., HOTAIR is an lncRNA that binds to the PRC2 complex and targets it at some genes involved in tumor suppression. Its up-regulation is reported in different cancer types (Gupta et al., The datasets show that this lncRNA is up-regulated in gastric adenocarcinoma compared with normal tissues. H19 is an lncRNA which is implicated as having both oncogenic and tumor suppression properties. These two controversial roles of H19 may be attributed to the nature of H19 function or context in different tissues. Our results may support its oncogenic role in gastric carcinogenesis.There is a significant up-regulation in gastric adenocarcinoma tissues compared with normal ones in our results drawn from databases Table . H19 is MEG3 is an lncRNA which is identified as having an inhibitory role in tumor growth. This lncRNA is the first one proposed to have a tumor suppressor role (Zhang et al., MEG3 is down-regulated in gastric adenocarcinoma compared with normal tissues.HOTAIR, H19, and MEG3 may potentially be suitable candidates for study in order to find some biomarkers or therapeutic targets. Hajjari et al. found a significant up-regulation of HOTAIR lncRNA in gastric adenocarcinoma tissues compared with normal ones by Real-time PCR (Hajjari et al., H19 levels were increased in gastric cancer cells and tissues compared with normal controls (Yang et al., Altogether, based on the results, it seems that some lncRNAs such as HOTAIR and H19 on cell proliferation and metastasis (Yang et al., The different expression of certain cancer type-specific lncRNAs can be exploited for the development of novel biomarkers as lncRNA expression (Gibb et al., HOTAIR and H19 as potential biomarkers or therapeutic targets in this type of cancer.Our results, drawn from microarray databases, may help researchers to investigate the role of lncRNAs in gastric cancer progression. Large scale and follow-up studies are necessary to consider lncRNAs such as"}
{"text": "Decision-Making Experiments under a Philosophical Analysis: Human Choice as a Challenge for Neuroscience.\u201d As the first editor of the issue I want to briefly comment on each of the articles highlighting its achievements and prospects for the future.This is an opinion article on the special research topic now turned into an e-book called \u201cTo what extent a decision to deceive someone is conditioned by social pressure of being caught in a lie and suffering the consequences of it? This socially relevant question is addressed in Sip et al. . DeceptiDeneve  presentsOsman  empiricaReviews' section we have a very innovative article by Nakao et al. (In the o et al. . This meHeinzelmann et al.  discusseTaking as a standpoint Stephens and Anderson's  already Lucci  proposesSmaldino and Richerson  approachVolz and Gigerenzer  differenper se, it contends that compatibilism of responsibility and mechanism is possible. Their arguments function in hypothetical manner: if agents can be accountable for policies that in some sense determine decisions, they can be held responsible for those decisions, even if they do not have conscious access to the reasons for those decisions.Shadlen and Roskies  argue fo"}
{"text": "Dear Editor,I read with interest the recently published article by Imani et al., in your"}
{"text": "Was it a vision, or a waking dream? .Reminiscent of Wilder Penfield's famous experiments, Neurologists in France have reported a remarkable case in which intraoperative electrical stimulations of the posterior cingulate cortex (PCC) in a conscious patient induced transient dreamlike states with vivid visual imagery  in an epilepsy patient by Herbet et al. . The PCCUpon reading Herbet et al.'s report, we were struck by similarities between the subjective reports given post-PCC stimulation and those we observed after controlled administration of the classic hallucinogen, psilocybin  sleep relative to waking (Braun et al., So, how might disrupting DMN activity be the cause of dreamlike visions? One way to address this question is to look for clues from studies on REM-sleep and other dreamlike states. Firstly, it is worth noting that the MTLs are major subcortical nodes of the DMN (Supekar et al., quality of consciousness (Carhart-Harris et al., In summary, we were struck by similarities between Herbet et al.'s findings with direct electrical stimulation of the PCC and those of our own with psilocybin and neuroimaging. Their case provides some causative support for the notion that the PCC is centrally involved in mediating the The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Neurotrophins are important proteins that regulate survival, development and function of neurons. They are produced by a variety of cells and exert their effects upon binding to specific tyrosine kinase receptors. The first neurotrophin to be identified was Nerve Growth Factor (NGF). From the pioneer studies performed by Rita-Levi Montalcini, awarded with the Nobel Prize, other neurotrophins have been identified and this family of neurotrophic factors now includes Brain Derived Neurotrophic Factor (BDNF), Neurotrophin 3 and Neurotrophin 4. Their function as pro-survival proteins has been consolidated but subsequent studies have demonstrated that neurotrophins may also play a role in some pathological conditions. This is the focus of this special issue of Current Neuropharmacology. et al., addresses the involvement of neurotrophins, NGF and BDNF in particular, in Alzheimer\u2019s disease and the possibility of using neurotrophin-based therapies.The paper by Allen et al., summarize studies that support the involvement of neurotrophins in the lower urinary tract (LUT) dysfunction and suggest the use of urinary neurotrophins as biomarkers of LUT pathologies.Frias et al., addresses the involvement of neurotrophins in depression, a poorly understood pathology with an increasing prevalence in Western countries.The paper by Neto et al., addresses the involvement of neurotrophins in neuropathic pain, a complex pathology difficult to tackle with, and its importance as targets for neuropathic pain treatment. The paper by Siniscalco et al., summarize the clinical uses of stem cell-based administration of neurotrophins for the treatment of spinal cord injury.Teng This issue is published in memory of David Dawbarn, who passed away unexpectedly in January 2010. David dedicated most of his work at the Bristol University to understanding the importance of neurotrophic factors in Alzheimer\u2019s disease, unraveling the molecular interactions between neurotrophins and their high-affinity receptors. His research was a key factor to the design of new therapies for the treatment of Alzheimer\u2019s disease, pain and asthma. He is greatly missed by the scientific community, friends and family."}
{"text": "The objective of this paper is to provide a review on the psychiatric comorbidity research in India based on the data published in the last six decades. The comorbidity data world over reflects that it is a much more common phenomenon than observed in routine clinical practice. In India, research into this domain of psychiatry has been limited, with comorbidity reported to be as high as 60%. In the few publications in this area, most of the authors have looked into substance related comorbidity. Small numbers of studies have looked into comorbid conditions in child psychiatry, especially mental retardation and very few studies have looked at other comorbidities. The landmarks in the studies in the area of psychiatric comorbidity have been highlighted in this review article. The term comorbidity was first introduced by Feinstein in 1970 to denote those cases in which a \u2018distinct additional clinical entity\u2019 occurred during the clinical course of a patient having an index disease. economic36Similar results have been obtained from the Australian National survey of Mental Health and wellbeing. Comorbidet al.[To compare substance use in mentally ill and the normal population Dube et al. conducteet al.[Cannabis has been socially accepted substance in India and has been used in traditional Indian medicine. The psychological consequences of chronic cannabis use have been studied by many Indian researchers. In India it was Dhunjbhoy, who firset al. analyzedet al.[Trivedi et al. screenedet al.[Kishore et al. assessedet al.[Goswami et al. examinedet al.[In a group of 70 patients with schizophrenia, Aich et al. found thet al.[In another study on 30 subjects with alcohol dependence, by Vohra et al. 23 (76.6et al.[In a study examining the comorbidity in alcohol dependence by Singh H.N. et al. the prevet al.[Hundred subjects who met the criteria for current manic episode were recruited from a psychiatric hospital and were evaluated for substance abuse by Suresh et al. 50% of tMendhekar and Mehta publisheS.S. Raju studied et al.[A study conducted in the child psychiatry unit of a tertiary psychiatric hospital by Khess R.J. et al. evaluateet al.[In a cross sectional study, Bhattacharyya et al. found thGreydanus and Pratt in a revet al.[Karande et al. documentet al. evaluateet al.et al.[Girimaji SR et al. at NIMHAEvaluation and diagnosis of comorbid disorder is of paramount importance in order to modify treatment schedules and improve patient outcomes. In the present times, comorbid diagnosis should be an expectation and not an exception. Studies have consistently shown in the past that appropriate psychopharmacology of a known psychiatric disorder ensures better outcome for both the index mental illness and comorbid diagnosis with special reference to substance use. At the same time we now have some literature bringing out the fact that the treatment of both index and comorbid conditions is necessary, for example, integrated mental health and substance abuse treatment is the best treatment practice. Treatment of patients with comorbid diagnosis should be individually matched and based on assessment of diagnoses, level of disability, stage of change, treatment, rehabilitative goals or strengths, and level of care. Treatment should also be stage specific including individual and family interventions, community reinforcement and contingency management. Each of these areas need further research in relation to specific comorbidity combinations. It can be seen that the research so far has started to address some of the above issues but many of them remain unexplored."}
{"text": "As animals navigate through the environment, they use internal and external sensory cues to update their movements and successfully locate food or nest sites. The rich repertoire of spatial behaviors characteristic of many species has spurred intense research into the neural basis for representing external space. For many years, the mammalian hippocampus has been considered a structure crucial for supporting the creation or storage of spatial information (O\u2019Keefe and Dostrovsky, Since the discovery of grid cells, computational modeling has been a key tool in generating hypotheses and theories to explain the origin of periodic and hexagonal firing patterns (For a review see Giocomo et al., in vitro studies described a myriad of biophysical properties which also showed a strong dorsal-ventral organization in mEC (Giocomo et al., in vitro finding that theta band oscillations measured in single mEC neurons decrease in frequency along the dorsal-ventral axis (Giocomo et al., in vitro slice recordings showing a decrease in the frequency of the theta band resonance after the application of cholinergic agonists (Heys et al., A prominent feature of grid cells is their spatial scale, which is organized topographically, increasing progressively from dorsal to ventral medial entorhinal cortex (mEC; Hafting et al., Spatial representations are thought to depend not only on grid cells but also on a multitude of other functionally specialized neurons in the parahippocampus. One of these specialized neuronal classes is head direction cells, which respond strongest when an animal faces a particular direction in the environment, irrespective of their behavior or location at the time (Taube et al., The apparent flexibility in grid scale under conditions of novelty, experience, or fragmentation of the spatial environment may be reflected by hippocampal place cell signals, which have been proposed as downstream targets for the grid cell output (Solstad et al., One way to gain a deeper understanding of how these different spatial signals interact in the parahippocampal circuit is to study and compare their developmental time course. Work in very young animals has already demonstrated that specific features of place cells reach adult levels at an earlier age than grid cells (Langston et al., This Research Topic provides a unique collection of new data and discussion covering a broad scope of questions aimed at understanding the neural representation of external space. We encourage the reader to sample the full range of articles."}
{"text": "Uterine contractions during labor are discretely regulated by rhythmic action potentials (AP) of varying duration and form that serve to determine calcium-dependent force production. We have employed a computational biology approach to develop a fuller understanding of the complexity of excitation-contraction (E-C) coupling of uterine smooth muscle cells (USMC). Our overall aim is to establish a mathematical platform of sufficient biophysical detail to quantitatively describe known uterine E-C coupling parameters and thereby inform future empirical investigations of physiological and pathophysiological mechanisms governing normal and dysfunctional labors. From published and unpublished data we construct mathematical models for fourteen ionic currents of USMCs:  For over 50 years it has been known that uterine smooth muscle (myometrium) generates spontaneous action potentials (APs) Modifications of myometrial cell electrophysiological characteristics during pregnancy are evident. The resting membrane potential of myometrial cells becomes progressively more positive towards term There is increasing awareness of the benefits of developing mathematical descriptions of uterine function The general mathematical formulae used for parameter modeling are given in the Mathematical descriptions of the biophysical characteristics of this current are given in et al., et al., et al., et al., Properties of et al., et al., et al., et al., i.e. prior to peak current at each voltage step being reached, from Jones et al., et al., There is little information available for voltage-dependent activation time constants of myometrial et al., et al., Simulated time tracings of oto  of  .et al., et al., Peak With in vitro experimental conditions: It is possible that the reported Mathematical descriptions of the biophysical characteristics of this current are given in Modeling of The equation for Mathematical description of the biophysical characteristics of this current are given in et al., et al., et al., et al., et al., et al., et al., et al., et al., The equation for Mathematical description of the biophysical characteristics of this current are given in We have considered the electrophysiological data of several major types of potassium currents described from myometrial cells of rat and human myometrium: (two) voltage-gated potassium currents  and TEA. As such, we developed mathematical models predominantly based upon the more abundant information of electrophysiological characteristics of human myometrial C1 and C2 of Wang et al., et al., et al., The equations of et al., et al., et al., et al., et al., et al., Activation time constants of  et al., . We ther5 cells,  or   and via the via PMCA when the cell was stimulated by ten short depolarization pulses between In myometrial cells from near-term pregnant rats, intracellular et al., et al., et al., et al., bringing in extracellular calcium at resting membrane potentials of et al., et al., et al., extrude intracellular We modified a myometrial intracellular calcium model We have modeled three major plasmalemmal calcium fluxes: the voltage-dependent membrane channels permeable to et al., The parameters for The There are three et al., et al., viaWe used an electrogenic PMCA activity in rat myometrial cells has been characterized in fractionated plasma membranous vesicles with a reported ATP-dependent uptake with half saturation at Our ability to integrate the information obtained from the above biophysically detailed models of individual ionic fluxes into simulations of APs and the ensuring changes in Myometrial cells can produce different forms of APs including those consisting of a single spike, a burst of spikes or a plateau-type. A first task of validation was to assess if integration of our individual ionic current models and et al., We began to assemble a model of AP configuration that incorporated all of the currents and ion fluxes described above. However, under physiological conditions of ionic concentrations The USMC model is excitable and responds to a brief stimulus with an all-or-none AP. The voltage threshold is The range of AP shapes reported for the pregnant rat myometrium at The cell model is validated with voltage-clamp and current-clamp experimental data from pregnant rat myometrial cells at ance by  .The extraction of the mathematical descriptions for modeling calcium-dependent force changes is denoted in  (equations 3 and 8\u20139) and et al., A final step in our validation of the model was to establish if it was able to accommodate the integration of uterine smooth muscle electrical, The model could also reproduce several additional published E-C coupling datasets of V(t), Our approach has resulted in a number of advances for our understanding of uterine smooth muscle E-C coupling. The model encompasses the most comprehensive biophysical description of ion channel and exchanger electric currents applied to the myometrium with 14 separate electrogenic components, summarized in in vitro solutions and at different temperatures. Although this neglects any species-specific quantitative differences in uterine electrogenicity and E-C coupling, it presently is unavoidable. It is also common in biophysical modeling approaches when it is rare that all information is available for one cell type from one species. However, an advantage of the comprehensive assembly of this mathematical model is that it enables identification of gaps in our knowledge of myometrial electrogenesis. This will inform future empirical work in several ways.As with any mathematical model of biological phenomena there are limitations. The 14 electrogenic currents are likely to be an underestimate of the number of ion channel contributors to myometrial AP form. This highlights a lack of sufficient biophysical detail on other currents. In biophysical modeling of cells and tissues, it is often the case that some published electrophysiological information on particular currents is of insufficient detail to furnish biophysical modeling of all its steady-state and dynamic characteristics. Therefore, data from different resources with close cell types, or the same type of cells from different species, are used. This is the same case for the present model. The model is a hybrid containing information primarily from rat myometrium but also from human myometrium and cells expressing smooth muscle ion channel subunits, and this data has been obtained from experiments using different e.g. there are many putative pharmacological blockers/openers First, the putative contribution of many ion channel subtypes to myometrial function has often been extrapolated from molecular data (mRNA or protein) which is incomplete  or pharmacological data utilizing compounds of weak specificity  function at late pregnancy was developed from the integration of data of individual ionic currents, calcium dynamics and contraction. A glossary of symbols used in the equations is given in e.g., from human USMC, or clonal cells expressing rat-derived proteins, then this has been mentioned.The individual membrane current components that were modeled were (i) four inward currents: L-type and T-type y) describes the time-dependent activation or inactivation profile of the channel conductance where et al., Most of the membrane currents were modeled with Hodgkin-Huxley type formulation in the following form:et al., i.e., time-independent. Herein we have included the temporal dynamics of membrane calcium currents in et al., Bursztyn The geometry of a uterine smooth muscle cell is assumed to be two cone shapes joined end-to-end at their bases Force development during uterine contraction was modeled with a simple first-order ordinary differential equation:Action potentials were induced in the whole cell model by applying an external stimulus current Click here for additional data file.Figure S2Different inactivation kinetics of myometrial (PDF)Click here for additional data file.Figure S3Divalent ion concentration versus (PDF)Click here for additional data file.Figure S4Experimental current tracings of (PDF)Click here for additional data file.Figure S5Experimental current tracings of (PDF)Click here for additional data file.Figure S6Modeling the dynamics of (PDF)Click here for additional data file.Figure S7Modeling simultaneous changes in V and (PDF)Click here for additional data file.Figure S8Modeling force output consequent to spike APs or plateau-like APs.(PDF)Click here for additional data file.Table S1Definitions of the equation symbols.(PDF)Click here for additional data file.Table S2Definition of gating variables for individual currents and force, and the corresponding experimental temperature and species.(PDF)Click here for additional data file.Table S3Initial values of the dynamics variables used in model simulations.(PDF)Click here for additional data file.Table S4Constant parameter values used in model simulations.(PDF)Click here for additional data file.Appendix S1Equations used in the model simulations.(PDF)Click here for additional data file.Appendix S2Model source code.(BZ2)Click here for additional data file."}
{"text": "We clarify that our view does in fact place motivation and emotion center-stage in the anxiety-ERN relationship.We reiterate that there is currently little compelling evidence that an enlarged ERN in anxious individuals reflects \u201cthe disposition to respond more strongly to uncertain threat\u201d  that worry-related anxiety was associated with an enlarged ERN in the presence of unaltered behavioral performance, (2) that loading working memory with non-valenced information  also enlarged the ERN, and (3) that worriers with an enlarged ERN performed better in school than worriers with relatively smaller ERNs, but similarly to non-worriers. These results strongly suggest that an enlarged ERN among individuals high in worry serves a compensatory function.The findings in support of our CEMH are not well explained by Proudfit et al.'s perspective that an enlarged ERN in anxiety reflects a heightened threat response. Principally, their perspective does not account for the meta-analytic finding that worry demonstrates the most robust link with the enlarged ERN. In fact, their view is that worry is not necessary for enhanced ERN in anxiety. It is likewise unclear how their position would explain the other findings we reported in support of our CEMH (listed above). Thus, our first concern with Proudfit et al.'s conceptualization is that their threat sensitivity proposal does not capture a number of anxiety-ERN findings.r = \u22120.07 vs. r = \u22120.38 with the outlier included; See Appendix for details of this reanalysis). The ERN is also unrelated to perfectionistic concerns about mistakes  measures of threat sensitivity are interrelated. To date, little compelling evidence exists for this multivariate relationship. Specifically, the ERN is uncorrelated with other physiological markers of defensive responding to errors, including error-related skin conductance, heart rate changes (Hajcak et al., To provide evidence for their threat sensitivity hypothesis Proudfit et al. cite a study wherein undergraduates scoring high on negative affect showed increased ERN and increased error-related skin conductance (Hajcak et al., Perhaps most problematic for their view are the data showing that obsessive compulsive patients fail to demonstrate an especially large ERN to errors that are punished with monetary loss (Endrass et al., per se. For example, behavioral indicators from Bartholow et al. suggest that individuals in the alcohol group were well aware of their mistakes and even made appropriate adjustments to their mistakes compared to the no-substance control group. It also seems important to point out that, in fact, Bartholow et al.'s results may be supportive of our CEMH in that alcohol may have reduced worry and therefore reduced the ERN. The same may also be true of other studies showing that anxiolytic agents reduce the amplitude of the ERN (e.g., Johannes et al., Flipping this \u201cintegral affect\u201d notion on its head, Proudfit et al. cite Bartholow et al.  who showFinally, the interesting developmental considerations outlined by Proudfit et al. do not rule out the possibility that enhanced ERN in anxiety reflects compensatory processes. Proudfit et al. have shown that the ERN is unchanged (Meyer et al., We emphasize that developmental considerations are important for both theoretical and practical reasons. Likewise, we agree with Proudfit et al. that intensive longitudinal studies across significant periods of development will help clarify whether the ERN is a cause or a consequence of anxiety. On this point, if the ERN emerges as an endophenotype for anxiety it could certainly reflect compensatory processes. Nonetheless, we simply believe the existing developmental literature is too sparse and inconsistent to serve as a strong basis for drawing inferences about the functional relationship between anxiety and ERN.To reiterate, the motivation in developing the CEMH was to understand the functional significance of the elevated ERN characteristic of many individuals with heightened anxiety. We do not attempt to provide an overarching account of the much broader and thornier relation between anxiety and threat. This is a critical distinction between our view and that of Proudfit et al. Our central claim, one that we believe is better supported by the existing data, is that the enlarged ERN characteristic of some anxious individuals and patients reflects compensatory cognitive control.Finally, although we have outlined our disagreements with Proudfit et al.'s position, there is clearly benefit for this line of research\u2014and for science in general\u2014to having opposing views on the same findings. Future work in this area ideally should attempt to directly adjudicate between our view and that of Proudfit et al., as well as develop alternatives that may ultimately prove more accurate. Our view and that of Proudfit et al. also leverage somewhat different literatures\u2014cognitive science/neuroscience versus affective-motivational science/ neuroscience, respectively\u2014and so clearly a union of such synergistic perspectives will eventually be needed. At the heart of the anxiety-ERN relationship is likely an interplay of cognition and emotion/motivation, to the extent that the two are meaningfully separable (Shackman et al.,"}
{"text": "Psychological research uses multifarious assessment strategies to describe and to explain emotional and cognitive processes accompanying behavior in order to predict future behavior. However, laboratory assessments and questionnaire approaches dominate psychology, which has been criticized lately  will deliver valid and reliable information.Society for Ambulatory Assessment\u2014Understanding Behavior in Context defines AA as any use of \u201c\u2026 infield methods to assess ongoing behavior, physiology, experience, and environmental aspects of humans \u2026\u201d .Another methodological question is raised if research seeks to gain data out of subjects' real life. If the ecological validity should be convincing research has to go into everyday life using a suitable approach to get valid and reliable data. Ambulatory Assessment (AA) or ecological momentary assessment is an appropriate and promising approach for infield real time investigations. The European Psychologist edited by Ebner-Priemer et al. ;moods, affective reactions, symptoms like aches, commentaries;psychological tests infield;behaviors ;environmental conditions ;bio-markers .Although electronic diaries have gained increasing interest in psychology to assess variables of interest in real time, and although accelerometers are quite popular in sports and exercise science to objectively assess physical activity and movement pattern in everyday life, the combination of both methods is still alarmingly rare. To give researchers, in the context of physical activity and exercise psychology, guidance in the advantages and benefits of combining e-dairies with accelerometers, we invited experts to report their original studies. It resulted in a reader giving an impression of the fruitfulness of AA in this special field.The reader starts with a position statement done by the editors themselves (Kanning et al., This statement is followed by an article written by Bossmann et al.  looking Bussmann , the nexThe same author, together with his co-author (Bussmann and van den Berg-Emons, theory article. They tested the feasibility and validity of an EMA self-report protocol using electronic surveys on mobile phones. It is feasible and data are valid, but the volume of physical activity is underestimated, especially for those persons underweight or normal weight.An original research article done by Dunton et al.  follows Ebner-Priemer et al.  highlighKanning  uses objFrom work and leisure time the next text goes to pupils in elementary schools. K\u00fchnhausen et al.  asked ifMurphy et al.  originalSchwerdtfeger et al.  report aTwo articles in which von Haaren is a contributor (von Haaren et al., Given the combination of texts the reader has a colorful bouquet of different inquiries in his hands and we hope this launches more studies in the natural environment assessing behavior in real settings."}
{"text": "Sir,TGFBR1 and colorectal cancer risk in Caucasian and Ashkenazi populations\u2019 .We appreciate the data and comments provided by et al criticise the lack of a detailed description of the subjects studied by In their letter, Abadie et al point out that the significant discrepancies observed among studies, mostly between the first , very different from the average ASE value 1.07  obtained by Abadie et al in CRC cases, also using the SNaPshot technology . This observation suggests that the difference in the study population is not the cause of discrepancies between the original and subsequent reports.Abadie et al indirectly support that SNaPshot is especially sensitive to RNA quality. et al ensured very high RNA quality, probably explaining why SNaPshot provided consistent values among SNPs and low s.d.'s between independent replicates, even for rs7871490, a SNP located in a complex repetitive stretch.The results shown by Abadie et al clarifies the role of ASE of TGFBR1 in CRC susceptibility. Current evidence suggests that differences observed among studies are not directly attributable to study population or technique, provided high-quality RNA is used for allele expression experiments, and that allele-specific expression of TGFBR1 is not a strong risk factor for CRC.The letter by Abadie"}
{"text": "However, we have some concerns regarding the rigour of assessment of elements of the evidence base and the authors\u2019 accuracy in presentation of this evidence. The largest randomised controlled trial referenced  is that of Mathur et al.et al states that Mathur et al showed CHO supplements reduced length of hospital stay. This is at odds with Mathur\u2019s own conclusion: \u2018Preoperative CHO treatment did not improve postoperative fatigue or length of hospital stay after major abdominal surgery.\u2019We read with interest the review of Jones et alet al investigated whole-body protein kinetics via a stable isotope labelled amino acid technique and not whole-body protein. This protein kinetic study looked at changes in protein balance before and after colorectal surgery. Whole-body protein balance was shown to be negative at a set point in time during the preoperative fast and again at a set point during the early postoperative period. The rate of loss of protein mass at this instant was faster in the group receiving low dose preoperative CHO than in the high dose group. To interpret this as meaning whole-body protein did not change in the perioperative period in the group receiving high dose CHO is erroneous.Furthermore, the work of Svanfeldt et al have shown a reduced loss of muscle mass postoperatively in patients receiving CHO,et aldo measure total body protein in lower GI surgery but have not as yet demonstrated that CHO can significantly attenuate the perioperative loss of total body protein.While Yuill We agree that measures to minimise the stress response to surgery will benefit our patients. Evidence exists that supports the implementation of ERAS programmes,"}
{"text": "Without blood vessels, tumors cannot grow beyond a critical size. Angiogenesis is regulated by a balance of pro- and anti-angiogenic molecules  still remains controversial . No significant correlation for CD31 between mRNA and protein levels by immunohistochemistry implies that in the typical slow growth of PC, the angiogenesis dynamics are also quite low (Steiner et al., Despite its importance as a prognostic indicator in untreated tumors, MVD has not been shown to be a valid measure to guide or evaluate anti-angiogenic treatment (Hlatky et al., A non-invasive imaging technique that could reflect MVD would hold great promise in tumor detection and characterization (Jain et al., status of neovascularity, but there are still several open questions, including whether angiogenesis is a canonic hallmark of PC, and the absence of a powerful method of quantifying the reversal of neovascularity.Scientific knowledge develops through the evolution of new concepts, and this process is usually driven by new methodologies that provide previously unavailable observation. The potential broad applicability of the Fractal geometry makes it possible to explore the range of the morphological variability of neovasculature that can be produced in nature, thus increasing its diagnostic importance in cancer research (Taverna et al.,"}
{"text": "Dear Editor,I read with interest the published article by Bayani et al.  in your Bayani et al.  reportedFinally I would like to mention that adding to educational approach for health care workers and more attending to health precautions during work, vaccination of non-immune individuals against HAV infection in this high risk group is wisdom strategy now , 9. Vacc"}
{"text": "International Journal of Environmental Research and Public Health by Chari et al. [et al. for analysis do not provide comparable information on regression coefficients for the blood lead level-IQ relationship. The coefficients differ from one another more on the basis of unequal blood lead metrics, ages of blood lead measurement, and differences in covariate adjustments and standardization, than the difference postulated by Chari et al. to correspond to low vs. high SES populations.A recent publication in i et al.  provides Although it has long been observed that there is an inverse association between SES and blood lead levels, the authors go beyond this observation to hypothesize that differences in the dose-response relationship between blood lead and IQ exist depending on the SES status of the population. As a result, they conclude that EPA\u2019s decision framework for development of the National Ambient Air Quality Standard (NAAQS) for lead should result in a lower NAAQS in order to protect these susceptible populations. However, Chari et al.\u2019s analysis is not adequate for this purpose.In , Chari eet al. rely on four publications that examine the blood lead-IQ relationship as a function of SES status: Dietrich et al. [et al. [et al. [et al. [et al. and McMichael et al. employed the Mental Development Index (MDI) of the Bayley Scales of Infant Development, administered at 6 months by Dietrich et al. and at 2 years by McMichael et al. Harvey employed the British Ability Scales, administered at 2 years, and Tong et al. employed the Wechsler Intelligence Scale for Children (WISC-R), administered at 11\u201313 years. IQ testing at these various ages obviously takes different forms, and after control for confounders, there is little correlation between the MDI and IQ administered at later ages  to 11\u201313 years , while the blood lead metric includes a measure of early childhood , lifetime average , and age 2.5 years, approximately peak blood lead . Further, the McMichael et al. and Tong et al. studies are of the same Port Pirie children, but at different ages. Blood lead levels are a function of age, peaking at approximately age 2\u20133 years, and declining into adolescence. Regression coefficients describing the relationship between blood lead level and IQ vary as a function of the age of blood lead measurement and the blood lead metric. This can be seen in Lanphear et al. [et al.). The difference in coefficients in the McMichael et al. and Tong et al. studies may result in part from the age difference. Comparisons of different SES groups must be based on regression coefficients for the same blood lead metric and approximately the same age, or adjusted in some way for the impact of variable blood lead metrics and ages at time of measurement. Although Chari et al. note that the variable blood lead metrics are a limitation of their analysis, they don\u2019t indicate the direction of bias associated with this limitation and the subsequent impact on their conclusions. The difference in coefficients proposed by Chari et al. for high and low SES populations is similar to the difference seen between studies of children at different ages, suggesting if this bias were considered that there might be no difference in dose-response relationships at different SES levels.Children\u2019s ages at the time of blood lead measurement range from 10 days (Dietrich r et al.  where foet al. study are hematocrit-adjusted. This adjustment would also have an impact on the magnitude of the regression coefficient, and complicate the comparison of this result to those of other studies.Blood lead levels reported in the Dietrich et al. analysis comes from the authors\u2019 extrapolation of the log-linear regression coefficients to a blood lead level of 2 \u00b5g/dL, well below the average blood lead levels in each of the studies. Although extrapolation of linear coefficients to lower blood lead levels may produce a bias towards underestimating effects, extrapolation of log-linear coefficients may produce a bias in either direction. As an example of the impact on the dose-response slope resulting from this extrapolation, Chari et al. extrapolate and linearize the regression coefficient from Dietrich et al. at 2 \u00b5g/dL to be \u22122.35. However, a later publication on the same data set by Dietrich et al. [et al. for high vs. low SES children, suggesting again that there might be no difference in dose-response relationships at different SES levels.Additional uncertainty in the Chari h et al.  reports et al. should have indicated the direction of this bias. Further, Harvey et al. reported a standardized regression coefficient. The value of a standardized coefficient, which can vary from negative to positive one, is not comparable to an unstandardized coefficient. Although Chari et al. acknowledge that some coefficients are adjusted and others are not, they neither note the direction of bias associated with this limitation, nor note the lack of comparability with the Harvey et al. standardized regression coefficient.Complicating the comparison of coefficients among these four studies further, some of the coefficients are adjusted for covariates while others are not, and some are standardized while others are not. The regression coefficients from the McMichael study are unadjusted, while those from the other three studies are adjusted. This difference matters: Bellinger  notes thet al. cite two studies that give this comparison: McMichael et al. and Tong et al. As noted above, these two studies are of the same children, and it is perhaps not surprising that a similar result is found. However, in neither study did the authors find a statistically significant impact of SES on the blood lead-IQ relationship.Although the comparison across studies is complicated by the various types of regression coefficients, and the mixed ages, blood lead metrics and cognitive tests, it remains worth reviewing the results found within a study between the high and low SES categories. Chari et al. also did not find statistical significance. Before adjustment for covariates, Harvey et al. reported a correlation between blood lead and IQ that was larger and negative for the manual labor class. Harvey et al. [et al. [et al. [et al. included the younger children from the first study where the father is engaged in manual labor as low SES in their analysis, but did not include the older children from the second study where the result was the opposite.The study by Harvey y et al.  present  [et al.  report t [et al.  found thet al. found statistical significance, in an analysis of the Cincinnati cohort based on blood lead levels at age of ten days. However Dietrich et al. [et al. also note that an SES effect was not seen in the Cincinnati cohort in later years.Only the study by Dietrich h et al.  also exaet al. are similar to or less than the differences between regression coefficients expected as a result of mixing blood lead metrics, children\u2019s ages, adjusting or not adjusting for covariates, and comparing standardized and non-standardized regression coefficients. Further, the studies selected by Chari et al. show little or no statistical significance of an SES effect on the relationship between blood lead and IQ. As a result, the Chari et al. analysis does not support a need to modify the Pb NAAQS for protection of low-SES populations. At this time, the methods by which to consider non-chemical stressors in risk assessment are an active area of investigation and debate within the scientific community and among policy makers. The Chari et al. analysis does not inform this debate for the impact of SES on the relationship between blood lead and cognitive impacts. An appropriate analysis would need to focus, at a minimum, on a data set for the same blood lead metric, in children with blood lead measures and cognitive testing at approximately the same age.In summary, the differences in regression coefficients describing the blood lead-IQ relationship between low and high SES populations as put forward by Chari"}
{"text": "The eukaryotic cell possesses specialized pathways to turn over and degrade redundant proteins and organelles. Each pathway is unique and responsible for degradation of distinctive cytosolic material. The ubiquitin-proteasome system and autophagy  act synergistically to maintain proteostasis. Defects in this equilibrium can be deleterious at cellular and organism level, giving rise to various disease states. Dysfunction of quality control pathways are implicated in neurodegenerative diseases and appear particularly important in Parkinson's disease and the lysosomal storage disorders. Neurodegeneration resulting from impaired degradation of ubiquitinated proteins and \u03b1-synuclein is often accompanied by mitochondrial dysfunction. Mitochondria have evolved to control a diverse number of processes, including cellular energy production, calcium signalling and apoptosis, and like every other organelle within the cell, they must be \u2018recycled.\u2019 Failure to do so is potentially lethal as these once indispensible organelles become destructive, leaking reactive oxygen species and activating the intrinsic cell death pathway. This process is paramount in neurons which have an absolute dependence on mitochondrial oxidative phosphorylation as they cannot up-regulate glycolysis. As such, mitochondrial bioenergetic failure can underpin neural death and neurodegenerative disease. In this review, we discuss the links between cellular quality control and neurodegenerative diseases associated with mitochondrial dysfunction, with particular attention to the emerging links between Parkinson's and Gaucher diseases in which defective quality control is a defining factor.http://dx.doi.org/10.1111/bph.2014.171.issue-8This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit  They aret\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., Neurons have an absolute dependence on mitochondrial oxidative phosphorylation for their ATP supply, with very limited capacity for glycolysis  gene and is associated with PD as it appears that similar underlying defects in autophagy and mitochondrial dysfunction may link the neurodegenerative aspect of these two disorders  as the most prevalent of the group  and the autophagic pathways: chaperone-mediated (CMA), macro, micro as well as organelle specific , or more recently reported, the mitochondria . The process of mitophagy is remarkably specific; by uncoupling a single mitochondrion via photo-irradiation, this and only this mitochondrion will be degraded  and PARK2 encoding the E3 ubiquitin ligase Parkin -dependent manner , PINK1 fails to import and accumulates on the OMM where it remains trapped at the TOM complex, recruiting Parkin to the OMM where it exerts its E3 ligase activity  is not clear.Although a complex multi-step process, regulation of mitophagy under the PINK1/Parkin (Mfn2?) system does seem logical. However some doubts remain as to the physiological relevance of this pathway. Although well characterized, experimental demonstration of this model pathway relies on complete depolarization of the \u0394\u03a8et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., CMA is one of the lysosomal pathways of proteolysis. It is markedly different to conventional autophagy as no vesicular transport is involved; instead, cytosolic proteins are recognized and delivered to the lysosome by chaperones in a molecule-by-molecule-dependent manner Dice, . In thiset\u2009al., et\u2009al., Under normal circumstances CMA is induced under starvation conditions with heat shock protein 40 (Hsp40) stimulating Hsc70 activity, which then binds substrate proteins in an ATP-dependent manner. Hsc70  transport the cytosolic protein to the membrane of the lysosome where they bind to lysosome-associated membrane protein 2A , a small 76 amino acid polypeptide with poly-ubiquitin marking the substrate for transportation to the proteasome  and soma (body)  were fragmented with a reduced ability to buffer Caet\u2009al., GM1-gangliosidosis is a rare inherited disorder that is generally characterized by progressive neurodegeneration  was observed in astrocytes as well as abnormal mitochondrial morphology and a decrease in \u0394\u03a8m  or BD are recessively inherited neurodegenerative disorders, characterized by lysosomal accumulation of subunit c of the ATP synthase within neurons   and is responsible for the conversion of its substrate glucocerebroside to glucose and ceramide  suggesting that damage is mediated by ROS generation from CI . In this system, knockout (KO) of GCase in primary neurons and astrocytes caused defects in the autophagy pathway with reductions in LC3-I/II and Atg5/12 levels, suggesting the presence of a negative feedback loop upstream of lysosomal involvement (Osellame et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., in vivo (Spencer et\u2009al., et\u2009al., et\u2009al., et\u2009al., There appears to be a strong clinical association between these two classes of disease. As the lysosome is central to the autophagy process, it is not unreasonable to assume this pathway is integral in protecting against neurodegeneration (Xilouri and Stefanis,"}
{"text": "We aget al. In consequence, as shown in et al. [et al. [et al. [et al. to engender uncertainty and affect mortality estimates. We regard them as minor compared with the \u2018safety margin\u2019 factor of 8 \u00d7 10\u22127 by which Perry et al. inflated the estimated mortality through deliberate choice of a small value of the logit slope, designed to give worst-case mortality.Regarding sensitivity analysis, it is important to allow for the fact that depositions of pollen in the field occur at far lesser concentrations than the LC50s for the three species considered by Perry n et al.  is vanis [et al. ,4 slope  [et al.  would reet al. model is that it provides a transparent, structured and simple approach to exposure analysis that may be followed for other species and taxa in other settings, if sufficient data become available. Further, in its derivation of an integrated mortality\u2013distance relationship, it offers the opportunity for relatively accurate laboratory-based estimation of mortality\u2013dose relationships to supplement relatively inaccurate determinations of mortality in the field. We agree with Lang et al. that species' sensitivity to particular GM events that express different forms of Cry1 proteins is an important determinant of mortality; also that further data would be welcome on the mortality\u2013dose relationships (particularly regarding the slopes) for a range of species, especially those of conservation concern. However, we disagree that we have been incautious regarding the implications of our results for conclusions regarding regulatory policy. We therefore reaffirm the robustness of our conclusion from our model that, after accounting for large-scale exposure effects, the \u2018estimated environmental impact of MON810 pollen on non-target Lepidoptera is low\u2019.The value of the Perry"}
{"text": "The biological basis of psychiatric disorders has been the focus of research in various studies across the world including India. In this selective overview we summarize findings of various EEG, neuro-imaging and blood related studies that have been reported in the Indian Journal of Psychiatry. The biological basis for psychiatric disorders has been increasingly becoming a major research focus over the past many decades in various countries. Similar trends have been observed in Indian psychiatry too. In this selective overview, we have attempted to summarize various biological investigations that have been reported in the Indian J Psychiatry over the past many decadeset al.[et al.[Studies involving schizophrenia subjects have primarily looked at blood levels of various chemicals. In addition, EEG studies have observed REM sleep defects and neuro-imaging studies have looked at perfusion defects in relevant brain regions. Rao et al. examinedl.[et al. assessedet al.[Prakash and Sethi assessedet al. studied et al.[Kuruvilla et al. studied et al. studied et al.[There was a two fold increase in prolactin level but no correlation between baseline serum prolactin level and severity of baseline psychopathology. Authors concluded that baseline prolactin may not be a reliable indicator of psychopathology and prognosis. Singh et al. studied et al.[Tiwari et al. assessedet al.[Das et al. in theirGong and colleagues studied Studies examining for brain abnormalities in schizophrenia using neuroimaging techniques have reported Significant hypo-perfusion in frontal as well as temporal areas in childhood onset patients.FDG-PET study revealed that participants With negative symptoms of schizophrenia had significantly decreased metabolism in all regions of the brain as compared to the positive type. The positive syndrome of schizophrenia was associated with significantly increased glucose metabolism in the medial temporal regions, basal ganglia and left thalamic regions. Hypo metabolism was also noted in the cerebellum.et al.[Studies in bipolar affective disorder have mainly focused on clinical correlates of serum lithium levels. Srinivasan et al. assessedet al.[Kuruvilla et al. reportedet al.[Prakash and Sethi examinedet al. examinedet al.[Khandelwal et al. studied et al.[Shukla et al. studied et al.[et al.[Geetha et al. studied l.[et al. examinedet al.[Solanki et al. assessedet al.[Mishra et al. studied Verma and colleagues studied 2-relaxometry technique .[Tharyan and colleagues studied l. 2007).et al.[Shah and colleagues comparedet al. studied In conclusion, review of research studies focusing on biological investigations in psychiatry suggest varied parameters that have been examined with mixed findings. It is possible that uncertainties of these observations are mainly implicated upon the heterogeneity of these disorders. This emphasizes the need for \u2018endophenotype-based\u2019 research approaches that might help us to advance our understanding of various psychiatric disorders."}
{"text": "Sir,et al . The median time to progression .Previous work has also shown treatment response to metronomic cyclophosphamide and dexamethasone in castration refractory prostate cancer; Glode et al  publisheet al (et al (It is possible that response to metronomic chemotherapy is, in part, influenced by the histology of the primary tumour. The study by Khan et al  containel (et al  shows beThe use of dexamethasone concurrently with cyclophosphamide could have contributed to the response demonstrated in our patients. However, as stated above, virtually all of our patients had been treated previously with corticosteroids, and so we believe the use of cyclophosphamide was responsible for most of the clinical benefit seen.In conclusion, we believe that metronomic treatment with cyclophosphamide is a well tolerated and useful treatment in heavily pre-treated patients with metastatic castration refractory carcinoma of the prostate, and warrants further investigation."}
{"text": "Radiofrequency catheter ablation is a well established modality of treatment for ventricular tachycardia (VT). But it may not be successful in certain cases when the re-entrant circuit is situated deep within the myocardium and inaccessible to both endocardial and epicardial ablation. One of the earliest reports on transcoronary ethanol ablation of refractory ventricular tachycardia was by Inoue H et al in 1987 . BrugadaQi XQ et al  also repVerna E et al  describeRecent reports by  Sacher F et al  and Toku"}
{"text": "Since the discovery of dendritic cells (DCs) by Ralph Steinman and Zanvil Cohn 40\u2009years ago , the rolV600 mutant melanoma patients, and by Palombo et al. (We begin this research topic with an Opinion article by Rolf Zinkernagel  and a reo et al. , who desA recurring theme in many of the articles presented herein is that tumor immune evasion arises not only from a simple failure of the tumor microenvironment to support DC maturation but also from an active recruitment and exploitation by tumors of immature, tolerogenic DC that suppress adaptive responses. Seliger and Massa  review mex vivo-generated DC or in vivo-targeted DC. In addition to highlighting the need to better understand tumor microenvironmental factors that should be targeted to improve the efficacy of DC-associated immune stimulation in cancer patients, the authors identify a variety of other factors that must further be studied to optimize these therapies, including mechanisms of antigen delivery to endogenous DC; the frequency, route, and site of DC vaccination; methods of DC activation both ex vivo and in vivo; and the particular DC subsets that should be employed or targeted during immunization. These and other factors are considered more specifically in the context of DC-based therapies in acute and chronic myeloid leukemia patients by Sch\u00fcrch et al. (V600 mutation. Finally, Toubai et al. (Because of the potential of DC to serve as both targets of and delivery agents for tumor immunotherapies, significant efforts have been focused on how best to utilize these cells in the treatment of cancer. Gallois and Bhardwaj  review mh et al. , in ovarh et al. , and in h et al. . Additioh et al.  offer ini et al.  review tWe conclude this collection of articles with a review by Chmielewski et al. , who desAs the intricacies of DC biology and the influence of tumors on DC phenotype and function continue to be uncovered, additional insights into the role of these cells in the induction, regulation, and maintenance of anti-tumor immune responses will continue to shed light on mechanisms of tumor immune escape and inform the design of novel therapies to enhance anti-tumor immunity. It is our hope that the advances highlighted herein and the questions raised for future consideration will generate additional discussion, drive experimental inquiry, and bring into focus the significance of tumor/DC interactions and their impact on overall anti-tumor immunity. Such emphasis is sure to bring rapid advancements in this field and will ultimately lead to the development of more effective cancer immunotherapies and improved clinical outcome in cancer patients in the future.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Many studies have associated environmental exposure to chemicals with neurological impairments (NIs) including neuropathies, cognitive, motor and sensory impairments; neurodevelopmental disorders (NDDs) including autism and attention deficit hyperactivity disorder (ADHD); neurodegenerative diseases (NDGs) including Alzheimer\u2032s disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). The environmental chemicals shown to induce all these diseases include persistent organic pollutants (POPs), the plastic exudates bisphenol A and phthalates, low molecular weight hydrocarbons (LMWHCs) and polynuclear aromatic hydrocarbons (PAHs). It is reported here that though these chemicals differ widely in their chemical properties, reactivities and known points of attack in humans, a common link does exist between them. All are lipophilic species found in serum and they promote the sequential absorption of otherwise non-absorbed toxic hydrophilic species causing these diseases. From 1990 to 2010, mental and behavioral disorders increased by more than 37%, Parkinson's disease increased by 75%, Alzheimer's disease doubled, autism increased by 30% and attention deficit hyperactivity disorder (ADHD) increased by 16% , which once absorbed can remain in the body's adipose tissue for up to 30 years or more and can be transferred to serum . As used here, total lipophilic load refers to the total concentration of all exogenous lipophilic chemicals found in serum, without specification of individual chemical species.As discussed below, exposures to POPs, plastic exudates, PAHs and LMWHCs have been found to be associated with neurological disorders. The POPs include polychlorinated biphenyls (PCBs), organochlorine pesticides (OCs), dioxins and furans and polybrominated diphenyl ethers (PBDEs). Plastic exudates include BPA and phthalates. LMWHCs include benzene, toluene, ethyl benzene, xylenes, C3\u2013C8 aliphatics, gasoline, chlorinated methanes and ethanes and chlorinated ethylenes.et al.,et al., Escudar-Gilabert et al.,et al.,et al.,et al.,et al.,POPs, PAHs, LMWHCs, BPA and phthalates all have been shown to penetrate the blood-brain barrier (BBB) , as well as peripheral nervous system maladies (neuropathies)  \u2013 polychlorinated bipehenyls (PCBs) ;  ; ALS , phthalates, BPA and hydrocarbons. These chemicals come from a variety of chemical classes that include chlorinated and brominated hydrocarbons, esters, ethers, polynuclear aromatic hydrocarbons, mononuclear aromatic hydrocarbons and straight chain aliphatic hydrocarbons. These chemicals differ widely in chemical properties, reactivity and rates of metabolism and elimination from the body.et al.,et al.,et al.,et al.,et al.,et al.,et al.,The lipophiles associated with induction of neurological disorders can be long-lived POPs, which once absorbed can remain in the body's adipose tissue for up to 30 years or more and can be transferred to serum . Until now, however, no single mechanism that accounts for the induction of a broad spectrum of neurological diseases has been proposed. The association with the onset of widely differing NIs, NDDs and NDGs with exposures to POPs, BPA, phthalates, PAHs and LMWHCs, chemicals which differ widely from each other, yet all of them are able to penetrate the blood-brain barrier, strongly suggests a lipophile-dependent mechanism for the induction of CVDs. The concept of lipophilic chemicals serving to assist the penetration of hydrophilic therapeutic drugs through the blood-brain barrier is well established  from which they can pass to the blood and be transported around the body , absorbed even at toxic concentrations, are more rapidly metabolized/eliminated. Nevertheless, they persist in body serum for days to weeks , coronary heart disease , endocrine disruption  and lipophilic pharmaceuticals, examples of which are statins, taken regularly (Culver et al.,et al.,People are routinely exposed to many other lipophilic chemicals that are retained in body serum. These include mycotoxins produced by mold and found in wet environments and in comtaminated food (Brasel et al.,et al.,The prevalence of neurological diseases discussed here as well as the other diseases cited have all increased dramatically in the past half century. For example, the prevalence of the bipolar disorder and of schizophrenia has increased in the range of 40% from 1990 to 2010 (Murray et al.,et al.,et al.,As previously discussed, PAHs emanating from the combustion of fossil fuels and tobacco are considered to induce many environmental diseases. Several of the studies cited have made the association with inhalation of fine particles rather than with the PAHs (Costello As seen in et al.,et al.,et al.,et al.,et al.,It is to be noted that although the literature relating neurological disease to other exogenous lipophilic chemicals is scanty, mycotoxin exposures have been associated with neurological disease (Pestka The prevalence of neurological diseases, including NIs, NDDs and NDGDs is increasing rapidly throughout the world. The evidence presented here strongly suggests that this increase is due in large part to increased exposure to exogenous lipophilic chemicals which, though varying widely in structure, toxicology, chemical reactivity and retention time in the body, render the body susceptible to attack via subsequent exposure to low levels of hydrophilic toxins that would otherwise not be absorbed. The lipophilic chemicals can be POPs that are metabolized and eliminated slowly, or BPA, phthalates, PAHs, LMWHCs and other lipophilic species that are eliminated from the body more rapidly, but are constantly replenished in the body from polluted air and water and contaminated food. The accumulation of lipophilic chemicals in the body proceeds until a critical lipophilic load level is reached, at which point the body is vulnerable to attack by low levels of toxic hydrophilic chemicals that would otherwise not be toxic. Sequential absorption of lipophiles followed by hydrophiles provides a unified explanation of how low levels of rather different environmental pollutants are responsible for the alarming increase of neurological diseases."}
{"text": "Neurodegenerative disorders such as Parkinson's diseases (PD) and Huntington's diseases (HD), neuronal injuries following trauma and neuronal cell death following strokes are major debilitating affections that are often accompanied by motor and cognitive dysfunctions with limited treatment options. Cell transplantation therapies have been considered for the last three decades as a serious avenue to explore with the ultimate aim to replace lost neurons with \u201cnew ones\u201d initially originating from fetal neuroblasts and recently deriving from various sources of stem cells.One of the many factors affecting the success of cell transplantation therapies is host immune response to the graft. This came as an evidence when attempts of cell therapy was undertaken with the use of human fetal neuroblasts or porcine fetal neuronal tissue for a time envisaged as a potential useful cell source for xenotransplantation in the human brain. However, and as Bonnamain et al.  describePauly et al.  focus onGiven that the use of fetal tissue as a cell source for neural transplantation is not without causing logistical and ethical problems, a significant research activity has been oriented toward finding alternative sources of neural cells. Among these, pluripotent stem cells seem to be an obvious choice as these cells are theoretically able to differentiate into any cell type of any organ. As Benchoua and Onteniente  put it iThe paper of Denham et al.  reviews in vitro. They detail the use of a combined photolithographic technique to create a topography of micropatterned substrates composed of extracellular matrix providing the cells with appropriate cues for their differentiation. Although these cellular models are far from mimicking the characteristics of neuronal cells in vivo, they can set the basis for new avenues to explore the differentiation of stem cells in vitro after adjustment of the proper microenvironment in order to obtain the requested specific neuronal subtype.Garc\u00eda-Parra et al.  propose in vivo area, de Chevigny et al. (In the y et al.  present Following transplantation, axons derived from transplanted neurons need to find their way and innervate target areas. Our own findings showed that embryonic mesencephalic dopamine neurons transplanted in the substantia nigra in an animal model of PD are able to extend axons toward the striatum (Gaillard et al., The review by Saha et al.  is focusAlthough cell transplantation in the damaged brain is not likely to be routinely performed in the near future, the different paths that are evoked in this series of reviews should yield safer, more effective and physiologically relevant transplantation procedures."}
{"text": "Autism spectrum disorders (ASDs) are a group of developmental psychiatric disorders characterized by impaired social interaction and communication, and by restricted, repetitive and stereotyped behaviors and interests , has been found to be associated with autism, supporting genetic defects in cholesterol metabolism can cause autism   which encode key enzymes  in the cholesterol metabolic pathway and cholesterol concentrations are altered in the brain in a development dependent manner (Buchovecky et al., RTT is caused largely by mutations in the X-linked methyl CpG-binding protein 2 gene (Disturbances in cholesterol homeostasis in ASDs raise the question of how changes in cholesterol metabolism might be involved in the development of autism. Cholesterol is not uniformly distributed in biological membranes, but concentrated in lipid rafts, together with other lipids like sphingolipids (Pfrieger, Lipid rafts are specialized membrane structures that form an organized portion of the membrane with concentrated signaling molecules and link to the cytoskeleton (Simons and Toomre, Mecp2 mutant mice has identified that a nonsense mutation in SQLE, which is an obligate rate-limiting enzyme in cholesterol biosynthesis, diminished some of RTT related phenotypes (Buchovecky et al., Mecp2 mutant mice (Buchovecky et al., Interestingly, genetic or pharmacological manipulation of cholesterol metabolism has been found to alleviate ASD associated animal behaviors. In the aforementioned study, a mutagenesis screen in Noteworthily, the effect of statin treatment has also been observed in animal models of other ASDs, including fragile X syndrome and neurofibromatosis type 1 (Li et al., It is important to note, cholesterol may regulate protein function not only through altering lipid rafts but also by direct interactions with the proteins. However, it is very challenging to discriminate between these possibilities for any specific type of protein because it is unreasonable to test the effect of cholesterol on the function of a membrane protein in an environment without lipid rafts (Levitan et al., Despite the controversies in lipid raft research, it is now clear that lipid rafts which represent dynamic structural components of cellular membranes do play roles in neuronal signaling and that dysregulation of lipid rafts can lead to diseases (Allen et al.,"}
{"text": "Interprofessional collaboration (IPC) is an integral part of the practice of Medicine and Family Medicine. The World Health Organization (WHO) defines IPC as occurring when \u201cmultiple health workers from different professional backgrounds work together with patients, families, carers and communities to deliver the highest quality of care\u201d WHO, . To provThe delivery of responsive, effective, and high-quality patient care is indeed a complex activity. It demands health care professionals collaborate in an effective manner (Reeves et al., Competence, or the knowledge and skills base underlying a particular profession, can also be considered a profession's \u201ccognitive map.\u201d Good teamwork relies on a joint understanding of one's own as well as other team members' cognitive map (Drinka and Clark, Defining one's own professional competencies is therefore an important first step in effective IPC. One approach to gathering the necessary information to determine what competencies are required for a particular profession is to ask those already active and skilled in the profession itself. This approach was used by the CFPC in the development of the competency\u2013based objectives in family medicine using practicing family physicians as their source of information (Allen et al., Another approach includes consultation with others. Realizing the importance of patients, physicians, and other health care professionals in the delivery of health care, research in the 1990's by the Ontario provincial government in Canada sought both public and other health care professionals input in an attempt to define the expectations of physicians performance. The results showed significant difference of opinion between physicians and other health care professionals on items referring to distribution of responsibility, control, and authority of physicians within the health care system at that time (Neufeld et al., Pharmacists represent the one health care profession all family physicians are most likely to collaborate with in providing optimal patient care. A recent UK study on the collaborative relationship between community pharmacy and general medicine, highlighted the dynamic nature of the relationship and the key components of collaboration. These included the importance of trust, communication, professional respect, and \u201cknowing each other\u201d when referring to roles, abilities and responsibilities (Bradley et al., Our research team is exploring pharmacist's expectations of the competent family physician using an adaptation of the CFPC's original competency questionnaire distributed to practicing family physicians (Allen et al., Continued research in this area is essential to deepen our understanding of the essential components of the interprofessional relationship. Understanding and clarifying role expectations is central to this and can provide valuable information when designing and reviewing professional competency frameworks and IPE curricula. As more research becomes available, the effectiveness of these programs on outcomes such as IPC in clinical practice and patient care should be reviewed."}
{"text": "The Hippo signaling pathway comprises a series of cytoplasmic tumor suppressor proteins including Merlin and the Lats1/2 and MST1/2 kinases, and is thought to play a critical role in determining the sizes of organs and tissues. The Hippo pathway is regulated upstream by extracellular mechanosensory signaling arising from cell shape and polarity, as well as by a variety of extracellular signaling molecules. When active, the pathway maintains the transcriptional activators Yes-associated protein (YAP) and TAZ in phosphorylated forms in the cytoplasm, preventing cell proliferation. When the Hippo pathway is inactivated, YAP and TAZ are translocated to the nucleus and induce the expression of a variety of proteins concerned with entry into the cell division cycle, such as cyclin D1 and Fox M1, as well as the inhibition of apoptosis. The failure of the Hippo pathway has been implicated in the development of many different types of cancer but there is limited information available as to its involvement in melanoma. We hypothesize here firstly that the Hippo pathway is involved in maintaining density of cutaneous melanocytes on the basement membrane at the junction of the epidermis and the dermis, and secondly, that its function is disturbed in melanoma. We have analyzed a series of 23 low passage human melanoma lines as well as cultured normal melanoma, and find that melanocytes, as well as all melanoma cell lines examined express TAZ. Melanocytes and most melanoma lines also express YAP. E-cadherin, an upstream regulator of the Hippo pathway, and Axl, a receptor tyrosine kinase regulated by the Hippo pathway, are expressed in melanocytes and in several melanoma cell lines. These observations, together with published evidence for the presence of Merlin, Lats1/2, and MST1/2 in melanocytes and melanoma cells, support the hypothesis that the Hippo pathway is an important component of melanocyte and melanoma behavior. Drosophila that together were found to control organ size. These genes specify a series of kinases and adaptor proteins including Hippo (Hpo), Warts (Wts), and Salvador (Sav), loss of function of which results in flies with enlarged, folded eyes and excess head cuticle, a \u201chippopotamus-like\u201d phenotype , the homolog of Yorkie in Studies of the Hippo pathway suggest it has a three-dimensional \u201csense\u201d that is communicated across the whole organ and controls both cell proliferation and apoptosis. A possible example of such organ size control is provided by liver; it has been known for many years that surgical reduction of liver volume leads to extensive cell division and regeneration until the liver approaches its original size. The Hippo pathway has been hypothesized to have a role in this process  constitutes one of the main causes of cell injury and death  (Tschop et al., To collect evidence for the involvement of the Hippo pathway in melanoma, a series of melanoma lines developed in this laboratory (Marshall et al., CTGF (Braig et al., GLI2 (Alexaki et al., It is known that from animal models of melanoma that proliferation and invasiveness are promoted by YAP-TEAD (Lamar et al., RASSF1 is frequently inactivated by promoter hypermethylation in a variety of human tumors including melanoma (Spugnardi et al., GRIN2 gene, which codes for a subunit of the glutamate ionotropic receptor, is mutated in approximately 25% of melanomas (Wei et al., NF2 gene, which encodes Merlin (Figure FAT4 gene is recurrently mutated in several types of human cancer including melanoma (Katoh, Our previous studies have suggested that two changes may be important to distinguish melanoma cell lines from cultured melanocytes: the partial loss of serum dependence of some intracellular signaling pathways (Kim et al., n Figure  have beea Katoh, .One of the fascinating features of the Hippo pathway is that it is able to integrate several different types of signaling, including those induced by cellular shape and adhesion changes, stress responses, and fluctuating concentrations of extracellular signaling molecules. It mediates cellular decisions on the control of proliferation, motility and cell death, and existing evidence indicates a complex and possibly redundant series of intracellular pathways (Halder et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Since the first seminal reports of young infants' abilities to use both acoustic (e.g., Mandel et al., The goal of the current Research Topic is to provide a cutting-edge snapshot of this active research field integrating original research papers using both behavioral and neurophysiological techniques with review articles providing ideas for general frameworks capturing those findings.Three reviews and one methods article offer global and thought-provoking views on basic principles and computational mechanisms that are operative in early language learning. Seidl and Cristia  provide Two of the original research papers applied neurophysiological methods. Minagawa-Kawai et al.  report aAnother set of research articles focuses on the contribution of prosodic information to the perception of sentential structure. Wellmann et al.  evaluateThe largest group of papers deals with specific questions related to speech segmentation. Bosch et al.  investigFinally, our Research Topic contains one study which analyzes infant speech production during the second year of life. Yamashita et al.  study EnAs a compendium of current research efforts in the field of early language learning mechanisms we are confident that this Research Topic offers novel and stimulating ideas for those who are new to the field and would like to get a timely overview as well as for experts who are interested in current developments."}
{"text": "Qiliqiangxin (QL), a traditional Chinese medicine, was approved by China Food and Drug Administration for the treatment of heart failure in 2004 (Li et al., Recent progress in studying QL on improving exercise tolerance and patients' quality of life highlighted that QL may be through a variety of biological mechanisms to exert its beneficial effects. One possible mechanism may be the regulation of the balance between pro-inflammatory and anti-inflammatory cytokines in cardiomyocytes (Xiao et al., Traditionally, the adult mammalian heart is regarded as a post-mitotic organ without any regenerative capacity (Rosenzweig, In conclusion, we think QL may mimic a phenotype of physiological hypertrophy and induce heart regeneration, which is beneficial for heart failure."}
{"text": "A funding organization was incorrectly omitted from the Funding Statement. The Funding Statement should read: \"This study was financially supported by Projects SAF2009-08570 and SAF2012-35474 from the Ministerio de Econom\u00eda y Competitividad of Spain and Fondo Europeo de Desarrollo Regional (FEDER). EGS has a fellowship from the Gobierno de La Rioja of Spain, and CL has a fellowship from the Ministerio de Econom\u00eda y Competitividad of Spain. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\""}
{"text": "Dear Editor,et al.[Nocardia brasiliensisbrazilienses / Nocardia asteroides.[We read with interest the rare case of disseminated orbital actinomycetoma reported by Shanbagh et al. The authteroides. We wouldet al., which described a 26-year-old male who was found to have multiple discharging sinuses on the scalp, with orbital and intracranial invasion.[The authors\u2019 claim to be the first in reporting orbital invasion of actinomycetoma is misplaced. A quick literature search revealed a report by Patil invasion.2et al. have described the characteristic moth-eaten appearance of the frontal bone along with orbital and intracranial invasion, in the case reported by them.[Figure 3 in the article is wrongly labelled as computed tomography (CT) scan of orbit while it shows pictures of magnetic resonance imaging (MRI). The authors have described the osteolytic changes seen in longstanding undiagnosed cases of actinomycosis. However, by them.et al.[et al. described a case of orbital actinomycosis in a patient with a history of carcinomas of the breast and kidney.[et al. described a case of orbital actinomycosis with a small ill-defined lesion in the posterolateral orbit.[It may be of interest to note that orbital actinomycosis has been also reported by Pagliani and Sullivan et al.4 Pagliand kidney. A CT scad kidney. Sullivan"}
{"text": "To the Editor: Floret et al. argue convincingly that natural disasters, including severe floods and windstorms, tend not to result in epidemics of infectious disease  and 2002\u20132004 (\u2248870 cases). Sporadic cases of shigellosis were not seasonal.Two hurricanes resulted in heavy rainfall in Baltimore during the study period ."}
{"text": "We approach this challenge through a network-centric perspective, as we believe that brain function is fundamentally determined by patterns of connectivity between neurons, and the resulting dynamics. This is in contrast to traditional computational neuroscience techniques that focus on models of individual neurons and compartments. Progress, in consequence, is essential on (at least) three major fronts: measurement front spans the range from multi-electrode recordings to whole-brain measurements using imaging. Several basic scientific questions arise: What do we need to measure in brain networks? Are there theoretical constraints that would dictate this? How do we design our experiments to generate the most meaningful data? How do we record from awake/behaving animals, or even from multiple animals interacting socially?The analysis front consists of creating network models from the measurements. Some promising techniques explore the estimation of networks using causality. However, several open questions remain: How do we define the fundamental units within the network? Are these units fixed or do they evolve dynamically? How do we infer connectivity between network elements? How do we identify functional clustering, based on the individual neuronal features? How do we quantify and interpret the activity of multiple neurons via multi-unit recordings, especially when there is no stimulus-response paradigm?The modeling front can proceed in several directions. From the extracted network we can identify topological regularities, such as motifs and cycles. An interesting research direction is to analyze the relationship between the structure of the network, as represented by its motifs, and its function. A growing body of work is examining the relationship between network structure and phenomena such as stability and synchrony. For instance, neurons in the hippocampus could be modeled as a network wherein hubs consisting of hub neurons promote synchrony, while cycles in this network may cause instability. The theme of synchrony as an important network phenomenon emerges in several articles in this research topic  subjects and normals have been reported, among other psychiatric and neurodegenerative conditions. Cortical network properties ultimately determine how different network oscillation states are established and maintained and defining these principles could explain why there is impaired synchronization between different brain areas in schizophrenics and Parkinson's patients. Overall, network-based measures capture better the dynamics of brain processes, and provide features with greater discriminative power than point-based measures.The articles in this research topic cover these different aspects of cortical networks. To guide the reader, we provide below a brief summary of each article, and relate it to the overall theme of the research topic.Rothganger et al.  present Ratnadurai-Giridharan et al.  develop Bhattacharya et al.  present Dey et al.  use RestAlonso et al.  test a sAlmeida-Filho et al.  study muin vitro. Their simulations support the proposed underlying biological mechanisms: the increase of neuronal response latency to ongoing stimulations and temporal or spatial summation required to generate evoked spikes.Vardi et al.  propose Tibau et al.  monitoreRiera et al.  describeFor the past several decades, theoreticians and experimentalists alike have focused on neuronal synchrony and on the important roles that it might play in brain function, from \u201cThe Binding Problem\u201d in perception Gray,  to ConscCanavier et al.  address Konstantoudaki et al.  explore Nie et al.  make useCavallari et al.  investigThivierge et al.  investigChary and Kaplan  investigLatorre et al.  implemenKaplan and Lansner  address Eguchi et al.  use a deThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Early human development from late gestation to the neonatal period is a critical time in the individual's life span. Preterm birth or medical issues affecting the brain function during late gestation or the first months of life may lead to an avalanche of neurodevelopmental problems, including cognitive deficits and motor disability, with lifelong consequences for the individuals, their families, the health care system and the society  is a well-established diagnostic tool for fetal surveillance. Two original research papers describe the findings of studies performed with fMCG to estimate the development of the autonomic nervous system. It is known that, around 32 weeks of gestation, four fetal behavioral states (quiet and active sleep and awakeness) can be identified by combining fetal heart rate variability (fHRV) and fetal movements. Br\u00e4ndle et al.  confirmer et al.  proved tin utero.To understand the normal functional development of the fetal brain, periods of developmental vulnerability should be identified to assess the function of the fetal nervous system and open a window on novel prenatal diagnostics and prognostics. MRI has become increasingly feasible and clinically important in fetal brain studies due to its higher tissue resolution and better visualization of normal and pathological development of macroscopic anatomy or white matter microstructure and connections. Jakab et al.  employedDespite the advancements in monitoring techniques and perinatal care, clinicians still have limited means to predict neurodevelopmental outcomes and plan early intervention. In their opinion article, Giampietri et al.  offer a The development of functional connectivity patterns from infancy to childhood were studied also by Berchicci et al. , who invFinally, electroencephalography (EEG) is the most commonly used technique to non-invasively assess neonatal brain activity, but the main challenge in interpreting EEG signals is the quantitative characterization of the spontaneous \u201cbackground activity\u201d in sick neonates. Matic et al.  applied The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "In this opinion article we examine the relationship between penetrometer resistance and soil depth in the field. Assuming that root growth is inhibited at penetrometer resistances > 2.5 MPa, we conclude that in most circumstances the increases in penetrometer resistance with depth are sufficiently great to confine most deep roots to elongating in existing structural pores. We suggest that deep rooting is more likely related to the interaction between root architecture and soil structure than it is to the ability of a root to deform strong soil. Although the ability of roots to deform strong soil is an important trait, we propose it is more closely related to root exploration of surface layers than deep rooting. However, roots which extend into burrows followed them to their end. Ehlers et al. . The pores were created by burying a two\u2010dimensional geotextile at 20\u2009cm, with the different pore\u2010density treatments. Although no genotypic differences were found, this approach would seem to provide a method to assess genotypes. Either McKenzie et al. (et al. (et al.,In an interesting field study, McKenzie et al.  comparede et al.  were unl (et al.  that roo et al., will becet al. (et al. (The basis for the location of soil pores by roots seems to be a relatively unexplored area and given the increases in soil strength with depth Fig.  it wouldet al.  found th (et al.  also repet al.If we accept the thesis that deep root penetration is facilitated by exploiting existing pore networks, then the question arises of whether an ability to penetrate a hard layer is useful. Actually, we maintain that it is useful. Roots which deform soil are likely to have better root\u2013soil contact and improved ability to extract water and nutrients from the soil in the shallower layers. At depth, roots in pores are less well connected hydraulically to soil, although White & Kirkegaard  show thaWhile the tendency for deeper roots to be found in pores is well reported (e.g. Lynch & Wojciechowski,"}
{"text": "Analogical reasoning is a landmark of human cognition. Based on the realization that the elements of two situations are organized by similar systems of relations, analogical inferences allow the transfer of knowledge structures from a better-known situation  to a target situation that is relatively less understood .Experimental research has demonstrated that the retrieval of base analogs from long term memory in response to the proceesing of a target analog is infrequent in the lack of semantic similarities between both situations  the referendum on the independence of Quebec, Blanchette and Dunbar  obtainedh et al.  providedh et al.  failed th et al.  or sellih et al. , both exh et al.  expert mh et al.  novice pAnother explanation for the frequent use of distant analogies in naturalistic studies might arise from comparing the psychological constraints of naturalistic analogy generation against those of classical experimental studies. The standard experimental procedure comprises an encoding phase, during which participants learn the base analogs, and a transfer phase, where experimenters present participants with either a semantically close or a semanically distant target situation, and assess whether its processing elicits the spontaneous retrieval of the base analog. Based on this procedure, differences accross conditions were typically taken to demonstrate the centrality of surface similarities during analogical transfer. In contrast with this highly controlled environment\u2014in which transfer can only originate in the retrieval of the critical base analog from memory\u2014in naturalistic settings participants are free to generate analogies by means of retrieving their own base analogs (Blanchette and Dunbar, The fact that the core components of our retrieval mechanisms are invariably set to favor semantically close base analogs (Gentner et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Beta-band oscillations in basal ganglia-cortical loops have been shown to be linked to motor function in both healthy and pathological states Brown, . As wellThe Journal of Neuroscience, Bartolo et al. (In a recent study published in o et al.  examinedThey found that LFPs in the beta band exhibit interval tuning and showed a preference for intervals with duration around 800 ms, similar to the preferred duration observed in medial premotor cortex neurons (Merchant et al., The present study and previous work from this group (Merchant et al., The present study only addresses internal timing in regular sequences and it is not yet known how temporal jitter would affect the putaminal beta-band activity. In irregular sequences, beta-band modulation may remain the same or change as a function of the amount of jitter. As natural sounds are rarely presented in a temporally regular context, future work needs to address how the brain perceives time in irregular sequences. Related to this question, Fujioka et al.  used magTemporal processing in irregular sequences has been shown to be preferentially mediated by a network based in the cerebellum whilst timing in regular sequences is carried out by a striato-frontal network (Teki et al., Bartolo et al.  only briIn summary, this stimulating work on the role of putamen during internally driven timing behavior significantly adds to previous work by Merchant and colleagues based on recordings from medial premotor cortex (Merchant et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Production of biogas from agricultural biomass or organic wastes is an important source of renewable energy. Although thousands of biogas plants (BGPs) are operating in Germany, there is still a significant potential to improve yields, e.g. from fibrous substrates. In addition, process stability should be optimized. Besides evaluating technical measures, improving our understanding of microbial communities involved into the biogas process is considered as key issue to achieve both goals. Microscopic and genetic approaches to analyse community composition provide valuable experimental data, but fail to detect presence of enzymes and overall metabolic activity of microbial communities. Therefore, metaproteomics can significantly contribute to elucidate critical steps in the conversion of biomass to methane as it delivers combined functional and phylogenetic data. Although metaproteomics analyses are challenged by sample impurities, sample complexity and redundant protein identification, and are still limited by the availability of genome sequences, recent studies have shown promising results. In the following, the workflow and potential pitfalls for metaproteomics of samples from full-scale BGP are discussed. In addition, the value of metaproteomics to contribute to the further advancement of microbial ecology is evaluated. Finally, synergistic effects expected when metaproteomics is combined with advanced imaging techniques, metagenomics, metatranscriptomics and metabolomics are addressed. Over the past 10 years, conversion of biomass to methane in biogas plants (BGPs) has become a reliable source of renewable energy. In 2013, about 7500 BGPs produced 3.5% of the annual electricity demand in Germany  experimental design, (ii) sampling, (iii) protein purification, (iv) protein separation, (v) liquid chromatography (LC)-tandem mass spectrometry MS/MS), (vi) bioinformatics and (vii) examining the protein identification Figure\u2009.et\u2009al., et\u2009al., et\u2009al., et\u2009al., Reproducible scientific studies require carefully planned and documented experiments. In order to correlate metaproteome data from different BGPs with process data, at least a minimum set of meta-information has to be provided, comprising BGP design, process temperature, pH value, nitrogen content, inocula, gas composition and volume as well as feed composition. In addition, technical and biological replicates are required. However, for most industrial scale BGPs, no true replicates exist, because each BGP is individual concerning its construction and operational parameters. An acceptable workaround would be to sample at least two independent technical replicates at close time points. Otherwise, investigations using lab-scale equipment are required to complement studies. Here, critical process conditions can be applied without risking the crash of a full-scale fermenter. Depending on the scientific question, simplifying the complex microbial community by feeding a synthetic medium  sampling before feeding and at same time of the day, (ii) mixing the BGP before sampling and (iii) discarding sufficient material before sampling in order to flush the sample port.et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., Sample preparation includes cell lysis, protein extraction, protein quantification and separation. Main problems during cell lysis and protein extraction are the high amount of sample impurities and the different levels of microbial community organization, such as scattered microorganisms, biofilms on the substrates or granules  evolved in the proteomic community as a standard (Elias et\u2009al., The problem of metaproteomics in contrast to other proteomics with pure or defined mixed cultures is that the taxonomic composition of complex microbial communities is not known and the database cannot be reduced to keep the number of false positive hits low. In this context, the idea of Jagtap and colleagues  to repeaet\u2009al., et\u2009al., et\u2009al., de novo sequencing of peptides using acquired spectra (Frank and Pevzner, et\u2009al., de novo results requires manual inspection. Therefore, a more straightforward strategy is sequencing the metagenome of the analysed sample.In the next step, protein identification is achieved based on identified peptides (Bradshaw et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., After successful protein identification, the importance of a single identification can be improved by acquiring meta-information concerning taxonomy and function from repositories, e.g. UniProt (Consortium, et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., For a better survey, taxonomic composition can be visualized in a Krona plot (e.g. Krona plot for a mesophilic/thermophilic BGP: Figure\u2009et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., Shifting to protein functions, overview plots, such as a Voronoi Treemap (Bernhardt et\u2009al., Tools for the characterization of microbial communities (Table\u2009Coprothermobacter and Methanothermobacter in a thermophilic reactor treating thermally pretreated sludge (Gagliano et\u2009al., et\u2009al., et\u2009al., et\u2009al., In microbial ecology, a wide mixture of different methods are commonly applied to investigate a specific problem. Hence, knowledge of how to combine these methods is important. First of all, a standardization of sample preparation is essential. With regard to the use of multi-omic approaches, the sample preparation workflow should comprise most analytes namely DNA, RNA, proteins and metabolites in an adequate manner (Roume es Table\u2009, metaproet\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., So far, only a few metaproteome studies of BGPs were carried out Table\u2009 (Abram eet\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., While in early metaproteome studies, only a few proteins were detected (Abram Actinobacter, Bacteriodia, Bacilli, Chlostridiales, Thermotogae and different Proteobacter groups. Archaeal proteins were dominated by the orders Methanobacteria and Methanomicrobia. A comparison of phylogenetic profiles derived from metaproteomics and molecular biological studies revealed significant differences in the relative abundance of methanogens [about 20\u201330% in metaproteome data compared with the 4% derived by metagenomics (Hanreich et\u2009al., et\u2009al., Gelria by metaproteomics, although it was highly abundant in the pyrosequencing data. In this case, the bias might have been introduced by the lack of protein entries for Gelria in the UniProt database.The majority of the identified bacterial proteins belonged to the orders et\u2009al., et\u2009al., et\u2009al., Besides proteins from Archaea and Bacteria, several proteins from plants and animals are frequently identified in samples from BGPs. They are originated from plant feedstock or manure and represent the incomplete usage of substrate. In addition, a few proteins were identified to belong to Fungi (Kohrs Caldicellulosiruptor and that celluloses were degraded by the cellulosome of Clostridium thermocellum. Surprisingly, L\u00fc and colleagues (Clostridium proteolyticus, indicating its function as predator or scavenger of dead biomass. The observed proteolytic activity nicely confirmed a study (Binner et\u2009al., As already discussed, the main advantage of metaproteomics is the functional characterization of microbial communities together with the phylogenetic assignment. L\u00fc and colleagues  showed, lleagues  also obset\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., For the subsequent fermentation step, mainly proteins from sugar uptake, glycolysis and to some extent from the pentose phosphate pathway were identified. This is in accordance with carbohydrates as the major substrate of biogas production. Whether the Entner\u2013Doudoroff pathway is of relevance for fermentation (Abram de novo synthesis of methionine, lysine and threonine surpassing their low proportion in maize protein (Ridley et\u2009al., Amino acids derived from feedstock proteins are fermentable substrates and precursors for synthesis of microbial biomass. Based on metaproteome data, Heyer and colleagues  reportedIn contrast to the previous steps of the biogas process, the investigation of acetogenesis is even more challenging. In fact, L\u00fc and colleagues  were ablet\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., Proteins involved in methanogenesis are highly abundant in metaproteomes. Nearly all enzymes of the hydrogenotrophic and the acetoclastic pathway were identified. Under psychrophilic and mesophilic conditions, the acetoclastic pathway is favoured (Abram et\u2009al., et\u2009al., Although MS-based metaproteomes of different samples show some similarities due to high abundance of methanogenic enzymes and also the presence of similar dominating phylogenetic groups, each BGP seems to have its own protein signature. Surprisingly, separation of proteins by SDS-PAGE is sufficient to produce individual protein patterns (Heyer In depth, analysis of microbial communities in BGPs is required to use their full potential for biogas production. The comparison of methods for the characterization of microbial communities and recent results regarding the functional and taxonomic composition of these microbial communities obtained by various research groups showed that metaproteomics is developing into a powerful tool for the exploration of the biogas process. Besides identifying major pathways of biomass degradation, it links single metabolic pathways with microbial taxa. Each BGP shows its own, time stable protein pattern. Strong alterations in this pattern can be linked with process disturbances, and some enzymes were identified as potential biomarkers for process monitoring and fault detection.Metaproteome analysis of BGPs is still hampered, however, by sample impurities, sample complexity, redundancy of protein identifications and a lack of genome sequences required for protein identifications. Nevertheless, the presented workflow overcomes at least parts of these problems. In the future key issues to be addressed include comprehensive sample preparation, a suitable protein separation, grouping of redundant proteins and the incorporation of meta-information from online repositories. In particular, more efficient protein extraction, improved MS and new algorithms for the verification of protein identification are urgently required to further improve this workflow and to exploit the full potential of metaproteomics. In addition, it has to be taken into account that metaproteomics is no stand-alone approach. For comprehensive analysis of microbial communities, metaproteomics should be applied in concert with microscopy, cytometry, metagenomics, metatranscriptomics and metabolomics."}
{"text": "Arabidopsis root development is coordinated via a localized auxin concentration maximum in the root tip, requiring the regulated expression of specific genes. However, little is known about how hormone and gene expression patterning is generated.\u2022 Patterning in \u2022 Using a variety of experimental data, we develop a spatiotemporal hormonal crosstalk model that describes the integrated action of auxin, ethylene and cytokinin signalling, the POLARIS protein, and the functions of PIN and AUX1 auxin transporters. We also conduct novel experiments to confirm our modelling predictions.aux1 mutant, the amounts of cytokinin, ethylene and PIN protein, and PIN protein patterning in wild-type and mutant roots. Modelling analysis further reveals how PIN protein patterning is related to the POLARIS protein through ethylene signalling. Modelling prediction of the patterning of POLARIS expression is confirmed experimentally.\u2022 The model reproduces auxin patterning and trends in wild-type and mutants; reveals that coordinated PIN and AUX1 activities are required to generate correct auxin patterning; correctly predicts shoot to root auxin flux, auxin patterning in the \u2022 Our combined modelling and experimental analysis reveals that a hormonal crosstalk network regulates the emergence of patterns and levels of hormones and gene expression in wild-type and mutants. Arabidopsis root development and response to varying environmental conditions involves a complex network of overlapping interactions between plant signalling hormones and gene expression known as \u2018hormonal crosstalk\u2019. Hormone concentrations in the cells are a function of multiple factors such as hormone biosynthesis, long- and short-range transport, rate of influx and efflux by carrier proteins, and hormone activation, inactivation and degradation  peptide function. The PLS gene of Arabidopsis transcribes a short mRNA encoding a 36-amino-acid peptide that is required for correct root growth and vascular development  Heynh have been described previously , 1% sucrose, and 2.5% Phytagel (Sigma)) at 22 \u00b1 2\u00b0C as previously described  ecotypes and the \u22121 propidium iodide as previously described . Statistics were carried out using Excel (Microsoft). Results were visualized as average intensities with error bars representing SD of the mean.Confocal images (for GFP imaging) were taken with a Leica SP5 microscope  after counterstaining tissues with 10 mg ml\u22125 and 10\u221210, respectively. Much smaller convergence tolerances for both iterations are also tested, and the numerical results show that further reduction of convergence tolerances for both iterations does not improve the accuracy of numerical simulations.The set of partial differential equations, which describes spatiotemporal dynamics of hormonal crosstalk in the root Figs, is solvhttp://imagej.nih.gov/ij). The output of ImageJ is the intensity of each pixel in an experimental image. The relative intensity over the whole image shows the relative hormone response or protein concentration patterning for any measured component. The detailed method for using ImageJ to analyse experimental images is described in Supporting Information In this work, experimental images were analysed using ImageJ  follow experimental trends , the modelled cytokinin concentration in the vascular and pericycle cells is higher than that in the epidermal cells, a result similar to experimental observations. Nevertheless, the trend of cytokinin patterning along the longitudinal root axis still differs between the experimental images and modelling results . These rArabidopsis root is similar to the experimentally determined auxin IAA2::GUS response patterning, with an auxin maximum established at or close to the QC , showing that modelling results are robust to variations in parameter values. We then used the model to study the level and patterning of hormones and gene expression in pls mutant and pls etr1 double mutant show that auxin flux from shoot to root in the pls mutant is significantly lower than that for wild-type. This effect reduces the total amount of auxin in the root tip and reduces auxin responses in the pls root. The auxin flux into the root, and the root auxin content for the pls etr1 double mutant also recover approximately to the value of the wild-type . In the pls mutant, the suppression of X is relaxed owing to the loss of PLS function. This enhances the rate of PIN1 biosynthesis at the region near the tip and therefore PIN1 patterning shows an increasing concentration trend from the proximal to the distal region. In addition, in the pls mutant, the auxin concentration decreases  is similar to the corresponding experimental trend. However, a noticeable difference for the pls etr1 double mutant can be identified. This indicates the limitation of our model for analysing this double mutant.Therefore, the overall effects of auxin, ethylene and cytokinin result in opposite trends in PIN1 patterning in wild-type and Patterning of PIN2 protein was also analysed . ModelliPLS gene of Arabidopsis, which transcribes a short mRNA encoding a 36-amino-acid peptide  and PIN7 (which is positively regulated by cytokinin) are localized at similar positions  enzymes. While ARR5::GUS expression, as a proxy for cytokinin distribution; Werner et al., et al., et al., Our modelling results for cytokinin concentration patterning  are quanet al., ARR5::GUS images (Werner et al., ARR5::GUS images measure the activation of the ARR5 promoter by cytokinin, therefore indicating the activity of cytokinin signalling rather than cytokinin concentration. Bishopp et al. (ARR5 expression, is regulated by auxin in the xylem axis. This could indicate that ARR5::GUS images represent the effects of both cytokinin and AHP6 concentration, and therefore might not solely reflect cytokinin concentration. Third, it has been demonstrated that cytokinin is transported from the shoot to the root in the phloem (Bishopp et al., et al., This discrepancy leads to the following possibilities. First, the experimental data (Nordstrom p et al.  have diset al., et al., et al. (et al., et al., et al., et al. (Based on experimental results (Nordstrom , et al.  have sho, et al. .et al., et al., In root development, the complexity of hormonal signalling includes many aspects. This work has shown that the spatiotemporal dynamics of hormonal crosstalk, which integrates hormonal crosstalk at a cellular level with root structure, is able to explain two important aspects \u2013 the steady-state level and the patterning of hormones/hormone responses and gene expression. Recent studies have shown that growth and hormonal patterning can affect each other (De Rybel et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., All recent modelling and experimental work (Chickarmane"}
{"text": "Bacillus subtilis the process involves the differentiation of cell fate within an isogenic population and the production of communal goods that form the biofilm matrix. Here we review recent progress in understanding the regulatory pathways that control biofilm formation and highlight developments in understanding the composition, function and structure of the biofilm matrix.Biofilm formation is a social behaviour that generates favourable conditions for sustained survival in the natural environment. For the Gram-positive bacterium  In the biofilm individual cells are held together by a self-produced extracellular polymeric matrix commonly comprised of polysaccharides, proteins and DNA  and the tapA-sipW-tasA (hereafter tapA) operon , it facilitates continued transcription of slrR. This means that cells accumulate high levels of SlrR in a self-reinforcing negative feedback loop . To date, only a subset of proteins encoded by the eps operon has been studied in any detail. EpsA and EpsB act as a tyrosine kinase modulator and tyrosine kinase, respectively, and both are required for biofilm formation . The prevalence of each sugar was largely dependent on the integrity of the eps operon  that prevented expression of this enzyme (Leiman et\u2009al., d-amino acid inhibition of biofilm formation was not observed (Leiman et\u2009al., et\u2009al., et\u2009al., B. subtilis completely lacks the biosynthetic pathway required for norspermidine synthesis and, consistent with this, detection of norspermidine within biofilm samples was not possible despite utilization of two separate detection methods (Hobley et\u2009al., et\u2009al., et\u2009al., B. subtilis remains a much-debated topic within the field. Further investigation will be required to determine whether the reduction in biofilm biomass observed in late-stage biofilms is the result of an organized disassembly process or simply the result of the onset of sporulation by the majority of the population after exhaustion of the nutrient supply.The second method of biofilm dispersal would involve degradation or disruption of the macromolecules in the extracellular environment. Consistent with this mechanism of dispersal, production of extracellular proteases has been correlated with late stages of biofilm formation (Marlow et\u2009al., The environmental signals and regulatory pathways that control entry into biofilm formation have been well studied and it is known that they largely converge to control the production of the biofilm matrix components (Vlamakis"}
{"text": "Dictyostelium in response to nutritional starvation and stress. Here, the trypanosome signalling pathway is discussed in the context of these conserved pathways and the possible contributions of opposing \u2018slender retainer\u2019 and \u2018stumpy inducer\u2019 arms described. As evolutionarily highly divergent eukaryotes, the organisation and conservation of this developmental pathway can provide insight into the developmental cycle of other protozoan parasites, as well as the adaptive and programmed developmental responses of all eukaryotic cells.African trypanosomes, parasites that cause human sleeping sickness, undergo a density-dependent differentiation in the bloodstream of their mammalian hosts. This process is driven by a released parasite-derived factor that causes parasites to accumulate in G1 and become quiescent. This is accompanied by morphological transformation to \u2018stumpy\u2019 forms that are adapted to survival and further development when taken up in the blood meal of tsetse flies, the vector for trypanosomiasis. Although the soluble signal driving differentiation to stumpy forms is unidentified, a recent genome-wide RNAi screen identified many of the intracellular signalling and effector molecules required for the response to this signal. These resemble components of nutritional starvation and quiescence pathways in other eukaryotes, suggesting that parasite development shares similarities with the adaptive quiescence of organisms such as yeasts and  The ability of cells to sense their surroundings and respond to changes in the environment is fundamental to their survival. Monitoring cell density and its regulation is especially beneficial, ensuring the availability of nutrients and space and preventing the accumulation of toxic metabolic waste. This capacity of cells to sense their critical density, referred to as quorum sensing (QS), requires signal molecule/s that serve as reporters of the population density and signal relay components that transmit this information within the cell, causing it to generate a response. The response to increased cell numbers is often a switch to quiescence , a response that promotes survival of the cells under conditions of dwindling resources.African trypanosomes, the causative agents of sleeping sickness in humans and \u2018nagana\u2019 in livestock, are protozoan parasites that alternate their lives between a mammalian host and an insect vector, the tsetse fly. In the mammalian bloodstream, the parasites are \u2018pleomorphic\u2019 (i.e. of different morphologies) and undergo a developmental transition from rapidly proliferating long \u2018slender\u2019 forms to non-dividing short \u2018stumpy\u2019 forms, upon attaining a critical cell density Fig.\u2009. The slein vitro is linked to their cell density, and this is irrespective of their initial seeding density  before differentiation and proliferation arrest in G1/G0 as stumpy forms can occur  as auto inducers of QS signalling cascades. The AHLs are freely diffusible molecules that can bind to and activate a transcriptional activator, which in turn induces expression of target genes. Another class of molecules that mediate similar effects is the 4-quinolones. On the other hand, Gram-positive bacteria use small post-translationally processed peptides as signal molecules. These peptides have been shown to interact with a histidine kinase two-component signal transduction system  secrete a soluble, low molecular weight, heat stable factor/s termed stumpy induction factor (SIF). SIF is of parasite origin, and its accumulation in the culture medium/blood stream, with increasing parasite density, is proposed to act as the trigger for the slender to stumpy differentiation. This factor is believed to act on the same population that produces it, such that it induces an autocrine response. Monomorphs, in contrast, seem to be \u2018signal-blind\u2019 to the factor they produce, thus providing them with a growth advantage et\u2009al., et\u2009al., et\u2009al., et\u2009al., Lack of information on the chemical identity of SIF has made it difficult to understand the production of the signal, its turnover and the molecular cascade involved in relaying this signal. Early studies on slender forms noted a two- to threefold increase in cyclic AMP (cAMP) levels at peak parasitaemia followed by a decline in its levels during the transition to stumpy forms  or threonine (Thr) residues, making Ser/Thr protein phosphatases (PPs) key players in the eukaryotic cell. The Ser/Thr protein phosphatases of type 1 (PP1) are the most abundant and among the best characterised protein phosphatase family. The PP1 catalytic subunit can interact with a large number of regulatory proteins, resulting in a conformational change of the phosphatase and a specific dephosphorylation of the target. Protein tyrosine phosphatases (PTPs), which also include dual-specificity phosphatases, dephosphorylate proteins at the tyrosine residues and play a major role in signal transduction. The ability of phosphatases to interact with multiple substrates explains their involvement in a wide range of cellular activities although there is limited information on their role in trypanosome biology. Nonetheless, a tyrosine phosphatase in et\u2009al., et\u2009al., 1998; 2002et\u2009al., et\u2009al., T.\u2009brucei. For example, one could speculate that PP1 acts upstream of AMPK in the SIF pathway such that AMPK depletion by RNAi might prevent the cell-cycle arrest generated upon PP1 overexpression, although PP1 might also have other targets in the pathway. Dual specificity phosphatases (DsPhos) in yeast have also been shown to regulate cell growth via regulation of the protein kinase A (PKA) cascade  plays a vital role in glucose signalling by interacting with a large number of regulatory proteins (e.g. Reg1). Glc7 is then capable of inactivating 5'AMP-activated protein kinase (AMPK) (Snf1 in yeast), which in turn transmits the glucose starvation signal  being identified in the RNAi screen for stumpy inducers. The RNAi-mediated ablation of PKA-R (found in the flagellar matrix) in monomorphs inhibited the motility of the parasites  has a potentially comparable function in cell cycle inhibition, as its depletion via RNAi results in prolonged cell proliferation and maintenance of slender forms  act as major regulators of cellular energy homeostasis in eukaryotic cells. The AMPK cascade is regulated by the AMP:ATP ratio and hence acts as an energy sensor. A decline in ATP levels, along with a concomitant rise in AMP, activates this kinase, which then phosphorylates a range of downstream targets to bring about changes that reduce catabolic processes within the cell. AMPKs are thus capable of responding to a reduction in ATP levels (that may be brought about by nutrient depletion) by pushing the cell towards a state of reduced activity, in order to maintain the AMP:ATP ratio. Interestingly, AMPK is also known to be an inhibitor of the mTOR pathway  cascade in yeast is involved in stress responses as well as cell cycle regulation. This cascade, which involves a module of three protein kinases  that sequentially activate one another by phosphorylation, form a crucial part of intracellular signalling pathways in eukaryotic cells \u2013related kinases or NEKs, a class of serine/threonine kinases, were originally identified in a genetic screen for cell division cycle mutants in et\u2009al., et\u2009al., In summary, both protein phosphatases and protein kinases have been identified as regulators of the transition between slender and stumpy forms, though the targets upon which they operate are unknown. Nonetheless, phosphorylation is an expected contributor to the regulation of the signalling molecules themselves and also the effector molecules for differentiation upon which they may act, such as RNA binding proteins. Phosphoproteomic datasets analysing cultured bloodstream and procyclic forms   drive stumpy formation suggests they are fundamental components of a conserved cell communication or cell quiescence pathway found in other kinetoplastids. One observation from Table\u2009 and HYP2et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al.  in pleomorphs inhibited growth and also increased the rate of slender to stumpy transition et\u2009al., Combined, one can speculate that trypanosomes have a dual mechanism for controlling differentiation, comprising of a slender retention (SR) as well a SI arm Fig.\u2009. A set oet\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., A less investigated but crucial aspect of the differentiation process is the timing of the onset of the commitment to differentiation from the long, slender to the short, stumpy form. Although asymmetric division was suggested to be the means by which trypanosomes underwent commitment and morphological transformation  of stumpy-like forms in vitro has led to the discovery of various components of the SIF pathway (Mony et\u2009al., in silico information, the existing literature as well as experimental data from other eukaryotes (Fig.\u2009et\u2009al., Plasmodium (Ikadai et\u2009al., T.\u2009cruzi and Leishmania spp. The evolutionarily ancient position of trypanosomes in the eukaryotic lineage also has the potential to inform understanding of the molecular basis of cellular quiescence in other cells including those of mammals, whose breakdown is a key contributor to the development of many cancers.With the development of tools such as the genome-wide RNAi (Alsford tes Fig.\u2009, validat"}
{"text": "Imagine yourself walking down the street. The act of initiating the first step triggers an increased firing of some medium spiny neurons (MSNs) in the striatum. These MSNs are part of the direct pathway in the basal ganglia complex (for a review on the basal ganglia, see Parent and Hazrati, Nature, Cui et al. (in-vivo photometry to observe what is active in the striatum when mice are performing an operant task. The changes in fluorescence intensity of GCaMP3, a calcium indicator, correlated to the MSN activity. In particular, Cui et al. (In a recent publication in i et al.  describei et al.  observedThe Journal of Neuroscience. In their experiment, Freeze et al. (For every action, there is an equal and opposite reaction. The opposite reaction to the Cui et al.  paper ise et al.  investigNevertheless, it is critical that we should approach the conclusions of the Freeze et al.  paper wiIn light of the results in Cui et al. , it is pLet us return to that walk down the street. When we make those first steps during action initiation, both dMSNs and iMSNs are concurrently active to help funnel the coarse cortical afferents through the basal ganglia. This type of pruning allows the dMSNs to help activate the right sets of muscles to move forward while permitting the iMSNs to help inhibit other muscles that can disrupt our balance or the forward motion. Ultimately, it is a coordinated effort between the two pathways that gets us to the final destination.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "In its recent edition the Archives of Toxicology have published a transcriptome-based classifier that identifies developmental toxicants acting as histone deacetylase inhibitors. The authors, Eugen Rempel and colleagues from Dortmund Technical University, demonstrate that based on only eight genes the gene expression pattern of developmental toxicants acting as histone deacetylase inhibitors can be identified. They used a test system that recapitulates generation of neuroectoderm from pluripotent stem cells (Balmer et al., 2014; Leist ein vitro overlapped with concentrations known to cause teratogenic effects in humans in vivo. A next challenge in test system development is to develop expression signatures which indicate that specific toxic mechanisms are active. In this respect the present work of Rempel et al., using a set of structurally not related compounds acting by a similar mechanism, represents an important proof of concept (Rempel et al., 20156]; Grinbal., 2011; Liu et al., 2011; Xi et aal., 2011; Oesch eal., 2011; Stapletal., 2011; Ejaz an"}
{"text": "The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.The following information is missing from the Funding section: This study was supported by an unrestricted grant from UCB Pharma (The authors have also provided an updated Competing Interests statement: This study was supported by an unrestricted grant from UCB Pharma. Jo\u00e3o Eurico Cabral da Fonseca received this grant as the head of Rheumatology Research Unit at Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa. This does not alter our adherence to PLOS ONE policies on sharing data and materials."}
{"text": "Possibilities in auxiliary technique combinations with small- and wide-angle X ray scattering are described, as well as more complicated sample environments used in X-ray and neutron scattering. via either simultaneous or independent measurements, has advanced understanding of the driving forces that lead to the structures and morphologies of materials, which in turn give rise to their properties. The simultaneous measurement of different data regimes and types, using either X-rays or neutrons, and the desire to control parameters that initiate and control structural changes have led to greater demands on sample environments. Examples of developments in technique combinations and sample environment design are discussed, together with a brief speculation about promising future developments.Small- and wide-angle X-ray scattering  are standard tools in materials research. The simultaneous measurement of SAXS and WAXS data in time-resolved studies has gained popularity due to the complementary information obtained. Furthermore, the combination of these data with non X-ray based techniques,  The earliest SAXS beamline was constructed in Hamburg, in order to elucidate the mechanism by which muscles contract (Rosenbaum q range  would be projected onto a limited number of detector pixels.A conventional SAXS/WAXS beamline has two detectors placed several metres apart to collect SAXS and WAXS data simultaneously. With the lower divergence of third-generation synchrotron X-ray sources, the compromise between under- and over-focusing of the beam between the two detectors is reduced to an acceptable level. While high collimation allows the collection of both SAXS and WAXS data on a single detector, this arrangement will be detrimental to the low-angle information content, where a very large et al., 2004et al., 2006et al., 2013et al., 1995et al., 2012For some time, the photon flux delivered by most beamlines exceeded the capabilities of the detectors available. However, with the introduction of efficient high count-rate semiconductor-based photon-counting detectors (Schmitt It is not practicable to provide here a comprehensive overview of the developments in online time-resolved techniques used in combination with SAXS/WAXS (\u2018hyphenated\u2019 techniques) and the accompanying more complicated sample environments. Instead, we try to give a flavour of some of the developments, with an emphasis on materials science experiments. Where possible, hints as to the timeline of how certain areas have developed in the last 20\u2005years are given.2.et al., 2007et al., 2009et al., 2011et al., 2012et al., 2010et al., 2013The combination of techniques is not always beneficial. If the timescale over which samples are modified is such that it is also feasible to perform independent experiments without introducing a notable error margin between the experiments, then one is better off carrying out optimized independent experiments. In combinations, often at least one of the experiments yields suboptimal, but still useable, data. The only advantage of combining techniques is the synergy that results when data sets are obtained simultaneously from a single sample with, for example, a well characterized thermal history or other provenance. The longer limit we define, somewhat arbitrarily, as being 1\u20132\u2005min per time frame. The limit on the fast side is in general no longer set by the available X-ray flux or the detectors. Where the fastest of the older generation of CCD area detectors could collect data at rates of 15\u2005Hz with a limited dynamic range  and interception by the X-ray beam can then be varied to provide time resolution. In this case the problem of radiation damage is overcome as well.Very fast reactions can be studied using microfocus techniques, where a miniature extruder, et al., 1998et al., 2000et al., 1998et al., 1998et al., 2003When combining techniques one has to be aware of the fact that there might be differences in sensitivity for certain aspects of the experiments. For example, in an extended debate on polymer crystallization that raged roughly between 1998 and 2005, a proposal was made that the distinction between a nucleation and growth crystallization model, and a spinodal-like phase-separation model that preceded crystallization, could be made by the sequential occurrence of scattering and diffraction intensity in the SAXS and WAXS regimes , if we assume that no heat exchange will take place between the irradiated area and its surroundings. This does not suggest that any sample will heat up appreciably, since the adiabatic approximation is somewhat rigorous. However, if the thermal sensor of the temperature controller is some distance away from the position where the beam hits the sample, it is not advisable to over-interpret a combination of online DSC and X-ray scattering, since a thermal gradient will almost certainly exist and indeed has been shown experimentally  , where q is as defined in \u00a71et al., 2005When hierarchical length scales are involved, the simplest experimental option is to combine SAXS and WAXS in the conventional transmission mode. Realistically, on most beamlines this can render data over a continuous scattering vector range 3 \u00d7 10550-b-PFS50, in decane solution can be mentioned  image of a sample which is to be studied by SAXS is invaluable, since it narrows down the nearly limitless possibilities for data interpretation which are possible when relying only on first principles and SAXS data Fig.\u00a03. Anotheret al., 1995stratum corneum, the top protective layer of human skin  tail organizations. Direct correlations between these parameters and the improper skin barrier function suffered by eczema patients were established in this way.The combination of SAXS with Fourier-transform IR spectroscopy (FT\u2013IR) has been shown to be useful in determining the extent to which chemical reactions have progressed and what this means for structure formation  which was uniaxially oriented  in a quasi-simultaneous mode  muscles  and a mid-block of poly(methacrylic) acid, which exhibits a coil\u2013globule transition as a function of pH, has been set up as a free-running motor system by applying a periodically changing pH. The idea was also to show that the cycling in length of the block copolymer reaction could be repeated The above two examples highlight some of the most challenging experiments known to the authors. However, it is clear that not every experiment requires a very complicated setup. To determine the phase diagram of a block copolymer or liposome solution, a simple heating stage and a night of beamtime might be sufficient. What it is important to realise is that such complicated experiments are feasible, and it only requires the will to do them and the perspiration of beamline users and staff to make them a reality.7.in extremis, is required. Most synchrotron laboratories have several beamlines and organization units dealing with extreme conditions. The parameters that are most often classified as \u2018extreme\u2019 in this context are temperature and pressure. The application of the most extreme conditions is not employed very often in SAXS. This is most likely due to the fact that moderate temperatures are already sufficient to modify the long-range structures that can be studied with SAXS, and extremes of temperature and pressure have a more profound effect on the shorter atomic or molecular length scales.Sometimes the variation of a single parameter, but then et al., 2008et al., 1996et al., 2008et al., 1999et al., 2010P-jump type experiments. The cells share common features, including custom PTFE (polytetrafluoroethylene) spring seals for work above 0.4\u2005GPa. Recent improvements to cell design have included a dedicated sample-loading port which allows the windows, often diamond, to be left in place during experiments, thus alleviating the problems of background subtraction which were evident in previous designs. Scientifically, the cells have been used to study the distinction between pressure and thermal or chemical denaturation in biological proteins  of 3\u00a0\u00d7\u00a010\u22124\u2005\u00c5\u22121  has been introduced, which transfers spin polarization from electrons to nuclei, thereby aligning the nuclear spins to the same extent that the electron spins are aligned (Abragam, 19618.3.et al., 2010et al., 2006et al., 2007et al., 2010et al., 2010et al., 2011Polymerization solutions are models of living systems, in that the species and content of the solutes change as time proceeds. Anionic copolymerization of styrene and isoprene monomers in a dilute solution, with deuterated benzene as the solvent, has been studied by means of combined time-resolved SANS, size-exclusion chromatography, NMR and UV\u2013Vis spectroscopy (Zhao 9.et al., 2012Crystallization studies have been an important driving force for technique developments in time-resolved SAXS/WAXS. The technology for constructing sample environments to make such experiments possible, even at microsecond timescales, has been developed. The difference in sensitivity between SAXS and wide-angle diffraction/scattering events with respect to their ability to shed light on the earliest stages of crystallization, mentioned earlier, has evoked two different responses. The first was to develop very high count-rate single photon-counting WAXS detectors that were at least an order of magnitude more sensitive and efficient than the photon-counting detectors used for SAXS experiments. However, this is an approach that will only bring improvements until one reaches the intrinsic limits, dictated by physics, where differences in technique sensitivity become manifest. Beyond that point one has to revert to different approaches. One of these methods is the use of pair distribution function analysis (Tyrsted ad hoc and quite often open to debate. Attempts to utilize similar methods to those used for solution scattering for particle growth have been carried out, but the methods remain cumbersome (Shaw et al., 2002In data analysis great strides can still be made. Protein solution scientists have been well served by data packages that allow them to squeeze the last piece of information out of their low-information-content data sets consisting of the scattering curves of monodisperse proteins. However, when dealing with time-resolved data from polydisperse particles and high matrix backgrounds, most analysis methods are still et al., 2011et al., 2014When dealing with different experimental data sets obtained in a single time-resolved experiment, it is often not difficult to correlate events. One plots the development of a SAXS invariant on the same graph as the variations in the spectroscopic absorption band, takes a ruler and determines what comes first. However, when subtle effects are in play and the data are noisy, as one can expect in a time-resolved experiment, the situation might become more complicated. Fortunately, there have been some interesting recent developments. Several years ago, two-dimensional correlation analysis on SAXS\u2013WAXS data sets was attempted in order to determine the exact correlation between parameters obtained from the different data sets (Smirnova 10.We have attempted to give a flavour of what is currently feasible in combining techniques with small- and wide-angle scattering. This is by no means an exhaustive review but rather an attempt to make the case; if one thinks that a combination of techniques might deliver results that would otherwise not be available, one should not be afraid to try. On modern SAXS beamlines many things are possible. It might require some hard work and collaboration with the beamline scientists, but that should also be part of the fun of experimenting!"}
{"text": "Correlations between particulate organic carbon (POC) and mineral fluxes in the deep ocean have inspired the inclusion of \u201cballast effect\u201d parameterizations in carbon cycle models. A recent study demonstrated regional variability in the effect of ballast minerals on the flux of POC in the deep ocean. We have undertaken a similar analysis of shallow export data from the Arctic, Atlantic, and Southern Oceans. Mineral ballasting is of greatest importance in the high-latitude North Atlantic, where 60% of the POC flux is associated with ballast minerals. This fraction drops to around 40% in the Southern Ocean. The remainder of the export flux is not associated with minerals, and this unballasted fraction thus often dominates the export flux. The proportion of mineral-associated POC flux often scales with regional variation in export efficiency (the proportion of primary production that is exported). However, local discrepancies suggest that regional differences in ecology also impact the magnitude of surface export. We propose that POC export will not respond equally across all high-latitude regions to possible future changes in ballast availability. Our previous analysis, based on limited data sets derived from Wilson et al. [Klaas and Archer [Le Moigne et al. [Wilson et al., Wilson et al. [Teff; namely, that Teff is high in calcite-dominated regions and low in opal-dominated regions. While this is the global Teff pattern reported by some studies [Fran\u00e7ois et al., Henson et al., Lam et al., Teff [Buesseler and Boyd, Martin et al., Rynearson et al., Smetacek et al., Further analysis of the global data set of deep particle flux by n et al.  has showd Archer  and Le Me et al.  and othen et al.  hypotheseff). Here we examine the variability in surface mineral ballast Ccs using 234Th-derived estimates of POC and mineral flux in the Arctic, Atlantic, and Southern Oceans (95 data points). We discuss the implications of our results for the role of minerals in the export of POC from the surface ocean.However, it is still unclear how the impact of ballasting on shallow POC export varies regionally and how it is linked to export efficiency  particles collected on Nitex screen using an in situ stand-alone pumping system deployed at a single depth beneath the mixed layer (from 20 to 70\u2009m). Particles were then rinsed off the screen using thorium-free seawater, and the particle suspension split into equal subsamples. Each split was then analyzed for one of the following: 234Th, POC, BSi, and particulate inorganic carbon (PIC) as in Le Moigne et al. [These fluxes were then converted to estimates of downward particle flux using the POC:e et al. .234Th approach has the great advantage of providing a large data set of surface export fluxes, albeit with the caveat that some of the seasonal variability of export flux may be missed. While this is unlikely to be a major issue in low-latitude areas where the seasonal cycle in export is weak [Waniek et al., Waniek et al., Using the Lambert et al. [Kuss and Kremling [Le Moigne et al. [Honda and Watanabe [Planquette et al., \u22121) for stations in the plumes of chlorophyll a associated with South Georgia and the South Sandwich Islands and the average value from nonplume stations around Crozet [Planquette et al., \u22121) for our nonplume stations. Table S1 summarizes the values of PAl used for each station. Lithogenic fluxes were estimated as (100/8*Al) [Honda and Watanabe, Gehlen et al., Salter et al., The aluminum concentration in large particles (PAl) was not measured; therefore, literature values were taken from t et al.  and KussKremling  to estime et al.  and HondWatanabe . For theHonda and Watanabe [Le Moigne et al. [total flux) into four portions, three of which are considered to be associated with the mineral phases BSi (POCBSi), calcite (POCpic), and lithogenic material (POClith). The fourth portion is the residual POC flux, which is considered the non-associated fraction (POCres). MLRA takes the following form:We examined the relationship between mineral and POC fluxes using two different techniques. Initially, we used multiple linear regression analysis (MLRA) as in Watanabe  and Le Me et al. . MLRA dia, b, and c are defined as Ccs [Klaas and Archer, d is the nonassociated portion of POC [Armstrong et al., Honda and Watanabe, Le Moigne et al., Wilson et al. [Wilson et al., We then used the geographically weighted regression (GWR) technique. The application of GWR to ocean particle flux data was carefully described and tested by n et al. . We follNakaya et al., http://www.st-andrews.ac.uk/geoinformatics/gwr/gwr-software/). We used an adaptive Gaussian Kernel, which groups the data by the nearest neighbor approach. The Akaike Information Criterion, corrected for small sample bias (AICc) [Akaike, Wilson et al. [We used the GWR 4.0 software [ Akaike, , was usen et al. . We alsoIn the following section, we briefly describe the magnitude of surface POC and mineral export fluxes Figure\u2009. The higPIC export Figure\u2009b shows sR2 of 0.22 and an AICc of 1139 (Table\u2009R2 to 0.52 and reduced the AICc to 1098 (Table\u2009p\u2009<\u2009< 0.001). Formally, we reject the null hypothesis that there is no difference between the GWR and MLRA models. Finally, the test of geographical variability  is high in the SO as previously observed [Le Moigne et al., \u22122 d\u22121, with the lowest values seen in the Arctic and the North Atlantic subtropical gyre  and SO  Figures\u2009j, and 2mWilson et al., Le Moigne et al., Milliman et al., Ragueneau et al., Wilson et al., To fully understand the interaction between mineral and POC fluxes, one needs to assess the variation of mineral-associated POC fluxes not only at depth [Teff, of flux through the mesopelagic [Fran\u00e7ois et al., eff, we now compare our mineral-associated POC export data to the global pattern of PEeff reported by Siegel et al. [It has been suggested that minerals influence the transfer efficiency, l et al. .Siegel et al. [eff in their data set from the HLNA (0.1\u20130.25), where our analysis shows the highest proportion PIC- and BSi-associated POC export , where a lower proportion of the total POC export is mineral associated than in the HLNA  [Siegel et al., In the subtropical gyres, where the spatial variability of mineral-associated POC export is reduced and the proportion of the POC flux associated with minerals is low Figures\u2009g and 2m,eff. While we can only compare our export data to the climatology of PEeff reported by Siegel et al. [eff at the time of sampling), the comparison suggests the following:Iversen and Ploug, Schmidt et al., Klaas and Archer [Sanders et al. [There are fundamental differences in the ways minerals promote POC export in different oceanic provinces. We know that mineral ballast can have different ballasting properties (particle nucleation and/or added density) depending on mineral type. For example, calcite-ballasted particles generally sink faster than opal-ballasted ones [d Archer  and Sands et al. .eff. For instance, ecosystem functions such as the packaging of slowly sinking phytoplankton cells into large, fast-sinking fecal pellets may increase PEeff regardless of the proportion of POC associated with minerals in the material grazed.Factors other than the magnitude of mineral-associated POC flux are also likely to influence PEThe proportion of POC flux carried by mineral does not so clearly correlate with the PEl et al.  (and noteff in the SO, potentially due to grazing intensity [Maiti et al., Pabortsava, We suggest that these processes are potentially more important in the SO and the subtropical gyres than in the HLNA. This is consistent with observations of an inverse relationship between primary production and PEArmstrong et al., Honda and Watanabe, 2 levels [Kwon et al., Globally, POC not associated with minerals often dominates total POC export out of the surface ocean Figure\u2009k. While eff presented by Siegel et al. [eff in the SO and the subtropical gyres. Ecosystem processes like grazing intensity may be more important in these regions.Surface mineral-associated POC fluxes are highly variable Figures\u2009i\u20132k, butl et al. , suggestOur analysis reveals two important messages:eff, Siegel et al. [Teff.Comparing mineral-associated POC export with the global pattern of PEl et al.  has provTeff derived from sea surface temperature are low [Henson et al., Engel et al., Engel et al., Le Moigne et al., Teff in the HLNA is higher than proposed by Henson et al. [Buesseler and Boyd, Martin et al., Rynearson et al., Teff is also estimated to be low [Henson et al., Teff in high-latitude diatom-dominated regions [Assmy et al., Henson et al., Lam et al., Wilson et al., Teff [Smetacek et al., In the HLNA, estimates of n et al. , as was eff/low Teff occurring at high latitudes and low PEeff/high Teff occurring at low latitudes [Henson et al., eff and Teff are likely to be driven in turn by factors beyond just sea surface temperature. Thus, not all high-latitude regions are identical, and they cannot be described by the same \u201cballast\u201d parameterization in ocean carbon models. For instance, POC export in the HLNA and the SO are unlikely to respond in the same way to any reduction in ballast mineral availability, as might be caused by ocean acidification, increased sea temperature, or deepening of the wind mixed layer [Sarmiento et al., Zondervan, Falkowski et al., 2.Our results suggest that viewing the BCP as a two end-member system with high PE"}
{"text": "As such, Safavi and co-workers draw into question this conclusion, based on evidence indicating that neural activity in frontal areas, in particular in the lateral prefrontal cortex, reflects the contents of consciousness in paradigms that do not involve active report.Like any other field, the field of consciousness research benefits from a careful distinction between the concepts involved. An example is the distinction between the state of being conscious  and the contents of consciousness . A similar type of distinction can contribute to the resolution of a debate regarding the role of the frontal cortex in conscious perception. In a recent publication Safavi et al.  respondecontent of consciousness, and neural activity that brings about changes in consciousness during perceptual bistability. Safavi et al. (Here we aim to bring these two positions closer together by making an explicit distinction between neural activity that reflects the i et al.  bring foi et al. . Fr\u00e4sslei et al. . Fr\u00e4ssleAs a further point, the \u201cbinocular flash suppression\u201d paradigm that provides much of the empirical basis of Safavi and colleagues' argument, manipulates the content of awareness while explicitly avoiding spontaneous switches in perception. This provides a further indication that Fr\u00e4ssle et al.'s claims regarding perceptual switches can exist side-by-side with Safavi et al.'s claims regarding stable perception. Indeed, the next paragraph will summarize evidence that frontal involvement in coding the contents of consciousness does not imply frontal involvement in perceptual switches.Whereas the anatomical distribution of activity that reflects the content of consciousness during bi-stable perception depends on the stimulus employed (Logothetis and Schall, As a final remark we would like to stress, as others have (Safavi et al., In conclusion, we agree with the notion, emphasized by Safavi and colleagues, that the field of consciousness research will benefit from an integrated view of evidence from various experimental and neuroscientific paradigms (Aru and Bachmann, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Thirty percent of patients with epilepsy experience seizures despite optimal anticonvulsant drug treatment. Stress is frequently identified by patients with epilepsy as a precipitant of seizures (Spector et al., However, in this commentary we would like to specify that contrary to what it is claimed by the authors, decreasing arousal, using relaxation biofeedback is not the method proposed by Nagai et al. . On the The motivation for believing that EDA relaxation biofeedback may be beneficial for patients with epilepsy comes is understandable given the relationship between stress and increased skin conductance level. It is known that stress and anxiety are commonly reported triggers of seizures Fenwick, . Thus, iDespite strong theoretical underpinnings there is little direct knowledge about the neural mechanisms underlying EDA biofeedback on seizure onset. Scrimali et al.  suggest As evidence of the clinical efficacy of EDA arousal biofeedback in the management of epileptic seizures, Nagai et al.  report aIn conclusion, EDA biofeedback has great potential as a non-pharmacological therapy for the management of refractory epilepsy. The methodology is grounded on theory, and on increasing knowledge regarding the underlying neural mechanisms, and the approach deserves greater clinical attention. There also remains a need for continuing clinical research, such as the case study report by Scrimali et al. . DespiteThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Normal ageing is characterized by cognitive decline across a range of neurological functions, which are further impaired in Alzheimer\u2019s disease (AD). Recently, alterations in zinc (Zn) concentrations, particularly at the synapse, have emerged as a potential mechanism underlying the cognitive changes that occur in both ageing and AD. Zn is now accepted as a potent neuromodulator, affecting a variety of signaling pathways at the synapse that are critical to normal cognition. While the focus has principally been on the neuron: Zn interaction, there is a growing literature suggesting that glia may also play a modulatory role in maintaining both Zn ion homeostasis and the normal function of the synapse. Indeed, zinc transporters (ZnT\u2019s) have been demonstrated in glial cells where Zn has also been shown to have a role in signaling. Furthermore, there is increasing evidence that the pathogenesis of AD critically involves glial cells (such as astrocytes), which have been reported to contribute to amyloid-beta (A\u03b2) neurotoxicity. This review discusses the current evidence supporting a complex interplay of glia, Zn dyshomeostasis and synaptic function in ageing and AD. Currently, normal ageing is considered to be associated with an overall decline in cognition occurring via structural and functional brain changes over a period of time  depression and schizophrenia  exist as chelatable Zn  and also maintaining the architecture of gray matter (Kettenmann and Verkhratsky, 2+ levels in response to synaptic transmission (Morris et al., 2+ influx through NMDA receptors. A recent study by Han et al. (Additionally, astrocytes increase intracellular Can et al. , which gn et al. . This deThe role of Zn at synapses is particularly germane to both normal and pathological ageing. Neuroplasticity deteriorates in normal ageing and loss of synapses is a key indicator and currently the best correlate of cognitive decline in AD (Takahashi et al., Though the link has previously not been made, the evidence presented here suggests that there may be an interaction between neurons, astrocytes, Zn and glutamate that is critical to normal synaptic health and function, potentially affecting neurotransmission and other cellular cascades involved in cognition, as discussed earlier. This is an area of research that clearly needs further investigation, as the diminished learning and memory abilities seen in ageing may be caused by a failure in neuron-glia communications at the synapse that disrupts Zn homeostasis to result in downstream modifications to, among other things, synaptic ion channels.In addition to the role of astrocytes at the synapse, recent studies investigating microglia suggest this tripartite system may be just as constraining to synaptic research as the previous model. Currently, the literature is dominated by what is thought to be the primary function of microglia; surveying the environment for damage and protecting neural material (Stollg and Jander, 2+ and a subsequent increase in neuronal voltage-gated K+ currents as caused by the release of ROS from activated microglia lead to neuronal cell death. This suggests the primary mechanism of neuronal apoptosis may in fact, be the earlier damage to glial cells. This is accordance with findings by Kaindl et al. (in vitro (Kaindl et al., Microglia also release cytokines, which have central physiological roles in synaptic plasticity, neurogenesis and learning and memory in the normal brain (Morris et al., l et al. , 2012 th2+ in the progression from normal to pathological ageing is illustrated in Figure Both Zn and glia appear to have multifarious roles within the brain, especially within synapses. Indeed, synaptic loss is the fundamental feature of the ageing brain that links neuropathology to cognitive decline in AD (Talantova et al., Herein evidence supporting a link between Zn, glia and cognitive decline has been presented and discussed. The research thus far suggests the possibility of a feedback loop between Zn homeostasis, synaptic excitation, neurons, astrocytes and microglia. Perhaps the most appropriate definition is that of Morris et al.  that a sThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Brain histamine promotes wakefulness and orchestrates disparate behaviors and homeostatic functions. Recent evidence suggests that aberrant histamine signaling in the brain may also be a key factor in addictive behaviors and degenerative disease such as Parkinson's diseases and multiple sclerosis. The intent of this research Topic is to provide an overview of the recent advances in the understanding of the many functions of brain histamine and to propose neurobiological substrates and mechanisms of action that might explain the reasons why the histaminergic system is a potential target for therapeutic interventions. This may justify the search for new histaminergic compounds.The authors that contributed to this e-book offered several approaches to the study of brain histamine function. Tomasch et al.  synthesiHistamine acts as a modulator of several neurotransmitters in the brain and its role in promoting wakefulness has for long overshadowed other important functions. In fact, histamine signaling controls feeding behavior in a complex fashion and it has been considered for long a satiety system as brain histamine decreases the drive to consume food. In their paper, Ishizuka and Yamatodani  demonstr3 receptor (which regulates histamine and other neurotransmitters' release), decreases alcohol drinking in several behavioral tasks, like operant alcohol administration and \u201cdrinking in the dark\u201d paradigm (Nuutinen et al., 3 receptor is a key element in alcohol drinking and place preference, the role of histamine in these behaviors is poorly understood and deserves further investigation.Brain histamine is crucial for motivation and goal-directed behaviors as reviewed by Torrealba et al. . The aut3 receptor signaling in the brain to acquire and store short- and long- term memories has been documented extensively. However a limited number of studies have investigated the role of the H3 receptor in anxiety. By using novel behavioral test, Abuhamdah et al. (3 receptor providing new evidence that the H3R may have a role in fear-induced avoidance responses, but not in anxiety. In addition, Vohora and Bhowmik (The importance of Hh et al.  present  Bhowmik  providedDysfunctions of the histaminergic system may also contribute to the pathogenesis of multiple sclerosis and its murine model of experimental autoimmune encephalomyelitis, although the role of the different histamine receptors is complex and still controversial (Passani and Ballerini, 2, Yanovsky et al. (2-induced arousal in hepatic encephalopathy and obstructive sleep apnoea.Histaminergic neurons are sensitive to COy et al.  showed tRecent evidence summarized by Blandina et al.  suggest In conclusion, we believe that this Research Topic offered an inter-disciplinary forum that improved our current knowledge of the role of brain histamine. It also provided the necessary drive to stimulate innovation in clinical practice to manage and treat neurological disorders.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The previous contribution of Duffy and colleagues suggests that a chain of behavioral events starting during childhood precedes the development of full-blown bipolar disorder. In this vein, the recent contribution of Keown-Stoneman and colleagues brings a new perspective to the study of prodromal symptoms of bipolar disorder. In 2010, Duffy et al. showed that subjects diagnosed with bipolar disorder (BD) followed a predictable sequence of prodromal symptoms (Duffy et al. Generally, staging models imply that natural history of the disorder moves through a predictable temporal progression, and provision of stage-appropriate treatment can modify such course. Some medical specialties such as cardiology and oncology have advanced in this field, developing strategies to prevent both the onset and the development of established disease. In the same way, bipolar disorder identified in the early stages may be less treatment refractory with a greater probability of response to monotherapy (Scott et al. In 2007, Berk et al. presented a staging model of the longitudinal course of bipolar disorder and the temporal impact of interventions (Berk et al. In the same vein, Kapczinski et al. presented a staging model that emphasizes the assessment of patients in the inter-episodic period and includes the following: latent phase\u2014individuals who present mood and anxiety symptoms and increased risk for developing threshold bipolar disorder; stage I\u2014patients with bipolar disorder who present well-established periods of euthymia and absence of overt psychiatric morbidity between episodes; stage II\u2014patients who present rapid cycling or current axis I or II comorbidities; stage III\u2014patients who present a clinically relevant pattern of cognitive and functioning deterioration, as well as altered biomarkers; and stage IV\u2014patients who are unable to live autonomously and present altered brain scans and biomarkers (Kapczinski et al. Moreover, a recent task force of the International Society for Bipolar Disorders has performed a systematic review on staging models for bipolar disorders (Kapczinski et al. In conclusion, the current paper (Keown-Stoneman et al."}
{"text": "Over the last 20 years, work surrounding theories of embodiment and the role of the putative mirror neuron system (MNS) in humans has been hotly debated. In 2000, Ramachandran . Thus, eTwo of the articles in this collection addressed how the human MNS might underlie the physiological mechanisms that give rise to human emotions. In \u201cMotor empathy is a consequence of misattribution of sensory information in observers,\u201d Mahayana et al.  used TMSIn \u201cLanguage comprehension warps the mirror neuron system,\u201d Zarr et al.  asked paTwo articles used neuroimaging to identify the neural correlates of embodiment. In an fMRI study entitled \u201cHand specific representations in language comprehension,\u201d Moody-Triantis et al.  asked paTwo other theoretical/opinion articles also steer away from stricter MNS interpretations and suggest that the motor system influences action perception but is not its sole critical component. In \u201cHomuncular mirrors: misunderstanding causality in embodied cognition,\u201d Mikulan et al.  propose Additionally, we included two response pieces to Bach et al.'s proposal, one by Osiurak  and the Intriguingly, in \u201cObservation and imitation of actions performed by humans, androids and robots: an EMG study,\u201d Hofree et al.  show thaAll of these works expand our understanding of the human MNS by extending previous work and delimiting the boundaries of how we should interpret those findings. As a group, contributing authors seem to agree on less strict interpretations of embodiment and the human MNS, suggesting these are strong contributors to various aspects of action and cognition, but do not represent the sole basis of language, learning, or comprehension. Future work should further explore the precise mechanisms underlying the links between action planning, execution, and semantic processing, as well as the relative dependence of distinct cognitive processes on mirror activity.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The discovery that somatic cells can be induced into a pluripotent state by the expression of reprogramming factors has enormous potential for therapeutics and human disease modeling. With regard to aging and rejuvenation, the reprogramming process resets an aged, somatic cell to a more youthful state, elongating telomeres, rearranging the mitochondrial network, reducing oxidative stress, restoring pluripotency, and making numerous other alterations. The extent to which induced pluripotent stem cell (iPSC)s mime embryonic stem cells is controversial, however, as iPSCs have been shown to harbor an epigenetic memory characteristic of their tissue of origin which may impact their differentiation potential. Furthermore, there are contentious data regarding the extent to which telomeres are elongated, telomerase activity is reconstituted, and mitochondria are reorganized in iPSCs. Although several groups have reported that reprogramming efficiency declines with age and is inhibited by genes upregulated with age, others have successfully generated iPSCs from senescent and centenarian cells. Mixed findings have also been published regarding whether somatic cells generated from iPSCs are subject to premature senescence. Defects such as these would hinder the clinical application of iPSCs, and as such, more comprehensive testing of iPSCs and their potential aging signature should be conducted. TERRA levels are positively correlated with telomere length and may act as regulators of telomerase expression (Schoeftner & Blasco, et al., These results indicate that, although telomerase activity is clearly reconstituted during the reprogramming process, there is a significant variability in telomere length among various iPS cell lines. This length is sensitive to passage number and can even vary among cell lines derived from the same tissue or parental cell type. This is not unique, however, as it was recently shown that substantial variability in telomere length and telomerase expression exists for ESCs as well. For both iPSCs and ESCs, telomere length was found to be highly correlated with proliferation efficiency and developmental pluripotency (Huang et al., et al., et al., et al., et al., et al., Aging in somatic cells is accompanied by mitochondrial dysfunction and oxidative stress Fig.  (Passos et al., et al., et al., et al., et al., et al. obtained more mixed results (Fig. et al., It was recently shown that the reprogramming process reorganizes mitochondria, causing them to adopt the immature morphology, distribution, and DNA content characteristic of the pluripotent state. Like ESCs, these human iPSCs also displayed reduced levels of oxidative stress, decreased amounts of intracellular ATP, and increased production of lactate. Expression of nuclear factors involved in mitochondrial biogenesis was also comparable (Prigione lts Fig. , findinget al., et al., et al., et al., It is currently possible to generate iPSCs from human centenarian cells (Lapasset et al., et al., et al., et al., et al., Using human tissue, Boulting and colleagues (Boulting et al. reported that reprogramming efficiency declined with age. Knockdown of the Ink4/Arf locus, which encodes for tumor suppressors and is upregulated with age, was sufficient to rescue the age-dependent defect in reprogramming efficiency (Li et al., et al., lamin A/C cause defects in the nuclear envelope and underlie Werner syndrome and Hutchinson Gilford progeria, two diseases of accelerated aging. Recently, iPSCs were generated from patients suffering from these disorders. Compared to their donor fibroblasts, these iPSCs had normal nuclear membrane morphology, suggesting that the reprogramming process could rejuvenate nuclear defects (Ho et al., A few age-related genes have been identified that play inhibitory roles in the reprogramming process. Using mouse and human fibroblasts, Li Although additional age comparisons are necessary, these results suggest that mammalian aging may decrease reprogramming efficiency (for an overview of donor age of the generated iPSC lines, see Table Recent data have emerged suggesting that cells derived from iPSCs may exhibit signs of premature senescence (please see Fig. et al. reprogrammed human skin fibroblasts into iPSCs and then produced differentiated cell lines derived from three iPSC-teratoma explants. Although one line exhibited elongated telomeres, the other two displayed telomere lengths comparable to the input fibroblasts (Suhr et al., et al., et al., et al. successfully differentiated human iPSCs into multiple cell types, although the efficiency was markedly lower than it was for ESCs. Moreover, the authors observed that, unlike cells derived from ESCs, somatic cells derived from iPSCs exhibited early senescence and possessed dramatic defects in expansion capability (Feng et al., et al., Suhr Although it is too early to conclusively determine, issues of premature senescence may, like telomere length, vary considerably from line to line. Subsequent research drawing detailed comparisons between cell types derived from multiple ESC and iPSC lines will help resolve this contention.et al., et al., et al., It is quite clear that the reprogramming reverses many aspects of aging. Even iPSCs derived from senescent and centenarian cells exhibit a more youthful signature, displaying elongated telomeres and gene expression profiles comparable to ESCs (Lapasset et al., et al., et al., et al. found no correlation between the differentiation potential of an iPSC clone and the type of progenitor cell used. Instead, the authors observed that differentiation propensity varied substantially from clone to clone (Nasu et al., et al., et al., et al., et al., et al., et al., Telomere length, for example, has been observed to be shortened (Vaziri et al., That variations in differentiation propensity are observed in iPSCs derived from the same donor (Nasu"}
{"text": "Thirty years after the discovery that neurons are generated in the adult brain (Altman and Das, in vivo (Feng et al., in silico (Weisz and Argibay, However, two By taking advantage of the rabies virus to retrogradely infect monosynaptic neurons (Wickersham et al., Previous studies show that newly formed synapses between adult-generated dentate gyrus neurons and CA3 pyramidal neurons can compete with or even displace previously-established synapses (See references in Deng et al., Bergami et al.  show thaThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Humans who eat fish are exposed to mixtures of healthful nutrients and harmful contaminants that are influenced by environmental and ecological factors. Marine fisheries are composed of a multitude of species with varying life histories, and harvested in oceans, coastal waters and estuaries where environmental and ecological conditions determine fish exposure to both nutrients and contaminants. Many of these nutrients and contaminants are thought to influence similar health outcomes . Therefore, our understanding of the risks and benefits of consuming seafood require balanced assessments of contaminants and nutrients found in fish and shellfish. In this paper, we review some of the reported benefits of fish consumption with a focus on the potential hazards of mercury exposure, and compare the environmental variability of fish oils, selenium and mercury in fish. A major scientific gap identified is that fish tissue concentrations are rarely measured for both contaminants and nutrients across a range of species and geographic regions. Interpreting the implications of seafood for human health will require a better understanding of these multiple exposures, particularly as environmental conditions in the oceans change. Clupeififormes) . Neverthiformes) , Table 2Interpretation of these results may be complicated by measurement error introduced by differing methods used for fish sampling and analysis, but some broad patterns in the data are interesting. Analysis of published EPA\u00a0+\u00a0DHA values found no statistically significant effect of type of habitat , or temperature of habitat, or their interaction on the PUFA content in fish. To visualize the results of ANOVA, a two-dimensional graph of the PUFA content in the groups of species was created . Since ESardinops sagax from temperate waters, shad Hilsa macrura from warm waters and herring Clupea harengus from cold waters were all similar    studies in a Norwegian lake, the selenium to mercury molar ratio was a better predictor of trout metallothionein levels than was either selenium or mercury (S\u00f8rmo et al., et al., et al., et al., et al., et al., et al., et al., et al., There is a long-running interest in nutrient-toxicant interactions between mercury and selenium (Ganther et al., et al., et al., et al., In recent years due to the interest in selenium to mercury molar ratios, a number of studies have assessed mercury and selenium concentrations and the selenium to mercury molar ratios for a variety of fish species from field samples as well as fish purchased from supermarkets (Burger et al., et al., et al., et al., et al., et al., In general, studies of selenium to mercury molar ratios have found that mercury concentrations were positively related to fish length and trophic level but selenium concentrations were not, and selenium to mercury molar ratios are more strongly related to mercury content than selenium content (Karimi et al., et al. (et al., Recent research is beginning to address the need to quantify the overall nutritional and toxicological value of different types of fish and shellfish based on concentrations of multiple nutrients and contaminants in edible tissues. A recent study found unique, relative concentrations of mercury, omega-3 fatty acids, and selenium, or mercury-nutrient signatures, across seafood taxa et al., . Specifi, et al.  found th et al., . Future et al., et al., et al., et al., et al., et al., et al., et al., Advice describing both the types and amounts of seafood consumption, while complex, is necessary to better manage risks and benefits of seafood consumption (Oken et al., et al., et al., To conduct appropriate human health risk assessment for contaminants such as mercury requires an understanding of how mercury, fish oils and selenium co-exposures affect the human body. This work can be informed by studies from marine biology and fisheries science, coupled with epidemiological biomonitoring, anthropological and food science investigations into the role of culinary preparation and gut processing on mercury and nutrient bioavailability (Laird et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Our current ability to properly estimate the risks and benefits to humans of seafood consumption are hampered by the common approaches of separately studying either contaminants or nutrients in fish. To date there are few studies in which fish tissue concentrations have been measured for both contaminants and nutrients across a range of species and geographic regions, even for the restricted set of chemicals considered in this review. There is tremendous variability between and within fish species in their mercury, EPA and DHA concentrations, leading to different versions of the \u2018fish intake\u2019 exposure across participants in epidemiological studies (Greenland & Robins,"}
{"text": "One strand of evidence comes from Proffitt, who has shown that changing a person's ability to act affects how they judge their ability to perform an upcoming task. The most famous example  mentally simulate things they doWe do this simulation ahead of time, in anticipation of an encounterThis simulation will require more effort with out-group members, because they do things differently to youThis increased simulation effort will affect your judgment of distance, as per ProffittTherefore out-group members should look further awaySoliman et al.  applied The results seem promising; for example, American and Arab participants who rated themselves with an interdependent self-construal did rate their in-group members as closer than did participants with an independent self-construal. Soliman et al. argue that these results support an analysis of culture within Proffitt's embodied framework, which would be interesting if true because it would let us talk about both perceptual and cultural effects within a unified framework.There is a major problem, however. Proffitt's research very clearly shows that increasing the effort required to perform a task only affects distance perception related to that task. For example, making walking harder by fatiguing the legs increases the perceived distance if you plan to cross it by walking, but not if you plan to cross it by throwing (Witt et al., Task specificity is central to Proffitt's theory. In a recent debate, Firestone  highlighonly way in which a friend could help make a hill look more climbable is by doing something that recalibrates the embodied hill-climbing system. Discovering what this something is would be an invaluable contribution to the unification Soliman et al. propose, but it remains to be done.Soliman et al. rest their non-task-specific analysis on one paper (Schnall et al., Soliman et al.  claim thThe current data (plus Schnall et al., I am personally all in favor of an embodied approach to unifying psychology, but as I have argued (Wilson and Golonka, The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Recent, primarily technology-based advances in microbial ecology have opened an immense treasure chest of microbial diversity that has been observed in the vast majority of all investigated habitats. Additionally, habitats which were assumed to be sterile for a long time are now known to be colonized by diverse microorganisms; e.g. within the placenta and stomach of humans or reproductive organs of plants. Through the implementation of new techniques, deeper insights into the structure of microbiomes mainly by amplicon sequencing and microscopy have been gained. Now the current focus of research is on analysis of their function implementing meta-(genomic/epigenomic/transcriptomic/proteomic) techniques. The management of the accumulated metadata and the gleaning of new information is the challenge we are facing, but that challenge will be solved in the near future Jansson, . By looket\u2009al., et\u2009al., Enterobacteriaceae play a substantial role within the vegetable microbiome ; however, the microbiome in/on our diet opens many more potential insights into the complex interactions. A third example is the indoor microbiome, which has enjoyed enormous attention during the last years due to the fact that we spend most of our time in built environments. The indoor microbiome is also a mixture of variably fixed niches such as bathtubs, kitchen sinks, furniture etc., as well as more moving carriers of microbiomes including the inhabitants (humans and pets), outside air and also of plants (indoor plants as well as outside vegetation). Although we know who contributes to the composition of the indoor microbiome, we don't know how those influences affect the function of the microbial ecosystem. The indoor microbiome is also strongly shaped by cleaning procedures. Can indoor plants and their microbiome positively contribute to human health? Is there an optimal rate of microbial turnover and exchange? All these questions can be answered by studying the shared fractions of microbiome or \u2018microbiome connections\u2019. In the three microbiomes presented above, organisms of all domains of life, archaea, bacteria and eukaryotic microorganisms interact to fulfill ecosystem functions. Most of the published studies so far focused only on one microbial group, and therefore it is necessary to make a short note on the interplay between microorganisms from different kingdoms. Recent research has shown that there is a lot of interaction between members of the different groups; e.g. bacteria and fungi interact in the broad range between symbiosis and antagonism (Frey-Klett et\u2009al., In recent decades, deeper insight into many aquatic and terrestrial microbial communities was gained using omics approaches. Although this is now possible, considerable time must be invested in the future in order to assemble all pathways and understand the interactions within microbiomes Jansson, . In contet\u2009al., et\u2009al., et\u2009al., Sphagnum mosses, stress protection is identified as the main function (Bragina et\u2009al., et\u2009al., The control of microbial growth is an important area of microbiology, which resulted in significant advances in agriculture, medicine and food science. Biological control is an environmentally sound and effective means of reducing pathogens and pests and their symptoms through the use of natural antagonists or enemies. While in the past mainly single organisms were used, often correlated with inconsistent effects, it is now possible to develop predictable microbiome-based biocontrol strategies (Berg Looking even further ahead, I see the continued development and implementation of ABTs and advanced biocontrol products like pro-, pre- or synbiotics containing synergistic microbial consortia or those which induce specific beneficial microbiomes that will contribute to the maintenance and enhancement of microbial diversity for plant and human health and for our environment. The idea to restore the \u2018missing microbes\u2019 Blaser,  is not o"}
{"text": "Boea hygrometrica  regulatory genes involved in dehydration stress responses. Moving into resurrection plants we were fortunate to have received such a comprehensive review by Dinakar and Bartels  covering five continents, almost six, although unfortunately we did not quite get there. We were certainly incredibly fortunate for the kind responses of colleagues in Africa (Berjak and Pammenter,  Bartels  of the v Bartels  have dona et al. . The auta et al.  show thaMedicago truncatula, a seed model system, by Terrasson et al. (S. stapfianus, to buttress their hypotheses on how senescence may be differentially activated and suppressed in resurrection plant evolution. The first sequenced genome of a resurrection plant, the Chinese B. hygrometrica (reviewed here by Mitra et al., at the end of the beginning\u201d in our quest to understand the remarkable biological secrets of these fascinating plants.Farrant and Moore  proposedn et al. . This won et al.  and procn et al.  on the rThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Most studies of plant viruses have focused on the acute viruses that cause disease in crop and ornamental plants. These viruses are transmitted horizontally, often by insect vectors, and are occasionally transmitted vertically. Although known for at least four decades, the persistent viruses of plants are very poorly studied. These viruses were previously called \u201ccryptic\u201d because they did not appear to illicit any symptoms in infected plants  RNA genome, based on their RdRp, and encode a large polyprotein that does not have any apparent coat protein, but encodes a number of additional domains that appear to be derived from diverse sources  RNA genomes, and encode only an RNA dependent RNA polymerase (RdRp) and a coat protein. Of the well-characterized persistent plant viruses, those in the Viruses of fungi have very similar lifestyles to plant persistent viruses, and several virus families are shared between plants and fungi. Phylogenetic evidence indicates that virus transmission has occurred within and between the two kingdoms (Roossinck, Cryphonectria hypovirus 1 that suppresses the disease phenotype of the chestnut blight fungus led to a search for other examples that could be exploited to mitigate the effects of plant pathogenic fungi .Deep sequencing is proving to be a useful technique for just about everything these days, and the methods have been applied to metagenomic studies of viruses. Unlike studies of other microbes, viruses cannot be analyzed through the use of any universal conserved sequences or motifs, and a variety of techniques have been employed to enrich for viral nucleic acids before sequence analysis. Studies in aquatic viruses have been reported for a number of years (Angly et al., Different methods of detection have yielded different levels of persistent viruses. Use of dsRNA-enriched samples yielded very high levels of persistent viruses in plants (Roossinck, Virus discovery in fungi is very limited. Most analyses have been done on fungi of economic importance such as plant pathogenic fungi. A survey of viruses from endophytic fungi derived from two plant species in a wild plant community indicated that the diversity of viruses in this system was much greater than the diversity of fungi, which was in turn much greater than the diversity of plants (Feldman et al., In most cases of fungal virus studies, viruses have been discovered from cultured fungi. This eliminates the majority of fungi, which are not culturable (Blackwell, Partitviridae and the Endornaviridae are recognized by the International Committee for the Taxonomy of Viruses (King et al., Totiviridae and Chrysoviridae families that traditionally are considered fungal viruses (Roossinck, Sclerotinia sclerotiorum was shown to be infectious as a purified virus particle, although it is not clear if this is a mechanism for transmission in nature (Yu et al., Cryphonectria hypovirus (Liu et al., Heterobasdion (Vainio et al., Plants and fungi share several families of viruses. The Heterobasidion species, virus lifestyle was dependent on the fungal environment (Hyder et al., Persistence and high levels of vertical transmission in parasites are correlated with commensal or mutualistic lifestyles (Villarreal, The abundance of persistent viruses in plants and fungi imply functions that may contribute to the biology of the host. Unfortunately we have little ecological data about these viruses, and since they often cause no disease they have not been the subject of intensive study. Data-mining from transcriptomic, genomic and metagenomic studies may allow us to address the true ecological role of these viruses. For example, the partitiviruses have poly-A tails, and may be detectable in transcriptome analyses (Jiang et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Although pathological gambling (PG) is a prevalent disease, its neurobiological and psychological underpinnings are not well characterized. As legal gambling increases in prominence in a growing number of casinos as well as on the internet, the potential for a rise in PG diagnoses warrants investigation of the disorder. The recent reclassification of PG as a behavioral addiction in the DSM-5 raises the possibility that similar cognitive and motivational phenotypes may underlie both gambling and substance use disorders. Indeed, in this Research Topic, Zack et al.  tested tIn this Research Topic, Paglieri et al.  report aVentral striatal activation is thought to be critical for the attribution of incentive salience to reward-related cues. In this Research Topic, Lawrence and Brooks  found thTwo papers in this Research Topic suggest a role for cortisol in modulating incentive motivation in the ventral striatum. Li et al.  demonstrIn this Research Topic, Clark and Dagher  provide The investigation of neural mechanisms underlying PG is currently at an early stage. As emphasized by Potenza  in this The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "White sharks are highly migratory and segregate by sex, age and size. Unlike marine mammals, they neither surface to breathe nor frequent haul-out sites, hindering generation of abundance data required to estimate population size. A recent tag-recapture study used photographic identifications of white sharks at two aggregation sites to estimate abundance in \u201ccentral California\u201d at 219 mature and sub-adult individuals. They concluded this represented approximately one-half of the total abundance of mature and sub-adult sharks in the entire eastern North Pacific Ocean (ENP). This low estimate generated great concern within the conservation community, prompting petitions for governmental endangered species designations. We critically examine that study and find violations of model assumptions that, when considered in total, lead to population underestimates. We also use a Bayesian mixture model to demonstrate that the inclusion of transient sharks, characteristic of white shark aggregation sites, would substantially increase abundance estimates for the adults and sub-adults in the surveyed sub-population. Using a dataset obtained from the same sampling locations and widely accepted demographic methodology, our analysis indicates a minimum all-life stages population size of >2000 individuals in the California subpopulation is required to account for the number and size range of individual sharks observed at the two sampled sites. Even accounting for methodological and conceptual biases, an extrapolation of these data to estimate the white shark population size throughout the ENP is inappropriate. The true ENP white shark population size is likely several-fold greater as both our study and the original published estimate exclude non-aggregating sharks and those that independently aggregate at other important ENP sites. Accurately estimating the central California and ENP white shark population size requires methodologies that account for biases introduced by sampling a limited number of sites and that account for all life history stages across the species' range of habitats. Apex predators play an important role in marine community structure through both consumptive and non-consumptive effects on prey Carcharodon carcharias) is one of the largest and most widely known shark species, is cosmopolitan in distribution, and is known to aggregate off the coasts of California, Baja California Mexico, South Africa, New Zealand and southern Australia. While some life history aspects are poorly quantified, their diet The white shark  and State of California endangered species lists. Under the Federal Endangered Species Act, an endangered species is defined as \u201cany species which is in danger of extinction throughout all or a significant portion of its range.\u201d As limited resources are best used in protecting species that are truly at risk of extinction, unwarranted petitions may draw resources away from more deserving species.et al. Orcinus orca: 1145 individuals in the ENP, Gulf of Alaska and Aleutian Islands) and the polar bear , suggesting that healthy white shark populations should be of similar magnitude. Although the comparison to air breathing mammals may be inappropriate, the central California abundance estimate of Chapple et al. et al. Chapple et al.'s et al.'s We therefore revisit Chapple et al. Chapple et al.'s Closed population models fundamentally assume that a population under study does not include birth, death, immigration or emigration over the period of sampling. Although violated routinely in practice, provided these changes occur randomly, only a loss of precision should result, with estimates remaining unbiased et al. Satellite tagging of white sharks at aggregation sites off central California has revealed clear seasonal movement patterns, with sharks present near coastal and insular pinniped rookeries during the fall and swimming to an offshore focal zone or Hawaii in the spring and summer et al. Jorgensen et al. et al.'s Long-term photo identification of five individual sharks at the Farallon Islands from 1987 to 2008 showed that all individuals were absent from data records for periods of 1\u20139 yrs et al. et al. et al. study.Chapple et al. h model of Otis et al. et al. Therefore, based on their own data, Chapple et al. et al. et al. The technique employed by Chapple et al. et al. Chapple et al. et al. et al. study represents only a sub-sample of central California as they did not sample elsewhere, particularly other known white shark aggregation sites in the region, notably A\u00f1o Nuevo Island The most serious violation of the assumptions of the models employed by Chapple White sharks are known to enter and leave the sampled aggregation sites during the time that the photo-identification study was conducted, and hence they would not be available for sampling during the purportedly closed sampling periods Recent stable isotope analyses also suggest that some white sharks do not specialize on mammals but instead forage mostly on bony fishes and perhaps squid et al. Several factors we discuss above could have a positive bias resulting in an overestimation of population size , while several other factors could lead to a negative bias resulting in an underestimation of population size . While the net effect of certain biases cannot be determined, our detailed analysis of the assumptions required of the mark recapture model chosen by Chapple We now evaluate the potential numerical effects of the biases associated with the differential residency patterns apparent at those two aggregation sites.et al. et al. Having evaluated the hypergeometric model and assumptions used by Chapple et al. et al. Fearnbach et al. et al. ix, indicating if the individual was alive across five simulated years:et al. itx\u200a=\u200a1), then at time t+1 its status was given as a Bernoulli random variable with parameter it\u03c6, the survival probability from time t to t+1. If an individual was not within the population during the previous time steps 1,\u2026,t , then probability of entry into the population between intervals t and t+1 was a Bernoulli trial with parameter \u03b3it\u200a=\u200a1. For simplicity we assumed a stable population, fixing survival at \u03c6it\u200a=\u200a0.857 and entry into the sub-population, through birth, at \u03b3it+1 \u200a=\u200a0.153 ity is the identification history for shark i at time t, ip represents the probabilityof individual i being observed at any given time. These individual probabilities were simulated using conservative detection probabilities drawn from the time-averaged posterior resident and transient distributions of Fearnbach et al. To illustrate the potential bias induced by non-random sampling, we compared the hypergeometric approach of Chapple ru \u223c N for residentstu \u223c N for transientset al. across a range of sub-population mixtures, from all residents to mostly (90%) transients. By simulating across this range of population mixtures we were able to explore the effect of varying proportions of transients on estimates of population size. We consider the parent detection distributions to be conservative because marine mammals must surface to breathe and therefore are expected to be more frequently available for sampling than sharks that do not need to surface at all. Our approach included some probability of death and birth through time, which Chapple Given the presence of both deaths and births in the simulated sub-population, two sources of hypergeometric bias become apparent through time. First, there are high and increasingly positive biases in the estimated number of individuals for sub-populations of residents only, even over two survey years . This ocSecond, because the model cannot distinguish individuals, cumulative hypergeometric sub-population estimates  are consistently low-biased, relative to the discovery curve for the known simulated population . This reet al. study. Such an estimate would require a stratified-random survey that sampled all insular and coastal aggregation sites as well as juvenile and other adult habitats, throughout the region. However, it is feasible to use the Chapple et al. data, accounting where possible for the biases discussed above, to estimate the minimum population required  to account for the estimated number of sharks that visit the Farallon Islands and Tomales Point sites.Our simulation results clearly show the large biases expected in a hypergeometric model given realistic population dynamics for a large, highly-mobile marine predator population. Failure to recognize that sub-populations sampled at a fixed locations include both resident and transient individuals generated downward population biases of between 22\u201333% in the first two years of sampling when 70% of individuals are transient We now address those calculations using demographic modelling.et al. et al. et al. et al. et al.'s minimum population sizes for all life stages of white sharks whose matures and sub-adults consistently visit these two locations. We do not extrapolate beyond this minimum number to estimate a total population size for white sharks in the ENP as data are lacking.To extrapolate a population estimate for mature and sub-adult white sharks in central California to all life stages in the ENP, Chapple et al.'s et al. et al. et al. 's In extending Chapple et al. et al.'sWe then used natural mortality and life history estimates based on an assumed longevity of 30 years and increased fertility to insure that lambda equaled 1.0, based on life history information in Mollet and Cailliet Demographic analyses are a useful method for estimating population sizes and age distribution, and have been applied to several species of sharks, including white sharks et al. et al. et al. et al. et al. The size-frequency and sex of the sharks sampled by Chapple et al. et al. Chapple et al. The sex ratio of our sample data from Jorgensen We used established demographic methodology et al. et al.'s et al. We then fit the size (age) frequency data for the 130 animals enumerated by Jorgensen et al. Our results demonstrate that Chapple Recent length-at-age estimates of five male sharks from central California and eight sharks from the northwest Atlantic  suggest that growth rates may be much slower than our growth model predicts and that longevity may be much longer  et al.'s et al.'s Our demographic analysis, based on Chapple Formal listing of a species as \u201cendangered\u201d places substantial demands on governments, which must devote considerable resources to protecting listed species, and on segments of the public, who must forgo social and economic opportunities to comply with applicable laws. Consideration and listing of species that are not under the threat of biological extinction may divert resources away from those that are genuinely at risk. It therefore is critical that the best possible information be used in listing reviews to minimize undue burdens and insure that limited resources are applied to recovery of the neediest species. Unfortunately there is considerable incentive for some conservation organizations to quickly support listing species, often after minimal critical scientific review, as listings can be cited as tangible achievements in the effort to preserve the environment and attain other conservation goals.et al. et al. et al. et al. et al. Chapple et al. In stating that the ENP white shark population is small relative to other apex predators such as killer whales and polar bears, Chapple et al. Our new estimate is comparable to white shark population estimates from other locations and, importantly, our estimate is similar to that from a recent independent status review of the ENP white shark population, which estimated \u223c3,000 individuals. The status review team had access to virtually all available data from white shark researchers throughout the eastern North Pacific and used multiple modeling approaches A mark-recapture study using photo-ID techniques at two adjacent white shark aggregations in Gaansbi, South Africa resulted in an abundance estimate of 908 (808\u20131008) sharks. This sub-population abundance is more than three times the Chapple et al. et al. et al. et al. Genetic techniques were used to estimate the effective population size of white sharks off southern Australia at approximately 1,512 individuals Elasticity analyses have typically concluded that juvenile survival exerts the greatest influence on population growth rate of sharks in general et al. minimum estimate for the numbers of predominantly male sharks that annually return to two pinniped rookeries in central California; we suspect, however the estimate of 328 (222\u2013433) from the Chao model et al. Despite the many flaws outlined here, the Chapple"}
{"text": "Drug addiction is manifested by a compulsive drive to take licit or illicit substances despite repeated severe adverse consequences  and nitric oxide (NO), followed by the propagation of free radicals that damage cells  has also been studied in animal models of addiction  because they generate oligodendrocytes during early postnatal development (Nishiyama, Oligodendrocytes are cell types responsible for providing myelin for rapid propagation of action potentials Nave, . The brain utero (Cao et al., At present, there is very little information available on the potential effects of drugs of abuse on oligodendrocytes. For example, Lin et al.  used a 3Animal studies have also revealed certain white matter abnormalities after extended cocaine use. For example, George et al.  investigThese animal studies are consistent with the suggestion that myelin dysfunction might account for some of the deficits in white matter integrity described in studies of humans addicted to various substances (Cadet et al., Microglial cells are the immune cells that reside in the brain parenchyma (Sierra et al., In addition to their toxic effects, microglia can alter neuronal excitability by affecting both inhibitory and excitatory synaptic transmission (Sierra et al., Addiction of licit and illicit substances can be viewed as maladaptive plastic responses to exposure to agents that impact the expression of various genes and proteins in the brain. Some of these proteins are known to be involved in developmental processes that are dormant during adulthood Cadet, . Drug-inThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Environmental Health Perspectives, James et al. reported that life-time exposure to low levels of inorganic arsenic in drinking water was associated with increased risk of coronary heart disease (CHD). The study was well performed and reported, except for the omission of two possible confounders related to an individual\u2019s drinking water\u2014magnesium content and total hardness.In a recent issue of Several studies worldwide have demonstrated a relationship between low levels of magnesium in drinking water, or softness, and an increased risk of death from myocardial infarction . A recen"}
{"text": "Autophagy is a major cellular degradation pathway in which materials are delivered to the vacuole in double-membrane vesicles known as autophagosomes, broken down, and recycled (Li and Vierstra, Several contributions to the Research Topic address the emerging concept of selective autophagy, well established in animal cells but only described recently in plants. Zientara-Rytter and Sirko  in a resArticles also discuss the selective autophagy of cellular organelles. Lee et al.  review rVeljanovski and Batoko  also disAuxenochlorella protothecoides in a research article. They analyze lipid droplet degradation and show that while macroautophagy is induced during the heterotrophic to autotrophic transition, lipid bodies are degraded in the vacuole by a microautophagy-like mechanism. Hanamata et al. (The degradation of lipid droplets by autophagy-related mechanisms is also a theme of the Research Topic. Zhao et al.  study tha et al.  discuss a et al. , as breaFinally, Ren et al.  review tThis collection highlights some of the recent advances in our understanding of plant autophagy and its role in numerous physiological processes and we hope that it will stimulate further discussion and research into this exciting topic.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "To ensure the addition of only high quality scientific works to the field of scholarly publication, paper [We have been made aware that text, figures and experimental data reported in the title paper  are duplet al. . At the et al.  had alren, paper  is retra"}
