miladalsh/processed_scinews_dataset · Datasets at Hugging Face

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Mosquito control is a crucial global issue for protecting the human community from mosquito-borne diseases. There is an urgent need for the development of selective and safe reagents for mosquito control. Flavonoids, a group of chemical substances with variable phenolic structures, such as daidzein, have been suggested as potential mosquito larvicides with less risk to the environment. However, the mode of mosquito larvicidal action of flavonoids has not been elucidated. Results Here, we report that several flavonoids, including daidzein, inhibit the activity of glutathione S -transferase Noppera-bo (Nobo), an enzyme used for the biosynthesis of the insect steroid hormone ecdysone, in the yellow fever mosquito Aedes aegypti . The crystal structure of the Nobo protein of Ae. aegypti (AeNobo) complexed with the flavonoids and its molecular dynamics simulation revealed that Glu113 forms a hydrogen bond with the flavonoid inhibitors. Consistent with this observation, substitution of Glu113 with Ala drastically reduced the inhibitory activity of the flavonoids against AeNobo. Among the identified flavonoid-type inhibitors, desmethylglycitein (4′,6,7-trihydroxyisoflavone) exhibited the highest inhibitory activity in vitro. Moreover, the inhibitory activities of the flavonoids correlated with the larvicidal activity, as desmethylglycitein suppressed Ae. aegypti larval development more efficiently than daidzein. Conclusion Our study demonstrates the mode of action of flavonoids on the Ae. aegypti Nobo protein at the atomic, enzymatic, and organismal levels. Background Mosquitos act as vectors of many infectious diseases caused by a huge number of pathogens and parasites, epitomized by the spread of malaria [ 1 ]. Despite decades of intensive research, the effective and sustainable management of mosquito vector populations remains a difficult challenge [ 2 , 3 ]. Among vector mosquito species, the mosquitos of the genus Aedes , which includes the yellow fever mosquito Ae. aegypti , are competent vectors of several human infectious viruses, such as the dengue virus, yellow fever virus, and Zika virus. As the Aedes mosquitos are widely distributed, they are recognized as an important factor in the global burden of infectious diseases. Many insecticides have been developed and applied for the control of Aedes vectors [ 2 , 4 ]. However, emergence of resistance in wild Ae. aegypti populations has reduced the efficiency of insecticides [ 4 , 5 , 6 , 7 , 8 ]. For example, although pyrethroids and organophosphates are the most widely used and effective insecticides against Ae. aegypti , resistance to these insecticides has been reported [ 4 ]. In the case of pyrethroid resistance, mutations in a voltage-gated sodium channel gene have been shown to induce a type of resistance known as the knockdown resistance , which has been globally observed in the Ae. aegypti populations [ 4 ]. Therefore, a new insecticide, whose chemical structure and target differ from those of the currently used insecticides, is highly desirable. Flavonoids, which are secondary metabolites from plants and other microorganisms that can affect many aspects of insect development and physiology [ 9 ], can exert larvicidal activity against Ae. aegypti [ 10 ]. For example, flavonoid extracts or purified flavonoids from several plants exhibit larvicidal activity against Ae. aegypti and other vector mosquitos [ 11 , 12 , 13 , 14 , 15 , 16 ]. Culture broths of a species of the actinomycete Streptomyces show toxicity to Ae. aegypti larvae, and this was revealed to be due to several flavonoids, including genistein and daidzein [ 17 ]. It is generally expected that flavonoids are relatively safe, showing less risk to the environment with minimal impacts on animal and human health, and are thought to be beneficial to human health [ 18 , 19 , 20 ]. Therefore, flavonoids could be preferable lead compounds for developing an environment-friendly insecticide to control Ae. aegypti [ 21 , 22 ] . However, the underlying mechanism of action of these flavonoids at the molecular, cellular, and organismal levels remains largely unknown. Although some flavonoids are known to inhibit acetylcholine esterase activity, no correlation is found between larvicidal activity and acetylcholine esterase inhibition [ 14 ]. It is important to understand the modes of action of the flavonoids on larvicidal activity against Ae. aegypti for the development of safe and biorational flavonoidal insecticides for future resistance management. Here, we report that some flavonoids act as the inhibitors of the Ae. aegypti Noppera-bo (AeNobo) protein, which belongs to the glutathione S -transferase (GST) epsilon subfamily. Nobo plays a specialized role in the biosynthesis of the principal insect steroid hormones, ecdysteroids [ 23 , 24 , 25 ]. Similar to other ecdysteroidogenic enzymes [ 26 ], genetic studies have demonstrated that Nobo is required for molting and metamorphosis (i.e., ecdysteroid-dependent developmental processes) in the fruit fly Drosophila melanogaster and the silkworm Bombyx mori [ 23 , 24 , 25 ]. As ecdysteroids are particularly important for the life cycle of insects, it is expected that a chemical inhibitor of ecdysteroidogenic enzymes, including Nobo, would be an insect growth regulator (IGR) that impacts insect development without affecting organisms other than insects [ 27 , 28 ]. Our group has developed a high-throughput screening system to identify chemical compounds that inhibit in vitro enzymatic activity of recombinant purified Nobo proteins [ 29 ]. Using this system, we previously isolated multiple inhibitors of D. melanogaster Nobo (DmNobo) and succeeded in an integrated structure biological analysis to partly reveal the mode of action of these inhibitors, including the vertebrate female sex hormone 17β-estradiol [ 30 , 31 ]. In this study, we expanded our strategy to the AeNobo recombinant protein to identify potential AeNobo inhibitors and demonstrate their mode of action. Results Identification of several flavonoids as AeNobo inhibitors According to a Basic Local Alignment Search Tool database search, an Ae. aegypti gene closest to the D. melanogaster nobo gene is LOC5569853 , annotated by the Ae. aegypti genome database (Locus tag: AaeL_AAEL007955). The GenBank data Accession number XM_001658698.3 predicts that LOC5569853 encodes a protein having 271 amino acid (aa) residues, while another GenBank database EAT40301.1 predicts that LOC5569853 encodes a 220-aa protein. We realized that the", "role": "user" }, { "content": "When most people think of flavonoids, natural compounds found in plants and other organisms, their nutritional benefits probably come to mind first. But these compounds may have another health benefit: Researchers from Japan have discovered that certain flavonoids inhibit development in mosquitoes that can spread disease. In a study published this month in BMC Biology, researchers from the University of Tsukuba have revealed that particular flavonoids inhibit an enzyme involved in the formation of a key insect hormone in the yellow fever mosquito, Aedes aegypti. Mosquito-borne diseases are a major component of the worldwide burden of infectious disease in humans. Aedes aegypti is from a group of mosquitoes that can spread a number of viruses that cause infectious diseases in humans, including dengue fever, yellow fever, and Zika. In the wild, A. aegypti has begun to show resistance to insecticides, revealing a need for new types of pesticides for targeting this species. \"Flavonoids—a type of metabolic product from plants, fungi, and other organisms—can interfere with insect development and physiology, and have the ability to kill larvae of A. aegypti,\" says senior author of the study, professor Ryusuke Niwa. \"Flavonoids are thought to be relatively safe for the environment, as well as human and animal health.\" To investigate how flavonoids can kill mosquito larvae, the researchers analyzed the activities of several flavonoids in A. aegypti, including daidzein, which has previously been identified as a larvicide for this species. The team found that the flavonoids inhibit the activity of glutathione S-transferase Noppera-bo (Nobo); in A. aegypti, Nobo is an enzyme involved in the biosynthesis of the hormone ecdysone. Ecdysone is an insect steroid hormone, or ecdysteroid, required for the initiation of metamorphosis and regulation of molting. Because ecdysteroids are key to the life cycle of insects, chemical inhibitors of enzymes involved in making these hormones, including Nobo, are thought to be insect growth regulators (IGRs) that disrupt development in insects without affecting other organisms. \"We also discovered that, of the flavonoids we tested, desmethylglycitein (DMG) was the most efficient Nobo inhibitor in this species, even more so than daidzein,\" says professor Niwa. \"DMG showed larvicidal activity against A. aegypti, and indicated promise for DMG-based insecticides in the future.\" The high prevalence of resistance in mosquitoes to current insecticides in some areas urgently requires the development of new insecticides with different chemical structures and targeting pathways from those currently in use. The results of this study offer a new avenue for developing new IGRs that are environmentally friendly and can be used for the control of mosquito populations by inhibiting the biosynthesis of ecdysteroids. The article, \"Molecular action of larvicidal flavonoids on ecdysteroidogenic glutathione S-transferase Noppera-bo in Aedes aegypti,\" was published in BMC Biology. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background Mosquito control is a crucial global issue for protecting the human community from mosquito-borne diseases. There is an urgent need for the development of selective and safe reagents for mosquito control. Flavonoids, a group of chemical substances with variable phenolic structures, such as daidzein, have been suggested as potential mosquito larvicides with less risk to the environment. However, the mode of mosquito larvicidal action of flavonoids has not been elucidated. Results Here, we report that several flavonoids, including daidzein, inhibit the activity of glutathione S -transferase Noppera-bo (Nobo), an enzyme used for the biosynthesis of the insect steroid hormone ecdysone, in the yellow fever mosquito Aedes aegypti . The crystal structure of the Nobo protein of Ae. aegypti (AeNobo) complexed with the flavonoids and its molecular dynamics simulation revealed that Glu113 forms a hydrogen bond with the flavonoid inhibitors. Consistent with this observation, substitution of Glu113 with Ala drastically reduced the inhibitory activity of the flavonoids against AeNobo. Among the identified flavonoid-type inhibitors, desmethylglycitein (4′,6,7-trihydroxyisoflavone) exhibited the highest inhibitory activity in vitro. Moreover, the inhibitory activities of the flavonoids correlated with the larvicidal activity, as desmethylglycitein suppressed Ae. aegypti larval development more efficiently than daidzein. Conclusion Our study demonstrates the mode of action of flavonoids on the Ae. aegypti Nobo protein at the atomic, enzymatic, and organismal levels. Background Mosquitos act as vectors of many infectious diseases caused by a huge number of pathogens and parasites, epitomized by the spread of malaria [ 1 ]. Despite decades of intensive research, the effective and sustainable management of mosquito vector populations remains a difficult challenge [ 2 , 3 ]. Among vector mosquito species, the mosquitos of the genus Aedes , which includes the yellow fever mosquito Ae. aegypti , are competent vectors of several human infectious viruses, such as the dengue virus, yellow fever virus, and Zika virus. As the Aedes mosquitos are widely distributed, they are recognized as an important factor in the global burden of infectious diseases. Many insecticides have been developed and applied for the control of Aedes vectors [ 2 , 4 ]. However, emergence of resistance in wild Ae. aegypti populations has reduced the efficiency of insecticides [ 4 , 5 , 6 , 7 , 8 ]. For example, although pyrethroids and organophosphates are the most widely used and effective insecticides against Ae. aegypti , resistance to these insecticides has been reported [ 4 ]. In the case of pyrethroid resistance, mutations in a voltage-gated sodium channel gene have been shown to induce a type of resistance known as the knockdown resistance , which has been globally observed in the Ae. aegypti populations [ 4 ]. Therefore, a new insecticide, whose chemical structure and target differ from those of the currently used insecticides, is highly desirable. Flavonoids, which are secondary metabolites from plants and other microorganisms that can affect many aspects of insect development and physiology [ 9 ], can exert larvicidal activity against Ae. aegypti [ 10 ]. For example, flavonoid extracts or purified flavonoids from several plants exhibit larvicidal activity against Ae. aegypti and other vector mosquitos [ 11 , 12 , 13 , 14 , 15 , 16 ]. Culture broths of a species of the actinomycete Streptomyces show toxicity to Ae. aegypti larvae, and this was revealed to be due to several flavonoids, including genistein and daidzein [ 17 ]. It is generally expected that flavonoids are relatively safe, showing less risk to the environment with minimal impacts on animal and human health, and are thought to be beneficial to human health [ 18 , 19 , 20 ]. Therefore, flavonoids could be preferable lead compounds for developing an environment-friendly insecticide to control Ae. aegypti [ 21 , 22 ] . However, the underlying mechanism of action of these flavonoids at the molecular, cellular, and organismal levels remains largely unknown. Although some flavonoids are known to inhibit acetylcholine esterase activity, no correlation is found between larvicidal activity and acetylcholine esterase inhibition [ 14 ]. It is important to understand the modes of action of the flavonoids on larvicidal activity against Ae. aegypti for the development of safe and biorational flavonoidal insecticides for future resistance management. Here, we report that some flavonoids act as the inhibitors of the Ae. aegypti Noppera-bo (AeNobo) protein, which belongs to the glutathione S -transferase (GST) epsilon subfamily. Nobo plays a specialized role in the biosynthesis of the principal insect steroid hormones, ecdysteroids [ 23 , 24 , 25 ]. Similar to other ecdysteroidogenic enzymes [ 26 ], genetic studies have demonstrated that Nobo is required for molting and metamorphosis (i.e., ecdysteroid-dependent developmental processes) in the fruit fly Drosophila melanogaster and the silkworm Bombyx mori [ 23 , 24 , 25 ]. As ecdysteroids are particularly important for the life cycle of insects, it is expected that a chemical inhibitor of ecdysteroidogenic enzymes, including Nobo, would be an insect growth regulator (IGR) that impacts insect development without affecting organisms other than insects [ 27 , 28 ]. Our group has developed a high-throughput screening system to identify chemical compounds that inhibit in vitro enzymatic activity of recombinant purified Nobo proteins [ 29 ]. Using this system, we previously isolated multiple inhibitors of D. melanogaster Nobo (DmNobo) and succeeded in an integrated structure biological analysis to partly reveal the mode of action of these inhibitors, including the vertebrate female sex hormone 17β-estradiol [ 30 , 31 ]. In this study, we expanded our strategy to the AeNobo recombinant protein to identify potential AeNobo inhibitors and demonstrate their mode of action. Results Identification of several flavonoids as AeNobo inhibitors According to a Basic Local Alignment Search Tool database search, an Ae. aegypti gene closest to the D. melanogaster nobo gene is LOC5569853 , annotated by the Ae. aegypti genome database (Locus tag: AaeL_AAEL007955). The GenBank data Accession number XM_001658698.3 predicts that LOC5569853 encodes a protein having 271 amino acid (aa) residues, while another GenBank database EAT40301.1 predicts that LOC5569853 encodes a 220-aa protein. We realized that the<|im_end|> <|im_start|>assistant When most people think of flavonoids, natural compounds found in plants and other organisms, their nutritional benefits probably come to mind first. But these compounds may have another health benefit: Researchers from Japan have discovered that certain flavonoids inhibit development in mosquitoes that can spread disease. In a study published this month in BMC Biology, researchers from the University of Tsukuba have revealed that particular flavonoids inhibit an enzyme involved in the formation of a key insect hormone in the yellow fever mosquito, Aedes aegypti. Mosquito-borne diseases are a major component of the worldwide burden of infectious disease in humans. Aedes aegypti is from a group of mosquitoes that can spread a number of viruses that cause infectious diseases in humans, including dengue fever, yellow fever, and Zika. In the wild, A. aegypti has begun to show resistance to insecticides, revealing a need for new types of pesticides for targeting this species. "Flavonoids—a type of metabolic product from plants, fungi, and other organisms—can interfere with insect development and physiology, and have the ability to kill larvae of A. aegypti," says senior author of the study, professor Ryusuke Niwa. "Flavonoids are thought to be relatively safe for the environment, as well as human and animal health." To investigate how flavonoids can kill mosquito larvae, the researchers analyzed the activities of several flavonoids in A. aegypti, including daidzein, which has previously been identified as a larvicide for this species. The team found that the flavonoids inhibit the activity of glutathione S-transferase Noppera-bo (Nobo); in A. aegypti, Nobo is an enzyme involved in the biosynthesis of the hormone ecdysone. Ecdysone is an insect steroid hormone, or ecdysteroid, required for the initiation of metamorphosis and regulation of molting. Because ecdysteroids are key to the life cycle of insects, chemical inhibitors of enzymes involved in making these hormones, including Nobo, are thought to be insect growth regulators (IGRs) that disrupt development in insects without affecting other organisms. "We also discovered that, of the flavonoids we tested, desmethylglycitein (DMG) was the most efficient Nobo inhibitor in this species, even more so than daidzein," says professor Niwa. "DMG showed larvicidal activity against A. aegypti, and indicated promise for DMG-based insecticides in the future." The high prevalence of resistance in mosquitoes to current insecticides in some areas urgently requires the development of new insecticides with different chemical structures and targeting pathways from those currently in use. The results of this study offer a new avenue for developing new IGRs that are environmentally friendly and can be used for the control of mosquito populations by inhibiting the biosynthesis of ecdysteroids. The article, "Molecular action of larvicidal flavonoids on ecdysteroidogenic glutathione S-transferase Noppera-bo in Aedes aegypti," was published in BMC Biology. <|im_end|>

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323, 20461, 872, 3941, 315, 1957, 13, 18591, 59776, 315, 3892, 18779, 263, 17390, 439, 90895, 45, 39619, 68642, 10771, 311, 264, 14967, 8949, 33365, 7694, 13782, 4729, 2778, 11, 459, 90895, 13, 264, 797, 88, 418, 72, 15207, 18585, 311, 279, 423, 13, 68012, 540, 2352, 13348, 78, 15207, 374, 28195, 20866, 24961, 18, 1174, 63951, 555, 279, 90895, 13, 264, 797, 88, 418, 72, 33869, 4729, 320, 43, 3466, 4877, 25, 362, 6043, 43, 83041, 2818, 11194, 25875, 570, 578, 9500, 26913, 828, 9742, 290, 1396, 52120, 62, 4119, 23654, 25169, 13, 18, 56978, 430, 28195, 20866, 24961, 18, 3289, 2601, 264, 13128, 3515, 220, 15828, 42500, 13935, 320, 5418, 8, 71783, 11, 1418, 2500, 9500, 26913, 4729, 469, 835, 13074, 1721, 13, 16, 56978, 430, 28195, 20866, 24961, 18, 3289, 2601, 264, 220, 8610, 12, 5418, 13128, 13, 1226, 15393, 430, 279, 128257, 198, 128256, 78191, 198, 4599, 1455, 1274, 1781, 315, 18779, 263, 17390, 11, 5933, 32246, 1766, 304, 11012, 323, 1023, 44304, 11, 872, 43226, 7720, 4762, 2586, 311, 4059, 1176, 13, 2030, 1521, 32246, 1253, 617, 2500, 2890, 8935, 25, 59250, 505, 6457, 617, 11352, 430, 3738, 18779, 263, 17390, 69033, 4500, 304, 83201, 430, 649, 9041, 8624, 13, 763, 264, 4007, 4756, 420, 2305, 304, 82806, 40023, 11, 12074, 505, 279, 3907, 315, 26132, 3178, 31529, 617, 10675, 430, 4040, 18779, 263, 17390, 69033, 459, 49242, 6532, 304, 279, 18488, 315, 264, 1401, 27080, 36908, 304, 279, 14071, 34653, 50646, 11, 362, 59626, 264, 797, 88, 418, 72, 13, 12847, 42196, 1481, 17334, 19338, 527, 264, 3682, 3777, 315, 279, 15603, 23104, 315, 50600, 8624, 304, 12966, 13, 362, 59626, 264, 797, 88, 418, 72, 374, 505, 264, 1912, 315, 83201, 430, 649, 9041, 264, 1396, 315, 42068, 430, 5353, 50600, 19338, 304, 12966, 11, 2737, 294, 833, 361, 34653, 11, 14071, 34653, 11, 323, 82026, 13, 763, 279, 8545, 11, 362, 13, 264, 797, 88, 418, 72, 706, 22088, 311, 1501, 13957, 311, 27080, 76195, 11, 31720, 264, 1205, 369, 502, 4595, 315, 61257, 369, 25103, 420, 9606, 13, 330, 3968, 402, 263, 17390, 29096, 955, 315, 41861, 2027, 505, 11012, 11, 81540, 11, 323, 1023, 44304, 2345, 4919, 40978, 449, 27080, 4500, 323, 78152, 11, 323, 617, 279, 5845, 311, 5622, 83861, 315, 362, 13, 264, 797, 88, 418, 72, 1359, 2795, 10195, 3229, 315, 279, 4007, 11, 14561, 26775, 355, 10647, 22652, 10196, 13, 330, 3968, 402, 263, 17390, 527, 3463, 311, 387, 12309, 6220, 369, 279, 4676, 11, 439, 1664, 439, 3823, 323, 10065, 2890, 1210, 2057, 19874, 1268, 18779, 263, 17390, 649, 5622, 50646, 83861, 11, 279, 12074, 30239, 279, 7640, 315, 3892, 18779, 263, 17390, 304, 362, 13, 264, 797, 88, 418, 72, 11, 2737, 3067, 307, 3059, 258, 11, 902, 706, 8767, 1027, 11054, 439, 264, 45555, 85, 14842, 369, 420, 9606, 13, 578, 2128, 1766, 430, 279, 18779, 263, 17390, 69033, 279, 5820, 315, 35169, 589, 6473, 328, 93791, 521, 452, 18994, 64, 70566, 320, 45, 39619, 1237, 304, 362, 13, 264, 797, 88, 418, 72, 11, 19554, 78, 374, 459, 49242, 6532, 304, 279, 49554, 74767, 315, 279, 36908, 384, 4484, 1065, 606, 13, 469, 4484, 1065, 606, 374, 459, 27080, 77848, 36908, 11, 477, 384, 4484, 22604, 590, 11, 2631, 369, 279, 61568, 315, 88848, 16751, 10934, 323, 19812, 315, 22337, 1303, 13, 9393, 384, 4484, 22604, 17390, 527, 1401, 311, 279, 2324, 11008, 315, 41911, 11, 11742, 68642, 315, 56067, 6532, 304, 3339, 1521, 44315, 11, 2737, 19554, 78, 11, 527, 3463, 311, 387, 27080, 6650, 40242, 320, 1953, 43427, 8, 430, 24927, 4500, 304, 41911, 2085, 28987, 1023, 44304, 13, 330, 1687, 1101, 11352, 430, 11, 315, 279, 18779, 263, 17390, 584, 12793, 11, 951, 76, 42972, 23797, 68175, 258, 320, 8561, 38, 8, 574, 279, 1455, 11297, 19554, 78, 70785, 304, 420, 9606, 11, 1524, 810, 779, 1109, 3067, 307, 3059, 258, 1359, 2795, 14561, 22652, 10196, 13, 330, 8561, 38, 8710, 45555, 45775, 26966, 5820, 2403, 362, 13, 264, 797, 88, 418, 72, 11, 323, 16717, 11471, 369, 20804, 38, 6108, 27080, 76195, 304, 279, 3938, 1210, 578, 1579, 38009, 315, 13957, 304, 83201, 311, 1510, 27080, 76195, 304, 1063, 5789, 77720, 7612, 279, 4500, 315, 502, 27080, 76195, 449, 2204, 11742, 14726, 323, 25103, 44014, 505, 1884, 5131, 304, 1005, 13, 578, 3135, 315, 420, 4007, 3085, 264, 502, 62803, 369, 11469, 502, 358, 8796, 82, 430, 527, 57340, 11919, 323, 649, 387, 1511, 369, 279, 2585, 315, 50646, 22673, 555, 20747, 5977, 279, 49554, 74767, 315, 384, 4484, 22604, 17390, 13, 578, 4652, 11, 330, 44, 43943, 1957, 315, 45555, 45775, 26966, 18779, 263, 17390, 389, 384, 4484, 22604, 590, 29569, 35169, 589, 6473, 328, 93791, 521, 452, 18994, 64, 70566, 304, 362, 59626, 264, 797, 88, 418, 72, 1359, 574, 4756, 304, 82806, 40023, 13, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Insults to the developing cerebellum can cause motor, language, and social deficits. Here, we investigate whether developmental insults to different cerebellar neurons constrain the ability to acquire cerebellar-dependent behaviors. We perturb cerebellar cortical or nuclei neuron function by eliminating glutamatergic neurotransmission during development, and then we measure motor and social behaviors in early postnatal and adult mice. Altering cortical and nuclei neurons impacts postnatal motor control and social vocalizations. Normalizing neurotransmission in cortical neurons but not nuclei neurons restores social behaviors while the motor deficits remain impaired in adults. In contrast, manipulating only a subset of nuclei neurons leaves social behaviors intact but leads to early motor deficits that are restored by adulthood. Our data uncover that glutamatergic neurotransmission from cerebellar cortical and nuclei neurons differentially control the acquisition of motor and social behaviors, and that the brain can compensate for some but not all perturbations to the developing cerebellum. Introduction Cerebellar injury in preterm infants is often associated with movement disorders, language impairments, and social deficits 1 , 2 . Preterm injuries affect the exponential phase of granule cell proliferation, although they often also alter the early development of all glutamatergic neurons in the cerebellum. The resulting defects lead to long-term changes in gray matter volume in the cerebellar cortex that are correlated to the severity of neural deficits in infants 3 , 4 , 5 , 6 . Cerebellar cortical injuries further impact the development and function of downstream cerebellar nuclei neurons, which serve as the predominant output from the cerebellum and link it to the rest of the motor network 7 . Accordingly, cerebellar defects can also impair the development and function of the cerebral cortex 8 , 9 . The combined injury to the cerebellum and neocortex may help explain the broad neural deficits observed in many infants that experience cerebellar injury during the perinatal period. Accumulating evidence suggests that the site of injury within the developing cerebellum may determine behavioral outcomes. When damage is confined to the cerebellar nuclei neuron axons that project and travel through the superior cerebellar peduncle, affected patients (typically children) can develop posterior fossa syndrome, which is hallmarked by ataxia, mutism, and changes in social interactions 10 , 11 . Intriguingly, over time, patients largely recover these impaired neural functions with only minor residual symptoms, most commonly persisting in their motor coordination 12 , 13 . Patients and apes with lesions localized to the cerebellar nuclei mainly demonstrate motor symptoms with limited recovery following the injury 14 , 15 . When the cerebellar cortex is the primary site of the lesion, deficits in social cognition, language, and motor performance arise, but they often persist following the initial injury with limited recovery, especially in the non-motor domains affecting cognition, sociability, language, and affect 1 , 2 . Similarly, studies in rodents have provided compelling evidence that disrupting cerebellar cortical function during development can lead to motor impairments, altered vocalizations, and social deficits 16 , 17 , 18 , 19 , 20 , 21 . These clinical outcomes illustrate that while damage to the cerebellar cortex or to the downstream cerebellar nuclei neurons during infancy is sufficient to impair motor function, language, and social behavior, there are instances when the cerebellum can remarkably overcome perturbations and restore functions. Importantly, the degree of compensation may be linked to the cerebellar neurons that are primarily affected by the lesion, suggesting a unique role for each cerebellar neural subtype in the regulation of cerebellar-associated behaviors. These studies have inspired the need for a deeper examination of how the relatively few neuron types in the cerebellum contribute to a wide range of motor and non-motor functions. However, it remains largely unknown where in the circuit cerebellar-associated behaviors originate, whether the same neuronal subtypes contribute equally to the acquisition of these diverse behaviors, and whether the perturbation of all neuronal subtypes can be equally compensated for during development. Additionally, it remains specifically unexplored how the cerebellar nuclei contribute to the acquisition of different behaviors during postnatal life. Dissecting how cerebellar cortical and cerebellar nuclei neurons contribute to the acquisition of different cerebellar-dependent behaviors requires the use of non-invasive and cell-type specific manipulations during circuit development. Fortunately, the cellular architecture of the cerebellar anlage lends itself to precise genetic approaches. The embryonic cerebellum arises from two distinct lineages that interact to form the cerebellar circuits 22 . The unique identities of the lineages can be used to manipulate GABAergic or glutamatergic cerebellar neurons. The Ptf1a lineage that originates in the ventricular zone gives rise to GABAergic neurons, including GABAergic cerebellar nuclei neurons and Purkinje cells 23 . In contrast, the Atoh1 lineage is derived from the rhombic lip and gives rise to glutamatergic neurons, including glutamatergic granule cells and cerebellar nuclei neurons (Fig. 1a, b, c ) 24 , 25 . Granule cells are the most abundant neuron type in the cerebellum, and they provide the predominant synaptic input to Purkinje cells 26 . In turn, Purkinje cells send convergent projections to their principal targets–glutamatergic and GABAergic cerebellar nuclei neurons 27 . The cerebellar nuclei neurons form the main output of the cerebellum through parallel pathways that project throughout the brain and spinal cord 28 . Fig. 1: Conditional Vglut2 deletion from Atoh1 lineage neurons. a Schematic showing how conditional deletion of VGluT2 only affects fast neurotransmission in VGluT2-expressing neurons. b Schematic of cerebellar connectivity and vesicular transporter expression for the glutamate subtypes (VGluT1 and VGluT2) in the cerebellar circuit in P7 control mice and Atoh1 Cre/+ ;Vglut2 fl/fl conditional knockout mice. c Same as b , but in adult mice. For a – c VGluT1 (blue); VGluT2 (orange); Control mice (black); Atoh1 Cre/+ ;Vglut2 fl/fl mice (reddish purple). d Expression of Vglut2 (green) with DAPI (purple, left) or tdTomato (purple, right) in the cerebellar nuclei (CN) and granule cell layer (gcl) of adult Atoh1 Cre/+ ;Rosa26 lsl-tdTomato mice. e Expression of Vglut2 (green) and DAPI (purple) in the CN and gcl of adult control mice and Atoh1", "role": "user" }, { "content": "The cerebellum, a major part of the hindbrain in all vertebrates, is important for motor coordination, language acquisition, and regulating social and emotional behaviors. A study led by Dr. Roy Sillitoe, professor of Pathology and Neuroscience at Baylor College of Medicine and investigator at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children's Hospital, shows two distinct types of cerebellar neurons differentially regulate motor and non-motor behaviors during development and in adulthood. The study, published in Nature Communications, provides the first in vivo evidence supporting the critical role of a specific subset of excitatory glutamatergic neurons in acquiring motor and sensory/emotional behaviors. Further, it shows that neurons present in different regions of the cerebellum contribute differently to motor versus non-motor behaviors during development and in adulthood. Cerebellar circuits are established by two major types of neurons The cerebellar nuclei are present in the deepest layer of the cerebellum. These nuclei are encased by an outer highly convoluted sheet of tissue called the cerebellar cortex, which contains most of the other types of neurons in the cerebellum. The cerebellar cortex receives information from most parts of the body and other brain regions. These inputs are integrated by many types of cerebellar neurons and the deep-set cerebellar nuclei—the sole output structures in the cerebellum—then send those signals to the other parts of the brain. During development, cerebellar injury in preterm infants is often associated with movement disorders, language impairments, and social deficits. However, growing evidence in patients and animal models suggests that the site of injury and its relative severity determines the type and extent of the resulting symptoms. Unraveling the function of two types of cerebellar neurons \"Our goal in undertaking this study was to determine if excitatory neurons in the cerebellar cortex and cerebellar nuclei act differentially to establish and maintain motor and social behaviors during developmental stages and in adulthood,\" lead author, Dr. Meike van der Heijden, a postdoctoral fellow in the Sillitoe lab at the time of the study, said. \"Several recent studies have hinted at discrete roles for various cerebellar neuronal types and these findings inspired us to conduct a deeper examination of how relatively few neuron types in the cerebellum contribute to a wide range of motor and non-motor functions. When we embarked on this study, very little was known about how circuit cerebellar-associated behaviors originate, and whether the same neuronal subtypes contribute equally to the acquisition of these diverse behaviors.\" Dr. van der Heijden and graduate student in the Sillitoe lab, Alejandro G. Rey Hipolito, focused on the excitatory glutamatergic neuronal lineages in the cerebellum because it is commonly believed that these neuronal lineages drive the majority of cerebellar behaviors. Dissecting the functional contributions of these two neuronal lineages in the acquisition of different cerebellar-dependent behaviors requires the use of non-invasive and cell-type- specific manipulations during circuit development. They employed a combination of intersectional genetics and behavioral paradigms which allowed them to address this question with unparalleled precision and specificity in mice models of various developmental ages. Neurons of the cerebellar cortex control social behaviors whereas cerebellar nuclei neurons regulate motor function The team found silencing the excitatory lineages in the cerebellar cortex and cerebellar nuclei in early postnatal stages by genetically removing the Vglut2 gene from Atoh1-expressing neurons caused severe impairments in both motor and social vocalization behavior in early prenatal stages. However, by the time these Atoh1mutant mice reach adulthood, natural molecular transitions result in the normalization of the cerebellar cortex function, which to their surprise coincided with the restoration of social behaviors and only mild motor deficits in these mice. This finding indicated that early social deficits and delayed acquisition of normal social behaviors in these mice were likely due to the progressive normalization of the function of cerebellar cortex neurons. To test if this hypothesis was true, they eliminated neurotransmission from a subset of glutamatergic nuclei neurons using Ntsr1-cre driver. Upon repeating the same behavioral paradigms, they did not observe any social deficits but observed severe motor deficits in early postnatal mice that were fully resolved with age. \"Together, several major novel findings emerged from our experiments,\" co-first author, Alejandro Rey Hipolito, said. \"First, we were surprised to find that silencing the excitatory neurons did not impair all the cerebellar functions. Second, we observed that glutamatergic neurotransmission from cerebellar cortical versus cerebellar nuclei neurons regulates the acquisition of motor and social behaviors differentially—the cerebellar cortex neurons control the acquisition of social skills whereas the cerebellar nuclei affect the establishment of motor behaviors. Finally, it appears that the brain is able to compensate for some, but not all, perturbations that occur in the developing cerebellum.\" \"This study has not only led to several important discoveries about the roles of different cerebellar neurons but has opened several interesting questions about the role of inhibitory GABAergic nuclei neurons in compensating for the loss of excitatory glutamatergic neurons and restoring the function, which we intend to explore in the future,\" Dr. Sillitoe, added. \"Moreover, these findings offer several exciting and new possibilities to regulate specific cerebellar lineages to restore motor and non-motor functions after brain injury and disease.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Insults to the developing cerebellum can cause motor, language, and social deficits. Here, we investigate whether developmental insults to different cerebellar neurons constrain the ability to acquire cerebellar-dependent behaviors. We perturb cerebellar cortical or nuclei neuron function by eliminating glutamatergic neurotransmission during development, and then we measure motor and social behaviors in early postnatal and adult mice. Altering cortical and nuclei neurons impacts postnatal motor control and social vocalizations. Normalizing neurotransmission in cortical neurons but not nuclei neurons restores social behaviors while the motor deficits remain impaired in adults. In contrast, manipulating only a subset of nuclei neurons leaves social behaviors intact but leads to early motor deficits that are restored by adulthood. Our data uncover that glutamatergic neurotransmission from cerebellar cortical and nuclei neurons differentially control the acquisition of motor and social behaviors, and that the brain can compensate for some but not all perturbations to the developing cerebellum. Introduction Cerebellar injury in preterm infants is often associated with movement disorders, language impairments, and social deficits 1 , 2 . Preterm injuries affect the exponential phase of granule cell proliferation, although they often also alter the early development of all glutamatergic neurons in the cerebellum. The resulting defects lead to long-term changes in gray matter volume in the cerebellar cortex that are correlated to the severity of neural deficits in infants 3 , 4 , 5 , 6 . Cerebellar cortical injuries further impact the development and function of downstream cerebellar nuclei neurons, which serve as the predominant output from the cerebellum and link it to the rest of the motor network 7 . Accordingly, cerebellar defects can also impair the development and function of the cerebral cortex 8 , 9 . The combined injury to the cerebellum and neocortex may help explain the broad neural deficits observed in many infants that experience cerebellar injury during the perinatal period. Accumulating evidence suggests that the site of injury within the developing cerebellum may determine behavioral outcomes. When damage is confined to the cerebellar nuclei neuron axons that project and travel through the superior cerebellar peduncle, affected patients (typically children) can develop posterior fossa syndrome, which is hallmarked by ataxia, mutism, and changes in social interactions 10 , 11 . Intriguingly, over time, patients largely recover these impaired neural functions with only minor residual symptoms, most commonly persisting in their motor coordination 12 , 13 . Patients and apes with lesions localized to the cerebellar nuclei mainly demonstrate motor symptoms with limited recovery following the injury 14 , 15 . When the cerebellar cortex is the primary site of the lesion, deficits in social cognition, language, and motor performance arise, but they often persist following the initial injury with limited recovery, especially in the non-motor domains affecting cognition, sociability, language, and affect 1 , 2 . Similarly, studies in rodents have provided compelling evidence that disrupting cerebellar cortical function during development can lead to motor impairments, altered vocalizations, and social deficits 16 , 17 , 18 , 19 , 20 , 21 . These clinical outcomes illustrate that while damage to the cerebellar cortex or to the downstream cerebellar nuclei neurons during infancy is sufficient to impair motor function, language, and social behavior, there are instances when the cerebellum can remarkably overcome perturbations and restore functions. Importantly, the degree of compensation may be linked to the cerebellar neurons that are primarily affected by the lesion, suggesting a unique role for each cerebellar neural subtype in the regulation of cerebellar-associated behaviors. These studies have inspired the need for a deeper examination of how the relatively few neuron types in the cerebellum contribute to a wide range of motor and non-motor functions. However, it remains largely unknown where in the circuit cerebellar-associated behaviors originate, whether the same neuronal subtypes contribute equally to the acquisition of these diverse behaviors, and whether the perturbation of all neuronal subtypes can be equally compensated for during development. Additionally, it remains specifically unexplored how the cerebellar nuclei contribute to the acquisition of different behaviors during postnatal life. Dissecting how cerebellar cortical and cerebellar nuclei neurons contribute to the acquisition of different cerebellar-dependent behaviors requires the use of non-invasive and cell-type specific manipulations during circuit development. Fortunately, the cellular architecture of the cerebellar anlage lends itself to precise genetic approaches. The embryonic cerebellum arises from two distinct lineages that interact to form the cerebellar circuits 22 . The unique identities of the lineages can be used to manipulate GABAergic or glutamatergic cerebellar neurons. The Ptf1a lineage that originates in the ventricular zone gives rise to GABAergic neurons, including GABAergic cerebellar nuclei neurons and Purkinje cells 23 . In contrast, the Atoh1 lineage is derived from the rhombic lip and gives rise to glutamatergic neurons, including glutamatergic granule cells and cerebellar nuclei neurons (Fig. 1a, b, c ) 24 , 25 . Granule cells are the most abundant neuron type in the cerebellum, and they provide the predominant synaptic input to Purkinje cells 26 . In turn, Purkinje cells send convergent projections to their principal targets–glutamatergic and GABAergic cerebellar nuclei neurons 27 . The cerebellar nuclei neurons form the main output of the cerebellum through parallel pathways that project throughout the brain and spinal cord 28 . Fig. 1: Conditional Vglut2 deletion from Atoh1 lineage neurons. a Schematic showing how conditional deletion of VGluT2 only affects fast neurotransmission in VGluT2-expressing neurons. b Schematic of cerebellar connectivity and vesicular transporter expression for the glutamate subtypes (VGluT1 and VGluT2) in the cerebellar circuit in P7 control mice and Atoh1 Cre/+ ;Vglut2 fl/fl conditional knockout mice. c Same as b , but in adult mice. For a – c VGluT1 (blue); VGluT2 (orange); Control mice (black); Atoh1 Cre/+ ;Vglut2 fl/fl mice (reddish purple). d Expression of Vglut2 (green) with DAPI (purple, left) or tdTomato (purple, right) in the cerebellar nuclei (CN) and granule cell layer (gcl) of adult Atoh1 Cre/+ ;Rosa26 lsl-tdTomato mice. e Expression of Vglut2 (green) and DAPI (purple) in the CN and gcl of adult control mice and Atoh1<|im_end|> <|im_start|>assistant The cerebellum, a major part of the hindbrain in all vertebrates, is important for motor coordination, language acquisition, and regulating social and emotional behaviors. A study led by Dr. Roy Sillitoe, professor of Pathology and Neuroscience at Baylor College of Medicine and investigator at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children's Hospital, shows two distinct types of cerebellar neurons differentially regulate motor and non-motor behaviors during development and in adulthood. The study, published in Nature Communications, provides the first in vivo evidence supporting the critical role of a specific subset of excitatory glutamatergic neurons in acquiring motor and sensory/emotional behaviors. Further, it shows that neurons present in different regions of the cerebellum contribute differently to motor versus non-motor behaviors during development and in adulthood. Cerebellar circuits are established by two major types of neurons The cerebellar nuclei are present in the deepest layer of the cerebellum. These nuclei are encased by an outer highly convoluted sheet of tissue called the cerebellar cortex, which contains most of the other types of neurons in the cerebellum. The cerebellar cortex receives information from most parts of the body and other brain regions. These inputs are integrated by many types of cerebellar neurons and the deep-set cerebellar nuclei—the sole output structures in the cerebellum—then send those signals to the other parts of the brain. During development, cerebellar injury in preterm infants is often associated with movement disorders, language impairments, and social deficits. However, growing evidence in patients and animal models suggests that the site of injury and its relative severity determines the type and extent of the resulting symptoms. Unraveling the function of two types of cerebellar neurons "Our goal in undertaking this study was to determine if excitatory neurons in the cerebellar cortex and cerebellar nuclei act differentially to establish and maintain motor and social behaviors during developmental stages and in adulthood," lead author, Dr. Meike van der Heijden, a postdoctoral fellow in the Sillitoe lab at the time of the study, said. "Several recent studies have hinted at discrete roles for various cerebellar neuronal types and these findings inspired us to conduct a deeper examination of how relatively few neuron types in the cerebellum contribute to a wide range of motor and non-motor functions. When we embarked on this study, very little was known about how circuit cerebellar-associated behaviors originate, and whether the same neuronal subtypes contribute equally to the acquisition of these diverse behaviors." Dr. van der Heijden and graduate student in the Sillitoe lab, Alejandro G. Rey Hipolito, focused on the excitatory glutamatergic neuronal lineages in the cerebellum because it is commonly believed that these neuronal lineages drive the majority of cerebellar behaviors. Dissecting the functional contributions of these two neuronal lineages in the acquisition of different cerebellar-dependent behaviors requires the use of non-invasive and cell-type- specific manipulations during circuit development. They employed a combination of intersectional genetics and behavioral paradigms which allowed them to address this question with unparalleled precision and specificity in mice models of various developmental ages. Neurons of the cerebellar cortex control social behaviors whereas cerebellar nuclei neurons regulate motor function The team found silencing the excitatory lineages in the cerebellar cortex and cerebellar nuclei in early postnatal stages by genetically removing the Vglut2 gene from Atoh1-expressing neurons caused severe impairments in both motor and social vocalization behavior in early prenatal stages. However, by the time these Atoh1mutant mice reach adulthood, natural molecular transitions result in the normalization of the cerebellar cortex function, which to their surprise coincided with the restoration of social behaviors and only mild motor deficits in these mice. This finding indicated that early social deficits and delayed acquisition of normal social behaviors in these mice were likely due to the progressive normalization of the function of cerebellar cortex neurons. To test if this hypothesis was true, they eliminated neurotransmission from a subset of glutamatergic nuclei neurons using Ntsr1-cre driver. Upon repeating the same behavioral paradigms, they did not observe any social deficits but observed severe motor deficits in early postnatal mice that were fully resolved with age. "Together, several major novel findings emerged from our experiments," co-first author, Alejandro Rey Hipolito, said. "First, we were surprised to find that silencing the excitatory neurons did not impair all the cerebellar functions. Second, we observed that glutamatergic neurotransmission from cerebellar cortical versus cerebellar nuclei neurons regulates the acquisition of motor and social behaviors differentially—the cerebellar cortex neurons control the acquisition of social skills whereas the cerebellar nuclei affect the establishment of motor behaviors. Finally, it appears that the brain is able to compensate for some, but not all, perturbations that occur in the developing cerebellum." "This study has not only led to several important discoveries about the roles of different cerebellar neurons but has opened several interesting questions about the role of inhibitory GABAergic nuclei neurons in compensating for the loss of excitatory glutamatergic neurons and restoring the function, which we intend to explore in the future," Dr. Sillitoe, added. "Moreover, these findings offer several exciting and new possibilities to regulate specific cerebellar lineages to restore motor and non-motor functions after brain injury and disease." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Tomato ( Solanum lycopersicum ) has rapidly become a valuable model species for a variety of studies including functional genomics. A high-throughput method to obtain transgenic lines sooner than standard methods would greatly advance gene function studies. The goal of this study was to optimize our current transformation method by investigating medium components that would result in a decreased time for recovery of transgenics. For this study, 6-day-old cotyledon explants from Solanum lycopersicum cultivar M82 in vitro-grown seedlings were infected with the Agrobacterium tumefaciens strain LBA4404 containing the binary vector pBI121. This vector contains the β-glucuronidase reporter gene and the neomycin phosphotransferase II selectable marker gene that confers resistance to kanamycin. Modification of our standard plant regeneration medium with indole-3-acetic acid (IAA) at concentrations of either 0.05 or 0.1 mg/l decreased the recovery time for transgenic lines by 6 weeks as compared to our standard medium that contains zeatin as the only plant growth regulator. We observed 50 and 54 % transformation efficiency on plant regeneration medium containing 0.05 and 0.1 mg/l IAA, respectively. Moreover, addition of 1 mg/l IAA to the root induction medium resulted in earlier root development than medium that did not contain IAA. Addition of IAA to the plant regeneration and rooting media did not have any negative effects on plant development. Recovery of transgenic lines in a shorter time results in higher throughput for the introduction of gene constructs and has the potential to decrease the time and resources needed to complete investigations of gene function. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Tomato, Solanum lycopersicum , is a member of the Solanaceae family, which contains approximately 3000 plant species and includes some of the most economically important food crops. It is native to South America and was brought to Europe in the 1500s and then to North America in the 1800s (Jones 1998 ). Tomato is a perennial plant that has two different growth habits, determinate and indeterminate. There are two different market types of tomatoes, fresh market and processing. According to the Agricultural Marketing Resource Center, in 2014 the US dollar value for fresh market tomatoes was 1.14 and 1.325 billion for processing types, which are used to make products such as juice, sauces, and ketchup (Bombarely et al. 2011 ). In addition to being an economically important food crop, tomato is an excellent source of health beneficial nutrients including beta-carotene and lycopene. Over the years, utilization of tomato as a model plant species has increased because of readily available resources such as mutant populations (Emmanuel and Levy 2002 ), bioinformatics tools (Bombarely et al. 2011 ), and a high quality reference genome (Consortium 2012 ). In addition, since the very first report of Agrobacterium -mediated transformation of tomato by McCormick et al. ( 1986 ), there have been other reports of successful transformations of different genotypes (Chyi and Phillips 1987 ; Fillatti et al. 1987 ; Frary and Earle 1996 ; Park et al. 2003 ; Sun et al. 2006 ; Van Eck et al. 2006 ) and methods to improve transformation efficiency (Dan et al. 2016 ). A key aspect for the adoption of a model plant species is the availability of efficient transformation methodology. This was certainly the case for Arabidopsis , which is by far the most widely used model for plant research programs (Somerville and Koornneef 2002 ). While there are several methods available for plant transformation, Agrobacterium tumefaciens -mediated transformation has become the most extensively used method (Gelvin 2003 ; Pitzschke and Hirt 2010 ). Despite its effectiveness for gene transfer in tomato, there is still need for improvement. Improving methodology to decrease the time from introduction of a gene construct of interest to recovery of stable transgenics would improve the throughput and shorten the timeframe for studies that utilize tomato transgenic lines. We were interested in finding an approach to decrease the time to obtain transgenic lines of the processing type tomato M82 because this genotype is used for gene function studies in our lab as well as others (Brooks et al. 2014 ; Xu et al. 2015 ). We chose to start by investigating supplementation of our standard plant regeneration and rooting media with a growth regulator that had the potential to speed up plant development (Van Eck et al. 2006 ). Cytokinins and auxins are important hormones that influence growth and developmental processes in plants. Interactions between cytokinins and auxins have been shown to be necessary for the shoot apex growth (Gupta and Rashotte 2012 ; Shimizu-Sato et al. 2009 ). Auxin has also been shown to play a role in the specification of the root apical meristem (Friml et al. 2003 ; Gupta and Rashotte 2012 ; Sabatini et al. 1999 ). The hormonal interactions can be utilized in the area of tissue culture to leverage the presence of the hormones in the medium. In this study, we report the effects of the addition of the auxin, indole-3-acetic acid (IAA) on the recovery time of M82 transgenic lines. Materials and methods Plant material Seeds of Solanum lycopersicum cv M82 were surface sterilized in 20 % (v/v) bleach solution containing Tween-20 for 20 min followed by 3 rinses in sterile water. Seeds were germinated in Magenta GA7 boxes (Caisson Labs, Logan, UT) that contained 50 ml of Murashige and Skoog (MS) (Murashige and Skoog 1962 ) (Caisson Labs) based medium containing 2.15 g/l MS salts, 100 mg/l myo-inositol, 2 mg/l thiamine, 0.5 mg/l pyridoxine, 0.5 mg/l nicotinic acid, 10 g/l sucrose and 8 g/l Sigma agar (Sigma-Aldrich, St. Louis, MO). Cultures were maintained at 24 °C under a 16 h light/8 h dark photoperiod at 57–65 µE m −2 s −1 . One day prior to infection with Agrobacterium , cotyledon explants and feeder layer plates were prepared. Feeder layers were prepared before cutting the explants by dispensing 2 ml of a 1-week-old NT1 suspension culture onto KCMS medium [4.3 g/l MS salts, 100", "role": "user" }, { "content": "Tomatoes are already an ideal model species for plant research, but scientists at the Boyce Thompson Institute (BTI) just made them even more useful by cutting the time required to modify their genes by six weeks. While looking for ways to make tomatoes and other crop plants more productive, BTI Assistant Professor Joyce Van Eck and former postdoctoral scientist Sarika Gupta developed a better method for \"transforming\" a tomato—a process that involves inserting DNA into the tomato genome and growing a new plant. By adding the plant hormone auxin to the medium that supports growth of tomato cells, they can speed up the plant's growth, ultimately accelerating the pace of their research. They describe this advance in a study published in Plant Cell, Tissue and Organ Culture. Typically, transformation works by using a soil bacterium called Agrobacterium tumefaciens to insert a new segment of DNA into the cells of tomato seedling tissues. The transformed cells are transplanted onto plant regeneration medium, which contains nutrients and hormones that cause the tissue to grow into a tiny new plant. These plantlets are then transferred to root induction medium where they grow roots, before being planted in soil and hardened in the greenhouse. In the new method, the Van Eck lab adds auxin to the regeneration and rooting media. The addition reduces the length of the procedure from 17 weeks to just 11. A researcher transfers a tomato plantlet into root induction medium to encourage the growth of roots. Credit: Sheryl Sinkow \"If you can speed up the plant development, which is what the auxin is doing, you can decrease the time it takes to get genetically engineered lines,\" said Van Eck. Researchers in the Van Eck lab perform tomato transformations routinely, as a research method to understand how individual genes affect tomato growth and development. Their new protocol not only saves time, but uses fewer materials, and saves money. The researchers can then finish experiments sooner and potentially run more projects at once. The project came out of a collaboration with Cold Spring Harbor Laboratory to identify gene pathways that could be used to breed crops with higher yields. \"We're looking at the genes and gene networks involved in stem cell proliferation, meristem development and flowering and branching,\" said Van Eck, \"with the end goal being that maybe genes that we identify in tomato, which is strictly being used as a model, might help us understand what can be done to increase yield in other crops.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Tomato ( Solanum lycopersicum ) has rapidly become a valuable model species for a variety of studies including functional genomics. A high-throughput method to obtain transgenic lines sooner than standard methods would greatly advance gene function studies. The goal of this study was to optimize our current transformation method by investigating medium components that would result in a decreased time for recovery of transgenics. For this study, 6-day-old cotyledon explants from Solanum lycopersicum cultivar M82 in vitro-grown seedlings were infected with the Agrobacterium tumefaciens strain LBA4404 containing the binary vector pBI121. This vector contains the β-glucuronidase reporter gene and the neomycin phosphotransferase II selectable marker gene that confers resistance to kanamycin. Modification of our standard plant regeneration medium with indole-3-acetic acid (IAA) at concentrations of either 0.05 or 0.1 mg/l decreased the recovery time for transgenic lines by 6 weeks as compared to our standard medium that contains zeatin as the only plant growth regulator. We observed 50 and 54 % transformation efficiency on plant regeneration medium containing 0.05 and 0.1 mg/l IAA, respectively. Moreover, addition of 1 mg/l IAA to the root induction medium resulted in earlier root development than medium that did not contain IAA. Addition of IAA to the plant regeneration and rooting media did not have any negative effects on plant development. Recovery of transgenic lines in a shorter time results in higher throughput for the introduction of gene constructs and has the potential to decrease the time and resources needed to complete investigations of gene function. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Tomato, Solanum lycopersicum , is a member of the Solanaceae family, which contains approximately 3000 plant species and includes some of the most economically important food crops. It is native to South America and was brought to Europe in the 1500s and then to North America in the 1800s (Jones 1998 ). Tomato is a perennial plant that has two different growth habits, determinate and indeterminate. There are two different market types of tomatoes, fresh market and processing. According to the Agricultural Marketing Resource Center, in 2014 the US dollar value for fresh market tomatoes was 1.14 and 1.325 billion for processing types, which are used to make products such as juice, sauces, and ketchup (Bombarely et al. 2011 ). In addition to being an economically important food crop, tomato is an excellent source of health beneficial nutrients including beta-carotene and lycopene. Over the years, utilization of tomato as a model plant species has increased because of readily available resources such as mutant populations (Emmanuel and Levy 2002 ), bioinformatics tools (Bombarely et al. 2011 ), and a high quality reference genome (Consortium 2012 ). In addition, since the very first report of Agrobacterium -mediated transformation of tomato by McCormick et al. ( 1986 ), there have been other reports of successful transformations of different genotypes (Chyi and Phillips 1987 ; Fillatti et al. 1987 ; Frary and Earle 1996 ; Park et al. 2003 ; Sun et al. 2006 ; Van Eck et al. 2006 ) and methods to improve transformation efficiency (Dan et al. 2016 ). A key aspect for the adoption of a model plant species is the availability of efficient transformation methodology. This was certainly the case for Arabidopsis , which is by far the most widely used model for plant research programs (Somerville and Koornneef 2002 ). While there are several methods available for plant transformation, Agrobacterium tumefaciens -mediated transformation has become the most extensively used method (Gelvin 2003 ; Pitzschke and Hirt 2010 ). Despite its effectiveness for gene transfer in tomato, there is still need for improvement. Improving methodology to decrease the time from introduction of a gene construct of interest to recovery of stable transgenics would improve the throughput and shorten the timeframe for studies that utilize tomato transgenic lines. We were interested in finding an approach to decrease the time to obtain transgenic lines of the processing type tomato M82 because this genotype is used for gene function studies in our lab as well as others (Brooks et al. 2014 ; Xu et al. 2015 ). We chose to start by investigating supplementation of our standard plant regeneration and rooting media with a growth regulator that had the potential to speed up plant development (Van Eck et al. 2006 ). Cytokinins and auxins are important hormones that influence growth and developmental processes in plants. Interactions between cytokinins and auxins have been shown to be necessary for the shoot apex growth (Gupta and Rashotte 2012 ; Shimizu-Sato et al. 2009 ). Auxin has also been shown to play a role in the specification of the root apical meristem (Friml et al. 2003 ; Gupta and Rashotte 2012 ; Sabatini et al. 1999 ). The hormonal interactions can be utilized in the area of tissue culture to leverage the presence of the hormones in the medium. In this study, we report the effects of the addition of the auxin, indole-3-acetic acid (IAA) on the recovery time of M82 transgenic lines. Materials and methods Plant material Seeds of Solanum lycopersicum cv M82 were surface sterilized in 20 % (v/v) bleach solution containing Tween-20 for 20 min followed by 3 rinses in sterile water. Seeds were germinated in Magenta GA7 boxes (Caisson Labs, Logan, UT) that contained 50 ml of Murashige and Skoog (MS) (Murashige and Skoog 1962 ) (Caisson Labs) based medium containing 2.15 g/l MS salts, 100 mg/l myo-inositol, 2 mg/l thiamine, 0.5 mg/l pyridoxine, 0.5 mg/l nicotinic acid, 10 g/l sucrose and 8 g/l Sigma agar (Sigma-Aldrich, St. Louis, MO). Cultures were maintained at 24 °C under a 16 h light/8 h dark photoperiod at 57–65 µE m −2 s −1 . One day prior to infection with Agrobacterium , cotyledon explants and feeder layer plates were prepared. Feeder layers were prepared before cutting the explants by dispensing 2 ml of a 1-week-old NT1 suspension culture onto KCMS medium [4.3 g/l MS salts, 100<|im_end|> <|im_start|>assistant Tomatoes are already an ideal model species for plant research, but scientists at the Boyce Thompson Institute (BTI) just made them even more useful by cutting the time required to modify their genes by six weeks. While looking for ways to make tomatoes and other crop plants more productive, BTI Assistant Professor Joyce Van Eck and former postdoctoral scientist Sarika Gupta developed a better method for "transforming" a tomato—a process that involves inserting DNA into the tomato genome and growing a new plant. By adding the plant hormone auxin to the medium that supports growth of tomato cells, they can speed up the plant's growth, ultimately accelerating the pace of their research. They describe this advance in a study published in Plant Cell, Tissue and Organ Culture. Typically, transformation works by using a soil bacterium called Agrobacterium tumefaciens to insert a new segment of DNA into the cells of tomato seedling tissues. The transformed cells are transplanted onto plant regeneration medium, which contains nutrients and hormones that cause the tissue to grow into a tiny new plant. These plantlets are then transferred to root induction medium where they grow roots, before being planted in soil and hardened in the greenhouse. In the new method, the Van Eck lab adds auxin to the regeneration and rooting media. The addition reduces the length of the procedure from 17 weeks to just 11. A researcher transfers a tomato plantlet into root induction medium to encourage the growth of roots. Credit: Sheryl Sinkow "If you can speed up the plant development, which is what the auxin is doing, you can decrease the time it takes to get genetically engineered lines," said Van Eck. Researchers in the Van Eck lab perform tomato transformations routinely, as a research method to understand how individual genes affect tomato growth and development. Their new protocol not only saves time, but uses fewer materials, and saves money. The researchers can then finish experiments sooner and potentially run more projects at once. The project came out of a collaboration with Cold Spring Harbor Laboratory to identify gene pathways that could be used to breed crops with higher yields. "We're looking at the genes and gene networks involved in stem cell proliferation, meristem development and flowering and branching," said Van Eck, "with the end goal being that maybe genes that we identify in tomato, which is strictly being used as a model, might help us understand what can be done to increase yield in other crops." <|im_end|>

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1,967

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Photosynthesis, a process catalysed by plants, algae and cyanobacteria converts sunlight to energy thus sustaining all higher life on Earth. Two large membrane protein complexes, photosystem I and II (PSI and PSII), act in series to catalyse the light-driven reactions in photosynthesis. PSII catalyses the light-driven water splitting process, which maintains the Earth’s oxygenic atmosphere 1 . In this process, the oxygen-evolving complex (OEC) of PSII cycles through five states, S 0 to S 4 , in which four electrons are sequentially extracted from the OEC in four light-driven charge-separation events. Here we describe time resolved experiments on PSII nano/microcrystals from Thermosynechococcus elongatus performed with the recently developed 2 technique of serial femtosecond crystallography. Structures have been determined from PSII in the dark S 1 state and after double laser excitation (putative S 3 state) at 5 and 5.5 Å resolution, respectively. The results provide evidence that PSII undergoes significant conformational changes at the electron acceptor side and at the Mn 4 CaO 5 core of the OEC. These include an elongation of the metal cluster, accompanied by changes in the protein environment, which could allow for binding of the second substrate water molecule between the more distant protruding Mn (referred to as the ‘dangler’ Mn) and the Mn 3 CaO x cubane in the S 2 to S 3 transition, as predicted by spectroscopic and computational studies 3 , 4 . This work shows the great potential for time-resolved serial femtosecond crystallography for investigation of catalytic processes in biomolecules. Main The first X-ray structure of PSII was determined to a resolution of 3.8 Å in 2001 (ref. 5 ) revealing the protein’s architecture and the overall shape and location of the OEC. In 2011, Shen and co-workers achieved a breakthrough in the structural elucidation by dramatically improving crystal quality, enabling determination at 1.9 Å resolution 6 . This structure showed the OEC at near atomic resolution. However, the OEC was probably affected by X-ray damage, a fundamental problem in X-ray crystallography. The X-ray damage problem may be overcome through the use of serial femtosecond crystallography (SFX) 2 , 7 , 8 , an advance enabled by the advent of the X-ray free electron laser (XFEL). In SFX, a stream of microcrystals in their mother liquor is exposed to intense 120 Hz femtosecond XFEL pulses, thereby collecting millions of X-ray diffraction ‘snapshots’ in a time-frame of hours. Each X-ray FEL pulse is so intense that it destroys the sample; however, the pulse duration is so short that diffraction is observed before destruction occurs 9 . Conventional X-ray structures correspond to a temporal and spatially averaged representation of biomolecules, leading to a ‘static’ picture. To capture dynamic processes such as water oxidation in PSII, time-resolved X-ray data can be collected using SFX 10 , 11 , 12 . Conformational changes may be observed at a time-resolution ranging from femtoseconds to microseconds by combining visible laser excitation with the SFX setup and varying time delays between the optical pump and the X-ray probe snapshot. As partial reflections from crystals in random orientations are recorded, many snapshots must be collected for adequate sampling of the full reflections and three-dimensional reconstruction. A time-resolved pump-probe experiment was performed in 2010 using PSI-ferredoxin crystals as a model system, in which changes in diffraction intensities, consistent with a light-induced electron transfer process in the PSI-ferredoxin complex and dissociation of the PSI-ferredoxin complex were seen 10 . The catalytic reaction in PSII is a dynamic process. The oxygen evolution reaction is catalysed by the oxygen-evolving complex (OEC), in which the electrons are extracted from the OEC in four sequential charge separation events through the S-state cycle (Kok cycle), as shown in Fig. 1a (see ref. 1 for a review). SFX diffraction and X-ray emission spectroscopy (XES) were reported investigating the dark S 1 state and the single flash (S 2 state) of PSII 13 . The XES data show that the electronic structure of the highly radiation sensitive Mn 4 CaO 5 cluster does not change during femtosecond X-ray exposure 13 . However, the quantity and quality of X-ray diffraction data was insufficient to determine if any structural changes occurred. Figure 1: Experimental schemes for the time-resolved serial femtosecond crystallography experiments on photosystem II. a , S-state scheme of the oxygen-evolving complex depicting changes the oxidation state of the 4 manganese ions of the Mn 4 CaO 5 cluster in the S-state cycle (*note that the oxidation states of the Mn atoms in the S 4 state are still under debate). The scheme also indicates the reduction of the plastoquinone (PQ) to plastoquinol (PQH 2 ) in the Q B site. The blank boxes represent the unoccupied PQ B binding site. b, Experimental setup. The crystal-stream of photosystem II, was exposed to two subsequent optical laser pulses at 527 nm before interacting with the femtosecond X-ray FEL pulses. With a FEL frequency of 120 Hz and triggering of the laser at 60 Hz, X-ray diffraction patterns from crystals in the dark state and ‘light’ double-flash state alternate. c , Laser excitation scheme. The first 527 nm laser pulse excited the crystals 110 μs after the trigger pulse. The delay time between the first and second 527 nm laser pulse was 210 μs, with X-ray diffraction data collected 570 μs after the second laser pulse. PowerPoint slide Full size image We report on microsecond time-resolved SFX experiments conducted at the CXI instrument 14 at the Linac Coherent Light Source (LCLS) 15 . The experimental setup is shown in Fig. 1b, c . We developed a multiple-laser illumination scheme that progressively excites the OEC in dark-adapted PSII nano/microcrystals by two laser pulses from the dark S 1 state via the S 2 state to the double-flash putative S 3 state. Not all PSII centres progress to the next S-state by a single saturating flash which could lead to heterogeneities. Therefore the S-state reached in the double-flash experiment is indicated as ‘putative S 3 state’ here. The diffraction patterns collected", "role": "user" }, { "content": "An international team, led by Arizona State University scientists, has published today in Nature a groundbreaking study that shows the first snapshots of photosynthesis in action as it splits water into protons, electrons and oxygen, the process that maintains Earth's oxygen atmosphere. \"This study is the first step towards our ultimate goal of unraveling the secrets of water splitting and obtaining molecular movies of biomolecules,\" said Petra Fromme, professor of chemistry and biochemistry at ASU. Fromme is the senior author and leader of the international team, which reported their work in \"Serial time-resolved crystallography of photosystem II using a femtosecond X-ray laser,\" in the July 9 on-line issue of Nature. Photosynthesis is one of the fundamental processes of life on Earth. The early Earth contained no oxygen and was converted to the oxygen-rich atmosphere we have today 2.5 billion years ago by the \"invention\" of the water splitting process in Photosystem II (PSII). All higher life on Earth depends on this process for its energy needs and PSII produces the oxygen we breathe, which ultimately keeps us alive. The revealing of the mechanism of this water splitting process is essential for the development of artificial systems that mimic and surpass the efficiency of natural systems. The development of an \"artificial leaf\" is one of the major goals of the ASU Center for Bio-Inspired Solar Fuel Production, which was the main supporter of this study. \"A crucial problem facing our Center for Bio-Inspired Fuel Production (Bisfuel) at ASU and similar research groups around the world is discovering an efficient, inexpensive catalyst for oxidizing water to oxygen gas, hydrogen ions and electrons,\" said ASU Regents' Professor and Center Director Devens Gust. \"Photosynthetic organisms already know how to do this, and we need to know the details of how photosynthesis carries out the process using abundant manganese and calcium. \"The research by Fromme and coworkers gives us, for the very first time, a look at how the catalyst changes its structure while it is working,\" Gust added. \"Once the mechanism of photosynthetic water oxidation is understood, chemists can begin to design artificial photosynthetic catalysts that will allow them to produce useful fuels using sunlight.\" In photosynthesis, oxygen is produced at a special metal site containing four manganese atoms and one calcium atom connected together as a metal cluster. This oxygen-evolving cluster is bound to the protein PSII that catalyzes the light driven process of water splitting. It requires four light flashes to extract one molecule of oxygen from two water molecules bound to the metal cluster. Fromme states that there are two major drawbacks to obtaining structural and dynamical information on this process by traditional X-ray crystallography. First, the pictures one can obtain with standard structural determination methods are static. Second, the quality of the structural information is adversely affected by X ray damage. \"The trick is to use the world's most powerful X-ray laser, named LCLS located at the Department of Energy's SLAC National Accelerator Laboratory,\" said Fromme. \"Extremely fast femtosecond (10-15 second) laser pulses record snapshots of the PSII crystals before they explode in the X-ray beam, a principle called 'diffraction before destruction.'\" In this way, snapshots of the process of water splitting are obtained damage free. The ultimate goal of the work is to record molecular movies of water splitting. The team performed the time-resolved femtosecond crystallography experiments on Photosystem II nanocrystals, which are so small that you can hardly see them even under a microscope. The crystals are hit with two green laser flashes before the structural changes are elucidated by the femtosecond X-ray pulses. The researchers discovered large structural changes of the protein and the metal cluster that catalyzes the reaction. The cluster significantly elongates, thereby making room for a water molecule to move in. \"This is a major step toward the goal of making a movie of the molecular machine responsible for photosynthesis, the process by which plants make the oxygen we breathe, from sunlight and water,\" explained John Spence, ASU Regents' Professor of physics, team member and scientific leader of the National Science Foundation funded BioXFEL Science and Technology Center, which develops methods for biology with free electron lasers. ASU recently made a large commitment to the groundbreaking work of the femtosecond crystallography team by planning to establish a new Center for Applied Structural Discovery at the Biodesign Institute at ASU. The center will be led by Petra Fromme. Student role in research An interdisciplinary team of eight ASU faculty members from the Department of Chemistry and Biochemistry (Petra Fromme, Alexandra Ros, Tom Moore and Anna Moore) and the Department of Physics (John Spence, Uwe Weierstall, Kevin Schmidt and Bruce Doak) worked together with national and international collaborators on this project. The results were made possible by the excellent work of current ASU graduate students Christopher Kupitz, Shibom Basu, Daniel James, Dingjie Wang, Chelsie Conrad, Shatabdi Roy Chowdhury, Jay-How Yang and ASU doctoral graduates and post-docs Kimberley Rendek, Mark Hunter, Jesse Bergkamp, Tzu-Chiao Chao and Richard Kirian. Two undergraduate students Danielle Cobb and Brenda Reeder supported the team and gained extensive research experience by working hand in hand with graduate students, researchers and faculty at the free electron laser at Stanford. Four ASU senior scientists and postdoctoral researchers (Ingo Grotjohann, Nadia Zatsepin, Haiguang Liu and Raimund Fromme) supported the faculty in the design, planning and execution of the experiments, and were instrumental in evaluation of the data. The first authorship of the paper is jointly held by the ASU graduate students Christopher Kupitz, who's dissertation is based on the development of new techniques for the growth and biophysical characterization of nanocrystals; and Shibom Basu, who devoted three years of his doctoral work to the development of the data evaluation methods. \"It is so exciting to be a part of this groundbreaking research and to have the opportunity to participate in this incredible international collaboration,\" said Kupitz, who will graduate this summer with a Ph.D. in biochemistry. \"I joined the project because it fascinates me to work at the LCLS accelerator on this important biological project.\" \"The most exciting aspect of the work on Photosystem II is the prospect of making molecular movies to witness the water splitting process through time-resolved crystallography,\" added Basu. National and international collaborators on the project include the team of Henry Chapman at DESY in Hamburg, Germany, who with the ASU team and researchers at the MPI in Heidelberg pioneered the new method of serial femtosecond crystallography. Other collaborators included a team led by Matthias Frank, an expert on laser spectroscopy and time-resolved studies with FELs at Lawrence Livermore National Laboratory, and the team of Yulia Pushkar at Purdue University, who supported the work with characterization of the crystals by electron paramagnetic resonance. \"We're tantalizingly close,\" said Chapman of the Center for Free-Electron Laser Science at DESY and a pioneer in X-ray free laser studies of crystallized proteins. \"I think this shows that we really are on the right track and it will work.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Photosynthesis, a process catalysed by plants, algae and cyanobacteria converts sunlight to energy thus sustaining all higher life on Earth. Two large membrane protein complexes, photosystem I and II (PSI and PSII), act in series to catalyse the light-driven reactions in photosynthesis. PSII catalyses the light-driven water splitting process, which maintains the Earth’s oxygenic atmosphere 1 . In this process, the oxygen-evolving complex (OEC) of PSII cycles through five states, S 0 to S 4 , in which four electrons are sequentially extracted from the OEC in four light-driven charge-separation events. Here we describe time resolved experiments on PSII nano/microcrystals from Thermosynechococcus elongatus performed with the recently developed 2 technique of serial femtosecond crystallography. Structures have been determined from PSII in the dark S 1 state and after double laser excitation (putative S 3 state) at 5 and 5.5 Å resolution, respectively. The results provide evidence that PSII undergoes significant conformational changes at the electron acceptor side and at the Mn 4 CaO 5 core of the OEC. These include an elongation of the metal cluster, accompanied by changes in the protein environment, which could allow for binding of the second substrate water molecule between the more distant protruding Mn (referred to as the ‘dangler’ Mn) and the Mn 3 CaO x cubane in the S 2 to S 3 transition, as predicted by spectroscopic and computational studies 3 , 4 . This work shows the great potential for time-resolved serial femtosecond crystallography for investigation of catalytic processes in biomolecules. Main The first X-ray structure of PSII was determined to a resolution of 3.8 Å in 2001 (ref. 5 ) revealing the protein’s architecture and the overall shape and location of the OEC. In 2011, Shen and co-workers achieved a breakthrough in the structural elucidation by dramatically improving crystal quality, enabling determination at 1.9 Å resolution 6 . This structure showed the OEC at near atomic resolution. However, the OEC was probably affected by X-ray damage, a fundamental problem in X-ray crystallography. The X-ray damage problem may be overcome through the use of serial femtosecond crystallography (SFX) 2 , 7 , 8 , an advance enabled by the advent of the X-ray free electron laser (XFEL). In SFX, a stream of microcrystals in their mother liquor is exposed to intense 120 Hz femtosecond XFEL pulses, thereby collecting millions of X-ray diffraction ‘snapshots’ in a time-frame of hours. Each X-ray FEL pulse is so intense that it destroys the sample; however, the pulse duration is so short that diffraction is observed before destruction occurs 9 . Conventional X-ray structures correspond to a temporal and spatially averaged representation of biomolecules, leading to a ‘static’ picture. To capture dynamic processes such as water oxidation in PSII, time-resolved X-ray data can be collected using SFX 10 , 11 , 12 . Conformational changes may be observed at a time-resolution ranging from femtoseconds to microseconds by combining visible laser excitation with the SFX setup and varying time delays between the optical pump and the X-ray probe snapshot. As partial reflections from crystals in random orientations are recorded, many snapshots must be collected for adequate sampling of the full reflections and three-dimensional reconstruction. A time-resolved pump-probe experiment was performed in 2010 using PSI-ferredoxin crystals as a model system, in which changes in diffraction intensities, consistent with a light-induced electron transfer process in the PSI-ferredoxin complex and dissociation of the PSI-ferredoxin complex were seen 10 . The catalytic reaction in PSII is a dynamic process. The oxygen evolution reaction is catalysed by the oxygen-evolving complex (OEC), in which the electrons are extracted from the OEC in four sequential charge separation events through the S-state cycle (Kok cycle), as shown in Fig. 1a (see ref. 1 for a review). SFX diffraction and X-ray emission spectroscopy (XES) were reported investigating the dark S 1 state and the single flash (S 2 state) of PSII 13 . The XES data show that the electronic structure of the highly radiation sensitive Mn 4 CaO 5 cluster does not change during femtosecond X-ray exposure 13 . However, the quantity and quality of X-ray diffraction data was insufficient to determine if any structural changes occurred. Figure 1: Experimental schemes for the time-resolved serial femtosecond crystallography experiments on photosystem II. a , S-state scheme of the oxygen-evolving complex depicting changes the oxidation state of the 4 manganese ions of the Mn 4 CaO 5 cluster in the S-state cycle (*note that the oxidation states of the Mn atoms in the S 4 state are still under debate). The scheme also indicates the reduction of the plastoquinone (PQ) to plastoquinol (PQH 2 ) in the Q B site. The blank boxes represent the unoccupied PQ B binding site. b, Experimental setup. The crystal-stream of photosystem II, was exposed to two subsequent optical laser pulses at 527 nm before interacting with the femtosecond X-ray FEL pulses. With a FEL frequency of 120 Hz and triggering of the laser at 60 Hz, X-ray diffraction patterns from crystals in the dark state and ‘light’ double-flash state alternate. c , Laser excitation scheme. The first 527 nm laser pulse excited the crystals 110 μs after the trigger pulse. The delay time between the first and second 527 nm laser pulse was 210 μs, with X-ray diffraction data collected 570 μs after the second laser pulse. PowerPoint slide Full size image We report on microsecond time-resolved SFX experiments conducted at the CXI instrument 14 at the Linac Coherent Light Source (LCLS) 15 . The experimental setup is shown in Fig. 1b, c . We developed a multiple-laser illumination scheme that progressively excites the OEC in dark-adapted PSII nano/microcrystals by two laser pulses from the dark S 1 state via the S 2 state to the double-flash putative S 3 state. Not all PSII centres progress to the next S-state by a single saturating flash which could lead to heterogeneities. Therefore the S-state reached in the double-flash experiment is indicated as ‘putative S 3 state’ here. The diffraction patterns collected<|im_end|> <|im_start|>assistant An international team, led by Arizona State University scientists, has published today in Nature a groundbreaking study that shows the first snapshots of photosynthesis in action as it splits water into protons, electrons and oxygen, the process that maintains Earth's oxygen atmosphere. "This study is the first step towards our ultimate goal of unraveling the secrets of water splitting and obtaining molecular movies of biomolecules," said Petra Fromme, professor of chemistry and biochemistry at ASU. Fromme is the senior author and leader of the international team, which reported their work in "Serial time-resolved crystallography of photosystem II using a femtosecond X-ray laser," in the July 9 on-line issue of Nature. Photosynthesis is one of the fundamental processes of life on Earth. The early Earth contained no oxygen and was converted to the oxygen-rich atmosphere we have today 2.5 billion years ago by the "invention" of the water splitting process in Photosystem II (PSII). All higher life on Earth depends on this process for its energy needs and PSII produces the oxygen we breathe, which ultimately keeps us alive. The revealing of the mechanism of this water splitting process is essential for the development of artificial systems that mimic and surpass the efficiency of natural systems. The development of an "artificial leaf" is one of the major goals of the ASU Center for Bio-Inspired Solar Fuel Production, which was the main supporter of this study. "A crucial problem facing our Center for Bio-Inspired Fuel Production (Bisfuel) at ASU and similar research groups around the world is discovering an efficient, inexpensive catalyst for oxidizing water to oxygen gas, hydrogen ions and electrons," said ASU Regents' Professor and Center Director Devens Gust. "Photosynthetic organisms already know how to do this, and we need to know the details of how photosynthesis carries out the process using abundant manganese and calcium. "The research by Fromme and coworkers gives us, for the very first time, a look at how the catalyst changes its structure while it is working," Gust added. "Once the mechanism of photosynthetic water oxidation is understood, chemists can begin to design artificial photosynthetic catalysts that will allow them to produce useful fuels using sunlight." In photosynthesis, oxygen is produced at a special metal site containing four manganese atoms and one calcium atom connected together as a metal cluster. This oxygen-evolving cluster is bound to the protein PSII that catalyzes the light driven process of water splitting. It requires four light flashes to extract one molecule of oxygen from two water molecules bound to the metal cluster. Fromme states that there are two major drawbacks to obtaining structural and dynamical information on this process by traditional X-ray crystallography. First, the pictures one can obtain with standard structural determination methods are static. Second, the quality of the structural information is adversely affected by X ray damage. "The trick is to use the world's most powerful X-ray laser, named LCLS located at the Department of Energy's SLAC National Accelerator Laboratory," said Fromme. "Extremely fast femtosecond (10-15 second) laser pulses record snapshots of the PSII crystals before they explode in the X-ray beam, a principle called 'diffraction before destruction.'" In this way, snapshots of the process of water splitting are obtained damage free. The ultimate goal of the work is to record molecular movies of water splitting. The team performed the time-resolved femtosecond crystallography experiments on Photosystem II nanocrystals, which are so small that you can hardly see them even under a microscope. The crystals are hit with two green laser flashes before the structural changes are elucidated by the femtosecond X-ray pulses. The researchers discovered large structural changes of the protein and the metal cluster that catalyzes the reaction. The cluster significantly elongates, thereby making room for a water molecule to move in. "This is a major step toward the goal of making a movie of the molecular machine responsible for photosynthesis, the process by which plants make the oxygen we breathe, from sunlight and water," explained John Spence, ASU Regents' Professor of physics, team member and scientific leader of the National Science Foundation funded BioXFEL Science and Technology Center, which develops methods for biology with free electron lasers. ASU recently made a large commitment to the groundbreaking work of the femtosecond crystallography team by planning to establish a new Center for Applied Structural Discovery at the Biodesign Institute at ASU. The center will be led by Petra Fromme. Student role in research An interdisciplinary team of eight ASU faculty members from the Department of Chemistry and Biochemistry (Petra Fromme, Alexandra Ros, Tom Moore and Anna Moore) and the Department of Physics (John Spence, Uwe Weierstall, Kevin Schmidt and Bruce Doak) worked together with national and international collaborators on this project. The results were made possible by the excellent work of current ASU graduate students Christopher Kupitz, Shibom Basu, Daniel James, Dingjie Wang, Chelsie Conrad, Shatabdi Roy Chowdhury, Jay-How Yang and ASU doctoral graduates and post-docs Kimberley Rendek, Mark Hunter, Jesse Bergkamp, Tzu-Chiao Chao and Richard Kirian. Two undergraduate students Danielle Cobb and Brenda Reeder supported the team and gained extensive research experience by working hand in hand with graduate students, researchers and faculty at the free electron laser at Stanford. Four ASU senior scientists and postdoctoral researchers (Ingo Grotjohann, Nadia Zatsepin, Haiguang Liu and Raimund Fromme) supported the faculty in the design, planning and execution of the experiments, and were instrumental in evaluation of the data. The first authorship of the paper is jointly held by the ASU graduate students Christopher Kupitz, who's dissertation is based on the development of new techniques for the growth and biophysical characterization of nanocrystals; and Shibom Basu, who devoted three years of his doctoral work to the development of the data evaluation methods. "It is so exciting to be a part of this groundbreaking research and to have the opportunity to participate in this incredible international collaboration," said Kupitz, who will graduate this summer with a Ph.D. in biochemistry. "I joined the project because it fascinates me to work at the LCLS accelerator on this important biological project." "The most exciting aspect of the work on Photosystem II is the prospect of making molecular movies to witness the water splitting process through time-resolved crystallography," added Basu. National and international collaborators on the project include the team of Henry Chapman at DESY in Hamburg, Germany, who with the ASU team and researchers at the MPI in Heidelberg pioneered the new method of serial femtosecond crystallography. Other collaborators included a team led by Matthias Frank, an expert on laser spectroscopy and time-resolved studies with FELs at Lawrence Livermore National Laboratory, and the team of Yulia Pushkar at Purdue University, who supported the work with characterization of the crystals by electron paramagnetic resonance. "We're tantalizingly close," said Chapman of the Center for Free-Electron Laser Science at DESY and a pioneer in X-ray free laser studies of crystallized proteins. "I think this shows that we really are on the right track and it will work." <|im_end|>

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2,972

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Genebanks have the long-term mission of preserving plant genetic resources as an agricultural legacy for future crop improvement. Operating procedures for seed storage and plant propagation have been in place for decades, but there is a lack of effective means for the discovery and transfer of beneficial alleles from landraces and wild relatives into modern varieties. Here, we review the prospects of using molecular passport data derived from genomic sequence information as a universal monitoring tool at the single-plant level within and between genebanks. Together with recent advances in breeding methodologies, the transformation of genebanks into bio-digital resource centers will facilitate the selection of useful genetic variation and its use in breeding programs, thus providing easy access to past crop diversity. We propose linking catalogs of natural genetic variation and enquiries into biological mechanisms of plant performance as a long-term joint research goal of genebanks, plant geneticists and breeders. Main The establishment and maintenance of large ex situ collections of plant genetic resources (PGRs) were motivated by the impending loss of genetic diversity in crop plants when genetically uniform cultivars developed by systematic breeding began to replace traditional landraces worldwide 1 . Seeds stored in genebanks can be considered historic documents that provide information about the history of agriculture. Recent reports 2 , 3 on the joint analysis of DNA sequences of archeobotanical remains and extant diversity panels hosted in genebanks have highlighted the potential of, and challenges facing, plant archaeogenetics. However, genebanks were never meant to serve as purely conservational archives of crop diversity but had been instated with the forward-looking goal of preserving the ‘evolutionary potential’ of crops 4 . Long before environmentalism dominated public discourse, the genetic diversity represented by locally adapted landraces was considered vital for safeguarding future crop productivity. Despite the express goal of exploiting past diversity for crop improvement, the deployment of alleles originating from traditional landraces in elite breeding programs has seen only a few success stories to date. Notably, the dwarfing genes of the Green Revolution were introgressed into wheat and rice breeding lines from East Asian landraces 5 . Another example is the mlo alleles, which are prevalent in Ethiopian barley landraces 6 and confer broad-spectrum resistance to powdery mildew. In 1967, Krull and Borlaug stated that “the problem at present is less a lack of genetic variation but rather of efficiency in identifying and incorporating it” 7 . Five decades later, the consensus among genebank managers, plant geneticists and breeders is still that there is an urgent need for better ways to systematically evaluate and then realize the evolutionary potential of large seed collections locked away in cold rooms. In this Perspective, we aim to highlight how genomics-driven approaches to genebank management and pre-breeding can facilitate the characterization and utilization of PGRs. We provide a vision for the transformation of germplasm collections into bio-digital resource centers. Genebank genomics: molecular passport data for every seed A total of ~7.4 million accessions are stored in more than 1,750 genebanks worldwide 8 . Major challenges are (i) tracking the identity of accessions, (ii) avoiding unnecessary duplications within and between genebanks and (iii) maintaining the genetic integrity of accessions. The first two items are related to the practicalities of managing tens of thousands of seed lots, whereas the last point refers to the primary conceptual drawback of ex situ conservation: differential survival, drift and genetic erosion in storage and regeneration 7 . The traditional means of defining the identities of genebank material are passport records describing the taxonomy and provenance of accessions. Moreover, during successive rounds of seed multiplication, curators score highly heritable phenotypic characters as proxies for the underlying genetic makeup to monitor the authenticity of accessions. Recent studies in maize 9 and barley 10 have shown that affordable high-throughput genotyping provides ample amounts of single-nucleotide polymorphisms as defining characteristics of an accession. Clusters in analyses of population structure, such as principal component analysis 11 and model-based ancestry estimation 12 , differentiate accessions according to domestication status and geographic origin, and recapitulate distinctions in morphological and life-history traits that define gene pools in breeding and give rise to partial reproductive isolation. Thus, dense genotypic information can serve as molecular passport data to complement, corroborate and correct traditional passport records (Fig. 1 and Box 1 ). Although the implementation of this concept has been attempted for at least two decades 13 , 14 , the enormous increases in throughput afforded by high-throughput sequencing have only recently enabled dense genome-wide genotyping at the scale of tens of thousands of samples, that is, entire genebank collections. Benefiting from the availability of reference-genome assemblies for almost all major crop species, sequence-based genotyping overcomes the reproducibility issues of earlier marker platforms such as random amplification of polymorphic DNA or amplified fragment length polymorphism. Fig. 1: Genebank genomics as a tool for collection management. Dense genotypic information for all accessions held in genebanks will facilitate access to germplasm and guide conservation decisions. Drift during multiplication cycles may be monitored through repeated genotyping. Comparison of marker data between genebanks may complement traditional passport records and highlight duplicates and coverage gaps. Precision collections are panels of homozygous lines for all or a core set of the accessions of an inbred crop. Genetic data of a precision collection constitute a permanent resource underpinning genotype-to-phenotype mapping. Full size image In the context of genebank management, duplication refers to the inadvertent maintenance of two or more accessions tracing back to the same seed lot. Duplication enhances the workload of genebank managers and can misguide users, who, for example, might pick 1,000 barley accessions at random from the holdings of a major genebank and find that 20% of them are duplicates 15 . In contrast, safety backups are properly recorded in databases and, if entire collections are backed up, as in the case of the Svalbard Global seed vault, enable their recovery in case of catastrophic failure 16 . Finding duplicated accessions with genetic-marker data is beset with conceptual pitfalls arising from intra-accession diversity,", "role": "user" }, { "content": "The preservation of plant biodiversity is the task of the roughly 1,750 gene banks distributed around the world. They store plant samples and sometimes additional phenotypic or genetic information of around 7.4 million accessions of plant species in total. It is expected that with facilitated access to improved, quicker and cheaper sequencing and other omics technologies, the number of well-characterised accessions and the amount of detailed information that needs to be stored along with the biological material will grow rapidly and continuously. A team of scientists from the Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) in Gatersleben has now looked ahead into the upcoming challenges and possibilities of the future of gene banks by publishing a perspective paper in Nature Genetics. In the early to mid-20th century, it became increasingly apparent that crop landraces were slowly being replaced by modern crop varieties and were in danger of disappearing. In order to prevent loss of genetic diversity and biodiversity, the first gene banks were established with the mission to preserve these plant genetic resources. Today, gene banks function as biorepositories and safeguards of plant biodiversity, but most importantly as libraries that turn the genetic plant information and plant material into a freely accessible and valuable resource. As such, scientists, plant breeders and anyone around the world can request and use the data stored within more than 1,750 global gene banks for research or plant breeding purposes. The Gene Bank of the Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) in Gatersleben currently holds one of the world's most comprehensive collections of crop plants and their wild relatives, collating a total of 151,002 accessions from 2,933 species and 776 genera. The majority of the plant germplasm samples are stored as dry seed at -18°C, while accessions propagated vegetatively are permanently cultivated in the field (ex situ) or preserved in liquid nitrogen at -196°C. The online portal of the IPK gene bank allows users to view and sift through the stored plant accessions and their corresponding passport data, as well as to request plant material on a non-commercial scale. A new perspective paper authored by Dr. Martin Mascher and colleagues of the IPK now examines the current and upcoming challenges for gene banks, and the opportunities for their further advancement. The scientists identified three major challenges for gene banks that need attention. Two are caused by the basic demands of managing tens of thousands of seed lots, namely, the tracking of the identity of accessions, and the need to avoid unnecessary duplications within and between gene banks. The third challenge is that of maintaining the genetic integrity of accessions, due to the inherent drawbacks of using ex situ conservation such as differential survival, drift and genetic erosion in storage and regeneration. However, the authors suggest that a stronger genomic-driven approach towards gene banks might help when taking on these challenges. For example, traditionally, the \"passport data\" of the gene bank material describe the taxonomy and provenance of accessions. By adding single-nucleotide polymorphisms (SNPs) as defining characteristics of an accession, this genotypic information could serve as molecular passport data to complement and correct traditional passport records, as well as assist with the cleansing and prevention of duplicates and improve the quality and integrity of the collections. By implementing the shift towards bioinformatics and big data analytics in plant sciences, traditional gene banks, which focus on the preservation of germplasm collections, will be able to transform into bio-digital resource centres, which combine the storage and valorisation of plant materials with their genomic and molecular characterisation. Current funding scenarios of gene banks do not yet allow for the systematic generating of molecular passport data for each submitted plant sample at gene banks. However, first steps into the direction of high-throughput genotyping of entire collections have already been taken. This was previously showcased by an international research consortium led by the IPK, which characterised a world collection of more than 22,000 barley varieties on a molecular level through genotyping-by-sequencing. Some of the authors of the perspective paper had also been involved in this case-study and had contributed to the creation of the web-information-portal BRIDGE as a result. BRIDGE, short for \"Biodiversity informatics to bridge the gap from genome information to educated utilization of genetic diversity hosted in gene banks,\" is a data storage for the attained genomic barley information which links to the phenotypic information collated at the IPK hosted Federal Ex situ Gene Bank for Agricultural and Horticultural Crop Species. Whilst BRIDGE is already paving the way towards evolving the Gaterslebener Gene Bank into a \"one stop shop for facilitated and informed utilisation of crop plant biodiversity,\" international collaborations, such as the organisation DivSeek, are building the international framework for enabling gene banks, plant breeders and researchers globally to more efficiently process and mobilise plant genetic diversity, thus starting to bridge the gaps between bioinformaticians, geneticists and gene bank curators. Hence, a worldwide network of bio-digital resource centres, sharing data freely and thus help fostering research progress in plant science and plant breeding may become a reality in the near future. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Genebanks have the long-term mission of preserving plant genetic resources as an agricultural legacy for future crop improvement. Operating procedures for seed storage and plant propagation have been in place for decades, but there is a lack of effective means for the discovery and transfer of beneficial alleles from landraces and wild relatives into modern varieties. Here, we review the prospects of using molecular passport data derived from genomic sequence information as a universal monitoring tool at the single-plant level within and between genebanks. Together with recent advances in breeding methodologies, the transformation of genebanks into bio-digital resource centers will facilitate the selection of useful genetic variation and its use in breeding programs, thus providing easy access to past crop diversity. We propose linking catalogs of natural genetic variation and enquiries into biological mechanisms of plant performance as a long-term joint research goal of genebanks, plant geneticists and breeders. Main The establishment and maintenance of large ex situ collections of plant genetic resources (PGRs) were motivated by the impending loss of genetic diversity in crop plants when genetically uniform cultivars developed by systematic breeding began to replace traditional landraces worldwide 1 . Seeds stored in genebanks can be considered historic documents that provide information about the history of agriculture. Recent reports 2 , 3 on the joint analysis of DNA sequences of archeobotanical remains and extant diversity panels hosted in genebanks have highlighted the potential of, and challenges facing, plant archaeogenetics. However, genebanks were never meant to serve as purely conservational archives of crop diversity but had been instated with the forward-looking goal of preserving the ‘evolutionary potential’ of crops 4 . Long before environmentalism dominated public discourse, the genetic diversity represented by locally adapted landraces was considered vital for safeguarding future crop productivity. Despite the express goal of exploiting past diversity for crop improvement, the deployment of alleles originating from traditional landraces in elite breeding programs has seen only a few success stories to date. Notably, the dwarfing genes of the Green Revolution were introgressed into wheat and rice breeding lines from East Asian landraces 5 . Another example is the mlo alleles, which are prevalent in Ethiopian barley landraces 6 and confer broad-spectrum resistance to powdery mildew. In 1967, Krull and Borlaug stated that “the problem at present is less a lack of genetic variation but rather of efficiency in identifying and incorporating it” 7 . Five decades later, the consensus among genebank managers, plant geneticists and breeders is still that there is an urgent need for better ways to systematically evaluate and then realize the evolutionary potential of large seed collections locked away in cold rooms. In this Perspective, we aim to highlight how genomics-driven approaches to genebank management and pre-breeding can facilitate the characterization and utilization of PGRs. We provide a vision for the transformation of germplasm collections into bio-digital resource centers. Genebank genomics: molecular passport data for every seed A total of ~7.4 million accessions are stored in more than 1,750 genebanks worldwide 8 . Major challenges are (i) tracking the identity of accessions, (ii) avoiding unnecessary duplications within and between genebanks and (iii) maintaining the genetic integrity of accessions. The first two items are related to the practicalities of managing tens of thousands of seed lots, whereas the last point refers to the primary conceptual drawback of ex situ conservation: differential survival, drift and genetic erosion in storage and regeneration 7 . The traditional means of defining the identities of genebank material are passport records describing the taxonomy and provenance of accessions. Moreover, during successive rounds of seed multiplication, curators score highly heritable phenotypic characters as proxies for the underlying genetic makeup to monitor the authenticity of accessions. Recent studies in maize 9 and barley 10 have shown that affordable high-throughput genotyping provides ample amounts of single-nucleotide polymorphisms as defining characteristics of an accession. Clusters in analyses of population structure, such as principal component analysis 11 and model-based ancestry estimation 12 , differentiate accessions according to domestication status and geographic origin, and recapitulate distinctions in morphological and life-history traits that define gene pools in breeding and give rise to partial reproductive isolation. Thus, dense genotypic information can serve as molecular passport data to complement, corroborate and correct traditional passport records (Fig. 1 and Box 1 ). Although the implementation of this concept has been attempted for at least two decades 13 , 14 , the enormous increases in throughput afforded by high-throughput sequencing have only recently enabled dense genome-wide genotyping at the scale of tens of thousands of samples, that is, entire genebank collections. Benefiting from the availability of reference-genome assemblies for almost all major crop species, sequence-based genotyping overcomes the reproducibility issues of earlier marker platforms such as random amplification of polymorphic DNA or amplified fragment length polymorphism. Fig. 1: Genebank genomics as a tool for collection management. Dense genotypic information for all accessions held in genebanks will facilitate access to germplasm and guide conservation decisions. Drift during multiplication cycles may be monitored through repeated genotyping. Comparison of marker data between genebanks may complement traditional passport records and highlight duplicates and coverage gaps. Precision collections are panels of homozygous lines for all or a core set of the accessions of an inbred crop. Genetic data of a precision collection constitute a permanent resource underpinning genotype-to-phenotype mapping. Full size image In the context of genebank management, duplication refers to the inadvertent maintenance of two or more accessions tracing back to the same seed lot. Duplication enhances the workload of genebank managers and can misguide users, who, for example, might pick 1,000 barley accessions at random from the holdings of a major genebank and find that 20% of them are duplicates 15 . In contrast, safety backups are properly recorded in databases and, if entire collections are backed up, as in the case of the Svalbard Global seed vault, enable their recovery in case of catastrophic failure 16 . Finding duplicated accessions with genetic-marker data is beset with conceptual pitfalls arising from intra-accession diversity,<|im_end|> <|im_start|>assistant The preservation of plant biodiversity is the task of the roughly 1,750 gene banks distributed around the world. They store plant samples and sometimes additional phenotypic or genetic information of around 7.4 million accessions of plant species in total. It is expected that with facilitated access to improved, quicker and cheaper sequencing and other omics technologies, the number of well-characterised accessions and the amount of detailed information that needs to be stored along with the biological material will grow rapidly and continuously. A team of scientists from the Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) in Gatersleben has now looked ahead into the upcoming challenges and possibilities of the future of gene banks by publishing a perspective paper in Nature Genetics. In the early to mid-20th century, it became increasingly apparent that crop landraces were slowly being replaced by modern crop varieties and were in danger of disappearing. In order to prevent loss of genetic diversity and biodiversity, the first gene banks were established with the mission to preserve these plant genetic resources. Today, gene banks function as biorepositories and safeguards of plant biodiversity, but most importantly as libraries that turn the genetic plant information and plant material into a freely accessible and valuable resource. As such, scientists, plant breeders and anyone around the world can request and use the data stored within more than 1,750 global gene banks for research or plant breeding purposes. The Gene Bank of the Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) in Gatersleben currently holds one of the world's most comprehensive collections of crop plants and their wild relatives, collating a total of 151,002 accessions from 2,933 species and 776 genera. The majority of the plant germplasm samples are stored as dry seed at -18°C, while accessions propagated vegetatively are permanently cultivated in the field (ex situ) or preserved in liquid nitrogen at -196°C. The online portal of the IPK gene bank allows users to view and sift through the stored plant accessions and their corresponding passport data, as well as to request plant material on a non-commercial scale. A new perspective paper authored by Dr. Martin Mascher and colleagues of the IPK now examines the current and upcoming challenges for gene banks, and the opportunities for their further advancement. The scientists identified three major challenges for gene banks that need attention. Two are caused by the basic demands of managing tens of thousands of seed lots, namely, the tracking of the identity of accessions, and the need to avoid unnecessary duplications within and between gene banks. The third challenge is that of maintaining the genetic integrity of accessions, due to the inherent drawbacks of using ex situ conservation such as differential survival, drift and genetic erosion in storage and regeneration. However, the authors suggest that a stronger genomic-driven approach towards gene banks might help when taking on these challenges. For example, traditionally, the "passport data" of the gene bank material describe the taxonomy and provenance of accessions. By adding single-nucleotide polymorphisms (SNPs) as defining characteristics of an accession, this genotypic information could serve as molecular passport data to complement and correct traditional passport records, as well as assist with the cleansing and prevention of duplicates and improve the quality and integrity of the collections. By implementing the shift towards bioinformatics and big data analytics in plant sciences, traditional gene banks, which focus on the preservation of germplasm collections, will be able to transform into bio-digital resource centres, which combine the storage and valorisation of plant materials with their genomic and molecular characterisation. Current funding scenarios of gene banks do not yet allow for the systematic generating of molecular passport data for each submitted plant sample at gene banks. However, first steps into the direction of high-throughput genotyping of entire collections have already been taken. This was previously showcased by an international research consortium led by the IPK, which characterised a world collection of more than 22,000 barley varieties on a molecular level through genotyping-by-sequencing. Some of the authors of the perspective paper had also been involved in this case-study and had contributed to the creation of the web-information-portal BRIDGE as a result. BRIDGE, short for "Biodiversity informatics to bridge the gap from genome information to educated utilization of genetic diversity hosted in gene banks," is a data storage for the attained genomic barley information which links to the phenotypic information collated at the IPK hosted Federal Ex situ Gene Bank for Agricultural and Horticultural Crop Species. Whilst BRIDGE is already paving the way towards evolving the Gaterslebener Gene Bank into a "one stop shop for facilitated and informed utilisation of crop plant biodiversity," international collaborations, such as the organisation DivSeek, are building the international framework for enabling gene banks, plant breeders and researchers globally to more efficiently process and mobilise plant genetic diversity, thus starting to bridge the gaps between bioinformaticians, geneticists and gene bank curators. Hence, a worldwide network of bio-digital resource centres, sharing data freely and thus help fostering research progress in plant science and plant breeding may become a reality in the near future. <|im_end|>

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15207, 17469, 20258, 323, 649, 5906, 49470, 3932, 11, 889, 11, 369, 3187, 11, 2643, 3820, 220, 16, 11, 931, 81817, 2680, 919, 520, 4288, 505, 279, 58348, 315, 264, 3682, 15207, 17469, 323, 1505, 430, 220, 508, 4, 315, 1124, 527, 43428, 220, 868, 662, 763, 13168, 11, 7296, 60766, 527, 10489, 12715, 304, 32906, 323, 11, 422, 4553, 15661, 527, 22126, 709, 11, 439, 304, 279, 1162, 315, 279, 328, 838, 67019, 8121, 10533, 35684, 11, 7431, 872, 13654, 304, 1162, 315, 54677, 8060, 220, 845, 662, 43897, 56003, 2680, 919, 449, 19465, 70928, 828, 374, 9234, 295, 449, 44901, 82075, 40986, 505, 50938, 43256, 290, 20057, 11, 128257, 198, 128256, 78191, 198, 791, 46643, 315, 6136, 73119, 374, 279, 3465, 315, 279, 17715, 220, 16, 11, 11711, 15207, 14286, 4332, 2212, 279, 1917, 13, 2435, 3637, 6136, 10688, 323, 7170, 5217, 14345, 37941, 292, 477, 19465, 2038, 315, 2212, 220, 22, 13, 19, 3610, 2680, 919, 315, 6136, 9606, 304, 2860, 13, 1102, 374, 3685, 430, 449, 72849, 2680, 311, 13241, 11, 39392, 323, 23917, 62119, 323, 1023, 8019, 1233, 14645, 11, 279, 1396, 315, 1664, 80325, 4147, 2680, 919, 323, 279, 3392, 315, 11944, 2038, 430, 3966, 311, 387, 9967, 3235, 449, 279, 24156, 3769, 690, 3139, 19019, 323, 31978, 13, 362, 2128, 315, 14248, 505, 279, 2009, 581, 77, 450, 10181, 315, 18317, 84386, 323, 68420, 18317, 8483, 320, 3378, 42, 8, 304, 480, 11796, 273, 8123, 706, 1457, 7111, 8469, 1139, 279, 14827, 11774, 323, 24525, 315, 279, 3938, 315, 15207, 14286, 555, 23763, 264, 13356, 5684, 304, 22037, 84386, 13, 763, 279, 4216, 311, 5209, 12, 508, 339, 9478, 11, 433, 6244, 15098, 10186, 430, 19641, 4363, 81, 2492, 1051, 14297, 1694, 12860, 555, 6617, 19641, 36680, 323, 1051, 304, 8137, 315, 67503, 13, 763, 2015, 311, 5471, 4814, 315, 19465, 20057, 323, 73119, 11, 279, 1176, 15207, 14286, 1051, 9749, 449, 279, 9131, 311, 21813, 1521, 6136, 19465, 5070, 13, 11450, 11, 15207, 14286, 734, 439, 6160, 461, 17734, 323, 78020, 315, 6136, 73119, 11, 719, 1455, 23659, 439, 20797, 430, 2543, 279, 19465, 6136, 2038, 323, 6136, 3769, 1139, 264, 26662, 15987, 323, 15525, 5211, 13, 1666, 1778, 11, 14248, 11, 6136, 28875, 388, 323, 5606, 2212, 279, 1917, 649, 1715, 323, 1005, 279, 828, 9967, 2949, 810, 1109, 220, 16, 11, 11711, 3728, 15207, 14286, 369, 3495, 477, 6136, 40308, 10096, 13, 578, 24983, 8715, 315, 279, 2009, 581, 77, 450, 10181, 315, 18317, 84386, 323, 68420, 18317, 8483, 320, 3378, 42, 8, 304, 480, 11796, 273, 8123, 5131, 10187, 832, 315, 279, 1917, 596, 1455, 16195, 15661, 315, 19641, 11012, 323, 872, 8545, 29658, 11, 4631, 1113, 264, 2860, 315, 220, 9690, 11, 6726, 2680, 919, 505, 220, 17, 11, 25806, 9606, 323, 220, 23823, 84535, 13, 578, 8857, 315, 279, 6136, 82986, 501, 10753, 10688, 527, 9967, 439, 9235, 10533, 520, 482, 972, 32037, 11, 1418, 2680, 919, 86150, 13294, 8046, 527, 31859, 67166, 304, 279, 2115, 320, 327, 10109, 8, 477, 34683, 304, 14812, 47503, 520, 482, 5162, 32037, 13, 578, 2930, 24007, 315, 279, 6933, 42, 15207, 6201, 6276, 3932, 311, 1684, 323, 81844, 1555, 279, 9967, 6136, 2680, 919, 323, 872, 12435, 26536, 828, 11, 439, 1664, 439, 311, 1715, 6136, 3769, 389, 264, 2536, 74144, 5569, 13, 362, 502, 13356, 5684, 67213, 555, 2999, 13, 11826, 20459, 9211, 323, 18105, 315, 279, 6933, 42, 1457, 49095, 279, 1510, 323, 14827, 11774, 369, 15207, 14286, 11, 323, 279, 10708, 369, 872, 4726, 50925, 13, 578, 14248, 11054, 2380, 3682, 11774, 369, 15207, 14286, 430, 1205, 6666, 13, 9220, 527, 9057, 555, 279, 6913, 18651, 315, 18646, 22781, 315, 9214, 315, 10533, 10283, 11, 32125, 11, 279, 15194, 315, 279, 9764, 315, 2680, 919, 11, 323, 279, 1205, 311, 5766, 26225, 27444, 811, 2949, 323, 1990, 15207, 14286, 13, 578, 4948, 8815, 374, 430, 315, 20958, 279, 19465, 17025, 315, 2680, 919, 11, 4245, 311, 279, 38088, 89173, 315, 1701, 506, 10109, 29711, 1778, 439, 41264, 20237, 11, 34738, 323, 19465, 58097, 304, 5942, 323, 60517, 13, 4452, 11, 279, 12283, 4284, 430, 264, 16643, 81064, 32505, 5603, 7119, 15207, 14286, 2643, 1520, 994, 4737, 389, 1521, 11774, 13, 1789, 3187, 11, 36342, 11, 279, 330, 43769, 828, 1, 315, 279, 15207, 6201, 3769, 7664, 279, 72906, 323, 17033, 685, 315, 2680, 919, 13, 3296, 7999, 3254, 5392, 22935, 69044, 46033, 16751, 13978, 320, 19503, 21051, 8, 439, 27409, 17910, 315, 459, 85045, 11, 420, 4173, 37941, 292, 2038, 1436, 8854, 439, 31206, 26536, 828, 311, 23606, 323, 4495, 8776, 26536, 7576, 11, 439, 1664, 439, 7945, 449, 279, 60052, 323, 27344, 315, 43428, 323, 7417, 279, 4367, 323, 17025, 315, 279, 15661, 13, 3296, 25976, 279, 6541, 7119, 17332, 98588, 323, 2466, 828, 28975, 304, 6136, 36788, 11, 8776, 15207, 14286, 11, 902, 5357, 389, 279, 46643, 315, 82986, 501, 10753, 15661, 11, 690, 387, 3025, 311, 5276, 1139, 17332, 1773, 10444, 5211, 36282, 11, 902, 16343, 279, 5942, 323, 14448, 8082, 315, 6136, 7384, 449, 872, 81064, 323, 31206, 3752, 8082, 13, 9303, 11006, 26350, 315, 15207, 14286, 656, 539, 3686, 2187, 369, 279, 37538, 24038, 315, 31206, 26536, 828, 369, 1855, 14976, 6136, 6205, 520, 15207, 14286, 13, 4452, 11, 1176, 7504, 1139, 279, 5216, 315, 1579, 43847, 631, 4173, 67247, 315, 4553, 15661, 617, 2736, 1027, 4529, 13, 1115, 574, 8767, 83860, 555, 459, 6625, 3495, 75094, 6197, 555, 279, 6933, 42, 11, 902, 3752, 4147, 264, 1917, 4526, 315, 810, 1109, 220, 1313, 11, 931, 81817, 36680, 389, 264, 31206, 2237, 1555, 4173, 67247, 14656, 12, 6741, 11627, 13, 4427, 315, 279, 12283, 315, 279, 13356, 5684, 1047, 1101, 1027, 6532, 304, 420, 1162, 5594, 18339, 323, 1047, 20162, 311, 279, 9886, 315, 279, 3566, 81839, 12, 39053, 19333, 55256, 439, 264, 1121, 13, 19333, 55256, 11, 2875, 369, 330, 33, 3205, 3050, 6179, 29470, 311, 14497, 279, 13225, 505, 33869, 2038, 311, 33142, 50549, 315, 19465, 20057, 21685, 304, 15207, 14286, 1359, 374, 264, 828, 5942, 369, 279, 63260, 81064, 81817, 2038, 902, 7902, 311, 279, 14345, 37941, 292, 2038, 4631, 660, 520, 279, 6933, 42, 21685, 12411, 1398, 10109, 24983, 8715, 369, 60134, 323, 97209, 53915, 68420, 51567, 13, 71828, 19333, 55256, 374, 2736, 82568, 279, 1648, 7119, 42028, 279, 480, 11796, 273, 65, 804, 24983, 8715, 1139, 264, 330, 606, 3009, 8221, 369, 72849, 323, 16369, 4186, 8082, 315, 19641, 6136, 73119, 1359, 6625, 83663, 11, 1778, 439, 279, 22139, 8940, 40450, 11, 527, 4857, 279, 6625, 12914, 369, 28462, 15207, 14286, 11, 6136, 28875, 388, 323, 12074, 31550, 311, 810, 30820, 1920, 323, 29905, 1082, 6136, 19465, 20057, 11, 8617, 6041, 311, 14497, 279, 33251, 1990, 17332, 41540, 780, 5493, 11, 19465, 1705, 323, 15207, 6201, 2917, 3046, 13, 32140, 11, 264, 15603, 4009, 315, 17332, 1773, 10444, 5211, 36282, 11, 11821, 828, 26662, 323, 8617, 1520, 86644, 3495, 5208, 304, 6136, 8198, 323, 6136, 40308, 1253, 3719, 264, 8903, 304, 279, 3221, 3938, 13, 220, 128257, 198 ]