{"text": "This commentary on the articles published in the special section on the developmentand implementation of measurement feedback systems (MFSs) discusses three challenging themes in the process of MFS implementation: design and planning,organizational context, and sustainability and unintended consequences. It is arguedthat the implementation of MFSs is complex, but is an important step in improving outcomes in routine care for children and young persons. In the past decade, the implementation of measurement feedback systems (MFSs), also referred to as progress feedback or (routine) outcome monitoring, has taken a leap worldwide. Several countries have mandated the use of MFSs as part of routine care , and in other countries large public or private initiatives exist . By using an MFS, the client\u2019s progress in treatment is tracked by frequent administration of standardized measures. The MFS supports the clinician in deciding to adapt treatment when insufficient progress has been made. There are several feedback systems available , and by now MFSs have been introduced in a variety of settings , populations  and disorders  (Bickman et al. The first implementation theme is the design and planning of the introduction of the MFS. The way Dixon-Woods et al.  define tThe design of the MFS is another important factor within this theme. MFS design has been discussed in detail in several of the articles in this section (Bruns et al. The second theme that Dixon-Woods and colleagues address is organizational and institutional contexts, professions, and leadership. This is an important theme in the articles in this special section. Both Nadeem et al. and Gleacher et al. conclude that higher organizational and leadership support improved implementation of the MFS. Interviews with clinicians in the article by Bickman et al. shed a light on what type of support was particularly helpful: on-site implementation support, and having a local champion in using the MFS. These results are in line with the conclusion of Aarons et al.  that leaThe third theme mentioned by Dixon-Woods et al.  refers tThe issue of unintended consequences is a complex one. Research on the efficacy of MFSs has predominantly taken place in adult populations. To my knowledge, in youth mental health care only two randomized controlled studies have been conducted (Bickman et al. A different class of potential unwanted effects has to do with forming partnerships with the industry. Modern MFSs have become so technologically complex and costly that researchers often need to form partnerships with software developers in order to be able to develop a MFS (as for example was done by Bruns et al. The articles in this special section teach us that the implementation of MFSs is a complex process in which many challenges need to be faced. They also show us good examples of successful implementation processes or creative solutions to challenges faced, which will be extremely helpful to future implementers of MFSs. The implementation of MFSs in routine care has the potential to improve outcomes for large groups of future clients. This is especially important, given that the effect sizes of interventions in routine care are much smaller than those found in clinical trials (Hansen et al."}
{"text": "In humans, the only known inducer of VEGF111 is DNA damage but its natural presence in the uterus of the viviparous lizard, Saiphos equalis, suggests other mechanisms of regulation. Most interestingly, the possible relationship between the evolution of viviparity and the associated increased risk in developing cancer may be important in understanding the mechanisms underlying tumor development.Vascular endothelial growth factor is a secreted glycoprotein that acts on endothelial cells to induce developmental and physiological angiogenesis. It has also been implicated in angiogenesis occurring in several pathologies, most notably, cancer. Alternative splicing of VEGF mRNA transcripts results in several isoforms with distinct properties depending on their exon composition. Recently, a new isoform has been identified, VEGF Angiogenesis is a crucial process during tumor growth, invasion and metastasis for the rapid development and maintenance of a blood supply to developing tumors , a major mitogen that acts selectively on ECs to stimulate angiogenesis  and resveratrol (a phenol produced by some plants) inhibit VEGF111 production (Munaut et al., While hypoxia and hypoglycemia induce VEGF expression by increasing the stability of the mRNA transcript (Stein et al., in vivo, indicating its importance in tumor angiogenesis. Several anti-VEGF therapies have been developed as cancer treatments, some showing success in improving survival rates (review by Jain et al., Angiogenesis is critical in the growth of solid tumors, as a tumor cannot grow beyond a size of 2 mm without its own vascular support (Gimbrone et al., An issue that has recently emerged is the detrimental effects of VEGF inhibitors on treatment progression, particularly regarding increased malignancy and metastasis (Paez-Ribes et al., 111. Genotoxic drugs such as campothecin and mitomycin C, both of which induce VEGF111 production, are common chemotherapeutics, and thus it is possible that the production of VEGF111 during cancer therapy increases drug resistance (Mineur et al., 111 in angiogenesis and EC activation may provide a significant contribution to understanding this process.Genetic mutations, such as those caused by UV-B radiation and genotoxic drugs, are a major cause of cancer, resulting in abnormal cellular functions (Brash et al., 111 are poorly vascularized in comparison to tumors expressing other isoforms. However, the vessel density in the surrounding tissue is highest in the VEGF111 tumors compared to all other isoforms tested, which have significantly lower vessel density (Mineur et al., 111 to freely diffuse from its point of secretion because it is not restricted by extracellular matrix binding. VEGF111 has a longer half-life compared to VEGF165 and so its actions remain active for longer (Mineur et al., 111, would result in both a highly vascularized tumor and surrounding tissue, potentially increasing the ability to metastasize.When nude mice are injected with cells expressing equal concentrations of different VEGF isoforms, the vascular structures differ. Tumors expressing VEGF145 (Poltorak et al., 162 (Lange et al., 145 lacks exons 6b and 7, and is secreted primarily from cancer cell lines derived from the female reproductive system (Poltorak et al., 162 only lacks exon 7 and is secreted by ovarian carcinoma cells (Lange et al., in vitro and in vivo and their biological activity is similar to the other isoforms (Lange et al., 111 however, is that they still encode the site of plasmin cleavage, and thus lose their biological activity upon exposure to plasmin. Further investigation in mammalian cancers is necessary, however the presence of VEGF111 primarily in reproductive tissues of S. equalis raises questions whether this isoform may also be present in human reproductive tract cancers.Other VEGF isoforms have been identified in transformed cells including VEGFThere are similar molecular mechanisms between how tumors invade and metastasize compared to the trophoblastic invasion in hemochorial placentation that occurs in humans, particularly regarding angiogenesis (Murray and Lessey, 111 as both a potential stimulator of angiogenesis in mammalian tumors (Mineur et al., S. equalis during pregnancy (Murphy et al., S. equalis is transitioning between egg laying and giving live birth with a placenta (Stewart et al., 111 in EC biology may lead to a better understanding of this susceptibility.The discovery of VEGF111 could also be used as a potential therapeutic agent to increase vascularization in ischemic diseases and lesions. The presence of plasmin in chronic wounds results in rapid VEGF cleavage (Lauer et al., 111 to resist this degradation has recently been exploited to improve ischemia and wound healing (Labied et al., 111 to induce rapid angiogenesis and rapid EC proliferation compared to the other isoforms, which results in the earlier formation of a functional vasculature and blood supply to the ischemic region (Labied et al., 111 is necessary, but the initial data are promising.The high angiogenic activity of VEGF111 is an important advance in understanding the mechanisms by which tumors develop their dedicated blood supply and is critical in their ability to grow and metastasize rapidly. While there are several isoforms of VEGF, VEGF111 is the only isoform to resist proteolytic degradation and may provide further insights into the pathogenesis and treatment of diseases that are dependent on angiogenesis. Future work on this molecule should be directed at understanding the mechanisms underlying angiogenesis and has great promise in developing new therapeutics to target tumorigenesis and to treat ischemic diseases. This should involve examining the actions of VEGF111 on EC biology and its capacity to facilitate the formation of functional vessels in several models to specifically address its role in angiogenesis. This should encompass its actions in cancer, both as a potential contributor to metastasis during disease progression, and drug resistance during disease treatment. Further investigation should also expand on the previous work that focused on VEGF111 as a therapeutic agent. Its presence in the uterus of pregnant lizards provides a unique way to understand those mechanisms.VEGF plays a crucial role in normal developmental and embryological angiogenesis as well as contributing to the progression of several pathological conditions. The discovery of VEGFThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Understanding the human gut microbiota has garnered interest from researchers and clinicians to pharmaceutical companies looking at novel mechanisms to manipulate the microbiota for the benefit of the host. Studies on the gut microbiota can be loosely characterized into three areas that include investigating the microbiota's role in the physiology of the healthy gut, in the establishment of gastrointestinal disease, and in extra-intestinal manifestations. With deep sequencing technologies now in routine use in the research environment, novel members of the gut microbiota are coming to light, and our understanding of this complex ecosystem and its relationship to the host is slowly improving.Erysipelotrichaceae, which belongs to the Firmicutes phylum, in host physiology and/or disease are on the rise. However, more often than not, these organisms are mentioned in passing, despite the fact that members of this bacterial family appear to be highly immunogenic and can potentially flourish post-treatment with broad spectrum antibiotics  or animal models of IBD have also been observed; however, the evidence does not appear to be consistent -like transmural inflammation , these mice developed a more severe colitis upon treatment with dextran sodium sulfate than mice colonized by an IgA-negative consortium of bacteria  in diet-induced obese animals (Turnbaugh et al., Erysipelotrichaceae in obese individuals (Zhang et al., Erysipelotrichaceae taxa in a hamster model of hypercholesterolemia treated with an extract to improve cholesterol homeostasis (Mart\u00ednez et al., Erysipelotrichaceae to respond differently to diet or host health phenotypes (Zhang et al., Erysipelotrichaceae in mice on high-fat or western diet (Fleissner et al., Perhaps the strongest evidence for a role for Erysipelotrichaceae and host cholesterol metabolites (Mart\u00ednez et al., Erysipelotrichaceae (Etxeberria et al., More recently, in an important study examining the microbiota of hamsters whose cholesterol metabolism was modulated using dietary plant sterol esters, Martinez and colleagues provided strong evidence for a correlation between the levels of Erysipelotrichaceae. Harris and colleagues identified an accumulation of a specific taxon within Erysipelotrichaceae in mice with liver injury associated with parenteral nutrition, and observed a marked reduction in liver injury also corresponding to a decrease in the abundance of the same Erysipelotrichaceae taxon following antibiotic treatment (Harris et al., Erysipelotrichaceae corresponded to the soy oil based-lipid emulsion from the parenteral nutrition solution (Harris et al., Nutrition studies further support the influence of dietary fat on the abundance of Erysipelotrichaceae in CD patients undergoing low-fat (~13.5 g/1000 Kcal; Nahidi et al., Erysipelotrichaceae levels in IBD patients are likely to be associated with patient lipid or cholesterol phenotypes and/or patient diet, but may still have a significant impact on disease presentation and/or activity (Figure In support of these findings, our group has recently observed a decrease in the abundance of Erysipelotrichaceae and host lipid metabolism, warranting additional investigation into the metabolic profiles of these organisms, and the influence they have on the host. Partial loss of fatty acid biosynthesis has been reported in the genomes of some members of Erysipelotrichaceae (e.g., Erysipelothrix rhusiopathiae; Kwok et al., Erysipelotrichaceae may be correlated to inflammation (Dinh et al., Erysipelotrichaceae have on the host are required.Taken together, there is strong evidence supporting an association between NK conceived the idea and wrote the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Although perceiving the passage of time is a basic building block of cognitive processes and behavior such as expecting relevant events to happen, the neural underpinnings of interval timing are not well-understood as yet  at the interval onset which is not predicted by the SBF. However, the fluctuations in beta power, which are likely driven by dopamine levels in cortico-striatal circuits, may reflect mechanisms involved in interval timing (Kononowicz and van Rijn, There are some arguments worth considering in conjunction with the proposed interpretation of the theta effects. Firstly, as theta modulation is typically associated with memory Ward, , the obsParker et al.  also anaThe next consideration relates to the range of oscillatory power that was analyzed. Note that although Parker et al.  acknowleInterestingly, the theta effects reported by Parker et al.  also havIn conclusion, the study by Parker et al.  providesThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "However, there are occassions in which evolution follows a sort of cycling process. Each time an organism is confronted with a given selective situation, it follows a similar evolution path. However, once the selection pressure is resumed, the organism is outcompeted by non-evolved partners and the evolved lineage disappears. This type of process has been dubbed as \u201cshort sighted evolution\u201d  resides in ancient prey/predator relationships , most patients are infected by independent P. aeruginosa clones as the Liverpool strain , just by chance. Evolution during chronic infection allows the adaptation required to persist inside the infected host. However, this happens at the cost of de-adapting for growing in the original habitat, including resistance to natural predators (Friman et al., Short-sighted evolution is a common process in the evolution of microorganisms and has been explained in the frame of a source-sink situation (Sokurenko et al., P. aeruginosa shows that there are common evolution patterns among isolates producing chronic infections. Nevertheless, these mutations are rarely fixed (with the exception of some epidemic clones Yang et al., We can then conclude that while the acquisition and loss of genes are at the roots of the speciation of \u201cprofessional\u201d pathogens, speciation toward virulence is not necessarily required for bacterial opportunistic pathogens. This does not mean however these pathogens do not evolve for a better adaptation for growing in the human host. Indeed, the study of The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Escherichia coli (ETEC) is a water and food\u2010borne pathogen that infects the small intestine of the human gut and causes diarrhoea. Enterotoxigenic E. coli adheres to the epithelium by means of colonization factors and secretes two enterotoxins, the heat labile toxin and/or the heat stable toxin that both deregulate ion channels and cause secretory diarrhoea. Enterotoxigenic E. coli as all E. coli, is a versatile organism able to survive and grow in different environments. During transmission and infection, ETEC is exposed to various environmental cues that have an impact on survivability and virulence. The ability to cope with exposure to different stressful habitats is probably shaping the pool of virulent ETEC strains that cause both endemic and epidemic infections. This review will focus on the ecology of ETEC in its different habitats and interactions with other organisms as well as abiotic factors.Enterotoxigenic  Presence of ETEC in rivers, drinking water and in irrigation water has been shown  biofilm formation on sprouts and tomato roots grown in water  transcripts increase over time when ETEC are incubated in water . CsrA controls a large variety of physiological processes such as central carbon metabolism, motility and biofilm formation and has been linked to survival . DsbA is involved in the assembly of the mature LTAB5 holotoxin . Interestingly, ETEC expressing STp in combination with CS6, are significantly associated to diarrhoea in adults, and STp is induced in the presence of bile , which is involved in the secretion of LT toxin . Is has also been suggested that oligosaccharides have structures that resemble the binding sites of pathogenic bacteria and hence may hinder adherence and subsequent disease (Kunz et\u2009al., Mucins also contain oligosaccharide moieties. There is increasing evidence that oligosaccharides and glyco\u2010conjugates present in breast milk and on mucins might affect virulence\u2010related abilities of pathogenic microorganisms (Pacheco and Sperandio, et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., Bifidobacteria. The genera Bifidobacterium and Lactobacillus have been used as probiotics and have been implicated as protective against gastrointestinal pathogens. Lactobacilli were found to protect against Shigellosis (Lindsay et\u2009al., In vitro assays also indicated that Lactobacilli inhibits ETEC (Tsai et\u2009al., The human gastrointestinal tract harbours a diverse microbial community, which constitutes the microbiota. The microbiota is important for metabolic functions such as production of vitamins, metabolites and short chain fatty acids (den Besten et\u2009al., Proteobacteria increased in malnourished children while Bacteroidetes decreased. Particularly the Proteobacteria genera Escherichia and Klebsiella increased in the malnourished children although they did not display signs of diarrhoea. A recent study observed reproducible changes in the microbial community structure after ETEC and cholera infection. The authors found that diarrhoeal infectious species more or less could dominate the microbiota early in the infection. Re\u2010colonization of facultative anaerobic bacteria that metabolize oxygen introduced to the intestinal system through the diarrhoea then has to occur before the normal commensal obligate anaerobes can begin re\u2010colonizing the gut. Interestingly, a transient peak of Bacteroides was observed when the patients started to recover 7\u201310 days after acute infection and the microbiota was restored to normal diversity and structure after 1 month (David et\u2009al., Diarrhoea affects the poor and malnourished population in low\u2010income countries and poses a particular risk of morbidity and mortality for children. Healthy Bangladeshi children had a higher diversity of gut microbiota than malnourished children (Monira Giardia lamblia and ETEC were found to increase symptoms in children in Ecuador (Bhavnani et\u2009al., Giardia is contradictory, its immunomodulating properties have been linked to protection although epidemiological studies have clearly defined it as a pathogen (Solymani\u2010Mohammadi and Singer, Giardia in higher frequencies in asymptomatic children (Kotloff et\u2009al., E. coli population could be dominated by a single clone of ETEC in some individuals, while co\u2010infections of several ETEC clones were observed in other patients (Sahl et\u2009al., In addition, the interaction of several pathogens present might either enhance or decrease disease. Co\u2010infections of rotavirus, E. coli causing disease in humans have a tropism for the human intestine through the expression of colonization factors specific for human receptors. Enterotoxigenic E. coli is however also a zoonotic disease affecting piglets and calves, and most of the studies on ETEC gut ecology has been performed in piglets due to the economic impact of diarrhoeal deaths in weaning piglets. Porcine ETEC is responsible for neonatal and post\u2010weaning diarrhoeal infections (Berberov et\u2009al., et\u2009al., et\u2009al., et\u2009al., Enterotoxigenic Enteric microorganisms such as ETEC exist in two different environments, the environment outside of the human host where they survive and the gastrointestinal tract of the host where they cause infection  Fig.\u2009. In the We conclude that a more comprehensive understanding of the pathogenesis of ETEC bacteria in different ecological niches generates important information that can be exploited towards developing methods of controlling infection. Vaccines, oral rehydration solution and antibiotics are commonly used to prevent and treat diarrhoeal diseases, but it is evident that other factors such as diet, food additives and probiotica/microbiota might be able to modify, or even prevent, serious disease. The impact of the bacterial microbiota on ETEC in water and food environments has not yet been addressed at all to our knowledge but could potentially generate means to inhibit transmission pathways. Studies on ecological niches and their influence on survival and virulence of ETEC are therefore important in the continuing fight against diarrhoeal diseases."}
{"text": "In their paper, Baas et al. , take thThe authors did not mention the precise location of the stimulation contact, but previous work from the same group allowed us to piece together a more detailed view of the actual stimulation site. While the distal lead tip was implanted in the nucleus accumbens, the active contact was located in the ventral part of the anterior limb of the internal capsule (ALIC)  the stria terminalis, it is clear that the ALIC is a complex collection of fibers with various destinations (Lehman et al., Note that, if one would actually stimulate the human BST, this might produce various, and even contrasting effects, such as an overall decrease of anxious mood and associated somatic symptoms (as indexed by the Hamilton Anxiety Rating Scale in the DBS for OCD study Baas et al., Recently, major progress has been made in untangling the neuronal circuits of the BST using optogenetics, which allows for very precise manipulation of specific neuronal populations (Deisseroth, The optogenetic approach will undoubtedly continue to deepen our understanding of the BST, as it enables us to parcel out the roles of certain subdivisions or even cell types in the BST (Sparta et al., Apart from these neuroanatomical concerns, we feel that Baas and colleagues could have increased their chance of finding an effect of DBS on context conditioning by promoting the presumed BST activation with their behavioral paradigm. Most evidence for a role of the BST in contextual anxiety comes from animal research (Sullivan et al., In the real world, anxiety-evoking events occur in a complex environment that consists out of multiple stimuli and engages all our sensory modalities (Huff et al., As mentioned above, Baas et al.  providedRegarding the timing of acquisition and expression, it is noteworthy that in rodent context conditioning, training and testing usually take place on 2 days. Due to practical concerns, however, human conditioning experiments are often carried out in one session (but see Huff et al., We acknowledge the financial support of the Medtronic Chair for Stereotactic Neurosurgery in Psychiatric Disorders at KU Leuven."}
{"text": "Approaches to treating autism often emphasize the use of intensive training to gradually improve behavior. Harris et al.'s  recent rHistorically, the effects of ASD on learning mechanisms have received much less attention than its effects on social competence, despite the fact that the behaviors most diagnostic of ASD all depend heavily on generalization of past learning (Dawson et al., Harris et al.  discoverWhile the results reported by Harris et al.  clearly Past studies of perceptual learning in TD adults (Ahissar and Hochstein, Harris et al.  highlighEM developed the critique and wrote the initial commentary, BC developed the critique and edited the initial commentary, AS did background research for the commentary, evaluated the critique, and edited the commentary.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "De novo assembly of a complete transcriptome without the need for a guiding reference genome is attractive, particularly where the cost and complexity of generating a eukaryote genome is prohibitive. The transcriptome should not however be seen as just a quick and cheap alternative to building a complete genome. Transcriptomics allows the understanding and comparison of spatial and temporal samples within an organism, and allows surveying of multiple individuals or closely related species. De novo assembly in theory allows the building of a complete transcriptome without any prior knowledge of the genome. It also allows the discovery of alternate splice forms of coding RNAs and also non-coding RNAs, which are often missed by proteomic approaches, or are incompletely annotated in genome studies. The limitations of the method are that the generation of a truly complete assembly is unlikely, and so we require some methods for the assessment of the quality and appropriateness of a generated transcriptome. Whilst no single consensus pipeline or tool is agreed as optimal, various algorithms, and easy to use software do exist making transcriptome generation a more common approach. With this expansion of data, questions still exist relating to how do we make these datasets fully discoverable, comparable and most useful to understand complex biological systems? With the advent of Next Generation Sequencing (NGS) technologies and improved extraction methods to accurately purify RNA from smaller amounts of tissue or even single cells  within a cell including protein-coding and non-coding RNAs. Additionally, the transcriptome encompasses all alternative splice forms, alternatively polyadenylated, and RNA-edited transcripts. Together, these reflect the genes that are actively expressed in a particular tissue  assembled, summed contig length, mean transcript length, N50 value, and the proportion of reads that could be mapped back to the assembled transcripts  tool by Parra et al. , are available but are currently relatively slow or computationally intense to use. Another consideration for the annotation process is searching for repeat elements using programs such as RepeatMasker (http://www.repeatmasker.org) or the Tandem Repeats Finder , European Bioinformatics Institute , and DNA Data Bank of Japan . There are support pages and handbooks to help with submitting data, and these are available at the NCBI, EBI, and DDBJ websites. As well as raw sequence data, alignment files in BAM (Li et al., Whilst most journals require raw sequencing reads to be made publicly available in a database such as the Sequence Read Archive (SRA; Kodama et al., de novo transcriptome data (Mariette et al., de novo transcriptome data (Lesur et al., RNAbrowse is an alternative package with a web interface that can be used to store and visualize de novo transcriptome assembly data, where both BLAST and keyword searches can be performed. Another research group released their axolotl read and transcriptome assembly data on a website with a keyword search facility (Stewart et al., Apart from more complete packages such as afterParty and RNAbrowse, there are limited tools with web interfaces that are available for analysis of transcriptome data. CBrowse (Li et al., de novo transcriptome assembly is an important tool in the bioinformatician's arsenal. Whilst rapid progress in single molecule sequencing is being made, it is currently not mature and so assembly, annotation and assessment of transcriptomes from relatively short reads will continue to be essential. To make these methods truly useful, assemblies that are accurately assembled and annotated are essential, but also the availability and openness of assembled transcriptomes not simply raw data must become expected practice.As the desire to catalog and compare the varied transcriptomes of complex organisms continues, JM, AI, and RE wrote the paper, prepared figures, and reviewed drafts of the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Peptidoglycan performs the essential role of resisting turgor in the cell walls of most bacteria. It determines cell shape, and its biosynthesis is the target for many important antibiotics. The fundamental chemical building blocks of peptidoglycan are conserved: repeating disaccharides cross-linked by peptides. However, these blocks come in many varieties and can be assembled in different ways. So beyond the fundamental similarity, prodigious chemical, organizational and architectural diversity is revealed. Here, we track the evolution of our current understanding of peptidoglycan and underpinning technical and methodological developments. The origin and function of chemical diversity is discussed with respect to some well-studied example species. We then explore how this chemistry is manifested in elegant and complex peptidoglycan organization and how this is interpreted in different and sometimes controversial architectural models. We contend that emerging technology brings about the possibility of achieving a complete understanding of peptidoglycan chemistry, through architecture, to the way in which diverse species and populations of cells meet the challenges of maintaining viability and growth within their environmental niches, by exploiting the bioengineering versatility of peptidoglycan. Peptidoglycan is a component of nearly all bacterial cell walls and has a variety of functions. It is a huge single molecule (sacculus) surrounding the cytoplasmic membrane, and as such it enables the cell envelope to resist the turgor resulting from the difference in composition between the cytoplasm and the external environment. Furthermore, peptidoglycan is the anchoring point for proteins and other polymers. Another common function is interaction with a host: fragments of peptidoglycan shed by commensal or pathogenic bacteria being recognized by the immune system. The observed characteristics of peptidoglycan  are the result of a series of possible reactions which can occur both in the cytoplasm and in the cell wall itself Fig.\u2009A.N-acetylglucosamine and N-acetylmuramic acid carrying short peptides  and perpendicular (much like the later scaffold model) models were first articulated in the early 1970s  of negatively stained nds Fig.\u2009B, or bronds Fig.\u2009C, led toS.\u2009aureus, suggesting a far more complex and heterogeneous arrangement of peptidoglycan than had been proposed previously  population of bacteria, digested with an enzyme, reduced and pumped through a column which separates the resulting fragments based on their chemical properties with a strong emphasis on hydrophobicity /all muropeptides)] and glycan strand length. A range of cross-linking degrees have been measured for a variety of et\u2009al., et\u2009al., et\u2009al., et\u2009al., E.\u2009coli, average strand lengths between 18 and 60 disaccharides have been reported  was applied to measure strands  the addition of the pentaglycine \u2018branch\u2019 by three Fem-type amino acid transferases that are critical, as S.\u2009aureus is unable to form direct cross-links between the peptides  which are flipped from the inner to the outer leaflet of the cytoplasmic membrane . The action of these enzymes results in further muropeptide diversity.Typically the initial cross-linking reaction liberates the terminal D-alanine of the donor molecule creating a penta-tetrapeptide containing dimer, a penta-tetra-tetrapeptide containing trimer or related higher cross-linked multimers. So in general at this stage there are few possible muropeptide products: an un-cross-linked pentapeptide monomer and cross-linked species with penta and tetrapeptides, and such peptides are seen in HPLC muropeptide analyses. However we have discussed that, for example in S.\u2009aureus, a major chemical modification that occurs in the cell wall is O-acetylation of N-acetylmuramic acid  the cell wall is thick enough to accommodate the known length of the glycan strands in this orientation, leading to a scaffold interpretation of NMR data derived from small, soluble synthetic peptidoglycan fragments  or ECT images of the cell wall or of sacculi  outer surface features were visible in ECT images. Some of these appear superficially similar to those seen by AFM and may be related to those observed previously by TEM . Images of freeze etched S.\u2009aureus revealed two distinct surface textures demarked by thick lines  and the localization of short/long glycan chains on the sacculus, which is related to the distribution of glycan chain ends.We know that some muropeptides are not randomly distributed across the sacculus. D-alanine-D-alanine motifs are associated primarily with new insertion and adopt a range of species specific localizations, as are muropeptides containing artificially introduced D-amino acids after pulse labelling (Kuru E.\u2009coli and B.\u2009subtilis, poles are anything between one and in theory a large number of generations old, and in the cylindrical part of the cell old material is dispersed throughout the wall depending on insertion pattern and turnover rate. In B.\u2009subtilis cables of peptidoglycan are more apparent by AFM imaging on the inside of the sacculus than the outside \u2013 attributed to hydrolase activity (Hayhurst et\u2009al., et\u2009al., The peptidoglycan sacculus is an inherited structure, with some regions being several generations old. In S.\u2009aureus, orthogonal division leads to \u2018sectoring\u2019 of the cell wall with smaller sectors being generally made of older material (Turner et\u2009al., In Peptidoglycan has been the subject of much controversy over the decades, in some part due to its importance for bacterial life but also because it is the target for some of our most important antibiotics. Advances in understanding have consistently been underpinned by advances in experimentation, such as HPLC and imaging technologies, and further breakthroughs will likely require more technological leaps, most of which will be impossible to foresee!et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., in vivo. AFM and ECT both have demonstrable maximum resolutions far in excess of those which have been achieved in imaging peptidoglycan and further work with these techniques will likely yield more information on the fine structure of peptidoglycan and the way in which strands are arranged to form the larger architectural features, such as \u2018piecrusts\u2019 in S.\u2009aureus and \u2018cables\u2019 in B.\u2009subtilis. Variants of AFM can be used to visualize individual polymer chains in ambient conditions (Mullin and Hobbs, et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., in vivo that most of the direct imaging techniques cannot.There are a small but growing palette of fluorescent probes, which enable us to map moieties within the cell wall or isolated sacculus. An expanded repertoire of probes may allow us to address the biological function of aspects of variation in peptidoglycan across species and within the sacculus. Some probes may be combined with super-resolution imaging techniques such as stochastic optical reconstruction microscopy (STORM, Rust Peptidoglycan architecture on the scale of tens to hundreds of nm varies between species and within an individual cell. In Gram-negative bacteria AFM and ECT provide some level of access to the underlying structure, and while the agreement between the two techniques is not perfect, there are strong indications that peptidoglycan organization is similar in all Gram-negatives examined so far, albeit with some species specific characteristics. However, in Gram-positives there is at present no way of directly visualizing the interior structure of the sacculus. Here, there is great controversy as authors propose radically different models of internal structure based on the shape or surface features of the sacculus images.An overarching model of peptidoglycan covering all bacteria is a very appealing prospect, and we have seen that there are statements that can be made about peptidoglycan that apply to all, or to groups of species. However, when one begins to investigate the detail of peptidoglycan chemistry and architecture, diversity is soon revealed and we must be aware of the dangers of over-generalizing. Much of our current data, particularly on the internal structure of Gram-positive peptidoglycan, is indirect, for example in the form of surface images, or population averages. This sort of information puts constraints on the models we can put forward, but sadly does not make it obvious what our models should be. In this imperfect situation, it is critical proposed models are not over-generalized and take into account all available data.in situ. With this type of data we will begin to connect chemistry with architecture and explain the diversity of features that have been observed, yielding further insights into this polymer, which is so important for bacterial life and, through the action of antibiotics, for human health.New advances in high resolution imaging technology bring forward the possibility of directly visualizing peptidoglycan chemistry"}
{"text": "Brain activity is considered the physical correlate of mental activity. Accordingly, a change of the state of mind implies a change in the state of the brain and vice versa. This homology between brain activity and cognitive tasks is very difficult to measure due to their very high complexity, temporal and spatial dynamics, as well as individual variability. However, the advancing of technology allows the detection of some states of brain activity with reasonable accuracy and their translation into control messages for devices external to the brain . Moreover, studies on neurofeedback (NF) show that individuals can learn to modulate their own brain activity based on external feedback and thereby induce changes in cognition and behavior which can be used as therapy for various mental disorders.aspects of the training protocol such as instructions, task and feedback as well as psychological traits such as motivation, mood, locus of control, and empathy are investigated as determinants of BCI or NF performance. Moreover, the brain generates a large amount of coherent spontaneous activity independently of the BCI or NF task at hand which negatively impacts the reliable detection of brain activity patterns. Thus, the mechanisms and networks involved in gaining and maintaining control over brain activity as well as its prediction are addressed. Finally, as the ultimate goal of our research is to use BCI and NF for communication or control and therapy, respectively, novel applications for individuals with disabilities or disorders are discussed.Interestingly, roughly about one third of people succeed in controlling computerized devices with brain signals right away; one third gains control after training and one third does not achieve useful control even by using state-of-the-art BCI or NF technology. Various factors have been related to the individual success but to date, no general theoretical framework is available. In this Research Topic, the training protocol in BCI and NF. In the hypothesis and theory article of Lotte et al. (The first part of the research topic deals with the role of e et al. , probleme et al.  report te et al.  demonstrpsychological traits on performance are in line with the above presented results. Subramaniam and Vinogradov (The findings addressing the impact of nogradov  discuss nogradov  do not fnogradov  demonstrcontrol of brain activity are important to address. Ninaus et al. (Besides external and internal factors influencing performance, neurophysiological as well as peripheral physiological correlates of gaining and maintaining s et al.  demonstrs et al.  examine s et al.  investigpredict the ability to control a NF or BCI, Halder et al. (To r et al.  performer et al.  show thar et al.  includedapplications for individuals with disabilities or mental disorders. Risetti et al. (The last part covers potential i et al.  present i et al.  propose In summary, this Research Topic illustrates how different factors impact BCI and NF performance and provides new perspectives that need addressing in the future.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Why is it that some parasites cause high levels of host damage (i.e. virulence) whereas others are relatively benign? There are now numerous reviews of virulence evolution in the literature but it is nevertheless still difficult to find a comprehensive treatment of the theory and data on the subject that is easily accessible to non-specialists. Here we attempt to do so by distilling the vast theoretical literature on the topic into a set of relatively few robust predictions. We then provide a comprehensive assessment of the available empirical literature that tests these predictions. Our results show that there have been some notable successes in integrating theory and data but also that theory and empiricism in this field do not \u2018speak\u2019 to each other very well. We offer a few suggestions for how the connection between the two might be improved. The virulence of parasites is shaped by evolutionary trade-offs at different biological scales. At the host population scale, parasites that are able to best monopolize susceptible individuals tend to be most successful. However, the ability of a parasite to monopolize susceptible hosts is intimately tied to its ability to persist within hosts and to spread effectively between them. Therefore success at the host population scale is also tied to success at the scale of physiological interactions within a host  and the duration of infection (\u03bc\u00a0+\u00a0\u03bd\u00a0+\u00a0\u03b3)\u22121  and/or by prolonging the infection . Trade-off theory assumes that a parasite cannot simultaneously increase transmission and prolong infection, and so parasites are attempting to maximize R0 subject to these constraints. Although within-host processes may not be explicitly represented in the models, epidemiological trade-offs are thought to emerge from the dynamics of the within-host interactions between the immune system and parasite.Here, parasite fitness is the product of the rate at which new infections are caused by an infected host  with better water sanitation have lower virulence, perhaps because improving water sanitation reduces the opportunity for environmental transmission, thereby increasing the importance of direct transmission  had reduced environmental persistence (higher rates of inactivation), in apparent contradiction to the general theoretical expectation that more virulent parasites would persist longer in the environment .Note that all theoretical work summarized here assumes parasites are obligate rather than opportunistic. When parasites can grow in both the environment and the host (i.e. opportunistic parasites), none of these conclusions would necessarily hold. The addition of growth in the environment effectively creates another selective arena; thus how virulence should evolve will critically depend upon whether or not there is any linkage between virulence within-host and survival or growth in the environment. For example, empirical work on opportunistic parasites shows that selection for anti-predator adaptations in the environment can lead to decreased within-host virulence  to influence virulence expression in the other (e.g. the host). Thus, on the basis of both theory and data, it is unclear that any simple predictions will hold for vector-borne diseases.Empirical evidence for these predictions is equivocal. Correlational evidence for the hypotheses has been found for some human diseases Ewald, , 1994. AThe simple prediction for parasites that can be transmitted from parent to offspring is that vertical transmission should select for reduced virulence: because the parasite depends on host survival and reproduction for its transmission, virulence that increases mortality or reduces fecundity will be under strong negative selection Ebert, . In realet al.et al. . Mixed . et al.. This isvs horizontal transmission have shown that increasing vertical transmission reduces virulence, whereas increasing horizontal transmission increases virulence  and horizontal transmission Herre, . Studieset al.et al.et al.et al.et al.Classic life history theory predicts that reducing lifespan will increase reproductive effort at earlier ages  than parasites under selection imposed by late host mortality  high mutation rates, this assumption is likely overly restrictive. Moreover, this framework necessarily ignores potential evolutionary changes in virulence that might occur when epidemiology and evolution happen at similar rates. However, a number of authors have studied how virulence evolves during the epidemic, rather than endemic, phase of epidemiological dynamics  phage dominated early in an epidemic, but as prevalence increased, the less virulent  strain won out. One of the strengths of this study was that it was paired with a mathematical model for the system that predicted, a priori, both the qualitative and quantitative dynamics of virulence evolution.Experimental or observational evidence for this prediction is challenging to find, as it requires both that virulence is measured over the course of an epidemic and the ability to rule out alternative explanations for changes in virulence, such as host evolution or parasite evolution in response to other factors, like medical intervention. The classic reference for rapid evolution of virulence is of course the rabbit-et al.et al.et al.et al.et al.The overall consensus from the theoretical literature is that lower virulence will evolve in populations with restricted spatial movement, and higher virulence will evolve in populations with greater connectivity  . VaccinMultiple infection can arise because a host is infected with multiple strains of the same parasite or with multiple species of parasite. Infection with multiple strains of the same parasite can result from separate infection events of co-circulating strains, or because the parasite has a rapid mutation rate and generates strain diversity through mutation within the host. Biologically, distinctions between \u2018types\u2019 of multiple infection matter because they affect the relatedness of the co-infecting parasites and relatedness can influence the optimal virulence strategy for the parasite. For clarity and simplicity, we will use the term \u2018strains\u2019 to refer to the different parasites infecting a host, acknowledging that different \u2018strains\u2019 may actually represent different species of parasite.et al.There have been three primary theoretical frameworks used to study multiple infection. Under a superinfection framework, each host is infected by a single strain at a time, but strains can displace one another based on strain traits, like virulence  strains dominated transmission, and virulence experienced by the host was approximately equal to the virulence induced by the most virulent strain  was positively associated with both within-host competitive ability and transmission success, such that the most virulent strain dominated in mixed-strain infections  Cox, . This tyAlizon and van Baalen  study viet al.et al.et al.How immune-mediated apparent competition should affect virulence evolution is also unclear from an empirical perspective. Some early experiments with rodent malaria suggested that apparent competition might explain why avirulent strains suffer more in competition with virulent strains in immunocompetent mice than in immunocompromised mice  than single-strain infections , whereas low relatedness leads to the persistence of cheater strains and lower virulence  Spatiaet al.Outside of identifying broad and robust theoretical predictions, the purpose of this review was to evaluate the empirical evidence for these predictions. Previous authors have noted that the theoretical and empirical literatures are not easy to reconcile  or integrating into the cell's genome  and the potential for integration to prevent superinfection. They then used these models to predict key features of the evolutionary process and tested those predictions directly, a key advantage of working in bacteria-phage host-parasite systems. However, this approach has been successful in other systems as well: Gandon et al.  to be determined by the dynamics of the within-host model, which captures interactions between parasite strains, the immune system and parasite resources (Mideo et al.et al.et al.et al.et al.et al.et al. (Nested models (.et al.  illustraet al.Another interesting potential avenue for future theory development and theory/data integration is motivated by a consideration of the relative sensitivity of parasite fitness (Frank and Schmid-Hempel, et al.Despite the considerable theoretical literature surrounding virulence evolution, there is still a clear need for general theory in some areas. At the most basic level, almost all of the work summarized here assumed the existence of a trade-off between virulence and transmission. Other potential trade-offs, such as between virulence and recovery (Anderson and May, However, given the challenge of experimentally measuring the quantities implicated by current theory as crucial in shaping virulence evolution, we feel that the onus is on theoreticians to better connect mathematical models with empirical data. This connection could come through developing models of specific systems or by developing general theory that better captures common empirical measures of virulence, such as host morbidity or physiological condition."}
{"text": "We argued this finding is consistent with lexical selection by competition accounts, and might entail additional spread of activation to related concepts that share the non-distinctive feature via the appropriate category node . In their commentary, Montefinese and Vinson . Surprisingly, Montefinese and Vinson chose to cite Nieuwenhuis et al.  and by items (p = 0.003), of moderate to large effect size . It is worth emphasizing planned contrasts are typically conducted whether or not the overall F-test is significant; at least this is the convention according to introductory experimental design and statistics textbooks  were not listed in the McRae et al.'s . We concur with Montefinese et al.  vs. low production frequencies  according to McRae et al.'s  norms. WMini) produced interference when related objects were named at the basic level . Montefinese and Vinson (knee) might \u201cpermit further activation of its name as a potentially plausible alternative to the basic-level target name\u201d .Aside from dominance, another theoretical issue introduced by Montefinese and Vinson  in theird Vinson  speculatwheel). We note the similarity of this proposal with Mahon et al.'s (Montefinese and Vinson do not provide an adequate explanation of the mechanism by which merely raising the lexical activation level of a feature-level distractor representation would make it a plausible response when the instruction is to name the entire target object (e.g., in Hantsch et al.'s level-of-specificity manipulation above, Mini and CAR are appropriate names for a picture of a Mini as they both denote the entire object, unlike et al.'s  responseet al.'s , the reset al.'s  assumptinot significant at both of these SOAs within the same experiment (e.g., La Heij et al., Montefinese and Vinson's  more empAccording to the lexical selection by competition account, semantic interference is the result of a tradeoff between the priming of the target representation by the distractor and the priming of the distractor's lexical representation by the target (e.g., Roelofs, In conclusion, we find none of the theoretical, empirical, or statistical objections raised by Montefinese and Vinson  to be paThis work was supported by Australian Research Council Discovery Project Grants DP1092619 and DP150103997.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "This paper seeks to contribute to the characterization of the relation between osteogenesis and neurogenesis by approaching it from the field of the neurobiology of language and cognition; specifically, from an evolutionary perspective. It is difficult to ascertain how the hominin brain changed to support modern language and cognitive abilities because we can only rely on skull remains. But insights can be gained from fossils because the brain and the skull exhibit a tight relationship. Skull shape and brain shape and connectivity influence one another  to CBL, in turn linked to Noonan syndrome-like disorder, a condition involving facial dysmorphism, a reduced growth, and several cognitive deficits  with RUNX2 and FOXP2 has recently been experimentally demonstrated    and the BMP suite : most of them also interact with RUNX2. Consider, e.g., DLX2. It is involved in craniofacial development (Jeong et al., BMP2 promotes the differentiation of mesenchymal cells into bone cells (Dwivedi et al., Dlx1, Dlx2, Dlx5, and Runx2 (Bustos-Valenzuela et al., BMP2, BMP7 is involved in osteogenesis (Cheng et al., Other bone morphogenetic factors may well play a key role in the emergence of our language-readiness and our globular brain. Among them we wish highlight the DLX suite (particularly, Gli1+ cells within the suture mesenchyme as the main mesenchymal stem cell population for craniofacial bones. Ablation of these Gli1+ cells leads to craniosynostosis, known to be associated with cognitive deficits (Starr et al., Runx2 (Kim et al., Gli1 expression (Schreck et al., Gli1 is the direct response gene of Shh (Liu et al., FoxP2 lies downstream of Shh, as suggested by Scharff and Haesler (We further believe that the genetic aspects highlighted here may contribute not only to gain a better understanding of the way in which both aspects of our modernity emerged and interact, but specifically to tune the crosstalk between the osteogenic and neurogenic stem cell niches. Zhao et al.  have rec Haesler , who obs Haesler . Dysregu Haesler . As a ma Haesler . Most in Haesler  have sho Haesler . The latThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "We make three recommendations to inform the ongoing process of consolidating a key biodiversity areas standard: (i) thresholds for the threatened species criterion currently consider a site's share of a threatened species' population; expand these to include the proportion of the species' genetic diversity unique to a site; (ii) expand criterion for \u2018threatened species' to consider \u2018threatened taxa\u2019 and (iii) expand the centre of endemism criterion to identify as key biodiversity areas those sites holding a threshold proportion of the compositional or phylogenetic diversity of species (within a taxonomic group) whose restricted ranges collectively define a centre of endemism. We also recommend consideration of occurrence of EDGE species (i.e. threatened phylogenetic diversity) in key biodiversity areas to prioritize species-specific conservation actions among sites.\u2018Key biodiversity areas' are defined as sites contributing significantly to the global persistence of biodiversity. The identification of these sites builds from existing approaches based on measures of species and ecosystem diversity and process. Here, we therefore build from the work of Sgr\u00f3  Given tIn response to this demand, numerous systems have been developed for identifying important sites for biodiversity for different taxonomic groups, different ecosystems, and different countries and regions. The earliest such efforts were initiated by what is now the BirdLife International partnership, which developed standards for the identification of Important Bird Areas in the late 1970s , and hasHowever, while these taxon-, ecosystem- and theme-specific approaches to the identification of important sites have delivered substantial benefits by providing information on where site safeguard can make the greatest contributions towards reducing the rate of biodiversity loss , the proOver the last decade, the IUCN Species Survival Commission and World Commission on Protected Areas have been jointly leading this process. Building from an initial scientific paper , construOne implication of this definition is that it considers biodiversity comprehensively, in contrast to the focus of existing approaches on specific taxa or ecosystems. Thus, a challenge for the process of consolidating a global standard for the identification of key biodiversity areas has been to ensure that the criteria for site identification span scales and components of ecological organization. Noss  derived Here, we develop a general framework and three specific recommendations on how the process of consolidating a global standard for the identification of key biodiversity areas might address components of biodiversity below the species level, for consideration in the review of the draft standard. These include genetic diversity within species, phylogenetic diversity among species and the evolutionary processes which drive and maintain both of these . This pa2.et al. [The many ways in which biodiversity below the species level could be addressed in the key biodiversity area criteria can be organized through the framework presented by Sgr\u00f2 et al. , originaet al.  and Gastet al.  definitiet al. [per se. To \u2018increase connectedness and gene flow across environmental gradients' generally requires planning and action at the levels of entire landscapes or seascapes\u2014beyond individual sites. This is the case even where environmental gradients are very sharp , and certainly where they are represented by broad ecotones. For example, Smith et al. [Andropadus virens populations in tropical forest and those in forest-savannah, compared with low divergence (for the same level of gene flow) between tropical forest sites and between forest-savannah sites. There is some counter-evidence against this: Henry et al. [Ochotona princeps in British Colombia. In any case, the location of given key biodiversity areas along environmental gradients will be relevant in prioritizing their conservation and connectedness, where these are important for the persistence of the biodiversity feature triggering the site's identification [The relevance of the last two elements of the Sgr\u00f2 et al.  frameworh et al.  found hiy et al.  found lofication .a priori to the identification of key biodiversity areas. However, translocation (or reintroduction or restoration) could trigger the identification of new key biodiversity areas, if, as, and when such actions are successful enough to trigger the criteria for a new site in their own right [Meanwhile, given that key biodiversity areas are sites contributing significantly to the persistence of biodiversity features which they currently hold, to \u2018increase adaptability to future environments by translocation\u2019  is not relevant wn right .et al.'s [We also considered whether there might be any aims for incorporation of biodiversity below the species level in informing decision-making more broadly which were not proposed in Sgr\u00f2 et al.'s  frameworWe discuss each of the elements in turn, seeking to develop practical recommendations of how consolidating a global standard for the identification of key biodiversity areas might address components of biodiversity below the species level. In each case, we strive to strike a balance in how demanding we are of genetic and phylogenetic data availability. Thus, on the one hand, our proposals should be robust enough to be applied today in conditions of relatively sparse data availability, while on the other hand, they should be unlikely to destabilize site identification (e.g. through identification of orders of magnitude more sites), if, as, and when data volumes increase into the future.3.et al.'s [The first component of Sgr\u00f2 et al.'s  frameworet al.'s \u201327 and tet al.'s . This iset al.'s , assessiet al.'s \u201332.Given this, an argument can be constructed for ensuring that the criterion for presence of threshold populations of a threatened species triggering key biodiversity area identification be extended to also consider \u2018threatened genetic diversity\u2019. Thus, for criteria structured in the form of \u2018at least X% of the global population of a threatened species occur at a site\u2019, this population metric could be supplemented by one of \u2018X% genetic diversity of a threatened species being unique to the site\u2019. This would ensure that sites holding a disproportionately high genetic diversity of a threatened species triggered key biodiversity area identification, even if the population of the species at the site was relatively small and insufficient to trigger site identification in its own right. The use of a subcriterion requiring the presence of a threshold population of \u2018functional reproductive units' at the site would ensure that this extension does not trigger identification of sites holding tiny, unviable populations.Recommendation no. 1. Thresholds for the threatened species criterion currently consider a site's share of a threatened species' population; expand these to include the proportion of the species' genetic diversity unique to a site.et al. [et al. [et al. [While this recommendation would ensure that key biodiversity areas are indeed sites contributing significantly to the persistence of genetic diversity overall, these sites may be very different from those where genetic diversity contributes significantly to the evolution or persistence of the species in question. Thus, Petit et al. , for exa [et al.  found si [et al.  to human [et al. , is neut [et al. . Althoug [et al. , we cann [et al. . Sgr\u00f2 et [et al.  recognizThe general approach to addressing adaptive variation in practice has been to incorporate it into the definition of evolutionary significant units \u201342. The In the meantime, a rule of thumb for incorporating adaptive genetic diversity into the identification of key biodiversity areas could be simply to broaden the scope of the threatened species criterion to consider \u2018threatened taxa\u2019, as long as these are globally relevant. The IUCN Red List of Threatened Species , which pRecommendation no. 2. Expand criterion for \u2018threatened species' to consider \u2018threatened taxa\u2019.Lupinus in the Andes [Laupala crickets in Hawaii [While such a recommendation would in effect allow this criterion to support the conditions for future diversification, it is not framed as such given the very slow rate of macro-evolution relative to anthropogenic land-use impacts. The fastest documented rates of speciation are for he Andes , Laupalan Hawaii , and forn Hawaii . However4.et al.'s [The fourth component of Sgr\u00f2 et al.'s  frameworet al.'s \u201357.The last two decades have seen substantial advances in the compilation of phylogenies from molecular and other types of data, and their calibration to derive trees that incorporate time into their branch lengths using molecular clock approaches . These het al. [2, corresponding to the 25th percentile of the range-size distribution in the class Aves, and a minimum of two species to define an Endemic Bird Area; and (iii) the definition of the proportion of these restricted-range species necessary to confirm the site's identification as a key biodiversity area.The general form for key biodiversity area criteria for centres of endemism can be expressed as requiring that a site holds \u2018at least X% of the species within a taxonomic group whose restricted ranges collectively define a centre of endemism\u2019. This criterion encompasses three operational components: (i) the definition of the taxonomic group for consideration ; (ii) the definition of a maximum range size for species whose overlapping ranges can define a \u2018centre of endemism\u2019\u2014Stattersfield et al.  used 50 The second and third of these components could be extended to consider evolutionary refugia based on a site's complement of the phylogenetic diversity restricted to the centre of endemism . Such anRecommendation no. 3. Expand the centre of endemism criterion to identify as key biodiversity areas those sites holding a threshold proportion of the compositional or phylogenetic diversity of species (within a taxonomic group) whose restricted ranges collectively define a centre of endemism.5.While the definition of key biodiversity areas recommended by the framing workshop establishes them as important sites for biodiversity, this does not imply any particular kind of conservation management action upon them . This said, knowledge of where key biodiversity areas are and what biodiversity features trigger them is used by many different sectors of society for many different kinds of applications. These include conservation actions; the science of optimal allocation of resources for such conservation actions is known as systematic conservation planning ,71. MostBearing this in mind, one aspect of evolutionary history notable by its absence from the four recommendations above is the incorporation of the phylogenetic diversity unique to a species  into thet al. [et al. [Safi et al.  combinedet al.  proposes [et al.  and comb [et al.  and thre [et al. .Recommendation no. 4. Consider occurrence of species making the greatest contributions to maintaining phylogenetic diversity (i.e. EDGE species) in key biodiversity areas to inform prioritization of species-specific conservation actions among sites.6.The initial discussions of the IUCN Species Survival Commission and World Commission on Protected Areas process considered establishment of a new subcriterion for triggering key biodiversity area identification for sites contributing significantly to the global persistence of biodiversity through their importance in maintaining outstanding evolutionary process, possibly to sit alongside the criteria for outstanding ecological process (e.g. species congregations and aggregations). However, in subsequent deliberations, it proved impossible to establish a mechanism by which such a criterion could be put into operation. One possible final recommendation would therefore be to establish a non-operational criterion for sites of global significance for evolutionary process and leave the operationalization of this as a priority for future research.et al. [On reflection, the development of such a criterion appears to be unnecessary in any case. Our three recommendations for incorporation of components of biodiversity below the species level into existing key biodiversity area criteria appear to span aspects of composition, structure and function of genetic diversity, and also the breadth of mechanisms for putting this into practice proposed by Sgr\u00f2 et al. . Much wo"}
{"text": "For example, action potential duration  are circumferentially arranged (Streeter et al., The importance of the findings reported by Kindo et al.  reinforcThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "To the Editor: We read with interest the discussion between de Steenwinkel et al. and Werngren  generation and selection of resistant mutants. Thus, the frequency of 10\u20133 resistant CFUs selected on rifampin may represent not the frequency of preexisting mutants but rather frequency of mutants generated by a population of persisting (stressed) cells during exposure to low levels of antimicrobial drugs. We investigated the effect of transient exposure to rifampin on colony growth rate and post\u2013antimicrobial drug outgrowth on a panel of Beijing and non-Beijing M. tuberculosis strains, including some studied in the work of Steenwinkel et al.  and in-house software  was almost completely inhibited during the first 24 hours after rifampin exposure. In contrast, all the Beijing genotype strains studied showed residual growth in most colonies in the first 24 hours after rifampin exposure. At 1\u20135 days postexposure, the pattern remained the same; the Beijing strain colonies were more capable of persisting and exhibited slow but sustained growth after exposure to low concentrations of rifampin. To confirm that this effect was a result of persistence rather than generation of resistant mutants, we transferred the colonies growing after transient rifampin exposure of Beijing strain 1585 to a medium containing 8 mg/L rifampin. Their growth was completely inhibited, and molecular analysis did not detect any of the most prevalent rifampin resistance\u2013associated mutants (data not shown).rpoB gene mutants have shown to exhibit a stringent-like response  mutation frequency reported by de Steenwinkel et al. (M. tuberculosis strain mutation frequency reported by de Steenwinkel et al. (In summary, our data show that the high apparent"}
{"text": "Harmful Algal Blooms (HABs) affect the quality of fresh and marine waters and adversely affect both animals and humans. Public health risks include exposure to toxins through consumption of contaminated drinking water and fish and shellfish, and by recreating on or in contaminated waters. Federal and State professionals and researchers contributed to this Special Issue on HABs and Public Health with research papers and reviews on various aspects of public health including the occurrence and fate of toxins in the environment, monitoring efforts in freshwater and marine water systems, human health risk assessment, effectiveness of treatment techniques, and guideline development. et al. [et al. [et al. [et al. [et al. [et al. [Understanding the processes cyanobacteria and their toxins undergo in the environment is considered in the papers by Schmidt et al. , Fadel e [et al. , and Son [et al. . Schmidt [et al.  discusse [et al. . The aut [et al. . MicrocyHABs have an adverse impact in recreational waters by fouling beaches and shoreline, affecting the quality of the water, and limiting recreational activities such as fishing, swimming, and boating. The adverse effect of the occurrence of both marine and freshwater toxic algal blooms in recreational waters in Washington State was discussed by Trainer and Hardy , with a et al. [HABs also could be present in drinking water and could potentially affect drinking water treatment. Taste-and-odor problems have led some utilities to change processes during the drinking-water treatment to decrease tastes and odors in finished drinking water caused by algal blooms in the supply reservoir. Another problem is the presence of cyanobacterial cells and toxins in finished drinking water. In the paper by Szlag et al. , the autet al. [et al. [Human health risks from exposure to HABs is another topic discussed in this special issue. The paper by Hilborn and Beasley  used haret al. , with a  [et al. . In thiset al. [et al. [et al. [et al., and proved to be ineffective at low levels. However, although a reduction of toxins was observed, still a significant release of the toxins into the water was detected. Ultrasound treatment only caused minimal growth inhibition and some release of toxins into the water, showing the treatment to be ineffective at controlling cyanobacteria. In these proposals, toxin reducing bacterial strains are used in water reservoirs as another option that may help in the reduction of microcystins occurrence. The use of bioreactors to eliminate microcystins is suggested by Dziga et al. [Numerous techniques already exist for managing blooms in reservoirs. However, the effectiveness of these techniques is relative. For example, Bauza et al.  exposed  [et al. , the pap [et al.  also evaa et al.  as an alet al. [This special issue also includes a paper describing the development of guideline values for cyanotoxins in the state of Oregon. In the United States, drinking water contaminants are regulated under the Safe Drinking Water Act (SDWA). Currently, there are no regulations for cyanotoxins in drinking water under the SDWA, but EPA developed in June 2015, Health Advisories (HAs) for the cyanotoxins microcystins and cylindrospermopsin, to assist federal, state and local officials in protecting public health from exposure to these two toxins in drinking water systems. Regulations or guidelines have not been developed either for aquatic life, aesthetics, or recreation in any body of water under the Clean Water Act (CWA). In the absence of these guidelines, many US States, including Oregon  have dePublic health professionals have taken measures to protect public health by assessing and monitoring HABs occurrence and health effects, developing guidelines and HAB-related public health programs, and implementing remediation and treatment technologies. Despite these efforts, it is reasonable to say that the factors that promote HABs and their toxin production, the health impacts, and the fate of these blooms and their toxins in the environment is not totally understood. The different studies published in this special issue recognized these knowledge gaps including the spatial variability among cyanobacteria and their toxins in water and sediments, the complexity of monitoring and inconsistency in treatment techniques, and the importance of the development of guidelines for the protection of public health."}
{"text": "Brunner et al.  showed aIn contrast with the study of Brunner et al., HMA is most often exogenously induced by too liberal infusion of chloride-containing intravenous fluids for hydration and resuscitation purposes . HMA ind"}
{"text": "Pulmonary hypertension (PH) is a progressive and devastating disease of various causes that is associated with structural and functional disorder and inappropriately increased pressure of pulmonary small- to medium-sized vasculature. Extensive pulmonary vascular remodeling with narrowing lumen is well characterized in all forms of PH, which is hemodynamically defined by a mean pulmonary artery pressure exceeding 25 mmHg at rest  and mesenchymal \u03b1-SMA markers. Combined with this analysis result, the protein and mRNA expression patterns consolidate the notion of a key role of EndMT in PH pathology (Ranchoux et al., in vivo EndMT characteristics in these mouse models are comparable to those in human PH tissues. Excitingly, partial rescue of EndMT-related gene expression and phenotypes has been achieved by rapamycin (Ranchoux et al., Writing in The headline finding of these two studies is that the concept of\u00a0EndMT in PH has been initially proposed on the\u00a0basis of compelling experimental proofs (Good et al.,"}
{"text": "The understanding of the neural basis of limb apraxia (deficits in performing previously learned skilled movements) has benefited greatly from cognitive research on gesture processing and recognition, but the influence of this research on the treatment of apraxia is limited (Cantagallo et al., Apraxia typically results from left-brain lesions but impairs movements in both upper limbs equally. This is because disturbances affect the conceptual formulation of the movement rather than their executive ability Frey, . ResearcThis converges with results from the recent literature on the cognitive rehabilitation of limb apraxia (for reviews, see Buxbaum et al., Priming refers to a change in the nervous system triggered by prior exposure to a stimulus, which guides the order of activation in a given neural network according to previous experience (Pachalska et al., At a basic level, the common effects of RVF priming for both gestures, consistent with recent findings with fMRI (Kr\u00f3liczak and Frey, What do these results suggest for rehabilitation? First, more attention should be paid to the interdependence between motor and language functions when dealing with apraxic patients. \u201cIntersystemic gestural reorganization\u201d Luria, , a methoAdditionally, the deficits that apraxic patients often exhibit in gestural communication (Borod et al., Second, the differential effects found by Helon and Kroliczak  for tranThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Escherichia coli together with the use of non-optimal cloning vectors for the construction of metagenomic libraries generally results in an extremely low success rate for enzyme identification. The bottleneck arising from inefficient screening of enzymatic activities has been addressed from several perspectives; however, the limitations related to biased expression in heterologous hosts cannot be overcome by using a single approach, but rather requires the synergetic implementation of multiple methodologies. Here, we review some of the principal constraints regarding the discovery of new enzymes in metagenomic libraries and discuss how these might be resolved by using synthetic biology methods.There is a growing demand for enzymes with improved catalytic performance or tolerance to process-specific parameters, and biotechnology plays a crucial role in the development of biocatalysts for use in industry, agriculture, medicine and energy generation. Metagenomics takes advantage of the wealth of genetic and biochemical diversity present in the genomes of microorganisms found in environmental samples, and provides a set of new technologies directed towards screening for new catalytic activities from environmental samples with potential biotechnology applications. However, biased and low level of expression of heterologous proteins in  In the industrial context, many manufacturing processes that previously depended strictly on complex (and frequently harmful) chemical reactions have been superseded by much simpler and safer enzyme-based catalysis , then 4\u2009\u00d7\u2009108 potential proteins might be expected in just 1\u2009g of soil. Supposing that 40% of these proteins display catalytic activity  while still allowing growth of this organism. Alternatively, screening could be performed without subjecting the host to any selective pressure, for example in cases where the host organism is used to clone total metagenomic DNA and the screening is performed under regular growth conditions. In both cases, after the initial identification of the enzymes, characterization of the desired catalytic properties of the source clones can be made with crude culture extracts and selected enzymes may then be purified for a more detailed characterization. For instance, a novel alkaliphilic esterase active at 7\u00b0C was identified by screening a metagenomic library from Antarctic desert soil , which was probably a consequence of the expression of the correctly folded enzymes in E.\u2009coli. No cellobiohydrolases active against crystalline cellulose substrates have as yet been isolated from metagenomic libraries  (Cambray E.\u2009coli, several attempts have been focused on the use of alternative hosts to increase the rate of enzyme identification in metagenomic screening (Craig et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., In addition to genetic engineering of the more common hosts such as et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., in vivo strategy that has been used to identify specific enzymatic activities using engineered regulatory circuits coupled to a reporter gene, such as lacZ, green fluorescent protein or luciferase (Mohn et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., Currently available methods that are used to screen for new catalytic activities in metagenomic libraries frequently rely either on the use of chromogenic enzyme substrates (Hu in vitro evolution and rational design techniques for the improvement of their catalytic properties. However, the diversity of proteins identified using this strategy is restricted, the methods are time-consuming, costly and in the case of in vitro evolution, it is impossible to test all variants (Sommer et\u2009al., Classic approaches for isolating industrial enzymes involve their identification from cultured microorganisms, and more recently, this strategy has been expanded to include None declared."}
{"text": "Saccharomyces cerevisiae, which couples a wide array of technical advantages with a high degree of genetic, proteomic and mechanistic conservation. Indeed, this unicellular organism harbours regulatory pathways, such as those related to programmed cell death or nutrient signalling, that are crucial for ageing control and are reminiscent of other eukaryotes, including mammals. Here, we summarize and discuss three different paradigms of yeast ageing: replicative, chronological and colony ageing. We address their physiological relevance as well as the specific and common characteristics and regulators involved, providing an overview of the network underlying ageing in one of the most important eukaryotic model organisms.The identification and characterization of the molecular determinants governing ageing represents the key to counteracting age-related diseases and eventually prolonging our health span. A large number of fundamental insights into the ageing process have been provided by research into the budding yeast  Saccharomyces cerevisiae undergoes programmed cell death (PCD) with characteristic apoptotic changes initiated a new and exciting research field  or mating (haploid cells) guarantees genetic variation and consequently provides an adaptive advantage to the population. Upon failure of either one of these processes, triggering PCD cleans the population from infertile or damaged cells, thus ensuring fitness and survival. In this line, haploid cells undergo PCD upon long-term exposure to pheromones without subsequent mating  and an unusual form of autophagy that resembles PCD-associated mega-autophagy in plants. Besides these roles during sexual and asexual reproduction, additional physiological scenarios associated with PCD in yeast have been described, among which ageing has drawn most attention in the course of the last decade. Mostly, ageing is defined as the progressive loss of function in all constituents of living cells, leading to a decrease in both survival rate and reproductive capability. Several theories have been developed to explain the complex process of ageing, all of which are partly interrelated and mainly cluster into two categories, namely (a) the damage or error theories and (b) the programmed theories. The first group of theories, such as the \u2018free radical theory\u2019 or the \u2018somatic DNA damage theory\u2019, assumes environmental insults and subsequent accumulating damage as causative for ageing. In contrast, programmed theories, such as the \u2018programmed longevity theory\u2019, assume that ageing follows a biological clock and that lifespan and death are genetically programmed. To date, no consensus exists on the issue why organisms age.However, while multicellularity clearly benefits from, and even requires, controlled cellular demise to ensure normal development, tissue homeostasis and regulation and function of the immune system, the reason for the existence of PCD in unicellular organisms seems paradoxal at first, since death provides no advantage for an individual cell. If so, though, natural selection should have worked against the capability of unicellular organisms to undergo programmed suicide. Nevertheless, this trait was sustained throughout evolution, indicating an integral benefit even for single-celled species. In this case, it appears to serve the survival of a clonal population and raises the concept of \u2018altruistic\u2019 unicellular behaviour. As microbial life in natural habitats mainly occurs in clustered, social communities such as colonies and biofilms, which enable the cells to cope with ecological stresses and to efficiently adapt to a constantly changing environment, the death of an individual cell might be subsidiary to the survival of the \u2018multicellular\u2019 community. For et al., Yeast has become the leading model organism for the study of genetic and mechanistic factors that affect human ageing and disease. The pathways and downstream factors identified to govern yeast senescence seem to be conserved to a large degree in higher eukaryotes and have been instrumental in deciphering ageing modulators in major model organisms up to the mouse , phosphatidylserine externalization and DNA fragmentation , which are retained by the mother cell upon division. Whether the resulting shortened lifespan is due to ERCs themselves or rather to rDNA instability in general remains a matter of discussion. At least two players seem to be involved: the sirtuin Sir2p that suppresses, and the nucleolar protein Fob1p that promotes, homologous recombination in the rDNA. Accordingly, deletion of et al., et al., et al., et al., et al., et al., et al., The modulation of growth, metabolism and stress resistance through the nutrient-responsive Ras\u2013PKA and TOR\u2013Sch9 pathways is intimately connected to the regulation of replicative ageing: mutations or regimens  that compromise Ras\u2013PKA or TOR\u2013Sch9 signalling extend replicative lifespan  but has no effect on chronological lifespan under standard conditions, or even extends it under caloric restriction  stimulates the protein kinase Rim15p, which in turn promotes the activation of the stress-response transcription factors Msn2/4p and Gis1p, finally resulting in extended chronological lifespan (Pedruzzi et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., The complex nature of chronological ageing is mirrored by its manifold downstream effects, among them mutagenesis and replication stress (Fabrizio S. cerevisiae in its natural habitat mainly happens in the form of colony formation on solid surfaces, such as fruits and vegetables, a life style that hardly resembles the growth in liquid medium common in laboratory conditions. The growth of a single yeast colony can be divided into a phase of rapid growth, in which the cells genetically and biochemically largely resemble cells dividing in liquid culture, and a subsequent phase of slower growth, in which the colony starts to diversify. Cells at the colony periphery proliferate, while the cells in the colony centre enter stationary phase (Meunier and Choder, et al., et al., et al., et al., et al., The proliferation and ageing of et al., WHI2 (Leadsham et al., In the colony centre, the metabolism remains mostly unaltered. Cells exhibit accumulating oxidative stress and undergo PCD with typical apoptotic markers (V\u00e1chov\u00e1 and Palkov\u00e1, et al., tor1, \u0394sch9 and \u0394ras2 during chronological ageing in liquid culture, suggesting that these might represent typical traits for longevity. Highlighting the impact of mitochondrial respiration on colony development, respiratory deficiency has been shown to suppress the accumulation of ROS and apoptosis in yeast colonies (Ruckenstuhl et al., et al., Besides the differentiation into central and outer cellular sectors, the aged cells in the centre form two distinct subpopulations, starting after about 7\u2009days. Within the upper region, cells exhibit high stress resistance and an extended lifespan, while cells in the lower layers are sensitive to stress and die fast (C\u00e1p et al., et al., et al., Yeast ageing is a complex process involving multiple pathways that are engaged as a response to the manifold physiological situations encountered in nature. As a general phenomenon on which all ageing subtypes converge, PCD seems to be the physiological event that, by regulating cellular lifespan, controls population dynamics. By this altruistic death of single cells that eliminates damaged individuals, the clonal community ensures the possibility of adapting to the changing environment, thus promoting its long-term survival. This suggests that ageing might, at least to some extent, hold programmatic features as an adaptive response to cope with ever rearranging and challenging conditions. Necessarily, this idea leads to controversial group selection theories (Blagosklonny, Importantly, the environmental conditions dictate whether either proliferation, stationary behaviour or colony formation and differentiation is sustained, thus defining the distinct ageing paradigms. Thus, some regulatory and executing elements do not overlap while others do Figure\u2009. For exaet al., Besides the ageing subtypes observed under laboratory conditions, there might be more and/or their relevance might be relative in the wild. For instance, the apoptotic death of replicatively old mother cells, which do only represent a very minor percentage of the population, can hardly contribute to the fitness of a clone. As old mothers are very scarce, their death neither spares nor releases notable nutrients. Thus, the apoptotic death of replicatively old mother cells most probably does not represent an adaptive trait, but might solely represent the consequence of accumulating cellular damage. Under natural conditions, the portion of cells achieving a replicatively old status is probably even lower. In stationary phase, the biggest fraction will rather be composed of virgin cells, or cells that have undergone several divisions only. However, physiological changes related to replicative ageing that affect, for example, certain cellular stress resistances already occur after only four or five divisions (Sorokin"}
{"text": "NTR), that is required for hippocampal long-term depression  is a neurotrophic protein that is strongly expressed in the Central Nervous System (CNS) and supports neuronal growth and survival , might be an optimal tool to investigate the role of BDNF polymorphism in activity-dependent plasticity , unbalanced analysis might have affected statistical sensitivity (Hector et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "A critical issue in the field of time perception is whether or not explicit judgments about time are processed by some internal clock mechanism. A subsequent issue is whether or not this clock, if any, is central . There are several ways of marking time, including the use of signals delivered from different sensory modalities. In other words, do we have sensory specific representations of time, or is there an amodal\u2014central\u2014mechanism Bueti, ? This fuThe interest for the effect of modalities on perceived duration and sensitivity to time has grown recently. Researchers have reported that intervals marked by auditory signals are perceived as longer than time intervals marked by visual signals  reached with intermodal conditions. The recent data reported by Mayer et al.  are alsoThe stability of the Weber fraction over time reported by Mayer et al.  is a bitper se, but in the comparison of intra- and intermodal intervals. It is well-established that the discrimination of time intervals is much easier with auditory than with visual markers  over the primary auditory cortex, Kanai et al.  observedNote however that for intervals lasting 1.6 s, the large difference between the threshold value in AA and AV conditions is washed out when an explicit count of numbers is used for completing the task (Grondin et al., Recent EEG data, and more specifically the amplitude of the contingent negative variations recorded at fronto-central electrodes, revealed a basic difference between the AA condition and other modality conditions (Gontier et al., In brief, the different perceived durations and discrimination levels observed in the different intra- and intermodal conditions is a challenge for the single-clock hypothesis. An interpretation based only on sensory latencies (Mayer et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "C. elegans  which has been utilized to block exclusively gliotransmission -CA1 pyramidal neuron (excitatory) synapses. During repetitive or tetanic stimulation of SC, astrocytes showed short-term depression of cytosolic Ca2+ signals associated with a simultaneous short-term potentiation at SC-CA1 synapses. Moreover, chelation of Ca2+ in astrocytes resulted in enhanced synaptic transmission and short-term plasticity at SC-CA1 synapses. This finding adds to a growing body of evidence that astrocytes are critical for certain types of synaptic plasticity  conditional knockout mouse line that a battery of behavioral assessments  failed to reveal any behavioral deficits. The above studies are reviewed by Xie et al. (in vivo.Following up on work that proposed that Gq protein-coupled receptor Cae et al. , who als2+ increases that could bypass downstream signaling cascades, and which result in non-specific modulation of astrocyte function (Wang et al., Although optogenetics has proven to be clearly advantageous for studying neuronal correlates of behavior and functional connectivity in the brain (Friedman et al., What are the current obstacles that need to be overcome to advance the field? Jahn et al. , Xie et The goal of this Research Topic has been to summarize our most recent understanding of glial cells in the regulation of plasticity of neural circuits. It is abundantly clear that genetic approaches have been instrumental in elucidating the role of glia in plasticity and behavior and that outstanding issues are likely to be resolved in the near future with novel genetic tools. Thus, exciting times lie ahead for the study of astrocytes in the dish and the behaving brain.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "First, some dicotyledonous species  and other commelinid families consist of high silica accumulators in which silicification patterns and roles are highly consistent. The effects of water availability  is a dicotyledonous family of high silica accumulators, but given there are dissimilarities in silicification mechanisms, patterns and roles between the two families it is likely that high levels of silicon accumulation evolved independently in this family (e.g., Mitani and Ma, It is clear that some groups, such as the grasses, commelinids and some aquatic macrophytes (Schoelynck et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "In August 23 , The LanWe would like to thank all contributors for their valuable work helping us to present wide-ranged aspects in the field. Currently we know that a physical barrier due to the formation of tight junctions in cerebrovascular endothelial cells is the main component of the BBB. In this Research Topic, the implication of astrocyte functions in the protection of the BBB was reviewed (Cabezas et al., in vitro stroke model of the BBB was used to investigate how oxygen/glucose deprivation can affect tight junction proteins, as well as the expression of ABC-transporters (Neuhaus et al., Currently we know that the BBB is more than a physical barrier. Several drug- and xenobiotic-metabolizing enzymes are expressed in endothelial and glial cells, constituting a metabolic barrier. The expression of xenobiotic metabolizing enzymes in the BBB was discussed (Ag\u00fandez et al., It seems that there is also an antioxidant barrier, which protects the central nervous system against the oxidative stress. The endogenous protection against reactive oxygen species can occur through the increased expression of mitochondrial enzymes in astrocytes (Cabezas et al., N. caninum was evaluated (Jesus et al., Cells involved in the BBB can establish immune communications. Interactions between the microglia and the vascular system (Fonseca et al., The connection between the BBB and pain was reviewed, focusing on cellular and molecular mechanisms of BBB permeability induced by inflammatory or neuropathic pain and migraine (DosSantos et al., A century after the work of Goldmann, who contributed to the discovery of the BBB, several questions remains without answers. However, it is already known that BBB is far more than a physical barrier. Endothelial and glial cells also exert metabolic, antioxidant and immunological activities. It seems of great importance to understand the role of BBB in neurodegenerative diseases. Compounds that could show an ability to repair BBB injury, to suppress neuroinflammation and to provide neuroprotection remain to be discovered. The role of microglia and macrophages in the BBB needs to be better understood, if we want to design effective therapies against neuroinflammation. Efforts to discover strategies that could protect neurons in ischemic events continue to defy neuroscientists. Advances in biochemistry, molecular biology, and genetics will improve our knowledge about the BBB in the next 100 years.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Dear Editor,We read with great interest the recent article by Farzanegan et al. regarding the effect of lumbar discectomy on disability and depression in patients with chronic low back pain . Pain an"}
{"text": "Here, we review studies supporting the concept that telomeres are important cellular structures whose function not only is to count cell divisions, but also to act as molecular switches that can rapidly stop cell cycle progression permanently in response to a variety of stresses, including oncogenic signals.Telomeres, the ends of our linear chromosomes, can function as \u2018replicometers\u2019, capable of counting cell division cycles as they progressively erode with every round of DNA replication. Once they are critically short, telomeres become dysfunctional and consequently activate a proliferative arrest called replicative senescence. For many years, telomeres were thought to be autonomous structures, largely isolated from cell intrinsic and extrinsic signals, whose function is to prevent limitless cellular proliferation, a characteristic of most cancer cells. It is becoming increasingly evident, however, that telomeres not only count cell divisions, but also function as sensors of genotoxic stresses to stop cell cycle progression prematurely and long before cells would have entered replicative senescence. This stable growth arrest, triggered by dysfunctional telomeres that are not necessarily critically short, likely evolved as a tumor-suppressing mechanism as it prevents proliferation of cells that are at risk for acquiring potentially hazardous and transforming mutations both  The most common and deadly of these diseases is cancer. To counteract the development of cancer, these organisms developed a number of cell extrinsic and intrinsic tumor-suppressing mechanisms one of which is cellular senescence, a proliferative arrest that forces cells to exit the cell division cycle permanently. In cultured mammalian cells, senescence is activated in response to a number of signals including critical telomere erosion, oncogene activation, loss of tumor-suppressing pathways, as well as numerous cell extrinsic stresses  can be detected in cells of inactive and benign human neoplasms, suggesting a role for DNA damage checkpoints in initiating and stabilizing this proliferative arrest. Recent data suggest that the DDR primarily initiates at telomeres, revealing a potentially critical role for dysfunctional telomeres in suppressing cancer growth in humans. In the following sections, we will review our current understanding of cellular senescence induced by a variety of stimuli and stresses that affect telomere length and structure, as well as summarize studies that shed light into the likely causes for telomere dysfunction and cellular senescence in cells of inactive and benign human tumors.Cellular senescence was first described in the early 1960\u2019s by L. Hayflick, who observed that somatic human cells do not have the ability to divide indefinitely , cellular senescence can certainly be activated in the absence of any apparent telomere damage. Some cultured cell strains, for example, undergo cellular senescence without critical telomere erosion, visible DNA damage, or p53 activation. Instead, they initiate cellular senescence by upregulation of the Cdk inhibitor p16et al., et al., Activating mutations in certain proto-oncogenes can also lead to a permanent proliferative arrest called oncogene-induced senescence (OIS). Depending on the cell type, strength, and duration of the oncogenic signal, oncogenes induce cellular senescence through multiple and distinct pathways (Courtois-Cox et al., in vivo biological response of human cells encountering oncogenic signaling imbalances (Croce, First direct evidence that OIS can function as a tumor-suppressing mechanism in mouse model systems was published almost a decade ago and has since been verified in numerous other studies (Collado & Serrano, s Croce, . With fes Croce, .et al., et al., et al., et al., et al., et al., et al., et al., Precisely, how oncogenes cause DNA replication stress and DSBs is still not entirely clear. Cells expressing oncogenic H-Ras show signs of DNA hyper-replication, such as increased numbers of active replication origins as well as origins that appear to have initiated replication more than once per cell cycle (Di Micco Common fragile sites are chromosomal loci that exhibit discontinuities, such as gaps and breaks, when viewed on metaphase chromosomes. Cells cultured under conditions that cause DNA replication stress, such as incubation with the DNA polymerase inhibitor aphidicolin, display an increased number of these chromosomal abnormalities, revealing that CFS are generated while cells replicate DNA. Functional disruption of kinases ATR and Chk1, which function to signal a stalled replication fork, as well as deficiency in recombination factors Rad51, BRCA1, and BLM, that act during the recovery of a stalled replication fork, enhances CFS expression, which is consistent with the model that CFS are generated as a result of DNA replication fork stalling. Significantly, CFS are not randomly distributed on chromosomes. Rather, they appear at a limited number of discrete loci indicating that specific features inherent to CFS sequences present a challenge to the replication machinery. Indeed, CFS often contain sequences that are prone to forming secondary structures and therefore act as a natural barrier to replication fork progression (Durkin & Glover, et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., In recent years, it has become evident that CFS are much more abundant than previously thought. With the discovery that telomeres share many features of CFS, including the appearance of telomeric discontinuities on metaphase chromosomes following exposure to replication stresses (Martinez et al., et al., et al., et al., et al., et al., et al., Why telomeres impede replication fork progression is still subject to investigation. Repetitive DNA sequences, in general, are known to challenge efficient and accurate DNA replication. This is primarily due to an increased abundance of hairpin secondary structures, due to polymerase slippage, or primer template misalignments (Voineagu et al., et al., in vitro and in vivo (Fumagalli et al., et al., et al., Failure to restart DNA synthesis at stalled replication forks, telomeric or nontelomeric, generates DSBs, and consequently DDR foci, near the stalled fork and causes cells to arrest the cell division cycle (Jossen & Bermejo, Why should telomeres be resistant to DNA repair activities? Linear DNA molecules are inherently unstable and either rapidly become degraded or fused to other exposed DNA ends by cellular DNA repair mechanisms to suppress DDR signaling. One critical function of our chromosome ends, therefore, is to suppress chromosome degradation and prevent end fusions with telomeres of sister chromatids, or with telomeres of other chromosomes. One mechanism that this could be accomplished is if telomeres, or associated proteins, somehow inhibit the DNA damage repair machinery. Indeed, components of shelterin, including TRF2, inhibit the functions of essential DSB checkpoint kinases as well as DSB repair factors and thereby suppress telomere end-to-end fusions Sfeir, . As a coet al., et al., et al., et al., et al., et al., et al., At first thought, it might seem disadvantageous for the organism to prevent DSB repair in telomeric repeats. As our cells are frequently exposed to genotoxic stresses, occasional DSBs in telomeric sequences would force these cells to senesce prematurely, accumulate in our tissues, and potentially negatively impact tissue function as we age. Indeed, cells with persistent telomeric breaks, or dysfunctional telomeres, have been reported to increase in abundance in an aging-associated manner in tissue of mice (Hewitt et al., et al., et al., et al., et al., et al., de novo telomeric repeats to the exposed 3\u2032 overhang of a telomeric DSB or single-stranded nick close to a stalled telomeric replication fork, thereby preventing telomere dysfunction. This mechanism, which resembles chromosome healing, has been described previously in cells that display telomerase activity (Murnane, While telomerase cannot prevent formation of telomeric DDR foci in response to ionizing radiation, or even resolve these foci with high efficiency once generated (Fumagalli Murnane, .et al., et al., et al., Because telomerase suppresses the formation of a telomeric DDR in response to DNA replication stress, cells expressing hTERT are significantly less sensitive to hyperproliferative signals and stresses that impede replication fork progression. While somatic human cells undergo TDIS prematurely and rapidly in response to DNA replication stress induced by drugs, oncogenes, or impairment of DNA replication factors, cells that over express hTERT, or cancer cells that have reactivated telomerase expression, are generally insensitive to these treatments (Suram et al., et al., It is becoming increasingly evident that telomeres are far from being replicometers that simply count cell division cycles. Mounting evidence supports the model that telomeres also function as sensors of genotoxic events, capable of shutting down cell cycle progression prematurely before telomeres had eroded to critically short lengths. Furthermore, while telomere dysfunction can promote cancer progression by seeding the events that lead to genomic instability in cells with compromised DNA damage responses, it is also clearly beneficial for the organism as it promotes cell death and stabilizes cellular senescence as demonstrated both in animal model systems (Cosme-Blanco Cells with features of TDIS have been detected in inactive and benign lesions in the skin, as well as in colonic and breast epithelium. TDIS therefore can be activated in distinct cell types and throughout our tissues. While we don\u2019t yet have a thorough knowledge of what other tissues are protected from developing neoplasms due to activation of TDIS, future studies should reveal the entire extent to which this tumor-suppressing mechanism protects us from developing malignant cancers. Also still unresolved is how telomerase suppresses formation of dysfunctional telomeres and induction of TDIS in response to DNA replication stress. As this function requires its catalytic activity, it is also targetable using existing antitelomerase drugs which were designed to inhibit the telomere extending abilities of telomerase. The vulnerability of telomeres to oncogenic and hyperproliferative signals in the absence of telomerase activity could therefore be exploited by using drug combination cancer therapies, targeting both telomerase while inducing DNA replication stress. While much still remains to be learned about the role of dysfunctional telomeres during aging and cancer development, it is becoming increasingly evident that the beneficial and tumor-suppressing properties of telomere dysfunction are vital for human health."}
{"text": "Journal of Venomous Animals and Toxins including Tropical Diseases in 1995, special attention has been given to the publication of results from research studies on products developed from animal toxins [Since the foundation of the l toxins . For yeal toxins .Crotalus durissus terrificus associated with a fibrinogen-rich cryoprecipitate and coagulation factors extracted from buffalos [About 20\u00a0years ago the researchers of the Center for the Study of Venoms and Venomous Animals (CEVAP) at UNESP proposed to engage in prospecting for a new sealant from a serine protease extracted from the venom of buffalos ,3,4. Forbuffalos . In humabuffalos -10.Recently, we have investigated the effects of the fibrin sealant as a scaffold for mesenchymal stem cells in order to demonstrate the ability of cells to interact with the biological microenvironment . We obseet al.[Similarly, de la Puente et al.-14 develet al.-14.et al.[et al.[The results of de la Puente et al.-14 are il.[et al., since tThe author declares that there are no competing interests."}
{"text": "In his valuable commentary on our recent publication Ashley Craig pointed out that the observed \u201cstrong connection between mental distress and a disorder like cerebral visual injury is highly important for directing future research in the area.\u201d Within this context we wish to emphasize another significant factor: patients' quality of life that may be relevant as a potential mediator variable.cope with daily visual tasks. For brain-damaged patients the NEI-VFQ may be ideally conducted together with a neuroophthalmological supplement which is available in English and German (Raphael et al., Besides generic health-related quality of life, vision-related quality of life as assessed with questionnaires such as the National Eye Institute\u2014Visual Functioning Questionnaire (NEI-VFQ, Mangione et al., Recently, we have observed that a higher extent of vision-related quality of life in patients with cerebral visual injury was related to lower levels of mental distress (Gall et al., Dr. Craig also highlighted the other side of the hypothesis, i.e., that \u201cquality of life will improve should mental health problems be addressed\u201d (Gall et al., Brief Symptom Inventory (BSI, Franke, As pointed out in the commentary, very similar phenomena of elevated mental distress have been observed in patients with physical disorders after damage to the central nervous system Craig, . A next The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Moths (Lepidoptera) are the major nocturnal pollinators of flowers. However, their importance and contribution to the provision of pollination ecosystem services may have been under-appreciated. Evidence was identified that moths are important pollinators of a diverse range of plant species in diverse ecosystems across the world.2. Moth populations are known to be undergoing significant declines in several European countries. Among the potential drivers of this decline is increasing light pollution. The known and possible effects of artificial night lighting upon moths were reviewed, and suggest how artificial night lighting might in turn affect the provision of pollination by moths. The need for studies of the effects of artificial night lighting upon whole communities of moths was highlighted.3. An ecological network approach is one valuable method to consider the effects of artificial night lighting upon the provision of pollination by moths, as it provides useful insights into ecosystem functioning and stability, and may help elucidate the indirect effects of artificial light upon communities of moths and the plants they pollinate.4. It was concluded that nocturnal pollination is an ecosystem process that may potentially be disrupted by increasing light pollution, although the nature of this disruption remains to be tested. Any paper demonstrating the existence of a moth\u2013plant pollination interaction or providing evidence for such an interaction was considered relevant and included in the review. Levels of evidence supporting pollination interactions varied from observed flower visitation alone to proven dependence of the flower on moths for pollination , reportedly pollinated by moths of Geometridae and Pyralidae , visited by large numbers of moths in the genus Pyroderces  and diurnal pollinators; for example, The literature, therefore, contains numerous examples of moths serving as pollinators which, in many cases, are of considerable importance to individual species and to communities. A diverse selection of plant taxa in an equally wide range of ecosystems benefit from pollination by moths. It is important to consider how environmental change may threaten this ecosystem service.et al.,et al.,et al.,et al.,There are many drivers of environmental change, but artificial night lighting is one which is uniquely important for nocturnal organisms, through direct interaction with a light source such as a streetlamp, increased background illumination at night, and altered perception of photoperiod . Even at a low intensity, light caused reductions in age and mass at pupation in males and inhibited diapause in both sexes of a Noctuidae species in the laboratory  have simple eyes  that are sensitive to changes in light intensity  radiation (10\u2013400 nm), predominantly at longer wavelengths close to visible light  of interactions between species, such as plants and pollinators  Skeels  tend to interact with generalists (with many connections) more frequently than with other specialists (Dicks et al. (Most studies of plant\u2013pollinator networks to date have focused on diurnal interactions. Two exceptions considering nocturnal plant\u2013pollinator networks are Devoto et al.  and Banzet al. ; these aet al.,et al.,et al.,A variety of changes in moth abundance, composition of moth assemblages, and moth behaviour are all possible results of artificial lighting at night, but the overall effect on the whole community via disruption of pollination remains to be tested . Moths mWe believe that our findings in this review highlight a number of key priorities for future research . While wet al.,The effects of artificial night lighting on moths, too, should be investigated further. Many of the individual-level effects summarised above have not been empirically demonstrated to occur under natural conditions. Moreover, there are no published studies into the community-level effects of artificial night lighting on moths; this is a major research gap (Fox, In this review, we show the importance of moths as pollinators for a diverse range of plant species in ecosystems worldwide and, hence, their role in ecosystem functioning. We discuss the many ways in which moths are known to be affected by artificial night lighting, and suggest how these effects may, in turn, impact pollination interactions between moths and plants.The effects of artificial night lighting may go beyond simple declines in moth populations, with potential changes in the composition of moth assemblages and in the nature and frequency of interspecies interactions between moths and other taxa; this justifies an ecological network approach to the problem .Artificial night lighting may negatively affect a range of ecosystem services (Lyytim\u00e4ki,"}
{"text": "Dunaliella but also for the halophilic Archaea in blooms that occasionally develop in the lake when conditions become favorable (Oren, Halobacteriaceae have developed mechanisms to use not only phosphate ions but other phosphorus sources as well. Thus, the square archaeon Haloquadratum walsbyi possesses a gene cluster that allows uptake of phosphonates and cleavage of the stable carbon-phosphorus bond (Bolhuis et al., Phosphorus is a key element for life, and in many ecosystems phosphate is the limiting nutrient. This is also true for many hypersaline ecosystems. A well-known example is the Dead Sea, where the possibility of massive development of microbial blooms is determined by the excessively high concentrations of magnesium and calcium and phosphate is the limiting inorganic nutrient, not only for the alga le Oren, . It is tHalobacterium salinarum, Haloferax mediterranei, and Haloferax volcanii. Cell sorting of prokaryotes from saltern brines provided further evidence for polyploidy (Zhaxybayeva et al., Hfx. volcanii cells are starved for phosphorus, the number of genome copies is reduced from ~30 to ~2, allowing for about three additional cell division cycles. The degree of ploidy is thus determined by the level of available nutrients. The number of ribosomes is not decreased, showing that rRNA does not serve as a phosphorus reserve. In non-starved cells the amount of DNA-bound phosphorus is about twice that found in the ribosomes, making DNA more suitable as phosphorus storage material (Zerulla et al., DNA contains 10% phosphorus by weight. Many halophilic Archaea have discovered the advantage of DNA as a phosphorus storage polymer: they are commonly polyploid: some species may contain up to 30 genome copies (Breuert et al., Halobacteriales (Oren et al., Halorubrum spp. (Makhdoumi Kakhki et al., Halorubrum and a Halobacterium showed the activity (Birbir et al., Halogeometricum-affiliated isolates from salterns of Tamil Nadu, India (Manikandan et al., Halobacteriaceae was never ascertained. An ISI Web of Science search did not yield any papers dedicated to the properties of haloarchaeal DNases.Another way to obtain phosphorus is by degrading DNA outside the cells. Extracellular DNA is found in all environments, including hypersaline ones (Chimileski et al., Haloferax mating systems are based on direct contact between cells of the same species (Rosenshine et al., Halorubrum (Papke et al., Halobacteriaceae came from a metagenomic study in Deep Lake, an Antactic hypersaline lake. The four organisms dominating the community and belonging to different genera share contiguous up to 35-kb long regions of ~100% identity (DeMaere et al., Mechanisms of degradation of DNA to be used as a nutrient and to be taken up as a source of new genes may be related (Finkel and Kolter, Hfx. volcanii. They showed that exogenous double-stranded DNA can be used as a nutrient to supply essential phosphorus. Not all sources of DNA are equally suitable, and there is a large degree of specificity involved. DNA of the same species supports growth, but herring sperm DNA or Escherichia coli DNA were not effective. However, unmethylated E. coli DNA was metabolized. Thus, there is a bias against highly divergent methylated DNA.In a recent \u201cFrontiers in Microbiology\u201d paper, Chimileski et al.  studied Hvo_1477 was identified as a factor likely involved in DNA processing at the cell surface. It is the first identified archaeal extracellular DNA processing / uptake-related gene. Its deletion created a strain unable to grow on extracellular DNA. Hvo_1477 homologs are commonly found in genomes of Halobacteriaceae and other Archaea. Hvo_1477 codes for a 327 amino acid lipoprotein attached to the membrane, homologous with known Bacillus and Staphylococcus nucleases.The gene Use of DNA as a nutrient may be considered a form of natural DNA uptake or natural competence. However, natural competence requires internalization of intact DNA fragments and the presence of a complex molecular machine for binding and intracellular processing of DNA. Import of high-molecular-weight DNA through membranes of halophilic Archaea is yet to be conclusively demonstrated.The data presented have important implications for different disciplines including microbial ecology, nutrition, and evolution. They raise some intriguing questions:Halobacteriaceae?- To what extent is extracellular DNA exploited as a phosphorus source in natural communities of Hfx. volcanii were the sequestering of phosphorus to avoid starvation, why are not all types of DNA taken up with equal efficiency?- If the sole purpose of DNA uptake by - If DNA can be internalized, how does the cell decide whether to degrade it as a source of nutrient or explore the possibility that it may encode useful genetic material?The study by Chimileski et al. may thus lead to basic new insights in more than one field of microbiology.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Structural magnetic resonance imaging (MRI) techniques are a representative example of the current progress in neuroimaging and enable imaging neuroanatomy to be directly applied to clinical practice. Particularly the field of stereotactic and functional neurosurgery has begun to gain remarkable benefits from this revolutionary evolution. Such techniques are ideal for studying clinical populations considered for functional neurosurgery, especially when crucial structures of complicated neuronal networks are targeted. Another benefit is the possibility for a personalized treatment, as was well illustrated in the recent article by Lujan et al.  regardinLujan et al.  presenteThe findings of Lujan et al.  suggestein vivo  and obsessive-compulsive disorder  has yielded promising results (Schlaepfer et al., Thinking of cautions that unavoidably come with new technologies, we should keep in mind that DTI tracts are complex mathematical objects and the validity of tractography-derived information in clinical settings has yet to be fully established (Pujol et al., In conclusion, tractography appears as an imaging tool of great value in functional neurosurgery. It can reveal the spectrum of network changes associated with DBS and also the differences in the activated pathways which result from small differences in electrode location. Thanks to such modern structural MRI modalities, as tractography, we nowadays know that activation of a critical mass of unique anatomic connectivity may be necessary for achieving the desired DBS-induced therapeutic benefit. Finally, tractography enables personalized treatment, which appears to be crucial for a successful neuromodulation procedure, especially a DBS application.Dr. IM is the sole contributor of this article.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Our planet is experiencing rates of environmental change unprecedented in modern times, and an understanding of how microbes both mediate and respond to these shifts is an important research challenge (De Vries and Shade, Trait-based approaches can provide mechanistic links between community structure and function, and are gaining popularity in microbial ecology (Krause et al., As well, species-species interactions can affect the relationship between communities and processes. In the model presented by Folse and Allison , the impnirK genes, which are thought to be subject to HGT, is not related to N2O accumulation rates. Furthermore, for nirS and 16S rRNA genes, Salles et al. (Evolutionary dynamics can also alter relationships between structure and function. In a Perspectives Article, Choudoir et al.  advocates et al.  showed ts et al.  used mets et al.  used a mCommunity assembly processes may also alter the relationship between \u201cwho's there\u201d and \u201cwhat they do\u201d (Nemergut et al., Physical dynamics may also be key in regulating the relationship between structure and function. Schimel and Schaeffer  propose Together, the studies in this special issue highlight the role of a variety of ecological, evolutionary and physical dynamics in microbial community structure and function Figure . This boThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Nomura et al. show that the positive cAMP/PKA response is moderated by the co-activation of Gi-coupled receptors coexpressed in the same neuron (Nomura et al., 1 receptors that are tonically activated by the endogenous production of endocannabinoids (Ladarre et al., The articles in this Frontiers Research Topic describe how neurons integrate the signals carried by cyclic nucleotide. Three articles present original research, two papers provide provocative opinions about aspects of cyclic nucleotides signaling and four reviews provide timely summary and analysis of the state of the field. The three original articles illustrate how biosensors can reveal the details of signaling cascades in \u201cnative\u201d neurons, a major advance compared to the use of heterologous expression systems. Nomura et al.  quantifyIn an opinion piece, Iyengar proposes that spatially restricted elevation of cAMP levels and their action on downstream effectors may function as a scaling agent for computations by signaling networks Iyengar, . Goto, KPV was supported by Labex Bio-Psy. NS was supported by NIH, the Ellison Medical Foundation and the W. M. Keck Foundation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "In the past decade, human cortical activity has been shown to be modulated by applying direct low electrical current. The current flowing through the skull and brain between two surface electrodes increases excitability of the cortical tissue under the anode and decreases it under the cathode. This transcranial direct current stimulation (tDCS) improves motor adaptation to environmental change  on motor skill learning (Cantarero et al., Recently, the cerebellum has shown multimodal arrangements, providing an anatomical basis for this sensory-motor integration. Proville et al.  demonstrResults of Cantarero et al.  showed tThe effect of ctDCS on motor accuracy is unlikely related to the visual system which can hardly be improved. This effect may rather result from improved proprioception. Specifically, in the sequential visual isometric pinch task, improving proprioception would improve the ability to accurately match visual and muscle-force information. Based on studies testing cerebellar patients (e.g., Bhanpuri et al., M1 tDCS also immediately improves performance in a motor skill task, as demonstrated by Prichard et al. , and visIn conclusion, Cantarero et al.  study shThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "There is an error in the last sentence of the penultimate paragraph of the Discussion. The sentence should read:Our data indicated that the C allele  was related to higher MI values, thus corroborating the propositions of Norton et al. [6], Spichenok et al. [17], and Walsh et al., [18]."}
{"text": "While young fathers have been neglected in social research in the UK, over the past fifteen years a small but growing body of empirical evidence has emerged across a range of studies. This review article draws selectively on this literature to document the characteristics of young fathers in the UK and their lived experiences. It presents compelling evidence for the desire of young fathers to be engaged as parents, despite the sometimes multiple challenges that they face. The article begins with a demographic profile of young fathers and documents what is known of young fathers\u2019 relationships with their children, the child's mother and wider kin. It goes on to consider a range of practical issues facing young fathers. The article concludes with a consideration of young fathers\u2019 support needs and experiences of professional support, drawing out the implications for policy and professional practice. Concerns about youthful fertility are not new. In popular discourse young parents are often portrayed as being irresponsible, ignorant and as a threat to the social order Duncan, . Motherset al., et al., et al., et al., et al., et al., et al., Although young fathers are an under-represented research group, academic interest in fatherhood can be traced back to the 1970s in both the US and the UK. A rich and diverse body of work has emerged from the 1990s onwards, in line with changing patterns of partnering and parenting  in the time leading up to the birth and afterwards (Ayoola et al., et al., et al., The challenge, then, is one of changing the culture of professional practice so that young fathers are no longer discounted as \u2018hard to reach\u2019, \u2018disinterested\u2019, or \u2018risky\u2019 but sought out and welcomed as clients with a valuable contribution to make.If a young father refrains from seeking out professional support due to negative responses from practitioners or discriminatory attitudes, they risk being labelled as irresponsible or absent (Featherstone et al., When appropriate formal support is provided, this is linked to better psychological, emotional and economic wellbeing of young parents, better quality of parenting and may prevent serious case reviews from occurring Hadley, . ExampleOverall, this article indicates that young men's abilities to engage and sustain a fathering role are dependent on a number of complex and often interlinking factors such as education, training and employment opportunities, relationship status with the baby's mother, support levels from maternal and paternal grandparents, residence arrangements and access to formal service provision \u2013 many of which can become barriers for them to overcome.With regards to formal service provision, timely access to appropriate support can help a young man's positive transition into parenthood, promote fatherhood engagement and is shown to be beneficial, regardless of the father's relationship status with the baby's mother. However, commentators argue that provision for young fathers is still lacking. While young mothers encounter universal provision, such as midwifery and health visiting, such systematic contact with young fathers continues to be limited. Much more needs to be done to support and promote a father inclusive culture within policy and professional practice. Listening to the voices of young fathers and understanding their lived experiences can help overturn negative perceptions of them as parents and thereby contribute to better service provision. As Lammy : 11 obse"}
{"text": "Dear Friends,Warm GreetingsThe editorial team at Journal of Current Glaucoma Practice (JOCGP), the official Journal of International Society of Glaucoma Surgery, hopes to chronicle new developments in the field of glaucoma for you, ensuring a critical evaluation of existing and new techniques for better patient care. We are indeed grateful to the dynamic and illustrious editorial board for agreeing to join us in this endeavor.In this issue, Coote et al review the techniques of bleb revision for failing blebs. Stirbu et al review various materials and modalities for drainage tube repair.The role of selective laser trabeculoplasty and prostaglandin analogs in the current glaucoma treatment paradigm is discussed by Clement, in the perspectives section. Louati et al draw attention to the implications of long-term BAK use in patients of a chronic disease like glaucoma.Nuyen et al introduce the technique of imaging the lamina cribrosa using the swept-source optical coherence tomography in the diagnostics section. Maheshwari et al review the methods and implications of tonometry in glaucoma while assessment of diurnal fluctuations in intraocular pressure is dealt with, by Bhartiya et al.Ichhpujani et al discuss the extremely important assessment of knowledge, attitudes and self-care practices associated with glaucoma in hospital personnel.We hope you enjoy reading this issue of the JOCGP and will always welcome any comments, criticisms or suggestions that you may have.Looking forward to seeing you all at Glasgow in September.Best wishesShibal BhartiyaTarek ShaarawyTanuj Dada"}
{"text": "The global pandemic of non-vector borne environmental diseases may, in large part, be attributed to chronic exposures to ever increasing levels of exogenous lipophilic chemicals. These chemicals include persistent organic pollutants, semi-volatile compounds and low molecular weight hydrocarbons. Such chemicals facilitate the sequential absorption of otherwise not absorbed more toxic hydrophilic species that attack numerous body organs and systems, leading to environmental disease. Co-morbidities of non-communicable environmental diseases are alarmingly high, with as many as half of all individuals chronically ill with two or more diseases. Co-morbidity is to be anticipated, since all of the causative chemicals identified have independently been shown to trigger the individual diseases. All are triggered by a combination of genetic susceptibility and environmental exposure . Hypertension is about twice as common in diabetics as in those without diabetes and either disease can precede the other , semi-volatile exogenous chemicals (SVOCs) and low molecular weight hydrocarbons (LMWHCs). Examples of POPs are polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCs). Examples of semi-volatile compounds are bisphenol A, phthalates and polynuclear aromatic hydrocarbons. Examples of volatile organic compounds are 8 carbon or less aliphatic and single-chain aromatic hydrocarbons. POPs are slowly metabolized and eliminated and are stored in white adipose tissue, from where they are slowly released into the blood stream. SVOCs are more rapidly metabolized and eliminated andLMWHCs are very rapidly metabolized and eliminated, but continued exposure to SVOCs and LMWHCs leads to continuous levels in the blood as well. A steady state of lipophilic load is in effect in the body, and since lipophiles facilitate the absorption of hydrophiles, a body containing high levels of lipophiles is more likely to absorb toxic levels of hydrophiles when exposure to these occurs than one with low levels of lipophiles. This is shown by the dose-response relationships for the onset of T2D, cardiovascular disease and neurological disease .et al., et al., et al., One in four individuals with one of these diseases is likely to be stricken with at lease one more of these diseases (Bauer Eleven (11) types of environmental diseases are listed in et al., All the diseases in Further credence to the theory just proposed is provided by the following considerations:et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., A consideration of obesity is in order here. Body Mass Index (BMI) of 30 or greater is considered obese  are known trigger environmental diseases, including type 2 diabetes, cardovascular diseases and neurological diseases (Carocci et al., In conclusion, it has been previously shown that chemically sensitive individuals had numerous co-morbidities when exposed to LMWHCs (Zeliger"}
{"text": "These need antioxidant mechanisms, such as the local production of antioxidant molecules (such as glutathione and ascorbate) and antioxidant enzymes, for protection of the neuron and its component chemicals , glutathione (the major lipophilic antioxidant), carnosine, and the antioxidant enzyme superoxide dismutase (SOD) (Smythies, \u2014 In the retina, Neal et al.  showed t\u2014 Using slow-scan voltammetry following the injection of ascorbate oxidase into the rat striatum, Rebec and Wang  reported\u2014 Using microdialysis, Morales et al.  showed tHowever, less data is available about the antioxidant protection of catecholamines in and around the synapse. In this regard it is important to note that the major mode of interneuronal communication by dopamine is by volume transmission\u2014dopamine is released directly into the extracellular space modulated by the hydrophilic environment of the extracellular matrix (Rice and Cragg, Other than this, there is scant information of other antioxidant mechanisms in this system. However, a clue is offered from an obscure clinical source.Blake et al.  reportedIn a previous communication, Smythies  suggesteIron is a highly reactive molecule, and the only place within a neuron that free iron is known to exist is in endosomes, where, however, free dopamine is not to be found. With that said, there may be an alternate location worthy of consideration, that being the extracellular space between neurons. Here, as we have noted above, dopamine is present and functioning in its volume transmission role, as well as superoxide derived from NADPH-oxidase on the extracellular side of cell membranes (Oakley et al., 2O2 and toxic aldehydes (Kaludercic et al., per se lie outside the scope of this paper.It is well established that dopamine oxidation products, such as dopamine quinone and dopaminochrome, that play a role in the O'Brien cycle, can be highly neurotoxic (Smythies, Another aspect of redox mechanisms at the dopamine synapse may be related to its co-transmission with glutamate. Most if not all dopaminergic neurons in the midbrain utilize glutamate as a co-transmitter (Descarries et al., Our hypothesis for the cause of the desferrioxamine-prochlorperazine coma is predicated on the fact that the brain has two powerful antioxidant-protective mechanisms in play that both involve dopamine. The first mechanism is the activation of a series of antioxidant enzymes by the dopamine D2-receptor, which is blocked by prochlorperazine. The second is the O'Brien cycle that would collapse if deprived of iron by desferrioxamine. The brain may be able to operate in the absence of either of these mechanisms, but not both. A series of experiments are indicated to test this hypothesis. These would include repeating the rat experiment by Blake et al.  using a \u2014 Modulation of both GABAergic and glutamatergic functions (Frantseva et al., \u2014 Blockade of catecholamine and glutamate uptake by synaptic vesicles (Wang and Floor, \u2014 Inhibition of synaptic dopamine release (Chen et al., \u2014 Inhibition of an adenosine-mediated synaptic transmission in hippocampal slices (Masino et al., \u2014 Maintenance of essential cell populations in the brain (Dickinson et al., \u2014 Modulation of membrane and cytoskeletal properties in astrocytes and increasing their intercellular connections (Zhu et al., The implications of confirming that the O'Brien cycle is present and active in the brain are broad, and would extend well beyond a simple redox function or control of superoxide toxicity. The main product of the O'Brien cycle is hydrogen peroxide. This molecule is involved in a wide range of signaling pathways in the brain. For example:A general review of this topic is provided by Rice . ConceivThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "It is worth noting that in rodents, preOLs have been defined mostly by immunostaining profiles and it is not clear if they have a fleeting lifetime or they actually contribute as a stable subpopulation to the entire oligodendroglia lineage  OPCs receive a tonic muscarinic input capable to inhibit their differentiation into mature OLs and that (ii) disruption of this muscarinic-dependent pathway can increase the number of differentiated OLs, which improve myelin repair.Later, by using microarray analysis the authors found that M3 mAChR was a well-suited candidate to control hOPC differentiation into OLs. Application of muscarinic-agonist oxotremorine to hOPC cultures reduced the proportion of resultant OLs (Abiraman et al., in vivo is mediated by direct action of mAChRs expressed by hOPCs. Experiments performed by subcutaneous solifenacin injections cannot entirely rule out the indirect activation of other cell types such as white matter astrocytes (Butt et al., corpus callosum? In the study reviewed here, experiments performed in wild type mice showed similar results to those using the xenografted hOPCs paradigm: an increased number of callosal OLs after solifenacin treatment. A similar result was reported in mice treated with benztropine, an anticholinergic M1/M3 mAChR agent (Deshmukh et al., corpus callosum are glutamatergic (Restani et al., bona fide axon-OPC synapses in both control and demyelinating lesions (Ziskin et al., corpus callosum boundaries, as well as astrocytes present in white matter (Butt et al., corpus callosum, as it is involved in the correct transition from preOL to myelinating OLs (Michel et al., A crucial unanswered point, however, is whether the muscarinic antagonist effect In conclusion, Abiraman et al.  shed ligThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The two cases reported by Lukinmaa et al3 were limited in the same quadrant of the jaw, and hence, were declared by Cho et al4 as single hyperplastic dental follicles (SCHDF) and not MCHDF. Thus, the case report by Jamshidi et al2 should be suitably considered as the 9th case of MCHDF in the literature and not 11th in number.Multiple calcifying hyperplastic dental follicles (MCHDF) are disorders characterized by multiple unerupted teeth with abundant calcifications and rests of odontogenic epithelium in enlarged dental follicles.2 is given in the The detailed summary of all the nine cases, including the case reported by Jamshidi et al2 The reviewer stated that the statement by Jamshidi et al\u2014\u201cto date, 10 cases of MCHDF have been published worldwide\u201d\u2014was mainly based on the paper of Cho et al,4 in which the authors report five cases of MCHDF. Cho et al4 claim, in the beginning of the discussion section, that there were only five published cases of MCHDF before their paper, but continue to discuss, later in the text, that the two cases reported by Lukinmaa et al3 should be regarded as single calcifying hyperplastic dental follicle. Our reviewer stated that if the two cases of Lukinmaa et al3 are considered as single, not multiple, then the claim raised in this letter is reasonable.The concern raised in this letter was shared with a reviewer of the paper of Jamshidi et al.The author declares no competing interest with regards to authorship and/or publication of this article.2Table. Summary of multiple calcifying hyperplastic dental follicles cases until the report of Jamshidi et al"}
{"text": "In this commentary, we explain why the recent manuscript by Hardcastle et al. , which cMinimal doses of exercise for health are somewhat limited within exercise recommendations (Garber et al., 2 reserve (Ekkekakis et al., To advocate for decreased pleasure with increasing intensity, Hardcastle et al.  employ aIt is our opinion that the motivation provided by positive health improvements and the time-efficiency of SIT/HIIT exceeds their potential aversive effects. Moreover, the assumption that these protocols have low adherence is not confirmed, with studies in elderly individuals showing a preference for interval protocols (Guiraud et al., Further, SIT has shown to improve motivation, particularly with regard to appearance and maintenance of body mass, as well as quality of life scores in elderly sedentary people (Knowles et al., The studies used to convince the reader that SIT is strenuous and can increase feelings of low self-esteem, potential failure, and incompetence tended to address generic issues and did not specifically involve SIT or HIIT (Hein and Hagger, Additionally, the sense of self-esteem, motivation, and competence is relative and can be enhanced by health professionals, as we believe that few people should perform exercise without supervision or guidance with regard to medical clearance, gradual progression, and appropriate monitoring. In this context, the exercise intensity is relative to the individual's current health and emotional status. Often sedentary or obese people and individual's with medical restrictions, have such low physical fitness that it would be impossible to conduct MICE. For example, a person with COPD, if a 30 min exercise is recommended, should exercise at 2.4\u20133.5 km/h (Rugbjerg et al., Hardcastle et al.  argue thHardcastle et al.  should bThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Plasmodium host cell invasion. Fundamentally, while the essential or non\u2010essential nature of different parasite proteins is becoming clearer, their actual function and how each comes together to govern invasion are poorly understood. Furthermore, in recent years an emerging world view is shifting focus away from the parasite actin\u2013myosin motor being the sole force responsible for entry to an appreciation of host cell dynamics and forces and their contribution to the process. In this review, we discuss merozoite invasion of the erythrocyte, focusing on the complex set of pre\u2010invasion events and how these might prime the red cell to facilitate invasion. While traditionally parasite interactions at this stage have been viewed simplistically as mediating adhesion only, recent work makes it apparent that by interacting with a number of host receptors and signalling pathways, combined with secretion of parasite\u2010derived lipid material, that the merozoite may initiate cytoskeletal re\u2010arrangements and biophysical changes in the erythrocyte that greatly reduce energy barriers for entry. Seen in this light Plasmodium invasion may well turn out to be a balance between host and parasite forces, much like that of other pathogen infection mechanisms.Despite decades of research, we still know little about the mechanics of  Plasmodium  do.Systems biology has entirely transformed our understanding of the malaria parasites, protozoan pathogens from the genus et al., Plasmodium proteins described in any molecular detail  where host cell cytoskeletal re\u2010arrangement and re\u2010organization can be clearly seen during invasion  interaction then the merozoite will re\u2010orientate to its apex, without any additional energetic input  and reticulocyte binding\u2010like  protein families  core surface elements of the erythrocyte that link to its cytoskeleton \u2013 a hexagonal mesh underlying the lipid bilayer primarily consisting of spectrin and actin  in et al., et al., et al., et al., et al., et al., et al., et al., et al., The erythrocyte cytoskeleton is tethered vertically to the membrane through protein complexes such as the junctional and ankyrin complex  would now appear to be of key importance for sialic acid\u2010dependent and independent invasion. Basigin is a widely expressed multifunctional transmembrane protein implicated in inflammation and tumour invasion, but little is known with regard to its function or signalling mechanisms in the erythrocyte  or the ability of a protein to bind a defined receptor, functional classification must move towards assessing what proteins mechanistically do during invasion if we are to wholly understand the process. Combining these concepts, shifting our world view to a balanced interaction between parasite and host underpinning infection, we may discover new, and innovative, ways to stop the process as a way to treat or prevent disease.With so many uncertainties remaining regarding the roles of most"}
{"text": "The paper \u201cNonsyndromic Mandibular Symphysis Cleft\u201d by Leela Krishna Guttikonda et al. was interesting. However, we would like to point out a factual error in the discussion in this paper. In the seventh paragraph of discussion the authors have attributed one theory for the formation of this cleft to Rana et al. for an article published in Indian Journal of Plastic Surgery in 2004. This is factually incorrect.In that article the authors Rana et al.  have refWe feel that such errors should be avoided and due credit should be given to the first authors, namely, Oostrom et al."}
{"text": "Can you make yourself smarter? For over a century, cognitive enhancement has been an elusive endeavor in cognitive psychology. Training on a particular task meant specific, hardly-transferable, improvements (e.g., Ericsson et al., Before we delve into the means to maximize cognitive enhancement, let us rationalize our idea of combining interventions. The field of cognitive training has been at the core of fairly heated debates in the past few years; for example, what should count as evidence for the effectiveness of an intervention has brought much disagreement (see for example Boot et al., From a theoretical point of view, therefore, combining different interventions often obscures experimental results, as each combination needs to be compared against each single treatment it contains. However, when the goal is to benefit human populations, such combinations can be particularly powerful. For example, this idea has led to training programs bridging together physical and cognitive demands, either separately Shatil,  or withiThe past decade has seen the rise of brain stimulation techniques not only as a way to gain a more accurate understanding of human neural circuitry but also to alter patterns of neural activation. In essence, tDCS is a non-invasive stimulation technique that can either facilitate or suppress brain excitability by applying anodal or cathodal electrical stimulation through surface electrodes (Nitsche et al., One of the most effective uses of tDCS might be in combination with other methods of cognitive enhancement. In particular, recent research has shown that cognitive training can improve cognitive task performance (Anguera et al., Given the promising results of non-invasive brain stimulation in the laboratory, one might ask whether there is any way to further maximize the size and the durability of improvements. We argue that one possible approach is to combine brain stimulation with physical exercise. Cognitive enhancement has recently been associated with sport and exercise experience (Hillman et al., The impact of a combination of brain stimulations and physical training will ultimately depend on the identification of their precise neural underpinnings. To our knowledge, limited research has investigated the effect of combining physical exercise and brain stimulation, presumably because studies often aim to single out one source of facilitation instead of combining a variety of variables for maximized gain. However, studies have shown that the beneficial effect of aerobic fitness on cognition is most evident in the integrity of white matter (Voss et al., during the practice session. If we view the practice session as a form of cognitive training, these studies might suggest that there is much to be gained by combining cognitive training with brain stimulation (e.g., Ditye et al., When considering more complex activities such as sports, predicting the outcome of a combination with tDCS becomes slightly more complicated. This is because the cognitive demands of sustained sports training mostly tap long-term changes in cortical areas, and thus adding tDCS to stimulate the same areas might not produce an additive effect. This rationale is supported by a recent study by Bortoletto et al. , where aMoreover, one study recently demonstrated that tDCS-related enhancement in motor learning and temporal processing involves BDNF secretion that regulates synaptic plasticity (Fritsch et al., We have presented herein our views on combining tDCS with other well-established interventions such as physical exercise. The rationale we advocated goes beyond this particular combination, and others have been presented as valid, such as tDCS with cognitive training (e.g., Martin et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Preventing Chronic Disease, Moodley et al  and open-source free applications such as Ushahidi (www.ushahidi.com/product/ushahidi/).Although the main objective of Moodley et al was to provide a descriptive analysis of the intensity of SSB advertising, their approach to using technology deserves to be highlighted because it may be of great value to public health practitioners. To this end, Many recently published studies illustrate how this technological approach has been used in the field. Braun et al  providedBethlehem et al  discusseMobile technology is changing rapidly, and so are the innovative applications for using it. Curtis et al  collecteMoodley et al provide a case study of how a group of researchers with a defined research question for a well-documented public health concern used readily available low-cost technology to create a unique spatial database of environmental exposures. This approach has relevance to many different geographic settings and exposures, including data that may be available from commercial vendors but prohibitively expensive , as well as exposures that are more ephemeral, such as advertising billboards, where existing data sets may not be current for the period studied. Their data collection methods can be adopted by researchers and communities interested in various chronic disease\u2013related exposures or assets (either harmful or protective), such as alcohol and tobacco advertising, fast-food outlets, and farmers markets. Public health practitioners could either adopt their approach of using a handheld GPS in combination with a digital camera or use similar approaches that are available through ready-made commercial or open-source smartphone applications, as this brief sampling of literature suggests."}
{"text": "Synesthesia is a rare experience where one property of a stimulus evokes a second experience not associated with the first. For example, in lexical-gustatory synesthesia words evoke the experience of tastes (Ward and Simner, Several authors focus on discussing what synesthesia is and how it relates to typical cross-modal interactions. Mylopoulos and Ro  provide Moos et al.  touch onHaigh et al.  examine In addition to Simner's  proposalMoving to neural mechanisms, O'Hanlon et al.  provide Finally Chiou and Rich  discuss Several authors highlight that synesthetes show different performance on tasks that are not directly related to their synesthetic experience. For example, Chun and Hup\u00e9  address In relation to cognitive differences between synesthetes and non-synesthetes, Ward et al.  address In summary, this Research Topic provides a novel collection of articles on synesthesia addressing a range of issues. We envisage that many of these will provide productive new research areas, and conceptual frameworks for the future study of synesthesia and related processes.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "During speech production, Broca's area is not the only area that becomes active, but there is an extended brain system including not only cortical but also subcortical areas. Classical Broca's area represents just a step in the brain language production system. Noteworthy, damage in other areas of this language production system  can also result in language production deficits (Papathanasiou et al., In conclusion we propose that lesions confined to the canonical Broca's area do not result in classical Broca's aphasia due to the large functional connectivity of this area with adjacent frontal and subcortical areas.AA, Primary writing; BB, fMRI analyses; MR, literature review; final writing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The type I interferon system plays a critical role in host defense in health, and a growing body of literature suggests that type I interferon is a critical mediator of human autoimmune disease . Type I This Research Topic features a number of Original Research Articles, including a study by Mavragani et al. examining type I interferon levels in the organ-specific autoimmune disorders type I diabetes and autoimmune thyroid disease . They deThe Research Topic also features a number of Review Articles focusing on various disease states. Liu et al. review murine models of systemic lupus erythematosus that are interferon-inducible, providing model systems of autoimmunity related to type I interferon . Wu et aThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Modern life sciences, biotechnology and synthetic biology are heavily dependent on state-of-the-art genetic engineering. This has led to great advances in biomedical and biotechnological applications, such as the identification of novel drug targets, the production of pharmaceuticals by use of novel engineered pathways, high-yield production of enzymes and, last but not least, the production of biofuels.et\u2009al., et\u2009al., However, in some other large application areas, in particular food and environmental applications, the use of genetically engineered microbes, is far behind, or even non-existent  the use of laboratory transformation protocols like electroporation, and (iii) the use of specific selection markers, frequently antibiotic resistance genes. This technology has proven to be very specific, making the risk of unwanted modifications very low. Moreover, current genomic technologies like re-sequencing of strains by next generation sequencing (NGS) can identify any undesired event. Taken together the vast majority of scientists do agree that safety offered by GMO is by far larger than that of classically modified organisms  because these latter approaches give rise to large numbers of mutations or re-arrangements in the genome that have nothing to do with the desired phenotype. Despite this notion, many consumers and consumer organizations are reluctant to accept this and persist in expressing their (unfounded) fears. This debate has been going on for the last 30 years, without a good perspective for a change in opinion  have faced societal resistance ever since their first mention. The main objections against the use of genetically modified microorganisms, commonly put forward by opponents of gene technology, are their presumed uncontrolled use, \u2018unnatural'-ness, their likely spreading in the environment, possible negative effects on biodiversity, possible toxicity of new variants, supposed lack of good risk assessment protocols and negative effects on the economy of developing countries in view of intellectual property rights held mainly by multinationals. Genetically modified organisms are characterized by three main features: (i) the use of However, the wish still exists to produce healthier, better tasting, longer lasting, less processed, and attractive looking and smelling foods. Is there a way to circumvent the problems stated above?I think there is.et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., More than half a century ago, before the onset of genetic engineering, horizontal gene transfer was already known to occur in nature, via mechanisms such as conjugation, phage transduction and competence (McKay et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., With the advanced understanding of these processes, combined with the potential of millions of microbial strains in nature, current powerful technologies of re-sequencing by powerful, cheap and fast NGS, the use of biomolecular markers such as GFP, experimental evolution approaches and use of the aforementioned natural transfer methods, will now enable the screening of large numbers of environmental strains for suitable plasmids, conjugative transposons, phages and other transfer vehicles m (McKay None declared."}
{"text": "Dear Editor,The association of genetic factors with treatment induced hepatitis C clearance in Pakistani patients was recently demonstrated by Tipu et al. . They evCombined effect of SNPs which refers to independent impact of each SNP;Causal and Tag SNPs which is defined by the linkage disequilibrium (LD) between few tag SNPs and a causal SNP (sometimes undiscovered or untested).Most of the SNPs in IFNL region including the SNPs found by Tipu et al.  to be as"}
{"text": "The formation and uplift of mountain ranges constitute major geological phenomena that can have long-lasting effects on the evolutionary diversification of living organisms. They provide opportunities for adaptive evolution through an increase of spatial heterogeneity of the landscape, including elevation, and the generation of a wide variety of ecologically diverse biotopes, and affect the migration of organisms and the distribution of species since mountain ranges can act as both biological corridors and ecological barriers. Hence, it should come as no surprise that mountain ranges host a large proportion of the biological diversity on earth (Barthlott et al., Hypericum in the northern Andes (N\u00fcrk et al., Hypericum. This pattern of diversification is also seen in other endemic plant groups of the P\u00e1ramo flora, and the region has the highest average diversification rate among all biodiversity hotspots in the world (Madri\u00f1\u00e1n et al., Rapid diversification processes are documented for the P\u00e1ramo clade of the plant genus Campanula. Polyploid species of this genus are concentrated in the Campanula rotundifolia-complex, a mountain clade of Pliocene origin (Mansion et al., Penstemon species by Kramer et al. (Mutke et al.  report tr et al. .The different studies reported in this Research Topic clearly illustrate the potential effects of mountain uplift and formation on species diversification, at least in two major mountain regions of the world. A synthesis of biological diversification on mountains is, however, still far from being achieved and the potentially high complexity of the involved history, geography and biological processes encourages further research (Hoorn et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "DEAR EDITOR,et al, recently published in IJOTM [ I read with great interest an article of Ezzatzadegan, in IJOTM . They reI agree that the recent reports show a decline in the number of IFIs after kidney transplantation; however, IFIs are associated with high mortality after solid organ transplantation . In Tranet al, reported that Cryptococcus neoformans accounted for 50% of all IFIs [Aspergillus and Candida were responsible for more than 80% of IFIs in organ transplant recipients [et al, found\u2014they reported only one case of mucormycosis in their kidney transplant patients [On the contrary to what Ezzatzadegan, all IFIs , we founcipients . In 2410I appreciate that advanced age of recipients is a risk factor for developing IFI, as noted by Ezzatzadegan and colleagues , but in et al [According to Ezzatzadegan, et al , the meaet al . In our et al . In addiet al ,5."}
{"text": "Correlated and synchronous activity in populations of neurons has been observed in many brain regions and has been shown to play a crucial role in cortical coding, attention, and network dynamics  How are pairwise and higher order correlations generated in networks and which of them are important for a given network? and (2) How should we uncover and interpret spike train correlations in a given dataset?Four studies Zhou et al. , GrytskyZhou et al.  investigGrytskyy et al.  have addIn a complementary study, Barreiro et al.  have focJahnke et al.  focused A team lead by Sonja Gr\u00fcn has tackled the second question, how spike correlations may be detected in a given data set. Torre et al.  have extIn an opinion article, Zanin and Papo  also addA third group of studies in this Research Topic addresses the computational advantages of neuronal correlations in the brain. Kilpatrick  studied In another study, Dipoppa and Gutkin  found thPrevious works have showed that synchronization between neuronal ensembles might play an important role in the binding of features belonging to a same object (Engel and Singer, In a study where the LFP and single-cell activity were recorded in the hippocampal formation of epileptic patients, Alvarado-Rojas et al.  found thThese studies give conspicuous examples for the ambivalent nature of neuronal correlations: in some conditions correlations might be a signature of dynamic instability of the network, but in other conditions correlations might be used to perform complex and flexible computations, such as binding or information gating. Although these works have provided new clues about the role of neuronal correlations, there are yet many unsolved questions, such as how neuronal correlations are generated and propagated (Moreno et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The mapping of signalling networks is one of biology\u2019s most important goals. However, given their size, complexity and dynamic nature, obtaining comprehensive descriptions of these networks has proven extremely challenging. A fast and cost-effective means to infer connectivity between genes on a systems-level is by quantifying the similarity between high-dimensional cellular phenotypes following systematic gene depletion. This review describes the methodology used to map signalling networks using data generated in the context of RNAi screens. Specifically, signalling networks involve 1000s of different components, signalling pathways are highly interconnected, proteins act as part of large complexes, information propagation occurs via both linear and nonlinear ways (e.g. by feedback and oscillations) and these networks are dynamical in nature , it is clear that these representations are not reflective of Saccharomyces cerevisiae growing in one type of media , but failed in the late stages of cytokinesis. Thus, based on the shapes of the nuclei and the cell itself following gene depletion, we can infer that these genes regulate the same function (assembly of the contractile ring during cytokinesis), potentially make physical interactions, and may regulate the spatiotemporal activity of each other. All of these inferences regarding RacGAP50C, Rho1, Pbl and Pavarotti have in fact been validated using both forward genetic and biochemical methods in a number of different organisms , noisy (vary in nonmeaningful ways), and be highly correlated. For example, in Figure a priori, and then algorithms are used that select a subset of features that can discriminate these phenotypes from wild-type cells. Unsupervised approaches do not require any prior knowledge about the data, and attempt to identify the main trends of variability in the data by representing these trends in low-dimensional space. Principal component analysis (PCA) is a popular method of unsupervised dimensionality reduction. However, a caveat to using unsupervised methods like PCA is that it weighs features based on their variance rather than their relevance to the phenotypes of interest.Dimensionality reduction can be performed in either a supervised or unsupervised fashion. In supervised methods, a set of mutant phenotypes must be first identified et al., et al., We have previously made use of supervised approaches where we used machine learning algorithms to find combinations of features, or classifiers, that best explain our data (Bakal et al., et al., et al., et al., et al., et al., et al. generated models that assume different cells will have different phenotypes following depletion of the same gene by RNAi based on their position in multicellular colonies. Accounting for positional effects essentially \u2018normalizes\u2019 some of the phenotypic heterogeneity that is commonly observed following RNAi (Snijder et al., A nontrivial aspect to the analysis of high-content screens and the inference of signalling networks is how to derive a single phenotypic signature of highly heterogeneous cell populations. The most straightforward, and frequently used, method to calculate a single signature for a gene is to calculate the average phenotypic signature of cells from all populations where RNAi has depleted the gene, and this has been frequently used in the past. However, it is clear that even wild-type/untreated cells can exhibit high levels of phenotypic heterogeneity that may be driven by stochastic fluctuations in transcription, protein levels, signalling activity and cytoskeletal polymerisation (Mitchison & Kirschner, et al., et al., et al., Once a multidimensional gene specific signature has been calculated, measuring the similarity between signatures, and inferring connectivity, can be straightforward. A common method to infer interactions between genes is to use clustering methods that group gene signatures into \u2018phenoclusters\u2019 based on a given similarity metric, such as Euclidean Distance or Pearson correlation. In a screen for genes regulating cell morphology, we have shown that co-membership in a phenocluster strongly suggests that two genes encode members of the same signalling pathway/complex (Bakal One caveat to the use of similarity-based classification schemes such as hierarchical clustering is that phenoclusters are essentially complete graphs where each gene/protein is connected to all other in the cluster, and all clusters are ultimately connected to each other. Unfortunately, although clustering recapitulates the idea that many proteins that regulate a common function often act as part of large signalling complexes, it cannot be used to describe finer aspects of signalling network architecture and dynamics. For example, it is unlikely that all proteins assigned to a particular phenocluster physically interact. Moreover, using clustering it is essentially impossible to identify situations where a particular protein may act as an upstream regulator of another.et al., et al., et al., To overcome these problems, two methods have been successfully implemented to use phenotypic data generated by screens to infer more physiological aspects of signalling network architecture and dynamics. The first is to integrate phenotypic data with other data sources, such as coexpression or PPI data (Gunsalus In the past many groups, including our own, have been focused on development of the methods themselves, but the challenge now is to use these methods across many different cell lines and/or conditions in a genome-wide fashion to gain insight into how genetic backgrounds and environmental conditions affect network architecture. Furthermore, it is essential that new computational methods be developed which can be used to model aspects of signalling dynamics such as information flow, oscillatory behaviour and feedback. Finally, as imaging instrumentation becomes faster, and data storage ever cheaper, the task of analysing extremely large datasets in an efficient manner will require new solutions. In particular, solving the curse of dimensionality with regards to high-content data will require extensive collaborations between cell biologists and mathematicians."}
{"text": "Frontiers in Human Neuroscience) have tried to investigate how the semantic processing of graspable objects involves an activation of the motor cortex in line with the affordance hypothesis originally proposed by Gibson (Marino et al.  in theiry Gibson . They dey Gibson , 2005, iThere is mounting research evidence suggesting that the simple viewing of objects with action significance can stimulate the motor cortex into generating appropriate motor plans, even in cases that there is no action intention (Tucker and Ellis, per se, but instead an effect of purely attentional processes. Nevertheless, this is only an alternative proposition to the current findings by Marino et al. (premotor theory of attention, Rizzolatti et al., Furthermore, Cisek , 2007 hao et al.  and evenOverall, it is apparent that the affordance effect remains a compelling topic within cognitive psychology and neuroscience, as it is the need to better understand the underlying visual, attention and motor processes. Theories of a direct or indirect route between visual perception, semantic processing and motor planning may appear contradicting, but in our opinion it could be that they are all providing a valuable insight in the better understanding of human cognition and perception. Hence, it is important for future research to validate or expand upon these insights.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "M. avium subspecies paratuberculosis, hereafter referred to as MAP, is a significant veterinary pathogen that causes Johne's disease in ruminants, including cattle, sheep, and goats. This chronic intestinal disease is distributed worldwide and exacts a heavy economic toll on animal producers. For example, the dairy industry incurs substantial economic losses due to reduced milk production, premature culling, and reduced slaughter value (Raizman et al., MAP used has varied greatly in those studies. Then in 2007, an effort was made to standardize the challenge models used to test new vaccines for combating Johne's disease (Hines et al., Among the first large-scale vaccine trials for Johne's disease began in the early 1990s using killed whole cells in oil injected into cattle (Kormendy, MAP (Li et al., MAP (Shin et al., The genome sequence and re-sequence of MAP are thought to be the best approach for vaccination against Johne's disease. Although traditional inactivated and LAV candidates cannot satisfy the DIVA approach, they will completely stimulate both cell-mediated and humoral immune responses (Park et al., MAP infection, as suggested before in both the murine (Ghosh et al., Live attenuated vaccine strains of MAP through a series of three gated trials (Bannantine et al., relA (Park et al., To summarize the contributions to this research topic, the opening article reviews efforts by the Johne's disease research community to test available LAV strains of The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "As researchers in the field of self-control, we read the recent publication by Bushman et al.  with greFrom their results, Bushman et al.  concludeThe work by Bushman et al. draws on the proposal that \u201cself-control requires brain food in the form of glucose\u201d (p. 3). However, the glucose model of self-control . To date, however, experimental evidence is insufficient to support a significant role of glucose in self-control fatigue (Kurzban et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "In two behavioral experiments, Marino et al.  investigSome previous papers (Tucker and Ellis, In principle, one cannot rule out the attentional hypothesis, as an alternative explanation to the findings of Marino et al. . HoweverThe time course of the recruitment of the motor system during semantic processing of objects and nouns is still a matter of debate. However, there is increasing evidence of an early involvement of the motor system during semantic tasks involving language material. Neurophysiological studies (for review see Pulverm\u00fceller et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "We mistakenly did not cite the reference Gontia-Mishra et al.  in the tHansenula saturnus (Minami et al., Issatchenkia occidentalis (Palmer et al., Penicillium citrinum and Trichoderma asperellum, and a stramnopile, Phytophthora sojae (Jia et al., Arabidopsis thaliana, poplar, and tomato plant (McDonnell et al., As reviewed in Gontia-Mishra et al. , among eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "According to Liu et al.  acupunctLiu et al. criticise several trials because acupuncture was not used appropriately according to traditional practice. However, all treatments being offered to patients should be subject to the highest standards of clinical testing whether they conform to traditional practice or are innovative in nature.It is nearly two decades since the WHO asked for acupuncture to be tested by the best clinical methods and the world is still waiting for sound evidence to show that acupuncture is superior to placebo. Whilst there is an enormous quantity of poor quality positive studies there are now many high quality negative studies.Some Comments on Liu et al.'s Higher Rated Trials. Effective blinding and appropriate controls are essential elements of a good clinical trial. Only one study was rated by Liu et al. with a Jadad top score of 5: Park et al. [k et al. . This moIn contrast, Smith et al. , rated aComparing the results of these two studies, whilst one result was entirely to be expected the other was unpredictable. One result was physical and the other psychological. Park et al.'s rationale was a doubt concerning the safety of previous trials. Liu et al. may say that moxibustion was an inappropriate treatment. That is not the fault of Park et al. who were justified in undertaking a new study with superior methodology to test dubious results of previous studies.These two contrasting RCTs show that what is important is not a general comparison of overall rates of quality of blinding across positive and negative studies. Indeed, that comparison can be misleading. What matters is the quality and relevance of each individual study. In other words, each trial must be judged on its own merits. The minimal blinding in Smith et al. was irrelevant since the result was a foregone conclusion. The absence of a sham control was the most severe failing of this study. Double blinding and sham control in Park et al. meant the result was not a foregone conclusion.Other positive trials were given a high Jadad rating: Paterson et al. ; ShifletThese Studies All Have Serious Problems. Paterson et al.'s trial does not qualify for a Jadad score of 4 because it was not a double blind trial. It was an open trial exposed to high risk of bias.P = 0.047) though it was not for pain relief. The rationale for this reanalysis was to see if it confirmed another reanalysis using their methodology, on another trial from the set, in which acupuncture and amitriptyline were both found to be more effective than placebo for pain relief, contradicting the findings of the original trial. This means that the two reanalyses of the two earlier studies, using a different methodology to the original trials, which produced consistent results across the set of trials, themselves produced contradictory results. The relevance of their results is questionable.Shiflett and Schwartz reanalysed one trial out of a set of three, designed to assess the value of acupuncture and amitriptyline for pain relief from peripheral neuropathy in HIV males. The set of trials was negative. Employing different statistical methodology to the original trials, Shiflett and Schwartz found a nominal statistical difference for acupuncture (Liodden et al.'s trial does not qualify for a Jadad score of 4. It was an open trial, whose authors acknowledge was wide open to bias.Two trials employed commendable methodology: Modlock et al.  and PastThey both found acupuncture to fare no better than placebo.On the question of the validity of placebo forms of acupuncture, if acupuncture is so variably defined as to render a valid placebo form of acupuncture quite impossible, then acupuncture cannot claim to be more than a placebo on any other basis than pure faith.In relation to the vast variability of acupuncture, another trial included in Liu et al. is instructive: Rogha et al. . This waOn the evidence presented in the study by Liu et al. acupuncture trials worldwide are routinely exposed to high risk of bias, knowingly or otherwise. Good methodology results in acupuncture failing to outperform placebo."}
{"text": "Behavioral biologists are unlikely to make such a concession. Unless we accept separate lineage-specific definitions for animals and plants, a new definition should encompass a consensus between animal-oriented and plant-oriented biologists. Levitis et al.  an exclusive one, represented by the working definition proposed by Levitis et al. , possibls et al.  found suliving entities,\u201d understood as automomous agents .\u201d This would also legitimize the existing use of the concept of behavior in cell-level studies  in the physical space. By no means does the use of this word imply involvement of a mind or consciousness. In our sense, flipping a metabolically or genetically wired switch also is a choice if its probability depends on outside stimuli and internal settings (previous history) of the biological system concerned.Taking into account the considerations discussed above, we propose defining behavior as \u201cmore easily understood as developmental changes\u201d (Levitis et al., Nevertheless, a new definition may not be enough, unless accompanied by a certain shift of perspective. Carefully mapping the trench separating behavioral phenomena from those \u201cFC drafted the manuscript and performed the final editing. V\u017d and AM contributed ideas and parts of the text, and participated in editing the manuscript. All authors have approved the final version prior to submission.This work has been supported by the Ministry of Education, Youth, and Sports of the Czech Republic project LO1417.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "In a recently published paper using space-time satellite data to determine air temperature (Ta), Kloog et al. concluded that Ta during pregnancy was associated with lower birth weight and shorter gestational age in the study population. The results obtained pointed to associations between Ta and birth weight during the last trimester, and between Ta and preterm delivery and low birth weight during the entire pregnancy. These results agree with those obtained by There are many epidemiological studies reporting a nonlinear J- or U-shaped relationship between Ta and health indicators such as mortality  and morbA study conducted in Rome with time-series analysis methodology  showed tThis suggests heat waves are an acute stressor on pregnant women, not the chronic stressor described by Kloog et al. The mechanism is unclear by which high temperatures may increase the risk of preterm birth, but there is evidence in the literature that supports a relationship . This shAlthough Kloog et al. introduced Ta values with linear components, from our point of view introducing Ta as a linear component and not taking into account the effects of heat and cold separately minimizes the authors\u2019 ability to draw conclusions about potential impacts. The effects of high temperatures may be offset by cold temperatures. Therefore, it would be interesting to improve the analysis of Kloog et al. by taking into account the effect of Ta, but separating its effect by warm and cold seasons, especially for days within heat and cold waves."}
{"text": "In their recent article, Str\u00fcber et al.  demonstrAn important question is whether at these smaller time scales, the lack of prolonged entrainment during the post stimulation session necessarily reflect a lack of tACS efficacy. Alternatively, these results might also suggest that for 1s stimulation paradigms, we are simply looking at the wrong electrophysiological measure. At these smaller time scales, changes in measures such as spike rate adaptation (Fernandez et al., The effects of tACS on the underlying cortex often depends on the presence of an experimental task that actively recruits the underlying brain area or otherwise, produces a specific brain state. For instance, Kar and Krekelberg  demonstrChoosing the stimulation intensity is also a key consideration during tACS studies (Groppa et al., The Str\u00fcber et al.  study prThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "A growing number of studies in multicellular organisms highlight low or moderate frequencies of paternal transmission of cytoplasmic organelles, including both mitochondria and chloroplasts. It is well established that strict maternal inheritance is selectively blind to cytoplasmic elements that are deleterious to males \u2013 \u2019mother's curse\u2019. But it is not known how sensitive this conclusion is to slight levels of paternal cytoplasmic leakage. We assess the scope for polymorphism when individuals bear multiple cytoplasmic alleles in the presence of paternal leakage, bottlenecks and recurrent mutation. When fitness interactions among cytoplasmic elements within an individual are additive, we find that sexually antagonistic polymorphism is restricted to cases of strong selection on males. However, when fitness interactions among cytoplasmic elements are nonlinear, much more extensive polymorphism can be supported in the cytoplasm. In particular, mitochondrial mutants that have strong beneficial fitness effects in males and weak deleterious fitness effects in females when rare (i.e. \u2019reverse dominance\u2019) are strongly favoured under paternal leakage. We discuss how such epistasis could arise through preferential segregation of mitochondria in sex-specific somatic tissues. Our analysis shows how paternal leakage can dampen the evolution of deleterious male effects associated with predominant maternal inheritance of cytoplasm, potentially explaining why \u2019mother's curse\u2019 is less pervasive than predicted by earlier work. We first focus on paternal leakage in the population genetics model studied by Frank & Hurst  individual mitochondria mutate independently of each other with probability \u03bc, (iii) individuals then undergo sex-specific selection according to the equations in Table B mitochondria are sampled from the M original mitochondria  at a Birky, , 2001, aM = 200), polymorphism does not differ from the haploid model  impact on the parameter space in which polymorphism is found under paternal leakage. Considering an illustrative bottleneck size of additive  or  is ddominant . Howeverdominant d\u2013f, we fdominant , reducinWolbachia \u2013 is widely understood to lead to mother's curse . Consequently, the majority of detrimental fitness effects of these male-benefit mitochondria would be masked in females (as they lack these tissues), while positively contributing to fitness in males, for example by allowing for a rate of mitochondrial biogenesis and energy metabolism closer to the male optimum for such tissues.et al., et al., et al., et al., et al., Mytilus, in which male-benefit mitochondria are specifically targeted to male gonads and female-benefit mitochondria to male somatic tissues, demonstrates that the segregation of mitochondria to male-specific tissues can and does occur (Breton et al., A mechanism based on preferential segregation of different mitochondrial types to different somatic tissues is supported by a number of recent studies using highly sensitive genetic techniques. These have shown that mitochondria in heteroplasmic individuals do indeed segregate in a tissue-specific fashion (Battersby et al., Differential tissue segregation need not be specific for male tissues if the fitness effects of male-benefit mitochondria are recessive in female tissues but dominant in male tissues with high energetic demand, including reproductive tissues. Given that males typically have higher metabolic demands (Mittwoch, et al., et al., et al., et al., et al., We also showed that the severe homogenizing effect of bottlenecks in mitochondrial number could be important in those cases that favoured polymorphism. Bottlenecks are considered to be widespread in animals (Bergstrom & Pritchard, et al., et al., et al., et al., Although considerable attention has been devoted to the study of interactions between cytoplasm and nucleus (e.g. Rand et al., et al., et al., et al., et al., et al., Our study opens up several avenues for future work. Foremost, the current study considers leakage to be a fixed parameter, whereas it is likely to be a heritable character amenable to selection and evolutionary change. Modelling the evolution of leakage may shed light on the question of whether leakage is a sporadic aberration that mainly occurs in outbred or hybrid crosses (e.g. Fontaine"}
{"text": "Aluminium phosphide (AlP) is a cheap solid fumigant and a highly toxic pesticide which is commonly used for grain preservation. AlP has currently aroused interest with a rising number of cases in the past four decades due to increased use for agricultural and non-agricultural purposes. Its easy availability in the markets has increased also its misuse for committing suicide. Phosphine inhibits cellular oxygen utilization and can induce lipid peroxidation. Poisoning with AlP has often occurred in attempts to commit suicide, and that more often in adults than in teenagers. This is a case of suicidal consumption of aluminium phosphide by a 32-year-old young medical anesthetist. Toxicological analyses detected aluminium phosphide. We believe that free access of celphos tablets in grain markets should be prohibited by law. In India it is marketed as a tablet of celphos, alphos, quick phos, phostoxin, et al., This highly toxic chemical is cheap and usually formulated in tablets or pellets, granules and as powder. Upon contact with moisture, aluminium phosphide liberates phosphine, which is the active pesticidal component Sudakin, . Human tet al., et al., et al., et al. et al., In India, this poisoning was not known before 1980. The first case in India was reported in 1981 from M.G.M. Medical College, Indore (Kabra In France, aluminium phosphide is used for crop protection and because of its toxicity to humans and domestic animals, the use of AlP is strictly controlled and it cannot be freely supplied.This is a case of suicidal consumption of aluminium phosphide by a 32-year-old young medical anesthetist who was under training at a reputed hospital. He visited the walled city and hired a room in a suburb. He was determined to consume the lethal dose but due to the prolonged effect, he survived initially and started vomiting, alerted the hotel staff complaining of an upset stomach and was rushed to hospital. There on arrival he gave his details, fell unconscious and later succumbed to the effects of the poison, which was identified by the remaining unused tablets later recovered from his luggage at the hotel. The reason which was revealed by the investigating officer later was depression as he belonged to a disturbed family with problems that made him take this extreme step.post-mortem examination, cyanosis was present over the nail bed. On opening the body, fishy or garlicky smell of phosphine gas was present. All the internal organs were congested with petechial hemorrhages. The lungs were congested and edematous with rupture of alveoli, gastrointestinal mucosal congestion (On ngestion , and petetc. It is available in small and large packs containing grayish-white tablets weighing about 3 g each, containing 56% aluminium phosphide and 44% aluminium carbonate, capable of releasing 1 g of phosphine.Aluminium phosphide is marketed in India as tablets of Celphos, Quickphos, et al., et al., et al., Following oral ingestion, AlP reacts with water and stomach acid to produce phosphine gas, which may account in large part for its observed toxicity. Phosphine generated in the gastrointestinal tract is readily absorbed into the blood stream. Phosphine may denature or reduce oxyhemoglobin in addition to enzymes important for respiration and metabolism and may also affect cellular membranes. The exact mechanism of action of phosphine is still not clear. Some authors have claimed it to be an inhibitor of cytochrome oxidase in animals (Chefurka et al., Symptoms of severe toxicity by AlP ingestion include diarrhea, cyanosis, breathing difficulty, pulmonary edema, respiratory failure, tachycardia, hypotension, dizziness, and death. The most common abnormality seen in the serum of 42% of poisoned patients was hypoxemia with severe metabolic acidosis (Khosla et al. in Phosphides, like phosphine, are toxic to the central nervous system, which is excited and then depressed. Arora et al. in et al., et al., et al., et al., et al., et al., et al., et al., The results of postmortem examinations of victims of phosphine poisoning generally indicate hypoxia with evidence of local trauma in the gastrointestinal tract, liver, kidneys, and central nervous system. The fatal dose of aluminium phosphide was stated to be in the range of 150\u2013500 mg/70 kg by Chugh et al. in et al. and 100% in Jain et al. (et al. reported in The manner of death was reported to be suicidal in 87% of the cases by Dalbir n et al.  with allet al., et al., et al. et al. (et al., et al., Suicide was the most common mode of poisoning deaths, with overall mortality varying between 70\u2013100%. Mortality is higher in those who consume more than two tablets and none of the patients survived who had ingested more than 3 tablets (Siwach . et al.  the patt et al., . PoisoniExposure to phosphine gas released from ALP fumigants increases risks of major morbidity and mortality. People handling this fumigant must be aware of its lethal aspects. An important preventive measure lies in better regulated supply of ALP, which otherwise is an excellent and safe fumigant as it leaves little residue on grain. Legislative and administrative measures have been suggested to restrict and modify its supply in India. Unfortunately there has been a failure in their implementation. Except the largest producer of it in India, it has been marketed as granulated powder in 10 g plastic sachets. Vendors and shop keepers should not sell the tablets to young people and children without proper verification and confirmation."}
{"text": "Neurological Science, Park and colleagues investigated the relationship among gait and speech disorders in patients with Parkinson's disease (PD) (Park et al., In a recent study in The findings on the relationship among different motor processes were previously reported in the literature in healthy subjects as well as patient populations. For example, one study found an overlapped representation in the brain for hand and leg movement (Ehrsson et al., Nonetheless, research on the relationship among different motor effectors is rather limited. Most researchers focus on only one kind of motor process\u2014gait, speech, handwriting, eye movement or other. Thus, there is a dearth of knowledge on how the brain controls the different motor effectors, and whether they are similar or not. Further, it is not clear how and why such processes correlate. Park and colleagues suggest that executive and perceptual dysfunction may underlie both gait and speech deficits in PD, and that sensory cortex projections to the basal ganglia may be the neural mechanism underlying these deficits (Park et al., Computational modeling studies have the potential to explain why such motor processes correlate. Computational modeling approaches suggest that both gait, reaching, handwriting, and speech share more or less the same elemental motor processes, which include the selection of appropriate motor actions at every time step, sequencing of movements, coordination of different motor effectors, as well as correct performance of these responses. Other relevant processes include suppression of alternative motor plans (Aron et al., Motor cortical areas were repeatedly found to play a role in sequencing and maintaining motor plans in working memory to actively execute a plan (Dagher et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Sense of agency (SoAg) refers to the feeling of control over one's actions and forms an integral part of our cognitive and social lives  and neurological  disorders. While in recent years a number of studies have examined SoAg in these clinical groups, one group of individuals that have not yet been examined are those with mirror-touch synaesthesia (MTS). This opinion article seeks to explain why changes in SoAg may occur in MTS and also why mirror-touch synaesthetes could offer unique insights into the neurocognitive basis of SoAg.For most of us, observing another person being touched activates neural regions in the somatosensory cortex that are also involved in experiencing touch (e.g., Keysers et al., Recent studies (e.g., Aimola-Davies and White, This self-other blurring may be significant for SoAg. Experimental work in neurotypical individuals has shown how the deliberate blurring of the boundaries between self and other can have dramatic effects on SoAg. A good example of this is the so-called \u201cVicarious Agency\u201d illusion, first demonstrated by Wegner et al. . In thisconsequence of these fundamental disturbances in sense of ownership. Intriguingly, the relationship between agency and ownership can also work in the opposite direction. Previous research in neurotypical adults has shown that SoAg can play a role in structuring bodily awareness (e.g., Tsakiris et al., Another line of enquiry worth pursuing is whether or not these putative agency effects in MTS are mediated by the changes in the sense of body ownership associated with the condition (e.g., Aimola-Davies and White, A further benefit of examining of SoAg in MTS is that it may help constrain our understanding of how inter-individual differences in self-other representations involved in SoAg and sense of body ownership interact to structure bodily awareness. Indeed, it has been shown that patients with impairments in self-other discrimination perform poorly on agency tasks: in particular, Daprati et al.  showed tIn the context of existing models of SoAg there are also some specific predictions about agency processing in MTS that could be tested. For example, the so-called comparator model of SoAg (e.g., Blakemore et al., networks and mechanisms underpinning it (see David, The final benefit of research on MTS that we wish to highlight concerns the brain basis of SoAg. Although a great deal of work has been done on the neural correlates of SoAg, we still know relatively little about the neural In summary, MTS refers to a rare experience in which observing touch or pain to another person evokes a tactile experience on the observer's body. There is growing evidence to suggest that this is linked to a blurring of self-other representation. In this article we have discussed how this disturbance may produce changes in SoAg in MTS. We have also discussed the ways in which research on MTS can improve our understanding of the neurocognitive basis of SoAg. In light of these discussions we believe that future research on SoAg in MTS is likely to provide valuable insights, both for those with a primary interest in MTS and for those with a primary interest in SoAg.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "A single cell is inherently noisy. This noise is observed as a variability or heterogeneity between individual cells' responses in an isogenic population, and emerges from fundamental physical process governing state of the cell over time. In practice, states of two seemingly identical cells may be different in the same environment; and in fact the behavior of the population average my not correspond to any of the individual cells. Recent decades brought a technological breakthrough in many areas in our ability to measure and interpret cellular heterogeneity, including live-cell imaging  methods. They rely on targeting transcripts with fluorescently labeled oligonucleotide probes in fixed cells  that is capable of targeting transcripts, when tagged with a specific recognition motif  systems now enable measurements of up to 20 parameters simultaneously (Chattopadhyay et al., A major step change in the field occurred when the well-established \u201comics\u201d technology, in particular next generation sequencing was applied to single cells. This, over few recent years transformed our ability to measure cellular heterogeneity from monitoring few sometimes arbitrarily selected markers into unbiased genome-wide analyses (Eberwine et al., Single-cell genomics is still very much an emerging field and thus many questions remain about reproducibility of data and normalization standards required (Wu et al., The picture emerging from the single-cell methods is that of unprecedented, previously unobservable levels of noise and heterogeneity in single cells. This noise emerges via all-on-nothing (Tay et al., However, is the static measurement going to be sufficient for studying associations? One could expect that integrated genome-wide studies would enable correlating for example epigenetic, transcriptomic, and proteomic heterogeneity. However, existing analyses already suggested that this correlation might be in fact smaller than expected (Taniguchi et al., statistical power and causality comes from the quantitative and temporal rather than static measurements under informative perturbation. This is best exemplified by a number of theoretical analyses and inference of cellular noise (Bowsher and Swain, In the inference of dynamical systems the Biological systems are inherently complex, and a noisy cell is their common denominator. The single cell biology approach is ideally suited to resolve this noise and heterogeneity with further developments of more integrated and quantitative approaches.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The purpose of the research topic \u201cEcophysiology of root systems-environment interactions\u201d was to shed light on belowground processes\u2014in an effort to further enhance its understanding, but also to increase the awareness of the research community and funding bodies toward this utmost important part of plants and ecosystems.2 levels, a factor which in itself affects plant and root growth, but is also expected to increase the intensity of climatic and edaphic extremes. In addition, other stresses such as salinization and heavy metal contamination of soils are either increasing or continue to persist world-wide. To secure crop yield and soil quality, and to understand the functioning, and thus the resilience and resistance of pristine ecosystems under changing environmental conditions, an increased understanding of acclimation and adaptation processes is imperative. In the past, plant sciences' research has focused predominantly on parameters above ground\u2014resulting in disproportional less knowledge regarding root systems and the way root system functioning is affected by both internal and external factors. Similarly, soil scientists have often preferred studying bulk soil over the rhizosphere and as a consequence root-driven soil processes are still far less studied. Because it is \u201cbetter to light a candle than curse the darkness\u201d (Herron et al., Why is it important to increase our understanding and awareness? The new challenge of global climate change is driven by an increase in atmospheric CO2 can alter source\u2013sink relations of plant organs. In this research topic, Easlon and Bloom (2 levels. Addressing water availability, Carminati (Increased net photosynthesis and decreased shoot nitrogen and water use under elevated COnd Bloom  emphasizarminati  shows tharminati  address arminati  focus onThe response of roots to abiotic stress can be modified by some root-associated bacteria and fungi. This is expressed as modification of root morphology and whole plant ecophysiology, which often enhances plant growth under stress (Alavi et al., Besides abiotic stress, root-microbe and root-fauna interactions, plant-plant interactions below ground are common and can influence plant performance considerably. For example, Bolte et al.  show thaCryptomeria japonica root morphology than on root biomass. Studying ectomycorrhizal short roots, Ostonen et al. (Poplar demes. As highlighted by Fort (in situ and in silica (Bodner et al., In the past years an increasing awareness has developed that understanding root traits will help to understand plant functioning. Since resources are acquired by the root system, breeding for crops with root traits/phenotypes increasing water and nutrient acquisition should increase yields on infertile soils and under a range of other abiotic stresses such as drought (Comas et al., n et al.  found thn et al.  evidencen et al.  found di by Fort , their rFagus sylvatica fine roots in relation to different stand characteristics resulting from conversion of coppiced forests to high forests. The fine-root C:N ratio was higher in coppiced than in converted stands and showed an inverse relationship with fine-root turnover rate, illustrating a significant change of fine-root status under different management practices\u2014likely influencing e.g., the C sequestration potential of stands. Chairungsee et al. (In addition to articles on basic research which often accentuate the uncertainties in the field of root research, some articles already outline the application of knowledge of root traits in applied plant production systems. The study by Kerbiriou et al.  providese et al.  revealedWhen taken as a whole, the 28 contributions to this research topic cover many, although by no means all, aspects of root and rhizosphere research. The number of articles collected within a relatively short period of time, and other recently published special issues addressing root-environmental interactions (e.g., Annals of Botany, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Front. Integr. Neurosci. 7:47). Belmonte et al. (Biolinguistics). We hope that steps of the sort we take will eventually help us better understand the comorbidity, heterogeneity, and variability of ASD, but also the biological underpinnings of the human faculty of language.In their paper \u201cOral motor deficits in speech-impaired children with autism\u201d  and for the concomitant rewiring of different connections between cortical and sub-cortical  structures, which provide the scaffolding for our species-specific mode of cognition . Many components of these three sets show fixed changes in modern humans compared to Neanderthals/Denisovans, which affect their regulatory regions, their coding regions, or both. Overall, we think that most of the genetic changes that brought about our language-readiness did not occur in a mosaic fashion, but rather revolved around changes in skull/brain morphology and neural connectivity that resulted in a more globular brain.The first set of genes is centered around RUNX2 one finds CTNNB1  and the fronto-temporal network connecting Wernicke's and Broca's areas (Hickok and Poeppel, TBR1. Specifically, disruptions of TBR1 give rise to severe speech and language deficits, autistic problems, and moderate to severe intellectual disability (Palumbo et al., TBR1 interacts with FOXP2 (Deriziotis et al., TBR1 seems to act as a master regulator controlling several other ASD-candidate genes (Chuang et al., Auts2 regulators we find both Runx2 and Foxp2 (Oksenberg et al., TBR1 contributes to the establishment of neocortical connectivity with the thalamus (McKenna et al., Tbr1 haploinsufficiency also results in defective axonal projections of amygdalar neurons, which give rise to a deficit in ultrasonic vocalization, social interaction, and associative memory and cognitive flexibility (Huang et al., Returning to our initial concern of the heterogeneity, variability, and specifically, comorbidity between motor and cognitive disorders observed in ASD, this frequent outcome of research and of clinical practice may be explained by the fact that the three set of genes we highlight here, involved in different aspects of cognition and motor behavior, are functionally interconnected. For example, as we mentioned earlier, some people suffering from autism bear a defective copy of It is also of interest that many of the genes we have focused on have changed after our split from Neanderthals and Denisovans (see Boeckx and Ben\u00edtez-Burraco, In sum, we regard the motor approach to language dysfunction in autism of outstanding interest for autism research, but also for our understanding of the biological nature of the human faculty for language. We believe that the genetic aspects highlighted here may contribute to gain a better understanding of the way in which cognitive and motor behaviors affect each other in people with ASD.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Contemplative practices like meditation and mindfulness have recently gained increased acceptance in science and clinical practice, although a number of issues related to their phenomenology and to experimental designs still remain (Dahl et al., Significant progress has been made in the area of the neuroimaging of meditation and mindfulness, leading to increased understanding of the neural mechanisms underlying different techniques and stages of meditation (Lutz et al., The effects of meditation and mindfulness on physiological measures have been researched extensively. Although some of these findings have been challenged over the years, others, such as cortisol level decrease, enhanced immune response, decreased chronic pain, etc. have held. Recent findings of epigenetic changes due to relaxation response (Bhasin et al., Increasingly, studies point to beneficial effects of meditation and mindfulness on cognition, affect, and social behavior, though the findings can be contradictory at times and the effect sizes small (Braboszcz et al., The validity of introspection has been a perennial issues for contemplative traditions. Though experienced meditation practitioners may be more accurate in reporting their experiences than average subjects (Lutz et al., Meditation and mindfulness practices can also generate intense and unusual experiences and altered states of consciousness, such as states of reduced phenomenal content, or absorptions (Lutz et al., One of the most challenging issues for meditation studies is the lack of accurate indices of subjects' experience during meditation, independent from subjects' reports. Several neurophysiological measures have been proposed over the years, however, it is not likely that any single measure can adequately capture the complexity of meditation experience (Davis and Vago, Several persistent methodological issues have plagued meditation research studies since the early days (Nash and Newberg, The extraordinary multiplicity of meditation techniques and seemingly contradictory effects they produce pose a significant challenge for researchers. While the current research-oriented taxonomies have addressed this problem through categorizing meditation techniques into two or three major styles (Lutz et al., Contrary to popular \u201cone-size-fits-all\u201d approaches and advertisements, different meditations can have differential effects depending on one's psychological and physical makeup, and on the stage of one's practice. Adverse effects of meditation and mindfulness, which are often discounted in traditional contexts, can be significant and are only recently being studied in a systematic way (Garland et al., Taking meditation out of its cultural, religious, and philosophical contexts may miss the influences that these contexts can have on the observed results. Future research will need to include spiritual and religious motivations, ethical concerns, as well as interpersonal and cultural contexts (Nash and Newberg, Science alone, in its present form, may not be able to answer ontological and metaphysical questions about the nature of consciousness that are the focus of contemplative traditions (Delorme et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Warburg effect was first described as a mechanism by which the tumor cells rely on glycolysis to power proliferation and biosynthesis (Hsu and Sabatini, S. aureus sepsis, indicating that this pathway is important for septic responses.The mechanism of such metabolic switching remains unclear but a recent article by Cheng et al. sheds light on this crucial process (Cheng et al., This important study by Cheng et al. adds to a growing number of recent studies that have demonstrated that glycolytic flux and metabolic intermediates are drivers of immune responses. For example, macrophages exposed to LPS show a shift from oxidative phosphorylation to glycolysis (Rodr\u00edguez-Prados et al., Sepsis, a systemic inflammatory reaction to infection, is the leading cause of death in the world. The incidence of sepsis worldwide is 18 million every year with 30% mortality. The economic impact of sepsis is substantial with costs of up to $50,000/patient and $17 billion annually in United States alone (Slade et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Although orexinergic neurons are localized to less than 100,000 hypothalamic neurons in the human brain, orexin receptors exhibit overlapping and distinct expression throughout the CNS, with significant expression in brain regions associated with arousal and vigilance state, as well as reward and stress processing.The current special topics issue of Frontiers in Neuroscience \u201cInsomnia and Beyond\u2014Exploring the Therapeutic Potential of Orexin Receptor Antagonists\u201d comprises 20 papers from leaders in the orexin/hypocretin field presenting their latest findings and thorough reviews, and will undoubtedly serve as an important reference for others engaged in this field of study. Since the independent identification of the orexin/hypocretin system in 1998 by two teams investigating hypothalamic signaling  that have undergone clinical evaluation. Two pharmacological papers from Morairty et al. (1R and OX2R on non-REM and REM sleep architecture.The identification of a neuropeptide system with restricted expression, key functions in fundamental CNS processes and approachability of discrete GPCR subtypes has made orexin receptors valuable targets for the next generation of CNS therapeutics, with multiple teams actively characterizing small molecules to understand the pharmacology and potential therapeutic applications of targeting the orexin system. Equihua et al.  takes thy et al.  (work byy et al.  (Merck Ry et al.  (Kanazawy et al.  (Jansseny et al.  (team fo2R selective antagonist, and its effects on rodent models of ethanol addiction and depression relative to a DORA and OX1R selective antagonist. In addition, (Steiner et al., 1R blockade in a rat model of diet-induced obesity.With regard to other potential indications for OXR antagonists beyond insomnia, two manuscripts from teams at Lilly Research Laboratories and MUSC (Anderson et al., A further area of orexin research which is being actively investigated focuses on the impact of orexin signaling on sympathetic autonomous nervous system activation, both during sleep and wake stages, as well as during heightened arousal and stress. Two excellent reviews from leaders in the field Carrive,  provide Together with the increasing availability of pharmacological tools, investigations of the role of orexin in limbic emotional processing have also intensified during the last 3\u20134 years. Two detailed reviews shed light on this topic, from both academic and industry perspectives (Yeoh et al., Importantly, this special issue highlights the exquisite foundational and translational work being conducted by teams at leading academic and biopharmaceutical laboratories, focused on investigating a range of therapeutic opportunities. Although it has only been 16 years since the identification of the orexin/hypocretin system, the wealth of knowledge obtained thus far has set the stage for the next decade of orexin research. It is with great appreciation to the contributing authors and with much enthusiasm that we present this special topics issue of Frontiers in Neuroscience.Michel Steiner is employed by Actelion Pharmaceuticals. Christopher Winrow is employed by Merck. Both companies are actively involved in the development of orexin receptor antagonists for clinical applications."}
{"text": "The reference of the following sentence should be Adani et al.  rather t\u201cAdani et al. (2010) and Adani (unpublished) found that both English and Italian speaking children showed better performance in a sentence-picture matching task when the object and the subject of the object relative clause mismatched in number .\u201dAdani et al.  should tThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The idea that we can influence neurons with electricity is not new. Earlier this century patients were treated, and still are, with electro convulsive therapy as a treatment for severe depression Fink, . FortunaSo far, VNS has been used to study cognitive functioning only in patients with epilepsy and major depression (Vonck et al., In rats, it has been demonstrated that VNS leads to an intensity-dependent increase in brain NE in response to stimulation of the left vagus nerve (Roosevelt et al., NE plays an important role not only in PES but also in emotional memory (Chamberlain et al., VNS seems to increase the levels of free GABA in the cerebrospinal fluid (Ben-Menachem et al., In rats, VNS has been found to attenuate the systemic inflammatory response to endotoxin via ACh release (Borovikova et al., tVNS seems to exhibit an inverted U-shaped relationship between stimulation intensity and memory performance. Indeed, Clark et al.  showed ttVNS may be a useful tool to further investigate the neuromodulation of cognitive processes related to NE, GABA and ACh, the three main neurotransmitters targeted by VNS. Yet, in healthy humans studies on how tVNS may modulate noradrenergic, GABAergic and cholinergic cognitive functions are lacking. Keeping in mind safety guidelines, we suggest that future studies on tVNS should take into account stimulation intensity to achieve a better theoretical understanding of the effect of tVNS on cognition.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Vibrio parahaemolyticus is a very versatile halophilic organism that can adapt to a wide variety of environments and can cause infections in both humans and aquatic animals. This versatility in terms of host and habitat is attributable to the ability to acquire genes that improve fitness of the organism in different situations. Several genomic islands have been described in this organism. Human pathogenic strains are characterized by the presence of pathogenicity islands that encode certain specific Type Three Secretion Systems (TTSS) and hemolysins that are not present in most environmental strains (Chen et al., V. parahaemolyticus strains have plasmid borne virulence genes (Sirikharin et al., V. parahaemolyticus is associated with zooplankton like copepods in off-shore waters and same genotype has been found over large areas (Martinez-Urtaza et al., V. parahaemolyticus has been attributed to the El Nino phenomenon characterized by the arrival of equatorial warm waters to South American coast in a sequence of invasive waves lasting about 6 months in 1997 (Martinez-Urtaza et al., V. parahaemolyticus in environmental samples and in understanding their global spread.V. parahaemolyticus has global distribution, occurring wherever environmental conditions are favorable. V. parahaemolyticus is a model organism for the \u201cone health\u201d concept, which recognizes that human health is connected to the health of animals and the environment. In order to better manage both public health and aquatic animal health, we need a better understanding of the factors effecting the ecology of this organism, the virulence factors present in human and animal pathogenic strains.Thus, this organism has attracted attention of both seafood safety managers as well as aquatic animal health professionals. Being an autochthonous aquatic organism, V. parahaemolyticus: ecology, virulence, and detection. Lopez-Joven et al. discuss the prevalence of pathogenic and non-pathogenic strains in association with molluscs while Zavala-Norzagaray et al. describe Vibrio spp. associated with sea turtles in Mexico. Host colonization depends on the ability of the organism to acquire difficult to get nutrients such as iron. Le\u00f3n-Sicairos et al. describe strategies of V. parahaemolyticus to obtain iron. Improvements in the detection methods of pathogenic strains has been presented by Escalante-Maldonado et al. Genetic characterization of clinical and environmental strains has enabled Xu et al. to understand the emergence of indigenous and non-indegenous pathogen lineages. Genomic and molecular typing studies provide insights into the environmental reservoirs and genetic diversity of pathogenic and pandemic strains as described by Hazen et al., de Jes\u00fas Hern\u00e1ndez-D\u00edaz et al., L\u00fcdeke et al., and Haendiges et al. Function of genes involved in Type IV secretion system of V. parahemolyticus has been investigated by Yu et al. and conditions leading to loss of plasmid in this organism has been described by Letchumanan et al.Raghunath presented insights into the role of virulence genes involved in human infections. Thus, the articles presented in this research topic contribute to a better understanding of the ecology, virulence, and detection of this important aquatic organism that impacts for both public health and aquaculture.The papers in this research topic cover the three major aspects of pathogenic and pandemic All authors listed, have made substantial, direct, and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Bjorklund and Kipp  provide  Self-regulation is the capacity to select actions that lead to favorable outcomes and avoid actions that lead to unfavorable outcomes. Bjorklund and Kipp  examine However, Bjorklund and Kipp  propose In the 1970s, Walter Mischel created the delay of gratification paradigm to test children's ability to resist temptation and forgo a small immediate reward in order to obtain a larger delayed reward. The paradigm consists of preschool children being asked to observe one marshmallow, without touching or eating it. The research assistant leaves the child alone and if the child can resist the temptation to touch the marshmallow and is able to wait until the research assistant returns voluntarily, the child is given the opportunity to have two marshmallows. This elegant and simple paradigm allows researchers to test children's ability to select a large delayed reward in favor of small immediate reward , the results on a related measure (delay discounting) are contradictory. Delay discounting is a task used to measure impulsive choice by asking participants to select between a large reward delivered at variable delays  and a smaller immediate reward. As the length of the delayed reward increases, participants are more inclined to select the smaller immediate reward. However, there is variability in how quickly participants discount the value of the larger delayed reward and this variation can be used as a measure of impulsive choice; in other words, greater discounting is indicative of impulsive choice  and has projections to the nucleus accumbens (NAc), bed nucleus of stria terminalis (BNST), and the frontal cortex. GABAergic, glutamatergic, and opioid peptidergic systems modulate activity in the VTA and NAc , affinity (Kd), and binding potential (Bmax/Kd) using positron emission tomography (PET) and [11C]raclopride (a D2 receptor radioligand) in healthy adult volunteers. Their results indicate that generally, women have lower D2 receptor affinity in the striatum compared to men. The lower D2 receptor affinity suggests an increase in endogenous striatal dopamine concentrations in women  and confirmed that women have higher striatal dopamine synthesis capacity than men; furthermore, there was an effect of aging such that there was a decrease in dopamine activity with age in men but not women (Laakso et al., 11C]raclopride. In stark contrast to the findings reported by Laakso et al. (In addition to the above purely structural studies, numerous other research groups have investigated both structural and functional sex differences. For example, Pohjalainen et al.  investigo et al. , the reso et al.  study reo et al. ; howevero et al.  report to et al. . In the To explore the possibility that the MCLP is modulated by gonadal hormones in humans, Dreher et al.  obtainedThere are a few recent studies that suggest that females are less impulsive during fertile phases of the menstrual cycle (Pine and Fletcher, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The relationship of Gantzer muscle to the median and anterior interosseous nerve is debated.  \u00ccn an anatomical study with 80 limbs from 40 cadavers the incidence, origin, insertion, nerve supply and relations of Gantzer muscle have been documented.  The muscle was found in 54 forearms (68% of limbs) and was supplied by the anterior interosseous nerve. It arose from the deep surface of the flexor digitorum superficialis muscle, (42 limbs), coronoid process (eight limbs) and medial epicondyle (seven limbs). Its insertion was to the ulnar part of flexor pollicis longus muscle. The Gantzer muscle always lay posterior to both the median and anterior interosseous nerve.  The Gantzer muscle may contribute to the median nerve and anterior interosseous nerve compression. The muscle was found in 68% of limbs and should be considered a normal anatomical pattern rather than an anatomical variation. . The relation of Gantzer muscle with the anterior interosseous nerve and the median nerve is controversial. ManginiThe objective of this study was to analyze the incidence, origin, insertion, and innervation of the Gantzer muscle. We analyzed the anatomical and topographic relationship regarding the anterior interosseous nerve and the median nerve, verifying the possibility of Gantzer muscle being the cause of the anterior interosseous nerve and the pronator teres syndrome (median nerve compression near the elbow). The interosseous nerve compression causes weakness or paralysis of the flexor pollicis lungus, flexor digitorum profundus and square pronator muscle, and the median nerve compression causes paralysis of the muscles of the thenar region and changes in sensitivity in important discriminating area of the hand. In both situations the functional deficit is important, leading to prehension and digital pinch disability.The study was approved by the Ethics Committee of Faculdade de Medicina de Sorocaba da Pontif\u00edcia Universidade Cat\u00f3lica de S\u00e3o Paulo, Sorocaba, SP, Brazil.Eighty forearms of 40 adult cadavers belonging to the discipline of Anatomy, Faculdade de Medicina de Sorocaba (PUC-SP) were dissected to perform this study, 38 cadavers were male and two were female.Their ages ranged between 45 and 77 years old, 23 were white and 17 were non-white, 28 pieces were previously prepared with formaldehyde solution at 10% and 12 forearms were freshly dissected.Forearm deformed by trauma, malformations and scars were excluded.The dissection was performed through a midline incision on the forearm around the lower third of the arm; two flaps including skin and subcutaneous have been folded on the radial and ulnar sides, respectively, the same was done for the fascia of the forearm exposing, thus, all muscles.All the muscles of the forearm were dissected, analyzing its innervation and the presence of nerve communication between the nerves of the forearm. All anatomical variations found were registered, recorded and photographed. We used a 2.5x Keeler magnifying glass (Germany) for magnification. The relationship of the Gantzer Muscle with the previous interosseous and median nerves was analyzed.The incidence of the Gantzer muscle was acknowledged in 54 of the 80 dissected forearms (68%). In 42 forearms the muscle originated from the deep portion of the flexor superficialis muscle.  In eightThe Gantzer muscle was inserted in the flexor pollicis lungus in 36 forearms and in the flexor digitorum profundus in 21, totaling 57 insertions in 54 forearms. In three forearms, the Gantzer muscle was duplicate.  In two tThe Gantzer muscle presented fusiform shape entering through a tendon in the flexor pollicis lungus or flexor digitorum profundus.In all forearms we observed that the Gantzer muscle received exclusive innervation from the anterior interosseous nerve.  The anteIn 30 forearms the Gantzer muscle was positioned posterior to the anterior interosseous nerve, in 18 forearms it was located anterir to the nerve.  In six fOf the four forearms of two female corpses, we found the Gantzer muscle in only one. We recorded the Gantzer muscle bilaterally hypertrophied in six forearms of three male patients.et al.,et al.,et al.et al.et al.et al.et al.et al.The incidence of the Gantzer muscle was recorded in 54 of the 80 dissected forearms 68%). This is close to the percentage observed by Mangini 8%. This et al.Saxena et al.The important difference between our results with those of Tamang et al.et al.We noticed that the Gantzer muscle occurred more frequently bilaterally than unilaterally, agreeing with the findings of Jones et al.,et al.et al.et al.Regarding the most frequent location of Gantzer muscle origin a major disagreement stands among most authors. According to Manginiet al.We agree with Jones et al.et al.et al.et al.,13 who also dissected using a magnifying glass, showed results similar to ours.Regarding duplication, we recorded in three cases, Shirali et al.et al.et al.Regarding the insertion, Al Qattanet al.Our findings are very close to those of Jones et al.,et al.,et al.,et al.,et al.The classic Anatomy treaties such as Testutet al.We observed that the anterior interosseous nerve was more frequently crossed by the muscular component of Gantzer of muscle in only nine limbs (16.6%) the anterior interosseous nerve was crossed by the tendon component, which is in agreement with Oh et al.et al.It is controversial whether the Gantzer muscle can cause the anterior interosseous nerve syndrome or even the pronator teres syndrome. Ballesteros Al QattanKaplan and report Spinner7 since it was registered in 31 forearms dissected that the muscle is always situated posterior to the nerve as its tendon could pass anterior to the branch to the square pronator.Dellon and MackinnonWe affirm that the hypertrophied Gantzer muscle can cause the anterior interosseous nerve syndrome, but this was an uncommon finding in only six forearms (11%), all bilaterally we recorded the hypertrophied muscle.et al.Tabit et al.Hill The Gantzer muscle, especially when hypertrophied and positioned anterior to the median nerve and to the anterior interosseous nerve may be the cause of nerve compression. Present in 68% of cases, in our view, the Gantzer muscle should be considered a normal anatomical pattern and not an anatomical variation."}
{"text": "Sula granti) in the Galapagos. Their analysis covered two separate investigations: a human capture-restraint stressor applied to adult boobies, and observations of nestlings maltreated by Non-parental Adult Visitors (NAVs). The authors conclude that the temporal sequence of yawning following these stressors provides support for the newly termed arousal reduction hypothesis, an idea initially proposed by Dourish and Cooper  to a more relaxed state\u201d (p. 38), i.e., the arousal reduction hypothesis. This is quite misleading as the experiments reported were not designed as a direct test of this hypothesis, which is proposed later in the discussion. Useful development of the hypothesis would include a sketch of how it would work in the context of the results. In fact, the reported patterns\u2014nocturnal yawning by adult boobies and particularly yawning by nestlings in the absence of parents or responses by nearby nestlings\u2014raise doubts about evolved signal function, which generally requires selection in terms of receivers and senders  (Miller et al., Liang et al.  state thLiang et al.'s  own explIdeally, a new hypothesis illuminates and perhaps accounts for previously documented effects better than standing theories, but at the least, it should offer a better, internally coherent account of the data on which it is based. In this case, the arousal reduction hypothesis offers no clear explanation for previously reported empirical patterns, for example, yawning and ambient temperature variation (see Gallup, Overall we believe the results reported by Liang et al.  are impoThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Glioblastoma (GBM), a World Health Organization (WHO) grade IV astrocytoma, is the most common and difficult primary brain tumor to treat . They are invisible to the naked eye, typically measuring 1\u2013100 nm in diameter , a subclass of superparamagnetic MNPs, are the most effective types of MNPs that can be used for imaging purposes (Thorek et al., Hyperthermia for the treatment of different cancers has been well described in the past. Elevation of targeted areas of the body above 40\u00b0C can result in cancer cell death (Wust et al., While local or regional hyperthermia can be effective in treating cancer involving different parts of the body, treating brain tumors is difficult due to the surrounding skull (Jordan et al., Due to the side effects and toxicities of subjecting the entire brain to hyperthermia for extended periods of time, localized treatment is necessary for effective brain tumor therapy. Direct implantation of MNPs into brain tumors can bypass the BBB and allow for a maximum hyperthermic effect provided in a targeted manner Figure The localized hyperthermic effect, known as thermotherapy, involves the application of an alternating magnetic field (Maier-Hauff et al., Thermotherapy does induce the death of malignant cells (Marcos-Campos et al., in vitro samples (Issels, in vitro (Rhee et al., in vivo models. One explanation for this difference is that the vascular network within the tumor is abnormal which can lead to areas that have a difference in pH as well as decreased availability of oxygen (Issels, The decreased resistance to heat observed in GBM cells is not as clearly presented when conducting experiments with  Issels, . Cancer  Issels, .Thermotherapy involving the use of an AMF in conjunction with MNPs has proven to be an effective method for treating patients with GBM. Initial tests have shown that MNPs have minimal toxicities to patients, though further testing must be done to confirm these findings (Mahmoudi et al., With further research, scientists can bioengineer multitasking MNPs that can be used for imaging, drug delivery, and localized thermotherapy (Hadjipanayis et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "In the last few years, a growing amount of evidence highlighted the urgent need for research aimed at assessing mental health status in low- and middle-income countries (LMICs): this revealed a substantial gap between the burden caused by mental disorders and the resources devoted to prevent and treat them  over LMICs, with a great amount of studies carried out and published by authors affiliated with HICs (Fodor et al., In response to this call for an evaluation of a \u201cglobal mental health,\u201d substantial scientific effort was devoted to address the psychological and social needs of populations living in humanitarian settings in LMICs.European Journal of Psychotraumatology collected some of the work that has been done so far in LMICs. Manuscripts address important issues such as the quantification of effects of cumulative trauma exposure in war survivors (Wilker et al., This special issue of the The paper by Wilker et al.  analyzedHermenau et al.  undertooThe relation between traumatic experiences and spirit possession in LMICs is analyzed in a systematic review of 21 articles undertaken by Hecker et al. Pathological spirit possession is a phenomenon occurring globally and has particular relevance in LMICs. Reported prevalence rates differed conspicuously depending on cultural background and the particular study populations (Hecker et al., The systematic review carried out by Strohmeier and Scholte collected 14 studies focused on trauma-related mental health problems in national humanitarian staff. In line with current literature focused on mental health conditions in LMICs (Barbui & Tansella, Jansen et al.  propose This cluster of manuscripts approaches global mental health using different study designs, which report both the patients and staff perspectives. Aware of the complexity and extent of the topic, we believe that these papers will contribute to the scientific debate in this field and represent a relevant piece of work in the reasoning on how to orient further research pathways. This become even more important in this historical time frame, where populations living in humanitarian conditions and affected by different types of trauma \u2013 including refugees inside and outside Europe Turner, , asylum Marianna PurgatoDepartment of Mental HealthJohns Hopkins Bloomberg School of Public HealthJohns Hopkins University, Baltimore, MD, USAWHO Collaborating Centre for Research and Training in Mental Health and Service EvaluationDepartment of Neurological, Biomedical and Movement SciencesSection of Psychiatry, University of Verona, Verona, ItalyEmail: marianna.purgato@univr.itMiranda OlffDepartment of Psychiatry, Academic Medical CenterUniversity of Amsterdam, Amsterdam, The NetherlandsArq Psychotrauma Expert Group, DiemenThe Netherlands"}
{"text": "In recent years, it has been brought forth that dog-human relationships share several characteristics with the maternal bond that unites a child with their principal caregiver Serpell,  and thatIn an elegant first experiment in which domestic dogs and tamed wolves were reunited for 30 min with their owners, Nagasawa et al.  found thFirstly, bonding in humans undeniably has roots in the relationship between a child and their primary caregiver, which is usually their mother Feldman, . In NagaSecondly, given that all dogs tested by Nagasawa et al.  were aduThirdly, why did the two sub-groups of dogs (short and long gaze) respond differently to the reunion? In many species, including dogs , we were astonished to learn that at least one member of the research group participated in the study with his own two dogs (see Grimm, Despite the comments above, we agree that oxytocin, especially when nasally administered to dogs (see Experiment 2 in Romero et al., SF drafted the article based on written comments made by SF and VP about the research report published by Nagasawa et al.  in ScienThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Talhelm et al.  reportedWe think that some relevant detailed data have been overlooked in their analysis, which has significant implications for the paper's conclusion and subsequent discussions. When comparing wheat with rice statistics, the authors grouped the corn and soybeans farming area with the wheat area  = \u22120.60, P < 0.001, to that of rice at the provincial level; (3) In several provinces that were categorized by the authors as \u201cwheat provinces\u201d e.g., Jilin and Liaoning provinces (in contrast to the \u201crice provinces\u201d), there were actually many more rice fields than wheat  In Northern China, corn and wheat are equally important crops, and in many provinces corn is more widely planted than wheat; (2) Similar to wheat, the percentage of corn farm is also negatively correlated, r In NorthThese results suggest that there would be an equal chance for corn farming to affect population psychology in Northern China. The term \u201crice vs. wheat agriculture\u201d coined by Talhelm et al.  cannot aThe detailed data which were overlooked not only affect the conclusion of Talhelm et al. , but alsThus the theory would then predict that there should be psychological differences between rice-growing East/South East Asian and the rest of world. This prediction is inconsistent with the dominant view in psychology that Western populations show different psychological traits as compared with non-Western populations. Non-Westerns, which include groups as diverse as Arabs, East Asians, Russians, and farmers in Africa and South America, have been shown to rely more on holistic reasoning and have more interdependent views of self than Westerners (Henrich et al., This paper is well publicized, and has led to much discussion within both the general public and the scientific community, including a critical commentary by Ruan et al. . Many haFurthermore, the psychological differences observed by Talhelm et al.  cannot bIndeed, while the cost of wheat production is much less than that of rice, the cost of corn production is between the two or closer to that of rice in modern China (Garnaut et al., Talhelm et al.  providesThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The series of articles in this special edition reflect much of the current thinking in regards to the role of metals in aging and neurodegeneration, and highlight the deep involvement of metal ions in critical pathways that may contribute to onset/progression of neurological disease. Furthermore, metal homeostasis may impact directly on signaling cascades relevant to cognition, or may indirectly contribute to functional decline via an effect on specific pathologies in the degenerating brain. As such, the behavioral manifestations associated with normal and pathological aging may be remediated by therapeutics that intervene in metal ion dyshomeostasis.The broader perspective on the role of metal ions in cognition is outlined in the first two articles. Opazo et al.  provide The remaining articles are split out according to disease, beginning with ALS. Lovejoy and Guillemin  provide Dang et al.  then speBourassa et al.  tackle tThe next series of articles have a focus on AD, with discussions around both the mechanistic and therapeutic implications of altered metal ion homeostasis. McCord and Aizenman  provide Wong et al.  explore Hancock et al.  then revFinally, Bhattacharjee et al.  provide Finishing this section, Braidy et al.  briefly The next three articles focus on the role of metals in other conditions, and utilize a variety of different models. Sun et al.  examinedMalakooti et al.  then expC. elegans as a model system to explore the underlying mechanisms of PD. They propose that a failure in axonal transport is fundamental, with the subsequent impairment in trafficking of metal ion homeostasis proteins (focusing on iron) resulting in downstream oxidative stress and neuronal loss. They also note the potential for the loss of synaptic connections in this model.Finally, Chege and McColl  provide The last manuscript in this special edition is by Marx and Gilon , and preThe sum of these articles, which add to my own recent work in the area, present an overview of the many different pathways through which metals may intersect in the pathogenesis of a variety of neurodegenerative diseases, and which may subsequently manifest (directly or indirectly) in behavioral deficits.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "As the worldwide burden of chronic disease continues to rise, disease prevention and health promotion become increasingly important components of public health. Although many complementary and alternative medicine (CAM) practices have emphasized health promotion and the area of CAM health care holds much opportunity and challenge for issues of public health, CAM research to date has been dominated by more clinically restrictive issues , 2. HoweThis special issue includes original research papers and systematic reviews investigating the issues related to CAM practices in the public health arena as well as outcomes of CAM treatment for chronic disease prevention and/or management (tertiary prevention). Brucea javanica oil by Y. Liu et al.; a systematic review and meta-analysis of the efficacy of compound kushen on cancer pain by X. Ma et al.; an analysis of Qigong's effect on chronic fatigue syndrome by L. P. Yuen et al.; a systematic review of acupuncture for allergic rhinitis and asthma by L. Zhou et al.; and an analysis of the effects of guided imagery on patients on mechanical ventilation by B. Brakovich et al.There are 14 articles in this issue, from six countries and on a wide variety of topics. The topics addressed are almost equally divided between treatment of specific conditions of public health importance and disease prevention through risk factor reduction. A smaller number of articles address issues related to traditional medicine use among the general public. Articles on treatment of conditions include a large clinical study by J.-F. Tang et al. on safety and evaluation of Danhong injection; a basic science study onArticles on prevention and risk factor reduction were a randomized controlled trial of Tai Chi on weight loss, metabolic syndrome, and bone mineral density by T. C.-Y. Kwok et al.; an analysis of body constitution through Traditional Chinese Medicine by C.-H. Lee et al.; a survey of apitherapy use for disease prevention by S. Trumbeckaite et al.; an exploration of the possible effect of CAM on antibiotic resistance by W. B. V. Leeuwen et al.; and a survey of the effect of Traditional Chinese Medicine on decreasing stroke risk among users of corticosteroids for dermatitis by J.-L. Shen et al.Finally, F. Xu et al. described the validation of a questionnaire based on Traditional Chinese Medicine to assess health status; S. H. Ng et al. described use of the Theory of Planned Behaviour related to Traditional Chinese Medicine use; and G. D. Hughes et al. characterized the use of herbal medicines for noncommunicable disease.These articles tended to focus more on single herbal or other traditional preparations or procedures for both treatment and prevention, with very little emphasis on health behaviour, which is typically a cornerstone of public health programs. Behaviours related to diet, physical activity, and stress reduction are known to be increasingly important factors in determining the health of the public and are also areas of importance and emphasis for many CAM practitioners. It is necessary for CAM professions to become visible in this arena and for CAM research to extend into this direction rather than focusing narrowly on specific therapies if these efforts are to be recognized and utilized for the benefit of populations.Cheryl HawkCheryl HawkJon AdamsJon AdamsJan HartvigsenJan Hartvigsen"}
{"text": "The incidence of cardiac arrhythmia and heart failure continues to rapidly increase, leading to a growing epidemic which constitutes a serious financial burden for society  have identified common variants in the general population for atrial fibrillation. Yao et al. (In this issue, genetic aspects of arrhythmia were described by 3 different groups. Crump and Abbott  providedo et al.  gave an Duygu et al.  providedmiRNAs are endogenous non-coding RNAs which post-transcriptionally regulate gene expressions (Condorelli et al., Finally Stagnaro and Caramel  proposedIn conclusion, this research topic offers a detailed and updated summary about genetic and epigenetic basis of arrhythmia and heart failure, and provides a forum for discussion on ways to translate these genetic and epigenetic findings into novel therapies for arrhythmia and heart failure.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Vision is the process of extracting behaviorally-relevant information from patterns of light that fall on retina as the eyes sample the outside world. Traditionally, non-human primates have been viewed by many as the animal model-of-choice for investigating the neuronal substrates of visual processing, not only because their visual systems closely mirror our own  to investigate visual function. The experimental approaches covered by these studies range from psychophysics and electrophysiology to histology and genetics, testifying to the richness and depth of visual neuroscience in non-primate species. Below, we briefly summarize the contributions to this Research Topic.in-vivo electrophysiology and, in one case, genetic manipulation  focus on the visual system of two rodent species more commonly used as laboratory animals: rats and mice. Following a trend that has been established over the past 6\u20137 years, the mouse studies investigate tuning properties of visual neurons in low-level visual centers through LeDue et al.  investigLiu et al.  present In rats, Meier and Reinagel  investigIn a second study, Reinagel  investigRosselli et al.  also invRat pattern vision is also the topic of the study of Vermaercke et al. , who comTwo reviews focus on the plasticity of the rodent visual system during development (Priebe and McGee, Bonaccorsi et al.  provide Two other reviews compare the anatomy, connectivity, parcellation and hierarchical organization of the visual systems of different species, with a special focus on primates and rodents (Homman-Ludiye and Bourne, In a similar spirit, Laram\u00e9e and Boire  focus onWhile this Research Topic was mostly focused on non-primate systems, we included one exception: a review of what is known about the visual system of a new world monkey, the marmoset (Solomon and Rosa, Object recognition is a topic that is also addressed by two bird studies, one research article (Wood and Wood, Taking a broader view on avian vision, Soto and Wasserman  review tHigh-level visual functions, such as shape processing and object recognition, are also addressed by several behavioral studies on fish in this Research Topic.The perception of illusory shapes and boundaries is the subject of two reviews/opinions (Agrillo et al., Along these lines, Fuss et al.  present In their review, Rosa Salva et al.  stress tTwo other behavioral studies investigate object categorization (Newport et al., Siebeck et al.  examine Finally, one research article uses the retina of an amphibian, the bullfrog, to study the effect of dopamine on the processing of visual information (Xiao et al., The Topic also includes two articles focusing on motion perception and visual tracking behavior in insect models (Aptekar et al., Finally, in their review, Egelhaaf et al.  take a bAs the depth and breadth of the contributions to this Research Topic attest, \u201csimpler\u201d brains have a great deal to teach us about vision. From insects to fish, birds, amphibians, and finally mammals, research aimed at understanding vision in simple animal models is flourishing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "We were interested to read the article by Hjortebjerg et al. on the relationship between road traffic noise and behavioral problems in children. We were especially interested in the variables considered in this study, because we believe it is insufficient to assess the influence of the noise environment on behavioral disorders of children without also factoring in the impact of parents\u2019 mental and neurological health.EHP (Hjortebjerg et al. mentioned that environmental factors such as noise can cause anxiety and mood swings in adults, and an earlier study published in EHP  concludeEHP . Thus, i"}
{"text": "The cell surface of fungi, bacteria, and sea organisms is highly glycosylated. These glycans are oligo- or polysaccharide molecules that can be secreted or attached to protein or lipids forming glycoconjugates. They present extraordinary structural diversity that could explain their involvement in many fundamental cellular processes, including growth, differentiation, and morphogenesis. Considerable advances have been made on the structural elucidation of these glycans. Their primary structures were determined based on a combination of mass spectrometry and NMR spectroscopy techniques. The combination of these sensitive and powerful techniques has allowed us to increase our structural knowledge of a wide variety of glycans expressed by different fungi, bacteria and sea organisms.The Research topic \u201cGlycan diversity in fungi, bacteria, and sea organisms\u201d covered important aspects related to polysaccharides, glycoproteins and glycolipids from different organisms and their biological functions.Some contributions to this Research topic have highlighted the importance of glycosaminoglycans analogs with unique structures from different marine invertebrates. Many sulfated fucans (SFs), sulfated galactans (SGs), and glycosaminoglycans (GAGs) of new structures have been characterized and described (Vieira and Mour\u00e3o, Pomin  has descPav\u00e3o  emphasizSargassum muticum and Fucus vesiculosus, respectively (Deal et al., Plouguern\u00e9 et al.  reviewedThe diversity of the composition of the fungal cell surface and important aspects related to structure and function of fungal glycans has also been reviewed in this Research topic. These contributions highlighted the importance of surface molecules of fungal cells for the fungal pathogenesis, physiology, and immune recognition.Guimar\u00e3es et al.  focused A review from Barreto-Bergter and Figueiredo  showed tFonsecae monophora isolated from clinical and environmental origins.Burjack et al.  demonstrCryptococcus neoformans immunoreactive antigens by Teixeira et al. (Mannoproteins with different molecular masses were identified and characterized as a et al.  with potIn addition to glycans from sea organisms and fungal cells, this Research topic included a mini review on the lipopolysaccharide from bacteria. Serrato  has descAll these articles strongly indicate that knowledge on structure and functions of glycans from fungi, bacteria and sea organisms may open new perpectives allowing to identify specific targets for new generation of antifungal drugs, development of new classes of immunomodulators, antigens, and adjuvants and also marine carbohydrate-based drug development.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Finn et al. present an excellent summary of current and emerging methods by which to monitor preterm infants during stabilization in the delivery room, but I disagree with their characterization of the usefulness of Doppler ultrasound, and they fail to comment on the impact of delayed cord clamping on heart rate in the first minutes of postnatal life. Furthermore, I believe recent work using Electrical Cardiometry ICON device  to measuHR assessments in the DR are accurate compared with clinical and pulse oximetry assessments (Doppler ultrasound shows potential for clinical use, however future evidence is needed to support this conclusion.\u201d Phillipos et al. (via Bluetooth to an external recorder. This allows proper assessment and documentation of the neonatal heart rate at cesarean section and facilitates delayed cord clamping and resuscitation with the cord intact. Doppler ultrasound is established as a method for measuring and documenting the fetal heart rate, so it is hard to argue that this will not apply moments later when the fetus is ex-utero as a neonate.Doppler heart rate monitoring is a well-established standard for the fetal heart rate. The authors state that with Doppler ultrasound \u201cessments .\u201d The Phs et al.  do in fas et al. , 4. At ts et al.  in IrelaFinn et al. state \u201cHowever, clinical experience is required for accurate assessments and continuous measurements are not practical.\u201d After the first minute or so when oximetry is functioning, precordial Doppler is redundant but continuous measurements using a lightweight transducer makes continued hands-free measurements perfectly practical for several minutes after birth.What is the normal heart rate for term and preterm neonate during the first minutes after birth? Finn et al. point out that the standard charts  were derThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Traumatic brain injury (TBI) from penetrating or closed forces to the cranium can result in a range of forms of neural damage, which culminate in mortality or impart mild to significant neurological disability. In this regard, diffuse axonal injury (DAI) is a major neuronal pathophenotype of TBI and is associated with a complex set of cytoskeletal changes. The neurofilament triplet proteins are key structural cytoskeletal elements, which may also be important contributors to the tensile strength of axons. This has significant implications with respect to how axons may respond to TBI. It is not known, however, whether neurofilament compaction and the cytoskeletal changes that evolve following axonal injury represent a component of a protective mechanism following damage, or whether they serve to augment degeneration and progression to secondary axotomy. Here we review the structure and role of neurofilament proteins in normal neuronal function. We also discuss the processes that characterize DAI and the resultant alterations in neurofilaments, highlighting potential clues to a possible protective or degenerative influence of specific neurofilament alterations within injured neurons. The potential utility of neurofilament assays as biomarkers for axonal injury is also discussed. Insights into the complex alterations in neurofilaments will contribute to future efforts in developing therapeutic strategies to prevent, ameliorate or reverse neuronal degeneration in the central nervous system (CNS) following traumatic injury. Diffuse axonal injury (DAI), regarded as an integral process in all grades of traumatic brain injury (TBI), results typically from head rotational acceleration/deceleration, as well as the propagation of force through the brain following impact , DAI is better described as lesions in multiple, yet common, loci throughout the white matter tracts  in neurons and a major component of the axonal cytoskeleton (Perrot et al., in vitro, NFs are obligate heteropolymers in vivo and must include NFL (Lee et al., While NFL can form a homopolymer Neurofilaments are particularly long-lived proteins with NFL half-life estimated at approximately 3 weeks (Millecamps et al., The function of NFs is not fully understood. Although the importance of IFs for mechanical strength has been long recognized, the varied composition and regulation of neurofilaments suggest that they have a more complex role (reviewed in Capano et al., in vivo and in vitro models of trauma, although the effects of this upregulation are not yet characterized (Dash et al., Neurofilaments undergo a number of posttranslational modifications, including phosphorylation and glycosylation. Phosphorylation has been well characterized (reviewed in Dale and Garcia, It is thought that phosphorylation at these sites, particularly in NFM (Jacomy et al., in vitro stretch injury (Staal and Vickers, Neurofilament phosphorylation has also been intimately tied to myelination and axonal transport (de Waegh et al., Compared to phosphorylation, the role of NF glycosylation is less well studied. The head region of NFL and NFM are modified by the addition of O-linked N-acetylglucosamine moieties, while glycosylation occurs at the KSP repeats of NFH (Dong et al., NF accumulation in injury may develop out of primary mechanical failure of the NF network (Meythaler et al., In vivo and in vitro models of injury employing tacrolimus and cyclosporin A have demonstrated reductions in axonal pathology (Okonkwo and Povlishock, Pathways that may mediate side-arm shortening or loss include calcium-dependent calpain and calcineurin activation, which may be consequences of calcium accumulation post-injury. Evidence supporting calcineurin-mediated dephosphorylation as a factor in NF compaction comes from trauma studies investigating the impact of known calcineurin inhibitors. Similarly, evidence supporting calpain proteolysis of NF side-arms comes from a weight drop study demonstrating that administration of a calpain inhibitor prior to injury attenuated axonal pathology (Buki et al., In vitro studies using a fluid pressure pulse to induce a mild axonal stretch injury in unmyelinated axons have shown that by 48 h post injury, 51% of injured axons showed elevated SMI312 immunoreactivity for phosphorylated NFs (Chung et al., Rotational head injuries in pigs have demonstrated that NF compaction in axonal varicosities contain high levels of all NF subtypes, although NFL accumulates before NFM and NFH, suggesting a temporal sequence of cytoskeletal breakdown or differential subunit transport (Chen et al., In vitro axonal stretch injury with subsequent transmission electron microscopy has demonstrated that microtubule breakage occurs in abnormally convoluted axons post-injury (Tang-Schomer et al., NF compaction has long been thought to contribute to disrupted axonal transport in the setting of injury. Microtubules are essential for axonal growth and transport (Nixon and Yuan, Although both NF compaction and microtubule disruption were thought to contribute to axonal transport block after trauma, a growing body of evidence suggests that NF compaction and defective transport, as measured by APP, are separate pathophenotypes of DAI. Tacrolimus, a selective inhibitor of calcineurin-activated phosphatases (Liu et al., Although NF compaction and impaired axonal transport are largely distinct (DiLeonardi et al., Given the role of NFs in TBI and a range of neurodegenerative conditions, these proteins may be useful plasma biomarkers for axonal injury and neuronal damage Petzold, . It has In a population of pediatric TBI cases, patients whose initial computed tomography scan showed DAI had significantly higher serum levels of pNFH compared to those without DAI (\u017durek et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders characterized by impaired social communication, abnormal language development, restricted interests, and repetitive and stereotyped behaviors  and how that mechanism fails in fragile X syndrome  gene encoding the transcriptional repressor MeCP2 (Moretti and Zoghbi, Xu and Pozzo-Miller comment on a study which identified a novel AT-hook domain of MeCP2 that plays important roles in chromatin organization, providing a mechanism that determines the clinical course of Rett syndrome and related disorders (Baker et al., Bellini et al. provide an overview of post-translational modifications as a mechanism for MeCP2 to control its involvement in synaptic plasticity and homeostasis (Bellini et al., in vivo newborn neurons that mutations of MBD affect the roles of MeCP2 in neuronal development (Zhao et al., Rett syndrome is primarily caused by mutations in the methyl-CpG-binding protein 2 (Investigating the genes and genetic pathways involved in ASDs is essential to unraveling the pathogenesis of these disorders (Krumm et al., Deficits in synapses and neural circuits underlie cognitive dysfunction in ASDs (Zoghbi and Bear, The advances in technical approaches and disease models have provided unprecedented opportunities to investigate neural and synaptic deficits in ASDs. In addition to mouse and rat models, other animals such as drosophila and C. elegans are now used to study autism (Doll and Broadie, Mecp2y\u2212/ mice, suggesting that radical scavengers might be an option for treating neuronal dysfunction in Rett syndrome (Janc and Muller, Mecp2 knockout mice, demonstrating that histone deacetylase-6 is a potential pharmacological target for treating Rett syndrome (Xu et al., Pharmacological manipulation of neurotransmitter systems or signaling pathways linked to ASDs may provide therapeutic benefits for patients (Delorme et al., Lastly, Wang et al. provide a comprehensive review of current targeted pharmacological treatments for fragile X and Rett syndromes, and discuss related issues in both preclinical and clinical studies of potential therapies for ASDs (Wang et al., The increasing need for effective treatment of ASDs, together with the advancement of disease models and other technologies, are promoting studies toward identifying potential therapies. It is inspiring to see that research in animal models is translating into patients with ASDs. The successful development of mechanism-based treatment for autism will continuously require more extensive multidisciplinary collaboration among different research sectors (Katz et al., We thank the authors and reviewers for their efforts and hope that this research topic will enrich our knowledge of ASDs and spur new research interests in autism related biology.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "In plant glycobiology, free \u201cmetabolic\u201d carbohydrates consist of small sugars , sucrose-derived oligosaccharides , starch and its breakdown products  Are increased sugar levels associated with changed hormone levels in buds and how does this change over time? (ii) Do bud IAA levels depend on IAA biosynthesis from tryptophan within the bud, or is indol-3-aldehyde, a phloem-mobile lateral bud inhibitor (Nakajima et al., It cannot be excluded that light dependent signaling mechanisms, or any other positive factors, may have remained undetected in the pea apical dominance paper (Mason et al., Despite these critical notes, it should be recognized that the paper of Mason et al.  boosts fIn line with the earlier ideas of Allsopp , recent Clearly, we are only at the beginning of our understanding of the complexity of cellular sugar homeostasis, and deciphering how this exactly connects to hormonal regulatory mechanisms is an important challenge.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "This article reviews advances in decoding methods for brain-machine interfaces (BMIs). Recent work has focused on practical considerations for future clinical deployment of prosthetics. This review is organized by open questions in the field such as what variables to decode, how to design neural tuning models, which neurons to select, how to design models of desired actions, how to learn decoder parameters during prosthetic operation, and how to adapt to changes in neural signals and neural tuning. The concluding discussion highlights the need to design and test decoders within the context of their expected use and the need to answer the question of how much control accuracy is good enough for a prosthetic. The field of brain-machine interfaces (BMIs) for control of motor prostheses is quickly growing , yet due to its accuracy and execution speed the method has remained popular since its first use by Wu et al.  Aggarwa. While pLinear filtering, or discrete Wiener filtering, is fading in popularity. It is still used by some research groups, either because of its computational form (Badreldin et al., Several other methods have been used in the recent literature: kernel autoregressive moving average (KARMA; Wong et al., What values should a decoder predict? Ideally, a prosthetic should offer accurate, intuitive control that works under all likely usage contexts. In most prior work, desired positions or velocities of end-effectors were decoded. Homer et al. (r as the difference between the decoded cursor position and the previous cursor position. The cursor position\u2019s update is a linear combination of the decoded velocity and the decoded velocity vector rotated to the direction of \u0394r.r et al.  proposedDecoders aim to predict user intentions, and it is possible that intentions may be slightly different from the observed limb movements used for parameter fitting. Fan et al.  showed tTwo recent studies have explored decoding torque values, to allow a prosthetic to interact with objects with mass more naturally. Chhatbar and Francis  showed tBesides kinematics and forces, the target location of a reach may be directly decoded to improve the trajectory of the reach. Shanechi et al.  presenteTo address the need for BMI control of limbs with many degrees of freedom, an important consideration for clinical deployment, Wong et al.  used priBesides the biomimetic approach of designing a prosthetic so that it can be controlled like a natural limb, another approach is to use operant conditioning of neuron ensembles (for a review, see Sakurai et al., How should we model neural activity? Recent studies have explored the aspects of neural models beyond movement tuning, with the hope of improving user-friendliness. Considering that a system with high latency is difficult to control, Willett et al. (t et al.  trained In a clinical setting, it is important that a prosthetic can be turned off when not used, to avoid undesired movements. Aggarwal et al.  classifiXu et al.  includedWhich neurons should we include in decoding? BMI researchers have long sought ways to reduce computational load to decoders and noise in neural data by excluding irrelevant neurons. Several recent studies have provided tools for finding relevant neurons. Chen et al. (n et al.  used varCao et al.  determinAlso using a supervised approach, Brockmeier et al.  proposedHow can we design movement models to assist decoding? Kalman and point process filters include movement models which can encode prior beliefs about how variables change over time. Cleverly engineering these models may make prostheses easier to control. Two studies examined how to improve the user\u2019s ability to stop a BMI cursor when desired. Golub et al. (b et al.  designedb et al.  added a In a general examination of movement models, Gowda et al.  analyzedHow can we improve decoder parameters during decoding? To handle poor initial parameter fits or changes in neural tuning after practice, continuous learning of decoder parameters may be required in a clinical device. There has been much recent work, mostly from Jose Carmena\u2019s Lab (for a review, see Carmena, Information about the target locations of reaches can help improve the parameter learning process. Kowalski et al.  proposedIn Suminski et al.\u2019s  study, iMerel et al.  modeled Are neural signals stable over long time periods? There has been controversy as to whether updating of decoder parameters is required for long-term prosthetic usability. Recent studies have analyzed stability of signals over long time spans. Flint et al. (t et al.  and Schet et al.  showed tt et al.  found sit et al.  found siIf decoder updates are needed, how can we improve the accuracy of updates? Recent studies have proposed heuristics to improve adaptation. Zhang and Chase (nd Chase  used twond Chase  proposedBesides updating baseline firing rates via windowed estimates, other methods for tracking baseline changes have been proposed. Bishop et al.  found thk-means.Using a reinforcement learning approach to adaptation, two studies from the same group (Mahmoudi et al., As researchers focus more on practical hurdles to clinical deployment of neural prostheses, it becomes more and more important to develop and test BMI decoders in the contexts in which actual prostheses will be used, i.e., to control artificial limbs, natural limbs via functional electrical stimulation (Moritz et al., An important question which has been thus far neglected in the field is how much control accuracy is enough? Full restoration of human ability in terms of movement accuracy may come at computational and other costs, e.g., number of recording channels, which likely trade off against other figures of merit of a prosthetic system. While we should continually endeavor to improve BMI technology, from a practical standpoint, we should also answer the question of how much control is good enough, so that engineers can design systems with clear requirements in mind.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Nitrogen (N) is an essential element in biological systems and one that often limits production in both aquatic and terrestrial systems. Due to its requirement in biological macromolecules, its acquisition and cycling have the potential to structure microbial communities, as well as to control productivity on the ecosystem scale. In addition, its versatile redox chemistry is the basis of complex biogeochemical transformations that control the inventory of fixed  N in local environments, on a global scale and over geological time.Although many of the pathways in the microbial nitrogen cycle were described more than a century ago, additional fundamental pathways have been discovered only recently. These findings imply that we still have much to learn about the microbial nitrogen cycle, the organisms responsible for it and their interactions in natural and human environments. Progress in N cycle research has been facilitated by recent rapid technological advances, especially in genomics and isotopic approaches.nifH gene expression indicate complex regional and taxonomic sensitivities to micronutrient limitation.The papers in this issue reflect current research focus on N loss and input processes. The papers are ordered by topic beginning with N fixation, the only biological process that can increase the inventory of fixed N, Knapp  reviewedNext we include a series of papers about nitrification, a process which does not directly affect the fixed N inventory, but which links mineralization to the N loss processes by producing oxidized forms of N that can then be used as respiratory substrates. Nitrification has been the subject of increasing research interest since the discovery a decade ago that archaea were involved in ammonium oxidation. A large body of literature has since developed documenting the diversity, abundance and activity of ammonia oxidizing bacteria and archaea (AOB and AOA). For this collection, Casciotti and Buchwald  reviewedBeggiatoa mats, but even higher rates in sediments without mats. The presence of sulfide reduced denitrification rates, even though the community contained large numbers of sequences associated with taxa that are capable of linking sulfide oxidation with nitrate reduction. Kirkpatrick et al. (The next topic in the collection deals with the processes by which fixed N is lost from marine ecosystems. Low oxygen environments are of particular interest for nitrogen transformations because they are the sites of fixed N loss via denitrification and anammox. Francis et al.  report ok et al.  and Fuchk et al.  report ok et al. . In the k et al.  found thk et al.  report oFinally, we include a single paper on the use of nitrogen by the phytoplankton in the surface ocean. Bertrand and Allen  review tThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The controversial issue on the independent versus synergic functional role of the vomeronasal and main olfactory systems, motivated the present Research Topic , accessory-olfactory (AOB) bulbs, and primary olfactory cortex. The work by Pedraza and De Carlos  presentsThe initial dogma regarding VNS and MOS as independent sensory modalities was supported by the dissimilar centripetal distribution of their tributary fibers. However, with the refinement of the tract-tracing techniques numerous sites of central convergence between the two systems have emerged. Three original studies performed in adult mice deal with the connectivity of the MOS and VNS. The paper by Hintiryan et al.  providesIt is now clear that plasticity in the adult nervous system is more common than originally suspected (see Merkle et al., Four review articles present and analyze current concepts of the MOS-AOS interaction. In this framework, the assays by Su\u00e1rez et al.  and MuciThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "This is an end point mechanism for inhibiting chloride secretion-induced water drag and resulting secretory diarrhea. VIP in the extracellular space may be related to creating an antiviral environment, but at the cost of inducing secretory diarrhea, which upon chronic persistence may often be fatal and contribute to marked cachexia. Some recent hypotheses have suggested the plausible role of ENS-stimulated VIP release and its protective effects on intestinal epithelial barrier  approved to manage HIV and HAART- induced non-infectious diarrhea (Crutchley et al., In summary, HIV associated diarrhea remains a major cause of morbidity and mortality even now, with presentations comparable to the earliest report of \u201cslim disease\u201d, the cachectic manifestation, from rural Uganda (Serwadda et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Together, this suggests that a hyperbaric and thermal physiological bottleneck at bathyal depths contributes to bathymetric zonation. The peak of the unimodal diversity\u2013depth pattern typically occurs at these depths even though the area represented by these depths is relatively low. Although it is recognised that, over long evolutionary time scales, shallow-water diversity patterns are driven by speciation, little consideration has been given to the potential implications for species distribution patterns with depth. Molecular and morphological evidence indicates that cool bathyal waters are the primary site of adaptive radiation in the deep sea, and we hypothesise that bathymetric variation in speciation rates could drive the unimodal diversity\u2013depth pattern over time. Thermal effects on metabolic-rate-dependent mutation and on generation times have been proposed to drive differences in speciation rates, which result in modern latitudinal biodiversity patterns over time. Clearly, this thermal mechanism alone cannot explain bathymetric patterns since temperature generally decreases with depth. We hypothesise that demonstrated physiological effects of high hydrostatic pressure and low temperature at bathyal depths, acting on shallow-water taxa invading the deep sea, may invoke a stress\u2013evolution mechanism by increasing mutagenic activity in germ cells, by inactivating canalisation during embryonic or larval development, by releasing hidden variation or mutagenic activity, or by activating or releasing transposable elements in larvae or adults. In this scenario, increased variation at a physiological bottleneck at bathyal depths results in elevated speciation rate. Adaptation that increases tolerance to high hydrostatic pressure and low temperature allows colonisation of abyssal depths and reduces the stress\u2013evolution response, consequently returning speciation of deeper taxa to the background rate. Over time this mechanism could contribute to the unimodal diversity\u2013depth pattern.Bathymetric biodiversity patterns of marine benthic invertebrates and demersal fishes have been identified in the extant fauna of the deep continental margins. Depth zonation is widespread and evident through a transition between shelf and slope fauna from the shelf break to 1000 m, and a transition between slope and abyssal fauna from 2000 to 3000 m; these transitions are characterised by high species turnover. A unimodal pattern of diversity with depth peaks between 1000 and 3000 m, despite the relatively low area represented by these depths. Zonation is thought to result from the colonisation of the deep sea by shallow-water organisms following multiple mass extinction events throughout the Phanerozoic. The effects of low temperature and high pressure act across hierarchical levels of biological organisation and appear sufficient to limit the distributions of such shallow-water species. Hydrostatic pressures of bathyal depths have consistently been identified experimentally as the maximum tolerated by shallow-water and upper bathyal benthic invertebrates at  Introduction 407Origin of the deep-sea fauna and the colonisation of the deep sea 408Physiological limitation by low temperature and high hydrostatic pressure 410Tolerance of high hydrostatic pressure and low temperature 411Adaptations to high hydrostatic pressure and low temperature 413Bathymetric variation in evolution 415The stress-induced evolutionary mechanism in the deep sea 416Conclusions 418Acknowledgements 419References 419et al., et al., et al., et al., et al., Many macroevolutionary patterns display both ecological and biogeographical components. Clear bathymetric patterns have been identified in the extant biodiversity of the deep continental margins, a region covering approximately 40% of the total ocean surface area   of the Phanerozoic (Jablonski et al., et al., et al., Phylogenetic analyses have supported the relatedness of extant deep-sea and shallow-water species, predominantly consistent with diversification and invasion of deep-sea environments from shallow water, albeit over differing timescales. Bresiliid shrimp from deep-sea vents and seeps are reported to have radiated less than 20 Ma and from shallow ancestry (Shank et al., et al., et al., et al., Pagodulid snails appear to have radiated even more recently, from a shallow-water Antarctic lineage, and colonised the deep sea approximately 3 Ma (Barco ca. 250 Ma (see Raupach et al., et al., in situ (Osborn et al., et al., et al., et al., Echinus acutus is extending its bathymetric range, indicating that migrations to the deep sea are still occurring (Tyler & Young, Palaeontological and molecular data indicate that echinoids have made migrations to the deep sea over multiple timescales; generalist omnivores migrated to the deep sea in low numbers over the last 200 Myr in contrast to the majority of specialist detritivore clades, which made independent off-shelf migrations between approximately 75 and 55 Ma (Smith & Stockley, et al., et al., Reemergence from the deep sea has also been reported, e.g. for lithodid crabs (Hall & Thatje, et al., et al., et al., et al., Since shallow-water fauna are adapted to relatively warm conditions currently dominating the upper oceans except at high latitudes, the low temperatures prevalent in the deep sea are considered to limit invasion by such fauna (deep-sea temperature is typically between 4 and \u22121\u00b0C; Gage & Tyler, et al., et al., et al., In both warm and cold isothermal water columns the major limiting factor for range extension into the deep sea is predicted to be tolerance of high hydrostatic pressure (Young et al., et al., et al., et al., Thermal tolerance is proposed to relate directly to the physiological ability of an organism to avoid the transition from aerobic to anaerobic metabolism, with a systemic to molecular hierarchy of limitation (see P\u00f6rtner, et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., There are significant physical effects of hydrostatic pressure on proteins and lipoprotein membranes (reviewed by Pradillon, et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Listeria monocytogenes after exposure to 10\u00b0C for 4 h following culture at 37\u00b0C, has been reported to result in a 100-fold increase in survival of exposure to 300 MPa for 20 min (Wemekamp-Kamphuis et al., Cellular responses to thermal and hyperbaric environmental challenges can contribute directly to biogeographic limitation (e.g. see Tomanek, in situ temperatures at bathyal depths could support the contribution of hydrostatic pressure to bathymetric zonation.Evidently, hydrostatic pressure and temperature both have significant biological effects perturbing every level of biological organisation sufficiently to limit biogeographic range Table . It appeet al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Euphausia superba (George, Allocentrotus fragilis during adaptation to the deep-sea environment (Oliver et al., Maja brachydactyla appear to be greater under hyperbaric conditions, potentially critical in restricting bathymetric distributions (Thatje & Robinson, Recently, attempts to determine potential for invasion of the deep sea have focused on mollusc and echinoderm propagule tolerance of hydrostatic pressure and low temperature in shallow-water species, with and without close phylogenetic links to deep-sea species, in order to test the validity of theories of deep-sea colonisation (Young, Tyler & Emson,  George, . Whilst  George, , it is cet al., et al., et al., Palaemonetes varians tolerates pressures equivalent to 1000 m depth for at least a month and retains the ability to feed and successfully moult at this pressure, despite naturally inhabiting depths of less than 10 m (Cottin et al., et al., et al., Stephonyx biscayensis is determined by the combination of low-temperature and high-pressure effects (Brown & Thatje, Thorough investigation of both temperature and hydrostatic pressure tolerances of adult specimens of shallow-water species are few and focus on crustaceans, but have also demonstrated tolerance of pressures outside known natural distributions (Naroska, et al., et al., et al., et al., Existing studies of hyperbaric pressure tolerance of shallow-water benthic invertebrates consistently indicate limitation at bathyal depths ; Table 2et al., In vitro evidence indicates that critical enzyme functionality can be maintained under different pressure and temperature regimes by changes of relatively few amino acids at critical positions in a protein chain, or by the inclusion of stabilizing compounds in the intracellular matrix (Carney, Allocentrotus fragilis, in contrast to selection in the shallow-water urchin Stronglyocentrotus purpuratus (Oliver et al., et al., et al., et al., et al., et al., Allocentrotus fragilis contrasts with selection in the shallow-water urchin Stronglyocentrotus purpuratus and may reflect adaptation to environmental effects of the deep-sea (Oliver et al., The oxygen requirements of cold and deep-living species do not appear to be elevated (Childress  Carney, . Indeed,et al., Allocentrotus fragilis is in contrast to selection in the shallow-water urchin Stronglyocentrotus purpuratus and may indicate that membranes or membrane-related functions have undergone environmental selection (Oliver et al., et al., The reduced fluidity of bio-membranes under increased hydrostatic pressure and decreased temperature necessitates homeoviscous adaptations in membrane structure and composition (Hazel & Williams, et al., et al., Adaptations to high pressure can result in near pressure insensitivity, e.g. in malate dehydrogenases (see Somero, Hyperbaric and thermal effects do appear to have made significant adaptive demands on shallow-water organisms colonising the deep sea, further supporting the influence of these factors in establishing bathymetric zonation patterns. However, it is not immediately clear how the physiological effects of hydrostatic pressure or low temperature could contribute to the unimodal pattern of diversity with depth, despite diversity typically peaking at similar depths to the proposed physiological bottleneck even though the area represented by these depths is relatively low. Is there other evidence suggesting a cause for this bathymetric diversity phenomenon?et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Variation in the production of novel taxa has been identified as causative of another, somewhat analogous, evolutionary pattern in biodiversity. A meta-analysis of nearly 600 latitudinal biodiversity gradients assembled from the literature has corroborated the high generality of the latitudinal diversity decline, including for the marine environment of both hemispheres (Hillebrand, et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Although evolutionary rates reflect the interplay of mutation with selection and genetic drift Kimura, , moleculOver time a bathyal peak in evolutionary rate clearly could result in a unimodal pattern of diversity peaking at these depths, despite the relatively low area they represent. Consequently, it appears a distinct possibility that an evolutionary role for high hydrostatic pressure and low temperature may have been neglected. Indeed, reanalysis of existing diversity\u2013depth data using quadratic depth and temperature functions may offer evidence for such a role. But how could these factors stimulate the rate of evolution at bathyal depths?et al., et al., et al., Existing evidence suggests that adaptive radiation is the predominant mode of biological diversification (see Glor, et al., et al., et al., et al., et al., et al., et al., et al., et al., 2008d, 2011et al., et al., et al., et al., et al., et al., The ubiquitous cellular stress response affords cells a transient increase in tolerance to any form of damage-inflicting environmental challenge in larval and adult organisms, allowing time for stressor-specific adaptation to re-establish cellular homeostasis K\u00fcltz, , 2005. SParamunida suggests a period of rapid diversification following origination between 17 and 21 Ma (Cabezas et al., et al., Mutation in germ cells, adaptive canalisation during embryonic or larval development, release of hidden genetic variation or mutagenic activity, or activation or release of transposable elements in larvae or adults, increase genetic or phenotypic variation. Elevated variation unrelated to hydrostatic pressure tolerance may promote increased parapatric or sympatric speciation into vacant niches, whilst taxa remain bathymetrically constrained . Models et al., It is clear that understanding marine evolutionary dynamics demands increased knowledge of links between continental margin fauna (Clarke & Crame, Following climate-driven dysoxic mass extinctions in the deep sea, shallow-water organisms have recolonised the deep sea and the extant deep-sea fauna appears predominantly to comprise both ancient and more recent radiations of shallow-water lineages. The physiological effects of high hydrostatic pressure and low temperature across hierarchical levels of biological organisation appear capable of limiting the distribution of such shallow-water species. Experimental assessment of hyperbaric limitation across a range of shallow-water taxa supports the proposition of a physiological bottleneck at bathyal depths, imposed by the combined effects of high hydrostatic pressure and low temperature. Organisms inhabiting the deep sea appear to be functionally adapted to the high-pressure and low-temperature conditions that prevail, suggesting that hyperbaric and thermal effects have made significant adaptive demands on shallow-water organisms colonising deeper water. Together this supports the hypothesis that a hyperbaric and thermal bottleneck at bathyal depths contributes to bathymetric zonation.A unimodal pattern of diversity with depth typically peaks at similar depths to the proposed physiological bottleneck. It is recognised that speciation rates contribute to a similar latitudinal pattern in shallow-water diversity. Existing molecular and morphological evidence supports the proposition that bathyal depths are the primary site of adaptive radiation in the deep sea. We hypothesise that a peak in speciation rates at bathyal depths could establish the unimodal bathymetric biodiversity pattern over time.We hypothesise that demonstrated physiological effects of high hydrostatic pressure and low temperature may promote a stress\u2013novelty evolutionary mechanism, increasing mutagenic activity in germ cells, inactivating canalisation during embryonic or larval development, releasing hidden variation or mutagenic activity, or activating or releasing transposable elements in larvae or adults. In this scenario speciation rate is increased at bathyal depths resulting in production of novel taxa. Adaptation that increases tolerance to high hydrostatic pressure and low temperature allows colonisation of abyssal depths and reduces the stress\u2013evolution response, consequently returning speciation in deeper taxa to the background rate. Over time this mechanism could contribute to the unimodal diversity\u2013depth pattern."}
{"text": "This Research Topic focusses on both classes of models and considers several aspects and their relative merits that: span from synapses to the whole brain; comparisons of their predictions with EEG and MEG spectra of spontaneous brain activity; evoked responses, seizures, and fitting data\u2014to infer brain states and map physiological parameters.In general, mean field models of neural activity can be divided into two classes: neural mass and neural field models. The main difference between these classes is that field models prescribe how a quantity characterizing neural activity  evolves over Some of the contributions consider extensions of neural mass and field models and their relation with other classes of models, with a particular focus on modeling the action of anesthetics:Liley and Walsh  hypothesThe roles of neural mass, conductance based, and neural field models in dynamic causal modeling (DCM) are reviewed and explored by Moran et al. . These aModolo et al.  discuss The contribution of Pinotsis et al.  introducOther articles in this Research Topic relate to the use of field models to explain aberrant neural activity and dynamics recorded during cognitive tasks: Kerr et al.  integratFrequency-dependent effects in deep brain stimulation in epileptic patients are studied using computational modeling and intracerebral EEG data in Mina et al. . This paBhattacharya's paper (Bhattacharya, In Srinivasan et al.  the authIn another paper, Robinson et al.  explore Finally, beim Graben and Rodrigues  reduce aIn addition to papers focussing on applications, this Research Topic includes theoretical papers studying the mathematical aspects of mean field theory: Bressloff and Wilkerson  study riIn Gray and Robinson , the autRoy and Jirsa  show howThe above anthology of papers provides illustrative examples of recent advances in biophysical modeling. This line of work speaks to the hope that such models may help explain neural dynamics that underpin disorders like epilepsy or Parkinson's disease as well as normal functions like attention or working memory; an endeavor we hope the articles in this volume will progress.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Perrin's recent comment Perrin,  emphasizIn negative ALS clinical trials (UKMND-LiCALS Study Group et al., In conclusion, we believe that the potential beneficial effect of lithium for neurodegenerative disorders deserves serious reconsideration.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "We agree with Martin et al. that, as yet, late recurrence of hepatitis C virus (HCV) following treatment has not been studied in this highly exposed group of patients. To clarify the point made in our study,"}
{"text": "Of critical importance for clinical psychological science is why do people differ in their very ability to govern and regulate their thoughts and behaviors? This concern speaks to the paramount nature of executive function (EF) that encompasses a set of general-purpose cognitive control mechanisms regulating lower-level processes and, in turn, enabling self-regulation and self-directed behavior toward a goal Banisch, . ConsequWe are thankful to Snyder et al.  for recealerting , orienting , and executive (involving the top-down control of attention to resolve response conflicts). Because the notion of \u201cexecutive network of attention\u201d is defined as similarly to common EF, Snyder et al. (Theoretically, Snyder et al.  also uphr et al.  argued tFirst, a strict reading of their account is at odds with previous evidence of alerting and orienting networks impairments in a wide range of distinct psychopathological conditions (e.g., Lundervold et al., Second, because psychopathology is associated with impairments in the executive network of attention, Snyder et al.  argued tAltogether, although we agree with Snyder et al.  that an AH had the initial ideas and wrote the first draft of the manuscript. All authors then revised the manuscript critically and contributed to and have approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Adaptation and homeostasis, the ability to reach stable attractor states within changing environments, are the most typical characteristics of biological systems. A recent study by Benucci et al.  reportedWhile it is an intriguing idea, assigning V1 a role as a probability detector that integrates incoming information over a considerable time of multiple seconds, our own data (Nortmann et al., Although the stimulation protocols in the studies outlined here have differed in several aspects, we think a link between them exists. The biased stimulation protocol in Benucci et al.  inevitabRegardless of the underlying neural mechanisms: which benefits are provided by cortical adaptation in the hundreds of milliseconds up to second ranges? One may ask the question the other way around: which disadvantages are brought about by longer adaptation times? As often, the answer depends on the task. We suggest that this is when eye movements come into play. For inspection of fine details within natural scenes, high-frequency sampling is useful (Rucci et al., In the study by Benucci et al. , the denThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Materials with the much-loved perovskite structure are being used to develop and test new methods for interpreting local structural arrangements in crystals, and these methods are in turn uncovering unexpected new structural insight. Nature Materials published in September 2014). Indeed the nature of their phase transitions and phase transition sequences are probably some of the most extensively studied of all crystal systems.Crystallographers have been drawn to the family of perovskite-structured materials for over 70 years, both because their apparent structural simplicity  in 1970  obtained from careful diffraction experiments from powdered samples is correctly touted as a way to determine local structural arrangements  of single crystals; simplicity of measurement; differences in neutron or X-ray scattering contrast; impact of powder averaging etc. They then concentrate on two methods for analysing the PDFs \u2013 \u2018small box\u2019 and \u2018big box\u2019 methods. Again this is a choice that can only be made on a case-by-case basis: small box methods such as PDFgui  refinements (Tucker et al., 2007How to decide whether a single-crystal diffuse scattering measurement or pair distribution function measurement \u2013 or indeed a combination of the two \u2013 is preferable for a given structural disorder problem is the main topic of an article by Whitfield  al. 2016 in this RMCprofile (Tucker et al., 2007et al., 2014When assessing the big box methods the authors do not use the routinely available RMC codes such as e.g. Keeble et al., 2013et al., 2015et al. (2016There is now a wealth of evidence to show that the more local structure is investigated the more we are obliged to reassess our understanding of crystalline structure and behaviour and, perhaps typically, perovskite-structured systems are again at the forefront ( al. 2016 emphasiz"}
{"text": "Just as there is a huge morphological and functional diversity of neuron types specialized for specific aspects of information processing in the brain, astrocytes have equally distinct morphologies and functions that aid optimal functioning of the circuits in which they are embedded. One type of astrocyte, the Bergmann glial cell (BG) of the cerebellum, is a prime example of a highly diversified astrocyte type, the architecture of which is adapted to the cerebellar circuit and facilitates an impressive range of functions that optimize information processing in the adult brain. In this review we expand on the function of the BG in the cerebellum to highlight the importance of astrocytes not only in housekeeping functions, but also in contributing to plasticity and information processing in the cerebellum. It has been proposed that PCs remain in the upstate because calcium-dependent K+ channels gradually inactivate after hyperpolarization (Wang et al., + but under which conditions this happens in the intact brain requires further investigation.Astrocytes including BGs act as large sinks for redistribution of ionic gradients and could thereby have significant impact on neurotransmission and excitability of neurons (Newman et al., in vivo (Bekar et al., BGs like other astrocytes express receptors for the neurotransmitter noradrenaline and activation of such receptors can trigger calcium elevations (Salm and McCarthy, Possibly, noradrenaline release also contributes to BG activation during sensorimotor stimulation. Indeed during head-fixed treadmill locomotion (Nimmerjahn et al., In vivo two-photon microscopy recently revealed that zebrin-positive zones not only define sharp anatomical borders, but also show a sharp delineation of functional responses to sensory stimuli (Tsutsumi et al., The modular organization of the cerebellum into parasagittal zones as defined e.g., by Zebrin, or other markers Figure  has been+ (Wang et al., post hoc immunohistochemistry for zone-delimiting proteins, or transgenic mouse models that allow direct visual selection of BGs in cerebellar zones should advance our knowledge in this regard. A combination of targeted electrophysiology (Kitamura et al., BG are versatile in their function and highly integrated in the cerebellar circuit. However, many questions remain about their exact contribution to information processing in the cerebellum. High surface-to-volume ratios and thin stalks endow BG microdomains (Grosche et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Since its widespread introduction in the early 1980s, immunoglobulin therapy (IG) has been extensively investigated to understand its mechanism of action and clinical benefits. Research has also continued to improve its production. The survival benefits of IG for patients with primary immunodeficiency (PID) are accepted , or subcSimple replacement of the antibody defect in PID is now known to be an incomplete explanation of the mechanism of IG. A range of immunomodulatory and anti-inflammatory mechanisms are involved . These mThe increased demand for IG has also seen the rapid development of new manufacturing methods replacing the traditional Cohn fractionation system . This sylow B cells. Matucci et al. (This Research Topic of Frontiers in Immunology has been assembled by an editorial team which have experienced sufficient \u201cdark forebodings\u201d  regardini et al.  discuss i et al.  discuss Taken together, this body of work mitigates our \u201cdark forebodings\u201d regarding the lack of clarity on the mechanism of action of IG. More work is also needed to optimize therapeutic practice. Kerr et al.  note theThe final component of this Research Topic of Frontiers in Immunology examines the manufacture of IG therapies and its effect on the efficacy and safety of the products. Goldacker et al.  show thaOverall, the therapeutics of diseases caused by a deficiency or an inappropriate type of antibodies continues to be an exciting and fruitful area of clinical research, and well suited to contribute to the ongoing evolution in medicine toward more individualized and patient centric paradigms. We hope that this Research Topic of Frontiers in Immunology contributes to this debate. Such a wide debate between experts is necessary to enable the new challenges in immunoglobulin usage.Albert Farrugia provides contractual consulting services to companies which manufacture therapeutic immunoglobulin. Marcella Visentini and Isabella Quinti have no conflict of interest to declare."}
{"text": "A recent study by Forsaa et al.  details In this study, Forsaa et al.  utilizedForsaa et al.  suggest As shown by Forsaa et al's  long-terCurrently, complete understanding of the pathophysiology of dyskinesias and motor fluctuations remains elusive. However, both appear to be associated with the degree of dopamine depletion and the use of levodopa (L-Dopa) . This is limiting in that it is a fairly crude measure of \u201cfreezing,\u201d which may not allow for identifying of subtler aspects of gait. However, until recently, more expansive questionnaires detailing in-depth descriptions of FOG were unavailable (Nieuwboer et al., Given the high frequency of FOG in the PD population and its inherent negative consequences, more research into the pathophysiology, treatment and prevention of this symptom is necessary. Forsaa et al.  demonstrThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The Editorial on the Research TopicMechanical Loading and BoneTobias et al. and Janz et al. address important methodological issues concerning the use of accelerometers to record physical activity in a way that is relevant to mechanical loading of bone. Two separate papers by Toshihiro Sugiyama et al. discuss how understanding of skeletal responses to mechanical loading can help interpret the mechanism of action of bone anabolic drugs. The paper by Zengin et al. illustrates how understanding of mechanical loading responses can be used to interpret ethnic differences in skeletal structure. Of the six laboratory papers, those by Meakin et al. and Vazquez et al. focus on methodological approaches to study mechanical loading in vivo and in vitro, respectively. Four of the papers explore the mechanisms involved in mediating different aspects of mechanical loading responses of bone. Garc\u00eda-L\u00f3pez et al. report their findings concerning the mechanisms involved in the inhibition of bone resorption by cyclical mechanical strain in vitro; Kang and Robling review the role of the Wnt pathway in mechanotransduction; Alzahrani et al. review the mechanisms involved in distraction osteogenesis; and Betts and M\u00fcller review theories and models of mechanical regulation of bone regeneration after bone injury.This Research Topic comprises 11 interesting and topical articles describing a mixture of clinical and laboratory approaches to how mechanical loading influences the skeleton. Of the five clinical papers, those by Janz et al. use conventional counts per minute thresholds but apply a relatively high threshold denoting vigorous PA on the basis that such activity is more likely to be osteogenic, as borne out by their results. By contrast, Tobias et al. extracted the number of counts beyond specific g thresholds on the basis that these are more directly related to ground reaction forces.The papers by Tobias and Janz represent contrasting approaches to study the relationships between physical activity and bone measures based on accelerometry. While the former addresses the role of physical activity in preserving bone in older people, and the latter examines its role in bone accrual in childhood. Moreover, these papers utilize distinct approaches to extract relevant information about mechanical loading from accelerometry data. Toshihiro Sugiyama et al. suggest that the reason why gains in bone at the outer surface are limited is because simultaneous gains at the inner surface act to limit strain at the outer surface. In a further hypothesis article, the same authors, Sugiyama et al. suggest that the anti-sclerostin inhibitors blosozumab and romosozumab are particularly effective at simulating bone formation as a consequence of their ability to overcome negative feedback of the mechanostat by interfering with this process due to its dependence on sclerostin. In their review of ethnic differences in bone health, Ayse Zengin et al. conclude that differences in fracture rate between ethnic groups cannot adequately be explained by differences in areal bone mineral density, suggesting the need to describe these based on more detailed measures of bone structure. Differences in the latter may in turn reflect ethnic differences in muscle mass and force, or alternatively how the skeleton responds to mechanical loading by these factors.The remaining three clinical papers illustrate how understanding of mechanical loading responses can be used to explain findings from epidemiological to interventional studies of the skeleton. In their hypothesis article on teriparatide effects on bone, Meakin et al. and Vazquez et al. describe contrasting methodological approaches to studying the mechanisms that mediate mechanical loading responses. Meakin et al. describe how use of in vivo studies based on a range of animal models has contributed to our understanding of the type of strain stimulus to which the skeleton is most responsive. Vazquez focuses on in vitro models of mechanical strain responses, describing a novel 3D osteocyte\u2013osteoblast co-culture system.The papers by Garc\u00eda-L\u00f3pez et al. report that cyclical strain of osteoblast monolayers reduces expression of the bone resorptive cytokine RANKL, but surprisingly other cytokines that might be expected to mediate this response show a paradoxical increase in expression. The review by Kang and Robling focuses on the role of Wnt signaling in mediating osteogenic responses to mechanical strain and suggests that while LRP5 is known to be involved, the closely related receptor LRP6 may also play a hitherto unrecognized role.The remaining four laboratory papers describe different aspects of the mechanisms involved in mechanical loading responses. Alzahrani et al. discuss how characterization of the molecular pathways involved in mediating responses to mechanical loading can be used to select improved protocols for distraction osteogenesis, a surgical technique used to treat bony deformities via limb lengthening. Finally, in their paper, Betts and M\u00fcller review the different experimental studies, models, and theories that explain how mechanical stimuli are sensed and incorporated during bone regeneration as part of the healing process after bone injury.In their review article, Together, the 11 papers published in this Research Topic provide a good illustration of how mechanical loading underpins many facets of bone biology, including the pathogenesis and treatment of osteoporosis and other clinical disorders associated with skeletal fragility.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Recently, Bettina Maria Fischer and colleagues of the Institute of Toxicology in Karlsruhe have published data on a gene expression based predictive test system for chemical carcinogens . The auIdentification of chemical carcinogens represents a cutting-edge topic in toxicology (Liu et al., 2015; Bustaff"}
{"text": "Major depressive disorder (MDD) affects more than 10% of the population, although our understanding of the underlying aetiology of the disease and how antidepressant drugs act to remediate symptoms is limited. Major obstacles include the lack of availability of good animal models that replicate aspects of the phenotype and tests to assay depression-like behaviour in non-human species. To date, research in rodents has been dominated by two types of assays designed to test for depression-like behaviour: behavioural despair tests, such as the forced swim test, and measures of anhedonia, such as the sucrose preference test. These tests have shown relatively good predictive validity in terms of antidepressant efficacy, but have limited translational validity. Recent developments in clinical research have revealed that cognitive affective biases (CABs) are a key feature of MDD. Through the development of neuropsychological tests to provide objective measures of CAB in humans, we have the opportunity to use \u2018reverse translation\u2019 to develop and evaluate whether similar methods are suitable for research into MDD using animals. The first example of this approach was reported in 2004 where rodents in a putative negative affective state were shown to exhibit pessimistic choices in a judgement bias task. Subsequent work in both judgement bias tests and a novel affective bias task suggest that these types of assay may provide translational methods for studying MDD using animals. This review considers recent work in this area and the pharmacological and translational validity of these new animal models of CABs.http://dx.doi.org/10.1111/bph.2014.171.issue-20This article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit  Recently, there has been a move towards establishing translational methods for research into MDD, although the nature of this disease presents challenges for emulating aspects of the disorder in non-human species  are initially associated with a specific spatial location. Judgement bias is then evaluated by measuring the latency to approach both the reference locations and intermediate positions. A negative bias in this version of the task is seen when the animal makes a slower response to an intermediate position, indicating a reduced anticipation of finding the reward. Where an aversive food outcome such as quinine-treated food is used, the slowed responding is proposed to show an expectation that the intermediate location is associated with the aversive outcome. Using this approach, Richter et al.  showed t et al., , a congeet al., et al., Only one judgement bias study has been reported for mice where odour cues were used to predict rewarding or aversive food outcomes , retinoic acid (the active ingredient of the anti-acne medication roaccutane) or FG7142 (a benzodiazepine inverse agonist) that caused severe anxiety in humans (Dorow et al., et al., Pharmacological and psychosocial stress manipulations were used to assess the validity of the approach (Stuart et al., et al., et al., One potential issue with this task is the possibility that the drugs or affective state manipulations have a direct effect on learning and memory or appetite which thus leads to a subsequent bias in the memory of that experience. Initial experiments suggested that effects are not associated with impairments in learning, as animals performing the task show similar rates of learning on treatment and control discrimination learning sessions. Sedative effects can also be controlled for within the protocol as latencies to approach the bowl are recorded (Stuart et al., et al., et al., A possible criticism of the findings in the affective bias test is that response biases are seen after acute treatments. The field of depression has been dominated by the notion that antidepressant drugs have a delayed onset of clinical efficacy. This criticism has been applied to established assays of depression-like behaviour such as the FST and also used to support the improved validity of tests of anhedonia. However, a key issue with the delayed onset of action of antidepressant drugs is that this observation is based on the subjective reporting of mood in patients and does not necessarily mean that the acute biochemical effects of the drug are not relevant to its efficacy. In fact, the recent observation that acute treatment with antidepressant and prodepressant drugs in healthy volunteers can cause CABs (e.g. Harmer et al., Overall, the results for the affective bias task suggest this approach has good predictive and translational validity. The data obtained correspond well with similar acute drug studies carried out in healthy volunteers performing emotional recognition and characterization tasks (see Pringle et al., et al., et al., et al., et al., Although not necessarily defined specifically as a measure of CAB in MDD, probabilistic reversal learning tasks do offer a translational method to study how reward and punishment processing are altered in this disorder (Swainson et al., et al., A rodent probabilistic reversal learning task has been evaluated in one study where serotonergic manipulations, including the antidepressant, citalopram, were investigated in normal rats (Bari The focus of this review is two behavioural approaches which have been developed to study CABs in depression using rodents. Although still in the early days of development, results so far suggest that CABs can be studied in rodents, with both decision-making during ambiguous cue interpretation and learning and memory being similarly biased by affective states in rodents and humans.et al., et al., et al., et al., et al., et al., In terms of affective state induced cognitive biases, the results from judgement bias tasks provide robust and relatively well-replicated findings that animals in a putative negative affective state exhibit negative judgements when interpretation of ambiguous cues is evaluated. Results from the affective bias test also suggest that both stress-induced negative affective states and prodepressant drug treatments negatively bias reward-associated learning and memory, resulting in a relative decrease in the value attributed to a rewarding experience. These observations correspond well with data from patients with MDD (Mathews and MacLeod, et al., Pharmacological studies using these approaches are still limited and further studies in this area are needed. In terms of understanding the value of the tasks for preclinical drug development and safety pharmacology, more detailed studies using drugs with known antidepressant and prodepressant effects in humans would be of value. Pharmacological studies also offer a route to understanding more about the neural and neurochemical mediators of CABs and studies using rodents can help reveal the neurobiological processes which modulate these behaviours. This type of work has the potential to deliver a greater understanding of the relationship between CABs and MDD which may also reveal novel drug targets for improved treatments. The development of translational animal models of CABs in MDD can also be used to investigate the emerging cognitive neuropsychological hypothesis of MDD and antidepressant efficacy (Harmer,"}
{"text": "Their paper highlights the importance of clarifying the mental health challenges associated with eye diseases, such as macular degeneration and diabetic retinopathy (Mathew et al., Visual disorders are associated with a substantial economic and personal burden Rein, . The recGall et al.  argue thFurthermore, Gall et al.  also fouThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Recently published results seemed to show power law scaling of phase synchronization, a characteristic that we have previously interpreted as indicative of critical dynamics, in \u201cempty room\u201d MEG recordings. Here we show that the results we previously reported on scaling of phase synchronization in human MEG data are not compromised by these apparently anomalous results. By extensively reanalysing the empty room MEG data using identical methods to those previously used for analysis of human MEG data, we demonstrate the validity of our prior results and explain the anomalous empty room results.PLOS Computational Biology \u2026\u20261]\u2026a powThe editors of We accept the principle of this criticism. If power law scaling can be demonstrated, by PLI or any other metric, in MEG data recorded from an empty room then this is conceptually problematic for interpretation of power law scaling in human MEG data as a marker of self-organized criticality, or any other complex biological dynamics.To assess the extent to which this criticism actually applies to the results reported by , we haveWe begin by clarifying exactly how the MEG data in Kitzbichler et al.  were colThe paper by Shriki et al.  reportedThus, it was clear, on close review of the methods used in the two papers, that the results were based on different pre-processing pipelines and somewhat different estimators of phase synchronization. In short, the two methods differed in detail and they were not exactly the same.To investigate the impact of these differences in MEG pre-processing and estimation of phase synchronization, we reanalysed the Cambridge and NIMH data previously reported by Shriki et al. using the methods implemented by Kitzbichler et al. Specifically, we used a pre-processing pipeline that optionally included notch filtering to remove line noise, and we used the wavelet-based estimator of PLI as originally proposed.Some of the results of this reanalysis are summarised in Specifically in relation to Dr Farmer\u2019s comment that highlighted this issue and motivated our reanalysis of these data, we conclude that the methods and results reported by Kitzbichler et al. are not, in fact, compromised by the apparently problematic results reported by Shriki et al. The evidence for power law scaling of synchronization metrics in empty room data provided by Shriki et al. is not reproduced when exactly the same methods described by Kitzbichler et al. are applied to analysis of the empty room data reported by Shriki et al. We therefore consider that the observation of power law scaling in PLI measures on empty room data reported by Shriki et al.  does notCare should be taken when applying the PLI metric to new MEG data whose background noise structure may not be previously well understood. Standard pre-processing steps have to be applied, such as line-noise removal or signal-space separation, but one should be mindful of the fact that all of them also change the covariance structure of the data.More generally, we conclude from this analysis that it is indeed a useful \u201csanity check\u201d to test any proposed method for MEG analysis on data recorded from an empty room. Consistency of results between empty room and human recordings may be indicative of a confounding effect of the instrumentation or analysis: in this case, the presence of low amplitude line noise substantially contributed to the existence of power law scaling in the empty room data reported by Shriki et al. . We also"}
{"text": "This Research Topic presents knowledge on transition metal metabolism in various infections from the dual perspective of offender and defender.To date, the implication of divalent metals have been described in two different immune strategies that aim to fight microbial invaders. One consists in depriving microbes of essential divalent metals whereas the other aims at overloading invaders with toxic concentrations of metal. The contributions in this section present, in different situations, various aspects of this metal economy at the host-microbe interface.metal homeostasis as hosts interact with bacteria. Diaz-Ochoa et al.  a bacterium that does not require iron for its metabolism.Lastly, n et al.  review tn et al.  review Fn et al.  present The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Philosophical Transactions of the Royal Society.The summer of 2022 has seen remarkable hydrological conditions across much of the Northern Hemisphere. Europe has seen what could be the most severe drought conditions to hit the continent for more than 500 years , with exDrought risk in the Anthropocene\u2014reflects the recognition that the Earth System is human-influenced to an extent that we are said to be living in a new geological era [et al.  [et al. (Using machine learning to identify novel hydroclimate states) [First, it is clear that droughts are profoundly human-influenced, and we expect them to be even more\u00a0so in the future. The title of this themed issue\u2014ical era . Droughtections)  explains states)  use a neet al. in [et al.  [Besides anthropogenic climatic changes, human activity has impacted the Earth's surface and catchments through land use change, urbanization and infrastructure construction. These changes have modified the ways in which meteorological droughts propagate into hydrological droughts. The expansion of irrigated agriculture and water use in cities and industries means that human water withdrawals are often the most significant drivers of water scarcity. Since the introduction of the concept of planetary boundaries by Rockstr\u00f6m t al. in , there hndaries)  continueet\u00a0al.'s article (Benchmark worst droughts during the summer monsoon in India) [et al.'s article  [et al.  [Second, the processes by which droughts materialize are extraordinarily complex. They vary enormously across space. Readers will obtain insights into the complexity of local processes by reading the basin-scale and regional analyses in this themed issue, including Mishra n India) , which estralia) , which asystems)  illustraet al.'s article examines the response of birds in the Murray-Darling Basin, which adds to ongoing debates in the literature on the ecological impacts of droughts. Ecosystems are naturally resilient to droughts, but when they are already degraded because of other anthropogenic impacts, extreme droughts may push ecosystems into a state from which they cannot recover\u2014more research is required to establish under what conditions that hypothesis is true. This emphasizes the point that climate change needs to be viewed in the context of multiple stressors on the environment.Finally, droughts have multiple impacts and those impacts are profoundly modified by adaptation responses. Quentin\u00a0Grafton Barbier's  review aet al.  [et al. [et al. [et al. [et al.  [This themed issue documents important scientific advances that are improving understandings of droughts and the evidence needed for drought management. There have been rapid advances in drought forecasting, which are documented in the paper by AghaKouchak casting) . These a [et al.  for anal [et al.  demonstr [et al.  applies hailand)  reports As one would expect from the Chief Executive of England's Environment Agency (which has responsibility for regulating the water environment and drought planning), Sir James Bevan's concluding article (Drought risk in the Anthropocene: from the jaws of death to the waters of life)\u00a0 focuses"}
{"text": "In the recent article by Thomas et al.\u00a0, the autInfluence of vegetation structure, seasonality, and soil properties on rodent diversity and community assemblages in west Mount Kilimanjaro, TanzaniaThe authors apologize for the error."}
{"text": "Perinatal mental health problems, defined as mental health problems occurring from the start of pregnancy to one year after birth, substantially affect women's and children's quality of life in low- and middle-income countries. In South Africa, despite high prevalence and documented negative impacts, most women do not receive any care.A modelling study examined the costs of perinatal mental health problems, namely depression and anxiety, for a hypothetical cohort of women and their children in South Africa over part of their life course . In sensitivity analysis, additional impacts of post-traumatic stress disorder (PTSD) and completed suicide were included. Data sources were published findings from cohort studies, as well as epidemiological and economic data from South Africa. Data from international studies were considered where no data from South Africa were available.Lifetime costs of perinatal depression and anxiety in South Africa amount to USD 2.8 billion per annual cohort of births. If the impacts of PTSD and suicide are included, costs increase to USD 2.9 billion. This includes costs linked to losses in quality of life (USD 1.8 billion), losses in income (USD 1.1 billion) and public sector costs (USD 3.5 million).Whilst important progress has been made in South Africa with regards to mental health policies and interventions that include assessment and management of perinatal mental health problems, substantial underinvestment prevents progress. Findings from this study strengthen the economic case for investing in perinatal mental health care. In Soutet al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., In addition to causing substantial human suffering for women, there are well-established adverse impacts of untreated perinatal mental health problems on pregnancy outcomes, infant growth and development, and offspring educational attainments . We included all women aged 15 to 39 years who gave birth in 2017. This is the age range when most women or girls give birth. To estimate the economic impact of perinatal mental health problems during the antenatal period, adjustments were required to include women with still-births. For simplicity, no adjustments were made to reflect multiple births (e.g. twins) since this figure is very small. In line with the UK study  were estimated from the number of children exposed to perinatal psychological distress (which overlaps with depression and anxiety) based on work by MacGinty and colleagues , which include the impact of COVID-19 on GDP for 2020. For simplicity, and to reflect an uncertain outlook for economic recovery in South Africa, we applied 2020 GDP values for subsequent years.Disability weights and unit costs (multiplied by assumed disease durations) were assigned to adverse impacts for mothers and children. Our approach follows recommendations by the WHO to include costs borne by both government and wider society WHO, . Here, gEconomic consequences linked directly to mothers are losses in quantity and quality of life (measured by DALYs) and in productivity.et al., DALYs were calculated based on the number of women with depression or anxiety, disability weights and a duration of 3 months over which the problems last , productivity losses (linked to stunting) and hospital care (linked to severe lower respiratory tract infections in the first year after birth). Effects on DALYs were calculated for the additional number of children who experience severe lower respiratory tract infections in the first year after birth, asthma, or internalising or externalising mental health problems. Disability weights were for: severe infections to reflect severe lower respiratory tract infections; partly controlled asthma to reflect asthma; a weighted average for moderate depression or anxiety to reflect internalising problems ; moderate conduct disorder to reflect child externalising problems. There is no disability weight for stunting and so we did not include this in the calculation of quantity or quality of life losses.et al., et al., et al., et al., Depending on the data, different assumptions were made about disease durations or persistence of health impacts. The impact of children's mental health problems was assumed to persist for 40 years, a figure supported by national longitudinal study data up to 10 years later (Verkuijl https://www.labourguide.co.za). The strong negative links between stunting, lost school years and earnings \u2013 and the impact of perinatal depression on these outcomes \u2013 are well established from previous studies . In keeping with global methods  suicide during the perinatal period only in sensitivity analysis, as reliable data on suicide are particularly difficult to obtain in low- and middle-income countries  and to losses in income of USD 1.1 billion (USD 0.9 billion for mothers and 0.2 billion for children). Total societal costs are USD 2818 per woman giving birth if the impacts of PTSD and completed suicide are excluded and USD 2966 if they are included. The share of total costs falling on the public  sector is comparatively small: USD 3.5 million for the cohort, linked entirely to short-term costs for hospitalisations of the infant. Over 77% of the costs of reduced quality of life are linked to the child, whilst 85% of the costs of lost income are linked to the mother. If it is assumed that costs would occur at the same rate over a 40-year period, then total costs calculated here would be equivalent to a yearly cost of USD 0.12 billion for the total population in South Africa and USD 122 per child born per cohort of women and children.each year. Costs increase further when PTSD and completed suicide impacts are considered. To our knowledge, this is the first study to assess the long-term and intergenerational costs of perinatal mental health problems in South Africa. The study established the costs in one African country, which was feasible because relevant data sources were available, including data from large, well-conducted birth cohort studies. Whilst similar prevalence and impacts are likely to occur in other African countries, a lack of data currently prevents estimating those. The methodology employed here would be applicable to other countries where the necessary data are available and would thereby help to make the case for investment.Lifetime costs linked to perinatal mental health problems in South Africa are very high. If one considers the impacts of both perinatal depression and anxiety on women (for 10 years) together with the impacts on their children (for 40 years), these costs amount to USD 2.8 billion per cohort of women giving birth et al., et al., et al., et al., Our study has several strengths. By taking a long-term and intergenerational perspective on costs, it addresses a gap that commonly occurs because studies only consider the short-term costs to individuals with the condition, a limitation that has been highlighted by the WHO  suggesting a relatively higher burden of perinatal mental problems. This is supported by evidence of the higher prevalence and more substantial health and economic impacts of mental health problems in low-and middle-income countries compared with high-income countries (Howard et al., et al., et al., Results from this study are consistent with previous findings. It has been estimated that the yearly costs of depression and anxiety among the general adult population globally amount to USD 1.15 trillion (Chisholm et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Action is needed now to reduce the large human and economic costs of mental health problems to the population, which have been increasing as a result of the COVID-19 pandemic. This action should draw on local evidence for sustainable mental health financing strategies (Docrat This study demonstrates the substantial costs to women, their children and to society of unaddressed perinatal mental health problems in South Africa. To avert ongoing costs, sustained investment is required to address perinatal mental health problems. Future research on the return on investment of scaling evidence-based interventions would yield further valuable data for government decision making."}
{"text": "Skin diseases are widespread and a frequent occurrence in general practice. Providing access to medical care and high accuracy of diagnosis are important issues, specifically when it comes to distinguishing benign conditions from malignancies such as melanomas where early diagnosis and treatment increase overall survival and cure rates .Dermatologists diagnose skin lesions from dermoscopic or clinical images by performing visual inspection. To support the diagnostic process that might be slowed by an increasing workload as well as a lack of specialists in certain areas of the world, methods for computer-aided detection and computer-aided diagnosis for skin lesion image analysis have been developed . Among tThis Special Issue presents the latest advances in the use of machine learning techniques for image analysis of skin lesions. A total of six papers were selected for publication, including one review article and five papers with excellent technical contributions. All articles underwent a peer-review process with typically two rounds of review, with at least three experts in the field carefully reviewing each submitted paper.In their study titled \u201cUncovering and Correcting Shortcut Learning in Machine Learning Models for Skin Cancer Diagnosis\u201d, Nauta et al.  investigIn their study titled \u201cIntegrating Domain Knowledge into Deep Learning for Skin Lesion Risk Prioritization to Support Referral in Teledermatology\u201d, Carvalho et al.  present Chen et al. , in theiMoldovanu et al. , in theiKhan et al. , in theiKassem et al.  provide Diagnostics support team for their help in preparing and finalizing this Special Issue. We would also like to express our gratitude to all reviewers for their timely and professional comments.In this editorial, we briefly introduced the promising articles selected for this Special Issue and hope that they will inspire interested researchers to pursue future studies. Finally, we would like to thank all the authors who submitted their valuable manuscripts and the"}
{"text": "Loneliness and social isolation are critical for health and wellbeing. Social isolation is a well-established social determinant of health, and its ill effects have been well-recognized for decades. Over the last 20 years, researchers have increasingly advocated that our health and wellbeing are not only detrimentally affected by being alone but also by feeling lonely  . LonelinThe way in which loneliness and social isolation contribute to mental health and wellbeing may be different during the COVID-19 pandemic. This was particularly evident after public health measures such as social restrictions, including national or localized lockdowns, were implemented. Furthermore, quarantine or self-isolation was also recommended for reducing infection . It is pResearch interest in this topic has accelerated, with the number of publications about \u201csocial isolation\u201d or \u201cloneliness\u201d jumping significantly since 2020 . This reBentley et al.; Liu et al.; Okajima et al.; Mansour et al.; Chernova et al.; McDowell et al.; Peng et al.; Lv et al.; Luo et al.; Pilcher et al.) or \u201ccoronavirus\u201d  in the title, and another study  tracked changes over time during the pandemic. Two papers were unrelated to the pandemic . There was a report originally submitted to this Research Topic but it was eventually published in another section of this journal .Five studies analyzed young participants aged 13\u201329 years old. r people , none ofLiu et al.; Lim et al.; McDowell et al.; Lv et al.), three analyzed distress  and anxiety , and two analyzed sleep or sleep problems . In addition, there were international collaborations during the pandemic . The first study examined the association between loneliness and distress in the early stage of the pandemic in eleven countries . A subset of countries (three countries) in the study also repeated the analysis 3 months later and revealed that increased loneliness over time was associated with increased psychological distress . The second study examined how social restrictions contributed to the severity of loneliness, depression, and social anxiety in participants recruited from the United Kingdom, Australia, and the United States . The authors found that as social restrictions eased, loneliness and depression reduced, but there was an increase in social anxiety. Overall, the findings of these studies highlighted how sleep problems, social anxiety, and depression are interrelated (Most studies analyzed social isolation and loneliness and their impact on mental health symptoms or related issues. Four studies analyzed depression (pandemic . Two intrrelated . HoweverThe restrictions imposed on people's lives due to COVID-19 have come as a critical reminder of how fundamental social relationships are to our mental health and wellbeing. Countries around the world observed increasing rates of mental ill health during the pandemic and responded with significant government investment and policy changes to combat it .Overall, the pandemic and its associated consequences for health and wellbeing may have highlighted the critical need for being around people and being meaningfully connected to others around us. A deeper knowledge of loneliness and social isolation is required to allow us to better understand their impact on mental health and wellbeing.HK wrote the first draft of the manuscript. ML wrote sections of the manuscript. All authors contributed to the conception, manuscript revision, read, and approved the submitted version."}
{"text": "Since ancient times, natural products have always been used as remedies for more or less serious pathologies. The great advantage of traditional medicine lies above all in the wealth of experience obtained \u201cin the field\u201d by experimenting with different natural products and different preparations to deal with specific diseases.Only recently, starting from the information of traditional medicine, an attempt has been made to apply a more \u201cscientific\u201d approach, trying to actually evaluate which molecules present in the natural preparation have the therapeutic effect.The awareness of being able to \u201ctake a cue\u201d from the natural world in the process of developing new drugs has also developed from this approach, especially as these compounds are generally well tolerated and with reduced (or no) side effects.In this context, therefore, traditional medicine plays a predominant role in the discovery of new drugs based on natural products, leading to the continuous need to study new herbal matrices for pharmaceutical and nutraceutical purposes, coupled with a continuous progress of the techniques applied to the characterization of natural matrices and to the evaluation of the observed biological activities, in order to better identify the bioactive compounds.Herbal medicines contain hundreds or even thousands of primary and secondary metabolites, and it is a vital task for pharmacologists to explore which components contribute to the therapeutic effects of herbal medicines and which compounds do not. The complexity and low content of the chemical constituents of these metabolites in herbal medicines pose complex challenges. Up to now, the active components of most herbal medicines remain obscure, which hinders further pharmacological study and development of herbal medicines. In this scenario, the possibility of evaluating and characterizing herbal medicines is of great importance in order to obtain a product that is safe for human health, standardized, whose effects have been studied and evaluated from all points of view.in vivo characterization of metabolites by pharmaco-metabonomics techniques or ex vivo models focusing on the delivery, for example, in the gastrointestinal tract.In general, the absorption of these metabolites needs to be understood in order to evaluate their potential therapeutic effects. Up to now, pharmacologists have tried many methods and techniques to explore the pharmacodynamics of herbal medicines. This includes the in vivo, on new unreported biological activities or biological targets, and on new bioactive compounds as leads for the pharmaceutical industry.In this Research Topic, the main goal aims to attract innovative original contributions in the interdisciplinary area in order to understand the relative impact of different compounds/compound classes to reported pharmacological effects, but also to highlight the state of the art on profiling of metabolites\u2019 pharmacokinetics This result can be achieved through a multidisciplinary approach that involves not only pharmacology and botany, but also disciplines such as analytical chemistry , pharmaceutical chemistry, physiology, and biochemistry.Through an integration of these disciplines and knowledge, it is possible to describe and characterize most of the observed.In the papers accepted after peer review in this Research Topic, it is also highlighted that in recent years the search for products of natural origin that can be used as they are or as lead compounds for the pharmaceutical development of new drugs is increasingly a central element of scientific research.Zeng et al., Fan et al., and Wang et al. Today these uses are being rediscovered, however, trying to follow a more scientific and systematic approach, associating what has been traditionally observed with chemical characterization and innovative techniques for evaluating biological activity in order to find a possible correlation. Han et al., Wan et al., Zheng Li et al., and Xu et al., which report approaches to proteomics, metabolomics and new strategies, respectively, amply highlight this.What we have seen so far has foundations in the traditional use of many products of plant origin, as highlighted by He et al., Gao et al., and Yang et al., focus their attention on specific markers of some native products and try to evaluate their targets and their respective biological effects.Other authors such as Jing et al., Gao et al., Hui-Yu Li et al., and Zixuan Li et al., instead closely evaluate traditional uses with respect to specific pathways involved in various pathologies.Nan et al., Xuerui Wang et al., and Su et al., instead evaluate how pills and capsules containing natural products can show therapeutic and/or preventive effects against human pathologies. Interesting the work of Pan et al., which reports how metabolomics studies carried out by hyphenated analytical approaches of LC-MS allow to evaluate and correlate the effects of EGCG on A549 cells."}
{"text": "A recent meta-analysis by Vaz et al. explored the vestibular function before and after cochlear implantation (CI) objectivated by cervical vestibular evoked myogenic potentials (cVEMP), the caloric test, head impulse test, and the video head impulse test (vHIT) . A speciAlterations of Vestibular Function in Cochlear Implantation.raison d'\u00eatre of meta-analyses. Furthermore, Vaz et al. report the number of participants in the study of Rasmussen et al. to be 43, while the actual number being reported is 35 (Vaz et al. include data from the paper of both West et al. and Rasmussen et al. even though it is beyond doubt the same patients and preoperative outcomes that are being reported , 3. ThisVaz et al. wisely reflect on the reliability of the cVEMP following CI. However, they do not fully encapsulate the complexity of abnormal cVEMP results and by which caution they should be interpreted, despite critical evidence mounting , 5. SomeThe author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
{"text": "For the past 20 years, mesenchymal stromal cells (MSCs) has become the most studied cell population in the development of adult cell therapies for disease treatment . MSCs caetc  of the cell sheets to standardize the cell sheets release criteria in GMP facilities.There is still a debate around effective delivery and use of MSCs in treating diseases, by injection, by transplantation or by using the secreted extracellular vesicles. The cheapest and fastest methodology is the injection of isolated cells. Injection of cells showed encouraging results, but the long-term effects of MSCs are unknown in terms of treating the diseases, or impairing organ function due to random anchoring of the MSCs. In addition, the survival of injected MSCs is very low , which cvivo studies cannot be explained by the number of cells that reach their target . In addition to the topics mentioned, other crucial subjects about MSCs are presented and discussed in the research topic like priming by Berglund et al., alleviation of ischemia injuries by Arjmand et al. and Chua et al., development of tendinopathy animal model for MSC treatment by Meeremans et al., discovery of new drugs to accelerate MSC differentiation into osteoblast by Wang et al., use of immortalized MSC model for hormonal by Kulebyakin et al., tissue specificity of mesangiogenic progenitors cells by Barachini et al., transcriptional characterization of MSCs by Fan et al. and the impact of MSC senescence state used in clinical trials by Alves-Paiva et al. In order to continue progressing MSC field in clinical applications, academics, clinicians, and industry partners need to continue collaborating, sharing both knowledge and best practices that help to advance this field.Due to the lack of knowledge and experience in MSC clinical applications, federal agencies had to update their guidelines, and keep improving them in parallel to increased pre-clinical and clinical experiences. Food and Drug Administration is a perfect example of how the federal agencies are updating and adding complementary guidelines in the translational field of Cellular and Gene Therapies . From 19"}
{"text": "MrParse is a software package designed to aid decision making in molecular replacement (MR). It performs a sequence search to find search models, not only in the PDB, as would conventionally be performed, but also in the EBI AlphaFold database, and provides a series of analyses relevant to MR such as crystal pathology detection and sequence analysis. MrParse is a new pipeline to help to streamline the decision process in MR by consolidating bioinformatic predictions in one place. When reflection data are provided, MrParse can rank any experimental homologues found using eLLG, which indicates the likelihood that a given search model will work in MR. Inbuilt displays of predicted secondary structure, coiled-coil and transmembrane regions further inform the choice of MR protocol. MrParse can also identify and rank homologues in the EBI AlphaFold database, a function that will also interest other structural biologists and bioinformaticians.Crystallographers have an array of search-model options for structure solution by molecular replacement (MR). The well established options of homologous experimental structures and regular secondary-structure elements or motifs are increasingly supplemented by computational modelling. Such modelling may be\u00a0carried out locally or may use pre-calculated predictions retrieved from databases such as the EBI AlphaFold database.  At the time of writing, 86% of crystal structures deposited in the Protein Data Bank . The first broadly successful algorithms in the field , which in many cases produced predictions that resembled the target as closely as a different crystal form typically would . The often high accuracy of the predictions  makes the database a very significant new source of search models for MR.As MrParse, which addresses a number of issues in MR. It will find and rank search models from both the PDB and the AFDB, providing convenient visualization of the results. It also guides choices in unconventional MR through secondary-structure prediction and predictions of regions that are relevant to MR strategy such as coiled coils  and information about the crystal pathology calculated with CTRUNCATE . As in the PDB search, information from phmmer is used to create a visualization of the search results using Pfam Domain Graphics. For the EBI AlphaFold database, these visualizations are coloured by Predicted Local Distance Difference Test (pLDDT) on an orange to blue scale, where orange indicates very low confidence in the model and blue indicates very high confidence in the model. Additional information is provided about the quality of the AF2 models, including the average pLDDT and a new measure of structural quality called the H-score.H-score can be calculated with the following equation, where N represents a list of pLDDT scores and N, B factors using an algorithm developed for phaser.voyager . Interpreting pLDDT as B factors improves the likelihood of success in MR by downweighting the less reliable regions of the model . These hits all have high sequence identity to our target  and give high eLLG scores . When eLLG is much greater than 60, structure solution by MR is likely to be straightforward  all have lower predicted reliability in this region. Any matches are downloaded from the AFDB and trimmed to match the target sequence and undergo a pLDDT to estimated B-factor conversion to improve their performance in MR. These are downloaded into the models subdirectory in the MrParse run directory.The \u2018Structure predictions from the EBI AlphaFold database\u2019 panel Fig. 1, blue pr3.2.7dry is a crystal structure of Aspergillus oryzae Rib2 deaminase experimentally determined by Zn-SAD  that only covers a 71-residue region of the target protein with 31% sequence identity . This homologue was insufficiently similar to the target protein to succeed in MR. A search of the EBI AlphaFold2 database identified a number of models that covered a larger region of the target protein and with a higher sequence identity. MR with the model of Q12362, the best hit ranked by H-score , was successfully placed by Phaser  and rebuilt with Buccaneer .PDB entry 4.MrParse is designed to bring together a range of relevant information in a single place and present it with useful visualizations and sortable tables. For most effective use, it expects both diffraction data and a target sequence, but it can run without the former. Conventional MR using homologous structures identified in the PDB is supported by the presentation of potential search models, discovered by phmmer, with graphics that illustrate their extent relative to the target and numerical data that illustrate their size and characteristics. In the future, more sensitive HHpred , can be fed directly to programs such as Phaser  methods. The potential of these methods for MR of targets with novel or divergent folds has been recognized for some time (Rigden et al., 2008et al., 2012et al., 2007et al., 2015ab initio methods has historically not always been sufficient for MR and only smaller proteins were tractable using the earliest methods. This picture has changed rapidly in recent years with first AlphaFold (Senior et al., 2020AlphaFold2 (Jumper et al., 2021ab initio structure predictions. Databases based on earlier methods such as GREMLIN (Ovchinnikov et al., 2017PconsFam (Lamb et al., 2019C-QUARK (Wang et al., 2019et al., 2019et al., 2010et al., 2015et al., 2021et al., 2022Perhaps the most exciting and forward-facing aspect of MrParse currently provides a second graphical panel devoted solely to matches in the AFDB. These can be ranked by clicking on column headings for two measures of model quality: the novel H-score described here or the percentage sequence identity between the protein of interest and the model. While the experience of the CASP structure-prediction experiment suggests that many models serve, unaltered, as successful search models, downstream editing of models after retrieval via MrParse will sometimes be necessary (McCoy et al., 2022et al., 2021et al., 2021et al., 2022et al., 2021et al., 2017et al., 2020phmmer (Eddy, 2011CCP4. Happily, the 3D-Beacons initiative (Orengo et al., 2020MrParse in facilitating access to a wide range of potential MR search models, both experimental structures and predictions, will only grow in the future. In addition, its ability to search AFDB in particular and conveniently visualize the results is likely to prove useful to bioinformaticians and cryo-EM researchers (Kryshtafovych et al., 2021et al., 2021Presently, hits are found by a"}
{"text": "The refugee experience is associated with several potentially traumatic events that increase the risk of developing mental health consequences, including worsening of subjective wellbeing and quality of life, and risk of developing mental disorders. Here we present actions that countries hosting forcibly displaced refugees may implement to decrease exposure to potentially traumatic stressors, enhance subjective wellbeing and prevent the onset of mental disorders. A first set of actions refers to the development of reception conditions aiming to decrease exposure to post-migration stressors, and a second set of actions refers to the implementation of evidence-based psychological interventions aimed at reducing stress, preventing the development of mental disorders and enhancing subjective wellbeing. According to recent UNHCR figures, in 2 weeks over two million refugees were forcibly displaced from Ukraine to neighbouring countries UNHCR, . This poet al., The displacement and refugee experience are typically associated with loss of homes, hopes, possessions and disruption of personal, family and professional life projects. In addition, several potentially traumatic events may occur before migration, such as bombings, threats, captivity, torture, injury and witnessing death or injury of loved ones IASC, . Forciblet al., et al., et al., et al., et al., et al., et al., et al., et al., Owing to exposure to potentially traumatic events and other stressors and ongoing living difficulties, forcibly displaced refugees are at risk of developing mental health consequences, including worsening of subjective wellbeing and quality of life  has developed a number of low-intensity psychological interventions that may be scaled up as public health strategies to provide psychological support to refugee populations exposed to adversities WHO, . In addiAs the number of persons in need of protection is likely to substantially increase globally, driven by long-lasting wars as well as by new conflicts such as the Russo-Ukrainian war which broke out recently, national authorities are urged to develop reception and resettlement programs meeting the needs of vulnerable groups. Evidence-based psychological support should be an important component of such reception programs, aiming to prevent the deterioration of poor mental health towards full-blown psychiatric conditions."}
{"text": "Rosa canina fruit, and their use as recyclable and heterogeneous nanocatalysts for the degradation of dye pollutants in water\u2019 by Saba Hemmati et al., RSC Adv., 2018, 8, 21020\u201321028.Correction for \u2018Green synthesis of Pd nanoparticles supported on reduced graphene oxide, using the extract of  Samira Hossein Garakani\u2019s name was incorrectly reproduced on the author listing of the published article; the corrected form is shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
{"text": "We thank Kuo et al. for their comments  on our pMediation analysis is a dynamic and evolving field. Kuo et al. raise the use of the causal steps approach, which was developed in the 1980s . In our To address the validity, we based the models on sound theoretical frameworks from the available literature ,9,11. AdWe agree with Kuo et al. that students should be trained in multiple methods of mediation analyses in order to make informed decisions about the optimal approach for analyzing their data."}
{"text": "COMMENTARY ON Present and future bright and dark spots for coral reefs through climate change.https://doi.org/10.1111/gcb.16083This is a commentary on Sully et al., 2022,  Coral reefs are one of the most threatened habitats on earth with up to 67% of historical global extent now lost and much of the remaining intact coral reef systems facing unprecedented risk from climate change, overfishing and pollution (Eakin et al.,\u00a0The outlook is and continues to be gloomy for many of our coral reefs. Work from Hughes et al.\u00a0 and PandHowever, a small but significant shift being measured in coral reef trajectories may mean that coral reefs can survive these anthropogenic pressures if given enough time to recover and ongoing reduction in many of the local, direct pressures. While the recent Global Coral Reef Monitoring Network report (Souter et al., Sully et al.  add to t"}
{"text": "Significant advances have been recently made in the development of the genetic and genomic platforms. This has greatly contributed to a better understanding of gene expression and regulation machinery. Consequently, this led to considerable progress in unraveling evidence of the genotype-phenotype correlation between normal/abnormal embryonic development and human disease complexity. For example, advanced genomic tools such as next-generation sequencing, and microarray-based CGH have substantially helped in the identification of gene and copy number variants associated with diseases as well as in the discovery of causal gene mutations. In addition, bioinformatic analysis tools of genome annotation and comparison have greatly aided in data analysis for the interpretation of the genetic variants at the individual level. This has unlocked potential possibilities for real advances toward new therapies in personalized medicine for the targeted treatment of human diseases. However, each of these genomic and bioinformatics tools has its limitations and hence further efforts are required to implement novel approaches to overcome these limitations. It could be possible that the use of more than one platform for genotype-phenotype deep analysis is an effective approach to disentangling the cause and treatment of the disease complexities. Our research topic aimed at deciphering these complexities by shedding some light on the recent applications of the basic and advanced genetic/genomic and bioinformatics approaches. These include studying gene-gene, protein-protein, and gene-environment interactions. We, in addition, aimed at a better understanding of the link between normal/abnormal embryonic development and the cause of human disease induction. These included 26 original research articles, 3 case reports, 1 brief research report, 1 systematic review, and 1 opinion article (The current Research Topic (RT) was aimed at deciphering the molecular signaling pathways\u2019 interactions that orchestrate the complexity of embryonic development and human disease. Understanding these pathways should aid in developing targeted therapies. Several reports showed that many genes and/or microRNAs have a dual functional role during normal embryonic development and in human disease conditions . Hence,  article . The finin vitro experimental model. In a consortium study, Rieke and his colleagues Rieke et al., showed that SLC20A1 is involved in urinary tract and urorectal development. The study used morpholino to manipulate SLC20A1 function in the zebrafish embryo and the gene was analyzed in patients. The study showed that SLC20A1 was associated with bladder exstrophy-epispadias complex . Another research group in the RT used mouse embryonic retinal cells as their model and RNA-seq analysis to study perinatal glucose deprivation during early embryonic development and showed changes in gene expression during retinal neurogenesis. The study concluded that abnormal embryonic programming during retinogenesis could lead to retinopathy in patients with diabetes \u00d6zg\u00fcm\u00fcs et al. Mice blastocysts transfected with lentivirus aiming at establishing placenta-specific knockdown or overexpression mouse model were used to study the role of Osteoprotegerin (OPG) in gestational diabetes mellitus (GDM). The study showed that OPG regulates glucose homeostasis during pregnancy through a negative feedback mechanism Huang et al. Polycystic ovary syndrome (PCOS) is another important disease studied in the RT using mitochondrial sequencing of patient oocytes. Transcriptomic dynamics analysis at the single-cell level using the weighted gene co-expression network analysis (WGCNA) approach was applied to show that abnormal mitochondrial function may contribute to a deteriorated oocyte quality in patients diagnosed with polycystic ovary syndrome (PCOS). The authors concluded that the oocyte quality might be affected by mitochondrial function Qi et al. Sall4 is a developmental gene that plays a crucial role in the pluripotency of embryonic stem cells  derived from the bone marrow of osteoarthritis (OA) patients were used to show that the expression of several chemokines, and pro- and anti-inflammatory factors were upregulated. The authors concluded that BM-MSCs could be used for cartilage differentiation and repair Jafri et al. Another study showed that Thymoquinone natural product has anti-inflammatory properties in BM-MSCs derived from OA patients suggesting a therapeutic potential of this natural product Kalamegam et al. Moreover, Wharton\u2019s Jelly stem cell secretion was used in vitro to suppress human leukemia cells through cell cycle arrest and apoptosis induction Huwaikem et al.Human stem cells are an In summary, the research theme discussed above showed that analyzing gene expression and regulation during embryonic development could give clues to human disease induction and progression. Several developmental genes have a functional dual role in development and disease including SLC20A1, Osteoprotegerin, and SALL4. Stem cell-based therapies or regenerative medicine represent a highly promising alternative route for disease cure.A considerable number of articles in the RT aimed at using a wide range of genomic/genetic and/or bioinformatics tools to decode the biological complexity and identify causal genes in human diseases were published . These aJung et al. and Rieke et al., genome-wide association Bensenor et al., and whole exome-sequencing Naseer et al., Haque et al., and Ouyang et al. There was a tendency in several studies for using a combination of more than one genomic tool to critically discover the gene/marker/factor associated with the disease. For example, BHMT2 was identified as a new regulator for lipid metabolism in metabolic-associated fatty liver disease by combining RNA-seq analysis of the expression profile both in a mouse model and human patients Ma et al. In another study, RNA-seq was combined with the eQTL analysis to show the association of causal genes in Crohn\u2019s disease Jung et al. Moreover, a combined exome and mitochondrial sequencing were successfully used for the rapid diagnosis of suspected pediatric mitochondrial disorders Ouyang et al. Next-generation sequencing (NGS) combined with simple short tandem repeat (STR) marker haplotypes were both used to identify a mutation in the adenomatous polyposis coli (APC) of Chinese kindred diagnosed with familial adenomatous polyposis (FAP) Zhan et al.Authors of articles published in this RT applied several advanced genomic tools including RNA-sequencing Lv et al. Additionally, several studies identified novel genetic variants associated with many disorders and/or diseases such as developmental disorders Naseer et al., acute myocardial infarction Han et al., urolithiasis Chen et al., and endophenotypes in gestational diabetes Firneisz et al. Other RT studies identified copy number variants (CNVs) Zhou et al., gene mutations Kr\u00e4mer et al. and Zhan et al., and gene deletions Chelbi et al. and Song et al., with all, were shown to be associated with different human diseases.Targeted exome sequence (TES) was recommended in one of the RT studies as an effective approach for the genetic skeletal dysplasias (GSD) diagnosis Luo et al. This with no doubt gives hope to follow this approach for treatment in humans for Hemophilia A or any other mutation associated with other diseases.An interesting RT study used a genomic CRISPR/Cas9 mutation repair approach and showed for the first time successful treatment of Hemophilia A in a mouse model Bahlas et al., and to identify therapeutic targets for pulmonary arterial hypertension Li et al. Other tools such as Gene Expression Omnibus (GEO), Gene ontology (GO), Kyoto Encyclopedia of Gene, Genome (KEGG) enriched pathways, and STRING online database were applied to identify the functional interactions of the differentially expressed genes (DEGs) associated with the progression of stomach adenocarcinoma Yang et al.There have been significant advances in the use of bioinformatics tools and datasets available online that could be used for deciphering the complexity of human disease . In our In summary, the research theme described above focused on identifying causal genes, gene variants, copy number variants, mutations, or deletions associated with human diseases. A wide range of advanced bioinformatics tools was used to analyze the genomic data. Combined genomic/genetic/bioinformatics tools and model systems were applied to decipher the mechanistic complexity of the disease.Guo et al. Feng and his team used Cox regression analysis and LASSO algorithm on a considerable number of DNA replication-related genes to stratify the postoperative tumor-free margin (R0) treated pancreatic ductal adenocarcinoma (PDAC) patients with different recurrence risks. This study resulted in identifying novel DNA replication-related gene signatures Feng et al. A combined approach using NGS data, karyotyping, mutation detection analysis, and flow cytometry was shown to be a better protocol for targeted therapy of acute myeloid leukemia (AML) patients El Omri et al. In summary, this research theme showed that data collected from genomic and bioinformatics analysis were effectively used to evaluate the prognostic value of biomarkers in cancer.Gene ontology (GO), gene analysis using Kyoto Encyclopedia, genomes (KEGG) analysis, and gene enrichment analysis (GSEA) were all used to show that STEAP1 is a potential prognostic biomarker for lung adenocarcinoma (LAUD) We had two aims with this RT: the first was to study genes and/or microRNAs that play a dual function in embryonic development and disease and to deliver an update about the applications of the genomics and bioinformatics advanced tools for understanding the complexity of the disease. To a large extent, these aims were met and achieved in the RT. All accepted articles were divided into 3 categories. The results published in the first category of the RT supported the notion of previous reports showing that many genes function in a dual role manner in development and disease . Other rJafri et al., Kalamegam et al., and Huwaikem et al. In addition, stem cells can be also used for cell transplantation methods to cure diseases. For example, in this RT, Luo et al., showed successful CRISPR-mediated targeting of a Hemophilia A mutation, which may eventually one\u00a0day be offered in the clinic as a treatment option.Stem cell medical research aiming at developing therapies has been recently the promise for chronic disease treatment . The curNaseer et al., Naseer et al., Haque et al., Jung et al., Kr\u00e4mer et al., Zhan et al., Luo et al., Lv et al., Ma et al., Ouyang et al., and \u00d6zg\u00fcm\u00fcs et al.For the second aim/category of the RT, a considerable number of published studies applied a wide range of genomic tools to unravel the causal gene(s) in disease Jafri et al., Kalamegam et al., and Huwaikem et al. In several studies, there was a good use of the freely available gene expression datasets for disease analysis Chen et al., Firneisz et al., Guo et al., Li et al., Qi et al., Yang et al., Feng et al., Yang et al., and Bahlas et al. However, the use of these data presents many ethical challenges (There was, in addition, substantial use in these studies of many advanced bioinformatics tools aimed at analyzing the involved molecular signaling pathways controlling the disease induction and progression allenges . For theOur Research Topic aimed at expanding our knowledge of the use of advanced genomic and bioinformatics tools. Results from several articles showed that genes could play a dual functional role in embryonic development and human disease. Stem cell-based therapy and CRISPR/cas9 mutation repair approaches are promising strategies for therapy. Several combined genomic approaches were successfully used to decipher disease induction mechanisms. Advances made in genomic and bioinformatic applications for understanding the complexities of human disease should be of great help to clinicians in personalized therapy."}
{"text": "IUCrJ, 9, 728\u2013734Urzhumtsev & Lunin (2022). ] proposing a new method for the analytic modelling of inhomogeneous resolution in electrostatic potential volumes and electron density maps for improved real-space refinement.Commentary is given on a paper [ IUCrJ, Urzhumtsev & Lunin (2022Our experimental knowledge of structure in atomic detail is derived from the electron density or electrostatic potential map interpreted as an atomic model. Conversely, we calculate the theoretical map from our model and comparison of both sources is used to refine (Urzhumtsev & Lunin, 2019unin 2022 revisit et al., 2022et al., 2020The last decade has seen an expansion of powerful experimental structural techniques, the \u2018resolution revolution\u2019 in cryoEM (K\u00fchlbrandt, 2014In the absence of an analytic expression of the convolution between the Gaussian function accounting for displacement and the interference function limiting resolution, the latter has been recast into a shell decomposition allowing the calculation, in a closed analytical form, of the atomic model map distorted by restricted resolution and positional disorder.The particular implementation and large-scale refinement tests on real data remain to be explored for each envisaged application, and it is anticipated that such development will soon follow. Nevertheless, the present work provides proof of principle of the superior effect of accounting for Fourier ripples with synthetic data calculated for a protein model and establishes the computational advantages.et al., 2021et al., 2021et al., 2020et al., 2022The availability of accurate predicted models for protein components of macromolecular complexes (Jumper This development will enable real-space refinement in a more appropriate way and thus be welcomed by the community once implementations tailored to each envisaged application are available in refinement software. In the meantime, this theoretical proposal stirring discussion on how to best connect model and experiment for a critical and accurate assessment is timely, and is a development that will make ripples in the structural sciences."}
{"text": "Research shows persistent ethnic inequities in mental health experiences and outcomes, with a higher incidence of illnesses among minoritised ethnic groups. People with psychosis have an increased risk of multiple long-term conditions . However, there is limited research regarding ethnic inequities in multimorbidity in people with psychosis. This study investigates ethnic inequities in physical health multimorbidity in a cohort of people with psychosis.In this retrospective cohort study, using the Clinical Records Interactive Search (CRIS) system, we identified service-users of the South London and Maudsley NHS Trust with a schizophrenia spectrum disorder, and then additional diagnoses of diabetes, hypertension, low blood pressure, overweight or obesity and rheumatoid arthritis. Logistic and multinomial logistic regressions were used to investigate ethnic inequities in odds of multimorbidity , and multimorbidity severity , compared with no additional health conditions (no multimorbidity), respectively. The regression models adjusted for age and duration of care and investigated the influence of gender and area-level deprivation.On a sample of 20 800 service-users with psychosis, aged 13\u201365, ethnic differences were observed in the odds for multimorbidity. Controlling for sociodemographic factors and duration of care, compared to White British people, higher odds of multimorbidity were found for people of Black African , Black Caribbean  and Black British  ethnicity. Reduced odds were observed among people of Chinese  and Other ethnic  backgrounds. Increased odds of severe multimorbidity  were also observed for people of any Black background.Ethnic inequities are observed for multimorbidity among people with psychosis. Further research is needed to understand the aetiology and impact of these inequities. These findings support the provision of integrated health care interventions and public health preventive policies and actions. SLaM's catchment area comprises four ethnically diverse London boroughs  covering 1.3 million people. Access to clinical records was obtained via the Clinical Record Interactive Search (CRIS) system  algorithms, which eliminate the need for researchers to read and code large volumes of text (Perera SLaM service-users who meet the following inclusion criteria: (i) had a schizophrenia spectrum disorder .The results from the logistic regression analyses  showed tet al., et al., et al., et al., We investigated ethnic inequities in risks of multimorbidity in people with psychosis, using data from the electronic health records of South London and Maudsley NHS Trust. Black African, Black Caribbean and Black British people with psychosis have around 1.5 greater odds for multimorbidity, and around twice the odds for severe multimorbidity . People of Chinese ethnicity and Other ethnicity had reduced odds for multimorbidity. This is the first study that investigates potential ethnic inequities in multimorbidity among a cohort of people with psychosis. These findings are partly in line with a study that observed a greater risk of the development of diabetes among minoritised ethnic people within the first year of treatment for psychosis  that have a simple genetic basis, studies have failed to provide sound biological explanations for the ethnic inequities observed , to service-related factors  (De Hert et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., This study used data from one of the UK's largest secondary mental health facilities, serving an ethnically diverse community. The cohort of the study is representative of South London and Maudsley NHS Trust catchment, and the findings should be generalisable to other ethnically dense urban areas in the United Kingdom. Indeed, most ethnic minorities live in urban areas. Ethnicity was self-defined, within NHS categories; however we could not include other relevant factors that can be related to inequities in health, most importantly migration, which could be associated with potential related barriers in the use of health services and under-detection of health conditions, but also an investigation of the healthy migrant paradox (Helgesson et al., et al., et al., This study shows that Black people with psychosis are at higher risk of multimorbidity. Although this study is not focused on aetiology, the findings are consistent with adversity-related onset of disease, where marginalised ethnic groups face higher rates of psychosis and other health conditions when living with this severe mental illness (Dubath"}
{"text": "In their article, Liu et al  investigIn our recent study , althougIn any event, I agree with the conclusions of Liu et al  that add"}
{"text": "Autoimmune encephalitides\u2014including the paraneoplastic disorders associated with malignancy \u2014have come to be recognized as major and surprisingly common causes of potentially treatable neurological disease. The disorders, first thought to be rare autoimmune complications of cancer, are now recognized to occur in individuals with and without cancer and to involve antibodies directed against antigens found either at the neuronal cell surface or present in the neuronal cytoplasm or nucleus. Today, we know that conditions associated with antibodies to cell surface antigens may be paraneoplastic or non-paraneoplastic, are usually associated with non-lethal neuronal dysfunction, and are frequently treatable. In contrast, conditions associated with antibodies to intracellular neuronal proteins are usually found in patients with underlying systemic cancer, are characterized by neuronal death, and tend to respond poorly to treatment. At present, over 50 separate antineuronal antibodies have been associated with these disorders, with additional potentially clinically relevant autoantibodies being described every year.Greenlee et al.), discussion by Fredrich et al. and Ruiz-Garcia et al. of antibody testing in the diagnosis of these conditions in clinical practice; an intriguing case report by Bartley et al. regarding the use of phage display library in identifying anti-Yo antibody not detectable by immunofluorescence; characterization of antibody-mediated neurological syndromes by Garza and Piquet, Totland et al., and Liu et al.; articles concerning the use of biomarkers in studying these conditions as well as neuromyelitis spectrum disorders by Li Q. et al., Kammeyer et al., Mizenko et al., Chen et al., and Li Y. et al.; and a review by Zoccarato et al. of the important but less-studied area of paraneoplastic neuropathies. Each of these articles makes a valuable contribution the field.This Research Topic in Frontiers in Neurology addresses several aspects of autoimmune and paraneoplastic encephalitides as understood at this point in time. These include a review of pathogenesis . Although elegant work by Chefdeville et al. and Small et al. has analyzed expression of NMDAR and CDR2/CDR2L antigens in tumors of patients with anti-NMDAR and anti-Yo antibody responses . This is important because recent work strongly suggests that the pathogenic antigen involved in anti-Yo antibody response is not CDR2, as has long been assumed, but, rather, the related protein, CDR2L . An unanswered\u2014and significant\u2014question is how T lymphocytes might target neurons, given that normal adult neurons do not express the MHC class I molecules needed to allow recognition by cytotoxic T cells . The spectrum of immune mediated neuropathies has greatly expanded over the past decade and now includes neuronal surface antibodies such as CASPR2 . Some an et al.; , 16].ClinicalTrials.gov: NCT04372615) involving the CD19-specific monoclonal, inebilizumab, in NMDAR encephalitis represents an exciting and important step forward. Badly needed\u2014for patients with antibodies to neuronal surface antigens as well as patients with antibodies to intracellular neuronal antigens\u2014are actual studies, using standardized protocols involving the agents currently in use, such as corticosteroids, IVIG, PLEX, or rituximab singly or in combination. Such studies would be difficult to fund but could conceivably be carried out over time on a less formal multi-institutional basis and, like use of pre-clinical animal models, could provide invaluable information regarding treatment. Future studies also need to explore and validate more robust clinical outcomes measures beyond the modified Rankin scale, which is heavily weighted toward motor deficits and does not encompass cognitive impairment and psychiatric/behavioral sequelae seen in frequently seen in patients with autoimmune encephalitis. These future scoring systems could even help identify patients who may benefit from more aggressive/longer duration immunotherapy or more meaningful outcomes such as resumption of gainful employment or schooling.The final\u2014and clinically most important\u2014area has to do with treatment of affected patients. Although several authors such as Graus et al. and Abboud et al. have published excellent clinical guidelines for provisionally diagnosing these disorders and initiating immunomodulatory therapies , 17, treThe decade ahead promises to be fascinating in terms of advancement of knowledge and development of new diagnostic and therapeutic approaches for this important group of disorders.JG, NC, SC, and CV conceived and wrote the initial draft of this manuscript. JA and IH contributed to the final revision as submitted. All authors contributed to the article and approved the submitted version.This work was supported by a Merit Review Award from the United States Department of Veterans Affairs (JG) awards from the Western Institute for Biomedical Research (JG and SC) and by grants from Helse Vest (CV).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
{"text": "Perspectives are discussed on future directions for the field of marginal ice zone (MIZ) dynamics, based on the extraordinary progress made over the past decade in its theory, modelling and observations. Research themes are proposed that would shift the field\u2019s focus towards the broader implications of MIZ dynamics in the climate system. In particular, pathways are recommended for research that highlights the impacts of trends in the MIZ on the responses of Arctic and Antarctic sea ice to climate change.This article is part of the theme issue \u2018Theory, modelling and observations of marginal ice zone dynamics: multidisciplinary perspectives and outlooks\u2019. A notable example is the wave\u2013ice interaction model (WIM) proposed by Dumont et al.  and Will [et al. ,3, in wh [et al.  has also [et al. \u20133 emanatean, and   sixth assessment report (AR6). The IPCC provides the most authoritative scientific information on climate change for influencing high-level environmental and societal policies. In terms of MIZ science, the headline findings in the ce Basis  and the  Climate  are on t Climate  and CMIP Climate ), focus the importance of changing wave activity on sea ice is unclear due to limited process understanding [The sea ice and climate communities are showing increasing recognition of the MIZ as a crucial component of the ice-covered ocean ,25, and standing \u201332 is thet al.\u2019s [holy grail for MIZ research by Squire [et al. [The last comment should be heeded by the MIZ community, as it expresses the opinion that there is not yet sufficient confidence in understanding of the MIZ and its trends for it to influence policy. In fact, there are very few studies that connect the MIZ to climate-scale behaviours of either the Arctic or Antarctic ice covers, with the most notable exception being by Kohout et al.\u2019s  correlaty Squire , and they Squire ,11. Howe [et al. , who sho [et al. , who use. 4Squire  describe"}
{"text": "Prescribing for older patients presents several challenges. Older people often suffer from two or more chronic diseases (multimorbidity) and therefore use a greater number of medications compared to other age groups. As a result, they are more susceptible polypharmacy, and associated drug-related problems, including potentially inappropriate medication (PIM), drug ineffectiveness, drug interactions, and adverse drug events . ConsequMany studies  point ouAmbro\u017e et al.; Candeias et al.; Chen et al.; Kardas et al.; Kurczewska-Michalak et al.; Machado-Duque et al.; Perp\u00e9tuo et al.; Schneider et al.; Bobrova et al.) studied PIM and polypharmacy in older adults. Four of them  estimate the prevalence of PIM or polypharmacy in older adults.This Research Topic included 23 articles and nine of them  published in this Research Topic mapped available interventions and more complex strategies to prevent and manage polypharmacy in the older adults and discussed their potential implementation. The authors concluded that the development of strategies for the detection and prevention of drug-related problems is important to guide and support clinical decision-making and strengthen research into drug safety. This is an essential condition for achieving wide-ranging improvements in the management of older patients. Whilst different approaches have been identified to avoid drug-related problems in older patients, there is still insufficient information about their clinical importance or their public health impact. The authors also suggested that guidance on polypharmacy management in older adults is still limited. Initiatives to understand and conceptualize healthcare professional\u2019s barriers and enablers can be used to increase knowledge translation and strengthen capacity for appropriate interventions in routine clinical practice . This is important as there were concerns with excessive bleeding in the elderly when dabigatran, the first non-vitamin K antagonist oral anticoagulants (NOAC) was first launched  estimated the efficacy of propofol in adult or older patients with different conditions. Two systematics reviews  studied the efficacy and safety of drug use in secondary care. Gao et al. conducted a network meta-analysis to summarize all available evidence about relative effectiveness of different pharmacotherapy of macular edema secondary to retinal vein occlusion. Yu et al. conducted a cross-sectional study, analyzing the trends in the topical prescription\u2019s treatment of old patients with dry eye disease.Studies that analyzed the safety and efficacy of medications in other common problems in older patients were also included in this Research Topic. Two studies (Optimizing the use of medications is increasingly recognized as an important pillar in the health care of older people. Collectively, this Research Topic highlights pertinent concerns related to the safe use of medications in this age group and promotes awareness of optimizing older adults\u2019 medication regimens. The results demonstrate that improving the quality of medication use and medication safety are still important challenges for healthcare professionals who care for older patients. Other initiatives are required for this field to reach its full potential of optimizing drug use in older patient to improve their health care outcomes within available resources."}
{"text": "Early and intense epidemic of respiratory syncytial virus (RSV) in Denmark, August to December 2022\u2019 by Munkstrup et al., a publication error caused some of the citations to be incorrectly numbered. This was corrected on 26 January 2023, and we apologise for any inconvenience this error may have caused.In the article \u2018"}
{"text": "Projects that seek to address Code implementation need to understand the current landscape of corporate marketing activities in the government and health care settings and mobilize stakeholders from the government to the community when implementing these projects. Reinsma et al.See related article by ,Unethical marketing of commercial milk formulas remains a global challenge.GHSP, Reinsma et al.In a recent issue of ,While some of the challenges are due to limited resources, many complexities Reinsma et al.Systematic efforts to undermine breastfeeding by companies remain the norm, rather than the exception.,As described in detail by Baker et al.,The activities mentioned here are just a selection of corporate political activities undertaken in the Philippines. In light of this history, it is not surprising that coordinating with the government proved challenging. Political will is necessary to succeed in fully implementing and enforcing laws. Unfortunately, corporate actors play an enormous role in undermining them. Of course, such practices are hardly unique across settings.Reinsma et al.It's essential to listen to local communities' preferences for how they wish to be engaged in Code implementation efforts."}
{"text": "To the Editor: We read with great interest the recent article by Anzinger et al. (Anzinger et al.\u2019s results reinforce the findings of Sharp et al. (The introduction of chikungunya in the Americas has brought greater complexity to surveillance in the region, which includes some low-resource countries. It is essential to establish active and viable surveillance tools and, perhaps, new case definitions in order to better assess the population burden of this disease and the complications of acute and chronic cases."}
{"text": "Migraine in developmental age is a common pathology. It is estimated that more than 10% of children at the age of 10 suffer from it around the world. In recent years, this disorder has attracted attention for its peculiarities, which often differentiate it from that which occurs in adulthood.The purpose of this collection is to focus on the different characteristics present in the child and its most common and rarest forms.Vincenzo Raieli et al.  discuss Ilaria Frattale et al. , in theiThe gastroenterological episodic syndromes share a common pathogenetic mechanism with migraine due to the same embryologic origin of both enteric and central nervous tissues, which can exert direct effects on each other. In the trigger mechanisms of migraine, a crucial role is played by CGRP  and PACAP (pituitary adenylate cyclase-activating peptide), that mediate vasodilation, and serotonin, that mediates sensitization of the trigeminal neurons.Giovanni Prezioso et al.  created Luigi Francesco Iannone et al.  reviewedGenizi et al.  in a newThis Special Issue emphasizes the importance and heavy burden that migraine has in the pediatric population. Pediatric migraine has a great impact on school activities, family life and parents\u2019 work. Thus, appropriate resources should be dedicated to educating and treating children and adolescents with migraine."}
{"text": "In this setting, the aim of this Research Topic is to address the main topics about skin cancer from a multidisciplinary point of view. Cutaneous melanoma is certainly a hot issue, and this Research Topic includes articles about new classification, histological diagnosis, in-vivo technologies, new therapies. Umano et al., evaluated the value of Preferentially expressed Antigen in Melanoma (PRAME) for differential diagnosis of spitzoid melanocytic lesions in pediatric patients. Pediatric melanoma is also the topic of a retrospective study by Ryan et al., which provided clinical and prognostic information about this rare neoplasm in a challenging patient group. Ferrara and Argenziano., revised the WHO 2018 classification of cutaneous melanocytic neoplasms, with particular emphasis on intermediate melanocytic tumors and immunohistochemical and molecular algorithms needed to address the morphological ambiguous cases to a correct clinical management.Skin cancer is an extremely heterogenous group of neoplasms, including tumors of the epidermis , tumors of the dermal adnexa , tumors of melanocytes (cutaneous melanoma), tumors of soft tissue (angiosarcoma and other sarcomas) and tumors of neuroendocrine cells (Merkel cell carcinoma). Despite the better knowledge of its pathological and molecular features, actually skin cancer is a clinical challenge with relevant consequences in terms of morbidity and mortality. Indeed, skin cancer, including cutaneous melanoma and non-melanoma skin cancer, is the most common cancer worldwide. It has been calculated that 1 in 5 subjects will develop skin cancer by the age of 70 in the U.S., and more than 2 subjects die of skin cancer in the U.S. every hour  in the diagnosis of skin cancer, while Broggi et al., focused on the correlation between in vivo reflectance confocal microscopy and horizontal histopathology.In the last decades, the development of new technologies has dramatically changed the diagnosis of skin cancer, mainly cutaneous melanoma, and it is to be expected that technologies will acquire an ever-greater role in the next future . In the Zhang et al., immunotherapy is confirmed as a hot issue in cutaneous melanoma research. Palmieri et al., examine the potential role of molecular alterations linked to genetic instability in cutaneous melanoma as predictive biomarkers for response to immunotherapy. Zheng et al. examine current evidence about the effectiveness of immune checkpoint inhibitors therapy in advanced acral melanoma. Melanoma metastases of unknown primary is a relatively common clinical challenge and the recent improvements about clinical management, therapy and prognostic factors are evaluated by the retrospective study by Del Fiore et\u00a0al.With regards to the management, immunotherapy is certainly one of the most important novelty in the therapy of skin cancer in the last years, but the effectiveness of immunotherapy in advanced melanoma cannot be predicted . In the Pampena et al., define the clinical-dermoscopic findings of aggressive subtypes of basal cell carcinoma, while Russo et al., provide evidence that the expression of Carbonic Anhydrase IX may be used as a prognostic marker in basal cell carcinoma and has a potential therapeutic role for target therapy in advanced cases. Data about the use of sonidegib for the treatment of advanced basal cell carcinoma are detailed by Brancaccio et\u00a0al. Hashimoto et al., analyze the impact of mucosal involvement and surgical treatment on the survival of patients with extramammary Paget\u2019s disease. Bi et al., examine the different therapeutic chances for cutaneous angiosarcoma, while Feng et al., describe a case of recurrent Merkel cell carcinoma responding to Tyrosine Kinase Inhibitor Apatinib.Although most non-melanoma skin cancer is easily healed with surgery alone, some neoplasms are extremely relevant in terms of morbidity and mortality. This Research Topic includes several articles about the therapy and the prognostic evaluation of these neoplasms. Czepczynski et al.,Venanzi Rullo et al., describe the peculiar findings of non-melanoma skin cancer in patients affected by HIV. Immunodepression influences not only the epidemiology and the biology of skin cancer, but mainly the clinical management of the patients. Interestingly, Crisafulli et al. systematically review the cutaneous malignancy risk in patients treated for chronic inflammatory cutaneous diseases.Lastly, the general clinical context always plays an important role in the management of patients affected by skin cancer. A possible misinterpretation of PET/CT images caused by the recent COVID-19 vaccination is described in the case report by Altogether, the different contributions to this Research Topic offer a comprehensive analysis of improvements in diagnosis and therapy of skin cancer, highlighting the importance of a multidisciplinary approach to this heterogeneous group of neoplasms.All authors equally contributed to the manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
{"text": "The result is a well-balanced collection of research articles and comprehensive reviews that tackle fundamental questions about the formation, migration and multi-organ contributions of neural crest cells in diverse model organisms, while also reflecting the growing interest for applying these discoveries to understand and treat neurocristopathies in humans. These articles can be subdivided into four groups based on their links with:  syndrome in mice, Beauchamp et al. [The second group contains four articles that focus on the contribution of cranial and cardiac subpopulations of neural crest cells to craniofacial ,5, eye , and heap et al.  not onlyp et al.  add to tp et al.  review tIn the third group of articles, one focusses on lower urinary tract innervation  while thLast but not least, Mohamad et al. remind us that the abnormal development of neural crest cells can not only lead to congenital malformations, but also cancer, as reviewed here for malignant peripheral nerve sheath tumors that arise from neural crest-derived Schwann cells ."}
{"text": "This theme issue presents collaborative research by anthropologists, linguists, archaeologists, geneticists, historians and biogeographers, who work across disciplinary boundaries to investigate the Amazonian past. Amazonia is a fertile ground in which to develop such multidisciplinary approaches because its relative paucity of documentary records makes other sources of evidence regarding the past more important; because multidisciplinary approaches are well suited to address important unanswered questions in Amazonian history; and because a recent and dramatic reappraisal of the region's past make this an exciting time to conduct this sort of research. The papers in this theme issue feature different combinations of academic disciplines, and they address different geographical regions and historical periods, but all of them show how combining insights from different fields can help illuminate aspects of the Amazonian past that would otherwise remain obscure to them all. Interface Focus brings together the work of researchers who investigate the Amazonian past from a range of disciplinary perspectives. The issue grew out of a workshop held during the 2021 conference of the Society for the Anthropology of Lowland South America (SALSA), hosted by the University of Virginia, which featured collaborations among anthropologists, linguists, archaeologists, geneticists, historians and biogeographers. The challenge that these contributors have sought to address is a familiar one in the contemporary research landscape: each of those disciplines has made great strides in illuminating their respective aspects of the Amazonian past, but the increasing specialization and technical sophistication of the disciplines, and the volume of empirical data that they generate, has made it more difficult than ever to work across the disciplines to build an integrated historical picture. In light of this challenge, each of the contributions to this theme issue attempts the hard work of bringing together the data, methods, or theories of more than one discipline to clarify a specific aspect of the Amazonian past. The complexity of this endeavour is reflected in the long list of authors who have contributed their diverse disciplinary expertise to these papers.This theme issue of The papers address various geographical regions of Amazonia, which is a fertile ground in which to develop such multidisciplinary approaches. For one, Amazonia is characterized by a relative paucity of documentary records, which makes other sources of evidence regarding the past more important. Furthermore, South America remains today the historically \u2018least known continent\u2019 \u2014the Amazet al. [et al. [et al. [et al. [et al. [et al. [et al.'s [et al. [The papers in this theme issue vary in their geographical and temporal focus (though there is considerable overlap among them). Two papers examine the historical dynamics of the linguistically diverse Northwest Amazonian region around the Upper Rio Negro in Colombia and Brazil , while  [et al.  take a b [et al.  examine  [et al.  focuses  [et al. , Cay\u00f3n & [et al. , Arias e [et al. ) take a  [et al. . Michaelet al.'s  study of [et al.  do not m [et al. , with es [et al.  to about [et al. .et al. [et al. [The paper by van Gijn et al.  asks wha [et al.  set out The second paper in the theme issue, by Cay\u00f3n & Chacon , also exet al. [The third paper, by Arias et al. , zooms iet al. [et al. [The fourth paper, by Michael et al. , also exet al. , it brin [et al.  thus proet al. [Finally, like the previous paper, Zariquiey et al.  also focWithin the pages of this theme issue, the many contributing authors have reached beyond their own disciplinary expertise and attempted to reconcile their own data and analyses with those of their co-authors. These collaborations have required not only immersion in the technical aspects of other research fields, but also engagement with the markedly different perspectives and assumptions about human experience that underlie each one. Joint progress in such a context is hard-won, but the papers in this theme issue show how combining insights from different disciplines can help illuminate aspects of the Amazonian past that would otherwise remain obscure to them all."}
{"text": "We further emphasized in our concluding remarks that \u2018knowledge gaps still exist regarding the impact of administration of antibiotics in different compartments of dual-chamber bags and the stability and compatibility data of antifungal agents and narrow-spectrum antibiotics targeting specific species\u2019 and that \u2018future research is required in this area\u2019 .et al. [We agree with Ling et al.  that an"}
{"text": "Misfolded Proteins, paragraph 1 of the paper. The sentence previously stated:In the published article, there was an error. We stated that recent research had identified preeclampsia as a proteinopathy disease because misfolded proteins were found in urine and serum. We cited Cheng et al., 2021 with that statement. However, Cheng et al., 2021 found misfolded proteins in serum and did not study urine. We did not include Buhimschi et al., 2014, who made the finding in urine in the specified place in this paragraph. This statement, as mistakenly written, misrepresents the work of Cheng et al., 2021 and does not properly cite Buhimschi et al., 2014. As such, a correction has been made to \u201cRecent research has identified preeclampsia as a proteinopathy disease due to detectable misfolded proteins being found in the urine and serum of preeclampsia patients .\u201dThe corrected sentence appears below:\u201cRecent research has identified preeclampsia as a proteinopathy disease due to detectable misfolded proteins being found in the urine  and serum of preeclampsia patients .\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
{"text": "Intermolecular forces, determined by the critical balance of interacting components having physical and chemical natures, control most of the static and dynamic properties of matter such as their existence in solid, liquid and gaseous phases, with their relative stability, and their chemical reactivity. In particular, they form simple interacting systems that represent the weakly bound precursor states of myriad phenomena. In some cases, such states promote the following nucleation, leading to the formation of large clusters and nanostructures, and in others, they open the passage to specific configurations of the reaction transition state of elementary reactions. Therefore, the characterization of intermolecular forces at a high level of detail is a question of crucial interest in several advanced research fields and represents a challenge for both experimentalists and theoreticians that will open new avenues in the study of systems of increasing complexity and of applied interest.The core of this Special Issue is on the building up process that controls the transition from simple no covalent adducts to complex chemical structures. This Research Topic aims to underline the relationship between forces established among the particles of the system and other properties across different scales, i.e., from molecules, simple aggregates or small clusters to nanostructures and other types of matter at the mesoscale.The Special Issue has 13 papers written by 50 authors from different countries with theoretical or experimental contributions (or both) in this research area. The work of Gonz\u00e1lez-Veloso et al. [3 reaction, which is based on high-level ab initio calculations. The authors performed rigorous tests to analyze the quality and accuracy of the PES, from the Quasi-Classical Trajectory (QCT) calculations, and the results were compared with available experimental data. In turn, Raczy\u0144ski et al. [The paper from Espinosa-Garcia and co-workers  presentsL) by Borocci et al. [LAr to the L-ArBeO complexes. In another methodological contribution, V\u00e1zquez and collaborators [The role of i et al. . These aborators  have pro+ with helium has been investigated at the atomic level by Bartolomei et al. [NCa+ is The importance of the solvent effect in nonpolar solvents for the pyridone\u2013hydroxy\u2013pyridine tautomeric equilibrium and the dissociation of alkali metal halides have been studied by Shenderovich and Denisov . Specifii et al.  in a coma et al.  have als8The importance of intermolecular forces in the ionic polymerization process on large clusters of acetylene molecules to form polyaromatic hydrocarbons (PAHs) has been studied by Molina and Stein . They emn et al. .The formation of complex supramolecular structures via self-assembly of small molecules is a phenomenon also conducted by intermolecular forces. An example is the competition between hydrogen bonding and aromatic-rings stacking, which may lead to a dramatic change in the structure of biological systems. By using supersonic jet expansions, Zimmermann et al.  have preFern\u00e1ndez et al.  have appThus, as we have seen, these papers covered different aspects of the research presently carried out on intermolecular forces and showcase the diversity of methodologies employed by theoreticians and experimentalists, making this Special Issue an interesting contribution to this field of knowledge."}