2,368

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The repetitive nature and complexity of some medically relevant genes poses a challenge for their accurate analysis in a clinical setting. The Genome in a Bottle Consortium has provided variant benchmark sets, but these exclude nearly 400 medically relevant genes due to their repetitiveness or polymorphic complexity. Here, we characterize 273 of these 395 challenging autosomal genes using a haplotype-resolved whole-genome assembly. This curated benchmark reports over 17,000 single-nucleotide variations, 3,600 insertions and deletions and 200 structural variations each for human genome reference GRCh37 and GRCh38 across HG002. We show that false duplications in either GRCh37 or GRCh38 result in reference-specific, missed variants for short- and long-read technologies in medically relevant genes, including CBS , CRYAA and KCNE1 . When masking these false duplications, variant recall can improve from 8% to 100%. Forming benchmarks from a haplotype-resolved whole-genome assembly may become a prototype for future benchmarks covering the whole genome. Main Authoritative benchmark samples are driving the development of technologies and the discovery of new variants, enabling highly accurate clinical genome sequencing and advancing our detection and understanding of the impact of many genomic variations on human disease at scale. With recent improvements in sequencing technologies 1 , assembly algorithms 2 , 3 , 4 and variant-calling methods 5 , genomics offers more insights into challenging genes associated with human diseases across a higher number of patients 6 . Still, challenges remain for medically relevant genes that are often repetitive or highly polymorphic 7 , 8 . In fact, a recent study found that 13.8% (17,561) of pathogenic variants identified by a high-throughput clinical laboratory were challenging to detect with short-read sequencing 9 . These included challenging variants such as variants 15–49 bp in size, small copy-number variations (CNVs), complex variants and variants in low-complexity or segmentally duplicated regions. The Genome in a Bottle (GIAB) consortium develops benchmarks to advance accurate human genomic research and clinical applications of sequencing. GIAB provides highly curated benchmark sets for single-nucleotide variant (SNV) 10 , small insertion and deletion (INDEL) 10 and structural variant (SV) calling 11 . Here, we define SNVs as single base substitutions, while INDELs are defined as insertions and deletions smaller than 50 bp, in contrast to insertions and deletions larger than 50 bp, which we refer to as SVs. Furthermore, GIAB and the Food and Drug Administration (FDA) host periodic precisionFDA challenges providing a snapshot and recommendations for small variant calling enabling the high precision and sensitivity required for clinical research, with a recent challenge demonstrating the importance of including more difficult genomic regions 12 . Recently, GIAB focused primarily on a read mapping-based genome-wide approach integrating short-, linked- and long-read sequencing to characterize up to 92% and 86% of the autosomal bases for small variants and SVs, respectively 11 , 13 . GIAB also released a targeted assembly-based benchmark for the major histocompatibility complex (MHC) region, a highly diverse and repetitive region of the human genome that includes the human leukocyte antigen (HLA) genes 14 . Still, multiple regions of the genome are not fully resolved in existing benchmarks due to repetitive sequence, segmental duplications and complex variants (i.e., multiple nearby SNVs, INDELs and/or SVs) 15 . Many clinically relevant genes are in the remaining hard-to-assess regions. The clinical tests for these genes often require locus-specific targeted designs and/or employ multiple technologies and are only applied when suspicion of a specific disorder is high. Mandelker et al. categorized genes based on their repetitive content and identified 193 genes that cannot be fully characterized by short-read sequencing 7 . This gene set was constructed by identifying genes with low mapping quality in the clinical databases OMIM, HGMD and ClinVar. Subsequently, Wenger et al. showed that while short reads could not accurately map the full length of these genes, highly accurate long reads could fully map 152 (78.76%) of them 1 . The latest v4.2.1 GIAB small variant benchmark regions included at least 90% of the gene body for 110 of the 159 difficult genes on autosomes 13 . In contrast, the previous v3.3.2 GIAB small variant benchmark regions included at least 90% of the gene body for only 19 of 159 difficult genes 10 . Although v4.2.1 includes substantially more difficult genes, variant calls in the remaining most difficult genes still need to be assessed, and challenges remain with typical mapping-based approaches in some genes, even when using highly accurate long reads. To support ongoing advancements in clinical genome sequencing and bioinformatics, we present a more comprehensive benchmark of challenging, medically relevant genes (CMRGs) focusing on HG002, which has a broad consent from the Personal Genome Project for open genomic data and commercial redistribution 16 (Fig. 1 ). With the advent of highly accurate long reads, new approaches for haplotype-resolved (diploid) assembly have advanced rapidly 2 , 3 . Here, we focus on generating a benchmark for as many of these genes as possible using a whole-genome haplotype-resolved assembly. We curated a set of 273 medically relevant genes with ≤90% of bases included in previous GIAB benchmarks but fully covered by both haplotypes of a trio-based hifiasm assembly. The assembly included all phased small variants and SVs across these genes. Then, we delineated regions where we can provide reliable small variant and SV benchmarks, developing a prototype process for future whole-genome assembly-based benchmarks. Fig. 1: GIAB developed a process to create new phased small variant and SV benchmarks for 273 CMRGs. a , We developed a list of 4,701 autosomal potentially medically relevant genes. We generated a new benchmark for 273 of the 4,701 genes that were completely resolved by our hifiasm haplotype-resolved diploid assembly and ≤90% included in the v4.2.1 GIAB small variant benchmark for HG002 (v4.2.1 regions). b , We required that the entire gene region (pink) and the 20-kb flanking sequence on each side (blue) be completely resolved by both haplotypes in the assembly (Hifiasm Hap1 and Hifiasm Hap2), indicated with the Hifiasm dipcall bed track. In addition, we required that any segmental duplications overlapping", "role": "user" }, { "content": "The stretches of DNA that differ from person to person, called variants, are a major part of what makes us unique, but they can also put us at greater risk of disease. Although we can currently spell out between 80% and 90% of the millions that are in the human genome, the remaining variants may hold clues for treating an array of diseases. Today the list of variants yet to be decoded has shrunk sizably. A team led by researchers at the National Institute of Standards and Technology (NIST), Baylor College of Medicine and DNAnexus has characterized over 20,000 variants in 273 genes of medical importance. In a study published in the journal Nature Biotechnology, the researchers applied both cutting-edge and long-standing DNA sequencing methods to decipher the genetic codes of the variants with a high degree of certainty. Using their results, they formulated benchmarks that will help labs and clinics sequence the genes more accurately, which is critical for gaining a better understanding of a host of diseases and eventually developing treatments. \"Some of these genes, which have previously been very difficult to access, are suspected to have some connection to disease. Others have very clear clinical importance,\" said NIST biomedical engineer Justin Zook, a co-author of the study. \"SMN1, for example, is a gene we characterized that is directly associated with spinal muscular atrophy, a rare but severe condition.\" The new benchmark is the latest produced by the Genome in a Bottle (GIAB) consortium, a NIST-hosted collaborative effort aimed at improving DNA sequencing technologies and making them practical for clinical application. These benchmarks are highly accurate sequences of DNA that clinics and research labs can use as a kind of answer key when testing their own sequencing methods. By sequencing the same genome used to develop a benchmark and then comparing their result to the benchmark itself, they could learn how well they can detect certain variants. Over the years, producing benchmarks for some regions of the genome has proved much more difficult than others. There are several reasons, many of which are tied to the general approach people use to sequence DNA. Rather than sequencing entire genomes in one go, DNA sequencing technologies read out sequences of small fractions of DNA first, and then attempt to place them together correctly, similar to a puzzle set. Reference genomes, the first of which was completed by the Human Genome Project, are nearly full genomes, stitched together from several people's DNA, that serve as guides for where to place the puzzle pieces. Since we share close to 99.9% of our genetic makeup as a species, any human genome will have mostly the same code as the reference genome. This means putting together a genome is a matter of laying out the pieces based on where they match up with the reference. Most variants fall in line using this process. Certain types throw a wrench into it. In particular, a type called a structural variant can create large differences between a genome and a reference genome. They range from 50 up to thousands of letters, or bases, and take many forms, including inserted, deleted or rearranged code. The more distinct a genome is from the reference, the harder it is to use the reference as a guide, Zook said. Structural variants could cause labs to unintentionally misplace chunks of DNA, and, in a clinical setting, that sort of error may cause a disease-linked variant to evade detection or a harmless variant to create alarm. On top of the human costs, treatments prescribed needlessly or too late due to these mismeasurements could establish the need for more expensive or invasive treatments for patients down the road, driving up health care costs drastically. However, recent advances in sequencing technology have cleared some of these obstacles. In the new study, the GIAB consortium applied the latest technology to decode some of the most elusive regions of the human genome with either a known or suspected connection to diseases. A key player in the effort was high fidelity, or HiFi, sequencing, which can sequence longer stretches of DNA. Common DNA sequencing methods can read about a hundred bases, but with HiFi sequencing, you can accurately read tens of thousands at a time, Zook said. \"Instead of having a thousand-piece puzzle, where you have these little, tiny pieces that you have to put together, it's more like having a hundred-piece puzzle where you have bigger pieces that you can put together,\" Zook said. The team specifically employed HiFi with hifiasm, a state-of-the-art software tool that simultaneously solves another issue that has hampered DNA sequencing. Rather than reading both copies of an individual's chromosomes (one from mother, the other from father), previous methods sequenced an amalgamation of both, causing them to create errors and miss important details unique to each copy. With hifiasm, the researchers could independently spell out the separate copies of a person's genome. In the case of this study, the genome was from a single person, designated HG002, who had consented to publicizing their genetic code through the Personal Genome Project. The authors used these technologies in addition to previously established methods, leveraging the strengths of each at once. In the end, their approach allowed them to unearth the sequences of more than 20,000 variants—including dozens of the difficult-to-assess structural variants—across 273 genes, and did so with higher accuracy than could be achieved just using a single method. In addition to spinal muscular atrophy, the researchers characterized variants in genes connected to heart disease, diabetes, celiac disease and many other conditions. The team also unexpectedly encountered errors in the two reference genomes they were using. Some could cause sequencing methods to misread genes that cause serious conditions, including homocystinuria, which is associated with skeletal, cardiovascular and nervous system disorders and is usually detected through newborn screening, Zook said. With their newly benchmarked variants, the authors proposed corrections to the reference genomes they used. The benchmarks themselves are now publicly available for labs to put to good use. To do so, interested researchers or clinicians would first need to sequence HG002 samples, which can be accessed through the NIST Office of Reference Materials, and then check their results against the benchmarks. The study marks a significant step in the GIAB consortium's ongoing journey to improve the accuracy of DNA sequencing. But with thousands of important genes left to characterize containing variants that are difficult to pin down, the researchers aim to trudge on, applying the latest and greatest technologies as they become available. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The repetitive nature and complexity of some medically relevant genes poses a challenge for their accurate analysis in a clinical setting. The Genome in a Bottle Consortium has provided variant benchmark sets, but these exclude nearly 400 medically relevant genes due to their repetitiveness or polymorphic complexity. Here, we characterize 273 of these 395 challenging autosomal genes using a haplotype-resolved whole-genome assembly. This curated benchmark reports over 17,000 single-nucleotide variations, 3,600 insertions and deletions and 200 structural variations each for human genome reference GRCh37 and GRCh38 across HG002. We show that false duplications in either GRCh37 or GRCh38 result in reference-specific, missed variants for short- and long-read technologies in medically relevant genes, including CBS , CRYAA and KCNE1 . When masking these false duplications, variant recall can improve from 8% to 100%. Forming benchmarks from a haplotype-resolved whole-genome assembly may become a prototype for future benchmarks covering the whole genome. Main Authoritative benchmark samples are driving the development of technologies and the discovery of new variants, enabling highly accurate clinical genome sequencing and advancing our detection and understanding of the impact of many genomic variations on human disease at scale. With recent improvements in sequencing technologies 1 , assembly algorithms 2 , 3 , 4 and variant-calling methods 5 , genomics offers more insights into challenging genes associated with human diseases across a higher number of patients 6 . Still, challenges remain for medically relevant genes that are often repetitive or highly polymorphic 7 , 8 . In fact, a recent study found that 13.8% (17,561) of pathogenic variants identified by a high-throughput clinical laboratory were challenging to detect with short-read sequencing 9 . These included challenging variants such as variants 15–49 bp in size, small copy-number variations (CNVs), complex variants and variants in low-complexity or segmentally duplicated regions. The Genome in a Bottle (GIAB) consortium develops benchmarks to advance accurate human genomic research and clinical applications of sequencing. GIAB provides highly curated benchmark sets for single-nucleotide variant (SNV) 10 , small insertion and deletion (INDEL) 10 and structural variant (SV) calling 11 . Here, we define SNVs as single base substitutions, while INDELs are defined as insertions and deletions smaller than 50 bp, in contrast to insertions and deletions larger than 50 bp, which we refer to as SVs. Furthermore, GIAB and the Food and Drug Administration (FDA) host periodic precisionFDA challenges providing a snapshot and recommendations for small variant calling enabling the high precision and sensitivity required for clinical research, with a recent challenge demonstrating the importance of including more difficult genomic regions 12 . Recently, GIAB focused primarily on a read mapping-based genome-wide approach integrating short-, linked- and long-read sequencing to characterize up to 92% and 86% of the autosomal bases for small variants and SVs, respectively 11 , 13 . GIAB also released a targeted assembly-based benchmark for the major histocompatibility complex (MHC) region, a highly diverse and repetitive region of the human genome that includes the human leukocyte antigen (HLA) genes 14 . Still, multiple regions of the genome are not fully resolved in existing benchmarks due to repetitive sequence, segmental duplications and complex variants (i.e., multiple nearby SNVs, INDELs and/or SVs) 15 . Many clinically relevant genes are in the remaining hard-to-assess regions. The clinical tests for these genes often require locus-specific targeted designs and/or employ multiple technologies and are only applied when suspicion of a specific disorder is high. Mandelker et al. categorized genes based on their repetitive content and identified 193 genes that cannot be fully characterized by short-read sequencing 7 . This gene set was constructed by identifying genes with low mapping quality in the clinical databases OMIM, HGMD and ClinVar. Subsequently, Wenger et al. showed that while short reads could not accurately map the full length of these genes, highly accurate long reads could fully map 152 (78.76%) of them 1 . The latest v4.2.1 GIAB small variant benchmark regions included at least 90% of the gene body for 110 of the 159 difficult genes on autosomes 13 . In contrast, the previous v3.3.2 GIAB small variant benchmark regions included at least 90% of the gene body for only 19 of 159 difficult genes 10 . Although v4.2.1 includes substantially more difficult genes, variant calls in the remaining most difficult genes still need to be assessed, and challenges remain with typical mapping-based approaches in some genes, even when using highly accurate long reads. To support ongoing advancements in clinical genome sequencing and bioinformatics, we present a more comprehensive benchmark of challenging, medically relevant genes (CMRGs) focusing on HG002, which has a broad consent from the Personal Genome Project for open genomic data and commercial redistribution 16 (Fig. 1 ). With the advent of highly accurate long reads, new approaches for haplotype-resolved (diploid) assembly have advanced rapidly 2 , 3 . Here, we focus on generating a benchmark for as many of these genes as possible using a whole-genome haplotype-resolved assembly. We curated a set of 273 medically relevant genes with ≤90% of bases included in previous GIAB benchmarks but fully covered by both haplotypes of a trio-based hifiasm assembly. The assembly included all phased small variants and SVs across these genes. Then, we delineated regions where we can provide reliable small variant and SV benchmarks, developing a prototype process for future whole-genome assembly-based benchmarks. Fig. 1: GIAB developed a process to create new phased small variant and SV benchmarks for 273 CMRGs. a , We developed a list of 4,701 autosomal potentially medically relevant genes. We generated a new benchmark for 273 of the 4,701 genes that were completely resolved by our hifiasm haplotype-resolved diploid assembly and ≤90% included in the v4.2.1 GIAB small variant benchmark for HG002 (v4.2.1 regions). b , We required that the entire gene region (pink) and the 20-kb flanking sequence on each side (blue) be completely resolved by both haplotypes in the assembly (Hifiasm Hap1 and Hifiasm Hap2), indicated with the Hifiasm dipcall bed track. In addition, we required that any segmental duplications overlapping<|im_end|> <|im_start|>assistant The stretches of DNA that differ from person to person, called variants, are a major part of what makes us unique, but they can also put us at greater risk of disease. Although we can currently spell out between 80% and 90% of the millions that are in the human genome, the remaining variants may hold clues for treating an array of diseases. Today the list of variants yet to be decoded has shrunk sizably. A team led by researchers at the National Institute of Standards and Technology (NIST), Baylor College of Medicine and DNAnexus has characterized over 20,000 variants in 273 genes of medical importance. In a study published in the journal Nature Biotechnology, the researchers applied both cutting-edge and long-standing DNA sequencing methods to decipher the genetic codes of the variants with a high degree of certainty. Using their results, they formulated benchmarks that will help labs and clinics sequence the genes more accurately, which is critical for gaining a better understanding of a host of diseases and eventually developing treatments. "Some of these genes, which have previously been very difficult to access, are suspected to have some connection to disease. Others have very clear clinical importance," said NIST biomedical engineer Justin Zook, a co-author of the study. "SMN1, for example, is a gene we characterized that is directly associated with spinal muscular atrophy, a rare but severe condition." The new benchmark is the latest produced by the Genome in a Bottle (GIAB) consortium, a NIST-hosted collaborative effort aimed at improving DNA sequencing technologies and making them practical for clinical application. These benchmarks are highly accurate sequences of DNA that clinics and research labs can use as a kind of answer key when testing their own sequencing methods. By sequencing the same genome used to develop a benchmark and then comparing their result to the benchmark itself, they could learn how well they can detect certain variants. Over the years, producing benchmarks for some regions of the genome has proved much more difficult than others. There are several reasons, many of which are tied to the general approach people use to sequence DNA. Rather than sequencing entire genomes in one go, DNA sequencing technologies read out sequences of small fractions of DNA first, and then attempt to place them together correctly, similar to a puzzle set. Reference genomes, the first of which was completed by the Human Genome Project, are nearly full genomes, stitched together from several people's DNA, that serve as guides for where to place the puzzle pieces. Since we share close to 99.9% of our genetic makeup as a species, any human genome will have mostly the same code as the reference genome. This means putting together a genome is a matter of laying out the pieces based on where they match up with the reference. Most variants fall in line using this process. Certain types throw a wrench into it. In particular, a type called a structural variant can create large differences between a genome and a reference genome. They range from 50 up to thousands of letters, or bases, and take many forms, including inserted, deleted or rearranged code. The more distinct a genome is from the reference, the harder it is to use the reference as a guide, Zook said. Structural variants could cause labs to unintentionally misplace chunks of DNA, and, in a clinical setting, that sort of error may cause a disease-linked variant to evade detection or a harmless variant to create alarm. On top of the human costs, treatments prescribed needlessly or too late due to these mismeasurements could establish the need for more expensive or invasive treatments for patients down the road, driving up health care costs drastically. However, recent advances in sequencing technology have cleared some of these obstacles. In the new study, the GIAB consortium applied the latest technology to decode some of the most elusive regions of the human genome with either a known or suspected connection to diseases. A key player in the effort was high fidelity, or HiFi, sequencing, which can sequence longer stretches of DNA. Common DNA sequencing methods can read about a hundred bases, but with HiFi sequencing, you can accurately read tens of thousands at a time, Zook said. "Instead of having a thousand-piece puzzle, where you have these little, tiny pieces that you have to put together, it's more like having a hundred-piece puzzle where you have bigger pieces that you can put together," Zook said. The team specifically employed HiFi with hifiasm, a state-of-the-art software tool that simultaneously solves another issue that has hampered DNA sequencing. Rather than reading both copies of an individual's chromosomes (one from mother, the other from father), previous methods sequenced an amalgamation of both, causing them to create errors and miss important details unique to each copy. With hifiasm, the researchers could independently spell out the separate copies of a person's genome. In the case of this study, the genome was from a single person, designated HG002, who had consented to publicizing their genetic code through the Personal Genome Project. The authors used these technologies in addition to previously established methods, leveraging the strengths of each at once. In the end, their approach allowed them to unearth the sequences of more than 20,000 variants—including dozens of the difficult-to-assess structural variants—across 273 genes, and did so with higher accuracy than could be achieved just using a single method. In addition to spinal muscular atrophy, the researchers characterized variants in genes connected to heart disease, diabetes, celiac disease and many other conditions. The team also unexpectedly encountered errors in the two reference genomes they were using. Some could cause sequencing methods to misread genes that cause serious conditions, including homocystinuria, which is associated with skeletal, cardiovascular and nervous system disorders and is usually detected through newborn screening, Zook said. With their newly benchmarked variants, the authors proposed corrections to the reference genomes they used. The benchmarks themselves are now publicly available for labs to put to good use. To do so, interested researchers or clinicians would first need to sequence HG002 samples, which can be accessed through the NIST Office of Reference Materials, and then check their results against the benchmarks. The study marks a significant step in the GIAB consortium's ongoing journey to improve the accuracy of DNA sequencing. But with thousands of important genes left to characterize containing variants that are difficult to pin down, the researchers aim to trudge on, applying the latest and greatest technologies as they become available. <|im_end|>

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2,718

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Numerous studies have identified the proinflammatory, pronociceptive effects of morphine which ultimately exacerbate pain. Our novel endomorphin analog ZH853 does not produce proinflammatory effects on its own and gives potent, long-lasting analgesia. This study investigates whether ZH853’s lack of interaction with the neuroimmune system reduces the risk of prolonged pain. Methods Adult male Sprague-Dawley rats were subjected to one of two treatment paradigms. Either (1) chronic pain followed by chronic treatment with morphine, ZH853 or vehicle, or (2) chronic drug administered prior to pain induction. Complete Freund’s adjuvant (CFA) was injected or paw incision surgery was performed on the left hind plantar foot pad. Drugs were administered through Alzet osmotic minipumps at a rate of 1 μl/h for 5 days at appropriate doses based on prior experiments. Animals were tested for mechanical allodynia and thermal hyperalgesia using von Frey filaments and the Hargreaves apparatus, respectively. Additionally, several gait parameters were measured using the CatWalk XT. When all animals had recovered from pain, 1 mg/kg of naltrexone was administered to test for development of latent sensitization (LS). A second set of animals was used to investigate dorsal horn inflammation following CFA and drug treatment. ANOVAs were used to assess differences between drug treatment groups. Results As expected, morphine increased and prolonged pain in all experiments compared to vehicle treatment. However, ZH853 treatment reduced the overall time spent in pain and the severity of pain scores compared to morphine. ZH853 not only reduced inflammation versus morphine treatment but also, in some instances, acted as an anti-inflammatory drug compared to vehicle treatment. Finally, ZH853 prevented the development of LS while vehicle- and morphine-treated animals showed robust relapse to pain. Conclusions ZH853 has a favorable side effect profile versus morphine and provides superior analgesia in a number of pain states. We now know that chronic use of this compound reduces time spent in a chronic pain state, the opposite of common opioids like morphine, and reduces the risk of LS, making ZH853 an excellent candidate for clinical development in humans for inflammatory and postoperative pain. Background In addition to the well-known negative side effects of currently used opioids, including abuse liability, respiratory depression, tolerance, and others, several recent studies have shown a lesser-known side effect; chronic exposure to morphine and other opioids can paradoxically exacerbate and prolong pain hypersensitivity. Known as the “two hit” hypothesis, it has been proposed that injury causes pro-inflammatory signaling in the central nervous system (CNS) which is exacerbated by morphine such that pain is ultimately more intense and longer-lasting [ 1 , 2 ]. This exacerbation can occur with either order of stimulus (injury then drug or vice-versa) and can contribute to the transition from acute to chronic pain. The transition to chronic pain can also occur through another recently described mechanism known as “latent sensitization” (LS). LS is pathological pain following injury or inflammation that is “masked” during apparent recovery by endogenous opioid receptor function and “unmasked” by treatment with an opioid inverse agonist, such as naltrexone, or by stress [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. In this study, we compare the effects of morphine and a novel opioid on both the paradoxical exacerbation of pain and on LS, with the goal of assessing the new analog for preventing the transition from acute to chronic pain. We recently characterized a novel endomorphin [ 11 ] analog (ZH853) that shows antinociceptive effects equivalent to or greater than morphine, but with reduced abuse liability, respiratory depression, tolerance, hyperalgesia, impairment of motor coordination, and glial activation [ 11 ]. We also characterized the effectiveness of acute administration of the analog in alleviating several forms of chronic pain, including neuropathic, inflammatory, postoperative, and visceral pain [ 12 ]. This lead compound has been selected for development for clinical application and will be tested here for the effects of short term (3–5 days) chronic administration on the recovery from inflammatory and postoperative pain and the presence of LS. In this study, drugs were chronically infused either before or after pain. Recovery from pain was measured to determine whether ZH853 causes detrimental effects on pain similar to those reported with morphine use in humans and animals [ 1 , 2 , 13 ]. The drug-then-pain paradigm has been studied by several groups in different pain states. Some chronic pain patients who use opioids therapeutically are known to experience worse pain following surgery than non-opioid users, and that pain cannot always be controlled satisfactorily [ 14 , 15 ]. In rodent studies, Horvath et al. [ 16 ] showed that 7 or 14 days of chronic morphine infusion increased and prolonged both allodynia and thermal hyperalgesia, and the Watkins lab found that animals treated with morphine prior to chronic constriction injury or complete Freund’s adjuvant (CFA) had more intense and prolonged pain that correlated with a number of upregulated proinflammatory markers [ 2 ]. The reverse paradigm (pain then drug) is perhaps more clinically relevant but has been explored to a lesser extent. Recently, Grace et al. [ 1 ] found that morphine given after the induction of neuropathic pain prolonged hypersensitivity versus vehicle treatment, and this result was consistent with the effects of morphine treatment on postoperative pain [ 17 ]. Both studies found that morphine plus pain increased proinflammatory signaling in the spinal dorsal horn and that blocking inflammation pharmacologically blocks the effect of morphine on prolonged pain. Comprehensively described by Taylor [ 8 ], Corder [ 4 ], and Marvizon [ 3 , 6 ], LS and endogenous dependence are best thought of as two sides of the same coin; the phenomena are inextricably linked and cause a susceptibility to unmasking pain through either stress or chemical inactivation of Mu-opioid receptor (MOR) constitutive activity. The initial pain insult activates pain pathways (“accelerator”) and descending pathways induce constitutive activity at the MOR (MOR CA ) to counteract pain (“brake”). Over a long period of recovery from the injury, the body", "role": "user" }, { "content": "Morphine and other opioid-based painkillers are very effective at treating pain initially, but studies have shown that the drugs can make patients more pain-sensitive, prolonging their discomfort and increasing their risks of developing chronic pain. A new type of opioid developed by researchers at Tulane University and the Southeast Louisiana Veterans Health Care System doesn't have this side effect and accelerates recovery time from pain compared to morphine, according to a new study published in the Journal of Neuroinflammation. Previous pre-clinical studies at Tulane have shown that the drug is as strong as morphine but isn't addictive and causes fewer side effects. \"A drug that prevents the transition from acute to chronic relapsing pain would represent a true breakthrough in drug development for pain management,\" said senior study author James Zadina, professor of medicine, pharmacology and neuroscience at Tulane University School of Medicine and director of the neuroscience laboratory at the VA. \"Not only have the mechanisms behind the shift from acute to chronic pain been elusive, but efforts to thwart this transition have had little success.\" Scientists tested a novel opioid called ZH853 using rat models of inflammatory pain and pain after surgery. The drug is an engineered variant of the neurochemical endomorphin, which is found naturally in the body. Researchers treated rats with ZH853, morphine or a placebo. Rats treated with morphine for a few days recovered more slowly than those given a placebo. This was true whether the morphine was given before or after the injury, indicating that prior use—or abuse —of opioids could aggravate subsequent recovery from injury. \"Morphine provoked central nervous system glia to produce pro-inflammatory compounds that increased pain,\" Zadina said. \"ZH853 did not have this effect.\" When tested in the same inflammatory and postoperative pain conditions as morphine, the new drug unexpectedly accelerated recovery from the pain—in some cases slashing recovery time in half compared to both morphine and a placebo. In one group, pain lasted 32 days with no treatment, 46 days after morphine and only 11 days after ZH853. \"ZH853 diminished the amount of time in pain versus morphine in all tests,\" said study first author Amy Feehan, Ph.D., a Tulane neuroscience graduate student. \"This was an unexpected and unprecedented finding considering that opioids are known to increase and prolong many types of pain.\" Researchers also ran tests for a form of pain sensitivity that can be masked by changes in the body's endorphin system after an injury. When an injury causes pain, the body's endogenous opioid system engages to counteract it. If the opioid system is blocked—either by stress or an antagonist—the underlying pain can return even after the injury has healed and contribute to chronic pain. Unlike morphine, the new drug prevented this. \"With ZH853, the underlying pain was eliminated rather than simply masked,\" Zadina said. \"ZH853 attenuated or blocked two separate processes that contribute to the transition from acute to chronic pain, neuroinflammation and latent sensitization.\" Researchers hope to begin human clinical trials of the new drug within the next two years. \"I believe it's vitally important to treat chronic pain as a disease of the nervous system and treat the underlying pathology of chronic pain rather than just treating the symptoms as they arise,\" Feehan said. \"Current opioid treatments are effective in the short term for pain symptoms, but the downside is that pain ultimately can become worse because chronic opioid use can aggravate the immune system. ZH853 quiets the pain symptoms as well as morphine does, but it also diminishes inflammation, reducing recovery time and preventing relapse to pain later.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background Numerous studies have identified the proinflammatory, pronociceptive effects of morphine which ultimately exacerbate pain. Our novel endomorphin analog ZH853 does not produce proinflammatory effects on its own and gives potent, long-lasting analgesia. This study investigates whether ZH853’s lack of interaction with the neuroimmune system reduces the risk of prolonged pain. Methods Adult male Sprague-Dawley rats were subjected to one of two treatment paradigms. Either (1) chronic pain followed by chronic treatment with morphine, ZH853 or vehicle, or (2) chronic drug administered prior to pain induction. Complete Freund’s adjuvant (CFA) was injected or paw incision surgery was performed on the left hind plantar foot pad. Drugs were administered through Alzet osmotic minipumps at a rate of 1 μl/h for 5 days at appropriate doses based on prior experiments. Animals were tested for mechanical allodynia and thermal hyperalgesia using von Frey filaments and the Hargreaves apparatus, respectively. Additionally, several gait parameters were measured using the CatWalk XT. When all animals had recovered from pain, 1 mg/kg of naltrexone was administered to test for development of latent sensitization (LS). A second set of animals was used to investigate dorsal horn inflammation following CFA and drug treatment. ANOVAs were used to assess differences between drug treatment groups. Results As expected, morphine increased and prolonged pain in all experiments compared to vehicle treatment. However, ZH853 treatment reduced the overall time spent in pain and the severity of pain scores compared to morphine. ZH853 not only reduced inflammation versus morphine treatment but also, in some instances, acted as an anti-inflammatory drug compared to vehicle treatment. Finally, ZH853 prevented the development of LS while vehicle- and morphine-treated animals showed robust relapse to pain. Conclusions ZH853 has a favorable side effect profile versus morphine and provides superior analgesia in a number of pain states. We now know that chronic use of this compound reduces time spent in a chronic pain state, the opposite of common opioids like morphine, and reduces the risk of LS, making ZH853 an excellent candidate for clinical development in humans for inflammatory and postoperative pain. Background In addition to the well-known negative side effects of currently used opioids, including abuse liability, respiratory depression, tolerance, and others, several recent studies have shown a lesser-known side effect; chronic exposure to morphine and other opioids can paradoxically exacerbate and prolong pain hypersensitivity. Known as the “two hit” hypothesis, it has been proposed that injury causes pro-inflammatory signaling in the central nervous system (CNS) which is exacerbated by morphine such that pain is ultimately more intense and longer-lasting [ 1 , 2 ]. This exacerbation can occur with either order of stimulus (injury then drug or vice-versa) and can contribute to the transition from acute to chronic pain. The transition to chronic pain can also occur through another recently described mechanism known as “latent sensitization” (LS). LS is pathological pain following injury or inflammation that is “masked” during apparent recovery by endogenous opioid receptor function and “unmasked” by treatment with an opioid inverse agonist, such as naltrexone, or by stress [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. In this study, we compare the effects of morphine and a novel opioid on both the paradoxical exacerbation of pain and on LS, with the goal of assessing the new analog for preventing the transition from acute to chronic pain. We recently characterized a novel endomorphin [ 11 ] analog (ZH853) that shows antinociceptive effects equivalent to or greater than morphine, but with reduced abuse liability, respiratory depression, tolerance, hyperalgesia, impairment of motor coordination, and glial activation [ 11 ]. We also characterized the effectiveness of acute administration of the analog in alleviating several forms of chronic pain, including neuropathic, inflammatory, postoperative, and visceral pain [ 12 ]. This lead compound has been selected for development for clinical application and will be tested here for the effects of short term (3–5 days) chronic administration on the recovery from inflammatory and postoperative pain and the presence of LS. In this study, drugs were chronically infused either before or after pain. Recovery from pain was measured to determine whether ZH853 causes detrimental effects on pain similar to those reported with morphine use in humans and animals [ 1 , 2 , 13 ]. The drug-then-pain paradigm has been studied by several groups in different pain states. Some chronic pain patients who use opioids therapeutically are known to experience worse pain following surgery than non-opioid users, and that pain cannot always be controlled satisfactorily [ 14 , 15 ]. In rodent studies, Horvath et al. [ 16 ] showed that 7 or 14 days of chronic morphine infusion increased and prolonged both allodynia and thermal hyperalgesia, and the Watkins lab found that animals treated with morphine prior to chronic constriction injury or complete Freund’s adjuvant (CFA) had more intense and prolonged pain that correlated with a number of upregulated proinflammatory markers [ 2 ]. The reverse paradigm (pain then drug) is perhaps more clinically relevant but has been explored to a lesser extent. Recently, Grace et al. [ 1 ] found that morphine given after the induction of neuropathic pain prolonged hypersensitivity versus vehicle treatment, and this result was consistent with the effects of morphine treatment on postoperative pain [ 17 ]. Both studies found that morphine plus pain increased proinflammatory signaling in the spinal dorsal horn and that blocking inflammation pharmacologically blocks the effect of morphine on prolonged pain. Comprehensively described by Taylor [ 8 ], Corder [ 4 ], and Marvizon [ 3 , 6 ], LS and endogenous dependence are best thought of as two sides of the same coin; the phenomena are inextricably linked and cause a susceptibility to unmasking pain through either stress or chemical inactivation of Mu-opioid receptor (MOR) constitutive activity. The initial pain insult activates pain pathways (“accelerator”) and descending pathways induce constitutive activity at the MOR (MOR CA ) to counteract pain (“brake”). Over a long period of recovery from the injury, the body<|im_end|> <|im_start|>assistant Morphine and other opioid-based painkillers are very effective at treating pain initially, but studies have shown that the drugs can make patients more pain-sensitive, prolonging their discomfort and increasing their risks of developing chronic pain. A new type of opioid developed by researchers at Tulane University and the Southeast Louisiana Veterans Health Care System doesn't have this side effect and accelerates recovery time from pain compared to morphine, according to a new study published in the Journal of Neuroinflammation. Previous pre-clinical studies at Tulane have shown that the drug is as strong as morphine but isn't addictive and causes fewer side effects. "A drug that prevents the transition from acute to chronic relapsing pain would represent a true breakthrough in drug development for pain management," said senior study author James Zadina, professor of medicine, pharmacology and neuroscience at Tulane University School of Medicine and director of the neuroscience laboratory at the VA. "Not only have the mechanisms behind the shift from acute to chronic pain been elusive, but efforts to thwart this transition have had little success." Scientists tested a novel opioid called ZH853 using rat models of inflammatory pain and pain after surgery. The drug is an engineered variant of the neurochemical endomorphin, which is found naturally in the body. Researchers treated rats with ZH853, morphine or a placebo. Rats treated with morphine for a few days recovered more slowly than those given a placebo. This was true whether the morphine was given before or after the injury, indicating that prior use—or abuse —of opioids could aggravate subsequent recovery from injury. "Morphine provoked central nervous system glia to produce pro-inflammatory compounds that increased pain," Zadina said. "ZH853 did not have this effect." When tested in the same inflammatory and postoperative pain conditions as morphine, the new drug unexpectedly accelerated recovery from the pain—in some cases slashing recovery time in half compared to both morphine and a placebo. In one group, pain lasted 32 days with no treatment, 46 days after morphine and only 11 days after ZH853. "ZH853 diminished the amount of time in pain versus morphine in all tests," said study first author Amy Feehan, Ph.D., a Tulane neuroscience graduate student. "This was an unexpected and unprecedented finding considering that opioids are known to increase and prolong many types of pain." Researchers also ran tests for a form of pain sensitivity that can be masked by changes in the body's endorphin system after an injury. When an injury causes pain, the body's endogenous opioid system engages to counteract it. If the opioid system is blocked—either by stress or an antagonist—the underlying pain can return even after the injury has healed and contribute to chronic pain. Unlike morphine, the new drug prevented this. "With ZH853, the underlying pain was eliminated rather than simply masked," Zadina said. "ZH853 attenuated or blocked two separate processes that contribute to the transition from acute to chronic pain, neuroinflammation and latent sensitization." Researchers hope to begin human clinical trials of the new drug within the next two years. "I believe it's vitally important to treat chronic pain as a disease of the nervous system and treat the underlying pathology of chronic pain rather than just treating the symptoms as they arise," Feehan said. "Current opioid treatments are effective in the short term for pain symptoms, but the downside is that pain ultimately can become worse because chronic opioid use can aggravate the immune system. ZH853 quiets the pain symptoms as well as morphine does, but it also diminishes inflammation, reducing recovery time and preventing relapse to pain later." <|im_end|>

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292, 11, 47288, 11, 1772, 43719, 11, 323, 89116, 6784, 510, 220, 717, 21087, 1115, 3063, 24549, 706, 1027, 4183, 369, 4500, 369, 14830, 3851, 323, 690, 387, 12793, 1618, 369, 279, 6372, 315, 2875, 4751, 320, 18, 4235, 20, 2919, 8, 21249, 8735, 389, 279, 13654, 505, 47288, 323, 1772, 43719, 6784, 323, 279, 9546, 315, 30302, 13, 763, 420, 4007, 11, 11217, 1051, 27076, 2740, 72903, 3060, 1603, 477, 1306, 6784, 13, 35011, 505, 6784, 574, 17303, 311, 8417, 3508, 1901, 39, 25724, 11384, 65069, 6372, 389, 6784, 4528, 311, 1884, 5068, 449, 27448, 483, 1005, 304, 12966, 323, 10099, 510, 220, 16, 1174, 220, 17, 1174, 220, 1032, 21087, 578, 5623, 12, 3473, 2320, 467, 49340, 706, 1027, 20041, 555, 3892, 5315, 304, 2204, 6784, 5415, 13, 4427, 21249, 6784, 6978, 889, 1005, 84460, 9139, 27596, 2740, 527, 3967, 311, 3217, 11201, 6784, 2768, 15173, 1109, 2536, 30592, 72, 590, 3932, 11, 323, 430, 6784, 4250, 2744, 387, 14400, 8795, 5739, 1570, 510, 220, 975, 1174, 220, 868, 21087, 763, 21236, 306, 7978, 11, 15083, 85, 589, 1880, 453, 13, 510, 220, 845, 2331, 8710, 430, 220, 22, 477, 220, 975, 2919, 315, 21249, 27448, 483, 71308, 7319, 323, 44387, 2225, 682, 1094, 21557, 323, 29487, 17508, 278, 4282, 689, 11, 323, 279, 79388, 10278, 1766, 430, 10099, 12020, 449, 27448, 483, 4972, 311, 21249, 19477, 2538, 11134, 477, 4686, 78879, 753, 1008, 8783, 77282, 320, 34, 3711, 8, 1047, 810, 19428, 323, 44387, 6784, 430, 49393, 449, 264, 1396, 315, 709, 81722, 463, 258, 55097, 24915, 510, 220, 17, 21087, 578, 10134, 49340, 320, 92724, 1243, 5623, 8, 374, 8530, 810, 70432, 9959, 719, 706, 1027, 36131, 311, 264, 32415, 13112, 13, 42096, 11, 32171, 1880, 453, 13, 510, 220, 16, 2331, 1766, 430, 27448, 483, 2728, 1306, 279, 38156, 315, 98666, 589, 292, 6784, 44387, 87752, 48937, 19579, 7458, 6514, 11, 323, 420, 1121, 574, 13263, 449, 279, 6372, 315, 27448, 483, 6514, 389, 1772, 43719, 6784, 510, 220, 1114, 21087, 11995, 7978, 1766, 430, 27448, 483, 5636, 6784, 7319, 463, 258, 55097, 43080, 304, 279, 50112, 96146, 21281, 323, 430, 22978, 37140, 36449, 30450, 10215, 279, 2515, 315, 27448, 483, 389, 44387, 6784, 13, 1219, 31882, 28014, 7633, 555, 16844, 510, 220, 23, 10881, 356, 1382, 510, 220, 19, 10881, 323, 2947, 85, 17403, 510, 220, 18, 1174, 220, 21, 10881, 30302, 323, 842, 53595, 44393, 527, 1888, 3463, 315, 439, 1403, 11314, 315, 279, 1890, 16652, 26, 279, 44247, 527, 304, 39749, 292, 2915, 10815, 323, 5353, 264, 88636, 311, 653, 11508, 287, 6784, 1555, 3060, 8631, 477, 11742, 304, 23863, 315, 15130, 30592, 72, 590, 35268, 320, 44, 878, 8, 9129, 6844, 5820, 13, 578, 2926, 6784, 27224, 75042, 6784, 44014, 27179, 44988, 40622, 33611, 323, 44184, 44014, 49853, 9129, 6844, 5820, 520, 279, 72413, 320, 44, 878, 9362, 883, 311, 5663, 533, 6784, 27179, 1347, 731, 65312, 6193, 264, 1317, 4261, 315, 13654, 505, 279, 11134, 11, 279, 2547, 128257, 198, 128256, 78191, 198, 44, 16751, 483, 323, 1023, 48825, 6108, 6784, 11088, 388, 527, 1633, 7524, 520, 27723, 6784, 15453, 11, 719, 7978, 617, 6982, 430, 279, 11217, 649, 1304, 6978, 810, 6784, 57767, 11, 33482, 287, 872, 44776, 323, 7859, 872, 15635, 315, 11469, 21249, 6784, 13, 362, 502, 955, 315, 48825, 8040, 555, 12074, 520, 43316, 2194, 3907, 323, 279, 36664, 29974, 40432, 6401, 10852, 744, 3250, 956, 617, 420, 3185, 2515, 323, 14511, 988, 13654, 892, 505, 6784, 7863, 311, 27448, 483, 11, 4184, 311, 264, 502, 4007, 4756, 304, 279, 10139, 315, 32359, 258, 45864, 367, 13, 30013, 864, 31717, 258, 950, 7978, 520, 43316, 2194, 617, 6982, 430, 279, 5623, 374, 439, 3831, 439, 27448, 483, 719, 4536, 956, 57407, 323, 11384, 17162, 3185, 6372, 13, 330, 32, 5623, 430, 29034, 279, 9320, 505, 30883, 311, 21249, 1375, 2690, 287, 6784, 1053, 4097, 264, 837, 42445, 304, 5623, 4500, 369, 6784, 6373, 1359, 1071, 10195, 4007, 3229, 7957, 1901, 329, 2259, 11, 14561, 315, 16088, 11, 36449, 2508, 323, 93048, 520, 43316, 2194, 3907, 6150, 315, 19152, 323, 7690, 315, 279, 93048, 27692, 520, 279, 21571, 13, 330, 2688, 1193, 617, 279, 24717, 4920, 279, 6541, 505, 30883, 311, 21249, 6784, 1027, 66684, 11, 719, 9045, 311, 64788, 420, 9320, 617, 1047, 2697, 2450, 1210, 57116, 12793, 264, 11775, 48825, 2663, 1901, 39, 25724, 1701, 11494, 4211, 315, 47288, 6784, 323, 6784, 1306, 15173, 13, 578, 5623, 374, 459, 46036, 11678, 315, 279, 18247, 32056, 842, 316, 16751, 258, 11, 902, 374, 1766, 18182, 304, 279, 2547, 13, 59250, 12020, 32510, 449, 1901, 39, 25724, 11, 27448, 483, 477, 264, 43715, 13, 432, 1900, 12020, 449, 27448, 483, 369, 264, 2478, 2919, 26403, 810, 14297, 1109, 1884, 2728, 264, 43715, 13, 1115, 574, 837, 3508, 279, 27448, 483, 574, 2728, 1603, 477, 1306, 279, 11134, 11, 19392, 430, 4972, 1005, 51749, 11737, 2001, 1073, 84460, 1436, 46041, 349, 17876, 13654, 505, 11134, 13, 330, 44, 16751, 483, 76566, 8792, 23418, 1887, 2840, 689, 311, 8356, 463, 67595, 32246, 430, 7319, 6784, 1359, 1901, 329, 2259, 1071, 13, 330, 97011, 25724, 1550, 539, 617, 420, 2515, 1210, 3277, 12793, 304, 279, 1890, 47288, 323, 1772, 43719, 6784, 4787, 439, 27448, 483, 11, 279, 502, 5623, 51709, 49858, 13654, 505, 279, 6784, 49525, 1063, 5157, 93043, 13654, 892, 304, 4376, 7863, 311, 2225, 27448, 483, 323, 264, 43715, 13, 763, 832, 1912, 11, 6784, 36513, 220, 843, 2919, 449, 912, 6514, 11, 220, 2790, 2919, 1306, 27448, 483, 323, 1193, 220, 806, 2919, 1306, 1901, 39, 25724, 13, 330, 97011, 25724, 54182, 279, 3392, 315, 892, 304, 6784, 19579, 27448, 483, 304, 682, 7177, 1359, 1071, 4007, 1176, 3229, 29793, 41558, 10118, 11, 2405, 920, 2637, 264, 43316, 2194, 93048, 19560, 5575, 13, 330, 2028, 574, 459, 16907, 323, 31069, 9455, 13126, 430, 84460, 527, 3967, 311, 5376, 323, 33482, 1690, 4595, 315, 6784, 1210, 59250, 1101, 10837, 7177, 369, 264, 1376, 315, 6784, 27541, 430, 649, 387, 43248, 555, 4442, 304, 279, 2547, 596, 842, 16751, 258, 1887, 1306, 459, 11134, 13, 3277, 459, 11134, 11384, 6784, 11, 279, 2547, 596, 842, 53595, 48825, 1887, 69589, 311, 5663, 533, 433, 13, 1442, 279, 48825, 1887, 374, 19857, 2345, 50998, 555, 8631, 477, 459, 82159, 22416, 16940, 6784, 649, 471, 1524, 1306, 279, 11134, 706, 62320, 323, 17210, 311, 21249, 6784, 13, 27140, 27448, 483, 11, 279, 502, 5623, 32098, 420, 13, 330, 2409, 1901, 39, 25724, 11, 279, 16940, 6784, 574, 34373, 4856, 1109, 5042, 43248, 1359, 1901, 329, 2259, 1071, 13, 330, 97011, 25724, 57732, 660, 477, 19857, 1403, 8821, 11618, 430, 17210, 311, 279, 9320, 505, 30883, 311, 21249, 6784, 11, 18247, 258, 45864, 367, 323, 42767, 74633, 2065, 1210, 59250, 3987, 311, 3240, 3823, 14830, 19622, 315, 279, 502, 5623, 2949, 279, 1828, 1403, 1667, 13, 330, 40, 4510, 433, 596, 13458, 750, 3062, 311, 4322, 21249, 6784, 439, 264, 8624, 315, 279, 23418, 1887, 323, 4322, 279, 16940, 77041, 315, 21249, 6784, 4856, 1109, 1120, 27723, 279, 13803, 439, 814, 31889, 1359, 41558, 10118, 1071, 13, 330, 5520, 48825, 22972, 527, 7524, 304, 279, 2875, 4751, 369, 6784, 13803, 11, 719, 279, 52497, 374, 430, 6784, 13967, 649, 3719, 11201, 1606, 21249, 48825, 1005, 649, 46041, 349, 279, 22852, 1887, 13, 1901, 39, 25724, 7930, 1441, 279, 6784, 13803, 439, 1664, 439, 27448, 483, 1587, 11, 719, 433, 1101, 57160, 288, 37140, 11, 18189, 13654, 892, 323, 27252, 1375, 7629, 311, 6784, 3010, 1210, 220, 128257, 198 ]

2,126

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Introduction Mobile apps are software programmes that run on smartphones and other mobile devices. Mobile health apps can help people manage their own health and wellness, promote healthy living and gain access to useful information when and where they need it. The Brush DJ oral health app was developed to use the opportunity mobile apps offer to motivate an evidence-based oral hygiene routine. A literature review has found no research investigating the use of a mobile app to motivate evidence-based oral hygiene behaviour. Objective The objective of this preliminary investigation was to assess user perception of an oral health app to give a basis for future research and development of app technology in relation to oral health. Method A cross-sectional qualitative user perception questionnaire. Results One hundred and eighty-nine people responded to the questionnaire. Seventy percent (n = 113) of respondents reported that their teeth felt cleaner since using the app. Eighty-eight percent (n = 133) reported the app motivated them to brush their teeth for longer and 92.3% (n = 144) would recommend the app to their friends and family. Four broad themes relating to how the app helped toothbrushing were reported. These themes were motivation, education, compliance and perceived benefits. Conclusion A mobile app is a promising tool to motivate an evidence-based oral hygiene routine. Introduction Mobile applications (apps) Mobile apps are software programmes that run on smartphones and other mobile devices. 1 Over 75 billion apps have been downloaded from the Apple App Store 2 since its launch in 2008, 3 with over 50 billion apps downloaded from Google Play. 4 These apps have been downloaded onto just under 1 billion Apple iOS devices 5 and over 1 billion Android devices 6 around the world. As the number of these devices has increased, the price has reduced making them an affordable alternative to traditional mobile phones, with a £26 smartphone being available to UK consumers. 7 Global smartphone subscriptions have been predicted to grow to 5.6 billion by 2019. 8 It is not just adults who own a device capable of running mobile apps, with a reported 81% of 13–18-year-old phone owners in the UK owning a smartphone 9 and 88% of 16–24-year-olds. 10 The age of those able to use these devices is decreasing with OfCom reporting that six-year-olds understand digital technology better than adults. 11 As well as being used on smartphones, mobile apps can be used on tablet computers. In 2014 62% of children in the UK used a tablet computer at home, compared to 42% in 2013. 12 Health apps The US Food and Drug Administration states: 'The widespread adoption and use of mobile technologies is opening new and innovative ways to improve health and healthcare delivery. Apps can help people manage their own health and wellness, promote healthy living and gain access to useful information when and where they need it'. 1 It is estimated that in 2015 half-a-billion people will be using healthcare mobile apps, with this figure increasing to 50% of the estimated 3.4 billion smartphone and tablet users by 2018. 13 A survey carried out among patients in 2012 found 59% of respondents indicated that mobile health apps would change the way health information is sought and 50% felt that these apps will radically change the way they manage their chronic disease. 14 Mobile devices are a useful means to deliver health interventions because of their widespread adoption, powerful technical capabilities, portability – people tend to have their mobile phones on them at most times and form strong emotional attachments to them. 15 'Sick or well, we have come to love our mobile devices. They are a source of immediate gratification: a powerful link to those we love, access to pictures, sports scores, movies and gossip about friends. That little device is so positive, so beloved. It connects us to the world.' 16 This positive emotional attachment may benefit health promotion via a mobile device being accepted more readily than traditional means, especially among those who have grown up with the technology. People spend more time with their mobile phones than with their partners or at work, meaning health intervention can be delivered anytime and anywhere. Health apps have been developed to manage various common medical conditions such as diabetes, 17 asthma, 18 pain 19 and dermatological conditions. 20 This latter example highlights the need for careful selection and regulation of apps, as an analysis of apps claiming to be able to assess melanoma risk found three out of four of the apps incorrectly classified 30% or more of melanomas as 'unconcerning'. Oral health Poor oral health can affect someone's ability to eat, speak, smile and socialise normally, due to pain or social embarrassment. 21 Caries has been reported as the most common reason for children aged between five and nine being admitted to a hospital in England. The same report found that 70,000 children from birth to 16 years of age were admitted to hospital in England as a result of dental decay in 2012/13. 22 Hospital treatment has a significant financial cost to the NHS and therefore taxpayer. It is also a traumatic experience for the child, parent/carer and all those healthcare professionals involved. Surveys have reported periodontitis affects almost half of all adults in the UK. 23 Evidence of the daily oral hygiene tasks adults and children need to carry out to prevent caries and periodontal disease is known. 24 Evidence is also available that a significant percentage of the population do not accomplish these daily tasks, with 33% of men brushing less than twice a day 25 and 59% of women regularly skipping brushing at bedtime. 26 Oral health app The Brush DJ app was developed to use the opportunity mobile apps offer to motivate an evidence-based oral hygiene routine. The app aims to motivate users to brush for two minutes by playing music, taken either from a playlist, or randomly, from the music stored on the user's device and cloud. The idea of", "role": "user" }, { "content": "Research published in the British Dental Journal shows that Brush DJ, an app designed to encourage youngsters to adopt and maintain an effective oral health care routine using evidence-based techniques, is effective in its aims. Brush DJ was launched on the Apple App Store at the end of 2011 and in 2013 it was accepted into the NHS Choices Health Apps Library. By February 2015 Brush DJ, which is free with no advertisements or in-app purchases, had been downloaded on more than 197,000 devices in 188 countries. It can be used with any type of toothbrush. The app plays music for two minutes - the optimum time for brushing teeth - taken from a playlist or randomly from the user's own device or cloud. As well as encouraging tooth brushing for two minutes, it also reminds users to spit out after brushing but not to rinse, sets reminders to brush twice a day, use a mouthwash at other non-brushing times of the day, sets alerts for dental appointments and reminders to change toothbrushes once every three months. Fundamentally, it makes brushing teeth fun for youngsters. The British Dental Journal research was carried out by a team including a general dental practitioner and NHS Innovation Accelerator Fellow from York, a consultant orthodontist from Rotherham NHS Foundation Trust and a lead dental researcher, educator and Foundation Dean of the Peninsula Dental School from Plymouth University Peninsula Schools of Medicine and Dentistry. The research showed that 70 per cent of respondents reported their teeth felt cleaner since using the app and 88 per cent said that Brush DJ had motivated them to brush their teeth for longer. Ninety per cent said they would recommend the app to their friends and family. The research team concluded that not only had Brush DJ contributed to greater motivation for young people to care for their teeth more effectively, but it also has huge potential as a way to convey important oral health messages and information. Indeed, a recommendation from the study suggests that it would be reasonable to prescribe such an app in the same way in which fluoride toothpastes are currently prescribed in the UK. Ben Underwood, dentist, app developer, NHS Innovation Accelerator Fellow and Honorary University Fellow at Plymouth University Peninsula Schools of Medicine and Dentistry, led the study. He said: \"Brush DJ showed positive effect across four main themes - motivation, education, compliance and perceived benefits. The results of our study indicate that apps such as Brush DJ are beneficial to users and open the way for further research to extend their use and effectiveness still further.\" Professor Elizabeth Kay, Foundation Dean of the Peninsula Dental School from Plymouth University Peninsula Schools of Medicine and Dentistry, was a co-author on the study. She added: \"Caries and other dental health conditions are ultimately preventable, and the great thing about an app such as Brush DJ is that we can show that it has a positive effect for children. Bearing in mind that almost 26,000 children a year are aged between five and nine are admitted to hospital for dental treatment in the UK, for conditions which are on the whole preventable through better understanding and adoption of good oral health routines, the potential for Brush DJ and apps like it to reduce that number is huge. More research based on the findings from this study will help us to develop the app and investigate methods for its more widespread use.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Introduction Mobile apps are software programmes that run on smartphones and other mobile devices. Mobile health apps can help people manage their own health and wellness, promote healthy living and gain access to useful information when and where they need it. The Brush DJ oral health app was developed to use the opportunity mobile apps offer to motivate an evidence-based oral hygiene routine. A literature review has found no research investigating the use of a mobile app to motivate evidence-based oral hygiene behaviour. Objective The objective of this preliminary investigation was to assess user perception of an oral health app to give a basis for future research and development of app technology in relation to oral health. Method A cross-sectional qualitative user perception questionnaire. Results One hundred and eighty-nine people responded to the questionnaire. Seventy percent (n = 113) of respondents reported that their teeth felt cleaner since using the app. Eighty-eight percent (n = 133) reported the app motivated them to brush their teeth for longer and 92.3% (n = 144) would recommend the app to their friends and family. Four broad themes relating to how the app helped toothbrushing were reported. These themes were motivation, education, compliance and perceived benefits. Conclusion A mobile app is a promising tool to motivate an evidence-based oral hygiene routine. Introduction Mobile applications (apps) Mobile apps are software programmes that run on smartphones and other mobile devices. 1 Over 75 billion apps have been downloaded from the Apple App Store 2 since its launch in 2008, 3 with over 50 billion apps downloaded from Google Play. 4 These apps have been downloaded onto just under 1 billion Apple iOS devices 5 and over 1 billion Android devices 6 around the world. As the number of these devices has increased, the price has reduced making them an affordable alternative to traditional mobile phones, with a £26 smartphone being available to UK consumers. 7 Global smartphone subscriptions have been predicted to grow to 5.6 billion by 2019. 8 It is not just adults who own a device capable of running mobile apps, with a reported 81% of 13–18-year-old phone owners in the UK owning a smartphone 9 and 88% of 16–24-year-olds. 10 The age of those able to use these devices is decreasing with OfCom reporting that six-year-olds understand digital technology better than adults. 11 As well as being used on smartphones, mobile apps can be used on tablet computers. In 2014 62% of children in the UK used a tablet computer at home, compared to 42% in 2013. 12 Health apps The US Food and Drug Administration states: 'The widespread adoption and use of mobile technologies is opening new and innovative ways to improve health and healthcare delivery. Apps can help people manage their own health and wellness, promote healthy living and gain access to useful information when and where they need it'. 1 It is estimated that in 2015 half-a-billion people will be using healthcare mobile apps, with this figure increasing to 50% of the estimated 3.4 billion smartphone and tablet users by 2018. 13 A survey carried out among patients in 2012 found 59% of respondents indicated that mobile health apps would change the way health information is sought and 50% felt that these apps will radically change the way they manage their chronic disease. 14 Mobile devices are a useful means to deliver health interventions because of their widespread adoption, powerful technical capabilities, portability – people tend to have their mobile phones on them at most times and form strong emotional attachments to them. 15 'Sick or well, we have come to love our mobile devices. They are a source of immediate gratification: a powerful link to those we love, access to pictures, sports scores, movies and gossip about friends. That little device is so positive, so beloved. It connects us to the world.' 16 This positive emotional attachment may benefit health promotion via a mobile device being accepted more readily than traditional means, especially among those who have grown up with the technology. People spend more time with their mobile phones than with their partners or at work, meaning health intervention can be delivered anytime and anywhere. Health apps have been developed to manage various common medical conditions such as diabetes, 17 asthma, 18 pain 19 and dermatological conditions. 20 This latter example highlights the need for careful selection and regulation of apps, as an analysis of apps claiming to be able to assess melanoma risk found three out of four of the apps incorrectly classified 30% or more of melanomas as 'unconcerning'. Oral health Poor oral health can affect someone's ability to eat, speak, smile and socialise normally, due to pain or social embarrassment. 21 Caries has been reported as the most common reason for children aged between five and nine being admitted to a hospital in England. The same report found that 70,000 children from birth to 16 years of age were admitted to hospital in England as a result of dental decay in 2012/13. 22 Hospital treatment has a significant financial cost to the NHS and therefore taxpayer. It is also a traumatic experience for the child, parent/carer and all those healthcare professionals involved. Surveys have reported periodontitis affects almost half of all adults in the UK. 23 Evidence of the daily oral hygiene tasks adults and children need to carry out to prevent caries and periodontal disease is known. 24 Evidence is also available that a significant percentage of the population do not accomplish these daily tasks, with 33% of men brushing less than twice a day 25 and 59% of women regularly skipping brushing at bedtime. 26 Oral health app The Brush DJ app was developed to use the opportunity mobile apps offer to motivate an evidence-based oral hygiene routine. The app aims to motivate users to brush for two minutes by playing music, taken either from a playlist, or randomly, from the music stored on the user's device and cloud. The idea of<|im_end|> <|im_start|>assistant Research published in the British Dental Journal shows that Brush DJ, an app designed to encourage youngsters to adopt and maintain an effective oral health care routine using evidence-based techniques, is effective in its aims. Brush DJ was launched on the Apple App Store at the end of 2011 and in 2013 it was accepted into the NHS Choices Health Apps Library. By February 2015 Brush DJ, which is free with no advertisements or in-app purchases, had been downloaded on more than 197,000 devices in 188 countries. It can be used with any type of toothbrush. The app plays music for two minutes - the optimum time for brushing teeth - taken from a playlist or randomly from the user's own device or cloud. As well as encouraging tooth brushing for two minutes, it also reminds users to spit out after brushing but not to rinse, sets reminders to brush twice a day, use a mouthwash at other non-brushing times of the day, sets alerts for dental appointments and reminders to change toothbrushes once every three months. Fundamentally, it makes brushing teeth fun for youngsters. The British Dental Journal research was carried out by a team including a general dental practitioner and NHS Innovation Accelerator Fellow from York, a consultant orthodontist from Rotherham NHS Foundation Trust and a lead dental researcher, educator and Foundation Dean of the Peninsula Dental School from Plymouth University Peninsula Schools of Medicine and Dentistry. The research showed that 70 per cent of respondents reported their teeth felt cleaner since using the app and 88 per cent said that Brush DJ had motivated them to brush their teeth for longer. Ninety per cent said they would recommend the app to their friends and family. The research team concluded that not only had Brush DJ contributed to greater motivation for young people to care for their teeth more effectively, but it also has huge potential as a way to convey important oral health messages and information. Indeed, a recommendation from the study suggests that it would be reasonable to prescribe such an app in the same way in which fluoride toothpastes are currently prescribed in the UK. Ben Underwood, dentist, app developer, NHS Innovation Accelerator Fellow and Honorary University Fellow at Plymouth University Peninsula Schools of Medicine and Dentistry, led the study. He said: "Brush DJ showed positive effect across four main themes - motivation, education, compliance and perceived benefits. The results of our study indicate that apps such as Brush DJ are beneficial to users and open the way for further research to extend their use and effectiveness still further." Professor Elizabeth Kay, Foundation Dean of the Peninsula Dental School from Plymouth University Peninsula Schools of Medicine and Dentistry, was a co-author on the study. She added: "Caries and other dental health conditions are ultimately preventable, and the great thing about an app such as Brush DJ is that we can show that it has a positive effect for children. Bearing in mind that almost 26,000 children a year are aged between five and nine are admitted to hospital for dental treatment in the UK, for conditions which are on the whole preventable through better understanding and adoption of good oral health routines, the potential for Brush DJ and apps like it to reduce that number is huge. More research based on the findings from this study will help us to develop the app and investigate methods for its more widespread use." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The spin Seebeck effect, the generation of a spin current by a temperature gradient, has attracted great attention, but the interplay over a millimetre range along a thin ferromagnetic film as well as unintended side effects which hinder an unambiguous detection have evoked controversial discussions. Here, we investigate the inverse spin Hall voltage of a 10 nm thin Pt strip deposited on the magnetic insulators Y 3 Fe 5 O 12 and NiFe 2 O 4 with a temperature gradient in the film plane. We show characteristics typical of the spin Seebeck effect, although we do not observe the most striking features of the transverse spin Seebeck effect. Instead, we attribute the observed voltages to the longitudinal spin Seebeck effect generated by a contact tip induced parasitic out-of-plane temperature gradient, which depends on material, diameter and temperature of the tip. Introduction Spin caloritronics is an active branch in spintronics 1 , 2 . The interplay between heat, charge and spin transport opens a new area of fascinating issues involving the use of waste heat in electronic devices. One potentially useful effect for heat collecting 3 is the spin Seebeck effect (SSE) 4 which was observed in 2008. It was reported that a spin current perpendicular to an applied temperature gradient can be generated in a ferromagnetic metal (FMM) by the transverse SSE (TSSE) 4 . An adjacent normal metal (NM) converts the spin current via the inverse spin Hall effect (ISHE) 5 into a transverse voltage V , which is antisymmetric with respect to the external magnetic field H ( V ( H )=− V (− H ), see Fig. 1a ). In this geometry, the temperature gradient is typically aligned in-plane ( ∇ T x ) and can also induce a planar Nernst effect (PNE) in FMM with magnetic anisotropy 6 which is due to the anisotropic magnetic thermopower and symmetric with respect to H ( V ( H )= V (− H )). For pure ∇ T x in a ferromagnetic or ferrimagnetic insulator (FMI) there is no PNE, since there are no free charge carriers available. However, if the NM material is close to the Stoner criterion, a static magnetic proximity effect could induce a so called proximity PNE, which in general is present in spin polarized NM adjacent to a FMM and could also occur in a NM–FMI contact ( Fig. 1a ). Reports of previous experiments with pure ∇ T x can be found for NM/FMM 4 , 6 , 7 , 8 and for NM/FMI 9 . Figure 1: Summary of effects in SSE experiments. An overview of all possible effects is given for NM/FMM and NM/FMI bilayers depending on the symmetry of the transverse voltage V with respect to the external magnetic in-plane field H for antisymmetric magnetization reversal processes. A distinction is made between symmetric effects (blue), antisymmetric effects (yellow) and the effects, which are not possible in the considered system (red). ( a ) Pure in-plane ∇ T along the x direction parallel to the magnetic field vector H for TSSE measurements. In NM/FMM systems a PNE due to magnetic anisotropy in the FMM or a proximity PNE due to the spin polarization in the NM can exist. In NM/FMI a PNE is absent due to the lack of charge carriers in the FMI. ( b ) Pure out-of-plane ∇ T along the z direction perpendicular to the magnetic field vector H for LSSE measurements. In NM/FMM systems the ANE exists. In both NM/FMM and NM/FMI the proximity ANE can appear if the magnetic proximity effect generates a spin polarization at the interface. The LSSE is proved for NM/FMI systems and should be also present in NM/FMM systems. ( c ) In-plane and unintended out-of-plane ∇ T . A combination of all effects from a and b has to be considered. Full size image For the longitudinal SSE (LSSE) 10 the spin current flows directly from the FM into an adjacent NM parallel to the temperature gradient ( Fig. 1b ), which is typically aligned out-of-plane ( ∇ T z ). In NM/FMM bilayers the anomalous Nernst effect (ANE) can occur, but is absent in the FMI. In semiconducting materials the ANE contributes to the LSSE as already shown for Pt/NiFe 2 O 4 at room temperature 11 . In addition, if the NM would be spin polarized by the proximity to the FM, an additional proximity ANE could occur 12 ( Fig. 1b ). Reports of previous experiments with pure ∇ T z can be found for NM/FMM 11 and for NM/FMI 10 , 13 , 14 , 15 , 16 , 17 , 18 , 19 . As summarized in Fig. 1c an unintended ∇ T z can hamper the evaluation of TSSE experiments with applied ∇ T x . Heat flow into the surrounding area or through the electrical contacts can induce an additional ANE in NM/FMM bilayers and NM/magnetic semiconductors as discussed in literature 8 , 20 , 21 , 22 , 23 , 24 . But since, in principle, all the effects of an LSSE experiment can be present in the TSSE experiment with unintended ∇ T z , proximity Nernst effects and especially parasitic LSSE can also be present in NM/FMI bilayers as already mentioned recently 25 . This leads to four possible effects which are antisymmetric with respect to the external magnetic field, when the temperature gradient is not controlled very carefully (see Fig. 1c ). The prevalence of multiple thermoelectric effects in conducting ferromagnets poses a significant challenge for identifying any individual contribution to the total voltage signal. Previous reports on this matter 6 , 8 , 21 , 22 , 23 are thus limited in significance and could not unambiguously prove or disprove the existence of a TSSE. Here we report on the investigation of the TSSE on the magnetic insulators Y 3 Fe 5 O 12 (YIG) and NiFe 2 O 4 (NFO). We observe the influence of out-of-plane temperature", "role": "user" }, { "content": "An experiment at Tohoku University (Japan) in 2008 laid the foundations for research on 'spin caloritronics' – a field that aims to develop more effective and energy-saving data processing in information technology. Since then, many new spincaloric effects have been studied, but the key experiment in Japan could not be replicated. Researchers at Bielefeld University's Faculty of Physics have now found an explanation for this. They have published their findings in the journal Nature Communications. By applying a new measurement method available at major research facilities, they have also extended the experimental repertoire in spin caloritronics. These results can be found in the journal Physical Review Letters. As well as having an electrical charge, electrons possess an intrinsic angular momentum, called the electron spin. This spin generates a magnetic momentum and influences the spin of the neighbouring electrons in a solid state. In some materials, this can be used to transmit magnetic signals through a solid state without the electrons themselves moving. Because this does not involve the transport of an electric charge as in an electric current and it is also the spin that is passed on as information, the procedure is called spin current. 'Because the electrons themselves do not move, passing on the signal generates less heat. That is an advantage over electric current,' says Daniel Meier, a doctoral student in the 'Thin Films & Physics of Nanostructures' research group headed by Professor Dr. Günter Reiss. The scientists at Bielefeld are generating pure spin currents in magnetic materials that do not conduct electric current – so-called magnetic isolators. They are doing this with thin magnetic films made of nickel ferrite or iron garnet. 'Just as you can use electric current to build up an electric voltage in materials that conduct electricity, you can use a spin current to build up a spin voltage in magnetic isolators. This is called spin accumulation,' is how Dr. Timo Kuschel describes the parallels between classic electronics and spintronics. Kuschel is responsible for the spin caloritronics team in the research group headed by Günter Reiss. In the reported experiment, the team has now shown that thermal spin currents can be generated through differences in temperature. However, their explanation and their effect differ from what was originally anticipated. 'Nonetheless, the true effect is a very effective means of generating thermal spin currents. That is why we are naturally still very thankful to our Japanese colleagues for their research. It was the first experiment worldwide that got the ball rolling in the field of spin caloritronics,' says Günter Reiss. He is carrying out the experiments in cooperation with Universität Regensburg, the Walther-Meissner-Institute in Garching, and the Center for Materials for Information Technology in Alabama (USA). In addition, the researchers are also working on finding proof of spin accumulations. For this, they are using major research facilities such as the DESY (Deutsches Elektronen-Synchrotron) in Hamburg. 'The x-ray radiation generated in these electron storage rings is many times more intensive than x-ray sources in a university laboratory or a hospital,' says Christoph Klewe, who is doing his dissertation on the spin accumulation in bilayers of platinum and magnetic isolators. Previous experiments with x-ray radiation designed to detect spin accumulations did not produce clear results. Therefore, physicists at Bielefeld started searching for an unequivocal measurement method. 'With magnetic X-ray reflectometry, we have found a method that can also provide us with additional information compared to earlier approaches,' emphasizes Timo Kuschel. 'Magnetic X-ray reflectometry is still a new method and has yet to be applied in the field of spin caloritronics.' In cooperation with Osnabrück University, the scientists at Bielefeld University have published an article on this in Physical Review Letters. For Timo Kuschel, it is very clear that 'the findings ensure the need for further discussions and research in the field of spin caloritronics.' ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The spin Seebeck effect, the generation of a spin current by a temperature gradient, has attracted great attention, but the interplay over a millimetre range along a thin ferromagnetic film as well as unintended side effects which hinder an unambiguous detection have evoked controversial discussions. Here, we investigate the inverse spin Hall voltage of a 10 nm thin Pt strip deposited on the magnetic insulators Y 3 Fe 5 O 12 and NiFe 2 O 4 with a temperature gradient in the film plane. We show characteristics typical of the spin Seebeck effect, although we do not observe the most striking features of the transverse spin Seebeck effect. Instead, we attribute the observed voltages to the longitudinal spin Seebeck effect generated by a contact tip induced parasitic out-of-plane temperature gradient, which depends on material, diameter and temperature of the tip. Introduction Spin caloritronics is an active branch in spintronics 1 , 2 . The interplay between heat, charge and spin transport opens a new area of fascinating issues involving the use of waste heat in electronic devices. One potentially useful effect for heat collecting 3 is the spin Seebeck effect (SSE) 4 which was observed in 2008. It was reported that a spin current perpendicular to an applied temperature gradient can be generated in a ferromagnetic metal (FMM) by the transverse SSE (TSSE) 4 . An adjacent normal metal (NM) converts the spin current via the inverse spin Hall effect (ISHE) 5 into a transverse voltage V , which is antisymmetric with respect to the external magnetic field H ( V ( H )=− V (− H ), see Fig. 1a ). In this geometry, the temperature gradient is typically aligned in-plane ( ∇ T x ) and can also induce a planar Nernst effect (PNE) in FMM with magnetic anisotropy 6 which is due to the anisotropic magnetic thermopower and symmetric with respect to H ( V ( H )= V (− H )). For pure ∇ T x in a ferromagnetic or ferrimagnetic insulator (FMI) there is no PNE, since there are no free charge carriers available. However, if the NM material is close to the Stoner criterion, a static magnetic proximity effect could induce a so called proximity PNE, which in general is present in spin polarized NM adjacent to a FMM and could also occur in a NM–FMI contact ( Fig. 1a ). Reports of previous experiments with pure ∇ T x can be found for NM/FMM 4 , 6 , 7 , 8 and for NM/FMI 9 . Figure 1: Summary of effects in SSE experiments. An overview of all possible effects is given for NM/FMM and NM/FMI bilayers depending on the symmetry of the transverse voltage V with respect to the external magnetic in-plane field H for antisymmetric magnetization reversal processes. A distinction is made between symmetric effects (blue), antisymmetric effects (yellow) and the effects, which are not possible in the considered system (red). ( a ) Pure in-plane ∇ T along the x direction parallel to the magnetic field vector H for TSSE measurements. In NM/FMM systems a PNE due to magnetic anisotropy in the FMM or a proximity PNE due to the spin polarization in the NM can exist. In NM/FMI a PNE is absent due to the lack of charge carriers in the FMI. ( b ) Pure out-of-plane ∇ T along the z direction perpendicular to the magnetic field vector H for LSSE measurements. In NM/FMM systems the ANE exists. In both NM/FMM and NM/FMI the proximity ANE can appear if the magnetic proximity effect generates a spin polarization at the interface. The LSSE is proved for NM/FMI systems and should be also present in NM/FMM systems. ( c ) In-plane and unintended out-of-plane ∇ T . A combination of all effects from a and b has to be considered. Full size image For the longitudinal SSE (LSSE) 10 the spin current flows directly from the FM into an adjacent NM parallel to the temperature gradient ( Fig. 1b ), which is typically aligned out-of-plane ( ∇ T z ). In NM/FMM bilayers the anomalous Nernst effect (ANE) can occur, but is absent in the FMI. In semiconducting materials the ANE contributes to the LSSE as already shown for Pt/NiFe 2 O 4 at room temperature 11 . In addition, if the NM would be spin polarized by the proximity to the FM, an additional proximity ANE could occur 12 ( Fig. 1b ). Reports of previous experiments with pure ∇ T z can be found for NM/FMM 11 and for NM/FMI 10 , 13 , 14 , 15 , 16 , 17 , 18 , 19 . As summarized in Fig. 1c an unintended ∇ T z can hamper the evaluation of TSSE experiments with applied ∇ T x . Heat flow into the surrounding area or through the electrical contacts can induce an additional ANE in NM/FMM bilayers and NM/magnetic semiconductors as discussed in literature 8 , 20 , 21 , 22 , 23 , 24 . But since, in principle, all the effects of an LSSE experiment can be present in the TSSE experiment with unintended ∇ T z , proximity Nernst effects and especially parasitic LSSE can also be present in NM/FMI bilayers as already mentioned recently 25 . This leads to four possible effects which are antisymmetric with respect to the external magnetic field, when the temperature gradient is not controlled very carefully (see Fig. 1c ). The prevalence of multiple thermoelectric effects in conducting ferromagnets poses a significant challenge for identifying any individual contribution to the total voltage signal. Previous reports on this matter 6 , 8 , 21 , 22 , 23 are thus limited in significance and could not unambiguously prove or disprove the existence of a TSSE. Here we report on the investigation of the TSSE on the magnetic insulators Y 3 Fe 5 O 12 (YIG) and NiFe 2 O 4 (NFO). We observe the influence of out-of-plane temperature<|im_end|> <|im_start|>assistant An experiment at Tohoku University (Japan) in 2008 laid the foundations for research on 'spin caloritronics' – a field that aims to develop more effective and energy-saving data processing in information technology. Since then, many new spincaloric effects have been studied, but the key experiment in Japan could not be replicated. Researchers at Bielefeld University's Faculty of Physics have now found an explanation for this. They have published their findings in the journal Nature Communications. By applying a new measurement method available at major research facilities, they have also extended the experimental repertoire in spin caloritronics. These results can be found in the journal Physical Review Letters. As well as having an electrical charge, electrons possess an intrinsic angular momentum, called the electron spin. This spin generates a magnetic momentum and influences the spin of the neighbouring electrons in a solid state. In some materials, this can be used to transmit magnetic signals through a solid state without the electrons themselves moving. Because this does not involve the transport of an electric charge as in an electric current and it is also the spin that is passed on as information, the procedure is called spin current. 'Because the electrons themselves do not move, passing on the signal generates less heat. That is an advantage over electric current,' says Daniel Meier, a doctoral student in the 'Thin Films & Physics of Nanostructures' research group headed by Professor Dr. Günter Reiss. The scientists at Bielefeld are generating pure spin currents in magnetic materials that do not conduct electric current – so-called magnetic isolators. They are doing this with thin magnetic films made of nickel ferrite or iron garnet. 'Just as you can use electric current to build up an electric voltage in materials that conduct electricity, you can use a spin current to build up a spin voltage in magnetic isolators. This is called spin accumulation,' is how Dr. Timo Kuschel describes the parallels between classic electronics and spintronics. Kuschel is responsible for the spin caloritronics team in the research group headed by Günter Reiss. In the reported experiment, the team has now shown that thermal spin currents can be generated through differences in temperature. However, their explanation and their effect differ from what was originally anticipated. 'Nonetheless, the true effect is a very effective means of generating thermal spin currents. That is why we are naturally still very thankful to our Japanese colleagues for their research. It was the first experiment worldwide that got the ball rolling in the field of spin caloritronics,' says Günter Reiss. He is carrying out the experiments in cooperation with Universität Regensburg, the Walther-Meissner-Institute in Garching, and the Center for Materials for Information Technology in Alabama (USA). In addition, the researchers are also working on finding proof of spin accumulations. For this, they are using major research facilities such as the DESY (Deutsches Elektronen-Synchrotron) in Hamburg. 'The x-ray radiation generated in these electron storage rings is many times more intensive than x-ray sources in a university laboratory or a hospital,' says Christoph Klewe, who is doing his dissertation on the spin accumulation in bilayers of platinum and magnetic isolators. Previous experiments with x-ray radiation designed to detect spin accumulations did not produce clear results. Therefore, physicists at Bielefeld started searching for an unequivocal measurement method. 'With magnetic X-ray reflectometry, we have found a method that can also provide us with additional information compared to earlier approaches,' emphasizes Timo Kuschel. 'Magnetic X-ray reflectometry is still a new method and has yet to be applied in the field of spin caloritronics.' In cooperation with Osnabrück University, the scientists at Bielefeld University have published an article on this in Physical Review Letters. For Timo Kuschel, it is very clear that 'the findings ensure the need for further discussions and research in the field of spin caloritronics.' <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Extranodal natural killer/T-cell lymphoma (NKTL) is an aggressive type of non-Hodgkin lymphoma with dismal outcome. A better understanding of disease biology and key oncogenic process is necessary for the development of targeted therapy. Super-enhancers (SEs) have been shown to drive pivotal oncogenes in various malignancies. However, the landscape of SEs and SE-associated oncogenes remain elusive in NKTL. Methods We used Nano-ChIP-seq of the active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) to profile unique SEs NKTL primary tumor samples. Integrative analysis of RNA-seq and survival data further pinned down high value, novel SE oncogenes. We utilized shRNA knockdown, CRISPR-dCas9, luciferase reporter assay, ChIP-PCR to investigate the regulation of transcription factor (TF) on SE oncogenes. Multi-color immunofluorescence (mIF) staining was performed on an independent cohort of clinical samples. Various function experiments were performed to evaluate the effects of TOX2 on the malignancy of NKTL in vitro and in vivo. Results SE landscape was substantially different in NKTL samples in comparison with normal tonsils. Several SEs at key transcriptional factor (TF) genes, including TOX2, TBX21(T-bet), EOMES, RUNX2, and ID2 , were identified. We confirmed that TOX2 was aberrantly overexpressed in NKTL relative to normal NK cells and high expression of TOX2 was associated with worse survival. Modulation of TOX2 expression by shRNA, CRISPR-dCas9 interference of SE function impacted on cell proliferation, survival and colony formation ability of NKTL cells. Mechanistically, we found that RUNX3 regulates TOX2 transcription by binding to the active elements of its SE. Silencing TOX2 also impaired tumor formation of NKTL cells in vivo. Metastasis-associated phosphatase PRL-3 has been identified and validated as a key downstream effector of TOX2-mediated oncogenesis. Conclusions Our integrative SE profiling strategy revealed the landscape of SEs, novel targets and insights into molecular pathogenesis of NKTL. The RUNX3-TOX2-SE-TOX2-PRL-3 regulatory pathway may represent a hallmark of NKTL biology. Targeting TOX2 could be a valuable therapeutic intervene for NKTL patients and warrants further study in clinic. Introduction Extranodal natural killer/T-cell lymphoma (NKTL) is an Epstein-Barr virus (EBV) associated, aggressive non-Hodgkin lymphoma (NHL) that is predominantly localizes to the upper aerodigestive tract but can involve non-nasal sites [ 1 , 2 ]. The incidence of NKTL shows a significant ethnic and geographic predilection, constituting approximate 10% of NHL in Asia and South America, but only 1% in North America and Western Europe [ 1 , 2 ]. Combined chemotherapy-radiotherapy is standard treatment for NKTL patients, but often associated with high relapse rate and serious side effects [ 3 ]. New drugs, including anti-PD1 antibody pembrolizumab, have been explored [ 3 , 4 ]. Overall, treatment for NKTL patients remains a challenge in clinic [ 5 , 6 ]. Novel insight into the molecular mechanisms of this disease would guide the development of effective targeted therapies to improve the survival of NKTL patients, especially for those refractory or relapsed cases [ 7 ]. Gene expression profiling studies have reported deregulated signaling pathways underlying the pathogenesis of NKTL, including Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway, PDGF pathway, NOTCH-1 signaling pathway, NFκB pathway [ 8 , 9 , 10 , 11 ]. Increased expression of BIRC5 ( Survivin ), RUNX3 , AURKA ( Aurora Kinase A ), and EZH2 are found in NKTL tumors relative to normal NK cells and they play important roles in the disease progression [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Furthermore, alterations in epigenetic program have been implicated in the pathogenesis of NKTL [ 20 ]. Dysregulated microRNAs (miRNAs) possibly induced by MYC activation affect target pathways relevant to oncogenesis of NKTL [ 21 ]. Promoter hypermethylation-mediated silencing of tumor suppressor genes such as BIM1 , PRDM1 , p73 , DAPK1 , PTPN6 , and PTPRK , have been reported in NKTL patients and cell lines [ 22 , 23 ]. In addition, somatic mutations have been identified in epigenetic regulator genes, including ARID1A , ASXL3 , CREBBP , KMT2D ( MLL2 ), KDM6A , EP300 and TET2 in NKTL cases [ 11 , 24 ]. Enhancer is a region of DNA-regulatory elements that increases the activated transcription of a gene to higher levels via long-range chromatin interaction with its promoter [ 25 ]. Super-enhancers (SEs) are defined as large clusters of enhancers in proximity of 12.5 kb with one another [ 26 ]. SE regions are often characterized by high level bindings of acetylation of histone H3 lysine 27 (H3K27ac), coactivators and transcription factors (TFs). Common coactivators are mediator complex subunit 1 (MED1), bromodomain containing 4 (BRD4) and EP300 [ 27 , 28 , 29 ]. Aberrant assembly and activation of oncogenic SEs have been reported in various solid tumors and hematological malignancies [ 30 , 31 , 32 ]. However, the landscapes of SE and their biological functions roles in NKTL remain elusive. In this study, we aim to define the SE landscapes of NKTL for a better understanding of the molecular pathogenesis of NKTL and to identify novel therapeutic targets. Materials and methods NKTL cell line and patient samples A panel of NKTL cell lines including NKYS, NK-92, NK-S1, and HANK-1 were used in this study. Detailed characteristics of these NKTL cell lines and their culture conditions were described in supplemental Table S 1 . Normal NK cells were purchased from Lonza Bioscience (Basel, Switzerland). Primary tumor samples (NKTL4, NKTL9, NKTL10) and their matched normal tonsil tissues were collected at National Cancer Center Singapore with the approval from Institutional Review Board (CIRB Ref: 2018/3084) and informed consent. The clinicopathological characteristics of these 3 patients were presented in supplemental Table S 2 . Super-enhancer peak calling and identification Nano-chromatin immunoprecipitation followed by sequencing (NanoChIP-seq) was performed on 3 primary NKTL tumor samples and 3 normal tonsil tissues (controls), using polyclonal anti-H3K27ac (Abcam, ab4729) antibody. Library construction and sequencing on the Illumina HiSeq 4000 platform were performed by Exploit Technologies, A*Star (Singapore). Conventional ChIP-seq was conducted on HANK1 and NKYS cell lines using same anti-H3K27ac antibody. ChIP-seq datasets were", "role": "user" }, { "content": "A team of researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) has discovered that a transcription factor, TOX2, was aberrantly increased in patients with natural killer/T-cell lymphoma (NKTL). The increased TOX2 level leads to the growth and spread of NKTL, as well as the overproduction of PRL-3—an oncogenic phosphatase that is a known key player in the survival and metastasis of several other types of cancers. This breakthrough discovery presents a potential novel therapeutic target to treat NKTL. NKTL is an Epstein-Barr virus (EBV) associated, aggressive non-Hodgkin lymphoma (NHL) with very poor treatment outcomes in the advanced stages. It is prevalent in Asia and Latin America but rare in Europe and North America. Combined radiation therapy and chemotherapy is the consensus standard therapy for NKTL patients; however, they are also often associated with high relapse rate and serious side effects. Thus, improved knowledge of the molecular mechanism leading to NKTL progression, as well as the development of novel targeted therapy strategies, has to be addressed urgently. Professor Chng Wee Joo and Associate Professor Takaomi Sanda from CSI Singapore, along with Dr. Ong Choon Kiat from Duke-NUS Medical School, reported their findings in a paper published in journal Molecular Cancer on April 10, 2023. Collective efforts from Dr. Jianbiao Zhou, Dr. Tze-King Tan, Ms Sabrina Hui-Min Toh, Miss Sinan Xiong, and the rest of the team, have contributed to these pioneering revelations. Their findings are also the first to show the involvement of TOX2 and PRL-3 in NKTL. These findings were validated in both cell lines and in a large set of patient tumor samples. In addition, the team analyzed the clinical features of 42 NKTL cases in an independent cohort and found that TOX2 was not only overexpressed in NKTL primary tumors, but also negatively associated with patient survival. Currently, there are no TOX2-specific inhibitors. As such, targeting TOX2, or its downstream PRL-3, could be a valuable therapeutic intervention for NKTL patients and warrants further study in the clinic. Prof Chng, who is the co-lead author of the study, said, \"We have now identified novel treatment targets, TOX2 and the downstream PRL3, in NKTL, where new treatment is greatly needed. We can use different strategies to target these. Proteolysis-targeting chimera (PROTAC) targeting TOX2 to degrade TOX2 protein may be a viable NKTL therapy option.\" \"A humanized antibody, PRL3-zumab, has been approved for Phase 2 clinical trials in Singapore, US, and China to treat all solid tumors. With our findings from this study, it is definitely timely to evaluate PRL3-zumab's effect in patient with NKTL.\" \"Overall, treatment for NKTL patients remains a challenge in the clinic. Novel insight into the molecular mechanisms of this disease would guide the development of effective targeted therapies to improve the survival of NKTL patients, especially for those refractory or relapsed cases,\" said Dr. Jianbiao Zhou from CSI Singapore, the first author of this study. Moving forward, the group is currently testing novel agents for targeting TOX2 and PRL-3 in NKTL. The long-term goal is to bring these novel agents into clinical trials. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background Extranodal natural killer/T-cell lymphoma (NKTL) is an aggressive type of non-Hodgkin lymphoma with dismal outcome. A better understanding of disease biology and key oncogenic process is necessary for the development of targeted therapy. Super-enhancers (SEs) have been shown to drive pivotal oncogenes in various malignancies. However, the landscape of SEs and SE-associated oncogenes remain elusive in NKTL. Methods We used Nano-ChIP-seq of the active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) to profile unique SEs NKTL primary tumor samples. Integrative analysis of RNA-seq and survival data further pinned down high value, novel SE oncogenes. We utilized shRNA knockdown, CRISPR-dCas9, luciferase reporter assay, ChIP-PCR to investigate the regulation of transcription factor (TF) on SE oncogenes. Multi-color immunofluorescence (mIF) staining was performed on an independent cohort of clinical samples. Various function experiments were performed to evaluate the effects of TOX2 on the malignancy of NKTL in vitro and in vivo. Results SE landscape was substantially different in NKTL samples in comparison with normal tonsils. Several SEs at key transcriptional factor (TF) genes, including TOX2, TBX21(T-bet), EOMES, RUNX2, and ID2 , were identified. We confirmed that TOX2 was aberrantly overexpressed in NKTL relative to normal NK cells and high expression of TOX2 was associated with worse survival. Modulation of TOX2 expression by shRNA, CRISPR-dCas9 interference of SE function impacted on cell proliferation, survival and colony formation ability of NKTL cells. Mechanistically, we found that RUNX3 regulates TOX2 transcription by binding to the active elements of its SE. Silencing TOX2 also impaired tumor formation of NKTL cells in vivo. Metastasis-associated phosphatase PRL-3 has been identified and validated as a key downstream effector of TOX2-mediated oncogenesis. Conclusions Our integrative SE profiling strategy revealed the landscape of SEs, novel targets and insights into molecular pathogenesis of NKTL. The RUNX3-TOX2-SE-TOX2-PRL-3 regulatory pathway may represent a hallmark of NKTL biology. Targeting TOX2 could be a valuable therapeutic intervene for NKTL patients and warrants further study in clinic. Introduction Extranodal natural killer/T-cell lymphoma (NKTL) is an Epstein-Barr virus (EBV) associated, aggressive non-Hodgkin lymphoma (NHL) that is predominantly localizes to the upper aerodigestive tract but can involve non-nasal sites [ 1 , 2 ]. The incidence of NKTL shows a significant ethnic and geographic predilection, constituting approximate 10% of NHL in Asia and South America, but only 1% in North America and Western Europe [ 1 , 2 ]. Combined chemotherapy-radiotherapy is standard treatment for NKTL patients, but often associated with high relapse rate and serious side effects [ 3 ]. New drugs, including anti-PD1 antibody pembrolizumab, have been explored [ 3 , 4 ]. Overall, treatment for NKTL patients remains a challenge in clinic [ 5 , 6 ]. Novel insight into the molecular mechanisms of this disease would guide the development of effective targeted therapies to improve the survival of NKTL patients, especially for those refractory or relapsed cases [ 7 ]. Gene expression profiling studies have reported deregulated signaling pathways underlying the pathogenesis of NKTL, including Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway, PDGF pathway, NOTCH-1 signaling pathway, NFκB pathway [ 8 , 9 , 10 , 11 ]. Increased expression of BIRC5 ( Survivin ), RUNX3 , AURKA ( Aurora Kinase A ), and EZH2 are found in NKTL tumors relative to normal NK cells and they play important roles in the disease progression [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Furthermore, alterations in epigenetic program have been implicated in the pathogenesis of NKTL [ 20 ]. Dysregulated microRNAs (miRNAs) possibly induced by MYC activation affect target pathways relevant to oncogenesis of NKTL [ 21 ]. Promoter hypermethylation-mediated silencing of tumor suppressor genes such as BIM1 , PRDM1 , p73 , DAPK1 , PTPN6 , and PTPRK , have been reported in NKTL patients and cell lines [ 22 , 23 ]. In addition, somatic mutations have been identified in epigenetic regulator genes, including ARID1A , ASXL3 , CREBBP , KMT2D ( MLL2 ), KDM6A , EP300 and TET2 in NKTL cases [ 11 , 24 ]. Enhancer is a region of DNA-regulatory elements that increases the activated transcription of a gene to higher levels via long-range chromatin interaction with its promoter [ 25 ]. Super-enhancers (SEs) are defined as large clusters of enhancers in proximity of 12.5 kb with one another [ 26 ]. SE regions are often characterized by high level bindings of acetylation of histone H3 lysine 27 (H3K27ac), coactivators and transcription factors (TFs). Common coactivators are mediator complex subunit 1 (MED1), bromodomain containing 4 (BRD4) and EP300 [ 27 , 28 , 29 ]. Aberrant assembly and activation of oncogenic SEs have been reported in various solid tumors and hematological malignancies [ 30 , 31 , 32 ]. However, the landscapes of SE and their biological functions roles in NKTL remain elusive. In this study, we aim to define the SE landscapes of NKTL for a better understanding of the molecular pathogenesis of NKTL and to identify novel therapeutic targets. Materials and methods NKTL cell line and patient samples A panel of NKTL cell lines including NKYS, NK-92, NK-S1, and HANK-1 were used in this study. Detailed characteristics of these NKTL cell lines and their culture conditions were described in supplemental Table S 1 . Normal NK cells were purchased from Lonza Bioscience (Basel, Switzerland). Primary tumor samples (NKTL4, NKTL9, NKTL10) and their matched normal tonsil tissues were collected at National Cancer Center Singapore with the approval from Institutional Review Board (CIRB Ref: 2018/3084) and informed consent. The clinicopathological characteristics of these 3 patients were presented in supplemental Table S 2 . Super-enhancer peak calling and identification Nano-chromatin immunoprecipitation followed by sequencing (NanoChIP-seq) was performed on 3 primary NKTL tumor samples and 3 normal tonsil tissues (controls), using polyclonal anti-H3K27ac (Abcam, ab4729) antibody. Library construction and sequencing on the Illumina HiSeq 4000 platform were performed by Exploit Technologies, A*Star (Singapore). Conventional ChIP-seq was conducted on HANK1 and NKYS cell lines using same anti-H3K27ac antibody. ChIP-seq datasets were<|im_end|> <|im_start|>assistant A team of researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) has discovered that a transcription factor, TOX2, was aberrantly increased in patients with natural killer/T-cell lymphoma (NKTL). The increased TOX2 level leads to the growth and spread of NKTL, as well as the overproduction of PRL-3—an oncogenic phosphatase that is a known key player in the survival and metastasis of several other types of cancers. This breakthrough discovery presents a potential novel therapeutic target to treat NKTL. NKTL is an Epstein-Barr virus (EBV) associated, aggressive non-Hodgkin lymphoma (NHL) with very poor treatment outcomes in the advanced stages. It is prevalent in Asia and Latin America but rare in Europe and North America. Combined radiation therapy and chemotherapy is the consensus standard therapy for NKTL patients; however, they are also often associated with high relapse rate and serious side effects. Thus, improved knowledge of the molecular mechanism leading to NKTL progression, as well as the development of novel targeted therapy strategies, has to be addressed urgently. Professor Chng Wee Joo and Associate Professor Takaomi Sanda from CSI Singapore, along with Dr. Ong Choon Kiat from Duke-NUS Medical School, reported their findings in a paper published in journal Molecular Cancer on April 10, 2023. Collective efforts from Dr. Jianbiao Zhou, Dr. Tze-King Tan, Ms Sabrina Hui-Min Toh, Miss Sinan Xiong, and the rest of the team, have contributed to these pioneering revelations. Their findings are also the first to show the involvement of TOX2 and PRL-3 in NKTL. These findings were validated in both cell lines and in a large set of patient tumor samples. In addition, the team analyzed the clinical features of 42 NKTL cases in an independent cohort and found that TOX2 was not only overexpressed in NKTL primary tumors, but also negatively associated with patient survival. Currently, there are no TOX2-specific inhibitors. As such, targeting TOX2, or its downstream PRL-3, could be a valuable therapeutic intervention for NKTL patients and warrants further study in the clinic. Prof Chng, who is the co-lead author of the study, said, "We have now identified novel treatment targets, TOX2 and the downstream PRL3, in NKTL, where new treatment is greatly needed. We can use different strategies to target these. Proteolysis-targeting chimera (PROTAC) targeting TOX2 to degrade TOX2 protein may be a viable NKTL therapy option." "A humanized antibody, PRL3-zumab, has been approved for Phase 2 clinical trials in Singapore, US, and China to treat all solid tumors. With our findings from this study, it is definitely timely to evaluate PRL3-zumab's effect in patient with NKTL." "Overall, treatment for NKTL patients remains a challenge in the clinic. Novel insight into the molecular mechanisms of this disease would guide the development of effective targeted therapies to improve the survival of NKTL patients, especially for those refractory or relapsed cases," said Dr. Jianbiao Zhou from CSI Singapore, the first author of this study. Moving forward, the group is currently testing novel agents for targeting TOX2 and PRL-3 in NKTL. The long-term goal is to bring these novel agents into clinical trials. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Mitochondrial fatty acid synthesis (mtFAS) is essential for respiratory function. MtFAS generates the octanoic acid precursor for lipoic acid synthesis, but the role of longer fatty acid products has remained unclear. The structurally well-characterized component of mtFAS, human 2E -enoyl-ACP reductase (MECR) rescues respiratory growth and lipoylation defects of a Saccharomyces cerevisiae Δ etr1 strain lacking native mtFAS enoyl reductase. To address the role of longer products of mtFAS, we employed in silico molecular simulations to design a MECR variant with a shortened substrate binding cavity. Our in vitro and in vivo analyses indicate that the MECR G165Q variant allows synthesis of octanoyl groups but not long chain fatty acids, confirming the validity of our computational approach to engineer substrate length specificity. Furthermore, our data imply that restoring lipoylation in mtFAS deficient yeast strains is not sufficient to support respiration and that long chain acyl-ACPs generated by mtFAS are required for mitochondrial function. Introduction Fatty acids serve a living organism as building blocks of biomembranes, energy storage, cell signaling molecules and ligands in post-translational protein modification. Due to their economical and nutritional values there is a continuous interest in engineering of fatty acid synthesizing pathways in various host organisms to manipulate the carbon chain lengths and modifications of their products 1 , 2 , 3 . Frequently used approaches are heterologous expression of enzymes with different substrate specificity, generation of parallel alternative metabolic pathways or engineering of catalytic properties of endogenous enzymes of these pathways in the organisms used as biofactories. Applying structural knowledge, computer aided design and tools that allow in vivo testing of engineered variants provide avenues towards tailoring enzymes to exhibit desired properties. Aside from commercial value, appropriately designed proteins can also be helpful in the dissection of the physiological function of particular pathways. Recently the mitochondrial fatty acid synthesis pathway (mtFAS) has been identified as a mechanism to regulate mitochondrial respiratory chain (RC) function to meet the substrate availability (acetyl-CoA) to tricarboxylic acid cycle 4 , 5 . MtFAS follows the prokaryotic type II mode where individual enzymatic steps are carried out by separate enzymes (Fig. 1a ) Acyl groups synthesized by mtFAS are linked to 4-phosphopantetheine moiety of the acyl carrier protein (ACP) via a thioester bond. Acyl-ACPs form complexes with adapter proteins that contain a leucine-tyrosine-arginine motif (LYRM) 6 . Acyl-ACP-LYRM protein complexes facilitate assembly of mitochondrial respiratory complexes. Two acyl-ACP molecules can be found associated with LYRM proteins as components of complex I in the mitochondrial RC. Furthermore, an acyl-ACP-LYRM protein complex stabilizes the iron-sulfur cluster synthesis machinery and the LYRM protein, AltMiD51 associated with ACP, participates in the assembly of the large subunit of mitoribosomes 7 , 8 , 9 , 10 , 11 , 12 . MtFAS provides also the octanoic acid precursor required for the endogenous synthesis of lipoic acid, an essential cofactor in oxidative decarboxylation of α-ketoacids and glycine 13 . MtFAS is capable of generating fatty acids longer than eight carbons, but the precise function of these longer fatty acids has remained unclear. We are interested in studying the function of these long-chain acyl groups synthesized by mtFAS and associated with ACPs. The most convenient model to investigate basic aspects of mtFAS function is yeast Saccharomyces cerevisiae , serving as a fast read-out system and the function of a deleted yeast mtFAS enzyme can be replaced by counterparts from heterologous sources 14 , 15 . Fig. 1: Schematic representation of the mitochondrial fatty acid synthesis (mtFAS) pathway, wild-type and engineered MECR and the reaction catalyzed by MECR/Etr1. a Schematic depiction of the mtFAS pathway. The indicated abbreviations (yeast (blue) /human (red)): Mct1/MCAT malonyl-CoA transferase, ACP acyl carrier protein, Cem1/OXSM 3-ketoacyl-ACP synthase, Oar1/KAR1 ketoacyl reductase, Htd2/HTD2 3-hydroxyacyl-thioester dehydratase, Etr1/MECR enoyl-thioester reductase, Lip5/LIAS lipoic acid synthetase. b Schematic representation of the wild-type and engineered MECR. The shown wild-type and engineered enzymes are liganded with C16- and C8-ACP molecules, respectively. The fatty acyl binding cavity extends from the catalytic site near the nicotinamide group of NADPH towards Ile129, which identifies the end of the cavity in the wild-type MECR. The engineered MECR mutant (shown as G165X) possesses a shortened substrate binding cavity discontinuing the synthesis of long-chain fatty acyl-ACP species by mtFAS. c MECR/Etr1 catalyzes the reduction of 2E -enoyl substrates to their saturated counterparts in a NADPH-dependent manner. MECR accepts fatty acyl groups that are attached to either CoA or ACP via a thioester bond. Full size image The last step of mtFAS is carried out by 2E -enoyl-ACP thioester reductases MECR and Etr1 in human and yeast, respectively. These enzymes are members of the medium-chain dehydrogenase / reductase (MDR) superfamily 16 , catalyzing the NADPH-dependent reduction of 2E -enoyl thioesters into acyl thioesters (Fig. 1c ) 17 , 18 . Wild-type human MECR complements the yeast respiratory deficient phenotype of the Δetr1 strain. The crystal structures of the unliganded enzymes of human MECR and the Candida tropicalis Etr1, as well as the structures of the NADPH binary complex, and the NADPH-crotonoyl-CoA ternary complex of the latter enzyme have been solved 19 , 20 , 21 . The structure of MECR shows a bent cavity of sufficient dimensions to accommodate acyl substrates with carbon chain lengths from C4 to C16 19 . In vitro, MECR accepts fatty acyl groups that are attached to either CoA or ACP via a thioester bond as substrates. Here, we describe our work on molecular modeling and simulations guiding the engineering of MECR in order to obtain variants that are unable to accept long-chain fatty acyl substrates. We tested these variants in vivo in Etr1-deficient yeast followed by in vitro studies (Fig. 1b ). Our results show that unlike the wild-type human MECR, the engineered G165Q variant of MECR did not rescue the yeast respiratory deficient phenotype of the Δetr1 strain, although protein lipoylation was restored, demonstrating that the octanoyl/lipoyl synthesizing branch of the mtFAS is supported by enzyme variant. Our data indicate that provision of the octanoic acid precursor by mtFAS is not", "role": "user" }, { "content": "Cellular respiration is a complex and highly regulated process that allows cells to draw energy from nutrition. An international team of scientists in Finland, Germany and Poland have investigated the important role of long-chain fatty acids in guiding this process. The findings, published in Nature Communications, will shed light on the understanding of mitochondrial function that involve disruptions in cellular energy metabolism. They are tiny and highly efficient energy factories operating inside our cells. Often referred to as \"powerhouses,\" mitochondria extract most cellular energy from nutrition. Researchers from the University of Oulu, (Finland), the Heidelberg Institute for Theoretical Studies (HITS, Germany), and the University of Warsaw (Poland) have now succeeded in demonstrating how long-chain fatty acids regulate the amount of energy drawn in this process called cellular respiration. The discovery is ground-breaking as the importance of long-chain fatty acids produced by mitochondria in cellular respiration had not been previously known and the results open up a completely novel approach. \"This information helps us understand diseases that involve impaired mitochondrial function and cellular respiration much better than before,\" says M. Tanvir Rahman from the University of Oulu and lead author on the paper. The study is part of a more extensive research project investigating the connection between cellular respiration and the cell's nutritional state. The scientists used a protein engineering method, in which the mutants of the so-called MECR enzyme involved in mitochondrial fatty acid synthesis were designed using computational molecular modeling, along with structure determination by crystallography, and other experiments to validate the predictions. \"Our study is an example of a successful case of targeted protein modification,\" says researcher Kaija Autio from the University of Oulu. The experiments in this interdisciplinary study were carried out by biochemists and crystallographers from the Faculty of Biochemistry and Molecular Medicine of the University of Oulu and Biocenter Oulu, while the molecular modeling was done by computational biophysicists from the Heidelberg Institute for Theoretical Studies (HITS) and the University of Warsaw. \"This study really demonstrates the value of combining computational and experimental approaches to reveal complex biomolecular mechanisms,\" says Rebecca Wade from HITS. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Mitochondrial fatty acid synthesis (mtFAS) is essential for respiratory function. MtFAS generates the octanoic acid precursor for lipoic acid synthesis, but the role of longer fatty acid products has remained unclear. The structurally well-characterized component of mtFAS, human 2E -enoyl-ACP reductase (MECR) rescues respiratory growth and lipoylation defects of a Saccharomyces cerevisiae Δ etr1 strain lacking native mtFAS enoyl reductase. To address the role of longer products of mtFAS, we employed in silico molecular simulations to design a MECR variant with a shortened substrate binding cavity. Our in vitro and in vivo analyses indicate that the MECR G165Q variant allows synthesis of octanoyl groups but not long chain fatty acids, confirming the validity of our computational approach to engineer substrate length specificity. Furthermore, our data imply that restoring lipoylation in mtFAS deficient yeast strains is not sufficient to support respiration and that long chain acyl-ACPs generated by mtFAS are required for mitochondrial function. Introduction Fatty acids serve a living organism as building blocks of biomembranes, energy storage, cell signaling molecules and ligands in post-translational protein modification. Due to their economical and nutritional values there is a continuous interest in engineering of fatty acid synthesizing pathways in various host organisms to manipulate the carbon chain lengths and modifications of their products 1 , 2 , 3 . Frequently used approaches are heterologous expression of enzymes with different substrate specificity, generation of parallel alternative metabolic pathways or engineering of catalytic properties of endogenous enzymes of these pathways in the organisms used as biofactories. Applying structural knowledge, computer aided design and tools that allow in vivo testing of engineered variants provide avenues towards tailoring enzymes to exhibit desired properties. Aside from commercial value, appropriately designed proteins can also be helpful in the dissection of the physiological function of particular pathways. Recently the mitochondrial fatty acid synthesis pathway (mtFAS) has been identified as a mechanism to regulate mitochondrial respiratory chain (RC) function to meet the substrate availability (acetyl-CoA) to tricarboxylic acid cycle 4 , 5 . MtFAS follows the prokaryotic type II mode where individual enzymatic steps are carried out by separate enzymes (Fig. 1a ) Acyl groups synthesized by mtFAS are linked to 4-phosphopantetheine moiety of the acyl carrier protein (ACP) via a thioester bond. Acyl-ACPs form complexes with adapter proteins that contain a leucine-tyrosine-arginine motif (LYRM) 6 . Acyl-ACP-LYRM protein complexes facilitate assembly of mitochondrial respiratory complexes. Two acyl-ACP molecules can be found associated with LYRM proteins as components of complex I in the mitochondrial RC. Furthermore, an acyl-ACP-LYRM protein complex stabilizes the iron-sulfur cluster synthesis machinery and the LYRM protein, AltMiD51 associated with ACP, participates in the assembly of the large subunit of mitoribosomes 7 , 8 , 9 , 10 , 11 , 12 . MtFAS provides also the octanoic acid precursor required for the endogenous synthesis of lipoic acid, an essential cofactor in oxidative decarboxylation of α-ketoacids and glycine 13 . MtFAS is capable of generating fatty acids longer than eight carbons, but the precise function of these longer fatty acids has remained unclear. We are interested in studying the function of these long-chain acyl groups synthesized by mtFAS and associated with ACPs. The most convenient model to investigate basic aspects of mtFAS function is yeast Saccharomyces cerevisiae , serving as a fast read-out system and the function of a deleted yeast mtFAS enzyme can be replaced by counterparts from heterologous sources 14 , 15 . Fig. 1: Schematic representation of the mitochondrial fatty acid synthesis (mtFAS) pathway, wild-type and engineered MECR and the reaction catalyzed by MECR/Etr1. a Schematic depiction of the mtFAS pathway. The indicated abbreviations (yeast (blue) /human (red)): Mct1/MCAT malonyl-CoA transferase, ACP acyl carrier protein, Cem1/OXSM 3-ketoacyl-ACP synthase, Oar1/KAR1 ketoacyl reductase, Htd2/HTD2 3-hydroxyacyl-thioester dehydratase, Etr1/MECR enoyl-thioester reductase, Lip5/LIAS lipoic acid synthetase. b Schematic representation of the wild-type and engineered MECR. The shown wild-type and engineered enzymes are liganded with C16- and C8-ACP molecules, respectively. The fatty acyl binding cavity extends from the catalytic site near the nicotinamide group of NADPH towards Ile129, which identifies the end of the cavity in the wild-type MECR. The engineered MECR mutant (shown as G165X) possesses a shortened substrate binding cavity discontinuing the synthesis of long-chain fatty acyl-ACP species by mtFAS. c MECR/Etr1 catalyzes the reduction of 2E -enoyl substrates to their saturated counterparts in a NADPH-dependent manner. MECR accepts fatty acyl groups that are attached to either CoA or ACP via a thioester bond. Full size image The last step of mtFAS is carried out by 2E -enoyl-ACP thioester reductases MECR and Etr1 in human and yeast, respectively. These enzymes are members of the medium-chain dehydrogenase / reductase (MDR) superfamily 16 , catalyzing the NADPH-dependent reduction of 2E -enoyl thioesters into acyl thioesters (Fig. 1c ) 17 , 18 . Wild-type human MECR complements the yeast respiratory deficient phenotype of the Δetr1 strain. The crystal structures of the unliganded enzymes of human MECR and the Candida tropicalis Etr1, as well as the structures of the NADPH binary complex, and the NADPH-crotonoyl-CoA ternary complex of the latter enzyme have been solved 19 , 20 , 21 . The structure of MECR shows a bent cavity of sufficient dimensions to accommodate acyl substrates with carbon chain lengths from C4 to C16 19 . In vitro, MECR accepts fatty acyl groups that are attached to either CoA or ACP via a thioester bond as substrates. Here, we describe our work on molecular modeling and simulations guiding the engineering of MECR in order to obtain variants that are unable to accept long-chain fatty acyl substrates. We tested these variants in vivo in Etr1-deficient yeast followed by in vitro studies (Fig. 1b ). Our results show that unlike the wild-type human MECR, the engineered G165Q variant of MECR did not rescue the yeast respiratory deficient phenotype of the Δetr1 strain, although protein lipoylation was restored, demonstrating that the octanoyl/lipoyl synthesizing branch of the mtFAS is supported by enzyme variant. Our data indicate that provision of the octanoic acid precursor by mtFAS is not<|im_end|> <|im_start|>assistant Cellular respiration is a complex and highly regulated process that allows cells to draw energy from nutrition. An international team of scientists in Finland, Germany and Poland have investigated the important role of long-chain fatty acids in guiding this process. The findings, published in Nature Communications, will shed light on the understanding of mitochondrial function that involve disruptions in cellular energy metabolism. They are tiny and highly efficient energy factories operating inside our cells. Often referred to as "powerhouses," mitochondria extract most cellular energy from nutrition. Researchers from the University of Oulu, (Finland), the Heidelberg Institute for Theoretical Studies (HITS, Germany), and the University of Warsaw (Poland) have now succeeded in demonstrating how long-chain fatty acids regulate the amount of energy drawn in this process called cellular respiration. The discovery is ground-breaking as the importance of long-chain fatty acids produced by mitochondria in cellular respiration had not been previously known and the results open up a completely novel approach. "This information helps us understand diseases that involve impaired mitochondrial function and cellular respiration much better than before," says M. Tanvir Rahman from the University of Oulu and lead author on the paper. The study is part of a more extensive research project investigating the connection between cellular respiration and the cell's nutritional state. The scientists used a protein engineering method, in which the mutants of the so-called MECR enzyme involved in mitochondrial fatty acid synthesis were designed using computational molecular modeling, along with structure determination by crystallography, and other experiments to validate the predictions. "Our study is an example of a successful case of targeted protein modification," says researcher Kaija Autio from the University of Oulu. The experiments in this interdisciplinary study were carried out by biochemists and crystallographers from the Faculty of Biochemistry and Molecular Medicine of the University of Oulu and Biocenter Oulu, while the molecular modeling was done by computational biophysicists from the Heidelberg Institute for Theoretical Studies (HITS) and the University of Warsaw. "This study really demonstrates the value of combining computational and experimental approaches to reveal complex biomolecular mechanisms," says Rebecca Wade from HITS. <|im_end|>