{"text": "MHPSS is increasingly seen as a critical component to effective and responsible humanitarian programming. This review examines the extent to which MHPSS research generated since 2010 has contributed to the public health evidence base and how this has influenced and impacted programming and policy in humanitarian settings.n = 50) and a consultation process with qualitative key informant interviews (n = 19) and online survey responses (n = 52) to identify the facilitating and inhibiting factors for the two areas of inquiry and to understand the broader context in which knowledge is generated and taken up. The interviews were thematically analysed and the survey responses were descriptively analysed.This mixed-method study included a scoping literature review (The review identified a rapidly growing evidence base that has evaluated a range of MHPSS interventions. However, few studies examined long-term impacts of interventions, there was limited direct evidence on outcomes for children and adolescents and whole family approaches, and there were minimal replications of the same approach that could test efficacy across settings and population groups. A general shift was identified in the consultation process away from a focus on disorder towards the more positive aspects of wellbeing. However, there remained a mismatch in many studies included in the literature review, whereby the interventions were broad, community-based but the outcome measures used still focused on changes in symptoms of mental disorders.The evidence base for MHPSS has grown significantly over the last 10 years. However, several knowledge gaps remain, as does the divide between research and practice. Moving forward, MHPSS intervention research needs to be more responsive to the needs on the ground. As noted in the introduction, in reality most MHPSS programmes do not target people with a diagnosable mental disorder. We wanted to understand the scope and range of research on MHPSS interventions that do not set out to treat mental disorders \u2013 e.g., those interventions that are used more in practice.Selection criteria included studies published between January 2010 and April 2020 that described the testing, trialling or evaluation of MHPSS interventions delivered in humanitarian settings that were Studies were included on interventions that targeted non-specific psychological distress or wellbeing and other related psychosocial outcomes as their primary outcome measures . In addition, studies were included on interventions that were explicit in not targeting people meeting criteria for a mental disorder, even if scales for mental disorders were included as outcome measures, as long as the study was not looking for clinical change on these measures.Interventions included those integrated into basic humanitarian service provision, activities focused on community and family support, and psychological or social activities, provided in order to achieve MHPSS-related outcomes. Studies had to be based in lower-income countries or lower-middle income countries, in the context of a humanitarian response by governmental or non-governmental organisations (NGOs) to address the immediate impacts, aftermath or consequences of an emergency, including war, conflict, natural disaster and epidemic. The MHPSS interventions identified in the study targeted adults, children and/or adolescents. Inclusion and exclusion criteria are shown in Intervention outcome studies and studies focusing on participant experiences  were included. Where a purely quantitative design was used to measure outcomes, including experimental, quasi-experimental and prospective cohort studies, only controlled designs were included. Comparison groups could be those with no intervention, on a waiting list, other active interventions or usual care. Qualitative and mixed-methods studies were included even where the quantitative component had no pre-test or control group.et al., The following international databases were searched: PsycINFO (peer-reviewed), Medline, Web of Science, the Cochrane Library and Google Scholar. The search terms, as set out in et al., The grey literature search included the resources or publications section of the websites of 27 organisations and agencies working on MHPSS in emergencies  with the aim of capturing a cross-section of these two participant groups. The final sample included 19 key informant interview participants, which took place between May and June 2020 (two key informants requested to be interviewed together), and 52 survey respondents , and a second taking detailed notes of the interview content . Questions and answers were transcribed during the interview, cross-referenced with the sound recording to ensure clarity and annotated with comments and analysis.The quantitative survey data were analysed using descriptive statistics on Excel software. Thematic analysis was used for the qualitative data. A coding scheme was developed based on the broad themes of the topic guide and from the initial hand coding of the interview data. This involved systematically sorting through the data, labelling ideas and phenomena as they appeared and reappeared. The researchers trialled the coding scheme to isolate discrepancies and revised the scheme accordingly. All interview data were coded and analysed, with the coded transcripts being reviewed by a second researcher. The trends that emerged were critically analysed according to the study's aims.All procedures were approved by the Research Ethics Board of the London School of Economics (#2090). Informed consent was obtained from key informants and survey respondents, including the consent to use anonymised quotes in reporting and publications.et al., et al., A total of 11062 references were generated from the searches. After excluding duplicates and screening from title and abstract, the full-text reports of 737 remaining citations were retained and screened. A total of 50 research studies were included in the final review, of which one contributed to two study reports from two different data pools   How has knowledge on MHPSS interventions researched in humanitarian settings advanced in the past 10 years? And (2) How has MHPSS intervention research been taken up in policy and practice at various levels of the humanitarian system? To answer these questions within the frame of the data collected, the results are structured around seven core themes that emerged from the literature and the consultation process. The core themes that emerged to answer question one include (1) an unbalanced evidence base, (2) a broadening in scope, but with mismatched outcome measures and (3) the influence of the RCT. The core themes that emerged to answer question two include (4) some progress in policy and practice, (5) a geographic divide between decision-making and locally perceived needs, (6) a disconnection of country-level MHPSS practitioners and (7) hindrances to uptake.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., There was a geographic emphasis in the literature towards East, West and Central Africa, where two-thirds of the studies reported were located  stated,et al., et al., et al., et al., et al., et al., et al., et al., et al., The influence of the RCTHowever, a disconnect was identified in many of the studies reviewed, whereby the interventions were broad, community-based and geared towards positive outcomes, but the outcome measures used focused only on changes in symptoms of mental disorder. In several cases, there was a mismatch between the stated intervention aims and the focus of the research (including selected outcome measures). For example, in 12 studies Having RCTs that demonstrate the effectiveness of MHPSS interventions was seen by key informants as advancing the field: \u2018everyone loves an RCT, it adds an extra level of credibility to interventions\u2019 (Pr 1). Indeed, amongst the new interventions that have been adopted into MHPSS practice (see below), many have been researched through RCTs, indicating the influence of these research designs. The limitations of this research design were also acknowledged by key informants, for example, being less readily applied to community-focused interventions that address difficult-to-measure changes and complex social dynamics. The literature review confirmed that person-focused psychological interventions have been disproportionately studied through RCTs, whereas community-focused interventions, including reintegration programmes, reconciliation and healing interventions, community-led support and community support groups, were less likely to have a controlled design. A risk associated with this was noted by one global coordinator:Some progress in policy and practiceAlthough key informants agreed that RCTs are important to demonstrate effectiveness, given the controlled conditions required for an RCT, many felt that other types of research design are required to understand how an intervention works in real-world programme implementation. MHPSS evidence generated more recently was acknowledged to include \u2018a greater range of methods\u2019, and key informants also concluded that the global MHPSS community was increasingly placing greater \u2018legitimacy\u2019 and value on qualitative research. The literature review was able to capture this broader range of designs, including controlled before-and-after studies, mixed-methods and qualitative designs.et al., et al., et al., The consultation process indicated that MHPSS intervention research conducted over the last 10 years has influenced programmatic changes and uptake for several interventions, particularly scalable psychological interventions and a smaller number of broader, community-based interventions. Although not all intervention research has led to continued change or new programming, the following examples identified in the literature review and by key informants have been instrumental: (1) contextual refinement and implementation of newly developed scalable psychological interventions  sold to professionals in the South\u2019 (NaGov 2). The survey asked researchers for the single most important reason behind their choice of current/most recent MHPSS intervention research topic out of five options and found that 40%  with global research and research generated in country settings beyond their own, and none had heard of the 2010 MHPSS research priorities. This extended into a wider theme of \u2018fragile knowledge\u2019 and the disconnection of country-level based MHPSS practitioners from formal MHPSS intervention research findings. Country-level based MHPSS practitioners felt particularly disconnected from certain types of research, for example, research published primarily in academic journals: \u2018Another thing \u2013 who has access to journals? Field-based practitioners don't have access\u2019 (Co1). Although this lack of access to journals may be true for many country-based practitioners, headquarter-based key informants still reported that practice has been impacted by research, and this was further supported by survey findings.n\u00a0=\u00a08) of practitioners surveyed who were based in Europe and North America rated their familiarity with MHPSS intervention research from the past 10 years as either four or five out of five, but only 36% (n\u00a0=\u00a02) of practitioners based outside of Europe and North America did so. When asked how easy it is to access MHPSS research, 60% (n\u00a0=\u00a06) of practitioners in Europe and North America reported a four or five out of five, compared to only 27% (n\u00a0=\u00a06) of those based outside Europe and North America. Ninety-four per cent (n\u00a0=\u00a030) of all practitioners agreed somewhat or very much that information is expensive or in difficult-to-access closed communities or portals. The findings indicated that the pathway that research travels through organisations and into practice is multi-layered involving several different actors at different levels, each likely engaged in their own preferred channels.Hindrances to uptakeThe survey results demonstrated that 80% A further limit to the knowledge brokering process was that practitioners and policymakers lacked the time to access and become familiar with research. Ninety-four per cent of the practitioners surveyed agreed somewhat or very much that they lacked time to search for and engage in research learnings. As noted by one policymaker who was interviewed, this can present a \u2018Catch-22\u2019:\u2018How research findings can be digested in a way that is easy to understand and see how it related\u2026 How evidence can lead to higher quality, more effective programming.\u2019 (Co3)\u2018Key challenges with research projects and findings is the communication of them and that often they are not targeted to who needs to receive them.\u2019 (DoG1)\u2018We need to simplify the information. One-page policy brief, giving infographics if there is a need for that.\u2019 (NaGo2)The step of actively transforming and translating evidence from knowledge to practice was raised across all the stakeholder groups interviewed as being critical to the knowledge brokering process. The majority suggested that evidence products should be digestible, practical and focused on the end user, without losing the nuance of the findings. The following quotes are representative of the different stakeholder groups engaged.not focused on mental disorders which allowed for a broader perspective more likely to capture interventions commonly implemented in MHPSS programming.This study sought to answer how MHPSS interventions researched in humanitarian settings have advanced in the past 10 years and how the evidence has been adopted into policy and practice at various levels of the humanitarian system. The study was unique in that it focused on MHPSS interventions delivered in humanitarian settings that were et al.  found minimal or no change on these outcomes . Supporting and tracking change should be the responsibility of all parties involved in generating and using evidence-based interventions; this especially pertains to the resources allocated by donors. Adequate time and funds are needed for uptake activities on research projects, and for monitoring and evaluation of these activities against specified outcomes, to ensure tangible change and demonstrable impacts for people and communities.Researchers may find it challenging to isolate the changes which result from their research projects in emergency environments and monitoring the results of knowledge uptake is not a routine part of many research project or funding cycles. Supporting and tracking change should be the responsibility of all parties involved in generating and using evidence-based interventions; this especially pertains to the resources allocated by donors. Adequate time and funds are needed for uptake activities on research projects, and for monitoring and evaluation of these activities against specified outcomes, to ensure tangible change and demonstrable impacts for people and communities.et al., et al., et al.  mutual learning for all parties involved, (2) improved quality of research through the insights of partners, (3) buy-in for the intervention from key stakeholders and (4) more direct avenues for programme and policy change.Greater investment in collaborative research by funders, researchers, practitioners and their organisations, policy makers and people with lived experience would build the capacity and competencies of those involved, increase the likelihood of sustained buy-in from key stakeholders, and generate direct avenues to influence programming and policy change.v. (\u2018stress\u2019 AND \u2018reduction\u2019) might have yielded different results.The literature review was a scoping review rather than a systematic review, and in its balance of rigour and realism some relevant studies may not have been captured. By including only English language studies, relevant studies from non-Anglophone settings may have been omitted. Also, studies that focus on mental disorders were not included, but defining whether or not research is \u2018disorder-focused\u2019 is complex. Despite the robust rationale and rigorous selection process, another research team may have yielded different results. Using the search term \u2018evaluation\u2019 and \u2018stress reduction\u2019 Due to constraints from the COVID-19 pandemic, interviews were conducted remotely. As a number of potential key informants from national governments were engaged in their emergency response capacity, only two were interviewed. Fortunately, other key informants provided data on their interactions with national government actors, particularly senior practitioners and coordinators who work closely with this cohort. The same problem may have limited the number of respondents to the survey. The response to the survey was positive considering these circumstances; however, it was too small to disaggregate findings to a very granular level, e.g. comparing answers of community-based organisation staff with those working for international NGOs. The sample size was not large enough to provide statistically significant findings but was adequate for its intended purpose of triangulation with the qualitative interview data and considering the depth and detail of the form, the number of responses was judged to be satisfactory."}
{"text": "Research on flavonoids from plant sources is showing growing evidence of the versatile health benefits of flavonoids through in vitro and in vivo studies . As the This Special Issue harvested interesting advances in flavonoids with emphasis on green production and health aspects, which provide some suggestions for researchers and for industries in developing natural health agents. Research studies and reviews dealing with biological activity and healthy effects of polyphenols were also presented.The first review of this Special Issue by Dias et al.  deals wiA review by Giovinazzo et al.  aims to Following the anti-inflammatory function of naturally occurring polyphenol molecules, the study of Zhang et al.  focused The study of Gerardi et al.  investigIn the article of Piechocka et al. , the effThe article of Saeting et al.  deals wiThe study of Kim et al.  evaluateIn the research article by Shen T. et al. , a study"}
{"text": "In the recent article by Proesmans et al. , the firThe authors apologize for the error."}
{"text": "The current evidence indicates that the lateralized processing of social information is an integral part of the perception of the conspecifics  on the left rather than the right side (Karenina et al., Positional biases in aggressive interactions have been found in saiga male contests. A preference to keep the opponent to the left was found in retreating after fighting and chasing an escaping rival (Giljov et al., Another type of lateralized social behavior in saiga antelopes is male-female interactions. It has been found that males preferentially keep females on their right side when pursuing them to rejoin with the rest of the group (Giljov et al., Lateral biases in the social behavior of non-human primates have demonstrated that human social lateralizations are not unique Lindell, . HoweverThe use of forelimbs is lateralized in humans and the extent to which lateral biases in social interactions are determined by motor biases remains unclear. Even after decades of research, the question of the motor vs. emotional nature of cradling bias remains open (Ocklenburg et al., The role of motor biases in other lateralized human interactions is also far from being clear. Several studies tested the link between handedness and head-turning preference during kissing, and the results are conflicting (e.g., Barrett et al., Ungulates are a convenient model for the investigation of social lateralization since they are lacking these confounding factors. When forelimbs do not directly determine the relative positioning of interacting subjects, the interpretation of lateral preferences as manifestations of sensory lateralization becomes much more straightforward. Ungulates became popular models in laterality research partly for casual reasons such as their availability, e.g., as livestock (Leliveld, Even a brief comparison of the results of human and ungulate studies suggests some interesting conclusions and directions for future investigation. Left-sided biases in both mother's behavior toward her offspring and the young's positional choices relative to mother and age-mates in saiga antelope and several other ungulate species (Karenina and Giljov, If something in the lateralized social behavior of ungulates can be compared with human embraces, it's allogrooming in horses. In that case, human right-sided bias is not consistent with the results on ungulates (Farmer et al., In male-female interactions, the direction of lateral biases is not consistent between humans (Rodway and Schepman, Social behavior and, in particular, social coordination is assumed to be a driver for the emergence of population-level behavioral biases (Frasnelli and Vallortigara, AG and KK conceptualized and wrote initial draft. All authors contributed to the article and approved the submitted version."}
{"text": "One Health surveillance of West Nile and Usutu viruses: a repeated cross-sectional study exploring seroprevalence and endemicity in Southern France, 2016 to 2020\u2019 by Constant et al., published on 23 June 2022, the name of author Sylvie Lecollinet was spelled incorrectly. This was corrected on 5 July 2022 at the request of the authors.In the article \u2018"}
{"text": "They also challenge some of the conclusions we drew as regards the likelihood of fire\u2010mediated feedbacks causing alternate stable states (ASS) in forest\u2013savanna transitions.In their comment on Veenendaal et al. , Laris &et al.  November is the first major month of the fire season but for the more southerly forest\u2013savanna transition zone area this is more typically later on in December and/or January. This is illustrated in our Fig.\u00a0et al. .We also note that none of the three papers cited by Laris and Jacobs as supposedly neglected by us, but purportedly providing supporting evidence for their notion that fire timing is much more important than frequency in determining woody cover effects of fire actually, shows what Laris and Jacobs claim to say they do. Specifically, the Devine et al.  study  the occurrence of ASS should be more likely. Nevertheless, Van Langevelde et al. (Laris and Jacobs take issue with that conclusion but with the only evidence they cite as \u2018demonstrating\u2019 that ASS are already a documented phenomenon, namely Keeley & Rundel  being a e White, , and fore et al.  have sug"}
{"text": "In Response: We appreciate Minhaj et al. for their correspondence regarding our experience treating an imported case of monkeypox from an international traveler (Since our report of monkeypox in November 2021, there have been outbreaks of monkeypox throughout multiple countries (In our case report ("}
{"text": "Although it may not seem like it, chemical biology has existed for a long time from today\u2019s perspective. One of the earliest occurrences of the term \u201cchemical biology\u201d is in the book \u201cOn Fermentation\u201d by Alonzo E. Taylor 1871\u20131949), published in 1907 871\u20131949,  to the in vitro and in vivo studies of biological systems, where the study is based on the use of small molecules designed or identified on the basis of biochemical or cellular screening. These molecules are targeted to bind to biological structures, and the biological response is monitored . Thus, cIn general, it is thus possible to define chemical biology as the study of molecular mechanisms of biological processes through targeted designed molecules.In the shadow of the above definition, however, is the contribution of Hricovini et al. . An evolThe role of enzymes was investigated by Alnoch et al. , who stucis-urocanic acid and its chelating properties were investigated by Bossak-Ahmad et al. [Seminavis robusta were proposed by Bonneur et al. [Compounds with anticancer potential were designed by Li et al. (cationic pillar[6]arene as inductors of cell apoptosis)  and by Gd et al. . Interesr et al. .The application of spectroscopic techniques for the identification of superoxide dismutases was described by Kula-Maximenko et al. . Masar eAs can be seen from the above, chemical biology as a progressive multidisciplinary interface not only enjoys great and respected attention from the world\u2019s scientists and leading scientific teams, but is also widely supported by sponsors due to the expected significant achievements in the understanding of many diseases afflicting humanity in fast and effective solutions. Using a chemical biology platform, scientists use international research infrastructure  to make"}
{"text": "In the recent article by Cheon et al. , the corThe authors apologize for the error."}
{"text": "In a 2019 analysis of 479,809 adults from 13 nations in Latin America, Miranda and colleagues   from rural indigenous traditions is evident, but in urban and peri-urban areas, indigenous diet is transitioning to more processed foods and animal products . WHO STE 10,704)  indicateWHO STEPS data from Bolivia  also indCairo et al. provide findings clearly showing how obesity and overweight have reached the rural areas of Brazil. The emergence of processed and ultra-processed foods in diet patterns across the lifespan in Latin America is shown in pre-schoolers in Chile by Araya et al. and reviewed for the entire region by Matos et al.. Despite these strong trends, there remains a paucity of research infrastructure in Latin America for culturally tailored dietary intervention trials to reverse the nutrition transition away from cultural diets based on minimally processed whole plant foods and fewer animal products. The supplement continues the build of this emergent research infrastructure for dietary intervention. Sanchez Urbano et al. provide evidence of the feasibility and acceptability of dietary intervention advice in the Latin American context. Loureiro et al. provide insights from diet patterns in Brazilian adults, and Contreras-Guill\u00e9n et al. is innovating dietary recall methods for Argentina. Figueroa et al. tackle the question of whether a plant-based Mediterranean diet can be adapted for the Latin American region. Taken together, the supplement articles herein are a stride forward in the path to reverse the nutrition transition that is creating a sizable non-communicable disease burden in Latin America.In this landmark supplement of Frontiers of Nutrition, the authors from several Latin American nations provide findings that seed a plant-based research agenda for Latin America. The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
{"text": "Primates live in stable social groups in which they form differentiated relationships with group members and use a range of communication including facial expressions, vocalizations and gestures. However, how these different types of communication are used to regulate social interactions, and what cognitive skills underpin this communication, is still unclear. The aim of this special issue is to examine the types of cognitive skills underpinning the flexible and complex communication that is used to maintain the bonded social relationships found in primates and humans.This article is part of the theme issue \u2018Cognition, communication and social bonds in primates\u2019. What are the key challenges she faces? Clearly, she faces ecological challenges involving finding patchily distributed food resources and avoiding predation for her and her offspring . She alsAnthropoid primates differ from many other mammal species in living in stable social groups where members form long-term social relationships outside the contexts of mating and rearing offspring . Group lHowever, the specific ways in which primates use different of communication to meet the demands of group living, and what cognitive skills underpin these different types of communication, is still unclear ,21\u201323. Wet al. [The first two papers of this issue describe the key cognitive mechanisms underpinning the processing of social information in primates and how these are related to social and ecological factors. Roberts et al.  highlighet al.  use a meet al. [The next two papers examine associations between social and communicative complexity across a range of primate species. Fichtel & Kappeler  use a phet al.  focus onet al. [et al. [Some of the strongest evidence of intentionality in communication across the whole communicative repertoire comes from studies of gestures in great apes ,29,30. Iet al.  highlighet al.  focus onet al.  examine  [et al.  show thaet al. [et al. [et al. [et al. [In addition to gestural communication, primates use a range of vocalizations and facial expressions to meet the demands of group living ,24. The et al.  showed t [et al.  also exa [et al.  focus on [et al.  use thisOverall the articles in this special issue provide new insights into how communication is used to manage the demands of social life, and the cognitive processes underlying this, including flexible production of signals according to the socio-ecological context by signallers, and detecting and responding to signals by receivers. Several of the contributions also highlighted ongoing challenges in this area of research, including how to measure social, communicative and cognitive complexity within and between species and establishing the cognitive requirements of different types of communication for both signallers and receivers. We hope that this theme issue serves to provide an overview of the key findings in this area and a stimulus for future research."}
{"text": "Rosa canina fruit, and their use as recyclable and heterogeneous nanocatalysts for the degradation of dye pollutants in water\u2019 by Saba Hemmati et al., RSC Adv., 2018, 8, 22763\u201322763.Correction for \u2018Correction: Green synthesis of Pd nanoparticles supported on reduced graphene oxide, using the extract of  The affiliations in the original article were transposed; the corrected affiliations are as shown below.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
{"text": "Although mental health (MH) services and psychological support are tailored to fit the MH needs of those requiring these services in the UK, underutilisation persists. Current evidence suggests that ethnic minorities underutilise MH services with culture implicated in this trend. However, there is limited evidence from systematic reviews integrating the findings of primary studies on the role of culture in MH service utilisation among ethnic minorities. This review aims to synthesise and summarise evidence on the role of culture in MH service utilisation among ethnic minorities in the UK. Two reviewers searched CINAHL, APA PsycINFO and Medline databases using the Preferred Reporting Items for Systematic Review and Meta-Analysis. Two other reviewers screened the abstracts and full text, while three conducted data extraction and assessed study quality using the Critical Appraisal Skills Programme checklist for qualitative studies. One's culture was repeatedly identified to play a role in MH service utilisation among the ethnic minorities in the UK. The impact of cultural factors on service utilisation was through its effects on structure/institution, beliefs, stigma and perception of service. In addition, discrimination and other racism-related negative experiences during service use were found to inform perception and use of MH services. These findings suggest that MH services should be tailored to cultural differences to optimise service utilisation. As a result, populations such as the UK continue to experience increased diversity, partly explained by international migration. In addition, the literature suggests an association between migration and mental health (MH) disorders among the UK population  prioritised MH service provisions for ethnic minority communities to ensure equality in service utilisation. Race Relations (Amendment) Act of 2000 imposes responsibilities on public sector institutions ensuring racial equality and access to public services in the UK. As a result, the UK government developed the National Service Framework for Mental Health (1999) for combating any form of discrimination against those that require MH services, including ethnic minority groups. Furthermore, the Delivery Race Equality in Mental Healthcare (DRE) action plan was developed to ensure equality and remove discrimination against Black, Asian and Minority Ethnics (BAME) in the use and provision of MH service in England  framework to develop this review question, as shown in No review exists on the role of culture in MH service utilisation among the ethnic minority groups in the UK. Due to this gap, our systematic review will be of value in policy, practice and MH intervention development. Our findings add to solid evidence and enhance the understanding of the role of culture in MH service utilisation among the ethnic minority groups in the UK.The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was adhered to in this review. In addition, we registered the protocol for this study on the International Prospective Register of Systematic Reviews (PROSPERO) (registration number: CRD42020206615).et al., A vital part of this search strategy was using index Medical Subject Headings (MeSH) terms , ethnic minority population in the UK. There is evidence that MH illnesses are developed in adulthood, which informed adulthood criterion  conducted on MH utilisation but not directly on the ethnic minority in the UK; (b) secondary studies on MH utilisation of immigrants such as a systematic review (c) reported views of others such as health professionals or (d) that only their abstracts were available. Two researchers independently conducted the title and abstract sifting. Three researchers independently assessed full text for eligibility.et al.  Singh, , a checket al., et al., et al., et al., After quality assessment, the reviewers excluded one study as it did not meet up to 70% on the checklist , perception and beliefs of service users (four studies), cultural barrier (four studies) and stigma (five studies). In this synthesis process, a description of studies, tabulation and thematic analysis was carried out in stage five and reported in the sixth stage.The search from four databases yielded 2508 references, as presented in a PRISMA flow chart in The themes reported to affect MH service utilisation in this review are the following.et al., et al., et al., The structural factor theme involves factors found in the society that influence the MH utilisation of the patient. Factors found were nature and awareness of MH service, language, cultural competence of service, waiting times in service delivery, the attitude of staff, professional stigma against BAME and social stress (Edge and MacKian, et al., et al., et al., et al., et al., et al., et al. (et al., et al., et al., et al., The perception of MH service by service users theme had subthemes of the relationship between the service provider and the user, service user attitude and behaviour, personal experiences of using MH service, self-critical voice and difficulty in conceptualising mental illness (Edge and MacKian, , et al.  reportedet al., et al., et al., et al. (et al. (et al., et al., The last theme in this review was stigma, as reported by all five studies included in the synthesis. Resistance to psychiatric labelling, cultural identity and stigma, negative experience and racism, production of stigma and internal and external stigma were subthemes reported under stigma (Edge and MacKian, , et al.  defined , et al.  expresse, et al. . The par (et al.  also rep (et al.  found ps et al., . In anotet al., et al., et al. (A cultural barrier was a theme that four of our five studies reported. It had subthemes of cultural competence, staff attitude, cultural naivety, negative experiences, cultural belief, cultural insensitivity, cultural perception of family shame due to illness and discrimination (Edge and MacKian, , et al.  that theet al., This study aims to comprehensively explore and synthesise evidence to answer the question of the role of culture in MH service utilisation among people of ethnic minority groups in the UK. We included five studies in this review, with 166 participants. The studies identified and included in this study were all qualitative. There is an increase in the volume of qualitative studies conducted in clinical and health care research and the need to synthesise the themes identified in the literature (Munro et al. (One of the cultural factors found to play a role in MH service utilisation is the structure of MH services. Structural factors reported in this review are the nature of the service, the design and mode of service delivery and how compliant the interventions are with the cultural values of the BAME. This finding is consistent with the model on MH by Corrigan et al.  that stret al., et al., et al., The majority of the studies we reviewed in this study shows that the perception of both the patients, family community members about MH affected help-seeking. Our finding is consistent with the literature that attitude and perception about MH may influence MH service use (Gaston et al., et al., et al., et al., Even though self-stigma is a stronger predictor of MH service use than public stigma, this review found public and self-stigma mitigating against MH service use among ethnic minority groups (Nam This review outcome shows that cultural factors affect MH service utilisation among ethnic minority groups. The evidence suggests that subthemes of cultural competence, staff attitude, cultural naivety, negative experiences, cultural belief, cultural insensitivity, cultural perception of family shame due to illness and discrimination affect MH service utilisation. Although this is experiential evidence, there is a need for a quantitative examination of this topic to understand if this is transferable to a larger population. There is also a need for this study to be replicated among younger adults. Finally, there is a need to investigate if there is an impact of COVID-19 on MH service utilisation among this sample.The primary strength of the approach adopted in this systematic review is using qualitative methodology articles. The qualitative study allows for an in-depth understanding of the experiences of ethnic minority groups on MH service utilisation. Alongside this strength also comes the limitations of this study. First, all studies included in this synthesis were from the UK population; the findings can only apply to the MH service of ethnic minority groups in the UK. Also, studies included in this review were those conducted from 2010 to 2020, which can be a limitation. This review targeted studies that recruited people of an ethnic minority across the UK. Still, the studies included were conducted in London and Birmingham to represent the entire UK population. There were limited studies on MH service by the ethnic minority communities in other parts of the UK except for London and Birmingham.This study will be the first systematic review of literature evidence on the role of culture in MH service utilisation among ethnic minority groups in the UK. This systematic qualitative review shows that culture plays a vital role in utilising MH services among people of ethnic minority communities. Cultural factors such as professional and structural barriers, perception of MH service, beliefs, cultural barriers and stigma could be inhibiting BAME who require MH service from using the service. The second objectives of this review were to evaluate the quality of the existing evidence and synthesise and summarise the role of culture in MH service use. This review shows the need to prioritise cultural consideration in developing and implementing MH interventions. One therapeutic model cannot serve all in a culturally diverse society such as the UK. Ethnic community members should be key actors in formulating MH interventions to ensure cultural compatibility and enhance utilisation."}
{"text": "A key challenge for neural systems is to extract relevant information from the environment and make appropriate behavioral responses. The larval zebrafish offers an exciting opportunity for studying these sensing processes and sensory-motor transformations. Prey hunting is an instinctual behavior of zebrafish that requires the brain to extract and combine different attributes of the sensory input and form appropriate motor outputs. Due to its small size and transparency the larval zebrafish brain allows optical recording of whole-brain activity to reveal the neural mechanisms involved in prey hunting and capture. In this review we discuss how the larval zebrafish brain processes visual information to identify and locate prey, the neural circuits governing the generation of motor commands in response to prey, how hunting behavior can be modulated by internal states and experience, and some outstanding questions for the field. Furthermore they also display a relatively rich behavioral repertoire from a very early age, including a capacity for selective attention , and involves a series of rapid movements to intercept and ingest prey which can be moving rapidly  bouts of activity followed by inactivity lasting up to 1\u20132 s. A typical hunting event takes about 1\u20133 s and consists of about 1\u201310 bouts; the magnitude and variability of these numbers decrease over development : RGC axons terminate in 10 retinorecipient areas termed arborization fields (AFs)   as prey  of the optic tectum respond to a range of stimulus sizes from 3\u00b0 to 30\u00b0  could help keep track of both eye angle change during eye convergence  and hindbrain by a group of descending reticulospinal neurons (Gahtan et al., Two regions which might trigger these motor commands are the optic tectum and AF7, which both send descending connections carrying prey-related information to reticulospinal neurons (Semmelhack et al., Besides attempts to capture, hunting sequences can also be terminated by the fish appearing to give up and swim away, which have been termed abort events (Henriques et al., Execution of capture requires binocular integration, and the presentation of prey activates both contralateral and ipsilateral neuropil (Gebhardt et al., Behavior is modulated by internal states (Flavell et al., via alteration of visual responses in the tectum and such modulation is mediated by the HPI axis and the serotonergic system.Hunger state can also affect hunting behavior. Starvation increases the upper limit of the size of objects regarded as prey, and also increases tectal responses to small objects (Filosa et al., Hunting behavior is also affected by experience during development. During normal development measures of hunting efficiency and success increase (Avitan et al., In terms of neural changes, experience alters the functional link between different brain regions with strengthened connectivity between pretectum and optic tectum, cerebellum, and hindbrain (Oldfield et al., Drosophila have well-established circuit connectivity and have been used to study sensory-guided walking, flying and courtship behaviors (Seelig and Jayaraman, To elucidate the neural mechanisms underpinning sensory-driven behavior requires linking neural representations across interconnected circuits with well-characterized motor outputs. Multiple animal models have been used to tackle these questions, each of which has different strengths and limitations. How ecologically valid is our current understanding of larval zebrafish hunting behavior? The environments in which hunting has so far been studied in the lab are much simpler than the zebrafish's natural environment (Engeszer et al., To what extent do the conclusions drawn about neural circuits from head-fixed preparations generalize to freely moving fish? Assays have begun to be introduced which allow neural imaging in moving fish (Cong et al., How is information about prey position transmitted and transformed through the visual pathway to motor outputs? One hypothesis is that of topographic representations at each stage (Helmbrecht et al., What causes hunting events to be aborted? Could it be due to distraction by other stimuli, an updated assessment of the probability of the likelihood of success, noise in sensory representation, or perhaps some varying combination of these?Why does the initial turn toward the prey tend to undershoot the target? This has been suggested to reflect a general hunting strategy fish employ for maximizing hunting efficiency (Bolton et al., How are competing stimuli prioritized? While this has begun to be investigated for aversive stimuli (Fernandes et al., What is the purpose of the periodic oscillation between hunting and exploratory states, and how robust is this oscillation?How do neural representations vary between individuals, and how is this related to behavioral variations? A correlation has been demonstrated between hunting success and the quality of tectal representation of position (Avitan et al., What is the neural basis of evidence accumulation in natural prey hunting? While recent work has uncovered regions of the brain where evidence accumulation occurs in the context of the optomotor response (Bahl and Engert, How far in advance does neural activity predict behavior? Recent data from immobilized zebrafish has suggested that activity in the cerebellum can predict subsequent behavior many seconds in advance (Lin et al., Most work in this area has focused on larvae because of the relative ease of brain imaging at these ages. However, behavioral patterns change as the fish develops (Westphal and O'Malley, In summary, it is clear that zebrafish prey hunting still offers a rich seam of enquiry for understanding behavior, neural circuits, and most crucially the link between the two.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
{"text": "Solubility is one of the most important physicochemical properties, both from a practical and theoretical perspective. Various fields benefit from the knowledge of this fundamental property, including pharmaceuticals, food technology, materials engineering and purification or separation techniques, including green extraction. Furthermore, solvent selection is important in sustainable technologies design, which was also addressed in the aims list of this Special Issue. Since the early 1990s, a significant increase in solubility studies can be observed, and the interest in this topic is growing every year . This SpThe first paper published in this Special Issue was the work by Ghazwani et al. . This stIn a similar work by the Ghazwani et al. research group , the solThe work by Przyby\u0142ek et al.  focused +, Cl\u2212 and ClO4\u2212 can act as effective co-solvents of phenolic acids, which is important from a practical viewpoint.Nutraceuticals are frequently studied substances, and examples of this subject can also be found in this Special Issue. Furia et al.  studied In the study by Ortiz et al. , the solThe paper by Rahimpour et al.  raised aThe aspect of green solvent screening was considered by Przyby\u0142ek et al. by formulating and validating a new screening protocol for green and effective solvent screening . The solHaq et al.  examineda, was also highlighted.Finally, the authors of this editorial  providedMolecules, as well as all the reviewers who provided constructive remarks and the staff of Molecules at MDPI for their professional assistance. We hope that the articles published in this Special Issue will be of much interest to the scientific community and will contribute to the dissemination of knowledge on this topic among researchers. We would like to thank all of the authors who contributed to the \u201cNew Insights into Thermodynamics of Solutes in Neat and Complex Solvents\u201d Special Issue of"}
{"text": "Anxiety disorders are common chronic mental illnesses with complex causes, a high relapse rate, and a high prevalence of depressive symptoms  (Schartner et al., The co-morbidity of anxiety and depression presents a clinical treatment and diagnostic challenge that has plagued countless patients and physicians (Choi et al., Anxiety is a non-motor symptom that is common in AD and PD. Krashia et al.  have recJZ, PS, and HL conceived the article. JZ and HL wrote the first draft and reviewed and revised the manuscript. All authors contributed to the article and approved the submitted version."}
{"text": "Here the context is discussed of a newly reported metal-free perovskite with the H B-site\u2019 nodes connected by \u2018X-site\u2019 linkers into a cubic network with an \u2018A-site\u2019 ion sitting at each interstice [Fig. 1a)]. It is justly celebrated among crystallographers because it combines an extremely stable topology with a rather precarious geometry  above 1635\u2005K methylammonium ions can be inserted on the A site of halide-bridged perovskites  were first reported , 1c)]. This opens very powerful new possibilities for crystal engineering: we can change not only the size of these ions, but also their shape, chemistry  and physics .In particular, none of the et al., 1995et al., 2019et al., 2009et al., 2010et al., 2009et al., 2016Hybrid perovskites take after their inorganic counterparts in each of the ways described above. They undergo complex structural distortions, in several cases having incommensurately modulated phases . The structure of both polymorphs is clearly influenced by the varying degrees of disorder of the molecular components, both hydronium and dabco ions.Both polymorphs of the new material are intriguing in different ways. The \u03b1 polymorph, with the true perovskite topology, crystallizes in the chiral space group et al., 2022et al., 2020This work will be important to at least three frontiers in materials chemistry and physics. First, the topic of metal-free perovskites is rapidly evolving into a subfield in its own right (Cui After so many years of intense research, one might think that little remains to be discovered about the perovskite structure. But, as Budzianowski, Pet\u0159i\u010dek and Katrusiak have demonstrated, with a subtle change in chemistry, it retains its power to surprise crystallographers once again."}
{"text": "Chemical exposure can profoundly affect our health, some being voluntary (food and drugs) and some involuntary . The metabolism of these chemicals is essential for their detoxification, elimination, and, sometimes, their activation. Of the numerous enzymes involved in the metabolism of xenobiotics, this Special Issue concentrates on hydrolases. Hydrolytic proteins are part of a heterogeneous group of enzymes that catalyze bond cleavages through reactions with water, the most abundant substrate in nature. Hydrolases can add water to numerous chemical functions  in an efContrary to CYP450, which are more \u201cslow and steady wins the race\u201d enzymes , hydrolaIn light of these new findings, this Special Issue focuses on both the basic science and translational research of the biological roles of hydrolases in mammals, as well as their role in the metabolism of toxins and natural products. The Special Issue contains five reviews and nine research articles concerning the role of four substrate classes of hydrolases, as well as artificial amyloid hydrolases.Gautheron et J\u00e9ru [Morisseau et al. [Elbarbry et al. [Jamieson et al. [Overby et al.; Yang et al.; Davis et al. [Kesavan et al. [In this special issue, a review by  et J\u00e9ru  summarizu et al. ). This iy et al. ). This ln et al. ). Three s et al. ,10,11) hn et al. ).Rafiei et al. [Glycoside hydrolases catalyze the hydrolysis of glycosidic bonds (ether bonds) in complex sugars. These enzymes are ubiquitous and well known for their role in the biomass metabolism. Here, i et al.  reviewedChrab\u0105szczewska et al. [Roychoudhury and Hegde [Phosphatases are well known to oppose the action of kinases by removing phosphate groups from numerous substrates. The regulation of the phosphorylation of protein is used at the cellular level to regulate biological action and/or catabolism. Here, a research article by a et al.  delves dnd Hegde  brings uWang et al. [Proteasomes are cellular complexes of proteolytic enzymes (proteases) that regulate protein levels, especially misfolded proteins. Besides this constitutive role, proteasomes have roles in cell cycle regulation and cellular survival from stress. Recently, proteasomes have been the target of anticancer approaches illustrated by the approval of selective proteosome inhibitors for the treatment of multiple myeloma. Here, g et al.  review tDuran-Meza and Diaz-Espinoza [Amyloids are protein aggregates that have been associated with the onset of several diseases, such as Alzheimer\u2019s or Parkinson\u2019s disease. Nevertheless, amyloid aggregates represent a new kind of protein fold that has recently been utilized for the design of novel enzymatic activities. In their review, Espinoza  summarizThe articles and reviews in this Special Issue highlight how the vision of hydrolases has shifted from a role in metabolism to a more complex role in cellular signaling and regulation. This is underscored by the fact that hydrolases are now the target of drugs for several disease treatments, promising more research on this great family of enzymes."}
{"text": "The coronavirus disease 2019 (COVID-19) pandemic has highlighted the importance of mathematical modelling in informing and advising policy decision-making. Effective practice of mathematical modelling has challenges. These can be around the technical modelling framework and how different techniques are combined, the appropriate use of mathematical formalisms or computational languages to accurately capture the intended mechanism or process being studied, in transparency and robustness of models and numerical code, in simulating the appropriate scenarios via explicitly identifying underlying assumptions about the process in nature and simplifying approximations to facilitate modelling, in correctly quantifying the uncertainty of the model parameters and projections, in taking into account the variable quality of data sources, and applying established software engineering practices to avoid duplication of effort and ensure reproducibility of numerical results. Via a collection of 16 technical papers, this special issue aims to address some of these challenges alongside showcasing the usefulness of modelling as applied in this pandemic.This article is part of the theme issue \u2018Technical challenges of modelling real-life epidemics and examples of overcoming these\u2019. Since the onset of the COVID-19 pandemic, in a number of countries, including the UK, mathematical and statistical modelling has been at the forefront of informing the status of the epidemic and providing evidence around possible future scenarios to decision makers. Modelling gives a flexible theoretical framework which, parameterized with and calibrated to data, allows exploration of different transmission scenarios and evaluation of different interventions. Although mathematical modelling of infectious diseases has a long history, this pandemic highlighted its applicability and importance for real-time decision-making. The pandemic has also driven the development and application of novel mathematical and computational methods, some of which are presented in this special issue. Undertaking real-time modelling is challenging as it requires a trade-off between fast and less robust modelling and delayed but more robust modelling. The former can be appropriate when data is scarce and we know very little, like at the onset of the pandemic, or when new variants of the virus occur. The latter can be appropriate when we are faced with an already developed epidemic and changes in response may be necessary; for example when faced with a fragmented epidemic where the classic measures such as national reproduction number R values may not be appropriate or when developing and rolling out a vaccination strategy.During the current pandemic, most of the modelling groups involved in advising the UK Government have been undertaking responsive and real-time modelling, often balancing the need to give quick analysis outcomes with assuring accuracy and uncertainty quantification. While undertaking and publishing timely modelling results is important to advice on the current pandemic, as part of the lessons learned from this pandemic and in preparation for the next, it is important that modellers invest in testing the rigorousness in deriving outcomes. Real-time modelling and the vast amount of models developed in the last 24 months have highlighted gaps in the existing technical frameworks that ought to be addressed in preparedness for possible future pandemics.Much of the work in this edition was supported by the Royal Society Rapid Assistance in Modelling the Pandemic  initiatiThis special issue showcases a combination of articles that address overarching technical issues identified in the course of the current epidemic that would be relevant when modelling future ones. Through a series of articles, we generate a library of tools that promote open and transparent science and would be relevant as pandemic outbreak analysis tools in future.et al. [et al. [Although each of the articles within the collections makes a fruitful singular contribution to scientific modelling, there are themes that link them. et al.  presents [et al.  on the uet al. [et al. [et al. [Agent-based models (ABMs) figure prominently in this issue with \u20138 all uset al.  investigs et al.  and Hinc [et al.  are focuet al. [et al. [et al. [et al. [A measure that has been important for policy decision-making and public understanding of the pandemic is the basic reproduction number, d et al.  show how [et al.  use an Al et al.  use clase et al.  present et al. [et al. [et al. [et al. [et al. [Complementing the foregoing, which are concerned with particular models, are several papers that consider relationships between models and borrow methods from other aspects of mathematics to answer epidemiological questions. Fairbanks et al.  show how [et al.  also dem [et al.  also use [et al.  show how [et al.  borrow met al. [et al. [Finally, two papers take a high-level view and make recommendations about modelling in general. Mitchell et al.  emphasiz [et al.  tackle vIn summary, this special issue addresses a number of questions around modelling that have not been considered in the rapid responsive modelling of the ongoing epidemics. Via a collection of papers that include multiscale, cross-discipline mathematical and statistical modelling, and focus on technical aspects of modelling rather than solely applications, while being timely and relevant to the current pandemic, this special issue aims to withstand time and be relevant for possible future pandemics also."}
{"text": "The developmental origins of health and disease (DOHaD) hypothesis describes the effects of parental perturbations around the periconception, pregnancy, and perinatal window that may lead to changes in offspring development and an increased risk of disease . DOHaD, Excess dietary fructose is a major public health concern; in this context, the study by Smith et al.  investigGestational cannabis exposure has increased in recent times, despite limited evidence for its safety in the developing foetus. In the study by Oke et al. , prenataIn the two manuscripts from Shrestha et al., the effects of a maternal high omega 6 (linoleic acid) diet during pregnancy and in the weaning/postnatal period were investigated in the adolescent  and adulIt is well-understood that maternal obesity increases the risk of health complications in offspring. In the study of Tajaddini et al.  in this The placenta is key to organ development, and placental dysfunction can lead to foetal growth restriction, which is associated with perinatal morbidity and mortality. In the study by Moore et al. , placentThis Special Issue also included three review articles that summarised the recent findings associated with maternal cannabinoid exposure , maternaIn the review by Lee and Hardy , the impIn the review by Gombert and Codo\u00f1er-Franch , the rolDiabetic kidney disease (DKD) is a progressive disorder, which is increasing globally in prevalence due to the increased incidence of obesity and diabetes mellitus. Zaky et al.  discusseThe contributions of this Special Issue will provide some insight into the mechanisms which link a poor maternal environment and offspring metabolic health."}
{"text": "Suicide mortality rates are a strong indicator of population mental-health and can be used to determine the efficacy of prevention measures. Monitoring suicide mortality rates in real-time provides an evidence-base to inform targeted interventions in a timely manner and accelerate suicide prevention responses. This paper outlines the importance of real-time suicide surveillance in the context of policy and practice, with a particular focus on public health and humanitarian crises. The release of the WHO \u2018Live Life: an implementation guide for suicide prevention in countries\u2019 provides a comprehensive framework to support countries in developing and implementing national suicide prevention strategies WHO, b. A coreet al., et al., et al., et al., While broad aggregate-level data is important for the implementation of national strategies, small area-level data is essential to local suicide prevention efforts, of which the use of spatial epidemiological methods can increase the reliability of such data  pandemic in many countries, resulting in the publication of recommendations and guidance for responsible media reporting of suicide in relation to the pandemic (Baran et al., et al., et al., et al., Humanitarian crises such as pandemics, climate change and armed conflict are known to impact suicide rates (Bell In the third year of this ongoing global pandemic, the sudden invasion by Russia on Ukraine has plunged the world into a renewed catastrophe. Significant armed conflict has engulfed the nation, forcing millions of civilians to immediately evacuate their native land to escape war. The mass exodus of abruptly displaced individuals resulting from this evolving crisis adds to an already record global level of internally displaced individuals, refugees, and asylum seekers that reached 82.4 million at the end of 2020 and will undoubtedly continue to dramatically increase over the coming months and years (UN High Commissioner for Refugees, et al., et al., et al., et al., et al., et al., et al., et al., Individuals escaping conflict are at an elevated risk of experiencing a range of adverse mental health outcomes, resulting from exposure to extreme trauma (Steel et al., et al., et al., et al., The climate crisis poses an increasing environmental threat to humanity, triggering climate and eco-anxiety in the global population, particularly among children and young people (Taylor, Seasonal variation in suicide rates have been detected, hypothesised to be the result of factors such as weather-related changes or shifts in social interaction (Bando and Volpe, The concurrence of armed conflict, a pandemic and climate-related stressors, exacerbates the stressors experienced by individuals, resulting in increased anxiety and linked disorders such as anxiety disorders, in particular PTSD, which may lead to increased suicide risk. The link between disease outbreak and climate change indicates that future pandemics are unavoidable Taylor, . While eet al., et al., The recently observed rise in armed conflict in some parts of the world is a concerning trend given the threat of combat to human safety, as well as the capacity of countries to deal with a public health crisis during warfare. These concerns are further heightened by the anticipated adverse economic impact of these co-occurring crises on suicide rates, particularly given the risk of financial recession stemming from armed conflict and public health emergencies independently, together with the existing suicide risk directly associated with economic crisis (Oyesanya et al., The implementation of recommended components and practices applied by established real-time suicide surveillance systems elsewhere in the world, while adapting to regional/local circumstances and resource availability, would support the development of real-time suicide surveillance. Networking and knowledge exchange would further facilitate the development of real-time suicide surveillance systems through a learning process from peers with both experience and expertise in the innovative area of research (Baran"}
{"text": "The Role of Antioxidant Molecules and Melatonin in Cellular Protection\u201d, published in Antioxidants , would prefer to highlight the current knowledge and presents new contributions on oxidative stress-dependent signaling pathways in various pathophysiological conditions as well as new antioxidant strategies to prevent/treat the pathological status. This Special Issue comprises 5 research studies and 9 review articles providing important contributions to the Special Issue topic by distinguished experts.The collection of studies in this Special Issue, \u201cThe original study performed by Szeiffova Bacova et al.  explore To gain insight into the antioxidant role(s) and regulatory mechanism(s) of melatonin in yeast, Sunyer-Figueres  presenteLomovsky et al.  investigThe study of Ali et al.  identifiUsing an animal model of diabetic nephropathy, Hsiao et al.  investigExcellent review studies are also included in this Special Issue, emphasizing both the importance of oxidative stress in various chronic diseases and the impact of antioxidant molecules in fighting cellular injury.Sadanandan et al.  summarizThe review manuscript of Ikram et al.  reportedFerlazzo et al.  reviewedIn a systematic review, Sumsuzzman et al.  collecteF\u00e9lix et al.  summarizJaworek et al.  systematLangston-Cox et al.  conductePardo-Hern\u00e1ndez et al.  summarizThe review article of Favero et al. , Editor The Authors in the present Special Issue wants to emphasize that exogenous antioxidants have been recognized as one of the most promising therapeutic options toward the precautions and treatments of many oxidative stress-related diseases. In fact, over the past decade, several kinds of antioxidants have been evaluated for antioxidant therapy showing great effects. However, persist concerns regarding the inherent instability, limited free radical scavenging ability, nonspecific distribution and short cycle half-life limit or avoid their clinical application.With these limitations in mind, there are many opportunities for clinicians and researchers to conduct studies that would add a key contribution to the body of knowledge and would help the future management of several oxidative stress relevant diseases. This Special Issue will be helpful to Researchers in the development of innovative preventive or therapeutic strategies that may lead to a clinical translation soon.The Guest Editor wants to thank all the Authors and the Reviewers who contributed to the success of this Special Issue and the Antioxidants team for their valuable and constant support."}
{"text": "In Hejia Yuan et al.,Also, the Western band of the loading control in Figure"}
{"text": "Afghanistan's humanitarian crisis has severely impacted the mental health of frontline workers. With the introduction of the Taliban government, ongoing civil unrest, and other forms of violent attacks, healthcare workers (HCWs) continue to provide patient care despite minimal resources. A severe contraction in the economy, poor supply of medications, political turmoil, and insufficient humanitarian aid have added to pre-existing problems. High levels of insecurity and instability as well as decades of traumatic experiences have contributed to increasing mental health challenges amongst frontline workers. Despite the scarcity of mental health services, HCWs continue to persevere with their service to the community. However, inadequate interventions may have serious implications for HCWs bearing the brunt of multiple traumas. Thus, governmental and international involvement is needed to address both the economic and psychological needs of HCWs in Afghanistan. This is seen by the ratio of nine HCWs and two physicians per 10\u00a0000 people in the region (Lucero-Prisno III et al., et al., et al., et al., et al., et al., et al., Among this, the impact of war and consequences of the pandemic are primary negative contributors to the frontline workforce, according to a study done in 2020 (Lucero-Prisno III et al., et al., et al., The implications of ignoring this calamity include workplace detachment and lower self-efficacy which hinders provision of optimal quality patient care and decreases resilience amongst HCWs (Islam et al., et al., et al., et al., Amidst these concerns, gender inequality is prevalent in HCWs, with Afghanistan ranked as 171st among 188 countries in the Gender Inequality Index (Najafizada A major advancement took place recently when Taliban urged women HCWs to return to work, stating there will be no impediments to them while performing professional duties in attempts to re-establish basic services across the country Reuters, . In Afghet al., et al., et al., To better advance mental health care in Afghanistan, the allotment of finances and funds for mental health services, and undergraduate training are highly recommended. Devising national health policies and increased research in this area can help navigate the country through this ordeal. Furthermore, trainings to provide suitable psychological first aid and stress management workshops added to undergraduate and graduate-level curriculums could increase community well-being and support. In order to positively cope with the pandemic, several mechanisms and measures must be taken by preparing the HCWs through peer support programs and helping them recognize future challenges through supportive mentoring (Greenberg In conclusion, the political instability in Afghanistan is contributing to an impending mental health crisis for HCWs along with the incursion of the COVID-19 pandemic, economic complications, and ongoing civil unrest. As a result, reduced access to mental health has affected the workplace efficacy of HCWs in Afghanistan. Further research is warranted on understanding the impact of conflict on HCWs and help implement vital measures in devising healthcare policies, allocation of finances, and national training focused on mental health recovery."}
{"text": "In the recent article by David et al. , the worThe authors apologize for the error."}
{"text": "Obesity represents one of the most critical public health crises facing the world today. Excess weight is associated with reduced quality of life and poorer mental health outcomes, as well as increased incidence of medical conditions such as diabetes, heart disease, stroke, and multiple types of cancer. Taking into consideration that most individuals with obesity who attempt to lose weight by restricting their caloric intake will not be successful, greater focus has been placed on examining the neurobiological drivers of obesity , 2. In tObesity cannot be fully grasped without taking into account how an organism interacts with its food environment. Contreras-Rodriguez et al.  deliver Further support for the damaging impact of obesity on brain structure is provided in the review by Garcia-Garcia et al. . In theiKung et al.  seek to Godet et al.\u2019s  review fTo conclude, this special issue aims to serve as a helpful resource by providing updated reports on the state of neuroscience research in obesity and offering suggestions for improved methodological approaches to further advance scientific inquiry and mechanistic understanding of obesity."}
{"text": "In order to be consistent with other studies , we did not include this event and the authors did not include it in their analysis either.In the study by Katz et al., recommend using naturalistic data to evaluate the effect of lithium on suicide but this is problematic for various reasons. First, people who adhere to any treatment are generally healthier and have better outcomes than those who do not (Curtis et al., et al., Bschor et al., also cite data presented by Baldessarini and Tondo's (Bschor  Tondo's , but thiet al., Finally, we draw attention again to the fact that our results, which are based on a relatively large sample derived from modern randomised trials, are consistent with those from the large, high-quality, randomised trial designed to evaluate the efficacy of lithium in preventing suicidal behaviour, which was stopped early due to lack of effect (Katz"}
{"text": "Medicina, \u201cRecent Advances in Breast Cancer Diagnosis, Treatment, Psychology, Management, and Reconstruction\u201d, includes six articles that highlight new innovations with regard to breast cancer, including reconstruction and treatment options, socioeconomics and psychological issues among breast cancer patients, and an uncommonly described type of breast cancer.Breast cancer is the second most common cancer in women after skin cancer . New advIt is well known that the socioeconomic status of all cancer patients contributes to the availability of care and time of diagnosis, with many of these patients less likely to have the resources for regular screening. The study provided by Jensen et al.  examinedMedicina also showcases the considerable progress and continued innovation in oncoplastic reconstruction. Numerous techniques including autologous and implant reconstructions are available and widely used. The study by Sisti et al. [This Special Issue of i et al.  offers ai et al. ). These Finally, the case report by Nanev et al.  shows thThe papers published in this Special Issue showcase the continued need to approach breast cancer in a multidisciplinary fashion. The collaborative contributions reinforce that there is much to learn about the scientific and social aspects that affect breast cancer."}
{"text": "Gambling is a widely accessible form of consumption across numerous jurisdictions around the world Orford, , with itvia the fresh start mindset measurement were found on outcomes including the participants' attitude to the advertisement, their likelihood to buy the sunglasses in the advertisement, and the log-transformed value of the amount they were willing to pay for the sunglasses (Price et al., The fresh start mindset is \u201cdefined as a belief that people can make a new start, get a new beginning, and chart a new course in life, regardless of past or present circumstances\u201d (Price et al., Given the evidence discussed above, the fresh start mindset could be utilized in successful ways to counter gambling consumption harms. Specifically, when designing campaigns to promote those products or services which aim to reduce or prevent gambling consumption harms, marketers should consider when or how to potentially increase the likelihood of the fresh start mindset activation among their target customers. Dai et al.  discoverThe concept of busy mindset refers to the subjective perception of oneself as busy (Kim et al., Self-control issues are considered to be \u201cat the heart of problem gambling\u201d (Bergen et al., He and Cunha  argued tA preference for the default situation or the status quo seems to be present in consumers who experience negative impacts associated with gambling, with only a small percentage or a minority of pathological gamblers seeking help or treatment (Braun et al., Research on gambling consumption harms has been gaining momentum in recent years (e.g., Li et al., EL: conceptualization. EL and HT: drafting. EL, MB, and MR: critical revisions. All authors contributed to the article and approved the submitted version.HT was supported by the funding from CQUniversity's Enrich Research Employment Initiative when working on this manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
{"text": "In the recent article by Andersen et al. , the worThe authors apologize for the error."}
{"text": "Self-poisoning using pesticides is among the major methods of suicide worldwide, and accounts for one-fifth of suicides in 2006\u20132010 in South Korea. We investigated long-term trends in pesticide suicide rates in South Korea and factors related to these trends.We calculated age-standardised rates of pesticide suicide in South Korea (1983\u20132014) using registered death data. We used graphical approach and joinpoint regression analysis to examine secular trends in pesticide suicide by sex, age and area, and a time-series analysis to investigate association of pesticide suicide rate with socioeconomic and agriculture-related factors. Age, period and cohort effects were examined using the intrinsic estimator method.Age-standardised rate of pesticide suicide fluctuated between 1983 and 2000 before it markedly increased in 2000\u20132003 , followed by a gradual fall  in 2003\u20132011. Following the paraquat ban (2011\u20132012), there was a marked reduction  in 2011\u20132014. Trend in pesticide suicide was associated with divorce rate but not with other factors studied. Declines in pesticide suicide in 2003\u20132011 were most noticeable in younger groups and metropolises; by contrast, elderly adults aged 70+ living in rural areas showed an upward trend until after the 2011\u20132012 paraquat ban, when it turned downward. In the age\u2013period\u2013cohort modelling, having been born between 1938 and 1947 was associated with higher pesticide suicide rates.Pesticide suicide trend changed substantially in South Korea over the last three decades. Effective prevention should include close monitoring of trends and strong regulations of toxic pesticides. In 2012, an estimated 804\u00a0000 suicide deaths occurred worldwide, representing an annual global age-standardised suicide rate of 11.4 per 100\u00a0000 population .Pesticide self-poisoning is a major contributor to the global burden of suicide . Our analyses used cause-of-death data from 1983 onwards, as this is the first year for which suicide data stratified by sex and age are available. These registered death data included information on age, sex, area of residence and date of death. The cause of death is coded using the International Classification of Disease, Tenth Revision (ICD-10); suicides by pesticide poisoning were identified using code X68. The year 1991 was the earliest year for which complete individual-level mortality data were available. Aggregate mortality data were available before 1991, but they were not stratified by area. Therefore, the analyses of area-specific trends in pesticide suicides were restricted to the period from 1991 to 2014. Because some pesticide suicides may have been misclassified as deaths due to other causes, including undetermined death by pesticide poisoning (Y18); accident by pesticide poisoning (X48); and suicide (X69), undetermined death (Y19) and accident (X49) by poisoning using unspecified chemicals  were provided by Statistics Korea (http://kostat.go.kr). Estimated values for other years during the study period were based on linear interpolation. Information on paraquat regulations was included because paraquat is the most commonly involved pesticide in intentional pesticide poisoning. Information on paraquat regulations were obtained from the Korea Rural Development Administration (http://www.rda.go.kr). In South Korea, the re-registration of paraquat was cancelled from the end of November in 2011 and its sale was completely banned from the end of October in 2012. Information on potential risk factors for suicide such as unemployment rate , dependency ratio (ratio of the number of people aged 0\u201314 years plus the number aged 65 years and over to the number aged 15\u201364 years) and divorce rate (number of divorces per 1000 population) were collected from Statistics Korea. These socioeconomic factors have shown an association with overall suicide rates in South Korea  world standard population  was used to estimate the annual percent change for linear trends and the location of joinpoints as well as their 95% confidence intervals (CIs).We used graphical approaches and joinpoint regression analysis to investigate trends in overall pesticide suicide rates and rates by sex, age and area. Joinpoint regression analysis allowed the identification of possible underlying trends comprising linear segments and \u2018joinpoints\u2019,  and five times  higher in males and females, respectively, than that for all ages combined. After a decline in pesticide suicide mortality from 1983 to 1987, period effects increased over the next two decades, peaking between 2003 and 2007 , which was then followed by a marked fall from 2008 to 2014 in both sexes. The cohort effects were highest between the 1920s and 1960s, peaking in the cohorts born between 1938 and 1942 for males  and between 1943 and 1947 for females .The contributions of age, period and cohort effects on observed pesticide suicide trends, controlling simultaneously for all three parameters, are shown in Pesticide suicide rates changed markedly over the last 30 years in South Korea. The age-standardised pesticide suicide mortality rate fluctuated between 1983 and 2000 before markedly increasing from 2000 to 2003, peaking at 9.2 per 100\u00a0000 in 2004; it gradually decreased afterwards and rapidly declined following the 2011\u20132012 ban of paraquat. Pesticide suicide rates were higher in males than they were in females, increased with age, and were higher in rural than they were in non-rural areas. The increase in pesticide suicides before the mid-2000s was greatest in elderly adults aged 70+ years. Pesticide suicide rates decreased in most sex/age groups across all areas after the mid-2000s, but they continued increasing among elderly adults living in rural areas, among whom the 2011\u20132012 paraquat ban also had the largest impact on pesticide suicide trends. From the age\u2013period\u2013cohort analysis, there was a peak in the generation born between 1938 and 1947 and the relative risk was nearly three times the risk of all birth cohorts combined, independent of period and age effects.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., The increase in pesticide suicides in the 2000s in South Korea is unique compared with other industrialised Asian countries such as Japan (Kim et al., et al., et al., et al., et al., et al., The rise in pesticide suicides before the mid-2000s was most prominent among elderly adults. South Korea's increasing suicide rates since the 1990s was previously found to be most prominent in older people (Kim et al., et al., et al., The finding that the abrupt increase in pesticide suicide rates from around 2000 was moderated in the sensitivity analysis, which included data on pesticide suicide cases that were possibly misclassified, indicates that an improvement in the quality and comprehensiveness of suicide data around 2000 might have contributed to the increase in pesticide suicide rates. Certified pesticide suicides markedly increased from 2000 to 2003 in South Korea, which was a continuation of a previous upward trend from 1991 when we included possible misclassified pesticide suicides (Cha et al., et al., et al., et al., A decrease in pesticide suicide rates was observed in South Korea from 2004 to 2011, particularly among people living in metropolises and cities and in those aged below 70 years. However, this decrease was accompanied by a rise in use of hanging, particularly in females aged 20\u201359 years (Jee and Jo, et al., et al., et al., et al., et al., et al., et al., The finding that the paraquat ban influenced pesticide suicide trends was consistent with findings from previous analyses using data up to 2013 (Cha et al., Males are generally more vulnerable to suicide risk than females and male suicide rates were more sensitive to socioeconomic factors than female rates Girard, . The fluet al., et al., et al., et al., et al., et al., et al., et al., et al., The results from the age\u2013period\u2013cohort analysis were somewhat different from those of previous studies on overall suicides in South Korea (Lee, We have conducted in-depth analyses such as joinpoint regression analysis, Prais\u2013Winsten regression and age\u2013period\u2013cohort analysis to identify underlying trends and the factors that may have affected the trends in pesticide suicides in South Korea. The limitations of the study include the ecological design, the linear trend assumption of joinpoint and Prais\u2013Winsten regression analyses, and the unavailability of data pertaining to other potential risk factors for suicide.In conclusion, pesticide suicide trends changed substantially in South Korea over the last three decades and varied across demographic groups. In particular, the ban on paraquat appeared to be the most effective approach to reducing suicide in the male elderly population, who were at high risk of pesticide suicide. Therefore, strong regulations on toxic pesticides may help ameliorate the very high rates of suicide mortality observed in this population."}
{"text": "World Journal of Surgical Oncology by Liu et al. With this study, authors evaluated diagnostic accuracy of Xpert bladder cancer monitor in detecting recurrences. With this article, we highlight the strengths and limitations of the study.This article is a commentary on an article published in  Sir,I have reservations over inclusion of study by Valenberg et al. , as thisStudy authors have pooled overall data of study by Wallace et al.  that incLastly, use of different gold standard techniques by different studies is yet another limitation of this study which needs to be highlighted. Subgroup analysis according to the gold standard modality could also be performed.I read an article published by Liu et al.  in the FTo conclude, the results of this study need to interpret with caution due to abovementioned limitations and if possible needs revision for above mentioned points as they have potential to change the overall results."}
{"text": "Measurements of protein dense phases reveal the presence of highly ordered protein nanostructures. Such phases may be candidates for structural biology measurements on next-generation instruments for molecules that are difficult or impossible to crystallize. Acta Crystallographica Section F. This is far from an easy process, and when it succeeds there is an enormous variety in the size, shape and order found within these crystals (Svensson et al., 2019et al., 2021et al., 2015Methods to coax macromolecules into ordered lattices are bread and butter to the readers of et al., 2011et al., 2021et al., 2020The dense phases that proteins form during the crystallization process of salting-out have been largely ignored with respect to their macrostructure. The rise of the XFELs (Chapman While the number of examples is still perhaps limited, this study clearly shows that protein gels tend to contain microstructures. This can therefore be exploited to gain structural insights into systems that have proved difficult to crystallize and may shed light on the processes of crystallization itself. We look forward to seeing the first diffraction images from these fascinating protein phases."}
{"text": "We conducted an integrative review of the global-free maternity (FM) policies and evaluated the quality of care (QoC) and cost and cost implications to provide lessons for universal health coverage (UHC).Using integrative review methods proposed by Whittemore and Knafl , we searForty-three studies that met the criteria were all from developing countries and had implemented different approaches of FM policy. Review findings demonstrated that some of the quality issues hindering the policies were poor management of complications, worsened referral systems, overburdening of staff because of increased utilisation, lack of transport, and low supply of stock. There were some quality improvements on monitoring vital signs by nurses and some procedures met the recommended standards. Equally, mothers still bear the burden of some costs such as the purchase of drugs, transport, informal payments despite policies being \u2018free\u2019.FM policies can reduce the financial burden on the households if well implemented and sustainably funded. Besides, they may also contribute to a decline in inequity between the rich and poor though not independently. In order to achieve the SDG goal of UHC by 2030, there is a need to promote awareness of the policy to the poor and disadvantaged women in rural areas to help narrow the inequality gap on utilisation and provide a sustainable form of transport through collaboration with partners to help reduce impoverishment of households. Also, there is a need to address elements such as cultural barriers and the role of traditional birth attendants which hinder women from seeking skilled care even when they are freely available. The review complements the findings on the utilisation of services under FM policies \u2013 links with existing literature on utilisation because many prior analyses have mainly focused on comparing the changes in utilisation of services before and after the implementation of the free policies  and the cost implications about policy and practice that legislate for the free global maternity care?What lessons can we learn from the global FM policy to support the achievement of UHC?The review answers the following questions:et al., The study utilised the integrative literature review, which allows for the synthesis of several streams of literature  but not the quality or cost of the free maternal healthcare policy. First, all titles were screened for eligibility. Second, studies that met eligibility had their abstract further screened for eligibility after which full texts were screened for those studies that meet the eligibility criteria. All articles were included irrespective of the date. Figure\u00a0et al., et al., In this review, we did not do meta-analysis because there was much heterogeneity in the studies. We applied a mix of validated critical quality appraisal techniques .Additional file 1. The quality appraisal of 21 studies included in the review was rated as high because they reported sufficient details about the FM policy and highlighted robust methodologies with findings according to the appraisal tools used  and LMIC countries  as an influencer or a hinder to the achievement of QoC (Chama-Chiliba and Koch, This section reports on the elements of cost of maternal care from the perspective of the managers, service providers, and users through thematic analysis.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Twenty-three of the reviewed studies showed that households in different countries still bear the burden of OOP expenditure despite the implementation of FM policies (Nahar and Costello, et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., The OOP paid by the households differed based on type and complexity of delivery (Nahar and Costello, et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Five studies highlighted the element of catastrophic expenditure (Witter et al., et al., et al., et al., et al., et al., et al., et al., et al., Nine studies highlighted the financial effects free policies had on the facilities (Witter et al., et al., et al., et al., et al., et al., Health facilities in Ghana reported experiencing delayed reimbursement of funds meant for the free services and were thus faced with inadequate supplies and higher OOP for patients (Dalinjong et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., The review had mixed findings on informal payments from eight studies (Khan, et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Eight studies highlighted the survival tactics that families were adapting to meet the OOP (Nahar and Costello, et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Eleven studies showed that despite the policies being free or were subsidised to mothers, there was a difference in the benefits received based on wealth categories (Khan, et al., et al., et al., et al., et al., Only four studies highlighted concepts of the overall expenditure of the policy (Witter To the best of our understanding, this is first integrative review that has been done to analyse the effects of the FM policies on the quality and cost outcomes. The study reviewed the roles of FM policies on aspects of provision and experience of QoC following into the WHO standards for improving maternal and child health (World Health Organisation, et al., et al., et al., et al., et al., et al., et al., et al., There is adequate evidence to show that the policies have significantly played a role in improving the elements of provision of quality care. Our findings reveal that FM policies are associated with positive outcomes of evidence-based practices such as improved screening for key diseases such as syphilis and HIV in pregnancy, measuring vital statistics at ANC, reducing perinatal complications, and improving immunisation. The outcomes are in line with the achievement of SDG goals 3.1 and 3.2 (United Nations Development Programme, et al., et al., et al., et al., et al., et al., et al., et al., The experience of care by the women, who are the target of the FM policies, is significant. Our findings show that the women\u2019s positive cumulative experience, while utilising the services under the FM policies, could encourage them to either return for subsequent delivery or impel them to seek care elsewhere. Due to the ripple effect created by good word of mouth based of good experience, others could be encouraged to seek care. FM policies are likely to successfully boost the women\u2019s experience through excellent communication between HCWs and the mothers, which would eventually translate to the perception of respect, preservation of dignity, and feeling of sufficient emotional support (Hulton et al., et al., et al., et al., et al., There are two elements: HCWs and essential resources, which are cross-cutting on provision and experience of care. Our results have shown that HCWs play a significant role; thus, their competence and motivations, although affected by several factors, allow for the provision of better routine care under the FM policies. The motivation of HCWs is multi-faceted and has been studied by several authors (Sato et al., The review revealed that TBAs still play an essential role in society, and some women prefer them to midwives in hospitals despite FM policies. TBAs have the potential to alter the intended progress envisaged by most FM policies; hence, there is a need to involve them intelligently. Some of the TBAs are retired nurses and women prefer them because they provide better personal relationships and individualised attention during birth which many hospitals lack because of the increased number of deliveries because of the free policies. Other research has shown that some pregnant mothers perceive hospital staff and services poorly hence choose to deliver through the support of TBA (Oyerinde et al., et al., et al., et al., et al., et al., Our review elucidated adequate evidence of the financial implications of the FM policies on patients, providers and managers, and facilities. While the goals of the policy are to improve access to skilled birth and protect mothers from financial catastrophe, the review has shown that the free policies have, in most cases, reduced family expenditure on healthcare; however, they have not eliminated OOP payment. OOP payments from patients worsened the equity gap and hindered access (Abel-Smith and Rawal, Several studies have used different designs to show the gaps in QoC and outcomes and changes in the cost accompanying FM policies but have not shown whether the policies are the cause. Therefore, we propose that mixed-method studies or econometrics studies with intervention and control groups could be used to fully attribute the policies to changes in quality and cost of care. Also, with the debate around UHC taking shape, more political economy studies could be conducted to evaluate potential factors and designs of FM policies that can maximise on the QoC, utilisation, and cost through effective coverage measure.There are some limitations of the evidence from the review. For instance, our analysis was descriptive in nature, and alternate methods such as meta-analysis were not possible due to policy interventions, multiple outcomes, and the heterogeneity of studies. Also, we reviewed all studies without prior limitations of dates till 2018. There is a possibility that some studies related to our subject may have been published after 2018, but we wanted to focus on the period that captures best the discourse of initiation of UHC. Equally, some FM policies may have changed in design throughout the pilot periods or implementations, and we wanted to limit the heterogeneity.There is a gap in quality care and outcomes of the FM policies that can adequately be reduced if the design of the policies actively invests in quality as significant objective rather than just enhancing utilisation. The policies can reduce the financial burden of the households if well implemented and sustainably funded. Besides, they may also contribute to the relative decline in inequity between the rich and poor though not independently. In order to achieve the SDG and UHC goals that seek to ensure that everyone who requires healthcare is able to access quality service without suffering catastrophic expenditure, our study proposes the following Table\u00a0."}
{"text": "After more than 50 years from the original description, the modified Bentall procedure (MBP) still represents the gold-standard treatment for patients with aneurysms of the ascending aorta and with an aortic valve not amenable to repair.AORTA, Kasai et alIn the February 2020 issue ofKasai et al"}
{"text": "Meanwhile, Alexi et al. describe an assessment of the use of synthetic (computer-generated) body stimuli in measuring body size estimation, replicating the serial dependence effect that they previously demonstrated with photos of human bodies. D'Amour and Harris present a novel method of measuring body size estimation at various viewpoint angles using a psychophysical staircase procedure. In particular, their technique purports to measure the brain's representation of the participant's own body.The articles in this Research Topic can be grouped into several overlapping themes. A number of articles are concerned with establishing effective and rigorous systems of measurement for the various aspects of behavior connected with body image disturbance. Brooks et al.). This article observes the paradox that the same terminology (body size overestimation) is often used to describe opposite patterns of results by scientists with clinical vs. perceptual psychology backgrounds . Consideration of the assumptions of these sub-disciplines and the type of representations that they believe to be distorted can explain this paradox. The adaptation paradigm, which exposes participants to extreme bodies to cause a bias in size and shape judgements for subsequently seen bodies, is applied in several papers. Ambroziak et al. present a study investigating the locus of the adaptation effect, i.e., whether it affects the perception of the experimental stimuli or the stored representation with which these are compared. Brooks et al. and Gould-Fensom et al. employ this paradigm in investigating the neural representation of body adiposity for different genders or ethnicities, respectively. Brooks et al. demonstrated that body size aftereffects do not transfer completely between male and female bodies, suggesting that the neural populations responsible for body size estimation are somewhat selective for gender. However, Gould-Fensom et al. showed complete transfer of the effect between the bodies of Australians of European descent and Malaysians of Asian descent, suggesting that these neurons are not selective for ethnicity. In addition, this paper reminds us of the importance of including non-WEIRD populations in research on body image and chimes with recent evidence that adaptation effects themselves are not culturally or racially bounded, with ethnically diverse samples in low-media contexts still showing typical aftereffects from viewing high or low weight bodies  bodies is influenced by the presence of faces when visible. This \u201cinversion effect\u201d is also shown by Nazareth et al., for brief (17 ms) stimuli, when asked to identify human (vs. non-human) body stimuli, and is thought to indicate holistic processing for upright, but not for inverted stimuli. Although, Axelson et al. demonstrate body inversion effects even when faces are not visible, these effects increase when faces are present, suggesting a significant influence of faces on holistic processing for bodies. Ritter et al. also investigate the perception of faces, specifically the presence of an inversion effect for those diagnosed with Body Dysmorphic Disorder (BDD) compared with healthy controls. Although the BDD group were hypothesized to be less holistic in their processing of face stimuli, suggesting a reduced inversion effect, these participants showed no such abnormalities. Face perception is again central to Shi et al., who highlight the facial appearance dissatisfaction of those scheduled to undergo orthognathic (jaw) surgery to address a visible difference.The perception of body posture is tested further by Cass et al. use a visual search task to investigate attention as a function of observer body size, demonstrating biases toward bodies matching the observer's own in terms of BMI. Meanwhile, Kim et al.'s approach involves eye movement recording to establish the effects of observing thin-ideal images on restrained eaters' attention to pictures of food. In particular, restrained eaters who scored highly on neuroticism showed increased vigilance for food. Engel et al. use a dot probe task to investigate the possibility that attentional training may redirect participants' tendencies to focus on positive or negative parts of their own bodies. As attentional biases to positive/negative body parts were not clear at baseline, abolition of those biases was not possible. However, it remains to be seen whether an intervention such as this might be effective amongst those with more significant body image concerns .The link between attention and either the perceptual or attitudinal aspects of body image has been a topic of broad interest in recent years  women in urban and high-income populations. In that context, S\u00e1nchez-Cabrero et al. make an important step in further broadening the diversity of the literature by demonstrating the effectiveness of a body dissatisfaction intervention\u2014the IMAGINA program\u2014for a frequently overlooked group: older people. For all the elegance and rigor of basic science investigations, of which there are many in this collection, these translational studies are a reminder of the eventual goal of increasing our understanding of the underlying mechanisms of body image\u2014to make people's lives better. Furthermore, that mission must include the full range of those affected by the appearance pressures to which our distorted perceptual experience gives rise.Interventions to improve the attitudinal aspects of body image are the subject of several additional articles in this Research Topic. As Cash and Smolak  commenteKB wrote the original draft. LB, JB, and IS contributed important written material, edited the manuscript, and approved the final draft. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
{"text": "How do you find out whether rhythm control is the right strategy for your patient?Atrial fibrillation (AF) is a disease of advanced age and thus more common in an ageing population In this issue of the International Journal of Cardiology Heart & Vasculature, Hermans et al. This study provides some interesting insights that question the utility of ECV for symptom-rhythm correlation. In contrast to catheter ablation, ECV did not result in a significant symptom relief Hermans et al. are commended for evaluating the concept of ECV with a later outpatient follow-up In the last decades, several major rate versus rhythm control studies  came to the same conclusion: rhythm control was not superior in terms of morbidity or mortality and rate control was a legitimate primary treatment option Similar to previous studies the study by Hermans et al. confirms that SR correlates with relief, but AF recurrence after ECV is common in\u00a0>\u00a050% of the patients Hermans et al."}
{"text": "In the original article, there was an error. We incorrectly stated that \u201c\u2026in the case of parchment documents and leather objects, this method was used only by one group of researchers  were also previously detected on collagenous materials in many studies with the use of clone libraries construction, PCR-denaturing gradient gel electrophoresis, and microscopic methods . The culture-independent molecular methods ensured detection of more fungal taxa than culture-based molecular ones, which is consistent with results of analyses carried out by Wu et al. (\u201cThere are not many new scientific reports describing microbiological analyses of historical leather objects. Most of them are related to other collagen-based materials such as parchment. Strzelczyk and Karbowska-Berent  and Strzu et al. .\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
{"text": "Boyle et al. discuss the development and implementation of a Virtual Objective Structured Clinical Examination due to the COVID-19 pandemic lockdown precluding face-to-face Objective Structured Clinical Examinations, something we too as clinical medical students studying at University College London have experienced. We commend Boyle et al. for promptly creating and delivering this assessment. However, we believe this style of assessment has the potential to exacerbate the ethnic and social inequalities that currently exist within medical education. Going forward, it is imperative that the home environment is considered in an attempt to level the playing field. Dear Editor,We read with great interest the article by Boyle et al.  regardinWe commend Boyle et al.  for theiWe understand that this format of examination was a temporary measure put in place due to the COVID-19 pandemic. If this style of assessment was to be utilised again, medical schools would have longer than Boyle et al. . Followi"}
{"text": "This is an account of the crucial role played by a strong local Aboriginal workforce in health care delivery. We report on the personal experience of dedicated Aboriginal health professionals across Western Australia. Their understanding of what has worked in the provision of primary health care in their communities emphasises the importance of strong, local collaboration in the development of effective prevention programmes at a community level. The Strategy is focused on Aboriginal children aged 0\u20135 years. It recognises that for the prevention and treatment of ear disease to improve, agencies and service providers need to avoid duplication, and to adopt a consistent evidence-based approach to service provision \u2019 and \u2018exercise regularly\u2019 are not emphasised enough and are generally undervalued. They are often not understood by Aboriginal community members and therefore have limited impact. The final recommendations of the Working Group suggest ways to address this deficiency by stressing the importance of leadership by local Aboriginal health and education professionals in community-based prevention programmes  provided an evidence-based outline of their approach and experience of what has worked in their respective roles. The authors who are senior Aboriginal Health Workers also shared their stories and experiences of how they have been enabled, what has worked and what has not worked.et al. It was clear that the Indigenous PHC model proposed  was consistent with the ideas put forward by the group members.The first author also conducted a preliminary review of literature on PHC in Aboriginal Australia and was impressed by a 2018 scoping review conducted by Harfield et al., et al., et al., The collaborative approach taken by the Working Group is linked to the growing body of literature around opening up methods of working and learning together across the cultural divide  have been consistent in developing Aboriginal programme leadership, we have found this is not always the case for all health providers. Unfortunately, from personal experience, the majority of Aboriginal health professionals are not in senior positions within the health care system.et al. (Jongen et al., et al., et al., This experience is reiterated by Jongen et al.,As a consequence, Aboriginal team members are seldom involved in the planning of health care programmes (Fogarty et al. (et al., These messages and observations from across Western Australia are consistent with principles of the Indigenous PHC service delivery model proposed by Harfield et al.  and refl et al., . These net al., et al., et al., The impact of colonisation has had a profound influence on loss of traditional knowledge of health and wellbeing, ways of caring for country and loss of Indigenous languages Malcolm, . Other rBy integrating learnings that we have learned from our Aboriginal colleagues, we could make progress towards a collaborative service delivery approach. Such a model would integrate cultural values into its design and delivery, ultimately improving engagement with Aboriginal families.We acknowledge that the opinions of our Aboriginal informants cannot be simply generalised.Primary prevention programmes for health and wellbeing in Aboriginal communities should be given greater importance if we are to successfully reduce the impact of diseases of childhood. We argue that prevention programmes require Aboriginal leadership and greater collaboration to ensure that cultural values and practices are embedded in the delivery of PHC. Most importantly, we argue for the inclusion of culture in PHC programmes, acknowledging local diversity, and stress the importance of Aboriginal leadership, integrating their wisdom, experience, and understanding of Aboriginal families and their communities.et al. (et al. (Our findings from discussions with Aboriginal health professionals and their managers are consistent with the recommendations of Harfield et al. . We conc (et al. , that th"}
{"text": "To determine the sensitivity, specificity and accuracy of ultrasound to diagnose the patients with tendon rupture of upper extremity referred to Taleghani Hospital\u2019s center of Kermanshah in 2019.nd year resident in emergency medicine ward and the results were recorded in a checklist. Further examination of the tendon was performed as well as exploring the site for the patients after the patient was transferred to the orthopaedic service. Final result was recorded in the checklist. Data were analysed by SPSS software and sensitivity and specificity of ultrasound have been calculated.This was a diagnostic value study which performed on 113 patients with non-fracture penetrating hand trauma. In the first stage, all patients have been diagnosed with tendon injury by a first-year resident and then ultrasound was performed by a trained 2Results showed that ultrasound was able to identify 73 patients of 77 individuals with tendon injury. Of the patients with complete rupture, 45 individuals were correctly diagnosed based on the results of surgery in ultrasound test. Ultrasound and surgical findings were significantly different. Of the 36 individuals without confirmed rupture in surgery, 10 cases were diagnosed with tendon rupture by ultrasound. Of 52 cases of complete rupture based on surgical findings, 45 individuals were correctly diagnosed based on the results of surgery. Twenty-one patients were correctly diagnosed based on ultrasound out of 25 cases of partial rupture based on surgical findings.Overall, the results of the present study show that ultrasound is not very sensitive and specific in diagnosing of upper extremity tendon rupture and cannot be used as a reliable alternative in diagnosing of upper exteremity rupture; however, further studies is essential according to the limitations of this research. The limitations were low sample size in subgroups analysis based on the presence of complete or partial rupture and performing the ultrasound by an emergency medicine resident who is less experienced rather than radiologists. Tendon ruptures are common musculoskeletal injuries occurring along with penetrating trauma worldwide. These injuries are one of the most common musculoskeletal complaints responsible for 7% of all referrals to doctors in the United States . Approxiet al., [The present study was a functional diagnostic study. The sample size was determined in terms of the study by Mohamad-Rezaei et al.,  Based on the statistical population, 113 individuals with penetrating hand trauma have been enrolled in the study who referred to Taleghani Hospital Emergency ward of Kermanshah from March 22, 2018 to March 20, 2019. Inclusion criteria were penetrating trauma without fracture.All patients have been diagnosed with tendon injury by the first-year resident of emergency medicine at the first stage. Afterwards, the ultrasound was performed by the trained second-year resident of emergency medicine in the emergency department and the results were recorded in an out-of-file form. Ultrasound was performed using the Toshiba device at the time of admission. Following these steps, the patients was transferred to the orthopaedic services and the supplemental checking were also performed to examine and explore tendon site for the patients. At this stage, the patient\u2019s outcome was recorded in a separate form and kept in the patient\u2019s file. The results of ultrasound and orthopaedic evaluation were recorded in researcher\u2019s and patients\u2019 files after its completion in the operating room. The initial ultrasound results were compared with the gold standard method (orthopaedic exploration). Additionally, ultrasound sensitivity and specificity were determined. The final data were analysed by using a descriptive statistic . The statistical significance level of this study was considered as 0.05.This study was performed on 113 patients with penetrating tendon injuries. The mean age of patients was 31\u00b17.36 years old. Kappa coefficient was used to compare the diagnostic values of ultrasound and surgery .The fingers traumatic tendon rupture is a common finding in soft tissue injury of musculoskeletal trauma. In this regard, surgery is one of the alternative treatment options to treat tendon ruptures in the fingers; however, post-operative complications like adhesion around the tendon can be observed by using this method and even experienced surgeons in treated patients. In the majority of patients, rupture or injury diagnosis of the finger\u2019s tendon can be diagnosed by a history of trauma or clinical examination but CT scan findings are useful in cases when flexor tendon rupture cannot be diagnosed , 9. UsinNotably, there are limited findings on the efficacy of ultrasound in the diagnosis of tendon trauma in the fingers .et al., [et al., [et al., [In this study, 113 patients were studied with penetrating hand tendon injury. Of them, 86.7% were men and the mean age was 31 years old. In the study by Lee [et al.,  have bee[et al.,  were stuet al., [et al., [A study  in Netheet al.,  study wh[et al.,  in Chinaet al., [Ravnic et al.,  in the Uet al., , 15, 18,et al., [et al., [The present study found that flexor digitorum superficialis (FDS) and flexor digitorum profundus (FDP) were the most common traumatic tendons and resembling with other studies such as Bianchi et al.,  and Clav[et al., . These sTherefore, these tendons were most likely to have trauma according to the fact that most of the traumatic injuries are the hand volar surface and FDP and FDS tendons have the highest contact area. In the present study, we found that ultrasound is able to fully detect all individuals with complete tendon rupture to detect sensitivity, specificity, positive and negative predictive values as 100%. However, this diagnosis was different in incomplete rupture. It was also observed that sensitivity, specificity, positive predictive value and negative predictive value was 94.8%, 72.2%, 87.9% and 86.7%, respectively in the diagnosis of incomplete rupture. et al., [In a study of Lee et al.,  20 tendoet al., [Jeyapalan et al.,  study obet al., [et al., [Complete rupture was observed in 3 patients. Surgical and exploration procedures were performed for these patients whereas in 2 patients (66.66%) an obvious rupture was observed. The results analysis showed that ultrasound could prevent the additional exploration of traumatic patients. Shekarchi et al.,  found thet al.,  claimed [et al.,  showed tet al., [et al., [et al., [Wu et al.,  showed t[et al.,  showed t[et al.,  it was r[et al.,  also repIn conclusion, the present study show that ultrasound does not have high sensitivity and specificity in diagnosis of partial tendon rupture. Therefore, it cannot be used as a reliable alternative method for diagnosis of upper extremity partial rupture. However, further studies are necessary in this field due to the limitations of this study especially low sample size in subgroups\u2019 analysis based on the presence of complete or partial rupture and performing ultrasound by an emergency medicine resident who was less experienced than radiologists. Study Limitations and Suggestions\u25cf The results of clinical examinations were not evaluated.\u25cf Other imaging tools including CT scans and MRI were not evaluated in this study.\u25cf It is recommended that further studies must be conducted in this field and more patients should be evaluated.\u25cf It is suggested that another study should be performed in which patients will be divided into multiple groups and other imaging tools will be tested.\u25cf It is suggested that lower extremities\u00a0should also be considered in the future studies.\u25cf It is suggested that ultrasound must be performed by both emergency medicine physicians and radiologists to assess the degree of agreement between them in the future studies."}
{"text": "This Special Issue brings together an original research report, a fascinating case report, and three timely reviews on a variety of topics related to pediatric leukemia. The original research report by Dr. Tremolada and colleagues  addresseThe case report by Prudowsky et al.  describeThis Special Issue also brings us three outstanding reviews on pertinent and rapidly evolving issues in pediatric AML therapies. The review by Epperly and colleagues  from St.The review by Chen and Glasser  providesFinally, the review by Conneely and Stevens  describe"}
{"text": "The quest for meaning in life takes on new challenges and directions during late life. This mini-review draws on prior theory to analyze meaningfulness into six discrete dimensions  and covers research into how these apply and operate specifically during late life. Limited remaining time, concern with one's legacy, concerns with self-continuity and integration, variable challenges to self-worth, and prioritization of positivity emerge as key themes. Finding meaning in life is a potential concern for people of all ages, presumably except very young children. Meaning in life is widely regarded as an indicator of well-being Ryff, , and indLater life has been mooted as a time of particular relevance to meaningfulness concerns. Later life presents relatively few new opportunities for meaning while taking away some sources that may have been important during youth and middle age. In particular, the loss of social connection due to death or departure of loved ones can reduce meaning, given the central importance of relationships  is a theory developed to explain successful aging  stimuli, compared with younger adults (Charles et al., per se (Seeman et al., As a core need for meaning in life, efficacy means making a difference in the world, and especially to bring about progress toward those valued goals. Efficacy varies greatly among persons of any age; later in life it may well be that beliefs about efficacy, that is, self-efficacy and perceived control, may influence well-being and functionality more than efficacy There is a mixed literature regarding changes in self-esteem with increasing age; while some research supports declines in self-esteem in later life (e.g., Orth et al., Self-esteem plays an important role in buffering the effects of declines in health and functionality in later life (Sargent-Cox et al., Mattering was proposed by George and Park  as an imThe concept of mattering calls for further elucidation. Clearly the term resonates, because self-rated mattering among workers in organizations predicted a variety of positive outcomes (Reece et al., It may be difficult to sustain a sense that one's own life matters if one does not believe one's life matters to others. Taylor and Turner  discuss Comprehension was the third need postulated by George and Park . It compThere is an increasing literature examining age differences across the lifespan in self-continuity, defined as perceived associations of one's present self with past and future selves (L\u00f6ckenhoff and Rutt, As human longevity continues to increase, the keys to successful aging become ever more important. An emerging consensus holds that finding or maintaining meaning is part of successful aging. We have sought here to break meaningfulness down into more precisely defined and specific needs for meaning. Such an approach holds promise for elucidating the problems, challenges, and opportunities for maximizing meaning in late life.NP's expertise on aging combined with RB's expertise on meaning. Ideas emerged from discussion. Both authors wrote parts of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Escherichia coli and intestinal enterococci) which are not indicating the fecal pollution source. Microbial source tracking (MST) methods allow the identification of fecal pollution sources that is critical for management and remediation of water quality.Human and animal fecal pollution may adversely affect inland and coastal waters with negative consequences for water supplies, recreational water uses and shellfish production. Fecal pollution of waters is a significant health risk and can lead to economic losses due to shellfish bed closures, bathing prohibitions and serious limitations on water resources. Fecal contamination in water is currently evaluated by the enumeration of traditional fecal indicator bacteria  methods have been proposed. With the exception of chemical compounds, they are considered in the manuscripts of this special issue.Li et al.; Sinigalliano et al. and Toubiana et al.), street-level stormwater run-off  and in roof-harvested rainwater  in this Research Topic.Multiple varying sources of fecal pollution can influence water quality. Some widespread sources of fecal pollution such as discharges of untreated or treated wastewater, contamination by bathers and wild birds are investigated in beach waters . Those molecular markers targeting human fecal material, or pollution originating from livestock or birds are the methods of choice in at least 15 of the manuscripts in this current Research Topic. In an interesting trend, most studies looked for several sources and combined several methods and targets .Boukerb et al. used this approach to identify novel markers for avian and other sources. Liang et al. as well as Zimmer-Faust et al. applied the same method to investigate and model fecal pollution in rural rivers and coastal waters, respectively, combining it with PCR-based detection of host-associated MST markers.The 16S rDNA gene is also the target of bacterial community-based MST approaches by amplicon sequencing of this gene. Rytk\u00f6nen et al. explored the utility of targeting 16S rRNA instead of 16S rDNA as a template in MST studies. Furthermore, manuscripts of this Research Topic have shown that it may be relevant to complement the results from MST methods with chemical parameters indicative of pollution sources. Sinigalliano et al. used isotopic tracking of nitrogen inputs while Reynolds et al. investigated correlations of ammonium, total oxidized nitrogen, and phosphorus levels with MST marker levels.Byappanahalli et al. who investigated the influence of filter pore size on marker- and community-based MST approaches while Linke et al. demonstrated the strong impact inorganic turbidity can have on DNA based water quality analysis. These studies highlight the central importance of quality and process controls in MST investigations.Highly relevant technical issues of MST investigations were explored by Denissen et al. investigated the presence of Mycobacterium tuberculosis, Yersinia spp. and Listeria monocytogenes in roof-harvested rainwater. Derx et al. used Cryptosporidium and Giardia as index pathogens in a catchment wide QMRA approach.If the use of MST markers is currently coupled with the detection of FIB, it is also done in combination with the detection of human pathogens, especially in the context of quantitative microbial risk assessment (QMRA). Ahmed et al. show that MST markers can be useful indicator for the presence of AMR genes while Toubiana et al. combined genetic MST markers with AMR gene detection to assess bathers as sources of contamination.MST methods are also used to trace and investigate the spread of antimicrobial resistant strains and the pollution they originate from in the environment. Ballest\u00e9 et al. used host-associated bacteriophages as indicators for human pathogenic viruses. Kapoor et al. on the other hand used bacteriophages as a low-cost alternative for differentiate animal waste and human wastewater in Kolkata. Viral indicators together with genetic MST markers were also used as an input for a QMRA investigation by Kongprajug et al.Wu et al. used various machine learning approaches to predict sources of fecal pollution based on a broad set of parameters from land use to hydrological parameters. In another study, Green et al. used generalized linear mixed models and conditional inference trees to find predictive variable for pollution source in 68 streams in the Finger Lakes region of Upstate New York.The selection of MST markers for their combined use with each other or with other markers such as chemical ones, is becoming a useful methodological approach to determine sources of fecal contamination and improve the robustness of prediction models. The incorporation of new computational procedures such as machine learning, neural networks or in the future artificial intelligence is very likely to facilitate and improve these predictive models. Moreover, care may be taken to combine the information provided by MST markers in multilayer data studies with other information from water uses in each geographic region  and hydrological and geological data among others that will allow to have a holistic view of water resources and their exploitability by different agents and uses.On the other hand, MST studies in recent years are exploring whether the available MST markers can provide significant contributions to the control of waterborne pathogens, the transmission of antibiotic resistance through the water cycle, and to complement microbial quantitative risk assessments. It cannot be ruled out that some of the present MST markers, or others that may appear in the future, may play a key role in these topics.New contributions from metagenomic and proteomic techniques may, in the not-too-distant future, be new tools for improving the specificity and sensitivity of MST markers or for discovering new ones that provide greater accuracy in operational applications of these MST markers.MG, AB, and GR prepared the call for this Research Topic, edited the manuscripts that were submitted, and wrote this editorial. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
{"text": "The sea occupies more than 70% of the Earth\u2019s surface and includes more than 300,000 organisms with huge biodiversity. These organisms represent an enormous source of substances with relevant potential in the pharmacological field. The diversity and potential bioactivity of structures isolated from marine organisms have always played a crucial role in the search for and discovery of novel bioactive molecules that are potentially useful in pharmacological applications. The development of new lead compounds from the sea has always been the crucial aim of drug discovery . In thisThis Special Issue, as a continuation of the previous Special Issue, \u2018Synthesis of Marine Natural Products and Molecules Inspired by Marine Substances\u2019, includes three reviews and two articles that describe the synthetic strategies and biological activities of different classes of bioactive marine metabolites and analogs essential for future pharmacological applications.A review by Munekata et al.  focuses In a review by Kazmaier and Junk , cycloheA review by Martinez et al.  focuses In an article of Aljahdali et al. , a dockiIn an article by Xiao et al. , the firMarine Drugs for their support and kind help.As guest editor, I am grateful to all the authors who contributed their excellent results to this Special Issue, all the reviewers who carefully evaluated the submitted manuscripts, and"}
{"text": "Glaucoma is one of the main causes of blindness worldwide, among the various forms existing of this disease, the most diffuse is primary open-angle glaucoma but many other types of glaucoma are known. Nowadays, this disease is defined as a multifactorial optic neuropathy characterized by a progressive optic nerve damage causing loss of retinal ganglion cells and their axons, developing specific visual field abnormalities, affecting eyes with open anterior chamber angles.The goal of its treatment is to conserve the quality of life and the visual function of patients by lowering the intraocular pressure (IOP). Among the possible therapeutic options, physicians can choose a medical therapy with topical glaucoma drugs, laser, or surgical therapy.Last years have witnessed many innovations both in glaucoma diagnostics and in treatments.Lehmann et al. suggest considering retinal ganglion cell layer thickness as a very useful tool in highlighting the first alterations in eyes difficult to classify. Tong et al. provided an interesting review showing the relevance of OCT evaluations, both peripapillary and both in macular area to be very helpful in distinguish pre-perimetric glaucoma, early perimetric glaucoma and ocular hypertension.Early diagnosis is always considered a key factor in the successful management of every disease and more, the chronic and subtle ones such as glaucoma. OCT is considered an extremely important device also in glaucoma management. Chen X. et al. that detected a significant correlation between vessel density measured by OCT angiography and changes in IOP.Another interesting contribution about OCT and Glaucoma came from Hirooka et al. conducted a very interesting study evaluating morpho-functional changes in glaucoma eyes comparing results obtained with standardized automated perimetry (SAP), electroretinograms (ERG) and OCT showing data that could be very useful both in better understand this disease.Wen et al., purposing a low contrast visual acuity test to check visual acuity in glaucoma patients, and from Saifee et al., purposing a new software to extract data from SAP report imagines.Others helps in improving the timing and the sensitivity of glaucoma diagnosis came from Zhang N. et al., and the other one investigating the trends in treatment approaches by Storgaard et al. have been included in this Research Topic.Two very interesting reviews, one showing the prevalence of primary angle closure glaucoma by Chen J. et al. and the other one providing a new model of chronic ocular hypertension obtainable in laboratory by Mosaed et al..The more experimental studies purposed in this section are one related to the correlation between the plasma level of \u03949-tetrahydrocannabinol and the IOP fluctuations by Ma et al. suggested an innovative model of measuring ocular biomechanical properties.Zhu et al., purposed a brief report detailing the results of using a drug supposed to be a neuro-enhancer in glaucoma patients: Scutellarin, whereas Zhang H. et al. provided a study showing their experience in combining Microcatheter-Assisted Trabeculotomy and Deep Sclerectomy and Trabeculectomy in young glaucoma patients.About innovation in treatments, This sections provided very interesting and useful information to better manage the glaucoma patients.Altogether this collection of articles emphasizes the importance of measuring the CSF to assess visual function in both basic research and clinical settings. It presents some methods to perform and improve those measures, and considers their interpretation and implications.All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
{"text": "To the Editor:Owen et al.  recentlyWhile the authors must be congratulated for their interesting review on this relevant question, we think that their findings require some caution. First, none of the studies from the Owen et al.  report iBeyond these limitations, we fully agree with Owen et al.  that the"}
{"text": "Antioxidants, entitled The Significance of Redox Biomarkers in the Evaluation of the Antioxidant Profile In Vitro and In Vivo, ten research articles emphasize the significance of adopting reliable redox biomarkers to determine the antioxidant activities of bioactive compounds in vitro and to assess blood and tissue redox status in vivo. First, Chaouni et al. [The present Special Issue of i et al.  and de Ti et al.  highlighi et al. ,4, Maciei et al.  and Bouri et al. ) describi et al. , Matute i et al.  and Islai et al.  demonstri et al.  describeThe use of proton beams has been recently introduced as an alternative strategy to conventional radiotherapy against cancer and, to develop the research on this strategy, Chaouni et al.  have higIt is a fact that the pathophysiology of various diseases is redox-related, given that the impairment of redox equilibrium of blood and tissues is a clinical outcome. Therefore, the development of reliable redox biomarkers towards early diagnosis and evaluation of disease progression is a major challenge for the researchers in the field of Redox Biology. Approaching this essential issue, Toczewska et al.  have attO-glucoside, appear to be probably the main contributors of the vasorelaxing action observed during fruit juice consumption. Additionally, Islam et al. [Illicium henryi, against the lipopolysaccharide-induced acute liver damage in a murine model. The results of their study suggested that the therapeutic efficacy of the corresponding plant extract, which also exerted in vitro antioxidant activities, was attributed to the upregulation of Nrf2 and the downregulation of TLR4/NF-\u03baB signaling pathways, hence providing hepatoprotection against oxidative damage and inflammation. The negative effects of oxidative stress can be counterbalanced by antioxidants, hence the supplementation of bioactive compounds with antioxidant properties has risen to the forefront of scientific interest during the last decades. In this regard, Bouroutzika et al.  have invm et al.  have appFinally, Karydas et al.  have dev\u03a4he studies included in this Special Issue cover a wide range of topics that converge in highlighting the significance of adopting redox biomarkers in order to approach modern research issues both in vitro and in vivo. Undisputedly, redox biomarkers comprise a powerful tool to monitor the efficacy of antioxidant molecules in vitro and to evaluate the modifications of redox status in health and disease in in vivo models. Thus, the measurement of specific redox biomarkers is directed to shed light on complex queries in the field of Redox Biology."}
{"text": "Dear Editor:et al.Revista Brasileira de Medicina Tropical. However, I want to highlight an important point regarding the administration of rabies immunoglobulin.I read with considerable interest the article by Duarte The authors stated that most bites in the case of their patient cohort were on the hands  and head . It is well-known that suspected rabid bites on the hands and head are category III rabies exposure. Accordingly, in these patients, rabies vaccination and rabies immunoglobulin should be administered according to World Health Organization guidelines"}
{"text": "Aboriginal and Torres Strait Islander holistic health represents the interconnection of social, emotional, spiritual and cultural factors on health and well-being. Social factors  are internationally described and recognised as the social determinants of health. The social determinants of health are estimated to contribute to 34% of the overall burden of disease experienced by Aboriginal and Torres Strait Islander people. Primary health care services currently \u2018do what it takes\u2019 to address social and emotional well-being needs, including the social determinants of health, and require culturally relevant tools and processes for implementing coordinated and holistic responses. Drawing upon a research-setting pilot program, this manuscript outlines key elements encapsulating a strengths-based approach aimed at addressing Aboriginal and Torres Strait Islander holistic social and emotional well-being.The Cultural Pathways Program is a response to community identified needs, designed and led by Aboriginal and Torres Strait Islander people and informed by holistic views of health. The program aims to identify holistic needs of Aboriginal and Torres Strait Islander people as the starting point to act on the social determinants of health. Facilitators implement strengths-based practice to identify social and cultural needs , engage in a goal setting process and broker connections with social and health services. An integrated culturally appropriate clinical supervision model enhances delivery of the program through reflective practice and shared decision making. These embedded approaches enable continuous review and improvement from a program and participant perspective. A developmental evaluation underpins program implementation and the proposed culturally relevant elements could be further tailored for delivery within primary health care services as part of routine care to strengthen systematic identification and response to social and emotional well-being needs. Consultet al., et al., et al., et al., et al., et al., et al., Strengths-based, person centred and empowerment approaches are often used synonymously to describe the delivery of health care for Aboriginal and Torres Strait Islander people. These approaches promote individuals control over their own lives and focus on abilities and resources to enable self-determination , a secure web platform for managing online databases (Harris et al., et al., et al., et al., et al., et al., Reflective practice and clinical supervision are recognised by many professions for their role in supporting enhanced clinical practice as well as the health and well-being of the workforce (Koivu The Cultural Pathways Program utilises these existing frameworks as well as the knowledge and experience of program staff to implement a culturally relevant reflective practice and supervision model. An experienced Aboriginal clinician supports facilitators through a range of structures including weekly clinical yarning, one to one yarning and debriefing opportunities as required. Facilitators share perspectives, feelings, challenges, barriers and enablers in relation to both clinical practice as well as system, policy and organisational factors which impact the participant, Facilitator, or the program. Fundamentally, the supervision and reflective practice model are culturally grounded in relationships and yarning to support the cultural safety for Aboriginal and Torres Strait Islander participants whilst also enabling the retention and well-being of the Aboriginal and Torres Strait Islander workforce.et al., et al., Evaluating health programs and initiatives supports implementation across different contexts utilising insights into how and why they work and whether they have been effective (Lokuge There is a knowledge to action gap on how to assess and address the social determinants of health within clinical practice to inform the development of coordinated, culturally relevant and strength-based responses to meet the holistic social and emotional well-being needs of Aboriginal and Torres Strait Islander people and communities.et al., et al., et al., Primary health care services, often as the entry point for accessing health services, are well positioned to implement coordinated health equity responses which include addressing the social determinants of health (Pereira et al., et al., et al., The ability to implement holistic approaches to Aboriginal and Torres Strait Islander health through the intersection of health and social services requires adequate resources, training and support to clinical workforce (Andermann, The Cultural Pathways Program builds on existing approaches to contribute to practice-based evidence of culturally relevant case management approaches which can be utilised as part of routine care to strengthen the systematic identification and response in primary health care delivery. The combined understandings of the elements outlined in this manuscript provide a framework to inform service planning and tailored implementation which can strengthen social and emotional well-being responses for Aboriginal and Torres Strait Islander people."}
{"text": "Psychiatric treatments have specific and non-specific components. The latter has been addressed in an extensive literature on the placebo-effect in pharmacology and on common factors in psychotherapy. In the practice of mental health care, pharmacological, psychotherapeutic and social treatments are combined in complex interventions. This paper aims to review non-specific components across diverse psychiatric treatments and consider implications for practice and research.We conducted a non-systematic review of non-specific components across psychiatric treatments, their impact on treatment processes and outcomes, and interventions to improve them.The identified research is heterogeneous, both in design and quality. All non-specific components capture aspects of how clinicians communicate with patients. They are grouped into general verbal communication \u2013 focusing on initial contacts, empathy, clarity of communication, and detecting cues about unspoken concerns \u2013 non-verbal communication, the framing of treatments and decision-making. The evidence is stronger for the impact of these components on process measures \u2013 i.e. therapeutic relationship, treatment satisfaction and adherence than on clinical outcomes \u2013 i.e. symptoms and relapse. A small number of trials suggest that brief training courses and simple methods for structuring parts of clinical consultations can improve communication and subsequently clinical outcomes.Methodologically, rigorous research advancing current understandings of non-specific components may increase effectiveness across different treatments, potentially benefitting large numbers of patients. Brief training for clinicians and structuring clinical communication should be used more widely in practice. Various treatments have been established in psychiatry, based on different ideas, approaches and methods. They are usually classified as biological, psychological and social, with each category containing a wide range of treatments. These treatments consist of specific and non-specific components. The specific components are defined by the theoretical model for how and why the given treatment is effective.et al., In addition to these specific components, there are also other components that may have a therapeutic effect. For example, the way treatments are presented to patients may fill them with optimism resulting in more positive engagement and improved mood Thomas, . The suget al., et al., In psychiatry, there is a long history of considering non-specific treatment components, and the term \u2018non-specific\u2019 itself has occasionally been used in the literature since the 1960s  a wide search of disparate databases and sources, (b) forward and backward citation tracking, (c) safeguards against potential biases by using a team of researchers with different backgrounds and (d) some overlap of the searching, analysing and writing-up stages of the review  and three research psychologists at different career stages, educated in different countries.All non-specific components identified in the review capture aspects of how clinicians communicate with patients. They fell into the groups of general verbal communication, non-verbal communication, treatment framing and decision-making. Research evidence is first presented for these components and then for interventions to improve clinical communication.et al., et al., et al., et al., et al., et al., et al., et al., Extensive evidence shows that a more positive patient\u2013clinician relationship is associated with better adherence and more favourable clinical outcomes across treatments (Fenton et al., Good communication matters right from the very first contact. How psychiatrists introduce themselves can already make a difference. In an experimental study, patients preferred an introduction with an explanation about what to expect in the first consultation over brief introductions without explanation or longer introductions in which clinicians disclosed personal problems (Priebe et al., et al., et al., et al., Beyond the initial consultation, a central component of beneficial clinical communication is empathy which concerns sensing patients' emotions and concerns and making them feel understood (Rickels et al., et al., et al., et al., et al., A number of studies of video-recorded consultations have studied the empathy of psychiatrists in more detail and highlighted how they detect and respond to patients' hints about their concerns (Rimondini et al., Communication with patients is not solely verbal. Non-verbal behaviour, including posture, rate of speech, intonation and pitch of voice are critical in interpreting the meaning of verbal utterances and can convey additional messages. Non-verbal communication appears to be particularly relevant for showing that the clinician is listening, taking the patient seriously, demonstrating empathy and establishing a positive rapport (Beck et al., et al., Most research on non-verbal behaviour has been observational, exploring associations with patient satisfaction and treatment outcomes. One systematic review suggests that non-verbal indicators of clinician warmth and clinician listening are linked with greater patient satisfaction (Henry et al., Communication, including non-verbal communication, is reciprocal. The non-verbal behaviour of psychiatrists and patients with schizophrenia during a consultation has been shown to be linked: when psychiatrists showed more pro-social behaviour in the form of gestures and open posture \u2013 inviting rather than avoiding interaction \u2013 patients reciprocated. This was associated with higher patient satisfaction and lower symptom levels (Lavelle et al., Non-verbal clinical communication has been investigated also in experimental designs. A study of actors pretending to be clinicians found that manipulating gaze and body orientation had a significant effect on how empathetic participants perceived their clinicians to be (Brugel et al., et al., et al., et al., et al., Patient expectation has consistently been linked to variation in clinical outcome across a range of medical disciplines, including psychiatry (Carver and Dunham, et al., et al., et al., The majority of studies assessing the effect of treatment framing across different psychiatric conditions have focused on help-seeking behaviours and on the uptake of treatment. Findings from these studies have been mixed (O'Keefe and Jensen, et al., In addition to presenting a specific positive or negative treatment frame as discussed above, clinicians can express their optimism or scepticism about treatment in more general terms. An experimental study using video-clips of real psychiatrists manipulated how optimistic or sceptical they were about a possible pharmacological or psychological treatment. Patients who were newly referred to mental health services preferred an optimistic treatment presentation. However, this was not the case for patients who had already been in psychiatric services for more than 2 years and had experienced that treatments in psychiatry are not always, at least not for them, a resounding and lasting success (Priebe et al., Decision-making is central to most psychiatric treatment encounters, often relating to starting, reviewing or changing pharmacological or other treatments. Involving patients in the decision-making process is widely regarded as good clinical practice NICE, . The levet al., et al., et al., et al., et al., et al., Much of the recent literature uses the concept of shared decision-making which suggests that decisions about treatment should be arrived at in a shared and non-directive discussion between patient and clinician (Hamann et al., et al., et al., et al., Improving communication with involuntary patients may be particularly challenging (Thornicroft et al., et al., et al., et al., However, the precise preferences of patients for how decisions should be made can vary depending on patient characteristics, therapeutic situations \u2013 e.g. an acute emergency and a consultation in long-term treatments \u2013 and types of treatment (De Las Cuevas The importance of clinical communication raises the question of how clinicians' communication can be improved to make treatments more effective. Communication may be influenced through training or through interventions which structure communication during consultations, or both.et al., et al., A Cochrane review of communication training in the context of severe mental illness in psychiatry identified only one RCT in this area (Papageorgiou et al., et al., In a primary care study, training in the form of structured discussions was tested to help clinicians elicit concerns from parents and children and to raise their treatment expectations. Three 1-hour discussions around video examples of family-clinician communication were followed by practice sessions with patients and self-evaluation. The training reduced the distress of parents and for some children, impairment across a range of disorders (Wissow et al., et al., et al., et al., et al., An alternative to training practitioners is to modify the structure of clinician-patient communication. Some interventions focus on improving decision-making through the use of decision aids. They are typically checklists assessing patients' preferences and providing information about available treatments. They are intended to help patients and clinicians arrive at a treatment decision. A Cochrane review of the effects of decision aids in people facing treatment decisions across medicine identified 105 studies covering over 31\u00a0000 participants (Stacey et al., et al., There are a small number of interventions to structure part of the patient-clinician meeting and directly guide communication. Focusing on 20 common needs, a communication checklist asks patients before a consultation to indicate the areas they want to discuss with their psychiatrist (Van Os Although much less research in psychiatry has explored non-specific than specific treatment components, an increasing body of evidence highlights the importance of such components across treatments. The existing evidence suggests that the way clinicians generally communicate with patients both verbally and non-verbally, and how they frame treatments and involve patients in the decision-making process can influence uptake, adherence and outcomes of treatments. Overall, there is more evidence for the impact of non-specific components on process measures, such as satisfaction and adherence, than on clinical and social outcomes of treatments.The summarising nature of our review did not consider the methodological quality of the referenced studies. While the review included some high-quality RCTs and meta-analyses, overall the studies are heterogeneous in their design and quality. Many studies were exploratory in nature and the results should be interpreted with caution. Moreover, we did not specify effect sizes. Most studies of non-specific components were intended to establish only that the given component is relevant in principle. Hardly any studies were designed and implemented with sufficient rigour to determine the effect sizes.Future research should go beyond establishing the effects of widely acknowledged non-specific components. There is no need for further studies showing that patients are more likely to come back for the next appointment if their clinician shows empathy and addresses their concerns. What is required is research that advances our understanding of non-specific components and the underlying mechanisms. This may include experimental studies with clinical and non-clinical samples that test the effects of varying such components in ways that would be feasible in clinical practice.In RCTs, one might try to standardise the delivery of at least some non-specific components, in both the experimental and control groups. If achieved, this should reduce the variance in outcomes and therefore help to detect the effects of the specific treatment components being tested.In addition, research should aim not only to understand non-specific components better but also to utilise them more effectively. The few studies on improving clinical communication indicate that such improvements are possible and can lead to better outcomes.et al., et al., Much research on psychiatric treatments has focused on finding patient characteristics that predict a positive response to specific treatment methods. Recently, such efforts have sometimes been referred to as personalised medicine. For non-specific components, individual responsiveness may possibly vary even more than for specific ones. Which characteristics of the patient and context determine how best to communicate with the patient remains largely unknown. The literature provides some hints about patient characteristics and experiences predicting different responses to placebo or optimistic treatment framing (Bialik et al., et al., et al., Non-specific components are part of all treatments in practice, with one review suggesting that they explain up to 60% of the variance in outcomes (Walach Communication skills are important for all clinicians working in mental health care. Short and effective training courses exist and could be rolled out into routine care at limited costs. Another simple and even less expensive option for refining communication skills is video-recordings of consultations to review what works and what may be improved. Yet, neither training nor reviews of video-recordings are widely used in routine care.Beyond that, a focus on communication skills may have positive implications for clinicians working in psychiatric care. Improving communication skills will require more training and supervision, but might also be an opportunity to strengthen the specific professional profile of clinicians in psychiatry. Clinicians in routine psychiatric care are expected to engage and communicate with patients in widely varying settings and treatment situations. These include acute crises, involuntary treatment or long-term rehabilitation, with variable time frames and changing treatment goals. The challenge for clinicians is to develop and flexibly utilise a repertoire of skills to achieve the optimal benefit for the patient. These skills are likely to vary across individuals and be influenced by personal styles and individual strengths so that much of the training will have to be individualised. Yet, such training may provide clinicians in psychiatry with a relatively unique skill-set and strengthen their professional expertise.Over the last four decades, extensive research on specific treatment components has led to only limited improvement of effects of psychiatric treatments. A stronger focus on non-specific treatment components in both practice and research may improve the effectiveness of complex interventions with pharmacological, psychological and/or social approaches. This would potentially benefit large numbers of patients across settings and treatment methods and therefore have a substantial public health effect beyond the improvement of confined specific treatment components."}
{"text": "Myelination is a fundamental molecular event within the vertebrate central nervous system (CNS) where oligodendrocytes wrap around axons to form a myelin sheath which allows rapid \u201csaltatory\u201d conduction of action potentials along the axons  triggers the unfolded protein response (UPR), which aims or serves to maintain protein homeostasis by multiple mechanisms including attenuation of protein translation and the prevention of translocation of newly synthesized proteins from cytosol to ER  was found to be vital in the process of myelin thinning. This was confirmed by showing an exacerbation of myelin thinning, tremoring phenotypes, and a shortened lifespan in Sel1L and PLP double knockout mice compared to Sel1L deficient mice. This confirmed that diminished myelin protein translation was responsible for myelin thinning. They also ruled out the possibility of myelin thinning resulting neither from remyelination, (no myelin loss or oligodendrocyte death), nor from regeneration, (no increase in oligodendrocyte precursor cells or oligodendrocyte proliferation). Importantly, PERK inactivation in oligodendrocytes (Sel1L and PERK double knockout) restored myelin protein translation, reversed myelin thinning, attenuated tremoring phenotypes, prolonged survival, and prevented oligodendrocyte death compared to Sel1L deficient mice. The joint role of UPR and ERAD in myelin thinning as mediated by oligodendrocyte specific deficiency of Sel1L is summarized in In a recent study published in u et al.  providedu et al. . Specifiu et al.  was attrWhile Wu et al.  found noSimilar to these findings (Wu et al., In contrast to MS and other demyelinating diseases (Luo et al., In addition to the association of PERK activation in myelin thinning in Sel1L deficient mice (Wu et al., Since demyelination leads to slowed axonal conduction, electrophysiological recordings in the future can address to what extent myelin thinning in Sel1L knockout mice reduces the speed of conduction in the CNS axons (Mu et al., Taken altogether, this opinion article discussed the landmark work (Wu et al., MKS and MJH designed the scope, wrote and edited the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The National Institutes of Health define, rehabilitation technology as tools that help people recover their function after injury or illness. In recent years, advances in rehabilitation technology have created exciting opportunities and generated significant improvements in the autonomy and quality of life of people with neurological health conditions. Virtual reality (VR) in particular, is a rehabilitation technology that has rapidly risen to prominence and is achieving promising results in improving the sensorimotor function for people with neurological disabilities \u20133. VirtuGiven the growing interest in the use of technology in neurological rehabilitation, studies are needed to justify the safe effective use of Virtual Reality in clinical practice. This special issue aimed to collect insightful and multi-disciplinary evidence of the development, testing and application of virtual reality innovations for sensorimotor rehabilitation of neurological health conditions across the lifespan.Espy et al. presents a conceptual framework to guide clinical-decision making for the selection, adaptation, modulation, and progression of virtual reality or gaming when used as a therapeutic exercise modality. The study of Oliveira et al. found benefits in using virtual reality-based exercise in spatial navigation of institutionalized older persons. Cheng et al. investigated performance variability over time during learning of standing postural control tasks in a non-immersive virtual environment in children with cerebral palsy. Benady et al. studied the contribution of vision to locomotion in a dynamic immersive environments to support rehabilitation strategies for neurological disorders associated with gait impairments.Ten papers were published in this Research Topic with contributions to support practice. Tong et al.; Finley et al.; Al-Sharman et al.; Lubetzky et al.; Da silva et al. and Fluet et al.). Although evidence suggesting that non-custom commercial games can be successfully used in clinical settings, they have limitations such as calibration of a game's difficulty for persons with different abilities, game scores or progress measurements being to generic, lacking specificity in tracking the progress of persons with different abilities, and many require movements that cannot be performed by people with disabilities  and the movements of their intact limbs are mirrored in the avatar, providing participants with the illusion that their limbs respond as if they were both intact and functional. They found that repetitive exposure to VR intervention led to reduced pain and improvements in anxiety, depression, and a sense of embodiment of the virtual body.Finley et al. presented a custom VR game where individuals with Parkinson's disease have to complete a puzzle that consisted of a word with missing letters in the virtual environment. The player had to determine which letters were necessary to complete the puzzle, collect the necessary virtual letters as they floated in 3D space, and then place the letters in the appropriate location. Al-Sharman et al. created a non-immersive VR task to be used with Microsoft Kinect sensor and found improvement in participants with Parkinson's disease when asked to steer a helicopter up and down to collect coins and to avoid specific number of obstacles by moving from sitting to standing and vice versa. Lubetzky et al. created two VR tasks (one using stars on the sky and the other a busy street) with Head Mounted Displays (Oculus Rift) and found significant differences in performance between environments evaluating Postural and Head Control in individuals with unilateral vestibular hypofunction and monaural hearing. Da silva et al. in a study protocol presented two non-immersive custom virtual reality games developed for individuals with disabilities (movehero and moveletrando), both can be used with computer webcam. Fluet et al., presented different studies using a home-based virtual rehabilitation system and a robot assisted virtual rehabilitation to improve paretic hand and arm of persons with chronic stroke. They suggested that persons with stroke may adapt to virtual rehabilitation of hand function differently based on their level of impairment and stage of recovery.We believe that the studies published in this special issue present research on the benefits of using virtual reality in the rehabilitation for persons with neurological health conditions. It is noteworthy that many authors are integrating game mechanics into their virtual rehabilitation. The research will need to be ongoing to facilitate application to clinical practice.All authors read and approved the final editorial.HD was funded by the Elizabeth Casson Trust and the NIHR Oxford Health Biomedical Research Centre. CM was funded by Funda\u00e7\u00e3o de Amparo a Pesquisa do Estado de S\u00e3o Paulo (FAPESP)- Finance Code: 2017/24991-7 and Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico (CNPq). JD was funded by NIH (1R15AG063348-01).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
{"text": "People with Parkinson's disease (PD) have an increased risk of falling, which is often associated with the manifestation of freezing of gait (FOG) (Pelicioni et al., The main bottleneck to better understand when and why FOG emerges and how to manage it is the lack of valid markers of FOG, justifying the search for models of freezing in other effectors than in gait. Several instrumented methods for measuring FOG episodes in daily life as well as during standardized lab tests are currently in the validation pipeline (Mancini et al., Our group was one of the first to acknowledge the remarkable similarity between features of FOG and motor arrests when performing sequential finger and writing movements uni- and bimanually (Nieuwboer et al., As upper limb freezing was brought on when people with PD were subjected to similar motor challenges as in FOG, we recently investigated whether producing up-and-down strokes on a writing tablet within a funnel figure, with wide, narrow and transitioning pieces, elicited motor arrests similar to presenting a doorway to trigger FOG in a gait lab or in the home (Heremans et al., As for construct validity of non-gait freezing, a review on freezing episodes in a variety of tasks, i.e., handwriting, hand and foot tapping and speech revealed that the clinical manifestation of these events appeared to be overlapping (Vercruysse et al., As for \u201cfast funnel freezing,\u201d freezing events occurred in 23 out of 49 patients and its frequency was correlated to self-reported FOG severity, though this correlation was not found for %timeFR during the funnel task (Heremans et al., Prospective study conducted by Delval et al. demonstrated, that episodic events during foot-tapping, hand-tapping, and syllable repetition in early-stage PD patients without FOG were predictive of FOG emerging in the next two years, albeit in a small cohort of 30 subjects (Delval et al., Mobile neuroimaging techniques as well as local field potential recordings are increasingly applied to better understand the brain circuit dysfunctions underlying actual FOG episodes obtained during over-ground walking (Tard et al., As for seated EEG, one recent study demonstrated that movement initiation of a finger sequencing task displayed reduced beta-desynchronization in the SMA and this more so in freezers compared to non-freezers (Brugger et al., We have highlighted that studying freezing in other effectors has great potential as a model for investigating component-mechanisms of FOG. However, we also showed that further validation of non-gait freezing as a behavioral biomarker of FOG is indicated. Therefore, prospective cohort studies are needed including recently diagnosed patients with PD, as well as positive control groups with FOG to be able to track progression of both gait and non-gait freezing-severity. As for measuring repetitive finger movements, keyboards as well as tablets and smartphones technology could be used to quantify motor blocks (Trager et al., ND drafting manuscript. AN conceptualizing and revising manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
{"text": "Dear Editor, We read with interest the comment of Manzo et al. [o et al.  on our ro et al. . The autThe prevalence of neurological symptoms in pSS patients ranges between 8.5 and 70% . The reaet al. about the need for both a better assessment of cognitive dysfunction in pSS patients and searching for pSS in patients with CI, as they established in their systematic review [We also agree with the comment by Manzo c review .et al., which highlights the great importance of neurological manifestations, and CI in particular, in pSS patients.Whether CI or other neurological manifestations should be considered \u2018comorbidities\u2019 defined as \u2018simultaneous presence of more than one disease in a patient\u2019 or only clinical features of pSS in a specific system could be discussed. However, we think that that debate should not minimize the relevance of the message of Manzo Funding: No specific funding was received to carry out the work described in this article.Disclosure statement: The authors have declared no conflict of interest.Data are available upon reasonable request by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). All data relevant to the study are included in the article."}
{"text": "When restoring gene flow for conservation management, genetic variation should be viewed along a continuum of genetic divergence between donor and recipient populations. On the one hand, maintaining local adaptation (low divergence between donors and recipients) can enhance conservation success in the short term. On the other hand, reducing local adaptation in the short term by increasing genetic diversity (high divergence between some donors and recipients) might have better long\u2010term success in the face of changing environmental conditions. Both Hoffman et al. (2020) and a paper we previously published in a Special Issue on Maladaptation in Applied Conservation  provide frameworks and syntheses for how best to apply conservation strategies in light of genetic variation and adaptation. A key difference between these two studies was that whereas Derry et al. (2019) performed a quantitative meta\u2010analysis, Hoffman et al. (2020) relied on case studies and theoretical considerations, yielding slightly different conclusions. We here provide a summary of the two studies and contrast of the main similarities and differences between them, while highlighting terminology used to describe and explain main concepts. We were encouraged to see Hoffmann et al.  provide Both papers framed strategies in terms of meeting short\u2010term versus long\u2010term adaptation targets of genetic variation, which we referred to as managing for \u2018adaptive state\u2019 versus \u2018adaptive process\u2019. A key difference, however, was our use of quantitative meta\u2010analysis to evaluate effectiveness of different conservation strategies; Hoffmann et al.  relied oOne contrast between conclusions is that we found that genetic and evolutionary rescue tended to increase fitness across multiple generations relative to immediately after conservation intervention (figure 2 in Derry et al., Importantly, Hoffmann et al.  point ouIn conclusion, we hope that the frameworks of genetic mixing along a gradient generated in Derry et al.  and HoffThere is no conflicts of interest to declare."}
{"text": "To the editor,Recently in the Journal, Li et al.  reportedNevertheless, beyond all these limitations, we fully agree with Li et al.  that lar We would like to thank Dr. Jourffroy and Dr. Vivien for their interest in our manuscript  and for Dr. Jourffroy et al. argued that the study by Vincent et al.  should bTwo included studies , 5 incluWe agree with Dr. Jourffroy et al. that the infectious agent itself influences the outcomes of septic patients. We attempted to convey the message that culture positivity or negativity was not associated with mortality of sepsis or septic shock patients. A positive culture does not mean a severe infection, and a negative culture does not mean a mild infection. The clinical outcomes may be associated with not only the infection sources but also the management of the sepsis and septic shock."}
{"text": "We read with interest the recent publication by Wu et al. . Wu et aWu et al.  stated iWu et al.  did not Camp et al.  measuredWu et al.  providedIn conclusion, Wu et al.\u2019s provided radiographic evidence shows that the authors did not appreciate rotational deformities, with these being described as normal, which raises questions about the reliability of the provided radiographic measurements, with the use of ultrasound assistance possibly resulting in an increased rate of inadequate supracondylar humeral fracture reductions. This is in addition to the 42% mean increase of costs associated with the use of US because of the extra time under general anaesthetic in theatre, with Wu et al.  not havi"}
{"text": "Weisshaar. However, the neurobiology of CP is complex and its causal link to the underlying diseases remains unclear as described in two papers on encoding Schmelz and central processing of pruritus Najafi et al. Experimentally, pruritus can be induced by electrical stimulation Solinski and Rukwied, Meijer et al. and reduced by affective touch. Clinically, cholestatic pruritus might be related to bile salts, steroid metabolites, serotonin, protease-activated receptor agonists or most likely lysophosphatidic acids Langedijk et al., but probably not by endogenous opioids as shown by D\u00fcll et al. The long list of potential mediators reflects the current dilemma in pruritus research: many potential mediators have been identified but unfortunately, the clinical validation in representative patient cohorts is pending.Pruritus is a burdensome symptom and defined as chronic when lasting for at least 6 weeks according to the International Forum for the Study of Itch (IFSI) . ChronicDonglang et al. guide us through translational aspects of these animal models. Liu et al. describe an acute itch model by intradermal injection of low-dose formalin which may be employed as a screening tool for potential anti-itch drugs. Also, novel topics such as the role of the gut microbiota in pruritus was investigated in an animal model and described here . Jia et al. even describe a novel functional factor which is relevant for itch signal processing, and show that the transcription factor ZBTB20 (Zinc Finger And BTB Domain Containing 20), which is expressed in small primary sensory neurons, could modulate itch regulating TRP channels.Still, animal studies are indispensable to identify novel mechanisms. Ruppenstein et al., Kabashima and Irie, and Nemmer et al. Atopic dermatitis is the most frequent inflammatory dermatosis; Legat gives an overview on its pathophysiology including the relevant neuroimmune mechanisms and also provides information on the corresponding current treatment options. While atopic dermatitis is already well-understood regarding its pathophysiology, other pruritic dermatoses, systemic diseases and neuropathic entities are not. However, in past years, several entities reached a broader understanding and novel mechanisms or therapies have been identified. Accordingly, our authors report on the latest knowledge in chronic prurigo Zeidler et al., scabies St\u00e4nder and St\u00e4nder, pruritus related to therapy with immune checkpoint inhibitors Salinas et al., chronic kidney disease Krajewski et al. and neuropathic diseases Pereira et al. as well as sensitive skin condition , and vulvar pruritus Raef and Elmariah. For poorly understood cases of pruritus cannot be linked to inflammatory or neuropathic mechanisms Misery extends the concept of nociplastic changes in the pain field and suggests using the term pruriplastic pruritus for them.Itch induction in the skin is frequently based on inflammation and neuroimmune mechanisms. The latter refers to the bidirectional communication between cells releasing inflammatory mediators such as interleukin (IL) 4 or IL 31, neurotrophins such as nerve growth factor and neuropeptides released by sensory nerve fibers. The implications of such neuroimmune interactions is presented in three papers by L\u00fc\u00dfmann et al. describe that itch intensity and certain facets of mindfulness were associated with itch catastrophizing in AD patients. On the other hand, distraction might help to reduce itch as investigated by van Laarhoven et al. by training volunteers to reduce attention toward itch. Pruritus is a subjective symptom without objective measurement. Accordingly, patient reported outcomes are still the gold standard in the assessment of the course. However, the complex process of international harmonization and validation is still ongoing. Stepie\u0144 and Reich contribute to this topic by framing severity levels in a novel questionnaire.Mental factors are important for itch perception and its progression. In sum, this collection of articles combines several up to date aspects of the neurobiology and clinics of pruritus, including also new methods and innovative concepts in itch research.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.This article was supported by the German Research Foundation (DFG/NO FOR2690 to SS and MS).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
{"text": "High heterogeneity was found in the prevalence rates of mental disorders in adult asylum seekers and refugees in high-income countries. This may be related to different problems. Among them, there is a changing exposure to risk and protective factors for mental health at different phases of these people's life before migration, and during the migratory journey and resettlement. This study aimed at identifying and distinguishing time points in which distinct risk and protective factors for the mental health of asylum seekers and refugees may occur.Systematic review and narrative synthesis. A systematic search was carried out for the period January 2017\u2013August 2019, given the existence of systematic reviews of the evidence up to January 2017.Two hundred and fifty-two studies were identified with our search and 31 studies were included. The critical time points identified are: (a) before the travel; (b) during the travel; (c) at initial settlement in the host country; (d) when attempting to integrate in the host country; (e) when the immigration status is challenged or revoked. Some factors such as sense of belonging in the host country can be risk factors or protective factors depending on the time point.These five critical time points can guide the development and selection of well-timed preventive and treatment interventions. They could also be used to stratify samples in epidemiological studies and meta-analyses. At present, we know much more on risk factors than on protective factors. Knowing more about protective factors may inform the development of interventions to foster them. EMBASE, PsychINFO and OVID Medline databases were searched.Papers were included if: (a) at least 50% of the research participants were refugees and/or asylum seekers; (b) they assessed risk or protective factors for mental disorders; (c) they focused on adult populations (18 or older years of age); (d) they reported on studies carried out in high-income countries (according to the World Bank Classification); (e) they reported on primary research or were literature reviews, excluding opinion pieces; (f) they were published in full articles or full reports in scientific journals, excluding grey literature and conference presentations.Papers were excluded if they focused only on aspects other than risk and protective factors for mental disorders, e.g. interventions, prevalence rates without correlates, individuals\u2019 experience of care or barriers to access care. Qualitative studies which described patients\u2019 or clinicians\u2019 views about which were potential risks or potential factors for mental health were also excluded. They were deemed as \u2018non-focusing on risk and protective factors for mental health\u2019 given that they failed to demonstrate the actual association of those factors with mental health, only suggesting that this may be.From each paper identified, risk and protective factors were captured and summarised in an excel extraction table.The risk and protective factors identified from different studies were initially grouped together according to when they occurred, based on the usual framework .The analysis then continued with the aim of re-grouping risk and protective factors in more specific and discrete time points which generated the final time points described in the Results section.Our search identified 252 papers in the period January 2017\u2013August 2019. After removal of duplicates and screening according to inclusion criteria, 31 papers were included, i.e. 28 papers reporting on primary research and three literature reviews.The PRISMA diagram can be found in The main characteristics of the included studies are synthesised in Five time points were identified, in which all the risk and protective factors identified can be categorised. These time points are: (a) before travel; (b) during travel; (c) initial settlement in the host country; (d) integration in the host country; (e) challenges to or revocation of the immigration status.A summary of risk and protective factors at all of these time points can be found in These different time points can all be experienced by individuals who are forced to migrate from their countries. However, this is not necessarily the case for all of these individuals. For example, some of them may have their asylum applications rejected and never reach the status of a refugee. Others may integrate successfully and, hence, remain in the host country as naturalised citizens without their residence status being challenged.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Exposure to potentially traumatic events  in long-term resettled refugees (at least 5 years) than in those at first resettlement  with less of a focus on the factors associated to disorders with comparatively lower prevalence rates   social attitudes in host countries may influence the level of discrimination that refugees encounter, the investment in social integration programmes and the opportunities for refugees to flourish. This, in turn, could have a negative impact on asylum seekers\u2019 and refugees\u2019 mental health. Interventions provided within mental health services may not be able to address these issues on their own."}
{"text": "This collection of papers demonstrates a growing interest and maturity of experience within the field of patient and public involvement utilizing a range and various forms of involvement with different groups and communities. Many of the papers placed emphasis on dignity and respect, Faulkner et al, Warner et al.; others, for example Tyler et al., and Kuhne et al., highlighted the importance of listening to the patient voice. The need for shared decision making was referred to by Khan et al., having patients and young people as part of the research team was indicated in the work of Walker et al., where children and young people formed a project advisory group (CYPAG).The importance of relationships was considered key in the work of Mulvale et al., who incorporated integrative dynamics (ID) approach and experience\u2010based co\u2010design (EBCD) to overcome \u2018us vs them\u2019 thinking. Photovoice was the method of choice used by Weinstein and colleagues when working with individuals with long\u2010term mental illness, obesity and living in supportive housing.There are some careful explorations of appropriate methods to use with different and often marginalized groups and communities; for example, Corvin et al. examined the application of analytic hierarchy process (AHP) to inform the augmentation and implementation of an evidence\u2010based chronic disease self\u2010management programme for underserved Latinos living with both minor depression and chronic illness. Thomas and colleagues report an honest reflection of working with people from low\u2010income backgrounds throughout a research process; Warner et al outline a method of engaging with refugees at the early stages of research; Dewa et al explore the methods and the impact of working co\u2010productively with young people and saw significant impact on the research, researchers and co\u2010researchers.A patient\u2010targeted feedback intervention after depression screening using the Patient Health Questionnaire (PHQ\u20109) was the focus of work by Seeralan et al. It needs to be recognized that for a variety of reasons, patients may not want to participate as outlined by Bixo and colleagues. In their study involving young people being \u2018too tired/too sick to participate\u2019 was the most common barrier for non\u2010participation followed by lack of time and fear of needles. However, the young people identified different ways for increasing the likelihood for participation such as simplification of procedures and information, providing rewards and feedback, and building relationships before asking. The points raised by the young people are equally as applicable to all studies where PPI is a key aspect.Several papers report on evaluations of the impact of involving service users and/or carers in the research process. In a protocol paper, Littlewood et al describe a longitudinal process of evaluating impact of working with people who self\u2010harm, the results of which will be interesting to see. Matheson and Weightman take the exploration of process into the therapeutic realm by viewing it as a potential part of the co\u2010researchers' community re\u2010integration stage of therapy for complex post\u2010traumatic stress disorder (CPTSD), contributing to their empowerment through collective action. Morse et al, in working with both service users and carers, identify an ethical dilemma at the heart of the endeavour: the ownership of the story and who can speak for whom. Along with the other studies in this collection, it becomes clear that involvement cannot be regarded as simply instrumental; it has powerful ethical and political threads running through it.'service users have not fought for a voice at the table merely to help improve the research process, but because they have a right to be there'. They advocate looking beyond impact at the quality of participatory research in relation to the ethical demands of service users, the development of service user capacities and, crucially, sharing power in domains other than just research. This collection of papers suggests a growing maturity in approaches to PPI; however, there is still a need for understanding of the difference between participation, engagement and user\u2010led research alongside a shared respect for the different forms and fields of knowledge.Friesen et al explore some of these ethical dilemmas in more depth, by confronting the limitations of seeking evidence of impact. They suggest that our search for evidence of the impact of involvement obscures the ethical and political grounds behind involvement, the drive to address the imbalance of power within psychiatric knowledge\u2010making:"}
{"text": "Viruses constitute a significant part of the human microbiome, so wherever humans go, viruses are brought with them, even on space missions. In this mini review, we focus on the International Space Station (ISS) as the only current human habitat in space that has a diverse range of viral genera that infect microorganisms from bacteria to eukaryotes. Thus, we have reviewed the literature on the physical conditions of space habitats that have an impact on both virus transmissibility and interaction with their host, which include UV radiation, ionizing radiation, humidity, and microgravity. Also, we briefly comment on the practices used on space missions that reduce virus spread, that is, use of antimicrobial surfaces, spacecraft sterilization practices, and air filtration. Finally, we turn our attention to the health threats that viruses pose to space travel. Overall, even though efforts are taken to ensure safe conditions during human space travel, for example, preflight quarantines of astronauts, we reflect on the potential risks humans might be exposed to and how those risks might be aggravated in extraterrestrial habitats.  Viruses are a significant part of such enclosed communities  outbreak among the three Apollo 7 astronauts, which spread rapidly and reduced the ability of the astronauts to cooperate with the control center NASA, . The reaet al.,et al.,et al.,Most damaging UV radiation is filtered by Earth's atmosphere; therefore, all species on Earth are protected from most of the UVC, some UVB, and UVA to a lesser extent  coming from interstellar space  and human herpesviruses (HHV) types 1\u20133 ,  for several days, which guarantees that no microbes or spores can survive. In recent years, plasma sterilization has been considered an effective alternative due to its more convenient application  filters. They have been reported to efficiently filter out small aerosols  and regulatory T cell function, which have been described to maintain viral latency (Mehta et al.,Even though disinfection on space missions is thorough, it is impossible to completely neutralize the disease-inducing factors due to their prevalence in the human hosts, since a large portion of humanity is already latently infected with specific viruses. Latent infections are caused by viruses that, upon a single inoculation, can establish lifelong infections, like herpesviruses. et al.,et al.,et al.,Multiple studies have detected reactivation and shedding of viruses in human space and analog missions and environments (Pierson et al.,et al.,et al.,et al.,et al.,The reactivation of these viruses, some of which are associated with increased mortality (Ren et al.,et al.,et al.,et al.,et al.,et al.,In addition to infection by reactivation of latent viruses, there is also a possibility of virus infection on space missions that increases the risk of outbreaks in modules and habitats. Due to the limited possibility of identifying the cause of infection in space, it is challenging to recognize viral infections in addition to treating them. So, how can astronauts protect themselves from viral infections? Currently, most herpesvirus infections cannot be prevented through vaccines, with the exception of VZV, the causative agent of chickenpox and zoster (Papaloukas Currently, the standard safety procedure of human spaceflight is the preflight astronauts' quarantine and disinfection of cabins and equipment. However, we must consider the risk that some viral infections might go unnoticed during the quarantine period and cause significant harm once in the space station. Development of optimized methods for virus detection and calculating the impact of the space environment on virus spread will help address this problem and provide the basis for the development of improved protocols to control eventual outbreaks in space.g-forces or microgravity on viruses is underrepresented. It would be, for instance, interesting to test the influence of microgravity on viral spread throughout the body. Also, studies showed that hypergravity encourages the proliferation of healthy cells (Ciofani et al.,et al.,Viruses are a diverse biological group that is part of microbial communities in human-inhabited space modules. As such, they can influence astronauts' well-being and may pose a health threat to the crew. Intensive research is required in the field of space virology to improve the current knowledge on the dynamics caused by space stress. The effect of extreme Since the plans of future space missions tend to be more prolonged, preflight isolation and a healthy immune system might not be enough to protect astronauts against some viruses due to the overwhelming conditions during space travel. Hence, developing new methods for the detection and treatment of viral infections in space is a relevant topic."}
{"text": "To improve the medical waste management (MWM) standards in Tabriz community health centers (CHCs) through clinical audit process.Management of medical waste is not only a legally necessity but also a social responsibility in health systems. Owing to the potential risks for human health and environmental impacts, MWM is a global concern.This was an interventional research designed using clinical audit cycle that was implemented in Tabriz CHCs in 2016. MWM was assessed through observation, as well as reviewing relevant documents and interviews with waste workers in CHCs and completion of a researcher-made checklist. Intervention plans were developed and implemented based on the assessment results. To analyze the data, Excel 2016 software was used and information was reported as descriptive statistics through comparison of standards adherence before and after the interventions.Generally, 30% improvements in MWM standards adherence were experienced (45.8\u201375.1%) in the CHCs, after the interventions. The greatest improvement was observed in the dimensions of management and education, and separation and collection of medical waste, up to 30 and 28.5%, respectively.As the results demonstrated, standards of MWM processes were improved in Tabriz CHCs, due to the intervention. Moreover, it was experienced that using systematic method, stakeholders\u2019 participation and evidence-based planning would lead to process improvement. MWM was an ignored issue in primary care that must be more in attention. The used model of clinical audit process has six stages of which stages 3 and 4 were repeated after the intervention. The stages of clinical audit were carried out as follows:So, the two stages of clinical audit . The checklist consisted of four dimensions, including management and training, separation and collection, transportation and temporary storage, and sterilization and disposal.These include MWM methods and process standards approved by Commission on Infrastructure Affairs of the Islamic Consultative Assembly and Environmental Protection Organization of Iran (Number: 1901/56061) . First, the officers were provided with training sessions on standards and how to complete the checklist. Then, the assessment program was developed upon which the environmental health officers of the health complexes evaluated the status quo of MWM in CHCs under their own surveillance in August 2016. They have reported the assessment results to the Tabriz regional health center officers. The assessment was carried out by observing the ongoing processes along with reviewing the relevant documentations, interviews with process owners (waste workers and other related staff) in CHCs and then completing the checklist. Checklist questions were scored by assigning number one to standards adherence and zero to non-adherence. Next, the total score of all four dimensions was calculated and divided by the number of questions of each dimension to obtain the standard adherence both in general and separately for each dimension. Regarding that the dimension \u2018sterilization and disposal\u2019 only took place in Tabriz regional health center after collection of the waste from all CHCs in the city, data on this stage were only gathered and analyzed at this level. To verify the validity of the assessments, an external expert in the field of environmental health along with an expert from the Tabriz regional health center, randomly re-evaluated some CHCs.To examine the status of MWM process in CHCs, the assessment team was formed with the participation of environmental health officers of the health complexes  was evidenced in Tabriz CHCs. This achievement was based on four major key factors: staff participation, using systematic quality improvement method, evidence-based interventions and leadership commitment and support. Similarly, waste management improvement programs implemented in a Brazilian primary health care center were successful (Moreira and G\u00fcnther, et al., et al. (et al., et al., Interventions implemented in this study were not only supported by the assessment data but also by previous literature in Iran. Staff knowledge deficiency about waste management process was raised as one of the most important problems in Iran\u2019s primary health care centers (Mesdaghinia , et al. , which w et al., . Howeveret al., et al., et al., et al., et al., Medical waste separation and collection is the most important step in waste management. Previous studies in Iran have documented that only 25% of primary health care centers separate their hazardous waste correctly (Mesdaghinia et al., et al., et al., et al., et al., According to the evidences, lack of physical site for temporary storage, failure to comply with the standard duration of infectious waste temporary storage in CHCs and low education level of the waste workers who were responsible for collection and transportation of medical waste were among the most important reasons causing failure in temporary storage of medical waste in Iran (Mesdaghinia Our intervention plan led to 17.2% standards promotion in medical waste disposal process in Tabriz regional health center. Medical waste disposal inadequacy was mostly due to inappropriate autoclave process and equipment. As an important issue in medical waste disposal, autoclave performance control using Bowie-Dick test was suggested by literature to ensure the sterilization process which was ignored in Tabriz regional health center (Crossley, MWM standards improved about 30% in Tabriz CHCs. Using systematic and scientific quality improvement method \u2013 clinical audit, staff participation, leadership commitment and evidence-based decision-making would lead to primary health care processes quality improvement. This study has provided a scientific approach to quality improvements in MWM in primary health care centers, which has the capability to expand in other cities of Iran or other countries.This study was conducted using a systematic and scientific method and supported by the city health managers. All stakeholders in the MWM process participated in the development and implementation of interventions. It also covered all CHCs in Tabriz city.We do not have control group in the study. Moreover, due to the high cost of some interventions such as temporary storage space construction, they were not implemented."}
{"text": "Dear Editor,XPC, XPD, XRCC1, and XRCC3 might be associated with schizophrenia risk . There al., 2008; Derakhsal., 2008; Odemis al., 2008; Taghipoal., 2008). It hasal., 2008).ATM gene (MIM 607585) is one of the most significant genes in the DNA repair pathway encoding a vital checkpoint kinase. The ATM is critical in identifying and responding to DNA damage resulting in genome stability  and risk of schizophrenia  and risk of schizophrenia, therefore, the present case-control study was carried out.The  MIM 60755 is one al., 2020). Data oal., 2005). Statisal., 2005). Thus, al., 2008). To theIn our previous report  we provHere we used pooled samples for estimating the allelic frequency of the study polymorphisms in schizophrenia and control groups, as described previously . The PCP=0.020). The frequency of the G allele of rs609429 is positively associated with the risk of schizophrenia. Statistical analysis revealed no significant association between the allelic frequencies of rs611646 and rs228593 polymorphisms and the risk of schizophrenia  and seems to be involved in splicing, therefore, it is a functional polymorphism. The G allele leads to generation of a weak additional splicing region and subsequently, reduces the expression of ATM gene (Ang\u00e8le et al., 2003[ATM gene is a candidate locus for susceptibility to schizophrenia and the variant G allele of the rs609429 polymorphism may provide valuable insight into its association with schizophrenia. More association studies on larger samples from other populations are necessary to reveal the relevance of ATM polymorphisms as potential risk factors for schizophrenia and provide a deeper understanding of the genetic causes of the disease.Our present data suggest that the The authors are indebted to the participants for their close cooperation. None."}
{"text": "Labour market marginalisation (LMM), i.e. severe problems in finding and keeping a job, is common among young adults with attention-deficit/hyperactivity disorder (ADHD). This study aimed to disentangle the extent of LMM as well as the heterogeneity in patterns of LMM among young adults with ADHD and what characterises those belonging to these distinct trajectories of LMM.This population-based register study investigated all 6287 young adults, aged 22\u201329 years, who had their first primary or secondary diagnosis of ADHD in Sweden between 2006 and 2011. Group-based trajectory (GBT) models were used to estimate trajectories of LMM, conceptualised as both unemployment and work disability, 3 years before and 5 years after the year of an incident diagnosis of ADHD. Odds ratios (ORs) with 95% confidence intervals (CIs) for the association between individual characteristics and the trajectory groups of LMM were estimated by multinomial logistic regression.Six distinct trajectories of LMM were found: \u2018increasing high\u2019 (21% belonged to this trajectory group) with high levels of LMM throughout the study period, \u2018rapidly increasing\u2019 (19%), \u2018moderately increasing\u2019 (21%), \u2018constant low\u2019 (12%) with low levels of LMM throughout the study period, \u2018moderately decreasing\u2019 (14%) and finally \u2018fluctuating\u2019 (13%), following a reversed u-shaped curve. Individuals with the following characteristics had an increased probability of belonging to trajectory groups of increasing LMM: low educational level , single parents , those born outside the European Union/the Nordic countries , persons living in small cities/villages  and those with comorbid mental disorders, most pronounced regarding schizophrenia/psychoses , autism spectrum disorders , anxiety/stress-related disorders  and depression/bipolar disorder .About 61% of young adults were characterised by increasing LMM after a diagnosis of ADHD. To avoid marginalisation, attention should especially be given to young adults diagnosed with ADHD with a low educational level, that are single parents and who are living outside big cities. Also, young adults with comorbid mental disorders should be monitored for LMM early in working life. Databases 3\u22125 are hosted by the Swedish National Board of Health and Welfare.n\u00a0=\u00a02133). The final study population consisted of 6287 individuals.The study base consisted of 8420 young adults between 22 and 29 years of age who had their incident main or secondary diagnosis of ADHD from either inpatient or specialised outpatient healthcare between 2006 and 2011. The lower age limit was motivated as all the participants were eligible for all ingoing benefits of the measure LMM at least three years before their first diagnosis of ADHD in adult age. A diagnosis of ADHD was defined by the code F90 in the International Classification of Diseases, Version 10 (ICD-10). Those with a record of medication for ADHD  codes: N06BA01-13 and C02AC01-02) before the year of diagnosis were excluded .(I) Sociodemographic factors: sex, age, educational level, region of birth, family composition and type of living area measured on 31st of December in the year preceding CED  models were used to calculate trajectory groups of LMM from 3 years before to 5 years after the year of the incident diagnosis of ADHD. According to the founders/developers of the GBT model, the least complicated model based on existing knowledge, regarding both the number of trajectory groups and polynomial orders , is to be chosen (Jones More men (57%) than women were diagnosed with ADHD during the study period . A higheCompared to men, women had higher odds of following the \u2018increasing high\u2019 trajectory group of LMM  compared to the \u2018constant low\u2019 trajectory group of LMM . The oddEspecially high odds of belonging to the trajectory groups of \u2018increasing high\u2019 and/or \u2018rapidly increasing\u2019 LMM compared to those belonging to the trajectory groups of \u2018constant low\u2019 LMM were seen among those with comorbid schizophrenia/psychoses , autism spectrum disorders  and mental retardation  of belonging to the \u2018increasing high\u2019 trajectory of LMM compared to the \u2018constant low\u2019 trajectory of LMM. Those diagnosed by ADD had higher risk of belonging to \u2018rapidly increasing\u2019 trajectory of LMM compared to the \u2018constant low\u2019 trajectory of LMM.The results revealed that a majority (61%) of young adults diagnosed with ADHD in adult age had a poor prognosis regarding subsequent LMM following trajectory groups of increasing LMM on different levels during the study period. Young adults with comorbid mental disorders, most pronounced regarding schizophrenia/psychoses, autism spectrum disorders, depression/bipolar disorders, and anxiety/stress-related disorders had a high probability of following trajectory groups of increasing LMM during the study period. Also, those with a low educational level, persons with children living at home, single parents, and individuals living outside big cities had an increased probability of belonging to trajectory groups of increasing LMM.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Nearly two thirds of all young adults diagnosed with ADHD were found to have a poor prognosis regarding future LMM. Previous Swedish studies reported that the risk of having disability pension was high, about 10\u221215 times higher among individuals diagnosed with ADHD than among controls without ADHD (Virtanen et al., Studies have shown sex differences with regard to symptoms of ADHD (Gershon and Gershon, et al., et al., et al., The group of young adults over 24 years seemed to have a higher probability of following the trajectory of \u2018fluctuating\u2019 LMM compared to the younger group. Also, those over 24 years followed, to a greater extent, the \u2018increasing high\u2019 trajectory group of LMM. These findings are in line with other studies which conclude that the risk of LMM increases with age (Karlsson et al., et al., et al., et al., Single parents, diagnosed with ADHD, had an increased probability for belonging to the trajectory groups of \u2018moderately increasing\u2019 and \u2018rapidly increasing\u2019 LMM. Mothers diagnosed with ADHD are reported to struggle more regarding parenting compared to mothers without ADHD (Murray and Johnston, et al., et al., The risk of LMM was higher among those diagnosed with ADHD, who are born outside the European Union/the Nordic countries. The general risk of high LMM among non-European migrants with mental disorders has been reported by other studies (Helgesson et al., et al., et al., et al., et al., et al., et al., Young adults diagnosed with ADHD who had mental comorbidities as depression/bipolar disorders, anxiety/stress-related disorders, autism spectrum disorders, and schizophrenia/psychoses had a high probability of belonging to trajectory groups of increasing LMM. The lifetime prevalence of comorbid mental disorders was also found to be very high, also confirmed by other studies (Jacob et al., et al., et al., Comorbid disorders are to some extent a consequence of the problems which persons with ADHD encounter in everyday life. High severity of ADHD symptoms seems to correlate with higher rates of both anxiety and depression (Michielsen et al., In this study, we found an indication that a record of ADHD-medication during the year after the diagnosis of ADHD decreased the risk of permanent high LMM. Also, other studies have reported slight improvements regarding the possibility to work when taking medication (Geffen and Forster, et al., The main strengths of this study were the use of register data with high quality, including individual information on a vast number of sociodemographic and health-related covariates (Ludvigsson Limitations worth mentioning are that ADHD as well as all comorbid disorders were measured from visits to specialised healthcare. Hence, information on conditions treated in primary care has not been covered. Still, the number of young adults with ADHD might not have been severely affected, as those patients are mainly diagnosed and treated within specialised healthcare. Finally, data on sickness absence only includes information of spells longer than 14 days as the first two weeks are covered by the employers and information on unemployed individuals who are not registered by The Swedish Employment Agency is not covered by this study. This might slightly underestimate the risk of LMM among individuals with ADHD.Nearly two thirds of young adults diagnosed with ADHD in adult age are characterised by patterns of increasing LMM during the follow-up period. To avoid marginalisation, young adults with comorbid mental disorders must be monitored for LMM early in working life. Also, special attention must be given to young adults with low educational level, singles with children and those living in medium cities or villages."}
{"text": "The established contribution of genetic variation to drug response has the potential to improve drug efficacy and reduce drug toxicity . The uptVKORC1, CYP2D6, CYP2C19, and TPMT. Lee et al. [CYP3A5 has on chronic kidney disease progression. This example demonstrates that PGx variation may impact disease treatment through drug response as well as through physiological effects in kidney that may exacerbate kidney disease. Scheinfeldt et al. [Four of the special issue articles, Han et al. , Lee et e et al.  focused Two of the special issue articles, Silva et al.  and SchmSeveral of the studies included in this special issue focus more directly on the incorporation of PGx into clinical care. Gill et al.  focused Taken together, this body of work builds upon the extensive information already known about contributions of genetic variation to drug response and describes important gaps in this knowledge as well as challenges to the clinical implementation of pharmacogenomics that remain to be addressed. Several examples of clinical PGx implementation in a variety of settings highlight areas of ongoing improvement and momentum toward more broad integration of PGx testing."}
{"text": "Particularly in Brazil, little has been produced regarding the possibility of babies leading the process of the introduction of new foods. Meanwhile, more and more families are looking for this option.We have had access to the text published in December 2019 by Gomez et al.,Let us start with the excerpt in which it is stated that: \u201cWright et al.Wright et al.Now, let us comment on the following excerpt: \u201cCameron et al.The study cited, by Cameron et al.,The authors use the text by Fangupo et al.The study mentioned in the previous paragraph, conducted by BrownThus, we address the editors of Revista Paulista de Pediatria expecting that the observations brought up here can be made accessible to the joournal\u2019s audience, to prevent the training and updating of students, professionals and researchers from taking place on the basis of mistaken information.At your disposal."}
{"text": "The long-term goal of basic material research is to develop theoretical and experimental methodologies to advance the ability to produce materials with the desired compositions and properties that can be used in various applications. There is a wide range of physical, chemical, and biological methods to synthesize and process materials, in which plasmas undoubtedly have been playing a pivotal role since Irving Langmuir first introduced its concept . MoreoveThis Special Issue consists of five research papers and one review paper in which fundamental properties of APP have been explored to advance our understanding of plasma complex interactions ,3,4 in wThe review paper by Banerjee et al. provides a detailed description of APP deposition techniques for titanium dioxide films . They coIn their paper, Tsyganov et al.  describeIn another study of plasma-material modification, Czylkowski et al.  developeLapenna et al.  reportedThe work of Cejas et al. presents a numerical model that they developed to describe and simulate discharges in APPs . A peculAnother study also developed numerical methodologies that were used in three-dimensional models of fluid fields and their effects on plasma generation and fouling elimination . Bai et This Special Issue is a collection of papers that demonstrates the importance and necessity of addressing the challenge of understanding APP processes with materials better through different theoretical and experimental methodologies. These works presented original and novel solutions with which studies performed in lab-based settings can contribute greatly to industrial technologies to synthesize and manufacture important materials."}
{"text": "In the discussion and analysis of thermal properties  the Debye approximation is typically used to describe the collective behavior of lattice vibrations (phonons) in solid materials. Because the Debye model has been successful in explaining many properties of materials, particularly in contrast to the non-dispersive model considered by Einstein, the Debye model is often the starting point of introductory textbooks in solid state physics. Yet the more we learn about the full spectrum of lattice vibrations, and now can calculate detailed phonon dispersion relations for almost any crystalline solid, the more surprising it is that the linear dispersion Debye model works as well as it has for so long. A real density of vibrational states, for example, appears qualitatively different from the Debye model for all of the many optical branches and even half of the acoustic phonons Fig. .NSR by Chen et al., \u2018Rationalizing phonon dispersion for lattice thermal conductivity of solids\u2019 [In a recent work published in  solids\u2019 , the effet al. [et al. [The analytic model developed by Chen et al.  can be cet al.  overestiet al.  treats tr et al. , refers diffuson model [The \u2018BvK\u2013Pei\u2019 model  expands on model  to accouon model , which wOne possible takeaway from all of this is that maybe Einstein was not as wrong as we make it seem in introductory textbooks. That is, high-frequency optical vibrations in real materials at and above room temperature have a small, but non-negligible, contribution to thermal conductivity. These optical vibrations might actually be better described as more spatially localized (diffuson-like) vibrations  than ful"}
{"text": "Zhu et al.; Zheng et al.; Zhang et al.), dedicated image forms or even sophisticated waves using advanced methodologies . A variety of new aspects is studied in modern sciences to better understand how the brain works.Modern technological advances in portable technologies have made it possible to study the brain in its entirety, to promote convalescence after an accident and to help in the treatment of various brain diseases and disorders, to develop a greater perception of the world around us, etc. All of this is possible because the results of modern technologies allow us to better understand how the brain works. Readings and images from different sensors can be processed as digital values  signal from electrodes placed on the scalp. Experiment has shown how to approach potential disorders of the auditory function within the brain by using proposed Random Stimulation Rate (RSR) method which integrates a random interval between two adjacent stimuli. As a result an early diagnoses of auditory pathway abnormities was proposed.In Flynn et al. was presented a model of automatic emotion recognition by using neural network approach. In the research Authors analyzed combination of methodology underpinned by psychology and latest technology like iMotions biometric research platform to formulate model of relations between automatically and interactively captured responses of participants in a form of International Affective Picture System (IAPS) standard.In Zhu et al. was proposed Hierarchical Attentive Decoding (HAD) model where by exploring knowledge associations in sequence-to-sequence classification framework Authors proposed a model of adaptive assignment of multiple species from input texts.In Zhang et al. was presented a new idea for automatic diagnosis of patients with alcoholism by analyzing neural activity from electroencephalogram (EEG) signals in a two-dimensional perspective. Model works in a form of Transfer Learning with Convolutional Neural Network (CNN). Authors tested various configurations to find the best architecture.In Zheng et al. was presented a model to estimate mental fatigue by proposed Steady-State Visual Evoked Potential (SSVEP) from six stimulus paradigms: reverse vertical sinusoidal gratings, reverse horizontal sinusoidal gratings, reverse vertical square-wave gratings, brief-onset vertical sinusoidal gratings, reversal checkerboards, and oscillating expansion\u2013contraction concentric rings.In Ptito et al. was presented a discussion on new trends and possibilities sourced in research on technology and neuroscience to help blind people by using sensory substitution or cross-modal plasticity for brain to support vision sense.In Zhang et al. was presented a novel non-contact sensing technique to detect sensory ataxia and cerebellar ataxia, which reveal in poor body coordination and balance disorder. Authors present Romberg's test and gait analysis model which collect information for machine learning based classifiers. Results have shown high potential for further research and development.In All presented articles show important ideas for solving medical problems in brain sensing and activity by applied models of Artificial Intelligence. Editors are happy to present this collection to the scientific community, and hope that it will start a new trend on neuroscience development.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
{"text": "Gut microbiome research has bloomed over the past 15\u2009years. We have learnt a lot about the complex microbial communities that colonize our intestine. Promising avenues of research and microbiome\u2010based applications are being implemented, with the goal of sustaining host health and applying personalized disease management strategies. Despite this exciting outlook, many fundamental questions about enteric microbial ecosystems remain to be answered. Organizational measures will also need to be taken to optimize the outcome of discoveries happening at an extremely rapid pace. This article highlights our own view of the field and perspectives for the next 15\u2009years. Gut microbiome research has bloomed over the past 15\u2009years. However, many fundamental questions about enteric microbial ecosystems remain to be answered. This article highlights our own view of the field and perspectives for the next 15\u2009years. This should be accompanied by the use of quantitative and imaging methods as opposed to the widespread concept of relative abundance determination via sequencing approaches.The analysis of faecal samples has dominated the field. The intestine has a very specific microbial molecules and mechanisms regulating host pathophysiology will be an important endeavour for the next few years.There are so many reports on disturbances of the human gut microbiomes in disease conditions. The causal role of gut microbes in disease onset and progression has been demonstrated several times. In contrast, there are far less examples of molecular mechanisms identified to be important for microbe\u2010host interactions. Identifying more of the specific community and infrastructural measures are needed, e.g. new educational programmes for young scientists, efficient data processing and management strategies, easy access to materials (e.g. isolates) and published work. An endeavour that must include many stakeholders and should not increase the administrative burden on scientists further.As with all blooming fields of research, the strikingly rapid pace of reported findings in microbiome research has generated very heterogeneous results quality. To optimize and boost further progress, et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Cultivation\u2010free approaches have refashioned microbiome research and became first available to many researchers worldwide when high\u2010throughput 16S rRNA gene amplicon sequencing started to be affordable in 2007\u20132010 . In short, we can cultivate more than a minority (30\u201360% of sequence\u2010based diversity)  refer to the global coverage of sequence\u2010based diversity by any bacteria isolated so far. Despite earlier work on the establishment of individual strain collections  are also important ecosystem members, the diversity of which is still incomplete  will be important , fuelling the hopes of patients and physicians for novel treatment approaches with a significant clinical impact. The field needs to multiply efforts to reach practices that are up to the promises of microbiome\u2010based diagnostics and interventional strategies using or targeting the microbes themselves.et al., et al., et al., et al., et al., et al., Disturbances in gut microbial structure and functions have been associated with multiple diseases in the context of numerous studies, which have often been underpowered and not comparable, as exemplified by the association between microbiome changes and obesity  was a great success  for the treatment of recurrent et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Besides intervention strategies based on the direct use of microbes and communities thereof, targeted modification of the gut microbiota by external factors is on the rise again. The original concept of prebiotics was coined nearly 30\u2009years ago .Part of the endeavour to promote high\u2010quality microbiome science will be the management of an amazingly growing amount of data, especially sequencing data. This is a community effort that must be implemented at multiple levels: funding agencies (this is a costly enterprise), scientists , universities  and scientific journals (for policies that encourage proper handling of data). The real challenge is that these different layers are intricately connected: it will harm the field if journals implement very strict policies that further increase the burden on researchers and prevent them from publishing their findings if the other layers have not been addressed. Archiving systems for sequencing data already existing, but the quality of metadata is usually low, and the data are not re\u2010usable, or in a very limited manner. Initiatives such as the National Research Data Infrastructure financed by the German Research Foundation (DFG) will help  after birth and during the first years of life is a crucial process with life\u2010long consequences for the host. A lot remains to be elucidated to obtain a comprehensive picture of what happens during this very important window of opportunities. How does colonization occur? Where do the microbes originate from, what determine their establishment within the ecosystem, and how quickly do they evolve and adapt to their new environment? What are the main ecological forces driving community dynamics and attractor states of infant gut microbial communities? How can we best intervene to modulate them for long\u2010term beneficial effects on the host? Research on the innovative and integrative bioinformatic approaches to handle such data will continue being very important. At the same time, high\u2010end molecular work is accompanied by the renaissance of microbiome studies based on cultivation, which brings taxonomic and functional studies of isolates again in the forefront. In 15\u2009years from now, we will want to know as many ecosystem members as possible and have them available. The infrastructural needs that will be required to accommodate massive amounts of data and to maintain reliable and well\u2010curated biological resources (e.g. biobanks) will be correspondingly high, but worth the investment.The near future will also see the rise of microbiome studies being performed at unprecedented scales. The development of Microbiome editing will be a main topic to address in coming years. At the community level, this requires understanding major ecological factors driving community assembly and microbial interactions and being able to intervene by replenishing the ecosystem with important missing microbes (and their functions). At the strain level, there is a dire need for targeted genetic engineering of commensal microbes in vitro and in vivo. Progress in this area will generate breakthroughs in the field.Translational studies are needed. Expectations for clinical and population\u2010wide applications of microbiome\u2010based discoveries are high due to the popularity of our field. There are multiple possible tracks ahead, and it is hard to predict which ones will lead to successful outcome. As mentioned above, enhancing the power of diagnostic approaches via the gut microbiome will happen soon. It will take a little longer to implement treatments using the microbes themselves  due to regulatory hurdles and our yet\u2010incomplete understanding of microbial diversity and interactions. Nonetheless, multiple FMT trials in the context of C. difficile infection, inflammatory bowel diseases and cancer drug efficacy are ongoing. Concepts for personalized nutrition and precision medicine using stool microbiome profiles are there, but their validation and proof of efficacy will require large\u2010scale, multi\u2010centre, randomized trials. In the next 15\u2009years, a lot will come from research on the gut\u2010brain axis and interactions between gut microbes and the nervous system. Hopefully, work on microbiome\u2010based applications to help fighting malnutrition will also have a large positive impact by then.TC has ongoing scientific collaborations with Cytena GmbH and HiPP GmbH and is member of the scientific advisory board of Savanna Ingredients GmbH. MJGTV received research grants from 3M, Astellas Pharma, Biontech, DaVolterra, Evonik, Gilead Sciences, Glycom, Immunic, MaaT Pharma, Merck/MSD, Organobalance, Seres Therapeutics, Takeda Pharmaceutical. She also received speaker and/or consulting fees from Alb Fils Kliniken GmbH, Arderypharm, Astellas Pharma, Basilea, Bio\u2010M\u00e9rieux, DaVolterra, Farmak International Holding GmbH, Ferring, Gilead Sciences, Immunic AG, MaaT Pharma, Merck/MSD, Pfizer, Roche, Organobalance, SocraTec R&D GmbH. NS reports consultancy contracts with Zoe, Roche, Ysopia and Freya and is co\u2010founder of PreBiomics.Deutsche Forschungsgemeinschaft : Project no. 403224013 \u2013 SFB1382 and Project no.460129525 \u2013 NFDI4MicrobiotaTC coordinated the project. All authors wrote the manuscript and agreed with its final content."}
{"text": "Dear Editor,According to the centers for disease control and prevention (CDC), surgical site infections (SSIs) are the infections that occur after the surgery, either involving the skin or involving the deep tissues . SSIs aThe World Health Organization  recommeThe appropriate antibiotic and its dose are chosen depending on the microbial flora, its complications, and patient risk factors. Kannan et al. (2021) had donRecently we read with great interest the article by de Jonge et al.  had donTherefore, the results of de Jonge et al. (2021[The authors declare no conflict of interest."}
{"text": "Schaefer et al. in Cross-Kingdom RNAi of Pathogen Effectors Leads to Quantitative Adult Plant Resistance in Wheat.In this Research Topic, the focus is on recent research and developments in the use of RNAi techniques to protect plants. Cross kingdom effects of RNA expressed in plants primarily for pathogen control are discussed by Plant miRNA Cross-Kingdom Transfer Targeting Parasitic and Mutualistic Organisms as a Tool to Advance Modern Agriculture by Gualtieri et al..Pest as well as pathogen control is considered in Bachman et al. consider aspects of their research on dsRNA expressed in maize/corn for root worm beetle control in Sequence\u2013Activity Relationships for the Snf7 Insecticidal dsRNA in Chrysomelidae.Comparative Analysis of Chitin SynthaseA dsRNA Mediated RNA Interference for Management of Crop Pests of Different Families of Lepidoptera by Rana et al..The efficiency and efficacy of a system for lepidopteran control is discussed in The Use of Engineered Plant Viruses in a Trans-Kingdom Silencing Strategy Against Their Insect Vectors by Kolliopoulou et al..The potential for plants to express RNA viruses which can infect both plants and insects but which are pathogenic in their insect vectors is considered as a strategy for vector insect control in Biosafety of GM Crop Plants Expressing dsRNA: Data Requirements and EU Regulatory Considerations by Arpaia et al..The biosafety assessments of these and other host induced gene silencing (HIGS) systems are discuss in Barriers to Efficient Foliar Uptake of dsRNA and Molecular Barriers to dsRNA Activity in Plant Cells, these are discussed by Bennett et al..Exogenous application of dsRNA (SIGS) for pest and pathogen control is an attractive alternative but is confronted with several problems related to application, uptake, persistence, and efficacy. In Uslu et al. describe studies of high pressure spraying to improve efficacy in High-Pressure-Sprayed Double Stranded RNA Does Not Induce RNA Interference of a Reporter Gene.Tabein et al. discuss The Induction of an Effective dsRNA-Mediated Resistance Against Tomato Spotted Wilt Virus by Exogenous Application of Double-Stranded RNA Largely Depends on the Selection of the Viral RNA Target Region.In relation to virus control, Validating the Potential of Double-Stranded RNA Targeting Colorado Potato Beetle Mesh Gene in Laboratory and Field Trials by Petek et al..Research on control of a major insect pest is reviewed in https://iplanta.univpm.it/.These papers give an insight into the many areas of research on the potential applications for RNAi for crop protection. Some applications are being commercialized while others are at earlier stages of research (Taning et al., All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "We would like to thank Erren et al. for their interest in and comments on our recent paper \u201cTime-Restricted Feeding in Mice Prevents the Disruption of the Peripheral Circadian Clocks and Its Metabolic Impact during Chronic Jetlag\u201d .Erren et al. have commented that we provided a literature reference for the definition of chronodisruptors, but not for the definition of chronodisruption itself . We agre"}
{"text": "A recent study by Olejniczak  IUCrJ, Olejniczak et al. (2022b]pyridazine (C4H2N5Cl or CTP) to establish its structural and phase behaviour at pressure and temperature. The material is an example of a high-nitro\u00adgen-content organic compound and these systems have a comparatively high density but, conversely, are not observed to have the expected relatively short intermolecular contacts within their crystal structures. In their study, Olejniczak et al. examine these apparently anomalous structural characteristics and establish, via high-pressure crystallization, the phase behaviour and the effects of partial hydration.In this issue of  al. 2022 describeTo gain a more complete understanding of the properties of a crystalline system it is crucial that the effects of perturbing it from its equilibrium state, under the influence of some external stimulus, is investigated. The stimulus could be delivered by a variety of different forms, such as photo excitation or an applied electric field, but it is the thermodynamic parameters of temperature and pressure that are arguably the most fundamental and provide the most powerful means of driving significant structural change. The application of temperature and pressure are the principal drivers for chemical reaction and molecular synthesis, which form the foundations of chemistry and the chemical sciences. In the Earth and planetary sciences, high-pressure and variable-temperature studies provide a means of uncovering phenomena that are otherwise not directly observable but are, nevertheless, of crucial importance for an understanding of geological processes at extreme depths. Indeed, with most directly observable mineralogy only possible at the surface, or penetrating to very shallow depths, it is research in the Earth and planetary sciences that has initiated and progressed many of the innovations in high-pressure crystal chemistry.in-situ measurements from these hydraulic press devices, such as the Paris\u2013Edinburgh cell, which can be used for diffraction studies using either X-rays or neutrons, it was not until the advent of the gasketed diamond-anvil cell during the late 1960s that in situ measurement of samples held at high-pressure became accessible to less specialist laboratories. In the intervening decades the diamond-anvil cell has become the standard tool for the generation of high pressures and has been applied to a range of experimental techniques, such as Brillouin scattering (Whitfield et al., 1976et al., 1987et al., 1969et al., 2020The development of apparatus to maintain materials at high hydro\u00adstatic pressure has been an active area of research for many years with some of the earliest pioneering work conducted by Bridgman (Bridgman, 1941et al., 2005et al., 2003For high-pressure structural chemistry, such extremes of pressure and temperature are generally not required, as they can lead to molecular dissociation, and most studies are confined to fairly modest pressure and temperature regimes where the accurate variation in key bond lengths can be followed or structural phase relationships can be mapped. For studies using X-ray single-crystal diffraction methods, miniature Merrill\u2013Bassett style diamond-anvil cells can be used (Merrill & Bassett, 1974et al. reported in this issue comes in a remarkable and comprehensive span of work from this group who have been at the forefront of not only fundamental high-pressure structural chemistry but have also been providing a lead in technique development (Boldyreva, 2019The exemplary study of Olejniczak"}
{"text": "Following publication of the original article (Ding et al. The author group has been updated above and the original article (Ding et al."}
{"text": "In the original article, there was a mistake in the legend for References: \u201caLinseisen et al., 2000; bWanten and Calder 2007; cDriscoll et al., 2009; dVanek et al., 2012; eXu et al., 2012.\u201d\u00ae detailed fatty acids composition was referred from Linseisen et al., 2000 and this reference was missed out in the original In the original article, there was a mistake in"}
{"text": "Micronuclei is a cytogenetic term describing small nuclei composed of one to a few chromosomes or chromosomal fragments, which often result from abnormal cell divisions  . These sInterestingly, the cellular stress response machinery controls both the switching of genome stability and the dynamics leading to a spectrum of numerical and structural karyotypic variants  , and mediates genomic instability caused by p53 dysfunction (Xu et al., Genotoxic stress-induced micronuclei formation is associated with the activation of ER stress response or UPR that modulates DNA damage repair programs and sustains cell survival (Dufey et al., As of late, an increasing number of reports belonging to the second category that links ER stress to micronuclei clusters and polyploidy are being produced. Micronuclei clusters have been frequently observed in cancer, but many images of them were left unpublished due to their supposed lack of scientific worth (Hatch et al., ER stress response has been linked to drug-induced-chromosome fragmentation, a type of mitotic cell death, and micronuclei clusters (Stevens et al., The ER stress response represents a major regulating mechanism for cellular function under stress. Since both ER stress and micronuclei clusters can be linked to numerical molecular pathways, and the micronuclei are linked to genome chaos (Zhang et al., Depending on the context, the ER stress response can play paradoxical roles. Under normal circumstances, it maintains system stability by repairing and eliminating unrepairable cellular elements or cells; under crisis, it might promote changes by incomplete cell death, and genome chaos Heng, , 2019. IDuring tumorigenesis, high proliferation rates of cancer cells demand increased activities of ER protein folding and transport, a condition that triggers ER stress. As tumors grow, cancer cells experience nutrient starvation and hypoxia, which can induce the accumulation of unfolded or misfolded proteins in the ER and activation of the ER stress response (Hetz et al., EH, KZ, and HH drafted the manuscript. AM and GL participated in the initial observations and discussion. AM was a Summer Undergraduate Research Student of Center for Molecular Medicine and Genomics, Wayne State University. EH was a summer student. All authors involved in literature search and editing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
{"text": "The use of Alzheimer disease medication for the treatment of dementia symptoms has shown significant benefits with regards to functional and cognitive outcomes as well as nursing home placement (NHP) and mortality. Hospitalisations in these patient groups are characterised by extended length of stays (LOS), frequent readmissions, frequent NHP and high-mortality rates. The impact of Alzheimer disease medication on the aforementioned outcomes remains still unknown. This study assessed the association of Alzheimer disease medication with outcomes of hospitalisation among patients with Alzheimer disease and other forms of dementia.A dynamic retrospective cohort study from 2004 to 2015 was conducted which claims data from a German health insurance company. People with dementia (PWD) were identified using ICD-10 codes and diagnostic measures. The main predictor of interest was the use of Alzheimer disease medication. Hospitalisation outcomes included LOS, readmissions, NHP and mortality during and after hospitalisation across four hospitalisations. Confounding was addressed using a propensity score throughout all analyses.A total of 1380 users of Alzheimer disease medication and 6730 non-users were identified. The use of Alzheimer disease medication was associated with significantly shorter LOS during the first hospitalisations with estimates for the second, third and fourth showed a tendency towards shorter hospital stays. In addition, current users of Alzheimer disease medication had a lower risk of hospital readmission after the first two hospitalisations. These associations were not significant for the third and fourth hospitalisations. Post-hospitalisation NHP and mortality rates also tended to be lower among current users than among non-users but differences did not reach statistical significance.Our results indicate that Alzheimer disease medication might contribute to a reduction of the LOS and the number of readmissions in PWD. N-methyl-d-aspartate receptor (NMDA) antagonist memantine, which were both shown to improve functional and cognitive outcomes in a significant percentage of Alzheimer disease patients  and et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Hospitalisations among people with any type of dementia are associated with severe adverse outcomes  Hessen\u2019) /define daily dose (DDD) system. Participants were grouped into current users or non-users for each hospitalisation. Current users were defined as having a dispensation of Alzheimer disease medication which was dated before the hospitalisation and lasted at least until outcomes occurred or the outcome assessment ended  to ensure their exposure status throughout the outcome assessment. This was done by adding the package size in form of the DDD to the date of dispensation from the pharmacy (e.g. 100 DDDs last for 100 days). Hospitalised patients are provided with the necessary medication from the hospital and do not have to use the medications provided by the outpatient pharmacy. To account for this, the LOS of the hospitalisation was added to the date of dispensation and DDDs (e.g. package size of 100 days\u00a0+\u00a0LOS of 15 days lasts for 115 days). Alzheimer disease medication used in this study included ChEIs  and memantine.et al., et al., et al., et al., To accurately assess the effects of Alzheimer disease medication on the outcomes by minimising bias due to confounding high-dimensional propensity scores were constructed  Wilcoxon\u2013Mann\u2013Whitney tests for continuous variables, and Kruskal\u2013Wallis tests for median values with a level of statistical significance of p\u00a0<\u00a00.05. The association of Alzheimer disease medication with LOS was examined using multivariate linear regression for comparability to other studies analysing LOS  but after readmission or NHP were excluded to compare the risk of readmission and NHP of current users and non-users, because deceased participants might have a higher risk to be readmitted to the hospital or were transferred to a nursing home before their death. Furthermore competing risk analyses were conducted for NHP and readmission using Cox regression.v. 78.13 years). Furthermore, the proportions of patients with vascular dementia and other/unknown dementia types were higher among non-users than among users. At cohort entry, non-users more often had cardiovascular and pulmonary diseases, as well as diabetes than users. In contrast, prevalent depression and bone/joint diseases were more common among users.Summary statistics comparing Alzheimer disease medication users and non-users are shown in Propensity score adjusted outcomes of LOS and in-hospital mortality are reported in The propensity score adjusted outcomes within various time windows for readmission, NHP and mortality after hospitalisation are presented in Stratified estimates for LOS by patient subgroups are shown in Sensitivity analyses for the LOS, risk of readmission and NHP are shown in online Supplementary Tables S3 and S4, respectively. Excluding participants who deceased during hospitalisation did not alter the previous reported results significantly as the first hospitalisation still showed a significant reduction for current users compared to non-users  and the second and third hospitalisations tended to show a reduced LOS. Furthermore, rate ratios for the first, second and third hospitalisations still showed a significantly reduced LOS of 24 to 5% of current users.When excluding participants who deceased within 30, 60 and 90 days after discharge from the hospital but after readmission or NHP, the estimates for the risk of readmission remained similar, showing a significantly reduced risk of readmission for current users compared to non-users after the first two hospitalisations. Estimates for the third and fourth hospitalisations tended to show a risk reduction for current users. In addition, the estimates for NHP remained fairly similar as well with a significant risk reduction after the third hospitalisation. The estimates for competing risk analyses were nearly identical for readmission and NHP as compared to the analyses excluding deceased patients.In this comprehensive study with a large sample size, the association between Alzheimer disease medication and outcomes of hospitalisation among PWD was analysed. The current use of Alzheimer disease medication was associated with a temporal and significant reduction of LOS and the risk of readmission. This pattern was particularly pronounced for younger patients and within the first 3 months after diagnosis.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Only one other study conducted in Taiwan and partially comparable to the current study addressed the relationship between LOS and Alzheimer disease medication and found less inpatient days among long-term Alzheimer disease medication users compared to short-term users  as well as the ranges within each group  were comparable. Furthermore, information on nutritional status, education, clinical parameters and family support was not available. Immortal time bias is not an issue in our study as we neither included a fixed endpoint for exposure assessment after cohort entry nor was cohort entry based on the prescription of Alzheimer disease medication. Rather, we assessed the first four hospitalisations after cohort entry and then grouped participants into current users and non-users for each hospitalisation based on the provided definitions to ensure their exposure status during outcome assessment. Furthermore, the exposure time was included in the analyses. Hence, previously unexposed time was counted as such and not as exposed time.Our study has several limitations. The analysed data originate from a single German region, which limits the generalisability of our results. Additionally, the analysis relied on ICD-10-GM codes for billing purposes in the SHI-System, which should ensure a high degree of validity but was not externally validated. However, we tried to ensure a valid diagnosis of dementia, as well as the underlying aetiology by using diagnostic measurements as part of our case definition and all diagnoses made in the first year after cohort entry. In accordance with drug registration and indication, Alzheimer disease medication users had a higher percentage of Alzheimer disease diagnoses, while non-users had more diagnoses of vascular dementia. Whether this fully reflects off-label use of Alzheimer disease medication in vascular dementia or misdiagnosis cannot be determined. At any rate, this may have led to an underestimation of the actual impact of Alzheimer disease medication on outcomes, even if many cases of dementia possess shared Alzheimer and vascular pathology (Attems and Jellinger, Among the strengths of our study is the novel assessment of the relationship between Alzheimer disease medication and hospital outcomes. This includes the findings of a temporarily reduced LOS and risk of readmission among current Alzheimer disease medication users. Further strengths of our study include a large sample size, the differentiation between multiple hospitalisations and the inclusion of patients independently of their living situation, health status or nationality. Moreover, using the comprehensive propensity score methodology enabled a more reliable conclusion on the treatment effects of Alzheimer disease medication on outcomes of hospitalisation. Finally, based on the nature of the data, recall or interviewer bias was avoided.Alzheimer disease medication may contribute to a temporary reduction of LOS and readmissions in PWD, especially in those at a younger age when diagnosed with Alzheimer disease and also shortly after the primary diagnosis of dementia. Potential long-term effects on LOS and readmissions as well as benefits regarding NHP and mortality after hospitalisation could not be established with certainty and should be investigated in the future, ideally in much larger studies."}
{"text": "Following the publication of the original article , we wereTherefore, reference 131 was added to cite the original work of Budgell et al.The original article has been corrected."}
{"text": "One of the most dynamic fields in contemporary chemistry and engineering is catalysis, which is essential for multiple industries and the world\u2019s economy. The field of catalysis started to develop in Latin America 40 years ago in relation to the needs of emerging oil industries and technological infrastructures. Since then, numerous scientific collaborations have been established between different countries giving birth to the Iberoamerican Catalytic Society represented currently by the Iberoamerican Federation of Catalysis Societies . FISOCAT is a not-for-profit organization, integrated by 11 member countries , whose oThe scientific relationship between member countries is also reflected in the organization of a biannual scientific meeting \u201cCongreso Iberoamericano de Catalisis\u201d that started in 1968 in Spain with 51 participants. The meeting has since grown in relevance and in participation to gather more than 400 participants in the last two meetings celebrated in Portugal in 2018 and Mexico in 2020 . The for2 and biomass valorization, fine chemistry, and photocatalysis.This research topic gives proof not only of the vast scientific exchange between different catalysis groups, but also that Iberoamerican researchers are at the forefront of catalysis research. Contributions addressing major fundamental and industrial challenges have been included, showing the great expertise and enthusiasm of Iberoamerican researchers working in modern fields such as biogas conversion, CO2 capture and conversion, methane to methanol transformation, H2 storage, and biomass and polymeric waste upgrading.This research topic contains an excellent review by S\u00e1nchez-L\u00f3pez et al.  presenti2 and CH4/CO2 conversion are the main subjects of three more contributions presented by Gandara-Loe et al. (2-involved reactions for syngas production. Nickel can be used either as a monometallic substance or alongside La, Zr, K, or Ru, and these metals are charged to increase active phase stability and overall catalyst durability.COe et al. , Alvareze et al. , and Le e et al. . While tIn this research topic, biomass conversion is studied by Martin Kessler and Roberto Rinaldi  via mechThe isomerization of allyl alcohol over Ru-based catalysts is studied by Enciso et al. . In this2 sheets for photocatalytic pollutant degradation. The hybrid materials, designed to increase the photocatalytic efficiency under visible light, showed that the addition of carbon dots extended the light absorption and diminished the rate of recombination by promoting charge transfer. In another contribution by Soares et al. (The implementation of carbon-based catalysis is also reflected in this research topic. Shen et al.  studied s et al. , an actiAs has been mentioned in this editorial, the spirit of the research topic is to highlight the relevance of the work done by the Iberoamerican scientific community in the field of catalysis. The eight manuscripts included offer great representation of the quality and relevance of the contributions of Iberoamerican scientists and research groups to address the greatest challenges society and industry are facing as well as to contribute toward the development of the catalysis field. The topic editors expect that this research topic will serve as a representation of the work and collaborations in the area of catalysis developed in Iberoamerica, and to promote its growth and impact worldwide."}
{"text": "Dall\u2019Acqua et al., Ahmad et al., and Li et al. These authors report new extraction procedures and chemical profiles able to justify specific biological activities with the phytocomplex. From an industrial point of view, the availability of procedures and knowledge  is essential to obtain the scale-up and adequate quality control, particularly to the innovative instrument configurations able to improve not only the analytical performances  but also to reduce solvents consumption, time-per-analysis, and ruggedness, following the GAC  guidelines. Specifically, this research topic focuses on the biological activities of a specific plant-derived material and the discovery of innovative activities and new biological targets. In this field, more interesting are the papers from Zhang et al., Jin et al., Bla\u017eevi\u0107 et al., Chang et al., Schreck and Melzig. Furthermore, in Pharmacology and Ethnopharmacology, this collection focuses on specific effects ideally on identifiable targets. Specifically, some papers report interesting approaches/applications of natural products on health protection, such as Wang et al., Ye et al., Jiang et al., and Yong et al. This research topic also includes works on food supplements (Chen and Tsim) and an interesting paper related to a very recent problem related to the naturally derived products that are not fully identified and regulated by current legislation, especially concerning heavy metals . Other essential elements in this topic collection are two review papers, the first on the trends of adulterated and illegal food supplements in the EU based on the warnings of the Rapid Alert System for Food and Feed  and the second on the potential of edible and herbal plants for the prevention and management of COVID-19 .Nowadays, several natural products are used as food additives even if knowledge on their properties is not complete. Often, several techniques can be employed to improve extractions, workup, and isolation/purification of bioactive materials from natural sources. These findings are reported well and exposed in"}
{"text": "Social anxiety disorder (SoAD) in youth is often treated with a generic form of cognitive behavioural therapy (CBT). Some studies have suggested that primary SoAD is associated with lower recovery rates following generic CBT compared with other anxiety disorders.versus other primary anxiety disorders.This systematic review and meta-analysis investigated recovery rates following generic CBT for youth with primary SoAD Five databases  were searched for randomised controlled trials of generic CBT for child and/or adolescent anxiety.Ten trials met criteria for inclusion in the systematic review, six of which presented sufficient data for inclusion in the meta-analysis. Sixty-seven did not report data on recovery rates relative to primary diagnosis. While most individual studies included in the systematic review were not sufficiently powered to detect a difference in recovery rates between diagnoses, there was a pattern of lower recovery rates for youth with primary SoAD. Across the trials included in the meta-analysis, the post-CBT recovery rate from primary SoAD (35%) was significantly lower than the recovery rate from other primary anxiety disorders (54%).Recovery from primary SoAD is significantly less likely than recovery from any other primary anxiety disorder following generic CBT in youth. This suggests a need for research to enhance the efficacy of CBT for youth SoAD. It is common, with a lifetime prevalence of 12% , separation anxiety disorder (SAD) and specific phobia (SP) has recently been considered in a systematic review conducted by Oldham-Cooper and Loades . This reIt is clear from the discussed literature that SoAD is a common difficulty in young people with disabling implications. The suggestion from several trials that young people with SoAD experience poorer outcomes from CBT, coupled with the lack of overall clarity from reviews of the topic, necessitate further investigation. Better understanding of this issue is crucial, as this can inform the development and implementation of better psychological therapies for this common disorder in young people. The present review therefore set out to investigate diagnostic outcomes following generic CBT for young people with primary SoAD in comparison with those with other primary anxiety disorders. Specifically, we set out to investigate remission from primary anxiety diagnosis , at post-treatment, in children and/or adolescents with an average age of 7\u201318 years. In contrast to the Oldham-Cooper and Loades  review, https://www.crd.york.ac.uk (ID: CRD42019122593). The review followed PRISMA (2009) guidelines . The inclusion criteria were: (i) participants aged 7\u201318 years, or mean age of 8\u201317 years, (ii) RCTs of any type of CBT for anxiety disorders , (iii) includes validated diagnostic assessment at pre- and post-intervention  were searched for articles within the date range of 1990\u20132019. Hand forward and back searching was conducted by reviewing the reference lists of existing relevant reviews , language (English) and source . Although studies focusing on people with ASD or intellectual disabilities were excluded from the current review, the research team opted to manually remove these studies rather than state these in the search terms. This approach was used to minimise the risk of the electronic search erroneously excluding papers which met the inclusion criteria. For an example full electronic search, see Appendix Studies were initially screened based on title, and studies that clearly did not meet the inclusion criteria were excluded. This process was completed cautiously, and any studies which may have met inclusion criteria were reviewed further based on abstract at the next stage. Examples of papers that could clearly be excluded at title stage were those focused on anxiety in people with diagnosed ASD, those evaluating psychological therapies for anxiety disorders in adults only, and single case studies or other clearly non-RCT designs. Abstracts of remaining studies were then reviewed against the inclusion criteria. Again, if it was unclear from the abstract whether the study met inclusion criteria, it was carried forward to the full text review stage. The final stage was to review the full texts of all studies included based on abstract. The screening and selection process was completed by one researcher (R.E.) and in cases of ambiguity regarding whether studies met inclusion criteria, this was discussed and agreed with a second researcher (E.L.). Studies were included in the meta-analytic synthesis if they provided data on the number of participants who recovered from primary social anxiety and from other primary anxiety diagnoses.n = 8), authors were contacted to request this information. The required data for inclusion in meta-analysis was provided by four of these eight authors.Data were extracted from each of the papers by two independent researchers (R.E. and M.T.). Prior to data extraction, the research team agreed on which data would be sought for extraction. A spreadsheet was developed by the research team to enable the standardised collection of all relevant data from each paper where available. For trials in which the manuscript did not provide sufficient data for inclusion in meta-analytic synthesis , intervention characteristics  and diagnostic outcomes following CBT . All diagnostic outcome data were collected at the first assessment following completion of CBT only.et al., Risk of bias in individual studies was assessed using the Cochrane Collaboration Risk of Bias Tool (Higgins I2 = 0%). Recovery outcomes (number recovered from primary SoAD versus other primary anxiety disorders) were compared using odds ratio.Analyses for quantitative synthesis were conducted using RevMan software (version 5.3). The data included in this analysis were the number of participants who recovered from primary SoAD, the total number with primary SoAD, and equivalent numbers for all other primary anxiety disorders pooled. In the six trials included in the meta-analysis, the single most severe and impairing diagnosis based on youth or parent report was assigned as the primary diagnosis in accordance with ADIS-IV-C/P guidelines. Recovery from primary diagnosis is defined as being below ADIS-IV-C/P clinical severity thresholds for primary diagnosis based on both youth and parent report at post-treatment. A fixed effects model was used, as heterogeneity was acceptable (Risk of bias across studies (publication bias) was examined using a funnel plot.n = 2) or in response to requests made to the author (n = 4). These stages, and reasons for exclusion, are outlined in Fig.\u00a0After 956 titles were removed based on title, this left 479 to review based on abstract. At the full text stage, 130 texts were reviewed. Ten texts met criteria for inclusion in the review. Six papers provided sufficient data for inclusion in the meta-analytic synthesis, either in the original paper  across the seven studies which reported this information. Children and adolescents receiving CBT ranged in age from 5 to 17 years of age . Further details of the trials are shown in Table\u00a0Ten published articles were included in the review. These RCTs evaluated a range of formats of CBT, including three of individual CBT , it is not possible to prevent participants from knowing which condition they are in. Indeed, it has been suggested in a previous review that this criterion should not be assessed for psychotherapy trials, due to the nature of their design . Two trials  with this primary diagnosis. Furthermore, all results from individual studies regarding the proportion of young people who recovered must be interpreted with caution as the individual studies did not have sufficient statistical power to test the significance of this difference.The trials used a range of formats and statistical approaches to present results related to recovery following CBT for young people with different primary anxiety diagnoses. As shown in Table\u00a0et al., et al., et al., et al., Eight trials reported additional analyses of the association between primary diagnosis and recovery post-CBT. Of these, four , a fixed-effects model was used. The meta-analysis revealed that the likelihood of recovery from primary diagnosis was significantly lower for participants with primary SoAD than those with other primary anxiety disorders, OR = .52 , z = 3.41, p<.001. These results are shown in Fig.\u00a0In order to further examine the association between primary diagnosis and recovery following CBT, a meta-analysis was conducted on the number of young people who recovered from primary SoAD 95% CI: .6, .76, zC in Supplementary material).A funnel plot was examined of the six studies included in the meta-analysis. This did not indicate evidence of publication bias (see Appendix et al., et al., et al., et al., This review investigated the question of whether young people with primary SoAD were less likely to recover following generic CBT compared with those with other primary anxiety disorders. In the systematic review, the proportion of young people who recovered from primary SoAD was lower than the proportion who recovered from any other primary anxiety disorders in seven of the eight trials which presented these data. However, these trials did not individually have sufficient statistical power to test for the significance of these differences. In terms of the trial authors\u2019 own analysis of the relationship between primary diagnosis and recovery, four trials (Barrett et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al. et al., The results from the quantitative synthesis were clearer. When combining the results of six trials which presented sufficient data for inclusion (Arendt et al. (This review also builds on the conclusion of the 2014 review by Knight and colleagues (et al., et al., et al., et al. (These results have clear clinical and research implications. The finding that only 35% of young people with primary social anxiety recovered following generic CBT suggests that treating primary SoAD with current generic models of CBT is unlikely to enable recovery in the majority of cases. However, there is a lack of evidence to suggest what approach may improve CBT outcomes for this population. There is evidence of the effectiveness of social skills interventions for SoAD in pre-adolescent children (Beidel , et al.  are furtet al., et al., et al., et al., et al., It is unclear why young people with SoAD experienced poorer outcomes following generic CBT compared with those with other anxiety disorders. One explanation might be that there are specific processes that maintain SoAD, meaning recovery is less likely if these are not specifically addressed in therapy. For example, adult models of SoAD highlight the role of self-focused attention and negative observer-perspective images as key maintaining factors (Hackmann et al., et al., et al., versus generic CBT for SoAD will be observed in children compared with adolescents. Future reviews would therefore benefit from comparing outcomes not just between primary diagnoses but also between children and adolescents. Such a review would benefit from also considering outcomes of alternative psychological treatments which have an evidence base for the treatment of SoAD in children, such as social skills interventions (Beidel et al., et al., It was beyond the scope of this review to consider other predictors of outcome, or the interaction between primary diagnosis and other predictors. This is an important question, especially given findings in one of the included trials (Arendt et al., This review has a number of strengths. It included trials of CBT across a range of formats, increasing the generalisability of results. All outcomes were based on validated diagnostic tools, and from RCTs published in peer-reviewed journals. Whilst these criteria led to the exclusion of at least one trial which reported outcomes consistent with the conclusions of this review from a non-RCT design (Crawley et al. (This review also has several limitations. The included papers represent a minority of trials of CBT for anxiety in children and adolescents, as 67 were excluded from the current review as they did not present sufficient data on recovery rates relative to primary diagnosis. It is possible that this led to bias in our findings, for example it could be possible that trials finding evidence of a difference in recovery rates between diagnoses were more likely to report these data. However, the symmetrical funnel plot provides evidence to suggest that results were not affected by such publication bias. A further limitation is that study screening and selection was primarily completed by only one researcher. Although this process was completed cautiously and followed clearly specified inclusion and exclusion criteria, and ambiguities were discussed and agreed within the research team, a more rigorous approach would have been for double coding of studies by a second researcher. The present review also only focused on recovery outcomes at post-treatment, and therefore does not reflect different recovery outcomes which may have been observed at longer-term follow up. For example, Thirlwall et al. , 2017 hiThese limitations notwithstanding, this review has produced important findings with clear research and clinical implications. It has shown, from a small number of recent trials, that young people with primary SoAD are significantly less likely to be in remission from this diagnosis following generic CBT at post-treatment compared with young people with other primary anxiety disorders. This demonstrates the importance of reporting recovery rates relative to primary diagnosis in all trials of CBT for youth anxiety, and the urgent need for further research to enhance understanding of SoAD in young people in order to improve the efficacy of treatment for children and adolescents with this diagnosis."}
{"text": "When the Interagency Standing Committee (IASC) adopted the composite term mental health and psychosocial support (MHPSS) and published its guidelines for MHPSS in emergency settings in 2007, it aimed to build consensus and strengthen coordination among relevant humanitarian actors. The term MHPSS offered an inclusive tent by welcoming the different terminologies, explanatory models and intervention methods of diverse actors across several humanitarian sectors . Since its introduction, the term has become well-established within the global humanitarian system. However, it has also been critiqued for papering over substantive differences in the intervention priorities and conceptual frameworks that inform the wide range of interventions described as MHPSS. Our aims are to clarify those conceptual frameworks, to argue for their essential complementarity and to illustrate the perils of failing to adequately consider the causal models and theories of change that underlie our interventions.clinical and social-environmental. Using the examples of intimate partner violence and compromised parenting in humanitarian settings, we illustrate the complementarity of these two frameworks, as well as the challenges that can arise when either framework is inappropriately applied.We describe the historical backdrop against which the term MHPSS and the IASC guidelines were developed, as well as their impact on improving relations and coordination among different aid sectors. We consider the conceptual fuzziness in the field of MHPSS and the lack of clear articulation of the different conceptual frameworks that guide interventions. We describe the explanatory models and intervention approaches of two primary frameworks within MHPSS, which we label Clinical interventions prioritise the role of intrapersonal variables, biological and/or psychological, as mediators of change in the treatment of distress. Social-environmental interventions emphasise the role of social determinants of distress and target factors in the social and material environments in order to lower distress and increase resilience in the face of adversity. Both approaches play a critical role in humanitarian settings; however, the rationale for adopting one or the other approach is commonly insufficiently articulated and should be based on a thorough assessment of causal processes at multiple levels of the social ecology.Greater attention to the \u2018why\u2019 of our intervention choices and more explicit articulation of the causal models and theories of change that underlie those decisions , may strengthen intervention effects and minimise the risk of applying the inappropriate framework and actions to a particular problem. When the Interagency Standing Committee (IASC) adopted the term mental health and psychosocial support (MHPSS) in 2007, it aimed to bridge a contentious divide between advocates of substantively different frameworks for addressing mental health and psychosocial needs in humanitarian settings   and at multiple levels of the social ecology.not to rekindle or exacerbate the debate over which conceptual framework holds a greater claim to truth; on the contrary, we argue for multilevel interventions that integrate diverse perspectives that are grounded in an analysis of causal factors both historical and current, and at multiple ecological levels. Our hope is to draw attention to the importance of achieving greater clarity regarding the \u2018why\u2019 and \u2018how\u2019 of our intervention choices and to encourage more explicit articulation of the theories of change that underlie those decisions.Our purpose is biomedical, biological, psychological, trauma-focused, public health, holistic and psychosocial are among the more commonly used labels  two very different understandings of the term psychosocial within the MHPSS community. In the health sector, the term psychosocial usually refers to all non-pharmacological interventions aimed at alleviating distress and disorder and improving functioning , despite their different explanatory models, intervention methods and prioritised outcomes. Outside of the health sector, in contrast, the term psychosocial is often roughly analogous to what we are calling social-environmental. Thus, psychosocial approaches emphasise the role of setting-level variables, such as safety and support within the family and community, lack of access to income generation and educational opportunities and the adequacy of housing and other material resources, as these affect mental health and psychosocial wellbeing.It may be noted that we have not included a social-environmental helps side-step this confusion and reflects clearly the setting-level focus of this explanatory and intervention framework.We have no interest in advocating for one or the other definition of psychosocial, perhaps an important discussion but one which lies beyond the scope of this paper. We do note with concern, however, the confusion that may arise when such a widely used term is employed differently by different actors all working to strengthen the mental health of conflict-affected populations. We hope the term et al., et al., et al., Nearly 50 years ago, Caplan and Nelson observed that how we explain a problem generally determines how we go about trying to solve it , clinical interventions may be employed simultaneously with protective interventions. And if trauma symptoms persist after safety has been established, psychological treatment may then be indicated in order to restore emotional wellbeing. These multi-pronged approaches illustrate the sort of complementarity envisioned in the IASC guidelines.Finally, trauma symptoms may be multiply determined, with etiological roots in previous events as well as ongoing circumstances. A survivor of sexual assault may well be traumatised by her terrifying experience, but her distress may also reflect a realistic fear of social rejection by her family and community Kelly, . Similaret al., It is a truism that specifying the theoretical and causal mechanisms for any mental health intervention is an important step to achieving and demonstrating impact. Doing so forces us to articulate our understanding of those factors that we believe underlie or contribute meaningfully to the problems we wish to address. The specification of these variables allows us to develop a theory of change that explains and justifies our intervention methodology or treatment plan  is the norm. Miller  has illuet al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., As noted, one of the central challenges in developing theories of change for interventions in conflict-affected communities is the diversity of ongoing stressors to which people are exposed, combined with their history of exposure to violence and loss. Moreover, as we illustrated in the previous example, the striking nature of the violence from which people have escaped (or through which they may still be living in settings of ongoing conflict), can easily overshadow less obvious yet equally powerful and more immediate sources of distress. Recent research has built on a small number of earlier studies  and social-environmental frameworks may facilitate the development of sound theories of change by drawing our attention to both intrapersonal and environmental factors and processes, past and present, that affect mental health and wellbeing in humanitarian settings. This specification may in turn help ensure that our interventions reflect an appropriately multilevel analysis of causal factors and putative mediators of change. In this way, we can decrease the risk of overlooking key social determinants that might be contributing to distress, or conversely, of failing to consider the impact of prior trauma on mental health in settings where current stressors are especially salient. Stated differently, we believe that greater conceptual clarity can help researchers and practitioners better articulate the underlying mechanisms of the interventions they employ and the rationale for their intervention strategies.et al., et al., et al., et al., et al., et al., et al., This paper is also a call for multilevel interventions, and indeed, the available evidence on factors affecting mental health in humanitarian settings points in precisely this direction. However, despite repeated calls for interventions that target mediators of change at multiple levels of the social ecology, to date, few such ecological interventions are found in the literature. Numerous reviews reflect the same persistent reality: clinical and social-environmental interventions are seldom integrated into multilevel, integrated systems of support (Barenbaum et al., et al., social justice framework advocated by Tol (et al., In this paper, we have focused on what we regard as the two primary conceptual frameworks, clinical and social-environmental, that guide the development and selection of interventions in conflict-affected communities. However, we recognise that other conceptual frameworks inform the way mental health and psychosocial wellbeing are addressed in humanitarian settings. For example, spiritual beliefs and practices often play a powerful role in supporting healing and strengthening resilience in the wake of violence, displacement and natural disaster (Galappatti, d by Tol , whose r et al.,  and Cent et al., . Such fret al., et al., Conceptual frameworks are always rough approximations of real-world phenomena (Korzybski, Nonetheless, the frameworks we have described do correspond reasonably well to prevailing approaches to understanding and addressing the mental health and psychosocial needs of conflict-affected communities. More importantly, these frameworks are heuristically useful because they encourage us to be explicit about the causal models and theories of change that guide our interventions, drawing our attention to putative causal factors and potential targets of change at different ecological levels.It is certainly possible to maintain a distinction between conceptual frameworks and to better articulate causal models and theories of change while continuing to embrace the umbrella term MHPSS. Indeed, we are not suggesting that the term should be abandoned; on the contrary, it has served an important unifying function among individuals and organisations working from diverse perspectives to strengthen mental health in conflict-affected populations (Ventevogel,"}
{"text": "Echinococcus multilocularis in North America as a model. The aim was to propose an ecological framework for investigating the invasion of parasites that are trophically transmitted through predator\u2013prey interactions, showing how despite the complexity of the cycles and the interactions among multiple hosts, such parasites can overcome multiple barriers and become invasive. Identifying the key ecological processes affecting the success of parasite invasions is an important step for risk assessment and development of management strategies, particularly for parasites with the potential to infect people (i.e. zoonotic).In a fast-changing and globalized world, parasites are moved across continents at an increasing pace. Co-invasion of parasites and their hosts is leading to the emergence of infectious diseases at a global scale, underlining the need for integration of biological invasions and disease ecology research. In this review, the ecological and evolutionary factors influencing the invasion process of parasites with complex life cycles were analysed, using the invasion of the European strain of  Humans can get infected and develop AE by accidental ingestion of eggs , intensity and extent of the impact, and dynamics of invasion. Usually, an invasive alien species is defined as one that has been transported beyond the limits of its native range and has established a population in an area where it was not known to occur previously, resulting in negative impacts in the new environment  at a global level is associated with increased human travel, international trade and wildlife and/or domestic animal introductions (among other anthropogenic changes) which have allowed the spread of the parasite beyond historical endemic regions  as definitive hosts and freshwater snails as intermediate ones, was accidentally introduced to Europe. The parasite successfully found new intermediate and definitive hosts in native European species of snails , and ungulates (e.g. Dama dama), representing an example of multiple ecological fitting \u2013parasite associations. Still, the effectiveness of spillover to new hosts will depend on the ability of the parasite to use new resources. Mostly, parasites are considered resource specialists with restricted host ranges, which has led to the idea that when parasites become specialized, it is at the expense of their ability to perform in alternative hosts (Agosta Anguillicola crassus), a parasite of the Japanese eel (Anguilla japonica), was introduced into the United Kingdom, where successfully infected native European eels (Anguilla anguilla), causing infections with higher worm intensities and pathogenic effects than in Japanese eels  between the bivalve host Mytilus edulis and the invasive parasitic copepod Mytilicola intestinalis were observed in two different fronts of invasions in the North Sea, which was possibly related to local environmental differences , introduced in the European Wadden Sea, can be infected by the native trematode Renicola roscovita; still, it is not consumed by native birds (definitive hosts). Thus, the Pacific oyster acts as a dead-end intermediate host, reducing the transmission of the parasite . Through these interactions, the parasite can directly or indirectly affect host survival (population density-mediated effect) or host behaviour and life history (trait-mediated effect) , altering their ability to compete and ultimately affecting the outcome of invasion  in the UK, mediated through the transmission of a Parapoxvirus that was introduced with the arrival of the North American grey squirrel (Sciurus carolinensis)  transmitted through snails, facilitated the range expansion of North American white-tailed deer (Odocoileus virginianus), leading to dramatic decreases of moose  and caribou (R. tarandus) populations in the north-eastern United States in the mid-1900s , increasing its susceptibility to predation and thereby the probability of the parasite reaching the definitive host Moore, . Althouget al., et al., et al. , may prevent or increase tolerance to genetic depletion and inbreeding depression during the invasion process , immune response (apparent competition), or direct interference , using strains with different levels of virulence. The experiment showed a strong mutual competitive suppression of co-infecting strains in early stages of infection, resulting in decreasing effects of infection in the host  of Alaska and the Canadian Arctic. Only after the 1960s, the parasite was reported in the Northern Central region (NCR), which include 13 contiguous states of the USA and the southern area of three Canadian provinces   imported for sport hunting from France during the last century , as evidenced by the satellite tracking of natal dispersal by a young female between continents, from Svalbard Archipelago (Norway) to Ellesmere Island, Nunavut (Canada), in 76 days  is likely another important definitive host in that area, due to its larger home range, dispersal distances and increasing presence in urban environments  and deer mice (Peromyscus maniculatus), but also newly described hosts such as the southern red-backed vole (Myodes gapperi)  were recently confirmed as regular definitive host of E. multilocularis  and dispersal distances (50\u2013800\u00a0km) , since no suitable intermediate host was previously present  out of the eight parasites included in the IUCN list of worst invasive alien species has an indirect cycle (Hatcher et al., et al., et al., Many alien parasites are co-introduced with an alien host species, and the successful establishment of parasites with CLC is not unusual. A review by Lymbery et al.  found thet al. (Em in North America, we propose a framework (et al., et al., et al., et al., et al., et al., via the eco-evolutionary experience in previous environments, allowing individuals to survive as an infective propagule, find and infect new intermediate and definitive hosts, and to reproduce, completing their life cycle with the establishment of a self-sustaining population in the long-term (Agosta and Klemens, et al., et al., et al., et al., via direct or indirect effects on host behaviour and survival, thus, potentially promoting competition and predation and enhancing the transmission of the parasite (Hudson and Greenman, et al., et al., In the previous sections of this review, we identified ecological and evolutionary factors that could influence the invasion process of parasites with CLC. Based on the conceptual invasion frameworks developed by Colautti and MacIsaac  and Blacet al. , and theramework  to summaet al., et al., et al., The local or regional dispersal, and dominance of the parasite over other species/strains, would depend on the within-host intra- and interspecific interactions and the ability to exploit the shared resource, as well as the dispersal patterns and distribution of the host populations (Mideo, et al., Biological invasions are multifactorial, complex phenomena that involve largely idiosyncratic ecological characteristics. Despite the vast body of knowledge about underlying processes influencing invasion dynamics, there is an incomplete understanding of the interaction between macro and micro-evolutionary processes and what drives the potential for invasion. Additionally, the research on parasitism in the context of biological invasions has advanced very slowly, compared to the study of biological invasions by animals or plants (Ogden et al., et al., et al., E. multilocularis in North America is particularly important to our understanding of the specific factors influencing the invasion process of those parasites that are trophically transmitted in predator\u2013prey systems. Understanding the historical origins and complex components of these new host\u2013parasite mosaics is essential in formulating predictions about future invasions, and elucidate the effects of climate change and ecological disturbance on the potential for invasion. Moreover, since most parasites are introduced with their original hosts, there is a need for integration between the study of biological invasions and disease ecology, which would allow the design of comprehensive predictive frameworks assessing the risk of invasion and lead to possible management strategies. This mandates for multidisciplinary studies on mechanisms, effects, and the control of parasite invasions, focusing not only on host\u2013parasite interactions, but also on the broader impacts of these invasions at the ecosystem level.Although parasites with CLC may have to overcome more ecological and physiological barriers to invade new environments successfully, there are examples of colonization in heterogeneous environments, including parasites with high impact on animal and human health (Henttonen"}
{"text": "During the last few decades, biomimetics has attracted increasing attention in both basic and applied research and in various fields of industry and building construction. Biomimetics has a high innovation potential and opens up possibilities for the development of innovative technical products and production chains. The specific structures and functions that the vast number of organisms have evolved in adaptation to differing environments represent the basis for all biomimetic R&D projects. Novel sophisticated methods for quantitative analyses and simulations of the form\u2013structure\u2013function relationship at various hierarchical levels provide intriguing insights into multiscale mechanics and other functions of biological materials and surfaces. For the first time, it is possible to transfer biological structures and thus their properties into innovative biomimetic products by means of newly developed production methods and at reasonable cost.Animals, with their fascinating behaviour and movement processes, have long attracted interest, with plants only more recently having also been recognised as valuable concept generators for biomimetic research ,2. In geThe articles published in this Special Issue, \u201cBridging the Gap: From Biomechanics and Functional Morphology of Plants to Biomimetic Developments\u201d, cover theoretical considerations concerning the challenges of the biomimetic approach and potential pitfalls and include the entire development chain from basic research in the field of biomechanics and functional morphology of plants to simulations and the development of physical models for a better understanding of functional principles, finally leading to biomimetic products on the laboratory scale or demonstrator level. The size scale includes all hierarchical levels from microstructure to the entire plants.Niklas and Walker  detail tIn the second contribution, Wunnenberg et al.  describeMasselter et al.  present Klang and Nickel  describePoppinga et al.  show thaM\u00fchlich et al.  have anaKr\u00fcger et al.  have devThe articles published in this Special Issue, \u201cBridging the Gap: From Biomechanics and Functional Morphology of Plants to Biomimetic Developments\u201d, thus, give an up-to-date overview of current research topics in plant-inspired biomimetic research."}
{"text": "After a rigorous peer review process, twelve papers were accepted and published. These papers cover a wide range of topics including shoulder arthroscopy, arthroplasty and related neuropathies.This Special Issue focuses on \u201cNew trends in shoulder surgery from Biomechanics to the operating room\u201d, and aims to cover recent advancements as well as future trends in the field of shoulder surgical treatments. Lee et al.  evaluateThree papers published by the group of Romano et al. ,3,4 are The first one  proves tThe second paper  analyzesOur interest in this new prosthesis design has increased over the last decade too, showing better clinical outcomes while using an onlay curved lateralized cementless stem ,6.The third paper  emphasizTherefore, we are also proud to present the results of our study on the efficacy of the lateral acromioplasty . This teL\u00e4dermann et al.  comparedTherefore, L\u00e4dermann et al.  have pubThe study presented by Riedl et al.  showed tThe proper treatment for the long head of the biceps is a topic still debated. Treatments available range from tenotomy to tenodesis, which has been described using different systems and in different positions along the humerus. Our group has recently published a paper comparing high and subpectoral tenodesis during rotator cuff repair .Pascarella et al.  tested aThree review papers complete this Special Issue.Bozzi et al. , with thYon CJ et al. demonstrate that arthroscopic revision Bankart repair might lead to an improvement in clinical outcomes and reasonable satisfaction with proper patient selection .Giovannetti de Sanctis et al.  compare Given these different contributions, it is evident that shoulder surgery still has fundamental questions that remain unanswered.We would like to thank the Editor in Chief for his support throughout the preparation of this Special Issue. We are grateful to all the anonymous reviewers who devoted their precious time reviewing the papers submitted to this Special Issue. Their reviews helped us select the best papers to be included in this Special Issue. We would like also to thank all authors who contributed to this Special Issue.Hopefully you will enjoy reading this selection of articles, as we did, and you will find them informative and helpful in keeping yourself up to date in the field of shoulder surgery."}
{"text": "Antibiotic resistance occurs when bacteria or fungi develop the ability to defeat drugs designed to kill them. Antimicrobial resistance (AMR) threatens the effective prevention and treatment of an ever\u2010increasing range of severe infections caused by microbes such as bacteria, viruses, fungi and other parasites. AMR poses a serious security threat to global health. About 700\u2009000 people die each year worldwide due to drug\u2010resistant diseases according to the World Health Organization. In addition, antimicrobial resistance can affect people at any stage of their lives and has important repercussions in health care and the in veterinary and agriculture industries, making it one of the world\u2019s most urgent public health problems.The increasing prevalence and the global spread of antimicrobial resistance is becoming alarming and fighting this threat is a public health priority. This challenge a collaborative global approach across sectors to detect, prevent and respond to this menace. Every country should consider the following actions to prevent resistant infections and their spread: data implementation and tracking systems to monitor resistance. In addition to these important actions, it is also critical to join the global effort to develop new drugs, diagnostics, vaccines and therapeutics to treat infections.et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., As one of the top journals in the field of microbiology, Microbial Biotechnology is attracting an increasing number of key publications from research institutes and universities worldwide. In this special issue on \u2018New Advances into antimicrobial research\u2019 scientists explore a wide range of topics including\u2009the evolution, spread, and blocking of antimicrobial resistance (Zheng None declared."}
{"text": "The development of innovative and sustainable materials for use in asphalt pavement applications has received increasing attention over the past 20 years, also thanks to the growing interest in the circular economy approach, which is replacing the linear one ,4,5,6. HMaterials aimed at collecting research focused on the development of innovative and sustainable asphalt materials, as well as on mixture and structural design. With the aim of seeking the right material to solve market-driven challenges, the following aspects were investigated:Performance evaluation of innovative materials, such as renewable materials and graphite nanoplatelets;Investigation of the possible employment of wastes  in asphalt pavement applications.Accordingly, this Special Issue of The research performed by numerous universities and scientific centres from Europe, Asia and North America demonstrated that innovative/high-performance materials can be employed in asphalt pavement applications only if their behaviour is comparable to that of the conventional asphalt materials, for which the design approaches were originally conceived and validated.Materials. The issues covered can be divided into five main topics:Characterization of recycled materials in asphalt concrete mixtures, such as waste of sanitary ceramics , crumb rInvestigation of natural  or bio-bStudy of rheological and fatigue behaviour of bituminous materials with  and withEvaluation of lubricant characteristics of graphite nanoplatelets ;Fatigue life prediction model for materials employed on long-span steel bridge decks .Twenty universities and scientific centres contributed with their original research papers to this Special Issue of Andrzejuk et al.  evaluateZhang et al.  investigThe study presented by Gawdzik et al.  was aimeThe aim of the research presented by Li et al.  concerneIn the paper presented by Ferrotti et al.  a trial The research performed by Slabonski et al.  concerneNciri  et al. sThe research presented by Gaudenzi et al.  involvedThe aim of the research presented by Al-Mohammedawi et al.  concerneThe objective of the study performed by Yan et al.  was to eIn the paper presented by Xu et al. , a fatigMaterials demonstrates the interest attracted by the exploration of innovative materials for use in asphalt concrete pavements. The issues covered proved that the international scientific community is not only looking for innovative, but also sustainable materials, which meet the needs of the present without compromising the ability of future generations to meet their own needs. Recycled materials such as crumb rubber, renewable bio-materials and reclaimed asphalt, as well as graphite nanoplatelets and natural materials used as rejuvenators, tend toward the circular economy model, which aims at enhancing the resource efficiency by exploiting wastes that can be used as raw materials in different processes.The number of papers published in this Special Issue of"}
{"text": "To the Editoret al. [I read with interest the article \u2018Capsular thinning on magnetic resonance arthrography is associated with intra-operative hip joint laxity in women\u2019 by Packer et al.  in the Jet al. [On page 300 of the article at Fig. 1, the authors describe thickness of the hip joint capsule at the left image and the width of the anterior hip joint recess at the right image. When we compare this study with similar study by Magerkurth et al.  which thNone declared."}
{"text": "Hamstring strain injury (HSI) is the most common non-contact injury representing 37% of all muscle traumas in professional sport  long head reaches ~110% of its length (Schache et al., It has also been reported that force production capabilities of the muscle and the velocity at which this occurs are influenced by muscle architecture such as pennation angle, muscle thickness and fascicle length (Alonso-Fernandez et al., Nonetheless, despite the positive effects of different prevention and rehabilitation programs, the percentage of HSI and its recurrence rate is still very high. This suggests, that they are not fully effective. A probable reason for this is that they are based on different methodological approaches while none of them take all the biomechanical aspects of this problem into account. There are many theories describing the causes of hamstring injuries, but some point is probably missing. It should be underlined that we live in a three-dimensional world, where all movements are performed on three planes.The potential relationship between pelvis position and HSI was suggested by some authors. Higashihara et al. , MendiguAnother important issue is that hamstring muscles work differently depending on gait cycle phase. It has been reported that the BF operates as a hip extensor and adductor as well as a knee flexor, abductor and external-rotator (Schache et al., In our previous study (Oleksy et al., \u0141O and AM: study concept and design, data analyses and interpretation, literature search, writing and editing the manuscript. JP and OM: data collection. AS and RK: study concept and design, data interpretation, editing the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Due to their large surface-area-to-volume ratio and enhanced chemical reactivity, nanoparticles have attracted interest among researchers in the upstream petroleum industry for oil recovery applications. Nanoparticles have been studied as additives to waterflooding from day one of production as well as additives at later-stage waterflooding (secondary and tertiary recoveries). Many types of nanoparticles have been tested, and the aims of the nanoparticles have been either to reduce the mobility of the injected fluid relative to that of oil or to increase the ratio of viscous to interfacial forces .Nanomaterials, \u201cApplication of Nanoparticles for Oil Recovery\u201d, includes eight research articles that demonstrate advances in the understanding of the behavior of nanoparticles during fluid flow in porous media and give more knowledge of recovery mechanisms when using nanoparticles in oil recovery. The research works presented here cover core flooding and microfluidic studies of the injection of various nanoparticle suspensions  for enhanced oil recovery (EOR), nanostabilized CO2 foam flooding, investigation of stability of nanosuspensions under various conditions, and mathematical modelling of injection processes of polymer with nanoparticles.The research on nanotechnology for oil recovery has shown potential, but the mechanisms for oil recovery are not fully understood. This Special Issue of Studies on the use of surface-functionalized particles for special reservoir rock and fluid properties and reservoir conditions might be the way forward for understanding the oil recovery mechanisms involved. An article in this Special Issue by Bila and Tors\u00e6ter  investigThe stability of nanoparticles is important for a successful application of nanofluids for enhanced oil recovery. Hadia et al.  studied 2 foam is used to recover oil and in CO2 storage. The behavior of nanoparticle\u2013surfactant foam formulations is not well understood, and the experimental work by Alcorn et al. [Previous research has shown that nanoparticles can increase the stability of surfactant-based foams. Stable foams are especially important in processes where COn et al.  presentsDavarpanah  presentsThe stability of a nanoparticle suspension at reservoir conditions is still creating uncertainty in the evaluation of nanoflooding processes. Li et al.  studied The experimental study by Rueda et al.  showed tAadland et al.  conducteRezaei et al.  investig"}
{"text": "To study urinary pathologies using mouse models, as well as the efficacy of a given treatment or intervention, the voluntary voiding behavior of mice must be addressed. The void spot assay (VSA) is an increasingly common method used in the field that is simple, inexpensive, and noninvasive (Chen et al., The study by Ruetten et al.  seeks toOne of the most challenging aspects of the VSA when performed as an endpoint test is the analysis of overlapping urine spots and the distinction between small voluntary void spots and deposits that result from carryover associated with the tail and paws. Another limitation is the temporal resolution that leads, for example, to the inability to assess whether a small void spot constitutes a voiding event by itself or is the dribbling product after other, larger spot. Then, combining this new approach of analysis to real\u2010time recording of the voiding events using methods such as video monitoring (Hou et al., Overall, Ruetten et al.  describeThe author has declared that no conflict of interest exists."}
{"text": "The main source of arsenic exposure to humans worldwide is the diet, in particular, drinking water, rice, and seafood. Although arsenic is often considered toxic, it can exist in food as more than 300 chemical species with different toxicities. This diversity makes it difficult for food safety and health authorities to regulate arsenic levels in food, which are currently based on a few arsenic species. Of particular interest are arsenolipids, a type of arsenic species widely found in seafood. Emerging evidence indicates that there are risks associated with human exposure to arsenolipids . Still, more research is needed to fully understand the impact of arsenolipid exposure, which requires establishing interdisciplinary collaborations. The reaAlthough arsenic ranked first in the 2019 Substance Priority List , its health effects strongly depend on the dose and toxicity of the arsenic-containing molecules  of exposure.\u22121  only consider iAs . Their existence was first suggested in the early 20th century Sadolin, ; howeveret al., et al., Given their complex chemical structure , researcet al., et al., et al., et al., et al., et al., et al., et al., et al., The use of pure arsenolipid standards is key for the successful characterization of these species. However, their synthesis is not trivial and, while no commercial standard exists, only synthetic routes to a few arsenolipids are available to date . The ability to then traverse the intestinal barrier and reach the bloodstream is referred to as bioavailability, which controls further access to other organs for biotransformations  or bioaccumulation. Both AsFAs and AsHCs can be released from krill oil and seaweed in the stomach (Chavez-Capilla, et al., in vitro and disregarded the potential role of gut microbiota on AsFA and AsHC bioaccessibility and bioavailability.Experiments using an intestinal barrier model found that more than 50% AsHCs and up to 13% AsFAs remain unchanged after intestinal absorption (Meyer et al., et al., et al., et al., Recent research shows that the salivary microbiota can begin transforming dietary methylated arsenic and arsenosugars in the mouth (Calatayud et al., \u22121 were found in their breast milk, where 2\u201361% accounted for AsFAs and AsHCs (Stiboller et al., et al., et al., et al., The bioavailability of AsFAs and AsHCs from food has been demonstrated after detecting them in the breast milk of Norwegian mothers (Stiboller et al., In this regard, a correlation between the maternal gut microbial diversity and the arsenic metabolites in breast milk after fish consumption has been observed and additional work is underway to understand this correlation (Lenters et al., et al., et al., et al., et al., Drosophila melanogaster and tuna fish (Niehoff et al., et al., The significance of these findings is irrefutable and emphasizes the need to further investigate the role of maternal gut microbiota in protecting infants from AsFA and AsHC exposure, and the impact of these arsenic species on newborn health. For instance, emerging evidence supports an association between AsHC exposure and the development of neurodegenerative disorders (Niehoff et al., et al., et al., Toxicological studies using rat brain tissues showed that AsHCs can negatively affect the mechanism underlying learning and memory in infants (Zheng et al., Caenorhabditis elegans as a model organism (Bornhorst et al., et al., et al., et al., et al., In addition, the biotransformations of AsFAs and AsHCs have only been studied using human liver cells (Chavez-Capilla, et al., et al., et al., Nonetheless, the consequences of AsFAs and AsHCs entering the citric acid cycle are not yet understood, as this could deplete cells of the energy required for essential metabolic processes (Meyer et al., While there is evidence on the potential harm of AsFA and AsHC exposure to humans, a more comprehensive risk assessment is still needed for authorities to update the current regulations on arsenic in food. To date, only a few studies estimate the potential health risk of seafood consumption based on the existing evidence on AsHCs (Amin Due to the methodological limitations hindering the proper isolation, synthesis, and analysis of most arsenolipids, current work has only focused on AsFAs and AsHCs, but all other arsenolipid species and their potential toxicity should also be researched. To conduct high-quality research on this field, scientists need pure arsenolipid standards and certified reference materials. Synthesizing new standards is essential to study additional arsenolipid species in isolation and to advance in the development of analytical methods to identify and quantify new arsenolipids in biological samples. Certified reference materials aid in validating analytical methods and ensuring reliable results.in vitro and in vivo experiments are required. Gene manipulation in cell cultures has been used before to elucidate synthetic routes for some arsenic species (Xue et al., To better understand the metabolism of arsenolipids, new Further toxicological and epidemiological studies should also include representative patterns of arsenolipid exposure in different populations and at environmentally relevant concentrations to produce data for health risk assessments. Hence, an interdisciplinary collaboration between organometallic chemists, analytical chemists, gut microbiologists, toxicologists, and epidemiologists is the way forward to successfully unravel arsenolipid transformations in humans."}
{"text": "Affordable, reliable and high-quality child and elderly care services are essential for employees to do teleworking in an efficient manner."}
{"text": "Arbuscular mycorrhizas (AM) are widespread symbiotic associations between 78% of vascular plant species globally (Tedersoo et al., AM development is a conserved process across extant host species with limited morphological variations in the symbiotic structures (Choi et al., The study of fungal accommodation has revealed that host cell rearrangement, calcium-mediated signals and major changes in gene expression extend to neighboring, uncolonized cells (Genre et al., Medicago truncatula on which hyphopodium formation had occurred, supporting the hypothesis that cell divisions determinants are co-opted by the plant cell in preparation of interface compartment construction. More recently, combined microscopy, flow cytometry and gene expression studies have revealed that the activation of cell division- related processes occurs since the early steps of AM development, often at a distance from the colonizing hyphae (Carotenuto et al., Daucus carota expressing a GFP fusion with TPLATE (Russo et al., Several studies had reported an increase in ploidy in mycorrhizal roots of different angiosperms (Berta et al., MtAPC/C subunit 2 (Tarayre et al., MtCCS52A (Cebolla et al., MtVAG1, and MtTOPO-VI B (Bergerat et al., MtHist-H4 (Lepetit et al., Furthermore, taking advantage of the correlation between flow cytometry data and detailed nuclear size measurements through confocal imaging, the precise localization of inner cortical cells with different levels of increased ploidy in the AM colonized areas was achieved (Carotenuto et al., In addition, uncolonized split cells often displayed lower ploidy than their neighboring undivided cells, suggesting that cell division and endoreduplication combine to generate the resulting mixed population of cells with diverse ploidy levels (Carotenuto et al., These observations outlined a previously unpredicted scenario of cell cycle reactivation in response to AM colonization. Attempting to explain the origin and role of these conserved and histologically localized responses, a few additional considerations should be discussed.Firstly, cell divisions in the inner cortex have been observed when intraradical hyphae were limited to epidermal and outer cortical layers but not in later stages; by contrast, as demonstrated by combined flow cytometry and microscopy data, recursive endoreduplication cycles appear to be active for a longer period of time, with arbusculated and neighboring cells reaching levels of 128C ploidy, corresponding to up to 5 cycles of endoreduplication (Carotenuto et al., Secondly, the observation of both cell division and ploidy increase at a distance from arbuscules or colonizing hyphae suggests the existence of a yet unidentified signaling process reactivating the cell cycle before fungal arrival.in situ studies of cell ploidy in uncolonized roots of M. truncatula (Carotenuto et al., In addition, the concentration of both ectopic cell divisions and endocycle events to the inner cortex envisages a remarkable correlation with the accommodation of arbuscules, which normally develop in the same cell layer. Cell proliferation, with its limited occurrence, appears to have a secondary role, if any, in the generation of additional space for arbuscule accommodation. By contrast, the sparse cell divisions observed in AM colonized areas might relate to the developmental fate of cortical cells. In the roots of most plants, in fact, cortical cell differentiation is determined with an endocycle that doubles their DNA content from 2C to 4C (Cebolla et al., Besides tissue differentiation, endoreduplication is also common in plant interactions with diverse microbes: replicating DNA produces multiple copies of each gene, intensifying cell responsiveness to microbial signals. Examples are numerous, from pathogens and parasites (de Almeida Engler and Gheysen, in vivo imaging of GFP-TPLATE fusions revealed a strong accumulation of TPLATE at sites of PPA assembly and at sites of cell-to-cell hyphal passage, where the perifungal membrane fuses with the plasmalemma, in striking analogy with cell plate fusion with the cell membrane at the end of mitosis (Russo et al., The requirement of a specific rearrangement in the host cell organization for arbuscule accommodation is apparent from a simple observation of the structural and functional complexity of the periarbuscular interface (Luginbuehl and Oldroyd, If the recruitment of cell division processes to assemble the extensive periarbuscular interface now appears more convincing, developmental restraints could contribute to explain why sparse cell division and diffuse endoreduplication are limited to the cortex. Dong et al.  have recBy discussing the developmental and evolutionary context where cell cycle processes interweave with AM symbiosis, a scenario emerges  where thde novo a fully functional symbiotic interface\u2014as in modern plants\u2014appears unrealistic. By contrast, stimulating cell divisions in differentiated organs could have been a more amenable strategy to generate both crack openings in the surface tissues (an entry route that is conserved in many extant plant-microbe interactions; Ib\u00e1\u00f1ez et al., We currently have no information on how the earliest land plants acquired the ability to host a symbiotic fungus inside their cells. One can speculate that initial surface interactions provided an advantageous exchange of nutrients, pressing toward more intimate contacts, such as the penetration of fungal hyphae between the plant cells and eventually inside their lumen. In this context, creating Both authors made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
{"text": "Following the publication of the original article (Ajenjo et al. The changes have been highlighted and are shown in Additional file The original article (Ajenjo et al. Additional file 1."}
{"text": "Lactobacillus and Bifidobacterium have been introduced as probiotics and have been consumed throughout the world. Probiotics can regulate the microecological balance of the digestive tract, inhibit the growth and adhesion of pathogenic bacteria, and ameliorate inflammation, thereby supporting a healthy digestive tract. Prebiotics are substrates that are selectively utilized by host microorganisms conferring a health benefit and they can also defense against pathogens and modulate gut microbiota  with or without galacto-oligosaccharides fought against enterotoxigenic Escherichia coli F4 in an early weaned piglet model. Research of Wang Y. et al. showed that dietary Lactobacillus plantarum P8 supplementation improved the growth performance as well as the intestinal health of broilers infected with Eimeria. Wang T et al. and Ast\u00f3 et al. found probiotics had potential application to treat alcoholic liver disease induced by liquor and functional gastrointestinal disorders, respectively. Furthermore, the results from Ke et al. and Buddhasiri et al. showed the effects of probiotics in controlling pathogens infection, such as Cronobacter spp. and Salmonella. Other functions of probiotics have attracted more and more attention, such as the antifungal effect shown by Somashekaraiah et al. More and more researches showed that the marine active substances act beneficial effects on animals' health through the intestine. The modulating effect of astaxanthin on gut microbiota has been reported by Gao et al. in this Research Topic. These studies have expanded our understanding on this Research Topic; however, further studies are still needed to fully elucidate the underlying mechanisms.We received 14 submissions in this Research Topic, and finally seven research articles and one review passed the strict peer review process and were accepted for publication. The studies in this Research Topic show that the function of probiotics occurs mainly in the intestine. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
{"text": "Multiple disorders are associated with a decrease in cerebral extracellular pH, including brain ischemia, seizures, and neurodegenerative diseases like multiple sclerosis (Vergo et al., Frontiers in Cellular Neuroscience (Alijevic et al., A Swiss study from 2+-independent mechanisms (Wang et al., This new study from Kellenberger's laboratory significantly adds to the ASIC field by detailing how ASIC1a reacts to pH changes that last longer than 4 s (Alijevic et al., All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Introduction section, paragraph 3, page 2. References Calzone et al. (In the original article, there were missing citations in the e et al.  and Stace et al.  have nowFor women, sex hormones interact with the mechanisms governing body fluid balance and circulating levels of fluid regulatory hormones are altered by changes in estrogen and progesterone concentration (Stachenfeld et al., The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
{"text": "Dear Editor,We ponder upon the study of Ali M. et al  publisheThe study has some methodological insufficiencies and there was room for improvement assessing the agreement. The de\u2010attenuated correlation usually improves the energy\u2010adjusted agreement between the competing dietary methods (Chen et al., Authors declare no competing interests.SR and NS conceived the idea, SR wrote the first draft; NS, ABT and SI provided feedback and evaluated to finalise. All the authors read and approved the final version."}
{"text": "PLoS Medicine article, entitled \u201cA critical reassessment of the role of mitochondria in tumorigenesis,\u201d Salas et al. [In their et al.  reviewedSDHD subunit gene of mitochondrial complex II (succinate dehydrogenase) in the year 2000 [SDHB,SDHC, andSDHD subunit genes in hundreds of index cases and families with hereditary and sporadic paragangliomas and pheochromocytomas [The causal link between mitochondrial abnormalities and tumorigenesis was provided by the positional cloning of the hereditary paraganglioma gene at chromosome band 11q23 as thecytomas .Although it is clear that Salas et al. question specifically the mutations in mtDNA of tumors, they did not acknowledge the causal link between mitochondria and cancer provided by the discovery of nuclear-encoded mitochondrial gene mutations. This is especially important because, in their unfortunate title and in their conclusion, the authors seem to make a sweeping statement against the role of mitochondria in cancer. It is essential to emphasize to readers that it is the mtDNA, but not mitochondria, which has a questionable role in tumorigenesis."}
{"text": "I do not like it at all to 10 = I like it a lot) for old and new excerpts.Implicit emotional memory refers to unconscious retrieval of past emotional experiences  and a series of neural networks  that show age-related differences (from newborns to older adults, e.g., Perani et al., In sum, while Narme et al.'s data are some of the first to focus on implicit emotional memory in aging, it has to be acknowledged that the study of emotional memory-music interaction is complex. For example, a familiarity and fluency-based interpretation of the interaction between implicit memory and emotion cannot be ignored. In addition, controlling for explicit contamination (e.g., Fairfield et al., The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Obsessive Compulsive Disorder (OCD) is a debilitating psychiatric disorder characterized by intrusive, negative thoughts (obsessions) and repetitive behaviors (compulsions).A puzzling feature of OCD is the inability of patients to utilize external information to terminate obsessional thinking. Recently, Stern et al.  suggesteIn this commentary, we expand on the study of Stern et al. , discussStern et al.  examinedGiven the authors' conclusion, the number of target detection task errors within the patient group should be greatest in the internally focused conditions; this, however, is not supported by Figure 2 , they exhibited more OCD-like behaviors than participants who were prompted to have low perceived responsibility  (Lopatka and Rachman, To investigate the physiology of attentional switching in OCD, Stern et al.  studied This finding is interesting in light of a hypothesis proposed by Gon\u00e7alves et al.  that sugsafety cue?The findings of Stern et al.  have proAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Here, wet al. are associated with a particular interpretation of our language. While our original paper emphasized the importance of precision of language, for reasons of brevity, we are not able to engage with all such criticisms here and do not feel it is productive to get into a prolonged debate about how we or they may have phrased things better. We will simply state that where we offered a critique of their tone or interpretation, we did so having carefully read their research, corresponded with co-workers about it, and then raised specific concerns about how it could be perceived. We remain willing to clarify our concerns in correspondence should the authors wish.Many of the issues raised by Brown et al. were concerned over our criticism of their statement that \u2018burning is considered particularly detrimental to peat-forming Sphagnum species'. As they acknowledge in their comment, there was a single reference provided in their review paper with regard to Sphagnum sensitivity to managed fires [et al. [Sphagnum [Sphagnum biomass could be lost. However, during management fires, this is unlikely owing to Sphagnum's very high moisture content. Smouldering combustion might occur during severe fires in periods of drought. Although there is palaeoecological data that provides circumstantial evidence that some Sphagnum species may be sensitive to land-use intensification and burning [Sphagnum can regenerate following burning [Sphagnum in general and severe wildfire effects should not be confounded with the outcomes of prescribed burns. It remains unclear why a managed (thus low severity) fire should be particularly detrimental to Sphagnum, because it has the ability to regenerate from stems many centimetres below the capitulum [et al. will understand that our concern was that they were propagating a highly generalized supposition  which remains largely unsupported in the scientific literature.Brown ed fires . We refe [et al.  for theiSphagnum  reveals Sphagnum \u201310. Burn burning ,12, ther burning ,14 and t burning . There iapitulum  and fireapitulum . We hopeet al. criticize us for disagreeing with their concerns about the controllability of prescribed fires, in particular the potential for combustion of moss and litter layers. It would obviously be ludicrous to state that consumption of such layers is physically impossible. Rather, we pointed out that available experimental evidence suggests that this can be minimized by burning under appropriate fuel moisture conditions [Brown nditions . We alsonditions  for furtRegarding our critique of the release, and press coverage, of the non-peer-reviewed EMBER report , we acknet al. and Douglas et al., we clearly stated that the participants were a mixture of senior  undergraduates and graduate students studying ecosystem restoration. Undergraduate students were predominantly majors in environmental science or forestry, fisheries and wildlife. We did not collect data on the participants' gender, nor did we collect data on their race, age, marital status, sexual orientation or socio-economic background. Readers were assigned to random groups and were asked to reach a consensus which they reported for the group as a whole. This approach does not lend itself to formal statistical analysis but is a legitimate qualitative approach to a socio-scientific question [With regard to criticism of our perception study by Brown question . Our repet al. criticize us for inconsistency in our description of the seasonal distribution of wildfires in the UK. We are happy to clarify any misunderstanding. If readers examine the reference in question [Douglas question  they wilet al.'s interpretation of their MODIS data [et al. [et al. [A number of the authors here have previously outlined their concerns regarding Douglas DIS data  and why  [et al.  on this  [et al. ,24. We w [et al.  reportedet al. [et al. [et al. have at their disposal an extremely valuable dataset that could be used to interpret variation in fire regimes. We would encourage them to consider Romme [With regard to our estimation of fire rotations, criticized in Douglas et al. , we clea [et al.  to make  [et al. ) and anner Romme  and we let al. are correct that there is growing pressure being placed on the use of managed burning by water companies (for instance burn bans on the significant areas of peatland they own) owing to concern regarding dissolved organic carbon, DOC). As we outlined in our paper, there is currently no clear consensus that existing evidence suggests managed burning alone drives increased DOC concentrations or has negative consequences for C storage . Many existing studies suffer from complexities introduced by interacting disturbances, including fire, grazing and drainage. We demonstrated that assessments of habitat condition are overly simplistic and do not account for the ecological role of fire in peatlands. Douglas et al. advocate a precautionary response to these challenges; this might be appropriate in some locations where services such as drinking water are of critical importance. Given existing uncertainty there is no guarantee that such changes will provide the desired benefits. A passive Adaptive Management approach [status quo associated with grouse moor management  is appropriate everywhere either. We would point out that wildfire control and fuel reduction treatments may be important in areas where burning ceases. Although this requires further study, the results reported in Allen et al. [Our paper outlined why we believe that wholesale changes in management should be considered carefully as we currently have little evidence of what the environmental consequences of actions such as the total cessation of burning would be. Douglas approach  is theren et al.  highlighet al. suggest we have added to the partisan tone of the debate. We are content that our paper has instead rebalanced the conversation regarding peatland fire management and subjected it to a rigorous assessment from the perspective of fire ecology. Specific criticisms we have made while demonstrating our points should be kept in perspective\u2014science proceeds by debate and the formulation of questions or hypotheses, followed by evidence gathering to address the questions and then further debate. The complex questions associated with the effects of fire in peatlands are best addressed by appreciating perspectives and expertise from a range of different disciplines. We hope Brown et al. and Douglas et al. will be willing to reflect on and appreciate ours. We retain admiration for much of their work aside from our disagreements here.In their conclusion, Brown"}
{"text": "Over 30 authors contributed 15 articles toward this research topic. Collectively this body of work represents a bridge between music informatics and music cognition, covering a broad range of research topics.Research addressing problems or needs fundamental to one domain but borrowing methods, approaches, and/or insights from the other domain.Research addressing problems or needs common to both domains and borrowing methods and insights from either of the two domains.Research addressing problems or needs of one domain with strong implications for the other domain.We can categorize these fifteen articles into one of the following groups or a combination of them, since the groups are not mutually exclusive:Baker and M\u00fcllensiefen; Barone et al.; Casey; Foubert et al.; Kim; McAdams et al.; McFee et al.; Siedenburg and M\u00fcllensiefen; Stober; van der Weij et al.; Vempala and Russo). Two articles   explore issues that fall mainly within the space of music informatics, while the two remaining articles   explore areas with research motivations relevant to both music cognition and music informatics. This cursory analysis might suggest that only limited interactions between these domains exist. With the majority of interactions biased toward music cognition, one might argue that this fragile new bridge is at risk of collapse!Eleven articles  attempt to elucidate underlying mental processes related to music. These articles may be thought of as predominantly aligned with music cognition  use feature extraction methods hailing from music informatics. In other words, the dependence of these studies on music informatics should not be understated. Additionally, most of these eleven articles have moderate to strong implications for music informatics. Likewise, the two articles that fall predominantly within music informatics, have implications for music cognition.However, a closer examination of the articles reveals a richer and balanced network of interactions. Of the eleven articles that are predominantly aligned with music cognition, no less than six (Since all the articles present research in more than one key area within music informatics and music cognition, they may be thought of as forming dynamic clusters that may be characterized differently depending on one's vantage point. The key areas driving these clusters include but are not limited to: statistical and computational modeling, machine learning, music and emotion, musical preference and engagement, rhythm and meter perception, musical timbre and instrument identification, music similarity, music representation, structural segmentation, implied harmony, music therapy, and big data analysis.Baker and M\u00fcllensiefen, Kim, McAdams et al., van der Weij et al., Vempala and Russo, use computational modeling as a means to explain or interpret behaviors associated with music cognition. van der Weij et al. use a probabilistic model of meter expectation to explain the effects of enculturation. But their model is generative and borrows techniques from machine learning, thus bridging into music informatics. Both McAdams et al. and Vempala and Russo explore music and emotion. While McAdams et al. examine perceived emotion based on the acoustic properties of timbre, Vempala and Russo explore higher-level emotion judgments through a classic cognitive modeling framework using machine learning methods. Baker and M\u00fcllensiefen look at how similarity in compositional structure affects salience and recognition, specifically through the use of Wagner's leitmotives. Among all the computational modeling studies, Kim's gradient frequency neural network for estimating implied harmony, is the only biologically inspired low-level computational model consisting of tonotopically tuned nonlinear oscillators.Stober and Casey present findings on music representation as assessed by neural activity\u2014a topic that intersects music cognition, music information retrieval, and cognitive neuroscience. Stober explores music imagery information retrieval through EEG recordings whereas Casey examines neural representation of music in naturalistic listening conditions through fMRI. Both studies strongly depend on machine learning and deep learning methods. Stober's work also highlights the need for sharing open datasets. Open science is a practice common to music informatics and one that is fast gaining ground in music cognition. This approach promotes collaborative research endeavors and encourages replicability of research findings.Both Siedenburg and M\u00fcllensiefen focus on music similarity judgments, Thoret et al. look at timbre and the modulation power spectrum as feature sources for musical instrument identification. Thoret et al.'s work is similar to, McAdams et al. since both inspect the role of timbre in music perception. However, given the importance of automatic source recognition in music informatics, it can be argued that Thoret et al.'s work on instrument identification is more closely aligned with music informatics than music cognition.Several studies in this topic address the importance of timbre in music. While Barone et al., Kaneshiro et al., and Janssen et al. emphasize the role of corpus analysis methods in music informatics and music cognition. Janssen et al. uses a folk music corpus to study the relationship between musical memory and melodic variation with pattern matching\u2014research that is more traditionally aligned with music cognition but has clear implications for music informatics. Barone et al. and Kaneshiro et al. focus on the analysis of big data - an area that has become especially relevant since the advent of cloud storage and high performance computing resources. Barone et al. examine statistical regularities in music download patterns of listeners. Specifically, they look at genre and emotion preference using acoustic features. Their work serves as yet another example of research problems fundamental to music cognition using methods borrowed from music informatics.Kaneshiro et al. also explore musical behavior of listeners at scale. They study the types of musical events within a piece of music that lead to enhanced engagement of the listener. Despite addressing issues related to perception and preference in music cognition, their work adheres more to music informatics because of its application areas comprising music discovery, multimedia search, and musical engagement.McFee et al.'s work focuses on the analysis of musical structure, and its role in hierarchical music segmentation by annotators. They present ways to overcome limitations during the occurrence of inter-annotator disagreements because of ambiguous musical structure. Segmentation algorithms are an active area of music informatics while perception of musical structure is also integral to music cognition. As such, this research falls well within the scope of both music informatics and music cognition.Foubert et al.'s article stands out as the only article with application in music therapy. Their research is based on the hypothesis that abnormal timing deviations during musical improvisation can be used as predictors of interpersonal relationship instability\u2014a characteristic of borderline personality disorder. A statistical model motivated from music cognition, with rhythm and tempo-based pattern matching features borrowed from music informatics, is used to diagnose patients with borderline personality disorder.Krumhansl's article presents the results of an extensive survey on the contexts in which people heard popular music in their lifetimes, and how they developed their preferences for music. The survey shows several interesting results about the progression of music listening across the life span of different participants. The results also provide more insights and context about different effects such as generational effects, song specific age effect, decade effect, influence of emotion on memory and preference, among others. This study has relevance for music informatics in particular, and for the music industry more generally.Given the breadth of research occurring at the intersection of music informatics and music cognition, these 15 articles represent a small sampling. Nonetheless, through their range and diversity of topics, these articles give us a sense of the nature and scope of research at this intersection. Hence, we can safely conclude that, far from risk of collapse, the bridge between music informatics and music cognition is built on solid foundations. The diversity of interactions explored in this topic suggests that this bridge is sustainable and that it will continue to support fruitful activity for decades to come.NV was responsible for writing. FR was responsible for writing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Such a possibility may be considered a remote prospect by majority of virologists because of the prevailing perspective that positive strand RNA viruses do not need to synthesize DNA to complete their life cycle neither do they have any reverse transcriptase to generate a complementary DNA. Since there seems to be no chance of reverse transcription , it becomes easy to infer that a DNA stage (i) does not exist and (ii) is not functionally important. We argue that these inferences are not true. The current paradigm is that DNA transcribed from the RNA of these viruses does not exist in the host genome; and it requires a robust evidence of POSTRAITE to refute this generally held belief. In this paper we will demonstrate that such affirmation already exists.Scientific literature is filled with papers that don't even consider the possibility of RNA to DNA synthesis in these viruses and their host genome integration. But we propose that there is a genuine likelihood despite the absence of reverse transcriptase and integrase in their genomes. In order to give a scientific basis to this apparently radical proposition, we need to establish atleast one obligatory and one supportive postulate viz. (i) experimental evidence of a positive strand RNA viral genome (devoid of reverse transcriptase and integrase) integration into host genome (obligatory) and (ii) speculation of possible function/s such an integration may serve the virus (supportive). If, there is evidence of the virus antigens being found in the nuclei of the host cells, our proposition may imbibe further strength. The mechanism of host genome integration, in principle, can be true with many other diseases where the viral genome has sequence based similarities to certain regions of the host genome. This conceptual model is coherent and may pave way to deciphering mechanisms of many complex viral diseases (in addition to Zika virus mediated brain defects). But for such a mechanism to be true, POSTRAITE needs to be a biological verity. Establishing the likelihood of such a biological reality is the basic aim of the present paper and can be achieved by finding satisfactory answers for the above mentioned obligatory and supporting postulates.Aedes mosquito genomes) by Suzuki et al.  have not been reported to reverse transcribe into cDNA. As an example of Zika virus, an RNA polymerase on the NS5 subunit of the Zika virus polyprotein has been indicated for viral genome replication (RNA-dependent-RNA polymerase activity), without the involvement of reverse transcriptase (Godoy et al., i et al. . Their fi et al. . This inIn an interesting study, Klenerman et al.  reportedRNAs are relatively unstable molecules; for that reason the genomes of RNA viruses are susceptible to various host cell mechanisms aimed at exonucleolytic mRNA decay/destruction (Moon et al., Though the complete lifecycle of positive strand RNA viruses is thought to be exclusively cytoplasmic, their presence in the host cell nuclei have, nevertheless, been documented (Buckley and Gould, Though the supposition of positive strand RNA virus genome integration to host genome is currently considered improbable but this phenomenon is, nevertheless, a reality and has already been reported. This concept has a lot of information to offer from safety concerns of RNA based gene therapies to viral etiology of previously thought non-infectious diseases. The etiobiology of neurodegenerative disease may further be understood under this umbrella (Li et al., MF and AK: conceived the idea, wrote the manuscript, and revised the manuscript; HS, VP, and PK: wrote and revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Miyagami et al.  evaluateConsidering the predictive performance of hyperuricemia on several lifestyle-related diseases is an optimistic interpretation. The internal and external validation of the prediction model must be done through bootstrapping and split-validation, respectively .We studied the article written by Miyagami et al.  that pubTherefore, according to the above explanation, it is necessary considering to this point in interpretation of results of this study for readers."}
{"text": "Niu et al.; Ranjbaran and Galiana; Pearson et al.; Sharif Razavian et al.; Malik et al.), elucidate control theories , shed light on systemic mechanisms , suggest testable hypothesis , and aid design of rehabilitation or therapeutic strategies . The 14 articles reflected these different aspects of computational modeling in bridging this gap between functions of neural circuits and observable behaviors. This research topic demonstrated that computational modeling is playing a more and more prominent role in sensorimotor control studies.There exists a gap from experimental data to the understanding of neural control of movements. This research topic was dedicated to promote computational modeling approach that can facilitate data interpretation . This approach has evolved from a \u201cblack-box\u201d type of modeling to building biologically and neurophysiologically realistic, multi-scale models. The success of the latter approach hinges on the assumption that the models represent the underlying computations of neural signal processing in central sensorimotor system.Lan and He), or to propose new testable hypotheses , and investigated a viable switching strategy for the timing of nystagmus. Simulation results replicated experimental data well in all conditions. Li et al. used a corticospinal, virtual-arm model to investigate the central coordination of alpha and gamma controls to muscles and their muscle spindles for movement generation. Simulation results indicated that simple patterns of alpha and gamma drives are sufficient to control a range of movements, and that propriospinal neurons  of the pedunculopontine tegmental nucleus (PPTg) in a Parkinsonian monkey. This model predicted how different DBS stimulation parameters produced different activations of the nerve fibers surrounding the PPTg.An important motivator of computational modeling is the potential use of this body of knowledge to design new, efficacious interventions for treating movement disorders  and The Ministry of Science and Technology of China (No. 2011CB013304). VC is supported by startup funds from The Chinese University of Hong Kong.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Research gaps in understanding flood changes at the catchment scale caused by changes in forest management, agricultural practices, artificial drainage, and terracing are identified. Potential strategies in addressing these gaps are proposed, such as complex systems approaches to link processes across time scales, long\u2010term experiments on physical\u2010chemical\u2010biological process interactions, and a focus on connectivity and patterns across spatial scales. It is suggested that these strategies will stimulate new research that coherently addresses the issues across hydrology, soil and agricultural sciences, forest engineering, forest ecology, and geomorphology. Land use change impacts on floods are poorly understood at the catchment scaleNumerous synergies are identified in exploring the effects of changed agricultural practices, artif. drainage, terracing, and forest coverA cross\u2010disciplinary systems approach aided by long\u2010term field studies and a focus on flow connectivity are needed to make major advances Large areas have been deforested or drained, thus either increasing or decreasing antecedent soil moisture and triggering erosion. Hillslopes were modified for agricultural production, thus changing flow paths, flow velocities, and water storage, and consequently flow connectivity and concentration times. The intensification of agricultural practices has resulted in the formation of platy dense soil horizons with preferential lateral flow which may reduce and/or retard vertical infiltration in the soils, but cause an intensification of lateral mass flow besides the reduced filter and buffer processes in deeper soil horizons. It is likely that hydrologically significant changes will continue in the next decades due to loss of agricultural land and forests [Gupta et al. [Alila et al. [Studies that examine the impact of land use changes on streamflow and floods often obtain contradictory results for the same kind of change. Although results from individual studies are legitimate, it is difficult to obtain general statements on the impacts since each study takes a rather narrow and study specific perspective. Some recent publications such as the paper of a et al.  on the ra et al.  about thHollis, In this commentary, the main research gaps concerning the impact of land use change on floods are identified, and strategies for addressing them are proposed. The focus of this paper is on the role of agricultural practices, drainage, terracing, and forest change. The impacts of land use change due to urbanization are also important, but are not further considered in this paper, because processes related to urbanization [e.g., 22.1Gaal et al., Brown et al., Zink et al., Wilson et al., Floods are the outcome of coupled processes with widely diverging time scales [Acreman and Holden, Nicolis and Nicolis, Sivapalan and Bl\u00f6schl, Cerd\u00e0 et al., The time scales involved in the process interactions may range from event to seasonal to centennial scales. For example, drainage of peatlands may initially result in lower water tables and an increase in water storage capacity. However, oxidation of peat triggered by lower water tables results in loss of peat thickness over time, which then reduces the storage capacity. The short\u2010term response to drainage may therefore be different from the long\u2010term response which is more strongly affected by feedbacks [2.2Dooge [O'Connell et al., Spatial scales are equally important as time scales when attempting to understand land use change impacts on floods. Below we are referring to three different spatial scales following Dooge , 1986: tBl\u00f6schl et al., Western et al., Van Dijk et al., Fraser et al., Band et al., Pfister et al., Gucinski et al., Guzman et al., Silgram et al., Band et al., Holden, While, in the past, the emphasis of upscaling has usually been on understanding random spatial variability, the spatial connectivity of flow processes is now increasingly recognized as a key determinant of land use change effects [Bl\u00f6schl et al., Bathurst et al., Owing to the spatial variability of flow processes, land use change effects on floods vary with the catchment scale. The impact of land use changes usually decreases with increasing catchment area for a finite size of the disturbance [Viglione et al., Hess et al., Robinson, King et al., Brown et al., O'Connell et al., Bradshaw et al., As the catchment scale increases, it becomes more difficult to identify any land use change effects on floods from observed discharge data due to multiple controlling factors and process interactions [Against the backdrop of the issues of scale and scaling, below the most important research gaps for each of the land use change types are discussed.33.1Gaillard et al., 6 km2 of forest was lost in the years 2000\u20132012 and 0.8 \u00d7 106 km2 of new forest was gained [Hansen et al., Messier et al., Teuffel et al., Since the Neolithic age, forests have been lost to cropland and grassland at large scales [Brown et al., Andr\u00e9assian, Brown et al., Bathurst et al., Alila et al., The effects of forest cover on the flood regime are ambiguous. Experimental studies show that forest cover, compared to grassland, may reduce average catchment discharge as a result of (i) increased rainfall interception, (ii) increased transpiration, (iii) reduced soil moisture, and (vi) increased permeability of soils [e.g., Vose et al., Bernsteinov\u00e1 et al., Rawlins et al., Evaristo et al., Effects of forest change that are more indirect include increased surface runoff on forest roads and increased soil erosion and the development of gullies after deforestation which both may enhance floods in steep terrain [e.g., Vieira et al., While it is clear that the soil structure responds slowly to deforestation, afforestation, and reforestation, the exact time scales related to such changes and their controls are not well understood. It is necessary to understand better how fast preferential flow pathways in the subsurface evolve, but there is currently a lack of simple methods for quantifying these flow pathways in the field. Another open question is how forest management activities, affecting the age and composition of the forest, translate into changes in soil structure and consequently soil moisture. Clearly, soil moisture affects flow paths, including the type of runoff generation mechanism (overland flow versus subsurface stormflow), but more research in experimental catchments is needed to better understand the impacts on flood generation and on the frequency and magnitude of floods. Finally, forest fires and waxy leaf litter may lead to hydrophobic soil surfaces [3.22 of agricultural land is affected by soil deformation (including compaction and shearing), mostly because of poor agricultural practices such as using heavy machinery [Batey, D\u00f6rner and Horn, Zink et al., Alaoui et al., Iversen et al., Holman et al., Deasy et al., Schwen et al., Gieska et al., Fraser et al., Zumr et al., Potter, Band et al., Alaoui and Goetz, Globally, about 680,000 kmy Batey, . Plot\u2010scLeitinger et al., Hartge and Horn, Peng and Horn, Kellner and Hubbart, The response of soils to varying agricultural practices is a multiscale process. While soil deformation leads to immediate changes of soil properties [e.g., 3.32 of land have been drained globally [Framji et al., Fohrer et al., Tiemeyer et al., Duncan et al., Changnon et al., Zucker and Brown, Blann et al., Rycroft and Robinson, Acreman and Holden, Rahman et al., Holden et al., Over the past century, around 2,000,000 km3.4Dotterweich, Gallart et al., Dagnew et al., Gallart et al., Agnoletti et al., Agnoletti, Dudal, Romero\u2010D\u00edaz et al., Although no reliable global inventory is readily available, the construction of terraces has been widespread throughout the world for millennia to facilitate cultivation, harvesting, and irrigation, reduce soil erosion, and increase soil storage capacity [4Understanding the impacts of land use change on flood generation across different space and time scales requires a new research thrust. Even though the research questions in the land use change categories discussed here are quite diverse, common threads emerge. Systems thinking to link processes across time scales, controlled long\u2010term field experiments at the plot scale, a focus on connectivity and spatial patterns, and organizing a coherent research theme within and across disciplines are believed to be the pillars of progress in this area.4.1Pires and Perdig\u00e3o, Perdig\u00e3o and Bl\u00f6schl, Harte, The seemingly overwhelming complexity of land use change effects as evidenced by the diverse and often contradictory research results published in the literature may perhaps be best addressed by adopting a broader perspective of system approaches that explicitly quantify the interactions of processes across multiple spatiotemporal scales, drawing methodological inspiration from nonlinear geophysics [4.2Holl\u00e4nder et al., Zacharias et al., There is a long history of plot\u2010scale experiments in soil and agricultural sciences, paired catchment studies in forest science, and short\u2010term field experiments and long\u2010term catchment monitoring in hydrology and geomorphology. These different strands of research need to be better integrated in order to test hypotheses on land use change effects on floods, assisted by system models. A number of factors will be central to the integration: (i) Long\u2010term observations of variables that are directly relevant for understanding land use change effects are needed, such as the joint mechanical and hydraulic properties of soils as a function of agricultural activities, or changes in the efficiency of drainage pipes. Tailored field experiments, such as lysimeters and measurements of surface runoff on sloping (and convergent) ground would be part of the monitoring setup. (ii) Catchment\u2010scale studies (including paired catchments) should not only address afforestation/deforestation but also other land use changes . (iii) Similar to system models, a focus on memory effects  is needed, facilitated by long\u2010term observations of, for example, change in soil structure and decay of terraces. (iv) Confounding factors may mask the land use change effects. If possible, controlled and/or known boundary conditions should therefore be established in order to enhance the comparability and repeatability of individual studies. Globally, there is a strong effort being made in a number of environmental disciplines toward multivariable long\u2010term observations, such as in ecology and critical zone research, and a similar trend can be observed in hydrology [4.3Spatial\u2010scale issues from the plot to the catchment scale have been the main barrier to progress in identifying causal relationships between land use change and floods. It is believed that major progress can come through adopting connectivity of flow paths and their spatial patterns as unifying themes in identifying causal mechanisms. While the local inputs will differ, depending on the type of land use change and hydrological context, similarities in the aggregation behavior along the flow paths may suggest similarities in the effects of soil compaction, drainage, terracing, and forest change. Connectivity should be treated as a dynamic rather than a static characteristic of catchments, implying that not only flow connectivity at the flood event scale is of interest but also how it evolves over time, e.g., due to soil physical processes, erosion and decaying drainage systems. Five steps are envisaged in the analysis: (i) Characterization of flow connectivity at different spatial scales with a focus on the dynamic response of soils and land cover to extreme precipitation events, patterns of infiltration capacity and surface runoff. High\u2010resolution remote sensing methods such as Lidar or ground penetrating radar, and terrestrial methods such as distributed temperature sensing, may assist in characterizing the connectivity structure and the flow paths. (ii) Developing macroscale conceptualizations of flow resistance (both on the surface and in the subsurface) that represent the effective behavior of small\u2010scale land use related features  not explicitly resolved at the scale of catchment models. (iii) Quantifying the effects of land use changes on connectivity, and identifying the factors controlling the importance of the location of the disturbance relative to the topography and the catchment outlet, based on modeling and field studies. This may lead to inferential relationships of how land use changes modify the spatial organization of the flow paths. (iv) Analyzing the effect of changes in connectivity on changes in floods, again based on modeling and field studies. (v) Deriving scaling relationships or parameterizations to upscale local\u2010scale land use change impacts to the catchment scale, as a function of flow connectivity and flow dimensionality .4.4Bl\u00f6schl et al., Mutema et al., Koutsoyiannis et al., Montanari et al., As, ultimately, one would like to understand the generic principles underlying flood response to land use changes rather than those of one particular catchment, it is essential to generalize the findings obtained locally. Generalization can move along a number of complementary avenues. (i) A typology could be developed to assist in the synthesis in terms of types of land use changes , runoff generation mechanisms, and other hydrological characteristics such as soils, vegetation, topography, landscape type, and climate. A common framework for organizing the results, including criteria of similarity, will need to be implemented for such an analysis. (ii) For all land use change categories, a meta\u2010analysis of reported studies would be useful to synthesize the findings from the existing literature. This analysis could also be used to rank the studies by the magnitudes of their impact which would assist in identifying worst\u2010case scenarios of land use change impacts on flood generation, and it could form the basis for a data\u2010based regionalization of land use change impacts on floods as a function of scale. There are some attempts of meta\u2010analyses in hydrology [e.g., 5Perdig\u00e3o and Bl\u00f6schl, As humankind is witnessing increasing floods in many places around the world there is an urgent need to better understand one of the critical drivers of flood regime changes. Numerous synergies have been identified here in addressing research gaps of understanding the effects of changes in agricultural practices, drainage, terracing, and forest management on floods. Clearly, there is a need to fully exploit the experience gained in the past in diverse fields such as hydrology, soil and agricultural sciences, forest science, and geomorphology, and come up with a coherent research thrust. The most promising progress is expected through four avenues: (i) Complex system approaches to the coevolution of the landscape structure at varying time scales ["}
{"text": "Various factors such as perception of social support, expectations of life, healthy behaviors and outlooks, religious conviction may affect quality of life in dialysis patients.et al., titled \u201cfactors associated with the quality of life of adults subjected to hemodialysis in a city in northeast Brazil\u201d have been completely observed by authors.The authors declared no competing interests.No funding from any source."}
{"text": "Switching between two tasks impairs human performance\u2014resulting in what is known as task-switching costs (TSCs): Human participants perform more slowly and are more error-prone in switch trials compared to repeat trials (Vandierendonck et al., Meier et al.  put forwTo address this issue, Meier et al.  conducteThere is a problem with the deductive reasoning by Meier et al. . StudiesApplying the same reasoning as Meier et al.  to the rAnother possibility is that human participants can eliminate distractions by focussing on single tasks when switching between different tasks (Stoet and Snyder, Meier et al.  made a vAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The term \u2018metabolome\u2019 was introduced to the scientific literature in September 1998.To mark its 18-year-old \u2018coming of age\u2019, two of the co-authors of that paper review the genesis of metabolomics, whence it has come and where it may be going. Escherichia coli and yeasts (Saccharomyces cerevisiae and Schizosaccharomyces pombe) RNA molecules in a cell, tissue, or organ) had the twin advantages of being most closely related to genomics and that it could be pursued using similar techniques\u2014either by hybridisation of complementary nucleic acid strands or cDNA sequencing. Like the other functional\u2019omes the transcriptome is context-dependent\u2014it changes with the changing physiological, pathological, or developmental state of the cell. For yeast cells, the relationship between the genome and transcriptome is approximately one-to-one; introns and, therefore, differential splicing of mRNAs are rare in yeast  and those of Kevin Brindle (in Cambridge) and Hans Westerhoff/Karel van Dam (in Amsterdam). The idea was that we should be able to elucidate the role of genes of unknown function by comparing the metabolomes of their deletion mutants with those of the deletion mutants of genes of known function. This concept, often called \u201cguilt by association\u201d Oliver , and a sHowever, the most important outcome of this study was that metabolomics was rapidly embraced across the biological research community, and especially by plant biologists Fiehn  despite In a 2004 review Kell , and itsConsequently, the space available does not permit us to be even faintly comprehensive about the development of metabolomics\u2014the papers in this journal provide an excellent starting point\u2014but the massive improvement in mass spectrometric and chromatographic methods is clearly a huge driver (Dettmer et al. The importance of metabolomics databases (Haug et al. 13C labelling for measuring fluxes (Zamboni et al. An important trend is the use of \u201cIt has been said that we always overestimate what we can do in two years and underestimate what we can do in twenty.\u201dP. Ball & L. Garwin (Ball and Garwin Given the above caveat, we do not seek to be overly predictive, but some trends are obvious. The improvement in sample scale (with (Dunn et al. Another trend will be further automation of instrument tuning (Bradbury et al. At least as judged by their appearance in the literature, some enzymes in a given organism are much more greatly studied than are others, a phenomenon referred to as \u2018publication asymmetry\u2019 (C\u00e9sar-Razquin et al. Biological studies will be much aided by the ability to manipulate genomes at will. Henrik Kacser, as a major part of his motivation for developing MCA in the first place, had long ago explained why much more sensitive analyses are possible with haploids than with diploids (Kacser and Burns The original paper (Oliver et al."}
{"text": "In the original article Zhu et al.  was not C. hutchinsonii chromosomal DNA with the primers 3198upF/3198upR, and 3198downF/3198downR, respectively, and ligated into the pYT313 plasmid (Zhu et al., To generate the pYT3198 plasmid, two DNA fragments corresponding to approximately 2 kb of chu_3198 up- and downstream regions were amplified from The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Moreover, convincing concentration-response relationships were obtained and metabolite patterns could be associated with specific mechanisms of toxicity, such as peroxisome proliferation and liver enzyme induction or inhibition (Ramirez et al., 2017[in vitro hepatotoxicity prediction. Limitations are that the HepG2 cells show major metabolic differences compared to human hepatocytes. Moreover, the present study did not yet include a systematic comparison of negative and positive controls at in vivo relevant concentrations, which remains a challenge for the future. Hepatotoxicity is one of the most frequent forms of systemic toxicity of drugs and a leading cause for drug withdrawal from the market. To improve the possibilities to predict hepatotoxicity, Tzutzuy Ramirez and colleagues from BASF in Ludwigshafen recently tested a metabolomics based Currently, mechanisms of hepatotoxicity represent a major focus in toxicological research (Kyriakides et al., 2016; Ghallab"}
{"text": "E. coli lab strain (note this is only about 25% of the known E. coli TAs) and presented results that indicate that the resulting \u039410 strain was strongly affected for persistence upon treatment with ciprofloxacin or ampicillin  and polyphosphate (polyP) (Maisonneuve et al., In a recent paper published in Frontiers in Microbiology, Ramisetty et al.  questionparE toxin expression might have generated multiple genomic rearrangements and therefore lead to a fitness decrease.While Ramisetty et al. actually confirmed that the \u039410 strain is less persistent than the wild-type strain when treated with ciprofloxacin or ampicillin (Ramisetty et al., lon, \u0394relA\u0394spoT, and \u0394ppk mutants were not affected (Shan et al., lon mutant (Theodore et al., lon strain was strongly affected but the decrease in persistence was solely dependent on SulA, a SOS cell division inhibitor and Lon substrate, since the double \u0394lon\u0394sulA mutant presents similar persister frequency to that of the wild-type strain (Theodore et al., Other groups investigated the implication of the 10 TAs as well as that of Lon, ppGpp, and polyP in persistence to various classes of antibiotics. While the \u039410 strain was less persistent upon gentamycin treatment (contrary to what is reported in Ramisetty et al., yefM-yoeB TAs appears to be the only system producing mRNA cleavage (Christensen et al., ppk-ppx strain, thereby confirming that polyP is not required to activate the yefM-yoeB system (Ramisetty et al., in vitro, polyP deactivates Lon rather than activating it (Osbourne et al., This body of data from different groups casts serious doubts about the polyP-dependent TAs regulation model. Strikingly, this model implies that the Lon protease degrades the antitoxins of interest in a polyP-dependent manner and at comparable rates. While most antitoxins appear to be indeed susceptible to Lon (Christensen et al., Still regarding antitoxin degradation, surprising discrepancies between papers of Maisonneuve et al. , 2013 anAs a conclusion, the link between the stringent response, endoribonuclease encoding type II toxin-antitoxin systems and persistence appears to be weak. Type II endoribonucleases toxins and ppGpp are clearly not the only players for generating persister cells. Multiple reports indicate that other molecular mechanisms are involved in persister cell formation such as type II toxins with cell wall synthesis inhibition activity or type I toxins as well as the SOS response (Lioy et al., Knowing that TAs are very diverse and abundant in prokaryotic genomes, that they are part of the accessory genome and they move by horizontal gene transfer (Anantharaman and Aravind, All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Jack et al.  argue thJack et al. obtain the key result on the basis of study 8 in their paper, which uses a large sample of responses to questionnaire-based measures of empathizing, religious belief, religious practice, and socially desirable responding. Using the Crowne-Marlowe  and through the denial measure of desirability .While the additional result goes beyond the focus on religious belief that Jack et al. have, it does help to locate their study in the broader discussion of the relationship between religiosity and prosociality. In a recent review of this literature, Shariff  argues tShariff thinks that the difference between self-reported and behavioral measures is at least in part due to \u201ca tendency for the religious to be higher in impression management and self-enhancement.\u201d This view also receives support from Sedikides and Gebauer's  review oJack et al.'s result that socially desirable responding does not mediate in the relationship between empathizing and religious belief runs counter to those results. At least in this case, impression management and self-enhancement do not appear to play a role in connecting self-reported measures. So, the fact that the data gathered by Jack et al. shows socially desirable responding playing this role in the case of empathizing and frequency of religious practice is particularly interesting. Given that these are two considerations typically taken into account to measure religiosity and that neither Shariff nor Sedikides and Gebauer distinguish between them in their studies, it might be that Jack et al. have happened upon a methodologically important difference. In particular, if their results were to stand up to further scrutiny, it might be that problems with validity of self-reported religiosity could be lessened by asking about religious belief rather than religious practice.This interpretation, however, can only be preliminary due to a couple of problems with Jack et al.'s methodology. By using Mechanical Turk to recruit their subjects from any country, Jack et al. could not control whether those subjects live in countries where Sedikides and Gebauer would expect self-reporting religiosity to be an element of self-enhancement (see also Stavrova and Siegers, KT: co-wrote the commentary. AW: carried out the statistical analysis and co-wrote the commentary.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Seaman et al.  comparedSeaman et al.  mostly cMoving to a residential care facility is mostly perceived as a stressful, negative experience by older adults, associated to feelings of loss, and suffering (Lee et al., What are then the mechanisms that can explain this increased risk aversion? Theory and research suggest that risk aversion may reflect older people's motivation-based strategy to cope with the demanding circumstances, be it of life decisions or laboratory tasks. To explain this argument further, we turn to several studies that used the BART to investigate age differences in risk taking. Koscielniak et al.  found thResearch shows that older adults manage with their deteriorating cognitive processing through selective allocation of cognitive resources Hess, . For insTo translate this back to the context of Seaman et al.'s study , old aduAll authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Antimicrobial peptides (AMPs) are a natural class of antibiotics that are present in all domains of life .One major challenge in the development of AMPs as novel drugs is enhancing their activity against Gram-negative bacteria. A nice example is the study by 13C MAS NMR , and by Grage et al., who showed that membrane thinning, which has been proposed as part of the mode of action of AMPs . For cellular mode of action studies, te Winkel et al. provided detailed guidance on how to analyze the capacity of membrane-active compounds to dissipate the membrane potential in bacteria using voltage-sensitive dyes. The broad range of antibacterial mechanisms of AMPs and the stress response of bacteria toward these molecules has been extensively reviewed by Omardien et al. Finally, the growing evidence that AMPs are not just unselectively disrupting membrane bilayers but actually targeting specialized membrane foci is discussed by Rashid et al.The mechanism of AMPs has been investigated on the molecular level by Ciesielski et al., who provided new insight into how amphotericin B and natamycin recognize membrane sterols using In conclusion, AMPs are a structurally and mechanistically diverse group of promising antibiotic agents with great clinical potential. More and more evidence is emerging that their mechanisms involve a much wider variety of interactions with membrane components than previously assumed. This research topic has brought together different viewpoints of AMP research from molecules to systems and we hope that this collection will promote future collaborations across fields to investigate these promising compounds.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.http://www.nwo.nl/en, STW-Vici 12128).LH was financially supported by the Netherlands Organization for Scientific Research (NWO, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Critical Care by ten Hoorn et al. [With great interest we read the article in n et al. . We apprSeveral studies have been reported on tracheotomized ventilator-dependent critically ill patients who are able to speak with a speaking valve in the respiratory circuit. Speech by tracheotomized ICU patients during mechanical ventilation with a deflated cuff had already been described by Manzano :512-517). In recent years we are aware of at least three articles addressing the issue of enabling speech during weaning of tracheotomized patients off the ventilator. Egbers et al. [:512-517)Critical Care to draw their attention to this possibility, which has considerable potential to enable speech in tracheotomized patients who are (not yet) able to sustain longer periods of spontaneous breathing trials.Although it was partially beyond the scope of the literature search by ten Hoorn et al. (search closed December 2015), we would like the readers of"}
{"text": "Evidence accumulates linking obesity and diabetes with cognitive dysfunction. At present the mechanism(s) underlying these associations and the relative contribution of diet, adiposity, and metabolic dysfunction are unknown. In this perspective key gaps in knowledge are outlined and an initial sketch of a neuropsychological profile is developed that points toward a critical role for dopamine (DA) adaptations in neurocognitive impairment secondary to diabetes and obesity. The precise mechanisms by which diet, metabolic dysfunction, and adiposity influence the DA system to impact cognition remains unclear and is an important direction for future research. T2D is associated with cognitive decline, brain dysfunction, and dementia (Biessels et al., The majority of human studies linking T2D to cognitive decline are performed in older individuals with long-standing diagnoses of diabetes (Stoeckel et al., 2max, and BMI (Khan et al., Perhaps the most important limitation of the current literature is the failure to disentangle effects of metabolic dysfunction on cognition from those of adiposity and diet. Obesity has been associated with altered brain structure and function in animal models and in metabolically and neurologically healthy adults and children (Elias et al., To date, studies have rarely taken obesity and diet into account when examining the relationship between T2D and cognition. For example, patients with T2D exhibit reduced activity in the default mode network (Musen et al., Failure to account for confounds between diet, obesity, and metabolic dysfunction also pervade the animal literature. Rats prone to develop diabetes upon HFD are often used as a model of T2D (Levin and Routh, Importantly, when more than one variable is measured interactions between adiposity, diet, and impaired glucose tolerance are revealed. In obese humans without T2D, insulin sensitivity mediates the relationship between working memory-related activation in the right parietal cortex and BMI (Gonzales et al., In summary, the relative contribution of diet, impaired glucose tolerance, and adiposity to neurocognitive impairment is largely unexplored and unknown.1c, which reflects the mean glucose concentration over a period of 8\u201312 weeks is the most frequently used measure. Fasting blood glucose concentrations are also frequently measured, which reflect nocturnal hepatic gluconeogenesis that is influenced by hepatic insulin sensitivity, but a recent review found that studies often fail to report whether measurements are taken at the same time of day (Geijselaers et al., 1c shows the strongest association to insulin resistance, followed by post-prandial measures. Fasting glucose, by contrast, seems to be unrelated to cognitive performance (Geijselaers et al., 1c was associated with executive dysfunction (Bruehl et al., Another factor clouding the association between T2D and cognitive impairment is the use of a variety of methods to characterize glycemia, each of which reflect different, and sometimes independent, aspects of glucose metabolism (Geijselaers et al., Insulin receptors are widely distributed in the brain, with the highest concentrations in the olfactory bulb, hypothalamus, cerebral cortex, cerebellum, and hippocampus (Havrankova et al., One promising avenue for future research is in using intranasal insulin in combination with neuroimaging methodologies and neuropsychological testing to assess the role of central insulin resistance in neurocognition (Tschritter et al., Although obesity and T2D are occasionally associated with global measures of brain atrophy (Enzinger et al., There is also strong evidence from animal work that HFD produces hippocampal insulin resistance (Biessels and Reagan, This emerging neuropsychological profile provides an important insight into the pathophysiological mechanism that gives rise to neurocognitive impairment in obesity and T2D. Brain functions associated with diabetes and obesity tend to rely upon DA signaling Figure . For exaThere are consistent findings in the animal literature that HFD, and adiposity alter DA signaling at the cellular, and molecular levels (Anderzhanova et al., In summary, a consensus is emerging that obesity and diabetes are accompanied by cognitive impairments and brain dysfunction and that at least some of these effects are secondary to their onset. Multiple mechanisms have been proposed to underlie these associations but at present it is unclear which mechanism, or mechanisms, are critical. Also unclear is whether diet, obesity and metabolic dysfunction have distinct and/or converging pathways to neurocognitive impairment. However, work emerges to suggest that all three factors may influence DA signaling, which is provocative since the cognitive impairments that characterize diabetes and obesity uniformly rely upon the integrity of the DA system. It is therefore proposed that adaptations in DA signaling secondary to diet, adiposity and metabolic dysfunction underlie much of the neurocognitive impairment observed in diabetes and obesity.The author confirms being the sole contributor of this work and approved it for publication.This work was supported by NIH NCI R01CA180030 awarded to DMS and Ivan de Araujo.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Upon publication, it was noticed that in the original version of the article (Dong et al."}
{"text": "Many such devices can operate interactively and autonomously thanks to electronics, which receive feedback from the physical environment via sensors. Sensorics deals with design, manufacture and the processing of signals from sensors. It is a rapidly evolving research area owing to the abundance of physical properties it is necessary to deal with in the newly developed devices, a number on par with the phenomena and materials available to do so.Contemporary science is, on the one hand, becoming more and more specialized and deals with smaller and smaller objects. On the other hand, it studies many interesting phenomena that occur at the borders between two or more \u2018traditional\u2019 scientific fields. This is especially true in the case of materials science, which fuses different parts of physics, chemistry and biology, and whose results require This Focus Issue includes seven selected papers with subjects related to nanoprocessing and sensorics that were presented at the nanoMA 2015 conference. The meeting was devised by members of the consortium working on a Framework 7 (FP7) grant project titled \u2018Photonic Applications of Nanoparticle Assemblies and Systems\u2019 (PhANTASY) within the Marie Curie International Research Exchange Scheme (IRSES).Schopf et al.  used indKhan and Corbett  showed tx). This combination of bottom-up and top-down processes enables the connection of CMOS technologies via planar processes.Majima et al.  fabricatZhou and Azumi  reviewedCollins et al.  reviewedShrestha et al.  preparedRyan et al.  preparedThe nanoMA 2015 conference was organized jointly by the National Institute for Materials Science (NIMS), Tsukuba, Japan, and Tyndall National Institute UCC Cork, Ireland. Both institutes are national flagships that carry out fundamental research in materials science using nanotechnology and deliver innovative solutions for industrial applications."}
{"text": "In recent years several neuropsychological and psychiatry studies employed the psychobiological model of temperament and character  had to rely on visual cues (arrows pointing up or down) in order to actively expect the high or low salience of the following pictures . Furthermore, correlations between PPI maps and temperamental traits were ran, focusing specifically on NS (exploratory/impulsive vs. indifferent/reflective), HA (worrying/anxious vs. relaxed/confident), and RD  TCI temperaments.In a recent study, Li et al.  have proCritically, concerning FC, Li et al. found that both the right dACC and the right AI (the two areas used as PPI seed regions) showed positive FC with parts of the CEN and negative FC with posterior visual areas and parts of the default mode network (DMN) as a function of high versus low salience expectancy. Moreover, with regard to FC and personality correlation, Li et al.  found reAs argued by Li et al., the findings confirmed that the SN is important for internal salience evaluation and for the control of goal-directed behavior; more critically, they showed that SN activity, and its integration with other brain networks during salience processing, can be modulated by specific temperamental traits.The study by Li et al.  thus sheIn their study, Li et al. used only positive and neutral pictures in the salience expectancy task, and only temperament traits were put into relation with salience processing and SN function. Hence, it would be interesting to see in future studies whether using more stressful stimuli in similar expectancy tasks  discloses the mediating role of other temperaments . For example, past research has shown that HA affects behavior and brain functions when negative emotional stimuli are used in visual attention tasks, especially under conditions of uncertain expectations (Most et al., The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The composition and function of the mammalian gut microbiota has been the subject of much research in recent years, but the principles underlying the assembly and structure of this complex community remain incompletely understood. Processes that shape the gut microbiota are thought to be mostly niche\u2010driven, with environmental factors such as the composition of available nutrients largely determining whether or not an organism can establish. The concept that the nutrient landscape dictates which organisms can successfully colonize and persist in the gut was first proposed in Rolf Freter's nutrient niche theory. In a situation where nutrients are perfectly mixed and there is balanced microbial growth, Freter postulated that an organism can only survive if it is able to utilize one or a few limiting nutrients more efficiently than its competitors. Recent experimental work indicates, however, that nutrients in the gut vary in space and time. We propose that in such a scenario, Freter's nutrient niche theory must be expanded to account for the co\u2010existence of microorganisms utilizing the same nutrients but in distinct sites or at different times, and that metabolic flexibility and mixed\u2010substrate utilization are common strategies for survival in the face of ever\u2010present nutrient fluctuations. The gut microbiota is the community of commensal, beneficial, and pathogenic microorganisms that inhabit the gastrointestinal tract of humans and other animals. Forces that shape the composition of the gut microbiota, as well as other microbial communities, can include stochastic processes such as dispersal, genetic diversification, and ecological drift. However, deterministic interactions between species, individuals, and the environment also create defined niches and thereby influence community composition. The ecological niche was described by Charles Elton in 1927 as the ecological component of a habitat related to an organism's tolerances and requirements, with a focus on its nutrient\u2010foraging capacities Elton, . ImportaThe gut environment and potential niche space can be determined by the host in a variety of ways. The host immune system can act as an environmental filter to limit or expand available niches. However, niche space in the gut is thought to be largely determined by the abundance and types of nutrients derived from host diet as well as secreted into the gut by the host. This review will focus on key aspects of nutrient niches in the gut microbiota, considering the gut as a dynamic ecosystem in which spatial and temporal heterogeneity in the nutrient landscape shape the composition of the microbiota.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Hundreds to thousands of co\u2010existing species of microorganisms inhabit the mammalian gut  due to its superior iron uptake capacities , and a decrease in Firmicutes and Actinobacteria, who presumably rely on the presence of dietary fibres  and Streptococcus spp.  and XIVa, which may grow on fermentation products such as acetate and lactate that are secreted by abundant facultative anaerobes  as well as Bifidobacterium adolescentis and Parabacteroides distasonis (for RS type 4) (Mart\u00ednez et al., et al., B. adolescentis as well as Faecalibacterium prausnitzii in humans (Ramirez\u2010Farias et al., 13C\u2010labeled inulin are Bacteroides uniformis, Blautia glucerasea, Clostridium indolis and Bifidobacterium animalis (Tannock et al., Stool is often used as a proxy for the intestinal microbiota due to relative ease of sampling. However, the mammalian intestinal tract has multiple compartments with different physicochemical and nutrient conditions and, as a consequence, different microbial communities Fig. . In the 5\u2212106 cells in the mucus compared to 1011\u22121012 in the lumen (De Weirdt and Van de Wiele, Lachnospiraceae, Ruminococcaceae, Bacteroidaceae and Coriobacteriaceae (Ouwerkerk et al., et al., Bacteroides spp. and lactic acid bacteria including Leuconostoc spp., Weissella spp. and Lactococcus spp. were also found to be abundant in the mucosa\u2010associated microbiota (Hong et al., Roseburia intestinalis and E. rectale, butyrate producers belonging to Clostridium cluster XIVa, also preferentially colonize mucins in an in vitro gut model (Van den Abbeele et al., Firmicutes, mainly Lachnospiraceae and Ruminococcaceae (Nava et al., et al., Bacteroides fragilis (Macfarlane and Gibson, et al., Different communities are observed not only along the length of the intestinal tract but also along its cross\u2010sectional axis Fig. . The epiet al., et al., Desulfovibrio spp. (Willis et al., B. thetaiotaomicron, which secretes a sialidase but lacks the capacity to metabolize sialic acid, supports the growth of pathogens such as Clostridium difficile and S. Typhimurium (Ng et al., E. coli was found to replicate preferentially in the mucus during re\u2010growth after antibiotic treatment, possibly due to the utilization of sialic acid and other mucosal monosaccharides (Wadolkowski et al., et al., Ruminococcus gnavus, for example, produces an intramolecular trans\u2010sialidase that acts on mucin and other glycoproteins, releasing 2,7\u2010anhydro\u2010Neu5Ac instead of sialic acid (Tailford et al., The ability to metabolize the glycans and peptide backbone of mucin glycoproteins is likely to be a key factor in determining which microorganisms physically associate with the mucus layer. Non\u2010mucolytic bacteria, however, are also found in the mucus layer (Li et al., et al., Clostridiales (Kashyap et al., Lachnospiraceae was also identified as indicator species in individuals lacking a functional FUT2 gene (Rausch et al., et al., Bacteroides thetaiotaomicron induces fucosylation, while Lactobacillus murinus does not (Umesaki et al., et al., et al., B. thetaiotaomicron can live in the mucus layer, in close proximity with the host epithelium. Interestingly, while B. thetaiotaomicron is able to induce fucosylation, a mutant unable to use L\u2010fucose as a carbon source is much less effective in inducing fucosylation (Bry et al., Interestingly, genetically\u2010dictated changes in the host mucus carbohydrate landscape can impact the gut microbiota. The FUT2 gene encodes an \u03b1\u20101,2\u2010fucosyltransferase responsible for the fucosylation of secreted mucin glycans and lack of a functional copy of this gene alters the composition of the gut microbiota (Rausch et al., E. coli could persist if they were the first colonizers of germ\u2010free mice and then a complex conventional microbiota was introduced, but E. coli could not establish in mice that had already been colonized by a conventional microbiota. While Freter's interpretation of this phenomenon was that there was competition for free adhesion sites on the intestinal wall (Freter et al., Clostridium difficile protects against a subsequent challenge with epidemic C. difficile, most likely due to the occupation of the vacant nutrient niche by the non\u2010epidemic strain (Nagaro et al., E. coli that have improved growth on mucosal sugars, but that the non\u2010motile population does not completely outcompete motile E. coli in vivo (Leatham et al., et al., et al., et al., envZ mutant prevents expansion of non\u2010motile E. coli in di\u2010associated mice, suggesting that the mutation confers higher affinity for certain adhesion sites and that E. coli can reside in the mucus layer in mixed biofilms scavenging simple sugars released locally by other organisms (Leatham\u2010Jensen et al., et al., et al., et al., Freter postulated that in addition to competition for nutrients, competition for adhesion sites may also play an important role in survival in the intestines (Freter et al., et al., et al., et al., et al., The Restaurant hypothesis suggests that fine\u2010scale spatial structuring would be important to overall ecosystem diversity Fig. C. Analyset al., R. bromii leads to increased starch utilization by a number of other gut species (Ze et al., R. bromii is thought to be a keystone species. Co\u2010culture of Akkermansia muciniphila, a mucus degrader, enhances growth of Bacteroides vulgatus in mucin as the sole carbon source, thus functioning as a keystone species in the utilization of mucosal compounds (Png et al., et al., et al., Functional redundancy, or the co\u2010existence of functionally\u2010similar organisms, is often considered to be an important feature of the gut ecosystem that contributes to robustness and resilience (Moya and Ferrer, Bacteroides are able to use a wide range of polysaccharides and a number of closely\u2010related species can co\u2010exist in the gut by cross\u2010feeding, resulting in complete polysaccharide utilization. For instance, Bacteroides ovatus releases glycoside hydrolases to break down inulin, but can utilize inulin without extracellular degradation (Rakoff\u2010Nahoum et al., B. ovatus, however, allows B. vulgatus to use cleaved inulin products which would have been unavailable to it (Rakoff\u2010Nahoum et al., et al., B. vulgatus, in turn, increases B. ovatus fitness, presumably through detoxification of inhibitory substances or production of growth\u2010promoting factors. These secreted glycoside hydrolases can be viewed as public goods, yielding polysaccharide breakdown products that allow the growth of other organisms otherwise unable to grow on it. Production of public goods results in a complex polysaccharide utilization network that contributes to the creation of organized ecological units within the gut microbiota (Rakoff\u2010Nahoum et al., et al., Bacteroidales, but also Firmicutes and other less abundant members of this ecosystem (Walker et al., et al., Members of the Assembly of the gut microbiota is largely deterministic and driven by the nutrient landscape created by diet and host secretions. The realized metabolic niche of members of the microbiota is shaped both by nutrient availability as well as the presence of other competing or cooperating species and resulting niche partitioning Figs  and 2. Fin situ metabolic niche of individual members of the microbiota is needed in order to better comprehend the relative importance of the above\u2010mentioned processes. As metabolic strategies that define the realized niche are highly dependent on ecological context, this is best explored by direct analysis of the complex microbiota. To dissect these niches, specialized tools that allow for study of the activity of complex microbial communities should be applied. These include metatranscriptomics (Franzosa et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., A deeper understanding of the"}
{"text": "Stresses, either abiotic or biotic, severely affect agricultural productivity and world agriculture is facing the challenge of increasing the productivity in order to pace up with the increasing food demand of the growing population. These stresses have been reported to negatively affect the biomass and yield of crops up to 70%  metabolism of metabolites also tend to play important roles in detoxification processes. Similar to this, Zhu et al. showed that MEB2, a vacuolar gene, was involved in storing and detoxifying excess iron in Brassica napus. Another work performed by Yang et al. showed that high temperature stress leads to an accumulation of NtMYC2a which activates the synthesis of nicotine and jasmonic acid. Similarly, Huang and Wang, Ksouri et al., Cao et al., and Wu et al. also showed that transcriptional factors influence plants resistance under stress conditions.Research articles included a number of aspects of plant responses to abiotic stresses, from molecular mechanisms of plant stress tolerance to other approaches used to mitigate these stresses in crop plants. Wang et al. studied the involvement of several transporters e.g., Li et al. observed improved photosynthetic activity, nitrogen metabolism and amino acid production by applying brassinosteroids to Camellia sinensis. Similarly, Gondor et al. showed an improvement in flavonoid biosynthesis after exogenous application of salicylic acid. Li et al. showed that synergistic priming of maize seeds with salicylic acid and H2O2 improves hormone metabolism and their transduction, stimulating energy supply and antioxidant systems, which in turn help maize seedlings to tolerate chilling stress. Studies by Agarwal et al., Sharma et al., Per et al., Cheng et al., Gruszka et al., and Patanun et al. also proved the involvement of brassinosteroids, salicylates, and jasmonates under a number of abiotic stresses. In general, the common mechanism of action suggested in these studies was up-regulation of genes associated with antioxidant protection, expression of specific transcription factors, and activation of specific responsive pathways, including hormone homeostasis.Hormones are not only involved in regulating growth and developmental processes, but their exogenous applications may also help to improve the plant yield. 2S and glycerol. H2S was found to regulate changes in polyamine and sugar metabolism and thus providing drought tolerance , while glycerol application provided tolerance against powdery mildew disease by inducing expression of pathogenesis-related genes . Other than these, research articles also explored the possible involvement of E-subgroup pentatricopeptide repeat protein family under abiotic stress . Furthermore, He et al. showed that phytochrome B regulates expression of DREB1 gene to enhance cold tolerance.Among different exogenous mitigants, not only the role of hormones was explored, but some research articles also studied the impact of other mitigants like HOverall, these articles give a clear picture of ongoing dynamic research on phytohormones and other compounds in preventing negative effects of abiotic stresses. The impact of several stresses on the transcriptome, phytohormone profile, and regulatory processes at the cellular level was also elucidated, with an emphasis on the interaction between stresses and hormonal cross-talk. We hope that these compiled articles will give a fresh, new insight into this topic, providing new ideas to pave the way for future research.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The mini-review by Uphill et al. highlights the prominence of psychological issues in sport through various media. The review also highlights gaps in the research in conceptions in mental health, interventions needed, and collaborative work that remains outstanding. The review used the Keyes  model asA coach ill-equipped to deal with their own psychological issues may see a change in their coaching behavior which may impact their performance in training and competitive situations. A potential consequence of this would be an increase in negative coaching behaviors  which may impact their athletes (Badami et al., While there is advocacy for mental health support services for athletes, evidence of similar services for coaches is scarce. Sebbens et al.  developeCoaches are typically hired to achieve an improvement on past team performance (Pierce et al., Creating a positive coaching climate and a positive organizational culture (Fletcher and Wagstaff, There is an opportunity to present a short intervention such as that alluded to in Sebbens et al.  in all cThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer BO and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review."}
{"text": "Understanding how and why recombination rate varies is a major challenge in biology. Most theoretical and empirical work has been devoted to understanding the role of recombination in the evolution of sex\u2014comparing between sexual and asexual species or populations. How recombination rate evolves and what impact this has on evolutionary processes within sexually reproducing organisms has received much less attention. This Theme Issue focusses on how and why recombination rate varies in sexual species, and aims to coalesce knowledge of the molecular mechanisms governing recombination with our understanding of the evolutionary processes driving variation in recombination within and between species. By integrating these fields, we can identify important knowledge gaps and areas for future research, and pave the way for a more comprehensive understanding of how and why recombination rate varies.Recombination, the process by which DNA strands are broken and repaired, producing new combinations of alleles, occurs in nearly all multicellular organisms and has important implications for many evolutionary processes. The effects of recombination can be  Recombination is inations ,2, but a alleles , and desividuals . AlthougWhen considering this question: \u2018Why does recombination rate vary?\u2019, there is much focus on the evolutionary advantage of sex, but much less attention given to understanding why recombination varies between sexually reproducing organisms. For us, as a group of evolutionary biologists who have observed variation in recombination rate in sexually reproducing organisms\u2014we considered this an important knowledge gap. Hence, we proposed this special issue \u2018Evolutionary causes and consequences of recombination rate variation in sexual organisms' with the aim to bring this question to the fore and to encourage more researchers to investigate if and how recombination rate varies, whether it responds to natural or sexual selection, and how it influences fundamental evolutionary processes within sexually reproducing organisms, such as adaptation and speciation.To understand the evolution of recombination, like any trait, we need information on the heritability and plasticity of the trait, on how the trait influences fitness, and on the molecular mechanisms controlling the trait. In this respect, we know a lot about recombination\u2014recombination is heritable, many populations harbour additive genetic variation for it, and it can respond to selection in the laboratory . RecombiAddressing the question \u2018Why does recombination rate vary?\u2019 necessitates understanding both direct and indirect effects of selection. However, most researchers often do not consider selection operating at these different scales simultaneously. For example, population geneticists often view recombination as a population parameter that is under indirect and long-term selection, whereas developmental biologists consider the direct, short-term effects that an altered rate of recombination has on individual traits like fertility. One goal of this Special Issue is to try to better integrate these different perspectives. Thus, we sought contributions from the \u2018population genetics\u2013evolutionary\u2019 perspective \u201316 as weThe Special Issue opens with a general review of how and why recombination rate varies across eukaryotes. It includes an analysis of data from the largest collection of linkage maps to date and an overview of the processes that explain variation in recombination rate\u2014from genome architecture to evolutionary explanations. The review introduces many of the concepts and evolutionary theories that are explored in greater depth in the proceeding articles. Although empirical data for recombination are growing rapidly, progress in explaining this variation has been slow. Dapper & Payseur  argue thet al. [et al. [Daphnia, a genus that contains both sexual and asexual parthenogenetic species. In cyclically parthenogenic species for which linkage maps have been made, we observe a very high recombination rate per megabase compared to other crustaceans [Variation in recombination may be explained by variation in the sexual system and the evolutionary consequences of different reproductive modes. For example, selfing and inbreeding species may benefit from high rates of recombination because it can increase genetic diversity and allelic shuffling, and there is some evidence to support this . Howeveret al.  build a  [et al.  acknowlestaceans . These aA notable pattern to emerge from empirical data is the observation that the distribution of recombination events is distinctly non-random across the genome. Variation is observed at many genomic scales: between chromosomes, between megabase regions within chromosomes and across regions spanning only a few kilobases. Between closely related species, there is often more variation in the distribution of recombination events compared to the total frequency of these events, suggesting that the rate at which recombination evolves is likely to depend on the genomic scale ,17. Variet al. [et al. [Estimates of recombination at the fine genomic scale can provide information about how recombination influences or is influenced by genetic elements and neighbouring DNA sequence. Recombination is often higher in sequence regions with high gene density and GC content and lower in sequence regions that are enriched for simple repeats and transposable elements (TE). Although these patterns are known from a wide range of eukaryotes, the proximate and ultimate mechanisms driving these correlations are poorly understood. To begin to address this problem, Kent et al.  provide et al. . Kent et [et al.  propose Another commonly observed pattern in sequence data is a positive correlation between recombination rate and nucleotide diversity. This relationship can be driven by the mutagenic effects of recombination , but it Caenorhabditis elegans [Drosophila [et al. [trans-acting factor has provided a great deal of insight into how and why hotspot activity varies between species [et al. [A pervasive pattern to emerge from accumulating fine-scale recombination data is that in many species, recombination is localized to small genomic regions referred to as hotspots. Hotspots are present in a wide range of species, but absent from some well-known model species such as  elegans  and Drososophila . Progres [et al.  provide  [et al. ,15. One  species . The rap species  and PRDM species . The selDrosophila melanogaster has been instrumental in the development of this field and Stevison et al. [D. pseudoobscura as a proof of concept and to provide new data in less characterized species [et al. [Variation in recombination is not solely due to genetic factors: a multitude of environmental factors both extrinsic and intrinsic have been found to alter recombination frequency and distribution. Experimental work in n et al.  review t species . Alves e [et al.  explore  [et al. .et al. [et al. [within a group of selected loci are determined by an unlinked locus, alleles at the locus conferring condition-dependent recombination can readily invade a population with a fixed recombination rate. These modelling results agree with theoretical studies that indicate that in diploids, direct effects\u2014where the locus determining recombination influences recombination between itself and the group of selected loci\u2014are unlikely to lead to plasticity in recombination rate. Interestingly, the simulations in the paper also demonstrate that plasticity in recombination rate requires that the population spends relatively equal time in different selective environments\u2014if the majority of time is spent in a single environment, a single, fixed rate of recombination is favoured [While there are many environmental cues known to influence recombination, temperature and condition are perhaps the most well known. Morgan et al.  provide et al. . The secet al. . Previou [et al.  construcfavoured .good, the bad and the variable.In conclusion, in spite of exciting recent results, understanding how and why recombination rate varies across the genome and across taxa remains a major challenge in biology. For this reason, we present a series of contributions that critically evaluate theoretical and empirical developments on variation in recombination rate between taxa ,17,18 an"}