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2,050

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract PIEZO1 is a mechanosensitive channel that converts applied force into electrical signals. Partial molecular structures show that PIEZO1 is a bowl-shaped trimer with extended arms. Here we use cryo-electron microscopy to show that PIEZO1 adopts different degrees of curvature in lipid vesicles of different sizes. We also use high-speed atomic force microscopy to analyse the deformability of PIEZO1 under force in membranes on a mica surface, and show that PIEZO1 can be flattened reversibly into the membrane plane. By approximating the absolute force applied, we estimate a range of values for the mechanical spring constant of PIEZO1. Both methods of microscopy demonstrate that PIEZO1 can deform its shape towards a planar structure. This deformation could explain how lateral membrane tension can be converted into a conformation-dependent change in free energy to gate the PIEZO1 channel in response to mechanical perturbations. Main Piezo channels are mechanosensitive, nonselective cation channels that mediate force-detection in eukaryotic cells 1 , 2 , 3 . They transduce mechanical stimuli in many different physiological processes, including touch sensation 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 . As a consequence, deficiency or gain-of-function mutations have been linked to diseases, underscoring their medical importance 12 , 13 , 14 , 15 . Piezo channels are large proteins (>2,500 amino acids) with 38 predicted transmembrane helices per subunit 1 . Several partial molecular structures of mouse PIEZO1 have recently been determined using cryo-electron microscopy (cryo-EM) 16 , 17 , 18 . These structures show a triskelion-shaped homotrimer with a central pore module, a C-terminal extracellular domain and long, bent arms projecting away from the central threefold axis, with helical beams near the attachments of the arms to the pore module 16 (Extended Data Fig. 1a ). Transmembrane helix (TM)37 and TM38 form the pore module. The arms are formed from TM13 to TM36, which are arranged in six four-helical repeats (Extended Data Fig. 1b ). In cryo-EM structures, the detergent micelle follows a curved contour to satisfy the non-planar shape of PIEZO1 (Extended Data Fig. 1a , bottom), and in lipid vesicles PIEZO1 causes the membrane to curve locally into a dome 16 . It has previously been suggested that the arms of PIEZO1 might act as levers to sense force for gating 18 , 19 , 20 , and a model for sensing membrane tension, through the change in in-plane area that results from dome-flattening, has previously been proposed 16 . Various mechanical stimuli 3 , 4 , 5 , 21 , 22 have been used to activate PIEZO1 that—when open—give rise to a single channel conductance of about 29 pS, with a substantial inactivation period 2 , 19 . These methods of activation could be consistent with either of the classical models for mechanical gating: the ‘lateral membrane tension’ model 16 , 21 , 22 , 23 , 24 , 25 , 26 (Fig. 1a ) and the ‘tethered spring’ model 19 , 23 , 27 , 28 , 29 (Fig. 1b ). Owing to the complexity of cell membranes and membrane patches 30 , 31 and the potential multitude of pathways that lead to channel activation 19 , 20 , 32 , 33 , the quantitative and mechanistic identification of force transduction remains challenging. Fig. 1: Proposed activation mechanisms of PIEZO1. a , Lateral membrane tension model. Changes in membrane properties (for example, tension or curvature) lead to a gating force applied onto PIEZO1. b , Tethered spring model. The PIEZO1 channel is activated through interactions with the cytoskeleton or the extracellular matrix. CED, C-terminal extracellular domain. Full size image In this study, we analyse PIEZO1 channels in lipid vesicles of different sizes to determine how the radius of curvature of the vesicle influences the shape of PIEZO1. We also analyse PIEZO1 reconstituted into supported lipid membranes using high-speed atomic force microscopy (HS-AFM), which can simultaneously provide structural and dynamical information on single biomolecules 34 , and—importantly for the investigation of a mechanosensitive channel—permits the application of controlled force during image acquisition 35 . These data characterize the structural response of PIEZO1 to mechanical force, the biologically relevant physical stimulus for this channel. Behaviour of PIEZO1 channels in lipid vesicles We used cryo-EM to study PIEZO1 channels embedded in vesicles that consisted of 1-palmitoyl-2-oleoyl- sn -glycero-3-phosphocholine (POPC), 1,2-dioleoyl- sn -glycero-3-phospho- l -serine (DOPS) and cholesterol at a 8:1:1 (w:w:w) ratio (Fig. 2a ). In the absence of PIEZO1, these vesicles form spheres because the membrane bending energy is minimized 36 . Single PIEZO1 channels are visible in some of the vesicles (Fig. 2a , inset). In projection, and when viewed down the pore axis, the arms bend at the elbow either clockwise or anticlockwise, depending on whether a channel is being viewed from its extracellular or its intracellular surface. PIEZO1 reconstitutes with a preferred orientation in which its extracellular surface faces the inside of a vesicle—probably owing to its intrinsic curvature. Averages of these projected views fit well to top and bottom views of the atomic model of PIEZO1 16 , 17 , 18 , which indicates that PIEZO1 reconstituted in vesicles has a structure similar to PIEZO1 in detergent 16 , 17 , 18 (Fig. 2b ). Fig. 2: Reconstitutions of PIEZO1 in vesicles exhibit various orientations in cryo-EM micrographs. a , PIEZO1 channels reconstituted in POPC:DOPS:cholesterol (8:1:1) vesicles (≥1,000 images). Top- and bottom-view or side-view particles are highlighted by white or yellow arrowheads, respectively. Inset, magnified and contrast-adjusted top-view PIEZO1 with left-handed curved arms (red arrowheads). b , Averages of the top-view ( n = 322) and bottom-view ( n = 120) PIEZO1 compared to the structural model (RCSB Protein Data Bank code (PDB) 6B3R). The handedness of the three arms in projection permits the determination of PIEZO1 orientation. Scale bars, 20 nm. Full size image Viewed from the side, it is evident that PIEZO1 distorts vesicles into a teardrop shape, with the channel located at the region of highest curvature (yellow arrowheads", "role": "user" }, { "content": "A team of scientists from Weill Cornell Medicine and The Rockefeller University has illuminated the basic mechanism of Piezo proteins, which function as sensors in the body for mechanical stimuli such as touch, bladder fullness, and blood pressure. The discovery is a feat of basic science that also opens up many new paths of investigation into the roles of Piezo proteins in human diseases and potential new therapeutic strategies. In the study, published Aug. 21 in Nature, the scientists used advanced microscopy techniques to image the Piezo1 protein at rest and during the application of mechanical forces. They confirmed this complex protein's structure and showed essentially how it can convert mechanical stimuli into an electrical signal. \"Our analysis shows that tension on the cell membrane in which Piezo1 is embedded can flatten and widen the protein's structure,\" said co-senior author Dr. Simon Scheuring, a professor of physiology and biophysics in anesthesiology at Weill Cornell Medicine. Dr. Scheuring and his laboratory collaborated on the study with the laboratory of Dr. Roderick MacKinnon, a professor of molecular neurobiology and biophysics at The Rockefeller University. Dr. MacKinnon was co-recipient of the Nobel Prize in Chemistry in 2003 for his work determining the structures and mechanisms of ion channel proteins. Piezo1 and Piezo2 are very large and complex proteins with unique structures. They are embedded within the membranes of certain cell types, and their function is to transduce mechanical force on cells into electrical signals that alter cell activity. Piezo1 proteins work for example in bladder cells to detect when the bladder is full, and in blood vessel-lining cells to detect and help regulate changes in blood pressure. Piezo2 proteins work in sensory nerve endings in the skin and joints, helping to mediate the senses of touch, pain, and proprioception—the sense of how one's limbs are arranged. Triskelion architecture of Piezo1. Credit: Weill Cornell Medical College Advances in imaging techniques have enabled scientists in recent years to determine the basic structure of Piezo1—a structure that Piezo2 is thought to mostly share. From above this structure has a three-armed, propeller or \"triskelion\" appearance. From the side it looks like a shallow bowl embedded in the cell membrane, with an ion channel at its center. The latter, when opened, allows a flow of calcium and other positively charged ions into the cell. The basic mechanism by which mechanical force opens the ion channel has remained mysterious. But in the new study Dr. Scheuring and Dr. MacKinnon and their colleagues, including lead author Dr. Yi-Chih Lin, a postdoctoral associate in anesthesiology, were able to get a clearer picture of how it works. Side view of Piezo1. Red line indicates structural changes when ion channel is open. Credit: Weill Cornell Medical College They combined cryo-electron microscopy with a less well-known technique called high-speed atomic force microscopy, which produces an image of an object essentially by feeling its surface with a super-sensitive mechanical probe. They showed with these methods that Piezo1 is a springy structure that normally bends the cell membrane where it sits, but will flatten out when, for example, a mechanical force is applied to the cell membrane. \"As the membrane tension increases, the structure of Piezo1 flattens and stretches out to occupy a larger area, which in turn opens the ion channel,\" Dr. Scheuring said. He noted the possibility that other stimuli that stretch and flatten the Piezo1 structure, such as a pulling force on its arms from the inside or on an external domain called the CED from the outside the cell, in principle could open the ion channel—making it a suitably versatile mechanism for the wide range of cell types and physiological functions in which it works. Proposed mechanisms of action of Piezo1 in response to force. Left: Changes in membrane properties, such as tension or curvature, lead to a force that opens Piezo1. Right: Piezo1 channel is activated when structures inside or outside the cell push or pull on the ion channel. Credit: Weill Cornell Medical College Moreover, given this wide range of cell types—in organs including the lungs, bladder, intestines, and pancreas, as well as in blood vessels and the sensory nervous system—the discovery of the basic Piezo-protein mechanism could lead to new ways of understanding and treating many human diseases. To take one example, Dr. Scheuring said, if the membranes of cells lining blood vessels contain excess cholesterol they would become stiffer, increasing the background tension on embedded Piezo 1 proteins and potentially disrupting these proteins' normal ability to detect and help regulate blood pressure. \"Our finding leads to a great many predictions about Piezo proteins' roles in disease that we and others can now go and investigate,\" he said. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract PIEZO1 is a mechanosensitive channel that converts applied force into electrical signals. Partial molecular structures show that PIEZO1 is a bowl-shaped trimer with extended arms. Here we use cryo-electron microscopy to show that PIEZO1 adopts different degrees of curvature in lipid vesicles of different sizes. We also use high-speed atomic force microscopy to analyse the deformability of PIEZO1 under force in membranes on a mica surface, and show that PIEZO1 can be flattened reversibly into the membrane plane. By approximating the absolute force applied, we estimate a range of values for the mechanical spring constant of PIEZO1. Both methods of microscopy demonstrate that PIEZO1 can deform its shape towards a planar structure. This deformation could explain how lateral membrane tension can be converted into a conformation-dependent change in free energy to gate the PIEZO1 channel in response to mechanical perturbations. Main Piezo channels are mechanosensitive, nonselective cation channels that mediate force-detection in eukaryotic cells 1 , 2 , 3 . They transduce mechanical stimuli in many different physiological processes, including touch sensation 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 . As a consequence, deficiency or gain-of-function mutations have been linked to diseases, underscoring their medical importance 12 , 13 , 14 , 15 . Piezo channels are large proteins (>2,500 amino acids) with 38 predicted transmembrane helices per subunit 1 . Several partial molecular structures of mouse PIEZO1 have recently been determined using cryo-electron microscopy (cryo-EM) 16 , 17 , 18 . These structures show a triskelion-shaped homotrimer with a central pore module, a C-terminal extracellular domain and long, bent arms projecting away from the central threefold axis, with helical beams near the attachments of the arms to the pore module 16 (Extended Data Fig. 1a ). Transmembrane helix (TM)37 and TM38 form the pore module. The arms are formed from TM13 to TM36, which are arranged in six four-helical repeats (Extended Data Fig. 1b ). In cryo-EM structures, the detergent micelle follows a curved contour to satisfy the non-planar shape of PIEZO1 (Extended Data Fig. 1a , bottom), and in lipid vesicles PIEZO1 causes the membrane to curve locally into a dome 16 . It has previously been suggested that the arms of PIEZO1 might act as levers to sense force for gating 18 , 19 , 20 , and a model for sensing membrane tension, through the change in in-plane area that results from dome-flattening, has previously been proposed 16 . Various mechanical stimuli 3 , 4 , 5 , 21 , 22 have been used to activate PIEZO1 that—when open—give rise to a single channel conductance of about 29 pS, with a substantial inactivation period 2 , 19 . These methods of activation could be consistent with either of the classical models for mechanical gating: the ‘lateral membrane tension’ model 16 , 21 , 22 , 23 , 24 , 25 , 26 (Fig. 1a ) and the ‘tethered spring’ model 19 , 23 , 27 , 28 , 29 (Fig. 1b ). Owing to the complexity of cell membranes and membrane patches 30 , 31 and the potential multitude of pathways that lead to channel activation 19 , 20 , 32 , 33 , the quantitative and mechanistic identification of force transduction remains challenging. Fig. 1: Proposed activation mechanisms of PIEZO1. a , Lateral membrane tension model. Changes in membrane properties (for example, tension or curvature) lead to a gating force applied onto PIEZO1. b , Tethered spring model. The PIEZO1 channel is activated through interactions with the cytoskeleton or the extracellular matrix. CED, C-terminal extracellular domain. Full size image In this study, we analyse PIEZO1 channels in lipid vesicles of different sizes to determine how the radius of curvature of the vesicle influences the shape of PIEZO1. We also analyse PIEZO1 reconstituted into supported lipid membranes using high-speed atomic force microscopy (HS-AFM), which can simultaneously provide structural and dynamical information on single biomolecules 34 , and—importantly for the investigation of a mechanosensitive channel—permits the application of controlled force during image acquisition 35 . These data characterize the structural response of PIEZO1 to mechanical force, the biologically relevant physical stimulus for this channel. Behaviour of PIEZO1 channels in lipid vesicles We used cryo-EM to study PIEZO1 channels embedded in vesicles that consisted of 1-palmitoyl-2-oleoyl- sn -glycero-3-phosphocholine (POPC), 1,2-dioleoyl- sn -glycero-3-phospho- l -serine (DOPS) and cholesterol at a 8:1:1 (w:w:w) ratio (Fig. 2a ). In the absence of PIEZO1, these vesicles form spheres because the membrane bending energy is minimized 36 . Single PIEZO1 channels are visible in some of the vesicles (Fig. 2a , inset). In projection, and when viewed down the pore axis, the arms bend at the elbow either clockwise or anticlockwise, depending on whether a channel is being viewed from its extracellular or its intracellular surface. PIEZO1 reconstitutes with a preferred orientation in which its extracellular surface faces the inside of a vesicle—probably owing to its intrinsic curvature. Averages of these projected views fit well to top and bottom views of the atomic model of PIEZO1 16 , 17 , 18 , which indicates that PIEZO1 reconstituted in vesicles has a structure similar to PIEZO1 in detergent 16 , 17 , 18 (Fig. 2b ). Fig. 2: Reconstitutions of PIEZO1 in vesicles exhibit various orientations in cryo-EM micrographs. a , PIEZO1 channels reconstituted in POPC:DOPS:cholesterol (8:1:1) vesicles (≥1,000 images). Top- and bottom-view or side-view particles are highlighted by white or yellow arrowheads, respectively. Inset, magnified and contrast-adjusted top-view PIEZO1 with left-handed curved arms (red arrowheads). b , Averages of the top-view ( n = 322) and bottom-view ( n = 120) PIEZO1 compared to the structural model (RCSB Protein Data Bank code (PDB) 6B3R). The handedness of the three arms in projection permits the determination of PIEZO1 orientation. Scale bars, 20 nm. Full size image Viewed from the side, it is evident that PIEZO1 distorts vesicles into a teardrop shape, with the channel located at the region of highest curvature (yellow arrowheads<|im_end|> <|im_start|>assistant A team of scientists from Weill Cornell Medicine and The Rockefeller University has illuminated the basic mechanism of Piezo proteins, which function as sensors in the body for mechanical stimuli such as touch, bladder fullness, and blood pressure. The discovery is a feat of basic science that also opens up many new paths of investigation into the roles of Piezo proteins in human diseases and potential new therapeutic strategies. In the study, published Aug. 21 in Nature, the scientists used advanced microscopy techniques to image the Piezo1 protein at rest and during the application of mechanical forces. They confirmed this complex protein's structure and showed essentially how it can convert mechanical stimuli into an electrical signal. "Our analysis shows that tension on the cell membrane in which Piezo1 is embedded can flatten and widen the protein's structure," said co-senior author Dr. Simon Scheuring, a professor of physiology and biophysics in anesthesiology at Weill Cornell Medicine. Dr. Scheuring and his laboratory collaborated on the study with the laboratory of Dr. Roderick MacKinnon, a professor of molecular neurobiology and biophysics at The Rockefeller University. Dr. MacKinnon was co-recipient of the Nobel Prize in Chemistry in 2003 for his work determining the structures and mechanisms of ion channel proteins. Piezo1 and Piezo2 are very large and complex proteins with unique structures. They are embedded within the membranes of certain cell types, and their function is to transduce mechanical force on cells into electrical signals that alter cell activity. Piezo1 proteins work for example in bladder cells to detect when the bladder is full, and in blood vessel-lining cells to detect and help regulate changes in blood pressure. Piezo2 proteins work in sensory nerve endings in the skin and joints, helping to mediate the senses of touch, pain, and proprioception—the sense of how one's limbs are arranged. Triskelion architecture of Piezo1. Credit: Weill Cornell Medical College Advances in imaging techniques have enabled scientists in recent years to determine the basic structure of Piezo1—a structure that Piezo2 is thought to mostly share. From above this structure has a three-armed, propeller or "triskelion" appearance. From the side it looks like a shallow bowl embedded in the cell membrane, with an ion channel at its center. The latter, when opened, allows a flow of calcium and other positively charged ions into the cell. The basic mechanism by which mechanical force opens the ion channel has remained mysterious. But in the new study Dr. Scheuring and Dr. MacKinnon and their colleagues, including lead author Dr. Yi-Chih Lin, a postdoctoral associate in anesthesiology, were able to get a clearer picture of how it works. Side view of Piezo1. Red line indicates structural changes when ion channel is open. Credit: Weill Cornell Medical College They combined cryo-electron microscopy with a less well-known technique called high-speed atomic force microscopy, which produces an image of an object essentially by feeling its surface with a super-sensitive mechanical probe. They showed with these methods that Piezo1 is a springy structure that normally bends the cell membrane where it sits, but will flatten out when, for example, a mechanical force is applied to the cell membrane. "As the membrane tension increases, the structure of Piezo1 flattens and stretches out to occupy a larger area, which in turn opens the ion channel," Dr. Scheuring said. He noted the possibility that other stimuli that stretch and flatten the Piezo1 structure, such as a pulling force on its arms from the inside or on an external domain called the CED from the outside the cell, in principle could open the ion channel—making it a suitably versatile mechanism for the wide range of cell types and physiological functions in which it works. Proposed mechanisms of action of Piezo1 in response to force. Left: Changes in membrane properties, such as tension or curvature, lead to a force that opens Piezo1. Right: Piezo1 channel is activated when structures inside or outside the cell push or pull on the ion channel. Credit: Weill Cornell Medical College Moreover, given this wide range of cell types—in organs including the lungs, bladder, intestines, and pancreas, as well as in blood vessels and the sensory nervous system—the discovery of the basic Piezo-protein mechanism could lead to new ways of understanding and treating many human diseases. To take one example, Dr. Scheuring said, if the membranes of cells lining blood vessels contain excess cholesterol they would become stiffer, increasing the background tension on embedded Piezo 1 proteins and potentially disrupting these proteins' normal ability to detect and help regulate blood pressure. "Our finding leads to a great many predictions about Piezo proteins' roles in disease that we and others can now go and investigate," he said. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The cosmological applications of atomic clocks 1 , 2 , 3 so far have been limited to searches for the uniform-in-time drift of fundamental constants 4 . We point out that a transient-in-time change of fundamental constants can be induced by dark-matter objects that have large spatial extent, such as stable topological defects 5 built from light non-Standard Model fields. Networks of correlated atomic clocks, some of them already in existence 6 , such as the Global Positioning System, can be used as a powerful tool to search for topological defect dark matter, thus providing another important fundamental physics application for the ever-improving accuracy of atomic clocks. During the encounter with an extended dark-matter object, as it sweeps through the network, initially synchronized clocks will become desynchronized. Time discrepancies between spatially separated clocks are expected to exhibit a distinct signature, encoding the defect’s space structure and its interaction strength with atoms. Main Despite solid evidence for the existence of dark matter ( ∼ 25% of the global energy budget in the Universe and ρ DM ≃ 0.3 GeV cm −3 in the neighbourhood of the Solar system 7 ), its relationship to particles and fields of the Standard Model (SM) remains a mystery. Although searches for particle dark matter (DM) are being actively pursued 8 , there is also significant interest in alternatives, among which is DM composed from very light fields. Depending on the initial field configuration at early cosmological times, such light fields could lead to dark matter via coherent oscillations around the minimum of their potential, and/or form non-trivial stable field configurations in physical three-dimensional space if their potential allows such a possibility. This latter option, which we will generically refer to as topological defects (TDs), is the main interest of our paper. The light masses of fields forming the TDs could lead to a large, indeed macroscopic, size for a defect. Their encounters with the Earth, combined with the DM–SM coupling, can lead to novel signatures of dark matter expressed generically in terms of ‘transient effects’. These effects, coherent on the scale of individual detectors, are temporary shifts in the frequencies and phases of measuring devices, rather than large energy depositions as is the case for microscopic DM. In this paper we suggest the possibility of a new search technique for the topological defect dark matter (TDM), based on a network of atomic clocks. Atomic clocks are arguably the most accurate scientific instruments ever built, reaching a 10 −18 fractional inaccuracy 1 , 2 . Attaining this accuracy requires that the quantum oscillator be well protected from environmental noise and that perturbations be well controlled and characterized. This opens the intriguing prospect of using clocks to study subtle effects, and it is natural to ask if such accuracy can be harnessed for dark-matter searches. To put our discussion on concrete grounds, we introduce a collection of light fields beyond the SM that can form TDs of different dimensionality: monopoles (0D), strings (1D) and domain walls (2D). The exact nature of such defects depends on the composition of the dark sector and on the self-interaction potential 5 . For this paper we take a simplified approach, calling ϕ a generic light field from the dark sector, whether it be scalar or vector, that forms a network of TDs at some early stage of cosmological history. The transverse size of the defect is determined by the field Compton wavelength d , which is in inverse relation to the typical mass scale of the light fields, d ∼ ℏ /( m ϕ c ). The fields we are interested in are ultralight: for an Earth-sized defect, the mass scale is 10 −14 eV . In our simplified approach we capture only the gross features of TDs (ref. 5 ), and call A the amplitude of the field change between inside and outside a TD, A = ϕ inside − ϕ outside , also choosing the outside value of the field to be zero. The energy density of TDM averaged over a large number of defects is controlled by the energy density inside the defect, ρ inside ∼ A 2 / d 2 , and the average distance between the defects, L , through the natural scaling relation: where n = 0,1,2 for monopoles, strings or domain walls, and we measure A in units of energy. The right combination of parameters can give a significant contribution to, or even saturate ρ DM . The average time between ‘close encounters’ with TDs, r ≤ d , is set by the galactic velocity of such objects v g , The velocity of galactic objects around the Solar system is an input parameter that is relatively well known, and for the purpose of estimates one can take v g ≃ 10 −3 × c ≈ 300 km s −1 . If the parameter is of the order of a few years or less, then it is reasonable to think of a detection scheme for TD crossing events. The most crucial question is how the fields forming the defect interact with the SM. All possible types of interaction between TDs and SM fields can be classified using the so-called ‘portals’, a collection of gauge-invariant operators of the SM coupled with the operators from the dark sector 9 . Throughout the remainder of this paper, we will be interested in a more general form of the SM–TD interaction, in the form of the quadratic scalar portal, Because inside the TD, by assumption, ϕ 2 → A 2 and outside ϕ 2 → 0, this portal renormalizes masses and couplings only when the TD core overlaps with the quantum device. Here m e , p and ψ e , p are electron and proton masses and fields, and F μν are electromagnetic tensor components. The appearance of high-energy scales Λ X in the denominators of (2) signifies the effective nature of these operators, implying that at these scales the scalar portals will be replaced by", "role": "user" }, { "content": "The everyday use of a GPS device might be to find your way around town or even navigate a hiking trail, but for two physicists, the Global Positioning System might be a tool in directly detecting and measuring dark matter, so far an elusive but ubiquitous form of matter responsible for the formation of galaxies. Andrei Derevianko, of the University of Nevada, Reno, and his colleague Maxim Pospelov, of the University of Victoria and the Perimeter Institute for Theoretical Physics in Canada, have proposed a method for a dark-matter search with GPS satellites and other atomic clock networks that compares times from the clocks and looks for discrepancies. \"Despite solid observational evidence for the existence of dark matter, its nature remains a mystery,\" Derevianko, a professor in the College of Science at the University, said. \"Some research programs in particle physics assume that dark matter is composed of heavy-particle-like matter. This assumption may not hold true, and significant interest exists for alternatives.\" \"Modern physics and cosmology fail dramatically in that they can only explain 5 percent of mass and energy in the universe in the form of ordinary matter, but the rest is a mystery.\" There is evidence that dark energy is about 68 percent of the mystery mass and energy. The remaining 27 percent is generally acknowledged to be dark matter, even though it is not visible and eludes direct detection and measurement. \"Our research pursues the idea that dark matter may be organized as a large gas-like collection of topological defects, or energy cracks,\" Derevianko said. \"We propose to detect the defects, the dark matter, as they sweep through us with a network of sensitive atomic clocks. The idea is, where the clocks go out of synchronization, we would know that dark matter, the topological defect, has passed by. In fact, we envision using the GPS constellation as the largest human-built dark-matter detector.\" Quantum physicist Andrei Derevianko of the University of Nevada, Reno has contributed to the development of several novel classes of atomic clocks and now is proposing using networks of synchronized atomic clocks to detect dark matter. His paper on the topic is published in the journal Nature Physics. Credit: University of Nevada, Reno Their research was well-received by the scientific community when the theory was presented at renowned scientific conferences this year, and their paper on the topic appears today in the online version of the scientific journal Nature Physics, ahead of the print version. Derevianko is collaborating on analyzing GPS data with Geoff Blewitt, director of the Nevada Geodetic Laboratory, also in the College of Science at the University of Nevada, Reno. The Geodetic Lab developed and maintains the largest GPS data processing center in the world, able to process information from about 12,000 stations around the globe continuously, 24/7. The two are starting to test the dark matter detection ideas by analyzing clock data from the 30 GPS satellites, which use atomic clocks for everyday navigation. Correlated networks of atomic clocks such as the GPS and some ground networks already in existence, can be used as a powerful tool to search for the topological defect dark matter where initially synchronized clocks will become desynchronized. The time discrepancies between spatially separated clocks are expected to exhibit a distinct signature. Blewitt, also a physicist, explained how an array of atomic clocks could possibly detect dark matter. \"We know the dark matter must be there, for example, because it is seen to bend light around galaxies, but we have no evidence as to what it might be made of,\" he said. \"If the dark matter were not there, the normal matter that we know about would not be sufficient to bend the light as much as it does. That's just one of the ways scientists know there is a massive amount of dark matter somewhere out there in the galaxy. One possibility is that the dark matter in this gas might not be made out of particles like normal matter, but of macroscopic imperfections in the fabric of space-time. \"The Earth sweeps through this gas as it orbits the galaxy. So to us, the gas would appear to be like a galactic wind of dark matter blowing through the Earth system and its satellites. As the dark matter blows by, it would occasionally cause clocks of the GPS system to go out of sync with a tell-tale pattern over a period of about 3 minutes. If the dark matter causes the clocks to go out of sync by more than a billionth of a second we should easily be able to detect such events.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The cosmological applications of atomic clocks 1 , 2 , 3 so far have been limited to searches for the uniform-in-time drift of fundamental constants 4 . We point out that a transient-in-time change of fundamental constants can be induced by dark-matter objects that have large spatial extent, such as stable topological defects 5 built from light non-Standard Model fields. Networks of correlated atomic clocks, some of them already in existence 6 , such as the Global Positioning System, can be used as a powerful tool to search for topological defect dark matter, thus providing another important fundamental physics application for the ever-improving accuracy of atomic clocks. During the encounter with an extended dark-matter object, as it sweeps through the network, initially synchronized clocks will become desynchronized. Time discrepancies between spatially separated clocks are expected to exhibit a distinct signature, encoding the defect’s space structure and its interaction strength with atoms. Main Despite solid evidence for the existence of dark matter ( ∼ 25% of the global energy budget in the Universe and ρ DM ≃ 0.3 GeV cm −3 in the neighbourhood of the Solar system 7 ), its relationship to particles and fields of the Standard Model (SM) remains a mystery. Although searches for particle dark matter (DM) are being actively pursued 8 , there is also significant interest in alternatives, among which is DM composed from very light fields. Depending on the initial field configuration at early cosmological times, such light fields could lead to dark matter via coherent oscillations around the minimum of their potential, and/or form non-trivial stable field configurations in physical three-dimensional space if their potential allows such a possibility. This latter option, which we will generically refer to as topological defects (TDs), is the main interest of our paper. The light masses of fields forming the TDs could lead to a large, indeed macroscopic, size for a defect. Their encounters with the Earth, combined with the DM–SM coupling, can lead to novel signatures of dark matter expressed generically in terms of ‘transient effects’. These effects, coherent on the scale of individual detectors, are temporary shifts in the frequencies and phases of measuring devices, rather than large energy depositions as is the case for microscopic DM. In this paper we suggest the possibility of a new search technique for the topological defect dark matter (TDM), based on a network of atomic clocks. Atomic clocks are arguably the most accurate scientific instruments ever built, reaching a 10 −18 fractional inaccuracy 1 , 2 . Attaining this accuracy requires that the quantum oscillator be well protected from environmental noise and that perturbations be well controlled and characterized. This opens the intriguing prospect of using clocks to study subtle effects, and it is natural to ask if such accuracy can be harnessed for dark-matter searches. To put our discussion on concrete grounds, we introduce a collection of light fields beyond the SM that can form TDs of different dimensionality: monopoles (0D), strings (1D) and domain walls (2D). The exact nature of such defects depends on the composition of the dark sector and on the self-interaction potential 5 . For this paper we take a simplified approach, calling ϕ a generic light field from the dark sector, whether it be scalar or vector, that forms a network of TDs at some early stage of cosmological history. The transverse size of the defect is determined by the field Compton wavelength d , which is in inverse relation to the typical mass scale of the light fields, d ∼ ℏ /( m ϕ c ). The fields we are interested in are ultralight: for an Earth-sized defect, the mass scale is 10 −14 eV . In our simplified approach we capture only the gross features of TDs (ref. 5 ), and call A the amplitude of the field change between inside and outside a TD, A = ϕ inside − ϕ outside , also choosing the outside value of the field to be zero. The energy density of TDM averaged over a large number of defects is controlled by the energy density inside the defect, ρ inside ∼ A 2 / d 2 , and the average distance between the defects, L , through the natural scaling relation: where n = 0,1,2 for monopoles, strings or domain walls, and we measure A in units of energy. The right combination of parameters can give a significant contribution to, or even saturate ρ DM . The average time between ‘close encounters’ with TDs, r ≤ d , is set by the galactic velocity of such objects v g , The velocity of galactic objects around the Solar system is an input parameter that is relatively well known, and for the purpose of estimates one can take v g ≃ 10 −3 × c ≈ 300 km s −1 . If the parameter is of the order of a few years or less, then it is reasonable to think of a detection scheme for TD crossing events. The most crucial question is how the fields forming the defect interact with the SM. All possible types of interaction between TDs and SM fields can be classified using the so-called ‘portals’, a collection of gauge-invariant operators of the SM coupled with the operators from the dark sector 9 . Throughout the remainder of this paper, we will be interested in a more general form of the SM–TD interaction, in the form of the quadratic scalar portal, Because inside the TD, by assumption, ϕ 2 → A 2 and outside ϕ 2 → 0, this portal renormalizes masses and couplings only when the TD core overlaps with the quantum device. Here m e , p and ψ e , p are electron and proton masses and fields, and F μν are electromagnetic tensor components. The appearance of high-energy scales Λ X in the denominators of (2) signifies the effective nature of these operators, implying that at these scales the scalar portals will be replaced by<|im_end|> <|im_start|>assistant The everyday use of a GPS device might be to find your way around town or even navigate a hiking trail, but for two physicists, the Global Positioning System might be a tool in directly detecting and measuring dark matter, so far an elusive but ubiquitous form of matter responsible for the formation of galaxies. Andrei Derevianko, of the University of Nevada, Reno, and his colleague Maxim Pospelov, of the University of Victoria and the Perimeter Institute for Theoretical Physics in Canada, have proposed a method for a dark-matter search with GPS satellites and other atomic clock networks that compares times from the clocks and looks for discrepancies. "Despite solid observational evidence for the existence of dark matter, its nature remains a mystery," Derevianko, a professor in the College of Science at the University, said. "Some research programs in particle physics assume that dark matter is composed of heavy-particle-like matter. This assumption may not hold true, and significant interest exists for alternatives." "Modern physics and cosmology fail dramatically in that they can only explain 5 percent of mass and energy in the universe in the form of ordinary matter, but the rest is a mystery." There is evidence that dark energy is about 68 percent of the mystery mass and energy. The remaining 27 percent is generally acknowledged to be dark matter, even though it is not visible and eludes direct detection and measurement. "Our research pursues the idea that dark matter may be organized as a large gas-like collection of topological defects, or energy cracks," Derevianko said. "We propose to detect the defects, the dark matter, as they sweep through us with a network of sensitive atomic clocks. The idea is, where the clocks go out of synchronization, we would know that dark matter, the topological defect, has passed by. In fact, we envision using the GPS constellation as the largest human-built dark-matter detector." Quantum physicist Andrei Derevianko of the University of Nevada, Reno has contributed to the development of several novel classes of atomic clocks and now is proposing using networks of synchronized atomic clocks to detect dark matter. His paper on the topic is published in the journal Nature Physics. Credit: University of Nevada, Reno Their research was well-received by the scientific community when the theory was presented at renowned scientific conferences this year, and their paper on the topic appears today in the online version of the scientific journal Nature Physics, ahead of the print version. Derevianko is collaborating on analyzing GPS data with Geoff Blewitt, director of the Nevada Geodetic Laboratory, also in the College of Science at the University of Nevada, Reno. The Geodetic Lab developed and maintains the largest GPS data processing center in the world, able to process information from about 12,000 stations around the globe continuously, 24/7. The two are starting to test the dark matter detection ideas by analyzing clock data from the 30 GPS satellites, which use atomic clocks for everyday navigation. Correlated networks of atomic clocks such as the GPS and some ground networks already in existence, can be used as a powerful tool to search for the topological defect dark matter where initially synchronized clocks will become desynchronized. The time discrepancies between spatially separated clocks are expected to exhibit a distinct signature. Blewitt, also a physicist, explained how an array of atomic clocks could possibly detect dark matter. "We know the dark matter must be there, for example, because it is seen to bend light around galaxies, but we have no evidence as to what it might be made of," he said. "If the dark matter were not there, the normal matter that we know about would not be sufficient to bend the light as much as it does. That's just one of the ways scientists know there is a massive amount of dark matter somewhere out there in the galaxy. One possibility is that the dark matter in this gas might not be made out of particles like normal matter, but of macroscopic imperfections in the fabric of space-time. "The Earth sweeps through this gas as it orbits the galaxy. So to us, the gas would appear to be like a galactic wind of dark matter blowing through the Earth system and its satellites. As the dark matter blows by, it would occasionally cause clocks of the GPS system to go out of sync with a tell-tale pattern over a period of about 3 minutes. If the dark matter causes the clocks to go out of sync by more than a billionth of a second we should easily be able to detect such events." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Urolithin A (UA) is a natural dietary, microflora-derived metabolite shown to stimulate mitophagy and improve muscle health in old animals and in preclinical models of aging 1 . Here, we report the results of a first-in-human clinical trial in which we administered UA, either as a single dose or as multiple doses over a 4-week period, to healthy, sedentary elderly individuals. We show that UA has a favourable safety profile (primary outcome). UA was bioavailable in plasma at all doses tested, and 4 weeks of treatment with UA at doses of 500 mg and 1,000 mg modulated plasma acylcarnitines and skeletal muscle mitochondrial gene expression in elderly individuals (secondary outcomes). These observed effects on mitochondrial biomarkers show that UA induces a molecular signature of improved mitochondrial and cellular health following regular oral consumption in humans. Main During aging, there is progressive decline in the cell’s capacity to eliminate its dysfunctional elements by autophagy 2 . Accumulating evidence has highlighted the decrease in the specific autophagy, or recycling, of dysfunctional mitochondria, known as mitophagy, in aging skeletal muscle 3 . This can result in poor mitochondrial function in the skeletal muscle, and has been closely linked to slow walking speed and poor muscle strength in elderly individuals 4 , 5 . Consequently, improving mitochondrial function in elderly people by restoring levels of mitophagy represents a promising approach to halt or delay the development of age-related decline in muscle health. UA is a first-in-class natural food metabolite that stimulates mitophagy and prevents the accumulation of dysfunctional mitochondria with age, thereby maintaining mitochondrial biogenesis and respiratory capacity in cells, and, in the nematode Caenorhabditis elegans , improving mobility and extending lifespan 1 . In rodents, UA improves endurance capacity in young rats and in old mice either fed a healthy diet or placed under conditions of metabolic challenge 1 . Recently, UA was shown to have a favourable safety profile following a battery of standardized toxicological tests, including subchronic exposure for 90 d in rodent models 6 , and received a favourable review by the US Food and Drug Administration under the agency’s generally recognized as safe (GRAS) notification program 7 . In this report, we detail the outcome of a first-in-human, randomized, double-blind, placebo-controlled clinical study with UA in healthy, sedentary elderly individuals, and describe its safety, bioavailability and beneficial impact on key biomarkers of mitochondrial health ( NCT02655393 ). Physiological endpoints were not evaluated as part of this study, as the 4-week intervention was considered too short in comparison to the extended protocols (minimum 3 months) deemed necessary to improve muscle strength or physical performance parameters in elderly individuals 8 . This phase 1 study was a two-part study, with a single ascending dose (part A) followed by a multiple ascending dose (part B). As the first objective of the study was safety assessment, the dose escalation was designed to progress from the lowest to the highest UA dose investigated in both parts of the study. Dose escalation to the next higher UA dose was always twofold higher than the previous dose (see Methods and Supplementary Table 1 for the decision tree and stopping rule criteria to advance to the next higher UA dose). During part A of the study, three cohorts of eight subjects each (24 subjects) received either placebo or UA in a two-period design separated by a minimum 3-week wash-out period and at single ascending doses of 250, 500, 1,000 or 2,000 mg, either in soft gels or admixed with food (Fig. 1a , also the CONSORT diagram in Supplementary Fig. 1 ). In part B of the study, three cohorts of 12 elderly subjects were given either placebo or UA at 250, 500 or 1,000 mg once daily in soft gels for 28 d (Fig. 1a and Supplementary Fig. 1 ). The lowest dose of 250 mg was chosen on the basis of preclinical studies, where the equivalent daily dosing of 50 mg per kg (mpk) of body weight in mice demonstrated efficacy on mitochondrial and muscle function after a 6-week oral intervention 1 . Clinical study treatment groups were evenly matched for age, sex and body mass index, and all of the subjects were sedentary at the time of inclusion in the study (Supplementary Tables 2 and 3 ). All enrolled subjects completed the study, there were no major deviations in the clinical protocol or in product intake, and no subjects were excluded in the final analysis for the main study endpoints (Supplementary Fig. 1 ). Fig. 1: UA phase 1 study design, pharmacokinetic analysis and impact on plasma acylcarnitines in elderly individuals. a , Simplified schema of the clinical study design. The dose escalation was designed to progress from the lowest to the highest UA dose investigated in both parts of the study. Dose escalation to the next higher UA dose was always twofold higher than the previous dose. During part A, UA was administered as a single ascending dose, ranging from 250 to 2,000 mg on fasting, and at 500 and 1,000 mg in a fed state with a high-protein yogurt food matrix. Muscle biopsies were collected at pre-dose and 8 h after oral administration of UA only in the 2,000 mg group. During part B, UA was administered once daily in the morning on fasting for 28 d. Plasma and muscle biopsies were collected at pre-dose and at day 28 for biomarker activity measurements (see arrows). The corresponding CONSORT diagram is represented in Supplementary Fig. 1 . b , Dose-dependent increase in plasma UA, UA-glucuronide and UA-sulfate maximum concentrations and exposure during the 96-h sampling period following its administration on the last day of the 28-d treatment period for 250, 500 and 1,000 mg doses ( n = 9 biologically independent samples). Data represent mean ± s.e.m. c , Change in plasma levels of acylcarnitines compared to baseline (day 28 (D28) versus pre-dose (D –1)) ( n = 9 biologically independent samples). Data represent geometric mean ± 95% confidence interval. # 0.05", "role": "user" }, { "content": "Urolithin A, a metabolite of biomolecules found in pomegranates and other fruits, could help slow certain aging processes. EPFL spin-off Amazentis, in conjunction with EPFL and the Swiss Institute of Bioinformatics, has published a paper in the journal Nature Metabolism outlining the results of their clinical trial. It is a fact of life that skeletal muscles begin to lose strength and mass once a person reaches the age of 50. A recent clinical trial involving two EPFL entities—spin-off Amazentis and the Laboratory of Integrative Systems Physiology (LISP) – showed that urolithin A, a compound derived from biomolecules found in fruits such as pomegranates, could slow down this process by improving the functioning of mitochondria—the cells' powerhouses. A joint paper presenting the results of the trial, published today in Nature Metabolism, also demonstrates that ingesting the compound poses no risk to human health. Slowing mitochondrial aging The claim that healthy eating is the key to longer life might seem too convenient—but it is now further backed by scientific evidence. Pomegranate, a fruit prized by many civilizations for its health benefits, contains ellagitannins. When ingested, these molecules are converted into a compound called urolithin A (UA) in the human gut. The researchers found that UA can slow down the mitochondrial aging process. The catch is that not everyone produces UA naturally. To get around that problem, and to make sure all participants received an equal dose, the team synthesized the compound. Some 60 elderly people, all sedentary yet in good health, took a single dose of between 250 and 2,000 mg of UA. The researchers observed no side effects when compared with the control group, who were given a placebo. The participants were then split into four groups, each receiving a placebo, or a 250, 500 or 1,000 mg daily dose of UA for 28 days. Again, no adverse health impacts were found, even after prolonged ingestion. The team then assessed the efficacy of UA by looking at cellular and mitochondrial health biomarkers in the participants' blood and muscle tissue. The results were compelling: UA stimulates mitochondrial biogenesis—the process by which cells increase mitochondrial mass—in the same way as regular exercise. UA is the only known compound that re-establishes cells' ability to recycle defective mitochondria. In young people, this process happens naturally. But as we age, our body starts to lose its power to clean up dysfunctional mitochondria, causing sarcopenia (loss of skeletal muscle mass) and the weakening of other tissues. The team focused on slowing, or even reversing, this natural effect of aging. The paper, published today, also confirms that the compound is safe to eat. Amazentis, based at EPFL's Innovation Park, hopes to harness the promising results to quickly bring the product to market. \"These latest findings, which build on previous preclinical trials, really crystallize how UA could be a game-changer for human health,\" says Johan Auwerx, a professor at LISP, the EPFL lab involved in the trial. An article published in 2016 showed that the lifespan of nematode worms exposed to UA increased by 45 percent—from around 20 to 30 days—when compared with the control group. Likewise, older mice showed 40 percent better endurance while running after two weeks of treatment. The compound may thus have even more secrets to reveal about its benefits for human health. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Urolithin A (UA) is a natural dietary, microflora-derived metabolite shown to stimulate mitophagy and improve muscle health in old animals and in preclinical models of aging 1 . Here, we report the results of a first-in-human clinical trial in which we administered UA, either as a single dose or as multiple doses over a 4-week period, to healthy, sedentary elderly individuals. We show that UA has a favourable safety profile (primary outcome). UA was bioavailable in plasma at all doses tested, and 4 weeks of treatment with UA at doses of 500 mg and 1,000 mg modulated plasma acylcarnitines and skeletal muscle mitochondrial gene expression in elderly individuals (secondary outcomes). These observed effects on mitochondrial biomarkers show that UA induces a molecular signature of improved mitochondrial and cellular health following regular oral consumption in humans. Main During aging, there is progressive decline in the cell’s capacity to eliminate its dysfunctional elements by autophagy 2 . Accumulating evidence has highlighted the decrease in the specific autophagy, or recycling, of dysfunctional mitochondria, known as mitophagy, in aging skeletal muscle 3 . This can result in poor mitochondrial function in the skeletal muscle, and has been closely linked to slow walking speed and poor muscle strength in elderly individuals 4 , 5 . Consequently, improving mitochondrial function in elderly people by restoring levels of mitophagy represents a promising approach to halt or delay the development of age-related decline in muscle health. UA is a first-in-class natural food metabolite that stimulates mitophagy and prevents the accumulation of dysfunctional mitochondria with age, thereby maintaining mitochondrial biogenesis and respiratory capacity in cells, and, in the nematode Caenorhabditis elegans , improving mobility and extending lifespan 1 . In rodents, UA improves endurance capacity in young rats and in old mice either fed a healthy diet or placed under conditions of metabolic challenge 1 . Recently, UA was shown to have a favourable safety profile following a battery of standardized toxicological tests, including subchronic exposure for 90 d in rodent models 6 , and received a favourable review by the US Food and Drug Administration under the agency’s generally recognized as safe (GRAS) notification program 7 . In this report, we detail the outcome of a first-in-human, randomized, double-blind, placebo-controlled clinical study with UA in healthy, sedentary elderly individuals, and describe its safety, bioavailability and beneficial impact on key biomarkers of mitochondrial health ( NCT02655393 ). Physiological endpoints were not evaluated as part of this study, as the 4-week intervention was considered too short in comparison to the extended protocols (minimum 3 months) deemed necessary to improve muscle strength or physical performance parameters in elderly individuals 8 . This phase 1 study was a two-part study, with a single ascending dose (part A) followed by a multiple ascending dose (part B). As the first objective of the study was safety assessment, the dose escalation was designed to progress from the lowest to the highest UA dose investigated in both parts of the study. Dose escalation to the next higher UA dose was always twofold higher than the previous dose (see Methods and Supplementary Table 1 for the decision tree and stopping rule criteria to advance to the next higher UA dose). During part A of the study, three cohorts of eight subjects each (24 subjects) received either placebo or UA in a two-period design separated by a minimum 3-week wash-out period and at single ascending doses of 250, 500, 1,000 or 2,000 mg, either in soft gels or admixed with food (Fig. 1a , also the CONSORT diagram in Supplementary Fig. 1 ). In part B of the study, three cohorts of 12 elderly subjects were given either placebo or UA at 250, 500 or 1,000 mg once daily in soft gels for 28 d (Fig. 1a and Supplementary Fig. 1 ). The lowest dose of 250 mg was chosen on the basis of preclinical studies, where the equivalent daily dosing of 50 mg per kg (mpk) of body weight in mice demonstrated efficacy on mitochondrial and muscle function after a 6-week oral intervention 1 . Clinical study treatment groups were evenly matched for age, sex and body mass index, and all of the subjects were sedentary at the time of inclusion in the study (Supplementary Tables 2 and 3 ). All enrolled subjects completed the study, there were no major deviations in the clinical protocol or in product intake, and no subjects were excluded in the final analysis for the main study endpoints (Supplementary Fig. 1 ). Fig. 1: UA phase 1 study design, pharmacokinetic analysis and impact on plasma acylcarnitines in elderly individuals. a , Simplified schema of the clinical study design. The dose escalation was designed to progress from the lowest to the highest UA dose investigated in both parts of the study. Dose escalation to the next higher UA dose was always twofold higher than the previous dose. During part A, UA was administered as a single ascending dose, ranging from 250 to 2,000 mg on fasting, and at 500 and 1,000 mg in a fed state with a high-protein yogurt food matrix. Muscle biopsies were collected at pre-dose and 8 h after oral administration of UA only in the 2,000 mg group. During part B, UA was administered once daily in the morning on fasting for 28 d. Plasma and muscle biopsies were collected at pre-dose and at day 28 for biomarker activity measurements (see arrows). The corresponding CONSORT diagram is represented in Supplementary Fig. 1 . b , Dose-dependent increase in plasma UA, UA-glucuronide and UA-sulfate maximum concentrations and exposure during the 96-h sampling period following its administration on the last day of the 28-d treatment period for 250, 500 and 1,000 mg doses ( n = 9 biologically independent samples). Data represent mean ± s.e.m. c , Change in plasma levels of acylcarnitines compared to baseline (day 28 (D28) versus pre-dose (D –1)) ( n = 9 biologically independent samples). Data represent geometric mean ± 95% confidence interval. # 0.05<|im_end|> <|im_start|>assistant Urolithin A, a metabolite of biomolecules found in pomegranates and other fruits, could help slow certain aging processes. EPFL spin-off Amazentis, in conjunction with EPFL and the Swiss Institute of Bioinformatics, has published a paper in the journal Nature Metabolism outlining the results of their clinical trial. It is a fact of life that skeletal muscles begin to lose strength and mass once a person reaches the age of 50. A recent clinical trial involving two EPFL entities—spin-off Amazentis and the Laboratory of Integrative Systems Physiology (LISP) – showed that urolithin A, a compound derived from biomolecules found in fruits such as pomegranates, could slow down this process by improving the functioning of mitochondria—the cells' powerhouses. A joint paper presenting the results of the trial, published today in Nature Metabolism, also demonstrates that ingesting the compound poses no risk to human health. Slowing mitochondrial aging The claim that healthy eating is the key to longer life might seem too convenient—but it is now further backed by scientific evidence. Pomegranate, a fruit prized by many civilizations for its health benefits, contains ellagitannins. When ingested, these molecules are converted into a compound called urolithin A (UA) in the human gut. The researchers found that UA can slow down the mitochondrial aging process. The catch is that not everyone produces UA naturally. To get around that problem, and to make sure all participants received an equal dose, the team synthesized the compound. Some 60 elderly people, all sedentary yet in good health, took a single dose of between 250 and 2,000 mg of UA. The researchers observed no side effects when compared with the control group, who were given a placebo. The participants were then split into four groups, each receiving a placebo, or a 250, 500 or 1,000 mg daily dose of UA for 28 days. Again, no adverse health impacts were found, even after prolonged ingestion. The team then assessed the efficacy of UA by looking at cellular and mitochondrial health biomarkers in the participants' blood and muscle tissue. The results were compelling: UA stimulates mitochondrial biogenesis—the process by which cells increase mitochondrial mass—in the same way as regular exercise. UA is the only known compound that re-establishes cells' ability to recycle defective mitochondria. In young people, this process happens naturally. But as we age, our body starts to lose its power to clean up dysfunctional mitochondria, causing sarcopenia (loss of skeletal muscle mass) and the weakening of other tissues. The team focused on slowing, or even reversing, this natural effect of aging. The paper, published today, also confirms that the compound is safe to eat. Amazentis, based at EPFL's Innovation Park, hopes to harness the promising results to quickly bring the product to market. "These latest findings, which build on previous preclinical trials, really crystallize how UA could be a game-changer for human health," says Johan Auwerx, a professor at LISP, the EPFL lab involved in the trial. An article published in 2016 showed that the lifespan of nematode worms exposed to UA increased by 45 percent—from around 20 to 30 days—when compared with the control group. Likewise, older mice showed 40 percent better endurance while running after two weeks of treatment. The compound may thus have even more secrets to reveal about its benefits for human health. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Since the discovery of induced pluripotent stem cells (iPSCs), numerous approaches have been explored to improve the original protocol, which is based on a two-dimensional (2D) cell-culture system. Surprisingly, nothing is known about the effect of a more biologically faithful 3D environment on somatic-cell reprogramming. Here, we report a systematic analysis of how reprogramming of somatic cells occurs within engineered 3D extracellular matrices. By modulating microenvironmental stiffness, degradability and biochemical composition, we have identified a previously unknown role for biophysical effectors in the promotion of iPSC generation. We find that the physical cell confinement imposed by the 3D microenvironment boosts reprogramming through an accelerated mesenchymal-to-epithelial transition and increased epigenetic remodelling. We conclude that 3D microenvironmental signals act synergistically with reprogramming transcription factors to increase somatic plasticity. Main The manipulation of mammalian cell morphology can induce a variety of behavioural changes including proliferation, migration, apoptosis and differentiation 1 , 2 , 3 , 4 , 5 , 6 , 7 . These morphologically driven processes are directly controlled by the cell microenvironment, and there is mounting evidence that biophysical signals conveyed by the extracellular matrix (ECM) are responsible for these changes in cell fate 8 , 9 , 10 . On a molecular level, shape-induced cell fate changes are controlled by changes in gene expression patterns, which themselves are precisely regulated by chromatin organization through a number of different post-translational histone modifications such as acetylation and methylation 11 . Reprogramming of somatic cells is considered to be a multi-step process characterized by an early and late phase of transcriptome and proteome resetting 12 . Notably, genome-wide analysis has revealed that intermediate cell populations that eventually form iPSCs are characterized by the activation of genes responsible for cytoskeleton organization during the first three days of reprogramming 13 , and quantitative proteomic analysis has shown strong induction of proteins related to the regulation of chromatin organization during the same time frame 14 . Taken together, cytoskeletal and epigenetic alterations are two critical events that mark the initiation phase of the reprogramming process. Although previous studies have demonstrated profound effects of the ECM on cell shape and accompanying alteration in chromatin structure, and recent work has revealed that iPSC generation can be influenced by biophysical parameters in 2D culture 15 , the role of 3D microenvironmental cues on somatic-cell reprogramming remains unexplored. To characterize these essential early events in establishing the pluripotent state of iPSCs, we report a new reprogramming strategy using chemically defined 3D ECMs (ref. 5 ). Such matrices permit a precise control over the physiochemical characteristics of the cellular microenvironment that is unachievable in 2D culture systems. We demonstrate that biophysical effectors linked to 3D cell confinement induce immediate alterations in cell morphology that facilitate mesenchymal-to-epithelial transition (MET), as well as histone modifications essential for the initiation of reprogramming. These results suggest previously unknown mechanisms underlying somatic-cell reprogramming and highlight the functional importance of the interaction between cells and their ECM in the regulation of cell fate. 3D microenvironments to promote pluripotency To find an optimal synthetic microenvironment for iPSC generation, we first used mouse embryonic stem cells (ESCs) to determine 3D matrix compositions that best promote ESC self-renewal and pluripotency. To do so, we modulated the mechanical properties of enzymatically crosslinked poly(ethylene glycol) (PEG)-based hydrogels by varying polymer content 16 , 17 . Additionally, to mimic the biochemical features of native ECMs, we functionalized the otherwise inert PEG network with the fibronectin-derived adhesion peptide RGDSP (arginine-glycine-aspartate-serine-proline). We then encapsulated ESCs in soft gels (shear modulus G ′ = 300 ± 35 Pa, as determined by rheometry) using either matrix metalloproteinase (MMP)-degradable (containing the MMP substrate GPQG ↓ IWGQ; ↓ indicating the cleavage site) or -nondegradable (containing the MMP-insensitive sequence GDQGIAGF) PEG networks 18 . The results clearly showed that degradable gels allowed for better cell proliferation ( Supplementary Fig. 1a–c ). We further quantified ESC proliferation in gels of variable stiffness and cell seeding density ( Supplementary Fig. 1d–h ). These experiments, consistent with our recently published data 19 , showed that degradable and soft gels, at a seeding density of 1,000 cells μl −1 , resulted in optimal proliferation rates similar to the 2D control condition, and gave rise to the highest levels of pluripotency marker expression ( Supplementary Fig. 1i ). Indeed, following encapsulation in 3D gels, individual ESCs were uniformly distributed throughout these matrices and expanded into colonies of cells positive for NANOG, OCT4 and alkaline phosphatase ( Fig. 1a–f ). Furthermore, Alamar blue assays confirmed sustained viability in PEG-based hydrogels (data not shown). Notably, whereas ESCs cultured in two dimensions rapidly differentiated following LIF removal, 3D-encapsulated cells maintained their typical undifferentiated morphology and Oct4 –GFP expression as much as nine days after removal of LIF ( Fig. 1g–i ), suggesting that spatial confinement of cells in the 3D microenvironment plays a role in maintaining pluripotency. Figure 1: 3D PEG hydrogel cultures maintain ESC pluripotency. a – c , ESC colony growth 1, 3 and 5 days after encapsulation in PEG hydrogels. BF, bright field. d , Immunostaining for NANOG (the inset shows the relative DAPI staining). e , Oct4 -driven GFP expression. f , Alkaline phosphatase (AP) staining. g , h , Oct4 –GFP expression of ESCs grown without LIF in three dimensions for one week ( g ) or in two dimensions ( h ). Insets show the bright-field images with undifferentiated and differentiated morphologies in 3D and 2D conditions, respectively. i , Flow cytometry analysis of Oct4 –GFP expression of ESCs cultured in 2D and 3D conditions with or without LIF. Scale bars, 100 μm. Full size image iPSC generation in defined 3D microenvironments The promising results obtained with 3D ESC culture prompted us to use the same 3D microenvironment formulation for iPSC generation. To assess whether reprogramming to pluripotency could be achieved in a 3D context, we employed a well-defined mouse model system based on the drug-inducible expression of the four Yamanaka factors 20 ( Fig. 2a ). Pou5f1 tm 2( EGFP", "role": "user" }, { "content": "EPFL scientists have developed a new method that turns cells into stem cells by \"squeezing\" them. The method paves the way for large-scale production of stem cells for medical purposes. Stem cells are now at the cutting edge of modern medicine. They can transform into a cells of different organs, offering new ways to treat a range of injuries and diseases from Parkinson's to diabetes. But producing the right type of stem cells in a standardized manner is still a serious challenge. EPFL scientists have now developed a gel that boosts the ability of normal cells to revert into stem cells by simply \"squeezing\" them into shape. Published in Nature Materials, the new technique can also be easily scaled up to produce stem cells for various applications on an industrial scale. There are different types of stem cells, but the ones that are of particular medical interest are the so-called \"induced pluripotent stem cells\" or iPSCs. These are derived from mature, adult cells that have been genetically reprogrammed to behave like stem cells (which is why they are \"induced\"). iPSCs can then be regrown into a whole range of different cells types, e.g. liver, pancreatic, lung, skin etc. There have been many attempts to design a standardized method for generating such stem cells. But even the most successful methods turn out to not be very effective, especially for use on a large scale. A major issue is that existing techniques use the two-dimensional environment of a petri dish or cell culture flask, whereas cells in the body exist in a three-dimensional world. The lab of Matthias Lutolf at EPFL has now developed a new method that may help to overcome these challenges. The approach uses a three-dimensional cell culture system. Normal cells are placed inside a gel that contains normal growth nutrients. \"We try to simulate the three-dimensional environment of a living tissue and see how it would influence stem cell behavior,\" explains Lutolf. \"But soon we were surprised to see that cell reprogramming is also influenced by the surrounding microenvironment.\" The microenvironment in this case, is the gel. The researchers discovered that they could reprogram the cells faster and more efficiently than current methods by simply adjusting the composition - and hence the stiffness and density - of the surrounding gel. As a result, the gel exerts different forces on the cells, essentially \"squeezing\" them. As a new phenomenon, this is not entirely understood. However, the scientists propose that the three-dimensional environment is key to this process, generating mechanical signals that work together with genetic factors to make the cell easier to transform into a stem cell. \"Each cell type may have a 'sweet spot' of physical and chemical factors that offer the most efficient transformation,\" says Lutolf. \"Once you find it, it is a matter of resources and time to create stem cells on a larger scale.\" The greater impact of this discovery is possibly quantity. The technique can be applied to a large number of cells to produce stem cells on an industrial scale. Lutolf's lab is looking into this, but their main focus is to better understand the phenomenon, and to find the 'sweet spots' for other cell types. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Since the discovery of induced pluripotent stem cells (iPSCs), numerous approaches have been explored to improve the original protocol, which is based on a two-dimensional (2D) cell-culture system. Surprisingly, nothing is known about the effect of a more biologically faithful 3D environment on somatic-cell reprogramming. Here, we report a systematic analysis of how reprogramming of somatic cells occurs within engineered 3D extracellular matrices. By modulating microenvironmental stiffness, degradability and biochemical composition, we have identified a previously unknown role for biophysical effectors in the promotion of iPSC generation. We find that the physical cell confinement imposed by the 3D microenvironment boosts reprogramming through an accelerated mesenchymal-to-epithelial transition and increased epigenetic remodelling. We conclude that 3D microenvironmental signals act synergistically with reprogramming transcription factors to increase somatic plasticity. Main The manipulation of mammalian cell morphology can induce a variety of behavioural changes including proliferation, migration, apoptosis and differentiation 1 , 2 , 3 , 4 , 5 , 6 , 7 . These morphologically driven processes are directly controlled by the cell microenvironment, and there is mounting evidence that biophysical signals conveyed by the extracellular matrix (ECM) are responsible for these changes in cell fate 8 , 9 , 10 . On a molecular level, shape-induced cell fate changes are controlled by changes in gene expression patterns, which themselves are precisely regulated by chromatin organization through a number of different post-translational histone modifications such as acetylation and methylation 11 . Reprogramming of somatic cells is considered to be a multi-step process characterized by an early and late phase of transcriptome and proteome resetting 12 . Notably, genome-wide analysis has revealed that intermediate cell populations that eventually form iPSCs are characterized by the activation of genes responsible for cytoskeleton organization during the first three days of reprogramming 13 , and quantitative proteomic analysis has shown strong induction of proteins related to the regulation of chromatin organization during the same time frame 14 . Taken together, cytoskeletal and epigenetic alterations are two critical events that mark the initiation phase of the reprogramming process. Although previous studies have demonstrated profound effects of the ECM on cell shape and accompanying alteration in chromatin structure, and recent work has revealed that iPSC generation can be influenced by biophysical parameters in 2D culture 15 , the role of 3D microenvironmental cues on somatic-cell reprogramming remains unexplored. To characterize these essential early events in establishing the pluripotent state of iPSCs, we report a new reprogramming strategy using chemically defined 3D ECMs (ref. 5 ). Such matrices permit a precise control over the physiochemical characteristics of the cellular microenvironment that is unachievable in 2D culture systems. We demonstrate that biophysical effectors linked to 3D cell confinement induce immediate alterations in cell morphology that facilitate mesenchymal-to-epithelial transition (MET), as well as histone modifications essential for the initiation of reprogramming. These results suggest previously unknown mechanisms underlying somatic-cell reprogramming and highlight the functional importance of the interaction between cells and their ECM in the regulation of cell fate. 3D microenvironments to promote pluripotency To find an optimal synthetic microenvironment for iPSC generation, we first used mouse embryonic stem cells (ESCs) to determine 3D matrix compositions that best promote ESC self-renewal and pluripotency. To do so, we modulated the mechanical properties of enzymatically crosslinked poly(ethylene glycol) (PEG)-based hydrogels by varying polymer content 16 , 17 . Additionally, to mimic the biochemical features of native ECMs, we functionalized the otherwise inert PEG network with the fibronectin-derived adhesion peptide RGDSP (arginine-glycine-aspartate-serine-proline). We then encapsulated ESCs in soft gels (shear modulus G ′ = 300 ± 35 Pa, as determined by rheometry) using either matrix metalloproteinase (MMP)-degradable (containing the MMP substrate GPQG ↓ IWGQ; ↓ indicating the cleavage site) or -nondegradable (containing the MMP-insensitive sequence GDQGIAGF) PEG networks 18 . The results clearly showed that degradable gels allowed for better cell proliferation ( Supplementary Fig. 1a–c ). We further quantified ESC proliferation in gels of variable stiffness and cell seeding density ( Supplementary Fig. 1d–h ). These experiments, consistent with our recently published data 19 , showed that degradable and soft gels, at a seeding density of 1,000 cells μl −1 , resulted in optimal proliferation rates similar to the 2D control condition, and gave rise to the highest levels of pluripotency marker expression ( Supplementary Fig. 1i ). Indeed, following encapsulation in 3D gels, individual ESCs were uniformly distributed throughout these matrices and expanded into colonies of cells positive for NANOG, OCT4 and alkaline phosphatase ( Fig. 1a–f ). Furthermore, Alamar blue assays confirmed sustained viability in PEG-based hydrogels (data not shown). Notably, whereas ESCs cultured in two dimensions rapidly differentiated following LIF removal, 3D-encapsulated cells maintained their typical undifferentiated morphology and Oct4 –GFP expression as much as nine days after removal of LIF ( Fig. 1g–i ), suggesting that spatial confinement of cells in the 3D microenvironment plays a role in maintaining pluripotency. Figure 1: 3D PEG hydrogel cultures maintain ESC pluripotency. a – c , ESC colony growth 1, 3 and 5 days after encapsulation in PEG hydrogels. BF, bright field. d , Immunostaining for NANOG (the inset shows the relative DAPI staining). e , Oct4 -driven GFP expression. f , Alkaline phosphatase (AP) staining. g , h , Oct4 –GFP expression of ESCs grown without LIF in three dimensions for one week ( g ) or in two dimensions ( h ). Insets show the bright-field images with undifferentiated and differentiated morphologies in 3D and 2D conditions, respectively. i , Flow cytometry analysis of Oct4 –GFP expression of ESCs cultured in 2D and 3D conditions with or without LIF. Scale bars, 100 μm. Full size image iPSC generation in defined 3D microenvironments The promising results obtained with 3D ESC culture prompted us to use the same 3D microenvironment formulation for iPSC generation. To assess whether reprogramming to pluripotency could be achieved in a 3D context, we employed a well-defined mouse model system based on the drug-inducible expression of the four Yamanaka factors 20 ( Fig. 2a ). Pou5f1 tm 2( EGFP<|im_end|> <|im_start|>assistant EPFL scientists have developed a new method that turns cells into stem cells by "squeezing" them. The method paves the way for large-scale production of stem cells for medical purposes. Stem cells are now at the cutting edge of modern medicine. They can transform into a cells of different organs, offering new ways to treat a range of injuries and diseases from Parkinson's to diabetes. But producing the right type of stem cells in a standardized manner is still a serious challenge. EPFL scientists have now developed a gel that boosts the ability of normal cells to revert into stem cells by simply "squeezing" them into shape. Published in Nature Materials, the new technique can also be easily scaled up to produce stem cells for various applications on an industrial scale. There are different types of stem cells, but the ones that are of particular medical interest are the so-called "induced pluripotent stem cells" or iPSCs. These are derived from mature, adult cells that have been genetically reprogrammed to behave like stem cells (which is why they are "induced"). iPSCs can then be regrown into a whole range of different cells types, e.g. liver, pancreatic, lung, skin etc. There have been many attempts to design a standardized method for generating such stem cells. But even the most successful methods turn out to not be very effective, especially for use on a large scale. A major issue is that existing techniques use the two-dimensional environment of a petri dish or cell culture flask, whereas cells in the body exist in a three-dimensional world. The lab of Matthias Lutolf at EPFL has now developed a new method that may help to overcome these challenges. The approach uses a three-dimensional cell culture system. Normal cells are placed inside a gel that contains normal growth nutrients. "We try to simulate the three-dimensional environment of a living tissue and see how it would influence stem cell behavior," explains Lutolf. "But soon we were surprised to see that cell reprogramming is also influenced by the surrounding microenvironment." The microenvironment in this case, is the gel. The researchers discovered that they could reprogram the cells faster and more efficiently than current methods by simply adjusting the composition - and hence the stiffness and density - of the surrounding gel. As a result, the gel exerts different forces on the cells, essentially "squeezing" them. As a new phenomenon, this is not entirely understood. However, the scientists propose that the three-dimensional environment is key to this process, generating mechanical signals that work together with genetic factors to make the cell easier to transform into a stem cell. "Each cell type may have a 'sweet spot' of physical and chemical factors that offer the most efficient transformation," says Lutolf. "Once you find it, it is a matter of resources and time to create stem cells on a larger scale." The greater impact of this discovery is possibly quantity. The technique can be applied to a large number of cells to produce stem cells on an industrial scale. Lutolf's lab is looking into this, but their main focus is to better understand the phenomenon, and to find the 'sweet spots' for other cell types. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract An attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) vaccine, PfSPZ Vaccine, is highly protective against controlled human malaria infection (CHMI) 3 weeks after immunization, but the durability of protection is unknown. We assessed how vaccine dosage, regimen, and route of administration affected durable protection in malaria-naive adults. After four intravenous immunizations with 2.7 × 10 5 PfSPZ, 6/11 (55%) vaccinated subjects remained without parasitemia following CHMI 21 weeks after immunization. Five non-parasitemic subjects from this dosage group underwent repeat CHMI at 59 weeks, and none developed parasitemia. Although Pf-specific serum antibody levels correlated with protection up to 21–25 weeks after immunization, antibody levels waned substantially by 59 weeks. Pf-specific T cell responses also declined in blood by 59 weeks. To determine whether T cell responses in blood reflected responses in liver, we vaccinated nonhuman primates with PfSPZ Vaccine. Pf-specific interferon-γ-producing CD8 T cells were present at ∼ 100-fold higher frequencies in liver than in blood. Our findings suggest that PfSPZ Vaccine conferred durable protection to malaria through long-lived tissue-resident T cells and that administration of higher doses may further enhance protection. Main In 2015 there were an estimated 214 million clinical cases and 438,000 deaths due to malaria 1 , primarily caused by Pf in children in sub-Saharan Africa. A highly effective vaccine is urgently needed to prevent malaria in individuals and to facilitate elimination of malaria from defined geographic areas. To achieve these goals, we established an interim target of >85% sterile protection against Pf infection for >6 months 2 . There is currently no malaria subunit vaccine that approaches this level of protection. The most extensively studied candidate malaria vaccine, RTS,S (a subunit vaccine based on the Pf circumsporozoite protein (PfCSP)), confers sterilizing protection against controlled human malaria infection (CHMI) in about 22% of healthy malaria-naive adults 5 months after vaccination 3 . In a phase 3 field study, the efficacy of RTS,S against clinical malaria was 26% and 36% in young infants and children between the ages of 5 and 17 months, respectively, through 38–48 months of follow-up following a four-dose regimen on a 0-, 1-, 2-, and 20-month schedule 4 . Therefore, it is necessary to investigate alternative vaccination strategies that confer long-lived sterilizing protection 5 , 6 . Sustained sterilizing immunity against the pre-erythrocytic stages of Pf has been observed in humans immunized by whole-parasite approaches using mosquitoes for vaccination 7 , 8 . In a study of malaria-naive adults, 5/6 subjects exposed to >1000 irradiated mosquitoes carrying attenuated PfSPZ were protected when CHMI occurred 23–42 weeks after immunization 8 . To advance from using mosquitoes for inoculation of attenuated PfSPZ toward a clinical product, we previously reported that immunization by intravenous (i.v.) injection of radiation-attenuated, aseptic, purified, cryopreserved PfSPZ, a product called Sanaria PfSPZ Vaccine 9 (hereafter referred to as PfSPZ Vaccine), was well tolerated and immunogenic (the VRC 312 study) 10 , 11 . PfSPZ Vaccine induced a dose-dependent increase in PfSPZ-specific antibodies and frequencies of multifunctional T H 1 cytokine–producing CD4 T cells and γδ T cells in the blood. For vaccine recipients that underwent CHMI 3 weeks after final immunization, Pf parasitemia was observed in 3/9 and 0/6 subjects who received four or five doses of 1.35 × 10 5 PfSPZ, respectively, whereas parasitemia was observed in 5/6 unvaccinated controls, demonstrating that PfSPZ Vaccine confers high-level, short-term protection. The next critical milestones for PfSPZ Vaccine were to assess the durability of vaccine efficacy and to investigate the immune correlates and mechanisms of protection. Results PfSPZ Vaccine efficacy at 21 weeks To assess the durability of protection, subjects from the VRC 312 study were re-enrolled for repeat CHMI with the homologous Pf clone 3D7. Because vaccine efficacy (VE) is assessed at multiple time points in the same vaccinated subjects, we defined vaccine efficacy as first VE (VE at first CHMI), subgroup VE (VE among the subgroup of subjects who were not parasitemic after the first CHMI and returned for repeat CHMI), and cumulative VE (first VE × subgroup VE). VE is calculated as '1 − relative risk', where relative risk is the ratio of the infection rate among the vaccinated subjects divided by the infection rate among the controls. Thus, VE is always adjusted to account for those cases in which the infection rate in the controls is not 100%. Six subjects who had received four or five doses of 1.35 × 10 5 PfSPZ by i.v. injection and had not developed parasitemia following CHMI at 3 weeks 14 underwent repeat CHMI 21 weeks after the final vaccination. Four of six subjects developed parasitemia, as compared to 6/6 unvaccinated control subjects ( Supplementary Fig. 1a,b ), for a subgroup VE of 33% ( P = 0.23). For this dosage group, the first VE was 76% (ref. 11 ), and therefore the cumulative VE was 25%. Thus, 1.35 × 10 5 PfSPZ administered four or five times did not confer adequate protection at 21 weeks. Additionally, eight subjects in the VRC 312 study who were parasitemic at a prior CHMI (six immunized subjects and two unvaccinated controls) underwent repeat CHMI, and all of them developed parasitemia ( Supplementary Fig. 1c,d ). Thus, a single previous episode of Pf parasitemia followed by drug treatment did not confer protection to a subsequent CHMI. Therefore, only vaccinated subjects who did not develop parasitemia following their first CHMI underwent repeat CHMI in the following studies. Study design We assessed in a new study (VRC 314) whether increasing the dosage of PfSPZ Vaccine from 1.35 × 10 5 to 2.7 × 10 5 PfSPZ per dose affected VE. With this higher dose, we tested three-dose (group 1) and four-dose (groups 4 and 5) regimens. A fourth group of subjects received 1.35 × 10 5 PfSPZ four times, followed by a fifth dose of 4.5 × 10 5 PfSPZ (group 3), to determine whether a higher final dose improved VE, as compared to that for subjects who received five doses of 1.35 × 10 5 PfSPZ ( Fig. 1a", "role": "user" }, { "content": "Malaria infects hundreds of millions of people every year, and kills more than half a million, most of them under the age of 5 years. There is no vaccine. But now, a new study by researchers at the University of Maryland School of Medicine has found that an experimental malaria vaccine protected adults from infection for more than a year. The study, a Phase 1 trial, was published in the journal Nature Medicine. \"These results are really important,\" said Kirsten E. Lyke, a researcher at the University of Maryland School of Medicine. \"Malaria has such a devastating effect on children, especially in Africa. This vaccine has the potential to help travelers, military personnel and children in malaria-endemic areas.\" Known as PfSPZ Vaccine, the treatment was developed and produced by Sanaria Inc., of Rockville, Maryland, with support from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. Lyke and her colleagues, working with NIAID scientists, conducted a clinical evaluation of the vaccine, which involved exposing a small number of willing healthy adults to the malaria-causing parasite Plasmodium falciparum (P. falciparum) in a controlled setting. The parasite is transmitted to humans via the bite of infected mosquitos. The PfSPZ Vaccine consists of live, but weakened, P. falciparum, specifically, the early developmental form of the parasite. Previous research had shown that the vaccine worked for three weeks after immunization. This study analyzed its longer term effects. The trial enrolled 101 healthy adults aged 18 to 45 years, who had never had malaria. Of these, 59 participants received the vaccine, while 32 participants were not vaccinated. Vaccine recipients were divided into groups to assess various variables, including dose, number of immunizations, and route of administration. Participants were exposed to the bites of mosquitoes carrying the same P. falciparum strain from which the vaccine was derived. Scientists then took blood samples from participants to measure parasite levels for evidence of protection. IV administration appears to provide better protection than intramuscular injection, both in the short and long term. Overall, the study found that the vaccine provided protection for up to a year in more than half (55 percent) of subjects. In those people, it appeared to provide sterile protection, meaning the subjects not only didn't get malaria, but also could not further transmit malaria. Long-term, reliable protection is important for people who are vaccinated, but not actually exposed to malaria for months, such as travelers or military personnel. Durable protection is also important for mass vaccination campaigns aimed at interrupting transmission in places where the disease is widespread. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract An attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) vaccine, PfSPZ Vaccine, is highly protective against controlled human malaria infection (CHMI) 3 weeks after immunization, but the durability of protection is unknown. We assessed how vaccine dosage, regimen, and route of administration affected durable protection in malaria-naive adults. After four intravenous immunizations with 2.7 × 10 5 PfSPZ, 6/11 (55%) vaccinated subjects remained without parasitemia following CHMI 21 weeks after immunization. Five non-parasitemic subjects from this dosage group underwent repeat CHMI at 59 weeks, and none developed parasitemia. Although Pf-specific serum antibody levels correlated with protection up to 21–25 weeks after immunization, antibody levels waned substantially by 59 weeks. Pf-specific T cell responses also declined in blood by 59 weeks. To determine whether T cell responses in blood reflected responses in liver, we vaccinated nonhuman primates with PfSPZ Vaccine. Pf-specific interferon-γ-producing CD8 T cells were present at ∼ 100-fold higher frequencies in liver than in blood. Our findings suggest that PfSPZ Vaccine conferred durable protection to malaria through long-lived tissue-resident T cells and that administration of higher doses may further enhance protection. Main In 2015 there were an estimated 214 million clinical cases and 438,000 deaths due to malaria 1 , primarily caused by Pf in children in sub-Saharan Africa. A highly effective vaccine is urgently needed to prevent malaria in individuals and to facilitate elimination of malaria from defined geographic areas. To achieve these goals, we established an interim target of >85% sterile protection against Pf infection for >6 months 2 . There is currently no malaria subunit vaccine that approaches this level of protection. The most extensively studied candidate malaria vaccine, RTS,S (a subunit vaccine based on the Pf circumsporozoite protein (PfCSP)), confers sterilizing protection against controlled human malaria infection (CHMI) in about 22% of healthy malaria-naive adults 5 months after vaccination 3 . In a phase 3 field study, the efficacy of RTS,S against clinical malaria was 26% and 36% in young infants and children between the ages of 5 and 17 months, respectively, through 38–48 months of follow-up following a four-dose regimen on a 0-, 1-, 2-, and 20-month schedule 4 . Therefore, it is necessary to investigate alternative vaccination strategies that confer long-lived sterilizing protection 5 , 6 . Sustained sterilizing immunity against the pre-erythrocytic stages of Pf has been observed in humans immunized by whole-parasite approaches using mosquitoes for vaccination 7 , 8 . In a study of malaria-naive adults, 5/6 subjects exposed to >1000 irradiated mosquitoes carrying attenuated PfSPZ were protected when CHMI occurred 23–42 weeks after immunization 8 . To advance from using mosquitoes for inoculation of attenuated PfSPZ toward a clinical product, we previously reported that immunization by intravenous (i.v.) injection of radiation-attenuated, aseptic, purified, cryopreserved PfSPZ, a product called Sanaria PfSPZ Vaccine 9 (hereafter referred to as PfSPZ Vaccine), was well tolerated and immunogenic (the VRC 312 study) 10 , 11 . PfSPZ Vaccine induced a dose-dependent increase in PfSPZ-specific antibodies and frequencies of multifunctional T H 1 cytokine–producing CD4 T cells and γδ T cells in the blood. For vaccine recipients that underwent CHMI 3 weeks after final immunization, Pf parasitemia was observed in 3/9 and 0/6 subjects who received four or five doses of 1.35 × 10 5 PfSPZ, respectively, whereas parasitemia was observed in 5/6 unvaccinated controls, demonstrating that PfSPZ Vaccine confers high-level, short-term protection. The next critical milestones for PfSPZ Vaccine were to assess the durability of vaccine efficacy and to investigate the immune correlates and mechanisms of protection. Results PfSPZ Vaccine efficacy at 21 weeks To assess the durability of protection, subjects from the VRC 312 study were re-enrolled for repeat CHMI with the homologous Pf clone 3D7. Because vaccine efficacy (VE) is assessed at multiple time points in the same vaccinated subjects, we defined vaccine efficacy as first VE (VE at first CHMI), subgroup VE (VE among the subgroup of subjects who were not parasitemic after the first CHMI and returned for repeat CHMI), and cumulative VE (first VE × subgroup VE). VE is calculated as '1 − relative risk', where relative risk is the ratio of the infection rate among the vaccinated subjects divided by the infection rate among the controls. Thus, VE is always adjusted to account for those cases in which the infection rate in the controls is not 100%. Six subjects who had received four or five doses of 1.35 × 10 5 PfSPZ by i.v. injection and had not developed parasitemia following CHMI at 3 weeks 14 underwent repeat CHMI 21 weeks after the final vaccination. Four of six subjects developed parasitemia, as compared to 6/6 unvaccinated control subjects ( Supplementary Fig. 1a,b ), for a subgroup VE of 33% ( P = 0.23). For this dosage group, the first VE was 76% (ref. 11 ), and therefore the cumulative VE was 25%. Thus, 1.35 × 10 5 PfSPZ administered four or five times did not confer adequate protection at 21 weeks. Additionally, eight subjects in the VRC 312 study who were parasitemic at a prior CHMI (six immunized subjects and two unvaccinated controls) underwent repeat CHMI, and all of them developed parasitemia ( Supplementary Fig. 1c,d ). Thus, a single previous episode of Pf parasitemia followed by drug treatment did not confer protection to a subsequent CHMI. Therefore, only vaccinated subjects who did not develop parasitemia following their first CHMI underwent repeat CHMI in the following studies. Study design We assessed in a new study (VRC 314) whether increasing the dosage of PfSPZ Vaccine from 1.35 × 10 5 to 2.7 × 10 5 PfSPZ per dose affected VE. With this higher dose, we tested three-dose (group 1) and four-dose (groups 4 and 5) regimens. A fourth group of subjects received 1.35 × 10 5 PfSPZ four times, followed by a fifth dose of 4.5 × 10 5 PfSPZ (group 3), to determine whether a higher final dose improved VE, as compared to that for subjects who received five doses of 1.35 × 10 5 PfSPZ ( Fig. 1a<|im_end|> <|im_start|>assistant Malaria infects hundreds of millions of people every year, and kills more than half a million, most of them under the age of 5 years. There is no vaccine. But now, a new study by researchers at the University of Maryland School of Medicine has found that an experimental malaria vaccine protected adults from infection for more than a year. The study, a Phase 1 trial, was published in the journal Nature Medicine. "These results are really important," said Kirsten E. Lyke, a researcher at the University of Maryland School of Medicine. "Malaria has such a devastating effect on children, especially in Africa. This vaccine has the potential to help travelers, military personnel and children in malaria-endemic areas." Known as PfSPZ Vaccine, the treatment was developed and produced by Sanaria Inc., of Rockville, Maryland, with support from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. Lyke and her colleagues, working with NIAID scientists, conducted a clinical evaluation of the vaccine, which involved exposing a small number of willing healthy adults to the malaria-causing parasite Plasmodium falciparum (P. falciparum) in a controlled setting. The parasite is transmitted to humans via the bite of infected mosquitos. The PfSPZ Vaccine consists of live, but weakened, P. falciparum, specifically, the early developmental form of the parasite. Previous research had shown that the vaccine worked for three weeks after immunization. This study analyzed its longer term effects. The trial enrolled 101 healthy adults aged 18 to 45 years, who had never had malaria. Of these, 59 participants received the vaccine, while 32 participants were not vaccinated. Vaccine recipients were divided into groups to assess various variables, including dose, number of immunizations, and route of administration. Participants were exposed to the bites of mosquitoes carrying the same P. falciparum strain from which the vaccine was derived. Scientists then took blood samples from participants to measure parasite levels for evidence of protection. IV administration appears to provide better protection than intramuscular injection, both in the short and long term. Overall, the study found that the vaccine provided protection for up to a year in more than half (55 percent) of subjects. In those people, it appeared to provide sterile protection, meaning the subjects not only didn't get malaria, but also could not further transmit malaria. Long-term, reliable protection is important for people who are vaccinated, but not actually exposed to malaria for months, such as travelers or military personnel. Durable protection is also important for mass vaccination campaigns aimed at interrupting transmission in places where the disease is widespread. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Proteins adsorbing at nanoparticles have been proposed as critical toxicity mediators and are included in ongoing efforts to develop predictive tools for safety assessment. Strongly attached proteins can be isolated, identified and correlated to changes in nanoparticle state, cellular association or toxicity. Weakly attached, rapidly exchanging proteins are also present at nanoparticles, but are difficult to isolate and have hardly been examined. Here we study rapidly exchanging proteins and show for the first time that they have a strong modulatory effect on the biotransformation of silver nanoparticles. Released silver ions, known for their role in particle toxicity, are found to be trapped as silver sulphide nanocrystals within the protein corona at silver nanoparticles in serum-containing cell culture media. The strongly attached corona acts as a site for sulphidation, while the weakly attached proteins reduce nanocrystal formation in a serum-concentration-dependent manner. Sulphidation results in decreased toxicity of Ag NPs. Introduction The biological effects of engineered nanomaterials as drug delivery vehicles or as unintentionally released nanoparticles (NPs) are of strong current interest. Biomolecules—mainly proteins—adsorbing at NPs modify their surface properties and are proposed as important modulators of particle–cell interactions 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . A pragmatic distinction has been made between the relatively easily studied, strongly attached proteins as long-lived, hard coronas and the weakly attached, rapidly exchanging proteins as soft coronas 9 , 10 , 11 , 12 , 13 . The former are under focus with residence at the particles on timescales relevant for cellular binding and uptake 4 , 6 , 14 , whereas the role of the latter in modulating NP behaviour has yet to be established. Specific and different profiles of molecules concentrated within the hard corona at particles in biological media have been observed for different surface coatings 15 , charges 16 , 17 , sizes 15 , 18 and shapes 19 . The concept of a biological identity imprinted within the protein corona and which determines NP–cellular interactions 1 , 2 , 3 , 4 , 5 , 6 has been proposed 20 . Although the long-lived layer has been linked to particle aggregation 19 and cell association 6 , 14 , 21 , the correlation of protein composition to cellular uptake/toxicity is still relatively weak 4 , 22 , 23 . The involvement of soft corona in physical and/or chemical transformations of particle with potential implications for toxicity is so far unstudied, despite it forming a dense second layer around the strongly attached biomolecules 24 . In addition to protein corona formation, ion release is central to the toxicity of silver NPs and is an important parameter studied in vitro 25 , 26 , 27 and in vivo 28 . Oxidation contributes to ion release through the formation of Ag 2 O on the particles 29 , 30 , which is then dissolved in aqueous media 31 , 32 , 33 . Oxidative dissolution is an important step in Ag 2 S formation from/at Ag NPs 34 . Silver NP sulphidation has been receiving increasing attention, as the resulting sulphide is insoluble in water, decreasing the availability of Ag + and impacting antibacterial 35 and toxicological 36 , 37 , 38 effects. After identification of silver sulphide in sewage sludge 39 , interest in studying Ag 2 S was focused on wastewater plants 40 , 41 and aquatic environments 42 . Although most toxicity experiments are conducted in vitro , much less is known about such transformations of Ag NPs under these conditions. Thiols (for example, cysteine) have been proven to bind Ag + in biological environments 43 , 44 . Tracking the oxidation state of intracellular silver showed an evolution from Ag 0 to oxygen-bound and sulphur-bound Ag ions 45 , 46 . Formation of Ag 2 S in alveolar cells was proposed to explain decreased toxicity of silver nanowires 47 and their sulphidation in protein-free culture medium was recently studied 48 . A further step involves exploring chemical changes that occur in full culture media, in the presence of protein coronas, before cellular uptake. Here we demonstrate one clear role for the soft corona in modulating silver NP sulphidation in vitro , and highlight the interplay between strongly and weakly attached proteins for the chemical transformation of Ag NPs. We also suggest some potential implications for toxicity, without, however, establishing a clear direct connection between the soft corona and observed toxicological effects. We show for the first time a functional effect of rapidly exchanging proteins, which decreased the amount of nano-Ag 2 S formed at polyvinylpyrrolidone (PVP)-coated Ag NPs incubated in serum-supplemented cell culture media. We propose and study a mechanism for soft corona protein-assisted Ag + transport explaining reduced sulphide formation. Striking differences when going from in vitro to in vivo relevant protein concentrations are observed and discussed. As it is known that sulphidation decreases silver toxicity 36 , 37 , 38 , 47 , 49 , 50 , 51 , it is not surprising that under conditions where Ag NPs were partially or completely transformed into Ag 2 S in cell culture media, much less toxicity to J774 macrophages and different cytokine secretion profiles are seen compared with silver NPs. Results Protein coronas modulate nano-Ag 2 S formation at Ag NPs Upon incubation of PVP-coated, cubic or quasi-spherical Ag NPs in RPMI-1640 cell culture medium supplemented with fetal bovine serum (FBS), new NPs were observed to form close to the surface of the silver. Details regarding incubation are available in the Methods section, Particle incubation in cell culture media subsection. Figure 1a shows a typical transmission electron microscopy (TEM) image of nanocubes after 7 days in 1% serum, with the NPs forming a dispersed layer around the silver core (highlighted by arrows). X-rays elemental mapping ( Fig. 1b ) and energy-dispersive X-ray spectroscopy (EDS, Fig. 1c ) revealed the presence of sulphur. Co-localization of Ag and S matches the small NPs in the proximity of the silver surface", "role": "user" }, { "content": "A senior fellow at the Faculty of Chemistry, MSU, Vladimir Bochenkov, together with his colleagues from Denmark, have established the mechanism of interaction of silver nanoparticles with the cells of the immune system. The study is published in the journal Nature Communications. \"Currently, a large number of products contain silver nanoparticles—antibacterial drugs, toothpaste, polishes, paints, filters, packaging, medical and textile items. The functioning of these products lies in the capacity of silver to dissolve under oxidation and form ions Ag+ with germicidal properties. At the same time, there are in vitro research data showing silver nanoparticles' toxicity for various organs, including the liver, brain and lungs. In this regard, it is essential to study the processes occurring with silver nanoparticles in biological environments, and the factors affecting their toxicity,\" says Vladimir Bochenkov. The study is devoted to the protein corona—a layer of adsorbed protein molecules that is formed on the surface of the silver nanoparticles during their contact with the biological environment, for example, in blood. This protein corona masks nanoparticles and largely determines their fate, including the speed of the elimination from the body, the ability to penetrate to a particular cell type, the distribution between the organs, etc. According to the latest research, the protein corona consists of two layers: a rigid hard corona consisting of protein molecules tightly bound with silver nanoparticles; and a soft corona, consisting of weakly bound protein molecules in a dynamic equilibrium with the solution. Until now, the soft corona has been studied very little because of experimental difficulties—the weakly bound nanoparticles that were separated from the protein solution easily desorbed, leaving only the rigid corona on the nanoparticle surface. The size of the studied silver nanoparticles was 50 to 88 nm, and the diameter of the proteins that made up the crown were three to seven nm. Scientists managed to study the silver nanoparticles with the protein corona in situ, without removing them from the biological environment. Due to the localized surface plasmon resonance used for probing the environment near the surface of the silver nanoparticles, the functions of the soft corona have been primarily investigated. \"In the work, we showed that the corona may affect the ability of the nanoparticles to dissolve to silver cations Ag+, which determine the toxic effect. In the absence of a soft corona (quickly sharing the medium protein layer with the environment), silver cations are associated with the sulfur-containing amino acids in serum medium, particularly cysteine and methionine, and precipitate as nanocrystals Ag2S in the hard corona,\" says Vladimir Bochenkov. Ag2S (silver sulfide) famously easily forms on the silver surface even on the air in the presence of the hydrogen sulfide traces. Sulfur is also part of many biomolecules contained in the body, provoking the silver to react and be converted into sulfide. Formation of Ag2S nano-crystals due to low solubility reduces the bioavailability of the Ag+ ions, reducing the toxicity of silver nanoparticles to null. With a sufficient amount of the amino acid sulfur sources available for reaction, all the potentially toxic silver is converted into the nontoxic insoluble sulfide. This is what happens in the absence of a soft corona. In the presence of a soft corona, the Ag2S silver sulfide nanocrystals are formed in smaller quantities or not formed at all. Scientists attribute this to the fact that the weakly bound protein molecules transfer the Ag+ ions from nanoparticles into the solution, thereby leaving the sulfide uncrystallized. Thus, the soft corona proteins are vehicles for the silver ions. This effect, scientists believe, should be taken into account when analyzing the stability of silver nanoparticles in a protein environment, and in interpreting the results of the toxicity studies. Studies of the cell viability of the immune system (J774 murine line macrophages) confirmed the reduction in cell toxicity of silver nanoparticles at the sulfidation (in the absence of a soft corona). Vladimir Bochenkov's challenge was to simulate the plasmon resonance spectra of the systems involved and to create the theoretical model that allowed quantitative determination of silver sulfide content in situ around nanoparticles, following the change in the absorption bands in the experimental spectra. Since the frequency of the plasmon resonance is sensitive to a change in dielectric constant near the nanoparticle surface, changes in the absorption spectra contain information about the amount of silver sulfide formed. Knowledge of the mechanisms of formation and dynamics of the behavior of the protein corona, and information about its composition and structure are extremely important for understanding the toxicity and hazards of nanoparticles for the human body. Protein corona formation could be used to deliver drugs in the body, including for the treatment of cancer. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Proteins adsorbing at nanoparticles have been proposed as critical toxicity mediators and are included in ongoing efforts to develop predictive tools for safety assessment. Strongly attached proteins can be isolated, identified and correlated to changes in nanoparticle state, cellular association or toxicity. Weakly attached, rapidly exchanging proteins are also present at nanoparticles, but are difficult to isolate and have hardly been examined. Here we study rapidly exchanging proteins and show for the first time that they have a strong modulatory effect on the biotransformation of silver nanoparticles. Released silver ions, known for their role in particle toxicity, are found to be trapped as silver sulphide nanocrystals within the protein corona at silver nanoparticles in serum-containing cell culture media. The strongly attached corona acts as a site for sulphidation, while the weakly attached proteins reduce nanocrystal formation in a serum-concentration-dependent manner. Sulphidation results in decreased toxicity of Ag NPs. Introduction The biological effects of engineered nanomaterials as drug delivery vehicles or as unintentionally released nanoparticles (NPs) are of strong current interest. Biomolecules—mainly proteins—adsorbing at NPs modify their surface properties and are proposed as important modulators of particle–cell interactions 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . A pragmatic distinction has been made between the relatively easily studied, strongly attached proteins as long-lived, hard coronas and the weakly attached, rapidly exchanging proteins as soft coronas 9 , 10 , 11 , 12 , 13 . The former are under focus with residence at the particles on timescales relevant for cellular binding and uptake 4 , 6 , 14 , whereas the role of the latter in modulating NP behaviour has yet to be established. Specific and different profiles of molecules concentrated within the hard corona at particles in biological media have been observed for different surface coatings 15 , charges 16 , 17 , sizes 15 , 18 and shapes 19 . The concept of a biological identity imprinted within the protein corona and which determines NP–cellular interactions 1 , 2 , 3 , 4 , 5 , 6 has been proposed 20 . Although the long-lived layer has been linked to particle aggregation 19 and cell association 6 , 14 , 21 , the correlation of protein composition to cellular uptake/toxicity is still relatively weak 4 , 22 , 23 . The involvement of soft corona in physical and/or chemical transformations of particle with potential implications for toxicity is so far unstudied, despite it forming a dense second layer around the strongly attached biomolecules 24 . In addition to protein corona formation, ion release is central to the toxicity of silver NPs and is an important parameter studied in vitro 25 , 26 , 27 and in vivo 28 . Oxidation contributes to ion release through the formation of Ag 2 O on the particles 29 , 30 , which is then dissolved in aqueous media 31 , 32 , 33 . Oxidative dissolution is an important step in Ag 2 S formation from/at Ag NPs 34 . Silver NP sulphidation has been receiving increasing attention, as the resulting sulphide is insoluble in water, decreasing the availability of Ag + and impacting antibacterial 35 and toxicological 36 , 37 , 38 effects. After identification of silver sulphide in sewage sludge 39 , interest in studying Ag 2 S was focused on wastewater plants 40 , 41 and aquatic environments 42 . Although most toxicity experiments are conducted in vitro , much less is known about such transformations of Ag NPs under these conditions. Thiols (for example, cysteine) have been proven to bind Ag + in biological environments 43 , 44 . Tracking the oxidation state of intracellular silver showed an evolution from Ag 0 to oxygen-bound and sulphur-bound Ag ions 45 , 46 . Formation of Ag 2 S in alveolar cells was proposed to explain decreased toxicity of silver nanowires 47 and their sulphidation in protein-free culture medium was recently studied 48 . A further step involves exploring chemical changes that occur in full culture media, in the presence of protein coronas, before cellular uptake. Here we demonstrate one clear role for the soft corona in modulating silver NP sulphidation in vitro , and highlight the interplay between strongly and weakly attached proteins for the chemical transformation of Ag NPs. We also suggest some potential implications for toxicity, without, however, establishing a clear direct connection between the soft corona and observed toxicological effects. We show for the first time a functional effect of rapidly exchanging proteins, which decreased the amount of nano-Ag 2 S formed at polyvinylpyrrolidone (PVP)-coated Ag NPs incubated in serum-supplemented cell culture media. We propose and study a mechanism for soft corona protein-assisted Ag + transport explaining reduced sulphide formation. Striking differences when going from in vitro to in vivo relevant protein concentrations are observed and discussed. As it is known that sulphidation decreases silver toxicity 36 , 37 , 38 , 47 , 49 , 50 , 51 , it is not surprising that under conditions where Ag NPs were partially or completely transformed into Ag 2 S in cell culture media, much less toxicity to J774 macrophages and different cytokine secretion profiles are seen compared with silver NPs. Results Protein coronas modulate nano-Ag 2 S formation at Ag NPs Upon incubation of PVP-coated, cubic or quasi-spherical Ag NPs in RPMI-1640 cell culture medium supplemented with fetal bovine serum (FBS), new NPs were observed to form close to the surface of the silver. Details regarding incubation are available in the Methods section, Particle incubation in cell culture media subsection. Figure 1a shows a typical transmission electron microscopy (TEM) image of nanocubes after 7 days in 1% serum, with the NPs forming a dispersed layer around the silver core (highlighted by arrows). X-rays elemental mapping ( Fig. 1b ) and energy-dispersive X-ray spectroscopy (EDS, Fig. 1c ) revealed the presence of sulphur. Co-localization of Ag and S matches the small NPs in the proximity of the silver surface<|im_end|> <|im_start|>assistant A senior fellow at the Faculty of Chemistry, MSU, Vladimir Bochenkov, together with his colleagues from Denmark, have established the mechanism of interaction of silver nanoparticles with the cells of the immune system. The study is published in the journal Nature Communications. "Currently, a large number of products contain silver nanoparticles—antibacterial drugs, toothpaste, polishes, paints, filters, packaging, medical and textile items. The functioning of these products lies in the capacity of silver to dissolve under oxidation and form ions Ag+ with germicidal properties. At the same time, there are in vitro research data showing silver nanoparticles' toxicity for various organs, including the liver, brain and lungs. In this regard, it is essential to study the processes occurring with silver nanoparticles in biological environments, and the factors affecting their toxicity," says Vladimir Bochenkov. The study is devoted to the protein corona—a layer of adsorbed protein molecules that is formed on the surface of the silver nanoparticles during their contact with the biological environment, for example, in blood. This protein corona masks nanoparticles and largely determines their fate, including the speed of the elimination from the body, the ability to penetrate to a particular cell type, the distribution between the organs, etc. According to the latest research, the protein corona consists of two layers: a rigid hard corona consisting of protein molecules tightly bound with silver nanoparticles; and a soft corona, consisting of weakly bound protein molecules in a dynamic equilibrium with the solution. Until now, the soft corona has been studied very little because of experimental difficulties—the weakly bound nanoparticles that were separated from the protein solution easily desorbed, leaving only the rigid corona on the nanoparticle surface. The size of the studied silver nanoparticles was 50 to 88 nm, and the diameter of the proteins that made up the crown were three to seven nm. Scientists managed to study the silver nanoparticles with the protein corona in situ, without removing them from the biological environment. Due to the localized surface plasmon resonance used for probing the environment near the surface of the silver nanoparticles, the functions of the soft corona have been primarily investigated. "In the work, we showed that the corona may affect the ability of the nanoparticles to dissolve to silver cations Ag+, which determine the toxic effect. In the absence of a soft corona (quickly sharing the medium protein layer with the environment), silver cations are associated with the sulfur-containing amino acids in serum medium, particularly cysteine and methionine, and precipitate as nanocrystals Ag2S in the hard corona," says Vladimir Bochenkov. Ag2S (silver sulfide) famously easily forms on the silver surface even on the air in the presence of the hydrogen sulfide traces. Sulfur is also part of many biomolecules contained in the body, provoking the silver to react and be converted into sulfide. Formation of Ag2S nano-crystals due to low solubility reduces the bioavailability of the Ag+ ions, reducing the toxicity of silver nanoparticles to null. With a sufficient amount of the amino acid sulfur sources available for reaction, all the potentially toxic silver is converted into the nontoxic insoluble sulfide. This is what happens in the absence of a soft corona. In the presence of a soft corona, the Ag2S silver sulfide nanocrystals are formed in smaller quantities or not formed at all. Scientists attribute this to the fact that the weakly bound protein molecules transfer the Ag+ ions from nanoparticles into the solution, thereby leaving the sulfide uncrystallized. Thus, the soft corona proteins are vehicles for the silver ions. This effect, scientists believe, should be taken into account when analyzing the stability of silver nanoparticles in a protein environment, and in interpreting the results of the toxicity studies. Studies of the cell viability of the immune system (J774 murine line macrophages) confirmed the reduction in cell toxicity of silver nanoparticles at the sulfidation (in the absence of a soft corona). Vladimir Bochenkov's challenge was to simulate the plasmon resonance spectra of the systems involved and to create the theoretical model that allowed quantitative determination of silver sulfide content in situ around nanoparticles, following the change in the absorption bands in the experimental spectra. Since the frequency of the plasmon resonance is sensitive to a change in dielectric constant near the nanoparticle surface, changes in the absorption spectra contain information about the amount of silver sulfide formed. Knowledge of the mechanisms of formation and dynamics of the behavior of the protein corona, and information about its composition and structure are extremely important for understanding the toxicity and hazards of nanoparticles for the human body. Protein corona formation could be used to deliver drugs in the body, including for the treatment of cancer. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Among the caspases that cause regulated cell death, a unique function for caspase-7 has remained elusive. Caspase-3 performs apoptosis, whereas caspase-7 is typically considered an inefficient back-up. Caspase-1 activates gasdermin D pores to lyse the cell; however, caspase-1 also activates caspase-7 for unknown reasons 1 . Caspases can also trigger cell-type-specific death responses; for example, caspase-1 causes the extrusion of intestinal epithelial cell (IECs) in response to infection with Salmonella enterica subsp. enterica serovar Typhimurium ( S . Typhimurium) 2 , 3 . Here we show in both organoids and mice that caspase-7-deficient IECs do not complete extrusion. Mechanistically, caspase-7 counteracts gasdermin D pores and preserves cell integrity by cleaving and activating acid sphingomyelinase (ASM), which thereby generates copious amounts of ceramide to enable enhanced membrane repair. This provides time to complete the process of IEC extrusion. In parallel, we also show that caspase-7 and ASM cleavage are required to clear Chromobacterium violaceum and Listeria monocytogenes after perforin-pore-mediated attack by natural killer cells or cytotoxic T lymphocytes, which normally causes apoptosis in infected hepatocytes. Therefore, caspase-7 is not a conventional executioner but instead is a death facilitator that delays pore-driven lysis so that more-specialized processes, such as extrusion or apoptosis, can be completed before cell death. Cells must put their affairs in order before they die. Main Caspase-3 is the primary apoptotic executioner, and is sufficient among caspases to cause apoptosis. By contrast, the roles of other executioners—such as caspase-7—remain unknown. Exemplifying this, Casp3 –/– mice are perinatally lethal on the 129/SvJ background, whereas Casp7 –/– mice are healthy 4 . However, on the C57BL/6 background, caspase-7 can rescue Casp3 –/– mice 5 . This result leads to the present line of thinking that holds that caspase-7 is an inefficient back-up for caspase-3 that only works in certain conditions. Caspase-7 is required for IEC extrusion Although caspase-7 is expressed in most tissues 6 , it is highly expressed in the intestine and in isolated IECs 7 (Extended Data Fig. 1a–c ). After oral infection with S . Typhimurium, we observed many cleaved caspase-7-positive IECs in the caecum, all of which had a characteristic morphology that is indicative of ongoing extrusion into the lumen 8 (Extended Data Fig. 1d–f ). Caspase-7 is classically known to be activated by apoptotic caspases, including caspase-3. However, infection did not increase cleaved-caspase-3-positive cells, and Casp3 –/– mice retained increased levels of cleaved-caspase-7-positive cells (Extended Data Fig. 1g–i ). In wild-type mice, individual EpCAM + IECs extruded whereas neighbouring cells remained unperturbed in the monolayer during S . Typhimurium infection (Fig. 1a,b ). Notably, in Casp7 –/– mice, IECs extruded as clusters that remained attached to the apical epithelial surface (Fig. 1a,b ). Clusters became marked 24 h after infection; in an extreme example, 18 IECs were observed in a single extrusion cluster site (Fig. 1b and Extended Data Fig. 1j–l ). This clustered morphology has not to our knowledge been previously reported. Thus, caspase-7 is activated in extruding IECs in response to S . Typhimurium infection, but independently of the conventional apoptotic executioner caspase-3. Fig. 1: Caspase-7 facilitates IEC extrusion during S . Typhimurium infection and ameliorates gasdermin D pores. a , b , The indicated mice were infected with 5 × 10 6 S . Typhimurium and the caeca were collected 24 h later. Representative images ( a ) and quantification ( b ) of epithelial marker EpCAM + cell counts per extrusion site (arrows indicate extrusion sites). WT, wild type. c , Percentage of ruptured IEC organoids after treatment with FlaTox in pooled live-imaging experiments (related to Extended Data Fig. 2a ). d , Representative images of organoids 30 min after treatment with FlaTox, stained with phalloidin and for cleaved caspase-7. e , f , Representative images ( e ; full series are in Extended Data Fig. 4b ) and quantification ( f ) in live-cell imaging of PI intensity of wild-type and Casp7 –/– organoids treated with FlaTox. g , PI Intensity of wild-type, Gsdmd –/– and Gsdmd –/– Casp7 –/– organoids treated with FlaTox or control PBS. Data are representative of three experiments ( a , b , d – f ) or are pooled from 12 ( c ) or 3 ( g ) experiments. Scale bars, 50 μm ( a ); 20 μm ( d ). * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001 (two-sided Mann–Whitney U -test in b ; two-sided unpaired t -test in c ; two-way analysis of variance (ANOVA) with Sidak’s post-hoc test in f or with Tukey’s post-hoc test in g ). Data are median ± s.e.m. ( b ) or mean ± s.e.m. ( c , f , g ). Exact P values in Source Data. Source data Full size image During S . Typhimurium infection, IEC extrusion is initiated when caspase-1 is activated by NAIP–NLRC4; this complex detects bacterial proteins, such as flagellin, in the cytosol 2 , 3 . This can be mimicked in IEC organoid cultures by stimulation with FlaTox, an engineered toxin that delivers flagellin to the cytosol, which causes extrusion in organoid monolayers in a setting in which all cells activate caspase-1. We therefore examined caspase-7 function in this model of IEC extrusion. FlaTox-treated wild-type organoids ultimately collapse, concomitantly with the rupture of the inner contents into the surrounding matrigel. We visualized the morphology of extruding IECs, and in addition quantified organoid rupture as a proxy for overall extrusion dynamics. In Casp7 –/– organoids, the IECs also initiated extrusion; however, they remained attached to neighbouring IECs, formed clusters of defectively extruding cells and ultimately had a reduced incidence of organoid rupture (Supplementary Videos 1 , 2 , Fig. 1c and Extended Data Fig. 2a,b ). Casp3 –/– organoids retained normal levels of extrusion, cleaved caspase-7 and rupture (Extended Data Fig. 2c–e ). Therefore, caspase-7 is critical for the caspase-1-driven extrusion of IECs, and this occurs independently of caspase-3. Caspase-1 activates caspase-7 Caspase-1 is an inflammatory caspase that is highly", "role": "user" }, { "content": "Researchers have unmasked a component of the cell death process that could play a vital role in a better infection-fighting strategy. Scientists at the Duke University School of Medicine and the UNC School of Medicine partnered with researchers at the University of Virginia to identify the function behind caspase-7, an enzyme that is part of a cell's self-destruct program. While researchers have known the enzyme is involved in the process, its exact function has been unclear. The findings are published June 15 in the journal Nature. The researchers found that caspase-7 kicks off a Rube Goldberg series of events that allow the cell to die in an orderly fashion, said the study's senior author, Edward Miao, MD, Ph.D., a professor in the departments of Immunology and Molecular Genetics and Microbiology at Duke and previously an associate professor in the UNC Department of Microbiology & Immunology. An orderly cell death is essential for the immune response. Without the enzyme, however, the dying cell might violently explode and cause collateral damage. Miao said this research lays groundwork to explore exciting possibilities for therapeutic applications, especially if caspase-7 can be boosted or blocked. \"There is still so much we need to understand about the basic components of our cells, what they do and why,\" Miao said. \"If we can uncover this blueprint, it may become a map for understanding how disease moves in the body, allowing scientists to devise a more precise plan of action. With the discovery of caspase-7's role in the cell, we're one step closer to a complete schematic.\" In the study, the researchers found that caspase-7 serves as a timing device in cell death. It activates a protein, called acid sphingomyelinase or ASM, which kicks off a cell membrane repair mechanism, which in turn gives the cell enough time to get its affairs in order before dying. To identify the function of the caspase-7 enzyme, the team studied different infection models in genetically altered mice and cultured intestinal tissue. They looked at caspase-7's role in two types of orderly cell death—extrusion and apoptosis. Caspase-7's role was different in the context of different pathogens—Salmonella, Listeria, and a rare pathogen called Chromobacterium. With Salmonella, cells undergo an orderly manner of cell death called extrusion. In this context, researchers found the absence of caspase-7 caused the unnecessary death of healthy cells, which were the collateral damage of nearby infected cells failing to detach themselves, or extrude, from their neighbors. With Chromobacterium and Listeria, dying cells normally undergo a process called apoptosis, or programmed cell death. The lack of caspase-7 enabled the bacteria to survive an immune system attack, presumably because their infected cell host didn't accomplish some apoptotic task before exploding. If caspase-7 can be manipulated, Miao said a potential application is investigating the possibility of targeting the enzyme as a detonator of cell death to circumvent antibiotic resistance. Antibiotics are a standard and broad approach for fighting infection, but pathogens have devised strategies to adapt and resist. \"Antibiotics don't take into account that each pathogen has its own strategy—some of them are living outside cells, some are living inside cells. If a pathogen is inside the cell,\" he said, \"you could boost caspase-7 to allow the infected cell to die in the correct way. If you know the strategy that the pathogen is using, you can help the immune system by tweaking it in the correct direction.\" \"On the other hand, if you have a pathogen traveling outside of the cell, and cells are exploding inappropriately, maybe we could boost caspase-7 to keep them alive, thereby prevent excessive damage,\" Miao said, noting that this approach might be effective against sepsis. Miao said this enzyme could also potentially play a major role in triggering the immune system to fight cancer. \"Cancer cells are probably running the full Rube Goldberg machine and dying in an orderly manner,\" Miao said. \"When the immune system comes and looks around, it sees that everything seems to be in order and then leaves. \"If you could shut down the Rube Goldberg contraption, instead of putting itself away nice and neat, the tumor cell would be just dead on the floor,\" Miao said. \"This might cause the immune system to become alarmed and activated. Theoretically, that could cause the immune system to attack a tumor it would otherwise ignore.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Among the caspases that cause regulated cell death, a unique function for caspase-7 has remained elusive. Caspase-3 performs apoptosis, whereas caspase-7 is typically considered an inefficient back-up. Caspase-1 activates gasdermin D pores to lyse the cell; however, caspase-1 also activates caspase-7 for unknown reasons 1 . Caspases can also trigger cell-type-specific death responses; for example, caspase-1 causes the extrusion of intestinal epithelial cell (IECs) in response to infection with Salmonella enterica subsp. enterica serovar Typhimurium ( S . Typhimurium) 2 , 3 . Here we show in both organoids and mice that caspase-7-deficient IECs do not complete extrusion. Mechanistically, caspase-7 counteracts gasdermin D pores and preserves cell integrity by cleaving and activating acid sphingomyelinase (ASM), which thereby generates copious amounts of ceramide to enable enhanced membrane repair. This provides time to complete the process of IEC extrusion. In parallel, we also show that caspase-7 and ASM cleavage are required to clear Chromobacterium violaceum and Listeria monocytogenes after perforin-pore-mediated attack by natural killer cells or cytotoxic T lymphocytes, which normally causes apoptosis in infected hepatocytes. Therefore, caspase-7 is not a conventional executioner but instead is a death facilitator that delays pore-driven lysis so that more-specialized processes, such as extrusion or apoptosis, can be completed before cell death. Cells must put their affairs in order before they die. Main Caspase-3 is the primary apoptotic executioner, and is sufficient among caspases to cause apoptosis. By contrast, the roles of other executioners—such as caspase-7—remain unknown. Exemplifying this, Casp3 –/– mice are perinatally lethal on the 129/SvJ background, whereas Casp7 –/– mice are healthy 4 . However, on the C57BL/6 background, caspase-7 can rescue Casp3 –/– mice 5 . This result leads to the present line of thinking that holds that caspase-7 is an inefficient back-up for caspase-3 that only works in certain conditions. Caspase-7 is required for IEC extrusion Although caspase-7 is expressed in most tissues 6 , it is highly expressed in the intestine and in isolated IECs 7 (Extended Data Fig. 1a–c ). After oral infection with S . Typhimurium, we observed many cleaved caspase-7-positive IECs in the caecum, all of which had a characteristic morphology that is indicative of ongoing extrusion into the lumen 8 (Extended Data Fig. 1d–f ). Caspase-7 is classically known to be activated by apoptotic caspases, including caspase-3. However, infection did not increase cleaved-caspase-3-positive cells, and Casp3 –/– mice retained increased levels of cleaved-caspase-7-positive cells (Extended Data Fig. 1g–i ). In wild-type mice, individual EpCAM + IECs extruded whereas neighbouring cells remained unperturbed in the monolayer during S . Typhimurium infection (Fig. 1a,b ). Notably, in Casp7 –/– mice, IECs extruded as clusters that remained attached to the apical epithelial surface (Fig. 1a,b ). Clusters became marked 24 h after infection; in an extreme example, 18 IECs were observed in a single extrusion cluster site (Fig. 1b and Extended Data Fig. 1j–l ). This clustered morphology has not to our knowledge been previously reported. Thus, caspase-7 is activated in extruding IECs in response to S . Typhimurium infection, but independently of the conventional apoptotic executioner caspase-3. Fig. 1: Caspase-7 facilitates IEC extrusion during S . Typhimurium infection and ameliorates gasdermin D pores. a , b , The indicated mice were infected with 5 × 10 6 S . Typhimurium and the caeca were collected 24 h later. Representative images ( a ) and quantification ( b ) of epithelial marker EpCAM + cell counts per extrusion site (arrows indicate extrusion sites). WT, wild type. c , Percentage of ruptured IEC organoids after treatment with FlaTox in pooled live-imaging experiments (related to Extended Data Fig. 2a ). d , Representative images of organoids 30 min after treatment with FlaTox, stained with phalloidin and for cleaved caspase-7. e , f , Representative images ( e ; full series are in Extended Data Fig. 4b ) and quantification ( f ) in live-cell imaging of PI intensity of wild-type and Casp7 –/– organoids treated with FlaTox. g , PI Intensity of wild-type, Gsdmd –/– and Gsdmd –/– Casp7 –/– organoids treated with FlaTox or control PBS. Data are representative of three experiments ( a , b , d – f ) or are pooled from 12 ( c ) or 3 ( g ) experiments. Scale bars, 50 μm ( a ); 20 μm ( d ). * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001 (two-sided Mann–Whitney U -test in b ; two-sided unpaired t -test in c ; two-way analysis of variance (ANOVA) with Sidak’s post-hoc test in f or with Tukey’s post-hoc test in g ). Data are median ± s.e.m. ( b ) or mean ± s.e.m. ( c , f , g ). Exact P values in Source Data. Source data Full size image During S . Typhimurium infection, IEC extrusion is initiated when caspase-1 is activated by NAIP–NLRC4; this complex detects bacterial proteins, such as flagellin, in the cytosol 2 , 3 . This can be mimicked in IEC organoid cultures by stimulation with FlaTox, an engineered toxin that delivers flagellin to the cytosol, which causes extrusion in organoid monolayers in a setting in which all cells activate caspase-1. We therefore examined caspase-7 function in this model of IEC extrusion. FlaTox-treated wild-type organoids ultimately collapse, concomitantly with the rupture of the inner contents into the surrounding matrigel. We visualized the morphology of extruding IECs, and in addition quantified organoid rupture as a proxy for overall extrusion dynamics. In Casp7 –/– organoids, the IECs also initiated extrusion; however, they remained attached to neighbouring IECs, formed clusters of defectively extruding cells and ultimately had a reduced incidence of organoid rupture (Supplementary Videos 1 , 2 , Fig. 1c and Extended Data Fig. 2a,b ). Casp3 –/– organoids retained normal levels of extrusion, cleaved caspase-7 and rupture (Extended Data Fig. 2c–e ). Therefore, caspase-7 is critical for the caspase-1-driven extrusion of IECs, and this occurs independently of caspase-3. Caspase-1 activates caspase-7 Caspase-1 is an inflammatory caspase that is highly<|im_end|> <|im_start|>assistant Researchers have unmasked a component of the cell death process that could play a vital role in a better infection-fighting strategy. Scientists at the Duke University School of Medicine and the UNC School of Medicine partnered with researchers at the University of Virginia to identify the function behind caspase-7, an enzyme that is part of a cell's self-destruct program. While researchers have known the enzyme is involved in the process, its exact function has been unclear. The findings are published June 15 in the journal Nature. The researchers found that caspase-7 kicks off a Rube Goldberg series of events that allow the cell to die in an orderly fashion, said the study's senior author, Edward Miao, MD, Ph.D., a professor in the departments of Immunology and Molecular Genetics and Microbiology at Duke and previously an associate professor in the UNC Department of Microbiology & Immunology. An orderly cell death is essential for the immune response. Without the enzyme, however, the dying cell might violently explode and cause collateral damage. Miao said this research lays groundwork to explore exciting possibilities for therapeutic applications, especially if caspase-7 can be boosted or blocked. "There is still so much we need to understand about the basic components of our cells, what they do and why," Miao said. "If we can uncover this blueprint, it may become a map for understanding how disease moves in the body, allowing scientists to devise a more precise plan of action. With the discovery of caspase-7's role in the cell, we're one step closer to a complete schematic." In the study, the researchers found that caspase-7 serves as a timing device in cell death. It activates a protein, called acid sphingomyelinase or ASM, which kicks off a cell membrane repair mechanism, which in turn gives the cell enough time to get its affairs in order before dying. To identify the function of the caspase-7 enzyme, the team studied different infection models in genetically altered mice and cultured intestinal tissue. They looked at caspase-7's role in two types of orderly cell death—extrusion and apoptosis. Caspase-7's role was different in the context of different pathogens—Salmonella, Listeria, and a rare pathogen called Chromobacterium. With Salmonella, cells undergo an orderly manner of cell death called extrusion. In this context, researchers found the absence of caspase-7 caused the unnecessary death of healthy cells, which were the collateral damage of nearby infected cells failing to detach themselves, or extrude, from their neighbors. With Chromobacterium and Listeria, dying cells normally undergo a process called apoptosis, or programmed cell death. The lack of caspase-7 enabled the bacteria to survive an immune system attack, presumably because their infected cell host didn't accomplish some apoptotic task before exploding. If caspase-7 can be manipulated, Miao said a potential application is investigating the possibility of targeting the enzyme as a detonator of cell death to circumvent antibiotic resistance. Antibiotics are a standard and broad approach for fighting infection, but pathogens have devised strategies to adapt and resist. "Antibiotics don't take into account that each pathogen has its own strategy—some of them are living outside cells, some are living inside cells. If a pathogen is inside the cell," he said, "you could boost caspase-7 to allow the infected cell to die in the correct way. If you know the strategy that the pathogen is using, you can help the immune system by tweaking it in the correct direction." "On the other hand, if you have a pathogen traveling outside of the cell, and cells are exploding inappropriately, maybe we could boost caspase-7 to keep them alive, thereby prevent excessive damage," Miao said, noting that this approach might be effective against sepsis. Miao said this enzyme could also potentially play a major role in triggering the immune system to fight cancer. "Cancer cells are probably running the full Rube Goldberg machine and dying in an orderly manner," Miao said. "When the immune system comes and looks around, it sees that everything seems to be in order and then leaves. "If you could shut down the Rube Goldberg contraption, instead of putting itself away nice and neat, the tumor cell would be just dead on the floor," Miao said. "This might cause the immune system to become alarmed and activated. Theoretically, that could cause the immune system to attack a tumor it would otherwise ignore." <|im_end|>