{"text": "The production of biobutanol is hindered by the product's toxicity to the bacteria, which limits the productivity of the process. In situ product recovery of butanol can improve the productivity by removing the source of inhibition. This paper reviews in situ product recovery techniques applied to the acetone butanol ethanol fermentation in a stirred tank reactor. Methods of in situ recovery include gas stripping, vacuum fermentation, pervaporation, liquid\u2013liquid extraction, perstraction, and adsorption, all of which have been investigated for the acetone, butanol, and ethanol fermentation. All techniques have shown an improvement in substrate utilization, yield, productivity or both. Different fermentation modes favored different techniques. For batch processing gas stripping and pervaporation were most favorable, but in fed\u2010batch fermentations gas stripping and adsorption were most promising. During continuous processing perstraction appeared to offer the best improvement. The use of hybrid techniques can increase the final product concentration beyond that of single\u2010stage techniques. Therefore, the selection of an in situ product recovery technique would require comparable information on the energy demand and economics of the process. \u00a9 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:563\u2013579, 2017 Butanol is a commodity chemical used in a wide range of industries. It can be produced through biological or petrochemical routes. The original process route, started in 1913,Fermentation originally ceased being the main production route for butanol when it became economically uncompetitive with the petrochemical production of butanol. The main reasons for this were high substrate cost, low solvent yield (approximately 2 wt%), and high energy requirement for butanol recovery by distillation.in vitro production using immobilized enzymes,In situ product recovery (ISPR) should increase the concentration of ABE for downstream processing, thereby reducing the energy demand and operational expenditure of the plant.To overcome these problems, various strategies have been investigated, including: strain modifications to improve butanol tolerance,This paper provides a review of applied ISPR to ABE fermentations. The primary focus has been free cell (not immobilized or biofilm based) fermentations in a stirred tank reactor (STR), to allow for comparison of the various ISPR techniques. Other reactor configurations, such as immobilized bioreactors, have been considered if STR fermentations have not been performed. The techniques that have been experimentally combined with the ABE fermentation are gas stripping, vacuum fermentations, pervaporation, liquid\u2013liquid extraction, perstraction, and adsorption.et al.The aim of ISPR techniques is to remove the product from the vicinity of the cell as soon as it is formed,et al.et al.et al.Since 2012, there has been a dramatic increase in the number of reviews focusing on the ISPR from the ABE fermentation. Abdehagh in situ recovery fermentation and the non\u2010integrated (control) fermentation. These parameters have been selected as they are generally considered as the main parameters of comparison in experimental based literature, particularly productivity and yield. Substrate utilization was selected to demonstrate the improvements in the fermentation, particularly fermentation longevity due to reduced toxicity. Measurement of substrate can be considered more reliable compared to product concentration, which can be highly inaccurate based on product separation methods. The concentrated product is not always directly measured, sometimes being inferred from model solution data or assuming the yield is the same as the control fermentation To compare the ISPR techniques, the amount of substrate utilized, productivity, and yield have been used. The substrate utilized is the total amount of substrate consumed during the fermentation. The productivity is defined here as the mass (g) of ABE produced per liter of reactor volume per hour. The yield is the mass (g) of ABE produced per mass (g) of substrate used.This review differs from the previous reviews by taking a quantitative approach to the comparing the experimental data of the ISPR techniques and their impact on the fermentation. This review also considers the final concentration from each ISPR technique that will enter the downstream distillation process, where possible.et al.et al.Gas stripping is a separation technique that involves the removal of solvents via dissolution into a gas passing through the fermentation broth. This technique was studied by a range of authors from the mid 1980s , or application of other anaerobic gases such as oxygen\u2010free nitrogen,et al.,A wide range of studies have been performed for gas stripping, with Ezeji's body of workC. beijerinckii BA101. In the continuous fermentations performed by Ezeji et al.,Interestingly, there is a decrease in productivity when moving to a continuous fermentation compared to the fed\u2010batch fermentation, but it should be noted that this comparison is based upon only one strain et al.,et al.et al.et al.et al.et al.There are some results in Table et al.et al. et al.Gas stripping has limitations due to the low ABE concentration in fermentation broth, large quantities of water removed and high gas flow rates required.et al.Since 2013 there has been a flurry of investigations into hybrid separations. A major focus of the hybrid separation processes has been improving the efficiency of gas stripping. This has included investigations into multi\u2010stage gas stripping processes, increasing the temperature at which gas stripping is performed and hybrid gas\u2010stripping pervaporation processes,et al.et al.et al.et al. et al.et al.To achieve this higher concentration, Xue et al.Gas stripping has also been combined with pervaporation, using a carbon nanotube filled polydimethylsiloxane (CNT\u2010PDMS) membrane.et al.,et al.et al.These hybrid techniques apply a second/enhanced separation stage to the fermentation. Other than de Vrije Clostridium sp. used are strict anaerobes.et al.Vacuum fermentations have a reduced pressure in the fermenter, causing the ABE to \u201cboil off\u201d at fermentation temperature. Vacuum fermentations were first used in the ethanol industry to selectively remove ethanol from fermentation broths. The use of a vacuum for an ABE fermentation should be more straightforward than for an ethanol fermentation, as the et alet al.et al.et al.Mariano Two vacuum modes have been investigated: constant and cyclic. Cyclic vacuum fermentations were found to be considerably more competitive in terms of energy demand than traditional distillation. The cyclic vacuum process allows the concentration of butanol to build up, then reduces the concentration rapidly by applying a vacuum for 2 h, repeating this process throughout the fermentation.et al.et al.,All of the literature focusing on vacuum fermentations for the ABE process is a product of the same researchers.et al.et al.Mariano Generally, the conclusions over application of vacuum to ABE fermentations are not definitive, as there is not enough data Table . The appPervaporation utilizes a membrane between the fermentation broth and the gaseous phase,Pervaporation has been shown to increase the substrate utilization, productivity, and yield of ABE fermentations (see Table b\u2010polydimethylsiloxane\u2010b\u2010polystyrene (SDS),For pervaporation, the major decision to be made is the choice of membrane, as the ideal membrane should selectively allow the transfer of ABE while retaining butyric acid, acetic acid, water, and nutrients. The membrane also needs to be minimally fouling, so that it is not blocked by cells adhering to the membrane surface. Table et al.The membrane choice affects the selectivity and diffusion rates of the ABE, which will determine the concentration of the ABE in the permeate. Unfortunately, the selectivity is in competition with the flux. Improvements in flux can be made to pervaporation through the use of higher temperatures, for example, but this would require an additional step of microorganism removal prior to heating the pervaporation feed stream to 65\u201378\u00b0C), and cooling of the retentate prior to re\u2010addition to the bioreactor.\u201378\u00b0C, anet al.et al.et al.,The use of a composite membrane has also been proposed as a method of achieving non\u2010competitive flux and selectivity. Polymers have high flux, are relatively cheap and easy to fabricate into a membrane, but are prone to aging over a long time. Inorganic materials are often highly selective for butanol and have good strength but are expensive. By combining both materials together, the membrane should be more selective with a sufficient flux while not having a prohibitive cost for scale\u2010up.As pervaporation is an evaporative ISPR technique, the product is captured through condensation. The inefficiencies of condensation of ABE have already been discussed in the sections concerning gas stripping and vacuum fermentation. In the papers regarding these techniques, the inefficiencies of complete product capture are acknowledged, but this has not been the case for pervaporation. In Table Liquid\u2010liquid extraction (LLE) is a common technique in the processing industries. It exploits the differences between relative solubility of a compound in two immiscible components. Typically, the solvent used is an organic liquid which is immiscible in water, therefore when applied to a fermentation broth, the product will preferentially transfer from the aqueous phase into the organic phase.et al.There are a variety of key parameters that need to be considered, described in Table et al.et al.et al.et al.Ishii et al.\u22121.The downside of this was the final product concentration only reached 25.32 g ABE/L. Dibutylphthalate was used as an extractant by Wayman and Parekhet al.et al.et al.Other solvents have been tested with fermentations, such as decanol, dibutylphthalate, 2\u2010butyl\u20101\u2010octanol, and poly (propylene glycol) 1200.With LLE, the achieved yields are very low Table , especiaOne of the proposed advantages of ISPR techniques is the increased product titers, reducing the downstream separation energy demand. Unfortunately, the product concentration in the organic phase is rarely stated; rather the total product quantity/concentration based on the fermenter volume is specified. Without this concentration, it is difficult to assess the extraction efficiency in the same manner as evaporative techniques, where the final condensate concentration is stated.et al.et al.For an economically viable process, it is essential that the extractant is recyclable, meaning that the removal of ABE is straightforward. Unfortunately, removal of ABE from the extractant and regeneration of the extractant have not been discussed much in the literature. Roffler et al.,et al.,et al.To circumvent the re\u2010extraction step, Ishizaki Perstraction is a development from liquid\u2010liquid extraction experiments. It works on the same principles of mass transfer of ABE from the aqueous phase to an organic solvent, but the organic solvent and fermentation broth are separated by a membrane. The ABE transfers across the membrane into the organic phase. It is very similar to pervaporation, but has a liquid on the permeate side to provide the \u201cdriving force\u201d rather than a gas or vacuum. If the key criteria for LLE, outlined in Table et al.et al.et al.The main technique has been extraction into oleyl alcohol across a silicone membrane, as this has favorable partition characteristics for butanol.et al.et al.,et al.et al.C. acetobutylicum was used for the fermentation, this could reduce the chances of the bacteria coming into contact with the solvent at the membrane interface. The only acknowledgement of using a toxic extractant was by Tanaka et al.,There have been two examples, Shukla et al.et al.et al.One of the problems of LLE was the trade\u2010off between having a high partition coefficient and being non\u2010toxic to the bacteria. It was thought that the use of a membrane to aid the extractive process would allow for the use of extractants with higher partition coefficients. As seen in Table et al.\u22127 m/s for silicone, 0.4 \u00d7 10\u22127 m/s for neoprene, and 0.3 \u00d7 10\u22127 m/s for latex; meaning that the membrane choice will have a significant impact on the mass transfer in the system. No comparisons of polypropylene hollow fiber membranes and silicone have been performed. Grobben et al.et al.et al.The majority of research has used silicone tubing as the membrane, Table Comparing the fermentations in Table et al.Adsorption is the binding of a compound onto the surface of a solid adsorbent or resin. It is the oldest technique investigated for the use of ISPR from ABE fermentations. In 1948, Weizmann et al.et al.A wide range of adsorbents have been used in conjunction with the butanol and the ABE fermentation, and this list is continually evolving as new, more complex adsorbents become available. Some of the adsorbents used are activated carbon,et al.et al.et al.C. acetobutylicum ATCC 824, the product concentration could be increased due to the adsorption of products, reducing toxicity. The final broth concentration reached 10 g butanol/L; this is the same as the fermentation with no ISPR, and the same yield was observed in both fermentations.et al.ex situ adsorption column, combined with a fed\u2010batch fermentation using C. beijerinckii NCIMB 8052, saw no detrimental effects to the fermentation. The integrated and non\u2010integrated fermentation both had the same yield of 0.31, but the integrated fermentation had an increased total product concentration of 26 g ABE/L compared to 18.5 g ABE/L. No productivity was supplied for these fermentations.et al.et al.The majority of the adsorbents have not been tested while coupled to an ABE fermentation, rather using a model ABE solution instead. Thus, there is a small amount of fermentation data to compare in Table et al.,et al.et al.et al.et al.Weizmann A downside of adsorption is that it is inherently a batch process, as the ABE has to bind to the adsorbent and then, once it has reached capacity, desorption has to occur. In many experiments, batch adsorption was performed,Once the adsorbent has reached its capacity the ABE needs to be removed and the adsorbent regenerated. The main methods of adsorption are through increasing the temperature,Currently, no review has compared all possible ISPR techniques for ABE fermentations. One challenge is that it is difficult to make accurate comparisons between work performed by different groups, as different methods and procedures have been followed. This includes the use of different strains, media, reactor configurations, and mode of operation. To make a valid comparison between the different ISPR techniques, they have principally been compared in terms of their fermentation performance in STRs  can have a positive effect on the fermentation. This is due to the removal of the butanol inhibition allowing for complete utilization of the substrate and the possibility of prolonged fermentations. This is seen by the significant increase in substrate utilization in Tables Where overcoming product inhibition has been successfully demonstrated for any technique, the next step is to perform a fed\u2010batch fermentation which increases substrate loading and fermentation time giving higher productivity. Increases of substrate between 100 and 900% compared to the control fermentation are common, Tables et al.et al.et al.In literature, there have been some discrepancies between what is considered a fed\u2010batch and continuous process. There have been several occurrences where a fed\u2010batch fermentation has been called continuous in literature.Continuous fermentations can be performed, but the continuous removal of fermentation broth leads to a lower increase in yield than for fed\u2010batch fermentations Table . In spitet al.In recent years, there has been a growing trend to immobilized fermentations. A good example of this is Xue et al.One of the factors driving the application of ISPR to the ABE fermentation is the potential energy reduction, due to increased ABE concentration going to downstream processing. The energy associated with separation is generally not considered alongside the experimental results. Xue The review has compared six ISPR techniques based on available experimental data focusing on free cell fermentations. To mitigate the effects of various experimental methods, the % increase of substrate utilized, productivity, and yield was considered. The experimental data has successfully demonstrated that ISPR has a positive impact on the fermentation. The generation of models to represent the fermentation with integrated ISPR could help speed up developments in ISPR. They can help focus developments to the techniques which would provide the greatest improvements to the process. Experimental work can then be completed to validate the model results and confirm there are no biocompatibility issues. This will reduce the time and expense of testing every ISPR possibility experimentally, and provide a comparable baseline. The comparison of different experimental studies can also be improved through standardization of published experimental results for ISPR processes. This can be done by ensuring that enough data is provided to enable a mass balance of the process to be calculated, hence enabling an easier comparison; see supplementary material for a suggestive list of data to be included.From the comparison of STR fermentations, it is possible to say that all techniques exhibit improvements in fermentation productivity and that for different operating modes different techniques appear to be superior. For batch fermentations, gas stripping, and pervaporation were favorable, for fed\u2010batch: adsorption and gas stripping, and continuous perstraction has the greatest improvement. The use of novel two\u2010stage or hybrid techniques also needs to be considered, particularly their compatibility with free cell STR fermentations. This means that the decision on which technique to apply will be based on additional data such as energy consumption and an economic analysis. These should be considered alongside the fermentation data, and this would help to categorically state which is the best ISPR technique. Future work should include process optimization as part of trying new feedstocks, improved strains, or separating agents ."}
{"text": "I am working on the role of aberrant gene expression in the pathogenesis of nonfunctioning pituitary adenomas. I started my work with a search of the literature and deposited data from previous expression profiling experiments. Therefore, I have read the article \u201cIdentification of Differentially Expressed Genes in Pituitary Adenomas by Integrating Analysis of Microarray Data\u201d published by Zhao et al. with great interest . The autThis kind of study is essential to investigate molecular pathogenesis of pituitary adenomas as only a few microarray-based expression profiling studies were performed on samples of gland affected by this disease. Most of these investigations included a small number of patients, usually involving very few or no control samples from normal human pituitary tissue. Zhao et al. combined existing repositories of microarray data from three studies to collect expression profiles of 12 normal pituitary samples. According to the published methodology, six of these control samples are from the study reported by Hussaini et al. [The aim of the research of Zhao et al.  was the The integrative analysis of gene expression profiles in pituitary adenomas, based on the methodology used by Zhao et al., is still needed, and further research is expected to shed light on the pathogenesis of pituitary adenoma. Due to the fact that previously published large-scale expression analyses of pituitary adenomas included only a very small number of samples from normal pituitary, more subtle differences between normal and tumor tissue in the pituitary at the molecular level remain elusive. However, accurate selection of data is crucial for reliable outcome and its interpretation. For this reason, I feel obliged to point out the mistake that occurred in the analysis by Zhao et al.  and to e"}
{"text": "In future, the South African Department of Health aims to purchase services from accredited private service providers. Successful private audiology practices can assist to address issues of access, equity and quality of health services. It is not sufficient to be an excellent clinician, since audiology practices are businesses that must also be managed effectively.The objective was to determine the existing and required levels of practice management knowledge as perceived by South African audiologists.An electronic descriptive survey was used to investigate audiology practice management amongst South African audiologists. A total of 147 respondents completed the survey. Results were analysed by calculating descriptive statistics. The Z-proportional test was used to identify significant differences between existing and required levels of practice management knowledge.Significant differences were found between existing and required levels of knowledge regarding all eight practice management tasks, particularly legal and ethical issues and marketing and accounting. There were small differences in the knowledge required for practice management tasks amongst respondents working in public and private settings.Irrespective of their work context, respondents showed that they need significant expansion of practice management knowledge in order to be successful, to compete effectively and to make sense of a complex marketplace. Audioloet al., et al., The future of private audiology practices depends on how well audiologists are able to take their clinical training and practice management skills to the marketplace Metz, . This ban = 256) in the United States of America (USA) and Canada . The data was collected anonymously and treated with confidentiality. No identifying information of the respondents was reported and internet protocol addresses were not tracked. An informed consent letter formed part of the web-based survey and was the first page that respondents viewed once they clicked on the link. By completing the web-based survey respondents gave their consent to participate in the study on a voluntary basis.n = 326) and SASLHA (n = 1300) as their member databases are updated annually, and they were able to send the survey to all their members. Since there was no effective way to determine which of the SASLHA members practice only as speech-language therapists, a number of redundant emails were sent to speech-language therapists. Some audiologists are also registered with both the SAAA and SASLHA, meaning that some respondents might have received an invitation to participate twice. An email message providing the web address where the respondent could link directly to the survey was thus sent to a total of approximately 1626 prospective respondents. A total of 147 respondents completed the survey indicating a minimum response rate of 9%. A description of the respondents is given in The population of interest was registered audiologists and dually qualified speech-language therapists and audiologists working in public or private settings in South Africa \u2013 whether they are involved in practice management or not. A non-probability, convenience sampling strategy was employed. Because a large number of audiologists are still dually qualified, it was not possible to determine how many of the professionals are practicing only as audiologists. At the time of data collection there were 1749 audiologists and dually registered speech-language therapists and audiologists registered with the Health Professions Council of South Africa HPCSA, , but emaAccording to n = 11) as demographic information was obtained last in the web-based survey, and some respondents did not complete all the questions.There is also incongruity regarding the number of respondents employed in each province and the size of each province. Some provinces, such as the Northern Cape, were underrepresented in the survey. There were a few missing values  for statistical analysis. Results were quantitatively analysed by calculating descriptive statistics such as percentages, frequency distribution, measures of central tendency and standard deviation. This assisted in organising and summarising the data. The Z-proportional test  were also rated highly. Finance (91.8%), accounting (91.7%) and strategic management (91.7%) were considered by the respondents to be equally important. An ability to understand the financial drivers of a successful practice is a fundamental and long-lasting skill set that will benefit any professional regardless of his or her work setting Traynor, . RespondBy combining the two tables, differences in knowledge can be highlighted. The difference between the required and the existing levels of knowledge levels is indicated in et al. (p < 0.05). The results are in agreement with Henson et al. , organisational behaviour and human resources (p = 0.049) and operations and systems management (p = 0.000). Respondents working in a private setting had a higher existing knowledge regarding these three tasks. Respondents working in a private setting may gain more experience regarding marketing as they have to actively market their practices. It is possible that respondents working in the public sector might be overburdened by the demand for their services and therefore have limited knowledge regarding marketing. Respondents working in the private sector are solely responsible for organisational behaviour and human resources. In a public setting these responsibilities are handled collectively. The Z-proportional test revealed no significant differences between respondents working in a public and/or private context regarding their required levels of knowledge in all eight of the practice management tasks. The results indicated that there is a great need for knowledge regarding practice management irrespective of the working environment. Respondents work in a variety of employment contexts throughout their careers with various common traits; for example, they all have to conform to legal and ethical constraints. Therefore, the required level of knowledge regarding legal and ethical issues is high, regardless of the employment context.According to Respondents indicated in the text data section that their biggest strengths were patient satisfaction, successful marketing, and starting their own practices. Respondents indicated that a lack of training, knowledge, experience and sufficient finances were their biggest challenges in practice management in South Africa. In the open comments section of the survey, one respondent stated that \u2018a lack of knowledge and education before starting your own private practice is the biggest challenge in practice management in South Africa\u2019. The majority of respondents indicated that training is required to overcome these challenges.According to et al. , and departments of audiology at universities were rated highly. The latter indicated that respondents wanted to learn from lecturers with experience in the field, and that universities are held in high regard by the respondents. According to Fasokun, Katahoire and Akpovire , experieet al.  adult le et al., . The maj et al., , adult l et al., .Marketing was rated as the most important topic to be included in training (93.5%), which is in agreement with the required levels of knowledge as indicated by the respondents in et al., et al., et al. (et al. (et al. (et al., et al., This study found significant differences between respondents\u2019 self-perceived existing and required knowledge in all eight practice management tasks. Legal and ethical issues, as well as marketing and accounting, revealed the biggest differences. Respondents recognised that they need significant expansion of their practice management knowledge, skills and attitudes in order to be successful irrespective of their work context. The success of private audiology practices is also important for the future engagement between private and public sectors when the National Health Insurance system is implemented. To address these needs audiology programmes should incorporate aspects of all eight practice management areas that compose what is considered the most important body of knowledge for practice management (Henson , et al. , there a, et al.  states t, et al. , audiolo, et al. . There a (et al.  giving u (et al.  recommen et al., . Taking et al., A limitation of the current study is the fact that the results reported on are derived from a small sample of audiologists and dually qualified speech-language therapists and audiologists in South Africa. The response rate was below the desirable rate described in the literature (Maxwell & Satake,"}
{"text": "Quality of life (QoL) is an important outcome for people with dementia living in care homes but usually needs to be rated by a proxy. We do not know if relative or paid carer proxy reports differ. We conducted the first systematic review and meta-analysis of data investigating whether and how these proxy reports of QoL differ.dementia, QoL, proxy, and care home. Included studies either compared proxy QoL ratings or investigated the factors associated with them. We meta-analyzed data comparing staff and family proxy rated QoL.We searched four databases: Medline, Embase, PsychInfo, and CINAHL in October 2015 with the terms: n = 1,290; pooled effect size 0.06 (95% CI = \u22120.08 to 0.19)). Studies investigating factors associated with ratings  found family and staff ratings correlated with the resident's physical and mental health. Staff who were more distressed rated resident QoL lower. Relatives rated it lower when the resident had lived in the care home for longer, when they observed more restraint, or contributed more to fees.We included 17/105 papers identified. We found no difference between global proxy ratings of QoL (Relatives and staff proxy QoL ratings share a clear relationship to resident health and overall ratings were similar. Rater-specific factors were, however, also associated with scores. Understanding why different raters consider the QoL of the same person differently is an important consideration when evaluating the meaning of proxy rated QoL. Proxy raters\u2019 backgrounds may affect their rating of QoL. We hand-searched the references of all included papers and contacted authors of included papers to ask about other related literature. Where information from papers was missing, we contacted the authors to ask for the information.The review was registered on the International Prospective Register of Systematic Reviews (PROSPERO) on the 18th February 2015. Searches were conducted in October 2015 in Medline, Embase, PsychInfo, and CINAHL databases; using the search terms: We included studies in any language reporting quantitative ratings of QoL of people with dementia living in care homes and either (1) comparing two different proxy perspectives for the same individual or (2) describing the factors associated with proxy rated QoL.et al., 1.Was the population defined by a clear inclusion and exclusion criteria?2.Were the data collection methods standardized?3.Were the measures used for QoL valid, and reliable, and used in an appropriate way?4.Was there sufficient power to conduct the analysis, judged by a sample size of greater than 30 where a power analysis had not been conducted?SR extracted data and SR, OH, and AS independently rated quality using operationalized checklists for quantitative papers previously developed by our group , with five studies using the Alzheimer's Disease Related Quality of Life (ADRQL); other measures used (each in one paper) were: QoL in Late-Stage Dementia (QUALID); Dementia Quality of Life (DQOL); QUALIDEM; and a single item questionnaire. Five studies measured staff and family carer perspectives; ten studies only asked staff; and one only asked family carers to proxy-rate life quality.We identified 105 unique publications in the electronic database search, of which 16 met eligibility criteria. One additional paper was included from the references list of included papers, resulting in 17 included papers that reported 16 studies: five took place in the UK, six in other European counties, three in the USA, and one in each of Taiwan, Japan, and Australia. The majority of papers collected information using the Quality of Life-Alzheimer's Disease (QOL-AD)  collected data from both staff and relative perspectives. Data are described in et al., n = 3), these are also described in et al., et al., Four studies .Factors associated with a staff and relative rated QoL are summarized in et al., et al., et al., et al., et al., et al., et al., Lower staff and relative rated QoL was associated with: lower resident weight  with staff ratings of QoL but not with relative ratings   but this did not reach statistical significance for relative rated QoL   but relative ratings were not    and \u03b2 = \u22124.64 ) ) and observed restraint ) but the relationship with staff ratings was much smaller and did not reach significance ) , \u201cmarriage\u201d , \u201cfriends\u201d , \u201cability to do chores\u201d , and \u201cability to do things for fun\u201d . This paper also found that if the primary nurse rated the QoL, there was significantly more agreement with resident ratings (p < 0.05).Graske et al.  reportedet al.  over a three month period. In contrast, greater dependency  and more depressive symptoms  at baseline were associated with declining staff proxy-reported QoL.Beerens et al.  found thWhen comparing the overall means of groups we did not find a significant difference between global QoL scores between relative and staff proxy ratings for care home residents with dementia. In three of four studies examining this, there was a non-significant trend toward care staff rating QoL higher than family members, but we can conclude from existing data that any systematic difference in global ratings is small, and not of the magnitude of those reported between self and proxy reports of life quality in people with dementia. The majority of studies included used the QOL-AD and ratings from different proxy groups have not been compared for a number of other QoL measures used in people with dementia. This is an important consideration when evaluating validity of QoL measures for use in care homes. When papers compared ratings for individuals by looking at the correlation between staff and family carer rated QoL there was moderate agreement in two of three papers. These results suggests raters are considering similar things when rating QoL but that there are also some differences that are not reflected in the overall mean score of groups.et al., et al., et al., et al., Relatives and staff proxy QoL ratings share a clear relationship to resident physical and mental health, including: lower weight, use of antipsychotic medication, depression, higher physical disability, pain, poorer cognitive function, and lower capacity to carry out ADL. Rater-specific factors were also associated with the scores they give. Staff QoL ratings were associated with their own levels of stress and burnout. This fits with existing research in the community that shows that low proxy rated QoL is strongly influenced by the family carer's mood and experience of caring (Karlawish The fact that staff rated the QoL of residents who exhibited more agitation, challenging behavior and unmet needs lower, but relatives did not, could suggest that there are aspects of the resident's life that relatives are less aware of, or that staff's own feelings affect their ratings. Agitated and challenging behavior may be more likely to occur at times of personal care or may be more common when relatives are not there, thus, limiting a relatives exposure to these behaviors. Care home studies more commonly measure staff rated QoL, so associations with relative rated QoL have been less widely studied. The relevance of the context of the proxy rater was also demonstrated by the finding that lower relative proxy ratings of QoL were associated with a longer stay in the care home, as well as higher relative contribution to nursing home fees; possibly indicating burden for the relative.These results suggest it is important to collect data about the environment of the residents as it may explain some of the variation in ratings, particularly in samples with participants recruited from different care homes. Many care home residents with dementia do not have a family member who visits regularly; findings from studies of those that do in which proxy-ratings can be compared, can help us interpret and validate staff rated QoL measurements that are potentially available for all residents.Existing research suggests there is little difference between paid carer and family carer perspectives of QoL when comparing overall means scores of the QOL-AD and QUALID but that this different does not imply ratings are the same as they are not strongly correlated. This can be explained by the fact that different factors are associated with proxy reported QoL for staff and family members. Paid carer and family carer proxy rated QoL is lower with the presence of more stress in their own life and this may lead to differences in overall ratings in other more detailed QoL questionnaires or in differences between individuals and this should be explored in future research.et al., Proxy rated QoL is a vital outcome in a care home context and it is important to understand what is being measured. Future research should investigate the differences between different perspectives of QoL using different QoL measures that allow cost calculations. Cost effectiveness is an important outcome to ensure that interventions give value for money and the DEMQOL (Smith None.Sarah Robertson conducted the literature searches, data extraction, study quality appraisal, and prepared the first draft of the paper as part of her PhD project. Aisling Stringer and Olivia Hamilton independently conducted study quality appraisal and resolved any disagreements with Sarah Robertson. Gill Livingston, Claudia Cooper, and Juanita Hoe revised the paper critically and approved the final version for publication."}
{"text": "On the contrary, if a doctor doesn't clean the instruments before surgery, microorganisms will be there during the operation, and they may infect us, because the environment in the OR won't kill them.Rummel and Conley  argued ti.e., the bioload)\u201d of a mission will determine \u201cthe probability of microbes surviving either natural or human-mediated transfer\u201d .\u201d This means that the best candidates to be Special Regions on Mars are hypothetical, nonconfirmed, and unreachable, bringing our initial question to the table again: What exactly are we protecting with planetary protection policies on Mars?In the end, Rummel and Conley  acknowleet al.,et al.,Rummel and Conley  respondeIn any case, if we assume the premise that it is not so costly or difficult, then the question immediately arises as to why we are not investigating Special Regions today. This is not a rhetorical question; if it is not budget constraints, what is the reason that we have not conducted true life-seeking missions on Mars since Viking? Rummel and Conley  claimed et al.,et al.,i.e., La Duc et al.,Rummel and Conley  added thet al.,if (a big if) martian life is genetically similar to Earth's. Rummel and Conley ignored our disclaimer and then elaborated on the possibility that martian and Earth life would be genetically different; we do not object to those comments.Rummel and Conley  questionBut later in their response, Rummel and Conley alerted about the possibility of lateral gene transfer between terrestrial and martian biospheres \u201cif Earth life and martian life are related, or if martian life is unrelated but still uses DNA/RNA.\u201d This is in blatant contradiction to their previous argument that \u201cthere is a very real possibility that extraterrestrial life does not possess either RNA or DNA, which would make any question of sequence comparison irrelevant.\u201d Given that these authors used this argument before to discredit our points about identifying life on Mars, Rummel and Conley  should ni.e., Parro et al.,et al.,et al.,et al.,et al.,et al.,et al.,To address the core of this issue, it should be said that there are indeed plenty of other strategies proposed with which to search for extant life on Mars, and most of them do not involve DNA/RNA examination  under today's martian conditions? The answer is no. If such Earth organisms were introduced into an underground martian environment, they would be rendered lifeless in a time measured in minutes or less.Their discussion then shifts to \u201cself-calcifying crack-closing microbes used as a concrete additive\u201d on Earth. But could these or any other of the \u201ccertain organisms\u201d mentioned by Rummel and Conley , citing et al. , which aet al.,Rummel and Conley  stated tet al.,If martian microbes exist, they have been arriving at Earth for billions of years via meteorites, given that the trip from Mars to Earth is easier than from Earth to Mars, and it has been estimated that this happens 10 times more frequently  than the prospect of finding life on Mars. The search for life on Mars is one of the most fascinating scientific endeavors of our time. And interest in the search for life goes beyond the Mars science community, which is clear by the amount of press and media coverage missions to Mars receive.i.e., Grossman, et al.,et al.,et al.,et al.,et al.,et al.,et al.,et al., current habitability and expression of biosignatures contain evidence of extant life\u201d . ESA argues in the same way that a \u201cbasic question\u201d to answer in Mars exploration is whether \u201cwas there ever, or is there still, life on Mars\u201d and that spacecraft investigations \u201cshould include science packages to search for evidence of extinct or extant life\u201d ; indeed the objectives of the agency's first Mars rover, ExoMars, are \u201cto search for signs of past and present life on Mars\u201d . And the NASA Astrobiology Institute includes, among its main objectives, the \u201csearch for evidence of ancient climates, extinct life and potential habitats for extant life on Mars\u201d .At the same time, all Mars missions are put forward as relevant for life detection. For example, NASA's Science Goal 1 for Mars exploration states: \u201cOn Mars, we will therefore search for evidence of life in areas where liquid water was once stable, and below the surface where it still might exist To check the consensus and priorities of the Mars community, a good start would be that a forthcoming MEPAG meeting put this question on the table. If we are erroneous, and the Mars community were to agree with Rummel and Conley  that a m"}
{"text": "Wu et al.  describe2+-sensitivity  by almost 0.1 pCa units, with little or no effect on the maximum MgATPase activity or the maximum sliding speed of thin filaments in motility assays (Sommese et al., 2+-responsiveness of the myofilaments almost certainly results directly in reduced mechanical function of the heart during systole, to the detriment of the DCM patient. Remodeling of the DCM heart, however, depends in part on changes in gene expression. Mechanisms of altered gene regulation in cardiomyopathies have typically focused on changes in Ca2+-signaling, mechanosensing, and/or energy metabolism (Frey et al., The mutation studied by Wu et al.  is a poi2+ signal that activates systolic cardiac contraction (Figure Wu et al.  found thn Figure . Althougn Figure , 2016. IWu et al.  performeWu et al.  demonstrLC and PC wrote and edited the commentary, JD edited the commentary.The authors declare that the commentary was written in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer BB and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review."}
{"text": "Editorial on the Research TopicZika Virus ResearchThe considerable number of viral infectious disease threats that have emerged, since the beginning of the twenty-first century has shown the need to dispose global and coordinated responses to fight properly and efficiently against them. Severe acute respiratory syndrome 2003), avian influenza in humans (2005), AH1N1) pandemic influenza (2009), Middle East respiratory syndrome coronavirus (MERS-CoV) (2012 onward), and Ebola virus disease (2014\u20132015) are some of the most important examples  and Southeast Asia (where the two most important vectors are well distributed). Recently, some of these concerns have become reality, especially in Southeast Asia where several countries have reported autochthonous cases in the past months . Rather et al. also reviewed the results of preventive campaigns conducted in different parts of the world, which were based on different approaches like, for instance, avoiding unnecessary travel to infected areas and mosquito bites. They argue that these and other proactive measures could \u201cbe employed to effectively combat the epidemic transmission of the Zika virus.\u201dPrevention and control strategies have also been deeply discussed in the topic. One of the most applied examples has been given by Rather et al. provided an interesting and deep review about the scientific evidence supporting a causal relationship between ZIKV infection during pregnancy and congenital abnormalities. Coming closer to specific congenital and neurological problems, Yuan et al. commented a very interesting point of view regarding the teratogenic effects of Zika virus and the role of the placenta as natural barrier against the infection . Their results revealed abundant intrinsically disordered protein regions (IDPRs) in Zika virus polyprotein, capsid protein, and several non-structural proteins, which could play a role in the pathogenesis of the disease. In an interesting study of the mutational preference direction of Zika virus, Khrustalev et al. contributed with promising and useful data that may have further implications for vaccine development and for the understanding of the evolution of new Zika virus strains.Different virological aspects have also been well analyzed in the topic. Craig et al. and Saiz et al. crossed interesting points of view regarding the review article by Saiz et al.Short discussions by way of articles commentaries could not be missed in the topic. Munjal et al. gives a great overview of different advances in the development of therapies against Zika virus, while Shukla et al. focus their review on rapid detection strategies of the virus in order to have quick response mechanisms to fight efficiently against the disease and to prevent reaching epidemic levels. Wider approach has been given by Shankar et al., encompassing additional aspects related to virus genome, clinical manifestations, diagnosis, and vaccine development. The four classical steps of epidemic management  are also well addressed by Sharma and Lal. Mini reviews about Zika virus emergence at American and worldwide level have been also interestingly written by Fajardo et al. and Rather et al., respectively. With all this information, Saiz et al. elaborated a very pertinent compilation of data and information to arrange all that has been learned at virological, entomological, clinical, and epidemiological level, since the start of Zika epidemic in late 2015.Finally, some of the most relevant sources of knowledge of the Zika Virus research topic reside in several excellent reviews. We want to thank all the authors and reviewers for their valuable contributions to this research topic, and we hope that this collection of reviews, commentaries, and original articles will be helpful for clinicians, researchers, and students seeking for information about Zika virus.Main text has been redacted by RB-M. All authors revised and approved the Editorial.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The current edition of the journal brings forth diagnostic and surgical techniques in glaucoma. Mingguang He et al review the clinical applications of ultrasound biomicroscopy for the anterior segment, while Sathyan et al provide insight into the applications of optical coherence tomography in glaucoma diagnosis, and Kaushik et al review the uses of ocular response analyzer in determining corneal hysteresis. Khanna and Ichhpujani detail on the use of low vision devices in glaucoma, while Khurana et al give a perspective on drug-induced glaucoma. The Ex-PRESS shunt, a new microshunt for glaucoma surgery, is presented by Angmo et al in the treatment of neovascular glaucoma. We hope that the reader will find the articles of interest and help them in improving the standard of care in glaucoma patients.Editors"}
{"text": "Marko Curkovic in his letter  points oGoogle Scholar and Google Search are considered to be important sources of grey literature, governmental and institutional reports (Haddaway et al."}
{"text": "As a pertinent addition to the literature, the study highlights several concerns currently facing those in the transcranial electrical stimulation (tES) community.Tremblay et al.  investigtDCS has become increasingly popular as a result of research by Nitsche and Paulus , which dIn this context, the article by Tremblay et al. represents a milestone for tES research. Systematic studies of tDCS effects are currently in the minority and researchers are largely unaware of the influence subtle variations in stimulation parameters are likely to have on results. Those studies that do exist have utilized relatively complex designs and atypical stimulation parameters (weak current strengths, novel stimulation intervals and/or small electrodes e.g., Batsikadze et al., It cannot be ignored that the article reflects a series of non-significant results. None of the four assessed intensity/duration pairings altered corticospinal excitability in a manner that was statistically meaningful. Prominent inter-individual differences in response rates were likely to have contributed to these outcomes, with non-responders constituting up to 80% of the sample, but what does this variability mean for the future of tES?One may assess these findings in the context of recent meta-analyses, which demonstrate a lack of consistent effects on behavioral and neurobiological metrics, and decide to view them as a further blow to a field already marred by controversy (Horvath et al., Advocating the publication of non-significant results, like those of the article in question, will inevitably assist in the reformation of tES research\u2014especially where they originate from methods-driven investigations (Hanley et al., A number of issues concerning the validity of tES research are brought to light by Tremblay et al. . As outlThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "We welcome Jesus et al.\u2019s paper, which makes an important contribution to the under-researched area of the physical rehabilitation workforce. The authors present recommendations to \u201cadvance a policy and research agenda for ensuring that an adequate rehabilitation workforce can meet the current and future rehabilitation health needs\u201d (p. 1). We argue that their perspective could however be strengthened by adopting a stronger global perspective, including consideration of the needs of low-resource settings. In particular, we highlight the integral role of more effective sector and inter-sectoral governance, the opportunity to support the development of community-based rehabilitation (CBR), the lessons that can be learnt from human resources for health (HRH) research and practice more generally, and the recent developments in the global provision of assistive technologies. Each of these issues has important implications and contributions to make to advance the policy and research agenda for the global rehabilitation workforce. We welcome Jesus et al.\u2019s paper , which mJesus et al. propose a policy agenda, highlighting the need to \u201cadapt policy options to different contexts , even within a country\u201d (p. 1), and provide recommendations for both local and global policymakers. However, the six rehabilitation workforce challenges outlined by the paper do not sufficiently recognise the integral role of governance and leadership in addressing these, including strategies to increase the priority of rehabilitation on the health agenda. Dieleman and Hilhorst  specify With the rapidly growing ageing population, and the majority of persons with disabilities living in low- and middle-income countries (LMICs), there is a need to consider the global context when addressing rehabilitation workforce challenges , 10. JesWhile Jesus et al. focus on setting an agenda for physical rehabilitation, it is important to consider that often professionals working with people with physical disabilities may need to have a multi-faceted skillset . This caWhile the role of task-shifting in providing services was alluded to by Jesus et al., this approach deserves much more attention. The evidence for task-shifting in rehabilitation is slowly growing . HoweverOne of the most significant global initiatives in the field of physical rehabilitation is WHO\u2019s GATE  programme, which seeks to produce a step-change in the provision and use of affordable quality assistive technology (AT) . FollowiJesus et al. draw attention to the important and under-researched area of physical rehabilitation health workforce challenges. It is important that while setting a global agenda, such an effort should encompass the challenges and potential solutions for high-, medium- and low-resource settings, as well as urban and rural settings. We have sought to complement Jesus et al.\u2019s important article by highlighting some of the ways in which this can be done."}
{"text": "Herbal medicines play an important role globally in the health care sector and in industrialised countries they are often considered as an alternative to mono\u2010substance medicines. Current quality and authentication assessment methods rely mainly on morphology and analytical phytochemistry\u2010based methods detailed in pharmacopoeias. Herbal products however are often highly processed with numerous ingredients, and even if these analytical methods are accurate for quality control of specific lead or marker compounds, they are of limited suitability for the authentication of biological ingredients.To review the benefits and limitations of DNA barcoding and metabarcoding in complementing current herbal product authentication.Recent literature relating to DNA based authentication of medicinal plants, herbal medicines and products are summarised to provide a basic understanding of how DNA barcoding and metabarcoding can be applied to this field.Different methods of quality control and authentication have varying resolution and usefulness along the value chain of these products. DNA barcoding can be used for authenticating products based on single herbal ingredients and DNA metabarcoding for assessment of species diversity in processed products, and both methods should be used in combination with appropriate hyphenated chemical methods for quality control.DNA barcoding and metabarcoding have potential in the context of quality control of both well and poorly regulated supply systems. Standardisation of protocols for DNA barcoding and DNA sequence\u2010based identification are necessary before DNA\u2010based biological methods can be implemented as routine analytical approaches and approved by the competent authorities for use in regulated procedures. \u00a9 2017 The Authors. Phytochemical Analysis Published by John Wiley & Sons Ltd. Herbal medicines play an important role globally in the health care sector and in industrialised countries they are often considered as an alternative to mono\u2010substance medicines. Different methods have varying resolution and usefulness along the value chain of these products. DNA barcoding can be used for authenticating products based on single herbal ingredients and DNA metabarcoding for assessment of species diversity in processed products, and both methods should be used in combination with appropriate hyphenated chemical methods for quality control. The global market for herbal products is projected to reach US$115 billion by 2020, with Europe leading the market , herbal products fall into two main categories, herbal medicines and herbal food supplements , depending on their primary intended use. The EU directive 2004/24/EC, commonly referred to as the Traditional Herbal Medicinal Products Directive (THMPD) establishes a simplified procedure allowing the registration of herbal medicines as medicinal products , Echinacea sp. (coneflowers), Actaea racemosa L. (black cohosh), Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. (Siberian ginseng).As a result of these distinct legislative frameworks, the same herbal product may coexist under different categories. For instance, et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., One of the core interests of modern pharmacognosy refers to the identification and authentication of drug substances and to the quality of the resulting herbal medicines  for primary qualitative analysis, or alternatively using hyphenated methods  to enable also the quantification of the lead or marker compounds , with the focus on plant sampling, barcode regions, DNA extraction, purification and amplification, and the sequences reference database  Regel . Only 15% of investigated Veronica herbal products contained the target species Veronica officinalis L., whereas the main known adulterant, Veronica chamaedrys L., was detected in 62% of the products  and DNA barcoding, known as DNA metabarcoding, enables simultaneous high\u2010throughput multi\u2010taxa identification by using the extracellular and/or total DNA extracted from complex samples containing DNA of different origins (Taberlet , et al.  found th (et al.  found th et al., . Out of et al., et al., All these studies report varying degrees of authentication success. Therefore, obtaining a representative assessment of complex herbal mixtures is influenced by many factors, including the quality and type of raw material, as well as several elements of the analysis that can however be varied to optimise the results (Staats et al., et al., et al., et al., et al., et al., et al., et al., In the context of the quality control of herbal products, DNA barcoding and metabarcoding do not provide any quantitative nor qualitative information of the active metabolites in the raw plant material or the resulting preparation, and this narrows its applicability only to identification and authentication procedures. However, the use to identify and discern taxa at any developmental or processed stage from which DNA can be extracted is an essential advantage of DNA barcoding and metabarcoding (Hebert Both chemical and biological methods require comparison of detected compounds against reference standards. For chemical methods these can be lead or marker compounds, adulterants or more advanced computational scans of chemical databases. For biological DNA\u2010based methods there are similar advanced computational scans linked to well\u2010curated nucleotide sequence repositories. Chemical methods can be used in all stages for quality control and provide insights into the presence or absence of compounds defining a product. Biological methods based on DNA barcoding can be used for authentication of raw biological materials from cultivation or wild\u2010harvest at source or before manufacturing, but not accurately once the material is mixed with other biological material. Biological methods based on DNA metabarcoding can be used for authentication of finished products, post\u2010marketing control and pharmacovigilance, and provide insight into the total species diversity in a product.Each method has its benefits and limitations, and its specific strength when applied correctly in the herbal product value chain. Both DNA barcoding and metabarcoding have potential in the context of quality control of both well and poorly regulated supply systems. DNA barcoding can be used for authenticating products based on single herbal ingredients and DNA metabarcoding for assessment of species diversity in processed products, and both methods should be used in combination with appropriate hyphenated chemical methods for quality control. Standardisation of protocols for DNA barcoding and DNA sequence\u2010based identification are necessary before DNA\u2010based biological methods can be implemented as routine analytical approaches and approved by the competent authorities for use in regulated procedures."}
{"text": "Climate model simulations uniformly show drier and warmer summers in the Eurasian midcontinent during the mid\u2010Holocene, which is not consistent with paleoenvironmental observations. The simulated climate results from a reduction in the zonal temperature gradient, which weakens westerly flow and reduces moisture flux and precipitation in the midcontinent. As a result, sensible heating is favored over evaporation and latent heating, resulting in substantial surface\u2010driven atmospheric warming. Thus, the discrepancy with the paleoenvironmental evidence arises initially from a problem in the simulated circulation and is exacerbated by feedback from the land surface. This region is also drier and warmer than indicated by observations in the preindustrial control simulations, and this bias arises in the same way: zonal flow and hence moisture flux into the midcontinent are too weak, and feedback from the land surface results in surface\u2010driven warming. These analyses suggest the need to improve those aspects of climate models that affect the strength of westerly circulation. CMIP5/PMIP3 mid\u2010Holocene simulations in the Eurasian midcontinent are too dry and too warm relative to paleoclimatic observationsThis mismatch is attributed to simulation of weak westerlies and moisture fluxes, amplified by surface\u2010energy\u2010balance and surface\u2010water\u2010balance feedbackThe mismatch is similar to bias in climate model simulations for the present day The midHolocene experiment shows the response to changes in the seasonal and latitudinal distribution in insolation 6000\u00a0years ago, with greenhouse gas concentrations at preindustrial levels . We usen et al. . Long\u2010tepiControl simulation (circa 1850\u00a0Common Era (C.E.)). We therefore use National Centers for Environmental Prediction\u2010Department of Energy (NCEP\u2010DOE) Reanalysis 2 data .The mid\u2010Holocene (MH) has been a major focus for paleoenvironmental and paleoclimate synthesis. We use data from the Global Lake Status Database  over the Eurasian midcontinent in the CMIP5/PMIP3 midHolocene simulations compared to the piControl  and soil moisture (as measured by \u03b1). Drier (than piControl) conditions are most marked in the belt between 40\u00b0 and 60\u00b0N. Summer temperature is significantly higher than in the piControl  [see Bartlein et al., midHolocene simulations therefore appear to be too dry and too warm relative to the paleoclimatic observations.There is substantial agreement in the spatial and seasonal expression of the sign of change in the simulated climate variables across individual models see the , which aAlthough generally dry, the region of interest has a distinct summer wet season, when soil moisture is replenished by higher precipitation provided by increased moisture flux from westerly sources see the , and thepiControl over the first half of the year. Precipitation is lower than piControl through May and little different afterward  confirms that summer warming is a surface\u2010driven phenomenon , the latitudinal temperature gradient in the Northern Hemisphere was less steep than today during the winter (November through April) but steeper than today during summer , and much lower than observed in summer . As in the midHolocene case, the dry bias is exacerbated by the energy balance feedback: soil moisture is generally lower than in the reanalysis throughout the year, latent heat is lower and sensible heating higher than in the reanalysis. The mechanisms that give rise to biases in surface climates in the midHolocene simulations are thus operating in the piControl, and the circulation\u2010related variables are indeed weaker than in the reanalysis. This discrepancy is particularly noteworthy because the piControl climate is globally colder than the twentieth/21st centuries and the latitudinal temperature gradient steeper, and so a priori [Rind, The latitudinal temperature gradient in the s Figure\u00a0 is weakeri Rind, , the sim4Braconnot et al., Wohlfahrt et al., Otto\u2010Bliesner et al., Zhang et al., Braconnot et al., Harrison et al., Schmidt et al., Mauri et al., Perez\u2010Sanz et al., Izumi et al., Bonfils et al., Mauri et al., Randall et al., Flato et al., We have shown that the erroneous simulation of warmer and drier summers in Eurasia during the MH (relative to present) is ultimately caused by the weaker westerly circulation, which results in low precipitation in early summer and is a precondition for the operation of strong positive energy balance feedbacks in driving simulated temperature increases. Data\u2010model comparisons of regional paleoclimates have often focused on model benchmarking, i.e., diagnosis of the quantitative mismatch between simulated and observed climates [e.g., Kohfeld et al., Herold and Lohmann, Caley et al., Dietrich et al., In our analyses, we have compared reconstructions of surface climates to model outputs. We have not attempted to diagnose atmospheric circulation directly. Although there have been some attempts to reconstruct paleocirculation [e.g., midHolocene simulations. Such robustness in the simulated climate is often taken as a sign that the signal is correct, for example, in the interpretation of future regional climate changes [e.g., Ciscar et al., Flato et al., Harrison et al., The long\u2010term average differences in both circulation\u2010related and surface energy balance variables, both seasonally and in their spatial patterning, are remarkably similar across the suite of CMIP5/PMIP3 Jung et al., In conclusion, the simulation of circulation needs to be improved in order to simulate midcontinental Eurasian surface climates better, both in the mid\u2010Holocene and under modern conditions. It is generally assumed that increasing model resolution, through improving the representation of topography and land\u2010sea geography, will improve the simulation of circulation and atmospheric dynamics [Supporting Information S1Click here for additional data file.Data Set S1Click here for additional data file."}
{"text": "Parental investment theory Trivers,  stipulatper se (Allan et al., In contrast, Smith et al.  propose Research into sex-specific memory biases for mate-choice relevant stimulus is still in its infancy. Yet it is encouraging to see evidence for the impact of delineated selection pressures between men and women. The data from Fitzgerald et al.  is signiThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "This is illustrated by McKenna and co-workers [ Furthermore, as neutrons  are a non-destructive probe, the resulting structures are free from radiation damage even at room temperature  atom and proton , a sulfonamide, which binds with high affinity to human carbonic anhydrase isoform II  for both of the drugs against hCA II is similar (~10\u2005nM), they discuss the balance between enthalpic and entropic contributions towards drug binding, and using molecular dynamics simulations suggest that in the case of MZM, hydro\u00adphobic forces perhaps compensate for the loss of an extensive H-bonding network.In this issue of et al., 2013et al., 2016et al., 2015In recent years, a growing number of neutron structures have been deposited in the Protein Data Bank, including a number of other examples of enzyme-drug complexes, such as the recent structures of HIV-1 protease with the clinical inhibitors amprenavir (Weber"}
{"text": "The rational use of medicines is a goal that should not be attributed only to the meeting between health professional and user, because it goes beyond the limits of mere interaction between prescription and use that takes place in the doctor-patient relationship.This alleged rationality in the use of medicines would require a difficult alignment between distinct rationalities of the various actors that interact in the field of pharmaceutical services: federal, state, and municipal governments; universities and technical courses; health professionals; public and private health services; pharmaceutical industry and providers of supplies; patients and media.In this sense, the proposition \u201cI think, therefore I am,\u201d which would indicate the prominence of the Empire of reason, might fail, because \u201cwe think where we do not exist, or exist where we do not think\u201dHowever, this cannot move us away from the pursuit of a common vision that articulates the different actors of the field around a set of principles and agreements that can promote a quality use of medicines, namely: (1) strengthening the right to health care by universal health systems; (2) providing care with solutions in line with the needs of the population; (3) encouraging effective procedures; (4) promoting health and preventing diseases; and (5) setting in a transparent way the roles of the actors in the field.Thus, we seek to reverse the logic that the medicine is only one \u201cinput\u201d in the health care network, so that it can be seen as element of an interconnected chain that produces quality \u201coutcomes\u201dTo do so, we need: (1) easy access to essential medicines at costs that society can endure; (2) medicines that meet criteria of quality, safety, and efficacy; (3) quality use of medicines; (4) stimulus to industry segments that are viable and responsiblePesquisa Nacional sobre Acesso, Utiliza\u00e7\u00e3o e Promo\u00e7\u00e3o do Uso Racional de Medicamentos  to produce a comprehensive scenario of the situation of access and use of medicines in BrazilIn this context, governments and universities gathered around the Revista de Sa\u00fade P\u00fablica has published, in previous supplementThis Supplement deals with the evaluation of pharmaceutical services in the primary health care \u2013 indicating advances and challenges \u2013; the methods used; the concepts of what is meant by pharmaceutical services; clinical pharmaceutical activities carried out; the way how pharmaceutical services are being institutionalized in the cities; and how access to medicines occurs. Still, this supplement explores how the organization of the workforce, of the selection, availability, and dispensation of essential drugs in primary health care, and of the funding and management of pharmaceutical services takes place. Also, it examines patient-related aspects \u2013 access, use, rational use, polypharmacy, satisfaction, and quality of life.Costa et al.Although there are initiatives in the management of the Brazilian Unified Health System (SUS) to create some degree of standardization of procedures, Costa et al.However, Ara\u00fajo et al.Souza et al.And how are medicines selected for the health care network? Karnikowski et al.In addition, Leite et al.Regardless of the features in the selection and dispensation, Costa et al.Without adequate financial resources, there is no way to improve the selection and dispensing aspects and the quality of conservation and inventory of medicines. Faleiros et al.And how do health professionals act before this profile established so far? Carvalho et al.Patients, which are the main reason of health services, are treated in many ways.Bolsa Familia benefit. Only 9.8% had health insurance, with higher proportion in the South region and lower in the North and Midwest. Alcohol consumption and smoking were more present among men. Costa and SilveiraInterviews were carried out with 8,803 patients distributed in different parts of the CountryNascimento et al.From the patients\u2019 perspective, \u00c1lvares et al.Soeiro et al.In addition to the use of medicines, Ascef et al.The article by Lima et al."}
{"text": "Numerous studies have investigated whether additional abilities of artificial agents improve the interaction with their users. Typically, a specific capability was added to a baseline system and participants interacted with both versions. Questionnaires  capabilities contribute differently to an interaction and do not necessarily increase an artificial agent's comprehensibility. Conrad et al.  tested tIn sum, Conrad et al.  estimateThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Several review articles have been published on the history, biotechnology, and implications of CRISPR system recently  is a term that has become synonymous with genome editing. CRISPR enables researchers to modify genomic DNA The foundational discoveries that led to CRISPR biotechnology can be traced back to 1993 (Mojica et al., Shipman et al.  have recHuman and Animal Locomotion series, that of a galloping horse (Figures In their recent article, Shipman et al.  scale up Figures B,C. The Clustered regularly interspaced short palindromic repeats genomic loci consist of repeat sequences, typically 20\u201350\u2009bp in length, separated by variable spacer sequences of similar length (Bolotin et al., In the previous work, Shipman et al.  providedEscherichia coli type I\u2013E CRISPR\u2013Cas system.In their recent article, Shipman et al.  were ablShipman et al.  encoded However, the rigid strategy did not work very well because it ended up generating some sequences that were not very compatible with the CRISPR system. In addition, Shipman et al.  found thE. coli which, using Cas1/Cas2 activity, added them to the CRISPR arrays in their genomes. After retrieving all arrays, again from the bacterial population by high-throughput sequencing, they finally were able to reconstruct all frames of the galloping horse movie, and the order they appeared in with 90% accuracy (Figure To create the galloping horse movie, Shipman et al.  used a sE. coli. This sophisticated experimental approach could not only open entirely new possibilities of recording, archiving, and propagating data but it could also be engineered further into an effective memory device. The properties of Cas1 and Cas2 that were engineered into the molecular recording tool, together with the novel understanding of the sequence requirements for optimal spacers, enables a significantly scaled-up potential for recording in the genome memories/molecular experiences cellular structures are having during their growth and development, or exposure to stresses and pathogens in a chronological fashion.The interesting part of this research is not necessarily the image encoding but rather how Shipman et al.  utilizedThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Excessive menstrual bleeding\u2014menorrhagia is a common gynecologic disorder affecting women of reproductive age. Subjectively, menorrhagia is defined as a complaint of heavy cyclical menstrual bleeding occurring over several consecutive cycles (R\u00f6nnerdag and Odlind, Underlying bleeding disorders only have been recognized during the last two decades as a significant etiopathogenetic factor for menorrhagia formation. The available data from the literature show the frequency of hemostasis disorders in women with menorrhagia in the range of 10\u201320% (El-Hemaidi et al., Previous research has shown that in the population of women who suffer from menorrhagia, the frequency of disorders of hemostasis is 17% (Djukic et al., Studies have shown that physicians are not likely to consider a bleeding disorder as a possible cause of menorrhagia. Only 3% of them would refer patients to a specialist and four percent of gynecologists surveyed would consider von Willebrand's disease as a possible diagnosis in women with menorrhagia (Dilley et al., Disorders of hemostasis, especially the ones seldom recognized (Lukes et al., Certain lack of awareness of the potential of hemostasis disorders to cause abnormal bleeding is clearly present in the clinical gynecology. Besides there is a substantial need to develop more reliable clinical tools for the objective assessment of excessive menstrual bleeding. These circumstances lead to the underdiagnosed cases and suboptimal treatment of women with bleeding disorders, including unnecessary hysterectomy (Ranson and John, SD made conception of the work, data collection and interpretation. DL made data collection and interpretation. NJ made data collection. MV made conception of the paper, critical revision of the article and final approval.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The manuscripts in this thematic issue on musculoskeletal oncology present different techniques and address difficult topics that have received limited attention in the current literature. Because of the wide variety of clinical situations encountered with bone and soft tissue tumors, it is essential for oncologic surgeons to be both facile and versatile. The following manuscripts contain valuable techniques for readers to augment their surgical armamentarium and clinical acumen.et al. discuss the unique technique of thorascopic-assisted resection of a chondrosarcoma in a pediatric patient. Chondroid lesions can be a diagnostic challenge. A systematic review of malignant degeneration of synovial chondromatosis is discussed by Ng et al. In the third article, Conrad et al. discuss their experience with treating unicameral bone cysts.In the first article, Bawa et al. Infection and wound healing can be a significant challenge. Gupta et al. explores using negative pressure wound therapy and also a novel antibiotic spacer to address these issues.The remainder of articles focuses on techniques and issues related to surgical resection and reconstruction. The accuracy and precision of surgical navigation is explored by Gundle We hope that orthopaedic oncologists and general practitioners alike find this special issue both useful and interesting."}
{"text": "We read with great interest the paper entitled \u201cWorld's First Clinical Case of Gene-Activated Bone Substitute Application\u201d in Case Reports in Dentistry . We woulFirstly, it is important to understand that there is currently only one approved gene plasmid-based therapy on the world market. Indeed several authors in the Deev et al. paper actively participated in the development  of the VThis is why we focused on a completely new approach for gene activation of a demineralized bone allograft. We created a dual cassette expression plasmid, encoding for both proangiogenic vascular endothelial growth factor 165 (VEGF165) and proosteogenic bone morphogenetic protein 2 (BMP2). We believe that expression of both these growth factors not only stimulated angiogenesis, but also enhanced osteogenesis at the site of the bone graft transplantation.Similar to Deev et al., we demonstrated the effectiveness of gene-activated bone transplants in stimulating osteogenesis which, in our study, resulted in callus formation at the site of ulnar pseudarthrosis. Besides the many in vitro and in vivo animal studies expertly reviewed by Deev et al. , to our"}
{"text": "Brachiopods represent an animal phylum of benthic marine organisms that originated in the Cambrian. About 400 recent species are known from today's oceans  are expressed in the area that becomes the pedicle lobe and the posterior domain of the mantle lobe in T. transversa, and also in the posterior domain of the posterior lobe in N. anomala (Figure T. transversa showed a split into three subclusters similar to that observed in other spiralians, such as in the annelid Capitella teleata and the limpet mollusc Lottia gigantea (Schiemann et al., Scr and Antp in the shell-forming epithelia of N. anomala and T. transversa larva suggests a role of these genes during juvenile shell formation (Schiemann et al., Several studies have investigated the expression patterns of developmental genes in lecithotrophic brachiopod larvae (Altenburger et al., a Figure  (Altenbua Figure . Hox gena Figure . AnalysiT. transversa and N. anomala, it is possible to trace the body axes to the post-metamorphic body plan, and there are no signs of a folding event. Cohen et al. (N. anomala (Nielsen, N. anomala showed that larva settle with the posterior-most tip of the posterior larval lobe and that vental and dorsal valves are not secreted from the same tissues (Altenburger et al., The expression patterns of \u201canterior\u201d and \u201cposterior\u201d genes in lecithotrophic brachiopod larvae are in an anterior-posterior sequence similar to the expression domains as detected in, for example, annelids and sea urchin embryos (Wei et al., n et al.  based thNielsen, . HoweverKutorgina chengjiangensis clearly has a straight gut (Zhang et al., Since there is no folding event during metamorphosis in craniiform or rhynchonelliform brachiopods (Altenburger and Wanninger, Even though the data currently available do not allow for a conclusive hypothesis on the evolution of the brachiopod body plan, it is clear from the newly available gene expression data that the brachiopod fold hypothesis should be discarded and an alternative hypothesis for the evolution of brachiopod body plan is needed. One alternative scenario would involve a stem-group brachiopod with a tubular sclerite arrangement (Skovsted et al., AA designed the paper. AA, PM, GB, and LH wrote the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Evolutionary perspectives are vital to tackling a wide range of health challenges in today\u2019s world, including emerging infectious diseases, the evolution of antimicrobial resistance, increasing prevalence of autoimmune diseases, the obesity epidemic, threats to food safety, neurodegenerative disease, cancer and more. To address this scope of diseases, evolutionary medicine is highly interdisciplinary, drawing on perspectives and approaches in ecology, evolution, biological anthropology, and global health (which itself is very interdisciplinary). Some evolutionary medicine research programs focus on understanding why humans are vulnerable to disease, whereas others aim to apply evolutionary approaches to more effectively prevent or treat disease.Because of these broad health foci and approaches, it is challenging to distill core principles for evolutionary medicine. What are the major concepts that one must understand to enter this field of research, practice, and general understanding? For those of us who teach evolutionary medicine to undergraduates, this is particularly challenging and important to consider. It is obvious from discussions with many colleagues that our courses are as heterogeneous as the topics and approaches in evolutionary medicine itself, with professors gravitating toward their areas of familiarity and leaving gaps in our curricula. This is especially important for undergraduate courses, as this may be the only exposure that our future doctors, nurses, veterinarians, dentists and public health officials have to evolutionary medicine at a broad level.Evolution, Medicine and Public Health by Daniel Grunspan et al. [Some crucial guidance is now available in a paper just published in n et al. . In thiset al. [Grunspan et al.  pursued et al. , along wet al.\u2019s [et al.\u2019s [Grunspan et al.\u2019s  paper iset al.\u2019s  contribuEvolution, Medicine and Public Health will be publishing Foundational Clinical Briefs about each of the core principles that emerged from Grunspan et al.\u2019s [To advance these findings, et al.\u2019s  paper. Tet al.\u2019s , which aConflict of interest: None declared."}
{"text": "Oncotarget. The management of modifiable risk factors in traumatic brain injury victims has a main role in the patients outcome and a inappropriate treatment is followed by a worse prognosis. Knowledge about the mechanism of hyperglycemia, comorbidities, potential causes, effects and associated factors can improve the treatment process associated with adequate therapeutics could reduce the complications and modify outcome of these victims [We read with great interest the recent study by Shi et al  publishe victims , 2.A strong point of the paper is providing a meaningful view of mechanisms of hyperglycemia after traumatic brain injury and the pathway that lead to systemic dysfunctions and the role of comorbidities, including iatrogenic factors . HoweverLiu-DeRyke et al  describeThe review described by Shi et al  showed t"}
{"text": "Mycobacterium avium complex (MAC)] treatment and has been used in patients coinfected with HIV/AIDS  to a much lower degree than RIF , Mycobacterium leprae and other non-tuberculous mycobacteria and it yields higher MIC values against actively growing Mycobacteria , a member of rifamycin family, was approved by the FDA in 1992 and was recognized in 2009 as an essential medicine by WHO  in the rpoB gene in Mtb is significantly associated with mutations from codons 507\u2013533 of rpoB, within an 81 bp fragment of rpoB gene. A high level of rifamycin resistance (RIF and RFB) is exhibited by strains with mutations in codons 526 and 531  , reduced cell wall permeability, or inactivation of drugs\u2014was at play  were also associated with RIF resistance  and can be countered by using EPIs (De Vos et al., in vitro. Since RFB has exhibited reduced toxicity and other pharmacological advantages over RIF in HIV/AIDS patients, it should be tested in combination with molecules reported to increase drug efficacy and possess potential immunomodulatory activity in a murine model.There have been reports that rpoB mutation, but the method is time consuming: it takes several weeks to generate a susceptibility profile. This prolonged duration can result in a delay in treatment and the generation of drug resistance over time. Furthermore, there have been reports about the compensatory mutation in rpoA and rpoC regions that improve the fitness cost in RIF-resistant Mtb strains (De Vos et al., The conventional drug susceptibility assay can provide appropriate results for detecting Mtb in China and many other high TB burden countries. Furthermore, studies of this kind will be useful for developing combination treatment regimen effective against mycobacterial diseases based on rpoB gene mutations (Deshpande et al., rpoB gene and facilitate the analysis of drug resistance to RFB associated with double mutations in the rpoB gene.The current study is interesting and will help in epidemiology studies about the burden of RIF and RFB resistance against SS and ND have made substantial, direct and intellectual contribution to the work, critically reading an earlier version of this manuscript and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Executive functions are a set of top-down higher order cognitive processes that are vulnerable to sleep loss . Importantly, all these conditions may have different effects on cognitive functions. For instance, Shekleton et al.  suggesteThe inclusion of standardized measures of sleep disturbance and symptoms severity would additionally allow to explore the reciprocal relationships between poor sleep, executive functions and depression. As aforementioned, executive functions are impaired in major depression (Snyder et al., To conclude, the study of de Almondes et al.  highlighAB contributed writing the draft of the manuscript; CL contributed revising the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Pacific Water (PW) enters the Arctic Ocean through Bering Strait and brings in heat, fresh water, and nutrients from the northern Bering Sea. The circulation of PW in the central Arctic Ocean is only partially understood due to the lack of observations. In this paper, pathways of PW are investigated using simulations with six state\u2010of\u2010the art regional and global Ocean General Circulation Models (OGCMs). In the simulations, PW is tracked by a passive tracer, released in Bering Strait. Simulated PW spreads from the Bering Strait region in three major branches. One of them starts in the Barrow Canyon, bringing PW along the continental slope of Alaska into the Canadian Straits and then into Baffin Bay. The second begins in the vicinity of the Herald Canyon and transports PW along the continental slope of the East Siberian Sea into the Transpolar Drift, and then through Fram Strait and the Greenland Sea. The third branch begins near the Herald Shoal and the central Chukchi shelf and brings PW into the Beaufort Gyre. In the models, the wind, acting via Ekman pumping, drives the seasonal and interannual variability of PW in the Canadian Basin of the Arctic Ocean. The wind affects the simulated PW pathways by changing the vertical shear of the relative vorticity of the ocean flow in the Canada Basin. Pathways of the Arctic Pacific Water are investigated in ocean modelsVariability of the Pacific Water due to wind is examinedMechanisms of the Pacific Water variability are suggested In the Makarov Basin and above the Lomonosov Ridge, the thickness of the PW layer decreases to less than 150 m with the PW fraction decreasing to less than 60% [Ekwurzel et al., Jones and Anderson, Alkire et al., As it crosses the shallow Chukchi Sea, PW cools by \u223c0.7\u00b0C and loses \u223c0.6 \u00d7 10Aagaard and Carmack, Steele et al., Anderson et al., Carmack et al., Polyakov et al., Shimada et al., Steele et al., Woodgate et al., Rainville and Woodgate, The freshwater fraction of PW contributes significantly to the formation of a strongly stratified Arctic halocline [Giles et al., Woodgate, et al.One critical question is whether wind\u2010driven spin\u2010up of the Beaufort Gyre can increase the vertical shear in the upper ocean velocity, thin the halocline and allow vertical heat transfer from the Atlantic Water to the base of the sea ice and so substantially reduce sea ice cover [e.g., Jones [McLaughlin et al. [Steele et al. [McLaughlin et al. [Steele et al. [McLaughlin et al., Morison et al., Proshutinsky et al., Steele et al., Timmermans et al., Different circulation patterns of PW in the Arctic Ocean have been inferred from water properties by Jones , McLaughn et al. , and Stee et al. . The latn et al.  proposede et al.  analyzedMcLaughlin et al., Steele and Boyd, McLaughlin et al., Steele et al., McLaughlin et al., Steele et al., Swift et al., The lateral extent of PW across the Canada Basin and the Makarov Basin Figure  is thougAlkire et al., Morison et al., Arctic Climatology Project, Morison et al. [Woodgate et al., [The 2003\u20132005 return of the frontal zone between Canadian Basin and Eurasian Basin polar waters to the pre\u20101990s near\u2010climatological conditions and a partial return of PW into the Makarov Basin observed in 2003\u20132006 were accompanied by the shift of the Transpolar Drift from the Mendeleev\u2010Alpha Ridge toward the Lomonosov Ridge [ et al.,  found a Shtokman [Coachman et al. [Stigebrandt [Proshutinsky [Woodgate et al. [The sea level gradient between the Pacific and Atlantic Oceans as a mechanism for driving the inflow of PW through Bering Strait\u2014a hypothesis first proposed by Shtokman  and thenn et al. , Stigebrgebrandt , Proshuthutinsky , and Wooe et al. , 2010. CProshutinsky and Johnson, Steele et al., Coachman et al., Aagaard et al., Roach et al., Woodgate et al., Basin\u2010scale atmospheric circulation [e.g., Gudkovich, Aagaard and Carmack, Rampal et al., Sea ice conditions which influence both rates of air\u2010ocean momentum transfer and ocean stratification on seasonal and interannual scales [e.g., The present study is motivated by the questions formulated above and is driven by several hypotheses. We expect that the strength and patterns of PW circulation in the Arctic Ocean are highly variable and depend on at least three major factors, namely:Investigation of how these multiple factors influence the PW dynamics based on observational data alone is difficult because extensive long\u2010term measurements with high spatial resolution are required. Besides, because of the complexity of the PW dynamics due to the coinfluence of the factors mentioned above, it is difficult to clearly separate underlying physical processes using currently available observational data.To investigate PW dynamics in this paper, the results from regional and global models obtained in the coordinated AOMIP experiments, and in the follow\u2010up research under the umbrella of the Forum for Arctic Modelling and Observational Synthesis (FAMOS), were analyzed with the aim of answering the above questions. Six regional and global Ocean General Circulation Models  [Madec et al., The key components of six coupled sea ice\u2010ocean models employed in the Pacific Water model experiment are described in Table Holloway et al., Proshutinsky et al., Jahn et al., Johnson et al., Clement Kinney et al., K\u00f6berle and Gerdes, Karcher et al., Kauker et al., Aksenov et al., http://www.whoi.edu/projects/AOMIP.All the six models participated in the previous phases 2 and 3 of the AOMIP experiments and were described in AOMIP publications [Nurser and Bacon, The model horizontal resolution in the Arctic Ocean in the five models, COCO, ECCO2, ICMMG, NAOSIM, and ORCA, was similar, from 23 to 37 km, rendering these models as noneddying in the Arctic, whereas OCCAM was eddy permitting at the \u223c8 km resolution [e.g., Nguyen et al., Aksenov et al., \u22121 drift in the baroclinic circulation after \u223c20 years .Five models of the current model set  used NCEP atmospheric reanalyses and one model (ECCO2) used JRA25 atmospheric forcing. For the present experiments, models were integrated over 1989\u20132007 from 41 year long spin\u2010ups for ICMMG, NAOSIM, and ORCA, a 20 year long spin\u2010up of COCO, a 4 year long spin\u2010up of OCCAM, and no spin\u2010up for ECCO2. The latter was forced with an optimized atmospheric forcing and lateral boundary fluxes, reducing model drift [Woodgate et al., Clement Kinney et al., Two out of the six models were global (OCCAM and ORCA), three were regional , and one (ECCO2) was a model nested in an outer global model with optimized oceanic exchanges through the open lateral boundaries at 55\u00b0N in the Atlantic and Pacific oceans. In two regional models, ICMMG and NAOSIM, the annual mean barotropic inflow in Bering Strait was constrained to its mean annual climatological value of 0.8 Sv [Hunke and Dukowicz, Hibler, Therefore, although the present study was not set up as a controlled forcing experiment, the wind forcing across the entire model set except one model (ECCO2) was the same. Given that the four models  used the same elastic\u2010viscous\u2010plastic (hereafter EVP) rheology in sea ice dynamical model [2.2To examine the pathways of PW in the Arctic Ocean in the models, a \u201cpassive tracer,\u201d which does not affect water density and thus is passive with respect to ocean dynamics, was released in Bering Strait. The idea was to run models for the period 1989\u20132007 with an initial spin\u2010up for a 41 year from a state with the ocean and sea ice at rest (spin\u2010up period was shorter for some models) and to investigate PW tracer evolution, in particular area coverage and concentration, under the influences of external forcing. The challenge for this study was to identify periods that may represent a stable ocean circulation and link simulated PW tracer distribution patterns to external factors, such as PW inflow through Bering Strait and winds.Thompson and Wallace, Steele et al., Proshutinsky and Johnson, Proshutinsky et al., Under the assumption that wind forcing is the major factor responsible for ice and ocean circulation in the Arctic Ocean, we have used the AO index to identify periods of more or less stable atmospheric and oceanic circulation regimes. The AO index represents a dominant mode of the atmospheric sea level pressure (SLP) variability in the Northern Hemisphere [Steele et al., The analysis of model results was focused on ocean circulation from 1989 to 1996 (high AO and a cyclonic atmospheric circulation) and from 1997 to 2007  [Following the approach described above a set of three experiments was designed.Experiment 1. In the first coordinated experiment (hereinafter Exp1), at the beginning of the period 1989\u20131996  the passive PW tracer was set to unity through the whole water column at a section across Bering Strait, and to zero elsewhere , the tracer was released in Bering Strait as in Exp1 but throughout the period 1958\u20132007, starting on the 1 January 1958, on 0:00 hours GMT, in order to investigate possible drivers of PW variability and the PW contribution to Arctic fresh water. The experiment was performed with three models\u2014ICMMG, NAOSIM, and ORCA.Experiment 3. This experiment (hereinafter Exp3) was designed to test the sensitivity of the simulated ocean circulation to the horizontal resolution and atmospheric forcing and was performed only with the ORCA 1\u00b0, 1/4\u00b0, and 1/12\u00b0 global configurations, since there were three existing runs at different resolutions with the same model configuration. In the experiment, the passive PW tracer was released in Bering Strait as in Exp1 but throughout the period 1983\u20132007 in the ORCA 1\u00b0 configuration. The model stream functions of the ocean circulation, oceanic relative vorticity, and Ekman pumping for the cyclonic 1989\u20131996 and anticyclonic 1997\u20132007 periods were analyzed to examine forcing mechanisms for the PW dynamics and pathways.2.3For the analysis presented here, monthly and annual volume, heat and freshwater oceanic transports between the Arctic Ocean and Pacific and Atlantic oceans were calculated at key sections across Bering, Fram and Davis Straits and the straits of the Canadian Arctic Archipelago Figure .refS\u2009=\u200934.8, which is the estimated mean salinity of the Arctic [Aagaard and Carmack, amamoto\u2010Kawai et al., Rabe et al., Jahn et al., Monthly time series of PW content (PWC) and freshwater content (FWC) were obtained for each of the Arctic regions depicted in Figure Jones and Anderson [pwS\u2009=\u200932.0 [Jones et al., refS\u2009=\u200934.8 is taken, so PW is the product of PW fraction and a constant scaling factor (1\u2009\u2212\u2009pwS/refS). We also derived the vertically integrated content of the Pacific fraction of fresh water (PFWC)  [e.g., r et al.  and Curry et al.  .Oden in July\u2013August 2005, Arctic Ocean Section 2005 (hereinafter AOS05) which began from the Alaskan shelf in the vicinity of Barrow and crossed the Arctic Ocean and ended near Svalbard [Jones et al., Louis S. St\u2010Laurent summer cruises (hereinafter LSSL03/04) [Yamamoto\u2010Kawai et al., Simulated PW parameters and PW fractions in the Arctic Ocean were compared with published observed distributions of these parameters obtained from various Arctic cruises: (a) the trans\u2010Arctic cruise of the Ice Breaker Jones et al. [Jones and Anderson [Alkire et al., Carmack et al., Falck et al., The vertical distribution of PW fraction across the Fram and Davis Straits estimated by s et al.  and JoneAnderson  from end3All six models listed in Table Steele et al. [Nguyen et al. [Watanabe [The models' performance was assessed by examining the inflow through Bering Strait and the outflows through Fram and Davis Straits, with a focus on the upper circulation in the Arctic Ocean. Once validated, we used the model results to identify PW pathways through the Arctic Ocean and diagnose the Arctic freshwater content change due to changes in the PW storage in different regions of the Arctic Ocean. We did not investigate different types of PW as defined by e et al.  .3.1Karcher et al., Golubeva and Platov, Holloway et al., Gerdes et al., Watanabe, Aksenov et al., Popova et al., Nguyen et al., Jahn et al., Johnson et al., Clement Kinney et al., Clement Kinney et al. [In this section, only the comparison relevant to the present analysis is given, but more detailed assessments of each model may be found elsewhere [e.g., y et al. . It willFieg et al., \u22123 Sv\u2009=\u2009103 m3 s\u22121). These values are close to the observational estimates of 159\u2009\u00b1\u200934 mSv .3.2Carmack et al., 3 yr\u22121 at the end of the integration period.The mean summer 2003/2004 vertical distributions of the PW fraction in the Beaufort Sea and Central Arctic Ocean simulated in Exp1 were compared with the observations from the LSSL03/04 and AOS05 cruises in the same area  fraction of PW tracer above the Alaskan shelf slope at depths \u223c50\u201380 m Figure . This coDuring 1997\u20132004 in ICCMG, PW at the surface, as well as at \u223c100 m, initially follows the Mendeleev\u2010Alpha Ridge, then turns toward the Beaufort Sea, with part of this flow branching toward Fram Strait Figures i and 6i.Summarizing, all models participating in the analysis, except NAOSIM, simulate a shallower than observed PW layer in the Canada Basin. ECCO2 and NAOSIM show the best agreement of the PW distribution across the Arctic Ocean with the AOS05 measurements. On the other hand, ORCA demonstrates the best agreement between the observed during the LSSL03/04 cruise and simulated spatial mean PW fraction in the Beaufort Sea in the top \u223c200 m in 2003/2004, although the simulated PW fraction is too low in this model. In all models, the total simulated PW content is lower than observed, probably due to the relatively short periods of the PW tracer releases in Exp1 (\u223c10 years). One of the implications of this analysis is that the short\u2010period PW model tracer releases can be used for pathways examination but have a limited application in the analysis of the PW content in the Arctic Ocean.3.3Timmermans et al., For the 1989\u20131996 cyclonic, and 1997\u20132007 anticyclonic circulation regimes, the models simulate two pathways of PW in the Arctic Ocean Figures  and 6. TTimmermans et al., The shelf route enables PW to spread westward toward the Siberian shelf. If there were no wind, under the influence of the Pacific\u2010Atlantic ocean sea level pressure gradient, PW would flow into the Arctic and then turn east along the Alaskan Shelf slope due to the Coriolis force [e.g., Steele et al. [The models show several differences in simulating PW pathways. In the COCO and OCCAM models, PW mainly follows the western pathway Figure , wherease et al. . The patIn all models but COCO, which exhibits a sharp decrease of PW fraction with depth, the spread of PW is similar in the top 100 m Figure . In the Aksenov et al., The simulations show consistency between increased vertical downward Ekman velocity (pumping) between 1989\u20131996 and 1997\u20132004 and deepening of the pseudopotential density surfaces   in all six models shows maxima of 20\u201327 m in the Canadian Basin, decreasing toward the Eurasian Basin of the Arctic Ocean Figure . This paCarmack et al. [Although different in detail, the vertically integrated PFWC in the models exhibits a similar distribution with maxima in the Canadian Basin; a pattern which is also evident in the observations , the PWC is \u223c200 m in the Canadian Basin (not shown), similar to the observed value of \u223c220 m [e.g., Alkire et al., Abrahamsen et al., Karcher et al., In the last decade, with a strong anticyclonic atmospheric circulation dominating the Arctic Ocean , the Pacific\u2010Atlantic front has partially recovered to its pre\u20101990s position [e.g., In summary, long\u2010term variations in the vertically integrated total FW and PW distributions in the models reflect the cyclonic (high AO) and anticyclonic  circulation regimes and show accumulation of the total and Pacific fresh water in the Beaufort Sea during the anticyclonic years and a decrease of their storage during cyclonic years Figures  and 11.3 loss of Arctic freshwater content, and in the decade 1997\u20132007 with lower and neutral AO induces, when anticyclonic circulation was accompanied by a sharp increase in the freshwater storage  [Rabe et al., 3, whereas the ICMMG peak\u2010to\u2010peak change is \u223c6000 km3.We use the ICMMG, NAOSIM, and ORCA model results for 1958\u20132007 to quantify the contribution of PW to the Arctic freshwater content variability in our simulations. We use results from continuous tracer releases for five decades (Exp2). Figure e Figure . The modPW that accumulated in the Canadian Basin prior to the 1980s was exported from the Arctic, such that the PW remaining in the basin was at a minimum in the late 1990s. Since the end of the 1990s, the PW content increased in the model simulations, surpassing the 1980s level by the mid\u20102000s Figure .As in the FWC results above, the simulated interannual change of PWC is dominated by variations in the Canadian Basin. Correlations between PWC change in the Canadian Basin in 1981\u20132007 (this period was chosen to avoid drift of PWC at the beginning of the integrations) simulated in ICMMG, NAOSIM and ORCA and the AO are 0.7, 0.9 and 0.7, . Since the PFWC change is equal to the PWC change multiplied by a constant factor Appendix , it is aAt the interannual scale, correlations between FWC change and Ekman pumping  show accumulation of PW in the Canadian Basin during the anticyclonic 1997\u20132007 years and release of PW toward Fram Strait during the cyclonic 1989\u20131996 years. This is consistent with the accumulation of the surface fresh water due to negative curl of total surface stress over the Canadian Basin in anticyclonic years [e.g., Since five out of six models in this study were forced with the same NCEP atmospheric winds, we examined whether the differences among the model circulations and PW pathways were related to different model resolutions, especially associated with how the models simulate topographically guided rim currents and ocean eddies. To test this, a set of sensitivity experiments (Exp3) were carried out with the ORCA model. These experiments included runs of the ORCA model with horizontal resolutions of 1/4\u00b0, 1\u00b0, and 1/12\u00b0.Holloway et al. [Increasing model resolution from 1\u00b0 (not eddy resolving) to 1/4\u00b0  and 1/12\u00b0  resulted in a more anticyclonic barotropic circulation in the Canadian Basin Figure . Holloway et al.  found th4.2Proshutinsky et al., From model results and observations [Rabe et al., On interannual time scales, FWC in the Beaufort Gyre and Canadian Basin simulated by NAOSIM shows a notable covariability with Ekman pumping [4.3Falck et al. [Dodd et al. [Dodd et al., Steele et al., Karcher et al., de Steur et al., Rabe et al., We now compare observed and simulated PW export in three models ICMMG, NAOSIM, and ORCA with the long\u2010term PW tracer release Exp2) that reached quasi\u2010equilibrium of the PW tracer content in the Arctic Ocean. It should be noted that it takes \u223c20 years for the models to reach quasi\u2010equilibrium between the inflow through Bering Strait and outflow of PW tracer from the Arctic. k et al.  and Doddd et al.  reported that rea4.4Gerdes et al. [Jahn et al. [Jahn et al. [Forcing imbalances, relaxation techniques, unresolved eddies, and missing processes in the mixed layer and upper part of the halocline, such as salt release from sea ice, all affect the models' performance. Here we only address the effects of the model resolution and accuracy of the model bathymetry. Higher\u2010resolution models better resolve narrow straits in the Canadian Arctic Archipelago. The experiments with the ORCA global model at 1\u00b0, 1/4\u00b0, and 1/12\u00b0 horizontal resolution show that if the model configuration and forcing are the same, and the topography unchanged , higher\u2010resolution models simulate higher outflow west of Greenland and lower outflow east of Greenland. s et al.  found thn et al.  examinedn et al.  conclude5The dynamics of PW in the Arctic Ocean has been analyzed using model experiments with tracer releases in six coupled sea\u2010ice ocean models. In this intercomparison, we have analyzed PW pathways across the Arctic Ocean and through the Canadian Arctic Archipelago and Fram Strait and explained the drivers of the PW variability. In support of earlier proposed schematics of the PW circulation in the Arctic, the models simulated the two main pathways of PW. The eastward PW route follows the Alaskan shelf and then across the western Beaufort Sea and through the Canadian Arctic Archipelago and Baffin Bay in the Labrador Sea, while the western PW route leads along the Siberian shelf and then in the Transpolar Drift and through Fram Strait to the Nordic Sea and in the North Atlantic. The contribution of the pathways varied between models. In ICCMG, NAOSIM, and ORCA, there is a clear relationship between PW pathways and AO regimes: during the cyclonic years (1989\u20131996), the eastern pathway dominates, whereas during the anticyclonic years (1997\u20132007), the western one prevails. Other models do not show such a strong adherence to the AO circulation regimes.Variations in the storage of the PW and associated FWC in the Arctic Ocean over the last 50 years have been examined using models and comparison with observations. There was a decrease in Pacific freshwater storage during the 1980s to 1990s and an increase during the last decade. Variations in FWC were similar to those of the PWC with a minimum in the 1990s. The simulated 1990s to 2009 anomalies are comparable with the freshwater inventory obtained from hydrography. The PW outflow through Fram and Davis Straits reflected the changes in PW in the Arctic Ocean, with a decrease in the PW export during last two decades. The model transit time for PW to cross the Arctic Ocean was estimated at 10\u201315 years, and the time for the PW outflow to reach a quasi\u2010equilibrium was \u223c20 years. Sensitivity tests with ORCA were carried out to isolate the effects of model resolution, wind forcing, and Bering Strait on the dynamics of PW in the Arctic Ocean. In the ICMMG, NAOSIM and ORCA simulations, the Ekman convergence is a primary driver of the seasonal variability of PW in the Canadian Basin.Penduff et al., The most challenging issue of the present intercomparison study is that there are significant differences between the models and the observations, namely: (i) the models differ in their simulation of the upper ocean circulation in the Arctic Ocean and (ii) the models differ in simulating oceanic outflow into the North Atlantic, in particular disagreeing on the partitioning of the outflow between the Canadian straits and Fram Strait. The higher\u2010resolution models are expected to perform better in the Arctic where the Rossby deformation radius is small and the seafloor has complex small\u2010scale bathymetry. However, from the present study, it is not immediately obvious that such an improvement occurs. Moreover, a simplistic refinement of the model resolution in some cases paradoxically leads to stronger model biases, suggesting that model tuning for the high\u2010resolution models might be more challenging than for the lower\u2010resolution ones. In particular, the choice of mixing and advection schemes, lateral boundary conditions, and treatment of the oceanic bottom boundary layer have proven to be crucial for the simulations [Yang, Another probable source of the divergence in model results is the forcing. Despite five out six models in this study being forced with NCEP reanalysis, the surface ocean circulation differs significantly. As sea ice dynamics moderates the atmospheric momentum transfer to the ocean, differences in sea ice cover in the models lead to different forcing of the ocean. Figure In this study, we have not discussed observational accuracy. Detection of the PW is based on the fine discrimination of chemical tracers which are not strictly conservative, but involved in the ecosystem. The nitrate/phosphate and Si techniques remain the only means to observe PW in the Arctic, and, as there are not independent methods, the accuracy of these techniques has some limitations, which need to be better quantified.Model validation is a crucial part of the model development process. More data in the Arctic Ocean are now becoming available, including new data on ocean turbulence measurements, biogeochemical tracers, that are extensively used to identify water masses, and radionuclides to track the spread of the water masses. It is important for the ocean models to take advantage of the new observations and, vice versa, the observational campaigns could significantly benefit from robust high\u2010resolution model simulations."}
{"text": "Locating a stimulus on the skin is a well-described perceptual task, but little is known about how this ability remains stable under ecological conditions. Specifically, the effect of recent stimulation has been the subject of very few studies in the tactile domain Craig, , but is Day and Singer  found a In the study of Li et al.  these quIn summary, the two preliminary experiments showed that tactile spatial perception is stable with time and that vibro-tactile stimulation reduces sensitivity to a subsequently applied touch stimulus. The main experiment found that adaptation results in perceived spatial expansion. Li et al.  propose In a different test of such a model, my own study tested the effects of adaptation following exposure to tactile motion on the dorsal side of the forearm. The study used a 15 cm/s motion stimulus which moved along a 19 cm path but only touched the skin for 4.5 cm at the proximal and distal ends of motion. Exposure to this stimulation resulted in an inwards position shift  of a stimulus at the edge of the gap (Brooks et al., Li et al. have shown results for only one stimulus size of adaptation, but could the observed spatial expansion be size dependent? Calzolari et al.  show thaRather than considering aftereffects to arise as a result of fatiguing neurons, they might represent the optimization of perception to the recent statistics of the environment. In vision there is increasing evidence that perception is optimized to statistical regularities of the environment (Seri\u00e8s and Seitz, Unlike many previous studies, Li et al.  show preIn summary, it is clear that sustained pressure leads to repulsive spatial aftereffects. Li et al.  have shoThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Global mental health has rapidly attracted increasing attention by health policy makers and researchers during the last 10 years. The groundwork for this shift was laid in data being made available on the prevalence . Efforts by researchers and innovators supported by funders like the Grand Challenges Canada (GCC website), National Institute of Mental Health of USA (NIMH Hubs website), Department of International Development of UK (PRIME), European Commission  are extremely relevant towards this objective. In addition, a number of researchers are working towards generating and aggregating critical evidence that will help in achieving the objectives of global commitments.This issue of Global Mental Health is intended to shed light on some of the evidence and experience that are relevant to implementing each of the five key objections of the Action Plan. Those objectives are to: (1) update mental health laws in line with international human rights instruments; (2) improve service coverage for serious mental illness by 20%; (3) have at least two functioning multi-sectoral prevention/promotion programmes; (4) reduce national suicide rate by 10%; and (5) establish minimal biennial national core dataset collection and reporting. For each of these objectives we present overview/review papers that summarize the research literature relevant to meeting that objective, and original research papers that look at current areas of innovation and attention. This issue we hope therefore contributes towards filling the knowledge gaps for implementers working to reach the Action Plan objectives, as well as pointing out the needs and opportunities ahead in creating the learning to meet these goals.Taking up each of these objectives in turn, first Marianne Schulze provides an overview of human rights principles for developing policies and laws on mental health, highlighting the need for all policies and laws to conform to international human rights agreements like the UN Convention on the Rights of Persons with Disabilities. Szmukler & Bach  flesh thet al. (et al. (The idea of \u2018task sharing\u2019 or task-shifting describes the idea of optimizing the skillsets of non-specialized workers to provide much of the steps in mental health care and promotion, such as through community health workers. It is increasingly turned to as a model for achieving the expanded service coverage goal of the Action Plan, and closing treatment gaps more broadly. The paper by Javadi et al.  provides (et al.  then furet al. (et al. (In terms of prevention and promotion, Tol  provideset al.  describe (et al.  summarizet al. (et al. (Finally, timely and actionable information is a critical element in better planning. Lora & Sharan  provide et al.  in a stu (et al.  extend tThese papers, though not the last word in identifying knowledge gaps on the path towards achieving the goals of the WHO Action Plan, do illustrate how much we do know to build on moving forward, as well as where to sharpen future efforts in generating, aggregating and disseminating information and evidence for more effective implementation of global mental health activities."}
{"text": "Dear Editor,We read with interest the article by Fothergill et al.  presentiGiven the frequent use of flavouring substances in the food industry , as wellThe question therefore arises, why we were not able to reproduce the experimental findings of Fothergill et al. , but alsThis question becomes particularly relevant as the presumed role for cinnamon supplements in a glycemic control has repeatedly been suggested but hitherto not been firmly established ,10. Furt"}
{"text": "Biodiversity conservation is one of the grand challenges facing society. Many people interested in biodiversity conservation have a background in wildlife biology. However, the diverse social, cultural, political, and historical factors that influence the lives of people and wildlife can be investigated fully only by incorporating social science methods, ideally within an interdisciplinary framework. Cultural hierarchies of knowledge and the hegemony of the natural sciences create a barrier to interdisciplinary understandings. Here, we review three different projects that confront this difficulty, integrating biological and ethnographic methods to study conservation problems. The first project involved wildlife foraging on crops around a newly established national park in Gabon. Biological methods revealed the extent of crop loss, the species responsible, and an effect of field isolation, while ethnography revealed institutional and social vulnerability to foraging wildlife. The second project concerned great ape tourism in the Central African Republic. Biological methods revealed that gorilla tourism poses risks to gorillas, while ethnography revealed why people seek close proximity to gorillas. The third project focused on humans and other primates living alongside one another in Morocco. Incorporating shepherds in the coproduction of ecological knowledge about primates built trust and altered attitudes to the primates. These three case studies demonstrate how the integration of biological and social methods can help us to understand the sustainability of human\u2013wildlife interactions, and thus promote coexistence. In each case, an integrated biosocial approach incorporating ethnographic data produced results that would not otherwise have come to light. Research that transcends conventional academic boundaries requires the openness and flexibility to move beyond one\u2019s comfort zone to understand and acknowledge the legitimacy of \u201cother\u201d kinds of knowledge. It is challenging but crucial if we are to address conservation problems effectively. Biodiversity conservation is inherently a \u201cwicked\u201d problem  and the drivers of that trade, providing guidance for the development of conservation strategies , mentored by one biological anthropologist (Jo Setchell) and one social anthropologist (Sandra Bell).et al. et al. et al. et al. et al. et al. Conflicts over conservation endeavors, whether directly between wildlife and people or between stakeholders over wildlife conservation strategies and implementation, are a major threat to the long-term survival of wildlife and to the livelihoods of subsistence communities in developing countries, particularly near protected areas . Specifically, her observations of the effect of wildlife foraging on crops planted by her Gabonese colleagues\u2019 families, living in villages inside Loango National Park and in or close to the buffer zone of the park, sparked an interest in the implications of conservation for the people who live alongside the park.et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. When wildlife forages on crops, this behavior is often termed \u201ccrop-raiding,\u201d although the intention implied by \u201craiding\u201d is inappropriate Hill . We therEmilie based herself in two remote villages in Loango National Park for more than a year. She used a combination of participant observation, an ethnographic journal, and semistructured interviews to investigate the institutional and social context of crop-foraging, and quantitative survey methods to assess the biophysical aspect of crop-foraging by medium to large mammals.et al. Emilie first investigated the context of conservation at her study site, and how this limits, or intensifies, conflict over wildlife. She showed that protected areas were implemented as a top-down conservation strategy in Gabon. The process excluded local populations from the decision-making processes and eroded or prevented feelings of ownership over their natural resources in local people, thus contributing to institutional vulnerability. This lack of trust prevents communication that would be beneficial to both the people and the national park. Emilie also found that people in Loango have an understanding of sustainability that shares common ground with Western conservation principles. However, farmers cite crop-foraging as the major reason for disliking protected areas and conservation, and these sentiments can result in unobtrusive subversion of conservation efforts, such as feigning ignorance of known conservation laws and legal processes to oppose the imposition of conservation strategies while avoiding direct confrontation Fairet . In so dLoxodonta africana) caused the most crop damage, and crop-foraging by elephants followed rainfall and was higher in fields located near permanent water points, probably as a result of seasonal changes in the availability of water and access to the herbaceous vegetation present in swamps . Moreover, most fields at the study sites are isolated from each other, creating islands of agricultural land surrounded by wild habitat, and Emilie\u2019s results demonstrate that field isolation renders some fields more vulnerable to crop-foraging than others. These findings are valuable, as most sites where crop-foraging has been studied are located in East and South Africa in areas with high human density and a high degree of deforestation, while Gabon has very low human densities (<0.2 inhabitants/km2 at the study site) and extensive forest coverage  and natural science  allowed a holistic view of the problem. Emilie used this integrated framework to provide recommendations for the management of crop-foraging in Gabon protected areas network that were scientifically sound and socially appropriate Fairet .et al. et al. et al. Wildlife tourism has the potential to produce revenue that can be used for conservation as well as to promote public awareness of conservation issues  in Bouhachem forest, Northern Morocco. For her doctoral research, Si\u00e2n was thus able to practice participatory action research, a style of research that entails sustained engagement and building of trust with participants in a project. Si\u00e2n\u2019s aim was to investigate how effective ethnographic methods could be toward creating a conservation strategy that involves local people and draws on their extensive ecological knowledge.Conservation projects for individual species are more effective if they incorporate local people\u2019s knowledge and perceptions of that species  on Atlantic salmon  in Scotland  and the largest wild canid in the forest, the African wolf (Canis lupus lupaster), are relatively uncomplicated, relating directly to goats as prey and wolves as predators. The shepherds\u2019 relationship with their dogs (Canis familiaris) is more ambiguous. Shepherds appear to resent the presence of dogs, but accept their role as a protector of livestock. The position of dogs in Bouhachem society mirrors the position of dogs elsewhere, symbolically existing \u201cbetween the human and non-human worlds\u201d  in Kenya , to integrate the datasets, producing results that would not otherwise have come to light . Such interdisciplinary projects are challenging to conduct. Many authors have described the boundaries of understanding and communication between academic disciplines with regard to conservation (Campbell Interdisciplinary research can provide detailed understanding of the context of a conservation problem and make recommendations for improvement Robinson . Howeveret al. et al. The case studies we present serve to highlight the need for researchers to become skilled at bridging disciplinary boundaries to provide a better understanding of the complexity of the context in which conservation occurs (Chan"}
{"text": "Rehabilitation in the context of HIV management in Africa is still a neglected field which holds great promise for the improvement of the quality of life as well as integration of people living with HIV back into their communities and homes. However, rehabilitation has not been incorporated into HIV care despite the fact that a large number of people living with HIV experience disability. The dearth of literature and lack of models of care to roll out rehabilitation for people living with HIV in Africa are astounding. Well-resourced countries have emerging approaches on the management of disability in the context of HIV. However, epidemic countries are still lacking such an approach neglecting the devastating effects of disability on individual livelihoods and antiretroviral treatment adherence. Thus, rehabilitation needs to be integrated into the response to HIV. This article advocates for the development and implementation of a model of care to guide rehabilitation of people living with HIV in South Africa. The protocol submitted is a PHD in Health Sciences .et al.et al.et al.The World Health Organization's International Classification of Functioning, Disability and Health (ICF) has changed the disability paradigm from unilateral into multidimensional, in that disability is not only seen to affect an individual's body but their social being as well (World Health Organisation et al. (et al.et al. (et al.Worthington et al.  used qua. et al.. Worthin.et al.  explored. et al..et al.\u2019s (et al.As an imperative in the rehabilitation of people living with HIV, the authors of this article identified three concepts to be included in the rehabilitation framework for a South African setting bearing in mind the ICF and Worthington et al.\u2019s , 2009 coet al.\u2019s . Secondls et al.. Thirdlys et al. and a reet al., Community-based rehabilitation which utilises local resources in areas with limited infrastructure (Iemmi et al.Canada is amongst the leading countries addressing rehabilitation of people living with HIV and for over 15 years has mobilised a working group of stakeholders forming the Canadian Working Group on HIV and Rehabilitation CWGHR . CWGHR het al.et al.A Model of Care \u2018is a multifaceted concept, broadly defining the way in which health care is delivered including the values and principles; the roles and structures; and the care management and referral processes. Where possible the elements should be based on best practice evidence and defined standards and provide structure for the delivery of health services and a framework for subsequent evaluation of care\u2019 (Davidson et al.These shortfalls often promote a convergence between research and the health care setting (Davidson The strategies involved in the development of the Australian rehabilitation models of care have been summarised and presented in a synthesis of Australian models of care in rehabilitation  New Sou. The modet al.et al.Reflections on working models enable researchers and health practitioners to identify gaps and causes of challenges within the system. For instance, the South Australia Department of Health 2 identifiet al.In order to guide the process of model development one has to identify logical steps and processes (Davidson Initial steps towards the development of such a model have commenced. For example, Phase 1: understanding the health policy context in South Africa is explored in preliminary work on HIV and disability. Evidence has been provided by Hanass-Hancock, Strode and Grant  and Hanaet al. (et al. (et al. (Secondly, Phase 2: definition and understanding the current state of play: Nixon  clearly et al. , Hanass- (et al.  and Van  (et al.  concede et al.et al.et al.Thirdly, Phase 3: translating evidence-based research and expert opinion into best practice: although South Africa is effectual in research pertaining to HIV and disability (Cobbing et al.et al.Consequently Phases 4 and 5: consulting broadly with stakeholders and incorporating feedback, as appropriate to produce a finalised model of care and endorsement of the model of care by Advisory Group and Health Networks are not yet initiated in South Africa. However, with expert opinions and reflection we will be able to develop evidence-based and feasible interventions. Only after this process, we will be able to agree on a model of care that is suitable to South Africa and that will be able to feed into the broader health agenda in South Africa. Such a model should involve communication both formal and informal in repetitive meetings to share information and solicit feedback regarding the sustainability and the running of the model. Furthermore, evaluation is often achieved by involving key stakeholders to give feedback on the progress and impact of the model (Cormack et al.et al.The need to develop a model to guide rehabilitation of people living with HIV in South Africa is essential as we address the cumulative disabling effects of the virus and its treatment. The process of development of the model needs to adhere to key processes that have already been tested in resource-rich contexts and now need to be further tailored to meet the needs of a resource poor context. A framework as in"}
{"text": "Mycobacterium smegmatis  and negative control (SOD or TEMPOL) to justify the exceptional HPLC profile obtained in the experiment.Stoichiometric ratio of superoxide and oxyethidium formation is 1:1 in superoxide reaction with DHE . Although reaction rate constant of TEMPOL with superoxide is much lower than that of SOD it has a similar in vivo efficacy which is ascribed to its smaller size and higher pentrability , but not by TEMPOL, has a role in growth. Noteworthy, DPI is a non-specific inhibitor of flavoenzymes, in addition, it inhibits pentose phosphate pathway and tricarboxylic acid cycle  and generally ineffective against bacteria. In particular, mycobacterial ETC is more complex than mitochondrial ETC due to diversity of components and branching (Cook et al., SOD is a standard negative control for the detection of superoxide due to the fact that it reacts with superoxide at 1,000 times higher rate in comparison to DHE (Zielonka et al., DHE-HPLC assay needs a careful standardization and should be supported by another standard method of superoxide estimation to affirm its biological role (Forman et al., The author confirms being the sole contributor of this work and approved it for publication.The author declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The integration of information between functionally specialized and widely distributed brain regions  is fundamentally important for cognition (Bressler and Menon, Recently, Mahjoory et al.  investigMahjoory et al.  showed tThere are several important issues to bear in mind when considering the consistency of EEG measures in the source-space, not least of which is the physiological state of participants at the time of recording. The resting condition is a challenging state for source-level analysis, and likely represents a major source of inconsistency in the source localization and connectivity outcomes. Related to this is the arousal state of the subjects. This has been shown to affect physiological significance of source localization and alter connectivity estimates using various methods and modalities (Kaufmann et al., Based on the findings of Mahjoory et al. , we highThere are several limitations of Mahjoory et al. , many ofMahjoory et al.  presenteAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Dear Editor,I read with great interest the article by Khadir F et al. that was published in your prestigious journal discussing about the protective effects of arbutin on lipid peroxidation in cyclosporine-treated rats . The aut"}
{"text": "We agree with Moreau and Candidi  that theMost researchers in the last decade utilize the Sebanz et al.  definitiA more restrictive definition of joint action was first proposed by Bratman, , who disAccording to Sebanz et al. , \u201cour brRelated work on joint action (e.g., Gonzalez et al., While philosophical discussions within social neurosciences may have called for a shift away from \u201cisolation paradigms\u201d (Becchio et al., In summary, we suggest researchers adopt the broad definition of Sebanz et al.  as it prUtilizing the Sebanz et al.  definitiSSB and PJB have made substantial, direct, and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "We read with interest the recent article by Leckey et al., reporting that consumption of a ketone diester drink impaired 31 km cycling time trial performance , but no symptoms were reported with a single bolus (Clarke et al., d-isoform, not l-BHB; the only way to accurately detect both is using mass spectrometry analysis. Additionally, AcAc is unstable and rapidly degrades when stored for over 48 h (Price et al., 4 converts AcAc into a stabilized BHB derivative, which can be analyzed after longer storage (Lincoln et al., Finally, we wish to highlight the importance of analytical techniques in the study of ketone metabolism. Enzymatic assays of BHB only detect the per-se impaired performance, as implied in the title and abstract of this paper. Contrasting results from existing studies using different ketone compounds, performance tests, dosages, and analytic techniques highlight that further research is required to determine the role of exogenous ketones in athletic performance (Cox et al., To conclude, consumption of the AcAc diester was ergolytic in a 31 km cycling time trial in the doses and formulation studied by Leckey et al. However, it is unclear if this would be the case were dosing and formulation optimized to achieve higher BHB levels and improve tolerability. Given the nature of the GI symptoms described, it is unknown whether hyper-ketonemia All authors agreed on discussion points for the commentary. BS wrote the initial draft with help from AK. AP, KF, and DD extensively revised and edited commentary. All authors reviewed and agreed final version prior to submission.BS is an employee of HVMN Inc., which sells exogenous ketone products. She has the option to purchase stock in HVMN Inc. AP is a scientific consultant for Pruvit Ventures, which sells exogenous ketone supplement products. She is also an inventor on intellectual property related to exogenous ketone supplementation for various uses. DD is an inventor on intellectual property related to exogenous ketone supplementation for various uses. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Peripheral machine interfaces are an important field of exoprosthetic research since they facilitate the communication between human and robotic device and thus their collaboration. Castellini et al.  give a vFrom the users\u2019 perspective, predictability of motion behavior and transparency of control appear to be crucial for embodiment irrespective of the considered extremity (Castellini et al., One of the technical suggestions of Castellini et al. is the investigation of semi-autonomous systems. While this is promising due to decreasing cognitive effort, such devices need to be carefully designed since increased autonomy might reduce the users\u2019 experience of agency, i.e., the feeling to be able to control the device, and thereby embodiment. Correspondingly, some users prefer retaining control over improving task performance which might recommend to customize autonomy (Gopinath et al., While being less explored, afferent feedback to the user appears to be psychologically crucial for embodiment since it relies on multisensory integration of vision, touch, and proprioception (Giummarra et al., In conclusion, human-oriented approaches should be researched to enable considering users\u2019 experiences and assessment in device and control design (Beckerle et al., The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Hasan et al.  is problematic: The results of the cross-classification may still at least partially reflect stimulus effects. The current study thus shows no clear support for modality-dependent  or modality-independent (due to stimulus dependencies) identity classification as such.Hasan et al.  use a refamiliar person recognition (only) but could also be at least partially attributed to generic paired association learning: the study only included a small number of stimuli and each stimulus was presented on average 58 times per participant within the experiment, with the content of audio-only and video-only stimuli overlapping with that of the audiovisual stimuli. In such a design, associations between the stimuli representing the modalities could be formed, even for unrelated pairs of stimuli , potentially resulting similar classification outcomes: Tanabe et al. (It further remains unclear whether Hasan et al.  have shoe et al. , for exae et al.  study maWhile there are several methodological and conceptual issues in Hasan et al.'s  study, tThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The growing complexity of functional materials and the major challenges this poses to structural science are discussed. The diversity of structural materials science and the contributions that computation is making to the field are highlighted. IUCrJ.The growing complexity of many classes of functional materials poses major challenges to structural science to which technical developments and the increasingly predictive power of computation make key contributions. These themes are clearly illustrated by the articles published in the field during the last year and especially by those in et al.  has been intensively studied over several decades, owing both to the subtlety of its structural properties and to the very wide ranging applications arising from its piezoelectric behaviour. New insight into structural changes and phase relations is provided by the study of Zhang, Yokota  al. 2017. Using aet al. (20173.The paper represents a particularly elegant example of the elucidation of structure\u2013property relations in current materials science; while the continuing challenges posed by perovskite-structured materials is also illustrated in the work of Kang  al. 2017, which det al. (2017The theme of structural changes during phase transitions again forms the basis of the work of Matvienko  al. 2017, which ret al. (2018The characterization of disorder remains a perennial challenge in the structural science of materials. The work of Kim  al. 2018 provideset al. (2017et al. (2017et al. (2017The determination of structure\u2013function relationships in nano structures is an active and growing field, especially in supported nano-structured catalytic materials. Here, in addition to TEM, X-ray spectroscopy is providing powerful tools as illustrated by the recent work of Dann  al. 2017 and Roge al. 2017, which a al. 2017, which het al. (2017Computation now pervades all aspects of structural science. The growing power of structure prediction methods is highlighted by the recent work of Collins  al. 2017, which uBond-valence methods continue to provide a simple but useful approach to understanding and validating inorganic crystal structures. Chen & Adams 2017 report aet al. (2017Further illustration of the role of current computational methodologies is provided by the study of Ma  al. 2017, which uet al. (2017It is of interest to note how machine-learning techniques are contributing to the field as in the work of Park  al. 2017, which uIUCrJ.In conclusion, it is hoped that this brief editorial highlights the diversity of structural materials science and the contributions which computation is making to the field. Articles based on these topics will continue to be welcomed by"}
{"text": "Macromolecular Big Data provide numerous challenges and a number of initiatives that are starting to overcome these issues are discussed. However, recent systematic surveys have revealed that a large fraction of representative sets of studies published in biomedical journals cannot be reproduced in another laboratory. This increased focus on reproducibility has likely contributed to the growing rate of retractions among scientific publications  \u2013 was limited to atomic coordinates, and was later supplemented by the \u2018header\u2019 containing the metadata describing the parameters of data collection  the sheer size of the data, which is 2\u20133 orders of magnitude greater than structure factors, (2) difficulties in organizing, acquiring, curating and managing the associated metadata, and (3) the deep-rooted tendency of researchers to keep their data private. Progress in storage technologies has almost eliminated the first challenge \u2013 the cost of hardware required to accommodate diffraction data has dropped significantly. The other two challenges still remain formidable, as discussed in the paper by Kroon-Batenburg, Helliwell, McMahon and Terwilliger in this issue of et al., 2016et al., 2016et al., 2014et al., 2016et al., 2016The initiatives surveyed in the paper include dedicated diffraction data repositories such as the SBGrid . For obvious reasons, such datasets not only have to be associated with a detailed description of the protein, but must also include which compounds were introduced and None of the current diffraction data repositories provides much, if any, information about the macromolecular sample. Ideally, one would like to have structural data integrated with data from expression, purification, and crystallization \u2013 as well as information about biomedical experiments. Creation of such integrated resources remains a dream that may be a major goal of BD2K type of program."}
{"text": "The study of de Assis and de Almondes, Systematic reviews are considered to provide the highest level of evidence for assessing the effectiveness of therapeutic interventions  the definition and pursuit of the research question, (2) fails to meet established eligibility criteria and (3) lack of methodological quality assessment of the included studies.The research question distinguishes a systematic review from a narrative one and guides the search strategy and eligibility criteria. It generally contains a careful selection of PICO(S) criteria , Comparator(s), Outcome(s), and Study Design) , MEDLINE is the primary component of PubMed. Even accessing MEDLINE through other interface, its results are already covered in PubMed search. Also, accordingly to Cochrane, three main databases  are recommended to find relevant studies (Chandler et al., According to eligibility criteria, author cited that retrieved studies should \u201cfully\u201d meet the following inclusion criteria: aging subjects with cognitive impairments or dementia; at least one session of exercise; comparator criteria not presented; pre-post measures of BDNF and reported parameters of executive functions.Misjudgments are noticeable considering eligibility criteria indicated above and, following the established, only Baker et al.  and NascInconsistencies are also related to intervention and outcome criteria. Even though exercise type was not determined by de Assis and Almondes as the intervention criteria, retrieved studies only reported aerobic training and three resistance training studies were excluded, as observed on selection process flow-chart. Moreover, measures of BDNF and executable functions must be performed pre and post exercise protocol, but Suzuki et al.  reportedAs a final point, it is important to emphasize that de Assis and Almondes did not assess risk of bias of included studies. There is broad consensus among the scientific community on the relevance of assessing the methodological quality of the studies, especially when carrying out a research synthesis (Johnson et al., In sum, for all of the reasons stated above, we genuinely believe that it is important to point methodological issues regarding the conduction of systematic reviews aiming to improve quality of evidence synthesis that provide subsides to the evidence-based practice. Although we have outlined some major points in which we disagree in the de Assis and Almondes's review, we agree that \u201cexercise influence on cognition is still a poorly explored field\u201d and, even more importantly, that \u201cfurther experimental research should concern better control.\u201d Those statements provide courses on which any future research might proceed.FS contributed to the idea and writing. MM and RP contributed to the writing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Tephra layers in marine sediment cores from scientific ocean drilling largely record high\u2010magnitude silicic explosive eruptions in the Japan arc for up to the last 20 million years. Analysis of the thickness variation with distance of 180 tephra layers from a global data set suggests that the majority of the visible tephra layers used in this study are the products of caldera\u2010forming eruptions with magnitude (M)\u2009>\u20096, considering their distances at the respective drilling sites to their likely volcanic sources. Frequency of visible tephra layers in cores indicates a marked increase in rates of large magnitude explosive eruptions at \u223c8 Ma, 6\u20134 Ma, and further increase after \u223c2 Ma. These changes are attributed to major changes in tectonic plate interactions. Lower rates of large magnitude explosive volcanism in the Miocene are related to a strike\u2010slip\u2010dominated boundary (and temporary cessation or deceleration of subduction) between the Philippine Sea Plate and southwest Japan, combined with the possibility that much of the arc in northern Japan was submerged beneath sea level partly due to previous tectonic extension of northern Honshu related to formation of the Sea of Japan. Changes in plate motions and subduction dynamics during the \u223c8 Ma to present period led to (1) increased arc\u2010normal subduction in southwest Japan (and resumption of arc volcanism) and (2) shift from extension to compression of the upper plate in northeast Japan, leading to uplift, crustal thickening and favorable conditions for accumulation of the large volumes of silicic magma needed for explosive caldera\u2010forming eruptions. Increase in volcanic activity in Japan at \u223c8, 4\u20136, and \u223c2 MaTephra layers in distal sediment cores represent magnitude 6 or greater eruptionsTectonic changes driving rates of explosive volcanism in Japan Most drill sites that we used data from are typically several hundred kilometers from the nearest volcanic sources, allowing us to look at the very large magnitude volcanic events, which are able to deposit tephra further from source. Changes in rates of explosive eruptions are investigated in the overall data set, and also regionally: northeast Japan, Sea of Japan, and southwest Japan Figure . VisibleMahony et al. [Data collection methods are described in y et al. . This stThe record of visible tephra layers in ocean drilling cores is quantified for each core by the number of tephra layers per unit time interval. Numbers of tephra layers were initially counted per 100 ka for each drill hole. Next, the average numbers of tephra layers were calculated across all the drill holes with material to that age, for each 100 ka interval. These data were then averaged over 500 ka and 1 Ma intervals, and also for each region. These data are indicative of but do not represent the rate of volcanic events. Due to the averaging method being per drill hole with material of that age, we can include data from each individual drill hole rather than just using drill site composite records. This gives us a more complete record as there can be differences between drill holes just a few tens of meters apart.Wetzel, Jutzeler et al., There are several factors that control whether a particular volcanic event is recorded in a particular core. A tephra layer should ideally show great lateral consistency for a few hundred meters. However, a visible tephra layer may be present in one drill site and not in another, because of differences in tephra dispersal related to wind conditions and volcano location. Relatively small magnitude eruptions may form a visible tephra layer in cores close to the source but not in cores further away from the source. Visible tephra layers can be destroyed by bioturbation or erosion by bottom currents, with thinner layers being more prone to being destroyed. Sedimentation rate and paleoenviromental conditions can affect the rate of bioturbation, and so the preservation potential for tephra layers Wetzel, . Here thHere we choose to represent these data as a proxy for the volcanic event rates by averaging the number of tephra layers per unit time for a collection of cores Figure . We haveReimann and Filzmoser, McDonald, We have not calculated the variance of the number of tephra layers as it can be inappropriate to make an estimate for nonnormal distributions and problematic too for data which include zeros [e.g., Peaks in explosive volcanism in the mid 15\u201313 Ma) Miocene are based on only a few cores and require additional cores to confirm. Rates of large magnitude explosive volcanism using visible tephra layers as a proxy are low 13\u20138 Ma then increase from 8 Ma, and again at 2.5\u20132 Ma  or eroded Wetzel, .Crosweller et al., Brown et al., Wessel and Smith, We calibrated the magnitudes (M) of the eruptions that form visible tephra layers in Japanese ocean drilling cores by analysis of a global data set of 181 isopach maps of Quaternary tephra fall deposits from large\u2010magnitude explosive eruptions collated in the LaMEVE database  [Deligne et al., Deligne et al., Deligne et al. [Table e et al.  are deriFigure For each magnitude and 50 km distance bin, the number of events was calculated with thickness values recorded either at that distance or greater Table . Our anaFigure 4There is an excellent record of explosive volcanism on Japan in the form of detailed tephrochronology and records of caldera\u2010forming events. Here we compare land\u2010derived records with the ocean drilling data on visible tephra layers.4.1Geyer and Marti, Kiyosugi et al., Land\u2010based records of the Quaternary volcanic history of Japan were collected from the LaMEVE database and the Collapse Caldera DataBase (CCDB) [4.2Kimura et al., Yoshida et al., Machida, Kimura et al.'s [Kimura et al. [Kimura et al., Kimura et al. [Kiyosugi et al., Tephrochronology of land and lake deposits in Japan extend back to the Pliocene [et al.'s  terrestra et al.  record, a et al.  show a tKimura et al. [Yoshida et al. [Yoshida et al. [Machida, Over the last 5 Ma, a et al.  record 7a et al.  describea et al.  in the nMachida, . Finally5Ninkovich and Donn, Fiske et al., Carey et al., Our observations Figures  and 3 ofWe now consider these different factors in turn, starting with those that we infer are less important.5.1Sparks et al., Baines and Sparks, Machida and Arai, Suto et al., In Japan, dominant westerly stratospheric winds influence the deposition of tephra from small to intermediate magnitude eruptions. However, M\u2009>\u20096 caldera\u2010forming eruptions discharge tephra to heights of tens of kilometers into the atmosphere [5.2Sato and Amano, Otofuji et al., Tamaki et al., Late Cenozoic plate movements would not have affected the tephra layer record at the sites on the upper plate in Japan, due to relatively small horizontal tectonic motions of the core sites relative to volcanic sources. Sea of Japan opening occurred between 30 and 14 Ma [Hall, Mahony et al., Pickering et al., Regalla et al., Doubrovine and Tarduno, Ninkovich and Donn, There is obviously larger motion of core sites on the subducting plate relative to the volcanic sources over the time frame of our study. Fifteen southwest Japan sites are on the overriding plate, while eleven are on the subducting plate. During 18\u20137 Ma, the locations of the southwest Japan subducting plate cores would have moved northeast relative to the plate boundary at \u223c 5\u20138 cm/yr (\u223c50\u201380 km/Myr) [5.3Mahony et al., Pickering et al., Hall et al., Mahony et al., Faccenna et al., Our analysis indicates a marked increase in rates of large magnitude explosive volcanism since \u223c8 Ma. Major tectonic changes have occurred in Japan since 20 Ma. The plate boundary in southwest Japan was predominantly sinistral strike slip with a minor convergent component between 18\u20137 Ma [Kamata and Kodama, Mahony et al., Sato, Prior to 8 Ma, relative motion between the Philippine Sea Plate and southwest Japan was dominated by strike\u2010slip faulting (and perhaps some slow convergence) and was associated with low rates of back arc volcanism [We attribute the increase in rates of caldera\u2010forming explosive eruptions from 8 Ma in Japan to interacting tectonic and igneous processes. On the large scale, the onset of increasing explosive volcanism is attributed to both uplift and eventual exposure of NE Japan, as well as changes in plate boundary dynamics in both southwest and northeast Japan, which affected magma production and favored the generation of large volumes of silicic magma necessary for large caldera\u2010forming eruptions.Kodama et al., Sato, Regalla et al., Sato, Yoshida et al., Yoshida et al., Southern Kyushu has rotated 30\u00b0 anticlockwise since 6 Ma, accompanied by back\u2010arc extension and more rapid subduction [Seno and Maruyama, Seno, Hall, Mahony et al., Pickering et al., Pollitz, Sato, Regalla et al., Sato, Sato, Regalla et al., Between 8 and 5 Ma major changes occurred. Subduction of the Philippine Sea Plate became more arc normal [Prueher and Rea, Kamata and Kodama, Mahony et al., A further marked increase in large magnitude explosive volcanism is indicated in the marine tephra record around 2\u20131.5 Ma Table . This in6Yoshida et al., Kimura et al., The large\u2010scale physical processes of tectonics and volcanism/magmatism are inextricably linked, and we demonstrate how changes in tectonics can drive changes in the rate of large magnitude volcanic events. Our data set enables a comprehensive study of the ocean drilling programs cores located around Japan. Our detailed eruption deposits study and comparison with global thickness data from 180 deposits, reveals that tephra layers observed in ocean drilling cores located at least 100 km from source volcanoes are likely to be M\u2009>\u20096. This inference is also supported by comparison of the marine tephra record with the Pliocene\u2010Quaternary terrestrial tephra record and observed numbers of calderas. We observe increases in numbers of volcanic tephra layers at 8, 4\u20136, and \u223c2 Ma both in the data set as a whole, and also when divided by core location regions. The increase in numbers of volcanic tephra layers in northeast Japan starting at 8 Ma is broadly consistent with the increases in studies of the Pliocene\u2010Quaternary terrestrial record [Supporting Information S1Click here for additional data file.Data Set S1Click here for additional data file.Data Set S2Click here for additional data file."}
{"text": "Neuropsychiatric conditions are a leading cause of disability globally , potential participants cannot provide adequately informed consent  or unimportant to participants, then the research will have little future potential to inform acceptable and needed services for that community. Ideally, survey research would be embedded into ongoing mental health programming. If partnering with local mental health service providers is not possible\u2013and sadly in LMIC contexts mental health services will often not exist\u2013investigators can partner with governments, international NGOs, or community-based organizations interested in providing mental health services and can help them develop appropriate programs based on survey results. Through sustainable partnership, researchers can build the capacity of local organizations to use results to advocate for themselves for funding, policy reform, or new laws to improve mental health locally. If no potential organizational partner exists, groups of community members formed through participatory research or existing community social structures could serve the same role (see Vreeman . et al.  developeet al. (et al.At an absolute minimum, GMH researchers must act to keep participants safe during survey research and take steps to monitor any negative ramifications of the survey on individuals\u2019 safety or well-being. Murray et al.  present . et al.. Respondet al.The extent to which investigators are responsible for the mental health treatment of such participants, both in terms of time and resources, will vary. Investigators should consider the level of risk the individual undertook in participating, their dependency on the researcher to receive any form of care, and the depth of the relationship between the researcher and participant including the level of trust engendered when individuals provided sensitive details about their mental health (Belsky & Richardson, et al.et al.et al.et al.et al, Although we have focused on GMH research conducted in LMIC, many issues discussed apply equally to mental health research in high-income countries despite the potential for greater access to treatment resources in these contexts. Guidance on ethically conducting GMH research, including intervention research, is increasingly available (Ellis et al.The Working Group on Mental Health and Psychosocial Support convened at Harvard's Humanitarian Action Summit in 2009 argued that mental health research in disaster and conflict settings must directly benefit the community under study in order to be ethical (Allden"}
{"text": "The last 10\u00a0years have seen major advances in the understanding of the pathobiology of systemic lupus erythematosus (SLE). These improvements have led to discoveries of new molecules that target specific points in the immunological cascade that contribute to the immune hyperactivity and loss of tolerance in this heterogeneous autoimmune disease. Despite a large number of clinical trials assessing new molecules in patients with active SLE, belimumab (Benlysta\u00ae) is the only biologic agent that has been approved for clinical use. Whilst the track record of these large and expensive clinical trials has been disappointing, it has been very encouraging to see that investigators from industry and academia have not been dissuaded from further investment to fill the huge unmet need for better understanding of the immunopathology of SLE and the search for novel and effective treatments.This special issue of Immunologic Research brings together internationally acclaimed experts in the field of SLE to provide cutting edge updates in this rapidly moving research area We included original articles and reviews to cover basic science and clinical aspects of SLE including the possible role of infections and updates on the antiphospholipid syndrome (APS).+CD25++ Tregs of patients with active SLE, markers related to Treg function (CD27) and homing (CCR6) were altered. This is a controversial area with conflicting findings in the literature; therefore, this study suggests that analysing subpopulations of Tregs may be more fruitful in dissecting the potential role of these T cells in the pathogenesis of SLE.The first original article by Schmidt et al.  investigHormones are clearly important in the pathogenesis of SLE and, given that the disorder is 9\u201310 times more common in females, oestrogens must play a major role. Another hormone that is emerging is prolactin, produced by the anterior pituitary gland and other cells including immune cells. Jara et al.  review tSLE is commonly a disorder of young women of child-bearing age. Many large lupus centres have clinical services designed to counsel women and manage their pregnancies and the perinatal period. Martinez-Sanchez et al.  describeCardiovascular disease is over-represented in women with SLE and whilst the risks are considerably increased, the event rate of cardiovascular disease in SLE is relatively low, making this a difficult area to study when it comes to prevention trials. Szabo et al.  summarisWatad el al  follow tVitamin D levels are low in most, if not all, patients with SLE for a variety of reasons. Many patients are photosensitive and therefore have rigorous photoprotection strategies. Marinho et al.  argue peThe central role of the microbiome in the maintenance of health and its potential role in a variety of human diseases including autoimmune rheumatic diseases is just beginning to be explored. Katz-Agranov and Zandman-Goddard  provide The possible role of viral infections in the pathogenesis of SLE has long fascinated researchers especially given the central importance of the interferon signature in this disease. However, conclusive evidence has still not been demonstrated in the literature. Hod et al.  review tFurther insights into infections are described by Mahroum et al.  who descIt is well recognised that B cell malignancies are over-represented in patients with SLE. In a large study from Israel, Azrielant et al.  utilisedAntiphospholipid syndrome increases the risk of premature mortality and contributes significantly to morbidity in patients with SLE; therefore, the final section of this issue is devoted to this autoimmune thrombotic disorder. The classical autoantibodies associated with this syndrome are the lupus anticoagulant, anticardiolipin and anti-\u03b22 glycoprotein 1 antibodies. Alessandri et al.  describeStroke is a feared complication of APS, and Carmel-Neiderman et al.  assessedFinally, the early detection of subclinical vascular disease may be a powerful tool to predict future cardiovascular events. Saponjski et al.  used 64-This issue offers a compelling collection of incisive articles for the reader to get up to date with advances in the fields of SLE and APS, and we congratulate the many authors on their timely contributions."}
{"text": "In the past 20\u2009years of research regarding effects of mobile phone-derived electromagnetic fields (EMFs) on human cognition, attention has been one of the first and most extensively investigated functions. Different domains investigated covered selective, sustained, and divided attention. Here, the most relevant studies on this topic have been reviewed and discussed. A total of 43 studies are reported and summarized: of these, 31 indicated a total absence of statistically significant difference between real and sham signal, 9 showed a partial improvement of attentional performance (mainly increase in speed of performance and/or improvement of accuracy) as a function of real exposure, while the remaining 3 showed inconsistent results  or even a worsening in performance (reduced speed and/or deteriorated accuracy). These results are independent of the specific attentional domain investigated. This scenario allows to conclude that there is a substantial lack of evidence about a negative influence of non-ionizing radiations on attention functioning. Nonetheless, published literature is very heterogeneous under the point of view of methodology , dosimetry , and statistical analyses, making arduous a conclusive generalization to everyday life. Some remarks and suggestions regarding future research are proposed. Nowadays almost the totality of human beings on the Earth is directly or indirectly exposed to the electromagnetic fields (EMFs) emitted by mobile phones, base stations, and other types of wireless communication technologies. This is a logical consequence of the fact that there are more mobile devices than living people on the planet: the estimate of total world population was around 7.44 billion at the end of 2017  have been seen as one of the potentially mostly influenced aspects of human brain functioning. In the past years, these studies have been extensively reviewed  as wellHere, the main findings obtained in the last 20\u2009years of research with respect to mobile phone effects on human attention will be briefly reviewed and discussed. The focus will be on laboratory volunteer studies , involving only mobile phone-like signals and aimed to investigate attentional performance as a main outcome. Although some of these studies had multiple outcomes , only attentional performance results have been considered here. Literature search was conducted at the end of 2017 on both PubMed and WoS databases and covered the period between 1998 and 2017. Almost all the studies reported here have been conducted on healthy adults, while just a few of them investigated effects on adolescents or children and on patients . A summary of all included studies, with experimental characteristics  is reported in Table In the first study investigating the effects of MW emissions on the brain, visual monitoring was also tested . In a siPreece et al. published one of the first studies on attention and vigilance . The autKoivisto et al.  with a sJech et al.  for the A similar effect to the one evidenced by Koivisto et al.  was reported by Edelstyn and Oldershaw  after onCroft et al.  investigIn a study on university students, performance at different tasks was assessed, including an auditory vigilance test . ParticiCurcio et al.  exposed Hamblin et al.  studied In 2005, Haarala et al.  carried In a unique effort to simulate a real-life exposure, Besset et al.  planned Schmid et al.  in a metKeetley et al.  aimed atThe first study on individuals with IEI-EMF was carried out with a single-blind protocol, exposing participants for 30\u2009min . No effeSimilar to other studies that attempted to control for methodological limitations  of previously published studies, Russo et al.  enrolledTerao et al.  investigFritzer et al.  conducteTo disentangle the differential effects of different signals , an experimental study was carried out to assess the effects of 30\u2009min of irradiation on several attentional tasks . ResultsIn 2008, a study attempted to test the possible cumulative effects of brief (15\u2009min) and repeated (three times) exposures in a single daily session . By usinAnother study directly aiming at comparing the possible effects of GSM and UMTS signals was proposed by Kleinlogel et al. . FollowiIn a study mainly aimed at investigating EEG features during an auditory oddball paradigm, Stefanics et al.  exposed To investigate the impact of TETRA signals on cognitive function, Riddervold et al.  exposed In a high-resolution PET study, vigilance was assessed after 33\u2009min of GSM exposure : again, In the same year, another attempt to compare possible cognitive effects of GSM and 3G UMTS signals was carried out . Three tIn an fMRI study, attentional performance was assessed after 45\u2009min of GSM exposure by means of a somatosensory Go-No Go task . No expoIn the same vein of previously discussed Regel et al.\u2019s studies, Schmid et al.  exposed Recently, another study on adolescents was carried out  comparinTrunk et al.  investigTwo associate studies tested the effects of two levels of TETRA-like exposure (\u201clow\u201d and \u201chigh\u201d) on volunteers exposed for 150\u2009min , 55. In Recently, a single-blinded study was carried out to test the effect of both GSM and UMTS on a considerably large sample  composedVerrender et al.  aimed atFinally, a recent study was conducted on emergency physicians  to test The first studies on humans addressing attentional performance changes as a consequence of RF EMFs exposure date back to almost 20\u2009years ago. In this mini-literature review, of 43 studies, 31 indicated the absence of statistically significant differences between real and sham signal, 9 showed changes in the direction of a partial improvement of attentional performance as a function of real exposure, while the remaining three showed very mixed and contrasting results  have not been replicated in more methodologically sound studies : this is the case, for example, of the pioneering study by Koivisto et al.  who showThe same happened when sample size was controlled for: in some cases, the effect previously shown on sustained attention measures  was notOther very central methodological issues are related to both a correct dosimetry assessment and a comparability among different experimental settings. As shown in Table If we take into consideration all these differences in methodology and experimental setting, it becomes very difficult to come to a general conclusion on potential everyday life effects.On the basis of the present systematic review of literature, some future research issues can be outlined as well as aspects that would merit further investigation.As a first, it is mandatory to control for procedural aspects, by exposing participants for similar or equivalent periods of time: a rapid look at Table Linked to the previous issue is the one of medium- and long-term effects to repeated EMFs exposure: this is a very relevant exposure procedure because it mimics very well what happens in the real life. To date, only one study  tried toEven related to methods is the topic of sample characteristics. As stressed in previous reviews , indiviFinally, some more research should be carried out \u201con the field,\u201d namely on individuals that are exposed to RF EMF for working reasons . ThOn the basis of reviewed literature, we can reasonably conclude that there is no evidence of a negative influence of mobile phone emitted EMFs on different aspects of human attention. As pointed out in GC conceived of, wrote, and edited this review.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Intensive agriculture, which depends on unsustainable levels of agrochemical inputs, is environmentally harmful, and the expansion of these practices to meet future needs is not economically feasible. Other options should be considered to meet the global food security challenge. The plant microbiome has been linked to improved plant productivity and, in this microreview, we consider the endosphere \u2013 a subdivision of the plant microbiome. We suggest a new definition of microbial endophyte status, the need for synergy between fungal and bacterial endophyte research efforts, as well as potential strategies for endophyte application to agricultural systems. Agricultural practices are under pressure to provide increased yields to feed the growing global population, which is expected to reach 9.7 billion by 2050 DESA, . In the et al. , maceration or disruption, and then plating the tissues onto a medium which supports growth of the organisms. More sporadic within the literature are descriptions of controls undertaken to ensure that the outer tissue is indeed free of viable microorganisms. It is clear that plant tissue surface sterilization should be tailored to the tissue sample type. Here, we propose that the total final surface wash from the plant tissue section should be concentrated and cultured to determine the absence of viable organisms (Robinson , et al. .et al., et al. (et al. (Until recently, only 1% of microbes present in bulk soil have been amenable to culture. However, the development of an isolation chip, the \u2018ichip\u2019 (Nichols , et al.  seemingl (et al. , could bet al., et al., et al., The best strategy for the application of endophytes in agricultural systems is not yet known. The most obvious approach is to add inoculants to the soil or as seed dressings. There are reports of this approach being successful for sugar cane (e.g. Silva et al., Epichlo\u00eb, which protects grasses against root\u2010grazing nematodes, may be toxic to vertebrates (Schardl et al., Despite the success of a few well\u2010known endophyte\u2013plant relationships (Hardoim et al., et al., Several important questions remain unanswered concerning the practical use of endophyte \u2018supplements\u2019 in agriculture. However, with the correct management, they hold potential for the control of current and emerging pathogens, as well as biotic stresses, as we encounter deviation in these through climate change (Howden"}
{"text": "There seems to be a broad consensus among today's parents that early exposure to digital media is less enriching than real-life experiences (Wooldridge, Embodied cognition highlights that the development of cognitive processes crucially depends on active interactions between one's body and the environment (Barsalou, Radesky et al.  note thaHowever, going beyond Radesky et al. , simple Supporting Radesky et al. , while cMoreover, Eisen and Lillard  observedTo sum up, the extent to which the advantages of real-life learning might be substitutable by touchscreen devices seems to be heavily context-dependent. Even in the absence of joint engagement, which was shown to greatly benefit learning according to Radesky et al. , interacThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "C. difficile infections (CDI) with a cure rate of 85\u201390% after the first FMT  has been used as a treatmentof last resort for recurrent Caudovirales with decreased diversity, richness and evenness when compared to healthy controls. Longitudinal studies of patients who received FMT (n = 9) and standard therapy, vancomycin (n = 5) demonstrated that FMT led to the transfer of viruses from the donor to the recipients  or slightly higher Caudovirale richness.The patients that were administered FMT were divided into two groups of \u201cresponders\u201d and \u201cnon-responders\u201d based on whether they were cured of CDI or recurred after FMT. In particular, after FMT, they noticed a significant decrease in the abundance of Microviridae was observed in the patients before FMT when compared to the controls but this increased after FMT. Fifteen viral species were found to be enriched between FMT responders and non-responders. Viral species belonging to the Microviridae family such as Eel River Basin pequenovirus was the most abundant in the responders  of those who responded to the antibiotic therapy. However, the bacterial community was significantly affected (Zuo et al., Moreover, Zuo et al. performed 16S rRNA gene sequencing to determine changes in the bacterial community and noted increase in Broecker et al. investigated the long term bacterial and virome changes in a patient after FMT for recurrent CDI, and found the virome at several months post-FMT related to the donor virome (Broecker et al., Caudovirales order and from the family Microviridae which have double and single stranded DNA respectively (Kim et al., Caudovirales was implicated in the efficacy of FMT. However, in other intestinal diseases, it is not clear cut as to the role of Caudovirales likely due to other risk factors involved (Norman et al., Caudovirales richness was observed in patients with inflammatory bowel disease (Norman et al., There is no doubt that bacteriophages play a role in the intestinal microbiota with a potential to alter the composition and function of the host microbiota. The question is what constitutes a healthy gut phageome and how do they influence the human gut microbiota? Most of the phages in healthy human gut microbiota belong to the The next question one may be tempted to ask is, how stable is the \u201cphagebiota\u201d in individuals and what are the effects of antibiotic perturbations on the phageome? Research by Ly et al. showed that transmission of viruses was common between members of the same household over a 6-month period (Ly et al., C. difficile, though this is not trivial. Indeed, previous work revealed that using a single phage, \u03a6CD27 (Meader et al., C. difficile growth in vitro and in vivo (Nale et al., C. difficile growth in a batch fermentation model spiked with feces from four healthy volunteers (Nale et al., These studies have highlighted the underappreciated role viruses play in addition to bacterial colonization in the intestinal microbiota. However, as individual phages are specific in action toward their bacterial host, it would be advantageous to isolate phages that target pathogenic bacteria such as C. difficile infection. The ability to develop a synthetic mixture of phages as treatment for infectious diseases, will go a long way in this era of antibiotic resistance. Not only will this be beneficial in severe CDI, but could also be useful as a therapy for other diseases related to the intestinal microbiota.Much work remains to be done on phage therapy for The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "There is an old saying that you must walk a mile in someone's shoes to truly understand them. This mini-review will synthesize and discuss recent research that attempts to make humans \u201cwalk a mile\u201d in an artificial musculoskeletal system to gain insight into the principles governing human movement control. In this approach, electromyography (EMG) is used to sample human motor commands; these commands serve as inputs to mathematical models of muscular dynamics, which in turn act on a model of skeletal dynamics to produce a simulated motor action in real-time (i.e., the model's state is updated fast enough produce smooth motion without noticeable transitions; Manal et al.,  As the name implies, an essential component of an MMM is a musculoskeletal model: a mathematical representation of bones, muscles, and connective tissue. The model specifics depend on the application Winters, . For simFor a musculoskeletal model to produce functional movement the muscle models must be activated in a coordinated fashion; this is typically achieved in one of two ways. The first is by using a central nervous system (CNS) model that codifies the principles governing human movement control. In such models, muscle activation patterns are generated by minimizing a quantity of interest such as energy , biomechanics. Capitalizing on this strength, de Rugy et al.  used an The studies above have provided valuable insights into how the CNS controls movement; however, the simulated muscles functioned primarily as pure force generators. In reality, muscles have various mechanical properties that influence the translation between EMG and muscular force. In contrast to limb dynamics , i.e., the variance is proportional to the command magnitude Clamann, . It has Such an approach was taken by de Rugy et al. , who incWe will lastly touch upon the utility of MMMs is to gain insight into the effects of sensory feedback manipulations on movement control. Most studies using MMMs in this capacity focus on proprioceptive information because an MMM serves as a natural virtual prosthesis, and proprioception is typically impoverished with prosthetic devices (Antfolk et al., Many studies using MMMs or prosthetic arms have concentrated on kinetic feedback because interaction forces are critical for object manipulation yet cannot be directly perceived with vision (Chiel and Beer, Since motion can be visually perceived, kinematic vibrotactile stimulation should be most beneficial for MMM control when vision is absent. This has indeed been shown in studies using vibrotactile stimulation to convey hand position (Witteveen et al., An important caveat of using MMMs to test motor adaptation hypotheses is that an MMM acts in parallel with the actual neuromusculoskeletal system Figure  and simuFuture research should also investigate the ramifications of limb motion when controlling MMMs. While some studies maintain both real and simulated limbs in an isomeric state (e.g., de Rugy et al., This mini-review addressed the ways in which MMMs can serve as tools to probe fundamental questions in human sensorimotor control and learning including CNS coordination of force-sharing among muscles, adaptation to modifications of neural dynamics, and the limits of sensory feedback augmentation. The power of MMMs stems from the experimental control they offer: model dynamics are mathematically specified and are therefore known quantities, and manipulations can be performed selectively to control for confounds associated with real neuromuscular interventions. The main limitation is the challenge of validating human adaptations to simulated manipulations given that experimental analogs are often impossible. Nevertheless, the knowledge gained from creatively employing MMMs in research has significant implications for fields such as neuroscience, biomechanics, engineering, and rehabilitation.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Changes in expression in these genes have been observed in recognition, working and fear related memories across the brain. Despite the enormous amount of data supporting changes in their expression during learning and memory and the importance of those cognitive processes in psychiatric conditions, there are very few studies analyzing the direct implication of the IEGs in mental illnesses. In this review, we discuss the role of some of the most relevant IEGs in relation with memory processes affected in psychiatric conditions.Many psychiatric disorders, despite their specific characteristics, share deficits in the cognitive domain including executive functions, emotional control and memory. However, memory deficits have been in many cases undervalued compared with other characteristics. The expression of Immediate Early Genes (IEGs) such as,  The diagnoses of psychiatric disorders are based on a cluster of specific symptoms. The genetic, clinical and neuroimaging evidence suggests that they share important features including common affected functions  were used as an indirect marker to measure neuronal activity and, although many of them are routinely measured in thousands of labs around the world, their role in many biological processes is still unknown. The IEGs most commonly used to map neuronal activity, c-fos, Egr1 and arc are related in literature to learning and memory. Changes in their expression observed in a limited number of cells in regions associated with learning and memory lead to widespread use as readout of plastic changes subserving long-term memory formation and maintenance in specific neuronal populations , duration (short-term and long-term) and to the type of information that it is stored (explicit and implicit), which are reviewed somewhere else Eysenck, . We now extinction or reconsolidation. The reactivated memory trace becomes labile and is susceptible to being modified or disrupted in the process called reconsolidation. If there is a reinforcement of the original trace during retrieval, the reconsolidation\u2014a protein synthesis-dependent process\u2014re-stabilizes the original memory trace  in rats in which the infusion of the ASO produce deficits in spatial long-term memory  protein also known as Arg3.1, is one of the most characterized molecules involved in the consolidation of different types of memories. In contrast to Arc gene has specific sequences normally found in retroviruses such as HIV  together with changes in long-term plasticity  is a mood disorder with prominent disturbances in cognitive functions such as certain types of memory, executive function, and attention  mainly in nucleus accumbens neurons  and a physiological defect in response to that component. Anxiety disorders include simple phobia, social phobia\u2014which involves fear and avoidance of social situations\u2014, and panic disorder; they all share abnormal fear responses associated with different environmental stimuli but also differ in important and specific symptoms. For example, PTSD is a chronic neuropsychiatric disorder that results from a very strong traumatic event and it is characterized by intrusive and persistence fear related memories. The etiology of PTSD remains largely unknown but different neurobiological systems have been identified as participants in the disorder (Parsons and Ressler, The first opportunity to apply treatments designed to modify the formation and persistence of fear memories is around the aversive experience, mainly through pharmacological manipulations (Monfils et al., arc expression was observed along the septo-temporal axis of the hippocampus of PTSD susceptible rats (Nalloor et al., arc expression in the hippocampus is also involved in the perpetuation of fear related memories (Nakayama et al., Few studies have analyzed the role of IEG in PTSD related animal models, though they reported interesting results. Changes in Schizophrenia is characterized by profound cognitive deficits that are not alleviated by currently available medications. Many of these cognitive deficits involve dysfunction of the newly evolved, dorsolateral prefrontal cortex. The brains of patients with schizophrenia show atrophy in the dendrites of the pyramidal cells, particularly from dorsolateral prefrontal cortex (Weinberger et al., Egr1 expression is decreased in the dorsolateral prefrontal cortex of schizophrenic patients. This down-regulation correlates with the levels of gad1 mRNA, which is also down-regulated in schizophrenia (Yamada et al., Egr1 and related IEGs in frontal and striatal regions (de Bartolomeis et al., It has been shown that Egr1 (Kurian et al., Egr1 and other IEGs are also associated with response to antipsychotic drugs (MacGibbon et al., Searching for biological markers of schizophrenia in peripheral tissues, it was found that whole blood samples of patients suffering this disease have an increased expression of c-fos expression have been reported in schizophrenia related animal models. Acute treatment with the NMDA antagonist MK-801 produced deficits in novel object recognition, conditioned test aversion and a moderate increase in locomotion. Interestingly, animals treated with this drug showed increased levels of c-Fos expression in cortical regions associated with cognitive processing (Vishnoi et al., c-fos expression (Casta\u00f1\u00e9 et al., c-fos expression in the mPFC does not correlate with glutamic acid decarboxylase 67 expression as does Egr1 (Kimoto et al., c-fos regulation (Michaluk and Kaczmarek, Changes in arc was deleted in the whole brain, Manag\u00f2 et al. (The interaction between Arc and dopamine appears to be bidirectional. Using a genetic model in which \u00f2 et al.  found a \u00f2 et al. .c-fos and Egr1 expression in the striatum and nucleus accumbens (MacGibbon et al., c-fos expression in the medial prefrontal cortex (Robertson and Fibiger, Egr1 and an upregulation of FOS-like expression in the same structures (Verma et al., IEGs have not only been associated directly with particular psychiatric disorders but they have also been used as markers of the specific action of different psychiatric drugs that are related. Haloperidol, a typical antipsychotic drug induces changes in c-fos in the anterior insular cortex, the septum and the amygdala using different antidepressants. In the case of Egr1 a consistent change was found only in the amygdala (Slattery et al., c-fos in the frontal cortex following an acute stress experience (Beck and Fibiger, Antidepressants\u2019 activity has also been analyzed in relation to their effect on IEG expression. Acute administration of fluoxetine, imipramine, LiCl, or mirtazapine produced changes in IEG expression in different regions. There were changes found for Although these studies show changes in the expression of IEGs in apparent response to different drugs, they are correlational studies and do not address any role of these proteins in their mechanism of action. Despite this caveat, even these studies provide important information regarding circuits involved in learning and memory that can be affected in psychiatric disorders.Although the prolific use of IEGs in neuroscience, our understanding of their role in neurobiological processes remains insufficient. This is due at least to the large number of IEGs that are currently under study, but also because of the difficulty in fully comprehending their roles and their downstream effectors. Independently of this, IEGs are used as markers of synaptic activity and as that, are useful. Even more, when combined with modern techniques, like optogenetic or chemogenetics (Reijmers et al., FTG, CK, JFM, JHM and NVW conceived the content, wrote and organized the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Whilst a formal statistical analysis of any experimental data is always preferable in principle, in the case of Pilling et al. (PLoS ONE 8:e77193,  The focus of Schick et al.\u2019s 2017 [Schick et al.  criticisIn their analysis, Schick et al. categorise the mortality data into \u2018before\u2019, \u2018during\u2019 and \u2018after\u2019 exposure. However, the Pilling et al.\u2019s  trials wdf) for experimental error for oilseed rape and only ever two df for experimental error for maize. In both cases, it can be argued that this number of df is simply too few to generate a reliable estimate of experimental error. Also, with so few data points in any given analysis (i.e. four for oilseed rape and six for maize), it is difficult to see how it can be verified that the data meet the underlying assumptions upon which the validity of the analyses depend. Moreover, with so few data points it is difficult to see how Schick et al. could justify their choice of error distribution and link function ahead of other viable alternatives; this is important because alternative but equally justifiable choices could lead to very different results, particularly with regard to the whereabouts of the upper confidence limits. Thus, the Schick et al.\u2019s [With regard to the data analysis carried out by Schick et al., they are in danger of confusing two separate issues. The first is whether an approach based on estimated effect sizes and 95% confidence intervals is more informative than the one based solely on tests of significance. The second is whether either approach can generate reliable results given the limitations of the experimental design. Regardless of which approach is chosen, there is only ever one degree of freedom (et al.\u2019s  analyseset al.\u2019s  to not set al.\u2019s  results Ecotoxicological field testing and risk assessment for pesticides is a continually evolving area, as shown by the regular review of guidelines for regulatory testing. It is for this reason that Syngenta co-sponsored with Bayer a bespoke landscape-level honeybee neonicotinoid field effect study with UK Centre for Ecology and Hydrology . This beSchick et al.  criticisIn addition, since the publication of Pilling et al. , there hSchick et al.  focus on"}
{"text": "Recently published study of Ma et al. evaluates two relatively novel measures of fluid responsiveness, carotid blood flow and corrected carotid flow time (ccFT). Both measures have been recently quoted as possibly useful, technically simple, and noninvasive dynamic tools in predicting fluid responsiveness. Recently, more research interest has been focused on ccFT and, intrigued by the data presented in this study, we discuss here the impact of the data presented in the paper of Ma et al. to the significance of this metric as a potential tool in the assessment of fluid responsiveness. Dear Editor,It was a great pleasure to read about the study of Ma et al.  which evThe study of Ma et al. sheds a new light on the role of ccFT and is the first prospective clinical study to compare ccFT with the gold standard of cardiac output measurement, right heart catheterization (RHC). This study evaluated patients undergoing diagnostic RHC who were subjected to a passive leg raise maneuver (PLR) which mimics a fluid bolus and has been used to assess fluid responsiveness in shock . Unfortuchanges in this measures that may correlate better. Several studies have looked at the change of ccFT (\u2206ccFT) as a potential tool in the process of evaluation of fluid responsiveness and found that change in duration of ccFT in dehydrated patients receiving intravenous fluid resuscitation [In this study, ccFT did not correlate well with cardiac output which is not surprising. Flow time is a proxy for left ventricular ejection time, which has classically been considered to represent a static hemodynamic measure, along with other \u201cstatic\u201d preload indices , 7, and citation , 8, 9 orcitation  may be hcitation . Practiccitation .There are several methodological concerns worth bringing up in order to separate a moderate correlation of average ccFT and cardiac output presented in the study of Ma et al. and possible usefulness of the change in ccFT in fluid resuscitation of patients in shock. Patients undergoing RHC who were evaluated in the study of Ma et al. may have very little in common with the population of fluid under-resuscitated patients in shock who are usually evaluated with PLR and where the role of ccFT has been recently discussed as possibly relevant . The cohFrom the technical perspective, an interesting idea presented in the study of Ma et al. is an attempt to avoid the selection bias by averaging ccFT values of multiple (three) heart beats instead of taking a single value. Understanding the impact of breathing on cardiac rhythm, this concept is valid and important but the method may require further optimization as averaging should probably be taken in the context of respiratory cycle rather than randomly selecting three beats.There is a common agreement that the dynamic parameters have become a gold standard in fluid responsiveness assessment , but the"}
{"text": "The 18th and 19th centuries in England were characterised by a period of increasing industrialisation of its urban centres. It was also one of widening social and health inequalities between the rich and the poor. Childhood is well\u2010documented as being a stage in the life course during which the body is particularly sensitive to adverse socio\u2010economic environments. This study therefore aims to examine the relationship between health and wealth through a comprehensive skeletal analysis of a sample of 403 children (0\u201317\u2009years), of varying socio\u2010economic status, from four cemetery sites in London (c.1712\u20131854).Measurements of long bone diaphyseal length, cortical thickness, vertebral neural canal size, and the prevalence of a range of pathological indicators of health stress were recorded from the Chelsea Old Church (high status), St Benet Sherehog (middle status), Bow Baptist (middle status), and Cross Bones (low status) skeletal collections.Children from the low status Cross Bones site demonstrated deficient growth values, as expected. However, those from the high status site of Chelsea Old Church also demonstrated poor growth values during infancy. Fashionable child\u2010care practices  may have contributed to poor infant health amongst high status groups. However, differing health risks in the lower status group revealed the existence of substantial health inequality in London at this time. \u00a9 2016 The Authors International Journal of Osteoarchaeology Published by John Wiley & Sons Ltd. The industrial cities of the 18th and 19th centuries in England were notorious for their unhealthy living conditions. Urban districts increasingly experienced severe overcrowding, poor sanitation and ventilation, and high levels of air pollution Kay, . During et al.,The expanding cities posed significant health risks, particularly for the youngest members of society. Children are vulnerable to adverse environments, because of their under\u2010developed immune system and the physiological demands of growth Lewis, . Under cThis study assesses growth and skeletal indicators of stress in the skeletal remains of non\u2010adults (0\u201317\u2009years) excavated from cemeteries known to comprise different social status groups from London (c.1712\u20131856). The aim is to discern whether health stress was experienced in children throughout all levels of the social strata, or whether children of middle to high status groups were buffered through social privilege from the detrimental effects of urban life.London was a highly stratified society during the 18th and 19th centuries: the rich and the poor lived in relatively close proximity Booth, , but wouet al.,et al.,Social inequality is known to have a profound effect on the overall well\u2010being of a population, producing a social gradient in health that deteriorates as income lessens  were also reassessed in line with recent publications (see below) to construct crude prevalence rates of pathology.et al.,Dental age was assessed using standards for dental calcification Smith,  of both et al.,et al.,Tibial lengths for individuals within each sample were plotted against dental age to assess longitudinal growth (a proxy for growth in height in non\u2010adults). The tibia was selected because it is considered to be more sensitive than the other long bones to growth disruption  was assessed through measurement of cortical thickness. Cortical thickness (CT) is considered to be a more sensitive indicator of stress than longitudinal growth  size is an effective indicator of stress in early life Watts, , 2013b. et al.  providedet al.,et al.,Scatterplots were constructed for tibial length, femoral CT, and TR diameter to determine the homogeneity of the regression slopes Field, . Once itThe presence or absence of four pathological categories was determined using data collected from the WORD database , and on the mandible and maxillae , arising because of the disturbance of enamel formation in the developing teeth Hillson, , was recThe overall sample sizes for pathological analysis, longitudinal growth, appositional growth, and vertebral growth are provided in Table Figure Tibial lengths were plotted against dental age, with each data point representing one individual Figurea. All siFigure Measurements of transverse diameter for each individual were plotted against dental age Figure d. All ofAll four groups have a high rate of rickets, between approximately 12% and 17% Figure . The oveKay stated in 1832 that \u2018\u2026more than one\u2010half of the offspring of the poor\u2026die before they have completed their fifth year\u2019 p.42\u201343), and around 42% of total deaths in London between 1837 and 1838 were in those aged 5\u2009years and under . Poor maternal health may lead to intrauterine growth restriction, resulting in infants that are born small\u2010for\u2010gestational age (SGA) (Eveleth & Tanner, et al.,et al.,et al.,et al.,Overall, Cross Bones demonstrates the highest prevalence of pathology. Peaks in metabolic disease occurred from the perinatal stage, to 1\u20135\u2009years of age Table . ParticuCheadle, . In ordeStudies by Barker , 1994 anet al.,Inequalities in health are thus often rooted in early life and can continue to impact on health throughout the life course (Elgar All of the samples in this study were affected by high infant mortality and morbidity, but the lower status Cross Bones sample was most severely affected. While it is true that Chelsea Old Church also demonstrated some of the lowest growth values alongside Cross Bones, it must be considered that these deficiencies developed for very different reasons. Children of wealthier families were more likely to succumb to poor health because of fashionable child care practices, whereas mothers born and raised in poverty could pass on their health deficits to their children. This, combined with the detrimental external environment and disadvantageous family economy, meant that life chances at birth for the children of the poor were limited to a high risk of premature death, or a lifetime of poor health and hard labour Gowland, .While interesting patterns related to child health and social status in the 18th/19th centuries have been identified, it is important to consider the limitations that accompany studies such as these. The current issues surrounding the identification of sex in non\u2010adult individuals creates a limiting factor in the study of growth within adolescents, because of sex\u2010related differences in the pubertal growth spurt. Without knowing the proportion of males and females within an adolescent sample, it is not known whether the data is skewed towards higher or lower growth values for a particular age. Sample size is also an inherent issue in bioarchaeology. The requirement for well\u2010preserved skeletal elements for measurement often means that sample sizes are small. Additionally, differential preservation of skeletal elements between populations means that, as seen in this study, sample sizes of collections may be imbalanced. The use of modern data as a comparative sample to infer whether past skeletal populations were \u2018unhealthy\u2019 by present standards is also problematic, as this involves comparing those who did not survive childhood, and were thus inherently \u2018weaker\u2019, to healthy living children.et al. (Life in the city came with some significant health risks to all of its members. While undoubtedly the lower classes experienced a much higher risk of mortality and morbidity, this study revealed that some of these risks were also often felt by the upper classes, supporting recent research by DeWitte et al. , Hughes\u2010et al. , and Watet al. . Poor in"}
{"text": "The article by Zhang et al. (We evaluated the PCR primers/probes used by Zhang et al. . OverallAs proposed by Ngounga et al. (In metagenomics approaches, the number of reads detected and the distribution along the whole viral genome are essential parameters for viral detection. In practice, the search for mimivirus is complicated by the great genetic variability of the virus and the restricted availability of mimivirus culture systems to a few research laboratories ("}
{"text": "Reason for Corrigendum:In the original article, there was an error. A correction has been made to the Introduction, section \u2018Imaging Methods and Imaging Postures\u2019, first paragraph.superficial brain regions (Goldenholz et al., The sentence \u201cMEG outperforms EEG in terms of signal-to-noise ratio when accessing deeper brain regions (Goldenholz et al., The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Diffuse scattering provides evidence that variations are correlated across molecular boundaries in macromolecular crystals. In this case, the diffuse intensity is derived from the squared crystal transform, which is sharply peaked. In a modified version of the model, correlations terminate at the molecular boundary . In this case, the diffuse intensity is derived from the squared molecular transform of the asymmetric unit , which is continuous in reciprocal space. In both cases, the transform is blurred; shorter correlation lengths correspond to a larger scale blurring of the transform. Both models are optimized to maximize the agreement with the data, enabling a well controlled comparison.In this issue, Peck and co-workers (Peck ry Fig. 1b. In thet al., 2017et al., 2017et al., 2016et al., 2011et al., 2009et al., 2007et al., 2010To be consistent with the state of the art (Meisburger et al., 2018As illustrated in this issue (Peck"}
{"text": "Hemoptysis is a very common symptom in the practice of pulmonary physicians of India. We present a case of uncontrolled hemoptysis managed with bronchial artery embolization. Bronchial artery embolization is an effective treatment for patients with hemoptysis. Serious complications are rare, but may occur if the arterial supply to other structures is compromised. Massive hemoptysis usually originates from the systemic arterial supply to the lung. Episodes of hemoptysis may be managed by several approaches, depending on the urgency of the situation, ranging from medical management and bronchial artery embolization (BAE) to surgery. Bronchial artery embolization is a well-accepted and effective form of treatment for massive and recurrent hemoptysis. Bronchial arteries are small vessels that arise directly from the descending thoracic aorta and supply blood to the airways of the lung, esophagus, and lymph nodes.\u20103 BronchA 69-year-old male patient came with complaints of cough and hemoptysis from last one year. The symptoms were not relieved by conservative medications. There was no contact history with any case of pulmonary tuberculosis in the family or neighbourhood. Patient gave no history of any chronic illness, surgery or hospital admission in the past. The patient was a chronic smoker for the past 30 years. The patient was given a trial of anti tubercular treatment for six months but with no relief. Other than crepitations in right inframammary area, rest of the physical examination and routine laboratory work up was inconclusive. Repeated sputa examination for AFB were negative.Chest X-ray revealed unfolding of aorta, hazy right parahilar and para cardiac area . USG whoSources of pulmonary bleeding include the low pressure pulmonary circulation  and the high pressure bronchial circulation (at systemic blood pressure). Bronchial circulation arises from the aorta and therefore has systemic arterial pressure. The bronchial arteries are the main supply of the airways and the supporting structures of the lung while pulmonary arteries supply the lung parenchyma and respiratory bronchioles. Bronchial circulation is the source of massive hemoptysis in 90% of cases.et al.[10et al. and 97%.et al. The probet al.et al 2005[Bronchial artery embolization might be the only treatment option available to patients who are not fit to undergo surgery. Bronchia14et al 2008[et al 2005[et al 1999[et al 2004[\u00b5m Embosphere particles. The authors suggested that the Embosphere particles had crossed the bronchiopulmonary shunt into the systemic circulation. Severe but rare complications are neurological deficiencies and pulmonary necrosis.[5BAE is an alternative safe and effective nonsurgical treatment for patients with massive hemoptysis which can be done simultaneously on both sides. Success rate is about 88%. Intervent al 2008 reportedt al 1999 concludet al 1999 There hat al 1999, posterit al 1999 and Acutt al 1999 Vinaya et al 2004 reportednecrosis. Neurolognecrosis. Recurrenecrosis.515 ProximThis case has been presented with the view that in cases of hemoptysis, bronchial biopsy should not be jumped to and the possibility of vascular nature of the tumor should be kept in mind and thoroughly discussed so that if required bronchial artery embolization could be done to control hemoptysis and to avoid massive bleeding during bronchial biopsy."}
{"text": "Sir,et al's Letter to the Editor.We would like to clarify the results in \u2018Excessive annual BMI increase after chemotherapy among young survivors of testicular cancer\u2019 as a reply to Huddart et al's results, our study showed no influence of chemotherapy or any other treatment type on BMI compared to our healthy control material (Controls). Our results from the multivariate regression analysis indicated that in survivors of testicular cancer (TCSs), chemotherapy had an impact on the annual BMI increase independent of age and that the surgery group displayed no significant annual BMI increase , but our results do not show any impact on BMI, measured once in a cross-sectional study.We still conclude that young TCSs, especially after chemotherapy, are at risk of excessive annual BMI increase as compared to the normal population ("}
{"text": "We consider the problem of identifiability in the recently developed carcinogenesis models of Little and Wright (Math Biosci 2003 183 111\u2013134) and Little et al. (J Theoret Biol 2008 254 229\u2013238). These models, which incorporate genomic instability, generalize a large number of other quasi-biological cancer models, in particular those of Armitage and Doll (Br J Cancer 1954 8 1\u201312), the two-mutation model , the generalized multistage model of Little (Biometrics 1995 51 1278\u20131291), and a recently developed cancer model of Nowak et al. (PNAS 2002 99 16226\u201316231).Heidenreich Math Biosci 2003 183 111\u2013134) the number of identifiable combinations of parameters is at most two less than the number of biological parameters, thereby generalizing previous results of Heidenreich et al.  for the two-mutation model. For the more general model of Little et al. (J Theoret Biol 2008 254 229\u2013238) the number of identifiable combinations of parameters is at most We show that in the simpler model proposed by Little and Wright (We have shown that the previous results on parameter identifiability can be generalized to much larger classes of quasi-biological carcinogenesis model, and also identify particular combinations of identifiable parameters. These results are of theoretical interest, but also of practical significance to anyone attempting to estimate parameters for this large class of cancer models. In principle it may well be that some of these parameters may not be observed, or be possible to be derived from observed data via regression techniques. Such parameters are said to be redundant if the likelihood can be written using a strictly smaller parameter vector; otherwise they are irredundant. Rothenberg local identifiability, to mean that within a neighbourhood of each set of parameter values the likelihood differs for at least some data points. This notion has been extended by Little et al.gradient weak local identifiability and weak local identifiability. Little et al.weakly locally identifiable if the maxima of the likelihood are isolated; they defined parameters to be gradient weakly locally identifiable if the turning points (those for which the likelihood derivative with respect to the parameters is zero) are isolated. The results obtained by Little et al.There is a substantial literature on identifiability in stochastic models in various contexts et al.Heidenreich et al.et al.et al.et al.In this paper we consider the problem of identifiability in recently developed carcinogenesis models of Little and Wright et al.et al.et al.We consider the problem of parameter identifiability in a particular class of stochastic cancer models, those of Little and Wright et al.k cancer-stage mutations have occurred, no matter how many destabilizing mutations there have been. Once a cell has acquired a destabilizing mutation of type multiplicity of destabilization mutation types. It is to be expected that the more destabilizing mutations cells acquire of each type, the higher the cancer stage mutation rate is, but this is not intrinsic to the model. We write signature of the destabilizing mutation types. We habitually describe this model as of type The model of Little et al.Cells at different stages of the process are labelled by et al.et al.et al.In , where  . Assuminrameters , at mostet albsstep routine, Press et al.F02FAFThat there are likely to be exactly this number of estimable parameters is supported by numerical evaluation of the Hessian matrix of the hazard function. We make use of the solution of the system of ordinary differential equations defining the Hessian, outlined in \u22123 year\u22121, destabilizing mutation rates of 3.0\u00d710\u22123 year\u22121, intermediate cell proliferation rates of 1.0\u00d710\u22121 year\u22121, and intermediate cell death rates of 5.0\u00d710\u22121 year\u22121. For each of 1000 random sets of parameters we evaluated the Hessian by numerical integration, as outlined in F02FAFWe evaluated the Hessian matrix for a model with three cancer-stage mutations and one destabilizing mutation, and a model with two cancer-stage mutations and one destabilizing mutation; log-normal perturbations of all parameters were performed, assuming a geometric standard deviation (GSD) of 4, centred on models with cancer-stage mutation rates of 4.0\u00d710et al.et al.et al.We have shown that in the class of stochastic cancer models incorporating genomic instability developed by Little and Wright A weakness of the paper is that one cannot be absolutely sure  that the bound demonstrated by the mathematics of section 3 and et al.These results have obvious implications for the large number of other quasi-biological cancer models that are special cases of these models, in particular those of Armitage and Doll Our results imply that for the general class of cancer models considered here, only certain specific parameter combinations should be estimated in principle, and this is the case whatever the size of the dataset being considered. Whether for complex models for even this theoretically available number of parameters there is useful information is of course uncertain, and may well depend on the particular dataset and on the likely size of the parameters to be estimated. However, fits to a large population-based registry of colon cancer, as recently analysed by Little and Li Text S1Text S1(0.42 MB DOC)Click here for additional data file."}
{"text": "BMC Women's Health from the Estonian Postmenopausal Hormone Therapy trial has concluded that quality of life is not related to hormonal therapy use. The commentary article discusses this finding and considers other factors related to symptoms and quality of life during menopause. Important factors known to affect hot flushes and quality of life are smoking and high body weight. Since both these factors are modifiable, menopause is a suitable area for health promotion. However, evidence concerning lifestyle changes in symptom relief or increase of quality of life is weak. More trials in this area are needed before women may consider non-pharmacological treatment of symptoms as a reliable option for menopausal symptom cure.Menopausal health is important since this stage of life is not to be avoided. A recent article in  BMC Women's Health by Veerus et al [Menopause is not avoided by any woman but frequency and severity of menopausal symptoms vary. A recent article published in us et al  reportedus et al -4 and slus et al . The prous et al ,7. Crossus et al ,8. Aboutus et al . Howeverus et al ,8-11 andet al's Veerus study [et al [et al study [During recent years hormonal therapy (HT) has been introduced as a solution to menopausal symptoms. The Women's Health Initiative's (WHI) study results  showed t's study  was basey [et al  but in ty [et al . Both HEy [et al . A cruciy [et al . The resal study  was impoEarly onset of menopause  as well et al [et al [The quality of life of smokers and persons with high BMI is known to be low and an increase in hot flushes does not alleviate their situation, quite the opposite. There is a clear need for general health promotion and obesity prevention during the menopausal age in order to increase quality of life. Lifestyle changes, such as increasing physical activity, is one alternative to HT. Evidence on reducing cardiovascular disease by physical activity exists especially among postmenopausal women ,26. Howeet al  concludel [et al  study shet al [Menopausal transition may make women more aware of future health risks due to increased symptomatology and help-seeking behaviour. Motivation for health promotion may be further strengthened if women perceive life-style modifications as an alternative, non-pharmacological, way of managing menopausal symptoms. However, more evidence on effectiveness and efficacy of lifestyle changes, especially exercise, on decreasing hot flushes and increasing quality of life is urgently needed. In the future, menopause may act as a window of opportunity for health promotion and life-modifications. Studies from randomized trials such as Veerus et al  are neceRL originated the idea for the commentary article and is in charge of the article.The pre-publication history for this paper can be accessed here:"}
{"text": "Wandering spleen is a rare condition defined as a mobile spleen only attached with its pedicle. It can be complicated by a volvulus, which is a surgical abdominal emergency. Preventing infarction is the aim of a prompt surgery that can preserve the spleen and then proceed to splenopexy. We report a rare case of torsion of a wandering spleen associated with a dolichosigmo\u00efd. Wandering spleen is a rare condition characterized by the absence or underdevelopment of one or all of the ligaments that hold the spleen in its normal position in the left upper quadrant of the abdomen. It is an\u00ae 0 prepared on the upper and lower borders of the pedicle before the spleen replacement in its quadrant, which were knotted at the end; sigmoidectomy and colorectal anastomosis were performed. The patient recovery was uneventful. She was discharged on the sixth day.A 27-year-old woman presented to the emergency department after three days of abdominal pain, vomiting and constipation without fever. She had a recurrent constipation but no history of recurrent abdominal pain, abdominal mass, or trauma. On physical examination, abdominal distension was noted. There was a moderate diffuse abdominal tenderness more pronounced on the left side. Abdominal radiography showed an important colon distention especially at the upper left quadrant without air fluid levels . An abdoWandering spleen is defined as mobile spleen that is attached only by an elongated vascular pedicle, allowing it to migrate to any part of the abdomen or pelvis. It is a result of congenital anomalies in the development of the dorsal mesogastrium and the absence or malformation of normal splenic suspensory ligaments.3 The splHowever, acquired anomalies have been described and are attributed to laxity of the ligaments due to weakness of the abdominal wall, multiple pregnancies, hormonal changes or increase in size in the spleen. Both conPatients with a wandering spleen may be asymptomatic, present with a movable mass in the abdomen, or have chronic or intermittent abdominal pain because of partial torsion and spontaneous detorsion of the spleen.6 Torsion76Sonography showed the characteristic comma-shaped spleen in an ectopic position and the lack of splenic tissue in the left upper quadrant. Duplex Doppler color flow evaluation, provided optimal visualization of the organ and assessment of vascular supply. However,1Computed tomography is the preferred study for diagnosing a wandering spleen when torsion is suspected clinically or on other imaging studies. The CT manifestations included: (I) absence of the spleen anterior to the left kidney and posterior to the stomach, (II) a lower abdominal or pelvic mass with homogenous or heterogenous splenic parenchyma and an attenuation value less than that of normal splenic tissue, (III) whorled appearance of splenic vessels and surrounding fat only, and (IV) secondary findings such as ascites and necrosis of the pancreatic tail.797et al.[et al.[et al.[et al.[et al.[However, it is the whorled appearance of the splenic vessels and surrounding fat at the splenic hilum that is considered as specific of torsion of a wandering spleen. This sig11et al. fixed thl.[et al. fixed itl.[et al. and Peitl.[et al. used tral.[et al. sutured l.[et al. van der l.[et al. and Steil.[et al. dissectel.[et al.20 have ul.[et al.In the present case, the spleen was fixed by its pedicle using a technique inspired by the one described by stringel. In the sThe splenic torsion is sometimes associated with other manifestations like gastric or pancreatic tail volvulus.23 The on24The torsion of a wandering spleen is a rare abdominal emergency. Its diagnosis should be made in prompt time to prevent infarction of the spleen. Splenopexy by means of the extraperitoneal pocket creation appears to allow anatomic placement of the spleen along with the protection of the rib cage without the employment of biomaterials. Splenectomy should be performed only in patients with splenic torsion in whom massive infarction and thrombosis of the splenic vessels has occurred."}
{"text": "Dear Sir,et al.,[I have read with interest the article by Das et al., in whichet al., Morquio et al.,3The author has not mentioned the status of mental development or the results of echocardiography.In my opinion, this may be a patient with Morquio syndrome in view of the presence of hepatomegaly, cardiac valvular lesion, swollen alveolar ridges and gums with misaligned teeth, cloudy corneas, skeletal dysplasia, normal auditory functions, and normal intelligence."}
{"text": "Reported by Danovaro  Although there are only 22 described species, they have been recorded from a broad range of depths and settings ranging from shallow, coastal waters to methane seeps and hydrothermal vents, to the Izu-Ogasawara trench off Japan ,8. Loricet al., using aet al.[Why is this finding important? These metazoans have had to cope with multiple physiological stresses - extreme salinity, toxic sulfide levels and the absence of oxygen. Evolving adaptations to any one of these would be a challenge. Clues to the success of the Loricifera found by Danovaro et al. may lie et al. and appaet al., which tet al.. If suchet al.[et al.[The findings by Danovaro et al. may at fet al.. The thrl.[et al., represeet al.[What does it mean to have metazoans inhabiting anoxic environments? As exploration of low-oxygen settings has intensified, it has become apparent that metazoan life can persist at very low oxygen levels of only a few micromolar per kg. In such settings metazoans can play important functional roles in the recycling, bioturbation and burial of carbon and nitrogen ,14,5. Ofet al. it appeaet al.[Are there more metazoan taxa out there that can live without oxygen? Almost certainly. The finding by Danovaro et al. offers tet al. or in otet al. points tAre there metazoans on other planets with atmospheres different from our own? Our ability to answer this question would be strengthened considerably by more intensive studies of animal - microbe interactions in extreme settings of our own inner space - the deep ocean."}
{"text": "TB) difficult in countries with high prevalence of TB, and vice versa, but TB has also been linked to causation of sarcoidosis. All those who deal with such conditions would remember the cases, when TB, after successful treatment (or during it), is followed by a diagnosis of sarcoidosis and more commonly when patient being treated with steroids following with a diagnosis of sarcoidosis, land up with TB. In both of the clinical scenarios, the authenticity of the primary diagnosis has to be confirmed, before one can say that either of the conditions has lead to the other one.Relationship of tuberculosis (TB) with sarcoidosis has baffled physicians and researchers ever since the description of sarcoidosis. Not only sarcoidosis is a close clinical mimic of TB, which makes the diagnosis of sarcoidosis (et al. present an interesting viewpoint regarding an entity called \u2018tuberculous sarcoidosis\u2019. Further, the authors have even laid down the criteria for the diagnosis of tuberculous sarcoidosis.[In this issue of the journal, Shah coidosis. Tuberculcoidosis. However,et al. [originally by Wong et al.,[et al. [For example, in the illustrative case 1 described by Shah g et al., represeng et al., could beg et al., followedg et al., The illu,[et al.  are highSince sarcoidosis was first described, there has always been a belief that the disease is in some way related to TB. Sarcoido210Tropheryma whippelli as a causative agent for Whipple's disease[Of late, nucleic acid amplification of the genetic material of putative agents serves as an alternative method for isolating fastidious organisms. This method has been used successfully in identifying s disease and coros disease as an ags disease These res diseaseet al. are neither evidence-based nor play any role in day-to-day clinical practice.Based on the current understanding, we believe that there is no merit in the term \u201ctuberculous sarcoidosis\u201d; and the criteria laid down by Shah"}
{"text": "Most of the total body virus is located in lymphoid tissues, typically in association with follicular dendritic cells (FDCs) Viral clearance rates have been estimated in the blood, and different techniques have yielded a variety of estimates Virus production rates have also been estimated by several techniques. Because in other lentivirus infections, most notably visna virus, intracellular viral DNA levels increase approximately exponentially and then virus appears to be released rapidly in situ hybridization to estimate burst size. Assuming that the maximal HIV RNA count in a cell corresponds to the burst size, Haase et al.et al.et al.et al.Recent studies have combined image analysis with et al.et al.One can also attempt to measure burst size by directly imaging the extracellular viral particles surrounding an infected cell tion see , and theFinally, the most direct estimates for the total amount of virus produced per infected cell was achieved using single-cycle SIV to infect PBMC which were placed back in uninfected rhesus macaques. By measuring the total amount of virus produced and accounting for clearance, this experiment yielded a total production of approximately et al. and Chen et al. depend on the viral clearance rate, et al.et al.Summarizing, the latest production rate estimates converge on a few thousand to approximately per virion clearance rate of In one earlier modeling study a production rate of several thousand particles per cell was shown to be consistent with a viral half-life of 3\u20134 hours in the lymphoid tissue In this paper we attempt to reconcile the various estimates for the viral clearance rate, the viral production rate, and the amount of long-lived virus trapped on FDCs within one modeling framework in order to test whether there is a consistent interpretation explaining all observations. To do so we introduce compartmental models to analyze recent experimental data on viral clearance in various organs, and estimate the rates at which virus is exchanged between them.et al.A simple and direct approach to estimate the clearance rate of virus from the blood is to infuse virus particles into the blood, and monitor their disappearance by taking frequent blood samples. Zhang If most of the viral degradation indeed takes place in organs such as the liver If et al.et al.Using the estimated clearance rate from the blood of 0.2 minr organs . The estOnly 40.5% of the total radioactivity was recovered in the monkey 2 hr after injection. This could be due to a loss of radioactivity by viral degradation and removal of labeled molecules, or to accumulation of SIV in other body compartments, such as the gastrointestinal tract, that were not examined s organs .et al.et al.HIV-1 clearance rates from plasma have been estimated in chronically infected patients by plasma apheresis over a period of two hours. Plasma was removed at a rate of 39 mL per min, and was replaced by an equivalent volume of isotonic saline containing 5% albumin. On average, this procedure removed a total of approximately d et al., suggestet al.It is worth noting that the estimate for the efflux rate in humans of HIV-1 from plasma is more than 10-fold slower than the estimated plasma efflux rate of SIV in rhesus monkeys Since most virus production takes place in the lymphoid tissue, we modify a previously published compartmental model ex vivoIn this model we make a distinction between clearance and efflux. We speak of efflux when the number of virus particles is conserved, and speak of viral clearance in an organ only if the virus is being degraded there. Thus, these equations assume that there is no viral clearance from the blood; there only is efflux to the lymphoid tissue and to other organs that have viral clearance rates, The parameter in situ hybridization suggested that most of the virus in the lymphoid tissue is associated with the FDC network In a typical patient the FDC pool seems saturated, i.e., To consider the total virus load we add Eqs. (6)\u2013(9) yielding,et al.We can use the relationships between per capita clearance rate in LT, et al.For the more \u201crealistic\u201d example, of virus . The rec per day . When Chith FDCs , we find, i.e.,  . In thisAnalysis of the plasma apheresis experiments in humans provided estimates for the influx of virus from the LT into the blood . This caeriments . FinallyTo test whether the full model (Eqs. 6\u20139) is consistent with the plasma apheresis experiments, we make reasonable guesses for the other parameters of the model. Allowing rapid filling of the pool of virus bound to FDCs we set the number of FDC binding sites he blood , reducinaffected . Very siChoosing the efflux rates estimated in monkeys per capita viral clearance rates in lymphoid tissues. The larger the viral production rate per productively infected cell, and the more virus that is bound to FDCs (see per capita clearance rate of free virus in lymphoid tissue must be to balance viral production. Recent estimates of a burst size up to We have shown that the balance between viral production and viral clearance implies rapid FDCs see , the lary  to  d .et al.In our modeling work the rate of virion clearance, et al.The efflux and/or clearance rate of SIV from the blood of uninfected monkeys and of infected monkeys with a low viral load Finally, it may seem that the notion of a large FDC store of bound virus is incompatible with the rapid viral clearance rates seen in spleen and lymphoid tissues of uninfected macaques Rapid viral clearance in lymphoid tissue is not surprising. The lymphoid tissue contains more than In a previous paper we showed that the rate of viral clearance in lymphoid tissue would markedly affect the estimated life span, Summarizing, we have provided new estimates of viral efflux and clearance rates in various organs, including blood and lymphoid tissue. We have confirmed that the exchange rate from lymphoid tissue to the blood should be slow et al.in situ hybridization in lymphoid tissue, including measurements of the number SIV RNA copies on the surface of and in the vicinity of activated and resting CD4Reilly et al.To estimate viral production rates per virus producing cell from this data, one has to integrate the virus production function over the life span of the cells. Reilly Note that the estimates obtained in"}
{"text": "In response to the case report of Brugada-type Electrocardiographic Pattern Induced by Electrocution by R Rangaraj et al  , the ele"}
{"text": "Sir,et al.We read with great interest the article by Omoti et al.et al.et al.et al.However, we do not completely agree with the authors\u2019 contention that most reports of ocular involvement in lymphoma involve few patients. Cassoux et al.6The authors have comprehensively documented the ocular and adnexal involvement in a series of patients with systemic lymphomas. It would also be of interest to the ophthalmologists to look at it from the other point of view. Shields et al.Omoti The article also presents three cases of presumed lymphoma-associated retinopathy based only on features of hemorrhages and vasculitis. Although possible, we believe that angiocentric lymphomas are extremely rare and the classic presentation would be in the form of confluent, round, or geographic greasy-yellow subretinal pigment epithelium infiltrates. 8"}
{"text": "Sir,Br J Cancer  on the prognostic significance of molecular detection of melanoma cells in melanoma patients under adjuvant interferon . In our work, in 27 patients tested, one was already positive before operation becoming negative some time following operation. No data on that point are given on the 418 cases studied by Gogas et al. This type of information may permit further confirmation of a theory claiming that surgery manipulations may cause forced release of melanocytes to blood circulation (Gogas et al claim that no evidence for an interference of the so-called \u2018illegitimate transcription\u2019 (Gogas"}
{"text": "Although we know from Hodson's water hammer theory that Scars could occur in sterile reflux, Edwards and Smellie in theiret al, involvinl,[et al, wherein"}
{"text": "Sir,et al.[et al.[Chavan et al. sought tl.[et al. suggesteet al.[et al.[Is this scoring valid? I think not. No study has systematically examined long-term memory loss after ECT for us to assume that such memory loss does not exist. In fact, the available data suggests that at least some patients may experience extensive, protracted and possibly permanent memory disturbance after ECT. For example, Lisanby et al. describel.[et al. observedl.[et al. describel.[et al. suggesteAnd does ECT cause pain? It certainly might. Patients may reasonably be expected to consider the injection of the ECT premedication noxious and many patients do experience headache or bodyache for several hours after an ECT treatment.Items 3 and 12 therefore elicit attitudes more than knowledge; this is even more true for item 2, which states that ECT is an inhuman treatment. To some, it is; to others, it is not. There cannot be a correct position for an attitude; for example, there are proponents for and against the death sentence and who has the right to say which stance is correct? It is therefore necessary to separate items reflecting knowledge from those reflecting attitudes and, to view attitudes as positive and negative (rather than right or wrong), much as we did in a study which has now become a landmark reference in the field. Other me"}
{"text": "Sir,We read the article of Shukla and Barreto with interest. This sysThe basis of surgical strategy in solid cancer like gallbladder carcinoma must be the knowledge of local and disiminated spread of the cancer. Because of this, the background for actual recommendations of some authors of routine resection of the extrahepatic bile duct in gallbladder cancer appears completely unclear, particularly based on the well-known early and late complications of resection, anastomosis and reconstructions of the extrahepatic bile duct.et al.[Miyazaki et al. were theet al. In advanet al. This is The cited studies which advocate radical resection including resection of the extrahepatic bile duct mostly include even extended liver resection and an extended lymphadenectomy. For thiset al. and Wakai et al.[The importance of liver resection in surgical treatment of gallbladder carcinoma was recently \u2013 among many other authors \u2013 emphasized and proved by Araida ai et al.5 Oncologai et al.4et al.[Yamaguchi et al. found ouet al. If this The cited authors who advocate aggressive resection including resection of the extrahepatic bile duct are extraordinary experienced hepatobiliary surgeons. The results, especially the risks of these extended procedures cannot be compared and are not conferrable on a broad medical surgical supply level, and can therefore not be recommended generally.The paper of Shukla and Barreto makes an important contribution to a differentiated and censorious consideration of the resection of the extrahepatic bile duct as part of the surgical strategy in operative treatment of gallbladder carcinoma. The final eight conclusions of Shukla and Barreto cover up exactly with our concept and our attitude to this subject."}
{"text": "Biosensors are analytical devices being approachable for multiple analytes assay. Here, biosensors with intercepted acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) are presented as tool for assay of anticholinergic compounds such as pesticides, nerve agents and some natural toxins. Principle of assay is based on evaluation of cholinesterase activity and its pertinent decrease in presence of analyte. Nerve agents, pesticides, anticholinergic drugs useable for treatment of Alzheimer\u2032s disease as well as myasthenia gravis and aflatoxins are enlisted as compounds simply analyzable by cholinesterase biosensors. Nerve agents, insecticides such as organophosphates as well as carbamates and some drugs may be named , malaoxon, malathion, chlorpyrifos and dichlorvos may be listed as typical examples Marrs, . Toxicitet al., et al., Amperometric biosensors are a good alternative to the potentiometric ones. Amperometric biosensors provide linear output signal dependence on concentration of analyte in comparison with the logarithmic relationship typical for potentiometric sensors  and charge z; total mass of substances, which either precipitated or dissolved on the electrode, is expressed as m. An indifferent ion should be added to solution for polarization suppression.The meaning of symbols is common; et al., et al., et al., Biosensors are analytical devices consisting from biorecognition element and a proper sensor element  and oxygen or hydrogen peroxide amperometric transducer (Campanella et al., et al., et al., et al., et al., The second way being frequently performed for amperometric evaluation of AChE activity is based on replacement of native substrate acetylcholine by an alternative acetylthiocholine. The mechanism is lucidly depicted in Amperometric biosensors with intercepted cholinesterases are promising tools for evaluation of many anticholinergic compounds. Assay of pesticides, nerve agents and aflatoxins are typical analytes. The second way of biosensor performance is evaluation of drugs administered to patients suffering from Alzheimer\u2032s disease and myasthenia gravis."}
{"text": "Acute perinatal asphyxia is a major cause of death and neurological injury in newborn infants. Severe asphyxia can occur in infants around the time of birth for several reasons. The aim of our study was to find the most sensitive, easily obtainable and fast assessable parameter of the presence and quantification of asphyxia.In our study 39 term newborns , from vaginal deliveries admitted within 24 hours of life were monitored and parameters of blood count from venous blood were assessed. Laboratory findings of blood count parameters revealed significant differences between term asphyxial and healthy newborns in erythrocyte count and hemoglobin and hematocrit values.Hematological changes observed early after delivery can determine the duration of hypoxemia (acute vs. chronic) and asphyxia of short duration may be accompanied without occurrence of polyglobulia. Birth itself is a strong oxidative stress. Oxidative stress, excess of free radicals and their reactive metabolites in the organism, plays an important role in the pathogenesis of so called free-radical diseases, not only in adults but also in newborns  were determined.The study involved 39 term newborns , from vaginal deliveries admitted within 24 hours of life. In both groups of newborns, blood samples of venous blood were taken on the 1Blood count was determined by an automatic analyzer ADVIA 120  using an optical system for measurement. The number of erythrocytes, leukocytes and thrombocytes was assessed by the analyzer using a laser beam which registered the flow of cells in certain time intervals. Hemoglobin was measured colorimetrically. Using a laser beam, the size of erythrocytes was determined and further the value of hematocrit was calculated.p \u2264 0.05 was considered significant. The presence of asphyxia was the first factor  and the time of blood sampling was the second factor (1st and 5th day of life).For statistical analysis ANOVA followed by Fisher's post hoc test was used, This study complies with the guidelines for human studies and animal welfare regulations and subjects have given their informed consent. The study protocol has been approved by the Committee on Human Research in Medical School, Comenius University, Bratislava, Slovakia.Laboratory findings of blood count parameters revealed significant differences between term asphyxial and healthy newborns in erythrocyte count and hemoglobin and hematocrit values . We did et al., et al., Several changes in structure, function and amount of certain blood elements have been observed in asphyxia .In our study blood count variables were found to be affected differently than observed by other authors. In the blood samples obtained on the 1et al., et al. (In asphyxia, in the first 96h of life increased peripheral leukocyte counts may contribute to abnormal neurodevelopmental outcome (Morkos , et al. .th day of life a normal number of thrombocytes is established.Thrombocytes take part in hemostasis, influence coagulation cascade and are the main source of many biologically active substances. Thrombocytopenia can be observed during the first 2 days of life, on the 10st and 5th day of life. We agree with the finding of Phelan et al. (In either groups studied we did not confirm a statistically significant thrombocytopenia, though in the group of asphyxial newborns the levels of thrombocytes were slightly decreased on 1n et al. , that thIn spite of the recent decrease of perinatal morbidity and mortality, the risk of pre/postnatal CNS damage as a consequence of asphyxia did not decrease. The aim of current perinatology research is finding and determining the most sensitive, easily obtainable and fast assessable parameter of the presence and quantification of asphyxia.et al., et al., et al., The newborns have inadequate antioxidant protection and oxidative stress is a major cause of irreversible CNS damage in term asphyxial newborns. Studies have confirmed the helpful effects of antioxidant supplementation during hypoxemia (Pech\u00e1\u0148 et al., et al., In combination with other biochemical blood parameters (Brucknerov\u00e1"}
{"text": "Dear Sir,et al.[et al. have concluded that \"Simultaneous laparoscopic procedures can be done for urological diseases in selected patients, with the advantages of single anaesthesia and hospital admission without increasing the morbidity\".[With great interest, I read the recent publication on 'using concomitant laparoscopic procedures for urological diseases' by Maurya et al. Maurya erbidity\". Indeed, rbidity\"."}
{"text": "International Journal of Environmental Research and Public Health\u2019. I was invited to be the guest editor, and to oversee the refereeing process and subsequent selection of timely, relevant and high quality papers highlighting particularly novel aspects concerned with sustainability issues in environmental studies.This special issue \u2018Sustainability: Environmental Studies and Public Health\u2019 is part of the internationally leading \u2018Contributions that have a significant impact on solving public health problems were particularly encouraged. It follows that major public health issues, sustainable water management and environmental risk were topics of particular interest to the editorial team and reviewers. Ten papers comprising various scientific contributions including technical and critical review papers relevant for a world-wide audience were selected.et al. [et al. [Three comprehensive critical review papers were published. Remoundou and Koundouri  reviewedet al.  explored [et al.  reviewedet al. [et al. [Seven original papers were published in this special issue. Saarloos et al.  linked t [et al.  discusseThe human health theme features also strongly in this special issue. For example, Markandya and Chiabai  valued cet al. [Other papers had a clear international dimension. For example, Cross et al.  studied et al.  presenteet al.  assessedThe high diversity of excellent environmental and public health studies with a strong sustainability theme is likely to be of interest to a broad audience for decades to come. This special issue is not just a timely reference source for academics, but should particularly be of practical use for medical doctors, environmental scientists and engineers, and civil engineers concerned with public health engineering, environmental protection and sustainability.It is a pleasure to thank the members of the Editorial Board, all authors and co-authors and all referees for their valuable contributions to this special issue. Moreover, this most interesting publication would not have been possible without the efficient support from the Journal Office."}
{"text": "Sir,et al. published in December 2009 issue of IJA.[I read with interest the article titled \u201cComparison of Midazolam and Propofol for BIS-Guided Sedation during Regional Anaesthesia\u201d by Khurana e of IJA. I congraet al.[et al.[et al.[50 (BIS at which 50% of patients were unresponsive) of 65 for propofol alone but 76 for propofol with nitrous oxide. Iselin-Chaves et al.[50 of 64 for propofol alone and 72 for propofol with alfentanil.Several reports have suggested that BIS measurements may not be independent of the drug used. There is evidence that BIS is influenced by the choice of anaesthetic agent. In a study conducted by Ibrahim et al. wherein l.[et al. found BIl.[et al. found a As per the study protocol, the initial BIS targeted in both the midazolam and propofol groups was 75, with infusions manipulated intra-operatively to maintain BIS values in the 65\u201385 range. The incidence of awareness has been stated to be 20% in the midazolam group and 16.7% in the propofol group.et al.[However, in view of the above evidence, identical BIS values may not necessarily indicate identical levels of sedation for both midazolam and propofol as understood in clinical parlance. The authors\u2019 concern that assessment of depth of sedation by clinical means may itself alter such a depth is no doubt valid. Despite such concerns, however, it would have been interesting to note the levels of sedation at identical BIS levels for both groups and infer there from. Furthermore, the methods by which awareness during sedation, as defined by recall of intraoperative events, in the study under discussion were assessed, probably required greater elaboration. In this regard, specific memory tests for immediate and delayed recall as utilized by Ibrahim et al. might ha"}
{"text": "We appreciate the comments by Rylance et al. stimulated by our analysis of the global burden of disease due to outdoor air pollution . We acknIn the 2004 World Health Organization (WHO) comparative risk assessment, We agree with Rylance et al. that the approach used by"}
{"text": "We report two cases of plunging ranula, which had recurred after marsupialization. Both were successfully treated by removal of the ipsilateral sublingual gland. A brief review of the literature regarding the treatment options is presented. Ranula is an extravasation cyst found in the floor of the mouth. They develop from extravasation of mucus after trauma to the sublingual gland or obstruction of the ducts.\u20133 PlungiAn 8-month-old girl baby was referred with an intraoral swelling with extension into the submandibular and submental space. Marsupialization had been done at 2 months of age. A provisional diagnosis of plunging ranula was made. Magnetic resonance imaging (MRI) showed a thin walled cystic lesion on the left side involving the floor of the mouth in the sublingual region and extending inferiorly into the submental region, laterally into the submandibular region, superiorly into the left parapharyngeal region up to the pharynx . IntraorA 10-year-old girl presented with a recurrent intraoral swelling. She had undergone marsupialization for an intraoral swelling 2 months earlier at a local hospital. The clinical examination revealed a large cystic swelling of 3 \u00d7 4 cm with extension into the submental space with cross-fluctuation . The intRanula develops from extravasation of mucus after trauma to the sublingual gland or obstruction of the ducts.3 Ranula The pathophysiology involved in extravasation is hypertension in the duct due to obstruction leading to acinar rupture in the salivary gland and then extravasation of the mucus. The initial stage is a traumatic rupture of the excretory duct and the second stage is the extravasation and subsequent accumulation of saliva within the tissue, as shown by experimental studies.7 Ranula When these extravasation cysts extend into the submandibular or submental space, they are called plunging ranula. Its true incidence is unknown. The cause of plunging ranula is not known, but anomalies or obstruction of the salivary gland duct and naturally occurring defects in the mylohyoid muscle have been shown to be prerequisites for the extravasation. These cysts commonly extend into the submandibular triangle, occasionally they may extend superiorly into the parapharyngeal space as far as the base of the skull. They may extend inferiorly to the supraclavicular area and upper mediastinum or posteriorly into the retropharyngeal space.898Ranula is a clinical diagnosis, and imaging studies are done mainly to know the extension of swelling prior to surgery or when the diagnosis is unclear. Computed tomography and specifically the presence of \u201ctail sign\u201d is pathognomonic for the plunging ranula.\u201312 This et al[et al[et al[et al[et al[Surgery is the main stay for the management of ranulas. These include incision and drainage, excision of ranula, marsupialization, and marsupialization with packing or complete excision of the sublingual gland. Simple marsupialization has fallen into disfavor primarily because of the failure rate, which has been anywhere from 61% to 89%.[et al have tre al[et al suggeste al[et al had two  al[et al Mahadeva al[et al did not et al[et al[Other treatment modalities have also been utilized. Sclerotherapy with OK-432 is a good substitute for surgery. Recurrenet al used a h al[et al have perIn conclusion, removal of the ipsilateral salivary gland is the management of choice in ranulas. Intralesional sclerotherapy with OK-432 is a good option but may not be feasible due to nonavailability of the product universally."}
{"text": "We thank Guzzi et al. for their interest in our study on the association of environmental cadmium exposure and periodontal disease . There aThat dental amalgams are the major source of Cd body burden has been questioned , and fur"}
{"text": "Sir,et al., a diagnosis of Netherton's syndrome was made.et al. in his review of 43 patients described a male patient[Netherton's syndrome is characterized by the triad of ichthyosis linearis circumflexa, trichorrhexis invaginata (bamboo hair) and an atopic diathesis. Our case37e patient In our ce patient our patiWe report this case for its rarity and classical presentation."}
{"text": "It causes profound hemodynamic effects, especially when the rupture is acute. Like most other left-to-right shunts, it was only a matter of time before this rare defect also became amenable to transcatheter closure (TCC). Since the first report of TCC of RSOV by Cullen . in 1994 it was o94[et al. In this l.[et al. we too hl.[et al. Traditiol.[et al. Before oet al. have performed TCC for RSOV rupturing into the right atrium and the right ventricle using two Amplatzer duct occluders (ADOs).[Sen and coworkers attemptes (ADOs). Because s (ADOs).10 as wels (ADOs). have beeet al.[The technique is very similar to TCC of perimembranous VSD, given that the defect is just above the aortic valve instead of below. It entails crossing the defect from the left side, establishing the standard arteriovenous wire loop and deploying the device from the venous side under fluoroscopic and transesophageal echocardiographic (TEE) guidance. Although Arora et al. have useet al. Balloon et al. We have et al.[Residual shunting causing hemolysis in this high-flow defect and procedure-related AR are the potential complications of TCC of RSOV. Although Sen et al. have hadet al. We have et al. AlthoughIn summary, RSOV is yet another hole that can be successfully plugged by the interventional cardiologist. TCC can be considered a safe and effective alternative to traditional surgical correction in selected cases. However, a longer follow-up is necessary. Given the rarity of this defect, it would be essential to maintain a registry of such procedures."}
{"text": "Dear Editor,et al.[First, we appreciate the details with which Chalisgaonkar et al. have reaet al. and searet al.,[In the case report by Biswas et al., on the cIn all case reports of retinoblastoma in adults, retinocytoma was diagnosed as benign appearing areas in malignant tumor tissue and not as pre-existing lesions that turned malignant on follow-up. In our cet al.,[may have an effect on retinoblastoma due to circulating mutagens and immunosuppression.[Ours is the only case reported in literature where retinoblastoma was found in pregnancy. There is one case reported by Takahashi et al., six montpression."}
{"text": "Sir,et al. recommended that \u201ca precautionary approach when dealing with radio and microwave frequency radiation is recommended for the individual and the general population.\u201d[The cellular phone is a widely used tool at present. The interesting question is whether cellular phone has any effects on germ cell. Basically, the effect of cellular phone on health is believed to due to microwave emitted from the phone. The effect of microwave from cellular phone on germ cell is a controversial issue.2 The topulation.\u201d In this et al.[Focusing on the effect of cellular phone on ovary, according to the literature search, there is only one experimental report on this topic published by Gul et al. They reaet al. There aret al. reported on null correlation between exposure to cellular phone and testicular cancer in their case control study.[in vitro studies pointing to the possible effect of cellular phone on human spermatozoa.[et al. reported that radiation from cellular phone might induce reactive oxygen species production and DNA damage in human spermatozoa in vitro.[et al. also observed similar findings in their in vitro study and proposed that \u201ckeeping the cell phone in a trouser pocket in talk mode may negatively affect spermatozoa and impair male fertility.\u201d[et al.[in vitro studies usually depend on small number of tested samples. This makes the limited implication of the results.Focusing on the effect of cellular phone on testes, there are many reports on the effect of cellular phone on testicular cell. Effect of cellular phone on mammalian cells and sperm DNA as well as its effect on apoptosis is still controversial. In an exol study. However,rmatozoa.\u201310 De Iuin vitro. Agarwal rtility.\u201d A decrea.\u201d[et al. However,In conclusion, effect of cellular phone on the germ cell is still a myth. The previous reports usually pose some problems implying the need for further well-controlled studies for clarification on this topic."}
{"text": "Acute appendicitis is a common surgical problem however the diagnosis is often overlooked when it presents as a small bowel obstruction. In this report we present two cases of elderly patients who presented with small bowel obstruction and raised inflammatory markers. Both patients were successfully treated with a laparotomy, adhesiolysis and appendicectomy and went on to make a good recovery. Acute appendicitis may rarely present as small bowel obstruction . The sma9/L and 362 mg/L respectively. Her renal function was deranged with a creatinine of 251 \u03bcmol/L and a urea of 14.8 mmol/L. An abdominal film  fet al [Bose et al  reportedet al [Assenza et al  reportedet al [et al [However, variations of the above mechanisms have been reported. Zissin et al  report al [et al  presenteet al [et al [Appendicitis can be caused by an appendiceal mucocele and Mourad et al  report sl [et al  report aThe presentation of acute appendicitis in the elderly can be atypical which can result in a delayed diagnosis with potential for increased morbidity and mortality . PresentAcute appendicitis should be considered in the differential diagnosis of patients with small bowel obstruction presenting with raised inflammatory markers to avoid delays in management.CT: computerised tomography.Written consent was obtained from both patients for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.SH collected the data on both patients and contributed to the literature search and writing of the manuscript. KM conceived the idea and helped with the draft of the case report. DB interpreted the radiological images and contributed to the draft of the manuscript. LB was consultant in charge of patient 1 and contributed to the draft of the manuscript. PKS was the consultant in charge of patient 2 and contributed to the draft of the manuscript. All authors read and approved the final manuscript."}
{"text": "Dear Editor,et al.[We read with interest the article \"Amyloidosis of lacrimal gland\" by Prabhakaran et al. We wouldet al.,[et al.[The authors report that approximately 24 cases of primary localized amyloidosis of orbit have been reported. However, we believe that this number is likely to be higher. In a review article by Taban .,[et al.et al.,[et al.,[The authors mention that one bilateral case of isolated lacrimal gland amyloidosis has been reported. We wish to draw attention to one of the cases reported by Cheng et al., who had ,[et al., have desHertel's exophthalmometer is designed to measure axial proptosis and is unable to measure ocular displacement. We would value being educated as to how the authors were able to measure the displacement with the help of a Hertel's exophthalmometer. Perhaps the authors are merely implying that apart from having 2 mm of axial proptosis, the patient also had 2 mm of displacement.Lastly, was any reoccurrence noted? Recurrence has been said to occur in approximately one-third of cases as total excision is usually not possible in these patients."}
{"text": "The mixed epithelial stromal tumour is morphologically characterised by a mixture of solid and cystic areas consisting of a biphasic proliferation of glands admixed with solid areas of spindle cells with variable cellularity and growth patterns. In previous reports the seminal vesicle cystoadenoma was either considered a synonym of or misdiagnosed as mixed epithelial stromal tumour. The recent World Health Organisation Classification of Tumours considered the two lesions as two distinct neoplasms. This work is aimed to present the low-grade epithelial stromal tumour case and the review of the literature to the extent of establishing the true frequency of the neoplasm.We describe a low-grade epithelial stromal tumour of the seminal vesicle in a 50-year-old man. Computed tomography showed a 9 \u00d7 4.5 cm pelvic mass in the side of the seminal vesicle displacing the prostate and the urinary bladder. Magnetic resonance was able to define tissue planes between the lesion and the adjacent structures and provided useful information for an accurate conservative laparotomic surgical approach. The histology revealed biphasic proliferation of benign glands admixed with stromal cellularity, with focal atypia. After 26 months after the excision the patient is still alive with no evidence of disease.Cystoadenoma and mixed epithelial stromal tumour of seminal vesicle are two distinct pathological entities with different histological features and clinical outcome. Due to the unavailability of accurate prognostic parameters, the prediction of the potential biological evolution of mixed epithelial stromal tumour is still difficult. In our case magnetic resonance imaging was able to avoid an exploratory laparotomy and to establish an accurate conservative surgical treatment of the tumour. The mixed epithelial and stromal tumour (MEST) is morphologically characterised by a mixture of solid and cystic areas with a biphasic proliferation of glands admixed with solid areas of spindle cells, with variable cellularity and growth patterns. We report a low grade MEST of the seminal vesicle and we emphasize the diagnostic criteria and the different diagnosis as cystoadenoma.A 50-year-old man was admitted in November 2005 to our hospital with disuria, fever and gradual decrease in urinary stream for several months. On ultrasound (US) a hynomogeneous, hypoechoic pelvic mass of the posterior side of the bladder was demonstrated. Abdominal computed tomography (CT) revealed a 9 \u00d7 4.5 cm pelvic mass in the side of the seminal vesicles displacing the prostate and urinary bladder. On precontrast CT, the mass showed fluid heterogeneous content, well-defined margins, and irregular thin enhanced internal septa after intravenous contrast material administration. On axial spin-echo T1-weighted and axial and sagittal T2-weighted Fig.  magneticIn our case the low-grade MEST diagnosis was made in accordance with the World Health Organization (WHO) classification criteria . The leset al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., may be not accepted as conclusive because only three cases were considered. In our case US was only useful to detect the lesion, but both its site and relations with adjacent organs were not established. CT confirmed the presence, size, location, internal consistency, extension of the primary tumour, and the absence of distant metastases. MRI was useful in establishing the tumour origin from the seminal vesicles and its relations with the adjacent organs (Fig. These tumours have been considered to represent morphological variants of the same neoplasm, which may reveal local recurrence but not malignant transformation ,10. In tet al.,  and Son [et al.,  reported[et al., , Bullock[et al., , Damjano[et al., , Lundhus[et al., , should [et al.,  or becau[et al., , Baschin[et al., , Mazzucc[et al., , Gil et [et al., , the mes[et al., , the ben[et al., , should [et al.,  and Hosh[et al.,  the clas[et al.,  in low, [et al., . In the [et al.,  examined[et al.,  and Soul[et al., : obviousSVC and MEST are two distinct pathological entities with different histological features and clinical outcome. Predicting the potential biological behaviour of MEST remains difficult because accurate prognostic parameters are not available. In our case MRI was able to avoid an exploratory laparotomy and to establish an accurate conservative surgical treatment of the tumour.MEST: mixed epithelial and stromal tumour; US: ultrasound; WHO: World Health Organization; CT: Computed tomography; MRI: magnetic resonance imaging; CEA: carcinoembryonic antigen; PAP: prostate acid phosphatase; PSA: prostate specific antigen.Written informed consent was obtained from the patient for publication of this case report.The authors declare that they have no competing interests.IF collected the tissue specimen, made the histological diagnosis and images, revised the manuscript. IP made the radiological diagnosis, prepared radiological images. BM conceived the study and revised the manuscript.  ML, FF, GP: collected clinical records and wrote the manuscript. All authors read and approved the final manuscript."}
{"text": "Sir,et al[et al[I read with much interest the article of Creado et al which de al[et al concludeThis conclusion, though intuitively appealing, is not necessarily correct. An equally credible argument is that patients who are more severely ill increase the caregiver burden of illness and provoke maladaptative methods of coping, such as escape avoidance, fatalism and passivity, whereas patients who are less severely ill decrease the burden of illness and allow the unfolding of more adaptative methods of coping, such as expressive action and problem-solving.et al[Causality can never be proven from statistical associations. If variables A and B are significantly correlated, A may cause B, B may cause A or A and B may both be influenced by a third, measured or unmeasured, variable. In the last-mentioned instance, the third variable is known as a confounding variable. Creado et al opted toSeveral criteria have been outlined to help researchers interpret causality. These include the temporal sequence of the variables, the strength, consistency and specificity of the association, the presence of a dose-response type of relationship, and the existence of a credible explanation. However, the most definitive method of determining causality would stem from research that is based on randomized, controlled designs.et al[So, do the findings of Creado et al reflect A backward, stepwise, multiple regression analysis which examines the effects of measures of illness severity and measures of coping on burden of illness. This anaA path analysis which examines chains of influence among variables, and whether the data are consistent with the specified model of causality. Several It is hoped that these digressions on statistical and research methods guide these and future authors in their approach to hypothesis-setting and data analysis."}
{"text": "Bmal1 knockout mice and rescued by restoration of Bmal1 expression selectively in the dorsomedial hypothalamus was published in 2008 by Fuller et al and critiqued in 2009 by Mistlberger et al. Fuller et al have responded to the critique with new information. Here we update our critique in the light of this new information. We also identify and correct factual and conceptual errors in the Fuller et al response. We conclude that the original results of Fuller et al remain inconclusive and fail to clarify the role of Bmal1 or the dorsomedial hypothalamus in the generation of food-entrainable rhythms in mice.Evidence that circadian food-anticipatory activity and temperature rhythms are absent in  Bmal1 deficient mice fail to anticipate a daily mealtime, and that restoration of Bmal1 by adenoassociated viral vector restricted to the dorsomedial hypothalamus (DMH) rescues food-anticipatory circadian rhythms. The authors concluded that the clock gene Bmal1 and the DMH are both required for this circadian function. However, two other labs have found that Bmal1 null mice do anticipate a daily meal under the same conditions as those used by Fuller et al [Bmal1 in the entrainment of circadian anticipatory rhythms by food ['each of these points [is]incorrect'. Our objectives in this reply are to briefly revisit each point in the critique and to update our analysis in view of what little new information Fuller et al have provided. We also identify and correct factual errors and misconceptions in the Fuller et al response. Fuller et al conclude that 'in no case does [the new information] change our results or their import'. We agree: the results of Fuller et al substantially increased by food restriction and the other is dramatically decreased'. This statement is again not evidence-based. We 'deliberately' did not report absolute values in that paper because it is irrelevant, but provide them here  = 1.31, p = .21). During a subsequent 50 h food deprivation test, telemetry and motion sensor counts increased but remained below baseline levels .Fuller et al  in theirere Fig. . When fonot sufficient if food anticipation is weak or absent. Food-anticipation is clock-controlled foraging, and more sophisticated behavioral assays  should be employed to properly phenotype this circadian function.It bears emphasizing, the criterion for selecting a measure of food anticipatory activity (or physiology) should not be whether mean daily levels of this measure go up or down during food restriction. Rats and mice reduce total daily energy expenditure when calories are restricted, and this will be reflected in reduced activity at times of day when food is not expected. They are able to do this by utilizing a circadian clock to concentrate food seeking at the expected mealtime. General measures of activity, such as provided by telemetry or IR motion sensors, are adequate to detect food anticipation in neurologically intact, wildtype rats and mice, but such measures sometimes fail to detect circadian clock-controlled food anticipation revealed by foraging-related measures . The us4b. Fuller et al [consistently misrepresent what we [have shown and how we frame it\". This is a puzzling complaint. To remind the reader, the Saper laboratory [critical' for food entrainment. That is in the title of their paper. Fuller et al [Bmal1 expression in the DMH is sufficient to restore food anticipatory rhythms. Taken together, the two studies claim to have demonstrated that the DMH is both necessary and sufficient for food entrainment, and that his how we have summarized their findings. Fuller et al [This is not correct'. Yet, in the final paragraph of their response , they state that 'we stand by our findings that the DMH is necessary for organizing food entrained circadian rhythms, and that ...robust activation of ... clock genes in the DMH is sufficient to restore food-entrained rhythms'. There are many other food-entrainable circadian oscillators in brain and body, but if the DMH meet criteria for necessity and sufficiency, as claimed, then these other oscillators cannot also be both necessary and sufficient for food anticipatory activity rhythms.er et al  state th what we ,21have ser et al  say thatthe food entrainable oscillator uses the same output mechanisms through the DMH as does the SCN'. However, lesion data cannot establish whether the DMH is input, oscillator or output, only whether it is or is not 'critical'.Fuller et al  state thEuropean Journal of Neuroscience [learn cognitively' by 'classical conditioning' that food is delivered each day in the middle of the light period (either 5 or 6 h after lights-on). They attempt to support this argument by stating that in the Moriya et al DMH lesion study , food aya et al  are corrnot generate a conditioned response  if there is a 5\u20136 h gap between the CS onset and the US . Furthermore, if the CS (light) is omitted, then the CR (anticipation) should be absent. If food anticipatory activity were a CR to an association between light and feeding, then it would begin at light onset and would be completely absent in DD, not attenuated 25%. Food anticipation in Moriya et al [First, for classical conditioning to occur, the conditioned stimulus  and the unconditioned stimulus  need to be closely spaced in time if not contiguous. Classical conditioning does ya et al  exhibiteSecond, as is clearly stated in the figure legend, the waveforms in Fig. 8C in Moriya et al  illustrasic, radiofrequency) DMH lesions in Landry et al [not distorted, and major landmarks (fiber tracts and other nuclei) are clearly evident, permiting an accurate assessment of what structures are damaged or absent. Electrolytic and radiofrequency lesions are the only way to unambiguously remove the entire DMH. The neurotoxin used by the Saper group makes only partial lesions, and requires cell counting to estimate lesion size. Cell counting sounds rigorous but it is problematic if the cells are not phenotyped and the boundaries between areas are normally unclear or have become obscured by loss of cells. The rational approach to assessing whether a structure is necessary for a particular circadian behavior is to ablate the entire structure and surrounding area. If there is a loss of function, then cell-specific lesion techniques can be used to assess a role for fibers of passage or specific cell phenotypes. We and others find no loss of food anticipatory activity rhythms despite complete removal of the DMH and fibers of passage . As noted already [Although the Saper laboratory has claimed that the DMH is critical for the expression of food anticipatory activity rhythms , others s  in the LD or DD ,3, direcer et al  observed already ,23,25,26Science for many examples). Our critique is unusual only in its length. The response by Fuller et al [Two months prior to writing the critique  of Fulleer et al  only serThe authors declare that they have no competing interests.The manuscript was drafted by RM and the final version read, edited and approved by RB, EC, CE, GL, AK, PP and SS."}
{"text": "Placement of a percutaneous nephrostomy tube for drainage has been an integral part of the standard percutaneous nephrolithotomy (PCNL) procedure. However, in recent years, the procedure has been modified to what has been called \u2018tubeless\u2019 PCNL, in which nephrostomy tube is replaced with internal drainage provided by a double-J stent or a ureteral catheter. The objective of this article is to review the evidence-based literature on \u2018nephrostomy-free\u2019 or \u2018tubeless\u2019 PCNL to compare the safety, effectiveness, feasibility, and advantages of tubeless PCNL over standard PCNL. We performed a MEDLINE database search to retrieve all published articles relating to \u2018tubeless\u2019 PCNL. Cross-references from retrieved articles as well as articles from urology journals not indexed in MEDLINE, were also retrieved. The majority of the studies have shown \u2018tubeless\u2019 PCNL to be a safe and economical procedure, with reduced postoperative pain and morbidity and shorter hospital stay. tubeless PCNL has been found to be safe and effective even in patients with multiple stones, complex staghorn stones, concurrent ureteropelvic junction obstruction, and various degrees of hydronephrosis. The technique has been successful in obese patients, children, and in patients with recurrent stones after open surgery. Tubeless PCNL can be used with a favorable outcome in selected patients , with the potential advantages of decreased postoperative pain, analgesia requirement, and hospital stay. However, for extended indications, like supine PCNL, multiple, complex and staghorn stones, and concurrent PUJ obstruction, the evidence is insufficient and should come from prospective randomized trials. The important milestones in the history of percutaneous renal surgery include Goodwin's description of percutaneous nephrostomy in 1955 Wickham 3With the expanding experience of both the radiologists and the surgeons, the success rate of this procedure increased dramatically.7 In 1984et al. described \u2018mini-PCNL\u2019 with a 13F nephroscope followed by the placement of an 8F nephrostomy tube with a 7F double pigtail ureteric stent.[et al.[Chan ic stent. Maheshwat.[et al. reportedt.[et al.\u201319 HowevPreviously it was thought that nephrostomy tubes provide hemostasis along the tract, avoid urinary extravasation, and maintain adequate drainage of the kidney. However,et al.[It may be interesting to note that the idea of \u2018tubeless\u2019 existed even in the early years of evolution of PCNL. In 1984, Wickham[et al. reportedIn 1997, Bellman and associates challenget al.[Candela et al. showed tet al.\u201326 In moet al..To the best of our knowledge, there are only few studies in the literature comparing tubeless PCNL with standard nephrostomy drainage in randomized fashion .In the largest prospective randomized trial published yet, in 202 patients treated at our center, tubelesset al.[et al.,[et al.,[et al.[Desai et al. showed d.[et al., Tefekli ,[et al., and Sing.,[et al. have alset al.[Shah et al. comparedIn contrast, a randomized study by Marcovich and coworkers showed net al.,[et al.[Additional variations of the tubeless procedures have been described. Goh and Wolf, Lojanapet al., and Mour.,[et al. reported.,[et al.. Compareet al.[et al.[et al.[Karami et al. reportedl.[et al. in 128 pl.[et al. in a stul.[et al..et al.[Gonen et al. prospectet al.[One major disadvantage of tubeless PCNL with double-J stent is the need for postoperative cystoscopy to remove the stent. Bellman et al. suggesteet al..et al.[The use of tether was further modified by Bellman et al. by placiThe principle of maintaining the tether exiting from the flank may have several applications beyond routine stent placement after tubeless PCNL. In a standard PCNL, nephrostomy tube is left in when a second-look procedure is anticipated. However, it may be possible to leave only a stent with a tether in these cases as well. At the time of the second-look procedure, the tether could be used to pull the end of the stent to the level of the skin, and a guide wire could be passed antegrade into the bladder, thus reestablishing the access tract.et al.[\u00ae Loop stent to facilitate tubeless PCNL and minimize pain and narcotic use. The Polaris stent has two fine loops distally to minimize bladder irritation. Following PCNL, Polaris stent was placed antegradely in reverse orientation. The pigtail rested in the bladder and the loops in the nephrostomy tract with the string tether secured at the skin for simple, atraumatic removal. Authors reported that tubeless PCNL with the Polaris stent decreased postoperative pain and narcotic use, and allowed earlier discharge from the hospital.Berkman et al. presenteTotally tubeless approach was first reported by Wickham and coworkers. They staet al.[In a randomized study of 60 patients, Aghamir et al. assessedThese studies favor the suggestion that the best available drainage of the kidney is the normal peristalting ureter. According to this school of thought, the only indication for the placement of a ureteral stent is in the situation when the ureteropelvic junction (UPJ) or upper ureter is inflamed and edematous, or where there is UPJ obstruction, managed or unmanaged. However, this approach has not formed universal acceptability due to the concerns relating to the obstruction of ureter due to clots or stone fragments. Most authors seem to favor some kind of internal drainage in tubeless procedures.The traditional prone position used in PCNL is difficult and risky for patients with cardiopulmonary ailments and compromised respiratory functions, and in markedly obese patients. Sometimes it is impossible for the patient to lie prone because of problems with body habitus such as ankylosing spondylitis, severe lordosis or kyphosis, or hip or lower limb contractures.Supine PCNL, in addition to saving operating room time, has several benefits. Because the tract is inclined downward and more dependent in relation to the renal pelvis, the pressure within the pelvicaliceal system is low, and stone fragments tend to fall out spontaneously. The possibility of a stone falling into the renal pelvis and the ureter is also minimized. It also permits the patient to remain in the lithotomy position for simultaneous ureteral instrumentation if necessary.52On the other hand, PCNL in the supine position has limitations in upper caliceal puncture as the upper pole is more medial and posterior, and concealed deeply in the rib cage. Classical prone position provides a larger surface area for the choice of puncture site and a wider space for instrument manipulation.et al.,[Rana et al., in a stuFor reasons of safety, most investigators have focused on using tubeless PCNL only in selected patients with uncomplicated stones. The selection criteria for tubeless PCNL include stone burden <3 cm, a single access tract, no significant residual stones, no significant perforations, minimal bleeding, and no requirement for a secondary percutaneous procedure.However, in recent years, the tubeless technique has been applied for the treatment of multiple stones, branching and complex stones, staghorn stones, concurrent UPJ obstruction, and collecting systems with various degrees of hydronephrosis. The technique has been successful in obese patients, children, and patients with recurrent stones after open surgery.et al.[Shah et al. reportedRana and Mithani reportedet al.[Sofer et al. reportedet al.[Malcolm et al. publisheet al.[Jou et al. performeet al.[Falahatkar et al. achievedet al.[Salem et al. assessedet al.[Shah et al. reportedSeveral centers have reported their experience with bilateral tubeless PCNL.63 Shah aSingh and co-workers performeTubeless PCNL also has been performed in patients with ectopic kidneys. Matlaga and associates reportedet al.[Yang et al. reportedet al.[Tubeless PCNL using supracostal access was done for 72 patients by Shah et al. The outcet al.,[In a study by Sofikerim et al., 48 patieTwo hemostatic agents have been commonly used in PCNL: Gelatin matrix hemostatic sealant (GMHS) and fibrin glue . Gelatin70et al.[et al.[Nagele and Schilling et al.74 reportl.[et al. were thel.[et al.\u201378\u00ae) to seal the working tract and concluded that such sealing of the nephrostomy tract after totally tubeless PCNL did not decrease bleeding or urinary extravasation. In a prospective study of 50 patients, Singh et al. [\u00ae) in tubeless PCNL. They observed lower wound soakage/discomfort in the gelatin-assisted tubeless PCNL group as compared to controls.Aghamir and colleagues  used oxih et al.  evaluateet al.[et al.[et al.,[In 51 patients, Jou et al. reportedl.[et al. also rep.[et al., in theirPatients who undergo tubeless PCNL have significantly less pain postoperatively and require less analgesia dosage.Tubeless PCNL minimizes the hospital stay, allowing many patients to be discharged from hospital in less than 24 h.A tubeless procedure offers the advantage of passive dilation of the ureter caused by the indwelling double-J stent to facilitate passage of any unrecognized small stone fragments.The omission of a nephrostomy tube with the placement of an indwelling double-J stent is associated with rapid healing and minimal urine leakage.The general consensus is that the tubeless approach is feasible only in a selected population that generally excludes cases requiring two or more accesses, significant intraoperative bleeding, or situations with a likelihood of residual stone fragments.The other limitations to tubeless PCNL are the possibility of missed residual stone fragment  that become apparent later, as a tubeless operation precludes a \u2018second-look\u2019 procedure.The need for an additional procedure, that is, cystoscopy, to remove the double-J stent.\u2018Stent dysuria\u2019, which can be troublesome in some patients, and may even warrant the need of early double-J removal.One of the criticisms of this approach is that the ureteral stent does not necessarily provide drainage of the kidney. It is well established in animal models that stents cause a degree of obstruction and raise intrapelvic pressure.Tubeless PCNL can be used with a favorable outcome in selected patients , with the potential advantages of decreased postoperative pain, analgesia requirement, and hospital stay.Several retrospective studies have shown that its application can be extended even in patients with multiple, complex and staghorn stones, concurrent UPJ obstruction, solitary kidney, previous ipsilateral open surgery, raised serum creatinine level, with multiple or supracostal tracts, and in patients undergoing bilateral synchronous PCNL. The technique has been successful in obese patients, children, and patients with recurrent stones after open surgery. However, for all these extended indications, the available evidence is insufficient, and needs to be substantiated by prospective randomized trials."}
{"text": "Since publication of our article, \"An unusual and difficult diagnosis of intestinal obstruction: The abdominal cocoon. Case report and review of the literature.\" World J Emerg Surg. 2006, 1: 8 we believe that the case mentioned should have been described as a 'peritoneal encapsulation' rather than 'abdominal cocoon' as concluded in the original publication. Since publication of our article  we belieThe abdominal cocoon is a condition in which a variable length of healthy small bowel is enveloped in a fibrocollagenous membrane, giving the appearance of a cocoon. It is an unusual cause of intestinal obstruction in children and adolescents. It was first described and named in 1978 by Foo et al. .Peritoneal encapsulation was first described by Cleland in 1868 . PeritonIn our article  the pathThere are other case reports that have confused these two entities by mistake. For example Sayfan et al.  describe"}
{"text": "Ever since the development of Hybridoma Technology in 1975 by Kohler and Milstein, our vision for antibodies as tools for research for prevention, detection and treatment of diseases, vaccine production, antigenic characterization of pathogens and in the study of genetic regulation of immune responses and disease susceptibility has been revolutionized. The monoclonal antibodies being directed against single epitopes are homogeneous, highly specific and can be produced in unlimited quantities. In animal disease diagnosis, they are very useful for identification and antigenic characterization of pathogens. Monoclonal antibodies have tremendous applications in the field of diagnostics, therapeutics and targeted drug delivery systems, not only for infectious diseases caused by bacteria, viruses and protozoa but also for cancer, metabolic and hormonal disorders. They are also used in the diagnosis of lymphoid and myeloid malignancies, tissue typing, enzyme linked immunosorbent assay, radio immunoassay, serotyping of microorganisms, immunological intervention with passive antibody, antiidiotype inhibition, or magic bullet therapy with cytotoxic agents coupled with anti mouse specific antibody. Recombinant deoxyribonucleic acid technology through genetic engineering has successfully led to the possibility of reconstruction of monoclonal antibodies viz. chimeric antibodies, humanized antibodies and complementarily determining region grafted antibodies and their enormous therapeutic use. Antibodies are a mixture of closely related immune system proteins, with subtle but important differences. Conventional techniques for preparation of antibodies in antiserum against a particular antigen always result in the production of antibodies having different classes, specificities and affinities. The development of Hybridoma Technology by Kohler and Milstein2 has proThe development of hybridoma technology offered a number of advantages over the original art of polyclonal antibodies viz. (i) the generation of MAbs is now a standard and increasingly routine procedure, (ii) the use of impure antigen is tolerated since the detection of MAb of interest is largely dictated by the selection strategy, (iii) antibodies with selected properties or reactivities for specific structures could be selected and (iv) since the hybridoma cells line is immortal, there is an unlimited source of the MAb.in vitro and secrete a single monoclonal antibody[In hybridoma technology, a myeloma cell rendered drug sensitive through mutation in a growth essential gene hypoxanthine guanine phosphoribosyl transferase (HGPRT) is chemically fused with immune cells from a host immunized with the antigen of interest and the resulting cells are grown in medium containing the selective drug. Since the immune cells have a short life span in tissue culture and the myeloma cells are drug sensitive, the only cell that will survive are those myeloma cells which obtained a normal HGPRT gene from the immune cells. Such cells also have a high likelihood of carrying the immune cell's antibody gene resulting in the generation of a hybridoma that can grow continuously  antibody.Selection of hybridomas secreting desired antibodies is quite tedious. Screening assay should be rapid, reliable, versatile, sensitive and easily performed with a large number of samples. The most commonly used system fulfilling these criteria is the enzyme linked immunosorbent assay (ELISA). However, antibodies can also be detected by radio immunoassay (RIA), immune fluorescence and haemolytic plaque assays. In ELISA, an antigen is passively adsorbed to a plastic surface (polystyrene). The sample (serum/culture supernatant) is applied to the immobilized antigen. The monoclonal antispecies antibody enzyme conjugate is then added, followed by addition of substrate and spectroscopy. Selected hybridomas after screening are expanded to be frozen and cloned to generate monoclonal by limiting dilution method. The selected and desired MAbs can be purified by affinity chromatography, being more efficient and less tiresome. They are characterized by isotyping to determine the class/sub class of immunoglobulins by ELISA and western blot to test their ability to bind different antigen preparations.in vivo production in mice by ascites induction has been preferred for its cost effectiveness and high concentration of MAbs produced. But the growing ethical concern about mice and the improved cell culture techniques, led to an increased emphasis on in vitro methods being parallel to the in vivo methods both in capacity and cost effectiveness[in vitro production of MAbs which are released in culture medium at concentrations between 1 to 100 \u03bcg/ml[et al.[Since the inception of hybridoma technology, various approaches and technologies have been developed for large scale production of MAbs. For a long time, the ctiveness. Convent100 \u03bcg/ml. In the 100 \u03bcg/ml. But Treml[et al. have demDuring the past decades MAbs have found tremendous applications in therapeutics, drug targeting and had a profound impact on diagnostics. The diagnosis of any infectious disease often needs the demonstration of the causative organism or a specific antibody. In some infectious diseases such as reproductive or respiratory infections, the causative organism can be demonstrated throughout the course of infection. Specific antibody based tests identify the pathogens associated with the disease. MAbs recognizing unique antigenic determinants on pathogens can be developed. MAb can read with a single antigenic determinant (epitope) and this restricted reactivity allows for precise identification of the organism of interest which is the major advantage of MAbs over polyclonal antisera. In case of a pathogen occurring as sub type defined by unique antigenic differences, specific MAbs can be used whereas conventional antisera needs laborious absorption to remove cross reactive antibodies. Because of the specificity, homogeneity and unlimited availability of the MAbs, vast amount of work has been carried out on the production/development of MAbs diagnostic reagent tests against various pathogenic agents of veterinary importance.et al.[et al.[et al.[et al.[et al. in 1982[et al. in 1983[Production of monoclonal antibodies against mouse lymphocyte surface glycoprotein has been reported by Trowbridge, againstet al., againstl.[et al. and for l.[et al.. Falmandl.[et al. have usel.[et al. for anti. in 1982 and Weis. in 1983 have repTrichomonas vaginalis[Leishmania donovani[Trypanosoma congolense[Babesia bovis[P. carinii pneumonia have been reported by Kudryk et al.[et al.[et al[et al[The immuno diagnosis of protozoal and parasitic diseases has significantly been improved by MAb technology because the tests involving MAb as diagnostic reagents overcome the limitations of polyclonal antibodies. MAbs were found extremely useful in the rapid outbreak of East Coast Fever (ECF). MAbs ofvaginalis, Leishma donovani, Trypanoongolense, Babesiasia bovis. With imsia bovis\u201321. The sia bovis and theisia bovis. Productyk et al. and Natol.[et al., respectal.[et al and Hilg al[et al, respectet al.[Taylor et al. have comet al..et al.[et al[Candida albicans ATCC 26555 as an immunoglobulin G1 used for the recognition of high molecular mass proteins present in the cell wall of Candida albicans has been reported by Marcilla et al[Use of MAbs with magnetic particles to separate cell sub populations by negative selection as well as by positive selection has been reported by Vaccaro and Markenacin 199531. Quiliet al. have comal.[et al have stalla et al.Two easy-to-use commercial diagnostic assays, a dipstick ELISA and an immuno chromatographic card assay were evaluated for detection of IgM antibody to dengue virus with an in house IgM antibody capture microplate ELISA as a reference assay. Both commercial assays provide sensitive and specific detection of anti dengue virus IgM antibody and would prove useful in settings where the microplate ELISA is impractical.Monoclonal and recombinant antibodies provide a never ending source of molecules and can produce endless possibilities for novel genetic constructs. Antibodies are still very much in vogue and are now also being used in micro array analysis of the proteome using protein chips.et al.[et al[Skin derived anti leukoproteinase (SKALP), also known as elafin, is an epithelial proteinase inhibitor with antimicrobial properties that is not normally expressed in human epidermis, but is induced under inflammatory conditions and in some types of skin cancer. SKALP iet al. have deval.[et al.Y. pseudotuberculosis has been developed by Fedorova et al[et al.[et al[Monoclonal antibodies based competitive immunoassay for the detection of specific antibodies to ova et al. Peknicoal[et al. have deval.[et al.in vitro affinity maturation, large scale production of antibodies in transgenic animals and plants, chimeric and humanized antibodies, human MAbs from transgenic mice using conventional hybridoma techniques, intrabodies and so many. These and similar constructs will provide the basis of an incredible number of new therapeutic antibody based products, besides being a transition to less costly and smaller synthetic molecules like bioactive peptides etc. The time and cost of travelling from the laboratory to the clinic are shorter for MAbs than for many conventional drugs. Antibodies are relatively easy to detect, manipulate and test. The FDA now regards MAbs as biotechnology derived pharmaceuticals with relatively few reports of serious side effects. The public health possibilities of MAbs are fabulous. Additional MAbs are being investigated in treatment of a variety of cancers including B-cell lymphomas, multiple myeloma and colorectal cancer besides rheumatoid arthritis, allergic asthama and others characterized by chronic inflammation[et al[et al[et al[The diversity of antibody engineering technologies is amazing; synthetic combinatorial libraries, cell free libraries, lammation43. Sincelammation. The phaion[et al. Using a al[et al. Very re al[et al.The basic mechanism of a MAb is the same as an antibody produced by the body. However, when MAbs are used in the diagnosis and treatment of diseases, certain substances are often added to them to give them their therapeutic and diagnostic characteristics. They can also be used on their own to block or encourage certain responses from the immune system. In diagnosis, radioactive markers are attached to them to locate a certain kind of cell within the body. They are used in diagnostic imaging of internal organs and tumors.While the utility of MAbs as drugs that can specifically target a disease associated antigen is enormous, it has taken a quarter century for these molecules to be adopted as bonafide diagnostics. Despite their slow pace in drug development during the pioneering years, it is now estimated that there are nearly 500 MAb based therapies in the field. Major factors that have influenced the acceptance of MAbs as diagnostics include their drug safety profiles, technological advancements for facilitating MAb's discovery, their development and market success.Monoclonal antibodies generally exhibit exquisite specificity for the target antigen. The binding site on the antigen called the epitope, can be linear or conformational, and may comprise continuous or discontinuous amino acid sequences. The epitope is the primary determinant of the antibody's modulatory functions and depending on the epitope, the antibody may exert antagonist or agonist effect, or it may be non modulatory. The epitope may also influence the antibody's ability to induce antibody dependent cell mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC). MAbs exert their pharmacological effects via multiple mechanisms that include direct modulation of the target antigen, CDC, ADCC, and delivery of a radio nucleotide or immuno toxins to target cells.The monoclonal antibody production technology has revolutionized the world of Biotechnology. Advances in genetic engineering over the years have provided numerous ways to design MAbs that are more robust and efficacious compared with their original murine version. MAbs have not only been used as diagnostics, therapeutics, research reagents, drug targettor for various infectious diseases but also cancerous, metabolic and hormonal disorders. MAb technology in conjunction with recombinant DNA technology has successfully led to the reconstruction of chimeric antibodies, humanized antibodies and CDR grafted antibodies and has enormous potentials for therapeutic uses."}
{"text": "We thank Schaider et al. for their interest in our research on possible environmental causes of breast cancer in upper Cape Cod, Massachusetts . Our stuIn our study , we applFortunately, groundwater sources of drinking water in this area are subject to more protections today, and we agree that ongoing monitoring of known and emerging contaminants is important to maintain water quality."}
{"text": "Research in the medical field is a dynamic process without which science will be dead. It has more significance now as we are in the era of evidence-based medicine.et al.[The path of research is not without obstacles. Research needs proper infrastructure and sufficient funds apart from a dedicated group of workers. It demands honesty, commitment and time. In our country, the institution of healthcare gets priority over research for obvious reasons. Research is not preferred as a career by the majority. There are many challenges in the development of research in Asian countries which have been well described by Wong et al. Firstly,et al.\u20105 These Investigators have to overcome many challenges while conducting research in India. Inadequaet al.,[In spite of the limitations discussed earlier, there is a silver lining. In future, up to 65% of food and drug administration (FDA)-regulated trials are expected to be outsourced from the US. India and China have been projected as the favorite destinations for these clinical trials.[et al., It is adet al.,[et al.,[et al.,[Indian Journal of Ophthalmology (IJO). Their conclusion shows a heartening trend of nearly doubling of publications from 284 in 2001 to 460 in 2006 by Indian researchers. However, 50% of the publications came from only nine major eye hospitals in India. A Pubmed search of publications by Indian authors and institutions in 2008 yielded 16290 results as against 11307 in 2005. Hopefully, the 2009 amendment of the regulations of the Medical Council of India (MCI) for appointment of teachers will provide enough incentive for researchers to publish their completed research.[Completion of research has no meaning unless it is published in peer-reviewed journals. Dhaliwal et al., have rep,[et al., it was c,[et al., must be The scope for research in India is tremendous simply because India is a vast country with a rapidly improving economy. There are many organizations, such as the Indian Council of Medical Research (ICMR), Department of Biotechnology (DBT), Department of Science and Technology (DST) and others who are prepared to fund the appropriate research. ICMR has identified the scope of research in ophthalmology and has appointed coordinators for the various sub-specialties.There is a need to understand the nuances of research. Researchers should realize the importance of taking IRB/ethics committee approval before starting the study. It is now mandatory to take IRB/ethical clearance for the dissertation done during the Diplomate of the National Board (DNB) course. Many jouTo conclude, India is fast becoming a new destination for multicentric trials. It is time to wake up and educate ourselves with the nitty-gritty of research to reap the entire benefit from this favorable trend. We have a huge potential and we must explore it to its full capacity."}
{"text": "One of the objectives of extirpative oncological surgery is negative surgical margins. The gold standard of treatment of high-grade recurrent superficial bladder carcinoma and muscle-invasive organ-confined bladder carcinoma is radical cystectomy. Transitional cell carcinoma has always been associated with a pan urothelial malignant field change. Frozen section analysis (FSA) to assess negative ureteral margins has been reported from as early as the late 1960s and early 1970s. Based onin situ (CIS) of the urinary bladder.[in situ or solid tumors undergoing radical cystectomy for TCC with coexisting CIS in the bladder.[in situ of the ureteral margin has been discovered in up to 8.5% of patients undergoing radical cystectomy. Positive ureteral margin CIS has been associated with a high risk of upper tract recurrence, with CIS of the ureteral margins having a risk of 17% and negative histology of the ureteral margin having a 3% upper tract recurrence risk.[et al suggested that FSA of ureteral margins enables a more thorough removal of malignant urothelium. Frozen section analysis of the ureteral margins has been recommended by the European Association of Urology and the National Comprehensive Cancer Network for patients undergoing radical cystectomy with extensive CIS of the bladder. Ureteral CIS has most commonly been observed in patients with multifocal, high-stage, high-grade tumors and tumors involving the prostatic urethra.[The distal ureter has the highest incidence of urothelial malignancy in patients with carcinoma  bladder. The rang bladder.4 Local r bladder. Carcinom urethra.et al [et al[et al[With the above evidence it would seem justifiable to perform an FSA of all ureteral margins. However, evidence to the contrary is just as extensive and impressive. Sharma et al  discoveret al  suggesteal [et al in theiral [et al Upper tr al[et al found ur al[et al looked a al[et al making set al[It would seem reasonable to do FSA on palpable induration or frank tumor infiltration of the distal ureter discovered unexpectedly at the time of the operation. Similarly, in those with diffuse CIS the risk of ureteral involvement may be greater than average necessitating the need for an FSA. But should one do an FSA on patients with prostatic TCC with the increased risk of metastatic disease? In this subset the mainstay of treatment is effective chemotherapy which provides a greater survival benefit than the absolute eradication of distal ureteral atypia. An FSA iet al found 13The presence of positive CIS at the ureteral margin predicts risk of upper tract recurrence and not necessarily anastomotic recurrence. Routine FSA of the ureteral margins is probably unnecessary in the majority of patients undergoing radical cystectomy. In patients with high risk of upper tract recurrence, such as diffuse CIS or induration at the margins a frozen section analysis of the ureteral margins may be helpful in tailoring the operation. However, the practice of resecting the ureter to achieve a negative margin does not seem to prevent upper tract recurrence."}
{"text": "We read with great interest the article on human norovirus (hNoV) by Straub et al. (Straub et al. demonstrate through fluorescent in situ hybridization the presence of viral RNA through 5 passages in his system. This phenomenon could be similar to the findings of Duizer et al. ( Cryptosporidium parvum that supplement approved fluorescent microscopy assays do not result in amplification of the environmentally resistant hard-walled oocysts (We appreciate the comments provided by Chan et al., in response to our recently published article (Nonetheless, Leung et al.\u2019s assertion regarding the suitability of our method for the in vitro propagation of high titers of hNoV is valid for the medical research community. In this case, well-characterized challenge pools of virus would be useful for developing and testing diagnostics, therapeutics, and vaccines. As further validation of our published findings, we have now optimized RT quantitative PCR to assess the level of viral production in cell culture, where we are finding increases in viral titer. The magnitude and time course of these increases is dependent on both virus strain and multiplicity of infection. We are currently preparing a manuscript that will discuss these findings in greater detail, and the implications this may have for creating viral challenge pools."}
{"text": "Sir,Pemphigus is a collective term for a group of chronic bullous dermatoses characterized by an intraepidermal cleft and circulating antibodies against epithelial cell surface. To date, there are no objective criteria to map the disease activity and severity. Various studies have given different and confusing definitions for remission and control of the disease. Also, there are no universally accepted treatment regimens.2The study of activity and inactivity of the disease is important. Pemphigus is a chronic disorder with remission and exacerbation, even when patients are on treatment. Systemic steroids alone or in combination with other immunosuppressive drugs are the main stay of treatment. These drugs have to be given on long-term basis with considerable side effects, for example, osteoporosis, avascular necrosis, HPA-axis suppression, cataract, cushingoid features, myopathy, mood changes, and immunosuppression. Therefore, a system is required to monitor disease activity and inactivity so as to lower the dosage of the drug(s) and eventually withdraw and reintroduce when there is a relapse or activity reappear. Though no system is available to date that allows the withdrawal of drugs various clinical and laboratory monitoring may allow the lowering of dosage. In recent years dexamethsone cyclophosphamide in pulse doses is the treatment of choice for pemphigus. The therapy has claimed to induce remission for more than 10 years in many patients. This article is aimed at discussing the currently available clinical and laboratory systems for monitoring of pemphigus disease activity and inactivity.et al., describe a microscopic Nikolsky's sign in which tangential pressure given to an area before a biopsy produces changes in epidermis that are diagnostic of pemphigus vulgaris if in suprabasal level and pemphigus foliaceous if in intraepidermal. This is a useful sign in patients with old/infected blisters, no fresh/intact blisters, or when no facility of immunofluorescence is available in the hospital.[The formation of new blisters indicates active stage of the disease. The considerable clinical activity usually correlates with circulating antibodies titer and antibodies in skin. Presence of new blisters in patients on treatment call for increase in dose of steroid.\u20135 After hospital.et al.,[Oral lesions, despite presenting early, may last to clear.10 In addet al., noted whet al.,[et al.,[et al.,[et al.[How to grade severity of the disease? Frenandes et al., noted th,[et al., suggest ,[et al., report t.,[et al.IIF17 may beIn patients of clinical remission the decision about further reduction in dose of drug can be very difficult. Clinical criteria and IIF which are not sensitive enough to detect low levels of circulating antibody so cannot be used.12 In staet al.,[Desmoglein ELISA22 is a s23et al., demonstrBeta-glucuronidase: This lyActivity in pemphigus can be defined by: 1) presence of new blisters, 2) spontaneous peripheral extension of existing blisters, 3) positive Nikolsky's sign on lesion, perilesional, or normal appearing skin, 4) demonstration of circulating antibodies against cell adhesion molecules and/or non-desmoglein protein antigen, e.g., keratinocytes cholinergic receptors, 5) presence of IgG antibodies in epidermis demonstrated by DIF, even in clinically normal appearing skin."}
{"text": "Severe leptospirosis requires critical care and has a high mortality. We reviewed the literature to identify factors predicting mortality, and such predictors were classified according to the predisposition, infection, response, organ dysfunction (PIRO) concept, which is a risk stratification model used in severe sepsis.PUBMED was searched for all articles (English), with the key word leptospirosis in any field, within the last 20 years. Data were collected from 45 relevant papers and grouped into each component of the PIRO model.The following correlated with increased mortality: predisposition \u2013 increasing age and chronic alcoholism; infection - leptospiraemic burden; response - hemodynamic disturbances, leukocytosis; organ dysfunction \u2013 multiple organ dysfunction syndrome, pulmonary involvement and acute renal failure.Further research is needed to identify the role of infecting serovars, clinical signs, inflammatory markers, cytokines and evidence of hepatic dysfunction as prognostic indicators. It is hoped that this paper will be an initiative to create a staging system for severity of leptospirosis based on the PIRO model with an added component for treatment-related predictors. Leptospira. Initially, this genus was thought to have only two species. Currently, nine pathogenic species of Leptospira are identified, with another five being classified as \u201cintermediate,\u201d bringing the total number of possible pathogenic species to 14.[Leptospirosis is a zoonotic spirochaetal illness with considerable morbidity and mortality in areas of high prevalence. The causative organism is classified in the genus es to 14.An accurate assessment of the disease burden of leptospirosis is not easy due to diagnostic difficulties and under-reporting. The estimated incidence differs as to whether an endemic or a non-endemic area is considered . Such locMany infections are asymptomatic or pass off as a mild febrile episode. However, a small proportion develops a severe form of the disease with multiple organ dysfunction. The case fatality ratio in severe disease can exceed 40%.[The objectives of this review are two-fold. Firstly, it summarizes the mortality predictors for leptospirosis published by different authors. While some indicators are repeatedly cited as predictors of mortality, the significance of others is questionable. Secondly, an attempt is made to classify such predictors into a clinically relevant classification .It is our opinion that a simple detailed description of mortality indicators will not be of much use to a clinician in his practice. The clinician will be more interested in a systematic manner of application of such knowledge to predict mortality and identify the \u201cat risk\u201d patients early. The ideal method to integrate such information to an applicable clinical tool is to develop a valid classification and a scoring system.The PIRO model is a risk stratification system for severe sepsis. PIRO stands for predisposition (P), infection (I), response (R) and organ dysfunction (O) . This review classifies the prognostic indicators for severe leptospirosis according to the PIRO model but stops short of developing a scoring system. Available data were inadequate, and non-comparable due to differences in study methodology, to develop a valid scoring system. It is our opinion that such quantification is best handled by a well-designed, dedicated, prospective study rather than by a literature review. Still, this work serves as a concept paper to show the possibility and relevance of such a scoring system.A PUBMED search was performed for all articles with the key word \u201cleptospirosis\u201d in any field. The search was restricted to articles published in English within the last 20 years (1989\u2013May 2009) as they would contain more recent data. There were 1898 abstracts in the original search with these restrictions. The software, Endnote X1, was used to filter articles. Bibliographies of cited literature were also searched. All abstracts were read through independently by the three authors and relevant papers were identified for review of the full papers. Related papers were also included. We reviewed 163 selected papers.These sources were screened for a well-described methodology, accurate statistical analysis and an adequate sample size where relevant. Identification of prognostic indicators was performed by three reviewers independently blinded to each other. Later, they were classified into each component of the PIRO model by consensus. While such a classification was possible, the development of a scoring system based on it was not possible for the reasons mentioned above (non-comparability of data). Data sources included reviews published in core clinical journals, cohort studies, interventional studies, case control studies, cross-sectional analysis and epidemiological data. Suitable data were available in 45 papers from the initially selected 163. A summary of the cited literature is shown in Tables The following four sections are titled according to the four components of the PIRO model. Mortality predictors for leptospirosis reported by various authors are discussed under each subtopic.Three mortality indicators were reported in the literature that can be classified under predisposition: age, alcohol dependence and male sex. A summary of the studies in this regard is given in et al.et al.[et al.0,[et al.,[et al.[Five studies have reported age as an indicator. Cetin al.et al. describe[et al.0, in a pro,[et al., in a ret.,[et al. showed tet al.[Only Chawla et al. reportedet al.11 failedet al.,[Chronic alcoholism was reported to be significantly associated with death in two studies.12 Martinet al., in a retet al.[per se or due to hepatic dysfunction on a background of alcoholic liver disease is not clear.On analyzing the available evidence, the strongest predictor of mortality under \u201cpredisposition\u201d is increasing age. The evidence for poor outcome among males is limited (two large retrospective studies failed to show such an association).11 Jansenet al. suggesteWhile there are many predisposing factors for contracting leptospirosis , none of these have been reported to predict outcome after acquiring the infection.\u201318 Male et al.[4 leptospires/ml were associated with death. These findings were confirmed by Segura et al.[The classifiable material under this topic is minimal . Trucculet al. measuredra et al. in an inWe encountered difficulty in differentiating mortality indicators under response and organ dysfunction categories as such a division seemed arbitrary. Therefore, the items categorized under the response section are restricted to components of severe inflammatory response syndrome (SIRS) and a few other indicators such as abdominal pain and muscle tenderness .et al.[et al.[Pertuiset et al. report tl.[et al. identifil.[et al.\u201324 Leukol.[et al.et al.,[et al.[P = 0.03).Abdominal pain is also reported as a mortality indicator by Pertuiset et al., although.,[et al. describeet al., P = 0.02), platelet count <70,000  and high cerebrospinal fluid protein levels in patients with neuroleptospirosis .[Other indicators classifiable under this section include high tumor necrosis factor alpha (TNF \u03b1) levels (Tajiki < 0.001).26\u201328et al.[Of all these indicators, only hypotension was confirmed as a predictor of mortality in three independent studies with an adequate sample size.\u201324 Otheret al. observedThree organ systems are commonly cited as involved in severe leptospirosis: the lungs, the kidneys and the CNS .et al.[et al.[et al.,[11Although relatively uncommon, pulmonary involvement has been repeatedly and consistently incriminated as a mortality predictor in more than 10 studies. Pertuiset et al. and Dupol.[et al. reported.[et al., in a pro.[et al., dyspnoea.[et al., and the .[et al., are also.[et al.,1131\u201333th\u20136th days of disease and can progress rapidly to death within 72 h. Mortality rates from different studies vary between 30% and 60%. Different aspects of lung involvement such as clinical signs, radiographical evidence and ALI are all predictors of mortality.[While many manifestations of lung involvement are mild, pulmonary hemorrhage is associated with a high mortality. Patients also die from acute lung injury (ALI), acute respiratory distress syndrome and combined MODS. Respiratory symptoms appear on the 4ortality.35Acute renal failure (ARF) and its manifestations are also reported as mortality indicators. Oliguria and anuria are cited as independent predictors of mortality in six studies.62223253662223256212324478Bacterial infection, insults from the inflammatory process, and hemodynamic disturbances are thought to contribute to renal failure in leptospirosis. The basic pathology is an interstitial nephritis with tubular necrosis resulting in ARF. Manifestations of renal involvement vary from laboratory evidence  to clinically defined ARF with hyperkalaemia and elevated creatinine. It is es43et al.[P < 0.05). Esen et al.[P = 0.01) in deceased patients compared to survivors . According to Ko et al.,[et al.,[P < 0.037). Meningism and disorientation  are also reported as mortality indicators by Pappachan et al.[Central nervous system involvement is another predictor of severe disease and death. Covic et al. publisheen et al. also repo et al., who stud,[et al., reportinan et al.Three studies have independently associated altered mental status with death. However, many factors can cause altered mental status in severe leptospirosis, and thus this clinical feature is lacking in specificity. These studies also do not specify the criteria used to assess altered mental status and hence it is difficult to assess the uniformity of the findings.et al.[et al.,[Cardiac involvement in leptospirosis is underestimated. Describing the findings of 44 autopsies with a presumptive cause of death with leptospirosis-related complications, Charkurkar et al. reported.[et al., in his ret al.[et al.[et al. reported that a high Aspartate transaminase (AST)/alanine transaminase (ALT) ratio in late disease is associated with death.[et al.[Evidence for hepatic dysfunction is prominent during the clinical course of leptospirosis. However, many of these are not reported as predictors of mortality. Pappachan et al. reportedl.[et al. reportedth death. Bleedingh.[et al.MODS, which is the involvement of more than one organ system, has been shown to be associated with death in four studies .7304045730457304045et al.,[P = 0.01). In their study involving 35 critically ill patients with ARF, Vieira et al.[There were a few other predictors of mortality that could not be classified under the PIRO model. These were mainly treatment related. Andrade et al., in a twora et al. stated tra et al.There is a place for further research to determine the role of gender, infecting serovars, clinical signs, inflammatory markers, cytokines, biochemical parameters and markers of hepatic dysfunction as prognostic indicators. It is interesting to note that several recent studies in India have shown that clinical manifestations like pancreatitis and syndrome of inappropriate secretion of anti-diuretic hormone were more common than previously thought. In one study, the majority of patients with these presentations were anicteric. There may be many other predictors of mortality yet unidentified in relation to these presentations.Only articles published in English were included in the review. Therefore, it is possible that certain important papers were missed. Similarly, relevant information published beyond the time limits of our search have not been taken into account. Such gaps in data may affect the validity and generalizability of the conclusions.This review was synthesized as a concept paper to direct further research into mortality indicators of leptospirosis.It attempts tosummarize and discuss evidence on predictors of mortality in severe letospirosisdevelop a classification system for such factors based on the PIRO concept used for staging of severe sepsisOn analyzing the evidence on mortality indicators, some predictors  have been repeatedly and independently confirmed by different authors. Still, some other associations such as the impact of inflammatory markers and leukocytosis have not been assessed in detail. Many identified risk factors could be categorized into the four domains of the PIRO concept. However, treatment-related factors could not be incorporated into the existing model. In this regard, we propose to add a fifth domain of treatment (T) when modifying the PIRO concept for leptospirosis.While we managed to classify the mortality indicators, a scoring system to quantify the relative risk could not be developed due to differences of the methodologies and non-comparability of data. Such a scoring/staging system would be more scientifically valid if developed by a prospective study specially designed for such a purpose. It is hoped that our work will be a starting point to the development of a staging system to predict the severity of leptospirosis."}
{"text": "Rattus Norvegicus) and its effect on the reproductive functions in relation to the biochemical effects was studied. It was observed that the chronic dose of lead caused an elevation in the level of proteins, acid phosphatase, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase in all the soft tissues studied indicating tissue damage. It also inhibited the level of acetylcholinesterase in all the tissues. Fertility tests by pairing treated females with males showed that lead-treated female showed irregular estrous cycle and the fertility rate dropped to 40% as female pups of lead-treated mothers showed loss in weight, high mortality rate, poor growth rate, and late vaginal opening. Histological studies of ovary showed atresia in all the stages of folliculogenesis sustaining the poor fertility observations. The present study revealed that lead caused great tissue damage and affected reproductive performance of female rats at a chronic dose.Lead being a toxic cumulative poison and an environmental pollutant, experiments were conducted at an oral chronic dose of (60 mg/kg/day) for 90 days on adult female rats ( Alanineet al.[Daily oral administration of lead produced significant decrease in AChE level in liver, kidney, and ovary and nonsignificant decrease in plasma . The decet al. in calveet al. Acetylchet al. Thus decSignificant increase in the levels of proteins in liver, kidney, ovary and nonsignificant increase in proteins in plasma were observed following daily oral dosing of lead . The eleet al.[Five sets of experiments that were set up for the testing effect of lead on fertility of rats indicated that lead at a dose of 60 mg/kg caused 40% reduction in the fertility rate  as compaet al. reportedet al.[et al.[et al.[et al.[et al.[In addition to the observations made above, the treated females showed irregularity in estrous cycle. Der et al. and Ronil.[et al. have alsl.[et al., and decl.[et al.. Ronis el.[et al.12 also rl.[et al. Lead-fedl.[et al.. Lower bl.[et al. and Schwl.[et al. Furtherml.[et al.The above study concluded that lead has interaction with the vital body functions and reproductive parameters in rats. The dosage administered caused significant biochemical alterations and reduction in the weight of pups as well as the treated mothers. Lead caused high mortality rate in pups and also slows down their growth rate."}
{"text": "Accelerated Idioventricular Rhythm (AIVR) is a ventricular rhythm consisting of three or more consecutive monomorphic beats, with gradual onset and gradual termination. It can rarely manifest in patients with completely normal hearts or with structural heart disease. It is usually seen during acute myocardial infarction reperfusion. This manuscript aims to review the history of the main discoveries that lead to the identification and comprehension of this fascinating arrhythmia. The so called \"Accelerated Idioventricular Rhythm\" (AIVR) is a ventricular rhythm  consisting of three or more consecutive monomorphic beats, with gradual onset. Less commonly, AIVR is polymorphic. The discharge rate of the ectopic focus is similar to the sinus rate (isorhythmic) between 50 and 120 bpm. The ectopic focus manifests when the sinus rate slows down (below the ectopic focus) or when the ectopic focus accelerates above the intrinsic rate by 30-40 beats per minute. When both discharge rates (sinus and ectopic focus) are similar, isorhythmic dissociation, fusion and capture beats can be seen.AIVR is usually a benign and well-tolerated arrhythmia. Most of the cases will require no treatment and in rare situations such as sustained or incessant AIVR or when AV dissociation induces syncope, the risk of sudden death is higher, and the arrhythmia should be treated.Different terminology was used to describe AIVR: Non paroxysmal ventricular tachycardia (VT), isorhythmic slow VT, and the curious benevolent tachycardia.Non paroxysmal VT is currently a non accepted definition given the fact that AIVR is usually a ventricular rhythm at rate slower than 100 bpm, thus not meeting criteria to be called tachycardia.Rarely, AIVR can be detected in the youth and, in this subgroup, is usually benign  and requAIVR occurs infrequently in patients without demonstrable heart disease and, in this case, it has a good prognosis. When AIVR presents in individuals with no structural heart disease, the mechanism involved is usually an increased vagal tone and decreased sympathetic tone , as obseAIVR is frequently observed during the reperfusion phase that follows an acute myocardial infarction (AMI) . It remaA typical example of AIVR in the setting of normal structural heart can be seen in The main electrophysiological mechanism involved in AIVR is an abnormal calcium-dependent automatism (ectopic automaticity) that affect phase 4 of action potential (diastolic depolarization) . When AIThis manuscript aims to be a chronological historical review on the main findings that contributed to the understanding of this fascinating arrhythmia.Sir Thomas Lewis  a pioneer of the British cardiology showed the first ECG trace of AIVR case in his book entitled \"Mechanism and graphic registration of the heartbeat\"  , dedicatHarris  was the Mariot and Menendez  have intDessertene  describeAgust\u00edn Castellanos Jr  used theRothfeld et al  showed fRothfeld and Zucker , were thAgust\u00edn Castellanos Jr et al  reportedHasin and Rogel  presenteDelise et al  reportedBernard et al , describSclarovsky et al , showed Chiale et al , reporteMartini et al  describeTatu-Chitoiu , used thNakawa et al , showed Grimm et al  followedMarret et al  reportedDulac et al , reporteBonnemeier et al , determiTsai et al  reportedHsu et al , reporteThis intriguing arrhythmia could manifest in several different clinical scenarios. There are benign forms in subjects with no structural heart disease in which case, it usually requires no intervention, but sometimes it can present as a more severe arrhythmia, requiring treatment. Since its initial identification by Harris, major advances have been done in the understanding on the underlying mechanisms involved in the genesis of this arrhythmia. Abnormal calcium-dependent automatism that affects the phase 4 slope of the action potential (ectopic automaticity) has been identified as the main electrophysiological mechanism involved in AIVR. Autonomic imbalance has also been identified as a trigger of this abnormal rhythm. More recent reports showed that the presence of AIVR does not constitute a specific marker of complete reperfusion during the acute phase of a myocardial infarction, but it could indicate that the responsible vessel is open.  In this context, AIVR usually does not require specific treatment."}
{"text": "BMC Bioinformatics presents another ten! These papers have in common the fact that they are follow-on work to papers originally published in the proceedings of the BioNLP 2008 workshop at the annual meeting of the Association for Computational Linguistics (ACL). All have gone through a separate rigorous review process and represent an advance beyond the work originally presented at the workshop. Like the annual BioNLP workshop itself, they represent a wide cross-section of the type of work that goes on in BioNLP today.A recent posting to the BioNLP mailing list notes that the past few months of 2008 have seen the appearance of over fifty papers on biomedical natural language processing/text mining (BioNLP). This number  represents about as many papers on genomic language processing as existed in all of PubMed at the end of 2003  \u2013 just fAnnual BioNLP workshops have been held since 2002 in conjunction with the annual meeting of the ACL or its North American chapter. Whereas other venues, such as NLP sessions at biomedical informatics and computational biology meetings, provide excellent opportunities for presenting applications of NLP in the biomedical domain, the BioNLP workshop has consistently been a venue for presenting work in areas of fundamental BioNLP that is innovative and challenging from an NLP perspective.BMC Bioinformatics. Of 19 full papers and 5 posters submitted to the workshop, 10 were accepted as full papers and 18 as poster presentations. The combined expertise of the program committee allowed for providing three thorough reviews for each paper. The exceptionally high quality manuscripts accepted for presentation covered a wide area of subjects in clinical and biological areas, as well as methodological issues applicable to both sublanguages. Separately, those authors were invited to submit papers describing significant advances beyond their original papers and posters for inclusion in this supplement.Research in computational linguistics in the biomedical domain traditionally focuses on two major areas: fundamental advances in language processing; and application of language processing methods to bridge the gap between basic biomedical research, clinical research, and translation of both types of research into practice. The expanded and updated versions of the best papers in both areas presented at the BioNLP 2008 workshop have been selected by the Program Committee for publication in this supplement to In addition to the presented papers and posters, BioNLP 2008 featured two keynote talks.John Hutton, MD, Professor of Pediatrics and Director of Biomedical Informatics, Cincinnati Children's Hospital, presented a large academic medical center perspective on computational linguistics approaches to enhancing Clinical Decision Support Systems.LTC Hon Pak, MD, Chief, Advanced Information Technology Group Telemedicine and Advanced Technology Research Center (TATRC), U.S. Army Medical and Material Research Command, discussed the need for NLP in Department of Defense Military Health System (MHS).et al. [et al. [Two papers are dedicated to relation extraction. Airola et al.  present  [et al.  treat clet al. [As automatic named entity recognition (NER) significantly impacts all subsequent processes in BioNLP pipelines, it continues to be an active area of research. Corbett and Copestake  achieve et al.  combine et al. [Many NLP applications are believed to require determination of the sense of a recognized entity. For example, an automatic system that links research evidence to a patient's record needs information on the sense of discharge  in a given context to provide appropriate evidence. Wang and Matthews  demonstret al.  adapt anet al. [et al. [Creation of domain-specific resources is an important task that stimulates BioNLP research, once the resources are made available to the community. To that end, Tsuruoka et al.  present  [et al.  describeet al. [Determining authors' confidence in their findings  is another important area of research. Kilicoglu and Bergler  use lexiet al. .The authors declare that they have no competing interests."}
{"text": "Drosophila melanogaster has shown that two distinct axonal guidance receptors are precisely clustered in adjacent segments of the commissural axons both in vivo and in vitro, suggesting a cell\u2010intrinsic mechanism underlying the compartmentalized receptor localization. In Caenorhabditis elegans, a subset of interneurons exhibits calcium dynamics that are localized to specific sections of the axon and control the gait of navigation, demonstrating a regulatory role of compartmentalized neuronal activity in behaviour. These findings have led to a number of new questions, which are important for our understanding of neuronal development and function. How are these sub\u2010compartments established and maintained? What molecular machinery and cellular events are involved? What is their functional significance for the neuron? Here, we reflect on these and other key questions that remain to be addressed in this expanding field of biology.Neurons are highly polarized cells that consist of three main structural and functional domains: a cell body or soma, an axon, and dendrites. These domains contain smaller compartments with essential roles for proper neuronal function, such as the axonal presynaptic boutons and the dendritic postsynaptic spines. The structure and function of these compartments have now been characterized in great detail. Intriguingly, however, in the last decade additional levels of compartmentalization within the axon and the dendrites have been identified, revealing that these structures are much more complex than previously thought. Herein we examine several types of structural and functional sub\u2010compartmentalization found in neurons of both vertebrates and invertebrates. For example, in mammalian neurons the axonal initial segment functions as a sub\u2010compartment to initiate the action potential, to select molecules passing into the axon, and to maintain neuronal polarization. Moreover, work in  I.Neurons are specialized cells with a high level of polarization defined by the presence of three major compartments: the dendrites, a cell body (or soma) and an axon Fig.\u00a0A. DendriSome clear and well\u2010studied sub\u2010compartments within dendrites and axons, such as the dendritic spines and the presynaptic boutons, were recognized decades ago, in part due to their distinct morphology. Dendritic spines were first observed as protrusions on the dendrites through gold staining by Ramon y Cajal, and represent the dendritic sub\u2010compartments that receive inputs from a single axon Gray, . More adin vitro and in vivo models provide evidence of neurites with shared axonal and dendritic properties, axonal compartmentalization of membrane proteins, such as axon guidance receptors and ion channels, and clustering of intracellular components within neurites, which include protein aggregates, organelles and ions , which play critical roles in thermotaxis, navigation and learning  neurons, which control fertility, are bipolar, with a long dendrite that extends for about 1000\u00a0\u03bcm. For many years, scientists struggled to identify the axonal structure of these neurons until it was revealed that the process of the GnRH neurons functions as both an axon and a dendrite   repulsive cue , which are located in the olfactory bulb and are involved in odour discrimination, the \u03b23 subunit of gamma\u2010aminobutyric acid receptors (GABARs) is clustered in the soma and dendritic shafts but not in the spines  channels, which have also been implicated in regulating the electrical properties of these neurons et al.,et al.,et al.,Organelles such as mitochondria  and lysosomes  can adopt specific and dynamic localizations within neuronal sub\u2010compartments that reflect the functional needs of the cell Fig.\u00a0A. Early D. melanogaster), and the outer mitochondrial membrane molecule Miro, which acts as a calcium sensor  being smaller than the non\u2010synaptic forms (nsMito) C. elegans AWC neurons, a pair of olfactory neurons in the head of the animal, cyclic guanosine monophosphate (cGMP) regulates both olfactory sensation  et al.,et al.,et al.,et al.,et al.,et al.,et al.,et al.,et al.,A large body of literature has revealed that cells can compartmentalize not only proteins but also important inorganic molecules, such as calcium ions. Calcium is the most abundant signal transduction molecule controlling key physiological events, which include gene transcription, exocytosis, and cell death Clapham, , and is et al.,et al.,et al.,et al.,Neurons also exhibit additional sophisticated mechanisms of calcium compartmentalization important for complex neuronal functions. For example, detecting image motion is a fundamental function for vision that is regulated by the direction\u2010selective retinal ganglion cells de novo proteins in close proximity to their final functional milieu within different cellular compartments. In neurons, both coding RNAs (mRNAs) et al.,et al.,et al.,Polysomes, the ribosomal complexes for mRNA translation, are found at the base of dendritic spines of neurons in the dentate gyrus of the rat brain , with the goal of elucidating the molecular mechanisms for their axonal compartmentalization et al.,et al.,MicroRNAs (miRNAs), small non\u2010coding RNAs which are 21\u201325 nucleotides in length, play an important role in regulating gene expression. Binding of a miRNA to the 3\u2032 UTR of a target mRNA inhibits translation and/or leads to the degradation of the mRNA et al.,et al.,Circular RNAs (circRNAs) constitute a divergent class of RNAs which are mainly produced during RNA splicing of protein\u2010encoding genes. Their common characteristic, the form of a full loop, confers unique properties that have only recently started to emerge et al.,The long non\u2010coding RNAs (lncRNAs) are RNA molecules that are longer than 200 nucleotides and do not encode any protein. Many lncRNAs are enriched in the brain tissues and approximately 40% of them are expressed selectively in the mammalian brain  Synaptic mitochondria are crucial for neuronal function and have a specific proteome that differs from that of non\u2010synaptic mitochondria. What mechanisms underlie the association of different proteins with synaptic versus non\u2010synaptic mitochondria? (4) Although the compartmentalization of intracellular components has been shown to depend on either the cytoskeleton (as for organelles) or the association with scaffolding proteins (as for the glycolytic enzymes which cluster at the synapse in response to metabolic requirements), the mechanism of calcium compartmentalization in axons and dendritic spines remains largely unknown.However, some of these processes are still not fully elucidated and important questions remain to be addressed. (1) The dendron awaits the identification of the molecular pathways and genetic factors involved in its development and maintenance. (2) For unipolar neurons that contain functionally different synaptic domains, the molecular and cellular events that regulate the specificity of these domains remain to be characterized. For example, only UNC\u2010101, TTX\u20107, and two cyclin\u2010dependent kinase pathways have been identified as regulators of the polarity of RIA interneurons in VI.(1) The dendritic and axonal compartments of both invertebrate and vertebrate neurons often contain functional domains, which are characterized by distinct molecular distributions, activity patterns, and functional outputs. The formation of these sub\u2010compartments depends on the integration of intrinsic factors with external cues or on neuronal activity and external stressors.D. melanogaster commissural neurons, and compartmentalization of calcium at the tip of the growth cone to direct turning during navigation towards the target. Moreover, in C. elegans neurons the precise clustering of membrane receptors also plays a crucial role in the axonal compartmentalization of synapses.(2) During early development, axon guidance requires a cell\u2010autonomous axonal compartmentalization of receptors for guidance cues, as shown in the (3) Once neurons are fully developed, sub\u2010compartmentalization is still important for neuronal activity and plasticity. For example, compartmentalization of mitochondria at synapses is necessary to supply energy for synaptic transmission, while in the dendrites it is required for the activity\u2010dependent generation of new spines.C. elegans the level of the second messenger cGMP is locally regulated upon stimulation. The level of cytoplasmic calcium is also locally regulated in the axons of AIY or RIA interneurons of C. elegans to encode temporal neuronal activity.(4) A number of functional compartments contribute to distinct temporal properties of specific neurons. For example, glycolytic enzymes cluster at synaptic loci to support the elevated energy expenditure of high neuronal activity, through an interaction with synaptic scaffolding proteins. Moreover, in the AWC chemosensory neurons of"}
{"text": "Livestock is a major driver in most rural landscapes and economics, but it also polarises debate over its environmental impacts, animal welfare and human health. Conversely, the various services that livestock farming systems provide to society are often overlooked and have rarely been quantified. The aim of analysing bundles of services is to chart the coexistence and interactions between the various services and impacts provided by livestock farming, and to identify sets of ecosystem services (ES) that appear together repeatedly across sites and through time. We review three types of approaches that analyse associations among impacts and services from local to global scales: (i) detecting ES associations at system or landscape scale, (ii) identifying and mapping bundles of ES and impacts and (iii) exploring potential drivers using prospective scenarios. At a local scale, farming practices interact with landscape heterogeneity in a multi-scale process to shape grassland biodiversity and ES. Production and various ES provided by grasslands to farmers, such as soil fertility, biological regulations and erosion control, benefit to some extent from the functional diversity of grassland species, and length of pasture phase in the crop rotation. Mapping ES from the landscape up to the EU-wide scale reveals a frequent trade-off between livestock production on one side and regulating and cultural services on the other. Maps allow the identification of target areas with higher ecological value or greater sensitivity to risks. Using two key factors , we identified six types of European livestock production areas characterised by contrasted bundles of services and impacts. Livestock management also appeared to be a key driver of bundles of services in prospective scenarios. These scenarios simulate a breakaway from current production, legislation (e.g. the use of food waste to fatten pigs) and consumption trends . Overall, strategies that combine a reduction of inputs, of the use of crops from arable land to feed livestock, of food waste and of meat consumption deliver a more sustainable food future. Livestock as part of this sustainable future requires further enhancement, quantification and communication of the services provided by livestock farming to society, which calls for the following: (i) a better targeting of public support, (ii) more precise quantification of bundles of services and (iii) better information to consumers and assessment of their willingness to pay for these services. In this review, we attempt to explain the trade-offs and synergies derived from livestock production and analyse their relevance or irrelevance across spatial scales in search of options for a more sustainable livestock sector in Europe. We conclude by highlighting key aspects that need to be explored to further enhance, quantify and reveal the services provided by livestock farming to society.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Livestock is a major driver of rural landscapes and economics, but it also polarises debate over animal welfare, impact of animal product consumption on human health and on the environmental footprint of livestock production, including greenhouse gas (GHG) emissions and the relative inefficiency of energy and protein conversion into animal products  detev. ES dimensions in ruminant systems. Recent reviews  synergies between livestock production and other dimensions, especially a number of studies on the production et al., et al., et al., 2 fixation by legumes increases N availability and thus decreases the inputs needed for production. Daily animal intakes of forage and digestion were also shown to be higher when fed on grass\u2013legume mixtures  within UAA. These two criteria allow accounting for the variability of bundles of services as they are related to all main system characteristics: animal species, feeding strategy, manure management, etc. Based on Eurostat data for 2010, Hercule et al.  evaluate global options to ensure food security in a more sustainable way. These scenarios simultaneously account for production and its environmental footprint, but also for population growth, trade of livestock products and human health. They simulate a breakaway from current production, legislation (e.g. the use of food waste to fatten pigs) and consumption trends  most often in interaction with climate change. Scenarios are not forecasts or predictions but offer a dynamic view of livestock futures by exploring trajectories of change that broaden the range of plausible alternatives  and indirect (shifts in vegetation communities under elevated CO2) effects of climate change  has long aimed to support livestock farming in areas where farming systems face pedoclimatic constraints that limit their competitiveness, which is also a way to support territorial vitality and to preserve biodiversity and landscapes with strong heritage value. Beyond this, the CAP also integrated some of the environmental dimensions of livestock farming. In high livestock density areas, policies such as the EU Nitrates Directive aim to regulate the local nuisances of water and air pollution from intensive farming. For example, the Nitrates Directive led to a decrease in N cycling disruption by clustering crop and livestock production into specific areas to optimise crop fertilisation . Beyond information to consumers, the bundle of services framework highlights the entire range of regulating, cultural and rural vitality services provided by livestock farming. By doing this, it allows the implementation of policy pathways that optimise livestock contributions to the global food system while remaining within planet boundaries.Finally, it remains difficult to share the positive services provided by livestock farming  with consumers and citizens so that they can develop their own system of consumption ethics. This calls to investigate their willingness to pay for the services provided by livestock farming. Apart from organic farming and PDO products, which are usually based on strict production specifications, most product labels are indeed vague, unverified and unverifiable (Treves and Jones,"}
{"text": "The water in the structure is believed to act as a lubricating agent in the packing of hydrates, thus facilitating slippage of molecules in the plastic bending of the crystals under external mechanical stress.Khandavilli  Such plasticity phenomena have also been studied in molecular materials, such as globular hydro\u00adcarbons with predominantly dispersive interactions, where the plastic crystal is a mesophase between the solid and liquid states (Sherwood, 1979et al., 2005The terms elasticity, plasticity and brittleness in molecular solids typically depend on their intrinsic molecular arrangements and the rate of applied load (Reddy tert-butyl, meth\u00adoxy, chloro, bromo and aromatic groups among many others (Reddy et al., 2006et al., 2015et al., 2015et al., 2016et al., 2015et al., 2018et al., 2017et al., 2018Plasticity in molecular crystals can generally be obtained when the crystals are anisotropic and have facile slip planes, which weakly interact through dispersive noncovalent interactions, involving functional groups such as methyl, IUCrJ, Khandavilli et al. (2019et al., 2017et al., 2018et al., 2019et al. (2019et al., 2017Reporting in  al. 2019 have sho al. 2019, where w al. 2019 contrastet al. (2019Mechanical properties are fundamental properties, much like density, optical, thermal and electrical properties. Therefore, mechanical properties are relevant to all types of materials and their importance cannot be ignored when addressing problems in practical applications. Molecular level understanding is currently lacking for most mechanical processes, such as milling and flowability, that are important in designing flexible optoelectronics and manufacturing processes in pharmaceutical, fine chemical, agrochemical industries and so on. The solutions sought currently using empirical methods are tedious and expensive. Hence, further development of a scientific basis in this regard by systematic studies, such as Khandavilli  al. 2019, will re"}
{"text": "Recently Pascual and colleagues have contributed a study about the identity of cells that initiate metastasis . They iIn the past decade much progress has been made in understanding the principles that control formation of metastases (McGranahan et al, 2017; Adawy, In many tumor types high expression of proliferation associated genes has been shown to lead to an increased risk of metastasis (Schmidt et al., 2008; SiggelkIn conclusion, Pascual and colleagues bring forward an interesting concept that metastasis-initiating tumor cells rely on dietary lipids in a CD36 dependent manner. It remains to be shown, whether CD36 is a promising target for anti-cancer therapy."}
{"text": "Information on intoxication of livestock by plants in Brazil, in terms of cause, clinical signs and pathology, is compared with information on livestock poisoning by plants in South Africa. Plant poisoning, including mycotoxicosis, is considered to be one of three major causes of death in livestock in Brazil, which is one of the top beef producing countries in the world, with a cattle population of more than 200 million. Cattle production in South Africa is on a more modest scale, but with some 600 species of plants and fungi known to cause toxicity in livestock, as opposed to some 130 species in Brazil, the risk to livestock in South Africa appears to be much greater. The comparisons discussed in this communication are largely restricted to ruminants. Plantas T\u00f3xicas do Brasil, published in 2012  were important in cattle; the first two also affect sheep. Cardiac glycoside-containing plants occur worldwide but significant livestock poisoning has only been reported in southern Africa and, to a much lesser extent, in Australia  as well as Ateleia glazoviana (Fabaceae) may cause sudden death, with chronic heart lesions revealed at necropsy, like gousiekte, but more often the animals develop signs of congestive heart failure before death occurs. Two other syndromes, one involving abortions and the other involving neurological signs including lethargy are associated with poisoning by A. glazoviana  and poisoning, due to ingestion of Lantana spp., occur in both South Africa and Brazil. The intoxications present with the same clinical picture as in South Africa. While seneciosis is well known in Brazil, particularly in the southern states, and appears to show the same pattern as in South Africa, with cattle more often affected than small stock, Lantana poisoning appears to be less frequent, and only a single outbreak of diplodiosis has been recorded in Brazil  and geeldikkop are due to bile duct occlusion. In facial eczema, inflammatory bile duct occlusion is caused by sporidesmin. In geeldikkop the bile duct obstruction is due to accumulation of birefringent crystals that are produced as a result of steroidal saponins in the plants themselves , castor oil beans (Ricinus communis), Cestrum spp., Xanthium spp., Amaranthus spp., Solanum spp., Equisetum spp., Pteridium aquilinum (bracken fern), Leucaena leucocephala, Allium spp., Crotalaria spp., Vicia villosa, Aspergillus flavus, Aspergillus clavatus, Claviceps purpurea, Claviceps paspali and Fusarium spp.Other plant poisonings and mycotoxicoses that Brazil and South Africa have in common include those caused by cosmopolitan plants and fungi such as syringa  and is strongly suspected to be a glycoprotein storage disease based on the histopathological lesions  as well as Sida carpinifolia  are responsible for glycoprotein storage disease (Tokarnia et al. Ipomoea carnea, has also been reported to cause glycoprotein storage disease in goats in Mozambique (De Balogh et al. Solanum fastigiatum var. fastigiatum causes neurolipidosis, with clinical signs similar to those produced by S. tettense var. renschii in South Africa (Tokarnia et al. Lysosomal storage diseases that cause neurological disorders and pathology of the central nervous system have been described in both Brazil and southern Africa (Kellerman Prosopis poisoning. Cattle and goats are poisoned when large quantities of the pods of the highly invasive Prosopis glandulosa, also known as mesquite or Suidwesdoring, are ingested. It should be noted that Tokarnia et al. (Prosopis juliflora, a synonym of P. glandulosa (Nkonki et al. et al. Another peculiar neurotoxicity that has been described in both countries is a et al. , 2012 rea Nkonki . ClinicaSolanum malacoxylon and Nierembergia veitchii (Tokarnia et al. Systemic calcinosis as a result of plant poisoning has not been described in South Africa, but is associated with two plants in Brazil: et al. (An interesting poisoning that is reported by Tokarnia et al.  is a syset al. (Nolletia gariepina was confirmed by dosing trials, but in the field, the intoxication only occurred when cattle that had been penned for periods of 36\u201348 h without feed were released onto pastures where the plant was abundant (Du Plessis, Prozesky & Botha Although plant poisoning of livestock is reported to be important in Brazil, it appears to involve fewer plants than have been reported in South Africa. It is possible that in many parts of Brazil, plant intoxication is under-reported, as many of the poisonings described by Tokarnia et al.  occurred"}
{"text": "In recent years, there has been growing interest in the potential of video games to improve health and cognition (Russoniello et al., Rumination, traditionally associated with poor attentional control, has been suggested to lead to difficulty disengaging from negative thoughts; thus, rumination has been implicated in depression (Hsu et al., One factor that may limit the video games' effectiveness in reducing rumination is a temporal threshold for sufficient cognitive activation. In a meta-analysis, Bediou et al.  observedAnother possibility for the lack of a positive result is perhaps explained by the impact of video game genre, as studies have suggested different video game genres have differential effects on cognitive abilities. Indeed, a meta-analysis by Powers et al.  on the eTimely action games prioritize the precise timing of an action, whereas accurate action games prioritize the precise execution of an action. Given these definitions, it seems Boson X is most accurately classified as a timely action game, since it places emphasis on the precise timing of a series of jumps. According to Mond\u00e9jar et al. (Dobrowolski et al.  discusser et al. , timely,r et al. ; this per et al. .Furthermore, Bernstein et al.  recentlyK\u00fchn et al.  did not All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Chen et al.  provide Although the cerebellum has been implicated in higher-order domains functions\u2014from a network-based perspective (Koziol et al., AI: conception and design. AI and AG: drafting the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The recent work by Young et al.  demonstrRegarding the importance of removing DNA from dead cells during microbial analysis, similar conclusions have been drawn by studies of, for example, environmental samples (Carini et al., vPCR methodology is theoretically simple to use since it requires only a reagent and a light source; however, as with many techniques, a lack of practical experience with the technique led the authors to overlook some important considerations. vPCR is still relatively new, with the first paper by Nogva et al. . The sci2 for 5 min, and this percentage decreases to 3\u20135% after 20 min of exposure (Brusa et al., (Cuthbertson et al., In the paper by Young et al. , the autThe authors evaluated the effect of freezing the samples and concluded that freeze/thawing did not change the results for the stool samples. However, factors other than storage were not considered, so it remains unclear whether their conclusions were influenced by additional biases.The work of Young et al. is valuable, and the conclusions very clearly show the importance of overcoming bias due to DNA from dead cells in a microbial diversity analysis. We suggest that an additional warning about the importance of appropriate sample handling would be helpful to readers who may wish to conduct similar analyses.Both authors reviewed the original work and wrote this commentary.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Cross-modal interactions are common in sensory processing, and phenomena reach from changed perception within one modality due to input from another like in the well-known McGurk effect  is the earliest processing stage in the auditory pathway in which acoustic trauma leads to tinnitus-related changes and increased spontaneous firing rates (Kaltenbach et al., It is well-known that the DCN receives not only input from the cochlea, but also from the somatosensory system (Ryugo et al., For example, it is well-known that jaw movements lead to a modulation of tinnitus sensation in patients (Pinchoff et al., In addition, the finding that DCN responses to somatosensory stimulation are enhanced after noise-induced hearing loss (Shore et al., Finally, the finding that electro-tactile stimulation applied to the index finger significantly improves speech perception thresholds (Huang et al., In a previous paper we already discussed the possibility of superseding the internally generated neuronal noise by adding external acoustic noise, thereby suppressing the tinnitus percept (Krauss et al., Based on these observations we here speculate that stochastic resonance in one sensory modality driven by input from another modality may be a general principle, namely multisensory integration causing stochastic resonance like cross-modal enhancement. For example, it is known that the concept of stochastic resonance via internal noise applies also to visual perception (Aihara et al., In addition to the here proposed neuronal mechanism of somatosensory-driven stochastic resonance in the auditory system explaining the better hearing in the CI patients during finger tapping (Huang et al., Even though multisensory integration leading to improved perception has been reported earlier (Stein and Stanford, PK and HS wrote the manuscript. PK, HS, KT, and AS discussed possible interpretations of the cited studies and developed the hypothesis presented in this paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer SV and the handling editor declared their shared affiliation."}
{"text": "The Revolting Self to emphasize the disgust associated with low self-esteem and poor perception of body image.Body image is a complex mystery. Contributions to low self-esteem can be sorted out, one by one, until the source of the \u201cproblem\u201d is found. To tackle this vast concept, several professors gathered together from the United States, Europe, Italy, and other parts of the world. Their expertise focused on chronic pain, anxiety, sexual dysfunction, addiction, and mood disorders. They explored feelings of guilt, shame, disgust, and avoidance. More positive aspects of their work included research on ethics, pride, mindfulness, and decision-making abilities. These doctrines formed a thought-provoking book that emphasized the role of body image in eating disorders. This book was titled as disgust as the typical reaction to vomit, mucus, or fecal matter, which generally creates distinct facial expressions and certain avoidance behaviors (Overton et al., The book starts by defining The Revolting Self digs deeper into self-disgust and the negative emotions that follow, which include impaired moral judgment (Overton et al., Comprehensive Psychiatry conducted a research study on seventy-two participants to find that moral judgment is the same for both schizophrenics and populations without schizophrenia (McGuire et al., Alterations in moral judgment can manifest themselves into mental disorders, such as eating disorders (Overton et al., The Revolting Self states that \u201cacts of psycho-emotional disablism contribute to the social marginalization of disabled people and their cultural representation as less than human\u201d (Overton et al., The book goes on to explain that certain populations promote feelings of disgust. Those who feel that they are disabled are more likely to experience disgust and a low self-esteem (Overton et al., International Journal for Equality in Health agrees that individuals with a disability see themselves as \u201cless than human,\u201d which creates cultural and psychosocial inequalities (Agmon et al., American Journal of Public Health echoes this same thought by claiming that disabled individuals consist of over twelve percent of the population, so they should be considered a cultural group (Krahn et al., The perfect human with a small body mass, flawless skin and perhaps curves in just the right places. The book suggests that \u201csocial norms\u201d are what society uses to define the ideal human (Overton et al., There are other cultural features of disgust as well. The media paints a pretty picture of the Yale Journal of Biology and Medicine claims that obesity is the most negative of all the stigmas (Pryor et al., The The Revolting Self suggests that women are more prone to low self-esteem because they often hide natural behaviors, such as menstruation (Overton et al., Frontiers in Psychology looked closely at the relationship between sex and culture, which showed cultural differences in emotional reactions to sex (Zhao et al., Some cultures might promote thinness, while others may prefer a larger body frame. Either way, low self-esteem occurs in many people before they engage in sexual intercourse (Overton et al., The Revolting Self suggests that disgust can take on many dimensions.All of these key points compile to form the theory that a poor sense of body image leads to inward anger or harsh criticism toward oneself (Overton et al., Approval for publication has been granted by the author, who is the sole contributor to this book review.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The use of nanomaterials for food applications is a rapidly evolving field and, given the specific properties of nanomaterials and their tremendous potential, an increased number of material innovations that contribute to improved food quality and safety are foreseen. Although the possibilities are unlimited, and nanomaterials in the food area have been applied with different purposes , the devThis special issue is devoted to compiling several papers on these fascinating topics. Specifically, five research papers and one review paper are included in the special issue \u201cFood Packaging based on Nanomaterials\u201d. The manuscripts by Sharif et al.  and BugaCombining inherent antimicrobial polymers (like chitosan) with antimicrobial nanoparticles (like zinc oxide) was the approach used by Al-Naamani et al. . These hA different strategy was explored by Muriel-Galet et al.  in anothThe toxicological aspects of packaging nanomaterials are also covered in this Special Issue through the work of Bott and Franz , who stuThe Special Issue is completed with a review paper from Huang et al.  which coIn summary, this Special Issue of Nanomaterials entitled \u201cFood Packaging based on Nanomaterials\u201d compiles a series of original research articles and a review paper providing new insight on the preparation and on the wealth of applications of hybrid nanomaterials for food-packaging applications. We are confident that this Special Issue will provide the reader with an overall view of some of the latest prospects in this fast-evolving and cross-disciplinary field."}
{"text": "Caenorhabditis elegans small noncoding RNAs, known as microRNAs, by Ambros, Ruvkun, and colleagues in 1993; this revolution has wrought huge changes in all fields of biology and medicine by identifying a new layer of gene regulation. The most unbiased proof of their impact is the publication of over 100\u00a0000 papers on the topic of short or long noncoding RNAs, reporting their roles in cell fate, tissue organization, organism homeostasis, and circadian rhythms, their use as biomarkers, their involvement in a plethora of disease mechanisms, and, starting recently, their potential as drugs or drug targets in several clinical trials for various disorders.Revolutions bring great changes to societies. The noncoding RNA revolution began with the seminal discovery of Molecular Oncology on the topic of noncoding RNAs is focused on specific issues that have practical significance, rather than trying to encompass the full biology of these molecules.Due to this unprecedented coverage of the role of noncoding RNAs in almost all aspects of biology and pathology, this special issue of Joanne Weidhaas and Ye Yuan review microRNA\u2010associated polymorphisms that have been shown to be important biomarkers of cancer risk, prognosis, and treatment outcomes. This has great translational significance, as these predictive biomarkers can be used for patient selection into treatment groups in clinical trials (Yuan and Weidhaas, et\u00a0al., Anke van den Berg, Joost Kluiver, and colleagues cover the important topic of crosstalk between MYC and noncoding RNAs, and the significance for potential new therapeutic approaches in human cancers (Swier The review by Spina and Rossi gives an overview of the mutation landscape in the most frequent type of human leukemia, chronic lymphocytic leukemia, with a particular focus on noncoding lesions of the genome (Spina and Rossi, et\u00a0al., Martin Pichler and colleagues review the role of a highly expressed ncRNA, NEAT1, in carcinogenesis and discuss some contradictory reports related to its potential interaction with microRNAs (Klec et\u00a0al., Cristina Lo Nigro and colleagues discuss the roles of lncRNAs as regulators of cancer immunity, a particularly important topic in light of the recent success of several types of immunotherapies (Denaro et\u00a0al., Manuela Ferracin and colleagues report on the involvement of certain small and long noncoding RNAs in cutaneous melanoma, and the diagnostic and prognostic potential of microRNAs for this disease (Riefolo et\u00a0al., Ioana Berindan and colleagues focus on the roles of the miR\u2010181 family, one of the most frequently deregulated families of microRNAs in lung cancers, and their potential use as biomarkers and therapeutic targets for this deadly malignancy (Braicu In closing, we hope that this special issue will not only answer many of our readers\u2019 questions on this topic, but also raise new ones that will open new venues of research and lead to significant discoveries in this ongoing revolution."}
{"text": "We highlight empirical examples and present a conceptual model for the generation of resource polymorphism\u00a0\u2013\u00a0emphasizing eco evo devo, and identify current gaps in knowledge.A major goal of evolutionary science is to understand how biological diversity is generated and altered. Despite considerable advances, we still have limited insight into how phenotypic variation arises and is sorted by natural selection. Here we argue that an integrated view, which merges ecology, evolution and developmental biology (eco evo devo) on an equal footing, is needed to understand the multifaceted role of the environment in simultaneously determining the development of the phenotype and the nature of the selective environment, and how organisms in turn affect the environment through eco evo and eco devo feedbacks. To illustrate the usefulness of an integrated eco evo devo perspective, we connect it with the theory of resource polymorphism (i.e. the phenotypic and genetic diversification that occurs in response to variation in available resources). In so doing, we highlight fishes from recently glaciated freshwater systems as exceptionally well\u2010suited model systems for testing predictions of an eco evo devo framework in studies of diversification. Studies on these fishes show that intraspecific diversity can evolve rapidly, and that this process is jointly facilitated by ( I.et al., et al., Many key advances in evolutionary biology over the last century, such as the modern synthesis, have resulted from synergies among fields. Yet, our understanding of what drives the evolution of biological diversity is still limited\u00a0\u2013\u00a0not least because we often adopt a discipline\u2010specific focus. For instance, the fields of evolutionary ecology and population genetics have both yielded strong empirical evidence for the role of natural selection in the evolution of biological diversity Endler, , but theet al., et al., The origins of phenotypic variation have been a focus of the field of evolutionary developmental biology  and how this affects evolution  requires the integration of more than two approaches Givnish, . SubsequIII.(1)et al., Resource polymorphism is defined by the occurrence of intraspecific morphs that show differential resource use, usually through differences in feeding biology and habitat use  exploitation by a monomorphic population of a new or unexploited environment\u00a0\u2013\u00a0often with high levels of intraspecific competition; (ii) rapid phenotypic shifts, especially in behaviour, morphology and life history, primarily mediated through phenotypic plasticity; (iii) divergent selection and the evolution of specialized and more distinct morphological groups, accompanied by reduced phenotypic plasticity and, finally; (iv) reduced gene flow and the evolution of prezygotic and potentially postzygotic reproductive isolation Salvelinus), whitefish (genera: Coregonus and Prosopium), three\u2010spined stickleback (Gasterosteus aculeatus) and Eurasian perch (Perca fluviatilis)  makes them ecologically tractable. Their recent evolutionary divergence, and associated incomplete reproductive isolation (i.e. ongoing gene flow), opens a window to evolution where processes facilitating or impeding divergence can be studied along a so\u2010called \u2018speciation continuum\u2019  and Eurasian perch show greater survival in vegetated littoral habitats, whereas streamlined individuals survive better in open water when exposed to predation et al., et al., et al., et al., et al., et al., via niche construction, see Section I).The development of the field of eco\u2010evo dynamics has been motivated by the recognition that ecological and evolutionary processes can occur at similar time scales, and by our limited understanding of what defines a selection regime   and whitefish (Coregonus lavaretus)  et al., et al., et al., et al., et al., et al., et al., et al., et al., Many natural populations show substantial fluctuations in density over time  morphs in the sub\u2010Arctic Norwegian lake Fjellfrosvatn was characterized by temporally stable resource use, most likely reflecting predictable ecological conditions  to lakes has led to alterations in the visual conditions and changes in the resource base and, subsequently, to increased phenotypic divergence between littoral and pelagic Eurasian perch et al., et al., et al., et al., et al., et al., et al., PPARAa gene involved in mitochondrial regulation) appears to facilitate colonization of freshwater environments by marine fish et al., et al., et al., et al., et al., et al., et al., et al., et al., Understanding the molecular genetic basis of phenotypic change has long been a prevalent theme in research on polymorphic postglacial fishes. Recently, molecular genetic technologies have started to provide more direct insight into the genetic mechanisms underlying resource polymorphism in postglacial fishes than was possible with quantitative genetic approaches alone. For example, quantitative trait locus (QTL) mapping continues to yield valuable information on the genomic architecture  of traits involved in phenotypic divergence [e.g. Arctic charr  is variation in number of lateral armour plates in three\u2010spined stickleback. The ancestral marine type has bony armour plates along its body, while the derived freshwater types have variably reduced plate numbers , which are likely to have a complex genetic basis with gene\u00a0\u00d7\u00a0environment interactions Edwards, . For exa(3)As we understand better the genetic basis of complex phenotypic variation, we will also need to broaden our thinking to include dynamic gene\u2013environment interactions, such as phenotypic plasticity and transgenerational  effects. Cues from the offspring's own environment as well as the parental phenotype  jaw morphologies by benthic and limnetic food is associated with the effects of a regulatory locus, the patched 1 (ptch1) gene, which affects jaw structure through variable mediation of bone deposition around the cartilaginous precursor  showed that variation in eye and orbit size in surface fish was plastically increased by exposure of embryos to the low water conductivity typical of cave environments , exposure of larger embryos to stressful environments resulted in greater plasticity and a wider developmental trajectory than in smaller embryos  can respond to signals effected by yolk quantity    under relevant ecological conditions provides an important empirical focus to help integrate eco evo devo Fig.\u00a0. Such stIV.In certain resource\u2010polymorphic fishes, aspects of the eco evo devo framework have been examined, illustrating the strength of an integrated approach.(1)et al., et al., et al., et al., et al., et al., Littoral and pelagic individuals of Eurasian perch exhibit greater phenotypic divergence in lakes with invasive zebra mussels than in those without zebra mussels (Hirsch (2)et al., 1989a; Ahi et al., et al., et al., et al., et al., Salvelinus malma), differences in adult morphology are related to variable embryonic skull ossification . Research on craniofacial transcriptional dynamics in the progeny of benthic and pelagic Arctic charr morphs has identified a gene network, related to glucocorticoid (GC) signalling, that influences bone development and is expressed at higher levels in the benthic than the pelagic progeny et al., et al., et al., et al., Coregonus sp. \u201cBodenbalchen\u201d and a limnetic C. zugensis) species  during early divergence in novel environments  the role of spatial and temporal variability and discreteness of resources; (ii) the significance of transgenerational effects; (iii) the role of eco\u2010evo feedbacks across generations and eco\u2010devo feedbacks during ontogeny; and (iv) structuring of ecosystems and developmental architecture. We strongly advocate that future research should consider explicitly the integration of these processes rather than focusing on the alternatives (such as genes versus environment). Thus, we need studies that explore how evolutionary and developmental processes feed back on ecosystems, both in controlled mesocosms and field experiments (e.g. Lundsgaard\u2010Hansen et al., et al., et al., et al., In practical terms, rigorous tests of the different pathways of such an eco evo devo framework Figs\u00a0 and 4 arVIII.et al., et al.,et al.,We believe that the integration of multiple interacting processes into the eco evo devo framework proposed here Fig.\u00a0 will allWe emphasize that an eco evo devo approach is a powerful conceptual framework for understanding the complex integrated processes that ultimately determine the patterns of biological diversity in nature. Thus, we have discussed how natural selection is not an autonomous process that is only driven by factors external to the respective organisms, but also by intrinsic factors whereby organisms can shape their own external environment. The external factors that determine selection can often be the same as those that influence individual development through phenotypic plasticity. Thus, the snapshot of phenotype\u2013fitness relationships we often use to measure natural selection empirically may be a subset of much broader and highly dynamic eco evo devo processes. It follows that these relationships could be viewed as evidence for coordinated variation between dynamic intrinsic developmental factors, which affect the outward phenotype, and current ecological factors. We hope that future advances in evolutionary biology will accommodate more forcefully the role of development and apply a scientific thinking that fully integrates the sub\u2010fields of eco, evo and devo.Table S1. Examples of empirical evidence for different patterns of resource polymorphism in postglacial freshwater fishes including phenotypic distribution, trait type, ecological axis of divergence, and evidence of reproductive isolation.Appendix S1. Overview of resource polymorphism in fish in postglacial freshwater systems.Click here for additional data file."}
{"text": "In focusing on how organisms' generalizable functional properties (traits) interact mechanistically with environments across spatial scales and levels of biological organization, trait\u2010based approaches provide a powerful framework for attaining synthesis, generality and prediction. Trait\u2010based research has considerably improved understanding of the assembly, structure and functioning of plant communities. Further advances in ecology may be achieved by exploring the trait\u2013environment relationships of non\u2010sessile, heterotrophic organisms such as terrestrial arthropods, which are geographically ubiquitous, ecologically diverse, and often important functional components of ecosystems. Trait\u2010based studies and trait databases have recently been compiled for groups such as ants, bees, beetles, butterflies, spiders and many others; however, the explicit justification, conceptual framework, and primary\u2010evidence base for the burgeoning field of \u2018terrestrial arthropod trait\u2010based ecology\u2019 have not been well established. Consequently, there is some confusion over the scope and relevance of this field, as well as a tendency for studies to overlook important assumptions of the trait\u2010based approach. Here we aim to provide a broad and accessible overview of the trait\u2010based ecology of terrestrial arthropods. We first define and illustrate foundational concepts in trait\u2010based ecology with respect to terrestrial arthropods, and justify the application of trait\u2010based approaches to the study of their ecology. Next, we review studies in community ecology where trait\u2010based approaches have been used to elucidate how assembly processes for terrestrial arthropod communities are influenced by niche filtering along environmental gradients  and by abiotic and biotic disturbances . We also review studies in ecosystem ecology where trait\u2010based approaches have been used to investigate biodiversity\u2013ecosystem function relationships: how the functional diversity of arthropod communities relates to a host of ecosystem functions and services that they mediate, such as decomposition, pollination and predation. We then suggest how future work can address fundamental assumptions and limitations by investigating trait functionality and the effects of intraspecific variation, assessing the potential for sampling methods to bias the traits and trait values observed, and enhancing the quality and consolidation of trait information in databases. A roadmap to guide observational trait\u2010based studies is also presented. Lastly, we highlight new areas where trait\u2010based studies on terrestrial arthropods are well positioned to advance ecological understanding and application. These include examining the roles of competitive, non\u2010competitive and (multi\u2010)trophic interactions in shaping coexistence, and macro\u2010scaling trait\u2013environment relationships to explain and predict patterns in biodiversity and ecosystem functions across space and time. We hope this review will spur and guide future applications of the trait\u2010based framework to advance ecological insights from the most diverse eukaryotic organisms on Earth. I.et al., et al., et al., et al., Biodiversity is often described exclusively in terms of the distinct taxonomic entities (species) which it contains, and measured in terms of its taxonomic component, taxonomic diversity (e.g. species richness). Taxonomic approaches, however, offer limited insight into the evolutionary and mechanistic underpinnings of ecological phenomena; these have recently been studied using alternative approaches for describing biodiversity. For instance, phylogenetic approaches emphasize organisms' evolutionary affiliations, and measure the phylogenetic component of biodiversity, phylogenetic diversity i) traits are phenotypic entities that are strictly measured on individual organisms; and (ii) traits are functional, in the sense that their interactions with biotic and abiotic environments affect performance, and consequently organism fitness . These are twofold: et al., via their responses and effects. This makes it possible to aggregate and integrate different traits to explain structure and functioning mechanistically across different scales of organization   constrained to examining one particular ecological theory or question; the predictive value of trait\u2010based approaches essentially stems from their versatile potential to test different ecological theories empirically, and reveal mechanisms across different organizational scales. Much of the existing research on terrestrial arthropods has applied trait\u2010based approaches to investigate community assembly within the context of ecological filters , functional divergence (FDiv), and functional evenness (FEve); see Mouchet et al. et al., et al., In addition to the notable contributions of trait\u2010based studies on plants, trait\u2010based research on other taxa has considerable potential to improve ecological theory and practice. We suggest that terrestrial arthropods represent an ideal group for such work because their taxonomic and ecological diversity is unmatched. Most eukaryotic species on Earth are terrestrial arthropods Zhang, ; they aret al., et al., et al., et al., et al., et al., To facilitate trait\u2010based research on terrestrial arthropods, there is an abundance of information in the literature and extensive physical and digital collections via a functional group approach akin to that used in plants ; the number of groups within a particular scale of biological organization determined its functional diversity. Examples of widely used functional groupings include those for ants and termites, based on taxonomic relationships and diet specialization et al., et al., et al., et al., \u2018Community\u2019 refers to a set of species with shared ecological characteristics that coexist in the same area Chesson, . CommuniIn addition to establishing the overall deterministic nature of the assembly process, trait\u2010based approaches can be used to reveal how specific niche\u2010based mechanisms operate in community assembly. Thus far, trait\u2010based studies on terrestrial arthropods have predominantly investigated how the mechanism of niche filtering influences community assembly along various environmental gradients (see Section (a)et al., et al., et al., Niche filtering  occurs when the abiotic or biotic environment imposes barriers to establishment and/or survival, thus favouring the co\u2010occurrence of individuals with similar traits. It then follows that the typical signature of niche filtering is a non\u2010random pattern of clustering among trait values  in the emergent community et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al. et al., et al., et al. . Studies on European Lepidoptera report equivocal results. Some found evidence for functional clustering in homogenous habitats with shorter vegetation, where species with higher mobility, growth and fecundity were selected for et al. Disturbances are abiotic or biotic forces or processes that result in perturbations, where ecosystems deviate\u00a0\u2013\u00a0that is, are changed\u00a0\u2013\u00a0from their reference states Rykiel, . Below w(i)et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., In line with theoretical expectations Swengel, , trait\u2010b(ii)et al., et al., et al., et al., et al., et al., et al., et al., et al., Like fire, flood events generally act as strong niche\u2010filtering mechanisms across multiple taxonomic groups (Dziock (iii)et al., et al. et al., et al., et al., et al., et al., et al., et al., Knowledge of the effects of biodiversity on ecosystem functions (BEF relationships) is integral to safeguarding Earth systems and human wellbeing , as well as the specific techniques used (e.g. different ways of measuring the same ecosystem function). Spatial scale is another vital factor to consider and may explain interaction effects between functional identity and functional complementarity. For instance, research on plant communities suggests that functional identity better predicts BEF relationships at larger spatial scales, where niche filtering along environmental gradients leads to the clustering of trait values that in turn dominate communities and ecosystem functions et al., et al., et al., et al., et al., et al., et al., A fundamental assumption of the trait\u2010based approach is trait functionality; all studies should use traits that possess fitness\u2010functionality, and where BEF studies are concerned, those traits should also possess ecosystem\u2010functionality. However, these assumptions of trait functionality have not been explicitly tested for the overwhelming majority of terrestrial arthropods, and the problem is further compounded by the diversity of traits recorded for each species. For instance, some studies used multiple morphological measurements with limited evidence for the functionality of these separate \u2018traits\u2019 (Wiescher (a)et al. et al., et al., et al., Naturally, experiments involving performance measures along environmental gradients can only be undertaken for a fraction of terrestrial arthropods. However, standards for observational trait\u2010based studies can still be raised so as to enhance their potential for synthesis, generality and prediction. First, investigators should strive to justify explicitly the functionality of the traits used. In the absence of evidence, traits should at the very least be selected on the theoretical bases of their functionality\u00a0\u2013\u00a0that is, how their abiotic or biotic interactions may impact specific fitness components  and relevant ecosystem processes. Selecting traits in this manner will better facilitate a mechanistic understanding of observed empirical patterns (i.e. trait\u2013environment relationships) to generate good predictions. Essentially, only traits with demonstrable indirect or direct links to performance should be selected, while also balancing this with the important objective of maximizing the functional niche represented   environmental gradient (e.g. Gerisch (2)et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Intraspecific variation in phenotypic traits within a species may be generated through mechanisms such as local adaptation, parental conditions, ontogeny and phenotypic plasticity et al., et al., et al., Most if not all sampling methods bias detection towards particular species and away from others. When sampling methods consistently fail to detect certain species because of their particular traits or trait values (detection filtering), the effects on observed trait\u2013environment relationships may be substantial in situ will be most representative of the ecological relationships investigated, since these are the traits directly undergoing selection by, or affecting, the studied environment. Continuous data will better reflect changes in the intensities of a trait's interactions than discrete categorical data  one plant species; (ii) two plant species; and (iii) three plant species, etc.\u2019  one plant species; (ii) more than one species from the same genus; (iii) more than one genus from the same family; and (iv) more than one family from the same order, etc.\u2019  or categorical form . The particular source and structure of trait information used will affect the quality of results obtained. Where possible, investigators should prioritize the collection of primary data on traits, and in continuous form. Primary data on traits measured et al., et al., et al., http://carabids.org; Homburg et al., et al., et al., et al., et al., Of course, it will not always be feasible to collect primary data on traits. There is a general lack of knowledge on species' traits, ecological functions and interactions et al., et al., et al., et al., et al., The sheer biological diversity of terrestrial arthropods affords new and exciting opportunities for exploring the ecological effects of distinct phenotypes that are absent from other organisms. Many of these idiosyncratic traits have not been investigated in trait\u2010based studies thus far. Especially relevant to intraspecific variation are traits that reflect \u2018personality\u2019: temporally consistent individual differences in behaviour along one or more behavioural axes (Modlmeier (2)et al., et al., The biotic force of competition has traditionally been thought to shape community assembly by preventing individuals with very similar niches from coexisting  (e.g. storage effects and relative non\u2010linearities) mediated by species' niche differences, and the effects of differences in competitive abilities  that favour particular species over others in the absence of stabilization  as well as performance traits which may conceivably directly impact growth rates (e.g. fecundity) are not distinguished from traits that are assumed to reflect niche differences, which potentially contribute to A.Integrating modern coexistence theory with trait\u2010based ecology may provide a powerful paradigm for tackling the fundamental question of coexistence , dynamic , unstable  and quasi\u2010neutral  sensu Vellend, et al., et al., et al., et al., et al., et al., et al., via trait\u2010matching also has facilitated assessments of the impact of environmental changes on multiple trophic levels  with the functional components of BEF research (e.g. species' responses to and effects on their environments) have been proposed to improve prediction of the many ecosystem functions encompassing multi\u2010trophic interactions et al., i) describe the distribution of traits along environmental gradients and across spatial scales; then, using this information; (ii) explain the geographic distribution of organisms, biodiversity patterns, and ecosystem processes; and (iii) predict responses to environmental changes using trait\u2010based predictive functions and models , by providing insights into the spatial scaling of assembly processes (e.g. species interactions) across broad gradients (Violle et al., et al., et al., et al., The emerging field of functional biogeography investigates the patterns, causes, and consequences of the geographic distribution of trait diversity (Violle , et al.  showed tV.By focussing on the functional properties of individual organisms, trait\u2010based ecology provides a broad, mechanistic framework for synthesizing, explaining and predicting structure and function across different levels of biological organization.The time is ripe for a trait\u2010based ecology of terrestrial arthropods. Such work will improve understanding of the processes underlying patterns of diversity for complex ecological communities encompassing multiple trophic levels, and provide mechanistic insights to the functioning of essential ecosystem services such as pollination, biological control and nutrient cycling. For many terrestrial arthropods, taxonomic impediments have limited ecological research, and a focus on traits will be particularly useful for expediting understanding some of the interactions and functions of these taxa. The growing volume of data on the traits of terrestrial arthropods in databases and the wider literature, as well as physical and digital collections, will facilitate work on the generality of functional relationships across geographic regions and spatial scales.Findings from pioneering studies on the trait\u2010based ecology of terrestrial arthropods attest to the value of this burgeoning field. Here, trait\u2010based approaches have been especially useful for elucidating the specific mechanisms driving the deterministic assembly of diverse communities across different environmental gradients, as well as their responses to disturbances\u00a0\u2013\u00a0often revealing distinct patterns in functional diversity not detected by taxonomic and phylogenetic approaches. Preliminary work investigating terrestrial arthropod\u2010mediated ecosystem functions did not observe a consistent relationship between functional diversity and ecosystem function, although comparisons are strictly limited by differences among studies in terms of the focal scale, community characteristics and methods used.New studies expanding the scope of terrestrial arthropod trait\u2010based research will advance knowledge in longstanding as well as emerging areas in ecology. As previous studies mainly focused on the interactions between traits and abiotic environments, one immediate avenue for future work will be to explore how biotic interactions\u00a0\u2013\u00a0including various competitive, non\u2010competitive, and multi\u2010trophic interactions among species\u00a0\u2013\u00a0shape structure and function across different environmental gradients and spatial scales. At the same time, novel research on the functional biogeography of terrestrial arthropods may succeed in mapping global distributions of their functional diversity, thereby enhancing ecological forecasting and the management of ecosystem services in the face of climate change and the spread of invasive species. Importantly, such efforts will be undermined if trait functionality is not rigorously tested, if the effects of intraspecific variation are not accounted for, and if the collection of trait information is biased or inconsistent. The predictive value of future work also rests upon the willingness of researchers to go beyond describing patterns to identify mechanisms\u00a0\u2013\u00a0that is, by undertaking hypotheses\u2010driven investigations grounded in ecological theory. Future studies in terrestrial arthropod trait\u2010based ecology should thus explicitly address these aspects in the critical stages of study design, trait selection, sampling and measurement, as well as in the treatment and consolidation of trait data.Realizing trait\u2010based ecology's higher goal of synthesis, generality and prediction also demands taxonomic excellence\u00a0\u2013\u00a0to safeguard the accuracy and coherence of trait data. Thus it is important to recognize that functional approaches to describing biodiversity are ultimately complements, and not substitutes to taxonomic ones. While a focus on traits can help to overcome significant taxonomic impediments to the understanding of ecology, trait\u2010based research faces an even greater impediment\u00a0\u2013\u00a0the lack of information on the form and functionality of organisms. Especially in the hyper\u2010diverse terrestrial arthropods, basic data are lacking on diet, physiology, phenology and behaviour\u00a0\u2013\u00a0let alone information on how these vary intraspecifically along environmental gradients. In conclusion, we propose that reconciling contemporary trait\u2010based research with the long\u2010established study of taxonomy and natural history will pave the way for a more robust understanding of the mechanisms structuring arthropod diversity across space and time."}
{"text": "We appreciate the interest and comments from Joshi et al.  regardinFirst, the authors cite a paper by Anderson et al.  that demSecond, Joshi et al.  point toThe third comment involved concerns the differing levels of support in the Saslow et al.  and HallFourth, the concerns raised about the findings from Hallberg et al.  are riddUtility of Unrefined Carbohydrates in Type 2 Diabetes. Comment on Reversing Type 2 Diabetes: A Narrative Review of the Evidence, Nutrients 2019, 11, 766 [Furthermore, this review was not intended to be a systematic review, and therefore does not reflect the entirety of the current evidence. However, we feel that this review gives an accurate depiction of the evidence that exists for diabetes reversal. Joshi et al. present no evidence to support the title of their paper (presumably their point) We hope the above gives clarity to the issues raised by Joshi et al. . We appr"}
{"text": "Although violence is a vital public health problem, no prospective studies have tested for subsequent vulnerability to violence, as a victim or witness, in members of the general population with a range of psychiatric symptoms, or evaluated the importance of higher symptom burden on this vulnerability.We used successive waves of a household survey of Southeast London, taken 2 years apart, to test if association exists between psychiatric symptoms  and later victimisation, in the form of either witnessing violence or being physically victimised, in weighted logistic regression models. Statistical adjustment was made for prior violence exposure, sociodemographic confounders, substance/alcohol use and violence perpetration. Sensitivity analyses were stratified by violence perpetration, sex and history of mental health service use.After adjustments, psychiatric symptoms were prospectively associated with reporting any subsequent victimisation (odds ratio (OR) 1.88, 95% confidence interval (CI) 1.25\u20132.83), a two times greater odds of reporting witnessed violence  and reporting physical victimisation . One more symptom endorsed was accompanied by 47% greater odds of subsequent victimisation . In stratified analyses, statistical associations remained evident in non-perpetrators, and among those without a history of using mental health services, and were similar in magnitude in both men and women.Psychiatric symptoms increase liability to victimisation compared with those without psychiatric symptoms, independently of a prior history of violence exposure and irrespective of whether they themselves are perpetrators of violence. Clinicians should be mindful of the impact of psychiatric symptoms on vulnerability to victimisation, including among those with common psychiatric symptoms and among those who are not considered at risk of perpetrating violence. We hypothesise that the presence of psychiatric symptoms, and increasing number of symptom domains present, will be associated with later victimisation.et al., et al., et al., The South East London Community Health study   . Employment status was categorised into employed, student, unemployed and other  in the last 12 months. Finally, a binary \u2018overall victimisation\u2019 variable was created, reflecting endorsement of either being physically victimised or witnessing violence.et al., All statistical analyses were performed in STATA 14  participated in SELCoH-2  was found for a linear trend between the number of symptom domains endorsed and overall victimisation. Compared with those not endorsing any symptom domain, those reporting 3\u20134 symptom domains had more than three times the odds of reporting recently witnessed violence, and twice the odds of reporting physical victimisation, in adjusted models. For each further symptom domain endorsed, there was a 1.55-fold increase in the odds of later witnessed violence, a 1.3-fold increase in the odds of later physical victimisation, and a 1.47-fold increase in the odds of overall victimisation.After adjustment, endorsing any psychiatric symptom domain was associated with a greater than twofold increase in the odds of later witnessed violence, a 1.75-fold increase in the odds of being physically victimised and a close to twofold increase in the odds of overall victimisation see . StatistIn order to examine the influence of important potential confounders in more depth, we repeated the analyses shown in In a sample of Southeast London household residents, psychiatric symptoms, ascertained based on endorsement of epidemiological screening tools for different domains of psychopathology, were prospectively associated with later victimisation over a 3-year period, both overall, by being physically victimised, and as a witness, compared with those without symptoms at baseline. An increasing number of symptom domains predicted greater odds of victimisation over time. The association was not limited to perpetrators of violence, or to those without a history of mental health service use. Although associations between endorsing any psychiatric symptom domain and later victimisation were observed in both men and women, estimates for women were of greater magnitude.et al., et al., et al., et al., We suggest that our study significantly strengthens a limited literature (Silver et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al. found prospective association between a single scale reflecting psychiatric morbidity and violent experiences, but examined only individuals remaining in the study at age 46 (Hart et al., et al. (The psychiatric consequences of victimisation are well known, and include psychosis (Varese , et al.  reportedet al., et al., et al., et al., et al., et al., This study was longitudinal and based on a randomly selected baseline sample. Detailed measurements of psychopathology were gathered, and we used conservative cut-offs to identify individuals in whom we could be reasonably confident there were clinically relevant symptoms in the various domains. On the other hand, there was attrition, which reduced the precision of estimates and limited study power to estimate associations with specific symptom domains in detail, as planned. People with psychiatric symptoms might have been more or less liable to report victimisation compared with people without psychiatric symptoms, leading to misclassification and resulting over or underestimation of the main association. However, studies indicate that the recall of victimisation events is generally reliable (Schneider, et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Although our results suggest that psychiatric symptoms may increase liability to subsequent victimisation, the exact explanations remain unclear. Our findings may, for example, be consistent with a \u2018routine activities\u2019 model of victimisation where violent experiences arise from the convergence of motive, opportunity and lack of adequate safeguards against violence (Miethe et al., We present the first prospective evidence that people with common psychiatric symptoms, and higher number of symptoms, have greater vulnerability to victimisation than those without symptoms, not limited to those with a history of perpetrating violence, those using services or those with prior exposure to violence. Lifestyle factors such as hazardous alcohol use and drug use, as well as perpetration history, appear to account for some of this association. There is already evidence that people with psychiatric disorders are systematically excluded from the benefits of public health interventions addressing, for example, smoking (Szatkowski and McNeill,"}