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2,647

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The S. pyogenes (Sp) Cas9 endonuclease is an important gene-editing tool. Sp Cas9 is directed to target sites based on complementarity to a complexed single-guide RNA (sgRNA). However, Sp Cas9-sgRNA also binds and cleaves genomic off-targets with only partial complementarity. To date, we lack the ability to predict cleavage and binding activity quantitatively, and rely on binary classification schemes to identify strong off-targets. We report a quantitative kinetic model that captures the Sp Cas9-mediated strand-replacement reaction in free-energy terms. The model predicts binding and cleavage activity as a function of time, target, and experimental conditions. Trained and validated on high-throughput bulk-biochemical data, our model predicts the intermediate R-loop state recently observed in single-molecule experiments, as well as the associated conversion rates. Finally, we show that our quantitative activity predictor can be reduced to a binary off-target classifier that outperforms the established state-of-the-art. Our approach is extensible, and can characterize any CRISPR-Cas nuclease – benchmarking natural and future high-fidelity variants against Sp Cas9; elucidating determinants of CRISPR fidelity; and revealing pathways to increased specificity and efficiency in engineered systems. Introduction CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats—CRISPR-associated protein 9) has become a ubiquitous tool in the biological sciences 1 , 2 , with applications ranging from live-cell imaging 3 and gene knockdown/overexpression 4 , 5 to genetic engineering 6 , 7 and gene therapy 8 , 9 . Streptococcus pyogenes ( Sp ) Cas9 can be programmed with a ~100 nucleotide (nt) single-guide RNA (sgRNA) to target DNAs based on the level of complementarity to a 20 nt segment of the sgRNA 10 . Wildtype Sp Cas9 (henceforth Cas9) induces site-specific double-stranded breaks and the catalytically dead Cas9 (dCas9) mutant allows for binding without cleavage 3 , 5 . Apart from complimentary on-targets, Cas9-sgRNA also binds and cleaves non-complementary off-targets 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 . Off-target cleavage risks deleterious genomic alterations, which has so far impeded the widespread implementation of the CRISPR toolkit in human therapeutics 19 . Strong off-target sites are identified in silico by a growing set of tools. These tools use bioinformatics 20 , 21 , machine learning 22 , 23 , or heuristic 12 , 14 , 24 , 25 approaches to rank genomic sites based on distinctive off-target activity scores. Though such models can identify strong off-targets, they are not quantitative and cannot assess activity on the many lesser off-targets; nor can they predict how activity changes with exposure time and enzyme concentration—even though these parameters are frequently exploited to limit off-target activity in cells 26 . To implement quantitative activity prediction, Cas9 targeting must be modelled in physical terms. Existing physical models 24 , 27 , 28 assume binding equilibration before cleavage, and it remains unclear what predictive power such approaches can ultimately deliver in this non-equilibrium system 29 , 30 . To account for the nonequilibrium nature of the targeting reaction, we construct a mechanistic model that captures binding and cleavage reactions in kinetic terms. To gain insights into general mechanisms, we train and validate our model on high-throughput datasets that capture both binding and cleavage in bulk experiments 15 , 31 . Though we restrict our training to off-targets with two or less mismatches, we accurately predict the activities on all more highly mismatched off-targets in the same datasets, as well as those reported in two independent high-throughput datasets 11 . To reveal the physical basis of Cas9 fidelity on genomic scales, we extract the free-energy landscapes that control PAM binding, strand-replacement, and cleavage on any target. Our characterization of Cas9 supports the notion that observed differences in binding and cleavage activities 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 stem from a relatively long-lived DNA-bound RNA-DNA hybrid (R-loop) intermediate. This R-loop intermediate was recently observed directly in single-molecule experiments 42 , and our model predicts both its location and its conversion rates. Though the strengths of our model lies in that it allows us to calculate how (d)Cas9 activity evolves in time under various conditions, we also sought to compare our approach to existing binary off-target classifiers that identify strong off-targets. To this end, we reduce our quantitative activity predictor to a binary off-target classifier that outperforms the leading tools used today 12 , 24 , 28 , 43 . Results The kinetic model In Fig. 1a we show the reaction pathway that underpins the Cas9 targeting reaction on every target 44 . The reaction starts with Cas9-sgRNA ribonucleoprotein complex exiting the solution state to specifically bind to a 3nt protospacer adjacent motif (PAM) DNA sequence—canonically 5’-NGG-3’—via protein-DNA interactions 44 , 45 . Binding to the PAM sequence (state 0) opens the DNA double helix, and allows the first base of the target sequence to hybridize with the sgRNA 44 , 45 , forming the first R-loop state (state 1). The DNA double helix further denatures as the RNA-DNA hybrid is extended in the guide-target strand-replacement reaction 46 , 47 , 48 , 49 (state 2-20). The hybrid grows and shrinks in single-nucleotide steps, until it is either reversed and Cas9 dissociates, or it reaches completion at 20 base pairs (bp) in state 20. If the full hybrid is formed, Cas9 can use its HNH and RuvC nuclease domains to cleave both DNA strands 50 . Fig. 1: The reaction scheme and the implications of the model assumptions. a The general microscopic reaction scheme for PAM (blue rectangle) binding from solution, followed by strand replacement and eventual cleavage (Cas9 only). The bound states are labeled 0-20, starting with the PAM bound state, and ending with the state having a fully open R-loop (20 bp hybrid). b An example on-target free-energy landscape \${F}_{n}\$ (pink), and the resulting free-energy landscape when using our mechanistic-model assumptions on an off-target where mismatches enter the hybrid at length 3 and 15 bp (blue). Each mismatch (dashed red line) has an energetic cost \${{\\epsilon }}_{n}\$", "role": "user" }, { "content": "Researchers from the TU Delft have come up with a physical-based model that establishes a quantitative framework on how gene-editing with CRISPR-Cas9 works, and allows them to predict where, with what probability, and why targeting errors (off-targets) occur. This research, which has been published in Nature Communications, gives us a first detailed physical understanding of the mechanism behind the most important gene editing platform of today. The discovery of the CRISPR-Cas9 protein has greatly simplified gene editing, and raised hopes to find a cure to many hereditary diseases. However, routine and safe use of this technique in human therapeutics requires extreme precision and predictability of any off-target effects. A research team lead by Martin Depken at TU Delft's department of Bionanoscience has now demonstrated a new, physical-based model that greatly improves on existing models: not only does the model predict where the DNA is likely to be cut, but also with what probability this will happen. Physics-based approach to understand Cas9 gene-editing A great limitation of current bioinformatics models for gene editing lies in the fact that they are binary in nature: they classify targets on the genome as either likely or unlikely to be cut. These models focus only on very high-probability targeting errors (off-targets), and will miss the many lower probability off-targets that together could amount to the majority of editing errors in the genome. Now, the new physical model which the researchers created takes into account both high-probability and low-probability off-targets; it can be used to physically characterize any Cas9 variant and predict the probability that any site will be cleaved. Martin Depken explains his lab's new physics-based approach: \"In gene editing, you want to maximize the probability of cutting at the intended site, while minimizing the amount of cutting in the rest of the genome. It is therefore crucial to understand cutting in terms of probabilities. Drawing from experiments in single-molecule physics and structural data, we created a model that can do this. We changed the way in which to describe the gene editing from a binary choice to a complete probabilistic picture.\" Improving accuracy in gene editing By giving physical insights into why off-targets occur, this research also marks an important next step towards a more rational way of engineering new gene-editing platforms, and for characterizing, evaluating, and comparing existing ones. With their probabilistic description of gene-editing, the researchers also hope to help improve the risk assessment in genome editing by accounting for all possible off-targets. \"Together with our experimental collaborators at University of Texas at Austin, we've now benchmarked Cas9 with our model,\" says Depken. \"Our next goal is to do the same with other high-precision gene-editing platforms to understand how and why they differ. With this we hope to reveal the path to even higher precision in gene editing.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The S. pyogenes (Sp) Cas9 endonuclease is an important gene-editing tool. Sp Cas9 is directed to target sites based on complementarity to a complexed single-guide RNA (sgRNA). However, Sp Cas9-sgRNA also binds and cleaves genomic off-targets with only partial complementarity. To date, we lack the ability to predict cleavage and binding activity quantitatively, and rely on binary classification schemes to identify strong off-targets. We report a quantitative kinetic model that captures the Sp Cas9-mediated strand-replacement reaction in free-energy terms. The model predicts binding and cleavage activity as a function of time, target, and experimental conditions. Trained and validated on high-throughput bulk-biochemical data, our model predicts the intermediate R-loop state recently observed in single-molecule experiments, as well as the associated conversion rates. Finally, we show that our quantitative activity predictor can be reduced to a binary off-target classifier that outperforms the established state-of-the-art. Our approach is extensible, and can characterize any CRISPR-Cas nuclease – benchmarking natural and future high-fidelity variants against Sp Cas9; elucidating determinants of CRISPR fidelity; and revealing pathways to increased specificity and efficiency in engineered systems. Introduction CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats—CRISPR-associated protein 9) has become a ubiquitous tool in the biological sciences 1 , 2 , with applications ranging from live-cell imaging 3 and gene knockdown/overexpression 4 , 5 to genetic engineering 6 , 7 and gene therapy 8 , 9 . Streptococcus pyogenes ( Sp ) Cas9 can be programmed with a ~100 nucleotide (nt) single-guide RNA (sgRNA) to target DNAs based on the level of complementarity to a 20 nt segment of the sgRNA 10 . Wildtype Sp Cas9 (henceforth Cas9) induces site-specific double-stranded breaks and the catalytically dead Cas9 (dCas9) mutant allows for binding without cleavage 3 , 5 . Apart from complimentary on-targets, Cas9-sgRNA also binds and cleaves non-complementary off-targets 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 . Off-target cleavage risks deleterious genomic alterations, which has so far impeded the widespread implementation of the CRISPR toolkit in human therapeutics 19 . Strong off-target sites are identified in silico by a growing set of tools. These tools use bioinformatics 20 , 21 , machine learning 22 , 23 , or heuristic 12 , 14 , 24 , 25 approaches to rank genomic sites based on distinctive off-target activity scores. Though such models can identify strong off-targets, they are not quantitative and cannot assess activity on the many lesser off-targets; nor can they predict how activity changes with exposure time and enzyme concentration—even though these parameters are frequently exploited to limit off-target activity in cells 26 . To implement quantitative activity prediction, Cas9 targeting must be modelled in physical terms. Existing physical models 24 , 27 , 28 assume binding equilibration before cleavage, and it remains unclear what predictive power such approaches can ultimately deliver in this non-equilibrium system 29 , 30 . To account for the nonequilibrium nature of the targeting reaction, we construct a mechanistic model that captures binding and cleavage reactions in kinetic terms. To gain insights into general mechanisms, we train and validate our model on high-throughput datasets that capture both binding and cleavage in bulk experiments 15 , 31 . Though we restrict our training to off-targets with two or less mismatches, we accurately predict the activities on all more highly mismatched off-targets in the same datasets, as well as those reported in two independent high-throughput datasets 11 . To reveal the physical basis of Cas9 fidelity on genomic scales, we extract the free-energy landscapes that control PAM binding, strand-replacement, and cleavage on any target. Our characterization of Cas9 supports the notion that observed differences in binding and cleavage activities 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 stem from a relatively long-lived DNA-bound RNA-DNA hybrid (R-loop) intermediate. This R-loop intermediate was recently observed directly in single-molecule experiments 42 , and our model predicts both its location and its conversion rates. Though the strengths of our model lies in that it allows us to calculate how (d)Cas9 activity evolves in time under various conditions, we also sought to compare our approach to existing binary off-target classifiers that identify strong off-targets. To this end, we reduce our quantitative activity predictor to a binary off-target classifier that outperforms the leading tools used today 12 , 24 , 28 , 43 . Results The kinetic model In Fig. 1a we show the reaction pathway that underpins the Cas9 targeting reaction on every target 44 . The reaction starts with Cas9-sgRNA ribonucleoprotein complex exiting the solution state to specifically bind to a 3nt protospacer adjacent motif (PAM) DNA sequence—canonically 5’-NGG-3’—via protein-DNA interactions 44 , 45 . Binding to the PAM sequence (state 0) opens the DNA double helix, and allows the first base of the target sequence to hybridize with the sgRNA 44 , 45 , forming the first R-loop state (state 1). The DNA double helix further denatures as the RNA-DNA hybrid is extended in the guide-target strand-replacement reaction 46 , 47 , 48 , 49 (state 2-20). The hybrid grows and shrinks in single-nucleotide steps, until it is either reversed and Cas9 dissociates, or it reaches completion at 20 base pairs (bp) in state 20. If the full hybrid is formed, Cas9 can use its HNH and RuvC nuclease domains to cleave both DNA strands 50 . Fig. 1: The reaction scheme and the implications of the model assumptions. a The general microscopic reaction scheme for PAM (blue rectangle) binding from solution, followed by strand replacement and eventual cleavage (Cas9 only). The bound states are labeled 0-20, starting with the PAM bound state, and ending with the state having a fully open R-loop (20 bp hybrid). b An example on-target free-energy landscape ${F}_{n}$ (pink), and the resulting free-energy landscape when using our mechanistic-model assumptions on an off-target where mismatches enter the hybrid at length 3 and 15 bp (blue). Each mismatch (dashed red line) has an energetic cost ${{\epsilon }}_{n}$<|im_end|> <|im_start|>assistant Researchers from the TU Delft have come up with a physical-based model that establishes a quantitative framework on how gene-editing with CRISPR-Cas9 works, and allows them to predict where, with what probability, and why targeting errors (off-targets) occur. This research, which has been published in Nature Communications, gives us a first detailed physical understanding of the mechanism behind the most important gene editing platform of today. The discovery of the CRISPR-Cas9 protein has greatly simplified gene editing, and raised hopes to find a cure to many hereditary diseases. However, routine and safe use of this technique in human therapeutics requires extreme precision and predictability of any off-target effects. A research team lead by Martin Depken at TU Delft's department of Bionanoscience has now demonstrated a new, physical-based model that greatly improves on existing models: not only does the model predict where the DNA is likely to be cut, but also with what probability this will happen. Physics-based approach to understand Cas9 gene-editing A great limitation of current bioinformatics models for gene editing lies in the fact that they are binary in nature: they classify targets on the genome as either likely or unlikely to be cut. These models focus only on very high-probability targeting errors (off-targets), and will miss the many lower probability off-targets that together could amount to the majority of editing errors in the genome. Now, the new physical model which the researchers created takes into account both high-probability and low-probability off-targets; it can be used to physically characterize any Cas9 variant and predict the probability that any site will be cleaved. Martin Depken explains his lab's new physics-based approach: "In gene editing, you want to maximize the probability of cutting at the intended site, while minimizing the amount of cutting in the rest of the genome. It is therefore crucial to understand cutting in terms of probabilities. Drawing from experiments in single-molecule physics and structural data, we created a model that can do this. We changed the way in which to describe the gene editing from a binary choice to a complete probabilistic picture." Improving accuracy in gene editing By giving physical insights into why off-targets occur, this research also marks an important next step towards a more rational way of engineering new gene-editing platforms, and for characterizing, evaluating, and comparing existing ones. With their probabilistic description of gene-editing, the researchers also hope to help improve the risk assessment in genome editing by accounting for all possible off-targets. "Together with our experimental collaborators at University of Texas at Austin, we've now benchmarked Cas9 with our model," says Depken. "Our next goal is to do the same with other high-precision gene-editing platforms to understand how and why they differ. With this we hope to reveal the path to even higher precision in gene editing." <|im_end|>

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2,076

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Recently, four-dimensional (4D) functional nano-materials have attracted considerable attention due to their impact in cutting-edge fields such as nano-(opto)electronics, -biotechnology or -biomedicine. Prominent optical functionalizations, representing the fourth dimension, require precisely tailored light fields for its optimal implementation. These fields need to be like-wise 4D, i.e., nano-structured in three-dimensional (3D) space while polarization embeds additional longitudinal components. Though a couple of approaches to realize 4D fields have been suggested, their breakthrough is impeded by a lack of appropriate analysis techniques. Combining molecular self-assembly, i.e., nano-chemistry, and nano-optics, we propose a polarization nano-tomography of respective fields using the functional material itself as a sensor. Our method allows a single-shot identification of non-paraxial light fields at nano-scale resolution without any data post-processing. We prove its functionality numerically and experimentally, elucidating its amplitude, phase and 3D polarization sensitivity. We analyze non-paraxial field properties, demonstrating our method’s capability and potential for next generation 4D materials. Introduction Within the last decades, functionalized nano-systems have exceled contributing to future four-dimensional (4D) nano-materials and their applications in nano-(opto)electronics, -biotechnology, or -biomedicine 1 , 2 , 3 , 4 , 5 , 6 . For instance, peptides have been employed as functional components in nano-systems for disease treatments, or stimuli-responsive nano-carriers were applied for drug delivery 4 , 7 . Nowadays one can summarize the class of 4D materials generally as three-dimensionally (3D) nano-structured materials embedding an addressable functionality as fourth dimension. Most man-made nano-technology is based on top-down approaches governed by the concept of continuous miniaturization to the nano-scale. In contrast, nature implements a bottom-up approach as the prime strategy to construct dynamic, adaptive and learning systems at the nano-scale. This strategy includes self-assembly as an attractive route to the customization of 3D nano-structures that at the same time exhibit an electronic, magnetic, or optical functionality as fourth dimension 5 , 6 . Leading functionalities are addressed optically as, e.g., light-based material changes in azobenzenes on surfaces, which requires a light field of appropriate characteristics for its optimal implementation. Therefore, light needs to be precisely tailored in all three spatial dimensions as well as in all its degrees of freedom, namely amplitude, phase, and 3D polarization. Thus, for optimally addressing a 4D nano-material, the respective light fields need to be likewise nano-structured in 4D, only achievable in the non-paraxial regime. Converting paraxial to non-paraxial light by, e.g., tightly focusing (numerical aperture (NA) ≥ 0.7), initial radial electric field components are tilted and transformed into non-negligible longitudinal field contributions 8 , 9 as fourth dimension. Hence, focal 4D light fields are shaped 10 , 11 , 12 , 13 , 14 , 15 , 16 , which include complex topological structures as optical Möbius strips or ribbons 17 , 18 , 19 , 20 . Note that 3D polarization states and topologies as Möbius strips may also be realized by, e.g., off-axis interference of structured beams 21 . However, the desired nano-scale structure is achieved only in a tightly focused field. The 3D polarization nature as well as associated sub-diffractive, thus, nano-scale complexity of non-paraxial 4D fields 22 , 23 represent the required tool for the effective implementation of novel 4D functional nano-materials. However, the realization and application of these light fields is actually obstructed by the lack of appropriate analysis techniques. The benefit of using the complex 4D nature and nano-scale structure of non-paraxial fields represent at the same time a major difficulty impeding the application of metrology tools precisely working in the paraxial regime. Hence, there is an urgent demand for fast, thus, single-shot nano-tomographic techniques allowing for the immediate identification of focal fields including their amplitude, phase and 3D polarization. “Single-shot” refers to the fact that only a single measurement step, e.g., one camera image, is required for the field identification. Until now, a few limited approaches have been proposed 24 , 25 , 26 , but are failing to satisfy the topical demand since they are based on slow scanning techniques with multiple shots in combination with the requirement of precise knowledge of the scanning probe characteristics and extensive reconstruction algorithms. Here, we show a single-shot nano-tomographic approach that does not require any post-measurement data processing for the identification and investigation of 4D light fields. For this purpose, we combine nano-chemistry and nano-optics to analyze light fields by the functional 4D nano-material itself as sensor. We apply nature inspired bottom-up assembly of fluorescent sulforhodamine B molecules for the creation of a functional molecular nano-system, or, more precisely, self-organized functionalized nano-surfaces 27 , 28 . We develop these self-assembled monolayers (SAMs) 29 , 30 , 31 by exploiting the process of π – π -stacking, resulting in a fluorescent nano-tomographic detector. Crucially, respective fluorescence, i.e., the material’s fourth dimension, is sensitive to the amplitude, phase and 3D polarization of the exciting non-paraxial light field, which we prove numerically as well as experimentally. Hence, the created tool enables the qualitative single-shot analysis by a single camera image of complete transverse planes of a focal 4D field with spatial resolution at the nanometer-scale in all three spatial dimensions. Our approach finally enables the demanded experimental study of 4D structured fields, and thereby unlocks their potential arising in combination with 4D functional nano-systems. Results Tailored non-paraxial 4D light fields The appropriate demonstration of the nano-tomographic approach requires representative 4D light fields, fully-structured 32 , 33 , 34 in all its degrees of freedom. Hence, these fields need to embed amplitude, phase as well as polarization structuring of well-defined shape which can be tailored on demand. Therefore, we chose to customize non-paraxial light fields by holographic phase and polarization modulation in the paraxial regime. More precisely, we realize higher-order vector field of pure linear polarization with additional phase vortices and tightly focus these by a high-NA microscope objective (MO). Thereby, complexly shaped 4D fields of three-dimensional polarization \${{\\cal{E}}}({x,y,z}) = [{\\cal{E}}_{x}({x,y,z}),{\\cal{E}}_{y}({x,y,z}),{\\cal{E}}_{z}({x,y,z})]^{T}\$ are formed with non-neglectable longitudinal polarization component \${\\cal{E}}_z\$ . Note that also other kinds of fully-structured light fields could be applied for the demonstration of our nano-tomographic method’s", "role": "user" }, { "content": "Structured laser light has already opened up various different applications: it allows for precise material machining, trapping, manipulating or defined movement of small particles or cell compartments, as well as increasing the bandwidth for next-generation intelligent computing. If these light structures are tightly focused by a lens, like a magnifying glass used to start a fire, highly intense three-dimensional light landscapes will be shaped, facilitating a significantly enhanced resolution in named applications. These kinds of light landscapes have paved the way for such pioneering applications as Nobel prize awarded STED microscopy. However, these nano-fields themselves could not be measured, since components are formed by tight focusing which is invisible for typical measurement techniques. Up to now, this lack of appropriate metrological methods has impeded the breakthrough of nano-structured light landscapes as a tool for material machining, optical tweezers, or high-resolution imaging. A team around physicist Prof. Dr. Cornelia Denz of the Institute of Applied Physics and chemist Prof. Dr. Bart Jan Ravoo of the Center for Soft Nanoscience at the University of Münster (Germany) successfully developed a nano-tomographic technique which is able to detect the typically invisible properties of nano-structured fields in the focus of a lens—without requiring any complex analysis algorithms or data post-processing. For this purpose, the team combined their knowledge in the field of nano-optics and organic chemistry to realize an approach based on a monolayer of organic molecules. This monolayer is placed in the focused light field and replies to this illumination by fluorescence, embedding all information about the invisible properties. By the detection of this response the distinct identification of the nano-field by a single, fast and straightforward camera image is enabled. \"This approach finally opens the till now unexploited potential of these nano-structured light landscapes for many more applications,\" says Cornelia Denz, who is heading the study. The study has been published in the journal \"Nature Communications\". ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Recently, four-dimensional (4D) functional nano-materials have attracted considerable attention due to their impact in cutting-edge fields such as nano-(opto)electronics, -biotechnology or -biomedicine. Prominent optical functionalizations, representing the fourth dimension, require precisely tailored light fields for its optimal implementation. These fields need to be like-wise 4D, i.e., nano-structured in three-dimensional (3D) space while polarization embeds additional longitudinal components. Though a couple of approaches to realize 4D fields have been suggested, their breakthrough is impeded by a lack of appropriate analysis techniques. Combining molecular self-assembly, i.e., nano-chemistry, and nano-optics, we propose a polarization nano-tomography of respective fields using the functional material itself as a sensor. Our method allows a single-shot identification of non-paraxial light fields at nano-scale resolution without any data post-processing. We prove its functionality numerically and experimentally, elucidating its amplitude, phase and 3D polarization sensitivity. We analyze non-paraxial field properties, demonstrating our method’s capability and potential for next generation 4D materials. Introduction Within the last decades, functionalized nano-systems have exceled contributing to future four-dimensional (4D) nano-materials and their applications in nano-(opto)electronics, -biotechnology, or -biomedicine 1 , 2 , 3 , 4 , 5 , 6 . For instance, peptides have been employed as functional components in nano-systems for disease treatments, or stimuli-responsive nano-carriers were applied for drug delivery 4 , 7 . Nowadays one can summarize the class of 4D materials generally as three-dimensionally (3D) nano-structured materials embedding an addressable functionality as fourth dimension. Most man-made nano-technology is based on top-down approaches governed by the concept of continuous miniaturization to the nano-scale. In contrast, nature implements a bottom-up approach as the prime strategy to construct dynamic, adaptive and learning systems at the nano-scale. This strategy includes self-assembly as an attractive route to the customization of 3D nano-structures that at the same time exhibit an electronic, magnetic, or optical functionality as fourth dimension 5 , 6 . Leading functionalities are addressed optically as, e.g., light-based material changes in azobenzenes on surfaces, which requires a light field of appropriate characteristics for its optimal implementation. Therefore, light needs to be precisely tailored in all three spatial dimensions as well as in all its degrees of freedom, namely amplitude, phase, and 3D polarization. Thus, for optimally addressing a 4D nano-material, the respective light fields need to be likewise nano-structured in 4D, only achievable in the non-paraxial regime. Converting paraxial to non-paraxial light by, e.g., tightly focusing (numerical aperture (NA) ≥ 0.7), initial radial electric field components are tilted and transformed into non-negligible longitudinal field contributions 8 , 9 as fourth dimension. Hence, focal 4D light fields are shaped 10 , 11 , 12 , 13 , 14 , 15 , 16 , which include complex topological structures as optical Möbius strips or ribbons 17 , 18 , 19 , 20 . Note that 3D polarization states and topologies as Möbius strips may also be realized by, e.g., off-axis interference of structured beams 21 . However, the desired nano-scale structure is achieved only in a tightly focused field. The 3D polarization nature as well as associated sub-diffractive, thus, nano-scale complexity of non-paraxial 4D fields 22 , 23 represent the required tool for the effective implementation of novel 4D functional nano-materials. However, the realization and application of these light fields is actually obstructed by the lack of appropriate analysis techniques. The benefit of using the complex 4D nature and nano-scale structure of non-paraxial fields represent at the same time a major difficulty impeding the application of metrology tools precisely working in the paraxial regime. Hence, there is an urgent demand for fast, thus, single-shot nano-tomographic techniques allowing for the immediate identification of focal fields including their amplitude, phase and 3D polarization. “Single-shot” refers to the fact that only a single measurement step, e.g., one camera image, is required for the field identification. Until now, a few limited approaches have been proposed 24 , 25 , 26 , but are failing to satisfy the topical demand since they are based on slow scanning techniques with multiple shots in combination with the requirement of precise knowledge of the scanning probe characteristics and extensive reconstruction algorithms. Here, we show a single-shot nano-tomographic approach that does not require any post-measurement data processing for the identification and investigation of 4D light fields. For this purpose, we combine nano-chemistry and nano-optics to analyze light fields by the functional 4D nano-material itself as sensor. We apply nature inspired bottom-up assembly of fluorescent sulforhodamine B molecules for the creation of a functional molecular nano-system, or, more precisely, self-organized functionalized nano-surfaces 27 , 28 . We develop these self-assembled monolayers (SAMs) 29 , 30 , 31 by exploiting the process of π – π -stacking, resulting in a fluorescent nano-tomographic detector. Crucially, respective fluorescence, i.e., the material’s fourth dimension, is sensitive to the amplitude, phase and 3D polarization of the exciting non-paraxial light field, which we prove numerically as well as experimentally. Hence, the created tool enables the qualitative single-shot analysis by a single camera image of complete transverse planes of a focal 4D field with spatial resolution at the nanometer-scale in all three spatial dimensions. Our approach finally enables the demanded experimental study of 4D structured fields, and thereby unlocks their potential arising in combination with 4D functional nano-systems. Results Tailored non-paraxial 4D light fields The appropriate demonstration of the nano-tomographic approach requires representative 4D light fields, fully-structured 32 , 33 , 34 in all its degrees of freedom. Hence, these fields need to embed amplitude, phase as well as polarization structuring of well-defined shape which can be tailored on demand. Therefore, we chose to customize non-paraxial light fields by holographic phase and polarization modulation in the paraxial regime. More precisely, we realize higher-order vector field of pure linear polarization with additional phase vortices and tightly focus these by a high-NA microscope objective (MO). Thereby, complexly shaped 4D fields of three-dimensional polarization ${{\cal{E}}}({x,y,z}) = [{\cal{E}}_{x}({x,y,z}),{\cal{E}}_{y}({x,y,z}),{\cal{E}}_{z}({x,y,z})]^{T}$ are formed with non-neglectable longitudinal polarization component ${\cal{E}}_z$ . Note that also other kinds of fully-structured light fields could be applied for the demonstration of our nano-tomographic method’s<|im_end|> <|im_start|>assistant Structured laser light has already opened up various different applications: it allows for precise material machining, trapping, manipulating or defined movement of small particles or cell compartments, as well as increasing the bandwidth for next-generation intelligent computing. If these light structures are tightly focused by a lens, like a magnifying glass used to start a fire, highly intense three-dimensional light landscapes will be shaped, facilitating a significantly enhanced resolution in named applications. These kinds of light landscapes have paved the way for such pioneering applications as Nobel prize awarded STED microscopy. However, these nano-fields themselves could not be measured, since components are formed by tight focusing which is invisible for typical measurement techniques. Up to now, this lack of appropriate metrological methods has impeded the breakthrough of nano-structured light landscapes as a tool for material machining, optical tweezers, or high-resolution imaging. A team around physicist Prof. Dr. Cornelia Denz of the Institute of Applied Physics and chemist Prof. Dr. Bart Jan Ravoo of the Center for Soft Nanoscience at the University of Münster (Germany) successfully developed a nano-tomographic technique which is able to detect the typically invisible properties of nano-structured fields in the focus of a lens—without requiring any complex analysis algorithms or data post-processing. For this purpose, the team combined their knowledge in the field of nano-optics and organic chemistry to realize an approach based on a monolayer of organic molecules. This monolayer is placed in the focused light field and replies to this illumination by fluorescence, embedding all information about the invisible properties. By the detection of this response the distinct identification of the nano-field by a single, fast and straightforward camera image is enabled. "This approach finally opens the till now unexploited potential of these nano-structured light landscapes for many more applications," says Cornelia Denz, who is heading the study. The study has been published in the journal "Nature Communications". <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The non-target effects of pesticides are an area of growing concern, particularly for ecologically and economically important organisms such as bees. Much of the previous research on the effects of neonicotinoids, a class of insecticide that has gained attention for non-target effects, on bees focused on the consumption of contaminated food resources by a limited number of eusocial species. However, neonicotinoids are known to accumulate and persist in soils at concentrations 2 to 60 times greater than in food resources, and may represent an important route of exposure for diverse and ecologically important ground-nesting bees. This study aimed to assess the effect of chronic contact exposure to realistic soil concentrations of imidacloprid, the most widely used neonicotinoid pesticide, on bee longevity, development speed, and body mass. Cohorts of Osmia lignaria and Megachile rotundata were used as proxies for ground-nesting species. We observed species- and sex-specific changes to adult longevity, development speed, and mass in response to increasing concentrations of imidacloprid. These results suggest that chronic exposure to nesting substrates contaminated with neonicotinoids may represent an important route of exposure that could have considerable physiological and ecological consequences for bees and plant-pollinator interactions. Introduction For much of the past two decades, research on the lethal (e.g., increased mortality over 24–48 hours) and sublethal (e.g., reduced performance) non-target effects of neonicotinoids on pollinators has primarily focused on the consumption of contaminated pollen and nectar in honeybees and, more recently, bumblebees 1 . Although there appears to be no consistent effect on adult mortality rates in honeybees at dosages commonly recovered from pollen and nectar, a wide range of significant sublethal effects of acute and chronic exposure are well documented 2 . Observed sublethal effects include delayed larval development 3 , impaired mushroom body growth and neurological function 4 , 5 , 6 , and disruptions to reproduction including reduced production of reproductive female offspring 7 , 8 , 9 , 10 . While the consumption of neonicotinoids by honeybees and bumblebees may have important economic and ecological implications, there is also a need to assess additional routes of exposure and bee species to gain a better understanding of the non-target effects of neonicotinoids on bee communities as a whole. With most bees nesting underground 11 , prolonged contact with neonicotinoid contaminated soils may represent a significant route of exposure for many species. However, field-scale assessments of the effects of neonicotinoids on native bees have largely ignored the potential effects of contaminated nesting resources even when a number of affected species are ground-nesting and not thought to collect food resources from treated plants, e.g. 12 . While lethal concentrations of neonicotinoids are higher for contact than oral exposure 13 , soil concentrations of neonicotinoids often reach higher and more persistent levels than those in pollen and nectar. Soil concentrations of imidacloprid, a commonly used neonicotinoid, are often between 12–18 ppb, with values of up to 650 ppb reported, compared to 1–11 ppb in pollen and nectar 14 , 15 , 16 , 17 , 18 . Soils become contaminated with high concentrations of neonicotinoids as a result of much of the active ingredient, commonly applied as a seed treatment, spreading into the surrounding soil rather than being absorbed by targeted plants 16 , 19 , returning to the soil as treated plant material decomposes 20 , and having a relatively long half-life in soils 14 , 21 , 22 , 23 . Additionally, the long immature development period, relative to adult lifespan, exhibited by ground-nesting bees may amplify the effects of contaminated soils as the toxicity of neonicotinoids increases with exposure time 24 , 25 . The lack of an assessment of the effects of chronic contact exposure to realistic soil levels of neonicotinoids represents a major gap in our current knowledge, especially given the number of species at risk. Using imidacloprid, the most well-studied member of the neonicotinoid insecticide family 24 , 26 , we evaluated the sublethal effects of chronic contact exposure to realistic soil concentrations during immature development on Osmia lignaria Say, 1837 and Megachile rotundata (Fabricius, 1787). While not ground-nesting species themselves, O . lignaria and M . rotundata belong to genera containing ground-nesting species and were used previously to approximate the effects of soil conditions on soil-dwelling species 27 . The benefits to employing these species as proxies for ground-nesting bees are that they are easy to collect and rear and represent a worst case scenario of soil contact without a nest cell lining - structures that are highly variable within and between taxa 28 , 29 , 30 , 31 , 32 , 33 . We hypothesised that chronic contact exposure to imidacloprid would disrupt normal bee physiological functioning, possibly by altering the expression of genes associated with metabolism or detoxification 34 , 35 , 36 or reducing motor function 5 . These changes were expected to manifest as a decrease in body mass, development speed, or immature or adult longevity which could affect populations by reducing the total number of nest cells provisioned or altering emergence timing which disrupts mating and flower visitation. Due to differences in body mass (Table 1a ), life histories (Table 1b ), and the number of chromosomes (i.e., haplodiploid sex determination), we predicted that observed effects would be stronger for M . rotundata and male bees when compared to O . lignaria and female bees, respectively. Table 1 Differences in the ecology of and the methodologies used for Osmia lignaria and Megachile rotundata . Full size table Results The effects of chronic contact exposure to realistic soil concentrations of imidacloprid during immature development varied between O . lignaria and M . rotundata and often between males and females of the same species. In O . lignaria , we only detected an effect on adult female longevity which had an inverted u-shape, with a slight increase in longevity at low concentrations of imidacloprid and a decrease at high concentrations (Figs 1 and S1 – S3 ; Tables 2 – 4 ).", "role": "user" }, { "content": "Results from a new study suggest that bees might be exposed to pesticides in more ways than we thought, and it could impact their development significantly. The study, published in Nature's Scientific Reports, looks at the non-target effects of pesticides on ground-nesting bees, a group that actually makes up the majority of bee species. Non-target effects refer to the effects on organisms other than the ones intended. Much of the research currently available on non-target effects of pesticides has been limited to honey and bumble bees and their exposure to pesticides when collecting pollen and nectar. While these previous studies have shown that pesticide consumption by honey and bumble bees can have important ecological consequences, this new study is one of the first of its kind to determine the effects of contact with pesticides, such as those that occur in soils, that other bee species might encounter. \"This is an important piece of work because it's one of the first studies to look at realistic concentrations of pesticides that you would find in the soil as a route of exposure for bees. It's a very under-explored route, especially for some of the more solitary species that nest in the ground,\" said Nick Anderson, graduate student in entomology, led the study with his advisor, Alex Harmon-Threatt, professor of entomology. A key difference between ground-nesting bees and their honey and bumble bee cousins is their smaller nest sizes (both in size and number of bees) which are made by digging into the soil. Bee species that nest this way can stay in the ground up to 49 weeks out of the year, emerging for only 3 weeks to forage, mate, and lay eggs. This leaves a lot of time for the bees to be exposed to the chronic, low levels of pesticides found in the soil after agricultural land use. Results from the study showed that females and males responded differently to the pesticides, which could impact larger population dynamics. Credit: Jesse Wallace The researchers were particularly interested in a class of pesticides called neonicotinoids. Derived from nicotine, neonicotinoids are widely used for their effectiveness against insects such as Japanese beetles and emerald ash borers, but they can be toxic to pollinators. They also have a long half-life, meaning they can persist in the soil for long periods of time. Anderson and Harmon-Threatt used bees that are very close relatives to ground-nesting species because they are better suited for testing in the lab and have been used in previous research to approximate impacts on ground-nesting species. When the bees were exposed to neonicotinoids in the lab, the researchers looked at levels similar to those found in the field. Results showed that females grew larger and did not live as long, while males were smaller and lived much longer. This conclusion suggests that chronic and low-level exposure to pesticides might cause a hormetic response in bees, where, at low levels of pesticide exposure, bees appear to benefit in small ways. However, the long-term impacts of some of these changes might not be readily apparent. The researchers believe that these lower doses are causing changes in the bee's development, such as diverting energy from normal developmental processes to fortify physical and biochemical barriers to counter the effects of the pesticide. \"When you're doing neonicotinoid work on something like bees, I think people expect the conclusions to say whether it's good or it's bad, but a lot of the relationships we're seeing are more complicated than that. There are a lot of factors and developmental processes that can be affected,\" said Harmon-Threatt. \"As we develop new pesticides, we have to be able to understand the effects,\" said Anderson. \"Our work is part of that kind of risk assessment. We want to know what the implications are for ground-nesting bees so that when we're using the land for agriculture or trying to restore it, we can minimize the impact on these species.\" This study lays the foundation for the work that the Harmon-Threatt lab will be expanding upon in the field over the next five years. In 2018, Harmon-Threatt received a $1 million grant from the US Department of Agriculture's National Institute of Food and Agriculture to conduct research to better understand the role that soil contamination plays in bee diversity and conservation. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The non-target effects of pesticides are an area of growing concern, particularly for ecologically and economically important organisms such as bees. Much of the previous research on the effects of neonicotinoids, a class of insecticide that has gained attention for non-target effects, on bees focused on the consumption of contaminated food resources by a limited number of eusocial species. However, neonicotinoids are known to accumulate and persist in soils at concentrations 2 to 60 times greater than in food resources, and may represent an important route of exposure for diverse and ecologically important ground-nesting bees. This study aimed to assess the effect of chronic contact exposure to realistic soil concentrations of imidacloprid, the most widely used neonicotinoid pesticide, on bee longevity, development speed, and body mass. Cohorts of Osmia lignaria and Megachile rotundata were used as proxies for ground-nesting species. We observed species- and sex-specific changes to adult longevity, development speed, and mass in response to increasing concentrations of imidacloprid. These results suggest that chronic exposure to nesting substrates contaminated with neonicotinoids may represent an important route of exposure that could have considerable physiological and ecological consequences for bees and plant-pollinator interactions. Introduction For much of the past two decades, research on the lethal (e.g., increased mortality over 24–48 hours) and sublethal (e.g., reduced performance) non-target effects of neonicotinoids on pollinators has primarily focused on the consumption of contaminated pollen and nectar in honeybees and, more recently, bumblebees 1 . Although there appears to be no consistent effect on adult mortality rates in honeybees at dosages commonly recovered from pollen and nectar, a wide range of significant sublethal effects of acute and chronic exposure are well documented 2 . Observed sublethal effects include delayed larval development 3 , impaired mushroom body growth and neurological function 4 , 5 , 6 , and disruptions to reproduction including reduced production of reproductive female offspring 7 , 8 , 9 , 10 . While the consumption of neonicotinoids by honeybees and bumblebees may have important economic and ecological implications, there is also a need to assess additional routes of exposure and bee species to gain a better understanding of the non-target effects of neonicotinoids on bee communities as a whole. With most bees nesting underground 11 , prolonged contact with neonicotinoid contaminated soils may represent a significant route of exposure for many species. However, field-scale assessments of the effects of neonicotinoids on native bees have largely ignored the potential effects of contaminated nesting resources even when a number of affected species are ground-nesting and not thought to collect food resources from treated plants, e.g. 12 . While lethal concentrations of neonicotinoids are higher for contact than oral exposure 13 , soil concentrations of neonicotinoids often reach higher and more persistent levels than those in pollen and nectar. Soil concentrations of imidacloprid, a commonly used neonicotinoid, are often between 12–18 ppb, with values of up to 650 ppb reported, compared to 1–11 ppb in pollen and nectar 14 , 15 , 16 , 17 , 18 . Soils become contaminated with high concentrations of neonicotinoids as a result of much of the active ingredient, commonly applied as a seed treatment, spreading into the surrounding soil rather than being absorbed by targeted plants 16 , 19 , returning to the soil as treated plant material decomposes 20 , and having a relatively long half-life in soils 14 , 21 , 22 , 23 . Additionally, the long immature development period, relative to adult lifespan, exhibited by ground-nesting bees may amplify the effects of contaminated soils as the toxicity of neonicotinoids increases with exposure time 24 , 25 . The lack of an assessment of the effects of chronic contact exposure to realistic soil levels of neonicotinoids represents a major gap in our current knowledge, especially given the number of species at risk. Using imidacloprid, the most well-studied member of the neonicotinoid insecticide family 24 , 26 , we evaluated the sublethal effects of chronic contact exposure to realistic soil concentrations during immature development on Osmia lignaria Say, 1837 and Megachile rotundata (Fabricius, 1787). While not ground-nesting species themselves, O . lignaria and M . rotundata belong to genera containing ground-nesting species and were used previously to approximate the effects of soil conditions on soil-dwelling species 27 . The benefits to employing these species as proxies for ground-nesting bees are that they are easy to collect and rear and represent a worst case scenario of soil contact without a nest cell lining - structures that are highly variable within and between taxa 28 , 29 , 30 , 31 , 32 , 33 . We hypothesised that chronic contact exposure to imidacloprid would disrupt normal bee physiological functioning, possibly by altering the expression of genes associated with metabolism or detoxification 34 , 35 , 36 or reducing motor function 5 . These changes were expected to manifest as a decrease in body mass, development speed, or immature or adult longevity which could affect populations by reducing the total number of nest cells provisioned or altering emergence timing which disrupts mating and flower visitation. Due to differences in body mass (Table 1a ), life histories (Table 1b ), and the number of chromosomes (i.e., haplodiploid sex determination), we predicted that observed effects would be stronger for M . rotundata and male bees when compared to O . lignaria and female bees, respectively. Table 1 Differences in the ecology of and the methodologies used for Osmia lignaria and Megachile rotundata . Full size table Results The effects of chronic contact exposure to realistic soil concentrations of imidacloprid during immature development varied between O . lignaria and M . rotundata and often between males and females of the same species. In O . lignaria , we only detected an effect on adult female longevity which had an inverted u-shape, with a slight increase in longevity at low concentrations of imidacloprid and a decrease at high concentrations (Figs 1 and S1 – S3 ; Tables 2 – 4 ).<|im_end|> <|im_start|>assistant Results from a new study suggest that bees might be exposed to pesticides in more ways than we thought, and it could impact their development significantly. The study, published in Nature's Scientific Reports, looks at the non-target effects of pesticides on ground-nesting bees, a group that actually makes up the majority of bee species. Non-target effects refer to the effects on organisms other than the ones intended. Much of the research currently available on non-target effects of pesticides has been limited to honey and bumble bees and their exposure to pesticides when collecting pollen and nectar. While these previous studies have shown that pesticide consumption by honey and bumble bees can have important ecological consequences, this new study is one of the first of its kind to determine the effects of contact with pesticides, such as those that occur in soils, that other bee species might encounter. "This is an important piece of work because it's one of the first studies to look at realistic concentrations of pesticides that you would find in the soil as a route of exposure for bees. It's a very under-explored route, especially for some of the more solitary species that nest in the ground," said Nick Anderson, graduate student in entomology, led the study with his advisor, Alex Harmon-Threatt, professor of entomology. A key difference between ground-nesting bees and their honey and bumble bee cousins is their smaller nest sizes (both in size and number of bees) which are made by digging into the soil. Bee species that nest this way can stay in the ground up to 49 weeks out of the year, emerging for only 3 weeks to forage, mate, and lay eggs. This leaves a lot of time for the bees to be exposed to the chronic, low levels of pesticides found in the soil after agricultural land use. Results from the study showed that females and males responded differently to the pesticides, which could impact larger population dynamics. Credit: Jesse Wallace The researchers were particularly interested in a class of pesticides called neonicotinoids. Derived from nicotine, neonicotinoids are widely used for their effectiveness against insects such as Japanese beetles and emerald ash borers, but they can be toxic to pollinators. They also have a long half-life, meaning they can persist in the soil for long periods of time. Anderson and Harmon-Threatt used bees that are very close relatives to ground-nesting species because they are better suited for testing in the lab and have been used in previous research to approximate impacts on ground-nesting species. When the bees were exposed to neonicotinoids in the lab, the researchers looked at levels similar to those found in the field. Results showed that females grew larger and did not live as long, while males were smaller and lived much longer. This conclusion suggests that chronic and low-level exposure to pesticides might cause a hormetic response in bees, where, at low levels of pesticide exposure, bees appear to benefit in small ways. However, the long-term impacts of some of these changes might not be readily apparent. The researchers believe that these lower doses are causing changes in the bee's development, such as diverting energy from normal developmental processes to fortify physical and biochemical barriers to counter the effects of the pesticide. "When you're doing neonicotinoid work on something like bees, I think people expect the conclusions to say whether it's good or it's bad, but a lot of the relationships we're seeing are more complicated than that. There are a lot of factors and developmental processes that can be affected," said Harmon-Threatt. "As we develop new pesticides, we have to be able to understand the effects," said Anderson. "Our work is part of that kind of risk assessment. We want to know what the implications are for ground-nesting bees so that when we're using the land for agriculture or trying to restore it, we can minimize the impact on these species." This study lays the foundation for the work that the Harmon-Threatt lab will be expanding upon in the field over the next five years. In 2018, Harmon-Threatt received a $1 million grant from the US Department of Agriculture's National Institute of Food and Agriculture to conduct research to better understand the role that soil contamination plays in bee diversity and conservation. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Streptococcus pneumoniae evades C3-mediated opsonization and effector functions by expressing an immuno-protective polysaccharide capsule and Factor H (FH)-binding proteins. Here we use super-resolution microscopy, mutants and functional analysis to show how these two defense mechanisms are functionally and spatially coordinated on the bacterial cell surface. We show that the pneumococcal capsule is less abundant at the cell wall septum, providing C3/C3b entry to underlying nucleophilic targets. Evasion of C3b deposition at division septa and lateral amplification underneath the capsule requires localization of the FH-binding protein PspC at division sites. Most pneumococcal strains have one PspC protein, but successful lineages in colonization and disease may have two, PspC1 and PspC2, that we show affect virulence differently. We find that spatial localization of these FH-recruiting proteins relative to division septa and capsular layer is instrumental for pneumococci to resist complement-mediated opsonophagocytosis, formation of membrane-attack complexes, and for the function as adhesins. Introduction The invasive respiratory pathogens, Haemophilus influenzae, Neisseria meningitidis , and S treptococcus pneumoniae , have evolved similar strategies, such as the expression of polysaccharide capsules and complement Factor H (FH) recruiting surface proteins, to evade deposition of C3b and activation of the alternative pathway of the complement system 1 , 2 , 3 . The pneumococcal polysaccharide capsule is critical for virulence and is known to inhibit complement activity 4 . Localization sites of deposited complement on the bacteria in relation to the capsule are not known. The capsule is believed to form an external shield for C3 entry and for the covalent binding of C3b to underlying nucleophilic targets 5 , 6 , 7 . So far more than 97 capsular polysaccharides have been described, and all except for serotypes 3 and 37, are covalently anchored to the bacterial peptidoglycan via the wzy pathway 6 . The ovoid shape of pneumococci results from a combination of lateral and septal peptidoglycan synthesis. Pneumococcal growth occurs by formation of the lateral wall via a complex protein machinery referred to as the elongasome, while the septal wall is formed by a second machinery, which is assembled at the position for the FtsZ-ring 8 , the divisome 9 . The divisome drives membrane invagination and septal wall formation. To generate a new bacterial pole the septal wall needs to be split, requiring cell wall hydrolytic enzymes 10 , resulting in the formation of two new poles 11 . This process is highly variable leading to pneumococcal populations consisting of single cocci, diplococci and chains of different lengths 12 . The pneumococcal peptidoglycan not only contains covalently anchored capsular polysaccharide, but also a set of surface proteins carrying a LPxTG motif allowing sortase-mediated covalent linkage to lysine residues on the peptidoglycan stem peptides 13 . Another set of pneumococcal surface proteins, the choline-binding proteins, contain choline-binding motifs recognizing choline residues on teichoic acids of which wall teichoic acids (WTA) are covalently anchored to the peptidoglycan, while lipoteichoic acids (LTA) are anchored in the cytoplasmic membrane 14 . It is not known if there are differences in level and composition of cell wall associated macromolecules between the lateral and septal wall in the pneumococcus. The pneumococcal choline-binding protein PspC (CbpA) recruits FH from human serum that selectively inhibits amplification of deposited C3b, and accelerates the decay of the alternative pathway C3 convertase 15 , 16 , 17 . Apart from FH recruitment, different allelic forms of PspC have also been reported to interact with host factors like pIgR, vitronectin and SIgA 18 , 19 , 20 . While most pneumococcal strains carry one gene of pspC , the pneumococcal lineage CC138, successful in causing colonization and invasive disease, contains two closely linked pspC genes, pspC1 encodes a conventional choline-binding PspC (denoted PspC1 in CC138), and pspC2 a cell wall anchored LPxTG version of PspC (denoted PspC2), both able to bind human FH 21 , 22 , 23 . PspC2 lacks the motif responsible for pIgR interaction 24 . In the present study, we combine super-resolution imaging techniques, mutants affecting protein localization, and functional analyses to show that the division septum represents the pneumococcal Achilles heel in its capsular barrier defense against complement C3b deposition. To cope with the low content of capsular polysaccharide at division septa, pneumococci have evolved FH binding proteins localized at division sites, and allow complement entry while division septa are formed at these sites. We show that the spatial positioning of virulence-associated cell wall proteins such as PspC, relative to the division septum and the capsular layer, have profound implications for defence against complement-mediated opsonophagocytosis, and formation of membrane attack complexes (MACs), needed for bacteria in an inflamed environment. Our data also demonstrate that a complement evasive protein, depending on accessibility outside the capsular layer, may mediate bacterial attachment to epithelial cells, potentially favouring healthy colonization. Results C3b deposition occurs at or close to division septa Encapsulated pneumococcal strains of serotypes 4 (TIGR4), 2 (D39), and 6B (BHN418) were incubated with human serum, and deposited complement C3b was monitored by anti-C3b staining (Supplementary Table 1 , Fig. 1a ). Using confocal microscopy, C3b antibodies were in each of the three strains shown to recognize deposited C3b as discrete bands on the cells (Fig. 1a ). TEM images performed on the serotype 6B strain BHN418 revealed bulky complement deposits precisely localized at some but not all division septa (18 out of 80 visible septa), the latter seen as thin electron-dense bands (Fig. 1b ). Deposition of C3b was also confirmed by immunogold staining and TEM (Supplementary Fig 1 ). When the isogenic non-encapsulated mutant BHN418 Δcapsule was examined by TEM, C3b was found to be deposited all around the cells, and immunostaining with C3b antibodies revealed the same uniform staining pattern (Fig. 1c, d ). SEM images of encapsulated BHN418 showed regularly spaced elevations on the bacteria that were absent at some division septa (Fig. 1e , arrows). As these elevations were completely absent in the capsular mutant BHN418 Δcapsule (Fig. 1f ) we suggest that they represent the cell wall", "role": "user" }, { "content": "Successful pathogenic strains of pneumococci have two proteins that, owing to their location on the surface of the bacteria, enhance their survival and ability to cause disease, according to a study from Karolinska Institutet in Sweden published in Nature Communications . Pneumococcal infections are one of the most common causes of disease and death in the world. One reason for the pathogenic potential of these bacteria is that they produce a sugar casing. This capsule prevents the important immune component C3b from attaching to and attacking the bacteria. Researchers at Karolinska Institutet and the Royal Institute of Technology in Sweden have now studied in detail how pneumococci interact with the part of the immune system called the complement system, which includes C3b. The complement system often works as the first line of defence against foreign substances and cells, triggering a number of immune reactions in the body. The researchers show that the capsule is weak at the bacteria's point of division, which therefore presents an opening for C3b. By using super-resolution microscopy (STED) they found that C3b accumulates under the capsule primarily at the division sites. This accumulation can continue and cover the entire bacteria unless the pneumococcus can find a strategy to prevent it happening. The study also shows that a common surface protein on pneumococci called PspC1 is located right at the division site, where it recruits another protein called Factor H, which negatively regulates the complement system by, amongst other mechanisms, inactivating C3b. Some especially successful and pathogenic pneumococcal strains also express a closely related protein, PspC2, which is mainly localised at the bacterial poles. This separate location on the surface of the bacteria affects the two surface proteins' functions. Unlike PspC1, which binds Factor H, PspC2 affects the bacteria's ability to adhere to epithelial cells, which can be found in the respiratory tract, in mucus membranes and elsewhere. \"Our study shows that the precise localisation of bacterial surface proteins in relation to the capsule layer affects the role they will have in the disease development,\" says Birgitta Henriques-Normark, professor at the Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet. \"This is an important piece of the puzzle to understand how pneumococci avoid the immune system and cause everything from otitis and sinusitis to severe pneumonia and septicaemia.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Streptococcus pneumoniae evades C3-mediated opsonization and effector functions by expressing an immuno-protective polysaccharide capsule and Factor H (FH)-binding proteins. Here we use super-resolution microscopy, mutants and functional analysis to show how these two defense mechanisms are functionally and spatially coordinated on the bacterial cell surface. We show that the pneumococcal capsule is less abundant at the cell wall septum, providing C3/C3b entry to underlying nucleophilic targets. Evasion of C3b deposition at division septa and lateral amplification underneath the capsule requires localization of the FH-binding protein PspC at division sites. Most pneumococcal strains have one PspC protein, but successful lineages in colonization and disease may have two, PspC1 and PspC2, that we show affect virulence differently. We find that spatial localization of these FH-recruiting proteins relative to division septa and capsular layer is instrumental for pneumococci to resist complement-mediated opsonophagocytosis, formation of membrane-attack complexes, and for the function as adhesins. Introduction The invasive respiratory pathogens, Haemophilus influenzae, Neisseria meningitidis , and S treptococcus pneumoniae , have evolved similar strategies, such as the expression of polysaccharide capsules and complement Factor H (FH) recruiting surface proteins, to evade deposition of C3b and activation of the alternative pathway of the complement system 1 , 2 , 3 . The pneumococcal polysaccharide capsule is critical for virulence and is known to inhibit complement activity 4 . Localization sites of deposited complement on the bacteria in relation to the capsule are not known. The capsule is believed to form an external shield for C3 entry and for the covalent binding of C3b to underlying nucleophilic targets 5 , 6 , 7 . So far more than 97 capsular polysaccharides have been described, and all except for serotypes 3 and 37, are covalently anchored to the bacterial peptidoglycan via the wzy pathway 6 . The ovoid shape of pneumococci results from a combination of lateral and septal peptidoglycan synthesis. Pneumococcal growth occurs by formation of the lateral wall via a complex protein machinery referred to as the elongasome, while the septal wall is formed by a second machinery, which is assembled at the position for the FtsZ-ring 8 , the divisome 9 . The divisome drives membrane invagination and septal wall formation. To generate a new bacterial pole the septal wall needs to be split, requiring cell wall hydrolytic enzymes 10 , resulting in the formation of two new poles 11 . This process is highly variable leading to pneumococcal populations consisting of single cocci, diplococci and chains of different lengths 12 . The pneumococcal peptidoglycan not only contains covalently anchored capsular polysaccharide, but also a set of surface proteins carrying a LPxTG motif allowing sortase-mediated covalent linkage to lysine residues on the peptidoglycan stem peptides 13 . Another set of pneumococcal surface proteins, the choline-binding proteins, contain choline-binding motifs recognizing choline residues on teichoic acids of which wall teichoic acids (WTA) are covalently anchored to the peptidoglycan, while lipoteichoic acids (LTA) are anchored in the cytoplasmic membrane 14 . It is not known if there are differences in level and composition of cell wall associated macromolecules between the lateral and septal wall in the pneumococcus. The pneumococcal choline-binding protein PspC (CbpA) recruits FH from human serum that selectively inhibits amplification of deposited C3b, and accelerates the decay of the alternative pathway C3 convertase 15 , 16 , 17 . Apart from FH recruitment, different allelic forms of PspC have also been reported to interact with host factors like pIgR, vitronectin and SIgA 18 , 19 , 20 . While most pneumococcal strains carry one gene of pspC , the pneumococcal lineage CC138, successful in causing colonization and invasive disease, contains two closely linked pspC genes, pspC1 encodes a conventional choline-binding PspC (denoted PspC1 in CC138), and pspC2 a cell wall anchored LPxTG version of PspC (denoted PspC2), both able to bind human FH 21 , 22 , 23 . PspC2 lacks the motif responsible for pIgR interaction 24 . In the present study, we combine super-resolution imaging techniques, mutants affecting protein localization, and functional analyses to show that the division septum represents the pneumococcal Achilles heel in its capsular barrier defense against complement C3b deposition. To cope with the low content of capsular polysaccharide at division septa, pneumococci have evolved FH binding proteins localized at division sites, and allow complement entry while division septa are formed at these sites. We show that the spatial positioning of virulence-associated cell wall proteins such as PspC, relative to the division septum and the capsular layer, have profound implications for defence against complement-mediated opsonophagocytosis, and formation of membrane attack complexes (MACs), needed for bacteria in an inflamed environment. Our data also demonstrate that a complement evasive protein, depending on accessibility outside the capsular layer, may mediate bacterial attachment to epithelial cells, potentially favouring healthy colonization. Results C3b deposition occurs at or close to division septa Encapsulated pneumococcal strains of serotypes 4 (TIGR4), 2 (D39), and 6B (BHN418) were incubated with human serum, and deposited complement C3b was monitored by anti-C3b staining (Supplementary Table 1 , Fig. 1a ). Using confocal microscopy, C3b antibodies were in each of the three strains shown to recognize deposited C3b as discrete bands on the cells (Fig. 1a ). TEM images performed on the serotype 6B strain BHN418 revealed bulky complement deposits precisely localized at some but not all division septa (18 out of 80 visible septa), the latter seen as thin electron-dense bands (Fig. 1b ). Deposition of C3b was also confirmed by immunogold staining and TEM (Supplementary Fig 1 ). When the isogenic non-encapsulated mutant BHN418 Δcapsule was examined by TEM, C3b was found to be deposited all around the cells, and immunostaining with C3b antibodies revealed the same uniform staining pattern (Fig. 1c, d ). SEM images of encapsulated BHN418 showed regularly spaced elevations on the bacteria that were absent at some division septa (Fig. 1e , arrows). As these elevations were completely absent in the capsular mutant BHN418 Δcapsule (Fig. 1f ) we suggest that they represent the cell wall<|im_end|> <|im_start|>assistant Successful pathogenic strains of pneumococci have two proteins that, owing to their location on the surface of the bacteria, enhance their survival and ability to cause disease, according to a study from Karolinska Institutet in Sweden published in Nature Communications . Pneumococcal infections are one of the most common causes of disease and death in the world. One reason for the pathogenic potential of these bacteria is that they produce a sugar casing. This capsule prevents the important immune component C3b from attaching to and attacking the bacteria. Researchers at Karolinska Institutet and the Royal Institute of Technology in Sweden have now studied in detail how pneumococci interact with the part of the immune system called the complement system, which includes C3b. The complement system often works as the first line of defence against foreign substances and cells, triggering a number of immune reactions in the body. The researchers show that the capsule is weak at the bacteria's point of division, which therefore presents an opening for C3b. By using super-resolution microscopy (STED) they found that C3b accumulates under the capsule primarily at the division sites. This accumulation can continue and cover the entire bacteria unless the pneumococcus can find a strategy to prevent it happening. The study also shows that a common surface protein on pneumococci called PspC1 is located right at the division site, where it recruits another protein called Factor H, which negatively regulates the complement system by, amongst other mechanisms, inactivating C3b. Some especially successful and pathogenic pneumococcal strains also express a closely related protein, PspC2, which is mainly localised at the bacterial poles. This separate location on the surface of the bacteria affects the two surface proteins' functions. Unlike PspC1, which binds Factor H, PspC2 affects the bacteria's ability to adhere to epithelial cells, which can be found in the respiratory tract, in mucus membranes and elsewhere. "Our study shows that the precise localisation of bacterial surface proteins in relation to the capsule layer affects the role they will have in the disease development," says Birgitta Henriques-Normark, professor at the Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet. "This is an important piece of the puzzle to understand how pneumococci avoid the immune system and cause everything from otitis and sinusitis to severe pneumonia and septicaemia." <|im_end|>

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2,065

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Carbon dioxide is Mars’ primary atmospheric constituent and is an active driver of Martian surface evolution. CO 2 ice sublimation mechanisms have been proposed for a host of features that form in the contemporary Martian climate. However, there has been very little experimental work or quantitative modelling to test the validity of these hypotheses. Here we present the results of the first laboratory experiments undertaken to investigate if the interaction between sublimating CO 2 ice blocks and a warm, porous, mobile regolith can generate features similar in morphology to those forming on Martian dunes today. We find that CO 2 sublimation can mobilise grains to form (i) pits and (ii) furrows. We have documented new detached pits at the termini of linear gullies on Martian dunes. Based on their geomorphic similarity to the features observed in our laboratory experiments, and on scaling arguments, we propose a new hypothesis that detached pits are formed by the impact of granular jets generated by sublimating CO 2 . We also study the erosion patterns formed underneath a sublimating block of CO 2 ice and demonstrate that these resemble furrow patterns on Mars, suggesting similar formation mechanisms. Introduction The Martian atmosphere, which is comprised of over 95% CO 2 1 , interacts seasonally with the planetary surface. As temperatures fall between late autumn and early winter, a CO 2 deposit covers the surface 2 in thicknesses ranging from around a metre in the polar regions 1 , 3 to a few millimetres towards the equator 4 . The distribution of this dry ice is governed primarily by solar insolation 5 . In the early spring, as insolation increases, the dry ice begins to sublimate. This process is now recognised as an important agent in the formation of contemporary surface features on Mars. These features include the dendritic araneiform terrain of the south polar cryptic region 6 , 7 , 8 , linear gullies, their associated pits 9 , 10 , and sand furrows 11 . In this study we focus on linear gully pits and sand furrows; both active features which are observed to form and evolve on dunes under the current Martian climate. These features have no Earth analogues and the specific mechanisms responsible for their formation have yet to be fully understood and quantified. Furrows Furrows are shallow (~0.25 m) and narrow (~1.5 m) negative relief 11 , 12 , features which are observed on over 95% of the northern polar dunes 11 and are also found between 40°S and 72°S 13 . Their network patterns range from rectilinear, to dendritic and radial, tributary and distributary and their planforms can be linear or sinuous 12 (Fig. 1 ), though it is unclear what factors control this variety of patterns. Appearing to “defy gravity”, furrows extend upslope and transect existing aeolian ripples, and so while their patterns may resemble those eroded by fluvial activity on Earth, gravity-driven processes are unlikely to form them 12 . Figure 1 Examples of sand furrows on Martian Dunes. ( a ) Linear furrow (blue arrow) on sand dune in Chasma Boreale (all Chasma Boreale furrows are taken from HiRISE image ESP_026851_2590, latitude 78.65°, longitude 308.494°, solar incidence angle 56° with the Sun ~34° above the horizon). ( b ) sinuous (black arrow) furrow on sand dune in Chasma Boreale, ( c ) dendritic furrows (white arrows) on sand dunes at latitude −67.607°, 185.343° in the southern hemisphere (HiRISE image ESP_023270_1120. Solar incidence angle is 60° with the sun ~30° above the horizon). Yellow arrows point to boulders, red arrows point to dark fans and highlight their proximity to the furrows. ( d ) radial (green arrow) furrow on sand dune in Chasma Boreale. ( e ) rectilinear (purple arrow) and radial (green arrow) furrows on sand dune in Chasma Boreale. Images have been stretched to improve contrast as furrows are narrow, shallow and thus subtle features. HiRISE image credit: NASA/JPL/University of Arizona. Full size image Furrow Formation Hypotheses Furrows frequently form after the appearance of polygonal cracks in CO 2 ice. This led Bourke 12 to hypothesise that they were caused by cryoventing; that is, basal sublimation of CO 2 and consequent erosion. This is similar to Kieffer’s model for the dark spots and fans in the southern hemisphere 14 , but applied in the context of dunes. The cryoventing model proposes that in the spring, gas pressures increase at the ice-substrate interface until the overlying ice cracks. Gas rapidly exits, eroding material below the ice sheet to form furrows. A plume then deposits the sediment to form fans on the surface of the seasonal ice. The thickness of the overlying ice and dune topography are thought to have a strong influence on this process 15 . Close spacing of vents has also been noted to reduce cryoventing efficacy, with fewer furrows forming in locations where ice cracks are closer together 12 . Recent work has drawn a distinction between furrows in the northern hemisphere and “dendritic troughs” in the southern hemisphere 16 . While both show similar morphologies, furrows in the northern hemisphere are ephemeral features which disappear every year 17 . The dendritic troughs on south polar dunes endure, with new tributaries adding to the networks annually 16 . This study 16 has drawn a potential link in formation process between the highly dendritic araneiform terrain of the south polar cryptic region and furrows/dendritic troughs. It has been suggested that araneiform terrain (dubbed “spiders” in the literature) may develop over many years by a gradual connection of dendritic networks into a radial network, rather than forming in one event 16 . Noting the difference in environmental conditions between the hemispheres, it has been argued that furrows in the northern hemisphere do not develop into dendrites because of the high mobility of the material into which they are eroded 16 . However, the size distribution of the granular substrate in both hemispheres is poorly constrained. For the purpose of our purely morphological laboratory study we", "role": "user" }, { "content": "Researchers based millions of kilometres from Mars have unveiled new evidence for how contemporary features are formed on the Red Planet. Their innovative lab-based experiments on carbon dioxide (CO2) sublimation - the process by which a substance changes from a solid to a gas without an intermediate liquid phase - suggest the same process is responsible for altering the appearance of sand dunes on Mars. The research was led by a Trinity College Dublin team comprising PhD candidate in the School of Natural Sciences, Lauren Mc Keown, and Dr Mary Bourke, along with Professor Jim McElwaine of Durham University. Their work, which describes phenomena unlike anything seen on Earth, has just been published in the Scientific Reports. Lauren Mc Keown said: \"We've all heard the exciting news snippets about the evidence for water on Mars. However, the current Martian climate does not frequently support water in its liquid state—so it is important that we understand the role of other volatiles that are likely modifying Mars today.\" \"Mars' atmosphere is composed of over 95% CO2, yet we know little about how it interacts with the surface of the planet. Mars has seasons, just like Earth, which means that in winter, a lot of the CO2 in the atmosphere changes state from a gas to a solid and is deposited onto the surface in that form. The process is then reversed in the spring, as the ice sublimates, and this seasonal interplay may be a really important geomorphic process.\" Dr Bourke added: \"Several years ago I discovered unique markings on the surface of Martian sand dunes. I called them Sand Furrows as they were elongated shallow, networked features that formed and disappeared seasonally on Martian dunes. What was unusual about them was that they appeared to trend both up and down the dune slopes, which ruled out liquid water as the cause.\" Linear gullies on a dune in Matara Crater, Mars, Red and white arrows point to pits. Credit: NASA/JPL/University of Arizona \"At that time I proposed that they had been formed by cryo-venting—a process whereby pressurised CO2 gas beneath the seasonal ice deposit erodes complex patterns on the dune surface when the ice fractures and releases the gas in towering dust and gas geysers. I was delighted when Lauren joined the Earth and Planetary Surface Process Group in the Department of Geography to work on this phenomenon with Jim and myself. What was required was a demonstration of how sand would respond to sublimation of CO2 ice, and this published work is an important step in providing that required proof.\" The researchers designed and built a low humidity chamber and placed CO2 blocks on the granular surface. The experiments revealed that sublimating CO2 can form a range of furrow morphologies that are similar to those observed on Mars. Linear gullies are another example of active Martian features not found on Earth. They are long, sometimes sinuous, narrow carvings thought to form by CO2 ice blocks which fall from dune brinks and 'glide' downslope. Lauren Mc Keown said: \"The difference in temperature between the sandy surface and the CO2 block will generate a vapor layer beneath the block, allowing it to levitate and maneuver downslope, in a similar manner to how pucks glide on an ice-hockey table, carving a channel in its wake. At the terminus, the block will sublimate and erode a pit. It will then disappear without a trace other than the roughly circular depression beneath it.\" \"While gullies on Earth are commonly formed by liquid water, they almost always terminate in debris aprons and not pits. The presence of pits therefore provides more support for a hypothesis whereby CO2 blocks are responsible for linear gullies.\" Dendritic furrows formed by basal sublimation of a CO2 ice block in contact with a granular surface. Credit: Lauren Mc Keown and Dr Mary Bourke, Trinity College Dublin By sliding dry ice blocks onto the sand bed in the low humidity chamber, the group showed that stationary blocks could erode negative topography in the form of pits and deposit lateral levees. In some cases, blocks sublimated so rapidly that they burrowed beneath the subsurface and were swallowed up by the sand in under 60 seconds. Professor McElwaine said: \"This process is really unlike anything seen to occur naturally on Earth - the bed appears fluidised and sand is kicked up in every direction. When we first observed this particular effect, it was a really exciting moment.\" By generating 3-D models of the modified bed in each case, pit dimensions could be used to predict the range of block sizes that would erode the pits seen on Mars, which vary in diameter from 1 m to up to 19 m. A pit on Russell Crater megadune on Mars was observed to grow within one Mars Year to an extent predicted by these calculations, following the observation of a block within it the previous year. The next phase of work, supported by Europlanet Horizon 2020 funding, will see the team head to the Open University Mars Chamber to assess the influence of Martian atmospheric conditions on these new geomorphic processes and test a numerical model developed by Professor McElwaine. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Carbon dioxide is Mars’ primary atmospheric constituent and is an active driver of Martian surface evolution. CO 2 ice sublimation mechanisms have been proposed for a host of features that form in the contemporary Martian climate. However, there has been very little experimental work or quantitative modelling to test the validity of these hypotheses. Here we present the results of the first laboratory experiments undertaken to investigate if the interaction between sublimating CO 2 ice blocks and a warm, porous, mobile regolith can generate features similar in morphology to those forming on Martian dunes today. We find that CO 2 sublimation can mobilise grains to form (i) pits and (ii) furrows. We have documented new detached pits at the termini of linear gullies on Martian dunes. Based on their geomorphic similarity to the features observed in our laboratory experiments, and on scaling arguments, we propose a new hypothesis that detached pits are formed by the impact of granular jets generated by sublimating CO 2 . We also study the erosion patterns formed underneath a sublimating block of CO 2 ice and demonstrate that these resemble furrow patterns on Mars, suggesting similar formation mechanisms. Introduction The Martian atmosphere, which is comprised of over 95% CO 2 1 , interacts seasonally with the planetary surface. As temperatures fall between late autumn and early winter, a CO 2 deposit covers the surface 2 in thicknesses ranging from around a metre in the polar regions 1 , 3 to a few millimetres towards the equator 4 . The distribution of this dry ice is governed primarily by solar insolation 5 . In the early spring, as insolation increases, the dry ice begins to sublimate. This process is now recognised as an important agent in the formation of contemporary surface features on Mars. These features include the dendritic araneiform terrain of the south polar cryptic region 6 , 7 , 8 , linear gullies, their associated pits 9 , 10 , and sand furrows 11 . In this study we focus on linear gully pits and sand furrows; both active features which are observed to form and evolve on dunes under the current Martian climate. These features have no Earth analogues and the specific mechanisms responsible for their formation have yet to be fully understood and quantified. Furrows Furrows are shallow (~0.25 m) and narrow (~1.5 m) negative relief 11 , 12 , features which are observed on over 95% of the northern polar dunes 11 and are also found between 40°S and 72°S 13 . Their network patterns range from rectilinear, to dendritic and radial, tributary and distributary and their planforms can be linear or sinuous 12 (Fig. 1 ), though it is unclear what factors control this variety of patterns. Appearing to “defy gravity”, furrows extend upslope and transect existing aeolian ripples, and so while their patterns may resemble those eroded by fluvial activity on Earth, gravity-driven processes are unlikely to form them 12 . Figure 1 Examples of sand furrows on Martian Dunes. ( a ) Linear furrow (blue arrow) on sand dune in Chasma Boreale (all Chasma Boreale furrows are taken from HiRISE image ESP_026851_2590, latitude 78.65°, longitude 308.494°, solar incidence angle 56° with the Sun ~34° above the horizon). ( b ) sinuous (black arrow) furrow on sand dune in Chasma Boreale, ( c ) dendritic furrows (white arrows) on sand dunes at latitude −67.607°, 185.343° in the southern hemisphere (HiRISE image ESP_023270_1120. Solar incidence angle is 60° with the sun ~30° above the horizon). Yellow arrows point to boulders, red arrows point to dark fans and highlight their proximity to the furrows. ( d ) radial (green arrow) furrow on sand dune in Chasma Boreale. ( e ) rectilinear (purple arrow) and radial (green arrow) furrows on sand dune in Chasma Boreale. Images have been stretched to improve contrast as furrows are narrow, shallow and thus subtle features. HiRISE image credit: NASA/JPL/University of Arizona. Full size image Furrow Formation Hypotheses Furrows frequently form after the appearance of polygonal cracks in CO 2 ice. This led Bourke 12 to hypothesise that they were caused by cryoventing; that is, basal sublimation of CO 2 and consequent erosion. This is similar to Kieffer’s model for the dark spots and fans in the southern hemisphere 14 , but applied in the context of dunes. The cryoventing model proposes that in the spring, gas pressures increase at the ice-substrate interface until the overlying ice cracks. Gas rapidly exits, eroding material below the ice sheet to form furrows. A plume then deposits the sediment to form fans on the surface of the seasonal ice. The thickness of the overlying ice and dune topography are thought to have a strong influence on this process 15 . Close spacing of vents has also been noted to reduce cryoventing efficacy, with fewer furrows forming in locations where ice cracks are closer together 12 . Recent work has drawn a distinction between furrows in the northern hemisphere and “dendritic troughs” in the southern hemisphere 16 . While both show similar morphologies, furrows in the northern hemisphere are ephemeral features which disappear every year 17 . The dendritic troughs on south polar dunes endure, with new tributaries adding to the networks annually 16 . This study 16 has drawn a potential link in formation process between the highly dendritic araneiform terrain of the south polar cryptic region and furrows/dendritic troughs. It has been suggested that araneiform terrain (dubbed “spiders” in the literature) may develop over many years by a gradual connection of dendritic networks into a radial network, rather than forming in one event 16 . Noting the difference in environmental conditions between the hemispheres, it has been argued that furrows in the northern hemisphere do not develop into dendrites because of the high mobility of the material into which they are eroded 16 . However, the size distribution of the granular substrate in both hemispheres is poorly constrained. For the purpose of our purely morphological laboratory study we<|im_end|> <|im_start|>assistant Researchers based millions of kilometres from Mars have unveiled new evidence for how contemporary features are formed on the Red Planet. Their innovative lab-based experiments on carbon dioxide (CO2) sublimation - the process by which a substance changes from a solid to a gas without an intermediate liquid phase - suggest the same process is responsible for altering the appearance of sand dunes on Mars. The research was led by a Trinity College Dublin team comprising PhD candidate in the School of Natural Sciences, Lauren Mc Keown, and Dr Mary Bourke, along with Professor Jim McElwaine of Durham University. Their work, which describes phenomena unlike anything seen on Earth, has just been published in the Scientific Reports. Lauren Mc Keown said: "We've all heard the exciting news snippets about the evidence for water on Mars. However, the current Martian climate does not frequently support water in its liquid state—so it is important that we understand the role of other volatiles that are likely modifying Mars today." "Mars' atmosphere is composed of over 95% CO2, yet we know little about how it interacts with the surface of the planet. Mars has seasons, just like Earth, which means that in winter, a lot of the CO2 in the atmosphere changes state from a gas to a solid and is deposited onto the surface in that form. The process is then reversed in the spring, as the ice sublimates, and this seasonal interplay may be a really important geomorphic process." Dr Bourke added: "Several years ago I discovered unique markings on the surface of Martian sand dunes. I called them Sand Furrows as they were elongated shallow, networked features that formed and disappeared seasonally on Martian dunes. What was unusual about them was that they appeared to trend both up and down the dune slopes, which ruled out liquid water as the cause." Linear gullies on a dune in Matara Crater, Mars, Red and white arrows point to pits. Credit: NASA/JPL/University of Arizona "At that time I proposed that they had been formed by cryo-venting—a process whereby pressurised CO2 gas beneath the seasonal ice deposit erodes complex patterns on the dune surface when the ice fractures and releases the gas in towering dust and gas geysers. I was delighted when Lauren joined the Earth and Planetary Surface Process Group in the Department of Geography to work on this phenomenon with Jim and myself. What was required was a demonstration of how sand would respond to sublimation of CO2 ice, and this published work is an important step in providing that required proof." The researchers designed and built a low humidity chamber and placed CO2 blocks on the granular surface. The experiments revealed that sublimating CO2 can form a range of furrow morphologies that are similar to those observed on Mars. Linear gullies are another example of active Martian features not found on Earth. They are long, sometimes sinuous, narrow carvings thought to form by CO2 ice blocks which fall from dune brinks and 'glide' downslope. Lauren Mc Keown said: "The difference in temperature between the sandy surface and the CO2 block will generate a vapor layer beneath the block, allowing it to levitate and maneuver downslope, in a similar manner to how pucks glide on an ice-hockey table, carving a channel in its wake. At the terminus, the block will sublimate and erode a pit. It will then disappear without a trace other than the roughly circular depression beneath it." "While gullies on Earth are commonly formed by liquid water, they almost always terminate in debris aprons and not pits. The presence of pits therefore provides more support for a hypothesis whereby CO2 blocks are responsible for linear gullies." Dendritic furrows formed by basal sublimation of a CO2 ice block in contact with a granular surface. Credit: Lauren Mc Keown and Dr Mary Bourke, Trinity College Dublin By sliding dry ice blocks onto the sand bed in the low humidity chamber, the group showed that stationary blocks could erode negative topography in the form of pits and deposit lateral levees. In some cases, blocks sublimated so rapidly that they burrowed beneath the subsurface and were swallowed up by the sand in under 60 seconds. Professor McElwaine said: "This process is really unlike anything seen to occur naturally on Earth - the bed appears fluidised and sand is kicked up in every direction. When we first observed this particular effect, it was a really exciting moment." By generating 3-D models of the modified bed in each case, pit dimensions could be used to predict the range of block sizes that would erode the pits seen on Mars, which vary in diameter from 1 m to up to 19 m. A pit on Russell Crater megadune on Mars was observed to grow within one Mars Year to an extent predicted by these calculations, following the observation of a block within it the previous year. The next phase of work, supported by Europlanet Horizon 2020 funding, will see the team head to the Open University Mars Chamber to assess the influence of Martian atmospheric conditions on these new geomorphic processes and test a numerical model developed by Professor McElwaine. <|im_end|>

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2,478

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Slow-moving landslides, often with nearly imperceptible creeping motion, are an important landscape shaper and a dangerous natural hazard across the globe, yet their spatial distribution and geologic controls are still poorly known owing to a paucity of detailed, large-area observations. Here, we use interferometry of L-band satellite radar images to reveal 617 spatially large (4 \$\\times\$ 10 4 – 13 \$\\times\$ 10 6 m 2 ) and presently active (2007 – 2019) slow-moving landslides near the populous US West Coast (only 4.6% of these slides were previously known) and provide evidence for their fundamental controls by bedrock lithology and vertical land motion. We found that slow-moving landslides are generally larger and more spatially frequent in homogeneous bedrock with low rock strength, and they are preferentially located on hillslopes with geologically recent uplift. Notably, landslide size and spatial density in the relatively weak metamorphic rocks and mélange (due to pervasive tectonically sheared discontinuities, foliation, and abundant clay minerals) were two times larger than those in sedimentary and igneous rocks, and the hillslopes with landslides were found to be uplifting approximately three times faster than the average for the whole region. These results suggest that slow-moving landslides can be effectively uncovered by satellite radar imagery and their occurrence and character may be anticipated from vertical land uplift and bedrock lithology. Hence, our study provides understanding critical for reducing landslide hazards and quantifying landslide impacts on landscape change. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction Landslides are a geologic process crucial for landscape evolution (Burbank et al. 1996 ; Kelsey and Bockheim 1994 ; Roering et al. 2009 ; Simoni et al. 2013 ), and as a natural hazard, landslides annually cause 3.5 billion dollars of property loss and 25–50 casualties in the USA alone (Spiker and Gori 2003 ). Locating presently active landslides is a critical step towards preventing their future hazards and forecasting their impact on the landscape. However, conventional landslide-identifying approaches that rely on geologic maps and citizen-reported events (Guzzetti et al. 2012 ; Highland and Bobrowsky 2008 ; Jones et al. 2019 ) could easily miss numerous active yet slowly moving slides that lack readily identifiable features (e.g., fresh headscarps) or occur in rarely accessed lands. Slow-moving landslides persistently damage infrastructure and imply a force imbalance of the hillslope (Highland and Bobrowsky 2008 ). Additional forces such as earthquake shaking, coastal and stream erosion, intense rainfall, and other natural or anthropogenic disturbance could shift their present creeping behavior into rapid movement and cause catastrophic damages (e.g., Intrieri et al. 2018 ; Kilburn and Petley 2003 ; Schulz and Wang 2014 ; Xu et al. 2020b ). Discovering presently slow-moving landslides for future hazard prevention particularly requires approaches with high measurement accuracy and wide spatial coverage. However, few tools were available until the InSAR (Interferometric Synthetic Aperture Radar) method evolved into an effective means in the last two decades (Handwerger et al. 2019 ; Intrieri et al. 2018 ; Squarzoni et al. 2003 ; Xu et al. 2019 , 2020b ; Ye et al. 2004 ). InSAR utilizes interferometry of satellite-captured radar images (frequent repeated acquisitions since 1992) to achieve maximal millimeter-level measurements of ground displacement along the radar line-of-sight (LOS) direction (Ferretti et al. 2007 ; Nishiguchi et al. 2017 ). Multiple studies have focused on the precipitation-driven short-timescale dynamics of presently active, slow-moving landslides (e.g., Bennett et al. 2016b ; Handwerger et al. 2019 ; Kang et al. 2021 ; Mackey et al. 2009 ; Squarzoni et al. 2003 ; Xu et al. 2020b ; Ye et al. 2004 ); however, knowledge of their geologic controls is still poorly known owing to a lack of detailed, large-scale evidence, but such knowledge is essential for deciphering their characteristics and for preventing future hazards. Spatially large, slow-moving landslides are generally deep-seated (meters to hundreds of meters) (Bonzanigo et al. 2007 ; Highland and Bobrowsky 2008 ; Larsen et al. 2010 ) and may have been active for hundreds to thousands of years (Bonzanigo et al. 2007 ; Bovis and Jones 1992 ; Kelsey and Bockheim 1994 ; Mackey et al. 2009 ; Varnes and Savage 1996 ). Hence, their occurrence could be controlled by the lithology and structure of the underlying bedrock and by geologic processes (Clarke and Burbank 2010 ; Cruden and Varnes 1996 ; Lambe and Whitman 1969 ; Roering et al. 2005 ). In addition, vertical uplift (i.e., any upward movement of the land surface) in a geologic timescale (10 3 –10 5 years) could deliberately alter the force balance of hillslopes and regulate the denudation process (Burbank et al. 1996 ; Bennett et al. 2016a ; Larsen and Montgomery 2012 ; Roering et al. 2015 ), thereby potentially modulating occurrence and kinematics of long-term creeping landslides. Here, we apply the high-accuracy InSAR method over the entire US West Coast states (~ 8.6 × 10 5 km 2 ) to discover large, presently active landslides in both the high mountains and coastal neighborhoods inhabited by 47.8 million people (2019 census; USCB 2019 ). Based on the large-scale observations, we tested our hypotheses that the spatial density and size of slow-moving landslides are significantly controlled by bedrock type and that their occurrence and persistent motion reflect long-term land uplift. Materials and methods SAR interferogram generation and unwrapping We used radar interferometry of both the ALOS PALSAR (Advanced Land Observing Satellite–Phased Array type L-band Synthetic Aperture Radar) images from 2007 to 2011 and ALOS-2 PALSAR-2 images from 2015 to 2019 for identifying landslides near the US West Coast. The L-band SAR images were primarily utilized over the relatively densely vegetated US West Coast because of L-band sensor’s capability in vegetation penetration. SAR interferograms were generated by differencing the phase measurements of two SAR images. For each SAR interferogram, the interferometric phase of a SAR resolution element, \$\\phi\$ , is composed of multiple independent components: $$\\phi =W\\left\\{{\\phi }_{\\mathrm{def}}+{\\phi }_{\\mathrm{dem}}+{\\phi }_{\\mathrm{orb}}+{\\phi }_{\\mathrm{atm}}+{\\phi }_{\\mathrm{n}}\\right\\}$$ (1) where \${\\phi }_{\\mathrm{def}}\$", "role": "user" }, { "content": "SMU geophysicists have used satellite imagery to identify more than 600 slow-moving landslides occurring near the U.S. West Coast Fewer than 5% of these landslides in California, Oregon and Washington state had been previously identified. Geophysics professor Zhong Lu and his team at SMU (Southern Methodist University) were awarded nearly $1 million over the past 4 years from the NASA Interdisciplinary Research in Earth Science Program and the NASA Earth Surface and Interior Focus Area to study landslides on the West Coast. Most of the large landslides they found were in the mountain ranges of western Washington, southwestern Oregon and northwestern California. In some cases, the identified landslides were within 0.5 to 5 kilometers of multiple towns and roads. \"These landslides are currently moving slowly. But they're already in a state of force imbalance. So some other external forces, like earthquakes or rainfall, could shift them into a disaster,\" said Yuankun Xu, a postdoctoral researcher who works in Lu's SMU Radar Laboratory and lead author of a study published in the journal Landslides. Co-author Lu, Shuler-Foscue Chair at SMU's Roy M. Huffington Department of Earth Sciences, said, \"We don't want to give the impression that these landslides are in trouble tomorrow. No, these landslides have a life expectancy ranging from years to a thousand years.\" Still, the researchers urged policymakers in these western states to monitor the movement of the now-identified landslides so they can prevent a catastrophe from happening. \"I would be very concerned if living, working or commuting upon or near any of the landslides,\" said study co-author William H. Schulz, a research geologist in the USGS' Landslide Hazards Program. \"However, humans can and have successfully dealt with individual landslides and potentially unstable slopes in the past. Detailed studies performed by professionals involving engineering geologic characterization and modeling are needed for any landslide to accurately estimate and mitigate potential future hazards.\" Other scientists who helped with this study were Jinwoo Kim, SAR/InSAR Research Scientist at the SMU Radar Laboratory and Kelli Baxstrom, a research geologist in the USGS Landslide Hazards Program. Landslides kill thousands of people every year worldwide Landslides occur when masses of rock, soil or earth fall down a slope because of gravity. They cause thousands of deaths each year around the world, and in the United States alone, damage exceeds $2 billion annually from these slides. Yet, landslides can be hard to spot before they become a danger, when heavy rainfall suddenly causes the land to shift quickly. Of the 617 landslides detected in western US states, only 29 of them were already included in the national landslide database. These landslides are typically found through human-reported events and geological maps. \"The landslides that we previously knew about are ones that people can easily spot from the highway or in city areas,\" Lu said. \"Those are very rapid-moving landslides.\" Other landslides, however, are harder to identify due to tree cover or because there is no obvious crack in the topography, he explained. Xu, Lu and the rest of the research team used radar satellite images to unravel previously unidentified landslides from space. These images, taken from 2007 to 2011 and 2015 to 2019, came from radar instruments called Phased Array type L-band Synthetic Aperture Radar (PALSAR) mounted on the Japan Aerospace Exploration Agency's Advanced Land Observing Satellites. With this interferometric synthetic aperture radar technology (called InSAR, for short) the satellite images allow scientists to detect changes that aren't visible to the naked eye. The satellite technology can capture ground motion with a precision of sub-inches or better, at a spatial resolution of a few yards over thousands of miles, say the researchers. Essentially, any movement of the ground surface toward or away from the satellite can be measured and depicted as a \"picture.\" This picture shows how much the surface has moved or deformed during the time between images. Lu, a leading scientist in InSAR applications, used the same method to reveal in 2018 that sinkholes are expanding and forming in oilfield-dominated West Texas at a startling rate. In this current study, the geophysicist team collected a total of 7,073 images of the western US states from 2007 to 2011 and from 2015 to 2019 to see whether the land had shifted from previous images. The team focused on finding large, slow-moving landslides because these had the most potential to cause significant damage. They found that 70 percent of the landslides they identified moved at a consistent pace, sliding further down a slope from where they had been the year before. These landslides moved at rates of tens of centimeters to a few meters per year on average, Lu said. But Lu noted that climate change could accelerate how quickly these landslides become catastrophic, as \"climate change is producing abnormal climate situations.\" For instance, it's possible that record rainfall, similar to what was seen in Europe and China this year, could make some of the landslides on the West Coast worse. Those landslides ranged in size from the equivalent of 7 to 2,400 football fields. Though InSAR has been highly effective at detecting landslides, Lu said there are likely still more unidentified slow-moving landslides on the U.S. West Coast because extremely dense forests may hinder InSAR's capability to spot them. The InSAR satellite images are also less able to reveal landslide motions that are oriented perpendicular to the radar sensor's \"line of sight.\" SMU's high performance computer was critical to this study Xu said SMU's supercomputer was essential to analyzing at high speed the mammoth amount of data inherent in using the InSAR technique. \"It's the 'unsung hero,'\" Lu said. \"Without it, we wouldn't have been able to do this research.\" You can see where the slow-moving landslides were found here. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Slow-moving landslides, often with nearly imperceptible creeping motion, are an important landscape shaper and a dangerous natural hazard across the globe, yet their spatial distribution and geologic controls are still poorly known owing to a paucity of detailed, large-area observations. Here, we use interferometry of L-band satellite radar images to reveal 617 spatially large (4 $\times$ 10 4 – 13 $\times$ 10 6 m 2 ) and presently active (2007 – 2019) slow-moving landslides near the populous US West Coast (only 4.6% of these slides were previously known) and provide evidence for their fundamental controls by bedrock lithology and vertical land motion. We found that slow-moving landslides are generally larger and more spatially frequent in homogeneous bedrock with low rock strength, and they are preferentially located on hillslopes with geologically recent uplift. Notably, landslide size and spatial density in the relatively weak metamorphic rocks and mélange (due to pervasive tectonically sheared discontinuities, foliation, and abundant clay minerals) were two times larger than those in sedimentary and igneous rocks, and the hillslopes with landslides were found to be uplifting approximately three times faster than the average for the whole region. These results suggest that slow-moving landslides can be effectively uncovered by satellite radar imagery and their occurrence and character may be anticipated from vertical land uplift and bedrock lithology. Hence, our study provides understanding critical for reducing landslide hazards and quantifying landslide impacts on landscape change. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction Landslides are a geologic process crucial for landscape evolution (Burbank et al. 1996 ; Kelsey and Bockheim 1994 ; Roering et al. 2009 ; Simoni et al. 2013 ), and as a natural hazard, landslides annually cause 3.5 billion dollars of property loss and 25–50 casualties in the USA alone (Spiker and Gori 2003 ). Locating presently active landslides is a critical step towards preventing their future hazards and forecasting their impact on the landscape. However, conventional landslide-identifying approaches that rely on geologic maps and citizen-reported events (Guzzetti et al. 2012 ; Highland and Bobrowsky 2008 ; Jones et al. 2019 ) could easily miss numerous active yet slowly moving slides that lack readily identifiable features (e.g., fresh headscarps) or occur in rarely accessed lands. Slow-moving landslides persistently damage infrastructure and imply a force imbalance of the hillslope (Highland and Bobrowsky 2008 ). Additional forces such as earthquake shaking, coastal and stream erosion, intense rainfall, and other natural or anthropogenic disturbance could shift their present creeping behavior into rapid movement and cause catastrophic damages (e.g., Intrieri et al. 2018 ; Kilburn and Petley 2003 ; Schulz and Wang 2014 ; Xu et al. 2020b ). Discovering presently slow-moving landslides for future hazard prevention particularly requires approaches with high measurement accuracy and wide spatial coverage. However, few tools were available until the InSAR (Interferometric Synthetic Aperture Radar) method evolved into an effective means in the last two decades (Handwerger et al. 2019 ; Intrieri et al. 2018 ; Squarzoni et al. 2003 ; Xu et al. 2019 , 2020b ; Ye et al. 2004 ). InSAR utilizes interferometry of satellite-captured radar images (frequent repeated acquisitions since 1992) to achieve maximal millimeter-level measurements of ground displacement along the radar line-of-sight (LOS) direction (Ferretti et al. 2007 ; Nishiguchi et al. 2017 ). Multiple studies have focused on the precipitation-driven short-timescale dynamics of presently active, slow-moving landslides (e.g., Bennett et al. 2016b ; Handwerger et al. 2019 ; Kang et al. 2021 ; Mackey et al. 2009 ; Squarzoni et al. 2003 ; Xu et al. 2020b ; Ye et al. 2004 ); however, knowledge of their geologic controls is still poorly known owing to a lack of detailed, large-scale evidence, but such knowledge is essential for deciphering their characteristics and for preventing future hazards. Spatially large, slow-moving landslides are generally deep-seated (meters to hundreds of meters) (Bonzanigo et al. 2007 ; Highland and Bobrowsky 2008 ; Larsen et al. 2010 ) and may have been active for hundreds to thousands of years (Bonzanigo et al. 2007 ; Bovis and Jones 1992 ; Kelsey and Bockheim 1994 ; Mackey et al. 2009 ; Varnes and Savage 1996 ). Hence, their occurrence could be controlled by the lithology and structure of the underlying bedrock and by geologic processes (Clarke and Burbank 2010 ; Cruden and Varnes 1996 ; Lambe and Whitman 1969 ; Roering et al. 2005 ). In addition, vertical uplift (i.e., any upward movement of the land surface) in a geologic timescale (10 3 –10 5 years) could deliberately alter the force balance of hillslopes and regulate the denudation process (Burbank et al. 1996 ; Bennett et al. 2016a ; Larsen and Montgomery 2012 ; Roering et al. 2015 ), thereby potentially modulating occurrence and kinematics of long-term creeping landslides. Here, we apply the high-accuracy InSAR method over the entire US West Coast states (~ 8.6 × 10 5 km 2 ) to discover large, presently active landslides in both the high mountains and coastal neighborhoods inhabited by 47.8 million people (2019 census; USCB 2019 ). Based on the large-scale observations, we tested our hypotheses that the spatial density and size of slow-moving landslides are significantly controlled by bedrock type and that their occurrence and persistent motion reflect long-term land uplift. Materials and methods SAR interferogram generation and unwrapping We used radar interferometry of both the ALOS PALSAR (Advanced Land Observing Satellite–Phased Array type L-band Synthetic Aperture Radar) images from 2007 to 2011 and ALOS-2 PALSAR-2 images from 2015 to 2019 for identifying landslides near the US West Coast. The L-band SAR images were primarily utilized over the relatively densely vegetated US West Coast because of L-band sensor’s capability in vegetation penetration. SAR interferograms were generated by differencing the phase measurements of two SAR images. For each SAR interferogram, the interferometric phase of a SAR resolution element, $\phi$ , is composed of multiple independent components: $$\phi =W\left\{{\phi }_{\mathrm{def}}+{\phi }_{\mathrm{dem}}+{\phi }_{\mathrm{orb}}+{\phi }_{\mathrm{atm}}+{\phi }_{\mathrm{n}}\right\}$$ (1) where ${\phi }_{\mathrm{def}}$<|im_end|> <|im_start|>assistant SMU geophysicists have used satellite imagery to identify more than 600 slow-moving landslides occurring near the U.S. West Coast Fewer than 5% of these landslides in California, Oregon and Washington state had been previously identified. Geophysics professor Zhong Lu and his team at SMU (Southern Methodist University) were awarded nearly $1 million over the past 4 years from the NASA Interdisciplinary Research in Earth Science Program and the NASA Earth Surface and Interior Focus Area to study landslides on the West Coast. Most of the large landslides they found were in the mountain ranges of western Washington, southwestern Oregon and northwestern California. In some cases, the identified landslides were within 0.5 to 5 kilometers of multiple towns and roads. "These landslides are currently moving slowly. But they're already in a state of force imbalance. So some other external forces, like earthquakes or rainfall, could shift them into a disaster," said Yuankun Xu, a postdoctoral researcher who works in Lu's SMU Radar Laboratory and lead author of a study published in the journal Landslides. Co-author Lu, Shuler-Foscue Chair at SMU's Roy M. Huffington Department of Earth Sciences, said, "We don't want to give the impression that these landslides are in trouble tomorrow. No, these landslides have a life expectancy ranging from years to a thousand years." Still, the researchers urged policymakers in these western states to monitor the movement of the now-identified landslides so they can prevent a catastrophe from happening. "I would be very concerned if living, working or commuting upon or near any of the landslides," said study co-author William H. Schulz, a research geologist in the USGS' Landslide Hazards Program. "However, humans can and have successfully dealt with individual landslides and potentially unstable slopes in the past. Detailed studies performed by professionals involving engineering geologic characterization and modeling are needed for any landslide to accurately estimate and mitigate potential future hazards." Other scientists who helped with this study were Jinwoo Kim, SAR/InSAR Research Scientist at the SMU Radar Laboratory and Kelli Baxstrom, a research geologist in the USGS Landslide Hazards Program. Landslides kill thousands of people every year worldwide Landslides occur when masses of rock, soil or earth fall down a slope because of gravity. They cause thousands of deaths each year around the world, and in the United States alone, damage exceeds $2 billion annually from these slides. Yet, landslides can be hard to spot before they become a danger, when heavy rainfall suddenly causes the land to shift quickly. Of the 617 landslides detected in western US states, only 29 of them were already included in the national landslide database. These landslides are typically found through human-reported events and geological maps. "The landslides that we previously knew about are ones that people can easily spot from the highway or in city areas," Lu said. "Those are very rapid-moving landslides." Other landslides, however, are harder to identify due to tree cover or because there is no obvious crack in the topography, he explained. Xu, Lu and the rest of the research team used radar satellite images to unravel previously unidentified landslides from space. These images, taken from 2007 to 2011 and 2015 to 2019, came from radar instruments called Phased Array type L-band Synthetic Aperture Radar (PALSAR) mounted on the Japan Aerospace Exploration Agency's Advanced Land Observing Satellites. With this interferometric synthetic aperture radar technology (called InSAR, for short) the satellite images allow scientists to detect changes that aren't visible to the naked eye. The satellite technology can capture ground motion with a precision of sub-inches or better, at a spatial resolution of a few yards over thousands of miles, say the researchers. Essentially, any movement of the ground surface toward or away from the satellite can be measured and depicted as a "picture." This picture shows how much the surface has moved or deformed during the time between images. Lu, a leading scientist in InSAR applications, used the same method to reveal in 2018 that sinkholes are expanding and forming in oilfield-dominated West Texas at a startling rate. In this current study, the geophysicist team collected a total of 7,073 images of the western US states from 2007 to 2011 and from 2015 to 2019 to see whether the land had shifted from previous images. The team focused on finding large, slow-moving landslides because these had the most potential to cause significant damage. They found that 70 percent of the landslides they identified moved at a consistent pace, sliding further down a slope from where they had been the year before. These landslides moved at rates of tens of centimeters to a few meters per year on average, Lu said. But Lu noted that climate change could accelerate how quickly these landslides become catastrophic, as "climate change is producing abnormal climate situations." For instance, it's possible that record rainfall, similar to what was seen in Europe and China this year, could make some of the landslides on the West Coast worse. Those landslides ranged in size from the equivalent of 7 to 2,400 football fields. Though InSAR has been highly effective at detecting landslides, Lu said there are likely still more unidentified slow-moving landslides on the U.S. West Coast because extremely dense forests may hinder InSAR's capability to spot them. The InSAR satellite images are also less able to reveal landslide motions that are oriented perpendicular to the radar sensor's "line of sight." SMU's high performance computer was critical to this study Xu said SMU's supercomputer was essential to analyzing at high speed the mammoth amount of data inherent in using the InSAR technique. "It's the 'unsung hero,'" Lu said. "Without it, we wouldn't have been able to do this research." You can see where the slow-moving landslides were found here. <|im_end|>