{"text": "After decades of debate about the existence of non\u2010genetic inheritance, the focus is now slowly shifting towards dissecting its underlying mechanisms. Here, we propose a new mechanism that, by integrating non\u2010genetic and genetic inheritance, may help build the long\u2010sought inclusive vision of evolution. After briefly reviewing the wealth of evidence documenting the existence and ubiquity of non\u2010genetic inheritance in a table, we review the categories of mechanisms of parent\u2013offspring resemblance that underlie inheritance. We then review several lines of argument for the existence of interactions between non\u2010genetic and genetic components of inheritance, leading to a discussion of the contrasting timescales of action of non\u2010genetic and genetic inheritance. This raises the question of how the fidelity of the inheritance system can match the rate of environmental variation. This question is central to understanding the role of different inheritance systems in evolution. We then review and interpret evidence indicating the existence of shifts from inheritance systems with low to higher transmission fidelity. Based on results from different research fields we propose a conceptual hypothesis linking genetic and non\u2010genetic inheritance systems. According to this hypothesis, over the course of generations, shifts among information systems allow gradual matching between the rate of environmental change and the inheritance fidelity of the corresponding response. A striking conclusion from our review is that documented shifts between types of inherited non\u2010genetic information converge towards epigenetics (i.e. inclusively heritable molecular variation in gene expression without change in DNA sequence). We then interpret the well\u2010documented mutagenicity of epigenetic marks as potentially generating a final shift from epigenetic to genetic encoding. This sequence of shifts suggests the existence of a relay in inheritance systems from relatively labile ones to gradually more persistent modes of inheritance, a relay that could constitute a new mechanistic basis for the long\u2010proposed, but still poorly documented, hypothesis of genetic assimilation. A profound difference between the genocentric and the inclusive vision of heredity revealed by the genetic assimilation relay proposed here lies in the fact that a given form of inheritance can affect the rate of change of other inheritance systems. To explore the consequences of such inter\u2010connection among inheritance systems, we briefly review published theoretical models to build a model of genetic assimilation focusing on the shift in the engraving of environmentally induced phenotypic variation into the DNA sequence. According to this hypothesis, when environmental change remains stable over a sufficient number of generations, the relay among inheritance systems has the potential to generate a form of genetic assimilation. In this hypothesis, epigenetics appears as a hub by which non\u2010genetically inherited environmentally induced variation in traits can become genetically encoded over generations, in a form of epigenetically facilitated mutational assimilation. Finally, we illustrate some of the major implications of our hypothetical framework, concerning mutation randomness, the central dogma of molecular biology, concepts of inheritance and the curing of inherited disorders, as well as for the emergence of the inclusive evolutionary synthesis. I.et al., et al., et al., et al., There is currently a heated debate about the necessity to modernize the modern synthesis of evolution (a)et al., The existence of non\u2010genetic inheritance has long been debated et al., et al., et al., et al.,Today, the focus is slowly shifting towards the understanding of the mechanisms and evolutionary consequences of non\u2010genetic inheritance, which remains one of the major challenges of modern biology This review focuses on the molecular mechanisms of non\u2010genetic inheritance in order to unify them with genetic inheritance into a single inclusive evolutionary synthesis. During this process, a new framework emerges that we propose here as a working hypothesis. The main idea is that of the existence of a relay among inheritance systems from more labile to more stable forms of inherited information following a persistent environmental change. The idea of a relay among inheritance systems was suggested previously  in inheritance systems seem to converge towards epigenetics. When this is the case, this epigenetic stage may generate a final handover towards genetic encoding. In this hypothesis, epigenetic marking constitutes a major hub linking non\u2010genetic germline inheritance with genetic inheritance. A profound difference between the genocentric and the inclusive vision of heredity revealed by the genetic assimilation relay proposed here lies in the fact that a given form of inheritance can affect the rate of change of other inheritance systems. We then use a simple theoretical model to investigate consequences of this relay in inheritance systems. We find that this form of epigenetically facilitated mutational assimilation i) be genetic, (ii) involve the germline, or (iii) generate germline\u2010dependent transmission  overlapping, classification focuses on mechanisms of resemblance rather than patterns. It includes three categories of processes: simultaneous exposure effects, germline\u2010independent transmission and non\u2010genetic germline transmission (Anway (a)simultaneous exposure effects germline\u2010independent transmission non\u2010genetic germline transmission et al., et al., et al., et al., et al., The existence of various categories of inheritance mechanisms raises the question of their roles in evolution  that exists in two highly heritable morphs, the most common having flowers with a marked dorsoventral asymmetry, and a peloric form  where flowers have radial symmetry  affecting flower asymmetry, which appears to be silenced in the peloric morph. This shows the extent to which epigenetic and genetic variation produce patterns of phenotypic change that are very difficult to distinguish. Many other examples are provided in Table There are many instances in which a heritable phenotypic change first attributed to a genetic change (i.e. a change in the DNA sequence) was later proved to be due to a functionally efficient heritable change in epigenetic marks. The most famous example is that of the toadflax The relay starts when previously non\u2010transmitted variation becomes transmitted. For example, behavioural innovations are reinvented regularly until social learning eventually triggers transgenerational stability et al., et al., et al., et al., et al., germline\u2010independent transmission in which epigenetically induced maternal behaviour becomes the environmental cause of the reconstruction of similar epigenetic marks in their developing daughters, and continues over many generations, leading to persistent mother\u2013daughter resemblance in maternal care.The second step is when parental effects lead to heritable epigenetic marks arrow 2, Fig. , Fig. 2.More generally, parental capacity to modulate their offspring's epigenetic marks constitutes an ideal candidate inheritance mechanism for germline\u2010independent inheritance Stellaria longipes, this non\u2010genetic change has been linked to a lower level of DNA methylation  often can be transferred across generations (Cubas (4)et al., et al., germline\u2010independent transmission and non\u2010genetic germline transmission of behaviour.Epigenetics is also involved in long\u2010term memory systems, which can link cultural transmission to its potential epigenetic bases epigenetic germline transmission well after the disappearance of the environmental stress , this methylation pattern was transmitted to unexposed F1 and F2 offspring that then feared the same odour (but not a different odour) when first exposed to it.Mice provide another fascinating example of environmentally acquired traits that are directly epigenetically inherited over several generations (a)et al., et al., et al., et al., Perhaps the most direct pathway in the genetic assimilation relay from non\u2010genetic to genetic inheritance et al., et al., et al., et al., et al., At the larger scale of genomic regions , various studies suggest that the statistical link between epigenetic marks or chromatin state and mutation is very general  and local DNA\u2010sequence variation. This association was documented in a large epigenome\u2010wide association study in Chlamydomonas reinhardtii found that \u2018differences in methylation patterns were not associated with nearby genetic mutations\u2019  fraction of the population may take between 30 and 140 generations et al., et al., et al., et al., et al., et al., et al., et al., Drosophila and zebrafish, diverse classes of retrotransposons were recently shown to act \u2018as molecular stowaways to gain passage from their site of production \u2026 to the oocyte germ plasm\u2019  by epigenetic marks mutational assimilation\u2019 , and eventually become genetically encoded, provided that the new environment remains stable for sufficient time for this multi\u2010generation mechanism to induce mutations that can then be selected. It thus corresponds to a \u2018Intuitively, the proposed mechanism linking epigenetic and genetic changes has the potential to accelerate genetic evolution. Below, we present a model studying the extent to which this form of genetic assimilation can accelerate the genetic encoding of acquired heritable adaptations.III.et al., We now outline a model to explore the possible evolutionary consequences of epigenetically facilitated transfer of information between the environment and the epigenetic and genetic materials. The model simulates the evolution of populations experiencing a sudden environmental change that shifts an adaptive peak. We compare populations with specific strategies of hereditary transmission to assess how rapidly they can reach the new fitness peak. For that goal, as in previous studies (Herman (1)et al. , except when epigenes are costly to maintain (wcostly epigene peak < wgene peak). The population is limited to a fixed carrying capacity.The model is based on Klironomos et al. , with thet al.  and expls et al. , the ada(2)We explore a series of strategies of inheritance mechanisms Fig. . Importagenes\u2010only: individuals consist of only one genetic sequence, mutating with rate \u03bcgene. A similar strategy is \u2018epigenes\u2010only\u2019 . This amounts to the gene\u2010only strategy, with a higher mutation rate. All other strategies use both genes and epigenes. With the strategy genes\u2010and\u2010epigenes, genes and epigenes mutate independently (according to their respective mutation rates). These strategies correspond to the Klironomos et al. . This strategy is similar to that of Jablonka & Lamb . This simulates a situation where regulatory patterns, or maternal effects, are adaptively induced by the environment. In this strategy and the following ones, epigenetic marks generate new variation that is then open to selection in the model.The simplest strategy is s et al.  model. Wa & Lamb . This sicostly\u2010inducible\u2010mutagenic\u2010epigenes is identical to the inducible\u2010mutagenic\u2010epigenes one, except that the fitness peak for epigenes is inferior to the fitness peak for genes.We also explore the case where maintaining an epigenetic system is costly . The strategy flexible\u2010inducible\u2010mutagenic\u2010epigenes). This strategy can be thought of as simulating a situation of mutational assimilation i) individuals reproduce (according to their fitness), individuals in excess, if any, are randomly removed; (ii) for each remaining individual, the genetic and epigenetic sequences undergo possible mutations (according to their respective rates). Each simulation is run for 106 generations.Only one strategy of hereditary transmission is tested at a time. The starting population is monomorphic, offpeak . The dynamics consists of a succession of generations where:  is recorded, and the geometric average of the fitness since the beginning of the simulation is computed. The geometric average at a given time indicates which strategy would win (i.e. be more numerous) at this time , thus indicating the timescales at which the strategy is adaptive in comparison to the others.(4)As qualitative results depend only upon the relative orders of magnitude of the parameters, results are illustrated with a single set of parameters Fig. . HoweverWe found that the relative timescale of adaptation depends strongly on the mechanistic links between genetic and epigenetic mechanisms Fig. . In all genes\u2010only strategy , but genes then take longer to find their peak. This is because the presence of fit epigenes slightly decreases the relative fitness of fit genes, increasing the probability that fit genes are lost by drift. Thus, having both genes and epigenes accelerates phenotypic adaptation  at which point epigenes drift, leading to a higher proportion being in the non\u2010mutagenic stage, thus removing the mutation load on genes. This strategy represents our primary model of mutational assimilation, and replicates that of Jablonka & Lamb i) environmental change induces epigenetic change that interacts with TEs to produce germline genetic variation in specific loci, (ii) germline altered epigenetic patterns can be transmitted for many generations, and (iii) epigenetic marks are mutagenic, imply that the localization of genetic change is partly environmentally driven et al., C. elegans where neuron\u2010produced double\u2010stranded RNAs generate both intragenerational epigenetic silencing in somatic cells, and intergenerational epigenetic silencing in germ cells . At the across\u2010generations timescale, they affect the mutability of the very same DNA sequences, hence affecting evolutionary changes in the relevant functional DNA sequence over generations (Rey (3)Weismann's view was that acquired characters cannot be inherited Fig. . After tet al., et al., 4 for methylcytosine Another interesting twist in this vision concerns the central dogma of molecular biology, which was formulated in terms of sequence (i.e. primary structure) of macromolecules  of Fig. (5)Our review also underlines the lack of data causally linking epigenetic marks to mutation rates. In particular, such links may vary according to mutation type. In both germline and somatic cells, regions of closed chromatin show higher levels of base substitutions  as in Kronholm et al.  represenet al. , its det(6)Our goal is to help to integrate scientific approaches at the infra\u2010 and supra\u2010individual levels into a unified view accounting for the fact that the various inheritance systems interact as runners in a relay race, handing over heritable information between stages, hence potentially matching the timescales of inheritance with those of environmental variation. What we need now are models of informational dynamics integrating such a relay at the ecological and evolutionary timescales. Comparing Figs et al., et al., Although several theoretical studies have tackled questions such as the interaction between epigenetic and genetic evolution et al., et al., et al., et al., et al., et al., Inclusive inheritance has paramount medical implications by allowing the study of the various components of the inheritance of so\u2010called \u2018genetic disorders\u2019, which in fact may be substantially inherited non\u2010genetically et al., et al., Although the discovery of genetics dramatically improved our understanding of inheritance and evolutionary biology, it had the downside of considerably narrowing our vision of inheritance and evolutionary biology, hence pushing the role of other inheritance mechanisms out of view. One consequence of this is that established textbook examples of genetic determinism have later been revealed to be caused by epigenetic variation (Cubas V.(1) We revisited the diverse mechanisms of inheritance according to relevant timescales. We suggest the existence of shifts between inheritance mechanisms that produce a relay in information encoding that enables a lineage to match the pace of environmental change.(2) We reviewed the evidence for such potential shifts of information. Epigenetics appears as a major hub in this relay towards genetics, linking non\u2010genetic germline inheritance with genetic inheritance in a form of epigenetically facilitated mutational assimilation.(3) A theoretical model suggests that such mutational assimilation may considerably accelerate (or slow down) the genetic encoding of initially non\u2010genetically inherited adaptations, by a factor commensurate with that of the mutagenicity of epigenetic marks.(4) This view of inheritance has major practical implications, and opens the way for new studies at scales ranging from the molecular to the population levels.VI.2 ANR project (ANR\u201013\u2010BSV7\u20100007\u201001) to E.D. B.P. was also supported by the CAPA ANR project (ANR\u201013\u2010JSV7\u20100002), and is part of a project that received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (ERC consolidator grant agreement No ERC\u2010CoG681484\u2010ANGI). A.P. was supported by the Templeton World Charity Foundation, Inc. (grant TWCF0242). The opinions in this publication are those of the authors and do not necessarily reflect the views of the Templeton World Charity Foundation, Inc.Aur\u00e9lien Pocheville greatly helped in programming the model. At the time of writing, A.P. had a postdoctoral fellowship at the Centre for Philosophy of Science, University of Pittsburgh. Philippe Huneman helped in discussing several points in this review. We are thankful to the CNRS InEE pluridisciplinary research network (RTP) in Epigenetics in Ecology and Evolution (3E) for insightful discussions. This work was supported by the \u2018Laboratoires d'Excellences (LABEX)' TULIP (ANR\u201010\u2010LABX\u201041), as well as ANR funded Toulouse Initiative of Excellence \u2018IDEX UNITI\u2019 (ANR11\u2010IDEX\u20100002\u201002). E.D., S.B. and B.P. were supported by the Soc\u2010HTable S1. A description of published models of non\u2010genetic inheritance and genetic assimilation.Table S2. Description of the model parameters.Click here for additional data file."}
{"text": "IUCrJ features a significant step forward in X-ray PDF methodology for thin films, with substantial improvements in both sensitivity and time resolution.Atomic pair distribution (PDF) analysis has proven to be an exceptionally robust tool for probing the structure of amorphous, crystalline and crystallographically challenged materials. This issue of  While G(r) and I(Q) contain identical information, the PDF provides a unique \u2018real-space\u2019 view, giving the likelihood of finding pairs of atoms at a certain distance r. As assumptions regarding periodicity are not necessary, PDF analysis has proven particularly useful for nanomaterials  materials in the beam path. For bulk powders measured in the standard transmission geometry at modern synchrotrons, this is usually straightforward, as the signal-to-background ratio is large.In the case of thin films on thick substrates, background subtraction in a transmission geometry is critically important and at times a limitation. As film thicknesses decreases relative to the substrate, the contribution of the film to the scattered signal similarly decreases. The result is often that the measured signal is dominated by the substrate, while the signal from the film of interest is buried in noise. While this issue can be remedied by increasing measurement times compared with those for standard bulk powders, the necessary times are often unfeasible. This has limited the applicability of PDF analysis to thin films, imposing hard restrictions on both film thickness and temporal resolution.et al. (2019The recent work of Dippel  al. 2019 represenet al. successfully measured PDFs from crystalline and amorphous thin films down to 3\u2005nm, with count times on the order of one second. This represents a factor of ten decrease in the minimum detectable film thickness, and a decrease of several orders of magnitude in the measurement time. Beyond this, their subsequent analysis results agree with previous studies on the same materials, demonstrating robustness and reproducibility.Their work makes several key improvements on past GIPDF geometries. By using hard X-rays combined with a fast two-dimensional detector they achieve PDF resolutions and count times comparable with what is seen in more standard transmission geometries for bulk powders. Additionally, careful control over the beam footprint yields manageable instrumental resolution broadening. Using beamline P07 at PETRA III, Dippel et al., 2017et al., 2017et al., 2017et al., 2016et al., 2016et al., 2016et al., 2017et al., 2017et al. have successfully demonstrated the feasibility of the GIPDF technique, bringing within reach a whole new class of in situ and operando structure studies on thin film devices and functional materials.Thin films are particularly relevant in technological applications including energy storage and conversion (Gao"}
{"text": "In an interesting paper by Zhang et al. , flavor Zhang et al.  reportedIn rats, duodenal and jejunal glucose infusions conditioned similar flavor preference whereas ileal infusions were ineffective; yet infusions at all three sites increased blood glucose levels (Ackroff et al., Zhang et al.  assumed How reinforcing signals, generated by peripheral glucose and MDG, reach the brain is uncertain. Zhang et al.  dismisseIn summary, the Zhang et al.  study prAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Parental depression is a risk factor for the development of child internalizing  and externalizing problems  \u20134. EckshEckshtain et al.  found thOther factors that may have influenced the relationship observed between parental depression and child internalizing and externalizing problems are discussed below. We comment on a few factors that, if taken into consideration by Eckshtain et al. , may havSibling relationships have been implicated as potential influencing factors in children\u2019s internalizing and externalizing problems. Buist and Vermande  found thParental psychopathology has also been found to influence child behavior problems. Eckshtain et al.  measuredEckshtain et al.  did not All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.The authors declare that this manuscript was written in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Journal of Clinical Medicine was specifically dedicated to research evaluating the effects of exercise on cognitive function. This Special Issue published 23 articles dedicated to this topic (Cognitive function is associated with longevity and is of critical importance for optimal daily functioning . As suchis topic . These sSeveral interesting findings were observed from this collective body of work. As an example, Chen et al.  evaluate"}
{"text": "An important element of the initiation of meiotic recombination is histone H3 lysine 4 trimethylation (H3K4me3) that marks meiotic DSB sites (Borde et al., A paper recently published by Karanyi et al (Karanyi et al., Saccharomyces cerevisiae with an increased resolution for Hi-C experiments and tracked the behavior of this re-designed region during the first stages of meiotic prophase (Muller et al., in situ Hi-C (Rao et al., Ample cytological evidence supports the dynamic reorganization of meiotic chromosomes during the prophase of meiosis (Zickler and Kleckner, All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Hidradenitis Suppurativa: A Systematic Review Integrating Inflammatory Pathways Into a Cohesive Pathogenic Model\u201d by Vossen et al.  as defined by American College of Genetic Medicine (ACGM) criteria (uncertain significance.\u201d Genome Wide Association Studies (GWAS) as well as functional and proteomic data linking identified sequence variants to the inflammatory mechanisms driving HS are currently not available. Both areas of research are vital in further evaluating the role of genetic variants in HS pathogenesis. It remains plausible that a complex polygenic model better describes observations in some cases of familial HS  underlying the development of sinus tracts. Vossen et al.  discuss known unknowns\u201d in our understanding of this disease and the impact that bias in existing data may have in our current understanding of HS pathogenesis.Vossen et al.  are to bJF is responsible for the conception, design, writing, and review of this manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Dear editor Ferula and its bioactive constituents\u201d published by Avicenna Journal of Phytomedicine Umbelliprenin has different pharmacological effects such as cytotoxic and apoptosis inducing activities  mechanism (Iranshahi et al., 2018As it is mentioned in the article, we showed that umbelliprenin induced apoptosis in leukemic cell lines. dose- and time- dependently (Ziai et al., 2012The hormetic dose-response relationship becomes the object of considerable investigations on a broad range of chemicals over the past 2 decades (Calabrese, 2013Ferula and its bioactive constituents in future.In the end, we congratulate Iranshahi et al. for their article and we appreciate Avicenna Journal of Phytomedicine editorial board for their judicious concern on this topic. We are looking to read well-original and review articles regarding the beneficiary effects of the genus The authors declare no conflicts of interest."}
{"text": "Malignant diseases, as all chronic diseases, follow a distinct and specific trajectory that can lead to development of cachexia. When cachexia develops, patients will often have a stage of the disease with limited life expectancy. There are no proven and clinically effective interventions to improve quality of life and/or life expectancy in patients with cachexia.et al. in this issue of the journalIn this context, contribution by Anker et al.FigureOne of key messages from the paper by Anker et al.Although the work by Anker FigureIn line with cancer but also other disease awareness campaigns,The authors acknowledge the project  was financially supported by the Slovenian Research Agency.ML reports owning shares of Actimed Therapeutics."}
{"text": "Speech communication under adverse conditions (Mattys et al., Hardy et al.'s recent approach to degrading such information is to use sinewave speech: Sinusoids, which follow the center frequencies of the original utterance's formants, trace only modes of the supralaryngeal vocal tract resonant frequency (Remez et al., Vesicles of the neurotransmitter acetylcholine convey information from neuron-to-neuron Figure . ReductiHardy et al. presented persons with Alzheimer's disease and healthy elderly control adults with either clear speech or sinewave replicas. These stimuli were 3-digit lists such as \u201ceight hundred and eighty-seven\u201d Figure . To-be-aHaving Alzheimer's disease hampers perception of the degraded sinewave speech Figure  yet not An extant cognitive hearing science account of the influence of selective auditory attention on speech perception under adverse conditions adopts a cholinergic top-down control assumption (Marsh and Campbell, An unexplored corollary of this cholinergic top-down control assumption is that the cholinergic cortical attentional system, including the prefrontal cortices, controls an early filter (Sarter et al., Hardy et al.'s findings thus unleash the potential of a new cognitive hearing science. This science could establish how acetylcholine affects speech-in-noise performance in persons with hearing or cognitive impairments: Empirically undetermined is whether Hardy et al.'s cholinergic influence confines to a top-down focusing of the listening to attended speech information; be that signal degraded or obscured. During speech-in-noise perception and understanding, another cholinergic influence may also be upon the top-down selective inhibition of ascending to-be-ignored noise (Petersen et al., Some sobering words of caution are necessary: Without the design administering Donepezil to healthy controls, a question germane to the cholinergic top-down control assumption goes unaddressed. Could there be a cholinergic influence on speech perception in persons without Alzheimer's Disease? Hardy et al. do provide normative data that tend toward ceiling Figure , in whicTurning from theoretical caution to conservative assays of clinical potential, a subtle breakdown of the brain's network for language comprehension predicts the conversion of individuals with mild cognitive impairment into persons with Alzheimer's disease (Mazaheri et al., Both JM and TC made substantial contributions to the concept and interpretation in drafting the manuscript, approved the submitted materials, and have agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Brain states like sleep and vigilance, as well as fluctuating levels of arousal and attention, are characterized by diverse patterns of brain activity. These global dynamics are strongly driven by the activity of catecholaminergic neuromodulatory systems (Sara and Bouret, Using fMRI and pharmacological intervention, van den Brink et al.  sought tTo compare the spatial modes with well-known brain characteristics, the authors correlate these spatial modes with canonical resting-state FC networks (Smith et al., If the above were true, a strong coupling between the spatial modes and the localization of NE receptors would be expected. Indeed, using the receptor's transcriptional maps from the Allen Brain Institute (Hawrylycz et al., Humans interact with the dynamic nature of the world with a high temporal resolution. Placing van den Brink et al.  findingsThe results presented by van den Brink et al.  extend ovan den Brink et al.  contribuAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Late Jurassic to Early Cretaceous interval represents a time of environmental upheaval and cataclysmic events, combined with disruptions to terrestrial and marine ecosystems. Historically, the Jurassic/Cretaceous (J/K) boundary was classified as one of eight mass extinctions. However, more recent research has largely overturned this view, revealing a much more complex pattern of biotic and abiotic dynamics than has previously been appreciated. Here, we present a synthesis of our current knowledge of Late Jurassic\u2013Early Cretaceous events, focusing particularly on events closest to the J/K boundary. We find evidence for a combination of short\u2010term catastrophic events, large\u2010scale tectonic processes and environmental perturbations, and major clade interactions that led to a seemingly dramatic faunal and ecological turnover in both the marine and terrestrial realms. This is coupled with a great reduction in global biodiversity which might in part be explained by poor sampling. Very few groups appear to have been entirely resilient to this J/K boundary \u2018event\u2019, which hints at a \u2018cascade model\u2019 of ecosystem changes driving faunal dynamics. Within terrestrial ecosystems, larger, more\u2010specialised organisms, such as saurischian dinosaurs, appear to have suffered the most. Medium\u2010sized tetanuran theropods declined, and were replaced by larger\u2010bodied groups, and basal eusauropods were replaced by neosauropod faunas. The ascent of paravian theropods is emphasised by escalated competition with contemporary pterosaur groups, culminating in the explosive radiation of birds, although the timing of this is obfuscated by biases in sampling. Smaller, more ecologically diverse terrestrial non\u2010archosaurs, such as lissamphibians and mammaliaforms, were comparatively resilient to extinctions, instead documenting the origination of many extant groups around the J/K boundary. In the marine realm, extinctions were focused on low\u2010latitude, shallow marine shelf\u2010dwelling faunas, corresponding to a significant eustatic sea\u2010level fall in the latest Jurassic. More mobile and ecologically plastic marine groups, such as ichthyosaurs, survived the boundary relatively unscathed. High rates of extinction and turnover in other macropredaceous marine groups, including plesiosaurs, are accompanied by the origin of most major lineages of extant sharks. Groups which occupied both marine and terrestrial ecosystems, including crocodylomorphs, document a selective extinction in shallow marine forms, whereas turtles appear to have diversified. These patterns suggest that different extinction selectivity and ecological processes were operating between marine and terrestrial ecosystems, which were ultimately important in determining the fates of many key groups, as well as the origins of many major extant lineages. We identify a series of potential abiotic candidates for driving these patterns, including multiple bolide impacts, several episodes of flood basalt eruptions, dramatic climate change, and major disruptions to oceanic systems. The J/K transition therefore, although not a mass extinction, represents an important transitional period in the co\u2010evolutionary history of life on Earth.The  I.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., The Late Jurassic\u2013Early Cretaceous interval (164\u2013100\u2009Ma) represents a transitional period in the history of life on Earth, coeval with significant environmental fluctuations and changes in Earth systems processes et al., et al.  the base of the Calpionella Zone and the sudden decline in species of Crassicollaria; (ii) the explosive radiation of small, globular forms of Calpionella alpine  the first appearances of two subspecies of Nannoconus (a)et al., Early research into Phanerozoic macroevolutionary patterns led to the inclusion of the end\u2010Jurassic as one of eight mass extinction events based upon a 20% level of extinction et al., et al., et al., et al., et al., et al.  have noted a sharp decline in diversity around the J/K boundary et al., et al., et al., et al., i) the Indian Ocean  the Pacific Ocean, which is thought to have had a stable circulatory regime  the Atlantic Ocean with a distinct North\u2013South salinity gradient  carbonate platforms experienced severe growth crises et al., et al., et al., et al., et al., et al.  sea\u2010level curves show a peak in the Kimmeridgian\u2013early Tithonian, prior to a double\u2010dip decline and lowstand through the J/K boundary. This was followed by a slight rise to levels seen at the end of the Jurassic, before plummeting again in the Valanginian\u2013Hauterivian  is an indicator of the rate of erosion of continental crust relative to enrichment from hydrothermal sources, and therefore acts as a proxy for marine sedimentation rate: peaks in the strontium curve correspond to minimum levels of associated sedimentation, and vice versa , which might have created toxic oceanic conditions et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., During the Late Jurassic, periods of enhanced continental erosion and oceanic productivity, combined with increased sedimentation rates, were driven by a dominantly tropical or arid climate with frequent monsoons at low latitudes i) lowering air temperatures through direct insolation from ash and sulphate aerosols; (ii) increasing atmospheric toxicity and poisoning; (iii) acid rain and biocalcification crises; (iv) increasing atmospheric temperatures through release of greenhouse gases; and (v) ocean anoxia  10\u201320\u2009km thick sequences in the Jurassic to Early Cretaceous of Chile  evidence for a plume event  plume\u2010associated activity from the J/K boundary of the Liberian margin  Berriasian\u2013Hauterivian mantle plume activity in northern Israel  a 1500\u2009km wide magmatic province initiated in the Hauterivian\u2013Barremian of Australia (5)et al., et al., i) the 70\u201380\u2009km diameter Morokweng impact crater in the Kalahari Desert, South Africa, dated at 145\u2009\u00b1\u20092\u2009Ma  the 40\u2009km wide Mj\u00f8lnir crater in Norway, dated as 142\u2009Ma  the 22\u2009km wide crater at Gosses Bluff, Northern Territory in Australia, dated at 142.5\u2009Ma , in South America, Europe, Africa, Australia, and Asia. Presently, geochemical data are limited in extent, but there are multiple regional anomalies whereby trace metals  are enriched around the J/K boundary, suggesting extra\u2010terrestrial input on a global scale et al., Early investigations into the trajectory of diversity on a geological time scale typically used raw counts of fossil taxa, i.e. numbers of species, genera, and/or families through time  sampling bias; (ii) an external \u2018common cause\u2019, such as sea level; and/or (iii) redundancy, resulting from the non\u2010independence of sampling metrics and diversity . These methods seek to explain whether diversity is driven by:  and Fossilworks (http://www.fossilworks.org), synchronous with the progress in analytical techniques outlined above. Macroevolutionary studies that include the J/K interval have explored the effects of uneven sampling on vertebrate diversity at regional and global levels et al., et al., et al., et al., et al., Numerous studies have documented changes in sampling quality over the J/K boundary. Notable examples include the sharp decline in fossiliferous marine\u2010 , the total numbers of taxonomic occurrences, fossil\u2010bearing collections, and raw species diversity all show substantial declines over the J/K boundary (a)et al., et al., et al., et al., et al., et al., et al., et al., et al., Of all Mesozoic vertebrate groups, dinosaurs have the best\u2010sampled and most\u2010studied fossil record. Non\u2010avian dinosaur diversity halved from the Tithonian to Berriasian  of China , followed by an apparent dramatic decline over the J/K boundary, based on both raw et al., et al., et al., et al., Most Laurasian pterosaur taxa are known from Konservat\u2010Lagerst\u00e4tten, including the Late Jurassic Solnhofen Limestones of southeastern Germany  becoming extinct Unwin, , a patte(c)et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Thalattosuchian crocodylomorphs, comprising two major pelagic groups, Teleosauridae and Metriorhynchoidea, achieved the height of their diversity during the Late Jurassic . During this period, thalattosuchians achieved a broad ecological range, with a variety of feeding modes, craniofacial forms, dental morphologies, functional biomechanical behaviours, and a wide spectrum of body sizes et al., et al., et al., et al., Malawania, from the Early Cretaceous of Iraq, demonstrates that at least one basal non\u2010ophthalmosaurid lineage passed through the J/K boundary et al., Taxonomic diversity of Plesiosauria declined greatly across the J/K boundary, with the extinction of microcleidid and rhomaleosaurid taxa, known almost exclusively from Euamerica Bakker, . Recover(f)et al., et al. et al., et al., et al., et al., et al., Choristoderes were small\u2010 to medium\u2010sized semi\u2010aquatic middle\u2010tier predators of Laurasian ecosystems, whose placement within Diapsida remains enigmatic et al., Lepidosauria comprises the diverse and extant groups Rhynchocephalia and Squamata , Scincoidea (skinks), and the clade comprising Acrodonta and Pleurodonta (iguanians), are either close to the J/K boundary et al., et al., et al., Lissamphibia comprises anurans (frogs), caudatans , albanerpetontids  and gymnophionans (caecilians). Within Lissamphibia, there was a small increase in total diversity over the J/K boundary Fara, . Moleculet al., et al., et al., et al., In the Late Jurassic of North America, the lissamphibian fossil record documents a mixture of stem caudates and anurans, as well as the first North American crown caudate et al., et al., et al., et al., The Late Jurassic was an important time in the rise of modern\u2010day mammal clades, with the diversification of Theria (comprising Eutheria and Metatheria) occurring around 160\u2009Ma, during the Oxfordian Early studies found either a small increase Benton,  or smallet al., Neoselachia, the clade including all modern forms of shark, and Batoidea (skates and rays) both underwent a phase of high diversification rates during the latest Jurassic Kriwet, . This wa(4)et al., et al.  taxic invertebrate diversity have been superseded by global data sets and advanced analytical subsampling approaches et al., et al., et al., et al., Both raw and subsampled bivalve generic diversity declined at the J/K boundary Early studies found little evidence for a significant drop in brachiopod diversity at the J/K boundary Ager, . However(c)et al., et al., Coral diversity appears to have increased linearly through the J/K boundary based on subsampled estimates Alroy, ; however(d)et al., et al., The impact of sampling on global patterns of pre\u2010Cretaceous echinoderm diversity has yet to be explored in a manner similar to that of other marine invertebrate groups Alroy, , hinderi(e)All major hexapod groups passed through the J/K boundary  appear to have increased dramatically in diversity in the Late Jurassic (Kimmeridgian), followed by a burst of intra\u2010family diversification during the Early Cretaceous Late Jurassic and Early Cretaceous bryozoan faunas were almost entirely comprised of cyclostome stenolaemates et al., et al., et al., et al., In the Early Cretaceous, microfossil groups became the most volumetrically significant biogenic constituent of deep\u2010sea sediments for the first time et al., et al., Global studies indicate that foraminiferan standing diversity was not affected at the J/K boundary, but that extinction rates in the Middle\u2013Late Jurassic were of equal magnitude to the \u2018Big Five\u2019 mass extinctions, and accompanied by high origination rates et al., et al., Radiolarians experienced declining diversification rates throughout most of the Late Jurassic, in concert with a dramatic fall in their diversity et al., et al., et al., et al., et al., 13C values decreased through the J/K boundary; rather than being indicative of increased oceanic productivity, such isotopic trends are typically associated with decelerating hydrological cycling and increasingly oligotrophic conditions et al., et al., et al., et al., Cascales\u2010Mi\u00f1ana & Cleal  recentlyet al., et al., ,et al., During the Jurassic, floral diversity and productivity were highest at mid\u2010latitudes, due to the migration of productivity concentrations during greenhouse episodes et al., Whether or not there was a mass extinction at the J/K boundary is a multi\u2010faceted issue, and occluded by the relatively poor sampling and dating of earliest Cretaceous fossil\u2010bearing deposits Fig. , as wellVertebrate groups such as theropod and sauropod dinosaurs, rhamphorhynchid pterosaurs, marine crocodylomorphs and testudines, sauropterygians, and groups of fishes, all show evidence of a decline in diversity across the J/K boundary. However, in almost all of these cases, total net diversity of their more inclusive higher clade remained high, with heightened rates of speciation accompanying elevated rates of extinction. Within invertebrates, reef\u2010dwelling taxa, including corals and some arthropod groups, were the primary victims across the J/K boundary. Furthermore, ammonites, gastropods, brachiopods, foraminiferans, and calcareous phytoplankton all have documented drops in diversity or increased extinction rates at the J/K boundary. Currently, however, the evidence from the fossil record indicates that the J/K boundary cannot be regarded as a mass extinction of the same magnitude as the \u2018Big Five\u2019.(2)(a)et al., et al., et al., et al., There is some evidence for geographic selectivity of extinction in theropods through the J/K boundary, with the differentiation between coelurosaurian and non\u2010coelurosaurian\u2010dominated theropod faunas within Gondwana and Laurasia, respectively et al., et al., et al., et al., et al., et al., A faunal turnover is documented in sauropterygian taxa, along with the extinction of shallow marine and semi\u2010aquatic crocodylomorphs and testudines at the J/K boundary et al., et al., i) enhanced extinction through contraction of shallow marine ecosystems and increasingly anoxic bottom waters; and (ii) decreased preservation of sedimentary rocks, impacting upon on our ability to sample marine assemblages. This regression, combined with increased continental input, and a possible minor ocean anoxic event (a)et al., et al., et al., et al., et al., et al., et al., Recent developments in assessing the macroevolutionary and macroecological history of dinosaurs have provided insight into potential selectivity patterns in different subgroups. For example, there is a seemingly selective extinction of larger\u2010sized dinosaurs (sauropods and theropods) across the J/K boundary et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., The low ecological diversity of plesiosaurians and testudines might have been a distinct contributing factor to their decline and turnover at the J/K boundary There is strong evidence for a coupled ecological\u2013taxonomic mode of extinction and faunal turnover across the J/K boundary for both small\u2010 and large\u2010bodied terrestrial tetrapods. In a range of groups spanning the marine and terrestrial realms, including mammaliaforms, lissamphibians, and ichthyosaurs, ecological specialisation and plasticity plays a clear role, with surviving groups possessing broader morphologies, or key morphological adaptations that appear to be associated with higher survivability rates. For marine tetrapod groups in particular, it appears that the J/K interval represents a staggered cascade model of extinction, with different groups responding in a variety of ways to a range of ecological perturbations, and with fluctuations in sea level possibly acting as the principal driver of change .There is widespread evidence for a major faunal turnover in both the marine and terrestrial realms during the J/K interval. Whereas the effect of this is clearer in larger\u2010bodied organisms such as dinosaurs, we also see evidence for either competitive displacement or opportunistic replacement in smaller\u2010bodied groups such as lepidosaurs, lissamphibians and mammaliaforms. There is some evidence that pterosaurs and paravian theropods rapidly diversified and adopted new ecomorphotypes in the Early Cretaceous, including the explosive radiation of the most successful extant tetrapod group, birds, although the precise timing of these events is obscured by varying spatiotemporal sampling of these clades. Low\u2010latitude and shallow marine to semi\u2010aquatic faunas, including testudines, crocodylomorphs, and reef\u2010dwelling and sessile invertebrates, suffered the greatest diversity loss in the marine realm, whereas more mobile taxa with greater dispersal ability, such as ichthyosaurs, appear to have been relatively unaffected.i) at least three large bolide impacts in the latest Jurassic, one of which might have been bigger than the end\u2010Cretaceous Chicxulub impact  a Late Jurassic\u2013Cretaceous \u2018greenhouse\u2019 world, interrupted by a latest Jurassic \u2018cold snap\u2019 and corresponding aridity episode; (iii) a global drop in sea level to a eustatic lowstand through the J/K boundary  potentially heightened levels of anoxia, oceanic stagnation, and sulphur toxicity over the J/K boundary; (v) a series of repeated \u2018biocalcification crises\u2019 in the Early Cretaceous, along with two purported oceanic anoxic events in the Valanginian and Hauterivian; (vi) the emplacement of the Paran\u00e1 and Etendeka  and Ontong Java Plateau (Barremian\u2013early Aptian) flood basalts, the latter of which might have been three times as voluminous as the end\u2010Cretaceous Deccan volcanism; and (vii) some of the largest volcanic episodes in the history of the Earth, following the emplacement of the Shatsky Rise supervolcano at the J/K boundary. This series of environmental perturbations warrants further investigation in the context of potential biotic effects throughout this time.The Late Jurassic\u2013Early Cretaceous was a period of major environmental perturbations that have largely been ignored or overlooked in historical analyses of Mesozoic diversity dynamics, in favour of more \u2018exotic\u2019 extinction intervals. A range of evidence indicates the following major changes:  a ary Fig. ; (iv) poet al., The J/K boundary represents an opportunity to investigate the environmental and ecological factors governing recovery , and the biotic and abiotic drivers of these patterns. Substantial progress has recently been made in modelling the possible drivers of diversification and extinction, especially in terrestrial tetrapods , 2014b aAppendix S1. List of studies that analyse the magnitude of the J/K boundary extinction for different taxonomic groups. For further details on analytical statistics, see references cited within.Click here for additional data file."}
{"text": "Global inequity in access to and availability of essential mental health services is well recognized. The mental health treatment gap is approximately 50% in all countries, with up to 90% of people in the lowest-income countries lacking access to required mental health services. Increased investment in global mental health (GMH) has increased innovation in mental health service delivery in LMICs. Situational analyses in areas where mental health services and systems are poorly developed and resourced are essential when planning for research and implementation, however, little guidance is available to inform methodological approaches to conducting these types of studies. This scoping review provides an analysis of methodological approaches to situational analysis in GMH, including an assessment of the extent to which situational analyses include equity in study designs. It is intended as a resource that identifies current gaps and areas for future development in GMH. Formative research, including situational analysis, is an essential first step in conducting robust implementation research, an essential area of study in GMH that will help to promote improved availability of, access to and reach of mental health services for people living with mental illness in low- and middle-income countries (LMICs). While strong leadership in this field exists, there remain significant opportunities for enhanced research representing different LMICs and regions. We also complemented our database search with a review of the reference lists of included articles to ensure we did not overlook relevant studies  took place in an LMIC context as defined by World Bank criteria , purpose, country of origin, objectives, methods, situational analysis tool characteristics and use, inclusion of equity in study design, and limitations as described by the study authors. The inclusion and exclusion criteria and the data extraction categories were decided through discussion amongst authors JM, EEM and RWL, with further consultation with the full study team. We analysed the results using a combination of numerical descriptive summary and qualitative thematic analysis  of the 24 studies took place in Sub-Saharan Africa, 37.5% (n\u00a0\u00a0=\u00a0\u00a09) took place is South Asia and 8.3% (n\u00a0\u00a0=\u00a0\u00a02) two took place in East Asia. None were performed in Latin America, the Caribbean or Middle East and North Africa regions.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., For this analysis, studies are counted as \u2018single country\u2019 if they reported results from only one country in a paper, regardless of their broader affiliation with multi-country research programs. Of the studies, 14 (58.3%) took place in multiple countries, with high representation in this review of papers published by consortia such as the Programme to Improve Mental Health Care (PRIME)  conducted situational analyses and formative research to inform the development or design of mental health programmes or services. Objectives included the development of a package of community-based mental health and mobile health services  papers used situational analyses and formative research before developing specific clinical mental health interventions. These sought to: inform the design of acceptable and feasible interventions for the study context  of studies included qualitative research, using key informant and in-depth interviews and/or focus group discussions  of the studies reviewed secondary data; 14 used a specifically designed situational analysis tool and two studies did not use a tool. Tools used for situational analysis varied, with the majority (7) using the PRIME situational analysis tool, which was specifically designed for the PRIME study  of the studies used priority setting exercises as part of their situational analyses and formative research. Three of these studies (Jordans , et al.  also useet al., et al., et al., et al., The priority-setting workshops were used to inform the development of an intervention (Asher et al., et al., et al., et al. (et al., Three studies explicitly included equity considerations in their study designs (Abdulmalik , et al.  used a f et al.,  to guideet al.,'s (The overall goal of Hailemariam t al.,'s  study waet al.,'s (Mugisha t al.,'s  situatioet al., et al., et al., et al., et al., Five other studies implicitly addressed issues related to equity but did not incorporate it in their study design; that was addressed by discussing the impact of poverty on help-seeking (Angdembe et al., et al., et al., et al., et al., et al., Seven studies did not describe limitations related to situational analysis methodology (Ofori-Atta et al., et al., et al., et al., et al., et al., The most common limitation identified by those that did describe limitations of situational analyses related to use of secondary data (Hanlon et al., et al., et al., et al., Several studies without a qualitative component identified an inability to include findings on knowledge, attitudes and beliefs of stakeholders as a study limitation. Some authors indicated that complementary qualitative studies were being or would be untaken to capture this information (Hanlon et al., et al., et al., et al., et al., The most commonly cited limitation of qualitative studies was the limited scope of the study area and of study participants, which could limit generalizability of findings (Jordans et al., et al. (et al. (For studies using priority-setting exercises, limitations included the risk of social desirability bias due to the study's affiliation with the national government (Asher , et al.  describe (et al.  cite theThis review identified a number of themes that are important to implementation research in GMH, pointing both to gaps and strengths in the field. Improving GMH depends not only on implementing evidence-based interventions, but also on modifying and implementing interventions that anticipate local implementation barriers across behavioural, managerial, economic, and social domains. Understanding these complex barriers, and ensuring that equity in health can be championed, requires sophistication in the situational analysis. Our review explored various methodological approaches to situational analysis as a guide to enhancing implementation strategies. We discovered that relatively few studies address situational analyses in GMH, with additional key findings noting the paucity of local mental health system data and an absence of consideration of equity. Fortunately, our review also identified the development of several situational analysis tools that can serve as key resources, and a methodological strategy\u2014mixed methods\u2014that can address challenges.et al., et al., et al., et al., We found that the scope of published situational analyses and formative research in GMH is limited. Twelve of the studies included in the review were representative of the PRIME or EMERALD studies, which both include sites in Ethiopia, India, Nepal, South Africa and Uganda, while EMERALD also includes Nigeria (Lund Though outside the scope of this review, an informal search of situational analysis literature and tools from HICs also revealed a gap. There appears to be limited peer-reviewed literature detailing situational analysis tools and methods in mental health or the broader health sector in HICs, though some examples are found in the grey literature. For example, Alberta Health Services in the Canadian province of Alberta conducted a situational analysis of the use of impact assessments in the health sector (Alberta Health Services, et al., et al. (et al., Many of the studies included in this review used or developed situational analysis tools that provide a comprehensive and systematic template for the analysis of complex factors at multiple levels of a mental health system. The PRIME investigators developed their own tool, adapted from WHO-AIMS, to assess district-level mental health needs (Hanlon , et al.  develope et al., .et al., et al., et al., While the tools represent a considerable asset to GMH researchers, their potential to contribute to robust situational analysis research relies on the quality of their implementation and on the availability of secondary data. A major limitation identified by study authors was the often limited availability of mental health system data. Mental health information systems in LMICs are at varying stages of development and may be disjointed and under-resourced. Their strengthening has been identified as a priority in GMH (Ryan et al., et al., et al., Using mixed methods to conduct situational analyses could help to mitigate some of these challenges, along with the limitations of both qualitative research and priority setting exercises described above. Mixed methods approaches combine both quantitative and qualitative data collection, analysis and interpretation in order to provide a deeper understanding of phenomena (Johnson et al., Finally, only three of the 24 studies explicitly considered equity in their study design. While the PRIME situational analysis tool does include indicators related to equity, these were not explicitly discussed in the papers included in this review. Equity on a global scale is a fundamental concern of GMH, which aims to close the gap in treatment within and between countries, improving access to and availability of treatment and improving the lives of people suffering from mental disorders (Patel We only included English language studies in this review which may have led to the omission of relevant research in this area published in other languages. It is also likely that situational analyses and formative studies have been conducted in GMH using different terminology and were thus not identified with the search terms used in this scoping review. The use of MeSH terms in the search may also have yielded additional results. We are confident, however, that the review has captured a representative sample of the GMH literature on situational analysis methodology in GMH, and that it offers a useful overview of current practice and guidance on next steps in this important field of research.Implementation research is an essential area of study in GMH and will help to promote improved availability of, access to and reach of mental health services for people living with mental illness in LMICs. Formative research, including situational analysis, is an essential first step in conducting robust implementation research. While strong leadership in this field exists, there remain significant opportunities for enhanced research representing different LMICs and regions.This review of existing methodological approaches in situational analysis for GMH reveals limitations and opportunities that can inform the design of future studies. The field will benefit from prioritizing mixed methods approaches to implementation research and including equity considerations in the study design of formative research, including situational analyses."}
{"text": "In the final publication of \u201ciMicrobe: Tools and data-driven discovery platform for the microbiome sciences\u201d by Ken Youens-Clark et al., there was an erroneous typo in the title of the article. The typo has been corrected and the title appears correctly online.The Publisher regrets this error."}
{"text": "Drozdowska et al.; Etherton et al.; Fabian et al.; Fandler et al.; McKinley et al.; Taylor-Rowanet al.; van de Graaf et al.; Wouters et al.; Zhou et al.) to evaluate the current state of knowledge about reperfusion therapy with the goal of educating our readership about the patient selection paradigms, challenges in clinical trial design, and identifying future directions.Endovascular thrombectomy to recanalize large vessel occlusions in ischemic stroke patients is now proven to improve clinical outcomes in randomized trials \u20136. This Wouters et al.; . McKinley et al. also acknowledge that deconvolution techniques are highly susceptible to noise and artifacts; they list measures to overcome these issues e.g., by adoption of a smoother residue function; and they report machine learning methodologies to identify the tissue-at-risk. The authors suggest that the best algorithms are those which are based on neural networks and random forests . Finally, Etherton et al. summarize the neuroimaging paradigms and the clinical trials that tested reperfusion therapy in stroke patients with unknown time of symptom onset. Perfusion mismatch, DWI-FLAIR mismatch, and other mismatch paradigms are discussed, and prognostic value of some of these measures discussed . The authors propose that more patients can be offered reperfusion therapy by refining the approach to identify additional populations of stroke patients with unknown onset who may benefit . The target of therapy\u2014the tissue-at-risk (penumbra)\u2014is better defined now and therefore there is greater opportunity to test preclinical research findings in the contemporary standard of care. To this end, we include Fabian et al. and Zhou et al. in this collection who report their data about methods to enhance ischemic preconditioning and to reduce oxidative stress respectively in acute stroke. Also, recanalization is not equivalent to reperfusion, and the goal should be to succeed with both .We now know that the benefit of endovascular recanalization in ischemic stroke patients with a target perfusion mismatch profile is independent of the time since symptom onset \u201316. Howe et al.; ]. Wouterith both . A largeFandler et al. present one example as a case report highlighting excellent outcomes from endovascular therapy in a patient with ischemic stroke who had a stroke recurrence within 9 days of the first thrombectomy. The subsequent stroke occurred in exactly the same vascular territory, was associated with significant mismatch, and continued to show irregular shaped ulcerated plaque. Fandler et al. offered endovascular treatment with TICI 3 recanalization with excellent outcomes on follow up. She also received carotid thrombo-endarterectomy for the ulcerated plaque Fandler et al.. Patients treated off label are a highly heterogeneous group and therefore difficult to assess in randomized clinical trials. There is a need to collate these data in a registry setting.Endovascular stroke trials showed benefit in patients with proven large vessel occlusion and/or presence of mismatch. The investigators selected a population of patients with homogeneous clinical profile because the goal was to have a trial success , 5. In tDrozdowska et al. and Taylor-Rowan et al. touch upon some of the relevant issues. Drozdowska et al. reviewed prognostic scales used in acute stroke and inform the readers about the validity of commonly used prognostic scores. Outcome prediction tools guide a stroke physician's discussion with patient's family in regard to possible outcomes. It also offers a clinical trialist a tool to stratify the patient population enrolled in studies to investigate a differential response to the treatment. Drozdowska et al., in their review, recommend the need for studies to investigate clinical usefulness in existing scales. Outcome measures used in complex trials like stroke trials should be valid, reliable, and responsive endpoint; and their analyses should be robust and acceptable to the regulatory bodies. In their review article, Taylor-Rowan et al. inform issues relevant to the selection of outcome measures and suggest robust analytics.Suboptimal trial design may well have been responsible for some of the neutral stroke trials reported in the last two decades. This Research Topic thus informs the current state of knowledge with respect to recanalization strategies and also stimulates readers to identify important research questions and tackle them through a robust research methodology.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. Opinions are personal and do not reflect that of the regulatory bodies or the authors' employers.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Smoking is a well-established risk factor for dementia, but the effects of passive smoking are unclear. We aimed to examine links between passive smoking and dementia or cognitive impairment.We searched seven medical research databases: MEDLINE, Web of Science (Core Collection), Cochrane, EMBASE, PsycINFO, Scopus, and CINAHL Plus. Studies were included if they examined measures of passive smoking and either cognitive impairment or dementia.Of 1,425 records found, nine papers of varying methodologies were included after screening against inclusion criteria. Eight papers reported weak associations between passive smoking and either cognitive impairment or dementia. One paper only found this association alongside carotid artery stenosis. The papers\u2019 quality was variable, with only two deemed high quality.There is limited weak observational evidence linking passive smoking with an increased risk of cognitive impairment or dementia. However, the studies were methodologically diverse and of inconsistent quality, preventing firm conclusions. ConsequSome of the existing literature refers to \u201ccognitive impairment,\u201d a term which can encompass a variety of clinical syndromes including Mild Cognitive Impairment and static deficits.There have been no literature reviews to date on the links between passive smoking and dementia in adults. We, therefore, present the first systematic review on the association between passive smoking and both dementia and cognitive impairment.Two reviewers conducted a search of seven online databases: MEDLINE, Web of Science (Core Collection), Cochrane, EMBASE, PsycINFO, Scopus, and CINAHL Plus on 10th December 2014.et al., http:/journals.cambridge.org/ipg. Anticipating the field of research to be small, we intentionally kept our search terms broad and inclusive. We included studies with cognitive impairment or dementia as the outcome of interest and set no age limit in adults.\u201cPassive\u201d smoking is also referred to as \u201csecond-hand smoke,\u201d \u201cenvironmental tobacco exposure,\u201d or \u201cinvoluntary smoking.\u201d Its definition normally includes both smoke exhaled by a nearby smoker and \u201cside-stream\u201d smoke released into the environment by lit cigarettes or other smoked tobacco  independently used a standardized data extraction form to collect key process and outcome data. We collated these summary data and resolved any disagreements.et al., We created a tailored quality assessment tool with the aim of detecting selection bias, confounding, and information bias . Ethical approval was not sought as we did not conduct any primary research.Our search identified a total of 1,425 records from the databases listed in http:/journals.cambridge.org/ipg. We have summarized each paper's methods, findings, and our overall quality ratings in The studies differed in their methodology, reported outcomes, and statistical methods. We considered the possibility of meta-analysis and found it would not be appropriate to pool data for this reason (The Cochrane Collaboration, et al., et al., et al., et al., et al., et al., Nine papers were included in the final analysis, four of which reported research conducted in China (Chen, et al., et al., et al., et al., et al., et al., et al., et al., et al., All studies included standard cognitive tests and justified their use. Three studies also included clinical interview to verify diagnoses of dementia or the presence of cognitive impairment (Barnes et al., et al., To quantify exposure to passive smoking, two studies measured levels of cotinine, a metabolite of nicotine, which is an accepted biological marker of exposure to cigarette smoke (Llewellyn et al., et al., et al., et al., et al., et al., Six papers reported an association between increased levels of passive smoking and a form of cognitive impairment (Llewellyn Most papers reported an association between passive smoking and either cognitive impairment or dementia. However, overall there was a paucity of evidence and the majority of studies were at moderate risk of bias. In particular, all of the studies specifically examining dementia were only of satisfactory quality, and the highest quality research was limited to cognitive impairment. The papers\u2019 methodological heterogeneity prevented meta-analysis so we did not find convincing evidence of any associations.et al., et al., et al., Recent interest in this topic is reflected in the fact that all the papers identified were published since 2009, which complements contemporary research into the links between air pollution and dementia (Weuve et al., To our knowledge, there is only one other systematic review on the topic of passive smoking and cognitive impairment, presented in a 2013 paper alongside novel study data (Chen et al., Our review sought to be comprehensive by using broad search terms in multiple databases with no age limits in adults; this is reflected in the wide range of records returned by the search. The fact that no papers were found using citation tracking or bibliography searching provides further evidence suggesting that our search method was exhaustive. We included studies reporting both dementia and cognitive impairment, which is a term used inconsistently to describe a variety of clinical states. There is a lack of standardized quality assessment tools for systematic reviews of this type. We, therefore, created our own quality assessment tool structured around common causes of bias and based on existing guidelines for evaluating cohort studies (Hammer Our restriction to English-language publications may have led to the exclusion of potentially relevant research findings in other languages. Although the databases we searched were predominantly in English, some papers in other languages were excluded at the title screening stage.Overall, because outcome measures differed, it was impossible to directly compare the strengths of association between studies and to quantitatively meta-analyze the results. Therefore, conclusions from our review are limited to general observations on cognitive test results or diagnostic outcomes.et al., \u201cmost Chinese people are unaware of the health hazards of either active or passive smoking,\u201d with only 32% of people understanding that exposure to passive smoking carries health risks. Furthermore, there was variation between the papers\u2019 implied definitions of exposure to passive smoking. For example, one paper included structured questionnaires with more detail about exposure to cigarette smoke in different environments but this only applied to the last seven days (Orsitto et al., et al., A number of studies identified passive smoking through self-reporting which is open to criticism. In the studies based in China, high illiteracy rates (reported as 61% in one paper (Chen et al., Two papers used cotinine levels as a biomarker for passive smoking. Cotinine has a half-life of 15\u201319 hours (Benowitz, et al., et al., Four of the nine included papers were by the same first author and sampled different combinations of study participants from the same two cohorts. All of these papers identified cognitive impairment using the GMS-AGECAT algorithm. However, there were variations in how the categories were interpreted across the studies. For example, a score of 3 or more was defined as a \u201csevere dementia syndrome\u201d in one study (Chen et al., The outcome measures for cognitive function across the studies varied. In the papers exploring general cognitive impairment rather than dementia, outcomes included several different neuropsychological tests, with or without clinical assessment and participants\u2019 subjective experience of memory loss. One study used a prospective memory test, which may be less relevant to clinical dementia assessment (Heffernan and O'Neill, None of the studies included or mentioned power calculations. Most of the studies were of relatively large cohorts and the analyses may have been adequately powered but this was not formally discussed in the papers. None of the papers mentioned whether raters were blinded when deciding outcomes. In cases where a clinical diagnosis was made, no papers included clarification of whether this was repeated by a second professional.et al., Publication bias suggests that studies finding positive associations are more likely to be published. This could have led to the disproportionate representation of positive results in the literature we found (Guyatt et al., A potential source of confounding is the smoking history of participants. All studies acknowledged this but accounted for it in different ways, either by excluding former smokers, analyzing them separately or adjusting for smoking history in their analyses. In addition, people exposed to passive smoking may share lifestyle factors with smokers, adding further potential confounding (Koo et al., et al., Four of the nine papers studied combinations of participants from two cohort studies. These did not meet our exclusion criteria because each paper studied a different subset with some variation in methods and were not strictly duplications. We included and discussed all of these for transparency. One of the papers (Chen et al., In the analysis of some studies\u2019 results, ordinal data were used to make numerical calculations. This involved passive smoking being categorized as \u201cno, none at all,\u201d \u201cyes, some,\u201d or \u201cyes, a lot\u201d and each of these groups being allocated an \u201cexposure level\u201d number, 0, 1, or 2. The number of self-reported years of exposure to second-hand smoke was then multiplied by these \u201cexposure levels\u201d to give what the authors called a cumulative dose. The authors then performed calculations that inferred an increasing risk of dementia syndromes with increasing cumulative dose (Chen, \u201cdrinking in excess of UK Government guidelines for safe drinking\u201d but the mean alcohol consumption across the groups studied was 30\u201334 units per week. At the time of the paper's publication, this level of intake exceeded UK Government recommendations on sensible drinking (Department of Health, Our broad search strategy led to the inclusion of a study assessing the association of passive smoke on changes in prospective memory in a sample of undergraduate students (Heffernan and O'Neill, et al., et al., et al., All the studies we included were observational and therefore, cannot be used to infer causality; the possibility of residual confounding remains. However, evidence from animal and human studies supports a mechanistic link between tobacco smoking and cognitive impairment and dementia, probably due to microglial activation and neuroinflammation (Ghosh et al., et al., There is some evidence to suggest a link between exposure to passive smoking and poorer cognitive outcomes in children and adolescents (Yolton Other possible explanations for the associations found could be confounding factors, which have not yet been identified as risk factors for dementia and were therefore not accounted for. Only two of the papers we reviewed were graded as high quality, defined as having little or no risk of bias. Therefore, this may also have contributed to the direction of overall findings.None.L Stirland designed data collection and quality assessment tools, screened for relevant articles, extracted data, assessed papers' quality, and wrote the paper. C O'Shea extracted data, assessed papers' quality, and wrote the paper. T Russ conceived of the research question, supervised data collection, and edited the paper."}
{"text": "In a recent paper published in this journal (Hendrickson and Poole, Gemmata obscuriglobus, and cited additional references, mostly from their own labs. G. obscuriglobus is relevant to our discussion of genetic compartmentation because it is the best-studied member of a phylum with members that have been reported as possessing a compartment with similarities to the eukaryote nucleus (Fuerst, G. obscuriglobus that are normally associated with eukaryotes, including endocytosis-like processes (Lonhienne et al., Gemmata and related bacteria is a \u201cmatter of ongoing debate\u201d and respectfully disagree with Jogler and colleagues' conclusion (Jogler et al., G. obscuriglobus is neither compartmentalized or nucleated, a subsequent cryo-electron tomography study from an independent group (Sagulenko et al., Gemmata that resemble the eukaryote nuclear pore complex (Sagulenko et al., G. obscuriglobus cannot account for the observations that proteins associated with these pores are exclusive to inner membranes (Sagulenko et al., Gemmata so it is premature to refer to a paradigm shift as having taken place.Jogler et al.  recently Fuerst, . In addiGemmata.With characterization of the cellular architecture of this fascinating bacterium a subject of ongoing research, we are open to data that could show that Jogler and colleagues' interpretation is partially or even wholly correct. However, given the main focus of our paper, there seems to be limited value in weighing in on extensive debate on this topic when it was not germane to the primary point of our article. Indeed, the key point of our paper is wholly unaffected by Jogler and colleagues' concerns. It would have been utterly remiss of us to have discussed non-eukaryotic cases of genetic compartmentation and completely ignored the extensive literature on All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Petroclival meningiomas (PCMs) have always been a challenge for surgeons because of their difficult anatomical location. The role of radiology in providing precise indications regarding the tumour site and aggressiveness plays a major part in guiding the subsequent therapeutic process. The purpose of this review is to provide a set of the main radiological features helpful in the management of PCMs towards the most correct therapeutic approach.We aim to offer a radiological overview to allow the patient to be directed to surgery with the least possible risk of complications. Meningiomas are meningothelial cell neoplasms, which typically attach to the inner surface of the dura matter. They are a very frequent intracranial neoplasia, routinely diagnosed in clinical practice, representing approximately between 16% and 20% of overall endocranial tumours [According to the WHO classification of central nervous system tumours published in 2016 [The most common histology is represented by meningothelial meningioma, followed by fibrous and transitional subtypes: as a whole, they account for 80% of meningiomas . MeningiThis kind of neoplasia arises generally from the upper two-thirds of the clivus, intimately associated with the brainstem, basilar artery, perforating arteries, and multiple cranial nerves and is partially obscured by the temporal bone. This particular anatomical site makes frequent surgical problems easy to understand , as showet al [Castellano and Ruggiero first understood that posterior fossa meningioma could have different prognostic evolution, thanks to extensive postmortem examinations. They considered five categories: convexity, tentorial, posterior surface of the petrous bone, clivus and foramen magnum . Howeveret al  suggesteet al , 10. Moret al , to suchet al .Surgery of PCM can nowadays be performed with excellent results after a presurgical safety assessment, including a detailed analysis of imaging characteristics of magnetic resonance imaging (MRI). The radicability of tumour resection is strongly associated with some anatomical features, easily evaluable with the imaging: tumour size, composition and aggressiveness, adherence to the brainstem, proximity to the neurovascular structures and tumour extension into the cavernous, petrosal sinus. Preoperative magnetic resonance is always necessary in order to predict the difficulties related to surgical resection: until now, the imaging features that might help to predict the complications and the feasibility of surgery of PCMs are not yet well characterised. The purpose of our study is to review the main works in the literature to establish the radiological characteristics that allow the patient to be directed to surgery with the least possible risk of complications .We searched on PubMed for the terms \u2018meningioma\u2019, \u2018petroclival\u2019, \u2018surgery\u2019 and \u2018imaging\u2019 in varying combinations. Our analysis included recent papers with the largest numbers of patients, trying to identify the principle features that can be related to a successful surgery. Studies not regarding meningiomas of the petroclival region were excluded.et al [.Mayberg and Symon were the first authors who approached neuroimaging focussing on PCMs: the use of pre-operative computed tomography (CT) scans and cerebral angiography has reduced the overall mortality to 9%. . Sekhar et al , especiaet al .The petroclival region is a surgical space circumscribed anteriorly by the clivus, laterally by the petrous apex, medially by the brainstem and posteriorly by the internal acoustic canal. It goes from the dorsum sellae to the foramen jugularis. It is intersected by cranial nerves IV to XI and by the basilar artery with its branches .et al [3. This evaluation plays an important role in planning anterior petrosectomy. Although the portion of bone resected is a pyramid  so as to prevent mistakes caused by the three-dimensional area, in that study, to obtain a good plan, the images were collected and worked out by Orsix for Mac (Pixmeo Sarl) [et al [The most important tips and tricks are represented by estimating the volume of the osseous area of the Kawase space, acquired by CT, reported by Altieri et al . This areo Sarl) . In an M) [et al  on 51 paIn the literature, there are some important analyses to estimate radiological features capable to give the chance of a satisfactory tumour removal: meningiomas usually appear as round-lobular shaped masses in the extra-axial space with thin and definite margins. Some of the most important features of PCMs are summarised in This kind of lesion usually shows isointensity to slight hypointensity relative to grey matter on the T1-weighted sequence; whilst they appear isointense to slightly hyperintense relative to grey matter on the T2 sequence. After contrast administration, meningiomas typically demonstrate rapid, rich and homogeneous enhancement . Calcification is a typical finding, best studied on CT. On MRI, calcification is best identified on susceptibility-weighted images as areas of low signal intensityContrast is of great help in \u2018en plaque meningiomas\u2019 evaluation since they typically appear as asymmetric thickened sheets of enhancing dura .et al [et al [et al [et al [et al [et al [et al [et al [et al [et al [et al [Several studies have been performed assessing the correlation between the MRI findings and the histology of meningiomas. Almost all studies have shown that the signal intensity on T1-weighted images does not correlate with tumour histology or histological subtype; in fact, most meningiomas are isointense to the brain cortex regardless of tumour histology \u201331. Dataet al  showed tl [et al  demonstrl [et al  showed tl [et al  report tl [et al  describel [et al  results l [et al  and Chenl [et al , supportl [et al  evaluatel [et al . All patl [et al . With rel [et al  demonstrl [et al . This, tl [et al  also deml [et al , 14. On et al [et al [Good correlation was also demonstrated between tumour resectability and certain preoperative findings such as the presence or absence of an arachnoidal cleavage plane; an arachnoidal cleavage plane was preoperatively shown in 80% of totally resected PCM whilst this was not demonstrated in 88% of the subtotally removed tumours. On the other hand, brainstem oedema did not correlate with incomplete tumour removal. Up till this date, no clear correlation has been demonstrated between tumour consistency and surgical outcome. Also, the values of apparent diffusion coefficient (ADC) in MRI diffusion images seem to have an excellent prognostic value in identifying the behaviour of meningiomas: Hakyemez et al  reportedet al . Tang etl [et al  describe2 s\u22121 seems to be helpful in differentiating aggressive meningiomas from low-grade tumours, whilst an ADC cut-off of greater than 0.85 \u00d7 10\u22123 mm2 s\u22121 in identifying low-grade meningiomas [An ADC cutoff of less than 0.70 \u00d7 10\u22123 mmingiomas .et al [et al [A study of Rempel et al  underlinet al . More sol [et al , by estil [et al et al. performed texture and shape analysis to quantitatively evaluate tumour heterogeneity and morphology on 131 pts by three texture features and three shape features and they have found significant differences between high-grade and low-grade meningiomas related to features of texture and shape; so it can be reliable in the preoperative determination of meningioma grade and seems to have potentially effective clinical application [Reagrding this, there are also novel methods to predict preoperative meningioma grade. Peng lication . In anotlication .In the new era of precision medicine, radiomics is an emerging translational field of research aiming to find associations between qualitative and quantitative information extracted from clinical images and clinical data, with or without associated gene expression to support evidence-based clinical decision-making. The concept underlying the process is that both morphological and functional clinical images contain qualitative and quantitative information, which may reflect the underlying pathophysiology of a tissue. Radiomics\u2019 analyses can be performed in tumour regions, metastatic lesions, as well as in normal tissues. The radiomics quantitative features can be calculated by dedicated software, which accepts the medical images as an input. Despite many tools developed for this specific task being user-friendly in terms of use and well performing in terms of calculation time, it is still challenging to carefully check the quality of the input data and to select the optimal parameters to guarantee a reliable and robust output. The quality of features extracted, their association with clinical data, and also the model derived from them, can be affected by the type of image acquisition, postprocessing and segmentation. This article summarises the major issues regarding this multistep process, including radiomics, CT and MRI .The radiological features of PCMs are of great importance for clinicians in the choice of the most appropriate therapeutic approach.Where surgery is possible , radiological images play an important role in order to choose the best surgical approach.The profound knowledge of the radiological characteristics of the PCM is of great importance to assure the best management of patients with this type of lesion.Many new and innovative methods are being developed over recent years to analyse the radiological features of a meningioma, offering opportunities with great potential and interest.Nothing to declare.No funding was received for this article.All authors declare no conflict of interest."}
{"text": "Phantom limb pain (PLP) is a chronic pain disorder characterized by painful sensations that are perceived to arise from the missing limb, presumably due to structural and functional alterations in several regions of the brain (i.e., anterior midcingulate cortex, aMCC; Prei\u00dfler et al., In Prei\u00dfler et al. , particiIn addition to reporting a decrease in PLP among the participants after the training period, Prei\u00dfler et al.  also repRecent advances in VR technology provide a promising avenue for the future of PLP treatment. Similar to the myoelectric prosthetic arm protocol utilized by Prei\u00dfler et al. , immersiAlthough we discuss various beneficial approaches to reducing PLP, it is important to acknowledge that the benefits of the interventions discussed above vary among patients, with some patients who report no PLP reductions (see for example Ortiz-Catalan et al., In conclusion, PLP therapy has been extensively explored in the literature. In Prei\u00dfler et al. , the autAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The role of farm animals in the emergence and dissemination of both AMR bacteria and their resistance determinants to humans is poorly understood and controversial. Here, we systematically reviewed the current evidence that food animals are responsible for transfer of AMR to humans. We searched PubMed, Web of Science, and EMBASE for literature published between 1940 and 2016. Our results show that eight studies (18%) suggested evidence of transmission of AMR from food animals to humans, 25 studies (56%) suggested transmission between animals and humans with no direction specified and 12 studies (26%) did not support transmission. Quality of evidence was variable among the included studies; one study (2%) used high resolution typing tools, 36 (80%) used intermediate resolution typing tools, six (13%) relied on low resolution typing tools, and two (5%) based conclusions on co-occurrence of resistance. While some studies suggested to provide evidence that transmission of AMR from food animals to humans may occur, robust conclusions on the directionality of transmission cannot be drawn due to limitations in study methodologies. Our findings highlight the need to combine high resolution genomic data analysis with systematically collected epidemiological evidence to reconstruct patterns of AMR transmission between food animals and humans. E. coli is found in both human and food animal populations  explore the current evidence that food animals are of the source of resistant et al., E. coli, AMR terminologies, human, and food animal descriptors (www.liebertpub.com/fpd).A systematic literature search according to the PRISMA  guidelines  they reported only agents other than E. coli; (ii) they studied nonfood animals; (iii) they focused exclusively on food animals or humans without any overlap between the two populations and/or (iv) they focused exclusively on food of animal origin. Article searches and screening were performed by considering article titles and abstracts for inclusion according to the search criteria. Data extraction from studies was performed by one author (D.M.M.) and independently checked by another author (B.v.B.) using a customized checklist.Articles were included if they comprised an original research published in a peer reviewed journal, and investigated transmission of resistant For all included studies we categorized the direction of AMR transmission according to the authors' conclusions: (i) studies suggesting to provide evidence of transmission from food animals to humans with direction specified; (ii) studies suggesting to provide evidence of transmission from humans to food animals with direction specified; (iii) studies suggesting overlap indicating the possibility of between-host AMR transmission, with no direction specified; and (iv) studies suggesting no evidence of transmission in either direction.et al., The quality of evidence was assessed using a customized Grading of Recommendations Assessment, Development and Evaluation (GRADE) system  we did not perform a meta-analysis. However, we used Fisher's exact tests using R package \u201cstats\u201d  suggested to have data to support transfer of AMR bacteria and/or their AMR determinants from food animals to humans .Only one study (2%) based its conclusion regarding transmission on high resolution typing tools, 36 studies (80%) on intermediate resolution typing tools, six (13%) on low resolution typing tools, and two (5%) on co-occurrence of resistances . Overallet al., et al., et al., et al., Three studies suggested to find evidence for transfer of AMR bacteria from food animals to humans, two of which concluded there is transfer of resistant clones from poultry to humans (Al-Ghamdi et al., et al., et al., et al., et al., One study found identical ciprofloxacin-resistant isolates in chicken and humans, which they concluded was suggestive of food animal to human AMR transmission (Johnson E. coli isolates sourced from poultry and human patients (Leverstein-van Hall et al., et al., E. coli in humans in contact with tetracycline fed chicken and, therefore, suggested that chicken were a reservoir of AMR bacteria and plasmids for humans (Levy, Three studies suggested to support transmission of both AMR bacteria and their AMR determinants from food animals to humans. Two studies found similar sequence types, plasmid families and ESBL genes in ns Levy, .We found that studies suggesting to provide evidence of transmission of AMR from food animals to humans did not have distinct features compared to those suggesting overlap of resistance, with regard to study methodologies, food animal species, typing tools, or antibiotics tested. For most of these it is unclear why they suggested evidence of directional transmission when 25 broadly similar studies suggested only overlap of resistance.E. coli between humans and food animals. One of these studies found human and avian sequence types associated with multidrug resistance clustered together in a Bayesian phylogenetic tree (Ciccozzi et al., et al., E. coli phylogroups found that human, pig, and chicken isolates clustered together (Jakobsen et al., et al., Four studies suggested there was evidence of overlap of resistant et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Thirteen studies suggested there was evidence of overlap of AMR determinants in human and food animal isolates. Of the 13 studies, one study based on WGS and plasmid reconstruction found that clonally unrelated human and poultry isolates carried ESBL genes encoded on genetically identical plasmids (de Been E. coli and AMR determinants, with five of these finding that clonally related human and food animal isolates harbored similar ESBL gene types and plasmid types (Hu et al., et al., et al., et al., et al., et al., et al., E. coli pathotypes showed that human and food animal isolates clustered together (Jakobsen et al., Eight studies suggested there was evidence of overlap of resistant E. coli strains had distinct phylogenetic compositions (Graziani et al., E. coli isolates from sympatric children and chicken found that the isolates were source specific (Kariuki et al., Two studies found no evidence for transfer of resistant clones, with one of these studies finding that human and avian ciprofloxacin-resistant et al., et al., et al., Three studies reported no evidence for transfer of AMR determinants between food animals and humans with one of these studies reporting that human and porcine isolates had different distribution patterns of sulfonamide and tetracycline resistance genes (Schwaiger et al., et al., et al., et al., et al., et al., et al., Seven studies reported no evidence for transmission of bacterial clones together with AMR determinants between food animals and humans. These studies showed that human and food animal isolates belonged to different phylogenetic groups, and had different AMR genes and plasmid profiles (Maynard E. coli and their AMR determinants to humans. Some studies in our review suggested to provide evidence for the transfer of AMR from and between food animals and humans, while a larger number did not suggest to provide evidence of transmission in either direction. In addition to the differing nature of methods used to infer direction, studies in our review differed in sampling methodologies and antibiotics tested. These differences may have affected the conclusions made regarding the epidemiological connection between food animals and humans.We performed a systematic review to explore the evidence that food animals are responsible for the transfer of AMR E. coli clones and AMR determinants were indistinguishable in both food animal and human isolates. However, the demonstration of overlapping patterns should be interpreted with care as the direction of transmission is difficult to infer, and co-colonization from a shared source is also possible. Demonstrating the direction of transmission and thus the epidemiological history of pathogens and their determinants requires a quantitative description of relatedness, including phylogenetic analysis (Grad and Lipsitch, Much of the evidence regarding transfer of AMR was based on the demonstration that AMR et al., E. coli isolates were considered genetically indistinguishable based on MLST suggesting clonal transfer (Leverstein-van Hall et al., et al., et al., et al., Molecular techniques, such as MLST and PCR, used in most studies in our review, are limited in resolution (Didelot et al., et al., Just over half of the studies in our review did not consider spatiotemporal relationships between human and food animal isolates, a fundamental requirement for investigating transmission (Singer et al., None of the included studies provided a detailed overview of antibiotic usage in either human or food animal populations, or association between antibiotic usage and subsequent development of AMR. A recent systematic review has indicated that interventions that limit antibiotic use in food animals are associated with a reduction of AMR development in humans (Tang et al., et al., Although transfer of AMR from humans to food animals is likely Barber, , none ofet al., et al., Akin to the studies in our review, most AMR studies focus on a single bacterial type; however, rapid dissemination of AMR determinants frequently occurs between bacterial species, making it hard to track infection source (Sheppard et al., Our systematic review excluded studies focusing on transmission of resistant bacteria and/or their AMR determinants through food animal-sourced food products. However, we acknowledge the potentially significant role played by food products of food animal origin in dissemination of AMR as reported in a recent systematic review (Lazarus E. coli and their AMR determinants from food animals to humans. However, differences in study methodologies, such as lack of spatiotemporal overlap in sample collection, and the quality of typing tools used, suggest that transmission may occur, the evidence used to support the hypothesis is rarely compelling. The underlying problem is that demonstrating similarity or identity of AMR bacteria and/or AMR resistance determinants does not, by itself, provide information on directionality of transfer; this could be in either direction, or both, or neither but from a different source. Information on differential prevalence of resistance, and consumption of antibiotics, in the two populations may make stronger inference possible, but these data are rarely available.We have highlighted studies that suggest to provide evidence for transfer of resistant Taken together, by combining genomic data analysis and epidemiological approaches it may be possible to reconstruct the complex transmission dynamics of resistant bacteria and their AMR determinants between human and food animal populations. Although we still have some way to go before a truly comprehensive integration of data\u2014differential antibiotic usage data, detailed denominator data, information about the origin of the samples, human-food animal contact data, and pathogen sequence data\u2014is available, disentangling and quantifying transmission of resistant bacteria and their AMR determinants between humans and food animals may still be an attainable goal."}
{"text": "Cholestasis is defined as reduced bile flux, either caused by an obstruction of bile ducts or by compromised hepatocellular secretion (Pollheimer et al., 2014; FickertOne important discovery made by this method is that the most upstream domain of the biliary tract, bile canaliculi, responds differently to cholestasis than the more downstream interlobular ducts (Damle-Vartak et al., 2019[Recently, much effort has been invested to gain a better understanding of cholestasis (Ehrlich and Glaser, 2018; Sultan The author declares no conflict of interest."}
{"text": "Currently, just under six million people living in America are diagnosed with Alzheimer\u2019s disease or related dementia. Most people with dementia live in a community setting and are cared for by a family member. Persons living with dementia almost universally experience behavioral and psychological symptoms (BPSD), such as agitation, aggression, and rejection of care as well as functional dependence. These symptoms are related to negative outcomes for both the person living with dementia and the family caregiver. Prior research shows that nonpharmacologic interventions such as meaningful activities, education, and multicomponent interventions have promise in managing behaviors. This symposium focuses on preliminary outcomes from the Dementia Behavior Study (DBS), a Randomized Control study that examined the effect of the Tailored Activity Program (TAP) in a community setting on BPSD and functional dependence in persons living with dementia, and caregiver wellbeing . Gitlin et al will present outcomes of the primary aim (BPSD) and secondary aims  of the DBS. Pizzi et al explore the cost analysis of the TAP intervention versus the active control group. Scerpella et al describe the alerts and adverse events that were associated with the DBS. Marx et al present the relationship between race and caregiver readiness to participate in TAP. Regier et al explore the BPSD Rejection of Care and the association to caregiver burden. Tailoring interventions, such as activities may improve quality of life for both the person with dementia and the family caregiver."}
{"text": "HOTAIR can play their important roles by changing the chromatin states of the genome  and Polycomb Repressive Complex2 (PRC2) in order to recruit them on specific target genes. This RNA interacts with Polycomb repressive Complex2 (PRC2) and has a lot of targets such as HOXD. By this way, PRC2 can repress the desired genes leading into increased growth, proliferation, survival, metastasis, invasion, and drug resistance in some cancer cells  are RNAs with more than 200 nucleotides and are mostly transcribed by RNA polymerase II from different regions across the genome. They are currently known as key regulators of cellular function through different mechanisms such as epigenetic regulation, miRNA sponging, and modulating of proteins and enzyme cofactors   patients. Also, The rs1899663 is associated with prostate cancer risk in co-dominant, dominant and recessive inheritance models. Researchers have reported that this SNP changes the affinity for binding of PAX-4, SPZ1, and ZFP281 transcription factors which can alter the HOTAIR gene expression level (Taheri et al., Another SNP located in the intronic region of HOTAIR gene, one named \u201crs7958904\u201d is an exonic polymorphism. So, it seems that HOTAIR rs7958904 polymorphism can affect the secondary structure of HOTAIR.Among the SNPs in HOTAIR rs7958904 has been reported to be associated with decreased osteosarcoma (Zhou et al., HOTAIR rs7958904 can reduce osteosarcoma risk as well as HOTAIR expression level (Zhou et al., HOTAIR expression (Jin et al., HOTAIR in lung cancer (Jiang et al., HOTAIR function or expression (Xue et al., It is of noted that CC genotypes of HOTAIR have abnormal expression in the different human cancers. Different studies have revealed the cellular and molecular mechanisms in which HOTAIR is involved (Hajjari and Salavaty, HOTAIR in cancer susceptibility have been published. However, these studies are mostly derived from Asian population. Also, there are some controversial results on this field of study. With regard to the importance of HOTAIR regulation and function, more experiments on different populations, and ethnics are expected to reveal the importance of HOTAIR polymorphisms. Other polymorphisms in HOTAIR gene such Indel and CNV may be considered in future. However, the association between these SNPs and regulation/structure of HOTAIR has to be checked in various cancers. Also, we believe that whole genome sequencing projects can help to find the relation between the SNPs of this RNA with other SNPs in different cancers in future.MH designed and wrote the manuscript. SR worked on gathering the data and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Although there are some commendable aspects regarding the methodology, some major shortcomings could preclude the conclusions drawn by Choukem et al. Nevertheless, independent assessments of the performance of blood glucose monitoring systems are an important issue.In their article, Choukem  Choukem et al. purchased the BGMS from pharmacies, thus using meters and test strips that are representative of those used by end-users. In the study, capillary blood was applied, which typically is the type of sample used by diabetes patients, because they do not readily have access to, for example, venous blood. Rotating the order in which the BGMS are used helps minimizing potential order effects. This shows that the authors were aware of several potential influencing factors and tried to minimize their impact. However, the methods used in the study by Choukem et al. had some flaws: Such comparative assessments should use the same sample type for the investigated systems as well as for reference measurements, because glucose concentrations can be different in venous and in capillary blood samples [et al. state that requirements of ISO 15197 are not met. However, this statement can only be made with limits because of relevant methodological deviations from the recommended procedure as outlined in ISO 15197 [et al., therefore, it is impossible to verify whether BGMS fulfill ISO 15197 accuracy criteria or not.In their recent publication, Choukem et al.  report o samples . Further samples , so that samples . In addiet al. at least in part. In addition, some of the requirements regarding methodology as outlined in ISO 15197 were not adhered to by Choukem et al. Therefore, it is our opinion that the conclusions drawn by Choukem et al. may possibly have been different if these methodological flaws had been avoided. Nevertheless, we want to encourage Choukem et al. to perform further testing, as we believe that independent assessment of BGMS performance is an important issue.These methodological flaws could likely lead to reference measurement results being systematically different than BGMS measurement results. Although their individual contribution to a systematic difference is hard to pinpoint, their combined effect would explain the positive bias values found by Choukem The authors declare no competing interest."}
{"text": "Drosophila, only starved animals are used and the length of the starvation period influences the results  that end with a jump, but with some degree of independence between each maneuver, allowing the fly to stop the sequence if it chooses to Card and Dickinson (Drosophila escape response\u2014with either short or long take-offs\u2014that can be biased toward short take-offs by increasing stimulus speed (von Reyn et al., Drosophila escape responses involve more neural control elements than a single command neuron, allowing a variety of computational and decision steps to take place before the evasive behavior occurs. Another common defensive strategy is freezing, where the animal remains still, reducing its chances of being noticed. A new study showed that Drosophila flies adopt a freezing strategy in a state-dependent manner (Zacarias et al., In ickinson ,b and Caickinson . Each stDrosophila, but upon encountering female wasps, female flies adopt different strategies that include choosing food containing toxic levels of alcohol to lay their eggs (promoting the death of wasps' eggs and larvae; Kacsoh et al., Perhaps even more interesting is how the presence of parasitoid wasps affects oviposition in adult flies, as a mechanism to protect their offspring from a possible future threat. Parasitoid wasps are not dangerous to adult Interestingly, flies form a nonassociative long-term memory of the exposure and will lay fewer eggs or choose alcohol-enriched food to lay their eggs for 24\u201348 h after wasp exposure (Kacsoh et al., Drosophila uncovered part of the neuronal network involved in the decision to expand the wings, and showed the connection with the decision to perch, which required an assessment of the external factors (Peabody et al., Curiously, these two biogenic amines differently modulate phototaxis, in what it seems to be a goal-directed or value-based decision-making process. Phototaxis seems to be a special case of photopreference and manipulating the ability of flies to fly can reversibly shift it from approach to avoidance in walking flies (Gorostiza et al., These examples serve to demonstrate how innate behaviors can in fact be the outcomes of complex modulatory processes, careful assessment of factors and decisions, and not mere stereotypic and automatic responses. Through these examples, we can see some aspects that resemble cognitive components (Menzel et al., The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Uncontrolled immune response in the brain contributes to the progression of all neurodegenerative disease, including Alzheimer\u2019s disease (AD). Recent investigations have documented the prion-like features of tau protein and the involvement of microglial changes with tau pathology. While it is still unclear what sequence of events is causal, it is likely that tau seeding potential and microglial contribution to tau propagation act together, and are essential for the development and progression of degenerative changes. Based on available evidence, targeting tau seeds and controlling some signaling pathways in a complex inflammation process could represent a possible new therapeutic approach for treating neurodegenerative diseases. Recent findings propose novel diagnostic assays and markers that may be used together with standard methods to complete and improve the diagnosis and classification of these diseases. In conclusion, a novel perspective on microglia-tau relations reveals new issues to investigate and imposes different approaches for developing therapeutic strategies for AD. The most common cause of dementia is Alzheimer\u2019s disease (AD), a progressive neurodegenerative disease that affects nearly 50 million people in the world. Histopathological features of AD are extracellular amyloid-\u03b2 (A\u03b2) plaques and intracellular aggregation of hyperphosphorylated tau protein in a form of neurofibrillary tangles  during early embryonic development. Their appropriate response is crucial for maintaining homeostasis and to carry out the immune response in the CNS (Ginhoux et al., In the mature brain, microglia play an important role as the main immune agents. Under physiological conditions, microglial cells are in the resting state, but they actively survey the brain parenchyma with motile processes (Nimmerjahn et al., Neuroinflammation occurs in most neurodegenerative diseases (for review see Stephenson et al., MAPT gene and different RNA splicing can produce six tau isoforms in the human brain. Isoforms of tau have either three or four microtubule-binding repeats (Neve et al., in vitro findings, where we showed that exhaustive tau phosphorylation is either not essential for the stability of the putative tau oligomer once it is formed, or is necessary for initial oligomer formation (Boban et al., via non-cell-autonomous mechanisms, which leads to degeneration (Goedert et al., in vitro studies that describe the trans-synaptic spread of tau along anatomically connected brain regions. One study demonstrated this kind of propagation in transgenic mice that differentially express pathological human tau in the entorhinal cortex (Liu et al., In vitro studies also support the prion-like feature of tau (Kfoury et al., Tau protein is mainly expressed in neurons and is essential for microtubule assembly and stabilization of the cytoskeleton (Weingarten et al., via unconventional secretory pathways like other proteins lacking signal peptides (Rabouille et al., via exosomes. This mechanism was demonstrated in cell cultures in vitro such as M1C (Saman et al., via exosomes (Wang et al., 1\u201342 levels were detected up to 10 years prior to clinical diagnosis (Fiandaca et al., The prion-like hypothesis of tau transmission proposes that misfolded tau acts as a seed causing further misfolding of proteins inside healthy cells, implying that tau needs to be released outside of the cells. Tau released in the ISF can induce stronger microglial activation which in turn may promote the propagation of tau pathology. It is well known that the CSF levels of tau are elevated in AD patients (Zetterberg and Blennow, in vitro. Interestingly, microglia pretreated with NSAID attenuated tau overexpression (Lee et al., in vitro and in vivo. AT8 and PHF1 tau colocalized within hippocampal Iba1-expressing microglia, which convincingly demonstrate microglial uptake of tau (Asai et al., In vitro test supported this conclusion, showing more efficient phagocytic activity by microglia when compared to neurons and astroglia (Asai et al., in vitro and in vivo (Asai et al., It is well known that tau can mediate an inflammatory response in neurodegenerative disease. Many studies show microglial activation upon tau pathology (Bellucci et al., A recent study revealed one possible molecular mechanism that can explain noticed microglial changes in response to tau pathology and microglial contribution to tau propagation . AggregaThe harmful effect of tau protein oligomers and its potential to propagate through synaptically connected regions has been well established by recent evidence, along with microglial changes in close vicinity of tau pathology. Uncontrolled microglial response in the brain contributes to the progression of many neurodegenerative diseases and several lines of evidence suggest that inflammation may even precede the development of tau pathology in AD. Exosomes could be an important link between tau propagation and microglial activation. Reduction of microglial cells number and exosome synthesis inhibition reduces tau propagation (Asai et al., All animal experiments were conducted according to the Principles of Laboratory Animal Care and ARRIVE guidelinesG\u0160 conceived the manuscript. All authors edited the drafts of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "We are proud to present 14 papers with focus on teenager health in this Special Issue entitled \u201cTeenage Reproductive Health: Pregnancy, Contraception, Unsafe Abortion, Fertility\u201d.Maternal mortality is still globally high and reducing it is a top priority. Teenage pregnancies have more complications and are also unwanted in many cases. This contributes to the high maternal mortality with both obstetric complications and burden of unsafe abortion. Additionally, many teenagers live in areas with heavy pollution that affects the mother and the unborn child. Global public health is a very important issue that aims to prevent disease, prolong life, and promote physical, mental and social well-being. Teenagers are the future, and maternal death is a disaster that should be prevented. Hence, research should aim to improve teenage reproductive health and influence policy makers. There are a variety of topics in this issue, with some conclusions and ways forward as described in different papers.Oppong-Darko et al.  describeGrossman et al.  have a vvon Rosen et al.  describeNinsiima et al.  went deePradhan et al.  publisheContributions to international health science from Russian authors are rapidly increasing. Usynina et al.  discuss Lafontan el al. state that it is very simple and easy to use electronic baby monitoring in Tanzania . They caScientific literature from Kazakhstan is increasing and improving. The paper from Dauletyarova et al.  discusseAbortion policies are very important in teenager health in all parts of the world. Frederico et al.  discuss Tsikouras et al.  describeBack in Africa, Odland et al.  discuss Kemigisha et al.  deliver Clarke et al.  have theFinally, Sharma and Nam  describeInternational Journal of Environmental Research and Public Health as a starting point in their career. All papers have been through a thorough review process, and many of them are now basis for the study towards academic degrees and introduction to further studies. Due to the age connection, young scientists are writing about health issues for young people. Let us hope for a new Special Issue soon, with contributions from other parts of the world. Teenagers have special health concerns in a very important transition period from child to adult. This is independent of geography, culture and religion. In total, this Special Issue provides very useful information for all parts of the world, even for those who are not presented in this nice collection of papers.There is a very important public health aspect in all the published papers in this Special Issue. Another good development is that young scientists are using the"}
{"text": "The issue of how plants grow on saline soils is an interesting one in its own right, but commands added urgency in the context that irrigation and sea level rises are increasing the proportion of arable land that is salinized and that global demand for more food is leading to cultivation of marginal land.Terrestrial plants face formidable challenges when growing in saline conditions. High osmotic pressure around the roots can prevent efficient water absorption, yet the high concentrations of the sodium ion (NaNew Phytologist reminds us that these challenges are experienced by plants at cellular, tissue and whole organism levels. Major changes in energy metabolism are experienced by plants growing in saline conditions. Many of these changes relate to the decreased resource devoted to growth and the necessity for enhanced transport of ions that can be used to retain turgor, or to exclude those ions that leak into cells and tissues.\u2018Major changes in energy metabolism are experienced by plants growing in saline conditions.\u2019A collection of research papers and review articles in this issue of et al. (The Tansley review by Munns et al. (Flexibility in plant metabolism can provide adaptation to saline environments. In a thoughtful analysis, Fricke (et al. (Plant salinity tolerance involves complex \u2018decision\u2010making\u2019 by a plant: for example, how is turgor maintained in an energetically\u2010effective way that does not compromise metabolic activity? Munns et al. (The process of cation absorption and compartmentation \u2013 intracellularly and through the plant \u2013 comprises a further challenge to plants in saline conditions. Rubio et al. (Coping with salinity stress involves not just selective exclusion and competition between Na and K: glycophytic plants possess inherent leaks in their membranes that facilitate futile cycles in transport, particularly in the case of Na. Shabala et al. (As multicellular organisms, the manner in which plants handle salinity stress cannot be considered at the cellular level alone. Arsova et al., et al., et al. (The articles briefly summarized here are invaluable in pointing to recent advances and discoveries in plant salinity tolerance. But more important, perhaps, are the questions relating to the big unknowns that the authors raise. There were hopes two decades ago that developing an understanding of signal transduction pathways would lead to rapid developments in generating salt\u2010tolerant plants Sanders, . These h, et al.  based onet al. (st century genomics is ever\u2010growing and this \u2013 alongside the machine\u2010learning approaches to understanding phenotypic diversity in an environmental context \u2013 will be key to developing the predictive breeding approaches that are needed for the realization of salinity\u2010tolerant crops.\u2018\u2026 salinity tolerance is multigenic and needs to be viewed in a wider context than just that of membrane transport of NaCl.\u2019This collection of articles reminds us that salinity tolerance is multigenic and needs to be viewed in a wider context than just that of membrane transport of NaCl. Munns et al.  have proWider aspects of biodiversity should not be forgotten, either, as a way of devising strategies for crop improvement since there are many angiosperm species that are salt\u2010tolerant. There are clearly lessons to be learned from the physiological adaptations that enabled such species to live in saline soils and even in some cases to re\u2010colonize the sea."}
{"text": "Behavioral and Brain Sciences about the ideas of Baumeister et al. (e.g., Budescu and Maciejovsky, Baumeister et al.  proposedWe hold that the ideas of Baumeister et al. do not generalize beyond individualistic cultures, and do not generalize to all kinds of tasks. We begin by describing important differences between individualistic and collectivist cultures. Later, we distinguish between survival and development tasks. Ultimately, we argue that the benefit of individuation in groups may only apply to a small portion of the space defined by individualistic vs. collectivist cultures, and survival vs. development tasks, as schematically depicted in Figure Baumeister et al.  ignore cWe agree with the view that for many types of tasks, the promotion of individual identity can facilitate group success, whereas promoting shared identity can reduce success. However, we argue that this result applies most strongly to individualistic cultures, and may not be observed at all when testing collectivist cultures (also pointed out by Brown, Baumeister et al.  also ignThe probability of survival is increased by shared identity because shared identity promotes helping (Penner et al., In short, Baumeister et al.  have proZZ drafted the manuscript. CW provided revisions and language editing. YL, QX, and HL provided revisions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Indeed, FXS is considered a form of ASD (https://www.spectrumnews.org/news/fragile-x-syndromes-link-autism-explained/) and so are the murine models of this disease  in addition to a Nuclear Localization Signal (NLS) and a Nuclear Export Signal  is a neurodevelopmental disorder due to the silencing of Fragile X Mental Retardation 1  in the presence and in the absence of FMRP  motif, bound by FMRP in the GRK4 mRNA (G protein-coupled Receptor Kinase 4; Maurin et al., vivo. To do so, we computed an unpairing score for each base of each expressed transcript. We derived a score for each motif bound by FMRP and we compared the scores of motifs embedded in FMRP binding sites or present elsewhere in the transcript. Our analysis clearly shows that the CUGKA, GWRGA and UAY motifs present in regions bound by FMRP are more accessible to DMS modification in vivo than the unbound cognate motifs present in the same transcripts (Maurin et al., Importantly, we and others showed that the basis of FMRP/RNA interaction is the key to understand its function (Darnell et al., The second key point that should be considered to explain the double role of FMRP as repressor and enhancer of translation is represented by the interactors of FMRP, which can have different expression patterns (Bardoni et al., Another critical point is represented by the observation that, in the absence of FMRP, a set of its mRNA targets was shown to be less transported at the synapse (Dictenberg et al., Last but not least, the post-translational modification of FMRP can modify its function. For instance, sumoylation has been shown to have a strong impact on the ability of FMRP to interact with partners and generate complexes (Khayachi et al., are not modulated in the absence of FMRP, which in our opinion argues for a stronger implication of FMRP-containing mRNPs in storage/transport of mRNAs rather than in translational regulation. To date the role of FMRP was mainly studied in translational regulation probably due to its association to polyribosomes (Corbin et al., Fmr1-KO (Huber et al., In conclusion, it seems now the right time to renew the research on the mechanisms of action of FMRP. It is indeed remarkable that the study of Liu et al.  See Fig legend sFmr1-KO cells (Bechara et al., Fmr1-null mice (El Bekay et al., It is obvious that the function of this protein is intimately linked to the identification of a therapy for FXS, that, indeed, is still missing (Castagnola et al., The two authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The study of coat protein assemblies on membranes by cryo-electron tomography and subtomogram averaging is discussed, outlining the methodological advancements that enabled the gain of crucial structural insight. in vitro reconstitutions or in situ is summarized. These studies have answered long-standing questions regarding the mechanisms of membrane binding, polymerization and assembly regulation of coat proteins.Coat proteins mediate vesicular transport between intracellular compartments, which is essential for the distribution of molecules within the eukaryotic cell. The global arrangement of coat proteins on the membrane is key to their function, and cryo-electron tomography and subtomogram averaging have been used to study membrane-bound coat proteins, providing crucial structural insight. This review outlines a workflow for the structural elucidation of coat proteins, incorporating recent developments in the collection and processing of cryo-electron tomography data. Recent work on coat protein I, coat protein II and retromer performed on  The large body of cryo-EM work carried out for protein structure characterization has utilized single-particle electron microscopy , coat protein I (COPI), clathrin and retromer Fig. 1. The cytQuestions that remain unanswered about coat proteins address the mechanism of their association with the membrane and their global assembly. Cryo-ET is well suited to address these questions as it can allow the high-resolution analysis of coat proteins in the process of modifying membranes.2.We describe our workflow for the investigation of coat protein membrane assemblies by cryo-ET in Fig. 32.1.et al., 2004et al., 2006et al., 2002et al., 2007et al., 2010et al., 2004et al., 2002in vitro reconstitution studies with purified components assembled on artificial membranes , which can affect tilt series alignment by cross-correlation. High-contrast gold fiducial markers are typically added to emClarity and IMOD  correction is essential for the recovery of higher resolution information. Appropriate CTF correction relies on accurate defocus determination. Modern CTF detection software such as i.e. the tilt series), the finely aligned and pre-processed tilt series are back-projected from their assigned orientation angles. To gain contrast for better visualization in the initial phases of processing, filters can be applied during the reconstruction process. For initial tomogram visualization, weighted back-projection (WBP) with iterations of simultaneous iterative reconstruction technique (SIRT)-like filtering can be performed using the Etomo IMOD interface  the result to obtain a featureless membrane density. This is used for initial alignment of the subtomograms, which helps to define particle centres and can often constitute a first cleaning step. The subtomogram dataset is typically split in half and processed separately during further alignment, following a \u2018gold-standard\u2019 approach . Firstly, it revealed the association of the coat and the Sar1 GTPase with the membrane. We observed for the first time how the N-terminal amphipathic helix of Sar1 is associated with the membrane: a helical hook is bent by 90\u00b0 and inserts horizontally into the outer leaflet, running roughly parallel to the tube axis (Fig. 6et al., 2018Our recent cryo-ET and STA studies of ng Fig. 5a. Firstis Fig. 6. Also, tet al., 2001et al., 2007Moreover, our structure unveiled how the inner and outer coat are associated: through the binding of motifs embedded within the outer coat disordered C-terminal tails to two distinct sites on Sec23. Together with previous biochemical and X-ray crystallographic studies (Antonny 3.2.in vitro reconstituted assemblies and within the cell. Three consecutive studies have investigated the structure of COPI assembled in vitro from purified coatomer components on GUVs (Faini et al., 2012et al., 2015b; Dodonova et al., 2017in situ structural studies can reveal the interactions of coat proteins with cargo molecules. The power of in situ studies has been demonstrated in a recent study of COPI as a way of identifying protein\u2013protein interactions that are relevant in an intracellular context (Bykov et al., 2017in vitro mimics that seen in physiological contexts. Moreover, they identified a novel density that is not present in in vitro reconstitutions, which was attributed to cargo or cargo receptors as informed by previous biochemical knowledge regarding the cargo-binding site of \u03b2-COPI.Two other coat protein assemblies, COPI and retromer, were analysed by cryo-ET and STA of in vitro from purified retromer Vps5 components on liposomes was recently determined to subnanometre resolution (Fig. 5c; Kovtun et al., 2018in situ validation of the structure of retromer obtained from in vitro reconstitutions confirmed that in vitro reconstituted assemblies mirrored native retromer arrangements within the cell (Kovtun et al., 2018The structure of retromer as assembled 4.et al., 2016et al., 2015et al., 2015et al., 2017et al., 2018et al., 2015et al., 2017et al., 2017et al., 2015et al., 2012et al., 2010et al., 2015et al., 2017et al., 2016et al., 2012Cryo-ET and STA have been applied to the study of units that do not form arrays, such as bacterial secretion systems (Chang et al., 2016et al., 2013et al., 2017et al., 2018et al., 2015et al., 2017et al., 2016et al., 2019While some studies have demonstrated that near-atomic resolution is possible with STA (Schur et al., 2017Data processing also requires significant user expertise and manual intervention. The ongoing developments in automatic tilt series alignment procedures and the establishment of user-friendly software for STA will greatly benefit the speed of processing (Mastronarde & Held, 2017In vitro reconstitutions provide control over sample composition and enable studies of the effect of varying the reaction environment in a controlled manner. Additionally, investigating the effect of mutations, which is central to the validation of structural information, is technically straightforward and is isolated from possible off-target effects. However, isolation from potential interacting partners, especially transient interactors that have not been biochemically established, limits discovery and the collection of exhaustive structural data. Information is also lost regarding the cellular context of the complex of interest. In situ studies can bridge the gap between in vitro analysis with purified proteins and the cell, allowing the identification of novel interacting surfaces, validating in vitro structural information, and providing global spatiotemporal insight (Kovtun et al., 2018et al., 2017et al., 2016et al., 2017in situ structural determination are beyond the scope of this review, we note that automated and sophisticated technologies for identifying assemblies of interest through template-matching may allow higher throughput and lower subjectivity (Lu\u010di\u010d et al., 2013et al., 2015"}
{"text": "Shen et al.  examinedFEE). Below we discuss four such implications with the goal of inspiring further research and insights into this important topic.The methods and findings from this study have novel implications concerning facial expressions of emotion  and had shown that they rarely occurred (Porter and ten Brinke, The findings from Shen et al.'s  study anShen et al.'s  findingsFinally, the findings by Shen et al.  and a grDM and HH authors contributed equally to the ideas presented. The DM wrote the first draft of the paper. Both authors contributed equally to editing the first draft to its final version.The authors declare that they are employees of Humintell, a for-profit company that sells microexpression related products."}
{"text": "Original textP. patens mutant showed poorer recovery from salt and osmotic stress compared to the wild-type (WT), indicating that DHNs are indispensable for the alleviation of cell dehydration , indicating that DHNs are indispensable for the alleviation of cell dehydration (Saavedra et al., A DHN gene knockout Original textDHN genes are highly expressed under conditions of various types of stress, such as drought, cold, or high salinity (Yoon et al., Modified textDHN genes are highly expressed under conditions of various types of stress, such as drought, cold, or high salinity (Yoon et al., In the original article, we neglected to cite two previous studies. The authors apologize for this oversight. This error does not change the scientific conclusions of the article in any way.The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "They came to the conclusion that one component of the latter, mGPD, is responsible and a direct molecular target for metformin.+/NADH as co-factor [a Km value around 30 \u03bcM for glycerophosphate (GP)] and mGPD with FAD as co-factor. The mGPD has a high Km for GP (2 to 8 mM), is an important reactive oxygen species (ROS) producer  stimulation of succinate-driven OCR by metformin that has never been reported before. Third, high throughput screening for mGPD inhibitors with several thousands of chemicals yielded membrane permeable, high-affinity blockers such as iGP  but not metformin or related structures (Orr et al., Thus, the data by Calza et al.  and the After submission of the manuscript two publications came to our attention, which support the notion that mGPD must be removed from the list of direct molecular metformin targets. Alshawi and Agius  report tHG and OL discussed the topic and wrote the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Liu et al. have recently published a paper highlighting blood-derived miRNAs as possible early diagnostic biomarkers in Pancreatic Cancer by conducting a narrative review and meta-analysis titled, \u201cBlood-Derived microRNAs for Pancreatic Cancer Diagnosis: A Narrative Review and Meta-Analysis\u201d (Li et al., Despite this, Liu et al.'s study stands out by the virtue of being the most updated study regarding this subject, and is therefore expected to have the largest pool of clinical data to support its meta-analysis. However, the study published by Sun et al. in May 2018 in the journal Disease Markers, titled, \u201cSystematic Review and Meta-Analysis of Diagnostic Accuracy of miRNAs in Patients with Pancreatic Cancer,\u201d includes a pool of 40 studies for its meta-analysis when compared to Liu et al.'s 17 studies (Sun et al., Though, it is worth highlighting, that the results of Liu et al.'s study conform to the results presented in aforementioned, previously published papers. All previous studies unanimously declare that the sensitivity and specificity of multiple miRNA profiles are superior to that of single miRNA profiles for pancreatic cancer diagnosis. However, a few single miRNA have been suggested to be more valuable as indicators of pancreatic cancer, compared to other miRNA. Li et al, Sun et al, Wan et al, and Pei et al.'s studies, all describe miR-21 as a promising marker for pancreatic cancer (Wan et al., Additionally, we would like to note that previous studies evaluating diagnostic test accuracy have shown that Chi-square and I-square values alone for analysis of pooled meta-analysis data may not be sufficiently informative as they do not consider threshold effect. In random effects model of meta-analysis, Tau-square value may also be included as the estimated variation or heterogeneity between the effects for test accuracy observed in different studies (Lee et al., Finally, considering the current evidence presented by Li et al., and previous studies, it is clear that miRNAs have potential clinical utility as diagnostic and prognostic markers in Pancreatic Cancer. Although Li et al., study presents potentially interesting data and results, the highlighted issues need to be resolved before it may be considered robust enough a study to be cited by and used for future research in this field.RJ conceived of this critical review and led the development of the letter to the editor. RJ and CK wrote the first draft of the letter, and coordinated and integrated comments from co-authors. SS, and SB critically revised and edited successive drafts of the manuscript. All authors read and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Nanotechnology plays an important role in advancing treatment and diagnosis of a variety of human diseases. The use of nanocarriers often leads to better pharmacokinetic and safety profiles as well as enhanced bioavailability of the entrapped molecules. Several nanoparticle formulations have already been approved by Food and Drug Administration  or have advanced into clinical trials (Andre et al., Certain types of exosomes have been demonstrated to have higher drug delivery efficiency when compared to commonly used nanocarriers (Kim et al., 2O density cushion to eliminate non-exosome proteins and to further reduce sample volume (Escudier et al., Lack of an efficient standardized isolation and purification method is a major challenge for bringing exosome technology into the clinic. It has been reported that exosomes can be isolated and purified by single or combinations of different methods, including immunoaffinity capture, size exclusion, polymeric precipitation, ultracentrifugation, microfluidics techniques, and commercially available kits (Kim et al., in vivo would be an exciting next set of challenges.In addition to developing reliable isolation and purification methods, researchers have recently developed new strategies to load cargos into exosomes. A decade ago, two independent research groups described exosomes as carriers of information and demonstrated their ability to transfer information from one cell type to another (Ratajczak et al., G12D siRNA to target undruggable oncogenic Kras in pancreatic tumor cells in vivo (Kamerkar et al., G12D expression, suppression of cancer cell proliferation, and an increase in overall survival in a mouse model of pancreatic cancer (Kamerkar et al., Another area of intense research is the development of better methods to enhance targeting ability of exosomal nanoparticles for cancer treatment. By utilizing normal human foreskin fibroblast-derived exosomes, Kamerkar and colleagues recently demonstrated the ability of exosomes to efficiently deliver KrasIn summary, recent research has made significant progress in overcoming major barriers for using exosomes as a delivery system. Exosomes are ideal systems for delivering cancer therapeutics, owing to their size, surface expression profiles, low immunogenicity, low cytotoxicity, and long-term safety. Their use has opened a new promising avenue for cancer treatment. Scaling up the production of highly targetable therapeutic exosomes that can be used off-the-shelf which does not require generation from autologous source will be the next critical challenge to bring this promising delivery technology into the clinic.SW initial conceptualization of the article. MY and SW wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Investigations into the relationship between bodily illusions and pain perception are representing a relatively modern trend in cognitive science. Recently, Bauer et al.  publisheThe analgesic effects linked to the vision of the own body  were initially described by Longo et al. . AlthougRHI alone did not change the MPT values significantly\u201d and that this would be in contrast with Martini et al. (In their third control condition Bauer and colleagues asked their participants to close their eyes before the measurement of MPT, so they did not see any stimuli approaching the RH. During this condition a modulation of proprioceptive drift was reported and a high level of ownership was found, but no pain modulation was documented. The authors thus state that \u201cthe induction of the i et al. . Howeveri et al. , has notAnother point worth discussing might be the type of pain chosen to measure the participants' pain threshold: the majority of studies about visual analgesia during RHI/VHI paradigms made use of thermal or electrical stimuli. In Bauer's experiment mechanical stimuli were chosen. The authors explain their preference stating that \u201cMPT is assumed to be closer to clinical pain than thresholds measured with thermal stimuli,\u201d but unfortunately no explanations nor any references were provided to support their assertion. Mechanical, electrical and heat pain threshold have been shown to have some level of independence and can react differently to different modulators (for ex. Tong et al., qualitative data too. What is a praxis for clinical research with patients could be extended to healthy participants as well, to boost interpretability of data and comparability among studies.As a final point, given the high inter-subject variability and the complexity of the \u201cembodiment\u201d phenomenon (Longo et al., The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The publication titled \u201cVertebral Arteriovenous Fistula: An Unwelcome Thrill\u201d by Edwards and his colleagues provided a review of the etiology, pathophysiology, and management of vertebral AV fistulae .Our primary concern centers on the discussion of the possible etiology of their patient's vertebral AV fistulae and its possible relationship to chiropractic manipulation. Edwards et al. claim that \u201cnumerous prior cases of vertebral AVFs report induction by chiropractic manipulation\u201d which is the genesis of our communication. The patient in Edwards et al. case report had sought chiropractic care for chronic neck pain. Although their patient \u201cdid not associate onset of her symptoms with any known physical trauma\u201d Edwards et al. stated that \u201cit is therefore plausible that our patient's fistula was caused by unreported chiropractic manipulation, although this patient's fistula occurred in the distal cervical portion of her vertebral artery, where previous studies have determined that spontaneous vertebral AVFs form most commonly.\u201d opposite. We observed that the patient in our case report suffered from an intracranial AVF, an anatomical location immune to any effects of spinal manipulation. Our case report also observed that \u201cattending physicians initially believed the patient had experienced a rare complication from cervical manipulation, an impression that prevailed for several days, delaying proper intervention. The location and breadth of the patient's ischemia and the absence of similar cases in the literature, should have argued against chiropractic manipulation as the cause of the patient's ascending myelopathy. The admitting physician's prolonged focus on a possible complication from chiropractic manipulation may be characterized as an anchoring bias.\u201dWe believe Edwards et al. incorrectly cited our case report  as scienIn conclusion, we again thank Edwards et al. for providing an excellent overview of an uncommon vascular disorder. Edwards et al. held the role of an unreported chiropractic manipulation as \u201cplausible\u201d for the AVF in their case report. Contrary to the assertion of Edwards et al., our case report does not make an association between chiropractic manipulation and vertebral AVFs. Our case report demonstrated that the potential for attending clinicians to formulate inaccurate etiological opinions of causation is based solely on temporal association in patients with a history of receiving chiropractic manipulation."}
{"text": "The neurocognitive approach points out how reduced self-awareness is related to cerebral disorders, particularly concerning focal lesions, emotional and motivational determinants, and concurrent neuropsychological impairments Palermo, . Given ia lack of self-awareness of deficits.\u201d Indeed, executive-metacognitive dysfunctions have been formerly associated with loss of self-awareness across major neurocognitive disorders likely due to Alzheimer's Disease (AD) and frontotemporal dementia (Amanzio et al., In their brilliant mini-review, Bertrand and colleagues drew attention to the fact that neurological and neuropsychiatric patients can present severe\u2014and often underestimated\u2014impairments in metacognitive abilities that may result in \u201cmetacognition and perspective-taking as a key aspect for improving quality of life in AD patients. These authors specified that \u201cmetacognition refers to the monitoring and regulation of cognitive processes and its impairment can lead to a lack of self-awareness of deficits, or anosognosia\u201d (Bertrand et al., Focusing on AD, Bertrand et al.  dwelt onAnosognosia and reduced self-awareness are frequently used as synonyms in the literature and an overlap between them has been highlighted. This is a delicate question because according to the interpretation given to those terms, the methods of detection and interpretation of the phenomenon could change. This topic was recently treated by Mograbi and Morris . In theithe ability to consciously process information about ourselves in a manner that reflects a relatively objective view while maintaining our unique phenomenological or subjective sense of self \u201d (Prigatano, where the processing in turn operates in a modular manner at any level of the hierarchy, so that damage in one functional domain may result in a different kind of reduced self-awareness\u201d (Palermo et al., In our opinion, the notion of \u201cself-awareness\u201d is not entirely concerned with the concept of \u201canosognosia,\u201d since the former is a complex neuropsychological notion, defined as \u201cBertrand et al.  suggesteThis model was applied by Amanzio et al. , who addirrefutable liaison between executive system dysfuntion, metacognitive disabilities and the occurrence of reduced self-awareness. The issues raised in this commentary have implications in considering executive-metacognitive disabilities as a neuropsychological marker for reduced self-awareness in AD.In conclusion, reduced self-awareness is often observed in AD patients who have suffered major damage to the central executive system. This could be due to the fact that the central executive system is a metacognitive facility of interest in controlling the flow of information in tasks requiring initiation, planning, set-shifting, strategy allocation, monitoring and inhibition (Amanzio et al., We would like to conclude by drawing attention to the fact that this phenomenon is worthy of clinical investigation. Indeed, distinct major neurocognitive disorders, brain pathologies and mood disturbances exhibit executive-metacognitive abnormalities as part of the anomalies of overlapping neural pathways. In this context, ACC hypofunctionality seems to represent one of the relevant underpinnings of a lack of self-awareness (Amanzio et al., The commentary is based on a concept developed by SP who performed the review and critique processes as PI. All the authors listed have contributed to writing the commentary. All authors have approved the submission of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The ongoing interest in organic and perovskite solar cells comes from the forecasted excellent potential for low-cost solar electricity generation that these technologies offer. Organic and perovskite solar cells can be fabricated from abundant materials with high-throughput compatible processes on flexible substrates and promise near future large-scale electricity production as well as novel and alternative applications in buildings, portable electronics or in tandem thin film devices.Research activities on perovskite solar cells have been exploding over the last years and a simple title search including \u2018perovskite solar cell\u2019 in the web of science delivers well over 1500 hits for the time January\u2013October 2018 alone! Likewise, organic solar cells are still in the spotlight and recent advances with ternary blends and non-fullerene acceptors allow now for power conversion efficiencies exceeding 10% almost as a matter of routine.In this Focus Issue of Science and Technology of Advanced Materials, we present a collection of excellent research and review articles on recent milestones in materials development, device architectures and advanced characterization techniques that highlight the great progress that is being made in both photovoltaic technologies.The efficiency of ternary organic solar cells depends on the developing nanostructured network of donor and acceptor phases during film formation. In a typical ternary system for photovoltaic applications, a third sensitizing component is added to an underlying high-performing binary system. However, finding the ideal three-component composition by trial and error is a cumbersome process. The research paper of Makha and Heier et al.  demonstrNewman and Tsoi et al.  carried Two articles are dealing with \u2018photon management\u2019 in organic and perovskite solar cells. Zhang and Toudert  review rThe article of Pascual-San-Jos\u00e9 and Campoy-Quiles et al.  considerBeyond high efficiency, other critical factors are required for a photovoltaic concept to translate from the laboratory to a real-world technology. For perovskite specifically, there is a desire to replace lead, due to toxicology concerns. The review article by Zhang and Lin et al.  outlinesShen and Catchpole et al.  review tFinally, Neukom and Ruhstaller et al.  present We thank all authors that contributed to this Focus Issue."}
{"text": "The intent of this commentary is to constructively contribute to the recently published manuscript by Abbes et al.  by debatAbbes et al.  have selAnother relevant issue concerns the balance between PAP and fatigue, which was widely discussed by the authors (both in the introduction and in the discussion sections). Considering that the initial warm-up was a standard swimming workout (cf. Neiva et al., In swimming in particular, for potentiating performance, it is fundamental that muscular strength increments translate into increased ability to generate propulsive force in water, with technical aspects of swimming mechanics determining the extent to which increased force transfers into faster swimming velocity (Girold et al., The role of inter-individual variation in response to any training load should also be analyzed (Chen et al., Finally, we agree with Abbes et al.  in what JA, CB, and RF have fully reviewed and criticized the original article, drafted the commentary, reviewed, and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Mycobacterium within five genera. In this paper Mycobacterium vulneris  and incompatible with M. vulneris. Therefore, we sequenced the type strain of M. vulneris, DSM 45247T. The genome sequence we obtained (NCXM01000000) found its expected phylogenomic position within the slowly growing species of the Mycobacterium avium complex (Tortoli et al., M. vulneris (van Ingen et al., Mycolicibacterium is inappropriate and recommend the reinstatement of the previous basonym Mycobacterium vulneris (van Ingen et al., We have published a study concerning the genus M. vulneris (EU834055; van Ingen et al., M. vulneris and likely belong to the species M. porcinum. An effect of the misleading power of genomes such as CCBG00000000 present in GenBank. Moreover, a check of all genomes retrieved from GenBank allowed us to detect six further cases of mislabeling (Tortoli et al., Notably, a check of the NCBI WGS sequence database with the 16S rRNA gene sequence of The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Stephen Maisto, Mark Galizio, Gerard J. Connors , 2017, 512 pages, ISBN: 978-1337408974Kids born in the 1990s were prone to a diagnosis of Attention-deficit/hyperactivity disorder, or ADHD (Maisto et al., A psychopharmacology book written by Stephen Maisto, Mark Galizio, and Gerard Connors describes a variety of drugs in great detail. Two main groups of drugs in the book include stimulants and depressants. The drugs classified as depressants consist of alcohol and opiates, such as morphine derivatives or other analgesic drugs (Maisto et al., Amphetamines, methylphenidate, and other stimulants share nearly the same pharmacokinetics (Maisto et al., Journal of the International Neuropsychological Society agrees that in the past 25 years, prevalence of ADHD diagnosis has increased (Mahone and Denckla, But in the book's discussion on stimulants, the medication Ritalin prominently stands out. Methylphenidate carries the brand name of Ritalin, Concerta, or Daytrana. The book by Maisto and associates emphasizes the controversy of prescribing methylphenidate to children with ADHD (Maisto et al., Stephen Maisto and his team of researchers argue that any child can be diagnosed with ADHD (Maisto et al., Journal of Attention Disorders agrees that ADHD negatively impacts focus in school, which was tested on over two hundred college students (Jones et al., However, methylphenidate does improve academic performance and reduces problem-behaviors (Maisto et al., American Journal of Health System Pharmacy (Sugrue et al., The effectiveness of methylphenidate is demonstrated in a research study by the But there are physical side effects of methylphenidate, such as loss of appetite and weight (Maisto et al., Another treatment for ADHD are the amphetamines, such as Adderall or Vyvanse, which are closely rated to methylphenidate (Maisto et al., A drug that is shockingly similar to methylphenidate is methamphetamine, which was created in the nineteenth century (Maisto et al., The pharmacology book authored by Stephen Maisto, Mark Galizio, and Gerard Connors dives into the controversy that methylphenidate is addictive (Maisto et al., Drug Use & Abuse book (Maisto et al., There is even a large market for the illegal sale of methylphenidate (Maisto et al., The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "In her review paper, Dr. Ruth Itzhaki provides evidence that infection with herpes simplex virus type 1 (HSV1) makes a significant risk factor for Alzheimer's Disease (AD). She speculates that the use of antiviral drugs may decrease such a risk. In connection with this, it could be reminded that lithium is a drug, which anti-herpes properties have been documented both in experimental and clinical studies . This enzyme is important in the metabolism of amyloid precursor protein and the phosphorylation of the tau protein, the leading factors in the pathogenesis of the AD. Experimental studies on rats, using cortical and hippocampal neurons, showed that lithium treatment decreases the GSK3 mRNA (Mendes et al., The association between lithium treatment and a decreased risk of dementia was found in big cohorts and many case-control studies (Donix and Bauer, In patients with bipolar disorder, infection with herpes simplex virus type 1 was associated with impaired cognitive functioning (Dickerson et al., To conclude, let me mention two interesting recent papers where a connection between lithium level in drinking water and dementia was investigated. Kessing et al.  performeThe author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Half of all cancer patients may receive radiotherapy as part of their treatment. With the wealth of diverse data generated every day in the clinic, the radiation oncology community possesses a unique advantage in harnessing these massive data with the predictive power of machine learning methods for the benefit of millions of cancer patients undergoing radiotherapy worldwide. In this Research Topic \u201cMachine Learning with Radiation Oncology Big Data,\u201d a wide range of clinical applications involving various machine learning algorithms have been described and demonstrated, with the hope of ushering in more widespread applications of artificial intelligence in medicine, particularly in cancer radiotherapy in order to achieve a truly individualized radiation oncology and an evidence-based learning healthcare system.Zhang et al.- Knowledge-based treatment planning: Tseng et al.- Knowledge-based response-adapted radiotherapy: Elhalawani et al., Jethanandani et al.- Radiomics image analysis: Kang et al.- Radiogenomics and outcome modeling: Jackson et al.,  Ali et al., Men et al.- Automated contouring and nodule detection: Sanders and Showalter.- Comparative effectiveness research: Feng et al.- Machine learning in radiation oncology overview: Gabry\u015b et al.- Normal tissue complication probability modeling: Elhalawani et al. summarized the feedback of eight contestants who participated in a recent radiomics challenge in head and neck radiation oncology, and discussed some of the challenges in sharing and directing existing datasets toward clinical implementation of radiomics in radiation oncology.In this review paper, Tseng et al. discussed recent development in the knowledge-based response-adapted radiotherapy for personalized radiotherapy management. They addressed three specific questions that are necessary to realize it clinically: (1) what knowledge is needed, (2) how to estimate radiotherapy outcomes accurately, and (3) how to adapt optimally.Kang et al. presented an overview of machine learning algorithms in the application of radiogenomics to combine genomics signatures with radiotherapy. They summarized the important lessons learned for the proper integration of machine learning into radiogenomics analysis.Jackson et al. introduced a convolutional neural network approach for fully automated contouring of kidneys and automated radiation dose estimation in an unsealed source therapy, which provides comparable accuracy to humans while largely reducing the planning time.Jethanandani et al. explored the various applications of radiomics in magnetic resonance imaging of head and neck cancer, and identified the lack of standardization in study design as a major limitation to their clinical relevance.In a systematic review, Sanders and Showalter described their vision of combining big data with comparative effectiveness research methodologies within the framework of a rapid-learning healthcare system in order to accelerate discovery and realize a fully individualized radiation treatment.Feng et al. identified specific opportunities in a long chain of radiotherapy processes where machine learning could improve the quality and efficiency of patient care in radiation oncology, as well as the needs required to realize them at both the community and institutional levels.Ali et al. presented a robust non-invasive deep reinforcement learning method to predict the presence of lung nodules, a common precursor to lung cancer, based on 888 lung CT scans of the lung nodule analysis (LUNA) challenge.Zhang et al. proposed an ensemble approach to knowledge-based intensity modulated radiation therapy treatment planning, and demonstrated its advantages in terms of robustness against small training set sizes, mis-labeled cases, and dosimetric inferior plans.Gabry\u015b et al. investigated whether machine learning with dosimetric, radiomic, and demographic features can allow for more precise xerostomia risk assessment. They identified the need for the development of personalized data-driven risk profiles for normal tissue complication probability (NTCP) modeling.Men et al. developed an end-to-end deep deconvolutional neural network for segmentation of nasopharyngeal tumor volumes to improve the consistency of contouring and streamline radiotherapy workflows, but cautioned that careful human review and a considerable amount of editing would still be required.The 11 papers included in this Research Topic produced some promising results and offered visionary perspectives regarding the role of machine learning with radiation oncology big data. The clinical applications demonstrated here are considered just the tip of the iceberg of the incoming full-spectrum applications of human intelligence and artificial intelligence in radiation oncology. While still in its infancy stage, we envisage that artificial intelligence together with human intelligence can provide something much better than either one could perform alone in the near future.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Dear Editor,We have read the article by Meillon et al.  with greChandra et al.  presenteThe majority of the evaluated surgeries were performed under peribulbar or retrobulbar anesthesia. Lid ecchymosis, as a hemorrhagic complication, was present in 1 out of 804 patients. The complications of local anesthesia in cataract surgery were meticulously investigated by Alhassan et al.  in the CFinally, we would like to congratulate the authors for their excellent study in this very important field."}
{"text": "The export of newly synthesized proteins from the endoplasmic reticulum is fundamental to the ongoing maintenance of cell and tissue structure and function. After co-translational translocation into the ER, proteins destined for downstream intracellular compartments or secretion from the cell are sorted and packaged into transport vesicles by the COPII coat protein complex. The fundamental discovery and characterization of the pathway has now been augmented by a greater understanding of the role of COPII in diverse aspects of cell function. We now have a deep understanding of how COPII contributes to the trafficking of diverse cargoes including extracellular matrix molecules, developmental signalling proteins, and key metabolic factors such as lipoproteins. Structural and functional studies have shown that the COPII coat is both highly flexible and subject to multiple modes of regulation. This has led to new discoveries defining roles of COPII in development, autophagy, and tissue organization. Many of these newly emerging features of the canonical COPII pathway are placed in a context of procollagen secretion because of the fundamental interest in how a coat complex that typically generates 80-nm transport vesicles can package a cargo reported to be over 300\u00a0nm. Here we review the current understanding of COPII and assess the current consensus on its role in packaging diverse cargo proteins. Compartmentalization of cells is a common feature of all eukaryotes. This necessitates a transport system to traffic proteins between these compartments. The first membrane trafficking step for most newly synthesized membrane and secretory proteins is from the endoplasmic reticulum (ER) to the Golgi. The transport of proteins out of the ER is enabled by the coat protein complex type II (COPII) vesicles. Since our lab wrote a review on this topic in this journal in 2008  is caused by mutations in Sec23B . Originally named as a gene product fused to the Trk receptor, TFG has since been defined as a key component of the ER exit site , involved in the export of lipoproteins from the ER, has recently been shown to be involved in ERES structure , as well as TANGO1 and KLHL12 , has been shown to occur in interphase [. The Golgi-localized protein kinase CK1\u03b4 (Lord et al. Drosophila, mechanisms have been described that operate to protect the core COPII machinery at times of cellular stress such as amino acid starvation (Zacharogianni et al. The balance between protein folding and ER export is an under-developed area of the COPII field. There is substantial evidence of an important and direct role for COPII in multiple aspects of ER quality control. Notably, an atypical role for COPII has been described in segregating misfolded proteins within the ER (Kakoi et al. As with most areas of classical molecular cell biology much remains to be discovered about the COPII system. How it is adapted in different tissue contexts, in different organisms, and at different stages of development (Ishikawa et al. Salmonella (Santos et al. Listeria (Gianfelice et al. E. coli, and Citrobacter (Thanabalasuriar et al. COPII has defined roles in viral replication including the turnip mosaic virus (Jiang et al. The role of core membrane trafficking pathways in neuronal function remains a relatively underdeveloped field. Dendritic development requires the COPII pathway (Ye et al. Considerable advances in cell biology have been made using small molecule inhibitors. There is some scope here for further development and some early work in this area has already identified potential inhibitors of COPII-dependent budding (Yonemura et al. Our core understanding is also likely to be significantly advanced by more specific and targeted genetic manipulation. The possibilities of functional genomics, genome editing, and further work in model organisms are almost endless. Coupled with the impact of new imaging modalities (Liu et al."}
{"text": "Dear Editor,in vitro tests in toxicology is that a compound is either tested as toxic or non-toxic in vitro and this prediction is then compared to the human in vivo situation for validation. The performance of such binary classification tests is assessed by established metrics, for example, sensitivity as the proportion of actual toxic compounds that were predicted as such; or sensitivity that measures the proportion of compounds that are non-toxic and were correctly predicted as non-toxic by the in vitro test. A frequent scenario concerning predictive in vivo. Recently, Albrecht et al. , informs how well toxic blood concentrations in vivo can be estimated by the in vitro test system. The advantage of these new performance measures is that they can be used to optimize test systems. For example, the authors showed that the use of an EC10 instead of EC50 for cytotoxicity analysis in hepatocytes leads to a higher TSI. Moreover, TEI was improved, when gene expression was included into the test battery, meaning that the lower alert concentration of both, cytotoxicity and gene expression resulted in a better TEI than using the alert concentration of each test individually. Therefore, the TSI and TEI concept allows to modify a test and learn whether the modified version performs better than the original one. Of course, conclusions drawn from a training set of compounds need to be validated in an independent compound set to avoid overfitting. However, measures of the performance of binary classifications become suboptimal, when concentration or dose-dependent analyses are performed and the tests aim at predicting doses that cause an increased risk of toxicity in vivo toxicity by in vitro tests , partical., 2017, 2016[6]al., 2017; Jansen al., 2017), cardioal., 2017; Chaudhaal., 2017), develoal., 2017; Krug etal., 2017) and neual., 2017; Mel\u00e9ndeal., 2017; Shinde al., 2017, 2016[16The author declares no conflict of interest."}
{"text": "In doing so, Brocklehurst et al. cite earlier studies to the same effect dating back to 2009 by Schachner et al. [Brocklehurst et al.  present et al. ,3. The lr et al. ,5.et al. neglected to cite my even earlier work, starting in 2001 [et al. hypothesis [et al.My concern is that Brocklehurst  in 2001 \u20138, whichpothesis , first pet al. analyses cite my studies, they too did not explicitly relate that I had previously examined the contrasts between bird and crocodilian ribcage morphologies and came to similar conclusions. Perhaps that failing to cite the precedent literature contributed to Brocklehurst et al.'s ignorance of who first considered and refuted the Ruben et al. hypothesis.They are not the first to fail to cite some of my innovative arguments on the subject of archosaur respiration. It is especially pertinent to this discussion that while the two Schachner et al. 2009 and 2011 papers in my 2012 discussion of the subject because I was not aware of them. Had I known of the studies I would have included them, the more to support the anatomical comparative hypothesis I originated.I regret that I did not cite the Schachner Hopefully, this note will cause those in the future working on this aspect of archosaur evolution to cite the precedent literature properly, whether or not they agree with it."}
{"text": "This special issue is dedicated to the simulation as well as experimental studies of biomechanical behavior of biomaterials, especially those that are used for bone implant applications. It is worth noting that orthopedic trauma (fractures) alone represented one-half of all the disease or injury-related hospitalizations in 2004\u20132005 . IndividIn the research article written by Mebarki et al. , a solutThe effect of varying levels of medial collateral ligament deficiency on elbow joint stability was studied by Rahman et al.  using suDuring the last decade, the use of bioresorbable metals in biomedical applications  has been an area of considerable interest, with numerous investigations working towards the development of biodegradable bone fixation hardware and stents. Amerinatanzi et al.  developeThe last article in the special issue, written by Nematollahi et al. , provideBioengineering for their valuable contributions.The guest editing team of this special issue would like to thank the authors as well as the staff of"}
{"text": "People commonly reach for over-the-counter (OTC) pain medications to treat even the slightest physical discomfort, whether at work, at home, or on the go. Acetaminophen  tops the charts among popular painkillers, with estimates in the United States suggesting that nearly one in four adults consume a drug containing acetaminophen each week (Kaufman et al., An evolutionary mismatch occurs when there is a major divergence between modern contexts and ancestral environments (reviewed by Li et al., The experience of physical pain provides a clear example of a psychological adaptation. The unpleasantness of physical pain is highly adaptive and critical for survival. Pain draws our attention and serves to motivate responses to alleviate the discomfort. In ancestral conditions, this would have resulted in behavioral changes that functioned to reduce harm, minimize further damage, and prompt us to learn to avoid situations and actions that led to pain in the past. These benefits of physical pain are clearly witnessed among individuals unable to detect it, as those born with the rare condition of congenital insensitivity to pain often die in childhood due to the failure to notice injuries. Thus, there has been continuous selective pressure during the course of evolution to detect and reduce physical discomfort, and as a result most people possess a strong desire to avoid pain through behavioral changes that reduce exposure to harmful stimuli or events.Within modern environments, however, individuals suffering from pain can now bypass behavioral changes and simply treat their symptoms with OTC medication. In fact, acetaminophen has been recommended as the first line of treatment for acute lower back pain (reviewed by Koes et al., A distinct, yet somewhat similar, evolutionary mismatch comes from the fever reducing properties of acetaminophen and many other OTC pain medications. Research shows that acetaminophen and other OTC painkillers are effective and well-tolerated in treating febrile illness (McIntyre and Hull, More recent and thought-provoking lines of research show that acetaminophen can produce further mismatch with our evolved psychology by even diminishing our sensitivity to social experiences that are interpreted as painful or distressing (reviewed by Ratner et al., In a radical set of studies, DeWall et al.  found thFuture research should aim to examine the full range of psychoactive effects produced by acetaminophen and other OTC painkillers. Based on evidence supporting a general cortical dampening produced by acetaminophen (DeWall et al., To date, research examining the psychological effects of acetaminophen and other OTC painkillers is still in its infancy (Ratner et al., The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Cancer is still a global challenge worldwide with a high impact not only on human health, causing morbidity and mortality, but also on economics. Although significant advances have been obtained in early diagnosis and in the development of new drugs, there is still a need of new molecules that contribute to span and improve the actual therapeutic strategies.Natural compounds from animal, microbial, vegetal, or fungi origin represent countless sources of new compounds that can be used as anticancer drugs if their activity, bioavailability, and toxicity are adequate. There are some general  and specIn this special issue original research manuscripts including both pure compounds and whole natural extracts have been included. Chiang et al.  have useThis special issue also contains data on the use of whole extracts and complex mixtures. Araki et al.  present Momordica cochinensis seeds [The last original manuscript of this special issue also studies a complex mixture of natural compounds. Le et al. studied the anticancer potential of a whole natural extract obtained from is seeds . They peReviews are also included in this special issue covering different topics with significant relevance regarding cancer research. Two of these reviews are focused on the pure compound resveratrol. Resveratrol is a stilbene with a long list of biological activities , includiGreen tea polyphenols have been also reviewed in this special issue. Miyata et al.  present Probiotics are also included in this special issue. Hendler et al.  update tA global perspective on the use of natural compounds in cancer treatment is taken by Herranz et al. in their review . In thisFinally, this special issue has met its original objective, contributing to increase the scientific evidence on the use of natural compounds in cancer research and treatment. However, there is a long way ahead, and new studies and evidence must be obtained in the future. Nature is a limitless source of new drugs, but these new drugs must always be supported by strong scientific evidence."}
{"text": "These sAltogether, deciding for and following a specific career path is a developmental process  Wolter et al.), emotional aspects to empathy as predictor for math achievement , and cognitive aspects relate to visuospatial skills that are often seen as key aptitude for STEM with a clear gender difference in favor of men. Abad et al. as well as Sanchis-Segura et al. look deeper into the issue of visuospatial skills raising the point that tests for the respective skills are often subject to gender framing, a background context, that affects their results. Such background contexts can be also found in Hsieh et al.'s work that focuses on ethnicity and immigrant status as predictors for motivational beliefs.Person inputs may affect self-assessments, motivation, behavior, and thus attainments and can be seen as a starting point for a career path into STEM. If, for example, a person finds his or her aptitude in STEM lacking and conceives her or his talents being outside of STEM, she/he is hardly likely to go into a STEM field. Person inputs are investigated with respect to motivational, emotional, cognitive, or socio-demographic aspects. In the studies presented in this Research Topic motivational aspects relate to goal orientations  Sachnis-Segura et al., who discuss how tests for visuospatial performance are constructed (favoring predominantly men), and by Hsieh et al. and Watson et al. who both discuss differences between ethnicities that may include different cultural values.Background contextual affordances relate to culture and cultural norms in which a person is embedded. They provide an indirect impact on all contributions of this Research Topic. The impact of this factor becomes most obvious in the contributions by Learning Experiences(3) Banchefsky et al.;Deiglmayr et al.;H\u00f6hne and Zander). In a long-term process, learning experiences are related to attainments, outcomes, and subsequent feedback and thus mostly need a longitudinal design for their investigation. In the Research Topic, several longitudinal studies are concerned with these variables, especially Dietrich and Lazarides and Hsieh et al. who investigate the development of motivational belief patterns, and Vinni-Laakso et al. as well as Watson et al. who focus on the long-term development of students' self-concept.Learning experiences play a major role in the model of Lent et al.  by shapiSelf-Efficacy and Self-Concept Expectations(4) Watson et al. looks closer into the gender-related decline of the self-concept in mathematics. Factors contributing to such processes and to the development of a student's self-concept for STEM in general are investigated by Heyder et al. who explore the impact of teacher expectations as well as by H\u00f6hne and Zander who analyze the impact of belongingness. The impact of the self-concept on further developments is investigated by Han who analyzes the relationship between self-concept and achievements, by Luttenberger et al. as well as by Sobieraj and Kr\u00e4mer who focus on the relationship between self-concept and motivation in STEM, and by Sa\u00df and Kampa who investigate the impact of self-concept profiles on course selection. Finally, Dietrich and Lazarides as well as Vinni-Laakso et al. analyze to which degree motivational belief patterns are associated with math-related career plans.Self-efficacy expectations, for example, are subject-specific academic self-concept or ability beliefs. Self-efficacy expectations are a crucial aspect of career paths into STEM and often vary by gender. Large scale studies such as PISA OECD,  confirm Expectations About Outcomes(5) Deiglmayr et al. as well as H\u00f6hne and Zander investigate in a sample of female students and the degree to which such beliefs are associated with uncertainty and feelings of not belonging to the domain of STEM even though these students major in a STEM field. Luttenberger et al. investigate the degree to which such beliefs predict motivation in STEM and Lazarides and Lauermann explore how beliefs may affect students' career plans. Hsieh et al. as well as Dicke et al. analyze how such beliefs develop over a long range in different STEM subjects and finally Bailey et al. investigate STEM and non-STEM undergraduates as well as academics discussing to which degree undergraduates' beliefs about talent in academia mirror those of academics.While self-efficacy expectations focus on the estimation of one's own ability, outcome expectations result from an assessment to which degree one's own skills are sufficient to achieve satisfactory outcomes in a field. In this sense, Kessels  discusseContextual Influences Proximal to Choice Behavior(6) Bailey et al. investigate contextual influences exerted by others and take up the hypothesis, that university graduates transfer their  ability beliefs to undergraduates. Such phenomena are in the scope of several contributions of this Research Topic focusing on the influence of teachers , parents , or the peer-group . Apart from these personal influences, STEM subjects are often generally attributed stereotypically as being male, an aspect that is taken up by Makarova et al. as well as by Watson et al., and consequently female students in STEM often choose contexts that are to a lower degree regarded as being typically male subjects, for example biology instead of physics contexts if they are able to choose (see Wheeler and Blanchard). Such stereotypical perspectives may be reinforced by representations in TV, which is investigated by Wille et al. Generally, such stereotypical as well as traditional gender role beliefs taken up from personal contexts predict lower educational attainment and less inclination for studying STEM subjects\u2014an issue that is investigated by Dicke et al.Thereby, Interests and Task Values(7) Song et al. investigate the impact of interest and effort on persistence. However, as Schorr discusses, interest is often subject to pre-conditions including personal competency and outcome expectations. Similarly, Sobieraj and Kr\u00e4mer analyze to which degree self-perceptions are conjoined with interest-related characteristics such as intrinsic motivation. In this sense, Ertl and Hartmann as well as Watt et al. bridge the gap between interest and motivational profiles and respective choice goals and actions. Lazarides and Lauermann investigated this relation with respect to task values and career aspirations.Interests develop and deepen partly due to an individual's self-efficacy and outcome expectations\u2014however, they are also shaped by contextual influences, for example, when interests are regarded as being inappropriate for a specific gender or when pursuing them seems to require too much effort  Ertl and Hartmann analyze to which degree students' interests fit to their career aspirations and they find a worse fit between interest and aspirations for STEM than for other subjects. Watt et al. identify different motivational profiles and discuss that especially disengaged students show lower STEM aspirations. Motivation and motivational belief-patterns and their impact on career plans are also discussed by Dietrich and Lazarides as well as by Lazarides and Lauermann, while Vinni-Laakso et al. analyze the impact of self-concept profiles on science course selection. Makarova et al., finally, expand the view on choice-goal section by discussing the impact of gender-science stereotypes on students' choice goals.Choice goals can be defined as students' career aspirations that either can go along with a student's interests or reveal deviations. Here, Choice Actions(9) Sa\u00df and Kampa aim at explaining science course selection by the impact of self-concept profiles. Sobieraj and Kr\u00e4mer apply a retrospective approach for explaining differences between STEM and non-STEM master students with respect to competence, motivational, and volitional variables.Specific choice actions are less predominant in the Research Topic, possibly because the transformation from a choice goal to a choice action is difficult to observe and to operationalize. Despite of such difficulties, Performance Domains and Attainment(10) Banchefsky et al.) and to interest . Regarding outcomes, Ghazy et al. analyze the role of empathy for math achievement and math scores and find different effects for male and for female students. Han also focuses on math performance scores and find a stereotype effect impeding female pupils. Similarly, Wille et al. investigate STEM stereotypes in a learning context and their differential effects on scores, stereotype endorsement, and belongingness. Sanchis-Segura et al. find similar effects for visuospatial tasks. The effect of framing tasks differently is investigated by Wheeler and Blanchard focusing on how biological contexts may facilitate female students' familiarizing with the context of force rather than traditional physics contexts. Hoferichter and Raufelder investigate the impact of parents' support and pressure on STEM performance and disclose differential effects for female and male students.Ideally, those who have embarked on a STEM career and show persistence should experience satisfying outcomes such as high attainments , feelings of belonging, joy, or life satisfaction. The two contributions which look closer into these concepts show that students' persistence in STEM is related to a feeling of belonging  to adult STEM professionals . In between, all stages of formal education are well-covered including primary school , lower secondary school , and upper secondary school  with a clear focus on university education . Some of these contributions focus on longitudinal developments, for example Abad et al. on the development of visuospatial skills, Dietrich and Lazarides as well as Hsieh et al. on the development of motivational belief patterns, Hoferichter and Raufelder on grades and parental influences, Vinni-Laakso et al. and Watson et al. on students' self-concept, and Dicke et al. on the development of STEM professionals.A specific aim of this Research Topic is to shed light on critical incidents or milestones on a STEM pathway over the life-span. Therefore, the topic covers evidence from kindergarten , with respect to specific subjects as for example in comparisons of mathematics and biology (Hoferichter and Raufelder); research can also refer to science in general  or to a range of different subjects in the field of STEM . Contributions that focus on one subject mostly investigate mathematics as key subject in STEM , followed by computer science  and physics (Wheeler and Blanchard). To uncover the special characteristics of STEM, some authors compare STEM subjects with NON-STEM . The remaining contributions focus on rather general aspects regarding STEM .Although the term STEM raises the impression of being a homogeneous academic domain, there are different definitions which vary in their broadness and some of them even include life sciences and social sciences into STEM (for a discussion, see Ertl et al., Luttenberger, Steinlechner et al. finally comment on the development on an individual's STEM pathway from interests to a career goal and choice actions and its respective facilitation by shedding light on the importance of early career-related learning experiences as well as on removing external barriers on the path into STEM.BE, SL, RL, MJ, and MP wrote this editorial.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "In their correspondence, Hays et al.\u00a0raise two main critiques of our recently published article entitled \u201cUse of the KDQOL-36\u2122 for assessment of health-related quality of life among dialysis patients in the United States.\u201d First, Hays et al. expressed concerns regarding the comparison of mean scores on five Kidney Disease Quality of Life (KDQOL) subscales, given that the Physical Component Summary (PCS) and Mental Component Summary (MCS) are scored on a different numeric scale compared to the other three subscales. Second, Hays et al. note that the correlations reported in our manuscript between the general health perceptions item  and the 5 KDQOL subscales were inconsistent with findings derived from other KDQOL datasets. Here, we respond to these two critiques. We appreciate the detailed review and commentary on our manuscript  providedHays et al. raised an important question with regard to the correlation of the general health rating item and the 5 subscale scores as reported in our manuscript. Upon review, we have determined that indeed the correlations reported in our manuscript were based on analyses that included a coding error. This was an honest mistake that was not captured at the time of submission, and we thank Hays et al. for bringing this to our attention. Upon reanalysis, we find correlations that are broadly consistent with those reported by Hays et al., and our manuscript will be corrected to reflect these findings. Importantly, we have conducted a detailed review of the entire dataset and analysis underlying the remaining results presented in the manuscript and found no additional errors. Thus, we stand by all of the other results and conclusions as originally presented.Improving health-related quality of life, and the tools for its evaluation, remains a top priority for the entire end-stage kidney disease (ESKD) community. Like Hays et al., we believe that successful efforts in this regard will require the combined efforts of patients, providers, and researchers working in both industry and academia. We remain fully committed to participation in these collaborative endeavors."}
{"text": "Oxytocin in mutually-gazing humans and dogs: Rewarding or stress bonding?Nagasawa et al.  build onNagasawa et al.  proposedless on angry faces (Kis et al., eye region of angry faces while physiological arousal was lower (Somppi et al., We want to draw attention to findings that demonstrated that oxytocin may alter social attention by suppressing vigilance toward threatening social stimuli, which explains many of its observed prosocial effects. Moreover, altered social attention may be implicated in a role of oxytocin in social habituation processes, particularly in mammals, whereby an individual decreases their response to an unfamiliar, dominant, or emotional social stimulus after repeated exposure (Ebitz et al., aversive avoidance responses to newborns or potential partners (Insel and Young, Research from animals and human studies suggest a primal function of oxytocin in threat perception, with oxytocin reducing Oxytocin may facilitate attachment formation between humans and dogs through its function in threat-coping responses which increase trust (Tops et al., social reward often neglect the potential role of stress habituation and do not collect measures to support or refute these distinct theories. Taking the results of Nagasawa et al. (Studies which focus on identifying the role of oxytocin in a et al.  for examImportantly, both threat response and positive valence may direct gazing behavior, but the current study does not let us distinguish the two. Moreover, oxytocin responses triggered by low-level threat and by social reward and protection in other contexts may still be implicated in beneficial effects of living in good relationships with dogs impacting on human well-being, coping and health (Julius et al., As the first author, MT was involved in all steps of the process, and was the primary writer of the text. SH and FB-P contributed to the write-up.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Integrins are cell surface receptors that form the link between extracellular matrix molecules of the cell environment and internal cell signalling and the cytoskeleton. They are involved in several processes, e.g. adhesion and migration during development and repair. This review focuses on the role of integrins in axonal regeneration. Integrins participate in spontaneous axonal regeneration in the peripheral nervous system through binding to various ligands that either inhibit or enhance their activation and signalling. Integrin biology is more complex in the central nervous system. Integrins receptors are transported into growing axons during development, but selective polarised transport of integrins limits the regenerative response in adult neurons. Manipulation of integrins and related molecules to control their activation state and localisation within axons is a promising route towards stimulating effective regeneration in the central nervous system. I.The integrin receptor family plays a role in a variety of processes including the development of various tissues et al., et al., et al., The structure of integrins is well characterised and has been described in many reviews via many proteins. Firstly, talin, which interacts with the cytoplasmic tail of integrins, links them directly, or via vinculin, to the actin cytoskeleton. Secondly, focal adhesion kinase (FAK) is recruited to activated integrins and is a key signalling scaffold protein that activates downstream proteins such as paxillin and Src. Thirdly, integrin\u2010linked kinase (ILK) is another important signalling scaffold protein that phosphorylates downstream proteins. Conversely, \u2018inside\u2010out\u2019 signalling refers to the mechanism in which intracellular proteins bind integrins thereby inducing a conformational change that enhances the binding activity of integrins towards their ligands in the ECM, enabling intracellular signalling. Talin and kindlin, the main mediators of inside\u2010out signalling, are subject to various regulatory pathways that thereby affect integrin function et al., et al., in utero), leading to death by 4\u00a0weeks of age in the majority of cases  which in the CNS includes neurons, astrocytes, microglia, oligodendrocytes, and endothelial cells in situ hybridisation and reverse transcription polymerase chain reaction (RT\u2010PCR) studies et al., In order to assess the subcellular localisation of integrin receptors, immunohistochemical approaches or expression of labelled integrins are required. Determining whether integrins are expressed in the axonal or somatodendritic compartment is useful for understanding their potential function. In this regard, numerous studies have examined integrin expression in cultured cells, with fewer studies documenting expression in tissue sections. There are many studies demonstrating integrins in axons during embryonic development, using both immunohistochemistry and staining of cultured embryonic neurons. This is not surprising; integrins are necessary for axon growth during development . Some studies however have succeeded in localising endogenous integrins specifically (see Table\u00a0(3)et al., et al., et al., et al., et al., et al., et al., The neurons that have been shown to regenerate most readily are also those in which integrins are localised within axons. It is therefore interesting to link the subcellular localisation of integrins to the regenerative ability of the nervous system. As discussed above, DRGs express high levels of integrins in their axons and at least some RGC axons contain integrins (see Table\u00a0(4)et al., et al., Discussion on the diverse function of integrins in the somatodendritic compartment is beyond the scope of this review but a recent review can be found in Park & Goda . FurtherIII.et al., et al., et al., et al., et al., et al., Certain integrins are up\u2010regulated after peripheral nerve injury (Kloss (1)et al., et al., in vitro studies have shown that laminin promotes adhesion, migration and regeneration of sensory axons and Schwann cells. The laminin\u2010interacting integrins are \u03b11\u03b21, \u03b12\u03b21, \u03b13\u03b21, \u03b16\u03b21 and \u03b17\u03b21 with each bearing different affinities for the different isoforms of laminin et al., et al., et al., via an Arg\u2010Gly\u2010Asp (RGD) domain, which is also found on other matrix molecules such as tenascin\u2010C and some laminins.Fibronectin is another important component of the ECM that stimulates the pro\u2010regenerative state of PNS neurons. Fibronectin is a large glycoprotein that consists of two subunits which form a dimer  receptor in inflammatory cells. \u03b14\u03b21 and \u03b15\u03b21 integrins are expressed at high levels in native DRG neurons and growth cones of regenerating neurons et al., et al., et al., et al., et al., et al., et al., et al., in vivo. It would therefore be interesting to explore whether activation or overexpression of the collagen\u2010associated integrins is beneficial for regeneration in the PNS.Collagen is another ECM molecule that is highly up\u2010regulated after peripheral nerve injury and is synthesised by Schwann cells and fibroblasts et al., et al., et al., et al., et al., et al., et al., Tenascin\u2010C is a ligand for integrins et al., et al., in vitro, while neurite outgrowth was largely absent in controls  could enhance axonal regeneration (discussed in Section VI.3c).We hypothesised that low or absent integrin expression in CNS axons  (reviewed in Kwok (1)et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., in vitro et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., 2+, thereby inducing clathrin\u2010mediated endocytosis of integrins from the growth cones of Xenopus laevis spinal neurons  is another myelin\u2010derived axon\u2010repulsive molecule (Mukhopadhyay (3)et al., et al., et al., et al., et al., via activation of CSPG receptors such as protein tyrosine phosphatase \u03c3 (PTP\u03c3) et al., et al., et al., et al., et al., et al., et al., et al., et al., via the plexin (PLXN) co\u2010receptor  activation of endosomes that contain ADP\u2010ribosylation factor 6 (ARF6) removes integrins from the cell surface; and (ii) inactivation of R\u2010Ras GTPases, which normally activate integrins  signalling pathway  are classical axon\u2010guidance molecules that are mainly produced by migrating fibroblasts, pericytes and vascular cells in the core of the scar 2+) is widely used in in vitro experiments to enhance the ligand\u2010binding affinity of integrins to the ECM. Divalent cations such as Ca2+ and Mn2+ interact with metal\u2010ion binding sites of the \u03b1 integrin subunit and facilitate integrin signalling et al., et al., et al., in vivo. In addition, masking of epitopes due to integrin interactions with ECM ligands can reduce the efficiency of integrin\u2010binding antibodies et al., et al., et al., et al., et al., et al., The kindlins and talins are two families of intracellular proteins that bind to the cytoplasmic tail of \u03b2 integrins and activate the heterodimeric receptor. Integrin activation is ubiquitous throughout the body, but the exact mechanism of the \u2018inside\u2010out\u2019 activation by kindlin and talin is subject to intense debate (reviewed in Meves (a)et al., et al., et al., et al. et al., et al., et al., et al., et al., in situ hybridisation and RT\u2010PCR studies on whole\u2010brain lysate demonstrated that kindlin\u20102 mRNA is present in the brain, while kindlin\u20101 and kindlin\u20103 were not detected  enhanced the signalling of the integrins that are expressed by DRG neurons. Importantly, kindlin\u20101 promoted neurite outgrowth on the axon\u2010repulsive substrates aggrecan and Nogo\u2010A et al., et al., et al., et al., Integrin\u2010mediated regeneration is most successful when the appropriate integrin is both present and activated. Thus, co\u2010overexpression of kindlin\u20101 and \u03b19 integrin forms a strong stimulus for axonal regeneration in tenascin\u2010C\u2010rich areas such as the dorsal root entry zone and spinal cord after a dorsal root crush et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Integrins are expressed in developing neurons and have essential roles in the formation of a functional nervous system. They are important for migration  (2)et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., in vitro et al., et al., et al., et al., et al., b). These neurons were able to regenerate into BDNF\u2010secreting cell grafts that were placed into subcortical lesions . However, as elaborated above for integrin receptors, additional interventions would be required to enhance the transport of TrkB into the corticospinal tract to promote substantial regeneration after spinal cord injury. In addition, it had been shown in hippocampal slice cultures that the activation state of TrkB correlates with axonal sprouting , neurotrophin\u20103, and neurotrophin\u20104. These neurotrophic factors promote neuronal survival and axonal growth and are involved in synaptic plasticity in vitro . Consistent with the absence of the receptor in the axonal compartment, corticospinal tract axons were not able to regenerate through IGF\u2010secreting cell grafts that were transplanted into the lesion after a spinal cord injury in vivo . Interestingly, the latter study showed that the ceruleospinal and raphespinal axons did regenerate into these grafts. We therefore hypothesise that these two descending motor pathways retained IGFRs in their axonal compartments, but the authors did not examine the receptor expression in these neurons. A recent study took an alternative approach and delivered IGF\u20101 together with osteopontin into the sensorimotor cortex in order to promote corticospinal tract regeneration. Viral vector\u2010mediated delivery of both ligands in the cortex, but not IGF\u20101 or osteopontin alone, promoted axonal regeneration approximately 1\u00a0mm beyond the lesion site after spinal cord hemisection  and has been shown to promote neuronal survival and outgrowth  overcoming the transport block of the axon initial segment and; (ii) stimulation of anterograde transport by modulation of transport vesicles; or (iii) adding axonal localisation signals to growth promoting receptors to enter the axon.Integrins are important mediators of axonal regeneration in the injured nervous system. Integrins stimulate axonal regeneration when they are activated and localised at the growth cone to interact with the ECM. In order to use receptors as potential therapeutic targets to promote axonal regeneration, the mechanisms of axonal transport and trafficking need to be better understood. The successful use of activated integrins to promote regeneration of sensory axons leading to recovery of mechano\u2010 and temperature sensations X.(1) Integrins are localised at the growth cone of immature and regenerating neurons and connect the extracellular and intracellular compartments of the neuron.(2) Matching the extracellular matrix environment with the appropriate integrins promotes limited axonal regeneration of mature neurons.(3) Presence of integrins in the axon correlates with the regenerative capacity of neuronal pathways.(4) Integrins participate in spontaneous axonal regeneration after peripheral nerve injuries.(5) Axon\u2010repulsive molecules at the lesion site of spinal cord injuries inactive integrins and thereby inhibit axonal regeneration in the central nervous system.(6) Stimulation of integrin signalling can overcome the repulsive molecules at the site of injury and promote limited sensory axon regeneration in the central nervous system.(7) Integrins become excluded from the axon during maturation of most central nervous system neurons and this correlates with the loss of the regeneration ability of mature neurons.(8) Pioneering work targeting integrins to the axons of mature neurons to promote regeneration serves as a model for other regeneration\u2010associated receptors that are excluded, such as TrkB and IGF\u20101R.XI.This review was funded by a Nathalie Rose Barr award (NRB110) from the International Spinal Research Trust, a grant from the Medical Research Council (G1000864), an ERA\u2010NET NEURON grant AxonRepair (013\u201016\u2010002) and support from the Hersenstichting Nederland, NWO, and the Laboratory for Regeneration of Sensorimotor Systems at the Netherlands Institute for Neuroscience."}
{"text": "Dear Editor, et al. (2018) rightly draw attention toaffordability issues in most parts of the world, and we now know that over 50% of womenundergoing IVF do not need IVF (Prognostic factors in IUI analyses is a subject both topical and of importance ifpregnancy rates in IUI are to be improved. Although the recent retrospective study("}
{"text": "Transcriptomics has developed into an invaluable tool in chemical hazard identification . Analysis of these genes in hepatocytes incubated with compounds not present in the above mentioned set of 162 test substances showed that at least one of these seven genes was also deregulated in the set of independent compounds.To bridge this gap, Marianna Grinberg and colleagues from Dortmund University recently published the corresponding directory of rat hepatotoxicants . LaboraCurrently, hepatotoxicity represents a major research field in toxicology (Vartak et al., 2016; Godoy e"}
{"text": "We thank Daly-Smith et al. for taking the time to read the results of our pilot research study, describing it as an important and welcome contribution. Nonetheless, the authors argue six points against our conclusion. We contend that we addressed three of these points in our original discussion and disagree with their remaining points. Overall, their Commentary adds little to the topic of research into the Daily Mile\u2122 that we had not already raised in our discussion. Additionally, they attribute statements to us that we did not make and ignore the raising of key issues in our original article. Given this, we stand by our original peer-reviewed conclusion that introducing the Daily Mile\u2122 to the primary school day appears to be an effective intervention for increasing levels of moderate to vigorous physical activity, reducing sedentary time, increasing physical fitness and improving body composition, and that these findings have relevance for teachers, policy-makers, public health practitioners and health researchers. We thank Daly-Smith et al.  for takiDaly-Smith et al.  make sixDaly-Smith et al.  describeIt would have been preferable to assess both the intervention and control schools at the same time of year to avoid any seasonal impact on physical activity. However, we believe that October and March should be similar enough to allow comparison\u201d .arison\u201d Daly-Smith et al.  suggest Daly-Smith et al.  suggest introducing the Daily Mile to the primary school day appears to be an effective intervention for increasing MVPA and reducing sedentary time and it has measurable impacts on key aspects of metabolic health: body composition and physical fitness\u201d ."}
{"text": "Fungi and bacteria are the main terrestrial decomposers as they act in virtually all ecological niches  public databases (Sauget et al., Characterizing and identifying the constituents of microbial assemblages unravel surprising ways microorganisms affect ecosystems and human activities (Peay et al., Estimates on the number of fungi species vary considerably and even as many as 1.5 million species seems to be a conservative number (Hawksworth and L\u00fccking, NL, CS, and MP proposed and conducted the discussions that led to this opinion piece. MS and RC researched the literature and drafted the manuscript. NL, CS, and MP revised the manuscript. All authors approved the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "With interest, we read the recent paper by Nigro et al. on the differential diagnosis of hypernatremia in intensive care unit (ICU) . One of"}