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2,879

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Transformation optics has formulated a versatile framework to mold the flow of light and tailor its spatial characteristics at will. Despite its huge success in bringing scientific fiction (such as invisibility cloaking) into reality, the coordinate transformation often yields extreme material parameters unfeasible even with metamaterials. Here, we demonstrate a new transformation paradigm based upon the invariance of the eigenspectra of the Hamiltonian of a physical system, enabled by supersymmetry. By creating a gradient-index metamaterial to control the local index variation in a family of isospectral optical potentials, we demonstrate broadband continuous supersymmetric transformation in optics, on a silicon chip, to simultaneously transform the transverse spatial characteristics of multiple optical states for arbitrary steering and switching of light flows. Through a novel synergy of symmetry physics and metamaterials, our work provides an adaptable strategy to conveniently tame the flow of light with full exploitation of its spatial degree of freedom. 1 Introduction Our attempts at bending light on demand and arbitrarily transforming its spatial characteristics are rooted in the fundamentals of electromagnetics. The form-invariance of Maxwell’s equations under coordinate transformations led to the formulation of transformation optics [ 1 , 2 ]—the correspondence between the coordinate system and material parameters. Their equivalence allows electromagnetic field in a given coordinate system to be rearranged by designing the medium with the corresponding, spatially dependent dielectric permittivity and magnetic permeability, having consequently opened avenues to a series of intriguing functionality such as invisibility cloaking [ 3 , 4 , 5 , 6 , 7 , 8 ], illusion optics [ 9 ], etc. Nevertheless, although the excellent design flexibility provided by metamaterials [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ] enables a wide range of inhomogeneous and anisotropic optical properties, experimental realization of transformation optics, especially in the optical regime, has been in a stalemate for a decade because of optical extremity and singularity often resulting from the transformation. Additionally, in the original resonant meta-atom-based implementation, transformation optics is confined to narrowband operation [ 4 , 5 ]. Therefore, new schemes towards transformation optics with broadband parameter values within their achievable limits have become necessary. For example, conformal mapping [ 18 , 19 ] with spatially varying the local index of refraction has been demonstrated to perform the coordinate transformation using inhomogeneous Si nanostructures [ 20 , 21 ], yielding delicate phase-front control for multicolor carpet cloaking. This approach elucidated the possibility of the exploitation of gradient-index (GRIN) [ 22 , 23 ] to warp the space, but to achieve richer functionality other than bending the trajectories, a paradigmatic shift beyond traditional coordinate transformation is further required. Another intrinsic principle to formulate the transformation of a physical system is observing its Hamiltonian under transformation. For example, the invariance of the Hamiltonian under symmetry operation [ 24 , 25 , 26 ] endows us with insights into how a system can be transformed with a conserved quantity. In particular, supersymmetry (SUSY) [ 27 ], which originated from the description of the transformation between bosons and fermions [ 28 ], features the degenerate eigenenergy spectra between two distinct Hamiltonians, which has facilitated advanced control of the spatial characteristics of light [ 29 , 30 , 31 ]. For example, designed by unbroken SUSY under which the unpaired ground state exists between the original and the superpartner Hamiltonians, strategic coupling between the original optical system and its dissipative superpartner has triggered intriguing applications such as high-radiance single-mode microlaser arrays [ 32 , 33 ] and mode division multiplexing [ 34 ]. These previous experimental studies are based on lattice Hamiltonians, which can be factorized via matrix operation, and hence they constructed systems composed of a number of coupled discrete elements corresponding to coupled waveguides or resonators. In contrast, the extended method of SUSY that can generate an infinite number of strictly isospectral potentials has remained experimentally unexplored, since it requires an intrinsically different approach to realize arbitrary potentials, while its mathematical framework turns out to be ideal for the continuous Hamiltonian transformation to enable a distinct scenario for transformation optics [ 35 , 36 ] other than the traditional coordinate transformation. Here, we report the first experimental demonstration of continuous SUSY transformation by designing a novel GRIN metamaterial on a Si platform. We utilize the synergy of supersymmetry and the metamaterial to design spatially varying dielectric permittivity, which constitutes a two-dimensional map where arbitrary transformations are prescribed simultaneously to multiple optical states for routing, switching, and spatial mode shaping, while strictly maintaining their original propagation constants. Our result features broadband continuous SUSY transformation in optics, illuminating a novel path to fully utilizing the spatial degrees of freedom on a chip for versatile photonic functionalities. 2 Results and discussion Owing to the mathematical correspondence between the Schrödinger equation and the Helmholtz equation, we formulate the SUSY transformation by describing the potential of the Hamiltonian using the inhomogeneously distributed refractive index n(x) n(x) in the transverse dimension of an optical system. Likewise, the eigenvalue spectrum of the Hamiltonian is represented by the spectrum of the propagation constants calculated from n(x) n(x) (See Methods ). For an original optical potential {n}_{0}(x) {n}_{0}(x) , SUSY transformation [ 28 , 37 , 38 ] leads to a family of isospectral optical potentials {n}_{f}(x) {n}_{f}(x) with a free parameter {\\alpha }_{i} {\\alpha }_{i} : {n}_{f}^{2}\\left(x;{\\alpha }_{i}\\right)={n}_{0}^{2}\\left(x\\right)+\\frac{2}{{k}_{0}^{2}}\\frac{d}{dx}\\left(\\frac{1}{{I}_{m}\\left(x\\right)}\\frac{d{I}_{m}\\left(x\\right)}{dx}\\right) {n}_{f}^{2}\\left(x;{\\alpha }_{i}\\right)={n}_{0}^{2}\\left(x\\right)+\\frac{2}{{k}_{0}^{2}}\\frac{d}{dx}\\left(\\frac{1}{{I}_{m}\\left(x\\right)}\\frac{d{I}_{m}\\left(x\\right)}{dx}\\right) (1) where {I}_{m}\\left(x\\right)=\\underset{-\\infty }{\\overset{x}{\\int }}{\\psi }_{m}^{2}\\left({x}^{^{\\prime}}\\right)d{x}^{^{\\prime}}+{\\alpha }_{i} {I}_{m}\\left(x\\right)=\\underset{-\\infty }{\\overset{x}{\\int }}{\\psi }_{m}^{2}\\left({x}^{^{\\prime}}\\right)d{x}^{^{\\prime}}+{\\alpha }_{i} , and {\\psi }_{m}\\left(x\\right) {\\psi }_{m}\\left(x\\right) is the {m}^{th} {m}^{th} eigenstate of {n}_{0}(x) {n}_{0}(x) . By this means, one can conveniently delete the eigenstate {\\psi }_{m} {\\psi }_{m} and reinstate a new {\\psi }_{m} {\\psi }_{m} with the same propagation constant but different spatial characteristics of light depending on parameter {\\alpha }_{i} {\\alpha }_{i} . Hence, this mathematical operation can be understood as a reshaping process of {n}_{0}(x) {n}_{0}(x) , enabling the isospectral transformation of light by continuously varying the parameter {\\alpha }_{i} {\\alpha }_{i} (and thus {n}_{f}(x;{\\alpha }_{i}) {n}_{f}(x;{\\alpha }_{i}) )", "role": "user" }, { "content": "Transformation optics has formulated a versatile framework to mold the flow of light and tailor its spatial characteristics at will. The coordinate transformation often yields extreme material parameters unfeasible even with metamaterials. In a new paper published in eLight, a team of scientists, led by Professor Liang Feng from the University of Pennsylvania, have developed a new chip that can transfer different optical states to switch light flows. Their paper, titled \"Broadband continuous supersymmetric transformation: a new paradigm for transformation optics,\" seeks to provide an adaptable strategy to tame the flow of light. Attempts at bending light on demand and arbitrarily transforming its spatial characteristics are rooted in the fundamentals of electromagnetics. The form-invariance of Maxwell's equations under coordinate transformations led to the formulation of transformation optics. Their equivalence allows for the rearrangement of electromagnetic fields in a given coordinate system. It has left open avenues to a series of intriguing functionality such as invisibility cloaking and illusion optics. Metamaterials have excellent design flexibility and enable a wide range of optical properties. Experimental realization of transformation optics has been at a stalemate for a decade because of optical extremity and singularity often resulting from the transformation. Therefore, new schemes for transformation optics with broadband parameter values within achievable limits are essential. For example, conformal mapping with the spatially varying local index of refraction had been demonstrated. This technique can perform the coordinate transformation using inhomogeneous Si nanostructures. It can yield delicate phase-front control for multicolor carpet cloaking. This approach elucidated the possibility of exploiting gradient-index (GRIN) to warp the space. However, a paradigmatic shift beyond traditional coordinate transformation is further required to achieve richer functionality other than bending the trajectories. Here, the research team takes a different approach from conventional transformation optics: observing the Hamiltonian of the system under transformation. The invariance of the Hamiltonian under symmetry operation endows us with insights into how a system can be transformed with a conserved quantity. In particular, Supersymmetry (SUSY) features the degenerate eigenenergy spectra between two distinct Hamiltonians, which has facilitated advanced control of the spatial characteristics of light. Strategic coupling between the original optical system and its dissipative superpartner has triggered intriguing applications such as high-radiance single-mode microlaser arrays and mode division multiplexing. These previous experimental studies are based on lattice Hamiltonians, which can be factorized via matrix operation. Hence, they constructed systems composed of many coupled discrete elements corresponding to coupled waveguides or resonators. In contrast, the extended method of SUSY that can generate an infinite number of strictly isospectral potentials has remained experimentally unexplored since it requires an intrinsically different approach to realize arbitrary potentials. At the same time, its mathematical framework is ideal for the continuous Hamiltonian transformation to enable a distinct scenario for transformation optics. The research team reported the first experimental demonstration of continuous SUSY transformation by designing a novel GRIN metamaterial on a Si platform. The idea is to construct a metamaterial that can emulate arbitrary potentials to achieve advanced light control through transforming the optical media under supersymmetry. They utilized the synergy of supersymmetry and the metamaterial to design spatially varying dielectric permittivity. It constituted a two-dimensional map where arbitrary transformations are prescribed simultaneously to multiple optical states for routing, switching, and spatial mode shaping, while strictly maintaining their original propagation constants. Their result featured broadband continuous SUSY transformation optics. The interplay of supersymmetry and a metamaterial demonstrated in this study illuminated a novel path to fully utilizing a chip's spatial degrees of freedom for versatile photonic functionalities. The team's continuous SUSY transformation approach is scalable to a higher number of eigenstates and free parameters. It applies to more complicated index distribution, creating an ideal platform for on-chip space-division multiplexing in information technologies. Additionally, further extending the SUSY transformation into higher dimensions may provide a design strategy to exploit the full potential of metamaterials in the three-dimensional space. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Transformation optics has formulated a versatile framework to mold the flow of light and tailor its spatial characteristics at will. Despite its huge success in bringing scientific fiction (such as invisibility cloaking) into reality, the coordinate transformation often yields extreme material parameters unfeasible even with metamaterials. Here, we demonstrate a new transformation paradigm based upon the invariance of the eigenspectra of the Hamiltonian of a physical system, enabled by supersymmetry. By creating a gradient-index metamaterial to control the local index variation in a family of isospectral optical potentials, we demonstrate broadband continuous supersymmetric transformation in optics, on a silicon chip, to simultaneously transform the transverse spatial characteristics of multiple optical states for arbitrary steering and switching of light flows. Through a novel synergy of symmetry physics and metamaterials, our work provides an adaptable strategy to conveniently tame the flow of light with full exploitation of its spatial degree of freedom. 1 Introduction Our attempts at bending light on demand and arbitrarily transforming its spatial characteristics are rooted in the fundamentals of electromagnetics. The form-invariance of Maxwell’s equations under coordinate transformations led to the formulation of transformation optics [ 1 , 2 ]—the correspondence between the coordinate system and material parameters. Their equivalence allows electromagnetic field in a given coordinate system to be rearranged by designing the medium with the corresponding, spatially dependent dielectric permittivity and magnetic permeability, having consequently opened avenues to a series of intriguing functionality such as invisibility cloaking [ 3 , 4 , 5 , 6 , 7 , 8 ], illusion optics [ 9 ], etc. Nevertheless, although the excellent design flexibility provided by metamaterials [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ] enables a wide range of inhomogeneous and anisotropic optical properties, experimental realization of transformation optics, especially in the optical regime, has been in a stalemate for a decade because of optical extremity and singularity often resulting from the transformation. Additionally, in the original resonant meta-atom-based implementation, transformation optics is confined to narrowband operation [ 4 , 5 ]. Therefore, new schemes towards transformation optics with broadband parameter values within their achievable limits have become necessary. For example, conformal mapping [ 18 , 19 ] with spatially varying the local index of refraction has been demonstrated to perform the coordinate transformation using inhomogeneous Si nanostructures [ 20 , 21 ], yielding delicate phase-front control for multicolor carpet cloaking. This approach elucidated the possibility of the exploitation of gradient-index (GRIN) [ 22 , 23 ] to warp the space, but to achieve richer functionality other than bending the trajectories, a paradigmatic shift beyond traditional coordinate transformation is further required. Another intrinsic principle to formulate the transformation of a physical system is observing its Hamiltonian under transformation. For example, the invariance of the Hamiltonian under symmetry operation [ 24 , 25 , 26 ] endows us with insights into how a system can be transformed with a conserved quantity. In particular, supersymmetry (SUSY) [ 27 ], which originated from the description of the transformation between bosons and fermions [ 28 ], features the degenerate eigenenergy spectra between two distinct Hamiltonians, which has facilitated advanced control of the spatial characteristics of light [ 29 , 30 , 31 ]. For example, designed by unbroken SUSY under which the unpaired ground state exists between the original and the superpartner Hamiltonians, strategic coupling between the original optical system and its dissipative superpartner has triggered intriguing applications such as high-radiance single-mode microlaser arrays [ 32 , 33 ] and mode division multiplexing [ 34 ]. These previous experimental studies are based on lattice Hamiltonians, which can be factorized via matrix operation, and hence they constructed systems composed of a number of coupled discrete elements corresponding to coupled waveguides or resonators. In contrast, the extended method of SUSY that can generate an infinite number of strictly isospectral potentials has remained experimentally unexplored, since it requires an intrinsically different approach to realize arbitrary potentials, while its mathematical framework turns out to be ideal for the continuous Hamiltonian transformation to enable a distinct scenario for transformation optics [ 35 , 36 ] other than the traditional coordinate transformation. Here, we report the first experimental demonstration of continuous SUSY transformation by designing a novel GRIN metamaterial on a Si platform. We utilize the synergy of supersymmetry and the metamaterial to design spatially varying dielectric permittivity, which constitutes a two-dimensional map where arbitrary transformations are prescribed simultaneously to multiple optical states for routing, switching, and spatial mode shaping, while strictly maintaining their original propagation constants. Our result features broadband continuous SUSY transformation in optics, illuminating a novel path to fully utilizing the spatial degrees of freedom on a chip for versatile photonic functionalities. 2 Results and discussion Owing to the mathematical correspondence between the Schrödinger equation and the Helmholtz equation, we formulate the SUSY transformation by describing the potential of the Hamiltonian using the inhomogeneously distributed refractive index n(x) n(x) in the transverse dimension of an optical system. Likewise, the eigenvalue spectrum of the Hamiltonian is represented by the spectrum of the propagation constants calculated from n(x) n(x) (See Methods ). For an original optical potential {n}_{0}(x) {n}_{0}(x) , SUSY transformation [ 28 , 37 , 38 ] leads to a family of isospectral optical potentials {n}_{f}(x) {n}_{f}(x) with a free parameter {\alpha }_{i} {\alpha }_{i} : {n}_{f}^{2}\left(x;{\alpha }_{i}\right)={n}_{0}^{2}\left(x\right)+\frac{2}{{k}_{0}^{2}}\frac{d}{dx}\left(\frac{1}{{I}_{m}\left(x\right)}\frac{d{I}_{m}\left(x\right)}{dx}\right) {n}_{f}^{2}\left(x;{\alpha }_{i}\right)={n}_{0}^{2}\left(x\right)+\frac{2}{{k}_{0}^{2}}\frac{d}{dx}\left(\frac{1}{{I}_{m}\left(x\right)}\frac{d{I}_{m}\left(x\right)}{dx}\right) (1) where {I}_{m}\left(x\right)=\underset{-\infty }{\overset{x}{\int }}{\psi }_{m}^{2}\left({x}^{^{\prime}}\right)d{x}^{^{\prime}}+{\alpha }_{i} {I}_{m}\left(x\right)=\underset{-\infty }{\overset{x}{\int }}{\psi }_{m}^{2}\left({x}^{^{\prime}}\right)d{x}^{^{\prime}}+{\alpha }_{i} , and {\psi }_{m}\left(x\right) {\psi }_{m}\left(x\right) is the {m}^{th} {m}^{th} eigenstate of {n}_{0}(x) {n}_{0}(x) . By this means, one can conveniently delete the eigenstate {\psi }_{m} {\psi }_{m} and reinstate a new {\psi }_{m} {\psi }_{m} with the same propagation constant but different spatial characteristics of light depending on parameter {\alpha }_{i} {\alpha }_{i} . Hence, this mathematical operation can be understood as a reshaping process of {n}_{0}(x) {n}_{0}(x) , enabling the isospectral transformation of light by continuously varying the parameter {\alpha }_{i} {\alpha }_{i} (and thus {n}_{f}(x;{\alpha }_{i}) {n}_{f}(x;{\alpha }_{i}) )<|im_end|> <|im_start|>assistant Transformation optics has formulated a versatile framework to mold the flow of light and tailor its spatial characteristics at will. The coordinate transformation often yields extreme material parameters unfeasible even with metamaterials. In a new paper published in eLight, a team of scientists, led by Professor Liang Feng from the University of Pennsylvania, have developed a new chip that can transfer different optical states to switch light flows. Their paper, titled "Broadband continuous supersymmetric transformation: a new paradigm for transformation optics," seeks to provide an adaptable strategy to tame the flow of light. Attempts at bending light on demand and arbitrarily transforming its spatial characteristics are rooted in the fundamentals of electromagnetics. The form-invariance of Maxwell's equations under coordinate transformations led to the formulation of transformation optics. Their equivalence allows for the rearrangement of electromagnetic fields in a given coordinate system. It has left open avenues to a series of intriguing functionality such as invisibility cloaking and illusion optics. Metamaterials have excellent design flexibility and enable a wide range of optical properties. Experimental realization of transformation optics has been at a stalemate for a decade because of optical extremity and singularity often resulting from the transformation. Therefore, new schemes for transformation optics with broadband parameter values within achievable limits are essential. For example, conformal mapping with the spatially varying local index of refraction had been demonstrated. This technique can perform the coordinate transformation using inhomogeneous Si nanostructures. It can yield delicate phase-front control for multicolor carpet cloaking. This approach elucidated the possibility of exploiting gradient-index (GRIN) to warp the space. However, a paradigmatic shift beyond traditional coordinate transformation is further required to achieve richer functionality other than bending the trajectories. Here, the research team takes a different approach from conventional transformation optics: observing the Hamiltonian of the system under transformation. The invariance of the Hamiltonian under symmetry operation endows us with insights into how a system can be transformed with a conserved quantity. In particular, Supersymmetry (SUSY) features the degenerate eigenenergy spectra between two distinct Hamiltonians, which has facilitated advanced control of the spatial characteristics of light. Strategic coupling between the original optical system and its dissipative superpartner has triggered intriguing applications such as high-radiance single-mode microlaser arrays and mode division multiplexing. These previous experimental studies are based on lattice Hamiltonians, which can be factorized via matrix operation. Hence, they constructed systems composed of many coupled discrete elements corresponding to coupled waveguides or resonators. In contrast, the extended method of SUSY that can generate an infinite number of strictly isospectral potentials has remained experimentally unexplored since it requires an intrinsically different approach to realize arbitrary potentials. At the same time, its mathematical framework is ideal for the continuous Hamiltonian transformation to enable a distinct scenario for transformation optics. The research team reported the first experimental demonstration of continuous SUSY transformation by designing a novel GRIN metamaterial on a Si platform. The idea is to construct a metamaterial that can emulate arbitrary potentials to achieve advanced light control through transforming the optical media under supersymmetry. They utilized the synergy of supersymmetry and the metamaterial to design spatially varying dielectric permittivity. It constituted a two-dimensional map where arbitrary transformations are prescribed simultaneously to multiple optical states for routing, switching, and spatial mode shaping, while strictly maintaining their original propagation constants. Their result featured broadband continuous SUSY transformation optics. The interplay of supersymmetry and a metamaterial demonstrated in this study illuminated a novel path to fully utilizing a chip's spatial degrees of freedom for versatile photonic functionalities. The team's continuous SUSY transformation approach is scalable to a higher number of eigenstates and free parameters. It applies to more complicated index distribution, creating an ideal platform for on-chip space-division multiplexing in information technologies. Additionally, further extending the SUSY transformation into higher dimensions may provide a design strategy to exploit the full potential of metamaterials in the three-dimensional space. <|im_end|>

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335, 15511, 72, 92, 29252, 7288, 335, 15511, 72, 92, 551, 314, 77, 52635, 69, 92, 48922, 17, 11281, 2414, 2120, 26, 36802, 7288, 335, 15511, 72, 11281, 1315, 8, 1185, 77, 52635, 15, 92, 48922, 17, 11281, 2414, 2120, 59, 1315, 7405, 59, 38118, 90, 17, 92, 3052, 74, 52635, 15, 92, 48922, 17, 3500, 59, 38118, 90, 67, 15523, 13009, 11281, 2414, 11781, 38118, 90, 16, 92, 3052, 40, 52635, 76, 11281, 2414, 2120, 59, 1315, 9317, 59, 38118, 90, 67, 90, 40, 52635, 76, 11281, 2414, 2120, 59, 1315, 9317, 90, 13009, 11281, 1315, 8, 314, 77, 52635, 69, 92, 48922, 17, 11281, 2414, 2120, 26, 36802, 7288, 335, 15511, 72, 11281, 1315, 8, 1185, 77, 52635, 15, 92, 48922, 17, 11281, 2414, 2120, 59, 1315, 7405, 59, 38118, 90, 17, 92, 3052, 74, 52635, 15, 92, 48922, 17, 3500, 59, 38118, 90, 67, 15523, 13009, 11281, 2414, 11781, 38118, 90, 16, 92, 3052, 40, 52635, 76, 11281, 2414, 2120, 59, 1315, 9317, 59, 38118, 90, 67, 90, 40, 52635, 76, 11281, 2414, 2120, 59, 1315, 9317, 90, 13009, 11281, 1315, 8, 320, 16, 8, 1405, 314, 40, 52635, 76, 11281, 2414, 2120, 59, 1315, 11992, 59, 32109, 295, 20597, 59, 258, 38058, 335, 36802, 9146, 295, 46440, 15523, 59, 396, 3954, 36802, 31865, 335, 15511, 76, 92, 48922, 17, 11281, 2414, 2358, 87, 92, 48922, 61, 36802, 33438, 3500, 59, 1315, 66359, 46440, 92, 48922, 61, 36802, 33438, 3500, 10, 36802, 7288, 335, 15511, 72, 92, 314, 40, 52635, 76, 11281, 2414, 2120, 59, 1315, 11992, 59, 32109, 295, 20597, 59, 258, 38058, 335, 36802, 9146, 295, 46440, 15523, 59, 396, 3954, 36802, 31865, 335, 15511, 76, 92, 48922, 17, 11281, 2414, 2358, 87, 92, 48922, 61, 36802, 33438, 3500, 59, 1315, 66359, 46440, 92, 48922, 61, 36802, 33438, 3500, 10, 36802, 7288, 335, 15511, 72, 92, 1174, 323, 29252, 31865, 335, 15511, 76, 11281, 2414, 2120, 59, 1315, 8, 29252, 31865, 335, 15511, 76, 11281, 2414, 2120, 59, 1315, 8, 374, 279, 314, 76, 92, 48922, 339, 92, 314, 76, 92, 48922, 339, 92, 29824, 2513, 315, 314, 77, 52635, 15, 26628, 87, 8, 314, 77, 52635, 15, 26628, 87, 8, 662, 3296, 420, 3445, 11, 832, 649, 49170, 3783, 279, 29824, 2513, 29252, 31865, 335, 15511, 76, 92, 29252, 31865, 335, 15511, 76, 92, 323, 15601, 2513, 264, 502, 29252, 31865, 335, 15511, 76, 92, 29252, 31865, 335, 15511, 76, 92, 449, 279, 1890, 54743, 6926, 719, 2204, 29079, 17910, 315, 3177, 11911, 389, 5852, 29252, 7288, 335, 15511, 72, 92, 29252, 7288, 335, 15511, 72, 92, 662, 32140, 11, 420, 37072, 5784, 649, 387, 16365, 439, 264, 64793, 14550, 1920, 315, 314, 77, 52635, 15, 26628, 87, 8, 314, 77, 52635, 15, 26628, 87, 8, 1174, 28462, 279, 374, 437, 87675, 18475, 315, 3177, 555, 31978, 29865, 279, 5852, 29252, 7288, 335, 15511, 72, 92, 29252, 7288, 335, 15511, 72, 92, 320, 438, 8617, 314, 77, 52635, 69, 26628, 87, 26, 36802, 7288, 335, 15511, 72, 5525, 314, 77, 52635, 69, 26628, 87, 26, 36802, 7288, 335, 15511, 72, 5525, 883, 128257, 198, 128256, 78191, 198, 65363, 70985, 706, 60394, 264, 33045, 12914, 311, 29561, 279, 6530, 315, 3177, 323, 52056, 1202, 29079, 17910, 520, 690, 13, 578, 16580, 18475, 3629, 36508, 14560, 3769, 5137, 653, 90377, 1260, 1524, 449, 88848, 2229, 82, 13, 763, 264, 502, 5684, 4756, 304, 384, 14235, 11, 264, 2128, 315, 14248, 11, 6197, 555, 17054, 14851, 526, 43758, 505, 279, 3907, 315, 20355, 11, 617, 8040, 264, 502, 16797, 430, 649, 8481, 2204, 29393, 5415, 311, 3480, 3177, 28555, 13, 11205, 5684, 11, 25891, 330, 69424, 7198, 19815, 52790, 30559, 18475, 25, 264, 502, 49340, 369, 18475, 70985, 1359, 26737, 311, 3493, 459, 94848, 8446, 311, 82923, 279, 6530, 315, 3177, 13, 84400, 520, 58218, 3177, 389, 7631, 323, 86757, 46890, 1202, 29079, 17910, 527, 41976, 304, 279, 57940, 315, 54707, 3326, 25265, 13, 578, 1376, 3502, 959, 5397, 315, 59497, 596, 39006, 1234, 16580, 54070, 6197, 311, 279, 55986, 315, 18475, 70985, 13, 11205, 85262, 6276, 369, 279, 56427, 57733, 315, 66669, 5151, 304, 264, 2728, 16580, 1887, 13, 1102, 706, 2163, 1825, 73234, 311, 264, 4101, 315, 41765, 15293, 1778, 439, 100137, 3225, 5405, 1802, 323, 41919, 70985, 13, 6344, 309, 2229, 82, 617, 9250, 2955, 25152, 323, 7431, 264, 7029, 2134, 315, 29393, 6012, 13, 57708, 49803, 315, 18475, 70985, 706, 1027, 520, 264, 51451, 18543, 369, 264, 13515, 1606, 315, 29393, 6000, 488, 323, 7936, 30079, 3629, 13239, 505, 279, 18475, 13, 15636, 11, 502, 31956, 369, 18475, 70985, 449, 41925, 5852, 2819, 2949, 89253, 13693, 527, 7718, 13, 1789, 3187, 11, 26965, 278, 13021, 449, 279, 29079, 398, 29865, 2254, 1963, 315, 2098, 16597, 1047, 1027, 21091, 13, 1115, 15105, 649, 2804, 279, 16580, 18475, 1701, 304, 35940, 49122, 12095, 51593, 47194, 13, 1102, 649, 7692, 36301, 10474, 64726, 2585, 369, 2814, 74909, 28954, 5405, 1802, 13, 1115, 5603, 97298, 660, 279, 13336, 315, 71701, 20779, 22214, 320, 8796, 691, 8, 311, 47420, 279, 3634, 13, 4452, 11, 264, 49340, 780, 6541, 7953, 8776, 16580, 18475, 374, 4726, 2631, 311, 11322, 59774, 15293, 1023, 1109, 58218, 279, 86648, 13, 5810, 11, 279, 3495, 2128, 5097, 264, 2204, 5603, 505, 21349, 18475, 70985, 25, 46071, 279, 24051, 1122, 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9526, 750, 653, 69331, 1171, 2533, 433, 7612, 459, 10805, 1354, 2740, 2204, 5603, 311, 13383, 25142, 95358, 13, 2468, 279, 1890, 892, 11, 1202, 37072, 12914, 374, 10728, 369, 279, 19815, 24051, 1122, 18475, 311, 7431, 264, 12742, 15398, 369, 18475, 70985, 13, 578, 3495, 2128, 5068, 279, 1176, 22772, 30816, 315, 19815, 90129, 56, 18475, 555, 30829, 264, 11775, 15116, 691, 88848, 2229, 389, 264, 12095, 5452, 13, 578, 4623, 374, 311, 9429, 264, 88848, 2229, 430, 649, 66585, 25142, 95358, 311, 11322, 11084, 3177, 2585, 1555, 46890, 279, 29393, 3772, 1234, 52790, 1631, 33342, 13, 2435, 34716, 279, 93140, 315, 52790, 1631, 33342, 323, 279, 88848, 2229, 311, 2955, 29079, 398, 29865, 2815, 47262, 14175, 1468, 1968, 13, 1102, 65591, 264, 1403, 33520, 2472, 1405, 25142, 54070, 527, 32031, 25291, 311, 5361, 29393, 5415, 369, 30158, 11, 28865, 11, 323, 29079, 3941, 46620, 11, 1418, 26549, 20958, 872, 4113, 54743, 18508, 13, 11205, 1121, 15109, 41925, 19815, 90129, 56, 18475, 70985, 13, 578, 958, 1387, 315, 52790, 1631, 33342, 323, 264, 88848, 2229, 21091, 304, 420, 4007, 75648, 264, 11775, 1853, 311, 7373, 35988, 264, 16797, 596, 29079, 12628, 315, 11542, 369, 33045, 4604, 14338, 93180, 13, 578, 2128, 596, 19815, 90129, 56, 18475, 5603, 374, 69311, 311, 264, 5190, 1396, 315, 29824, 33169, 323, 1949, 5137, 13, 1102, 17208, 311, 810, 17395, 1963, 8141, 11, 6968, 459, 10728, 5452, 369, 389, 11843, 575, 3634, 12, 29864, 12842, 2635, 287, 304, 2038, 14645, 13, 23212, 11, 4726, 33459, 279, 90129, 56, 18475, 1139, 5190, 15696, 1253, 3493, 264, 2955, 8446, 311, 33294, 279, 2539, 4754, 315, 88848, 2229, 82, 304, 279, 2380, 33520, 3634, 13, 220, 128257, 198 ]

2,542

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Members of the interleukin-1 (IL-1) family are important mediators of obesity and metabolic disease and have been described to often play opposing roles. Here we report that the interleukin-36 (IL-36) subfamily can play a protective role against the development of disease. Elevated IL-36 cytokine expression is found in the serum of obese patients and negatively correlates with blood glucose levels among those presenting with type 2 diabetes. Mice lacking IL-36Ra, an IL-36 family signalling antagonist, develop less diet-induced weight gain, hyperglycemia and insulin resistance. These protective effects correlate with increased abundance of the metabolically protective bacteria Akkermansia muciniphila in the intestinal microbiome. IL-36 cytokines promote its outgrowth as well as increased colonic mucus secretion. These findings identify a protective role for IL-36 cytokines in obesity and metabolic disease, adding to the current understanding of the role the broader IL-1 family plays in regulating disease pathogenesis. Introduction Over the past 40 years, global levels of obesity have more than doubled. As obesity predisposes to the metabolic syndrome and has been definitively linked to coronary heart disease, stroke, type 2 diabetes and certain forms of cancer, this growing epidemic represents one of the most significant current global health challenges. In tandem with the emergence of this problem has been an increase in understanding the pathological mechanisms which link the obese state to the development of disease. Central to these mechanisms is the heightened state of systemic inflammation as a result of obesity. Since the seminal observations made by Hotamisligil et al., demonstrating the role of adipose tissue-derived TNF as an inhibitor of insulin signalling and first linking obesity-driven inflammation to type 2 diabetes 1 , it is now recognised that the nature of adipose tissue inflammation is a major contributor towards obesity-related diseases 2 , 3 , 4 . Further complexity is added through the instructive role of the gastrointestinal immune system in influencing the development of inflamed adipose tissue. It is now evident that changes in the homoeostatic barrier function of the gut can play a major role in the development of systemic inflammation in obesity 5 . In this context, it is perhaps unsurprising that the constituents of the intestinal microbiome are also emerging as an important factor in this regard. In healthy individuals, the gastrointestinal immune system plays an immunosurveillant role, in constant interaction with the intestinal microbiome which profoundly influences its activity. The role of the microbiota in the development of obesity-driven metabolic disease first emerged from studies on germ-free mice, which demonstrated reduced levels of experimental weight gain and improved glucose tolerance 6 , 7 . Moreover, the transfer of an ‘obese’ microbiome to germ-free mice can lead to significant increases in adiposity confirming the important instructive role in contributing to disease 8 . Similarly, changes in the composition of the intestinal microbiome have been associated with obesity and the development of metabolic disease in humans 9 , 10 . As well as contributing to obesity and disease, it is also becoming apparent that certain constituents of the microbiota can act opposingly to restrict adiposity. In recent times, it has been demonstrated that the presence of the bacteria Akkermansia muciniphila in the intestinal microbiome can act directly to suppress weight gain and impaired glucose tolerance in mice 11 . Many of these protective effects have now been recapitulated using a purified outer membrane protein, Amuc_1100, derived from A. muciniphila 12 . It is also noteworthy that several dietary interventions targeting obesity and glucose intolerance, and the glucose-lowering drug metformin, increase A. muciniphila abundance 11 , 13 , 14 , 15 . Significantly, follow-up studies have also demonstrated a clear association between the relative abundance of this bacterium in the microbiome and the metabolic health of obese patients 16 . Such observations suggest that the composition of the intestinal microbiome can be altered towards a more ‘healthy’ lean state, highlighting its potential as a therapeutic strategy, and placing the identification of the mechanistic pathways which can alter the composition of the microbiota as a particular area of interest. In this study, we identify the IL-36 family of cytokines as one such pathway. The IL-36 family of cytokines are a recently described subset of the larger IL-1 family which are emerging as important mediators of obesity-related metabolic disease 17 . The family consists of three separate agonistic ligands, designated IL-36α, IL-36β and IL-36γ, and a specific IL-36 receptor antagonist (IL-36Ra), all of which act through a specific IL-36 receptor 18 . Similar to the more extensively characterised ‘classical’ IL-1 cytokines, IL-1α and IL-1β, IL-36 cytokines are thought to act as important mediators of homoeostasis and inflammation, but in a more tissue-restricted manner. In this role, IL-36 cytokines are known to play a central role in orchestrating psoriatic inflammation in the skin and can also act as mediators of gastrointestinal inflammation and homoeostasis 19 , 20 , 21 , 22 , 23 . In contrast to these established roles of the IL-36 family, little information is available concerning how, and if, this cytokine family may influence obesity-induced systemic inflammation leading to metabolic syndrome. Related IL-1 family members have previously been studied in this context revealing opposing functions 17 , 24 . For example, IL-1β has long been implicated in the pathogenesis of both type 2 diabetes and atherosclerosis, and Canakinumab (anti-IL-1β-neutralising monoclonal antibody) is currently the focus of extensive clinical investigation for these indications 17 . In direct contrast, IL-18 and IL-33 have been demonstrated to play a protective role in animal models of obesity-driven metabolic syndrome, although the precise mechanisms through which this occurs have not been identified 17 , 24 . Moreover, there are currently no data to indicate that the microbiome may play a role in these protective effects. In this study, we demonstrate that IL-36γ expression is increased in the serum of clinically obese patients and these elevated expression levels are negatively correlated with both haemoglobin A1c (HbA1c) and fasting blood glucose (FBG) levels among patients with type 2 diabetes indicating a protective role for", "role": "user" }, { "content": "Scientists from the School of Medicine, Trinity College Dublin, have, for the first time, discovered a family of proteins that are associated with lower blood sugar levels among obese patients with type 2 diabetes. Their research is published today in the international journal Nature Communications. The study showed that patients with type 2 diabetes who have high levels of the protein, IL-36 cytokines, were found to have lower blood sugar levels, implying that those proteins are associated with better control of the patient's blood sugar levels and their disease. IL-36 cytokines are members of a larger family of proteins known as the interleukin-1 family which have emerged as central players in the development of obesity related disease. Researchers have linked the protective effects of these proteins with their ability to alter the make-up of the intestinal microbiome. Obesity causes an increased level of fatty acids and inflammation leading to insulin resistance. When the body is resistant to the insulin it produces it causes a high build-up of glucose or blood sugar, ultimately leading to type 2 diabetes. Obesity is now recognised as a global pandemic and has been definitively linked to a wide range of diseases including metabolic disorders such as diabetes, stroke and many types of cancer. The World Health Organisation state that global levels of obesity have more than doubled since 1980. In Ireland, according to the Healthy Ireland survey, 854,165 adults over 40 in the Republic of Ireland are at increased risk of developing (or have) type 2 diabetes. The economic burden of diabetes on the Irish health care system is becoming a major challenge for the government. Given the scale and global reach of the problem, current approaches aimed at reversing the tide of obesity driven disease are insufficient. The Trinity research team believe that there is an urgent need to achieve a greater understanding of the mechanisms associated with obesity related diseases. Lead scientist Dr. Patrick Walsh from the School of Medicine, Trinity, said: \"This study has added to a substantial body of work which has revealed the important function of the broader interleukin-1 family as mediators of metabolic health and disease. Our findings have opened the door to a deeper investigation of how IL-36 cytokines impact on the development of such diseases in humans and whether this can be exploited for the better treatment of patients.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Members of the interleukin-1 (IL-1) family are important mediators of obesity and metabolic disease and have been described to often play opposing roles. Here we report that the interleukin-36 (IL-36) subfamily can play a protective role against the development of disease. Elevated IL-36 cytokine expression is found in the serum of obese patients and negatively correlates with blood glucose levels among those presenting with type 2 diabetes. Mice lacking IL-36Ra, an IL-36 family signalling antagonist, develop less diet-induced weight gain, hyperglycemia and insulin resistance. These protective effects correlate with increased abundance of the metabolically protective bacteria Akkermansia muciniphila in the intestinal microbiome. IL-36 cytokines promote its outgrowth as well as increased colonic mucus secretion. These findings identify a protective role for IL-36 cytokines in obesity and metabolic disease, adding to the current understanding of the role the broader IL-1 family plays in regulating disease pathogenesis. Introduction Over the past 40 years, global levels of obesity have more than doubled. As obesity predisposes to the metabolic syndrome and has been definitively linked to coronary heart disease, stroke, type 2 diabetes and certain forms of cancer, this growing epidemic represents one of the most significant current global health challenges. In tandem with the emergence of this problem has been an increase in understanding the pathological mechanisms which link the obese state to the development of disease. Central to these mechanisms is the heightened state of systemic inflammation as a result of obesity. Since the seminal observations made by Hotamisligil et al., demonstrating the role of adipose tissue-derived TNF as an inhibitor of insulin signalling and first linking obesity-driven inflammation to type 2 diabetes 1 , it is now recognised that the nature of adipose tissue inflammation is a major contributor towards obesity-related diseases 2 , 3 , 4 . Further complexity is added through the instructive role of the gastrointestinal immune system in influencing the development of inflamed adipose tissue. It is now evident that changes in the homoeostatic barrier function of the gut can play a major role in the development of systemic inflammation in obesity 5 . In this context, it is perhaps unsurprising that the constituents of the intestinal microbiome are also emerging as an important factor in this regard. In healthy individuals, the gastrointestinal immune system plays an immunosurveillant role, in constant interaction with the intestinal microbiome which profoundly influences its activity. The role of the microbiota in the development of obesity-driven metabolic disease first emerged from studies on germ-free mice, which demonstrated reduced levels of experimental weight gain and improved glucose tolerance 6 , 7 . Moreover, the transfer of an ‘obese’ microbiome to germ-free mice can lead to significant increases in adiposity confirming the important instructive role in contributing to disease 8 . Similarly, changes in the composition of the intestinal microbiome have been associated with obesity and the development of metabolic disease in humans 9 , 10 . As well as contributing to obesity and disease, it is also becoming apparent that certain constituents of the microbiota can act opposingly to restrict adiposity. In recent times, it has been demonstrated that the presence of the bacteria Akkermansia muciniphila in the intestinal microbiome can act directly to suppress weight gain and impaired glucose tolerance in mice 11 . Many of these protective effects have now been recapitulated using a purified outer membrane protein, Amuc_1100, derived from A. muciniphila 12 . It is also noteworthy that several dietary interventions targeting obesity and glucose intolerance, and the glucose-lowering drug metformin, increase A. muciniphila abundance 11 , 13 , 14 , 15 . Significantly, follow-up studies have also demonstrated a clear association between the relative abundance of this bacterium in the microbiome and the metabolic health of obese patients 16 . Such observations suggest that the composition of the intestinal microbiome can be altered towards a more ‘healthy’ lean state, highlighting its potential as a therapeutic strategy, and placing the identification of the mechanistic pathways which can alter the composition of the microbiota as a particular area of interest. In this study, we identify the IL-36 family of cytokines as one such pathway. The IL-36 family of cytokines are a recently described subset of the larger IL-1 family which are emerging as important mediators of obesity-related metabolic disease 17 . The family consists of three separate agonistic ligands, designated IL-36α, IL-36β and IL-36γ, and a specific IL-36 receptor antagonist (IL-36Ra), all of which act through a specific IL-36 receptor 18 . Similar to the more extensively characterised ‘classical’ IL-1 cytokines, IL-1α and IL-1β, IL-36 cytokines are thought to act as important mediators of homoeostasis and inflammation, but in a more tissue-restricted manner. In this role, IL-36 cytokines are known to play a central role in orchestrating psoriatic inflammation in the skin and can also act as mediators of gastrointestinal inflammation and homoeostasis 19 , 20 , 21 , 22 , 23 . In contrast to these established roles of the IL-36 family, little information is available concerning how, and if, this cytokine family may influence obesity-induced systemic inflammation leading to metabolic syndrome. Related IL-1 family members have previously been studied in this context revealing opposing functions 17 , 24 . For example, IL-1β has long been implicated in the pathogenesis of both type 2 diabetes and atherosclerosis, and Canakinumab (anti-IL-1β-neutralising monoclonal antibody) is currently the focus of extensive clinical investigation for these indications 17 . In direct contrast, IL-18 and IL-33 have been demonstrated to play a protective role in animal models of obesity-driven metabolic syndrome, although the precise mechanisms through which this occurs have not been identified 17 , 24 . Moreover, there are currently no data to indicate that the microbiome may play a role in these protective effects. In this study, we demonstrate that IL-36γ expression is increased in the serum of clinically obese patients and these elevated expression levels are negatively correlated with both haemoglobin A1c (HbA1c) and fasting blood glucose (FBG) levels among patients with type 2 diabetes indicating a protective role for<|im_end|> <|im_start|>assistant Scientists from the School of Medicine, Trinity College Dublin, have, for the first time, discovered a family of proteins that are associated with lower blood sugar levels among obese patients with type 2 diabetes. Their research is published today in the international journal Nature Communications. The study showed that patients with type 2 diabetes who have high levels of the protein, IL-36 cytokines, were found to have lower blood sugar levels, implying that those proteins are associated with better control of the patient's blood sugar levels and their disease. IL-36 cytokines are members of a larger family of proteins known as the interleukin-1 family which have emerged as central players in the development of obesity related disease. Researchers have linked the protective effects of these proteins with their ability to alter the make-up of the intestinal microbiome. Obesity causes an increased level of fatty acids and inflammation leading to insulin resistance. When the body is resistant to the insulin it produces it causes a high build-up of glucose or blood sugar, ultimately leading to type 2 diabetes. Obesity is now recognised as a global pandemic and has been definitively linked to a wide range of diseases including metabolic disorders such as diabetes, stroke and many types of cancer. The World Health Organisation state that global levels of obesity have more than doubled since 1980. In Ireland, according to the Healthy Ireland survey, 854,165 adults over 40 in the Republic of Ireland are at increased risk of developing (or have) type 2 diabetes. The economic burden of diabetes on the Irish health care system is becoming a major challenge for the government. Given the scale and global reach of the problem, current approaches aimed at reversing the tide of obesity driven disease are insufficient. The Trinity research team believe that there is an urgent need to achieve a greater understanding of the mechanisms associated with obesity related diseases. Lead scientist Dr. Patrick Walsh from the School of Medicine, Trinity, said: "This study has added to a substantial body of work which has revealed the important function of the broader interleukin-1 family as mediators of metabolic health and disease. Our findings have opened the door to a deeper investigation of how IL-36 cytokines impact on the development of such diseases in humans and whether this can be exploited for the better treatment of patients." <|im_end|>

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1,832

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Electrification is critical to decarbonizing society, but managing increasing power densification in electrical systems will require the development of new thermal management technologies. One approach is to use monolithic-metal-based heat spreaders that reduce thermal resistance and temperature fluctuation in electronic devices. However, their electrical conductivity makes them challenging to implement. Here we report co-designed electronic systems that monolithically integrate copper directly on electronic devices for heat spreading and temperature stabilization. The approach first coats the devices with an electrical insulating layer of poly(2-chloro- p -xylylene) (parylene C) and then a conformal coating of copper. This allows the copper to be in close proximity to the heat-generating elements, eliminating the need for thermal interface materials and providing improved cooling performance compared with existing technologies. We test the approach with gallium nitride power transistors, and show that it can be used in systems operating at up to 600 V and provides a low junction-to-ambient specific thermal resistance of 2.3 cm 2 K W –1 in quiescent air and 0.7 cm 2 K W –1 in quiescent water. Main Thermal management infrastructure plays a key role in decreasing the energy consumption of electronic systems in, for example, data centres 1 , 2 and electric vehicles 3 , 4 , 5 . Efficient thermal management techniques using indirect liquid cooling 6 , 7 , 8 and immersion cooling 9 , 10 , 11 can enable heat removal with low energy consumption. Thermal management is also important for keeping device temperatures below their reliable operating limits, leading to increased reliability and higher system power densities 12 . Emergent wide-bandgap devices such as gallium nitride (GaN) and silicon carbide (SiC) transistors can tolerate junction temperatures up to 150 °C, but other components located nearby are often rated for lower operating temperatures (<100 °C), thus requiring efficient cooling techniques at the chip, board and system levels 13 . Conventionally, heat spreading is accomplished by adding a high-thermal-conductivity component to the heat-generating device 14 , thus reducing the overall junction-to-coolant thermal resistance 15 , 16 , 17 . Laptops, for example, use heat-spreading graphite, which is pressed against the electronics to facilitate heat dissipation 18 . One drawback of conventional heat spreaders is their inability to reach shadowed regions underneath devices. The absence of contact between the heat source (the junction) and the heat-spreading medium leads to less efficient cooling. Although heat-spreading methods based on diamond 19 and graphene 20 address this problem, they are not scalable. In this Article, we report a board-level heat-spreading technology in which the heat-spreading material can reach confined regions underneath devices on circuit boards and systems. The on-board devices are first coated with a high-dielectric-strength poly(2-chloro- p -xylylene) (parylene C) for electrical insulation 11 , 21 . Then, using successive depositions with thermal evaporation, electroless plating and electroplating, a conformal copper coating is monolithically grown on parylene C. The conformal copper reaches underneath the devices, creates contact with heat-generating regions and provides thermal dissipation routes from the top, bottom and sides of the package. The monolithic integration of copper also eliminates the need for a thermal interface material (TIM) 22 , 23 , typically required to fill air crevices between two mating solid surfaces even with efficient heat-spreading methods using heat pipes 24 and vapour chambers 25 . The application of TIMs requires compression to improve contact and reduce thermal impedance, which can compromise the reliability of chip-scale packages. To illustrate the capabilities of our approach, we integrate copper heat spreaders directly on GaN devices, and then characterize their electrothermal performance during steady-state and transient operations. Cooling in quiescent air or water highlights the potential for ultraefficient passive (non-pumped) cooling. Our approach offers improved performance compared with established copper heat sinks and copper-plane heat spreaders; further, by removing the need for large heat sinks, it could potentially be used to create compact and power-dense electronics. Heat spreader fabrication To demonstrate the integration of our coating (Fig. 1 ) with devices using different soldering methods, we designed printed circuit boards (PCBs) with two different GaN power transistors: a top-cooled GS66508T surface-mount device (SMD) and a top-cooled EPC2034 ball grid array (BGA) device. We start by depositing an electrical insulating layer of parylene C to prevent the electrical shorting of devices by the Cu coating (Fig. 1a ). Since parylene is deposited by chemical vapour deposition (CVD), it conformally covers all the exposed circuits, ensuring the electrical insulation of PCBs. Next, we proceed with growing Cu on top of parylene. We first deposit a nanometric seed metal layer via physical vapour deposition (PVD) such as thermal evaporation 26 . Since PVD methods cannot reach the shadowed regions underneath devices (Fig. 1b ), if we directly proceed with electroplating after thermal evaporation, the discontinuous film of Cu fails to drive the electrical current to the top of the devices, resulting in uncoated devices. To overcome this challenge, we added an electroless deposition step that bridges the PVD film and creates a continuous coating (Fig. 1c ). We attempted to use electroless deposition without the PVD step but failed to achieve high-quality coatings. After the electroless deposition step, we increase the thickness of the Cu coating to the desired level by electroplating Cu, resulting in a monolithically integrated Cu-coated heat spreader (Fig. 1d ). Fig. 1: Cu-coated heat spreader fabrication. a , Schematic showing the coating of GaN devices and PCBs with a layer of parylene C for electrical insulation. Parylene C is deposited via CVD, conformally covering the boards and reaching underneath the devices. b , Schematic of the deposition of a 20-nm-thick Cr layer followed by a 50-nm-thick Cu layer via PVD. The PVD Cu layer acts as a seed layer for the micrometre-thick electroless Cu deposition. c , Schematic of the electroless deposition of Cu to cover the shadowed regions underneath the devices and create a continuous Cu film that can drive electrical current from FR-4 to the top of the device. d , Schematic showing further growth of Cu using d.c.", "role": "user" }, { "content": "Electronic devices, including smartphones and tablet portable computers, are becoming increasingly advanced and compact. As their performance increases and their size decreases, these devices generate more heat, which can reduce their safety and cause them to break. In recent years, engineers have thus been trying to develop strategies that could prevent electronics from overheating. One proposed solution entails the use of heat spreaders, layers that promote the spread and dissipation of heat inside devices. Researchers at University of Illinois at Urbana-Champaign and University of California, Berkeley (UC Berkeley) have recently devised an alternative strategy that could cool electronics more efficiently than other existing solutions. Their strategy, introduced in a paper published in Nature Electronics, is based on the use of heat spreaders comprised of an electrical insulating layer of poly (2-chloro-p-xylylene) (Parylene C) and a coating of copper. \"Our recent paper was the culmination of our efforts to produce coating heat spreaders for high-efficiency electronics cooling,\" Tarek Gebrael, one of the researchers who carried out the study, told TechXplore. \"The motivation was to enable effective heat dissipation from power-dense electronics.\" Heat spreaders are cooling systems comprised of materials with a high-thermal conductivity, such as copper and aluminum. These systems can spread the heat generated by the devices across a larger surface area, making it easier for them to dissipate heat into the surrounding environment. \"The advantage of using our conformal coating heat spreaders is that they cover the electronic device entirely, including the top, bottom, and sides of the device,\" Gebrael explained. \"This is impossible with standard heat spreaders which are usually added on top of the device or with standard PCB copper planes. By achieving those conformal coatings, we were able to provide more routes for the heat to leave the electronic device, which translates into a better cooling performance.\" In the past, teams had developed similar techniques that prevent overheating by opening more \"routes\" for heat to leave electronic devices. Previously proposed solutions, however, utilize very expensive materials, such as diamond. This makes them difficult to develop and implement on a large scale. Gebrael and his colleagues evaluated their copper coated-heat spreaders in a series of tests and found that they performed extremely well. Specifically, their solution achieved up to a 740% increase in the power per unit volume compared to standard air-cooled copper heat sinks used today. \"This remarkable result derives from our spreaders' effectiveness in dissipating the heat, as well as the compact volume they occupy when applied on printed circuit boards,\" Gebrael said. \"This feature enables fitting more electronics in a smaller space without overheating issues, which is essential to create the platforms of future technologies (AI, augmented reality, etc.).\" In the future, the heat spreaders developed by this team of researchers could be used to cool down electronic devices more efficiently, without requiring expensive materials. Notably, the coating recipe they proposed combines processes that are already in use in the electronics industry. This could further facilitate its application in real-world settings and its commercialization. \"We are now investigating the reliability and durability of our coatings in specific environments (boiling water, boiling dielectric fluids, thermal cycling, and high-voltage environments) for long periods of time,\" Gebrael added. \"We want to make sure that our coatings retain their superior cooling performance. We are also implementing the coatings with full-scale power modules and GPU cards, whereas we used only simple test boards in the initial work.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Electrification is critical to decarbonizing society, but managing increasing power densification in electrical systems will require the development of new thermal management technologies. One approach is to use monolithic-metal-based heat spreaders that reduce thermal resistance and temperature fluctuation in electronic devices. However, their electrical conductivity makes them challenging to implement. Here we report co-designed electronic systems that monolithically integrate copper directly on electronic devices for heat spreading and temperature stabilization. The approach first coats the devices with an electrical insulating layer of poly(2-chloro- p -xylylene) (parylene C) and then a conformal coating of copper. This allows the copper to be in close proximity to the heat-generating elements, eliminating the need for thermal interface materials and providing improved cooling performance compared with existing technologies. We test the approach with gallium nitride power transistors, and show that it can be used in systems operating at up to 600 V and provides a low junction-to-ambient specific thermal resistance of 2.3 cm 2 K W –1 in quiescent air and 0.7 cm 2 K W –1 in quiescent water. Main Thermal management infrastructure plays a key role in decreasing the energy consumption of electronic systems in, for example, data centres 1 , 2 and electric vehicles 3 , 4 , 5 . Efficient thermal management techniques using indirect liquid cooling 6 , 7 , 8 and immersion cooling 9 , 10 , 11 can enable heat removal with low energy consumption. Thermal management is also important for keeping device temperatures below their reliable operating limits, leading to increased reliability and higher system power densities 12 . Emergent wide-bandgap devices such as gallium nitride (GaN) and silicon carbide (SiC) transistors can tolerate junction temperatures up to 150 °C, but other components located nearby are often rated for lower operating temperatures (<100 °C), thus requiring efficient cooling techniques at the chip, board and system levels 13 . Conventionally, heat spreading is accomplished by adding a high-thermal-conductivity component to the heat-generating device 14 , thus reducing the overall junction-to-coolant thermal resistance 15 , 16 , 17 . Laptops, for example, use heat-spreading graphite, which is pressed against the electronics to facilitate heat dissipation 18 . One drawback of conventional heat spreaders is their inability to reach shadowed regions underneath devices. The absence of contact between the heat source (the junction) and the heat-spreading medium leads to less efficient cooling. Although heat-spreading methods based on diamond 19 and graphene 20 address this problem, they are not scalable. In this Article, we report a board-level heat-spreading technology in which the heat-spreading material can reach confined regions underneath devices on circuit boards and systems. The on-board devices are first coated with a high-dielectric-strength poly(2-chloro- p -xylylene) (parylene C) for electrical insulation 11 , 21 . Then, using successive depositions with thermal evaporation, electroless plating and electroplating, a conformal copper coating is monolithically grown on parylene C. The conformal copper reaches underneath the devices, creates contact with heat-generating regions and provides thermal dissipation routes from the top, bottom and sides of the package. The monolithic integration of copper also eliminates the need for a thermal interface material (TIM) 22 , 23 , typically required to fill air crevices between two mating solid surfaces even with efficient heat-spreading methods using heat pipes 24 and vapour chambers 25 . The application of TIMs requires compression to improve contact and reduce thermal impedance, which can compromise the reliability of chip-scale packages. To illustrate the capabilities of our approach, we integrate copper heat spreaders directly on GaN devices, and then characterize their electrothermal performance during steady-state and transient operations. Cooling in quiescent air or water highlights the potential for ultraefficient passive (non-pumped) cooling. Our approach offers improved performance compared with established copper heat sinks and copper-plane heat spreaders; further, by removing the need for large heat sinks, it could potentially be used to create compact and power-dense electronics. Heat spreader fabrication To demonstrate the integration of our coating (Fig. 1 ) with devices using different soldering methods, we designed printed circuit boards (PCBs) with two different GaN power transistors: a top-cooled GS66508T surface-mount device (SMD) and a top-cooled EPC2034 ball grid array (BGA) device. We start by depositing an electrical insulating layer of parylene C to prevent the electrical shorting of devices by the Cu coating (Fig. 1a ). Since parylene is deposited by chemical vapour deposition (CVD), it conformally covers all the exposed circuits, ensuring the electrical insulation of PCBs. Next, we proceed with growing Cu on top of parylene. We first deposit a nanometric seed metal layer via physical vapour deposition (PVD) such as thermal evaporation 26 . Since PVD methods cannot reach the shadowed regions underneath devices (Fig. 1b ), if we directly proceed with electroplating after thermal evaporation, the discontinuous film of Cu fails to drive the electrical current to the top of the devices, resulting in uncoated devices. To overcome this challenge, we added an electroless deposition step that bridges the PVD film and creates a continuous coating (Fig. 1c ). We attempted to use electroless deposition without the PVD step but failed to achieve high-quality coatings. After the electroless deposition step, we increase the thickness of the Cu coating to the desired level by electroplating Cu, resulting in a monolithically integrated Cu-coated heat spreader (Fig. 1d ). Fig. 1: Cu-coated heat spreader fabrication. a , Schematic showing the coating of GaN devices and PCBs with a layer of parylene C for electrical insulation. Parylene C is deposited via CVD, conformally covering the boards and reaching underneath the devices. b , Schematic of the deposition of a 20-nm-thick Cr layer followed by a 50-nm-thick Cu layer via PVD. The PVD Cu layer acts as a seed layer for the micrometre-thick electroless Cu deposition. c , Schematic of the electroless deposition of Cu to cover the shadowed regions underneath the devices and create a continuous Cu film that can drive electrical current from FR-4 to the top of the device. d , Schematic showing further growth of Cu using d.c.<|im_end|> <|im_start|>assistant Electronic devices, including smartphones and tablet portable computers, are becoming increasingly advanced and compact. As their performance increases and their size decreases, these devices generate more heat, which can reduce their safety and cause them to break. In recent years, engineers have thus been trying to develop strategies that could prevent electronics from overheating. One proposed solution entails the use of heat spreaders, layers that promote the spread and dissipation of heat inside devices. Researchers at University of Illinois at Urbana-Champaign and University of California, Berkeley (UC Berkeley) have recently devised an alternative strategy that could cool electronics more efficiently than other existing solutions. Their strategy, introduced in a paper published in Nature Electronics, is based on the use of heat spreaders comprised of an electrical insulating layer of poly (2-chloro-p-xylylene) (Parylene C) and a coating of copper. "Our recent paper was the culmination of our efforts to produce coating heat spreaders for high-efficiency electronics cooling," Tarek Gebrael, one of the researchers who carried out the study, told TechXplore. "The motivation was to enable effective heat dissipation from power-dense electronics." Heat spreaders are cooling systems comprised of materials with a high-thermal conductivity, such as copper and aluminum. These systems can spread the heat generated by the devices across a larger surface area, making it easier for them to dissipate heat into the surrounding environment. "The advantage of using our conformal coating heat spreaders is that they cover the electronic device entirely, including the top, bottom, and sides of the device," Gebrael explained. "This is impossible with standard heat spreaders which are usually added on top of the device or with standard PCB copper planes. By achieving those conformal coatings, we were able to provide more routes for the heat to leave the electronic device, which translates into a better cooling performance." In the past, teams had developed similar techniques that prevent overheating by opening more "routes" for heat to leave electronic devices. Previously proposed solutions, however, utilize very expensive materials, such as diamond. This makes them difficult to develop and implement on a large scale. Gebrael and his colleagues evaluated their copper coated-heat spreaders in a series of tests and found that they performed extremely well. Specifically, their solution achieved up to a 740% increase in the power per unit volume compared to standard air-cooled copper heat sinks used today. "This remarkable result derives from our spreaders' effectiveness in dissipating the heat, as well as the compact volume they occupy when applied on printed circuit boards," Gebrael said. "This feature enables fitting more electronics in a smaller space without overheating issues, which is essential to create the platforms of future technologies (AI, augmented reality, etc.)." In the future, the heat spreaders developed by this team of researchers could be used to cool down electronic devices more efficiently, without requiring expensive materials. Notably, the coating recipe they proposed combines processes that are already in use in the electronics industry. This could further facilitate its application in real-world settings and its commercialization. "We are now investigating the reliability and durability of our coatings in specific environments (boiling water, boiling dielectric fluids, thermal cycling, and high-voltage environments) for long periods of time," Gebrael added. "We want to make sure that our coatings retain their superior cooling performance. We are also implementing the coatings with full-scale power modules and GPU cards, whereas we used only simple test boards in the initial work." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The function-optimized properties of biominerals arise from the hierarchical organization of primary building blocks. Alteration of properties in response to environmental stresses generally involves time-intensive processes of resorption and reprecipitation of mineral in the underlying organic scaffold. Here, we report that the load-bearing shells of the brachiopod Discinisca tenuis are an exception to this process. These shells can dynamically modulate their mechanical properties in response to a change in environment, switching from hard and stiff when dry to malleable when hydrated within minutes. Using ptychographic X-ray tomography, electron microscopy and spectroscopy, we describe their hierarchical structure and composition as a function of hydration to understand the structural motifs that generate this adaptability. Key is a complementary set of structural modifications, starting with the swelling of an organic matrix on the micron level via nanocrystal reorganization and ending in an intercalation process on the molecular level in response to hydration. Introduction For hundreds of millions of years, nature has evolved a large assortment of organic–inorganic hybrid materials such as bone, teeth, and shells. Each of these biominerals exhibits material properties that have been optimized to aid a particular function, such as navigation, protection, or mechanical support 1 , 2 . These properties arise from a three-dimensional multi-scale organization of the biomineral’s primary building blocks, e.g., inorganic nanocrystals, specialized proteins, and polysaccharides, from the molecular to the millimeter scale 3 , 4 , 5 . Biominerals with load-bearing functions are optimized, in particular, with respect to their mechanical properties, so as to provide sufficient stiffness to support the typical mechanical loads in the biomineral’s environment and enough toughness to resist crack propagation 3 . This optimization is achieved, first, by incorporating organic biopolymers within the inorganic phase, which increases the toughness of the inherently brittle mineral 6 , and second by organizing the basic building blocks of the tissue into higher-order structures 7 . This hierarchical organization creates a large number of internal interfaces that help to avoid crack propagation and significantly increases fracture toughness. A further advantage of a hierarchical structure is that it endows the organism with an additional level of constructional control, where the basic building blocks can be assembled into different structural motifs of different mechanical properties 8 . Altering the material properties of the biomineral in response to environmental stresses, generally requires active restructuring by remodeling by the organism. A time- and energy-consuming process that involves the resorption of the existing biomineral, followed by the precipitation of new tissue with a different structure and composition 9 , 10 . In this paper, we report that the load-bearing shells of the brachiopod Discinisca tenuis 11 are able to dynamically modulate their mechanical properties in response to a change in the environment without the need for remodeling via resorption and regeneration of the tissue, i.e., they switch from hard and stiff when dry to malleable when hydrated within minutes. Importantly, when hydrated the shell can freely bend to the point that it can be folded in two without fracturing. The effects that water and organic matrix hydration degree have on the mechanical properties of biominerals are well recognized 12 . Water, as a component of most biominerals, is known to increase the flexibility of materials such as bone, teeth, and shells. Modulation of hardness and elastic modulus/flexibility 13 by passive control of the water content of the tissue has been suggested to occur in non-mineralized insect cuticle 14 and in mineralized crustacean cuticles, both of which contain organic matrices composed of chitin and proteins 15 , 16 . In these cases, the changes in mechanical properties are due to the plasticizing role of water and do not involve major changes in the structure of the tissue 12 , 16 . However, none of these aforementioned mineralized tissues exhibit flexibility that is comparable to that of the mineralized D. tenuis shell when in their natural, hydrated state. We hypothesized that the extreme flexibility of the hydrated D. tenuis shell cannot be accounted for solely by the plasticizing effect of water as in these other examples. Rather, such reversibility between stiff and flexible as a function of hydration must have its origins in the structure of the D. tenuis shell with water promoting structural changes at different hierarchical levels. The mechanisms that underpin these changes in mechanical properties as a function of hydration are unknown. Chemically controllable material properties and the causal structural motives are of significant interest in the design of stimuli-responsive synthetic materials 17 . As such, there is imperative to determine how hydration alters the structure of the D. tenuis shell, and how these changes facilitate the modulation in mechanical properties. Using a combination of ptychographic X-ray tomography, electron microscopy, small- and wide-angle X-ray scattering, solid-state nuclear magnetic resonance spectroscopy, and mechanical testing, we characterized the shell’s hierarchical structure and composition as a function of hydration covering the micro- and nanoscales and provide an insight into molecular changes. We demonstrate that water absorption by the shell induces a complementary set of structural modifications, starting with the swelling of an organic matrix on the micron level, via nanocrystal reorganization and restructuring, and ending in the intercalation of water between the organic framework and the mineral on the molecular level. In combination, we propose that these changes endow the shell with its mechanical adaptability. We envisage that these observations will aid/ inspire the design of novel synthetic materials with properties that can be modulated in real-time. Results Global compositional analysis The shells of D. tenuis (Fig. 1a ) are an organic-inorganic composite material, where the mineral phase constitutes about 68 wt% of the dry shell 11 . The mineral phase is composed predominantly of carbonate-substituted fluorapatite crystals in the form of francolite 18 (Supplementary Fig. 1 ) with minor contributions of amorphous calcium phosphate, octacalcium phosphate, and tricalcium phosphate 19 . The remaining ~32 wt% of the shell consist of various organic fractions, of which chitin, glycosaminoglycans, and proteins make up the dominant portion 11 , 19 , 20", "role": "user" }, { "content": "An international research team with participation of the Paul Scherrer Institute PSI has deciphered why the protective cover of the brachiopod Discinisca tenuis becomes extremely soft in water and gets hard again in the air. The study appears today in the journal Nature Communications. The brachiopod Discinisca tenuis lives on the west coast of Africa. It has a mineral-rich shell that protects it from harmful environmental influences. Bathing the shell in water leads to a structural change in the material: The flat, hard shell becomes so flexible that it can even be folded up without breaking. With the help of the Swiss Light Source SLS, the researchers have deciphered exactly how this transformation takes place. The phenomenon was discovered by chance a few years ago by Fabio Nudelman, a materials chemist currently at the School of Chemistry, University of Edinburgh in Scotland. Maggie Cusack, who was recently appointed president of Munster Technological University in Ireland, had provided Nudelman with shells of the brachiopod Discinisca tenuis, which originally came from Namibia. When he wanted to wash the hard object, it suddenly became soft and flexible in contact with water. The shell had absorbed liquid and thereby changed its structure. The process was reversible: When the shell dried, it became hard and brittle again. Together with colleagues from six countries, Nudelman set out to discover what exactly takes place during this unexpected transformation. \"In its composition, the shell resembles bone,\" he explains. \"But bone doesn't change its structure when it gets wet.\" The same goes for clams: If the animals need to adapt the properties of their shell to different environmental conditions, they normally have to rework the material in a lengthy and energetically costly process, by resorbing and redistributing minerals. It doesn't work simply through the absorption of water. Johannes Ihli und co-author Klaus Wakonig at SLS’s cSAXS beamline. Credit: Paul Scherrer Institute/Markus Fischer Hybrid material with a special trick It was so-called cryo-tomography, performed at the Swiss Light Source SLS, that \"opened the door to reveal the secret,\" says Johannes Ihli, a PSI researcher at SLS. With this technique, the researchers examined the material as if under a very high-resolution microscope, and in fact at extremely low temperatures. \"At room temperature it would not have been possible, since the high-energy X-ray light would immediately alter the sensitive shell structure,\" Ihli explains. The brachiopod's shell, which is no more than half a millimeter thick, consists of a hybrid material: mainly inorganic mineral in which organic polymers made from proteins and sugars are embedded. Bones, clam shells, and teeth are structured in a similar way out of a mixture of organic and inorganic material. The mineral that constitutes the main component of the shell is a type of fluoroapatite—similar to the material that makes up the enamel of our teeth. Tiny nanocrystals of this material are arranged in layers. Nudelman compares it to brick walls: \"In this analogy, the bricks are the nanocrystals, and the mortar between the bricks consists of organic molecules such as chitin and proteins.\" As the researchers observed, this \"mortar\" can absorb large amounts of water, causing it to swell up. Through the storage of water, it changes its structure: It becomes soft, and the bricks become movable with respect to each other. \"Then water acts like a lubricant between the individual nanocrystals,\" Ihli explains. \"The crystals can then slip against each other.\" Through this movement, the shell becomes flexible. The researchers found a network of pores in the shell that was especially effective in guiding water inside and rapidly distributing it throughout the material. Evolutionary advantage Discinisca tenuis lives in large clusters in tidal zones on the coast where, depending on the tide, the animals are exposed to strong waves or calm waters. The researchers speculate that it is probably advantageous if the animals can quickly adapt the softness or hardness of their shell to the respective situation: \"This could prevent damage to the shell and thus be a key to the animals' survival,\" they write in the study. The phenomenon may even be more widespread than suspected: \"We don't know how many other animal species there might be that have this kind of property,\" says Nudelman. Aside from biology and evolution, the newly gained insights are also of interest for materials science: The development of a hard, brittle material whose stiffness can be controlled could hold promise for many applications. Sports clothing or helmets, for example, might be able to flexibly adapt to movements and always offer the protection required depending on the impact. Harnessing this phenomenon could also prove useful in developing bone-replacement materials. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The function-optimized properties of biominerals arise from the hierarchical organization of primary building blocks. Alteration of properties in response to environmental stresses generally involves time-intensive processes of resorption and reprecipitation of mineral in the underlying organic scaffold. Here, we report that the load-bearing shells of the brachiopod Discinisca tenuis are an exception to this process. These shells can dynamically modulate their mechanical properties in response to a change in environment, switching from hard and stiff when dry to malleable when hydrated within minutes. Using ptychographic X-ray tomography, electron microscopy and spectroscopy, we describe their hierarchical structure and composition as a function of hydration to understand the structural motifs that generate this adaptability. Key is a complementary set of structural modifications, starting with the swelling of an organic matrix on the micron level via nanocrystal reorganization and ending in an intercalation process on the molecular level in response to hydration. Introduction For hundreds of millions of years, nature has evolved a large assortment of organic–inorganic hybrid materials such as bone, teeth, and shells. Each of these biominerals exhibits material properties that have been optimized to aid a particular function, such as navigation, protection, or mechanical support 1 , 2 . These properties arise from a three-dimensional multi-scale organization of the biomineral’s primary building blocks, e.g., inorganic nanocrystals, specialized proteins, and polysaccharides, from the molecular to the millimeter scale 3 , 4 , 5 . Biominerals with load-bearing functions are optimized, in particular, with respect to their mechanical properties, so as to provide sufficient stiffness to support the typical mechanical loads in the biomineral’s environment and enough toughness to resist crack propagation 3 . This optimization is achieved, first, by incorporating organic biopolymers within the inorganic phase, which increases the toughness of the inherently brittle mineral 6 , and second by organizing the basic building blocks of the tissue into higher-order structures 7 . This hierarchical organization creates a large number of internal interfaces that help to avoid crack propagation and significantly increases fracture toughness. A further advantage of a hierarchical structure is that it endows the organism with an additional level of constructional control, where the basic building blocks can be assembled into different structural motifs of different mechanical properties 8 . Altering the material properties of the biomineral in response to environmental stresses, generally requires active restructuring by remodeling by the organism. A time- and energy-consuming process that involves the resorption of the existing biomineral, followed by the precipitation of new tissue with a different structure and composition 9 , 10 . In this paper, we report that the load-bearing shells of the brachiopod Discinisca tenuis 11 are able to dynamically modulate their mechanical properties in response to a change in the environment without the need for remodeling via resorption and regeneration of the tissue, i.e., they switch from hard and stiff when dry to malleable when hydrated within minutes. Importantly, when hydrated the shell can freely bend to the point that it can be folded in two without fracturing. The effects that water and organic matrix hydration degree have on the mechanical properties of biominerals are well recognized 12 . Water, as a component of most biominerals, is known to increase the flexibility of materials such as bone, teeth, and shells. Modulation of hardness and elastic modulus/flexibility 13 by passive control of the water content of the tissue has been suggested to occur in non-mineralized insect cuticle 14 and in mineralized crustacean cuticles, both of which contain organic matrices composed of chitin and proteins 15 , 16 . In these cases, the changes in mechanical properties are due to the plasticizing role of water and do not involve major changes in the structure of the tissue 12 , 16 . However, none of these aforementioned mineralized tissues exhibit flexibility that is comparable to that of the mineralized D. tenuis shell when in their natural, hydrated state. We hypothesized that the extreme flexibility of the hydrated D. tenuis shell cannot be accounted for solely by the plasticizing effect of water as in these other examples. Rather, such reversibility between stiff and flexible as a function of hydration must have its origins in the structure of the D. tenuis shell with water promoting structural changes at different hierarchical levels. The mechanisms that underpin these changes in mechanical properties as a function of hydration are unknown. Chemically controllable material properties and the causal structural motives are of significant interest in the design of stimuli-responsive synthetic materials 17 . As such, there is imperative to determine how hydration alters the structure of the D. tenuis shell, and how these changes facilitate the modulation in mechanical properties. Using a combination of ptychographic X-ray tomography, electron microscopy, small- and wide-angle X-ray scattering, solid-state nuclear magnetic resonance spectroscopy, and mechanical testing, we characterized the shell’s hierarchical structure and composition as a function of hydration covering the micro- and nanoscales and provide an insight into molecular changes. We demonstrate that water absorption by the shell induces a complementary set of structural modifications, starting with the swelling of an organic matrix on the micron level, via nanocrystal reorganization and restructuring, and ending in the intercalation of water between the organic framework and the mineral on the molecular level. In combination, we propose that these changes endow the shell with its mechanical adaptability. We envisage that these observations will aid/ inspire the design of novel synthetic materials with properties that can be modulated in real-time. Results Global compositional analysis The shells of D. tenuis (Fig. 1a ) are an organic-inorganic composite material, where the mineral phase constitutes about 68 wt% of the dry shell 11 . The mineral phase is composed predominantly of carbonate-substituted fluorapatite crystals in the form of francolite 18 (Supplementary Fig. 1 ) with minor contributions of amorphous calcium phosphate, octacalcium phosphate, and tricalcium phosphate 19 . The remaining ~32 wt% of the shell consist of various organic fractions, of which chitin, glycosaminoglycans, and proteins make up the dominant portion 11 , 19 , 20<|im_end|> <|im_start|>assistant An international research team with participation of the Paul Scherrer Institute PSI has deciphered why the protective cover of the brachiopod Discinisca tenuis becomes extremely soft in water and gets hard again in the air. The study appears today in the journal Nature Communications. The brachiopod Discinisca tenuis lives on the west coast of Africa. It has a mineral-rich shell that protects it from harmful environmental influences. Bathing the shell in water leads to a structural change in the material: The flat, hard shell becomes so flexible that it can even be folded up without breaking. With the help of the Swiss Light Source SLS, the researchers have deciphered exactly how this transformation takes place. The phenomenon was discovered by chance a few years ago by Fabio Nudelman, a materials chemist currently at the School of Chemistry, University of Edinburgh in Scotland. Maggie Cusack, who was recently appointed president of Munster Technological University in Ireland, had provided Nudelman with shells of the brachiopod Discinisca tenuis, which originally came from Namibia. When he wanted to wash the hard object, it suddenly became soft and flexible in contact with water. The shell had absorbed liquid and thereby changed its structure. The process was reversible: When the shell dried, it became hard and brittle again. Together with colleagues from six countries, Nudelman set out to discover what exactly takes place during this unexpected transformation. "In its composition, the shell resembles bone," he explains. "But bone doesn't change its structure when it gets wet." The same goes for clams: If the animals need to adapt the properties of their shell to different environmental conditions, they normally have to rework the material in a lengthy and energetically costly process, by resorbing and redistributing minerals. It doesn't work simply through the absorption of water. Johannes Ihli und co-author Klaus Wakonig at SLS’s cSAXS beamline. Credit: Paul Scherrer Institute/Markus Fischer Hybrid material with a special trick It was so-called cryo-tomography, performed at the Swiss Light Source SLS, that "opened the door to reveal the secret," says Johannes Ihli, a PSI researcher at SLS. With this technique, the researchers examined the material as if under a very high-resolution microscope, and in fact at extremely low temperatures. "At room temperature it would not have been possible, since the high-energy X-ray light would immediately alter the sensitive shell structure," Ihli explains. The brachiopod's shell, which is no more than half a millimeter thick, consists of a hybrid material: mainly inorganic mineral in which organic polymers made from proteins and sugars are embedded. Bones, clam shells, and teeth are structured in a similar way out of a mixture of organic and inorganic material. The mineral that constitutes the main component of the shell is a type of fluoroapatite—similar to the material that makes up the enamel of our teeth. Tiny nanocrystals of this material are arranged in layers. Nudelman compares it to brick walls: "In this analogy, the bricks are the nanocrystals, and the mortar between the bricks consists of organic molecules such as chitin and proteins." As the researchers observed, this "mortar" can absorb large amounts of water, causing it to swell up. Through the storage of water, it changes its structure: It becomes soft, and the bricks become movable with respect to each other. "Then water acts like a lubricant between the individual nanocrystals," Ihli explains. "The crystals can then slip against each other." Through this movement, the shell becomes flexible. The researchers found a network of pores in the shell that was especially effective in guiding water inside and rapidly distributing it throughout the material. Evolutionary advantage Discinisca tenuis lives in large clusters in tidal zones on the coast where, depending on the tide, the animals are exposed to strong waves or calm waters. The researchers speculate that it is probably advantageous if the animals can quickly adapt the softness or hardness of their shell to the respective situation: "This could prevent damage to the shell and thus be a key to the animals' survival," they write in the study. The phenomenon may even be more widespread than suspected: "We don't know how many other animal species there might be that have this kind of property," says Nudelman. Aside from biology and evolution, the newly gained insights are also of interest for materials science: The development of a hard, brittle material whose stiffness can be controlled could hold promise for many applications. Sports clothing or helmets, for example, might be able to flexibly adapt to movements and always offer the protection required depending on the impact. Harnessing this phenomenon could also prove useful in developing bone-replacement materials. <|im_end|>

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6439, 389, 279, 9909, 13962, 315, 10384, 13, 1102, 706, 264, 25107, 41947, 12811, 430, 36236, 433, 505, 28856, 12434, 34453, 13, 19710, 287, 279, 12811, 304, 3090, 11767, 311, 264, 24693, 2349, 304, 279, 3769, 25, 578, 10269, 11, 2653, 12811, 9221, 779, 19303, 430, 433, 649, 1524, 387, 48135, 709, 2085, 15061, 13, 3161, 279, 1520, 315, 279, 30791, 8828, 8922, 328, 7416, 11, 279, 12074, 617, 75277, 291, 7041, 1268, 420, 18475, 5097, 2035, 13, 578, 25885, 574, 11352, 555, 6140, 264, 2478, 1667, 4227, 555, 19797, 822, 452, 664, 64641, 11, 264, 7384, 8590, 380, 5131, 520, 279, 6150, 315, 42846, 11, 3907, 315, 41406, 304, 19627, 13, 62795, 356, 355, 474, 11, 889, 574, 6051, 21489, 4872, 315, 28982, 3751, 7146, 5848, 3907, 304, 14990, 11, 1047, 3984, 452, 664, 64641, 449, 44054, 315, 279, 1437, 31464, 454, 347, 11997, 85703, 936, 259, 1509, 285, 11, 902, 13517, 3782, 505, 31074, 67337, 13, 3277, 568, 4934, 311, 11623, 279, 2653, 1665, 11, 433, 15187, 6244, 8579, 323, 19303, 304, 3729, 449, 3090, 13, 578, 12811, 1047, 42101, 14812, 323, 28592, 5614, 1202, 6070, 13, 578, 1920, 574, 81193, 25, 3277, 279, 12811, 32720, 11, 433, 6244, 2653, 323, 95749, 1578, 13, 32255, 449, 18105, 505, 4848, 5961, 11, 452, 664, 64641, 743, 704, 311, 7142, 1148, 7041, 5097, 2035, 2391, 420, 16907, 18475, 13, 330, 644, 1202, 18528, 11, 279, 12811, 53291, 17685, 1359, 568, 15100, 13, 330, 4071, 17685, 3250, 956, 2349, 1202, 6070, 994, 433, 5334, 14739, 1210, 578, 1890, 5900, 369, 1206, 4214, 25, 1442, 279, 10099, 1205, 311, 10737, 279, 6012, 315, 872, 12811, 311, 2204, 12434, 4787, 11, 814, 14614, 617, 311, 312, 1816, 279, 3769, 304, 264, 35306, 323, 38556, 456, 2740, 34348, 1920, 11, 555, 594, 269, 7278, 323, 8873, 10831, 34072, 13, 1102, 3250, 956, 990, 5042, 1555, 279, 44225, 315, 3090, 13, 55205, 19589, 747, 2073, 1080, 43802, 82197, 86637, 263, 343, 520, 328, 7416, 753, 272, 50, 3027, 50, 24310, 1074, 13, 16666, 25, 7043, 5124, 32029, 10181, 14, 9126, 355, 63016, 50727, 3769, 449, 264, 3361, 14397, 1102, 574, 779, 19434, 16106, 78, 2442, 316, 5814, 11, 10887, 520, 279, 30791, 8828, 8922, 328, 7416, 11, 430, 330, 57228, 279, 6134, 311, 16805, 279, 6367, 1359, 2795, 55205, 19589, 747, 11, 264, 89278, 32185, 520, 328, 7416, 13, 3161, 420, 15105, 11, 279, 12074, 25078, 279, 3769, 439, 422, 1234, 264, 1633, 1579, 64036, 73757, 11, 323, 304, 2144, 520, 9193, 3428, 20472, 13, 330, 1688, 3130, 9499, 433, 1053, 539, 617, 1027, 3284, 11, 2533, 279, 1579, 65487, 1630, 30630, 3177, 1053, 7214, 11857, 279, 16614, 12811, 6070, 1359, 19589, 747, 15100, 13, 578, 1437, 31464, 454, 347, 596, 12811, 11, 902, 374, 912, 810, 1109, 4376, 264, 2606, 26402, 12314, 11, 17610, 315, 264, 26038, 3769, 25, 14918, 304, 61694, 25107, 304, 902, 17808, 46033, 388, 1903, 505, 28896, 323, 70913, 527, 23711, 13, 72399, 11, 60610, 44054, 11, 323, 18311, 527, 34030, 304, 264, 4528, 1648, 704, 315, 264, 21655, 315, 17808, 323, 304, 61694, 3769, 13, 578, 25107, 430, 42675, 279, 1925, 3777, 315, 279, 12811, 374, 264, 955, 315, 20236, 18812, 26844, 635, 2345, 65387, 311, 279, 3769, 430, 3727, 709, 279, 92848, 315, 1057, 18311, 13, 49074, 20622, 4309, 92475, 315, 420, 3769, 527, 28902, 304, 13931, 13, 452, 664, 64641, 43565, 433, 311, 25878, 14620, 25, 330, 644, 420, 56203, 11, 279, 50137, 527, 279, 20622, 4309, 92475, 11, 323, 279, 58560, 1990, 279, 50137, 17610, 315, 17808, 35715, 1778, 439, 523, 85986, 323, 28896, 1210, 1666, 279, 12074, 13468, 11, 420, 330, 93711, 277, 1, 649, 35406, 3544, 15055, 315, 3090, 11, 14718, 433, 311, 78353, 709, 13, 17331, 279, 5942, 315, 3090, 11, 433, 4442, 1202, 6070, 25, 1102, 9221, 8579, 11, 323, 279, 50137, 3719, 83679, 449, 5201, 311, 1855, 1023, 13, 330, 12487, 3090, 14385, 1093, 264, 54494, 519, 1990, 279, 3927, 20622, 4309, 92475, 1359, 19589, 747, 15100, 13, 330, 791, 48473, 649, 1243, 21818, 2403, 1855, 1023, 1210, 17331, 420, 7351, 11, 279, 12811, 9221, 19303, 13, 578, 12074, 1766, 264, 4009, 315, 72028, 304, 279, 12811, 430, 574, 5423, 7524, 304, 51346, 3090, 4871, 323, 19019, 50812, 433, 6957, 279, 3769, 13, 38321, 661, 9610, 11997, 85703, 936, 259, 1509, 285, 6439, 304, 3544, 28066, 304, 86559, 26467, 389, 279, 13962, 1405, 11, 11911, 389, 279, 43038, 11, 279, 10099, 527, 15246, 311, 3831, 17301, 477, 19858, 21160, 13, 578, 12074, 64601, 430, 433, 374, 4762, 76824, 422, 279, 10099, 649, 6288, 10737, 279, 8579, 2136, 477, 72003, 315, 872, 12811, 311, 279, 20081, 6671, 25, 330, 2028, 1436, 5471, 5674, 311, 279, 12811, 323, 8617, 387, 264, 1401, 311, 279, 10099, 6, 20237, 1359, 814, 3350, 304, 279, 4007, 13, 578, 25885, 1253, 1524, 387, 810, 24716, 1109, 24740, 25, 330, 1687, 1541, 956, 1440, 1268, 1690, 1023, 10065, 9606, 1070, 2643, 387, 430, 617, 420, 3169, 315, 3424, 1359, 2795, 452, 664, 64641, 13, 57194, 505, 34458, 323, 15740, 11, 279, 13945, 18661, 26793, 527, 1101, 315, 2802, 369, 7384, 8198, 25, 578, 4500, 315, 264, 2653, 11, 95749, 3769, 6832, 70334, 649, 387, 14400, 1436, 3412, 11471, 369, 1690, 8522, 13, 13482, 17895, 477, 65720, 11, 369, 3187, 11, 2643, 387, 3025, 311, 5882, 6623, 10737, 311, 19567, 323, 2744, 3085, 279, 9313, 2631, 11911, 389, 279, 5536, 13, 94999, 287, 420, 25885, 1436, 1101, 12391, 5505, 304, 11469, 17685, 5621, 16491, 7384, 13, 220, 128257, 198 ]

2,317

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Devices that rely on the manipulation of excitons—bound pairs of electrons and holes—hold great promise for realizing efficient interconnects between optical data transmission and electrical processing systems. Although exciton-based transistor actions have been demonstrated successfully in bulk semiconductor-based coupled quantum wells 1 , 2 , 3 , the low temperature required for their operation limits their practical application. The recent emergence of two-dimensional semiconductors with large exciton binding energies 4 , 5 may lead to excitonic devices and circuits that operate at room temperature. Whereas individual two-dimensional materials have short exciton diffusion lengths, the spatial separation of electrons and holes in different layers in heterostructures could help to overcome this limitation and enable room-temperature operation of mesoscale devices 6 , 7 , 8 . Here we report excitonic devices made of MoS 2 –WSe 2 van der Waals heterostructures encapsulated in hexagonal boron nitride that demonstrate electrically controlled transistor actions at room temperature. The long-lived nature of the interlayer excitons in our device results in them diffusing over a distance of five micrometres. Within our device, we further demonstrate the ability to manipulate exciton dynamics by creating electrically reconfigurable confining and repulsive potentials for the exciton flux. Our results make a strong case for integrating two-dimensional materials in future excitonic devices to enable operation at room temperature. Main Solid-state devices use particles and their quantum numbers for their operation, with electronics being the ubiquitous example. The need to improve power efficiency of charge-based devices and circuits is motivating research into new devices that would rely on other principles. Candidates so far include spintronics and photonics 9 , 10 . Excitons—electrically neutral quasi-particles formed by bound electrons and holes—can also be manipulated in solid-state systems. The development of such excitonic devices has so far been hindered by the absence of a suitable system that would enable room-temperature manipulation of excitons, limiting the expansion of the field. Here, we demonstrate room-temperature excitonic devices based on atomically thin semiconductors. These devices could open the way for wider studies and applications of excitonic devices in the academic and industrial sectors 11 . Many applications can be envisaged, because excitons could be used to efficiently couple optical data transmission and electronic processing systems. Although fast optical switches have already been demonstrated 12 , 13 , the comparably large size (about 10 μm) 14 , 15 of such devices limits packing density. This can be overcome in excitonic devices, the characteristic size of which is determined by that of electronic field-effect transistors (FETs). Owing to their finite binding energy E b , excitons can exist up to temperatures of around T ∝ E b / k B , where k B is the Boltzmann constant. In a conventional III–V-semiconductor coupled quantum well with a size of a few nanometres, the relatively small binding energy of around 10 meV permits the observation of excitons only at cryogenic temperatures (less than 100 K) 3 . To reach higher temperatures, different materials are required. To this end, systems with higher E b (in the range of tens of millielectronvolts) have been explored more recently, such as (Al,Ga)N/GaN (ref. 16 ) or ZnO (ref. 17 ). Two-dimensional semiconductors such as transition-metal dichalcogenides have even larger exciton binding energies, which can exceed 500 meV in some cases owing to strong quantum confinement 4 , 5 . This could enable the realization of excitonic devices that operate at room temperature 18 . Although intralayer excitons have relatively short lifetimes (about 10 ps) 7 , 19 , the spatial separation of holes and electrons in interlayer excitons results in lifetimes more than two orders of magnitude longer, well in the nanosecond range 6 . For the device presented here, we take advantage of interlayer excitons in an atomically thin MoS 2 –WSe 2 heterostructure. Type-II band alignment 20 , 21 (Fig. 1a ) results in charge separation between the constituent materials, with electrons and holes residing in MoS 2 and WSe 2 , respectively. The formation of indirect excitons is marked by the appearance of a new photoluminescence emission peak 22 , redshifted by about 75 meV with respect to the intralayer exciton of the WSe 2 monolayer. In Extended Data Fig. 1b we present a typical photoluminescence spectrum obtained from such a heterostructure on SiO 2 , in which the spectral signature of the interlayer exciton is clearly visible (dark blue line), together with the individual WSe 2 and MoS 2 monolayers (blue and red lines, respectively). Recent reports 23 suggest that excitons in the MoS 2 –WSe 2 system are not only spatially indirect, but also momentum-indirect owing to lattice mismatch. The phonon-assisted nature of the emission process further reduces the exciton recombination rate, yielding a longer lifetime 8 , 24 . Such an extended lifetime can be used to obtain interlayer exciton diffusion over a scale of micrometres, even at room temperature. Fig. 1: Interlayer excitons in the WSe 2 –MoS 2 van der Waals heterostructure. a , Type-II band alignment in the WSe 2 –MoS 2 heterostructure with intralayer ( X 0 ) and interlayer ( X i ) excitons. The red and blue areas represent the bands in the two materials and the heterobilayer. Positive and negative symbols indicate holes and electrons, respectively. b , Schematic depiction of the WSe 2 –MoS 2 heterostructure, showing the heterobilayer encapsulated in hexagonal boron nitride (h-BN) and the top and bottom gates. The interlayer exciton has a permanent out-of-plane dipole moment p that allows manipulation via the electric field E . c , False-colour optical image of the device, highlighting the different materials. d , e , Spatial maps of photoluminescence at 670 nm ( d ) and 750 nm ( e ), corresponding to MoS 2 and WSe 2 intralayer excitonic resonances, respectively. Photoluminescence is quenched in the heterostructure area owing to efficient charge transfer. Scale bars, 5 μm. a.u., arbitrary units. Full size image To obtain a pristine surface, the heterostructure is encapsulated in hexagonal boron nitride and", "role": "user" }, { "content": "Excitons could revolutionize the way engineers approach electronics. A team of EPFL researchers has created a new type of transistor—one of the components of circuits—using excitons instead of electrons. Notably, their exciton-based transistor functions effectively at room temperature, a hitherto insurmountable obstacle. They achieved this by using two 2-D materials as semiconductors. Their study, which was published today in Nature, has numerous implications in the field of excitonics, a promising new area of study alongside photonics and spintronics. \"Our research showed that by manipulating excitons, we had come upon a whole new approach to electronics,\" says Andras Kis, who heads EPFL's Laboratory of Nanoscale Electronics and Structures (LANES). \"We are witnessing the emergence of a totally new field of study, the full scope of which we don't yet know.\" This breakthrough sets the stage for optoelectronic devices that consume less energy and are both smaller and faster than current devices. In addition, it will be possible to integrate optical transmission and electronic data-processing systems into the same device, which will reduce the number of operations needed and make the systems more efficient. Higher energy level Excitons are actually quasiparticles, a term used to describe the interaction between the particles that make up a given substance rather than the substance itself. Excitons consist of an electron and an electron hole. The two are bound together when the electron absorbs a photon and achieves a higher level of energy; the \"excited\" electron leaves behind a hole in the previous level of energy, which, in band theory, is called a valence band. This hole, also a quasiparticle, is an indication of the missing electron in this band. Since the electron is negatively charged and the hole is positively charged, the two particles remain bound by an electrostatic force. This bond between the electron and the hole is called Coulomb attraction. And it is in this state of tension and balance that they form an exciton. When the electron finally falls back into the hole, it emits a photon. And with that, the exciton ceases to exist. Put more simply, a photon goes in at one end of the circuit and comes out the other; while inside, it gives rise to an exciton that acts like a particle. Double success It is only recently that researchers have begun looking at the properties of excitons in the context of electronic circuits. The energy in excitons had always been considered too fragile and the exciton life span too short to be of any real interest in this domain. In addition, excitons could only be produced and controlled in circuits at extremely low temperatures (around -173 degrees C). The breakthrough came when the EPFL researchers discovered how to control the life span of the excitons and how to move them around. They did this by using two 2-D materials: tungsten diselenide (WSe2) and molybdenum disulfide (MoS2). \"The excitons in these materials exhibit a particularly strong electrostatic bond and, even more importantly, they are not quickly destroyed at room temperature,\" explains Kis. The researchers were also able to significantly lengthen the excitons' lifespan by exploiting the fact that the electrons always found their way to the MoS2 while the holes always ended up in the WSe2. The researchers kept the excitons going even longer by protecting the semiconductor layers with boron nitride (BN). \"We created a special type of exciton, where the two sides are farther apart than in the conventional particle,\" says Kis. \"This delays the process in which the electron returns to the hole and light is produced. It's at this point, when the excitons remain in dipole form for slightly longer, that they can be controlled and moved around using an electric field.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Devices that rely on the manipulation of excitons—bound pairs of electrons and holes—hold great promise for realizing efficient interconnects between optical data transmission and electrical processing systems. Although exciton-based transistor actions have been demonstrated successfully in bulk semiconductor-based coupled quantum wells 1 , 2 , 3 , the low temperature required for their operation limits their practical application. The recent emergence of two-dimensional semiconductors with large exciton binding energies 4 , 5 may lead to excitonic devices and circuits that operate at room temperature. Whereas individual two-dimensional materials have short exciton diffusion lengths, the spatial separation of electrons and holes in different layers in heterostructures could help to overcome this limitation and enable room-temperature operation of mesoscale devices 6 , 7 , 8 . Here we report excitonic devices made of MoS 2 –WSe 2 van der Waals heterostructures encapsulated in hexagonal boron nitride that demonstrate electrically controlled transistor actions at room temperature. The long-lived nature of the interlayer excitons in our device results in them diffusing over a distance of five micrometres. Within our device, we further demonstrate the ability to manipulate exciton dynamics by creating electrically reconfigurable confining and repulsive potentials for the exciton flux. Our results make a strong case for integrating two-dimensional materials in future excitonic devices to enable operation at room temperature. Main Solid-state devices use particles and their quantum numbers for their operation, with electronics being the ubiquitous example. The need to improve power efficiency of charge-based devices and circuits is motivating research into new devices that would rely on other principles. Candidates so far include spintronics and photonics 9 , 10 . Excitons—electrically neutral quasi-particles formed by bound electrons and holes—can also be manipulated in solid-state systems. The development of such excitonic devices has so far been hindered by the absence of a suitable system that would enable room-temperature manipulation of excitons, limiting the expansion of the field. Here, we demonstrate room-temperature excitonic devices based on atomically thin semiconductors. These devices could open the way for wider studies and applications of excitonic devices in the academic and industrial sectors 11 . Many applications can be envisaged, because excitons could be used to efficiently couple optical data transmission and electronic processing systems. Although fast optical switches have already been demonstrated 12 , 13 , the comparably large size (about 10 μm) 14 , 15 of such devices limits packing density. This can be overcome in excitonic devices, the characteristic size of which is determined by that of electronic field-effect transistors (FETs). Owing to their finite binding energy E b , excitons can exist up to temperatures of around T ∝ E b / k B , where k B is the Boltzmann constant. In a conventional III–V-semiconductor coupled quantum well with a size of a few nanometres, the relatively small binding energy of around 10 meV permits the observation of excitons only at cryogenic temperatures (less than 100 K) 3 . To reach higher temperatures, different materials are required. To this end, systems with higher E b (in the range of tens of millielectronvolts) have been explored more recently, such as (Al,Ga)N/GaN (ref. 16 ) or ZnO (ref. 17 ). Two-dimensional semiconductors such as transition-metal dichalcogenides have even larger exciton binding energies, which can exceed 500 meV in some cases owing to strong quantum confinement 4 , 5 . This could enable the realization of excitonic devices that operate at room temperature 18 . Although intralayer excitons have relatively short lifetimes (about 10 ps) 7 , 19 , the spatial separation of holes and electrons in interlayer excitons results in lifetimes more than two orders of magnitude longer, well in the nanosecond range 6 . For the device presented here, we take advantage of interlayer excitons in an atomically thin MoS 2 –WSe 2 heterostructure. Type-II band alignment 20 , 21 (Fig. 1a ) results in charge separation between the constituent materials, with electrons and holes residing in MoS 2 and WSe 2 , respectively. The formation of indirect excitons is marked by the appearance of a new photoluminescence emission peak 22 , redshifted by about 75 meV with respect to the intralayer exciton of the WSe 2 monolayer. In Extended Data Fig. 1b we present a typical photoluminescence spectrum obtained from such a heterostructure on SiO 2 , in which the spectral signature of the interlayer exciton is clearly visible (dark blue line), together with the individual WSe 2 and MoS 2 monolayers (blue and red lines, respectively). Recent reports 23 suggest that excitons in the MoS 2 –WSe 2 system are not only spatially indirect, but also momentum-indirect owing to lattice mismatch. The phonon-assisted nature of the emission process further reduces the exciton recombination rate, yielding a longer lifetime 8 , 24 . Such an extended lifetime can be used to obtain interlayer exciton diffusion over a scale of micrometres, even at room temperature. Fig. 1: Interlayer excitons in the WSe 2 –MoS 2 van der Waals heterostructure. a , Type-II band alignment in the WSe 2 –MoS 2 heterostructure with intralayer ( X 0 ) and interlayer ( X i ) excitons. The red and blue areas represent the bands in the two materials and the heterobilayer. Positive and negative symbols indicate holes and electrons, respectively. b , Schematic depiction of the WSe 2 –MoS 2 heterostructure, showing the heterobilayer encapsulated in hexagonal boron nitride (h-BN) and the top and bottom gates. The interlayer exciton has a permanent out-of-plane dipole moment p that allows manipulation via the electric field E . c , False-colour optical image of the device, highlighting the different materials. d , e , Spatial maps of photoluminescence at 670 nm ( d ) and 750 nm ( e ), corresponding to MoS 2 and WSe 2 intralayer excitonic resonances, respectively. Photoluminescence is quenched in the heterostructure area owing to efficient charge transfer. Scale bars, 5 μm. a.u., arbitrary units. Full size image To obtain a pristine surface, the heterostructure is encapsulated in hexagonal boron nitride and<|im_end|> <|im_start|>assistant Excitons could revolutionize the way engineers approach electronics. A team of EPFL researchers has created a new type of transistor—one of the components of circuits—using excitons instead of electrons. Notably, their exciton-based transistor functions effectively at room temperature, a hitherto insurmountable obstacle. They achieved this by using two 2-D materials as semiconductors. Their study, which was published today in Nature, has numerous implications in the field of excitonics, a promising new area of study alongside photonics and spintronics. "Our research showed that by manipulating excitons, we had come upon a whole new approach to electronics," says Andras Kis, who heads EPFL's Laboratory of Nanoscale Electronics and Structures (LANES). "We are witnessing the emergence of a totally new field of study, the full scope of which we don't yet know." This breakthrough sets the stage for optoelectronic devices that consume less energy and are both smaller and faster than current devices. In addition, it will be possible to integrate optical transmission and electronic data-processing systems into the same device, which will reduce the number of operations needed and make the systems more efficient. Higher energy level Excitons are actually quasiparticles, a term used to describe the interaction between the particles that make up a given substance rather than the substance itself. Excitons consist of an electron and an electron hole. The two are bound together when the electron absorbs a photon and achieves a higher level of energy; the "excited" electron leaves behind a hole in the previous level of energy, which, in band theory, is called a valence band. This hole, also a quasiparticle, is an indication of the missing electron in this band. Since the electron is negatively charged and the hole is positively charged, the two particles remain bound by an electrostatic force. This bond between the electron and the hole is called Coulomb attraction. And it is in this state of tension and balance that they form an exciton. When the electron finally falls back into the hole, it emits a photon. And with that, the exciton ceases to exist. Put more simply, a photon goes in at one end of the circuit and comes out the other; while inside, it gives rise to an exciton that acts like a particle. Double success It is only recently that researchers have begun looking at the properties of excitons in the context of electronic circuits. The energy in excitons had always been considered too fragile and the exciton life span too short to be of any real interest in this domain. In addition, excitons could only be produced and controlled in circuits at extremely low temperatures (around -173 degrees C). The breakthrough came when the EPFL researchers discovered how to control the life span of the excitons and how to move them around. They did this by using two 2-D materials: tungsten diselenide (WSe2) and molybdenum disulfide (MoS2). "The excitons in these materials exhibit a particularly strong electrostatic bond and, even more importantly, they are not quickly destroyed at room temperature," explains Kis. The researchers were also able to significantly lengthen the excitons' lifespan by exploiting the fact that the electrons always found their way to the MoS2 while the holes always ended up in the WSe2. The researchers kept the excitons going even longer by protecting the semiconductor layers with boron nitride (BN). "We created a special type of exciton, where the two sides are farther apart than in the conventional particle," says Kis. "This delays the process in which the electron returns to the hole and light is produced. It's at this point, when the excitons remain in dipole form for slightly longer, that they can be controlled and moved around using an electric field." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Guidelines Hypothesis Interesting Images Letter New Book Received Obituary Opinion Perspective Proceeding Paper Project Report Protocol Registered Report Reply Retraction Short Note Study Protocol Systematic Review Technical Note Tutorial Viewpoint All Article Types Advanced Search Section All Sections Adolescents Aging Air Anthropogenic Circularity Biosafety Chemoenvironment Children's Health Climate Change Digital Health Disabilities Disaster Medicine Disease Prevention Emerging Contaminants Environment and Applied Ecology Environmental Analysis and Methods Environmental Chemistry and Technology Environmental Earth Science and Medical Geology Environmental Ecology Environmental Health Environmental Microbiology Environmental Remediation and Management Environmental Science and Engineering Exercise and Health Global Health Health Behavior, Chronic Disease and Health Promotion Health Care Sciences & Services Health Communication and Informatics Health Economics Health Informatics Health-Related Quality of Life and Well-Being Industrial Ecology Infectious Disease Epidemiology Injury Prevention and Rehabilitation Mental Health Nursing Occupational Safety and Health Oral Health Public Health Statistics and Risk Assessment Reproductive Health Skin Health Sport and Health Toxicology and Public Health Traumas Water Science and Technology Women's Health All Sections Special Issue All Special Issues 2nd Edition of Environmental Impact Assessment by Green Processes 2nd Edition of Health Literacy, Nutrition and Public Health 2nd Edition of Oral Inflammation and Chronic Autoimmune Diseases 2nd Edition of Protecting, Supporting and Promoting Appropriate Breastfeeding in the 21st Century 2nd Edition of Sleep Quality and Health-Related Outcomes 2nd Edition of Social Determinants of Health 2nd Edition of Treatment of Foot and Ankle Injury and Public Health 2nd Edition of Trends in Sustainable Buildings and Infrastructure 2nd Edition of Water Sports Implications for Training, Environment and Health 2nd Edition: Advances in Maternal and Child Healthcare 2nd Edition: Advances in Personalized Exercise Prescription for Chronic Disease Prevention and Rehabilitation 2nd Edition: Evidence-Based Nature for Human Health 2nd Edition: Movement Studies for Individuals with Visual Impairments 2nd Edition: Tobacco Smoke Exposure and Tobacco Product Use A More Sustainable and Healthier Future for All: What Works? Access, Health, Regulations, and Policy: Exploring Rural and Remote Drinking Water Supplies in North America Actions in EU MS for Combating Health Threats in the Maritime Transport Sector Active Commuting and Active Transportation Addiction Behavior Addictions and Cognitive Behavioral Therapy Approaches Addictions in Children and Adolescents Addressing Environmental Health Inequalities – Proceedings from ISEE Conference 2015 Adolescent Depression Prevention Advances in Big Data Analytics and Intelligence Advances in Earth System Science Advances in Endodontic Pain Control Advances in Environmental Biology Advances in Environmental Chemistry Advances in Environmental Economics Advances in Environmental Geotechnics Advances in Environmental Justice Advances in Environmental Modelling Advances in Environmental Neurotoxicology Advances in Environmental Sensor Networks Advances in Environmental Sustainability, Resilience, and Health Advances in Epidemiology Advances in Foot Disorders and Its Treatment Advances in Gastroenterology, Hepatology and Clinical Nutrition Advances in LGBTQ+ People's Health Advances in Mental Health, PTSD and Moral Injury Advances in Physical Diagnosis, Physiotherapy and Rehabilitation in Medicine and Dentistry Advances in Squamous Cell Cancer of the Head and Neck Advances in Substance and Drug Abuse Prevention Advances in Telehealthcare Advances in the Diagnosis and Management of Renal Diseases Advances in the Use of eHealth for Pain Management Advancing Health Equity for Sexual and Gender Minority Populations Ageing Well: The Role of Age-Friendly Environments Aging and Cognition Aging and Work Agrochemicals in the Agri-Food Chain Air Pollution and Carbon Dioxide Emissions Air Pollution Exposure and Health Risks Air Pollution Modeling Air Pollution, Climate Change, and Public Health: The Unavoidable Path towards Decarbonization Air Quality and Healthcare Associated Infections Alcohol Abuse: Newer Approaches to an Old Problem Alcohol and Drugs of Addiction, Aggression and Violence Alcohol and Health Alcohol and Public Health Alcohol Policy and Public Health Alcohol-Related Violence Alcoholism Allergic Disease Epidemiology Allergy and Environment Ambient Air Pollution and Health Vulnerability Anemia and Patients Blood Management Patient in Critical Care Animal Assisted Interventions and Activities for Health and Wellbeing Anti-cancer Activity for Cancer Prevention and Treatment Antibiotic Resistant and Pathogenic Bacteria in the Food Production Environment: Epidemiological Evolution and Control Antimicrobial Resistance Prevention and Control Antimicrobials and Antimicrobial Resistance in the Environment Application of Bio-Based Materials in Environmental Governance Application of Biostatistical Modelling in Public Health and Epidemiology Application of Robotic Devices for Neurologic Rehabilitation Application of Statistical Methods in Public Health and Medical Research Applications of Statistical and Data Science Methods in Public Health Applied Physiology and Exercise Testing in Endurance and Ultra-Endurance Sports Applying Clinical Psychology to Medical Conditions Arsenic Contamination, Bioavailability and Public Health Arsenic in Drinking Water: Current Perspectives and Future Directions Asbestos and Cancers: Exposure from Neighboring Factories and Mines, Contaminated Soil, and Slate Roofs Asbestos Exposure and Disease: An Update Asbestos Exposure and Health Impact Assessment of Public and Occupational Electromagnetic Field Exposure in New and Emerging Connectivity Exposure Scenarios Assessment, Management, and Policy-Making for Environmental Pollution Related to Land Use and Land Cover Atmospheric Change and Impact on Health Auditory Experience, Music and Voice across the Perinatal Period: Innovations in Theory, Research and Clinical practice Back and Neck Pain Bariatric Surgery: Nutritional, Metabolic and Public Health Aspects Bayesian Design in Clinical Trials Beyond Amyloid and Tau - Targeting Lipid Metabolism for Alzheimer’s Disease Biomarkers and Therapies Big Data and Mathematical Modeling in Biomedicine Biochemical and Genetics Tools for Monitoring Health and Risk of Disease Biodegradability and Environmental Sciences Biological and Agricultural Engineering Biological and Health Effects of Low Level Non-Ionising Electromagnetic Fields Biomarkers: Environmental Research and Public Health Bioprocesses for Air Pollution Control Biostatistics Reveals New Insights in Sports Science, Sports Medicine, and Health Birth Defect Prevention Blood Cells, Hematopoiesis, Molecules, Nanomedicine and Diseases Research Bone Health: Nutritional Perspectives Boredom in Health, Education and Sports Breastfeeding and Infant Health Building Related Illnesses Caffeine in the Diet: Health Implications, Safety Issues, and Molecular Mechanisms Cancer Prevention, Treatment, and Survivorship Cannabis, Cannabis-Based Products, and Cannabinoids for Medicinal Use Carbon Capture and Storage Carbon Dioxide (CO2), Emissions, Environmental and Public Health Impact Carbon Emissions and Environmental Protection Cardiac Rehabilitation in the Time of COVID-19 Cardiovascular Disease Self-Care Interventions Cardiovascular Diseases and Public Health Challenges for Health Inequalities Research during COVID-19 Pandemic Challenges in Positive Organizational", "role": "user" }, { "content": "Interactions between primary producers and bacteria impact the physiology of both partners, alter the chemistry of their environment, and shape ecosystem diversity. Several studies have documented that dinoflagellates-bacteria interactions have the potential to dramatically influence population dynamics. However, species-level information about the bacterial consortia characteristically associated with dinoflagellates still remains obscure. Recently, a research team led by Prof. Tang Yingzhong from the Institute of Oceanology of the Chinese Academy of Science (IOCAS) has provided new insights into the fundamental functions of bacteria consortia associated with the phycospheres of dinoflagellates and other harmful algal blooms (HABs)-forming microalgae. The study was published in International Journal of Environmental Research and Public Health on April 7. The researchers characterized the bacterial assemblages associated with 144 clonal cultures of harmful algae that have been established and cultured in the laboratory, including 130 strains of dinoflagellates (covering all major taxa of dinoflagellates) and 14 strains from other classes. The long-lasting bacterial associations to laboratory-raised algal cultures hinted bilaterally (i.e., mutualism) or at least unilaterally (i.e., commensalism) beneficial to the two partners. Bacterial communities of dinoflagellates displayed strong conservation across strains with an enrichment of Methylophaga from the class γ-proteobacteria and implied a potentially functional group of methylotrophs. \"While bacterial associations with thecate and athecate dinoflagellates displayed compositional and functional similarities, athecate dinoflagellates showed a more preferred niche for aerobic cellulolytic members in Actinobacteria phyla. This implies a plausibly proneness to utilize cellulose as energy source,\" said Dr. Deng Yunyan, first author of the study. \"Our results provide insightful understanding of the species composition and community functional profiles of dinoflagellate-associated bacterial assemblages,\" said Prof. Tang. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Guidelines Hypothesis Interesting Images Letter New Book Received Obituary Opinion Perspective Proceeding Paper Project Report Protocol Registered Report Reply Retraction Short Note Study Protocol Systematic Review Technical Note Tutorial Viewpoint All Article Types Advanced Search Section All Sections Adolescents Aging Air Anthropogenic Circularity Biosafety Chemoenvironment Children's Health Climate Change Digital Health Disabilities Disaster Medicine Disease Prevention Emerging Contaminants Environment and Applied Ecology Environmental Analysis and Methods Environmental Chemistry and Technology Environmental Earth Science and Medical Geology Environmental Ecology Environmental Health Environmental Microbiology Environmental Remediation and Management Environmental Science and Engineering Exercise and Health Global Health Health Behavior, Chronic Disease and Health Promotion Health Care Sciences & Services Health Communication and Informatics Health Economics Health Informatics Health-Related Quality of Life and Well-Being Industrial Ecology Infectious Disease Epidemiology Injury Prevention and Rehabilitation Mental Health Nursing Occupational Safety and Health Oral Health Public Health Statistics and Risk Assessment Reproductive Health Skin Health Sport and Health Toxicology and Public Health Traumas Water Science and Technology Women's Health All Sections Special Issue All Special Issues 2nd Edition of Environmental Impact Assessment by Green Processes 2nd Edition of Health Literacy, Nutrition and Public Health 2nd Edition of Oral Inflammation and Chronic Autoimmune Diseases 2nd Edition of Protecting, Supporting and Promoting Appropriate Breastfeeding in the 21st Century 2nd Edition of Sleep Quality and Health-Related Outcomes 2nd Edition of Social Determinants of Health 2nd Edition of Treatment of Foot and Ankle Injury and Public Health 2nd Edition of Trends in Sustainable Buildings and Infrastructure 2nd Edition of Water Sports Implications for Training, Environment and Health 2nd Edition: Advances in Maternal and Child Healthcare 2nd Edition: Advances in Personalized Exercise Prescription for Chronic Disease Prevention and Rehabilitation 2nd Edition: Evidence-Based Nature for Human Health 2nd Edition: Movement Studies for Individuals with Visual Impairments 2nd Edition: Tobacco Smoke Exposure and Tobacco Product Use A More Sustainable and Healthier Future for All: What Works? Access, Health, Regulations, and Policy: Exploring Rural and Remote Drinking Water Supplies in North America Actions in EU MS for Combating Health Threats in the Maritime Transport Sector Active Commuting and Active Transportation Addiction Behavior Addictions and Cognitive Behavioral Therapy Approaches Addictions in Children and Adolescents Addressing Environmental Health Inequalities – Proceedings from ISEE Conference 2015 Adolescent Depression Prevention Advances in Big Data Analytics and Intelligence Advances in Earth System Science Advances in Endodontic Pain Control Advances in Environmental Biology Advances in Environmental Chemistry Advances in Environmental Economics Advances in Environmental Geotechnics Advances in Environmental Justice Advances in Environmental Modelling Advances in Environmental Neurotoxicology Advances in Environmental Sensor Networks Advances in Environmental Sustainability, Resilience, and Health Advances in Epidemiology Advances in Foot Disorders and Its Treatment Advances in Gastroenterology, Hepatology and Clinical Nutrition Advances in LGBTQ+ People's Health Advances in Mental Health, PTSD and Moral Injury Advances in Physical Diagnosis, Physiotherapy and Rehabilitation in Medicine and Dentistry Advances in Squamous Cell Cancer of the Head and Neck Advances in Substance and Drug Abuse Prevention Advances in Telehealthcare Advances in the Diagnosis and Management of Renal Diseases Advances in the Use of eHealth for Pain Management Advancing Health Equity for Sexual and Gender Minority Populations Ageing Well: The Role of Age-Friendly Environments Aging and Cognition Aging and Work Agrochemicals in the Agri-Food Chain Air Pollution and Carbon Dioxide Emissions Air Pollution Exposure and Health Risks Air Pollution Modeling Air Pollution, Climate Change, and Public Health: The Unavoidable Path towards Decarbonization Air Quality and Healthcare Associated Infections Alcohol Abuse: Newer Approaches to an Old Problem Alcohol and Drugs of Addiction, Aggression and Violence Alcohol and Health Alcohol and Public Health Alcohol Policy and Public Health Alcohol-Related Violence Alcoholism Allergic Disease Epidemiology Allergy and Environment Ambient Air Pollution and Health Vulnerability Anemia and Patients Blood Management Patient in Critical Care Animal Assisted Interventions and Activities for Health and Wellbeing Anti-cancer Activity for Cancer Prevention and Treatment Antibiotic Resistant and Pathogenic Bacteria in the Food Production Environment: Epidemiological Evolution and Control Antimicrobial Resistance Prevention and Control Antimicrobials and Antimicrobial Resistance in the Environment Application of Bio-Based Materials in Environmental Governance Application of Biostatistical Modelling in Public Health and Epidemiology Application of Robotic Devices for Neurologic Rehabilitation Application of Statistical Methods in Public Health and Medical Research Applications of Statistical and Data Science Methods in Public Health Applied Physiology and Exercise Testing in Endurance and Ultra-Endurance Sports Applying Clinical Psychology to Medical Conditions Arsenic Contamination, Bioavailability and Public Health Arsenic in Drinking Water: Current Perspectives and Future Directions Asbestos and Cancers: Exposure from Neighboring Factories and Mines, Contaminated Soil, and Slate Roofs Asbestos Exposure and Disease: An Update Asbestos Exposure and Health Impact Assessment of Public and Occupational Electromagnetic Field Exposure in New and Emerging Connectivity Exposure Scenarios Assessment, Management, and Policy-Making for Environmental Pollution Related to Land Use and Land Cover Atmospheric Change and Impact on Health Auditory Experience, Music and Voice across the Perinatal Period: Innovations in Theory, Research and Clinical practice Back and Neck Pain Bariatric Surgery: Nutritional, Metabolic and Public Health Aspects Bayesian Design in Clinical Trials Beyond Amyloid and Tau - Targeting Lipid Metabolism for Alzheimer’s Disease Biomarkers and Therapies Big Data and Mathematical Modeling in Biomedicine Biochemical and Genetics Tools for Monitoring Health and Risk of Disease Biodegradability and Environmental Sciences Biological and Agricultural Engineering Biological and Health Effects of Low Level Non-Ionising Electromagnetic Fields Biomarkers: Environmental Research and Public Health Bioprocesses for Air Pollution Control Biostatistics Reveals New Insights in Sports Science, Sports Medicine, and Health Birth Defect Prevention Blood Cells, Hematopoiesis, Molecules, Nanomedicine and Diseases Research Bone Health: Nutritional Perspectives Boredom in Health, Education and Sports Breastfeeding and Infant Health Building Related Illnesses Caffeine in the Diet: Health Implications, Safety Issues, and Molecular Mechanisms Cancer Prevention, Treatment, and Survivorship Cannabis, Cannabis-Based Products, and Cannabinoids for Medicinal Use Carbon Capture and Storage Carbon Dioxide (CO2), Emissions, Environmental and Public Health Impact Carbon Emissions and Environmental Protection Cardiac Rehabilitation in the Time of COVID-19 Cardiovascular Disease Self-Care Interventions Cardiovascular Diseases and Public Health Challenges for Health Inequalities Research during COVID-19 Pandemic Challenges in Positive Organizational<|im_end|> <|im_start|>assistant Interactions between primary producers and bacteria impact the physiology of both partners, alter the chemistry of their environment, and shape ecosystem diversity. Several studies have documented that dinoflagellates-bacteria interactions have the potential to dramatically influence population dynamics. However, species-level information about the bacterial consortia characteristically associated with dinoflagellates still remains obscure. Recently, a research team led by Prof. Tang Yingzhong from the Institute of Oceanology of the Chinese Academy of Science (IOCAS) has provided new insights into the fundamental functions of bacteria consortia associated with the phycospheres of dinoflagellates and other harmful algal blooms (HABs)-forming microalgae. The study was published in International Journal of Environmental Research and Public Health on April 7. The researchers characterized the bacterial assemblages associated with 144 clonal cultures of harmful algae that have been established and cultured in the laboratory, including 130 strains of dinoflagellates (covering all major taxa of dinoflagellates) and 14 strains from other classes. The long-lasting bacterial associations to laboratory-raised algal cultures hinted bilaterally (i.e., mutualism) or at least unilaterally (i.e., commensalism) beneficial to the two partners. Bacterial communities of dinoflagellates displayed strong conservation across strains with an enrichment of Methylophaga from the class γ-proteobacteria and implied a potentially functional group of methylotrophs. "While bacterial associations with thecate and athecate dinoflagellates displayed compositional and functional similarities, athecate dinoflagellates showed a more preferred niche for aerobic cellulolytic members in Actinobacteria phyla. This implies a plausibly proneness to utilize cellulose as energy source," said Dr. Deng Yunyan, first author of the study. "Our results provide insightful understanding of the species composition and community functional profiles of dinoflagellate-associated bacterial assemblages," said Prof. Tang. <|im_end|>

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1,796

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Prevention of mother-to-child transmission (MTCT) of HIV remains a major objective where antenatal care is not readily accessible. We tested HIV-1–specific human neutralizing monoclonal antibodies (NmAbs) as a post-exposure therapy in an infant macaque model for intrapartum MTCT. One-month-old rhesus macaques were inoculated orally with the simian-human immunodeficiency virus SHIV SF162P3 . On days 1, 4, 7 and 10 after virus exposure, we injected animals subcutaneously with NmAbs and quantified systemic distribution of NmAbs in multiple tissues within 24 h after antibody administration. Replicating virus was found in multiple tissues by day 1 in animals that were not treated. All NmAb-treated macaques were free of virus in blood and tissues at 6 months after exposure. We detected no anti-SHIV T cell responses in blood or tissues at necropsy, and no virus emerged after CD8 + T cell depletion. These results suggest that early passive immunotherapy can eliminate early viral foci and thereby prevent the establishment of viral reservoirs. Main Recent advances in the discovery of human HIV NmAbs that have high potency and breadth of coverage have rekindled an interest in their use as pre-exposure prophylaxis, as well as therapeutic agents, including in the setting of MTCT, in which the time of exposure is known 1 , 2 . A combination of measures—including antiretroviral treatment (ART) of the mother and the infant, cesarean section and formula feeding—have diminished the rate of MTCT from 35% to less than 3% (ref. 3 ). Despite this reduction, HIV infects approximately 200,000 children yearly, primarily in places where ART is not available 4 . Treatment of babies with ART during both the early peripartum and the breast-feeding timeframes is recommended 5 , but risks remain, including the toxicities associated with long-term use and the development of drug-resistant viral variants 6 . Therefore, discovering less toxic methods to limit transmission to newborns would be advantageous 2 . In mucosal HIV and SIV transmission, the virus establishes a small founder population of infected cells after it has traversed the vaginal mucosal barrier 7 . This localized infection rapidly expands and spreads to local draining lymph nodes (LN), before disseminating systemically by 1 week after exposure 8 , 9 . Similarly in nonhuman primate (NHP) models of oral SIV exposure, the oral and esophageal mucosa and the tonsils are sites of early viral infection within 1 d post-exposure (d.p.i.), with rapid systemic dissemination, via the regional lymphatics, occurring within 1 week after exposure 10 , 11 . Because IgG from the circulation contributes substantially to the immunoglobulin pool in tissue and genital tract secretions, passively transferred neutralizing antibodies (NAbs) may have a protective effect by interaction with the virus at the mucosal level 12 , thus preventing systemic spread. In adult NHP models of mucosal SHIV transmission, there is abundant evidence for protective prophylactic efficacy with passively transferred human NmAbs 13 , 14 , 15 , 16 , 17 , 18 . In vitro , NmAbs have been shown to block HIV infection of dendritic cells and subsequent transmission to T cells 19 . Direct vaginal application of NAbs before challenge is protective in macaques 20 , and in HIV-exposed but uninfected humans, mucosal IgA can block transcytosis in vitro 12 . Vaccine-induced protection from vaginal challenge correlates with levels of glycoprotein 41 (gp41)-specific cervicovaginal IgA and IgG that have antiviral and transcytosis-blocking activities 21 . However, the tissue localization and the kinetics of passively transferred antibodies are still not well defined 13 , 22 . There is evidence for an impact by NmAbs in lowering plasma virus levels in established infections in NHP models 23 , 24 , 25 and in humans 25 , 26 . In NHP models, post-exposure prophylaxis using cocktails of the first-generation human NmAbs b12, 2G12, 2F5 and 4E10 partially prevented oral SHIV infection in newborns 24 . A single dose combining the newer, more-potent NmAbs VRC07-523 and PGT121 delivered 10 d after intravenous SHIV infection suppressed acute viremia and limited seeding of viral reservoirs in adult macaques 27 . We have shown that neutralizing polyclonal IgG purified from SIV- or SHIV-infected macaques that are injected subcutaneously (s.c.) can effectively control viremia and accelerate B cell responses, resulting in reduced pathogenesis in SIV-infected adults 28 and in SHIV-infected newborn macaques 29 , 30 . We hypothesized that a cocktail of two potent and broadly cross-reactive NmAbs, VRC07-523 and PGT121, would slow the initial virus expansion and reduce the chance of rapid escape in infant macaques exposed to pathogenic SHIV. We show that combined doses as low as 10 mg per kg body weight (mg/kg) administered 24 h after exposure can intercept replicating viral foci established by day 1 and prevent orally administered virus from establishing permanent viral reservoirs. Results Titration and biodistribution of subcutaneously administered antibodies in macaques We initially conducted studies to define the protective dose and kinetics of the CD4-binding site–directed NmAb VRC01 in blocking newborn macaques from oral SHIV SF162P3 infection after s.c injection and to determine the kinetics of passively transferred IgG in naive and infected macaques. First, we administered VRC01 to a total of seven male and female one-month-old macaques at 20 mg/kg ( n = 2) or 5 mg/kg ( n = 5) 24 h before SHIV exposure. We measured SHIV SF162P3 envelope–specific binding and neutralizing antibody kinetics in vivo . The time to maximal concentration in the plasma was 24 h, independent of dose, and the serum (plasma) half-life of VRC01 was 3.9–4.2 d ( Supplementary Fig. 1 ). Neither of the two macaques injected with the 20 mg/kg dose and only one of five macaques injected with the 5 mg/kg dose became infected. In this macaque, the magnitude and kinetics of virus in the plasma, termed the plasma virus load (PVL), were indistinguishable from that of control animals treated with IgG purified from naive macaques 30 ( Supplementary Fig. 1 ). These data are consistent with results from passive protection studies using VRC01 in juvenile and adult macaques 18 and guided the therapeutic", "role": "user" }, { "content": "Scientists at the Oregon National Primate Research Center today revealed that infant rhesus macaques treated with antibodies within 24 hours of being exposed to SHIV, a chimeric simian virus that bears the HIV envelope protein, were completely cleared of the virus. The study, published today in Nature Medicine shows that antibodies given after a baby macaque has already been exposed to SHIV can clear the virus, a significant development in the HIV scientific community. SHIV-infected nonhuman primates can transmit SHIV to their offspring through milk feeding, just as humans can transmit HIV from mother to child through breastfeeding and during childbirth (and only rarely during pregnancy). In humans, a combination of measures for mothers and infants, including antiretroviral therapy (ART), Cesarean section delivery and formula feeding (rather than breastfeeding), have decreased the rate of mother-to-child HIV transmission from 25 percent to less than 2 percent since 1994. Despite this decrease, approximately 200,000 children are infected with HIV each year worldwide, primarily in developing countries where ART is not readily available. \"We knew going into this study that HIV infection spreads very quickly in human infants during mother-to-child transmission,\" said Nancy L. Haigwood, Ph.D., senior author of the paper, and director and senior scientist, Oregon National Primate Research Center at Oregon Health & Science University. \"So we knew that we had to treat the infant rhesus macaques quickly but we were not convinced an antibody treatment could completely clear the virus after exposure. We were delighted to see this result.\" Haigwood and colleagues administered the anti-HIV-1 human neutralizing monoclonal antibodies (NmAb) subcutaneously on days 1, 4, 7 and 10 after the macaques were exposed to SHIV orally. The SHIV virus was found in multiple body tissues on day 1 in macaques without antibody treatment. Conversely, they observed an immediate impact of a single dose of antibodies at the start of the infection, with a significant difference in treated versus non-treated macaques. Early short-term administration of powerful antibodies effectively cleared the virus by day 14, with no virus detected at this time. Using highly sensitive methods, they did not detect the virus in any part of the body in 100 percent of the antibody-treated infant macaques for at least six months. Typically, HIV infection rapidly expands and spreads in humans to local draining lymph nodes before disseminating throughout the entire body one week after a person is infected. This study showed that, at least in this model system of oral SHIV exposure in newborn macaques, virus replication is detected in lymphatic tissues 24 hours after exposure and is not locally restricted, as has been suggested previously for humans, due to delays of 5 to 7 days before detection in the blood. The study showed that: 1) antibodies delivered subcutaneously are swiftly distributed to blood and tissues and maintain neutralizing activity at various sites, and, 2) that antibodies are effective at clearing the virus, a different mechanism than that of ART, which is a combination of several antiretroviral medicines used to slow the rate at which HIV makes copies of itself in the body. \"Other nonhuman primate studies with antiretroviral therapy suggest that treatment as early as three days after infection is too late to prevent establishment of the HIV reservoir,\" said Jonah B. Sacha, Ph.D., study co-author and assistant scientist, Oregon National Primate Research Center at OHSU. \"So using antibodies to clear the virus after infants have already been exposed could save thousands of lives\" if the approach works in human infants. The researchers noted that treating human babies with ART during the last month of gestation, the few days after delivery, and during breastfeeding timeframes, is recommended. However, risks remain, including toxicities associated with long-term ART use, the development of drug-resistant viral variants, and lack of access to prenatal care prior to delivery. This discovery indicates that using new methods, such as antibodies, to limit infection after exposure in newborns could be advantageous. The study authors acknowledge that several relevant questions remain unanswered for treatment of HIV-infected newborns and children born to HIV-positive mothers. These include practical and cultural issues of treating breastfeeding mothers and babies, if the antibodies will work in human infants exposed to HIV, as well as what the optimal antibody formulations will be. Clinical trials in which HIV-exposed newborns are treated with antibodies have begun in the U.S. and South Africa, following a phase I clinical trial in HIV-negative adults that showed the antibodies to be safe and well-tolerated in these individuals. The authors' findings help define the window of opportunity for effective treatment after exposure to HIV during birth. If these primate model results can be applied to human beings in a clinical setting, researchers are hopeful that treating infants who have already been exposed to HIV within 24 hours may provide protection from viral infection, even in the absence of ART. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Prevention of mother-to-child transmission (MTCT) of HIV remains a major objective where antenatal care is not readily accessible. We tested HIV-1–specific human neutralizing monoclonal antibodies (NmAbs) as a post-exposure therapy in an infant macaque model for intrapartum MTCT. One-month-old rhesus macaques were inoculated orally with the simian-human immunodeficiency virus SHIV SF162P3 . On days 1, 4, 7 and 10 after virus exposure, we injected animals subcutaneously with NmAbs and quantified systemic distribution of NmAbs in multiple tissues within 24 h after antibody administration. Replicating virus was found in multiple tissues by day 1 in animals that were not treated. All NmAb-treated macaques were free of virus in blood and tissues at 6 months after exposure. We detected no anti-SHIV T cell responses in blood or tissues at necropsy, and no virus emerged after CD8 + T cell depletion. These results suggest that early passive immunotherapy can eliminate early viral foci and thereby prevent the establishment of viral reservoirs. Main Recent advances in the discovery of human HIV NmAbs that have high potency and breadth of coverage have rekindled an interest in their use as pre-exposure prophylaxis, as well as therapeutic agents, including in the setting of MTCT, in which the time of exposure is known 1 , 2 . A combination of measures—including antiretroviral treatment (ART) of the mother and the infant, cesarean section and formula feeding—have diminished the rate of MTCT from 35% to less than 3% (ref. 3 ). Despite this reduction, HIV infects approximately 200,000 children yearly, primarily in places where ART is not available 4 . Treatment of babies with ART during both the early peripartum and the breast-feeding timeframes is recommended 5 , but risks remain, including the toxicities associated with long-term use and the development of drug-resistant viral variants 6 . Therefore, discovering less toxic methods to limit transmission to newborns would be advantageous 2 . In mucosal HIV and SIV transmission, the virus establishes a small founder population of infected cells after it has traversed the vaginal mucosal barrier 7 . This localized infection rapidly expands and spreads to local draining lymph nodes (LN), before disseminating systemically by 1 week after exposure 8 , 9 . Similarly in nonhuman primate (NHP) models of oral SIV exposure, the oral and esophageal mucosa and the tonsils are sites of early viral infection within 1 d post-exposure (d.p.i.), with rapid systemic dissemination, via the regional lymphatics, occurring within 1 week after exposure 10 , 11 . Because IgG from the circulation contributes substantially to the immunoglobulin pool in tissue and genital tract secretions, passively transferred neutralizing antibodies (NAbs) may have a protective effect by interaction with the virus at the mucosal level 12 , thus preventing systemic spread. In adult NHP models of mucosal SHIV transmission, there is abundant evidence for protective prophylactic efficacy with passively transferred human NmAbs 13 , 14 , 15 , 16 , 17 , 18 . In vitro , NmAbs have been shown to block HIV infection of dendritic cells and subsequent transmission to T cells 19 . Direct vaginal application of NAbs before challenge is protective in macaques 20 , and in HIV-exposed but uninfected humans, mucosal IgA can block transcytosis in vitro 12 . Vaccine-induced protection from vaginal challenge correlates with levels of glycoprotein 41 (gp41)-specific cervicovaginal IgA and IgG that have antiviral and transcytosis-blocking activities 21 . However, the tissue localization and the kinetics of passively transferred antibodies are still not well defined 13 , 22 . There is evidence for an impact by NmAbs in lowering plasma virus levels in established infections in NHP models 23 , 24 , 25 and in humans 25 , 26 . In NHP models, post-exposure prophylaxis using cocktails of the first-generation human NmAbs b12, 2G12, 2F5 and 4E10 partially prevented oral SHIV infection in newborns 24 . A single dose combining the newer, more-potent NmAbs VRC07-523 and PGT121 delivered 10 d after intravenous SHIV infection suppressed acute viremia and limited seeding of viral reservoirs in adult macaques 27 . We have shown that neutralizing polyclonal IgG purified from SIV- or SHIV-infected macaques that are injected subcutaneously (s.c.) can effectively control viremia and accelerate B cell responses, resulting in reduced pathogenesis in SIV-infected adults 28 and in SHIV-infected newborn macaques 29 , 30 . We hypothesized that a cocktail of two potent and broadly cross-reactive NmAbs, VRC07-523 and PGT121, would slow the initial virus expansion and reduce the chance of rapid escape in infant macaques exposed to pathogenic SHIV. We show that combined doses as low as 10 mg per kg body weight (mg/kg) administered 24 h after exposure can intercept replicating viral foci established by day 1 and prevent orally administered virus from establishing permanent viral reservoirs. Results Titration and biodistribution of subcutaneously administered antibodies in macaques We initially conducted studies to define the protective dose and kinetics of the CD4-binding site–directed NmAb VRC01 in blocking newborn macaques from oral SHIV SF162P3 infection after s.c injection and to determine the kinetics of passively transferred IgG in naive and infected macaques. First, we administered VRC01 to a total of seven male and female one-month-old macaques at 20 mg/kg ( n = 2) or 5 mg/kg ( n = 5) 24 h before SHIV exposure. We measured SHIV SF162P3 envelope–specific binding and neutralizing antibody kinetics in vivo . The time to maximal concentration in the plasma was 24 h, independent of dose, and the serum (plasma) half-life of VRC01 was 3.9–4.2 d ( Supplementary Fig. 1 ). Neither of the two macaques injected with the 20 mg/kg dose and only one of five macaques injected with the 5 mg/kg dose became infected. In this macaque, the magnitude and kinetics of virus in the plasma, termed the plasma virus load (PVL), were indistinguishable from that of control animals treated with IgG purified from naive macaques 30 ( Supplementary Fig. 1 ). These data are consistent with results from passive protection studies using VRC01 in juvenile and adult macaques 18 and guided the therapeutic<|im_end|> <|im_start|>assistant Scientists at the Oregon National Primate Research Center today revealed that infant rhesus macaques treated with antibodies within 24 hours of being exposed to SHIV, a chimeric simian virus that bears the HIV envelope protein, were completely cleared of the virus. The study, published today in Nature Medicine shows that antibodies given after a baby macaque has already been exposed to SHIV can clear the virus, a significant development in the HIV scientific community. SHIV-infected nonhuman primates can transmit SHIV to their offspring through milk feeding, just as humans can transmit HIV from mother to child through breastfeeding and during childbirth (and only rarely during pregnancy). In humans, a combination of measures for mothers and infants, including antiretroviral therapy (ART), Cesarean section delivery and formula feeding (rather than breastfeeding), have decreased the rate of mother-to-child HIV transmission from 25 percent to less than 2 percent since 1994. Despite this decrease, approximately 200,000 children are infected with HIV each year worldwide, primarily in developing countries where ART is not readily available. "We knew going into this study that HIV infection spreads very quickly in human infants during mother-to-child transmission," said Nancy L. Haigwood, Ph.D., senior author of the paper, and director and senior scientist, Oregon National Primate Research Center at Oregon Health & Science University. "So we knew that we had to treat the infant rhesus macaques quickly but we were not convinced an antibody treatment could completely clear the virus after exposure. We were delighted to see this result." Haigwood and colleagues administered the anti-HIV-1 human neutralizing monoclonal antibodies (NmAb) subcutaneously on days 1, 4, 7 and 10 after the macaques were exposed to SHIV orally. The SHIV virus was found in multiple body tissues on day 1 in macaques without antibody treatment. Conversely, they observed an immediate impact of a single dose of antibodies at the start of the infection, with a significant difference in treated versus non-treated macaques. Early short-term administration of powerful antibodies effectively cleared the virus by day 14, with no virus detected at this time. Using highly sensitive methods, they did not detect the virus in any part of the body in 100 percent of the antibody-treated infant macaques for at least six months. Typically, HIV infection rapidly expands and spreads in humans to local draining lymph nodes before disseminating throughout the entire body one week after a person is infected. This study showed that, at least in this model system of oral SHIV exposure in newborn macaques, virus replication is detected in lymphatic tissues 24 hours after exposure and is not locally restricted, as has been suggested previously for humans, due to delays of 5 to 7 days before detection in the blood. The study showed that: 1) antibodies delivered subcutaneously are swiftly distributed to blood and tissues and maintain neutralizing activity at various sites, and, 2) that antibodies are effective at clearing the virus, a different mechanism than that of ART, which is a combination of several antiretroviral medicines used to slow the rate at which HIV makes copies of itself in the body. "Other nonhuman primate studies with antiretroviral therapy suggest that treatment as early as three days after infection is too late to prevent establishment of the HIV reservoir," said Jonah B. Sacha, Ph.D., study co-author and assistant scientist, Oregon National Primate Research Center at OHSU. "So using antibodies to clear the virus after infants have already been exposed could save thousands of lives" if the approach works in human infants. The researchers noted that treating human babies with ART during the last month of gestation, the few days after delivery, and during breastfeeding timeframes, is recommended. However, risks remain, including toxicities associated with long-term ART use, the development of drug-resistant viral variants, and lack of access to prenatal care prior to delivery. This discovery indicates that using new methods, such as antibodies, to limit infection after exposure in newborns could be advantageous. The study authors acknowledge that several relevant questions remain unanswered for treatment of HIV-infected newborns and children born to HIV-positive mothers. These include practical and cultural issues of treating breastfeeding mothers and babies, if the antibodies will work in human infants exposed to HIV, as well as what the optimal antibody formulations will be. Clinical trials in which HIV-exposed newborns are treated with antibodies have begun in the U.S. and South Africa, following a phase I clinical trial in HIV-negative adults that showed the antibodies to be safe and well-tolerated in these individuals. The authors' findings help define the window of opportunity for effective treatment after exposure to HIV during birth. If these primate model results can be applied to human beings in a clinical setting, researchers are hopeful that treating infants who have already been exposed to HIV within 24 hours may provide protection from viral infection, even in the absence of ART. <|im_end|>

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9155, 64, 14295, 41772, 449, 279, 220, 20, 14060, 45870, 19660, 6244, 29374, 13, 763, 420, 9155, 20234, 11, 279, 26703, 323, 91468, 315, 17188, 304, 279, 32426, 11, 61937, 279, 32426, 17188, 2865, 320, 47, 31798, 705, 1051, 1280, 89747, 481, 505, 430, 315, 2585, 10099, 12020, 449, 39551, 38, 92600, 505, 50765, 9155, 64, 14295, 220, 966, 320, 99371, 23966, 13, 220, 16, 7609, 4314, 828, 527, 13263, 449, 3135, 505, 28979, 9313, 7978, 1701, 650, 7532, 1721, 304, 48770, 323, 6822, 9155, 64, 14295, 220, 972, 323, 33687, 279, 37471, 128257, 198, 128256, 78191, 198, 72326, 520, 279, 19313, 5165, 2394, 3509, 8483, 5955, 3432, 10675, 430, 31383, 436, 17082, 355, 9155, 64, 14295, 12020, 449, 59854, 2949, 220, 1187, 4207, 315, 1694, 15246, 311, 6570, 3166, 11, 264, 523, 3212, 292, 1675, 1122, 17188, 430, 30824, 279, 23495, 35498, 13128, 11, 1051, 6724, 23803, 315, 279, 17188, 13, 578, 4007, 11, 4756, 3432, 304, 22037, 19152, 5039, 430, 59854, 2728, 1306, 264, 8945, 9155, 20234, 706, 2736, 1027, 15246, 311, 6570, 3166, 649, 2867, 279, 17188, 11, 264, 5199, 4500, 304, 279, 23495, 12624, 4029, 13, 6570, 3166, 48336, 1599, 2536, 26380, 9036, 988, 649, 30382, 6570, 3166, 311, 872, 46471, 1555, 14403, 26040, 11, 1120, 439, 12966, 649, 30382, 23495, 505, 6691, 311, 1716, 1555, 65864, 323, 2391, 97294, 320, 438, 1193, 19029, 2391, 20209, 570, 763, 12966, 11, 264, 10824, 315, 11193, 369, 27698, 323, 42534, 11, 2737, 3276, 556, 33542, 85, 37478, 15419, 320, 3065, 705, 62463, 548, 276, 3857, 9889, 323, 15150, 26040, 320, 74303, 1109, 65864, 705, 617, 25983, 279, 4478, 315, 6691, 4791, 24384, 23495, 18874, 505, 220, 914, 3346, 311, 2753, 1109, 220, 17, 3346, 2533, 220, 2550, 19, 13, 18185, 420, 18979, 11, 13489, 220, 1049, 11, 931, 2911, 527, 29374, 449, 23495, 1855, 1060, 15603, 11, 15871, 304, 11469, 5961, 1405, 34979, 374, 539, 31368, 2561, 13, 330, 1687, 7020, 2133, 1139, 420, 4007, 430, 23495, 19405, 43653, 1633, 6288, 304, 3823, 42534, 2391, 6691, 4791, 24384, 18874, 1359, 1071, 35336, 445, 13, 14433, 343, 6798, 11, 2405, 920, 2637, 10195, 3229, 315, 279, 5684, 11, 323, 7690, 323, 10195, 28568, 11, 19313, 5165, 2394, 3509, 8483, 5955, 520, 19313, 6401, 612, 10170, 3907, 13, 330, 4516, 584, 7020, 430, 584, 1047, 311, 4322, 279, 31383, 436, 17082, 355, 9155, 64, 14295, 6288, 719, 584, 1051, 539, 22954, 459, 63052, 6514, 1436, 6724, 2867, 279, 17188, 1306, 14675, 13, 1226, 1051, 35072, 311, 1518, 420, 1121, 1210, 14433, 343, 6798, 323, 18105, 38018, 279, 7294, 11529, 3166, 12, 16, 3823, 21277, 4954, 96157, 12490, 278, 59854, 320, 69305, 5953, 8, 1207, 10453, 20933, 389, 2919, 220, 16, 11, 220, 19, 11, 220, 22, 323, 220, 605, 1306, 279, 9155, 64, 14295, 1051, 15246, 311, 6570, 3166, 98122, 13, 578, 6570, 3166, 17188, 574, 1766, 304, 5361, 2547, 39881, 389, 1938, 220, 16, 304, 9155, 64, 14295, 2085, 63052, 6514, 13, 82671, 11, 814, 13468, 459, 14247, 5536, 315, 264, 3254, 19660, 315, 59854, 520, 279, 1212, 315, 279, 19405, 11, 449, 264, 5199, 6811, 304, 12020, 19579, 2536, 88186, 9155, 64, 14295, 13, 23591, 2875, 9860, 8735, 315, 8147, 59854, 13750, 23803, 279, 17188, 555, 1938, 220, 975, 11, 449, 912, 17188, 16914, 520, 420, 892, 13, 12362, 7701, 16614, 5528, 11, 814, 1550, 539, 11388, 279, 17188, 304, 904, 961, 315, 279, 2547, 304, 220, 1041, 3346, 315, 279, 63052, 88186, 31383, 9155, 64, 14295, 369, 520, 3325, 4848, 4038, 13, 46402, 11, 23495, 19405, 19019, 52956, 323, 43653, 304, 12966, 311, 2254, 74109, 43745, 7954, 1603, 34000, 65383, 6957, 279, 4553, 2547, 832, 2046, 1306, 264, 1732, 374, 29374, 13, 1115, 4007, 8710, 430, 11, 520, 3325, 304, 420, 1646, 1887, 315, 21308, 6570, 3166, 14675, 304, 46397, 9155, 64, 14295, 11, 17188, 48891, 374, 16914, 304, 43745, 780, 39881, 220, 1187, 4207, 1306, 14675, 323, 374, 539, 24392, 22486, 11, 439, 706, 1027, 12090, 8767, 369, 12966, 11, 4245, 311, 32174, 315, 220, 20, 311, 220, 22, 2919, 1603, 18468, 304, 279, 6680, 13, 578, 4007, 8710, 430, 25, 220, 16, 8, 59854, 12886, 1207, 10453, 20933, 527, 56651, 4332, 311, 6680, 323, 39881, 323, 10519, 21277, 4954, 5820, 520, 5370, 6732, 11, 323, 11, 220, 17, 8, 430, 59854, 527, 7524, 520, 33850, 279, 17188, 11, 264, 2204, 17383, 1109, 430, 315, 34979, 11, 902, 374, 264, 10824, 315, 3892, 3276, 556, 33542, 85, 37478, 39653, 1511, 311, 6435, 279, 4478, 520, 902, 23495, 3727, 11236, 315, 5196, 304, 279, 2547, 13, 330, 11663, 2536, 26380, 550, 3509, 7978, 449, 3276, 556, 33542, 85, 37478, 15419, 4284, 430, 6514, 439, 4216, 439, 2380, 2919, 1306, 19405, 374, 2288, 3389, 311, 5471, 21967, 315, 279, 23495, 45512, 1359, 1071, 94728, 426, 13, 38437, 64, 11, 2405, 920, 2637, 4007, 1080, 43802, 323, 18328, 28568, 11, 19313, 5165, 2394, 3509, 8483, 5955, 520, 507, 12228, 52, 13, 330, 4516, 1701, 59854, 311, 2867, 279, 17188, 1306, 42534, 617, 2736, 1027, 15246, 1436, 3665, 9214, 315, 6439, 1, 422, 279, 5603, 4375, 304, 3823, 42534, 13, 578, 12074, 10555, 430, 27723, 3823, 24869, 449, 34979, 2391, 279, 1566, 2305, 315, 13033, 367, 11, 279, 2478, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The distribution of single-cell properties across a population of cells can be measured using diverse tools, but no technology directly quantifies the biochemical stimulation events regulating these properties. Here we report digital counting of growth factors in single cells using fluorescent quantum dots and calibrated three-dimensional deconvolution microscopy (QDC-3DM) to reveal physiologically relevant cell stimulation distributions. We calibrate the fluorescence intensities of individual compact quantum dots labeled with epidermal growth factor (EGF) and demonstrate the necessity of near-infrared emission to overcome intrinsic cellular autofluoresence at the single-molecule level. When applied to human triple-negative breast cancer cells, we observe proportionality between stimulation and both receptor internalization and inhibitor response, reflecting stimulation heterogeneity contributions to intrinsic variability. We anticipate that QDC-3DM can be applied to analyze any peptidic ligand to reveal single-cell correlations between external stimulation and phenotypic variability, cell fate, and drug response. Introduction Single-cell analytical techniques are reshaping our understanding of biology by revealing the distribution of gene expression and phenotype across a population of cells 1 , 2 . Applied together with systems biology models and information theory, it is now becoming clear that any population of genetically identical cells naturally exhibits substantial cell-to-cell variability that is integral to the emergence of ensemble biological functions 3 . This heterogeneity has important consequences, as rare cells, rather than cells near the ensemble mean, often dominate clinically meaningful pathogenic processes and drug resistance 4 , 5 , 6 . However, a void exists in experimental techniques to measure how cellular decision-making processes underlying population variability derive from extracellular biochemical signals, such as peptide growth factors and cytokines 7 , 8 , which cannot be easily measured at the single-cell level. Biochemical stimulation, the induction of an intracellular biochemical signal (e.g., receptor activation and translocation) by binding of an exogenous biochemical factor, is usually inferred indirectly from the resulting change in gene expression or cell phenotype 8 . Moreover, input factors are typically applied at stimulation extremes (zero and near saturation) 9 , whereas physiologically relevant tissue concentrations are in intermediate regimes ( c ~ 1–100 pM) 10 , 11 over which cells exhibit sensitive and heterogeneous dose–response relationships (EC 50 ~ 1–100 pM) 12 , 13 . At these concentrations, relevant tissue microdomain volumes (~10 pL) contain just tens to hundreds of factors 14 , 15 , such that signal stimulation is temporally and spatially stochastic 16 . Accurate quantification of initiating signals is therefore very challenging 17 and requires single-molecule sensitivity. Here we describe a technology platform to digitally count growth factors in single cells using fluorescent quantum dots (QDs) and calibrated three-dimensional (3D) deconvolution microscopy (QDC-3DM). As a prototypical example, we focus on epidermal growth factor (EGF) and EGF receptor (EGFR)-positive cells. Fluorescent QDs are used as tags for EGF due to their extremely high fluorescence intensity that is homogeneous and stable at the single-QD level 18 . For maximum signal detection and comprehensive counting of EGF with rapid image acquisition, wide-field excitation is used to collect complete 3D images of cells, and deconvolution is used to reassign photons to their originating focal volumes. We observe that this methodology is only accurate when applying QDs with infrared emission due to interfering fluorescence from cellular components across the visible spectrum. We apply QDC-3DM to analyze EGF-induced cell signaling variability in triple-negative breast cancer cells (MDA-MB-231) grown on micropatterned islands to spatially register signaling events across separate cells. Our results show proportionality between stimulation and both receptor internalization and inhibitor response, reflecting stimulation heterogeneity contributions to intrinsic variability at the single-cell level. Results Imaging and image analysis Figure 1a shows the overarching approach to measure the distribution of stimulation events of growth factors binding to cognate receptors, yielding a response distribution that plays an important role in the variability of signals and behavior between cells. Figure 1b summarizes the imaging and analysis methodology to measure absolute counts of growth factors, using two sequentially collected image stacks. A deconvolved high-resolution 3D epifluorescence image of cells is collected in three colors to distinguish QD-EGF conjugates (in red) spatially registered to the cell location by its fibronectin matrix (in green) and nucleus (in blue). The second image stack is a high temporal resolution video in the QD-EGF color channel. As described in detail in Methods, a three-step process is applied to count EGF molecules per cell: (1) Single QD-EGF spots are identified in videos by distinctive time-course intensity traces, I ( t ), for which two discrete intensities are present in two-dimensional (2D) images, \$I_{1{\\mathrm{QD}}}^{2{\\mathrm{D}}}\$ and \$I_{\\mathrm{B}}^{2{\\mathrm{D}}}\$ , respectively, corresponding to the intrinsic QD intensity and its background due to on-and-off intermittency of emission (i.e., blinking) 19 , 20 . (2) Volumetric intensities of single QDs from deconvolved 3D images are averaged to yield \$\\overline {I_{1{\\mathrm{QD}}}^{3{\\mathrm{DD}}}}\$ , the average intensity of a single QD-EGF. (3) The number of contributing QDs to each spot in 3D images, N QD,spot , is calculated by dividing the volumetric spot intensity by the single-QD intensity. Finally, the total number of QDs is then calculated across each cell to determine the number of EGF per cell, N EGF,cell : $$N_{{\\mathrm{EGF}},{\\mathrm{cell}}} = \\mathop {\\sum }\\limits_{{\\mathrm{spots}}} N_{{\\mathrm{QD}},{\\mathrm{spot}}} = \\mathop {\\sum }\\limits_{{\\mathrm{spots}}} I_{{\\mathrm{spot}}}^{3{\\mathrm{DD}}} \\cdot \\overline {I_{1{\\mathrm{QD}}}^{3{\\mathrm{DD}}}} ^{ - 1}.$$ (1) Fig. 1 Quantum dot (QD) calibrated three-dimensional (3D) deconvolution microscopy (QDC-3DM). a Schematic representation of the contribution of single-cell stimulation distribution (growth factor binding) to signaling response distribution (measured by receptor internalization). b Depiction of the QDC-3DM image analysis methodology to count growth factors in single cells. The process begins with acquisition of 3D fluorescence images of single cells to localize single QDs and spatially register their locations. A representative 3D image shows a cell stimulated with QD-epidermal growth factor (QD-EGF) (red) on an Alexa Fluor 488-labeled fibronectin substrate (green) with nucleus labeled with Hoechst (blue). Each 3D image is deconvolved and spatially correlated to two-dimensional (2D) videos in the QD color channel. In the first step shown at right, time traces of spot intensities are used to identify single QDs", "role": "user" }, { "content": "Whether healthy or diseased, human cells exhibit behaviors and processes that are largely dictated by growth factor molecules, which bind to receptors on the cells. For example, growth factors tell the cells to divide, move, and when to die—a process known as apoptosis. When growth factor levels are too high or too low, or when cells respond irregularly to their directions, many diseases can result, including cancer. \"It is believed that cells respond to growth factors at extreme levels of sensitivity,\" said University of Illinois at Urbana-Champaign Bioengineering Associate Professor Andrew Smith. \"For example, a single molecule will result in a major change in cell behavior.\" In a recent paper published in Nature Communications, Smith reported the invention of a new technology platform that digitally counts, for the first time ever, the amount of growth factor entering an individual cell. Prior to this, researchers inferred growth factor binding based on how the receiving cells responded when the growth factor molecules were introduced. \"We showed the first direct cause-and-effect relationships of growth factors in single cells,\" he said. \"We expect the outcomes to lead to a new understanding of cell signaling, how cells respond to drugs, and why cell populations become resistant to drugs, particularly toward improved treatments for cancer.\" Smith's technology platform tags each growth factor with a single engineered (10 nanometer) infrared fluorescent quantum dot, which can then be viewed using a three-dimensional microscope. In their study, they counted how many epidermal growth factor (EGF) molecules bound to human triple-negative breast cancer cells that were pre-patterned on island-like surfaces. EGF molecules typically signal cell division and lead to tissue growth. Numerous cancers have mutations in their EGF receptors. \"We used quantum dots as the fluorescent probe because they emit a lot more light compared to other conventional fluorescent probes such as organic dyes, and we can tune their wavelengths by changing their chemical composition,\" said Bioengineering doctoral student Phuong Le, the lead author of the paper. \"In our study, we demonstrated that quantum dots emitting light in the near-infrared wavelength allowed the most accurate counting of growth factors binding to cells.\" According to Le, the team also treated the breast cancer cells with quantum dot-tagged EGF in the absence and presence of pharmaceutical drugs that inhibit EGF signaling in cells. \"We found that the amount of EGF binding is inversely proportional to drug efficacy,\" Le said. \"This finding is significant as it means that signaling molecules present in the cancer cells' tumor—a place where signaling molecules are often misregulated—can enhance the cancer cells' resistance to pharmaceutical agents.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The distribution of single-cell properties across a population of cells can be measured using diverse tools, but no technology directly quantifies the biochemical stimulation events regulating these properties. Here we report digital counting of growth factors in single cells using fluorescent quantum dots and calibrated three-dimensional deconvolution microscopy (QDC-3DM) to reveal physiologically relevant cell stimulation distributions. We calibrate the fluorescence intensities of individual compact quantum dots labeled with epidermal growth factor (EGF) and demonstrate the necessity of near-infrared emission to overcome intrinsic cellular autofluoresence at the single-molecule level. When applied to human triple-negative breast cancer cells, we observe proportionality between stimulation and both receptor internalization and inhibitor response, reflecting stimulation heterogeneity contributions to intrinsic variability. We anticipate that QDC-3DM can be applied to analyze any peptidic ligand to reveal single-cell correlations between external stimulation and phenotypic variability, cell fate, and drug response. Introduction Single-cell analytical techniques are reshaping our understanding of biology by revealing the distribution of gene expression and phenotype across a population of cells 1 , 2 . Applied together with systems biology models and information theory, it is now becoming clear that any population of genetically identical cells naturally exhibits substantial cell-to-cell variability that is integral to the emergence of ensemble biological functions 3 . This heterogeneity has important consequences, as rare cells, rather than cells near the ensemble mean, often dominate clinically meaningful pathogenic processes and drug resistance 4 , 5 , 6 . However, a void exists in experimental techniques to measure how cellular decision-making processes underlying population variability derive from extracellular biochemical signals, such as peptide growth factors and cytokines 7 , 8 , which cannot be easily measured at the single-cell level. Biochemical stimulation, the induction of an intracellular biochemical signal (e.g., receptor activation and translocation) by binding of an exogenous biochemical factor, is usually inferred indirectly from the resulting change in gene expression or cell phenotype 8 . Moreover, input factors are typically applied at stimulation extremes (zero and near saturation) 9 , whereas physiologically relevant tissue concentrations are in intermediate regimes ( c ~ 1–100 pM) 10 , 11 over which cells exhibit sensitive and heterogeneous dose–response relationships (EC 50 ~ 1–100 pM) 12 , 13 . At these concentrations, relevant tissue microdomain volumes (~10 pL) contain just tens to hundreds of factors 14 , 15 , such that signal stimulation is temporally and spatially stochastic 16 . Accurate quantification of initiating signals is therefore very challenging 17 and requires single-molecule sensitivity. Here we describe a technology platform to digitally count growth factors in single cells using fluorescent quantum dots (QDs) and calibrated three-dimensional (3D) deconvolution microscopy (QDC-3DM). As a prototypical example, we focus on epidermal growth factor (EGF) and EGF receptor (EGFR)-positive cells. Fluorescent QDs are used as tags for EGF due to their extremely high fluorescence intensity that is homogeneous and stable at the single-QD level 18 . For maximum signal detection and comprehensive counting of EGF with rapid image acquisition, wide-field excitation is used to collect complete 3D images of cells, and deconvolution is used to reassign photons to their originating focal volumes. We observe that this methodology is only accurate when applying QDs with infrared emission due to interfering fluorescence from cellular components across the visible spectrum. We apply QDC-3DM to analyze EGF-induced cell signaling variability in triple-negative breast cancer cells (MDA-MB-231) grown on micropatterned islands to spatially register signaling events across separate cells. Our results show proportionality between stimulation and both receptor internalization and inhibitor response, reflecting stimulation heterogeneity contributions to intrinsic variability at the single-cell level. Results Imaging and image analysis Figure 1a shows the overarching approach to measure the distribution of stimulation events of growth factors binding to cognate receptors, yielding a response distribution that plays an important role in the variability of signals and behavior between cells. Figure 1b summarizes the imaging and analysis methodology to measure absolute counts of growth factors, using two sequentially collected image stacks. A deconvolved high-resolution 3D epifluorescence image of cells is collected in three colors to distinguish QD-EGF conjugates (in red) spatially registered to the cell location by its fibronectin matrix (in green) and nucleus (in blue). The second image stack is a high temporal resolution video in the QD-EGF color channel. As described in detail in Methods, a three-step process is applied to count EGF molecules per cell: (1) Single QD-EGF spots are identified in videos by distinctive time-course intensity traces, I ( t ), for which two discrete intensities are present in two-dimensional (2D) images, $I_{1{\mathrm{QD}}}^{2{\mathrm{D}}}$ and $I_{\mathrm{B}}^{2{\mathrm{D}}}$ , respectively, corresponding to the intrinsic QD intensity and its background due to on-and-off intermittency of emission (i.e., blinking) 19 , 20 . (2) Volumetric intensities of single QDs from deconvolved 3D images are averaged to yield $\overline {I_{1{\mathrm{QD}}}^{3{\mathrm{DD}}}}$ , the average intensity of a single QD-EGF. (3) The number of contributing QDs to each spot in 3D images, N QD,spot , is calculated by dividing the volumetric spot intensity by the single-QD intensity. Finally, the total number of QDs is then calculated across each cell to determine the number of EGF per cell, N EGF,cell : $$N_{{\mathrm{EGF}},{\mathrm{cell}}} = \mathop {\sum }\limits_{{\mathrm{spots}}} N_{{\mathrm{QD}},{\mathrm{spot}}} = \mathop {\sum }\limits_{{\mathrm{spots}}} I_{{\mathrm{spot}}}^{3{\mathrm{DD}}} \cdot \overline {I_{1{\mathrm{QD}}}^{3{\mathrm{DD}}}} ^{ - 1}.$$ (1) Fig. 1 Quantum dot (QD) calibrated three-dimensional (3D) deconvolution microscopy (QDC-3DM). a Schematic representation of the contribution of single-cell stimulation distribution (growth factor binding) to signaling response distribution (measured by receptor internalization). b Depiction of the QDC-3DM image analysis methodology to count growth factors in single cells. The process begins with acquisition of 3D fluorescence images of single cells to localize single QDs and spatially register their locations. A representative 3D image shows a cell stimulated with QD-epidermal growth factor (QD-EGF) (red) on an Alexa Fluor 488-labeled fibronectin substrate (green) with nucleus labeled with Hoechst (blue). Each 3D image is deconvolved and spatially correlated to two-dimensional (2D) videos in the QD color channel. In the first step shown at right, time traces of spot intensities are used to identify single QDs<|im_end|> <|im_start|>assistant Whether healthy or diseased, human cells exhibit behaviors and processes that are largely dictated by growth factor molecules, which bind to receptors on the cells. For example, growth factors tell the cells to divide, move, and when to die—a process known as apoptosis. When growth factor levels are too high or too low, or when cells respond irregularly to their directions, many diseases can result, including cancer. "It is believed that cells respond to growth factors at extreme levels of sensitivity," said University of Illinois at Urbana-Champaign Bioengineering Associate Professor Andrew Smith. "For example, a single molecule will result in a major change in cell behavior." In a recent paper published in Nature Communications, Smith reported the invention of a new technology platform that digitally counts, for the first time ever, the amount of growth factor entering an individual cell. Prior to this, researchers inferred growth factor binding based on how the receiving cells responded when the growth factor molecules were introduced. "We showed the first direct cause-and-effect relationships of growth factors in single cells," he said. "We expect the outcomes to lead to a new understanding of cell signaling, how cells respond to drugs, and why cell populations become resistant to drugs, particularly toward improved treatments for cancer." Smith's technology platform tags each growth factor with a single engineered (10 nanometer) infrared fluorescent quantum dot, which can then be viewed using a three-dimensional microscope. In their study, they counted how many epidermal growth factor (EGF) molecules bound to human triple-negative breast cancer cells that were pre-patterned on island-like surfaces. EGF molecules typically signal cell division and lead to tissue growth. Numerous cancers have mutations in their EGF receptors. "We used quantum dots as the fluorescent probe because they emit a lot more light compared to other conventional fluorescent probes such as organic dyes, and we can tune their wavelengths by changing their chemical composition," said Bioengineering doctoral student Phuong Le, the lead author of the paper. "In our study, we demonstrated that quantum dots emitting light in the near-infrared wavelength allowed the most accurate counting of growth factors binding to cells." According to Le, the team also treated the breast cancer cells with quantum dot-tagged EGF in the absence and presence of pharmaceutical drugs that inhibit EGF signaling in cells. "We found that the amount of EGF binding is inversely proportional to drug efficacy," Le said. "This finding is significant as it means that signaling molecules present in the cancer cells' tumor—a place where signaling molecules are often misregulated—can enhance the cancer cells' resistance to pharmaceutical agents." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Magnetic properties of superparamagnetic iron oxide nanoparticles are controlled mainly by their particle size and by their particle size distribution. Magnetic properties of multi-core iron oxide nanoparticles, often called iron oxide nanoflowers (IONFs), are additionally affected by the interaction of magnetic moments between neighboring cores. The knowledge about the hierarchical structure of IONFs is therefore essential for understanding the magnetic properties of IONFs. In this contribution, the architecture of multi-core IONFs was investigated using correlative multiscale transmission electron microscopy (TEM), X-ray diffraction and dynamic light scattering. The multiscale TEM measurements comprised low-resolution and high-resolution imaging as well as geometric phase analysis. The IONFs contained maghemite with the average chemical composition \$\\gamma\$ -Fe \$_{2.72\\pm 0.02}\$ O \$_4\$ . The metallic vacancies located on the octahedral lattice sites of the spinel ferrite structure were partially ordered. Individual IONFs consisted of several cores showing frequently a specific crystallographic orientation relationship between direct neighbors. This oriented attachment may facilitate the magnetic alignment within the cores. Individual cores were composed of partially coherent nanocrystals having almost the same crystallographic orientation. The sizes of individual constituents revealed by the microstructure analysis were correlated with the magnetic particle sizes that were obtained from fitting the measured magnetization curve by the Langevin function. Introduction In recent decades, magnetic iron oxide nanoparticles (IONPs) have emerged as one of the most promising nanomaterials for biomedical applications, for example as heat mediator for hyperthermia cancer treatment 1 , as carrier for drug delivery 2 or as contrast agent in magnetic resonance imaging 3 . The manifold applications of IONPs arise from a combination of excellent properties including superparamagnetic behavior, high saturation magnetization, good biocompatibility and the possibility to functionalize IONPs by attaching various bioactive molecules. IONPs usually consist of magnetite (Fe \$_3\$ O \$_4\$ ) and/or maghemite ( \$\\gamma\$ -Fe \$_2\$ O \$_3\$ ), which crystallize in a spinel-like structure with tetrahedrally and octahedrally coordinated iron cations. Magnetite (space group \$Fd{\\bar{3}}m\$ ) accommodates Fe \$^{2+}\$ and Fe \$^{3+}\$ cations on the Wyckoff positions 8 b and 16 c , respectively 4 . This distribution of the cations guarantees charge neutrality. However, in contrast to magnetite, some octahedral iron sites in maghemite must stay vacant to preserve the chemical composition Fe \$_2\$ O \$_3\$ that corresponds to Fe \$_{2.67}\$ O \$_4\$ in the spinel-like crystal structure. The oxygen sublattice is still fully occupied. It has been shown that the Fe vacancies tend to order, which leads to the formation of different crystal structures of \$\\gamma\$ -Fe \$_2\$ O \$_3\$ . The crystal structure of \$\\gamma\$ -Fe \$_2\$ O \$_3\$ with randomly distributed vacancies can still be described as a simple cubic spinel with the space group \$Fd{\\bar{3}}m\$ 5 . \$\\gamma\$ -Fe \$_2\$ O \$_3\$ with vacancies partially ordered only on one of two distinct octahedral sites was described in the space group \$P4_332\$ 6 , \$\\gamma\$ -Fe \$_2\$ O \$_3\$ with vacancies partially ordered on one of three distinct octahedral sites in the tetragonal space group \$P4_32_12\$ but with almost identical lattice parameters a and c 7 . \$\\gamma\$ -Fe \$_2\$ O \$_3\$ with fully ordered vacancies was described as a tetragonal superstructure in the space group \$P4_12_12\$ with \$c\\approx 3a\$ 8 . Vacancy ordering and the tetragonal distortion of the cubic spinel unit cell were originally reported for ‘microcrystalline’ \$\\gamma\$ -Fe \$_2\$ O \$_3\$ . However, the same phenomena were also observed in IONPs 9 , 10 , 11 . The chemical composition (the [Fe]/[O] ratio) and related ordering of vacancies influence the magnetic properties of IONPs. They depend strongly on the fractions of Fe \$_3\$ O \$_4\$ and \$\\gamma\$ -Fe \$_2\$ O \$_3\$ 12 , 13 , 14 , because Fe \$_3\$ O \$_4\$ shows a higher saturation magnetization than \$\\gamma\$ -Fe \$_2\$ O \$_3\$ 15 . The size of IONPs is another important factor affecting their magnetic properties. When it decreases below a certain threshold value, IONPs become superparamagnetic 16 as required for many biomedical applications 17 , 18 , 19 , 20 . The size threshold value is around 25 nm for Fe \$_3\$ O \$_4\$ and 30 nm for \$\\gamma\$ -Fe \$_2\$ O \$_3\$ 21 . Therefore, the size of IONPs needs to be tailored for the respective application in order to obtain the best possible combination of properties. However, when IONPs are significantly smaller, their saturation magnetization is reduced by a disorder of the spins either in the interior of the IONPs or in their surface layer. The spin disorder in the interior of the IONPs was explained by inhomogeneous ordering of the cation vacancies 22 .The spin disorder in the surface layer of IONPs is usually explained by the incomplete coordination of superficial iron ions and the likely occurrence of structural defects at the IONP rim 23 , 24 , 25 . At 300 K, a thickness of the disordered spin layer of 0.54 nm was reported by Sharifi Dehsari et al. 26 , whereas a thickness of 1 nm was reported by Millan et al. 25 (for IONPs larger than 3 nm). Furthermore, the different [Fe]/[O] ratio in magnetite and maghemite is a reason for their different oxidation stability. Under aerobic conditions, maghemite is much more stable than magnetite 27 . Thus, the exact phase composition and distribution of Fe \$_3\$ O \$_4\$ and \$\\gamma\$ -Fe \$_2\$ O \$_3\$ can vary, in particular, if IONPs are in contact with oxygen. While a full oxidization of the iron oxide to \$\\gamma\$ -Fe \$_2\$ O \$_3\$ was observed for smaller particles 28 , IONPs with intermediate sizes were found to contain non-stoichiometric Fe \$_{\\langle 3-\\delta \\rangle }\$ O \$_4\$ with \$2.667<\\langle 3-\\delta \\rangle <3\$ 12 , 28 . Large IONPs are generally assumed to have a core/shell structure with a Fe \$_3\$ O \$_4\$ core and an oxidized shell 12 , 13 , 28 , 29 , 30 , 31 . Recently, multi-core IONPs, often referred to as iron oxide nanoflowers (IONFs) 32 , 33 , 34 , 35 , 36 , 37 , 38", "role": "user" }, { "content": "Iron oxide nanoparticles are often used in medical technology as contrast agents for magnetic resonance imaging or as transport agents for drugs in the bloodstream, for example in tumor therapy. For these applications, the nanoparticles have to be biocompatible and superparamagnetic. Thus, they must be strongly magnetizable in a magnetic field and also must lose their magnetization when the magnetic field is switched off. Using analytical high-resolution transmission electron microscopy, a team at TU Bergakademie Freiberg investigated how the magnetic properties of the nanoparticles can further be improved via microstructure design. The researchers published their results in the current issue of Scientific Reports. The knowledge of the exact structure of the iron oxide nanoparticles sized between 20 and 30 nanometers helps to optimize the manufacturing process and to improve the magnetic properties of the particles systematically. Each particle consists of at least two superparamagnetic nanocrystalline cores and a shell that does not contribute to the magnetic properties. The maximum magnetization of the nanoparticles depends on the mutual orientation of the individual cores. How well are the cores oriented to each other? \"The current state of research assumed that a strong alignment of magnetic moments in multi-core iron oxide nanoparticles is enabled by the same crystallographic orientation of individual cores. However, our analyses showed that this is not necessarily true,\" says Stefan Neumann, research associate at TU Bergakademie Freiberg and the first author of the publication. \"Also other, but still specific crystallographic orientation relationships of the cores can promote their magnetic interaction. Nevertheless, a fully random alignment of the cores deteriorates the magnetic properties of the nanoparticles,\" says Neumann. \"In order to be able to produce highly superparamagnetic iron oxide nanoparticles for future applications in medicine on demand, we need knowledge of their internal structure,\" says co-author Prof. David Rafaja, head of the Institute of Materials Science at TU Bergakademie Freiberg. \"During the production of the nanoparticles, individual cores are formed first. When the cores get more time to align in the right way, then the magnetic properties of the nanoparticles can further be improved.\" Background: Analyzing ultra-fine particles The results were obtained within the priority program \"MehrDimPart—Highly Specific and Multidimensional Fractionation of Fine Particle Systems with Technical Relevance.\" The aim of the research is to develop technological approaches that enable a controlled production of highly specific and technologically relevant particle systems with desired properties. In addition to the team from TU Bergakademie Freiberg, scientists from the Karlsruhe Institute of Technology have also contributed to the current publication. The basic research behind this work was focused on the structure of the nanoparticles to be able to optimize the production of particles with specific magnetic properties. A toxicological study was not carried out. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Magnetic properties of superparamagnetic iron oxide nanoparticles are controlled mainly by their particle size and by their particle size distribution. Magnetic properties of multi-core iron oxide nanoparticles, often called iron oxide nanoflowers (IONFs), are additionally affected by the interaction of magnetic moments between neighboring cores. The knowledge about the hierarchical structure of IONFs is therefore essential for understanding the magnetic properties of IONFs. In this contribution, the architecture of multi-core IONFs was investigated using correlative multiscale transmission electron microscopy (TEM), X-ray diffraction and dynamic light scattering. The multiscale TEM measurements comprised low-resolution and high-resolution imaging as well as geometric phase analysis. The IONFs contained maghemite with the average chemical composition $\gamma$ -Fe $_{2.72\pm 0.02}$ O $_4$ . The metallic vacancies located on the octahedral lattice sites of the spinel ferrite structure were partially ordered. Individual IONFs consisted of several cores showing frequently a specific crystallographic orientation relationship between direct neighbors. This oriented attachment may facilitate the magnetic alignment within the cores. Individual cores were composed of partially coherent nanocrystals having almost the same crystallographic orientation. The sizes of individual constituents revealed by the microstructure analysis were correlated with the magnetic particle sizes that were obtained from fitting the measured magnetization curve by the Langevin function. Introduction In recent decades, magnetic iron oxide nanoparticles (IONPs) have emerged as one of the most promising nanomaterials for biomedical applications, for example as heat mediator for hyperthermia cancer treatment 1 , as carrier for drug delivery 2 or as contrast agent in magnetic resonance imaging 3 . The manifold applications of IONPs arise from a combination of excellent properties including superparamagnetic behavior, high saturation magnetization, good biocompatibility and the possibility to functionalize IONPs by attaching various bioactive molecules. IONPs usually consist of magnetite (Fe $_3$ O $_4$ ) and/or maghemite ( $\gamma$ -Fe $_2$ O $_3$ ), which crystallize in a spinel-like structure with tetrahedrally and octahedrally coordinated iron cations. Magnetite (space group $Fd{\bar{3}}m$ ) accommodates Fe $^{2+}$ and Fe $^{3+}$ cations on the Wyckoff positions 8 b and 16 c , respectively 4 . This distribution of the cations guarantees charge neutrality. However, in contrast to magnetite, some octahedral iron sites in maghemite must stay vacant to preserve the chemical composition Fe $_2$ O $_3$ that corresponds to Fe $_{2.67}$ O $_4$ in the spinel-like crystal structure. The oxygen sublattice is still fully occupied. It has been shown that the Fe vacancies tend to order, which leads to the formation of different crystal structures of $\gamma$ -Fe $_2$ O $_3$ . The crystal structure of $\gamma$ -Fe $_2$ O $_3$ with randomly distributed vacancies can still be described as a simple cubic spinel with the space group $Fd{\bar{3}}m$ 5 . $\gamma$ -Fe $_2$ O $_3$ with vacancies partially ordered only on one of two distinct octahedral sites was described in the space group $P4_332$ 6 , $\gamma$ -Fe $_2$ O $_3$ with vacancies partially ordered on one of three distinct octahedral sites in the tetragonal space group $P4_32_12$ but with almost identical lattice parameters a and c 7 . $\gamma$ -Fe $_2$ O $_3$ with fully ordered vacancies was described as a tetragonal superstructure in the space group $P4_12_12$ with $c\approx 3a$ 8 . Vacancy ordering and the tetragonal distortion of the cubic spinel unit cell were originally reported for ‘microcrystalline’ $\gamma$ -Fe $_2$ O $_3$ . However, the same phenomena were also observed in IONPs 9 , 10 , 11 . The chemical composition (the [Fe]/[O] ratio) and related ordering of vacancies influence the magnetic properties of IONPs. They depend strongly on the fractions of Fe $_3$ O $_4$ and $\gamma$ -Fe $_2$ O $_3$ 12 , 13 , 14 , because Fe $_3$ O $_4$ shows a higher saturation magnetization than $\gamma$ -Fe $_2$ O $_3$ 15 . The size of IONPs is another important factor affecting their magnetic properties. When it decreases below a certain threshold value, IONPs become superparamagnetic 16 as required for many biomedical applications 17 , 18 , 19 , 20 . The size threshold value is around 25 nm for Fe $_3$ O $_4$ and 30 nm for $\gamma$ -Fe $_2$ O $_3$ 21 . Therefore, the size of IONPs needs to be tailored for the respective application in order to obtain the best possible combination of properties. However, when IONPs are significantly smaller, their saturation magnetization is reduced by a disorder of the spins either in the interior of the IONPs or in their surface layer. The spin disorder in the interior of the IONPs was explained by inhomogeneous ordering of the cation vacancies 22 .The spin disorder in the surface layer of IONPs is usually explained by the incomplete coordination of superficial iron ions and the likely occurrence of structural defects at the IONP rim 23 , 24 , 25 . At 300 K, a thickness of the disordered spin layer of 0.54 nm was reported by Sharifi Dehsari et al. 26 , whereas a thickness of 1 nm was reported by Millan et al. 25 (for IONPs larger than 3 nm). Furthermore, the different [Fe]/[O] ratio in magnetite and maghemite is a reason for their different oxidation stability. Under aerobic conditions, maghemite is much more stable than magnetite 27 . Thus, the exact phase composition and distribution of Fe $_3$ O $_4$ and $\gamma$ -Fe $_2$ O $_3$ can vary, in particular, if IONPs are in contact with oxygen. While a full oxidization of the iron oxide to $\gamma$ -Fe $_2$ O $_3$ was observed for smaller particles 28 , IONPs with intermediate sizes were found to contain non-stoichiometric Fe $_{\langle 3-\delta \rangle }$ O $_4$ with $2.667<\langle 3-\delta \rangle <3$ 12 , 28 . Large IONPs are generally assumed to have a core/shell structure with a Fe $_3$ O $_4$ core and an oxidized shell 12 , 13 , 28 , 29 , 30 , 31 . Recently, multi-core IONPs, often referred to as iron oxide nanoflowers (IONFs) 32 , 33 , 34 , 35 , 36 , 37 , 38<|im_end|> <|im_start|>assistant Iron oxide nanoparticles are often used in medical technology as contrast agents for magnetic resonance imaging or as transport agents for drugs in the bloodstream, for example in tumor therapy. For these applications, the nanoparticles have to be biocompatible and superparamagnetic. Thus, they must be strongly magnetizable in a magnetic field and also must lose their magnetization when the magnetic field is switched off. Using analytical high-resolution transmission electron microscopy, a team at TU Bergakademie Freiberg investigated how the magnetic properties of the nanoparticles can further be improved via microstructure design. The researchers published their results in the current issue of Scientific Reports. The knowledge of the exact structure of the iron oxide nanoparticles sized between 20 and 30 nanometers helps to optimize the manufacturing process and to improve the magnetic properties of the particles systematically. Each particle consists of at least two superparamagnetic nanocrystalline cores and a shell that does not contribute to the magnetic properties. The maximum magnetization of the nanoparticles depends on the mutual orientation of the individual cores. How well are the cores oriented to each other? "The current state of research assumed that a strong alignment of magnetic moments in multi-core iron oxide nanoparticles is enabled by the same crystallographic orientation of individual cores. However, our analyses showed that this is not necessarily true," says Stefan Neumann, research associate at TU Bergakademie Freiberg and the first author of the publication. "Also other, but still specific crystallographic orientation relationships of the cores can promote their magnetic interaction. Nevertheless, a fully random alignment of the cores deteriorates the magnetic properties of the nanoparticles," says Neumann. "In order to be able to produce highly superparamagnetic iron oxide nanoparticles for future applications in medicine on demand, we need knowledge of their internal structure," says co-author Prof. David Rafaja, head of the Institute of Materials Science at TU Bergakademie Freiberg. "During the production of the nanoparticles, individual cores are formed first. When the cores get more time to align in the right way, then the magnetic properties of the nanoparticles can further be improved." Background: Analyzing ultra-fine particles The results were obtained within the priority program "MehrDimPart—Highly Specific and Multidimensional Fractionation of Fine Particle Systems with Technical Relevance." The aim of the research is to develop technological approaches that enable a controlled production of highly specific and technologically relevant particle systems with desired properties. In addition to the team from TU Bergakademie Freiberg, scientists from the Karlsruhe Institute of Technology have also contributed to the current publication. The basic research behind this work was focused on the structure of the nanoparticles to be able to optimize the production of particles with specific magnetic properties. A toxicological study was not carried out. <|im_end|>

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2,162

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Sudden cardiac death from arrhythmia is a major cause of mortality worldwide. In this study, we developed a novel deep learning (DL) approach that blends neural networks and survival analysis to predict patient-specific survival curves from contrast-enhanced cardiac magnetic resonance images and clinical covariates for patients with ischemic heart disease. The DL-predicted survival curves offer accurate predictions at times up to 10 years and allow for estimation of uncertainty in predictions. The performance of this learning architecture was evaluated on multi-center internal validation data and tested on an independent test set, achieving concordance indexes of 0.83 and 0.74 and 10-year integrated Brier scores of 0.12 and 0.14. We demonstrate that our DL approach, with only raw cardiac images as input, outperforms standard survival models constructed using clinical covariates. This technology has the potential to transform clinical decision-making by offering accurate and generalizable predictions of patient-specific survival probabilities of arrhythmic death over time. Main Sudden cardiac death (SCD) continues to be a leading cause of mortality worldwide, with an incidence of 50–100 per 100,000 in the general population in Europe and North America 1 , and accounts for 15–20% of all deaths 2 . Patients with coronary artery disease are at the highest risk of arrhythmic sudden cardiac death (SCDA) 3 , 4 . Although implantable cardioverter devices (ICDs) effectively prevent SCD due to ventricular arrhythmias, current clinical criteria for ICD candidacy—that is, left ventricular ejection fraction (LVEF) <30–35% 5 —capture only a mere 20% all SCDAs 6 , highlighting the critical need to develop personalized, accurate and cost-effective arrhythmia risk assessment tools to mitigate this enormous public health and economic burden. Several studies have identified risk factors for SCDA, and many risk stratification approaches have attempted to transcend LVEF 7 , 8 . However, limitations in these approaches have been barriers to their clinical implementation. Previous attempts have broadly stratified populations based on subgroup risk, failing to customize predictions to patients’ unique clinical features 9 . SCDA risk has been typically assessed at pre-defined finite time points, ignoring the likely patient-specific time evolution of the disease 10 . Additionally, in previous work, confidence estimates for predictions have been ‘one-size-fits-all’, varying only by risk subgroup, thus preventing the identification of low-confidence, potentially highly erroneous prediction outliers 11 . Moreover, few previous studies have validated their results externally or comprehensively compared model performance to standard approaches. A robust, generalizable SCDA risk stratifier with the ability to predict individualized, patient-specific risk trajectories and confidence estimates could considerably enhance clinical decision-making. Finally, although arrhythmia arises, mechanistically, from the heterogeneous scar distribution in the disease-remodeled heart, machine learning the features of that distribution has not been explored for risk analysis. Image-derived mechanistic computational models of cardiac electrical function that incorporate scar distribution have proven successful in predicting arrhythmia risk 12 ; however, they remain exceedingly computationally intensive. Therefore, computational models are impractical as a first-stage screening tool in a broad population. Using raw contrast-enhanced (late gadolinium enhancement (LGE)) cardiac images that visualize scar distribution in a DL framework, which additionally draws on standard clinical covariates, could overcome these limitations and lead to accurate patient-specific SCDA probabilities in fractions of a second. Here we present a DL technology for prediction of SCDA risk in patients with ischemic heart disease. Our approach, which we term Survival Study of Cardiac Arrhythmia Risk (SSCAR), embeds, within a survival model, neural networks to estimate individual patient times to SCDA ( T S C D A ). The neural networks learn from raw clinical imaging data, which visualize heart-disease-induced scar distribution, as well as from clinical covariates. The predicted patient-specific survival curves offer accurate SCDA probabilities at all times up to 10 years. The performance and high generalizability of the approach are demonstrated by testing on an external cohort, after internal cross-validation. Our technology represents a fundamental change in the approach to arrhythmia risk assessment, as SSCAR uses the data to directly estimate uncertainty in its predictions. Therefore, SSCAR has the potential to considerably shape clinical decision-making regarding arrhythmia risk, offering not a simple ‘at-risk/not-at-risk’ prediction but, instead, an estimate of the time to SCDA together with a sense of ‘how certain’ the model is about each predicted T S C D A . Results SSCAR overview The arrhythmia risk assessment algorithm in SSCAR is a DL framework that incorporates multiple custom neural networks (which fuse different data types), combined with statistical survival analysis, to predict patient-specific probabilities of SCDA at future time points. Figure 1 presents an overview of SSCAR. On the left and right, cardiac magnetic resonance (CMR) images and clinical covariates (yellow panel) are used as inputs to the two corresponding branches of the model. The goal of each of the branches is to predict the patient-specific survival curve. In the left branch, cardiac CMR images—visualizing the patients’ three-dimensional (3D) ventricle geometry and contrast-enhanced remodeled tissue—are used as input by a custom-designed encoder–decoder convolutional neural sub-network (red panel, left). This CMR sub-network is trained to reduce the dimension of the input (that is, encode) and to discover and extract imaging features associated with SCDA risk directly from the CMR images by learning and applying filters (that is, convolving). The encoder–decoder design of the sub-network ensures that resulting imaging features retain sufficient information to be able to reconstruct the original images (red panel, left, decoder path). In the right branch, the 22 clinical covariates in Table 1 are provided to a dense sub-network (green panel, right), which discovers and extracts non-linear relationships between the input variables. The outputs of the sub-networks are combined (ensembled) in a way that best fits the observed SCDA event training data (center path, dot-dashed) to estimate the most probable T S C D A and the uncertainty in the prediction. The output of the model is a per-patient cause-specific survival curve (bottom, blue). Fig. 1: Schematic overview of SSCAR. Top panel (yellow) shows patient data used in this study. SSCAR uses contrast-enhanced (LGE)-CMR images with the left ventricle automatically segmented (left inset) and", "role": "user" }, { "content": "A new artificial intelligence-based approach can predict, significantly more accurately than a doctor, if and when a patient could die of cardiac arrest. The technology, built on raw images of patient's diseased hearts and patient backgrounds, stands to revolutionize clinical decision making and increase survival from sudden and lethal cardiac arrhythmias, one of medicine's deadliest and most puzzling conditions. The work, led by Johns Hopkins University researchers, is detailed today in Nature Cardiovascular Research. \"Sudden cardiac death caused by arrhythmia accounts for as many as 20 percent of all deaths worldwide and we know little about why it's happening or how to tell who's at risk,\" said senior author Natalia Trayanova, the Murray B. Sachs professor of Biomedical Engineering and Medicine. \"There are patients who may be at low risk of sudden cardiac death getting defibrillators that they might not need and then there are high-risk patients that aren't getting the treatment they need and could die in the prime of their life. What our algorithm can do is determine who is at risk for cardiac death and when it will occur, allowing doctors to decide exactly what needs to be done.\" The team is the first to use neural networks to build a personalized survival assessment for each patient with heart disease. These risk measures provide with high accuracy the chance for a sudden cardiac death over 10 years, and when it's most likely to happen. The deep learning technology is called Survival Study of Cardiac Arrhythmia Risk (SSCAR). The name alludes to cardiac scarring caused by heart disease that often results in lethal arrhythmias, and the key to the algorithm's predictions. The team used contrast-enhanced cardiac images that visualize scar distribution from hundreds of real patients at Johns Hopkins Hospital with cardiac scarring to train an algorithm to detect patterns and relationships not visible to the naked eye. Current clinical cardiac image analysis extracts only simple scar features like volume and mass, severely underutilizing what's demonstrated in this work to be critical data. \"The images carry critical information that doctors haven't been able to access,\" said first author Dan Popescu, a former Johns Hopkins doctoral student. \"This scarring can be distributed in different ways and it says something about a patient's chance for survival. There is information hidden in it.\" The team trained a second neural network to learn from 10 years of standard clinical patient data, 22 factors such as patients' age, weight, race and prescription drug use. The algorithms' predictions were not only significantly more accurate on every measure than doctors, they were validated in tests with an independent patient cohort from 60 health centers across the United States, with different cardiac histories and different imaging data, suggesting the platform could be adopted anywhere. \"This has the potential to significantly shape clinical decision-making regarding arrhythmia risk and represents an essential step towards bringing patient trajectory prognostication into the age of artificial intelligence,\" said Trayanova, co-director of the Alliance for Cardiovascular Diagnostic and Treatment Innovation. \"It epitomizes the trend of merging artificial intelligence, engineering, and medicine as the future of healthcare.\" The team is now working to build algorithms now to detect other cardiac diseases. According to Trayanova, the deep-learning concept could be developed for other fields of medicine that rely on visual diagnosis. The team from Johns Hopkins also included: Bloomberg Distinguished Professor of Data-Intensive Computation Mauro Maggioni; Julie Shade; Changxin Lai; Konstantino Aronis; and Katherine Wu. Other authors include: M. Vinayaga Moorthy and Nancy Cook of Brigham and Women's Hospital; Daniel Lee of Northwester University; Alan Kadish of Touro College and University System; David Oyyang and Christine Albert of Cedar-Sinai Medical Center. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Sudden cardiac death from arrhythmia is a major cause of mortality worldwide. In this study, we developed a novel deep learning (DL) approach that blends neural networks and survival analysis to predict patient-specific survival curves from contrast-enhanced cardiac magnetic resonance images and clinical covariates for patients with ischemic heart disease. The DL-predicted survival curves offer accurate predictions at times up to 10 years and allow for estimation of uncertainty in predictions. The performance of this learning architecture was evaluated on multi-center internal validation data and tested on an independent test set, achieving concordance indexes of 0.83 and 0.74 and 10-year integrated Brier scores of 0.12 and 0.14. We demonstrate that our DL approach, with only raw cardiac images as input, outperforms standard survival models constructed using clinical covariates. This technology has the potential to transform clinical decision-making by offering accurate and generalizable predictions of patient-specific survival probabilities of arrhythmic death over time. Main Sudden cardiac death (SCD) continues to be a leading cause of mortality worldwide, with an incidence of 50–100 per 100,000 in the general population in Europe and North America 1 , and accounts for 15–20% of all deaths 2 . Patients with coronary artery disease are at the highest risk of arrhythmic sudden cardiac death (SCDA) 3 , 4 . Although implantable cardioverter devices (ICDs) effectively prevent SCD due to ventricular arrhythmias, current clinical criteria for ICD candidacy—that is, left ventricular ejection fraction (LVEF) <30–35% 5 —capture only a mere 20% all SCDAs 6 , highlighting the critical need to develop personalized, accurate and cost-effective arrhythmia risk assessment tools to mitigate this enormous public health and economic burden. Several studies have identified risk factors for SCDA, and many risk stratification approaches have attempted to transcend LVEF 7 , 8 . However, limitations in these approaches have been barriers to their clinical implementation. Previous attempts have broadly stratified populations based on subgroup risk, failing to customize predictions to patients’ unique clinical features 9 . SCDA risk has been typically assessed at pre-defined finite time points, ignoring the likely patient-specific time evolution of the disease 10 . Additionally, in previous work, confidence estimates for predictions have been ‘one-size-fits-all’, varying only by risk subgroup, thus preventing the identification of low-confidence, potentially highly erroneous prediction outliers 11 . Moreover, few previous studies have validated their results externally or comprehensively compared model performance to standard approaches. A robust, generalizable SCDA risk stratifier with the ability to predict individualized, patient-specific risk trajectories and confidence estimates could considerably enhance clinical decision-making. Finally, although arrhythmia arises, mechanistically, from the heterogeneous scar distribution in the disease-remodeled heart, machine learning the features of that distribution has not been explored for risk analysis. Image-derived mechanistic computational models of cardiac electrical function that incorporate scar distribution have proven successful in predicting arrhythmia risk 12 ; however, they remain exceedingly computationally intensive. Therefore, computational models are impractical as a first-stage screening tool in a broad population. Using raw contrast-enhanced (late gadolinium enhancement (LGE)) cardiac images that visualize scar distribution in a DL framework, which additionally draws on standard clinical covariates, could overcome these limitations and lead to accurate patient-specific SCDA probabilities in fractions of a second. Here we present a DL technology for prediction of SCDA risk in patients with ischemic heart disease. Our approach, which we term Survival Study of Cardiac Arrhythmia Risk (SSCAR), embeds, within a survival model, neural networks to estimate individual patient times to SCDA ( T S C D A ). The neural networks learn from raw clinical imaging data, which visualize heart-disease-induced scar distribution, as well as from clinical covariates. The predicted patient-specific survival curves offer accurate SCDA probabilities at all times up to 10 years. The performance and high generalizability of the approach are demonstrated by testing on an external cohort, after internal cross-validation. Our technology represents a fundamental change in the approach to arrhythmia risk assessment, as SSCAR uses the data to directly estimate uncertainty in its predictions. Therefore, SSCAR has the potential to considerably shape clinical decision-making regarding arrhythmia risk, offering not a simple ‘at-risk/not-at-risk’ prediction but, instead, an estimate of the time to SCDA together with a sense of ‘how certain’ the model is about each predicted T S C D A . Results SSCAR overview The arrhythmia risk assessment algorithm in SSCAR is a DL framework that incorporates multiple custom neural networks (which fuse different data types), combined with statistical survival analysis, to predict patient-specific probabilities of SCDA at future time points. Figure 1 presents an overview of SSCAR. On the left and right, cardiac magnetic resonance (CMR) images and clinical covariates (yellow panel) are used as inputs to the two corresponding branches of the model. The goal of each of the branches is to predict the patient-specific survival curve. In the left branch, cardiac CMR images—visualizing the patients’ three-dimensional (3D) ventricle geometry and contrast-enhanced remodeled tissue—are used as input by a custom-designed encoder–decoder convolutional neural sub-network (red panel, left). This CMR sub-network is trained to reduce the dimension of the input (that is, encode) and to discover and extract imaging features associated with SCDA risk directly from the CMR images by learning and applying filters (that is, convolving). The encoder–decoder design of the sub-network ensures that resulting imaging features retain sufficient information to be able to reconstruct the original images (red panel, left, decoder path). In the right branch, the 22 clinical covariates in Table 1 are provided to a dense sub-network (green panel, right), which discovers and extracts non-linear relationships between the input variables. The outputs of the sub-networks are combined (ensembled) in a way that best fits the observed SCDA event training data (center path, dot-dashed) to estimate the most probable T S C D A and the uncertainty in the prediction. The output of the model is a per-patient cause-specific survival curve (bottom, blue). Fig. 1: Schematic overview of SSCAR. Top panel (yellow) shows patient data used in this study. SSCAR uses contrast-enhanced (LGE)-CMR images with the left ventricle automatically segmented (left inset) and<|im_end|> <|im_start|>assistant A new artificial intelligence-based approach can predict, significantly more accurately than a doctor, if and when a patient could die of cardiac arrest. The technology, built on raw images of patient's diseased hearts and patient backgrounds, stands to revolutionize clinical decision making and increase survival from sudden and lethal cardiac arrhythmias, one of medicine's deadliest and most puzzling conditions. The work, led by Johns Hopkins University researchers, is detailed today in Nature Cardiovascular Research. "Sudden cardiac death caused by arrhythmia accounts for as many as 20 percent of all deaths worldwide and we know little about why it's happening or how to tell who's at risk," said senior author Natalia Trayanova, the Murray B. Sachs professor of Biomedical Engineering and Medicine. "There are patients who may be at low risk of sudden cardiac death getting defibrillators that they might not need and then there are high-risk patients that aren't getting the treatment they need and could die in the prime of their life. What our algorithm can do is determine who is at risk for cardiac death and when it will occur, allowing doctors to decide exactly what needs to be done." The team is the first to use neural networks to build a personalized survival assessment for each patient with heart disease. These risk measures provide with high accuracy the chance for a sudden cardiac death over 10 years, and when it's most likely to happen. The deep learning technology is called Survival Study of Cardiac Arrhythmia Risk (SSCAR). The name alludes to cardiac scarring caused by heart disease that often results in lethal arrhythmias, and the key to the algorithm's predictions. The team used contrast-enhanced cardiac images that visualize scar distribution from hundreds of real patients at Johns Hopkins Hospital with cardiac scarring to train an algorithm to detect patterns and relationships not visible to the naked eye. Current clinical cardiac image analysis extracts only simple scar features like volume and mass, severely underutilizing what's demonstrated in this work to be critical data. "The images carry critical information that doctors haven't been able to access," said first author Dan Popescu, a former Johns Hopkins doctoral student. "This scarring can be distributed in different ways and it says something about a patient's chance for survival. There is information hidden in it." The team trained a second neural network to learn from 10 years of standard clinical patient data, 22 factors such as patients' age, weight, race and prescription drug use. The algorithms' predictions were not only significantly more accurate on every measure than doctors, they were validated in tests with an independent patient cohort from 60 health centers across the United States, with different cardiac histories and different imaging data, suggesting the platform could be adopted anywhere. "This has the potential to significantly shape clinical decision-making regarding arrhythmia risk and represents an essential step towards bringing patient trajectory prognostication into the age of artificial intelligence," said Trayanova, co-director of the Alliance for Cardiovascular Diagnostic and Treatment Innovation. "It epitomizes the trend of merging artificial intelligence, engineering, and medicine as the future of healthcare." The team is now working to build algorithms now to detect other cardiac diseases. According to Trayanova, the deep-learning concept could be developed for other fields of medicine that rely on visual diagnosis. The team from Johns Hopkins also included: Bloomberg Distinguished Professor of Data-Intensive Computation Mauro Maggioni; Julie Shade; Changxin Lai; Konstantino Aronis; and Katherine Wu. Other authors include: M. Vinayaga Moorthy and Nancy Cook of Brigham and Women's Hospital; Daniel Lee of Northwester University; Alan Kadish of Touro College and University System; David Oyyang and Christine Albert of Cedar-Sinai Medical Center. <|im_end|>

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3025, 311, 44928, 279, 4113, 5448, 320, 1171, 7090, 11, 2163, 11, 25569, 1853, 570, 763, 279, 1314, 9046, 11, 279, 220, 1313, 14830, 22590, 2850, 988, 304, 6771, 220, 16, 527, 3984, 311, 264, 29050, 1207, 57832, 320, 13553, 7090, 11, 1314, 705, 902, 52114, 323, 49062, 2536, 62399, 12135, 1990, 279, 1988, 7482, 13, 578, 16674, 315, 279, 1207, 57832, 82, 527, 11093, 320, 1137, 3172, 839, 8, 304, 264, 1648, 430, 1888, 18809, 279, 13468, 7683, 6486, 1567, 4967, 828, 320, 3133, 1853, 11, 13046, 1773, 13883, 8, 311, 16430, 279, 1455, 35977, 350, 328, 356, 423, 362, 323, 279, 27924, 304, 279, 20212, 13, 578, 2612, 315, 279, 1646, 374, 264, 824, 2320, 16794, 5353, 19440, 20237, 16029, 320, 15205, 11, 6437, 570, 23966, 13, 220, 16, 25, 328, 82149, 24131, 315, 98465, 946, 13, 7054, 7090, 320, 28969, 8, 5039, 8893, 828, 1511, 304, 420, 4007, 13, 98465, 946, 5829, 13168, 84182, 4979, 320, 43, 11010, 7435, 10190, 49, 5448, 449, 279, 2163, 10594, 81, 2045, 9651, 86045, 320, 2414, 55959, 8, 323, 128257, 198, 128256, 78191, 198, 32, 502, 21075, 11478, 6108, 5603, 649, 7168, 11, 12207, 810, 30357, 1109, 264, 10896, 11, 422, 323, 994, 264, 8893, 1436, 2815, 315, 47345, 8163, 13, 578, 5557, 11, 5918, 389, 7257, 5448, 315, 8893, 596, 6759, 1503, 23492, 323, 8893, 36576, 11, 13656, 311, 14110, 553, 14830, 5597, 3339, 323, 5376, 20237, 505, 11210, 323, 45089, 47345, 2961, 61254, 3557, 11, 832, 315, 16088, 596, 99469, 323, 1455, 32854, 2785, 4787, 13, 578, 990, 11, 6197, 555, 53240, 45316, 3907, 12074, 11, 374, 11944, 3432, 304, 22037, 92976, 33945, 8483, 13, 330, 50, 39095, 47345, 4648, 9057, 555, 2961, 61254, 689, 9815, 369, 439, 1690, 439, 220, 508, 3346, 315, 682, 16779, 15603, 323, 584, 1440, 2697, 922, 3249, 433, 596, 12765, 477, 1268, 311, 3371, 889, 596, 520, 5326, 1359, 1071, 10195, 3229, 42701, 689, 1183, 44957, 12949, 11, 279, 28253, 426, 13, 61027, 14561, 315, 12371, 61860, 17005, 323, 19152, 13, 330, 3947, 527, 6978, 889, 1253, 387, 520, 3428, 5326, 315, 11210, 47345, 4648, 3794, 711, 10892, 484, 3046, 430, 814, 2643, 539, 1205, 323, 1243, 1070, 527, 1579, 46570, 6978, 430, 7784, 956, 3794, 279, 6514, 814, 1205, 323, 1436, 2815, 304, 279, 10461, 315, 872, 2324, 13, 3639, 1057, 12384, 649, 656, 374, 8417, 889, 374, 520, 5326, 369, 47345, 4648, 323, 994, 433, 690, 12446, 11, 10923, 16410, 311, 10491, 7041, 1148, 3966, 311, 387, 2884, 1210, 578, 2128, 374, 279, 1176, 311, 1005, 30828, 14488, 311, 1977, 264, 35649, 20237, 15813, 369, 1855, 8893, 449, 4851, 8624, 13, 4314, 5326, 11193, 3493, 449, 1579, 13708, 279, 6140, 369, 264, 11210, 47345, 4648, 927, 220, 605, 1667, 11, 323, 994, 433, 596, 1455, 4461, 311, 3621, 13, 578, 5655, 6975, 5557, 374, 2663, 54451, 19723, 315, 6938, 18029, 18925, 61254, 689, 32388, 320, 1242, 37490, 570, 578, 836, 682, 29246, 311, 47345, 1156, 20450, 9057, 555, 4851, 8624, 430, 3629, 3135, 304, 45089, 2961, 61254, 3557, 11, 323, 279, 1401, 311, 279, 12384, 596, 20492, 13, 578, 2128, 1511, 13168, 84182, 4979, 47345, 5448, 430, 51187, 23087, 8141, 505, 11758, 315, 1972, 6978, 520, 53240, 45316, 15429, 449, 47345, 1156, 20450, 311, 5542, 459, 12384, 311, 11388, 12912, 323, 12135, 539, 9621, 311, 279, 19557, 8071, 13, 9303, 14830, 47345, 2217, 6492, 49062, 1193, 4382, 23087, 4519, 1093, 8286, 323, 3148, 11, 35906, 1234, 1338, 4954, 1148, 596, 21091, 304, 420, 990, 311, 387, 9200, 828, 13, 330, 791, 5448, 6920, 9200, 2038, 430, 16410, 9167, 956, 1027, 3025, 311, 2680, 1359, 1071, 1176, 3229, 11824, 10466, 3380, 84, 11, 264, 4846, 53240, 45316, 74657, 5575, 13, 330, 2028, 1156, 20450, 649, 387, 4332, 304, 2204, 5627, 323, 433, 2795, 2555, 922, 264, 8893, 596, 6140, 369, 20237, 13, 2684, 374, 2038, 8340, 304, 433, 1210, 578, 2128, 16572, 264, 2132, 30828, 4009, 311, 4048, 505, 220, 605, 1667, 315, 5410, 14830, 8893, 828, 11, 220, 1313, 9547, 1778, 439, 6978, 6, 4325, 11, 4785, 11, 7102, 323, 22866, 5623, 1005, 13, 578, 26249, 6, 20492, 1051, 539, 1193, 12207, 810, 13687, 389, 1475, 6767, 1109, 16410, 11, 814, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Biorefineries produce impure sugar waste streams that are being underutilized. By converting this waste to a profitable by-product, biorefineries could be safeguarded against low oil prices. We demonstrate controlled production of useful carbon materials from the waste concentrate via hydrothermal synthesis and carbonization. We devise a pathway to producing tunable, porous spherical carbon materials by modeling the gross structure formation and developing an understanding of the pore formation mechanism utilizing simple reaction principles. Compared to a simple hydrothermal synthesis from sugar concentrate, emulsion-based synthesis results in hollow spheres with abundant microporosity. In contrast, conventional hydrothermal synthesis produces solid beads with micro and mesoporosity. All the carbonaceous materials show promise in energy storage application. Using our reaction pathway, perfect hollow activated carbon spheres can be produced from waste sugar in liquid effluence of biomass steam pretreatment units. The renewable carbon product demonstrated a desirable surface area of 872 m 2 /g and capacitance of up to 109 F/g when made into an electric double layer supercapacitor. The capacitor exhibited nearly ideal capacitive behavior with 90.5% capacitance retention after 5000 cycles. Introduction In the pursuit of a sustainable economy, both renewable energy and renewable chemical practices must be adopted. While the former can be produced from many sources, one feasible option for the combination of renewable energy and chemicals so far emanates from biorefineries 1 . However, with the current low oil price, biorefineries need improved profitability to compete with fossil fuels. This would require manufacturing of diversified products and effective utilization of byproducts for materials applications 1 , 2 . While lignin has been the center of attention for years as a co-product, the most overlooked byproduct is the impure sugar stream in liquid effluence from biorefinery pretreatment plants 3 . There exists a state-of-the-art technology that utilizes biomass, pretreated by acids or alkali, to break down amorphous carbohydrates to sugars for better cellulose accessibility 4 . Sugar content in the biomass pretreatment liquid effluence can contain maximum of 50% of the initial hydrolysable carbohydrate from the biomass 5 , 6 , 7 . Therefore, the efficiency of biorefineries can be improved significantly if this waste-stream sugar can be captured in a simple, cost-effective way without a need for extensive purification and apply it to materials design. However, a challenge, for biorefinery coproduct generation from the waste-stream, is the low concentration of soluble carbohydrates 1 . Concentrating this liquid effluence using waste heat, which is widely available in biorefineries, is achievable and already a common practice in Kraft pulping mills 1 , 6 . Utilization of this untapped biomass sugar could be prioritized and one of the potential applications can be its conversion to carbon particles with tunable morphologies as a medium for renewable energy storage, such as electric double layer (EDL) supercapacitors. Over the last decade, there has been growing interest in tailoring carbon sphere structures for different applications in renewable energy sectors. For EDL supercapacitor electrode applications, spherical carbon with a tunable porosity and controllable particle size distribution is of great interest 8 , 9 , 10 , 11 , 12 , 13 . The variety of structures can provide excellent performance for catalysis, adsorption, and energy storage 8 , 9 , 10 , 11 , 12 , 14 , 15 . Carbon spheres can be made from several methods 8 , 9 , 10 , 16 , 17 , 18 , 19 , 20 , 21 . One of the most inexpensive methods to date is hydrothermal carbonization (HTC). HTC is a relatively green technology and scalable to industrial production levels 9 . The HTC method is applicable to precursors with high moisture content much like the carbohydrates in pretreatment liquid effluence 22 . To better control the porosity, size, and shape of the carbon spheres, different strategies including templating and self-assembly were employed together with HTC 16 . Hard templating, which often uses silica as the template, can be one of the most straightforward ways to synthesize carbon spheres with a controllable morphology 14 , 23 . However, for silica hard templating, the most critical step is to obtain a template having strong interaction with the carbon precursor. The process is very tedious, and the removal of the template requires corrosive chemicals like sodium hydroxide or even hydrofluoric acid 13 , undesirable for green chemistry application. On the contrary, soft template synthesis does not require significant preparation or removal of the template 20 , 21 . We propose the synthesis of carbonaceous matter in a controllable manner using soft templating, followed by HTC and subsequent high temperature carbonization of solid HTC-derivatives. Emulsion (made from oil, water, and surfactant) and water-based HTC were carried out at different time-scales to study the evolution of spherical carbon products. The two synthesis routes were then correlated with the resulting carbon morphology, porosity, and surface characteristics. Furthermore, the carbon products derived from renewable sugar were investigated as EDL electrodes for supercapacitor application. Supercapacitors store energy based on two different principles: EDL capacitance from the pure electrostatic charge accumulation at the electrode interface, and (2) the pseudo -capacitance based on fast and reversible redox processes at characteristic potentials 17 . Out of these two mechanisms, we synthesized and characterized EDL supercapacitors and hence we will discuss the EDL supercapacitors only in this article. Surface activation of carbon products was conducted using KOH. We performed large-scale molecular dynamics (MD) simulations to understand the evolution and characteristics of the pore structures in an emulsion-based system. While previous studies have shown the possibility of producing carbon spheres from carbohydrates and even acid or alkaline pretreated biomass-derived hydrolyzed hemicellulose using HTC, detailed understanding on the structural evolution with respect to the hydrothermal reaction media is not fully understood 3 , 7 , 11 , 24 . In this study, we used sugarcane-derived table sugar as a model molecule to establish the physics and the carbon formation mechanism. We then corroborated our findings using the result from laboratory-made steam-pretreated liquid effluence from woodchips. After establishing that perfectly", "role": "user" }, { "content": "Biorefinery facilities are critical to fueling the economy—converting wood chips, grass clippings, and other biological materials into fuels, heat, power, and chemicals. A research team at the US Department of Energy's (DOE's) Oak Ridge National Laboratory has now discovered a way to create functional materials from the impure waste sugars produced in the biorefining processes. Using hydrothermal carbonization, a synthesis technique that converts biomass into carbon under high temperature and pressure conditions, the team transformed waste sugar into spherical carbon materials. These carbon spheres could be used to form improved supercapacitors, which are energy storage devices that help power technologies including smartphones, hybrid vehicles, and security alarm systems. The team's results are published in Scientific Reports, a Nature research journal. \"The significant finding is that we found a way to take sugar from plants and other organic matter and use it to make different structures,\" said Amit Naskar, a senior researcher in ORNL's Materials Science and Technology Division. \"Knowing the physics behind how those structures form can help us improve components of energy storage.\" By modifying the synthesis process, the researchers created two varieties of the novel carbon spheres. Combining sugar and water under pressure resulted in solid spheres, whereas replacing water with an emulsion substance (a liquid that uses chemicals to combine oil and water) typically produced hollow spheres instead. \"Just by substituting water for this other liquid, we can control the shape of the carbon, which could have huge implications for supercapacitor performance,\" said Hoi Chun Ho, a Ph.D. candidate working with Naskar at the Bredesen Center for Interdisciplinary Research and Graduate Education, a joint venture of ORNL and the University of Tennessee, Knoxville. The team also discovered that altering the duration of synthesis directly affected the size and shape of the spheres. To further explore the discrepancies between solid and hollow carbon structures, the team ran synthesis simulations on the Cray XK7 Titan supercomputer at the Oak Ridge Leadership Computing Facility (OLCF), a DOE Office of Science User Facility located at ORNL. They also used transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS) tools at the Center for Nanophase Materials Sciences (CNMS), another DOE Office of Science User Facility, to characterize the capabilities and structure of the carbon samples. \"We wanted to determine what kind of surface area is good for energy storage applications, and we learned that the hollow spheres are more suitable,\" said ORNL researcher Monojoy Goswami of CNMS and the Computer Science and Engineering Division. \"Without these simulations and resources, we wouldn't have been able to reach this fundamental understanding.\" With this data the team tested a supercapacitor with electrodes made from hollow carbon spheres, which retained about 90 percent capacitance—the ability to store an electric charge—after 5,000 charge cycles. Although supercapacitors cannot store as much energy as batteries can store, they have many advantages over batteries, such as faster charging and exceptionally long lifetimes. Some technologies contain both batteries to provide everyday energy and supercapacitors to provide additional support during peak power demands. \"Batteries often support smartphones and other electronic devices alone, but supercapacitors can be useful for many high-power applications,\" Ho said. \"For example, if a vehicle is driving up a steep hill with many passengers, the extra strain may cause the supercapacitor to kick in.\" The pathway from waste sugar to hollow carbon spheres to supercapacitors demonstrates new potential for previously untapped byproducts from biorefineries. The researchers are planning projects to find and test other applications for carbon materials derived from waste sugar such as reinforcing polymer composites with carbon fibers. \"Carbon can serve many useful purposes in addition to improving supercapacitors,\" Ho said. \"There is more work to be done to fully understand the structural evolution of carbon materials.\" Making use of waste streams could also help scientists pursue forms of sustainable energy on a broader scale. According to the ORNL team, biorefineries can produce beneficial combinations of renewable energy and chemicals but are not yet profitable enough to compete with traditional energy sources. However, the researchers anticipate that developing useful materials from waste could help improve efficiency and reduce costs, making outputs from these facilities viable alternatives to oil and other fossil fuels. \"Our goal is to use waste energy for green applications,\" Goswami said. \"That's good for the environment, for the biorefinery industry, and for commerce.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Biorefineries produce impure sugar waste streams that are being underutilized. By converting this waste to a profitable by-product, biorefineries could be safeguarded against low oil prices. We demonstrate controlled production of useful carbon materials from the waste concentrate via hydrothermal synthesis and carbonization. We devise a pathway to producing tunable, porous spherical carbon materials by modeling the gross structure formation and developing an understanding of the pore formation mechanism utilizing simple reaction principles. Compared to a simple hydrothermal synthesis from sugar concentrate, emulsion-based synthesis results in hollow spheres with abundant microporosity. In contrast, conventional hydrothermal synthesis produces solid beads with micro and mesoporosity. All the carbonaceous materials show promise in energy storage application. Using our reaction pathway, perfect hollow activated carbon spheres can be produced from waste sugar in liquid effluence of biomass steam pretreatment units. The renewable carbon product demonstrated a desirable surface area of 872 m 2 /g and capacitance of up to 109 F/g when made into an electric double layer supercapacitor. The capacitor exhibited nearly ideal capacitive behavior with 90.5% capacitance retention after 5000 cycles. Introduction In the pursuit of a sustainable economy, both renewable energy and renewable chemical practices must be adopted. While the former can be produced from many sources, one feasible option for the combination of renewable energy and chemicals so far emanates from biorefineries 1 . However, with the current low oil price, biorefineries need improved profitability to compete with fossil fuels. This would require manufacturing of diversified products and effective utilization of byproducts for materials applications 1 , 2 . While lignin has been the center of attention for years as a co-product, the most overlooked byproduct is the impure sugar stream in liquid effluence from biorefinery pretreatment plants 3 . There exists a state-of-the-art technology that utilizes biomass, pretreated by acids or alkali, to break down amorphous carbohydrates to sugars for better cellulose accessibility 4 . Sugar content in the biomass pretreatment liquid effluence can contain maximum of 50% of the initial hydrolysable carbohydrate from the biomass 5 , 6 , 7 . Therefore, the efficiency of biorefineries can be improved significantly if this waste-stream sugar can be captured in a simple, cost-effective way without a need for extensive purification and apply it to materials design. However, a challenge, for biorefinery coproduct generation from the waste-stream, is the low concentration of soluble carbohydrates 1 . Concentrating this liquid effluence using waste heat, which is widely available in biorefineries, is achievable and already a common practice in Kraft pulping mills 1 , 6 . Utilization of this untapped biomass sugar could be prioritized and one of the potential applications can be its conversion to carbon particles with tunable morphologies as a medium for renewable energy storage, such as electric double layer (EDL) supercapacitors. Over the last decade, there has been growing interest in tailoring carbon sphere structures for different applications in renewable energy sectors. For EDL supercapacitor electrode applications, spherical carbon with a tunable porosity and controllable particle size distribution is of great interest 8 , 9 , 10 , 11 , 12 , 13 . The variety of structures can provide excellent performance for catalysis, adsorption, and energy storage 8 , 9 , 10 , 11 , 12 , 14 , 15 . Carbon spheres can be made from several methods 8 , 9 , 10 , 16 , 17 , 18 , 19 , 20 , 21 . One of the most inexpensive methods to date is hydrothermal carbonization (HTC). HTC is a relatively green technology and scalable to industrial production levels 9 . The HTC method is applicable to precursors with high moisture content much like the carbohydrates in pretreatment liquid effluence 22 . To better control the porosity, size, and shape of the carbon spheres, different strategies including templating and self-assembly were employed together with HTC 16 . Hard templating, which often uses silica as the template, can be one of the most straightforward ways to synthesize carbon spheres with a controllable morphology 14 , 23 . However, for silica hard templating, the most critical step is to obtain a template having strong interaction with the carbon precursor. The process is very tedious, and the removal of the template requires corrosive chemicals like sodium hydroxide or even hydrofluoric acid 13 , undesirable for green chemistry application. On the contrary, soft template synthesis does not require significant preparation or removal of the template 20 , 21 . We propose the synthesis of carbonaceous matter in a controllable manner using soft templating, followed by HTC and subsequent high temperature carbonization of solid HTC-derivatives. Emulsion (made from oil, water, and surfactant) and water-based HTC were carried out at different time-scales to study the evolution of spherical carbon products. The two synthesis routes were then correlated with the resulting carbon morphology, porosity, and surface characteristics. Furthermore, the carbon products derived from renewable sugar were investigated as EDL electrodes for supercapacitor application. Supercapacitors store energy based on two different principles: EDL capacitance from the pure electrostatic charge accumulation at the electrode interface, and (2) the pseudo -capacitance based on fast and reversible redox processes at characteristic potentials 17 . Out of these two mechanisms, we synthesized and characterized EDL supercapacitors and hence we will discuss the EDL supercapacitors only in this article. Surface activation of carbon products was conducted using KOH. We performed large-scale molecular dynamics (MD) simulations to understand the evolution and characteristics of the pore structures in an emulsion-based system. While previous studies have shown the possibility of producing carbon spheres from carbohydrates and even acid or alkaline pretreated biomass-derived hydrolyzed hemicellulose using HTC, detailed understanding on the structural evolution with respect to the hydrothermal reaction media is not fully understood 3 , 7 , 11 , 24 . In this study, we used sugarcane-derived table sugar as a model molecule to establish the physics and the carbon formation mechanism. We then corroborated our findings using the result from laboratory-made steam-pretreated liquid effluence from woodchips. After establishing that perfectly<|im_end|> <|im_start|>assistant Biorefinery facilities are critical to fueling the economy—converting wood chips, grass clippings, and other biological materials into fuels, heat, power, and chemicals. A research team at the US Department of Energy's (DOE's) Oak Ridge National Laboratory has now discovered a way to create functional materials from the impure waste sugars produced in the biorefining processes. Using hydrothermal carbonization, a synthesis technique that converts biomass into carbon under high temperature and pressure conditions, the team transformed waste sugar into spherical carbon materials. These carbon spheres could be used to form improved supercapacitors, which are energy storage devices that help power technologies including smartphones, hybrid vehicles, and security alarm systems. The team's results are published in Scientific Reports, a Nature research journal. "The significant finding is that we found a way to take sugar from plants and other organic matter and use it to make different structures," said Amit Naskar, a senior researcher in ORNL's Materials Science and Technology Division. "Knowing the physics behind how those structures form can help us improve components of energy storage." By modifying the synthesis process, the researchers created two varieties of the novel carbon spheres. Combining sugar and water under pressure resulted in solid spheres, whereas replacing water with an emulsion substance (a liquid that uses chemicals to combine oil and water) typically produced hollow spheres instead. "Just by substituting water for this other liquid, we can control the shape of the carbon, which could have huge implications for supercapacitor performance," said Hoi Chun Ho, a Ph.D. candidate working with Naskar at the Bredesen Center for Interdisciplinary Research and Graduate Education, a joint venture of ORNL and the University of Tennessee, Knoxville. The team also discovered that altering the duration of synthesis directly affected the size and shape of the spheres. To further explore the discrepancies between solid and hollow carbon structures, the team ran synthesis simulations on the Cray XK7 Titan supercomputer at the Oak Ridge Leadership Computing Facility (OLCF), a DOE Office of Science User Facility located at ORNL. They also used transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS) tools at the Center for Nanophase Materials Sciences (CNMS), another DOE Office of Science User Facility, to characterize the capabilities and structure of the carbon samples. "We wanted to determine what kind of surface area is good for energy storage applications, and we learned that the hollow spheres are more suitable," said ORNL researcher Monojoy Goswami of CNMS and the Computer Science and Engineering Division. "Without these simulations and resources, we wouldn't have been able to reach this fundamental understanding." With this data the team tested a supercapacitor with electrodes made from hollow carbon spheres, which retained about 90 percent capacitance—the ability to store an electric charge—after 5,000 charge cycles. Although supercapacitors cannot store as much energy as batteries can store, they have many advantages over batteries, such as faster charging and exceptionally long lifetimes. Some technologies contain both batteries to provide everyday energy and supercapacitors to provide additional support during peak power demands. "Batteries often support smartphones and other electronic devices alone, but supercapacitors can be useful for many high-power applications," Ho said. "For example, if a vehicle is driving up a steep hill with many passengers, the extra strain may cause the supercapacitor to kick in." The pathway from waste sugar to hollow carbon spheres to supercapacitors demonstrates new potential for previously untapped byproducts from biorefineries. The researchers are planning projects to find and test other applications for carbon materials derived from waste sugar such as reinforcing polymer composites with carbon fibers. "Carbon can serve many useful purposes in addition to improving supercapacitors," Ho said. "There is more work to be done to fully understand the structural evolution of carbon materials." Making use of waste streams could also help scientists pursue forms of sustainable energy on a broader scale. According to the ORNL team, biorefineries can produce beneficial combinations of renewable energy and chemicals but are not yet profitable enough to compete with traditional energy sources. However, the researchers anticipate that developing useful materials from waste could help improve efficiency and reduce costs, making outputs from these facilities viable alternatives to oil and other fossil fuels. "Our goal is to use waste energy for green applications," Goswami said. "That's good for the environment, for the biorefinery industry, and for commerce." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Tillage is a common agricultural practice that helps prepare the soil and remove weeds. However, it remains unknown how tillage intensity has evolved and its effect on net greenhouse gas (GHG) emissions. Here, using a process-based modelling approach with a multi-source database, we examined the change in tillage intensity across the US corn–soybean cropping systems during 1998–2016 and the impact of tillage intensity on soil GHG emissions. We found that tillage intensity first decreased and then, after 2008, increased, a trend that is strongly correlated with the adoption of herbicide-tolerant crops and emerging weed resistance. The GHG mitigation benefit (−5.5 ± 4.8 TgCO 2 e yr −1 ) of decreasing tillage intensity before 2008 has been more than offset by increased GHG emissions (13.8 ± 5.6 TgCO 2 e yr −1 ) due to tillage reintensification under growing pressure of weed resistance. As weed resistance persists or grows, tillage intensity is anticipated to continue rising, probably increasing GHG emissions. Our results imply that farmers’ choices in managing herbicide resistance may help mitigate agricultural GHG emissions, underscoring the importance of an alternative strategy to control weeds. Main Emissions of greenhouse gases (GHGs), such as carbon dioxide (CO 2 ), methane (CH 4 ) and nitrous oxide (N 2 O), from agriculture (cultivation of crops and livestock) and deforestation account for about a quarter of global total GHG emissions 1 . In the United States, agriculture contributed ∼ 10% of total GHG emissions in 2018, a proportion that has increased by 10% since 1990, which represents a substantial increase compared with the national total GHG emission increase of 3.7% in the same period 2 . The agriculture sector provides a notable GHG mitigation potential 3 , but doing so requires a deep understanding of the sector’s GHG flux dynamics and their key environmental drivers including human management practices 4 . Tillage is an important cropping practice that helps prepare the soil and remove weeds. Although various definitions of tillage types exist in the literature, for our purposes, tillage practices can be grouped into three types, namely, conventional tillage, conservation tillage and no-till, which differ by degrees of soil disturbance and residue retention. Conventional tillage leaves less than 15% residual on the soil surface, while conservation tillage has at least 30% residue left and no-till keeps the soil covered 100% of the time 5 , 6 . Various tillage practices have different impacts on the physical, hydrological and biogeochemical processes in the soil. For example, conventional tillage practices (such as disc ploughing) not only promote soil organic carbon oxidation and decomposition but also accelerate soil erosion by increasing soil exposure to wind and rain 7 . On the other hand, no-till and conservation tillage (such as strip-till and mulch-till) have been widely adopted by farmers to conserve soil and water 8 . However, the no-till system contributes less than is often assumed to agricultural sustainability because it may retard springtime soil warming, increase weed, pest and disease pressures, and lead to crop yield loss 9 , 10 , 11 , 12 . There are many reasons why tillage intensity has mostly declined on the US cropped acres in the past decades. Reduced tillage has been widely adopted to suppress soil erosion, preserve moisture and reduce crop production cost in the use of fuel, labour and machinery 8 , 13 . The advent of herbicide-tolerant (HT) crops, commencing in the late 1990s, has made it possible to spray herbicide over the growing crops, further reducing reliance on tillage 14 . But the benefit of HT crop adoption in reducing tillage might not be sustainable in the long run as weed resistance has emerged to the main chemical used, glyphosate 15 . Evidence to date suggests that partial reversion to conventional tillage has resulted 16 , 17 . For example, a recent study 17 reveals that the shares of conservation tillage and no-till in soybean fields declined by 3.9% and 7.6%, respectively, when eight glyphosate-resistant weed species are identified, despite little initial effect on tillage practices upon first emergence of weed resistance. However, the consequences of the changing tillage intensity in soil GHG fluxes during this period remain unclear. In the United States, a wide variety of studies have been conducted to quantify the GHG mitigation potential of the agriculture sector 18 , 19 , 20 . More recent efforts have involved seeking policy and market solutions that promote additional mitigation practices 21 , 22 , 23 , 24 . Nonetheless, most existing tillage-related assessment and prediction activities either lack data to characterize the spatiotemporal patterns of tillage practices and their intensity changes or focus on the resultant fluxes of single GHGs. This limits the explicit characterization of system responses and hinders us from identifying and adopting sustainable management practices. Although the US Geological Survey developed tillage intensity maps for 1989–2004 by aggregating county-level survey into eight-digit hydrologic unit watersheds 25 , little is known about how tillage practices in the United States have changed in more recent years, especially given increasing concerns about herbicide-resistant weeds 13 , 16 , 26 . In addition, there is still limited understanding as to how tillage decisions are driven by environmental stressors such as herbicide and herbicide-resistant weeds, and how they together have affected GHG mitigation outcomes during recent decades. There is substantial evidence that using more intensive tillage is a coping strategy for many farmers faced with herbicide-resistant weeds, and this has raised concerns about negative environmental impacts 16 , 17 . Here we use a process-based land ecosystem model, a long-term farmers’ survey and time-series gridded data of environmental changes to examine the relationships between genetically engineered HT crop adoption, the emergence of weed resistance to herbicide and farmers’ decisions in tillage practices, and how historical tillage practices altered net GHG fluxes in agricultural land (Fig. 1 ). Our study in the United States could provide insightful information for other agricultural regions in the world that are impacted by growing weed pressure, herbicide resistance, intensifying", "role": "user" }, { "content": "A new study that combines survey data and cutting-edge computer modeling found a growing trend in tillage intensity in U.S. corn and soybean production in recent years has led to an increase in greenhouse gas emissions from agricultural fields. The study, published recently in the academic journal Nature Food, drew on years of survey data that asked thousands of U.S. farmers about their tillage practices. The researchers then plugged the relevant data into sophisticated ecosystem models to see how tillage decisions affect soil emissions of greenhouse gases, including carbon dioxide and nitrous oxide. The survey data indicate farmers relied less on tillage during the period between 1998 and 2008, but that trend began to reverse around 2009 when tillage intensity started to rise. Chaoqun Lu, an Iowa State University associate professor of ecology, evolution and organismal biology and lead author of the study, said the growing resistance of weeds to the common herbicide glyphosate likely contributed to increased tillage. Genetically engineered herbicide-tolerant crops hit the agricultural scene in the late 1990s, and their adoption freed farmers from some of their reliance on tillage as a method of weed control. But growing numbers of weed species with resistance to the herbicide have emerged over the decades, reducing the effectiveness of the herbicide and making tillage a more attractive weed control option once again. And as tillage intensity grows, more carbon and nitrogen stored in the soil release into the atmosphere in the form of greenhouse gases, Lu said. \"One of the interesting pieces that we found in this study is tillage intensity has shifted from a declining trend to an increasing trend since 2008,\" Lu said. \"Our regression analysis suggests this trend is correlated to the wide adoption of herbicide-tolerant crops before 2008 and emerging weed resistance after 2008. We can't assert a strict causal relationship, but regression analysis reveals a strong relationship between them.\" The survey asked questions about farmers' decisions on seed varieties and cultivation practice intensity. Survey topics included no-till, conservation tillage (e.g., ridge till, mulch till), and conventional tillage (e.g., moldboard plow, chisel plow, disk harrow). The data show no-till grew by roughly 12 million acres for corn production and nearly 17 million acres for soybeans between 1998 and 2008. But no-till corn acres declined by nearly a half million acres between 2009 and 2016 and declined by nearly 6 million soybean acres during that period, according to the survey. Corn acreage under conservation tillage and soybean acreage under conservation and conventional tillage showed similar trends, first declining between 1998 and 2008 before climbing back to previous levels by 2016. Feeding the data into the land ecosystem models shows that gains in tillage intensity since 2009 have offset the greenhouse gas mitigation benefits achieved during the tillage declines from 1998 to 2008. Lu said the study uncovers a relationship between weed resistance, seed technology and greenhouse gas emissions that could lead to a better understanding of how farm practices can mitigate climate change. Her team's previous research showed that nitrous oxide emissions from farmland in the U.S. Corn Belt have increased in recent years, largely due to the widespread application of nitrogen fertilizers to agricultural land. The added nitrogen is partially used by crops, but the remainder either stays in soils or is lost to the environment. During this process, microorganisms living in soils consume nitrogen-containing compounds and give off nitrous oxide as a byproduct. Meanwhile, soil organic matter decomposes and partially converts into carbon dioxide. Both are powerful greenhouse gases that have potential to warm the climate. Intensive tillage practices disturb the soil, alter soil moisture and aeration status, and stir heavy crop residue into soils, which together change the production rates of soil greenhouse gases and allow more of them to escape, Lu said. Lu pointed to the use of alternative herbicides to combat glyphosate-resistant weeds, or using glyphosate in fewer consecutive years, as well as the diversification of crops beyond corn and soybeans as options to control weeds without increasing greenhouse gas emissions. \"Without an effective strategy to control weeds, tillage intensity could continue to grow in the future and could undermine greenhouse gas mitigation achievements from other agricultural activities,\" Lu said. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Tillage is a common agricultural practice that helps prepare the soil and remove weeds. However, it remains unknown how tillage intensity has evolved and its effect on net greenhouse gas (GHG) emissions. Here, using a process-based modelling approach with a multi-source database, we examined the change in tillage intensity across the US corn–soybean cropping systems during 1998–2016 and the impact of tillage intensity on soil GHG emissions. We found that tillage intensity first decreased and then, after 2008, increased, a trend that is strongly correlated with the adoption of herbicide-tolerant crops and emerging weed resistance. The GHG mitigation benefit (−5.5 ± 4.8 TgCO 2 e yr −1 ) of decreasing tillage intensity before 2008 has been more than offset by increased GHG emissions (13.8 ± 5.6 TgCO 2 e yr −1 ) due to tillage reintensification under growing pressure of weed resistance. As weed resistance persists or grows, tillage intensity is anticipated to continue rising, probably increasing GHG emissions. Our results imply that farmers’ choices in managing herbicide resistance may help mitigate agricultural GHG emissions, underscoring the importance of an alternative strategy to control weeds. Main Emissions of greenhouse gases (GHGs), such as carbon dioxide (CO 2 ), methane (CH 4 ) and nitrous oxide (N 2 O), from agriculture (cultivation of crops and livestock) and deforestation account for about a quarter of global total GHG emissions 1 . In the United States, agriculture contributed ∼ 10% of total GHG emissions in 2018, a proportion that has increased by 10% since 1990, which represents a substantial increase compared with the national total GHG emission increase of 3.7% in the same period 2 . The agriculture sector provides a notable GHG mitigation potential 3 , but doing so requires a deep understanding of the sector’s GHG flux dynamics and their key environmental drivers including human management practices 4 . Tillage is an important cropping practice that helps prepare the soil and remove weeds. Although various definitions of tillage types exist in the literature, for our purposes, tillage practices can be grouped into three types, namely, conventional tillage, conservation tillage and no-till, which differ by degrees of soil disturbance and residue retention. Conventional tillage leaves less than 15% residual on the soil surface, while conservation tillage has at least 30% residue left and no-till keeps the soil covered 100% of the time 5 , 6 . Various tillage practices have different impacts on the physical, hydrological and biogeochemical processes in the soil. For example, conventional tillage practices (such as disc ploughing) not only promote soil organic carbon oxidation and decomposition but also accelerate soil erosion by increasing soil exposure to wind and rain 7 . On the other hand, no-till and conservation tillage (such as strip-till and mulch-till) have been widely adopted by farmers to conserve soil and water 8 . However, the no-till system contributes less than is often assumed to agricultural sustainability because it may retard springtime soil warming, increase weed, pest and disease pressures, and lead to crop yield loss 9 , 10 , 11 , 12 . There are many reasons why tillage intensity has mostly declined on the US cropped acres in the past decades. Reduced tillage has been widely adopted to suppress soil erosion, preserve moisture and reduce crop production cost in the use of fuel, labour and machinery 8 , 13 . The advent of herbicide-tolerant (HT) crops, commencing in the late 1990s, has made it possible to spray herbicide over the growing crops, further reducing reliance on tillage 14 . But the benefit of HT crop adoption in reducing tillage might not be sustainable in the long run as weed resistance has emerged to the main chemical used, glyphosate 15 . Evidence to date suggests that partial reversion to conventional tillage has resulted 16 , 17 . For example, a recent study 17 reveals that the shares of conservation tillage and no-till in soybean fields declined by 3.9% and 7.6%, respectively, when eight glyphosate-resistant weed species are identified, despite little initial effect on tillage practices upon first emergence of weed resistance. However, the consequences of the changing tillage intensity in soil GHG fluxes during this period remain unclear. In the United States, a wide variety of studies have been conducted to quantify the GHG mitigation potential of the agriculture sector 18 , 19 , 20 . More recent efforts have involved seeking policy and market solutions that promote additional mitigation practices 21 , 22 , 23 , 24 . Nonetheless, most existing tillage-related assessment and prediction activities either lack data to characterize the spatiotemporal patterns of tillage practices and their intensity changes or focus on the resultant fluxes of single GHGs. This limits the explicit characterization of system responses and hinders us from identifying and adopting sustainable management practices. Although the US Geological Survey developed tillage intensity maps for 1989–2004 by aggregating county-level survey into eight-digit hydrologic unit watersheds 25 , little is known about how tillage practices in the United States have changed in more recent years, especially given increasing concerns about herbicide-resistant weeds 13 , 16 , 26 . In addition, there is still limited understanding as to how tillage decisions are driven by environmental stressors such as herbicide and herbicide-resistant weeds, and how they together have affected GHG mitigation outcomes during recent decades. There is substantial evidence that using more intensive tillage is a coping strategy for many farmers faced with herbicide-resistant weeds, and this has raised concerns about negative environmental impacts 16 , 17 . Here we use a process-based land ecosystem model, a long-term farmers’ survey and time-series gridded data of environmental changes to examine the relationships between genetically engineered HT crop adoption, the emergence of weed resistance to herbicide and farmers’ decisions in tillage practices, and how historical tillage practices altered net GHG fluxes in agricultural land (Fig. 1 ). Our study in the United States could provide insightful information for other agricultural regions in the world that are impacted by growing weed pressure, herbicide resistance, intensifying<|im_end|> <|im_start|>assistant A new study that combines survey data and cutting-edge computer modeling found a growing trend in tillage intensity in U.S. corn and soybean production in recent years has led to an increase in greenhouse gas emissions from agricultural fields. The study, published recently in the academic journal Nature Food, drew on years of survey data that asked thousands of U.S. farmers about their tillage practices. The researchers then plugged the relevant data into sophisticated ecosystem models to see how tillage decisions affect soil emissions of greenhouse gases, including carbon dioxide and nitrous oxide. The survey data indicate farmers relied less on tillage during the period between 1998 and 2008, but that trend began to reverse around 2009 when tillage intensity started to rise. Chaoqun Lu, an Iowa State University associate professor of ecology, evolution and organismal biology and lead author of the study, said the growing resistance of weeds to the common herbicide glyphosate likely contributed to increased tillage. Genetically engineered herbicide-tolerant crops hit the agricultural scene in the late 1990s, and their adoption freed farmers from some of their reliance on tillage as a method of weed control. But growing numbers of weed species with resistance to the herbicide have emerged over the decades, reducing the effectiveness of the herbicide and making tillage a more attractive weed control option once again. And as tillage intensity grows, more carbon and nitrogen stored in the soil release into the atmosphere in the form of greenhouse gases, Lu said. "One of the interesting pieces that we found in this study is tillage intensity has shifted from a declining trend to an increasing trend since 2008," Lu said. "Our regression analysis suggests this trend is correlated to the wide adoption of herbicide-tolerant crops before 2008 and emerging weed resistance after 2008. We can't assert a strict causal relationship, but regression analysis reveals a strong relationship between them." The survey asked questions about farmers' decisions on seed varieties and cultivation practice intensity. Survey topics included no-till, conservation tillage (e.g., ridge till, mulch till), and conventional tillage (e.g., moldboard plow, chisel plow, disk harrow). The data show no-till grew by roughly 12 million acres for corn production and nearly 17 million acres for soybeans between 1998 and 2008. But no-till corn acres declined by nearly a half million acres between 2009 and 2016 and declined by nearly 6 million soybean acres during that period, according to the survey. Corn acreage under conservation tillage and soybean acreage under conservation and conventional tillage showed similar trends, first declining between 1998 and 2008 before climbing back to previous levels by 2016. Feeding the data into the land ecosystem models shows that gains in tillage intensity since 2009 have offset the greenhouse gas mitigation benefits achieved during the tillage declines from 1998 to 2008. Lu said the study uncovers a relationship between weed resistance, seed technology and greenhouse gas emissions that could lead to a better understanding of how farm practices can mitigate climate change. Her team's previous research showed that nitrous oxide emissions from farmland in the U.S. Corn Belt have increased in recent years, largely due to the widespread application of nitrogen fertilizers to agricultural land. The added nitrogen is partially used by crops, but the remainder either stays in soils or is lost to the environment. During this process, microorganisms living in soils consume nitrogen-containing compounds and give off nitrous oxide as a byproduct. Meanwhile, soil organic matter decomposes and partially converts into carbon dioxide. Both are powerful greenhouse gases that have potential to warm the climate. Intensive tillage practices disturb the soil, alter soil moisture and aeration status, and stir heavy crop residue into soils, which together change the production rates of soil greenhouse gases and allow more of them to escape, Lu said. Lu pointed to the use of alternative herbicides to combat glyphosate-resistant weeds, or using glyphosate in fewer consecutive years, as well as the diversification of crops beyond corn and soybeans as options to control weeds without increasing greenhouse gas emissions. "Without an effective strategy to control weeds, tillage intensity could continue to grow in the future and could undermine greenhouse gas mitigation achievements from other agricultural activities," Lu said. <|im_end|>

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2,248

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The liver is a dynamic organ which is both multifunctional and highly regenerative. A major role of the liver is to process both endo and xenobiotics. Cigarettes are an example of a legal and widely used drug which can cause major health problems for adults and constitute a particular risk to the foetus, if the mother smokes during pregnancy. Cigarette smoke contains a complex mixture of thousands of different xenobiotics, including nicotine and polycyclic aromatic hydrocarbons. These affect foetal development in a sex-specific manner, inducing sex-dependant molecular responses in different organs. To date, the effect of maternal smoking on the foetal liver has been studied in vitro using cell lines, primary tissue and animal models. While these models have proven to be useful, poor cell phenotype, tissue scarcity, batch-to-batch variation and species differences have led to difficulties in data extrapolation toward human development. Therefore, in this study we have employed hepatoblasts, derived from pluripotent stem cells, to model the effects of xenobiotics from cigarette smoke on human hepatocyte development. Highly pure hepatocyte populations (>90%) were produced in vitro and exposed to factors present in cigarette smoke. Analysis of ATP levels revealed that, independent of the sex, the majority of smoking derivatives tested individually did not deplete ATP levels below 50%. However, following exposure to a cocktail of smoking derivatives, ATP production fell below 50% in a sex-dependent manner. This was paralleled by a loss metabolic activity and secretory ability in both female and male hepatocytes. Interestingly, cell depletion was less pronounced in female hepatocytes, whereas caspase activation was ~twofold greater, indicating sex differences in cell death upon exposure to the smoking derivatives tested. Working on a manuscript? Avoid the common mistakes Introduction The liver is the body’s second largest organ playing a major role in the processing of xenotoxicants, which include alcohol, drugs and environmental pollutants. Cigarettes are an example of a widely used drug which can cause major health problems for adults, and constitute a particular risk to the developing foetus. Cigarettes contain a complex mixture of over 7000 different compounds (Rodgman et al. 2009 ) which include nicotine and the polycyclic aromatic hydrocarbons (PAHs). Nicotine is primarily metabolised by cytochrome P450 2A6 (CYP2A6) in the liver (Benowitz et al. 1994 ) into several metabolites, of which cotinine represents approximately 70–80% (Messina et al. 1997 ). PAHs are incomplete combustion products first identified as carcinogenic constituents of coal tar (Phillips 1983 ) and charcoal-grilled foods (Phillips 1999 ; Boström et al. 2002 ; Rodgman et al. 2009 ). PAHs are also detected in placental tissues and umbilical cord blood of smokers (Perera et al. 2005a ; Al-Saleh et al. 2013 ) reaching the foetal liver from the maternal circulation. This exposes the developing foetus to harmful agents and leads to corresponding changes in gene expression (O’Shaughnessy et al. 2011 ). In addition to toxicant exposure, smoking also disrupts foetal oxygen and carbon monoxide balance which can cause harmful effects, including impaired growth, premature birth, hormonal imbalances, increased predisposition to metabolic syndrome, liver disease and even death (Chen et al. 2006 ; Harvey et al. 2007 ; Rogers 2009 ; Mamsen et al. 2010 ; Fowler et al. 2011 , 2014 ; Hackshaw et al. 2011 ; Högberg et al. 2012 ; Behl et al. 2013 ; Filis et al. 2015 ). Moreover, it has been reported that maternal smoking affects the foetus in a sex-specific manner. For example, male offspring possess a higher risk of developing conduct disorders, whereas female offspring are predisposed to developing weight disorders and drug dependence (Weissman et al. 1999 ; Chen et al. 2006 ). In addition, maternal smoking induces sex-dependant molecular responses in the reproductive organs and the liver of the developing foetus (Fowler et al. 2008 ; O’Shaughnessy et al. 2011 ; Drake et al. 2015 ). To date, the effect of maternal smoking on the foetal liver has been studied in vitro using cell lines, primary tissue and animal models (Neumann 1986 ; Rao et al. 1988 ; Cho et al. 2006 , Choi et al. 2015 ; Baxter 2009 ; Sanchez et al. 2011 ; Van Kesteren et al. 2013 ; Williams et al. 2014 ). While these models have proven to be informative, the scarcity of human tissue, the rapid loss of cell phenotype, batch-to-batch variation and species differences have led to difficulties in data extrapolation toward the human. Moreover, the mature nature of primary cells used in vitro impairs the study of foetal development ‘in the dish’. In contrast to the above sources, human hepatocytes derived from pluripotent stem cells have been proven to represent a reliable human model to study liver biology in detail (Szkolnicka et al. 2014 , 2016 ; Villarin et al. 2015 ). To study the disruptive effects of smoking on human development, we have employed this renewable cell model. Pluripotent stem cell derived hepatoblasts were produced at scale from male and female cell lines. Following this, hepatocyte differentiation was performed in the presence of cotinine and PAHs and this led to sex-specific changes in cell biology. Methods and materials Cell culture and differentiation H9 and Man12 human embryonic stem cells (hESCs ) identity was confirmed using short tandem repeat typing. hESCs were cultured and differentiated as previously described (Cameron et al. 2015 ). Maintenance of hESCs was performed on pre-coated laminin 521 (Biolaminin) in mTeSR1 (STEMCELL Technologies) in a humidified 37 °C, 5% CO 2 incubator. For differentiation, hESCs were plated onto a pre-coated blend of laminins 521 and 111 (at a 1:3 ratio). Differentiation was initiated at 40% confluence by replacing serum-free medium with endoderm differentiation medium: RPMI 1640 containing 1× B27 (Life Technologies), 100 ng/mL Activin A (PeproTech), and 50 ng/mL Wnt3a (R&D Systems). The medium was changed every 24 h for 72 h. On day 3, endoderm differentiation medium was replaced with hepatoblast differentiation medium, and this was renewed every second day for a further 5 days. The medium consisted of knockout (KO)-DMEM (Life Technologies), Serum replacement (Life Technologies),", "role": "user" }, { "content": "Chemicals found in cigarette smoke have been shown to damage foetal liver cells. Scientists say the potent cocktail of chemicals in cigarettes is particularly harmful to developing liver cells and affects male and female foetuses differently. Researchers - led by the University of Edinburgh - have developed a novel way to study the effects of maternal smoking on liver tissue using embryonic stem cells. The stem cell technique will provide important information about the long-term effects of maternal cigarette smoking, say experts. The liver is vital in clearing toxic substances and plays a major role in regulating metabolism. Smoking cigarettes - which contain around 7000 chemicals - can damage foetal organs and may do lasting harm. Scientists used pluripotent stem cells - non-specialised cells that have the distinctive ability to be able to transform into other cell types - to build foetal liver tissue. Liver cells were exposed to harmful chemicals found in cigarettes, including specific substances known to circulate in foetuses when mothers smoke. The study showed that a chemical cocktail - similar to that found in cigarettes - harmed foetal liver health more than individual components. Findings also showed that cigarette chemicals damage the liver differently in male and female foetuses, with male tissue showing liver scarring and female tissue showing more damage to cell metabolism. The study was carried out in collaboration with the Universities of Aberdeen and Glasgow and is published in the journal Archives of Toxicology. Dr David Hay from the University of Edinburgh's Centre for Regenerative Medicine, said: \"Cigarette smoke is known to have damaging effects on the foetus, yet we lack appropriate tools to study this in a very detailed way. This new approach means that we now have sources of renewable tissue that will enable us to understand the cellular effect of cigarettes on the unborn foetus.\" Professor Paul Fowler, Director of the Institute of Medical Sciences at the University of Aberdeen, said: \"This work is part of an ongoing project to understand how cigarette smoking by pregnant mothers has harmful effects on the developing foetus. These findings shed light on fundamental differences in damage between male and female foetuses.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The liver is a dynamic organ which is both multifunctional and highly regenerative. A major role of the liver is to process both endo and xenobiotics. Cigarettes are an example of a legal and widely used drug which can cause major health problems for adults and constitute a particular risk to the foetus, if the mother smokes during pregnancy. Cigarette smoke contains a complex mixture of thousands of different xenobiotics, including nicotine and polycyclic aromatic hydrocarbons. These affect foetal development in a sex-specific manner, inducing sex-dependant molecular responses in different organs. To date, the effect of maternal smoking on the foetal liver has been studied in vitro using cell lines, primary tissue and animal models. While these models have proven to be useful, poor cell phenotype, tissue scarcity, batch-to-batch variation and species differences have led to difficulties in data extrapolation toward human development. Therefore, in this study we have employed hepatoblasts, derived from pluripotent stem cells, to model the effects of xenobiotics from cigarette smoke on human hepatocyte development. Highly pure hepatocyte populations (>90%) were produced in vitro and exposed to factors present in cigarette smoke. Analysis of ATP levels revealed that, independent of the sex, the majority of smoking derivatives tested individually did not deplete ATP levels below 50%. However, following exposure to a cocktail of smoking derivatives, ATP production fell below 50% in a sex-dependent manner. This was paralleled by a loss metabolic activity and secretory ability in both female and male hepatocytes. Interestingly, cell depletion was less pronounced in female hepatocytes, whereas caspase activation was ~twofold greater, indicating sex differences in cell death upon exposure to the smoking derivatives tested. Working on a manuscript? Avoid the common mistakes Introduction The liver is the body’s second largest organ playing a major role in the processing of xenotoxicants, which include alcohol, drugs and environmental pollutants. Cigarettes are an example of a widely used drug which can cause major health problems for adults, and constitute a particular risk to the developing foetus. Cigarettes contain a complex mixture of over 7000 different compounds (Rodgman et al. 2009 ) which include nicotine and the polycyclic aromatic hydrocarbons (PAHs). Nicotine is primarily metabolised by cytochrome P450 2A6 (CYP2A6) in the liver (Benowitz et al. 1994 ) into several metabolites, of which cotinine represents approximately 70–80% (Messina et al. 1997 ). PAHs are incomplete combustion products first identified as carcinogenic constituents of coal tar (Phillips 1983 ) and charcoal-grilled foods (Phillips 1999 ; Boström et al. 2002 ; Rodgman et al. 2009 ). PAHs are also detected in placental tissues and umbilical cord blood of smokers (Perera et al. 2005a ; Al-Saleh et al. 2013 ) reaching the foetal liver from the maternal circulation. This exposes the developing foetus to harmful agents and leads to corresponding changes in gene expression (O’Shaughnessy et al. 2011 ). In addition to toxicant exposure, smoking also disrupts foetal oxygen and carbon monoxide balance which can cause harmful effects, including impaired growth, premature birth, hormonal imbalances, increased predisposition to metabolic syndrome, liver disease and even death (Chen et al. 2006 ; Harvey et al. 2007 ; Rogers 2009 ; Mamsen et al. 2010 ; Fowler et al. 2011 , 2014 ; Hackshaw et al. 2011 ; Högberg et al. 2012 ; Behl et al. 2013 ; Filis et al. 2015 ). Moreover, it has been reported that maternal smoking affects the foetus in a sex-specific manner. For example, male offspring possess a higher risk of developing conduct disorders, whereas female offspring are predisposed to developing weight disorders and drug dependence (Weissman et al. 1999 ; Chen et al. 2006 ). In addition, maternal smoking induces sex-dependant molecular responses in the reproductive organs and the liver of the developing foetus (Fowler et al. 2008 ; O’Shaughnessy et al. 2011 ; Drake et al. 2015 ). To date, the effect of maternal smoking on the foetal liver has been studied in vitro using cell lines, primary tissue and animal models (Neumann 1986 ; Rao et al. 1988 ; Cho et al. 2006 , Choi et al. 2015 ; Baxter 2009 ; Sanchez et al. 2011 ; Van Kesteren et al. 2013 ; Williams et al. 2014 ). While these models have proven to be informative, the scarcity of human tissue, the rapid loss of cell phenotype, batch-to-batch variation and species differences have led to difficulties in data extrapolation toward the human. Moreover, the mature nature of primary cells used in vitro impairs the study of foetal development ‘in the dish’. In contrast to the above sources, human hepatocytes derived from pluripotent stem cells have been proven to represent a reliable human model to study liver biology in detail (Szkolnicka et al. 2014 , 2016 ; Villarin et al. 2015 ). To study the disruptive effects of smoking on human development, we have employed this renewable cell model. Pluripotent stem cell derived hepatoblasts were produced at scale from male and female cell lines. Following this, hepatocyte differentiation was performed in the presence of cotinine and PAHs and this led to sex-specific changes in cell biology. Methods and materials Cell culture and differentiation H9 and Man12 human embryonic stem cells (hESCs ) identity was confirmed using short tandem repeat typing. hESCs were cultured and differentiated as previously described (Cameron et al. 2015 ). Maintenance of hESCs was performed on pre-coated laminin 521 (Biolaminin) in mTeSR1 (STEMCELL Technologies) in a humidified 37 °C, 5% CO 2 incubator. For differentiation, hESCs were plated onto a pre-coated blend of laminins 521 and 111 (at a 1:3 ratio). Differentiation was initiated at 40% confluence by replacing serum-free medium with endoderm differentiation medium: RPMI 1640 containing 1× B27 (Life Technologies), 100 ng/mL Activin A (PeproTech), and 50 ng/mL Wnt3a (R&D Systems). The medium was changed every 24 h for 72 h. On day 3, endoderm differentiation medium was replaced with hepatoblast differentiation medium, and this was renewed every second day for a further 5 days. The medium consisted of knockout (KO)-DMEM (Life Technologies), Serum replacement (Life Technologies),<|im_end|> <|im_start|>assistant Chemicals found in cigarette smoke have been shown to damage foetal liver cells. Scientists say the potent cocktail of chemicals in cigarettes is particularly harmful to developing liver cells and affects male and female foetuses differently. Researchers - led by the University of Edinburgh - have developed a novel way to study the effects of maternal smoking on liver tissue using embryonic stem cells. The stem cell technique will provide important information about the long-term effects of maternal cigarette smoking, say experts. The liver is vital in clearing toxic substances and plays a major role in regulating metabolism. Smoking cigarettes - which contain around 7000 chemicals - can damage foetal organs and may do lasting harm. Scientists used pluripotent stem cells - non-specialised cells that have the distinctive ability to be able to transform into other cell types - to build foetal liver tissue. Liver cells were exposed to harmful chemicals found in cigarettes, including specific substances known to circulate in foetuses when mothers smoke. The study showed that a chemical cocktail - similar to that found in cigarettes - harmed foetal liver health more than individual components. Findings also showed that cigarette chemicals damage the liver differently in male and female foetuses, with male tissue showing liver scarring and female tissue showing more damage to cell metabolism. The study was carried out in collaboration with the Universities of Aberdeen and Glasgow and is published in the journal Archives of Toxicology. Dr David Hay from the University of Edinburgh's Centre for Regenerative Medicine, said: "Cigarette smoke is known to have damaging effects on the foetus, yet we lack appropriate tools to study this in a very detailed way. This new approach means that we now have sources of renewable tissue that will enable us to understand the cellular effect of cigarettes on the unborn foetus." Professor Paul Fowler, Director of the Institute of Medical Sciences at the University of Aberdeen, said: "This work is part of an ongoing project to understand how cigarette smoking by pregnant mothers has harmful effects on the developing foetus. These findings shed light on fundamental differences in damage between male and female foetuses." <|im_end|>

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5623, 44393, 320, 1687, 1056, 1543, 1880, 453, 13, 220, 2550, 24, 2652, 25507, 1880, 453, 13, 220, 1049, 21, 7609, 763, 5369, 11, 50150, 20149, 90974, 1877, 36814, 519, 31206, 14847, 304, 279, 42889, 36853, 323, 279, 26587, 315, 279, 11469, 12018, 64476, 320, 37, 65428, 1880, 453, 13, 220, 1049, 23, 2652, 507, 529, 63416, 7595, 2136, 88, 1880, 453, 13, 220, 679, 16, 2652, 42865, 1880, 453, 13, 220, 679, 20, 7609, 2057, 2457, 11, 279, 2515, 315, 50150, 20149, 389, 279, 12018, 22029, 26587, 706, 1027, 20041, 304, 55004, 1701, 2849, 5238, 11, 6156, 20438, 323, 10065, 4211, 320, 8989, 64607, 220, 3753, 21, 2652, 89000, 1880, 453, 13, 220, 3753, 23, 2652, 33680, 1880, 453, 13, 220, 1049, 21, 1174, 87673, 1880, 453, 13, 220, 679, 20, 2652, 92847, 220, 1049, 24, 2652, 48254, 1880, 453, 13, 220, 679, 16, 2652, 13000, 735, 5302, 268, 1880, 453, 13, 220, 679, 18, 2652, 13926, 1880, 453, 13, 220, 679, 19, 7609, 6104, 1521, 4211, 617, 17033, 311, 387, 39319, 11, 279, 82484, 315, 3823, 20438, 11, 279, 11295, 4814, 315, 2849, 82423, 11, 7309, 4791, 1481, 759, 23851, 323, 9606, 12062, 617, 6197, 311, 27129, 304, 828, 71462, 367, 9017, 279, 3823, 13, 23674, 11, 279, 15196, 7138, 315, 6156, 7917, 1511, 304, 55004, 3242, 4825, 279, 4007, 315, 12018, 22029, 4500, 3451, 258, 279, 12269, 24535, 763, 13168, 311, 279, 3485, 8336, 11, 3823, 58259, 57878, 14592, 505, 60217, 575, 64632, 19646, 7917, 617, 1027, 17033, 311, 4097, 264, 15062, 3823, 1646, 311, 4007, 26587, 34458, 304, 7872, 320, 50, 41796, 337, 21035, 64, 1880, 453, 13, 220, 679, 19, 1174, 220, 679, 21, 2652, 16959, 43840, 1880, 453, 13, 220, 679, 20, 7609, 2057, 4007, 279, 62642, 6372, 315, 20149, 389, 3823, 4500, 11, 584, 617, 20011, 420, 33268, 2849, 1646, 13, 1856, 324, 575, 64632, 19646, 2849, 14592, 58259, 677, 4354, 82, 1051, 9124, 520, 5569, 505, 8762, 323, 8954, 2849, 5238, 13, 23548, 420, 11, 58259, 79759, 60038, 574, 10887, 304, 279, 9546, 315, 48681, 83334, 323, 13174, 39, 82, 323, 420, 6197, 311, 1877, 19440, 4442, 304, 2849, 34458, 13, 19331, 323, 7384, 14299, 7829, 323, 60038, 473, 24, 323, 2418, 717, 3823, 44481, 14338, 19646, 7917, 320, 71, 1600, 34645, 883, 9764, 574, 11007, 1701, 2875, 67042, 13454, 20061, 13, 305, 1600, 34645, 1051, 89948, 323, 89142, 439, 8767, 7633, 320, 34, 91712, 1880, 453, 13, 220, 679, 20, 7609, 39306, 315, 305, 1600, 34645, 574, 10887, 389, 864, 23283, 660, 79533, 258, 220, 20767, 320, 33, 25947, 8778, 258, 8, 304, 296, 6777, 14899, 16, 320, 15642, 64655, 25579, 8, 304, 264, 67038, 1908, 220, 1806, 37386, 34, 11, 220, 20, 4, 7432, 220, 17, 49727, 859, 13, 1789, 60038, 11, 305, 1600, 34645, 1051, 88233, 8800, 264, 864, 23283, 660, 20955, 315, 79533, 1354, 220, 20767, 323, 220, 5037, 320, 266, 264, 220, 16, 25, 18, 11595, 570, 34496, 7246, 574, 33230, 520, 220, 1272, 4, 390, 41116, 555, 25935, 41529, 12862, 11298, 449, 842, 347, 4289, 60038, 11298, 25, 54874, 40, 220, 10513, 15, 8649, 220, 16, 18028, 426, 1544, 320, 26833, 25579, 705, 220, 1041, 7933, 93422, 15050, 258, 362, 320, 47, 752, 299, 35197, 705, 323, 220, 1135, 7933, 93422, 468, 406, 18, 64, 320, 49, 33465, 15264, 570, 578, 11298, 574, 5614, 1475, 220, 1187, 305, 369, 220, 5332, 305, 13, 1952, 1938, 220, 18, 11, 842, 347, 4289, 60038, 11298, 574, 12860, 449, 58259, 677, 4354, 60038, 11298, 11, 323, 420, 574, 36646, 1475, 2132, 1938, 369, 264, 4726, 220, 20, 2919, 13, 578, 11298, 44660, 315, 77173, 320, 56047, 7435, 8561, 2783, 320, 26833, 25579, 705, 94591, 14039, 320, 26833, 25579, 705, 128257, 198, 128256, 78191, 198, 64938, 53703, 1766, 304, 36213, 16603, 617, 1027, 6982, 311, 5674, 12018, 22029, 26587, 7917, 13, 57116, 2019, 279, 36875, 41010, 315, 26333, 304, 34576, 374, 8104, 28856, 311, 11469, 26587, 7917, 323, 22223, 8762, 323, 8954, 12018, 295, 4881, 22009, 13, 59250, 482, 6197, 555, 279, 3907, 315, 41406, 482, 617, 8040, 264, 11775, 1648, 311, 4007, 279, 6372, 315, 50150, 20149, 389, 26587, 20438, 1701, 44481, 14338, 19646, 7917, 13, 578, 19646, 2849, 15105, 690, 3493, 3062, 2038, 922, 279, 1317, 9860, 6372, 315, 50150, 36213, 20149, 11, 2019, 11909, 13, 578, 26587, 374, 16595, 304, 33850, 21503, 33155, 323, 11335, 264, 3682, 3560, 304, 58499, 39097, 13, 73699, 34576, 482, 902, 6782, 2212, 220, 7007, 15, 26333, 482, 649, 5674, 12018, 22029, 36853, 323, 1253, 656, 29869, 11682, 13, 57116, 1511, 60217, 575, 64632, 19646, 7917, 482, 2536, 93348, 4147, 7917, 430, 617, 279, 35947, 5845, 311, 387, 3025, 311, 5276, 1139, 1023, 2849, 4595, 482, 311, 1977, 12018, 22029, 26587, 20438, 13, 22617, 7917, 1051, 15246, 311, 28856, 26333, 1766, 304, 34576, 11, 2737, 3230, 33155, 3967, 311, 4319, 6468, 304, 12018, 295, 4881, 994, 27698, 16603, 13, 578, 4007, 8710, 430, 264, 11742, 41010, 482, 4528, 311, 430, 1766, 304, 34576, 482, 69525, 12018, 22029, 26587, 2890, 810, 1109, 3927, 6956, 13, 7531, 826, 1101, 8710, 430, 36213, 26333, 5674, 279, 26587, 22009, 304, 8762, 323, 8954, 12018, 295, 4881, 11, 449, 8762, 20438, 9204, 26587, 1156, 20450, 323, 8954, 20438, 9204, 810, 5674, 311, 2849, 39097, 13, 578, 4007, 574, 11953, 704, 304, 20632, 449, 279, 75898, 315, 80351, 323, 43997, 323, 374, 4756, 304, 279, 8486, 38329, 315, 67502, 2508, 13, 2999, 6941, 18276, 505, 279, 3907, 315, 41406, 596, 14821, 369, 3263, 75989, 19152, 11, 1071, 25, 330, 34, 44375, 668, 16603, 374, 3967, 311, 617, 34446, 6372, 389, 279, 12018, 64476, 11, 3686, 584, 6996, 8475, 7526, 311, 4007, 420, 304, 264, 1633, 11944, 1648, 13, 1115, 502, 5603, 3445, 430, 584, 1457, 617, 8336, 315, 33268, 20438, 430, 690, 7431, 603, 311, 3619, 279, 35693, 2515, 315, 34576, 389, 279, 86333, 12018, 64476, 1210, 17054, 7043, 75243, 11, 10783, 315, 279, 10181, 315, 13235, 23199, 520, 279, 3907, 315, 80351, 11, 1071, 25, 330, 2028, 990, 374, 961, 315, 459, 14529, 2447, 311, 3619, 1268, 36213, 20149, 555, 20895, 27698, 706, 28856, 6372, 389, 279, 11469, 12018, 64476, 13, 4314, 14955, 25351, 3177, 389, 16188, 12062, 304, 5674, 1990, 8762, 323, 8954, 12018, 295, 4881, 1210, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Immunotherapy with immune checkpoint blockade (ICB) has shown limited benefits in hepatocellular carcinoma (HCC) and other cancers, mediated in part by the immunosuppressive tumor microenvironment (TME). As p53 loss of function may play a role in immunosuppression, we herein examine the effects of restoring p53 expression on the immune TME and ICB efficacy. We develop and optimize a CXCR4-targeted mRNA nanoparticle platform to effectively induce p53 expression in HCC models. Using p53 -null orthotopic and ectopic models of murine HCC, we find that combining CXCR4-targeted p53 mRNA nanoparticles with anti-PD-1 therapy effectively induces global reprogramming of cellular and molecular components of the immune TME. This effect results in improved anti-tumor effects compared to anti-PD-1 therapy or therapeutic p53 expression alone. Thus, our findings demonstrate the reversal of immunosuppression in HCC by a p53 mRNA nanomedicine when combined with ICB and support the implementation of this strategy for cancer treatment. Introduction Loss of function in tumor suppressors is a driving force in tumorigenesis and the development of therapeutic resistance. The p53 tumor suppressor gene, a master regulator of cell cycle arrest, apoptosis, senescence, and other cellular pathways 1 , is frequently mutated in a myriad of human cancers, including hepatocellular carcinoma (HCC). Beyond cell autonomous tumor-suppressive effects, increasing evidence indicates that p53 protein can also regulate the immune tumor microenvironment (TME) by modulating interactions of tumor cells with immune cells 2 , 3 , 4 , 5 , 6 . For example, p53 has been shown to induce antitumor immune response via transcriptional regulation of genes encoding for key cytokines (e.g., TNF-α, IL-12, and IL-15) 7 , 8 , 9 , chemokines (e.g., CCL2, –20, and –28, and CXCL1, –2, –3, –5, and –8) 10 , 11 and pathogen recognition (e.g., Toll-like receptors, TLRs) 12 , 13 , all of which result in recruitment and activation of immune cells. Genetic restoration of p53 could induce the activation of myeloid cells to promote tumor antigen-specific adaptive immunity 14 and upregulate the NKG2D ligands on senescent tumor cells for activation of natural killer (NK) cells 15 . p53 may also play an important role in the suppression of pro-tumorigenic M2-type tumor-associated macrophage (TAM) polarization, thus facilitating antitumor immunity 16 , 17 . Moreover, recent studies suggest that immunogenic cancer cell death induced by cytotoxic agents may be associated with activation of the p53 pathway 18 , 19 . Despite these advances in understanding the role of p53, developing therapeutic approaches that directly and effectively address the loss of p53 function and its role in immunosuppression and immunotherapy resistance in HCC remains an elusive goal. HCC is the most prevalent liver cancer with a high mortality rate and dismal prognosis 20 , 21 , 22 . Enhancing anti-tumor immunity using immune checkpoint blockade (ICB), including anti-CTLA-4, anti-PD-1 (aPD1), and anti-PD-L1 (aPD-L1) antibodies, has demonstrated the potential to transform the therapeutic landscape of many cancers including HCC. However, responses are seen only in a limited fraction of patients, and majority of cancer patients do not benefit from the treatment. This may be mediated in part by insufficient tumor immunogenicity and the immunosuppressive TME. Different strategies are actively being developed to improve ICB therapy in HCC, with a major focus on combining ICB with other existing therapies (such as anti-VEGF therapy), which could significantly increase anti-tumor immunity. Such combinations have been shown to improve anti-tumor efficacy in animal models and increase the survival of patients in clinical trials 23 , 24 , 25 , 26 . However, an increasing majority of HCC patients show no responses, and thus, new combinatorial strategies are still desperately needed. In this work, we address the unmet need to implement p53 therapy and potentiate ICB response in HCC. We report a targeted mRNA nanoparticle (NP) platform designed to induce p53 expression and reprogram the TME, which we test in proof-of-concept studies in combination with ICB in p53 -null murine HCC models. We optimize the p53 mRNA NP platform for HCC targeting, evaluate its therapeutic efficacy in p53 -null HCCs growing in orthotopic and ectopic sites (alone or with aPD1 antibody), and study changes in the TME. This unique combinatorial strategy safely and effectively inhibits tumor growth in vivo, while prolonging survival and reducing ascites and metastases. Thus, combining p53 mRNA nanotherapy with ICB immunotherapy could become a transformative approach for the treatment of HCC and potentially other cancers involving p53 deficiency. Results Engineering and optimization of CXCR4-targeted mRNA NPs We previously developed a robust self-assembly strategy for formulating lipid-polymer hybrid NPs for mRNA delivery 27 , 28 , composed of the ionizable lipid-like compound G0-C14 for mRNA complexation, a biocompatible poly(lactic-co-glycolic acid) (PLGA) polymer for forming a stable NP core to carry the G0-C14/mRNA complexes, and a lipid-poly(ethylene glycol) (lipid-PEG) layer for stability. We here engineered the hybrid NPs (Fig. 1a ) for selective HCC targeting and high mRNA transfection efficiency. To improve HCC targeting, we modified the NPs with the targeting peptide CTCE-9908 (KGVSLSYRCRYSLSVGK; referred to as CTCE), which is specific to CXCR4, a chemokine receptor that is upregulated in cancer cells and is a validated selective target in HCC 29 , 30 . For comparison, we also prepared non-targeted NPs using a scrambled peptide (LYSVKRSGCGSRKVSYL; referred to as SCP). The CTCE or SCP peptide was first conjugated to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide(polyethylene glycol)-3000] (DSPE-PEG-Mal) by the thiol-maleimide Michael addition click reaction, with a high chemical yield (≥82%). The chemical structures of DSPE-PEG-CTCE and DSPE-PEG-SCP were confirmed by 1 H-NMR analysis (Supplementary Fig. 1 ). To optimize the targeting efficacy of the mRNA NPs, we examined the effect of CTCE peptide surface density on the cellular uptake of RIL-175 murine HCC cells. As shown in Fig. 1b , CTCE-conjugated enhanced green fluorescent protein (EGFP) mRNA NPs (referred to herein as CTCE-EGFP NPs) showed significantly greater cellular uptake compared to non-targeting SCP EGFP mRNA NPs (referred to as SCP-EGFP NPs) due to the active targeting ability of the CTCE peptide towards HCC cells. We found that 5% or 6% CTCE peptide provided maximum", "role": "user" }, { "content": "A team of researchers from Massachusetts General Hospital (MGH) and Brigham and Women's Hospital (BWH) has reprogrammed the tumor microenvironment of liver cancer by using mRNA nanoparticles. This technology, similar to the one used in COVID-19 vaccines, restored the function of the p53 master regulator gene, a tumor suppressor mutated in not just liver but also other types of cancer. When used in combination with immune checkpoint blockade (ICB), the p53 mRNA nanoparticle approach not only induced suppression of tumor growth but also significantly increased antitumor immune responses in hepatocellular carcinoma (HCC) laboratory models. The results of the study were published in Nature Communications. \"The reprogramming of the cellular and molecular components of the tumor microenvironment could be a transformative approach for treating HCC and other cancers,\" says co-senior author Jinjun Shi, Ph.D., with the Center for Nanomedicine at BWH, who developed the platform with MGH liver cancer biologist and co-senior author Dan G. Duda, DMD, Ph.D. \"By using this new approach, we're targeting specific pathways in tumor cells with mRNA nanoparticles. These tiny particles provide the cells with the instructions to build proteins, which, in the case of HCC, delayed tumor growth and rendered the tumor more responsive to treatment with immunotherapy.\" HCC is the most prevalent form of liver cancer, characterized by a high mortality rate and dismal prognosis for patients. Immune checkpoint blockers, a revolutionary new class of drugs that enable the body's immune system to recognize and attack cancer cells, have shown efficacy in treating HCC, but most patients do not benefit. To overcome this resistance, multiple strategies are being developed to improve ICBs by combining them with other existing therapies, such as anti-VEGF drugs and radiotherapy. However, even these approaches are expected to benefit only a small number of patients, creating an urgent need for new combination therapies. Encouraged by the success of mRNA in COVID-19 vaccines, Shi decided to apply the technology (with certain modifications) to targeting cancer cells. He teamed up with Duda, whose MGH lab had already created sophisticated animal models to analyze the microenvironment of liver tumors in response to immunotherapy. They developed and optimized an mRNA nanoparticle strategy to restore loss of function of p53, a tumor suppressor gene whose function is lost in more than one-third of HCC cases. In doing so, they uncovered evidence that p53 regulates the tumor microenvironment by modulating the interaction of cancer cells with immune cells as part of ICB therapy. \"In our previous work we had developed nanoparticles to target CXCR4—a chemokine receptor expressed by liver cancer cells—and selectively co-deliver drugs such as kinase inhibitors,\" explains Duda. \"We've now adapted this platform to use CXCR4 as a kind of ZIP code to selectively target the tumor with nanoparticles encapsulating therapeutic mRNAs. When we combined this nanomedicine with anti-programmed death receptor 1 (PD-1) antibodies, a standard immunotherapy for HCC patients, it induced global reprogramming of the tumor microenvironment and tumor response by restoring p53 expression.\" The next step for the team is to transfer their research from animal models to patients in a clinical trial. \"Scientists have struggled for decades to find an effective way to target the tumor suppressor pathways,\" emphasizes Shi. \"Our proof-of-concept study is an exciting development that clearly shows that p53 mRNA nanoparticles in combination with ICB not only works, but also could make a big difference by reversing immunosuppression in HCC and potentially other cancers.\" Shi is an associate professor of Anesthesia at Harvard Medical School (HMS). Duda is associate professor of Radiation Oncology at HMS and director of translational research in GI radiation oncology at MGH. Yuling Xiao, Ph.D., and Jiang Chen, MD, Ph.D., are the lead authors of the study and postdoctoral fellows at HMS. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Immunotherapy with immune checkpoint blockade (ICB) has shown limited benefits in hepatocellular carcinoma (HCC) and other cancers, mediated in part by the immunosuppressive tumor microenvironment (TME). As p53 loss of function may play a role in immunosuppression, we herein examine the effects of restoring p53 expression on the immune TME and ICB efficacy. We develop and optimize a CXCR4-targeted mRNA nanoparticle platform to effectively induce p53 expression in HCC models. Using p53 -null orthotopic and ectopic models of murine HCC, we find that combining CXCR4-targeted p53 mRNA nanoparticles with anti-PD-1 therapy effectively induces global reprogramming of cellular and molecular components of the immune TME. This effect results in improved anti-tumor effects compared to anti-PD-1 therapy or therapeutic p53 expression alone. Thus, our findings demonstrate the reversal of immunosuppression in HCC by a p53 mRNA nanomedicine when combined with ICB and support the implementation of this strategy for cancer treatment. Introduction Loss of function in tumor suppressors is a driving force in tumorigenesis and the development of therapeutic resistance. The p53 tumor suppressor gene, a master regulator of cell cycle arrest, apoptosis, senescence, and other cellular pathways 1 , is frequently mutated in a myriad of human cancers, including hepatocellular carcinoma (HCC). Beyond cell autonomous tumor-suppressive effects, increasing evidence indicates that p53 protein can also regulate the immune tumor microenvironment (TME) by modulating interactions of tumor cells with immune cells 2 , 3 , 4 , 5 , 6 . For example, p53 has been shown to induce antitumor immune response via transcriptional regulation of genes encoding for key cytokines (e.g., TNF-α, IL-12, and IL-15) 7 , 8 , 9 , chemokines (e.g., CCL2, –20, and –28, and CXCL1, –2, –3, –5, and –8) 10 , 11 and pathogen recognition (e.g., Toll-like receptors, TLRs) 12 , 13 , all of which result in recruitment and activation of immune cells. Genetic restoration of p53 could induce the activation of myeloid cells to promote tumor antigen-specific adaptive immunity 14 and upregulate the NKG2D ligands on senescent tumor cells for activation of natural killer (NK) cells 15 . p53 may also play an important role in the suppression of pro-tumorigenic M2-type tumor-associated macrophage (TAM) polarization, thus facilitating antitumor immunity 16 , 17 . Moreover, recent studies suggest that immunogenic cancer cell death induced by cytotoxic agents may be associated with activation of the p53 pathway 18 , 19 . Despite these advances in understanding the role of p53, developing therapeutic approaches that directly and effectively address the loss of p53 function and its role in immunosuppression and immunotherapy resistance in HCC remains an elusive goal. HCC is the most prevalent liver cancer with a high mortality rate and dismal prognosis 20 , 21 , 22 . Enhancing anti-tumor immunity using immune checkpoint blockade (ICB), including anti-CTLA-4, anti-PD-1 (aPD1), and anti-PD-L1 (aPD-L1) antibodies, has demonstrated the potential to transform the therapeutic landscape of many cancers including HCC. However, responses are seen only in a limited fraction of patients, and majority of cancer patients do not benefit from the treatment. This may be mediated in part by insufficient tumor immunogenicity and the immunosuppressive TME. Different strategies are actively being developed to improve ICB therapy in HCC, with a major focus on combining ICB with other existing therapies (such as anti-VEGF therapy), which could significantly increase anti-tumor immunity. Such combinations have been shown to improve anti-tumor efficacy in animal models and increase the survival of patients in clinical trials 23 , 24 , 25 , 26 . However, an increasing majority of HCC patients show no responses, and thus, new combinatorial strategies are still desperately needed. In this work, we address the unmet need to implement p53 therapy and potentiate ICB response in HCC. We report a targeted mRNA nanoparticle (NP) platform designed to induce p53 expression and reprogram the TME, which we test in proof-of-concept studies in combination with ICB in p53 -null murine HCC models. We optimize the p53 mRNA NP platform for HCC targeting, evaluate its therapeutic efficacy in p53 -null HCCs growing in orthotopic and ectopic sites (alone or with aPD1 antibody), and study changes in the TME. This unique combinatorial strategy safely and effectively inhibits tumor growth in vivo, while prolonging survival and reducing ascites and metastases. Thus, combining p53 mRNA nanotherapy with ICB immunotherapy could become a transformative approach for the treatment of HCC and potentially other cancers involving p53 deficiency. Results Engineering and optimization of CXCR4-targeted mRNA NPs We previously developed a robust self-assembly strategy for formulating lipid-polymer hybrid NPs for mRNA delivery 27 , 28 , composed of the ionizable lipid-like compound G0-C14 for mRNA complexation, a biocompatible poly(lactic-co-glycolic acid) (PLGA) polymer for forming a stable NP core to carry the G0-C14/mRNA complexes, and a lipid-poly(ethylene glycol) (lipid-PEG) layer for stability. We here engineered the hybrid NPs (Fig. 1a ) for selective HCC targeting and high mRNA transfection efficiency. To improve HCC targeting, we modified the NPs with the targeting peptide CTCE-9908 (KGVSLSYRCRYSLSVGK; referred to as CTCE), which is specific to CXCR4, a chemokine receptor that is upregulated in cancer cells and is a validated selective target in HCC 29 , 30 . For comparison, we also prepared non-targeted NPs using a scrambled peptide (LYSVKRSGCGSRKVSYL; referred to as SCP). The CTCE or SCP peptide was first conjugated to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide(polyethylene glycol)-3000] (DSPE-PEG-Mal) by the thiol-maleimide Michael addition click reaction, with a high chemical yield (≥82%). The chemical structures of DSPE-PEG-CTCE and DSPE-PEG-SCP were confirmed by 1 H-NMR analysis (Supplementary Fig. 1 ). To optimize the targeting efficacy of the mRNA NPs, we examined the effect of CTCE peptide surface density on the cellular uptake of RIL-175 murine HCC cells. As shown in Fig. 1b , CTCE-conjugated enhanced green fluorescent protein (EGFP) mRNA NPs (referred to herein as CTCE-EGFP NPs) showed significantly greater cellular uptake compared to non-targeting SCP EGFP mRNA NPs (referred to as SCP-EGFP NPs) due to the active targeting ability of the CTCE peptide towards HCC cells. We found that 5% or 6% CTCE peptide provided maximum<|im_end|> <|im_start|>assistant A team of researchers from Massachusetts General Hospital (MGH) and Brigham and Women's Hospital (BWH) has reprogrammed the tumor microenvironment of liver cancer by using mRNA nanoparticles. This technology, similar to the one used in COVID-19 vaccines, restored the function of the p53 master regulator gene, a tumor suppressor mutated in not just liver but also other types of cancer. When used in combination with immune checkpoint blockade (ICB), the p53 mRNA nanoparticle approach not only induced suppression of tumor growth but also significantly increased antitumor immune responses in hepatocellular carcinoma (HCC) laboratory models. The results of the study were published in Nature Communications. "The reprogramming of the cellular and molecular components of the tumor microenvironment could be a transformative approach for treating HCC and other cancers," says co-senior author Jinjun Shi, Ph.D., with the Center for Nanomedicine at BWH, who developed the platform with MGH liver cancer biologist and co-senior author Dan G. Duda, DMD, Ph.D. "By using this new approach, we're targeting specific pathways in tumor cells with mRNA nanoparticles. These tiny particles provide the cells with the instructions to build proteins, which, in the case of HCC, delayed tumor growth and rendered the tumor more responsive to treatment with immunotherapy." HCC is the most prevalent form of liver cancer, characterized by a high mortality rate and dismal prognosis for patients. Immune checkpoint blockers, a revolutionary new class of drugs that enable the body's immune system to recognize and attack cancer cells, have shown efficacy in treating HCC, but most patients do not benefit. To overcome this resistance, multiple strategies are being developed to improve ICBs by combining them with other existing therapies, such as anti-VEGF drugs and radiotherapy. However, even these approaches are expected to benefit only a small number of patients, creating an urgent need for new combination therapies. Encouraged by the success of mRNA in COVID-19 vaccines, Shi decided to apply the technology (with certain modifications) to targeting cancer cells. He teamed up with Duda, whose MGH lab had already created sophisticated animal models to analyze the microenvironment of liver tumors in response to immunotherapy. They developed and optimized an mRNA nanoparticle strategy to restore loss of function of p53, a tumor suppressor gene whose function is lost in more than one-third of HCC cases. In doing so, they uncovered evidence that p53 regulates the tumor microenvironment by modulating the interaction of cancer cells with immune cells as part of ICB therapy. "In our previous work we had developed nanoparticles to target CXCR4—a chemokine receptor expressed by liver cancer cells—and selectively co-deliver drugs such as kinase inhibitors," explains Duda. "We've now adapted this platform to use CXCR4 as a kind of ZIP code to selectively target the tumor with nanoparticles encapsulating therapeutic mRNAs. When we combined this nanomedicine with anti-programmed death receptor 1 (PD-1) antibodies, a standard immunotherapy for HCC patients, it induced global reprogramming of the tumor microenvironment and tumor response by restoring p53 expression." The next step for the team is to transfer their research from animal models to patients in a clinical trial. "Scientists have struggled for decades to find an effective way to target the tumor suppressor pathways," emphasizes Shi. "Our proof-of-concept study is an exciting development that clearly shows that p53 mRNA nanoparticles in combination with ICB not only works, but also could make a big difference by reversing immunosuppression in HCC and potentially other cancers." Shi is an associate professor of Anesthesia at Harvard Medical School (HMS). Duda is associate professor of Radiation Oncology at HMS and director of translational research in GI radiation oncology at MGH. Yuling Xiao, Ph.D., and Jiang Chen, MD, Ph.D., are the lead authors of the study and postdoctoral fellows at HMS. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Chronic inflammation triggers compensatory immunosuppression to stop inflammation and minimize tissue damage. Studies have demonstrated that endoplasmic reticulum (ER) stress augments the suppressive phenotypes of immune cells; however, the molecular mechanisms underpinning this process and how it links to the metabolic reprogramming of immunosuppressive macrophages remain elusive. In the present study, we report that the helper T cell 2 cytokine interleukin-4 and the tumor microenvironment increase the activity of a protein kinase RNA-like ER kinase (PERK)-signaling cascade in macrophages and promote immunosuppressive M2 activation and proliferation. Loss of PERK signaling impeded mitochondrial respiration and lipid oxidation critical for M2 macrophages. PERK activation mediated the upregulation of phosphoserine aminotransferase 1 (PSAT1) and serine biosynthesis via the downstream transcription factor ATF-4. Increased serine biosynthesis resulted in enhanced mitochondrial function and α-ketoglutarate production required for JMJD3-dependent epigenetic modification. Inhibition of PERK suppressed macrophage immunosuppressive activity and could enhance the efficacy of immune checkpoint programmed cell death protein 1 inhibition in melanoma. Our findings delineate a previously undescribed connection between PERK signaling and PSAT1-mediated serine metabolism critical for promoting immunosuppressive function in M2 macrophages. Main Macrophages, a critical component of the innate immune system, are a group of heterogeneous cells present in all tissues. Due to this wide distribution, macrophages are uniquely poised to exert essential processes for human health—from pathogen clearance, tissue repair and maintenance of homeostasis 1 , 2 . The ability of macrophages to serve these functions reflects their ability to execute disparate cellular programs in response to distinct extracellular cues. As a result, immunosuppressive (M2) and proinflammatory (M1) macrophages represent two distinct polarization phenotypes in response to either tumor and helminthic insults or bacterial and viral infection 3 . Moreover, the revitalization of immunometabolism and epigenetics research has uncovered new insights into these polarization phenotypes, revealing major and largely nonoverlapping alterations in gene expression that are closely associated with distinctive metabolic pathways 4 , 5 . These distinct phenotypes are dependent on cues from the surrounding microenvironment, and inflammatory milieus are known to impose stress signals that affect the energetic demands and cellular fitness of infiltrating immune cells 6 , 7 . However, to induce phenotypic changes, these signals must be incorporated and translated intracellularly. The major organelle responsible for coordinating extrinsic challenges and intrinsic cellular demands is the ER where the progression of inflammatory diseases can provoke the unfolded protein response (UPR). The UPR is commonly associated with the maintenance of proteostasis; however, recent findings show that activation of the UPR is linked to the development and function of immune cells 8 , 9 , 10 , including dendritic cells 11 , 12 , myeloid cell-driven immunosuppressive cells (MDSCs) 13 and also T cells 14 , 15 . The UPR signaling cascade is primarily initiated by the type I transmembrane kinase, inositol-requiring enzyme-1α (IRE1α), the type II transmembrane protein, activating transcription factor (ATF) 6 and PERK (encoded by Eif2ak3 ) 16 . Recent studies have suggested that IRE1α-mediated, X-box-binding protein (XBP1) signaling plays a crucial role in macrophages during inflammatory diseases 17 , 18 . Yet, these findings have reached inconclusive and/or contradictory conclusions. This raises an important question about whether other arms of the UPR contribute to the metabolic adaptation necessary to support the immunosuppressive characteristics of macrophages. Activated PERK phosphorylates the downstream mediator eukaryotic translation initiation factor 2α (eIF2α) 16 , leading to the induction of stress-responsive ATF-4 activation 19 . PERK signaling induces mitochondrial function 20 , whereas ATF-4 activation has been suggested to upregulate a set of targets involved in amino acid anabolism 21 . In the present study, we show that the PERK arm of the UPR is uniquely upregulated in macrophages responding to the helper T cell 2 (T H 2) cytokine interleukin-4 (IL-4) and also the tumor microenvironment (TME). This PERK signaling modality promotes mitochondrial respiration to fulfill cellular energy requirements while also signaling through ATF-4 to regulate PSAT1 activity to mediate the serine biosynthesis pathway. The process of PSAT1-mediated serine synthesis, in addition to supporting mitochondrial fitness, balances the production of α-ketoglutarate (α-KG) necessary for JMJD3-dependent histone demethylation and reinforces immunosuppressive M2 activation and cell expansion. These results highlight a previously uncharacterized role for PERK in cellular metabolism and epigenetic modification in M2 macrophages, and our findings may offer a new strategy for counteracting the immunosuppressive effects of M2 macrophages in human diseases. Results PERK supports macrophage immunosuppression To investigate the role of the ER stress response in immunosuppressive M2 macrophages, we first analyzed publicly available microarray and single-cell RNA-sequencing (RNA-seq) data and performed gene set enrichment analysis (GSEA) of IL-4/anti-IL-4 antibody complex (IL-4c)-treated mouse peritoneal macrophages (accession no. GSE54679 ) 22 and tumor-associated macrophages (TAMs) from patients with lung carcinoma (accession no. GSE97168 ) 23 . Our data indicated that, under IL-4 stimulation (Extended Data Fig. 1a ) and within the TME (Extended Data Fig. 1b ), macrophages upregulated genes associated with an ER stress response. By analyzing our RNA-seq dataset (accession no. GSE53053 ) 24 , we found that the PERK arm of the ER stress response was markedly induced by bone marrow-derived macrophages (BMDMs) after stimulation with IL-4 compared with naive (M0) and proinflammatory (M1) macrophages (Fig. 1a ). Moreover, we observed a positive correlation between CD68 messenger RNA of tumor macrophages and individual gene transcripts ( HSP5A , EIF2A , NFE2L2 and ATF4 ) of the PERK-signaling axis in different human cancer patient samples from The Cancer Genome Atlas (TCGA) program, including colon adenocarcinoma, lung adenocarcinoma and pancreatic ductal adenocarcinoma (Extended Data Fig. 1c ), suggesting that the activation of PERK may be required to support an immunosuppressive M2 phenotype. To confirm this, we stimulated BMDMs with the T H 2 cytokine IL-4 or assessed TAMs from animals bearing B16-F10 melanoma. We found that both IL-4-stimulated macrophages and TAMs exhibited a higher percentage of activated (phosphorylated) PERK protein compared with naive BMDMs and splenic macrophages from melanoma tumor-bearing mice, respectively (Fig. 1b,c and Extended Data Fig. 1d ). Of note, a conventional ER stress inducer, thapsigargin,", "role": "user" }, { "content": "Cancer researchers at Case Western Reserve University School of Medicine say they have successfully suppressed the growth of some solid tumors in research models by manipulating immune cells known as macrophages. The researchers say this discovery is significant because many solid tumor cancers, such as lung cancer, are difficult to treat. According to the National Cancer Institute, breast, lung, prostate and colorectal cancers—all of which are solid tumor cancers—account for almost half of all new cancer cases in the United States. In this new research, the scientists discovered that altering the macrophage metabolism—and, in doing so, influencing their relationship with T cells—suppressed the tumor's growth. The result was a significant reduction in overall tumor size in some mouse models. \"The race to find a cure for cancer never stops,\" said Stanley Huang, an assistant professor of immunology in the Department of Pathology at the School of Medicine, who led the research. \"Our research creates a pathway to a [potential] new form of cancer treatment for those with solid tumor cancers.\" The study appeared recently in the journal Nature Immunology. T cells and macrophages Generally, the body's immune response to disease involves mobilizing white blood cells that attack invaders like germs and bacteria. Macrophages are specialized white blood cells that consume invading cells to destroy pathogens. They are considered the \"frontline soldiers\" of the body's immune system and can activate T cells, which are another type of white blood cell. Yet, despite their typically protective role, macrophages can be co-opted by tumor cells to encourage tumor growth. Targeting macrophages and PERK protein As tumors grow and macrophages interact with the tumor cells, they create a response protein, which the study linked to tumor growth. Huang said the team believed it was possible to target macrophages and that particular protein—known to scientists by its shorthand, PERK (\"protein kinase R\" (PKR)-like endoplasmic reticulum kinase)—to block tumor growth. \"Knocking out PERK suppresses downstream metabolic signaling in tumor macrophages, resulting in more T cells to fight the cancer cells,\" said Huang. Findings and future steps The study's findings suggest that the PERK protein is involved in several key pathways of metabolism in macrophages—and when the gene is removed, macrophages can no longer promote tumor growth; meaning tumors become smaller. Follow-up experiments further revealed that combination treatment of a PERK inhibitor drug with an inhibitor called \"anti-PD-1\" could significantly reduce tumor growth. Next, the researchers hope to identify a clinical drug that will act as an inhibitor for the PERK protein. \"There are several strategies to enhance anti-tumor immunity like targeting or editing cell metabolism,\" Huang said. \"We can target genes and their pathways to enhance immune function and work toward future therapeutic treatment options.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Chronic inflammation triggers compensatory immunosuppression to stop inflammation and minimize tissue damage. Studies have demonstrated that endoplasmic reticulum (ER) stress augments the suppressive phenotypes of immune cells; however, the molecular mechanisms underpinning this process and how it links to the metabolic reprogramming of immunosuppressive macrophages remain elusive. In the present study, we report that the helper T cell 2 cytokine interleukin-4 and the tumor microenvironment increase the activity of a protein kinase RNA-like ER kinase (PERK)-signaling cascade in macrophages and promote immunosuppressive M2 activation and proliferation. Loss of PERK signaling impeded mitochondrial respiration and lipid oxidation critical for M2 macrophages. PERK activation mediated the upregulation of phosphoserine aminotransferase 1 (PSAT1) and serine biosynthesis via the downstream transcription factor ATF-4. Increased serine biosynthesis resulted in enhanced mitochondrial function and α-ketoglutarate production required for JMJD3-dependent epigenetic modification. Inhibition of PERK suppressed macrophage immunosuppressive activity and could enhance the efficacy of immune checkpoint programmed cell death protein 1 inhibition in melanoma. Our findings delineate a previously undescribed connection between PERK signaling and PSAT1-mediated serine metabolism critical for promoting immunosuppressive function in M2 macrophages. Main Macrophages, a critical component of the innate immune system, are a group of heterogeneous cells present in all tissues. Due to this wide distribution, macrophages are uniquely poised to exert essential processes for human health—from pathogen clearance, tissue repair and maintenance of homeostasis 1 , 2 . The ability of macrophages to serve these functions reflects their ability to execute disparate cellular programs in response to distinct extracellular cues. As a result, immunosuppressive (M2) and proinflammatory (M1) macrophages represent two distinct polarization phenotypes in response to either tumor and helminthic insults or bacterial and viral infection 3 . Moreover, the revitalization of immunometabolism and epigenetics research has uncovered new insights into these polarization phenotypes, revealing major and largely nonoverlapping alterations in gene expression that are closely associated with distinctive metabolic pathways 4 , 5 . These distinct phenotypes are dependent on cues from the surrounding microenvironment, and inflammatory milieus are known to impose stress signals that affect the energetic demands and cellular fitness of infiltrating immune cells 6 , 7 . However, to induce phenotypic changes, these signals must be incorporated and translated intracellularly. The major organelle responsible for coordinating extrinsic challenges and intrinsic cellular demands is the ER where the progression of inflammatory diseases can provoke the unfolded protein response (UPR). The UPR is commonly associated with the maintenance of proteostasis; however, recent findings show that activation of the UPR is linked to the development and function of immune cells 8 , 9 , 10 , including dendritic cells 11 , 12 , myeloid cell-driven immunosuppressive cells (MDSCs) 13 and also T cells 14 , 15 . The UPR signaling cascade is primarily initiated by the type I transmembrane kinase, inositol-requiring enzyme-1α (IRE1α), the type II transmembrane protein, activating transcription factor (ATF) 6 and PERK (encoded by Eif2ak3 ) 16 . Recent studies have suggested that IRE1α-mediated, X-box-binding protein (XBP1) signaling plays a crucial role in macrophages during inflammatory diseases 17 , 18 . Yet, these findings have reached inconclusive and/or contradictory conclusions. This raises an important question about whether other arms of the UPR contribute to the metabolic adaptation necessary to support the immunosuppressive characteristics of macrophages. Activated PERK phosphorylates the downstream mediator eukaryotic translation initiation factor 2α (eIF2α) 16 , leading to the induction of stress-responsive ATF-4 activation 19 . PERK signaling induces mitochondrial function 20 , whereas ATF-4 activation has been suggested to upregulate a set of targets involved in amino acid anabolism 21 . In the present study, we show that the PERK arm of the UPR is uniquely upregulated in macrophages responding to the helper T cell 2 (T H 2) cytokine interleukin-4 (IL-4) and also the tumor microenvironment (TME). This PERK signaling modality promotes mitochondrial respiration to fulfill cellular energy requirements while also signaling through ATF-4 to regulate PSAT1 activity to mediate the serine biosynthesis pathway. The process of PSAT1-mediated serine synthesis, in addition to supporting mitochondrial fitness, balances the production of α-ketoglutarate (α-KG) necessary for JMJD3-dependent histone demethylation and reinforces immunosuppressive M2 activation and cell expansion. These results highlight a previously uncharacterized role for PERK in cellular metabolism and epigenetic modification in M2 macrophages, and our findings may offer a new strategy for counteracting the immunosuppressive effects of M2 macrophages in human diseases. Results PERK supports macrophage immunosuppression To investigate the role of the ER stress response in immunosuppressive M2 macrophages, we first analyzed publicly available microarray and single-cell RNA-sequencing (RNA-seq) data and performed gene set enrichment analysis (GSEA) of IL-4/anti-IL-4 antibody complex (IL-4c)-treated mouse peritoneal macrophages (accession no. GSE54679 ) 22 and tumor-associated macrophages (TAMs) from patients with lung carcinoma (accession no. GSE97168 ) 23 . Our data indicated that, under IL-4 stimulation (Extended Data Fig. 1a ) and within the TME (Extended Data Fig. 1b ), macrophages upregulated genes associated with an ER stress response. By analyzing our RNA-seq dataset (accession no. GSE53053 ) 24 , we found that the PERK arm of the ER stress response was markedly induced by bone marrow-derived macrophages (BMDMs) after stimulation with IL-4 compared with naive (M0) and proinflammatory (M1) macrophages (Fig. 1a ). Moreover, we observed a positive correlation between CD68 messenger RNA of tumor macrophages and individual gene transcripts ( HSP5A , EIF2A , NFE2L2 and ATF4 ) of the PERK-signaling axis in different human cancer patient samples from The Cancer Genome Atlas (TCGA) program, including colon adenocarcinoma, lung adenocarcinoma and pancreatic ductal adenocarcinoma (Extended Data Fig. 1c ), suggesting that the activation of PERK may be required to support an immunosuppressive M2 phenotype. To confirm this, we stimulated BMDMs with the T H 2 cytokine IL-4 or assessed TAMs from animals bearing B16-F10 melanoma. We found that both IL-4-stimulated macrophages and TAMs exhibited a higher percentage of activated (phosphorylated) PERK protein compared with naive BMDMs and splenic macrophages from melanoma tumor-bearing mice, respectively (Fig. 1b,c and Extended Data Fig. 1d ). Of note, a conventional ER stress inducer, thapsigargin,<|im_end|> <|im_start|>assistant Cancer researchers at Case Western Reserve University School of Medicine say they have successfully suppressed the growth of some solid tumors in research models by manipulating immune cells known as macrophages. The researchers say this discovery is significant because many solid tumor cancers, such as lung cancer, are difficult to treat. According to the National Cancer Institute, breast, lung, prostate and colorectal cancers—all of which are solid tumor cancers—account for almost half of all new cancer cases in the United States. In this new research, the scientists discovered that altering the macrophage metabolism—and, in doing so, influencing their relationship with T cells—suppressed the tumor's growth. The result was a significant reduction in overall tumor size in some mouse models. "The race to find a cure for cancer never stops," said Stanley Huang, an assistant professor of immunology in the Department of Pathology at the School of Medicine, who led the research. "Our research creates a pathway to a [potential] new form of cancer treatment for those with solid tumor cancers." The study appeared recently in the journal Nature Immunology. T cells and macrophages Generally, the body's immune response to disease involves mobilizing white blood cells that attack invaders like germs and bacteria. Macrophages are specialized white blood cells that consume invading cells to destroy pathogens. They are considered the "frontline soldiers" of the body's immune system and can activate T cells, which are another type of white blood cell. Yet, despite their typically protective role, macrophages can be co-opted by tumor cells to encourage tumor growth. Targeting macrophages and PERK protein As tumors grow and macrophages interact with the tumor cells, they create a response protein, which the study linked to tumor growth. Huang said the team believed it was possible to target macrophages and that particular protein—known to scientists by its shorthand, PERK ("protein kinase R" (PKR)-like endoplasmic reticulum kinase)—to block tumor growth. "Knocking out PERK suppresses downstream metabolic signaling in tumor macrophages, resulting in more T cells to fight the cancer cells," said Huang. Findings and future steps The study's findings suggest that the PERK protein is involved in several key pathways of metabolism in macrophages—and when the gene is removed, macrophages can no longer promote tumor growth; meaning tumors become smaller. Follow-up experiments further revealed that combination treatment of a PERK inhibitor drug with an inhibitor called "anti-PD-1" could significantly reduce tumor growth. Next, the researchers hope to identify a clinical drug that will act as an inhibitor for the PERK protein. "There are several strategies to enhance anti-tumor immunity like targeting or editing cell metabolism," Huang said. "We can target genes and their pathways to enhance immune function and work toward future therapeutic treatment options." <|im_end|>

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2,196

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Spectroscopic measurements of dense plasmas at billions of atmospheres provide tests to our fundamental understanding of how matter behaves at extreme conditions. Developing reliable atomic physics models at these conditions, benchmarked by experimental data, is crucial to an improved understanding of radiation transport in both stars and inertial fusion targets. However, detailed spectroscopic measurements at these conditions are rare, and traditional collisional-radiative equilibrium models, based on isolated-atom calculations and ad hoc continuum lowering models, have proved questionable at and beyond solid density. Here we report time-integrated and time-resolved x-ray spectroscopy measurements at several billion atmospheres using laser-driven implosions of Cu-doped targets. We use the imploding shell and its hot core at stagnation to probe the spectral changes of Cu-doped witness layer. These measurements indicate the necessity and viability of modeling dense plasmas with self-consistent methods like density-functional theory, which impact the accuracy of radiation transport simulations used to describe stellar evolution and the design of inertial fusion targets. Introduction The physics of warm and hot dense matter can unravel the mysterious inner workings of planetary cores and stellar interiors 1 . These conditions span a large range of densities and temperatures ( ρ = 10 0 –10 6 g cm −3 and T = 10 3 –10 7 K), with pressures varying from ~1 Mbar (or, one million times that of Earth’s atmospheric pressure; 1 Mbar = 10 11 Pa) to ~500 Gbar (1 gigabar = 10 14 Pa). Understanding the physics of matter at such ultrahigh pressures can have many applications, including determining the age of the Universe through white dwarf cosmochronometry 2 , interpreting astrophysical observations 3 , 4 , 5 , and designing high-performance inertial fusion targets 6 , 7 , 8 . Thanks to technological advances in high-power lasers (including x-ray free electron lasers) and pulsed-power machines, this extreme state of matter can now be accessed in the laboratory 9 , 10 , 11 , but only for a short period of time (picosecond to microsecond timescales) depending on the driver and experimental geometry. Nonetheless, these techniques provide a unique “window” for interrogating the physics of matter at extreme conditions. The implosion spectroscopy measurements and model development presented in this work aim to reveal a more-detailed picture of atomic physics in dense-plasma environments at billion atmosphere (Gbar) pressures. Spherically-convergent techniques uniquely access the gigabar pressure regime in experiments, providing the necessary data to test atomic physics models for warm and hot dense plasmas. X-ray spectroscopy, a common and sometimes only means to diagnose and understand short-lived plasmas, measures x-ray emission and absorption with spatial, spectral, and/or temporal resolution 12 , 13 , 14 , 15 , 16 . Observing atomic line positions and spectral widths can reveal the physical processes that are occurring inside the system. Reliable atomic and plasma physics models are required to interpret these spectral signatures and have generally proven to be adequate for spectroscopically diagnosing classical/ideal plasmas 17 , 18 , 19 , 20 . In this regime, collisional-radiative equilibrium ( CRE ) models 21 , 22 are successfully used, which combine accurate atomic data from isolated atom calculations with appropriate continuum-lowering models to describe dilute plasma effects (e.g., ionization, screening, and broadening). This approach can provide guidance, for example, on the inference of plasma density and temperature 17 , 18 , 19 , 20 . However, with increasing energy density, experimental measurements over the last decade have revealed potential inconsistencies with traditional CRE treatments. For instance, experimental measurements 23 , 24 on the K-edge shift of solid-density aluminum plasmas (heated by x-ray free electron lasers) favored the continuum lowering model developed by Ecker and Kroll 25 , while shock-compression experiments 26 on the same material gave better agreement with a different continuum-lowering model by Stewart and Pyatt 27 . In addition, iron opacity measurements 28 at pressures below 1 Mbar showed very good agreement with traditional CRE -type opacity calculations, while significant disagreements 29 , 30 were found between measurements and theory at elevated densities and temperatures (for example, at around 10 Mbar for iron plasmas). It remains an “unsolved mystery” to this day, even though much effort has been applied to this open question from both theoretical and experimental perspectives 30 , 31 , 32 . Today, one can accurately compute the electronic energy levels of an isolated atom by solving the many-body Schrödinger or Dirac equations, for which the calculation precision can be improved systematically by varying the sophistication of the methods that are implemented, from the simplest Hartree–Fock method to advanced multi-configuration interactions. However, when atoms are put into a non-ideal (i.e., strongly-coupled and/or degenerate ) plasma environment, significant discrepancies appear between detailed spectroscopic measurements and calculations. One outstanding example is the inconsistency of hydrogen line broadening in the dilute, but cold ( n e = 10 15 –10 18 cm −3 and T = 10 3 –10 5 K) photospheric plasmas of white dwarfs 33 , in which plasma conditions inferred from the broadening of different lines in the same plasma can vary significantly, even amongst the best atomic physics models that are currently available. These variations can have significant implications for deducing the mass and age of white dwarfs by affecting the standard candle for cosmochronometry 2 . A similar situation occurs in warm dense plasmas under high-energy-density (HED) conditions, in which high-density effects (many-body coupling) and quantum electron degeneracy can drastically alter atomic physics relative to the isolated case. Reconciling how atomic physics changes in such non-ideal plasmas demands progress in both experiments and theory, which must account for the plasma environment self-consistently. Over the last few years, high-resolution absorption and fluorescence spectra have been used in magnetically driven inertial fusion (cylindrical liner) experiments to study the electronic structure of warm dense matter under extreme compression 16 , 34 . These studies have shown that a self-consistent field model based on density-functional theory (DFT) could reproduce K-edge and fluorescence line shifts at independently diagnosed, imploded plasma conditions (10 eV and n e = 10", "role": "user" }, { "content": "Most people are familiar with solids, liquids, and gases as three states of matter. However, a fourth state of matter, called plasmas, is the most abundant form of matter in the universe, found throughout our solar system in the sun and other planetary bodies. Because dense plasma—a hot soup of atoms with free-moving electrons and ions—typically only forms under extreme pressure and temperatures, scientists are still working to comprehend the fundamentals of this state of matter. Understanding how atoms react under extreme pressure conditions—a field known as high-energy-density physics (HEDP)—gives scientists valuable insights into the fields of planetary science, astrophysics, and fusion energy. One important question in the field of HEDP is how plasmas emit or absorb radiation. Current models depicting radiation transport in dense plasmas are heavily based on theory rather than experimental evidence. In a new paper published in Nature Communications, researchers at the University of Rochester Laboratory for Laser Energetics (LLE) used LLE's OMEGA laser to study how radiation travels through dense plasma. The research, led by Suxing Hu, a distinguished scientist and group leader of the High-Energy-Density Physics Theory Group at the LLE and an associate professor of mechanical engineering, and Philip Nilson, a senior scientist in the LLE's Laser-Plasma Interaction group, provides first-of-its-kind experimental data about the behavior of atoms at extreme conditions. The data will be used to improve plasma models, which allow scientists to better understand the evolution of stars and may aid in the realization of controlled nuclear fusion as an alternative energy source. \"Experiments using laser-driven implosions on OMEGA have created extreme matter at pressures several billion times the atmospheric pressure at Earth's surface for us to probe how atoms and molecules behave at such extreme conditions,\" Hu says. \"These conditions correspond to the conditions inside the so-called envelope of white dwarf stars as well as inertial fusion targets.\" A NASA image of plasma bursting from the sun. Plasma—a hot soup of atoms with free moving electrons and ions—is the most abundant form of matter in the universe, found throughout our solar system in the sun and other planetary bodies. A new study from University of Rochester researchers provides experimental data about how radiation travels through dense plasmas, which will help scientists to better understand planetary science and fusion energy. Credit: NASA Using X-ray spectroscopy The researchers used X-ray spectroscopy to measure how radiation is transported through plasmas. X-ray spectroscopy involves aiming a beam of radiation in the form of X-rays at a plasma made of atoms—in this case, copper atoms—under extreme pressure and heat. The researchers used the OMEGA laser both to create the plasma and to create the X-rays aimed at the plasma. When the plasma is bombarded with X-rays, the electrons in the atoms \"jump\" from one energy level to another by either emitting or absorbing photons of light. A detector measures these changes, revealing the physical processes that are occurring inside the plasma, similar to taking an X-ray diagnostic of a broken bone. A break from conventional theory The researchers' experimental measurements indicate that, when radiation travels through a dense plasma, the changes in atomic energy levels do not follow conventional theories currently used in plasma physics models—so-called \"continuum-lowering\" models. The researchers instead found that the measurements they observed in their experiments can only be explained using a self-consistent approach based on density-functional theory (DFT). DFT offers a quantum mechanical description of the bonds between atoms and molecules in complex systems. The DFT method was first described in the 1960s and was the subject of the 1998 Nobel Prize in Chemistry. \"This work reveals fundamental steps for rewriting current textbook descriptions of how radiation generation and transport occurs in dense plasmas,\" Hu says. \"According to our experiments, using a self-consistent DFT approach more accurately describes the transport of radiation in a dense plasma.\" Says Nilson, \"Our approach could provide a reliable way for simulating radiation generation and transport in dense plasmas encountered in stars and inertial fusion targets. The experimental scheme reported here, based on a laser-driven implosion, can be readily extended to a wide range of materials, opening the way for far-reaching investigations of extreme atomic physics at tremendous pressures.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Spectroscopic measurements of dense plasmas at billions of atmospheres provide tests to our fundamental understanding of how matter behaves at extreme conditions. Developing reliable atomic physics models at these conditions, benchmarked by experimental data, is crucial to an improved understanding of radiation transport in both stars and inertial fusion targets. However, detailed spectroscopic measurements at these conditions are rare, and traditional collisional-radiative equilibrium models, based on isolated-atom calculations and ad hoc continuum lowering models, have proved questionable at and beyond solid density. Here we report time-integrated and time-resolved x-ray spectroscopy measurements at several billion atmospheres using laser-driven implosions of Cu-doped targets. We use the imploding shell and its hot core at stagnation to probe the spectral changes of Cu-doped witness layer. These measurements indicate the necessity and viability of modeling dense plasmas with self-consistent methods like density-functional theory, which impact the accuracy of radiation transport simulations used to describe stellar evolution and the design of inertial fusion targets. Introduction The physics of warm and hot dense matter can unravel the mysterious inner workings of planetary cores and stellar interiors 1 . These conditions span a large range of densities and temperatures ( ρ = 10 0 –10 6 g cm −3 and T = 10 3 –10 7 K), with pressures varying from ~1 Mbar (or, one million times that of Earth’s atmospheric pressure; 1 Mbar = 10 11 Pa) to ~500 Gbar (1 gigabar = 10 14 Pa). Understanding the physics of matter at such ultrahigh pressures can have many applications, including determining the age of the Universe through white dwarf cosmochronometry 2 , interpreting astrophysical observations 3 , 4 , 5 , and designing high-performance inertial fusion targets 6 , 7 , 8 . Thanks to technological advances in high-power lasers (including x-ray free electron lasers) and pulsed-power machines, this extreme state of matter can now be accessed in the laboratory 9 , 10 , 11 , but only for a short period of time (picosecond to microsecond timescales) depending on the driver and experimental geometry. Nonetheless, these techniques provide a unique “window” for interrogating the physics of matter at extreme conditions. The implosion spectroscopy measurements and model development presented in this work aim to reveal a more-detailed picture of atomic physics in dense-plasma environments at billion atmosphere (Gbar) pressures. Spherically-convergent techniques uniquely access the gigabar pressure regime in experiments, providing the necessary data to test atomic physics models for warm and hot dense plasmas. X-ray spectroscopy, a common and sometimes only means to diagnose and understand short-lived plasmas, measures x-ray emission and absorption with spatial, spectral, and/or temporal resolution 12 , 13 , 14 , 15 , 16 . Observing atomic line positions and spectral widths can reveal the physical processes that are occurring inside the system. Reliable atomic and plasma physics models are required to interpret these spectral signatures and have generally proven to be adequate for spectroscopically diagnosing classical/ideal plasmas 17 , 18 , 19 , 20 . In this regime, collisional-radiative equilibrium ( CRE ) models 21 , 22 are successfully used, which combine accurate atomic data from isolated atom calculations with appropriate continuum-lowering models to describe dilute plasma effects (e.g., ionization, screening, and broadening). This approach can provide guidance, for example, on the inference of plasma density and temperature 17 , 18 , 19 , 20 . However, with increasing energy density, experimental measurements over the last decade have revealed potential inconsistencies with traditional CRE treatments. For instance, experimental measurements 23 , 24 on the K-edge shift of solid-density aluminum plasmas (heated by x-ray free electron lasers) favored the continuum lowering model developed by Ecker and Kroll 25 , while shock-compression experiments 26 on the same material gave better agreement with a different continuum-lowering model by Stewart and Pyatt 27 . In addition, iron opacity measurements 28 at pressures below 1 Mbar showed very good agreement with traditional CRE -type opacity calculations, while significant disagreements 29 , 30 were found between measurements and theory at elevated densities and temperatures (for example, at around 10 Mbar for iron plasmas). It remains an “unsolved mystery” to this day, even though much effort has been applied to this open question from both theoretical and experimental perspectives 30 , 31 , 32 . Today, one can accurately compute the electronic energy levels of an isolated atom by solving the many-body Schrödinger or Dirac equations, for which the calculation precision can be improved systematically by varying the sophistication of the methods that are implemented, from the simplest Hartree–Fock method to advanced multi-configuration interactions. However, when atoms are put into a non-ideal (i.e., strongly-coupled and/or degenerate ) plasma environment, significant discrepancies appear between detailed spectroscopic measurements and calculations. One outstanding example is the inconsistency of hydrogen line broadening in the dilute, but cold ( n e = 10 15 –10 18 cm −3 and T = 10 3 –10 5 K) photospheric plasmas of white dwarfs 33 , in which plasma conditions inferred from the broadening of different lines in the same plasma can vary significantly, even amongst the best atomic physics models that are currently available. These variations can have significant implications for deducing the mass and age of white dwarfs by affecting the standard candle for cosmochronometry 2 . A similar situation occurs in warm dense plasmas under high-energy-density (HED) conditions, in which high-density effects (many-body coupling) and quantum electron degeneracy can drastically alter atomic physics relative to the isolated case. Reconciling how atomic physics changes in such non-ideal plasmas demands progress in both experiments and theory, which must account for the plasma environment self-consistently. Over the last few years, high-resolution absorption and fluorescence spectra have been used in magnetically driven inertial fusion (cylindrical liner) experiments to study the electronic structure of warm dense matter under extreme compression 16 , 34 . These studies have shown that a self-consistent field model based on density-functional theory (DFT) could reproduce K-edge and fluorescence line shifts at independently diagnosed, imploded plasma conditions (10 eV and n e = 10<|im_end|> <|im_start|>assistant Most people are familiar with solids, liquids, and gases as three states of matter. However, a fourth state of matter, called plasmas, is the most abundant form of matter in the universe, found throughout our solar system in the sun and other planetary bodies. Because dense plasma—a hot soup of atoms with free-moving electrons and ions—typically only forms under extreme pressure and temperatures, scientists are still working to comprehend the fundamentals of this state of matter. Understanding how atoms react under extreme pressure conditions—a field known as high-energy-density physics (HEDP)—gives scientists valuable insights into the fields of planetary science, astrophysics, and fusion energy. One important question in the field of HEDP is how plasmas emit or absorb radiation. Current models depicting radiation transport in dense plasmas are heavily based on theory rather than experimental evidence. In a new paper published in Nature Communications, researchers at the University of Rochester Laboratory for Laser Energetics (LLE) used LLE's OMEGA laser to study how radiation travels through dense plasma. The research, led by Suxing Hu, a distinguished scientist and group leader of the High-Energy-Density Physics Theory Group at the LLE and an associate professor of mechanical engineering, and Philip Nilson, a senior scientist in the LLE's Laser-Plasma Interaction group, provides first-of-its-kind experimental data about the behavior of atoms at extreme conditions. The data will be used to improve plasma models, which allow scientists to better understand the evolution of stars and may aid in the realization of controlled nuclear fusion as an alternative energy source. "Experiments using laser-driven implosions on OMEGA have created extreme matter at pressures several billion times the atmospheric pressure at Earth's surface for us to probe how atoms and molecules behave at such extreme conditions," Hu says. "These conditions correspond to the conditions inside the so-called envelope of white dwarf stars as well as inertial fusion targets." A NASA image of plasma bursting from the sun. Plasma—a hot soup of atoms with free moving electrons and ions—is the most abundant form of matter in the universe, found throughout our solar system in the sun and other planetary bodies. A new study from University of Rochester researchers provides experimental data about how radiation travels through dense plasmas, which will help scientists to better understand planetary science and fusion energy. Credit: NASA Using X-ray spectroscopy The researchers used X-ray spectroscopy to measure how radiation is transported through plasmas. X-ray spectroscopy involves aiming a beam of radiation in the form of X-rays at a plasma made of atoms—in this case, copper atoms—under extreme pressure and heat. The researchers used the OMEGA laser both to create the plasma and to create the X-rays aimed at the plasma. When the plasma is bombarded with X-rays, the electrons in the atoms "jump" from one energy level to another by either emitting or absorbing photons of light. A detector measures these changes, revealing the physical processes that are occurring inside the plasma, similar to taking an X-ray diagnostic of a broken bone. A break from conventional theory The researchers' experimental measurements indicate that, when radiation travels through a dense plasma, the changes in atomic energy levels do not follow conventional theories currently used in plasma physics models—so-called "continuum-lowering" models. The researchers instead found that the measurements they observed in their experiments can only be explained using a self-consistent approach based on density-functional theory (DFT). DFT offers a quantum mechanical description of the bonds between atoms and molecules in complex systems. The DFT method was first described in the 1960s and was the subject of the 1998 Nobel Prize in Chemistry. "This work reveals fundamental steps for rewriting current textbook descriptions of how radiation generation and transport occurs in dense plasmas," Hu says. "According to our experiments, using a self-consistent DFT approach more accurately describes the transport of radiation in a dense plasma." Says Nilson, "Our approach could provide a reliable way for simulating radiation generation and transport in dense plasmas encountered in stars and inertial fusion targets. The experimental scheme reported here, based on a laser-driven implosion, can be readily extended to a wide range of materials, opening the way for far-reaching investigations of extreme atomic physics at tremendous pressures." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Protein design aims to build novel proteins customized for specific purposes, thereby holding the potential to tackle many environmental and biomedical problems. Recent progress in Transformer-based architectures has enabled the implementation of language models capable of generating text with human-like capabilities. Here, motivated by this success, we describe ProtGPT2, a language model trained on the protein space that generates de novo protein sequences following the principles of natural ones. The generated proteins display natural amino acid propensities, while disorder predictions indicate that 88% of ProtGPT2-generated proteins are globular, in line with natural sequences. Sensitive sequence searches in protein databases show that ProtGPT2 sequences are distantly related to natural ones, and similarity networks further demonstrate that ProtGPT2 is sampling unexplored regions of protein space. AlphaFold prediction of ProtGPT2-sequences yields well-folded non-idealized structures with embodiments and large loops and reveals topologies not captured in current structure databases. ProtGPT2 generates sequences in a matter of seconds and is freely available. Introduction Natural language processing (NLP) has seen extraordinary advances in recent years. Large pre-trained language models have drastically transformed the NLP field and with it, many of the tools we use in our daily lives, such as chatbots, smart assistants, or translation machines. Analogies between protein sequences and human languages have long been noted by us and others 1 , 2 . Protein sequences can be described as a concatenation of letters from a chemically defined alphabet, the natural amino acids, and like human languages, these letters arrange to form secondary structural elements (“words”), which assemble to form domains (“sentences”) that undertake a function (“meaning”). One of the most attractive similarities is that protein sequences, like natural languages, are information-complete: they store structure and function entirely in their amino acid order with extreme efficiency. With the extraordinary advances in the NLP field in understanding and generating language with near-human capabilities, we hypothesized that these methods open a new door to approach protein-related problems from sequence alone, such as protein design. Although protein sequences and human languages are not without dissimilarities, their analogies have stimulated applying NLP methods to solve protein research problems for decades 2 . Supervised NLP methods, where the input sequences are trained jointly with their labels to produce predictive models, have been applied to various tasks, such as detecting structural similarity or predicting stability 3 , 4 . A remarkable collection of supervised language models applied to biomolecules is available in the BioSeq-BLM platform 5 , 6 . Nevertheless, since the inception of the Transformer 7 , unsupervised learning, where the training occurs on unlabeled data, has emerged as a versatile tool for language modeling. Several Transformer-based models, such as TCR-BERT 8 , epiBERTope 9 , ESM 10 , ProtTrans 11 , or ProteinBERT 12 , have shown to be very competitive with other methods 13 , 14 . Most of these models use BERT-like 15 architectures and denoising autoencoding training objectives, i.e., they are pre-trained by corrupting the input tokens in some way and trying to reconstruct the original sentence 2 . Although these models could be adjusted for generation 16 , their most direct application is sequence embedding. Another important branch of language models benefits from autoregressive training, i.e., models are trained to predict subsequent words given a context. These models, the most well-known of which are possibly the GPT-x series 17 , excel at generating long, coherent text—sometimes to the extent that much debate has been raised about their potential misuse 18 . Protein autoregressive language models, such as ProGen 19 , 20 , 21 , RITA 22 , and DARK 23 have also been studied, and show the potential of autoregressive Transformers for protein design. Motivated by these works and the ever-increasing capabilities of English-speaking models such as the GPT-x series, we wondered whether we could train a generative model to (i) effectively learn the protein language, (ii) generate fit, stable proteins, and (iii) understand how these sequences relate to natural ones, including whether they sample unseen regions of the protein space. Here, we introduce ProtGPT2, an autoregressive Transformer model with 738 million parameters capable of generating de novo protein sequences in a high-throughput fashion. ProtGPT2 has effectively learned the protein language upon being trained on about 50 non-annotated million sequences spanning the entire protein space. ProtGPT2 generates protein sequences with amino acid and disorder propensities on par with natural ones while being “evolutionarily” distant from the current protein space. Secondary structure prediction calculates 88% of the sequences to be globular, in line with natural proteins. Representation of the protein space using similarity networks reveals that ProtGPT2 sequences explore ‘dark’ areas of the protein space by expanding natural superfamilies. The generated sequences show predicted stabilities and dynamic properties akin to their natural counterparts. Since ProtGPT2 has been already pre-trained, it can be used to generate sequences on standard workstations in a matter of seconds or be further finetuned on sequence sets of a user’s choice to augment specific protein families. The model and datasets are available in the HuggingFace repository 24 at ( ). Since protein design has an enormous potential to solve problems in fields ranging from biomedical to environmental sciences 25 , 26 , we believe that ProtGPT2 is a timely advance towards efficient high-throughput protein engineering and design. Results Learning the protein language The major advances in the NLP field can be partially attributed to the scale-up of unsupervised language models. Unlike supervised learning, which requires the labeling of each data point, self-supervised (or often named unsupervised) methods do not require annotated data, thus promoting the use of ever-growing datasets such as Wikipedia or the C4 Corpus 27 . Given both the growth of protein sequence databases and the lack of annotation for a significant part of the protein space, protein sequences have become great candidates for unsupervised training 4 , 10 , 11 and now offer the opportunity to encode and generate protein sequences. To achieve this goal, we trained a Transformer 7 to produce a model that generates protein sequences.", "role": "user" }, { "content": "Artificial intelligence (AI) has created new possibilities for designing tailor-made proteins to solve everything from medical to ecological problems. A research team at the University of Bayreuth led by Prof. Dr. Birte Höcker has now successfully applied a computer-based natural language processing model to protein research. Completely independently, the ProtGPT2 model designs new proteins that are capable of stable folding and could take over defined functions in larger molecular contexts. The model and its potential are detailed scientifically in Nature Communications. Natural languages and proteins are actually similar in structure. Amino acids arrange themselves in a multitude of combinations to form structures that have specific functions in the living organism—similar to the way words form sentences in different combinations that express certain facts. In recent years, numerous approaches have therefore been developed to use principles and processes that control the computer-assisted processing of natural language in protein research. \"Natural language processing has made extraordinary progress thanks to new AI technologies. Today, models of language processing enable machines not only to understand meaningful sentences but also to generate them themselves. Such a model was the starting point of our research. With detailed information concerning about 50 million sequences of natural proteins, my colleague Noelia Ferruz trained the model and enabled it to generate protein sequences on its own. It now understands the language of proteins and can use it creatively. We have found that these creative designs follow the basic principles of natural proteins,\" says Prof. Dr. Birte Höcker, Head of the Protein Design Group at the University of Bayreuth. The language processing model transferred to protein evolution is called ProtGPT2. It can now be used to design proteins that adopt stable structures through folding and are permanently functional in this state. In addition, the Bayreuth biochemists have found out, through complex investigations, that the model can even create proteins that do not occur in nature and have possibly never existed in the history of evolution. These findings shed light on the immeasurable world of possible proteins and open a door to designing them in novel and unexplored ways. There is a further advantage: Most proteins that have been designed de novo so far have idealized structures. Before such structures can have a potential application, they usually must pass through an elaborate functionalization process—for example by inserting extensions and cavities—so that they can interact with their environment and take on precisely defined functions in larger system contexts. ProtGPT2, on the other hand, generates proteins that have such differentiated structures innately, and are thus already operational in their respective environments. \"Our new model is another impressive demonstration of the systemic affinity of protein design and natural language processing. Artificial intelligence opens up highly interesting and promising possibilities to use methods of language processing for the production of customized proteins. At the University of Bayreuth, we hope to contribute in this way to developing innovative solutions for biomedical, pharmaceutical, and ecological problems,\" says Prof. Dr. Birte Höcker. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Protein design aims to build novel proteins customized for specific purposes, thereby holding the potential to tackle many environmental and biomedical problems. Recent progress in Transformer-based architectures has enabled the implementation of language models capable of generating text with human-like capabilities. Here, motivated by this success, we describe ProtGPT2, a language model trained on the protein space that generates de novo protein sequences following the principles of natural ones. The generated proteins display natural amino acid propensities, while disorder predictions indicate that 88% of ProtGPT2-generated proteins are globular, in line with natural sequences. Sensitive sequence searches in protein databases show that ProtGPT2 sequences are distantly related to natural ones, and similarity networks further demonstrate that ProtGPT2 is sampling unexplored regions of protein space. AlphaFold prediction of ProtGPT2-sequences yields well-folded non-idealized structures with embodiments and large loops and reveals topologies not captured in current structure databases. ProtGPT2 generates sequences in a matter of seconds and is freely available. Introduction Natural language processing (NLP) has seen extraordinary advances in recent years. Large pre-trained language models have drastically transformed the NLP field and with it, many of the tools we use in our daily lives, such as chatbots, smart assistants, or translation machines. Analogies between protein sequences and human languages have long been noted by us and others 1 , 2 . Protein sequences can be described as a concatenation of letters from a chemically defined alphabet, the natural amino acids, and like human languages, these letters arrange to form secondary structural elements (“words”), which assemble to form domains (“sentences”) that undertake a function (“meaning”). One of the most attractive similarities is that protein sequences, like natural languages, are information-complete: they store structure and function entirely in their amino acid order with extreme efficiency. With the extraordinary advances in the NLP field in understanding and generating language with near-human capabilities, we hypothesized that these methods open a new door to approach protein-related problems from sequence alone, such as protein design. Although protein sequences and human languages are not without dissimilarities, their analogies have stimulated applying NLP methods to solve protein research problems for decades 2 . Supervised NLP methods, where the input sequences are trained jointly with their labels to produce predictive models, have been applied to various tasks, such as detecting structural similarity or predicting stability 3 , 4 . A remarkable collection of supervised language models applied to biomolecules is available in the BioSeq-BLM platform 5 , 6 . Nevertheless, since the inception of the Transformer 7 , unsupervised learning, where the training occurs on unlabeled data, has emerged as a versatile tool for language modeling. Several Transformer-based models, such as TCR-BERT 8 , epiBERTope 9 , ESM 10 , ProtTrans 11 , or ProteinBERT 12 , have shown to be very competitive with other methods 13 , 14 . Most of these models use BERT-like 15 architectures and denoising autoencoding training objectives, i.e., they are pre-trained by corrupting the input tokens in some way and trying to reconstruct the original sentence 2 . Although these models could be adjusted for generation 16 , their most direct application is sequence embedding. Another important branch of language models benefits from autoregressive training, i.e., models are trained to predict subsequent words given a context. These models, the most well-known of which are possibly the GPT-x series 17 , excel at generating long, coherent text—sometimes to the extent that much debate has been raised about their potential misuse 18 . Protein autoregressive language models, such as ProGen 19 , 20 , 21 , RITA 22 , and DARK 23 have also been studied, and show the potential of autoregressive Transformers for protein design. Motivated by these works and the ever-increasing capabilities of English-speaking models such as the GPT-x series, we wondered whether we could train a generative model to (i) effectively learn the protein language, (ii) generate fit, stable proteins, and (iii) understand how these sequences relate to natural ones, including whether they sample unseen regions of the protein space. Here, we introduce ProtGPT2, an autoregressive Transformer model with 738 million parameters capable of generating de novo protein sequences in a high-throughput fashion. ProtGPT2 has effectively learned the protein language upon being trained on about 50 non-annotated million sequences spanning the entire protein space. ProtGPT2 generates protein sequences with amino acid and disorder propensities on par with natural ones while being “evolutionarily” distant from the current protein space. Secondary structure prediction calculates 88% of the sequences to be globular, in line with natural proteins. Representation of the protein space using similarity networks reveals that ProtGPT2 sequences explore ‘dark’ areas of the protein space by expanding natural superfamilies. The generated sequences show predicted stabilities and dynamic properties akin to their natural counterparts. Since ProtGPT2 has been already pre-trained, it can be used to generate sequences on standard workstations in a matter of seconds or be further finetuned on sequence sets of a user’s choice to augment specific protein families. The model and datasets are available in the HuggingFace repository 24 at ( ). Since protein design has an enormous potential to solve problems in fields ranging from biomedical to environmental sciences 25 , 26 , we believe that ProtGPT2 is a timely advance towards efficient high-throughput protein engineering and design. Results Learning the protein language The major advances in the NLP field can be partially attributed to the scale-up of unsupervised language models. Unlike supervised learning, which requires the labeling of each data point, self-supervised (or often named unsupervised) methods do not require annotated data, thus promoting the use of ever-growing datasets such as Wikipedia or the C4 Corpus 27 . Given both the growth of protein sequence databases and the lack of annotation for a significant part of the protein space, protein sequences have become great candidates for unsupervised training 4 , 10 , 11 and now offer the opportunity to encode and generate protein sequences. To achieve this goal, we trained a Transformer 7 to produce a model that generates protein sequences.<|im_end|> <|im_start|>assistant Artificial intelligence (AI) has created new possibilities for designing tailor-made proteins to solve everything from medical to ecological problems. A research team at the University of Bayreuth led by Prof. Dr. Birte Höcker has now successfully applied a computer-based natural language processing model to protein research. Completely independently, the ProtGPT2 model designs new proteins that are capable of stable folding and could take over defined functions in larger molecular contexts. The model and its potential are detailed scientifically in Nature Communications. Natural languages and proteins are actually similar in structure. Amino acids arrange themselves in a multitude of combinations to form structures that have specific functions in the living organism—similar to the way words form sentences in different combinations that express certain facts. In recent years, numerous approaches have therefore been developed to use principles and processes that control the computer-assisted processing of natural language in protein research. "Natural language processing has made extraordinary progress thanks to new AI technologies. Today, models of language processing enable machines not only to understand meaningful sentences but also to generate them themselves. Such a model was the starting point of our research. With detailed information concerning about 50 million sequences of natural proteins, my colleague Noelia Ferruz trained the model and enabled it to generate protein sequences on its own. It now understands the language of proteins and can use it creatively. We have found that these creative designs follow the basic principles of natural proteins," says Prof. Dr. Birte Höcker, Head of the Protein Design Group at the University of Bayreuth. The language processing model transferred to protein evolution is called ProtGPT2. It can now be used to design proteins that adopt stable structures through folding and are permanently functional in this state. In addition, the Bayreuth biochemists have found out, through complex investigations, that the model can even create proteins that do not occur in nature and have possibly never existed in the history of evolution. These findings shed light on the immeasurable world of possible proteins and open a door to designing them in novel and unexplored ways. There is a further advantage: Most proteins that have been designed de novo so far have idealized structures. Before such structures can have a potential application, they usually must pass through an elaborate functionalization process—for example by inserting extensions and cavities—so that they can interact with their environment and take on precisely defined functions in larger system contexts. ProtGPT2, on the other hand, generates proteins that have such differentiated structures innately, and are thus already operational in their respective environments. "Our new model is another impressive demonstration of the systemic affinity of protein design and natural language processing. Artificial intelligence opens up highly interesting and promising possibilities to use methods of language processing for the production of customized proteins. At the University of Bayreuth, we hope to contribute in this way to developing innovative solutions for biomedical, pharmaceutical, and ecological problems," says Prof. Dr. Birte Höcker. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Photoionisation time delays carry structural and dynamical information on the target system, including electronic correlation effects in atoms and molecules and electron transport properties at interfaces. In molecules, the electrostatic potential experienced by an outgoing electron depends on the emission direction, which should thus lead to anisotropic time delays. To isolate this effect, information on the orientation of the molecule at the photoionisation instant is required. Here we show how attosecond time delays reflect the anisotropic molecular potential landscape in CF 4 molecules. The variations in the measured delays can be directly related to the different heights of the potential barriers that the outgoing electrons see in the vicinity of shape resonances. Our results indicate the possibility to investigate the spatial characteristics of the molecular potential by mapping attosecond photoionisation time delays in the recoil-frame. Introduction Molecular systems are characterised by complex potential landscapes determined by their chemical composition and by the spatial arrangement of their constituents. In general, the electronic potential presents a non-spherical shape, which plays a key role in the stereo-dynamics of atom-molecule collisions 1 and molecule–molecule interactions 2 . As explained in textbooks, the effect and the spatial gradient of a potential can be unveiled by monitoring the motion of a probe charge immersed in that potential 3 . In atoms and molecules, this charge can be one of the electrons contained in the system, which must absorb enough energy from an external source to overcome the ionisation potential and to acquire the necessary kinetic energy to explore the potential landscape, while staying long enough in the molecular surroundings to sample its relevant features. This is ideally possible by using ultraviolet radiation, i.e. photon energies of a few tens eV. In a classical picture, an electron with 10 eV energy takes about 53 as to travel through the typical molecular extension of 1 Å. The extremely short timescale of this motion calls for the application of attosecond pulses, which can efficiently generate photoelectron wave packets and provide the necessary time resolution 4 , 5 , 6 , 7 . The dynamics of photoionising wave packets is usually investigated by means of pump-probe experiments, in which an isolated or a train of attosecond pulses in the extreme ultraviolet (XUV) range set the photoelectron wave packet free and a synchronised infra-red (IR) pulse probes the instant at which the electron enters the continuum 8 . Using this approach, the role of electronic correlation effects in the photoionisation of atoms has been investigated in real-time 9 , 10 , 11 . Attosecond time delays have also been reported in photoionisation in molecular systems, showing the relevance of nuclear motion in hydrogen 12 and the role played by shape resonances in N 2 O 13 and nitrogen 14 , 15 . Moreover, the role of the localisation of the initial wave function 16 and of a functional molecular group 17 has also been demonstrated. In atomic systems, the photoionisation time delays are usually decomposed into a term specific of the atomic potential (usually indicated as Eisenbud–Wigner–Smith delay 18 ) and a measurement-induced contribution due to the action of the IR probe pulse on the photoelectron wave packet moving in the long-range Coulomb potential 19 , 20 . While in atoms the influence of the latter term can be usually quantified through simple formulas independent of the specific target 20 and its angular dependence has been characterised 21 , in molecules the effect of the IR field on the measured time delays has not been characterised yet. In general, in the case of molecular systems, the contributions of the two terms cannot be disentangled 22 , which requires a more involved analysis. A fundamental prerequisite for the characterisation of the combined effect of the anisotropic molecular landscape and of the IR field is to have access to the orientation of the molecule at the photoionisation instant. This can be done by measuring the emission direction(s) of ionic fragment(s) after the interaction with the XUV radiation, which defines the recoil frame. Symmetric molecules consisting of only a few atoms are ideal to test these effects in this frame. On the one hand, small molecules present a limited number of photoionisation and photofragmentation pathways, making feasible the identification of the electronic level of the outgoing photoelectron and, under suitable conditions, the determination of the molecular orientation during the interaction with the ionising radiation. On the other hand, the symmetry of the molecule gives the opportunity to identify specific privileged directions in the recoil frame and to characterise the effect of the molecular potential along them. In this work we investigate the photoionisation dynamics induced by a train of attosecond XUV pulses on CF 4 molecules by means of photoelectron-photoion coincidence spectroscopy 23 . The advantage of this approach is the possibility to derive information on the molecular orientation at the instant of photoionisation by measuring in coincidence the momenta of the emitted electron and the fragment ions resulting from the ulterior dissociation of the molecular cation 24 . In this way, we have been able to unambiguously identify individual ionisation channels and obtain time-resolved recoil-frame photoelectron angular distributions (RFPADs) from which the variations of photoionisation delays with the electron emission direction have been extracted. The measured delays are in very good agreement with those obtained from calculated time-resolved RFPADs where all the transitions induced by the attosecond pulse train and the IR probe, in particular those induced in the continuum by the IR pulse, are taken into account in a time-dependent formalism. The agreement confirms the validity of our experimental approach and opens the route to orientation-specific exploration and understanding of molecular photoionisation delays. Results Recoil frame and XUV spectroscopy of CF 4 We focus on photoelectrons emitted from the Highest-Occupied Molecular Orbital of CF 4 , which is triply degenerate and belongs to the irreducible representation T 1 of the point group T d (see Fig. 1 a). The xyz system represents the molecular frame, where one fluorine atom (1) is", "role": "user" }, { "content": "How can researchers use the mechanism of photoionization to gain insight into complex molecular potential? This question has now been answered by a team led by Prof. Dr. Giuseppe Sansone from the Institute of Physics at the University of Freiburg. The researchers from Freiburg, the Max Planck Institute for Nuclear Physics in Heidelberg and groups at the Universidad Autonoma in Madrid/Spain and the University of Trieste/Italy have published their results in the journal Nature Communications. In the origin of photoionization, also called the photoelectric effect, an atom or molecule absorbs one quantum of light, usually indicated as photon, from an external field. The energy absorbed in this process is transferred to an electron, which is freed, leaving behind a singly charged ion. In several aspects and for several applications, the effect can be regarded as instantaneous, meaning that there is no significant time delay between the absorption of the photon and the instant when the electron is emitted. However, several experiments conducted in the last years have evidenced that tiny, but measurable delays lying in the attosecond range (1 as = 10-18 s) occur between these two processes. Generation of attosecond pulses \"Thanks to the advanced laser sources and specially designed spectrometers available in our laboratory, we can generate the shortest bursts of light, lasting only few hundreds of attoseconds,\" Sansone explains. \"Moreover, we can reconstruct the orientation of simple molecules when they absorb a photon from an external laser pulse. We have used such pulses to investigate the motion of the electrons after the absorption of a photon.\" Electrons experience paths with potential peaks and valleys The researchers found that on its way out from the molecule, the electron experiences a complex landscape characterized by potential peaks and valleys. These are determined by the spatial distribution of the atoms composing the system. The path followed by the electron during its motion can affect the time it takes to be freed. Extension to more complex molecular systems possible In the experiment, the team measured the time delays accumulated by the electrons emitted from CF4 molecules in different spatial directions were measured using an attosecond pulse train combined with an ultrashort infrared field. \"Combining this information with the characterization of the spatial orientation of the molecule, we can understand how the potential landscape and, in particular, potential peaks affect the time delay,\" says the Freiburg physicist. The work can be extended to more complex molecular systems and to potentials changing on ultrashort timescales. In general, Sansone emphasizes, this approach could give the possibility to map complex potential landscapes from within, with unprecedented temporal resolution. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Photoionisation time delays carry structural and dynamical information on the target system, including electronic correlation effects in atoms and molecules and electron transport properties at interfaces. In molecules, the electrostatic potential experienced by an outgoing electron depends on the emission direction, which should thus lead to anisotropic time delays. To isolate this effect, information on the orientation of the molecule at the photoionisation instant is required. Here we show how attosecond time delays reflect the anisotropic molecular potential landscape in CF 4 molecules. The variations in the measured delays can be directly related to the different heights of the potential barriers that the outgoing electrons see in the vicinity of shape resonances. Our results indicate the possibility to investigate the spatial characteristics of the molecular potential by mapping attosecond photoionisation time delays in the recoil-frame. Introduction Molecular systems are characterised by complex potential landscapes determined by their chemical composition and by the spatial arrangement of their constituents. In general, the electronic potential presents a non-spherical shape, which plays a key role in the stereo-dynamics of atom-molecule collisions 1 and molecule–molecule interactions 2 . As explained in textbooks, the effect and the spatial gradient of a potential can be unveiled by monitoring the motion of a probe charge immersed in that potential 3 . In atoms and molecules, this charge can be one of the electrons contained in the system, which must absorb enough energy from an external source to overcome the ionisation potential and to acquire the necessary kinetic energy to explore the potential landscape, while staying long enough in the molecular surroundings to sample its relevant features. This is ideally possible by using ultraviolet radiation, i.e. photon energies of a few tens eV. In a classical picture, an electron with 10 eV energy takes about 53 as to travel through the typical molecular extension of 1 Å. The extremely short timescale of this motion calls for the application of attosecond pulses, which can efficiently generate photoelectron wave packets and provide the necessary time resolution 4 , 5 , 6 , 7 . The dynamics of photoionising wave packets is usually investigated by means of pump-probe experiments, in which an isolated or a train of attosecond pulses in the extreme ultraviolet (XUV) range set the photoelectron wave packet free and a synchronised infra-red (IR) pulse probes the instant at which the electron enters the continuum 8 . Using this approach, the role of electronic correlation effects in the photoionisation of atoms has been investigated in real-time 9 , 10 , 11 . Attosecond time delays have also been reported in photoionisation in molecular systems, showing the relevance of nuclear motion in hydrogen 12 and the role played by shape resonances in N 2 O 13 and nitrogen 14 , 15 . Moreover, the role of the localisation of the initial wave function 16 and of a functional molecular group 17 has also been demonstrated. In atomic systems, the photoionisation time delays are usually decomposed into a term specific of the atomic potential (usually indicated as Eisenbud–Wigner–Smith delay 18 ) and a measurement-induced contribution due to the action of the IR probe pulse on the photoelectron wave packet moving in the long-range Coulomb potential 19 , 20 . While in atoms the influence of the latter term can be usually quantified through simple formulas independent of the specific target 20 and its angular dependence has been characterised 21 , in molecules the effect of the IR field on the measured time delays has not been characterised yet. In general, in the case of molecular systems, the contributions of the two terms cannot be disentangled 22 , which requires a more involved analysis. A fundamental prerequisite for the characterisation of the combined effect of the anisotropic molecular landscape and of the IR field is to have access to the orientation of the molecule at the photoionisation instant. This can be done by measuring the emission direction(s) of ionic fragment(s) after the interaction with the XUV radiation, which defines the recoil frame. Symmetric molecules consisting of only a few atoms are ideal to test these effects in this frame. On the one hand, small molecules present a limited number of photoionisation and photofragmentation pathways, making feasible the identification of the electronic level of the outgoing photoelectron and, under suitable conditions, the determination of the molecular orientation during the interaction with the ionising radiation. On the other hand, the symmetry of the molecule gives the opportunity to identify specific privileged directions in the recoil frame and to characterise the effect of the molecular potential along them. In this work we investigate the photoionisation dynamics induced by a train of attosecond XUV pulses on CF 4 molecules by means of photoelectron-photoion coincidence spectroscopy 23 . The advantage of this approach is the possibility to derive information on the molecular orientation at the instant of photoionisation by measuring in coincidence the momenta of the emitted electron and the fragment ions resulting from the ulterior dissociation of the molecular cation 24 . In this way, we have been able to unambiguously identify individual ionisation channels and obtain time-resolved recoil-frame photoelectron angular distributions (RFPADs) from which the variations of photoionisation delays with the electron emission direction have been extracted. The measured delays are in very good agreement with those obtained from calculated time-resolved RFPADs where all the transitions induced by the attosecond pulse train and the IR probe, in particular those induced in the continuum by the IR pulse, are taken into account in a time-dependent formalism. The agreement confirms the validity of our experimental approach and opens the route to orientation-specific exploration and understanding of molecular photoionisation delays. Results Recoil frame and XUV spectroscopy of CF 4 We focus on photoelectrons emitted from the Highest-Occupied Molecular Orbital of CF 4 , which is triply degenerate and belongs to the irreducible representation T 1 of the point group T d (see Fig. 1 a). The xyz system represents the molecular frame, where one fluorine atom (1) is<|im_end|> <|im_start|>assistant How can researchers use the mechanism of photoionization to gain insight into complex molecular potential? This question has now been answered by a team led by Prof. Dr. Giuseppe Sansone from the Institute of Physics at the University of Freiburg. The researchers from Freiburg, the Max Planck Institute for Nuclear Physics in Heidelberg and groups at the Universidad Autonoma in Madrid/Spain and the University of Trieste/Italy have published their results in the journal Nature Communications. In the origin of photoionization, also called the photoelectric effect, an atom or molecule absorbs one quantum of light, usually indicated as photon, from an external field. The energy absorbed in this process is transferred to an electron, which is freed, leaving behind a singly charged ion. In several aspects and for several applications, the effect can be regarded as instantaneous, meaning that there is no significant time delay between the absorption of the photon and the instant when the electron is emitted. However, several experiments conducted in the last years have evidenced that tiny, but measurable delays lying in the attosecond range (1 as = 10-18 s) occur between these two processes. Generation of attosecond pulses "Thanks to the advanced laser sources and specially designed spectrometers available in our laboratory, we can generate the shortest bursts of light, lasting only few hundreds of attoseconds," Sansone explains. "Moreover, we can reconstruct the orientation of simple molecules when they absorb a photon from an external laser pulse. We have used such pulses to investigate the motion of the electrons after the absorption of a photon." Electrons experience paths with potential peaks and valleys The researchers found that on its way out from the molecule, the electron experiences a complex landscape characterized by potential peaks and valleys. These are determined by the spatial distribution of the atoms composing the system. The path followed by the electron during its motion can affect the time it takes to be freed. Extension to more complex molecular systems possible In the experiment, the team measured the time delays accumulated by the electrons emitted from CF4 molecules in different spatial directions were measured using an attosecond pulse train combined with an ultrashort infrared field. "Combining this information with the characterization of the spatial orientation of the molecule, we can understand how the potential landscape and, in particular, potential peaks affect the time delay," says the Freiburg physicist. The work can be extended to more complex molecular systems and to potentials changing on ultrashort timescales. In general, Sansone emphasizes, this approach could give the possibility to map complex potential landscapes from within, with unprecedented temporal resolution. <|im_end|>

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1,813

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Non-alcoholic fatty liver disease (NAFLD) is a common condition that progresses in some patients to steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). Here we used healthcare records of 18 million adults to estimate risk of acquiring advanced liver disease diagnoses in patients with NAFLD or NASH compared to individually matched controls. Methods Data were extracted from four European primary care databases representing the UK, Netherlands, Italy and Spain. Patients with a recorded diagnosis of NAFLD or NASH (NAFLD/NASH) were followed up for incident cirrhosis and HCC diagnoses. Each coded NAFLD/NASH patient was matched to up to 100 “non-NAFLD” patients by practice site, gender, age ± 5 years and visit recorded within ± 6 months. Hazard ratios (HR) were estimated using Cox models adjusted for age and smoking status and pooled across databases by random effects meta-analyses. Results Out of 18,782,281 adults, we identified 136,703 patients with coded NAFLD/NASH. Coded NAFLD/NASH patients were more likely to have diabetes, hypertension and obesity than matched controls. HR for cirrhosis in patients compared to controls was 4.73 (95% CI 2.43–9.19) and for HCC, 3.51 (95% CI 1.72–7.16). HR for either outcome was higher in patients with NASH and those with high-risk Fib-4 scores. The strongest independent predictor of a diagnosis of HCC or cirrhosis was baseline diagnosis of diabetes. Conclusions Real-world population data show that recorded diagnosis of NAFLD/NASH increases risk of life-threatening liver outcomes. Diabetes is an independent predictor of advanced liver disease diagnosis, emphasising the need to identify specific groups of patients at highest risk. Peer Review reports Background Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide. NAFLD represents a spectrum of disease that includes simple steatosis, non-alcoholic steatohepatitis (NASH) and fibrosis [ 1 ]. The numbers of individuals presenting with end-stage complications of NASH, namely decompensated cirrhosis and hepatocellular carcinoma (HCC), are rising [ 2 , 3 ], and NASH is rapidly becoming the most common indication for liver transplantation [ 4 ]. Yet not all patients within the NAFLD spectrum progress, and for the majority, NAFLD is a benign condition [ 1 ]. A key clinical challenge is to identify the proportion of patients who are at high risk of developing advanced liver disease, so that interventions, including the many novel therapies in development, can be targeted to those at greatest need. Our current understanding of NAFLD epidemiology and progression largely derives from single-centre studies of small- or medium-sized cohorts and meta-analyses of these [ 5 , 6 , 7 ]. These studies, together with emerging data from placebo arms of therapeutic trials [ 8 ], have taught us that patients with existing evidence of progressive disease (e.g., fibrosis) are at risk of further progression to HCC and decompensated cirrhosis, albeit this may reflect a degree of lead-time bias. Such studies often involve formal assessment of well-phenotyped patients at inclusion but are, by design, selective and may not represent the ‘real-world’ situation for the majority of patients with NAFLD. Paired biopsy data have been reported, although the second biopsy is often performed because of clinical suspicion and not per study protocol, which may bias estimates of progression [ 9 ]. Real-world patients are socially and ethnically diverse, have comorbidities and concomitant medications or simply cannot commit to long-term studies or trials and therefore may not be represented by any of these study designs. Increasingly, real-world data derived from primary care electronic health records (EHR) of a sizeable proportion of the general population [ 10 , 11 ] are being used to address these issues. In many European countries, where healthcare is largely state-funded and there are low or absent primary care co-payments, the population has unrestricted access to healthcare via primary care physicians who act as gatekeepers for referral to secondary care [ 12 ]. People register with primary care centres at birth or when they move to an area in order to access healthcare; therefore, primary care EHR represent data that are as close to the ‘general’ population as possible. If a practice joins the database, all the patients at that practice are registered in the database and, although there is an option for individual patients to opt out, this is minimal (< 1%). In order to gain insights into the NAFLD spectrum of diseases in real-world patients, we extracted data from four large European primary care databases and identified a cohort of patients with a diagnosis of NAFLD or of NASH. Our aim in this study was to estimate the risk for patients with diagnoses of NAFLD or NASH to acquire a new diagnosis of cirrhosis and HCC and to understand the main predictors for this. Methods Databases Databases were accessed via the European Medical Information Framework (EMIF) network: The Health Search Database (HSD) in Italy [ 13 ], The Integrated Primary Care Information (IPCI) in the Netherlands [ 14 ], the Information System for the Development of Research in Primary Care (SIDIAP) in Spain [ 15 ] and The Health Information Network (THIN) in the UK [ 16 ] (Additional file 1 : Table S1). HSD collects electronic medical record data from a network of over 800 Italian GPs who are members of the Italian College of General Practitioners. IPCI is a longitudinal collection of electronic patient records from over 750 Dutch general practitioners, containing data from over 2 million patients. SIDIAP collects data from 274 primary care practices comprising 3414 basic care units [ 17 ], and THIN contains the electronic medical records of 11.1 million patients from 562 general practices in the UK, covering 6.2% of the UK population [ 18 ]. The data custodians for each database provided approval that the protocol of the study complied with local privacy laws. Anonymised data were extracted locally by each data custodian liaising with the EMIF Platform and using a data transformation tool called Jerboa Reloaded [ 10 ]. The data were then uploaded onto a secure remote server maintained by an independent academic centre (Erasmus Medical Centre Private", "role": "user" }, { "content": "Many patients with potentially deadly liver cirrhosis and liver cancer are being diagnosed at late advanced stages of disease, according to a study led by Queen Mary University of London and the University of Glasgow. The study of 18 million people across Europe also suggests the people living with type 2 diabetes are at particular risk of this 'silent disease' and should be monitored closely to prevent life-threatening disease progression. Non-alcoholic fatty liver disease (NAFLD) affects up to a quarter of people in the West and is the most common cause of liver disease around the world. It is closely associated with obesity and type 2 diabetes and its rise mirrors the social problems of poor diets and sedentary lifestyles. GPs are often unaware of the condition and patients often go undiagnosed. For the majority, NAFLD is a benign condition, but one in six people will go on to develop the aggressive form of disease, called non-alcoholic steatohepatitis (NASH), leading to liver injury, scarring and eventually in some to cirrhosis, liver failure and even liver cancer. By identifying which patients might go on to develop the more aggressive disease, interventions and treatments could be targeted to those at greatest need. In the largest study of its kind, published in the journal BMC Medicine, the team combined the healthcare records of 18 million European adults from the UK, Netherlands, Italy and Spain. They matched each NAFLD patient to 100 patients who did not have a recorded diagnosis, and looked to see who developed liver cirrhosis and liver cancer over time. Lead researcher Dr. William Alazawi from Queen Mary University of London said: \"We were surprised that the number of patients with recorded diagnoses of non-alcoholic fatty liver was much less than expected, meaning that many patients are actually undiagnosed in primary care. Even over the short time frame of the study, some patients progressed to more advanced, life threatening stages of disease, suggesting that they are being diagnosed very late. \"The public, doctors and policy makers need to be aware of this silent disease and strategies need to be put in place to tackle the root causes and avoid progression to life-threatening stages. \"People living with diabetes are at increased risk of more advanced, life threatening stages of disease, suggesting that we should be focusing our efforts in educating and preventing liver disease in diabetes patients.\" Naveed Sattar from the University of Glasgow added: \"Doctors treating patients with diabetes already have a lot to check on—eyes, kidneys, heart risks—but these results remind us that we should not neglect the liver, nor forget to consider the possibility of NASH. They also remind us that perhaps more efforts are needed to help our patients with diabetes lose weight and cut alcohol.\" More than 136,000 patients were identified with NAFLD/NASH and were more likely to have type 2 diabetes, hypertension and obesity than matched controls. The strongest association was observed in NAFLD/NASH patients who had a diagnosis of type 2 diabetes—they were more than twice as likely to develop aggressive liver disease. This suggests that diabetes could be a good predictor of liver disease progression. Looking at particular types of advanced liver disease, NAFLD/NASH patients were almost five times more likely to be diagnosed with cirrhosis and more than three and a half times more likely to be diagnosed with liver cancer. The study also found that NAFLD/NASH patients acquired diagnoses of life-threatening liver disease within a relatively short time (around 3.3 years). The researchers say that it is not feasible that this reflects true rates of disease progression. The acquisition of a new diagnosis in the healthcare record does not necessarily mean that disease progression has occurred at that time, nor that the advanced disease did not exist at the time of the initial diagnosis. This suggests that patients in Europe are being diagnosed at the later stages of disease, which are associated with greater risk of liver-related mortality. The results also suggests that primary care records under-estimate disease severity and that some patients with NAFLD diagnoses actually have advanced cirrhosis already. The research was funded by the European Union's Innovative Medicines Initiative and Dr. William Alazawi was funded by the Medical Research Council. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background Non-alcoholic fatty liver disease (NAFLD) is a common condition that progresses in some patients to steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). Here we used healthcare records of 18 million adults to estimate risk of acquiring advanced liver disease diagnoses in patients with NAFLD or NASH compared to individually matched controls. Methods Data were extracted from four European primary care databases representing the UK, Netherlands, Italy and Spain. Patients with a recorded diagnosis of NAFLD or NASH (NAFLD/NASH) were followed up for incident cirrhosis and HCC diagnoses. Each coded NAFLD/NASH patient was matched to up to 100 “non-NAFLD” patients by practice site, gender, age ± 5 years and visit recorded within ± 6 months. Hazard ratios (HR) were estimated using Cox models adjusted for age and smoking status and pooled across databases by random effects meta-analyses. Results Out of 18,782,281 adults, we identified 136,703 patients with coded NAFLD/NASH. Coded NAFLD/NASH patients were more likely to have diabetes, hypertension and obesity than matched controls. HR for cirrhosis in patients compared to controls was 4.73 (95% CI 2.43–9.19) and for HCC, 3.51 (95% CI 1.72–7.16). HR for either outcome was higher in patients with NASH and those with high-risk Fib-4 scores. The strongest independent predictor of a diagnosis of HCC or cirrhosis was baseline diagnosis of diabetes. Conclusions Real-world population data show that recorded diagnosis of NAFLD/NASH increases risk of life-threatening liver outcomes. Diabetes is an independent predictor of advanced liver disease diagnosis, emphasising the need to identify specific groups of patients at highest risk. Peer Review reports Background Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide. NAFLD represents a spectrum of disease that includes simple steatosis, non-alcoholic steatohepatitis (NASH) and fibrosis [ 1 ]. The numbers of individuals presenting with end-stage complications of NASH, namely decompensated cirrhosis and hepatocellular carcinoma (HCC), are rising [ 2 , 3 ], and NASH is rapidly becoming the most common indication for liver transplantation [ 4 ]. Yet not all patients within the NAFLD spectrum progress, and for the majority, NAFLD is a benign condition [ 1 ]. A key clinical challenge is to identify the proportion of patients who are at high risk of developing advanced liver disease, so that interventions, including the many novel therapies in development, can be targeted to those at greatest need. Our current understanding of NAFLD epidemiology and progression largely derives from single-centre studies of small- or medium-sized cohorts and meta-analyses of these [ 5 , 6 , 7 ]. These studies, together with emerging data from placebo arms of therapeutic trials [ 8 ], have taught us that patients with existing evidence of progressive disease (e.g., fibrosis) are at risk of further progression to HCC and decompensated cirrhosis, albeit this may reflect a degree of lead-time bias. Such studies often involve formal assessment of well-phenotyped patients at inclusion but are, by design, selective and may not represent the ‘real-world’ situation for the majority of patients with NAFLD. Paired biopsy data have been reported, although the second biopsy is often performed because of clinical suspicion and not per study protocol, which may bias estimates of progression [ 9 ]. Real-world patients are socially and ethnically diverse, have comorbidities and concomitant medications or simply cannot commit to long-term studies or trials and therefore may not be represented by any of these study designs. Increasingly, real-world data derived from primary care electronic health records (EHR) of a sizeable proportion of the general population [ 10 , 11 ] are being used to address these issues. In many European countries, where healthcare is largely state-funded and there are low or absent primary care co-payments, the population has unrestricted access to healthcare via primary care physicians who act as gatekeepers for referral to secondary care [ 12 ]. People register with primary care centres at birth or when they move to an area in order to access healthcare; therefore, primary care EHR represent data that are as close to the ‘general’ population as possible. If a practice joins the database, all the patients at that practice are registered in the database and, although there is an option for individual patients to opt out, this is minimal (< 1%). In order to gain insights into the NAFLD spectrum of diseases in real-world patients, we extracted data from four large European primary care databases and identified a cohort of patients with a diagnosis of NAFLD or of NASH. Our aim in this study was to estimate the risk for patients with diagnoses of NAFLD or NASH to acquire a new diagnosis of cirrhosis and HCC and to understand the main predictors for this. Methods Databases Databases were accessed via the European Medical Information Framework (EMIF) network: The Health Search Database (HSD) in Italy [ 13 ], The Integrated Primary Care Information (IPCI) in the Netherlands [ 14 ], the Information System for the Development of Research in Primary Care (SIDIAP) in Spain [ 15 ] and The Health Information Network (THIN) in the UK [ 16 ] (Additional file 1 : Table S1). HSD collects electronic medical record data from a network of over 800 Italian GPs who are members of the Italian College of General Practitioners. IPCI is a longitudinal collection of electronic patient records from over 750 Dutch general practitioners, containing data from over 2 million patients. SIDIAP collects data from 274 primary care practices comprising 3414 basic care units [ 17 ], and THIN contains the electronic medical records of 11.1 million patients from 562 general practices in the UK, covering 6.2% of the UK population [ 18 ]. The data custodians for each database provided approval that the protocol of the study complied with local privacy laws. Anonymised data were extracted locally by each data custodian liaising with the EMIF Platform and using a data transformation tool called Jerboa Reloaded [ 10 ]. The data were then uploaded onto a secure remote server maintained by an independent academic centre (Erasmus Medical Centre Private<|im_end|> <|im_start|>assistant Many patients with potentially deadly liver cirrhosis and liver cancer are being diagnosed at late advanced stages of disease, according to a study led by Queen Mary University of London and the University of Glasgow. The study of 18 million people across Europe also suggests the people living with type 2 diabetes are at particular risk of this 'silent disease' and should be monitored closely to prevent life-threatening disease progression. Non-alcoholic fatty liver disease (NAFLD) affects up to a quarter of people in the West and is the most common cause of liver disease around the world. It is closely associated with obesity and type 2 diabetes and its rise mirrors the social problems of poor diets and sedentary lifestyles. GPs are often unaware of the condition and patients often go undiagnosed. For the majority, NAFLD is a benign condition, but one in six people will go on to develop the aggressive form of disease, called non-alcoholic steatohepatitis (NASH), leading to liver injury, scarring and eventually in some to cirrhosis, liver failure and even liver cancer. By identifying which patients might go on to develop the more aggressive disease, interventions and treatments could be targeted to those at greatest need. In the largest study of its kind, published in the journal BMC Medicine, the team combined the healthcare records of 18 million European adults from the UK, Netherlands, Italy and Spain. They matched each NAFLD patient to 100 patients who did not have a recorded diagnosis, and looked to see who developed liver cirrhosis and liver cancer over time. Lead researcher Dr. William Alazawi from Queen Mary University of London said: "We were surprised that the number of patients with recorded diagnoses of non-alcoholic fatty liver was much less than expected, meaning that many patients are actually undiagnosed in primary care. Even over the short time frame of the study, some patients progressed to more advanced, life threatening stages of disease, suggesting that they are being diagnosed very late. "The public, doctors and policy makers need to be aware of this silent disease and strategies need to be put in place to tackle the root causes and avoid progression to life-threatening stages. "People living with diabetes are at increased risk of more advanced, life threatening stages of disease, suggesting that we should be focusing our efforts in educating and preventing liver disease in diabetes patients." Naveed Sattar from the University of Glasgow added: "Doctors treating patients with diabetes already have a lot to check on—eyes, kidneys, heart risks—but these results remind us that we should not neglect the liver, nor forget to consider the possibility of NASH. They also remind us that perhaps more efforts are needed to help our patients with diabetes lose weight and cut alcohol." More than 136,000 patients were identified with NAFLD/NASH and were more likely to have type 2 diabetes, hypertension and obesity than matched controls. The strongest association was observed in NAFLD/NASH patients who had a diagnosis of type 2 diabetes—they were more than twice as likely to develop aggressive liver disease. This suggests that diabetes could be a good predictor of liver disease progression. Looking at particular types of advanced liver disease, NAFLD/NASH patients were almost five times more likely to be diagnosed with cirrhosis and more than three and a half times more likely to be diagnosed with liver cancer. The study also found that NAFLD/NASH patients acquired diagnoses of life-threatening liver disease within a relatively short time (around 3.3 years). The researchers say that it is not feasible that this reflects true rates of disease progression. The acquisition of a new diagnosis in the healthcare record does not necessarily mean that disease progression has occurred at that time, nor that the advanced disease did not exist at the time of the initial diagnosis. This suggests that patients in Europe are being diagnosed at the later stages of disease, which are associated with greater risk of liver-related mortality. The results also suggests that primary care records under-estimate disease severity and that some patients with NAFLD diagnoses actually have advanced cirrhosis already. The research was funded by the European Union's Innovative Medicines Initiative and Dr. William Alazawi was funded by the Medical Research Council. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Marrow adipose tissue (MAT) accumulates in diverse clinical conditions but remains poorly understood. Here we show region-specific variation in MAT adipocyte development, regulation, size, lipid composition, gene expression and genetic determinants. Early MAT formation in mice is conserved, whereas later development is strain dependent. Proximal, but not distal tibial, MAT is lost with 21-day cold exposure. Rat MAT adipocytes from distal sites have an increased proportion of monounsaturated fatty acids and expression of Scd1/Scd2 , Cebpa and Cebpb . Humans also have increased distal marrow fat unsaturation. We define proximal ‘regulated’ MAT (rMAT) as single adipocytes interspersed with active haematopoiesis, whereas distal ‘constitutive’ MAT (cMAT) has low haematopoiesis, contains larger adipocytes, develops earlier and remains preserved upon systemic challenges. Loss of rMAT occurs in mice with congenital generalized lipodystrophy type 4, whereas both rMAT and cMAT are preserved in mice with congenital generalized lipodystrophy type 3. Consideration of these MAT subpopulations may be important for future studies linking MAT to bone biology, haematopoiesis and whole-body metabolism. Introduction Marrow adipose tissue (MAT) is a functionally distinct adipose depot, located within the skeleton, with the potential to contribute to both local and systemic metabolism 1 , 2 . Further accumulation of MAT occurs in a diverse range of clinical conditions including osteoporosis, ageing, gonadal dysfunction, type 1 diabetes and anorexia 2 , 3 . MAT formation is also induced with therapeutic interventions including radiation, chemotherapy, glucocorticoids and thiazolidinediones 1 , 3 . Despite these clinical findings, the regulation and function of MAT remains largely unclear. In many cases, MAT accumulation has been correlated with low bone mineral density, decreased bone formation and bone loss (reviewed in ref. 2 ). However, the presence of a direct relationship between MAT and bone remains controversial. For example, despite a clear correlation, increased MAT is not necessary for bone loss at the proximal tibia in rodent models of type 1 diabetes or ovariectomy-induced osteopenia 4 , 5 , 6 . In addition, histomorphometric studies in rats demonstrate that sites of high MAT have decreased ovariectomy-induced trabecular bone loss, with trabecular width in rat tibial metaphyses being greater at sites of high MAT (distal tibia) than at sites of low MAT (proximal tibia) 7 , 8 , 9 . The hypothesis that MAT is necessary for skeletal equilibrium is also supported by phenotypes of patients with congenital generalized lipodystrophy (CGL). A high proportion of patients with CGL1 or CGL2 (who lack MAT) develop pathological osteosclerosis and skeletal cysts between ages 10 and 20 years—the time in humans when MAT generally undergoes robust formation in a developmentally defined pattern in the affected skeletal regions 2 . In contrast, those with CGL3 or CGL4 (who retain MAT) fail to develop this pathology. These apparent contradictions emphasize the complex, context-specific relationship between MAT and bone, and likely the relationship between MAT and peripheral metabolism 1 , 10 . Although it is generally assumed that all marrow adipocytes are equivalent, a study by Tavassoli 11 in 1976 suggested that characteristics of red marrow adipocytes may differ to those of adipocytes within yellow marrow. In humans, formation of adipocytes within the yellow marrow occurs at or slightly before birth, regardless of prematurity, and accelerates between 4 and 8 weeks of age 2 , 12 . Early MAT formation occurs in distal skeletal regions including the hands, feet, distal tibia and tail (in rodents). Histologically, once this early MAT matures, the densely packed adipocytes resemble peripheral white adipose tissue (WAT) and are relatively devoid of active haematopoiesis. For the purposes of discussion in this paper, we define these areas as constitutive MAT (cMAT). After the initial peak, MAT accumulation continues in areas of red, haematopoietic marrow throughout life 13 . We refer to this population as regulated MAT (rMAT) and define it histologically as single adipocytes interspersed with sites of active haematopoiesis. It is important to note that, especially in larger species, both histological patterns may exist side by side. In rats and mice, however, these regions appear to be more spatially distinct. We hypothesized that the later-forming rMAT adipocytes would have characteristics distinct from the cMAT adipocytes that arise early in development. Herein, we address this hypothesis using mouse models to examine MAT formation and regulation during development and with cold exposure; lipidomics and proton magnetic resonance (MR) spectroscopy ( 1 H-MRS) to measure MAT lipid composition in rats and humans; MAT isolated from rats to quantify molecular differences in gene expression; and CGL3 and CGL4 mouse models that reveal a genetic basis for development of distinct rMAT and cMAT subpopulations. In sum, this evidence distinguishes rMAT from cMAT—a fundamental finding that may help to explain previous inconsistencies in the literature and inform future research on the relationship between MAT, bone, haematopoiesis and whole-body metabolism. Results Strain-specific MAT development in mice The postnatal development of MAT remains poorly characterized on a spatiotemporal level. We used osmium tetroxide staining to visualize and quantify MAT in the whole tibia of male C57BL/6J (B6) and C3H/HeJ (C3H) mice at 1, 4, 12 and 56 weeks of age ( Fig. 1 ). At 1 and 4 weeks, the initial phase of MAT development was similar in both strains. In the distal tibia, MAT formation and maturation accelerated rapidly after birth until the marrow space filled with adipocytes at 4 weeks of age. The amount of MAT distal to the junction of the tibia and fibula was similar between B6 and C3H strains through 12 weeks and remained relatively stable until 56 weeks in C3H animals ( Fig. 1a,b ). A parallel pattern of development occurred in the caudal vertebrae of the tail, with mature MAT filling the marrow space by 4 weeks of age ( Fig. 1c ). At this time, MAT in the tail vertebrae matched the histological appearance of cMAT as defined above. Figure 1: Quantification of MAT development in C57BL/6J and C3H/HeJ mice from 1 to 56 weeks of age. ( a ) Osmium-stained tibiae were scanned by μCT and were reconstructed", "role": "user" }, { "content": "While most of us worry about the fat cells building up on the fleshy parts of our bodies, scientists have started to pay serious attention to another kind of fat cell deep inside our bones, in what's called the marrow. Today, they've published new important clues about this little-understood kind of fatty tissue - including the discovery that there are two different types. Their results pave the way for more research on how marrow fat influences the rest of the body, and its role in a range of diseases including osteoporosis. In a paper published in Nature Communications, the team from the University of Michigan and other institutions describes research in rodents, and a small group of women, that led them to conclude that there are two kinds of fat cells in what scientists call marrow adipose tissue, or MAT. The findings deepen understanding of MAT, which makes up about 70 percent of the marrow in the adult human skeleton. They also make it clear that researchers need to take different MAT types into account when studying its role in disease. Why MAT matters Scientists have come to realize MAT plays a key role in our body's metabolism. MAT levels rise in many different diseases, from anorexia to type 1 diabetes, and also go up as we age and as bones get brittle and break down in osteoporosis. \"Reducing marrow fat has been mentioned as a target for osteoporosis therapy, but before such approaches go further we need to get a more targeted understanding of MAT and the effects of potential intervention,\" says Erica Scheller, Ph.D., DDS, who is transitioning from a postdoctoral fellowship at the U-M Medical School to a faculty position at Washington University in St. Louis. Scheller worked with senior author and U-M physiology professor Ormond MacDougald, Ph.D., and others to determine that MAT actually exists in two forms: regulated and constitutive. Their detailed analysis shows that the two kinds of cells store different types of fat molecules, that their genetic profile differs in very specific ways, and that they develop at different times in the life cycle and interact in different ways with the blood cell formation process that also happens in the marrow. Though the researchers can't yet see whether what they saw in mice holds completely true for humans, their study includes data from five women that agreed to let the researchers study the fat composition of their leg bone marrow using special scanners. Just as in the mice, the further down the leg bone, the more unsaturated fat there was inside the marrow. This is the first evidence in humans that two types of MAT exist, and the team will continue to study the bones of human. \"We're definitely finding that MAT is more complex than anyone originally thought, and that we have a long way to go in understanding it,\" says MacDougald, who is the John A. Faulkner Collegiate Professor of Physiology in the Department of Molecular and Integrative Physiology, and a professor of Internal Medicine in the Metabolism, Endocrinology & Diabetes division. \"We have a lot of it, and we need to do more to understand why it's there and what it's doing, and how it changes in different diseases.\" From here to tomorrow MacDougald, Scheller and their colleagues will continue to study the two forms of MAT in further studies in mice, and in bones removed from patients having hip replacement surgery and limb amputations. Getting healthy bone samples is harder, but over time they hope to flesh out the full picture of how the two forms of MAT form and act. The techniques they developed in their lab, which enable scientists to detect the characteristics of MAT, should be useful to scientists around the world studying bone marrow. And, the findings they've made should make MAT composition a key marker for scientists that study blood cell formation, bone biology and metabolism. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Marrow adipose tissue (MAT) accumulates in diverse clinical conditions but remains poorly understood. Here we show region-specific variation in MAT adipocyte development, regulation, size, lipid composition, gene expression and genetic determinants. Early MAT formation in mice is conserved, whereas later development is strain dependent. Proximal, but not distal tibial, MAT is lost with 21-day cold exposure. Rat MAT adipocytes from distal sites have an increased proportion of monounsaturated fatty acids and expression of Scd1/Scd2 , Cebpa and Cebpb . Humans also have increased distal marrow fat unsaturation. We define proximal ‘regulated’ MAT (rMAT) as single adipocytes interspersed with active haematopoiesis, whereas distal ‘constitutive’ MAT (cMAT) has low haematopoiesis, contains larger adipocytes, develops earlier and remains preserved upon systemic challenges. Loss of rMAT occurs in mice with congenital generalized lipodystrophy type 4, whereas both rMAT and cMAT are preserved in mice with congenital generalized lipodystrophy type 3. Consideration of these MAT subpopulations may be important for future studies linking MAT to bone biology, haematopoiesis and whole-body metabolism. Introduction Marrow adipose tissue (MAT) is a functionally distinct adipose depot, located within the skeleton, with the potential to contribute to both local and systemic metabolism 1 , 2 . Further accumulation of MAT occurs in a diverse range of clinical conditions including osteoporosis, ageing, gonadal dysfunction, type 1 diabetes and anorexia 2 , 3 . MAT formation is also induced with therapeutic interventions including radiation, chemotherapy, glucocorticoids and thiazolidinediones 1 , 3 . Despite these clinical findings, the regulation and function of MAT remains largely unclear. In many cases, MAT accumulation has been correlated with low bone mineral density, decreased bone formation and bone loss (reviewed in ref. 2 ). However, the presence of a direct relationship between MAT and bone remains controversial. For example, despite a clear correlation, increased MAT is not necessary for bone loss at the proximal tibia in rodent models of type 1 diabetes or ovariectomy-induced osteopenia 4 , 5 , 6 . In addition, histomorphometric studies in rats demonstrate that sites of high MAT have decreased ovariectomy-induced trabecular bone loss, with trabecular width in rat tibial metaphyses being greater at sites of high MAT (distal tibia) than at sites of low MAT (proximal tibia) 7 , 8 , 9 . The hypothesis that MAT is necessary for skeletal equilibrium is also supported by phenotypes of patients with congenital generalized lipodystrophy (CGL). A high proportion of patients with CGL1 or CGL2 (who lack MAT) develop pathological osteosclerosis and skeletal cysts between ages 10 and 20 years—the time in humans when MAT generally undergoes robust formation in a developmentally defined pattern in the affected skeletal regions 2 . In contrast, those with CGL3 or CGL4 (who retain MAT) fail to develop this pathology. These apparent contradictions emphasize the complex, context-specific relationship between MAT and bone, and likely the relationship between MAT and peripheral metabolism 1 , 10 . Although it is generally assumed that all marrow adipocytes are equivalent, a study by Tavassoli 11 in 1976 suggested that characteristics of red marrow adipocytes may differ to those of adipocytes within yellow marrow. In humans, formation of adipocytes within the yellow marrow occurs at or slightly before birth, regardless of prematurity, and accelerates between 4 and 8 weeks of age 2 , 12 . Early MAT formation occurs in distal skeletal regions including the hands, feet, distal tibia and tail (in rodents). Histologically, once this early MAT matures, the densely packed adipocytes resemble peripheral white adipose tissue (WAT) and are relatively devoid of active haematopoiesis. For the purposes of discussion in this paper, we define these areas as constitutive MAT (cMAT). After the initial peak, MAT accumulation continues in areas of red, haematopoietic marrow throughout life 13 . We refer to this population as regulated MAT (rMAT) and define it histologically as single adipocytes interspersed with sites of active haematopoiesis. It is important to note that, especially in larger species, both histological patterns may exist side by side. In rats and mice, however, these regions appear to be more spatially distinct. We hypothesized that the later-forming rMAT adipocytes would have characteristics distinct from the cMAT adipocytes that arise early in development. Herein, we address this hypothesis using mouse models to examine MAT formation and regulation during development and with cold exposure; lipidomics and proton magnetic resonance (MR) spectroscopy ( 1 H-MRS) to measure MAT lipid composition in rats and humans; MAT isolated from rats to quantify molecular differences in gene expression; and CGL3 and CGL4 mouse models that reveal a genetic basis for development of distinct rMAT and cMAT subpopulations. In sum, this evidence distinguishes rMAT from cMAT—a fundamental finding that may help to explain previous inconsistencies in the literature and inform future research on the relationship between MAT, bone, haematopoiesis and whole-body metabolism. Results Strain-specific MAT development in mice The postnatal development of MAT remains poorly characterized on a spatiotemporal level. We used osmium tetroxide staining to visualize and quantify MAT in the whole tibia of male C57BL/6J (B6) and C3H/HeJ (C3H) mice at 1, 4, 12 and 56 weeks of age ( Fig. 1 ). At 1 and 4 weeks, the initial phase of MAT development was similar in both strains. In the distal tibia, MAT formation and maturation accelerated rapidly after birth until the marrow space filled with adipocytes at 4 weeks of age. The amount of MAT distal to the junction of the tibia and fibula was similar between B6 and C3H strains through 12 weeks and remained relatively stable until 56 weeks in C3H animals ( Fig. 1a,b ). A parallel pattern of development occurred in the caudal vertebrae of the tail, with mature MAT filling the marrow space by 4 weeks of age ( Fig. 1c ). At this time, MAT in the tail vertebrae matched the histological appearance of cMAT as defined above. Figure 1: Quantification of MAT development in C57BL/6J and C3H/HeJ mice from 1 to 56 weeks of age. ( a ) Osmium-stained tibiae were scanned by μCT and were reconstructed<|im_end|> <|im_start|>assistant While most of us worry about the fat cells building up on the fleshy parts of our bodies, scientists have started to pay serious attention to another kind of fat cell deep inside our bones, in what's called the marrow. Today, they've published new important clues about this little-understood kind of fatty tissue - including the discovery that there are two different types. Their results pave the way for more research on how marrow fat influences the rest of the body, and its role in a range of diseases including osteoporosis. In a paper published in Nature Communications, the team from the University of Michigan and other institutions describes research in rodents, and a small group of women, that led them to conclude that there are two kinds of fat cells in what scientists call marrow adipose tissue, or MAT. The findings deepen understanding of MAT, which makes up about 70 percent of the marrow in the adult human skeleton. They also make it clear that researchers need to take different MAT types into account when studying its role in disease. Why MAT matters Scientists have come to realize MAT plays a key role in our body's metabolism. MAT levels rise in many different diseases, from anorexia to type 1 diabetes, and also go up as we age and as bones get brittle and break down in osteoporosis. "Reducing marrow fat has been mentioned as a target for osteoporosis therapy, but before such approaches go further we need to get a more targeted understanding of MAT and the effects of potential intervention," says Erica Scheller, Ph.D., DDS, who is transitioning from a postdoctoral fellowship at the U-M Medical School to a faculty position at Washington University in St. Louis. Scheller worked with senior author and U-M physiology professor Ormond MacDougald, Ph.D., and others to determine that MAT actually exists in two forms: regulated and constitutive. Their detailed analysis shows that the two kinds of cells store different types of fat molecules, that their genetic profile differs in very specific ways, and that they develop at different times in the life cycle and interact in different ways with the blood cell formation process that also happens in the marrow. Though the researchers can't yet see whether what they saw in mice holds completely true for humans, their study includes data from five women that agreed to let the researchers study the fat composition of their leg bone marrow using special scanners. Just as in the mice, the further down the leg bone, the more unsaturated fat there was inside the marrow. This is the first evidence in humans that two types of MAT exist, and the team will continue to study the bones of human. "We're definitely finding that MAT is more complex than anyone originally thought, and that we have a long way to go in understanding it," says MacDougald, who is the John A. Faulkner Collegiate Professor of Physiology in the Department of Molecular and Integrative Physiology, and a professor of Internal Medicine in the Metabolism, Endocrinology & Diabetes division. "We have a lot of it, and we need to do more to understand why it's there and what it's doing, and how it changes in different diseases." From here to tomorrow MacDougald, Scheller and their colleagues will continue to study the two forms of MAT in further studies in mice, and in bones removed from patients having hip replacement surgery and limb amputations. Getting healthy bone samples is harder, but over time they hope to flesh out the full picture of how the two forms of MAT form and act. The techniques they developed in their lab, which enable scientists to detect the characteristics of MAT, should be useful to scientists around the world studying bone marrow. And, the findings they've made should make MAT composition a key marker for scientists that study blood cell formation, bone biology and metabolism. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The hippocampus is composed of distinct anatomical subregions that participate in multiple cognitive processes and are differentially affected in prevalent neurological and psychiatric conditions. Advances in high-field MRI allow for the non-invasive identification of hippocampal substructure. These approaches, however, demand time-consuming manual segmentation that relies heavily on anatomical expertise. Here, we share manual labels and associated high-resolution MRI data (MNI-HISUB25; submillimetric T1- and T2-weighted images, detailed sequence information, and stereotaxic probabilistic anatomical maps) based on 25 healthy subjects. Data were acquired on a widely available 3 Tesla MRI system using a 32 phased-array head coil. The protocol divided the hippocampal formation into three subregions: subicular complex, merged Cornu Ammonis 1, 2 and 3 (CA1-3) subfields, and CA4-dentate gyrus (CA4-DG). Segmentation was guided by consistent intensity and morphology characteristics of the densely myelinated molecular layer together with few geometry-based boundaries flexible to overall mesiotemporal anatomy, and achieved excellent intra-/inter-rater reliability (Dice index ≥90/87%). The dataset can inform neuroimaging assessments of the mesiotemporal lobe and help to develop segmentation algorithms relevant for basic and clinical neurosciences. Design Type(s) repeated measure design • digital curation Measurement Type(s) nuclear magnetic resonance assay Technology Type(s) MRI Scanner Factor Type(s) Sample Characteristic(s) Homo sapiens • hippocampal formation Machine-accessible metadata file describing the reported data (ISA-Tab format) Background & Summary The hippocampus has been a focus of neuroscience research for decades. Highly segregated connectional properties have promoted its use as a model system. The hippocampus plays an important role in multiple cognitive processes, particularly declarative memory 1 , 2 ; its structural compromise is a hallmark of prevalent neurological and psychiatric disorders, such as temporal lobe epilepsy 3 , Alzheimer’s disease 4 , 5 , depression 6 , and schizophrenia 7 . Prior to the advent of sophisticated histological staining techniques 8 , the hippocampal formation was described as a single entity despite its complex histo-morphology. Since the description by Ramon y Cajal 9 , several histological subdivisions have been proposed 10 – 12 . Similarly, neuroimaging studies have generally considered the hippocampus as a single structure, constrained by limited spatial resolution 13 . Developments in high-field MRI at 3 Tesla and beyond, together with the use of phased-array head coils, offer new opportunities to appraise its internal structure by unveiling strata rich in white matter, and improved identification of the hippocampal sulcus, which separates Cornu Ammonis (CA) and subiculum from the dentate gyrus (DG). Paralleling advances in hardware, a number of studies have provided MRI-based guidelines to manually segment hippocampal subfields 14 – 23 . While substantial progress has been made, challenges remain, particularly when attempting to separate individual CA subfields from one another, which compromises reliability within and across analysts. From a practical perspective, manual segmentations require anatomical expertise and are often prohibitively time-consuming. Here, we share a dataset containing manual segmentations of hippocampal subfields together with submillimetric multi-spectral images in 25 healthy individuals. To facilitate local implementation and independent verification, we share detailed MR sequence information as well; importantly, all data were acquired in a clinically-feasible scan time on a widely available 3 Tesla MRI system. Opting for high reliability, segmentations were based on a protocol that divided the hippocampal formation into consistently identifiable subregions, guided by intensity and morphology of the densely myelinated molecular layer, together with few geometry-based boundaries flexible to overall mesiotemporal anatomy. Specifically, we combined presubiculum, parasubiculum, and subiculum proper into a single label (subiculum), joined CA1, 2, and 3 (CA1-3), and merged CA4 with the DG (CA4-DG). While segmentation relied primarily on T1-weighted (T1w) data, T2-weighted (T2w) images offered additional guidance. We provide the full set of multispectral images in high-resolution native and stereotaxic (MNI152) space, the manual labels, together with a probabilistic atlas that can inform functional and structural imaging assessments of the hippocampal formation. Moreover, our datasets can be used to develop new protocols, validate existing ones and design automated algorithms relevant for basic as well as clinical neurosciences. Methods Participants We studied 25 healthy individuals (12 males; 21–53 years, mean±s.d. age=31.2±7.5 years; Table 1 ), recruited through advertisement. All participants had normal or corrected-to-normal vision; none of them suffered from neurological, psychiatric, or somatic diseases. The Ethics Committee of the Montreal Neurological Institute and Hospital approved the study and written informed consent was obtained from all participants in accordance with the standards of the Declaration of Helsinki. Participants gave their written informed consent prior to scanning and received a monetary compensation. Table 1 Samples, subjects and data outputs. Full size table Scan parameters MRI data were acquired on a 3 Tesla Siemens TimTrio scanner using a 32-channel head coil. We obtained two sets of T1w images: a 3D magnetization-prepared rapid-acquisition gradient echo (MPRAGE) with millimetric resolution (repetition time (TR)=2,300 ms; echo time (TE)=2.98 ms; inversion time (TI)=900 ms; flip angle=9°; matrix size=256×256; field-of-view (FOV)=256×256 mm 2 ; 176 sagittal slices with 1 mm slice thickness resulting in 1×1×1 mm 3 voxels; iPAT=2, acquisition time=5.30 min), and a submillimetric 3D MPRAGE (TR=3,000 ms; TE=4.32 ms; TI=1,500 ms; flip angle=7°; matrix size=336×384; FOV=201×229 mm 2 ; 240 axial slices with 0.6 mm slice thickness resulting in 0.6×0.6×0.6 mm 3 voxels; acquisition time=16.48 min; to increase the signal-to-noise ratio, two identical scans were acquired, motion corrected, and averaged into a single volume). T2w images were obtained using a 2D turbo spin-echo sequence (TR=10,810 ms; TE=81 ms; flip angle=119°; matrix size=512×512; FOV=203×203 mm 2 , 60 coronal slices angled perpendicular to the hippocampal long axis, slice thickness=2 mm, resulting in 0.4×0.4×2.0 mm 3 voxels; acquisition time=5.47 min). Pre-processing MRI data files were converted from DICOM to MINC (*.mnc) format using dcm2mnc with dicom header anonymization. Images underwent automated correction for intensity non-uniformity and intensity standardization 24 . Millimetric and submillimetric T1w MRI volumes were linearly registered to the high-resolution MNI-ICBM152 template 25 , 26 . T2w images were linearly registered to the millimetric T1w MRI in native space; the resulting transformation matrix was concatenated with the matrix that mapped the millimetric T1w image to the MNI space, thereby linearly", "role": "user" }, { "content": "A new detailed map of the hippocampal region of the brain, compiled by researchers at the Montreal Neurological Institute and Hospital-The Neuro at McGill University, is helping the scientific community accelerate research and develop better treatments for patients suffering from epilepsy and other neurological and psychiatric disorders. The team of researchers, led by Dr. Neda Bernasconi, a neuroscientist specializing in the neuroimaging of epilepsy and co-founder of the Neuroimaging of Epilepsy Laboratory (NOEL) at The Neuro, set out to build and share a detailed model of the substructures making up one of the key centres of the brain involved in epilepsy: the hippocampus. The goal of their project, published on November 10 in Scientific Data, is to improve the tools available to researchers and clinicians working in the field around the globe. Epilepsy is a neurological disorder characterized by a sudden, brief change in the brain, expressed as a seizure. According to Epilepsy Canada, approximately one percent of Canadians suffer from the condition and more than 30% of patients with epilepsy do not respond to anti-epileptic drugs. For these individuals, the surgical removal of the brain tissue causing seizures is the only known effective treatment for controlling the condition and improving quality of life. In order to compile this hippocampal atlas, researchers used MRI imagery from a sample of 25 healthy individuals. They then used their expertise in brain anatomy to label all the substructures composing the region, providing a model of an average, healthy hippocampus. The end result is analogous to a Google street view of this particular part of the brain. With this tool, researchers will be better able to assess the pathology of their patients by comparing their data to the atlas and will more clearly be able to locate the areas in need of surgical intervention. A tool for brain diseases experts of all levels \"Our primary purpose was epilepsy. We wanted to be able to detect and identify different substructures in the hippocampus to enable us to be a lot more precise in our diagnosis and to pinpoint the affected region to better target treatments\", said Dr. Bernasconi. \"With this new submillimetric dataset, made available through open science, we are not just sharing MRI images, we are also transferring anatomical knowledge and providing a statistical map that can be used by researchers and clinicians of different levels of expertise anywhere in the world.\" These tools hold promising therapeutic implications for epilepsy, but also for other neurological and psychiatric disorders such as Alzheimer's disease, schizophrenia and depression. Crucially, the atlas provides researchers with a non-invasive way to assess the impact of therapies targeting this region of the brain and to thus develop better treatments to improve the quality of life for their patients. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The hippocampus is composed of distinct anatomical subregions that participate in multiple cognitive processes and are differentially affected in prevalent neurological and psychiatric conditions. Advances in high-field MRI allow for the non-invasive identification of hippocampal substructure. These approaches, however, demand time-consuming manual segmentation that relies heavily on anatomical expertise. Here, we share manual labels and associated high-resolution MRI data (MNI-HISUB25; submillimetric T1- and T2-weighted images, detailed sequence information, and stereotaxic probabilistic anatomical maps) based on 25 healthy subjects. Data were acquired on a widely available 3 Tesla MRI system using a 32 phased-array head coil. The protocol divided the hippocampal formation into three subregions: subicular complex, merged Cornu Ammonis 1, 2 and 3 (CA1-3) subfields, and CA4-dentate gyrus (CA4-DG). Segmentation was guided by consistent intensity and morphology characteristics of the densely myelinated molecular layer together with few geometry-based boundaries flexible to overall mesiotemporal anatomy, and achieved excellent intra-/inter-rater reliability (Dice index ≥90/87%). The dataset can inform neuroimaging assessments of the mesiotemporal lobe and help to develop segmentation algorithms relevant for basic and clinical neurosciences. Design Type(s) repeated measure design • digital curation Measurement Type(s) nuclear magnetic resonance assay Technology Type(s) MRI Scanner Factor Type(s) Sample Characteristic(s) Homo sapiens • hippocampal formation Machine-accessible metadata file describing the reported data (ISA-Tab format) Background & Summary The hippocampus has been a focus of neuroscience research for decades. Highly segregated connectional properties have promoted its use as a model system. The hippocampus plays an important role in multiple cognitive processes, particularly declarative memory 1 , 2 ; its structural compromise is a hallmark of prevalent neurological and psychiatric disorders, such as temporal lobe epilepsy 3 , Alzheimer’s disease 4 , 5 , depression 6 , and schizophrenia 7 . Prior to the advent of sophisticated histological staining techniques 8 , the hippocampal formation was described as a single entity despite its complex histo-morphology. Since the description by Ramon y Cajal 9 , several histological subdivisions have been proposed 10 – 12 . Similarly, neuroimaging studies have generally considered the hippocampus as a single structure, constrained by limited spatial resolution 13 . Developments in high-field MRI at 3 Tesla and beyond, together with the use of phased-array head coils, offer new opportunities to appraise its internal structure by unveiling strata rich in white matter, and improved identification of the hippocampal sulcus, which separates Cornu Ammonis (CA) and subiculum from the dentate gyrus (DG). Paralleling advances in hardware, a number of studies have provided MRI-based guidelines to manually segment hippocampal subfields 14 – 23 . While substantial progress has been made, challenges remain, particularly when attempting to separate individual CA subfields from one another, which compromises reliability within and across analysts. From a practical perspective, manual segmentations require anatomical expertise and are often prohibitively time-consuming. Here, we share a dataset containing manual segmentations of hippocampal subfields together with submillimetric multi-spectral images in 25 healthy individuals. To facilitate local implementation and independent verification, we share detailed MR sequence information as well; importantly, all data were acquired in a clinically-feasible scan time on a widely available 3 Tesla MRI system. Opting for high reliability, segmentations were based on a protocol that divided the hippocampal formation into consistently identifiable subregions, guided by intensity and morphology of the densely myelinated molecular layer, together with few geometry-based boundaries flexible to overall mesiotemporal anatomy. Specifically, we combined presubiculum, parasubiculum, and subiculum proper into a single label (subiculum), joined CA1, 2, and 3 (CA1-3), and merged CA4 with the DG (CA4-DG). While segmentation relied primarily on T1-weighted (T1w) data, T2-weighted (T2w) images offered additional guidance. We provide the full set of multispectral images in high-resolution native and stereotaxic (MNI152) space, the manual labels, together with a probabilistic atlas that can inform functional and structural imaging assessments of the hippocampal formation. Moreover, our datasets can be used to develop new protocols, validate existing ones and design automated algorithms relevant for basic as well as clinical neurosciences. Methods Participants We studied 25 healthy individuals (12 males; 21–53 years, mean±s.d. age=31.2±7.5 years; Table 1 ), recruited through advertisement. All participants had normal or corrected-to-normal vision; none of them suffered from neurological, psychiatric, or somatic diseases. The Ethics Committee of the Montreal Neurological Institute and Hospital approved the study and written informed consent was obtained from all participants in accordance with the standards of the Declaration of Helsinki. Participants gave their written informed consent prior to scanning and received a monetary compensation. Table 1 Samples, subjects and data outputs. Full size table Scan parameters MRI data were acquired on a 3 Tesla Siemens TimTrio scanner using a 32-channel head coil. We obtained two sets of T1w images: a 3D magnetization-prepared rapid-acquisition gradient echo (MPRAGE) with millimetric resolution (repetition time (TR)=2,300 ms; echo time (TE)=2.98 ms; inversion time (TI)=900 ms; flip angle=9°; matrix size=256×256; field-of-view (FOV)=256×256 mm 2 ; 176 sagittal slices with 1 mm slice thickness resulting in 1×1×1 mm 3 voxels; iPAT=2, acquisition time=5.30 min), and a submillimetric 3D MPRAGE (TR=3,000 ms; TE=4.32 ms; TI=1,500 ms; flip angle=7°; matrix size=336×384; FOV=201×229 mm 2 ; 240 axial slices with 0.6 mm slice thickness resulting in 0.6×0.6×0.6 mm 3 voxels; acquisition time=16.48 min; to increase the signal-to-noise ratio, two identical scans were acquired, motion corrected, and averaged into a single volume). T2w images were obtained using a 2D turbo spin-echo sequence (TR=10,810 ms; TE=81 ms; flip angle=119°; matrix size=512×512; FOV=203×203 mm 2 , 60 coronal slices angled perpendicular to the hippocampal long axis, slice thickness=2 mm, resulting in 0.4×0.4×2.0 mm 3 voxels; acquisition time=5.47 min). Pre-processing MRI data files were converted from DICOM to MINC (*.mnc) format using dcm2mnc with dicom header anonymization. Images underwent automated correction for intensity non-uniformity and intensity standardization 24 . Millimetric and submillimetric T1w MRI volumes were linearly registered to the high-resolution MNI-ICBM152 template 25 , 26 . T2w images were linearly registered to the millimetric T1w MRI in native space; the resulting transformation matrix was concatenated with the matrix that mapped the millimetric T1w image to the MNI space, thereby linearly<|im_end|> <|im_start|>assistant A new detailed map of the hippocampal region of the brain, compiled by researchers at the Montreal Neurological Institute and Hospital-The Neuro at McGill University, is helping the scientific community accelerate research and develop better treatments for patients suffering from epilepsy and other neurological and psychiatric disorders. The team of researchers, led by Dr. Neda Bernasconi, a neuroscientist specializing in the neuroimaging of epilepsy and co-founder of the Neuroimaging of Epilepsy Laboratory (NOEL) at The Neuro, set out to build and share a detailed model of the substructures making up one of the key centres of the brain involved in epilepsy: the hippocampus. The goal of their project, published on November 10 in Scientific Data, is to improve the tools available to researchers and clinicians working in the field around the globe. Epilepsy is a neurological disorder characterized by a sudden, brief change in the brain, expressed as a seizure. According to Epilepsy Canada, approximately one percent of Canadians suffer from the condition and more than 30% of patients with epilepsy do not respond to anti-epileptic drugs. For these individuals, the surgical removal of the brain tissue causing seizures is the only known effective treatment for controlling the condition and improving quality of life. In order to compile this hippocampal atlas, researchers used MRI imagery from a sample of 25 healthy individuals. They then used their expertise in brain anatomy to label all the substructures composing the region, providing a model of an average, healthy hippocampus. The end result is analogous to a Google street view of this particular part of the brain. With this tool, researchers will be better able to assess the pathology of their patients by comparing their data to the atlas and will more clearly be able to locate the areas in need of surgical intervention. A tool for brain diseases experts of all levels "Our primary purpose was epilepsy. We wanted to be able to detect and identify different substructures in the hippocampus to enable us to be a lot more precise in our diagnosis and to pinpoint the affected region to better target treatments", said Dr. Bernasconi. "With this new submillimetric dataset, made available through open science, we are not just sharing MRI images, we are also transferring anatomical knowledge and providing a statistical map that can be used by researchers and clinicians of different levels of expertise anywhere in the world." These tools hold promising therapeutic implications for epilepsy, but also for other neurological and psychiatric disorders such as Alzheimer's disease, schizophrenia and depression. Crucially, the atlas provides researchers with a non-invasive way to assess the impact of therapies targeting this region of the brain and to thus develop better treatments to improve the quality of life for their patients. <|im_end|>

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2,182

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background A fundamental concept in biology is that heritable material, DNA, is passed from parent to offspring, a process called vertical gene transfer. An alternative mechanism of gene acquisition is through horizontal gene transfer (HGT), which involves movement of genetic material between different species. HGT is well-known in single-celled organisms such as bacteria, but its existence in higher organisms, including animals, is less well established, and is controversial in humans. Results We have taken advantage of the recent availability of a sufficient number of high-quality genomes and associated transcriptomes to carry out a detailed examination of HGT in 26 animal species (10 primates, 12 flies and four nematodes) and a simplified analysis in a further 14 vertebrates. Genome-wide comparative and phylogenetic analyses show that HGT in animals typically gives rise to tens or hundreds of active ‘foreign’ genes, largely concerned with metabolism. Our analyses suggest that while fruit flies and nematodes have continued to acquire foreign genes throughout their evolution, humans and other primates have gained relatively few since their common ancestor. We also resolve the controversy surrounding previous evidence of HGT in humans and provide at least 33 new examples of horizontally acquired genes. Conclusions We argue that HGT has occurred, and continues to occur, on a previously unsuspected scale in metazoans and is likely to have contributed to biochemical diversification during animal evolution. Background The acquisition of genes from an organism other than a direct ancestor (that is, horizontal gene transfer (HGT) also called lateral gene transfer) is well known in bacteria and unicellular eukaryotes, where it plays an important role in evolution [ 1 ], with recent estimates suggesting that on average 81% of prokaryotic genes have been involved in HGT at some point [ 2 ]. However, relatively few cases have been documented in multicellular organisms [ 3 - 7 ]. Reports of HGT in animals are usually limited to the description of the transfer of only one or a few genes, making the extent of horizontal gene transfer in animals unclear. Examples include the transfer of fungal genes for carotenoid biosynthesis to the pea aphid, which results in a red pigmentation and is thought to be beneficial to the aphid [ 8 ] and the transfer of a cysteine synthase from a bacterium into the arthropod lineage (likely two independent transfers into a phytophagous mite ancestor and a lepidopteran ancestor), which allows the detoxification of cyanide produced by host plants [ 9 ]. This activity is also found in nematodes, where it may have been acquired by HGT from plants [ 9 ]. Other examples of putatively adaptive HGT have been characterised in plant-parasitic nematodes, which produce cell-wall degrading enzymes from a number of horizontally transferred genes [ 3 ], and the coffee berry borer beetle, where a mannanase has been transferred from bacteria allowing the hydrolysation of coffee berry galactomannan [ 10 ]. In exceptional cases, high levels of HGT in animals have been reported, but this has been attributed to the lifestyles of the recipient organisms. For example, in bdelloid rotifers, which are desiccation-tolerant asexuals, up to approximately 10% of transcripts derive from horizontally acquired genes [ 11 - 13 ]. Desiccation results in both DNA breakage [ 14 , 15 ] and loss of membrane integrity (reviewed in [ 16 ]), both of which may potentiate HGT. Another unusual example is the transfer of the entire genome (>1 Mb) of the bacterium Wolbachia into the fruit fly Drosophila ananassae , although relatively few Wolbachia genes are transcribed in this case [ 17 ]. Genes from Wolbachia are frequently transferred to invertebrates [ 17 , 18 ], probably because the long-term association (either parasitic or mutualistic) between the bacterium and its hosts maintains their genomes in close proximity. Furthermore, as Wolbachia frequently infects the testes and ovaries of its hosts, it has access to their germlines, a prerequisite for the transmission of the acquired genes to the next generation. These studies have led to the perception that HGT occurs very infrequently in most animals, especially in vertebrates [ 5 , 6 ]. Furthermore, there are concerns over the validity of the examples of HGT reported in humans [ 19 - 22 ]. The original report on the human genome sequence [ 19 ] described prokaryote-to-vertebrate HGT discovered by aligning human sequences to those of a small number of species (not many genomes were available at the time), including only two metazoans, D. melanogaster and Caenorhabditis elegans . Any proteins aligning to bacteria but not to these two metazoans, or to the other two eukaryotic proteomes used ( Arabidopsis thaliana and Saccharomyces cerevisiae ), were considered to be a result of prokaryote-to-vertebrate HGT. However, these four eukaryotic species do not contain orthologs of all ‘native’ human genes (that is, those not horizontally acquired), leading to incorrect identification of HGT (false positives) and the subsequent rejection of many cases by phylogenetic analyses [ 20 - 22 ]. The problem (the availability of a limited number of eukaryotic genomes for comparison in studies of HGT) has lessened in the intervening decade; thousands of proteomes (including several primates) are now available in UniProt, allowing prediction of HGT using alignment to hundreds of species and subsequent phylogenetic validation, as shown in recent work in invertebrates (for example, [ 12 , 23 , 24 ]). In the human, however, there have been no follow-up studies since the original genome paper, and the true scale of HGT in humans, and metazoans generally, remains unclear. To remedy this, we initially identified non-metazoan to metazoan HGT in multiple Drosophila , Caenohabditis and primate (including human) species. Due to the controversy surrounding the human studies [ 19 - 22 ], we then took our analysis a step further by comparing multiple closely related species and combining information on horizontally transferred (‘foreign’) genes found in more than one species in the group, thereby reducing mis-identification of HGT caused by spurious alignments. In this way, we identified up to hundreds of active foreign genes", "role": "user" }, { "content": "Many animals, including humans, acquired essential 'foreign' genes from microorganisms co-habiting their environment in ancient times, according to research published in the open access journal Genome Biology. The study challenges conventional views that animal evolution relies solely on genes passed down through ancestral lines, suggesting that, at least in some lineages, the process is still ongoing. The transfer of genes between organisms living in the same environment is known as horizontal gene transfer (HGT). It is well known in single-celled organisms and thought to be an important process that explains how quickly bacteria evolve, for example, resistance to antibiotics. HGT is thought to play an important role in the evolution of some animals, including nematode worms which have acquired genes from microorganisms and plants, and some beetles that gained bacterial genes to produce enzymes for digesting coffee berries. However, the idea that HGT occurs in more complex animals, such as humans, rather than them solely gaining genes directly from ancestors, has been widely debated and contested. Lead author Alastair Crisp from the University of Cambridge, UK, said: \"This is the first study to show how widely horizontal gene transfer (HGT) occurs in animals, including humans, giving rise to tens or hundreds of active 'foreign' genes. Surprisingly, far from being a rare occurrence, it appears that HGT has contributed to the evolution of many, perhaps all, animals and that the process is ongoing, meaning that we may need to re-evaluate how we think about evolution.\" The researchers studied the genomes of 12 species of Drosophila or fruit fly, four species of nematode worm, and 10 species of primate, including humans. They calculated how well each of their genes aligns to similar genes in other species to estimate how likely they were to be foreign in origin. By comparing with other groups of species, they were able to estimate how long ago the genes were likely to have been acquired. A number of genes, including the ABO blood group gene, were confirmed as having been acquired by vertebrates through HGT. The majority of the other genes were related to enzymes involved in metabolism. In humans, they confirmed 17 previously-reported genes acquired from HGT, and identified 128 additional foreign genes in the human genome that have not previously been reported. Some of those genes were involved in lipid metabolism, including the breakdown of fatty acids and the formation of glycolipids. Others were involved in immune responses, including the inflammatory response, immune cell signalling, and antimicrobial responses, while further gene categories include amino-acid metabolism, protein modification and antioxidant activities. The team were able to identify the likely class of organisms the transferred genes came from. Bacteria and protists, another class of microorganisms, were the most common donors in all species studied. They also identified HGT from viruses, which was responsible for up to 50 more foreign genes in primates. Some genes were identified as having originated from fungi. This explains why some previous studies, which only focused on bacteria as the source of HGT, originally rejected the idea that these genes were 'foreign' in origin. The majority of HGT in primates was found to be ancient, occurring sometime between the common ancestor of Chordata and the common ancestor of the primates. The authors say that their analysis probably underestimates the true extent of HGT in animals and that direct HGT between complex multicellular organisms is also plausible, and already known in some host-parasite relationships. The study also has potential impacts on genome sequencing more generally. Genome projects frequently remove bacterial sequences from results on the assumption that they are contamination. While screening for contamination is necessary, the potential for bacterial sequences being a genuine part of an animal's genome originating from HGT should not be ignored, say the authors. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background A fundamental concept in biology is that heritable material, DNA, is passed from parent to offspring, a process called vertical gene transfer. An alternative mechanism of gene acquisition is through horizontal gene transfer (HGT), which involves movement of genetic material between different species. HGT is well-known in single-celled organisms such as bacteria, but its existence in higher organisms, including animals, is less well established, and is controversial in humans. Results We have taken advantage of the recent availability of a sufficient number of high-quality genomes and associated transcriptomes to carry out a detailed examination of HGT in 26 animal species (10 primates, 12 flies and four nematodes) and a simplified analysis in a further 14 vertebrates. Genome-wide comparative and phylogenetic analyses show that HGT in animals typically gives rise to tens or hundreds of active ‘foreign’ genes, largely concerned with metabolism. Our analyses suggest that while fruit flies and nematodes have continued to acquire foreign genes throughout their evolution, humans and other primates have gained relatively few since their common ancestor. We also resolve the controversy surrounding previous evidence of HGT in humans and provide at least 33 new examples of horizontally acquired genes. Conclusions We argue that HGT has occurred, and continues to occur, on a previously unsuspected scale in metazoans and is likely to have contributed to biochemical diversification during animal evolution. Background The acquisition of genes from an organism other than a direct ancestor (that is, horizontal gene transfer (HGT) also called lateral gene transfer) is well known in bacteria and unicellular eukaryotes, where it plays an important role in evolution [ 1 ], with recent estimates suggesting that on average 81% of prokaryotic genes have been involved in HGT at some point [ 2 ]. However, relatively few cases have been documented in multicellular organisms [ 3 - 7 ]. Reports of HGT in animals are usually limited to the description of the transfer of only one or a few genes, making the extent of horizontal gene transfer in animals unclear. Examples include the transfer of fungal genes for carotenoid biosynthesis to the pea aphid, which results in a red pigmentation and is thought to be beneficial to the aphid [ 8 ] and the transfer of a cysteine synthase from a bacterium into the arthropod lineage (likely two independent transfers into a phytophagous mite ancestor and a lepidopteran ancestor), which allows the detoxification of cyanide produced by host plants [ 9 ]. This activity is also found in nematodes, where it may have been acquired by HGT from plants [ 9 ]. Other examples of putatively adaptive HGT have been characterised in plant-parasitic nematodes, which produce cell-wall degrading enzymes from a number of horizontally transferred genes [ 3 ], and the coffee berry borer beetle, where a mannanase has been transferred from bacteria allowing the hydrolysation of coffee berry galactomannan [ 10 ]. In exceptional cases, high levels of HGT in animals have been reported, but this has been attributed to the lifestyles of the recipient organisms. For example, in bdelloid rotifers, which are desiccation-tolerant asexuals, up to approximately 10% of transcripts derive from horizontally acquired genes [ 11 - 13 ]. Desiccation results in both DNA breakage [ 14 , 15 ] and loss of membrane integrity (reviewed in [ 16 ]), both of which may potentiate HGT. Another unusual example is the transfer of the entire genome (>1 Mb) of the bacterium Wolbachia into the fruit fly Drosophila ananassae , although relatively few Wolbachia genes are transcribed in this case [ 17 ]. Genes from Wolbachia are frequently transferred to invertebrates [ 17 , 18 ], probably because the long-term association (either parasitic or mutualistic) between the bacterium and its hosts maintains their genomes in close proximity. Furthermore, as Wolbachia frequently infects the testes and ovaries of its hosts, it has access to their germlines, a prerequisite for the transmission of the acquired genes to the next generation. These studies have led to the perception that HGT occurs very infrequently in most animals, especially in vertebrates [ 5 , 6 ]. Furthermore, there are concerns over the validity of the examples of HGT reported in humans [ 19 - 22 ]. The original report on the human genome sequence [ 19 ] described prokaryote-to-vertebrate HGT discovered by aligning human sequences to those of a small number of species (not many genomes were available at the time), including only two metazoans, D. melanogaster and Caenorhabditis elegans . Any proteins aligning to bacteria but not to these two metazoans, or to the other two eukaryotic proteomes used ( Arabidopsis thaliana and Saccharomyces cerevisiae ), were considered to be a result of prokaryote-to-vertebrate HGT. However, these four eukaryotic species do not contain orthologs of all ‘native’ human genes (that is, those not horizontally acquired), leading to incorrect identification of HGT (false positives) and the subsequent rejection of many cases by phylogenetic analyses [ 20 - 22 ]. The problem (the availability of a limited number of eukaryotic genomes for comparison in studies of HGT) has lessened in the intervening decade; thousands of proteomes (including several primates) are now available in UniProt, allowing prediction of HGT using alignment to hundreds of species and subsequent phylogenetic validation, as shown in recent work in invertebrates (for example, [ 12 , 23 , 24 ]). In the human, however, there have been no follow-up studies since the original genome paper, and the true scale of HGT in humans, and metazoans generally, remains unclear. To remedy this, we initially identified non-metazoan to metazoan HGT in multiple Drosophila , Caenohabditis and primate (including human) species. Due to the controversy surrounding the human studies [ 19 - 22 ], we then took our analysis a step further by comparing multiple closely related species and combining information on horizontally transferred (‘foreign’) genes found in more than one species in the group, thereby reducing mis-identification of HGT caused by spurious alignments. In this way, we identified up to hundreds of active foreign genes<|im_end|> <|im_start|>assistant Many animals, including humans, acquired essential 'foreign' genes from microorganisms co-habiting their environment in ancient times, according to research published in the open access journal Genome Biology. The study challenges conventional views that animal evolution relies solely on genes passed down through ancestral lines, suggesting that, at least in some lineages, the process is still ongoing. The transfer of genes between organisms living in the same environment is known as horizontal gene transfer (HGT). It is well known in single-celled organisms and thought to be an important process that explains how quickly bacteria evolve, for example, resistance to antibiotics. HGT is thought to play an important role in the evolution of some animals, including nematode worms which have acquired genes from microorganisms and plants, and some beetles that gained bacterial genes to produce enzymes for digesting coffee berries. However, the idea that HGT occurs in more complex animals, such as humans, rather than them solely gaining genes directly from ancestors, has been widely debated and contested. Lead author Alastair Crisp from the University of Cambridge, UK, said: "This is the first study to show how widely horizontal gene transfer (HGT) occurs in animals, including humans, giving rise to tens or hundreds of active 'foreign' genes. Surprisingly, far from being a rare occurrence, it appears that HGT has contributed to the evolution of many, perhaps all, animals and that the process is ongoing, meaning that we may need to re-evaluate how we think about evolution." The researchers studied the genomes of 12 species of Drosophila or fruit fly, four species of nematode worm, and 10 species of primate, including humans. They calculated how well each of their genes aligns to similar genes in other species to estimate how likely they were to be foreign in origin. By comparing with other groups of species, they were able to estimate how long ago the genes were likely to have been acquired. A number of genes, including the ABO blood group gene, were confirmed as having been acquired by vertebrates through HGT. The majority of the other genes were related to enzymes involved in metabolism. In humans, they confirmed 17 previously-reported genes acquired from HGT, and identified 128 additional foreign genes in the human genome that have not previously been reported. Some of those genes were involved in lipid metabolism, including the breakdown of fatty acids and the formation of glycolipids. Others were involved in immune responses, including the inflammatory response, immune cell signalling, and antimicrobial responses, while further gene categories include amino-acid metabolism, protein modification and antioxidant activities. The team were able to identify the likely class of organisms the transferred genes came from. Bacteria and protists, another class of microorganisms, were the most common donors in all species studied. They also identified HGT from viruses, which was responsible for up to 50 more foreign genes in primates. Some genes were identified as having originated from fungi. This explains why some previous studies, which only focused on bacteria as the source of HGT, originally rejected the idea that these genes were 'foreign' in origin. The majority of HGT in primates was found to be ancient, occurring sometime between the common ancestor of Chordata and the common ancestor of the primates. The authors say that their analysis probably underestimates the true extent of HGT in animals and that direct HGT between complex multicellular organisms is also plausible, and already known in some host-parasite relationships. The study also has potential impacts on genome sequencing more generally. Genome projects frequently remove bacterial sequences from results on the assumption that they are contamination. While screening for contamination is necessary, the potential for bacterial sequences being a genuine part of an animal's genome originating from HGT should not be ignored, say the authors. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The Pliocene fossil ‘Lucy’ ( Australopithecus afarensis ) was discovered in the Afar region of Ethiopia in 1974 and is among the oldest and most complete fossil hominin skeletons discovered. Here we propose, on the basis of close study of her skeleton, that her cause of death was a vertical deceleration event or impact following a fall from considerable height that produced compressive and hinge (greenstick) fractures in multiple skeletal elements. Impacts that are so severe as to cause concomitant fractures usually also damage internal organs; together, these injuries are hypothesized to have caused her death. Lucy has been at the centre of a vigorous debate about the role, if any, of arboreal locomotion in early human evolution. It is therefore ironic that her death can be attributed to injuries resulting from a fall, probably out of a tall tree, thus offering unusual evidence for the presence of arborealism in this species. Main It is rare when an early hominin fossil composed of multiple skeletal elements representing a single individual is discovered 1 , 2 , 3 , 4 , 5 , and rarer still when a cause of death can potentially be attributed to its remains 6 , 7 . A.L. 288-1, named Lucy and dated to 3.18 million years in age 8 , is represented by elements of the skull, upper limb, hand, axial skeleton, pelvis, lower limb, and foot, with some bilateral preservation ( Fig. 1a ), and is popularly described as 40% complete 9 . We studied the original fossil and computed tomographic (CT) scans of the skeleton to assess cause of death. Our observation that the skeleton is marked by post-mortem damage largely agrees with the original description 9 ; however, we differ from the original authors in proposing that a subset of fractures are likely to be perimortem and were produced by a vertical deceleration event, or a fall and impact from considerable height, and not by fossilization processes. Figure 1: Perimortem fractures in A.L. 288-1 postcranial skeleton consistent with vertical deceleration event. a , Lucy. b , c , Right humerus ( b , top: stereo, superior, medial up; bottom: lateral; c , stereo, posterior) preserves valgus head-shattering four-part proximal fracture. d , Hinge and spiral fracture elevated, displaced, and fractured right midshaft humeral bone fragment (stereo, lateral; see b ). e , Head of left humerus (stereo, medial) is fractured and compressed inferomedially to override the neck. f , Fracture of right distal radius (posterior, stereo view). g , Fractures in sacrum (stereo, anterior) and left innominate just lateral to sacrum. Fractured superior pubic ramus also visible as is puncture hole (arrow). h , Left-lateral asymmetry of fractured sacrum (stereo, posterior) and fractured, elevated, and bent retroauricular surface of left innominate. i , Left femoral neck fractures (stereo, lateral at top). j , Superoposteriorly fractured epiphysis of left distal femur (stereo, anterior) in discovery state with lateral extent sheared superiorly along lateral edge of shaft. Central portion of anterodistal shaft fractured and secondarily driven into trabeculae. k , Fracture of right tibial plateau (stereo, superior, medial to right) with major fracture across medial condyle that with other fractures ( l ; stereo, anterior, medial to right) depress the plateau and add valgus cant to shaft. m , Proximal portion of right distal tibia (stereo, posteromedial, superior at top) preserves small bone fragments broken loose and driven into medullary canal at spiral shaft fracture. n , Fractures on talar articular surface of right distal tibia (stereo, anterior, medial to right) open onto anterodistal surface of shaft. o , Right talus neck fracture (stereo, superior, medial to right). Together, n and o are consistent with a pilon fracture. Red lines are fractures; green lines in g , h denote sacroiliac joint and transverse lines of sacrum. Specimens in g and h are casts because it was not practical to articulate the fossils, and j is a cast because the original specimen was reconstructed. Scale bars ( a , 50 mm; b – f , i – o , 10 mm; g , h , 20 mm) are approximate, given stereo photo parallax. See Extended Data Figs 1 , 2 , 3 , 4 , Supplementary Note 1 , and Supplementary Videos 1 , 2 , 3 , 4 . PowerPoint slide Full size image Perimortem compressive fractures The most striking feature of the nearly complete right humerus (A.L. 288-1m) is that its proximal end is severely damaged 9 ( Fig. 1b, c ). Close examination shows that it underwent severe valgus head-shattering compression that drove the head fragments into the shaft, fracturing the greater and lesser tuberosities, and fracturing and dislocating a portion of the proximal shaft with the intertubercular groove ( Fig. 1b , bottom). The shaft of the right humerus was found as multiple segments with generally tight fits. The two major segments conjoin near the midshaft, where a fragment of displaced cortical bone reveals that the shaft underwent a spiral fracture that operated in the same direction as the compressive fracture at the head ( Fig. 1b, d , Supplementary Note 1 , and Extended Data Figs 1 , 2 ). Lucy’s right scapula (A.L. 288-1l) was found as three pieces with the major fragment preserving a complete and undamaged glenoid and neck along with a portion of the base of the coracoid process; the other two fragments preserve a short portion of the lateral border and the base of the acromion. This pattern matches that of the most common fractures of the scapula 10 . A fracture of the articular head, lesser tuberosity, greater tuberosity, and shaft of the humerus is classified as a four-part proximal humerus fracture 11 . Under natural conditions, this fracture is commonly caused by an impact following a vertical deceleration event when an accident victim consciously stretches out their arm in an attempt to break their fall. Compressive contact between the hand and the ground impacts the humeral articular head against the glenoid which,", "role": "user" }, { "content": "The famous human ancestor known as Lucy walked the Earth, but it was her tree climbing that might have led to her demise, a new study suggests. An analysis of her partial skeleton reveals breaks in her right arm, left shoulder, right ankle and left knee—injuries that researchers say resulted from falling from a high perch such as a tree. Lucy likely died quickly, said John Kappelman, an anthropologist at the University of Texas at Austin, who published the findings Monday in the journal Nature. \"I don't think she suffered,\" Kappelman said. But several other researchers, including Lucy's discoverer, disagree. They contend most of the cracks in Lucy's bones are well documented and came after her death from the fossilization process and natural forces such as erosion. How Lucy met her end has remained a mystery since her well-preserved fossil remains were unearthed more than four decades ago. Her discovery was significant because it allowed scientists to establish that ancient human ancestors walked upright before evolving a big brain. Lucy was a member of Australopithecus afarensis, an early human species that lived in Africa between about 4 million and 3 million years ago. The earliest humans climbed trees and walked on the ground. Lucy walked upright and occasionally used her long, dangling arms to climb trees. She was a young adult when she died. This Aug. 14, 2007, file photo shows a three-dimensional model of the early human ancestor, Australopithecus afarensis, known as Lucy, on display at the Houston Museum of Natural Science. It's a scientific estimation of what Lucy may have looked like in life. A new study based on an analysis of Lucy's fossil by the University of Texas at Austin suggests she died after falling from a tree. Several scientists, including Lucy's discoverer, reject that she plunged to her death from a tree. (AP Photo/Pat Sullivan, File) Tim White, a paleoanthropologist at the University of California, Berkeley, called the study's conclusion a \"misdiagnosis.\" The Texas researchers \"appear to have focused only on the cracks that they could attribute to an imagined fall, ignoring the additional abundant cracks,\" White said in an email. The split highlights the difficulty of pinpointing a cause of death from fossilized remains. Scientists rarely know how early humans died because skeletons are incomplete and bones tend to get crushed under sand and rocks. Over the years, Lucy's discoverer Donald Johanson has tried to solve the mystery. Lucy's skeleton, which is 40 percent complete, was recovered in Ethiopia in what was an ancient lake near fossilized remains of crocodiles, turtle eggs and crab claws. This undated image provided by the University of Texas at Austin shows the skeleton of Lucy, a fossil specimen of an early human ancestor, Australopithecus afarensis. A new study based on an analysis of Lucy's fossil by the university suggests she died after falling from a tree. Several scientists, including Lucy's discoverer, reject that she plunged to her death from a tree. (University of Texas at Austin via AP) \"There's no definitive proof of how she died,\" said Johanson of Arizona State University. The Texas team examined Lucy's bones and used high-tech imaging. Kappelman said the scans revealed multiple broken bones and no signs of healing, suggesting the injuries occurred around the time of death. He reconstructed her final moments: The 3-foot-6-inch (1.06-meter) Lucy fell from at least 40 feet and hit the ground at 35 mph. She landed on her feet before twisting and falling. Such an impact would have caused internal organ damage. Fractures on her upper arms suggest she tried to break her fall. Kappelman theorized that Lucy's walking ability may have caused her to be less adept at climbing trees, making her more vulnerable to falling from heights. UT Austin professor John Kappelman with 3-D printouts of Lucy's skeleton illustrating the compressive fractures in her right humerus that she suffered at the time of her death 3.18 million years ago Credit: Marsha Miller Not everyone agrees that her tree-climbing skills were lacking. Other scientists point out that there have been documented falls by chimpanzees and orangutans, which spend more time in trees than Lucy's species. \"Without a time machine, how can one know that she didn't just get unlucky and fall?\" William Harcourt-Smith of the American Museum of Natural History said in an email. This undated photo provided by the University of Texas at Austin shows the distal radius - a wrist bone - of Lucy, a fossil specimen of an early human ancestor, Australopithecus afarensis, undergoing computed tomographic scanning at the university in Austin, Texas. A new study based on an analysis of Lucy's fossil by the university suggests she died after falling from a tree. Several scientists, including Lucy's discoverer, reject that she plunged to her death from a tree. (Marsha Miller/University of Texas at Austin via AP) ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The Pliocene fossil ‘Lucy’ ( Australopithecus afarensis ) was discovered in the Afar region of Ethiopia in 1974 and is among the oldest and most complete fossil hominin skeletons discovered. Here we propose, on the basis of close study of her skeleton, that her cause of death was a vertical deceleration event or impact following a fall from considerable height that produced compressive and hinge (greenstick) fractures in multiple skeletal elements. Impacts that are so severe as to cause concomitant fractures usually also damage internal organs; together, these injuries are hypothesized to have caused her death. Lucy has been at the centre of a vigorous debate about the role, if any, of arboreal locomotion in early human evolution. It is therefore ironic that her death can be attributed to injuries resulting from a fall, probably out of a tall tree, thus offering unusual evidence for the presence of arborealism in this species. Main It is rare when an early hominin fossil composed of multiple skeletal elements representing a single individual is discovered 1 , 2 , 3 , 4 , 5 , and rarer still when a cause of death can potentially be attributed to its remains 6 , 7 . A.L. 288-1, named Lucy and dated to 3.18 million years in age 8 , is represented by elements of the skull, upper limb, hand, axial skeleton, pelvis, lower limb, and foot, with some bilateral preservation ( Fig. 1a ), and is popularly described as 40% complete 9 . We studied the original fossil and computed tomographic (CT) scans of the skeleton to assess cause of death. Our observation that the skeleton is marked by post-mortem damage largely agrees with the original description 9 ; however, we differ from the original authors in proposing that a subset of fractures are likely to be perimortem and were produced by a vertical deceleration event, or a fall and impact from considerable height, and not by fossilization processes. Figure 1: Perimortem fractures in A.L. 288-1 postcranial skeleton consistent with vertical deceleration event. a , Lucy. b , c , Right humerus ( b , top: stereo, superior, medial up; bottom: lateral; c , stereo, posterior) preserves valgus head-shattering four-part proximal fracture. d , Hinge and spiral fracture elevated, displaced, and fractured right midshaft humeral bone fragment (stereo, lateral; see b ). e , Head of left humerus (stereo, medial) is fractured and compressed inferomedially to override the neck. f , Fracture of right distal radius (posterior, stereo view). g , Fractures in sacrum (stereo, anterior) and left innominate just lateral to sacrum. Fractured superior pubic ramus also visible as is puncture hole (arrow). h , Left-lateral asymmetry of fractured sacrum (stereo, posterior) and fractured, elevated, and bent retroauricular surface of left innominate. i , Left femoral neck fractures (stereo, lateral at top). j , Superoposteriorly fractured epiphysis of left distal femur (stereo, anterior) in discovery state with lateral extent sheared superiorly along lateral edge of shaft. Central portion of anterodistal shaft fractured and secondarily driven into trabeculae. k , Fracture of right tibial plateau (stereo, superior, medial to right) with major fracture across medial condyle that with other fractures ( l ; stereo, anterior, medial to right) depress the plateau and add valgus cant to shaft. m , Proximal portion of right distal tibia (stereo, posteromedial, superior at top) preserves small bone fragments broken loose and driven into medullary canal at spiral shaft fracture. n , Fractures on talar articular surface of right distal tibia (stereo, anterior, medial to right) open onto anterodistal surface of shaft. o , Right talus neck fracture (stereo, superior, medial to right). Together, n and o are consistent with a pilon fracture. Red lines are fractures; green lines in g , h denote sacroiliac joint and transverse lines of sacrum. Specimens in g and h are casts because it was not practical to articulate the fossils, and j is a cast because the original specimen was reconstructed. Scale bars ( a , 50 mm; b – f , i – o , 10 mm; g , h , 20 mm) are approximate, given stereo photo parallax. See Extended Data Figs 1 , 2 , 3 , 4 , Supplementary Note 1 , and Supplementary Videos 1 , 2 , 3 , 4 . PowerPoint slide Full size image Perimortem compressive fractures The most striking feature of the nearly complete right humerus (A.L. 288-1m) is that its proximal end is severely damaged 9 ( Fig. 1b, c ). Close examination shows that it underwent severe valgus head-shattering compression that drove the head fragments into the shaft, fracturing the greater and lesser tuberosities, and fracturing and dislocating a portion of the proximal shaft with the intertubercular groove ( Fig. 1b , bottom). The shaft of the right humerus was found as multiple segments with generally tight fits. The two major segments conjoin near the midshaft, where a fragment of displaced cortical bone reveals that the shaft underwent a spiral fracture that operated in the same direction as the compressive fracture at the head ( Fig. 1b, d , Supplementary Note 1 , and Extended Data Figs 1 , 2 ). Lucy’s right scapula (A.L. 288-1l) was found as three pieces with the major fragment preserving a complete and undamaged glenoid and neck along with a portion of the base of the coracoid process; the other two fragments preserve a short portion of the lateral border and the base of the acromion. This pattern matches that of the most common fractures of the scapula 10 . A fracture of the articular head, lesser tuberosity, greater tuberosity, and shaft of the humerus is classified as a four-part proximal humerus fracture 11 . Under natural conditions, this fracture is commonly caused by an impact following a vertical deceleration event when an accident victim consciously stretches out their arm in an attempt to break their fall. Compressive contact between the hand and the ground impacts the humeral articular head against the glenoid which,<|im_end|> <|im_start|>assistant The famous human ancestor known as Lucy walked the Earth, but it was her tree climbing that might have led to her demise, a new study suggests. An analysis of her partial skeleton reveals breaks in her right arm, left shoulder, right ankle and left knee—injuries that researchers say resulted from falling from a high perch such as a tree. Lucy likely died quickly, said John Kappelman, an anthropologist at the University of Texas at Austin, who published the findings Monday in the journal Nature. "I don't think she suffered," Kappelman said. But several other researchers, including Lucy's discoverer, disagree. They contend most of the cracks in Lucy's bones are well documented and came after her death from the fossilization process and natural forces such as erosion. How Lucy met her end has remained a mystery since her well-preserved fossil remains were unearthed more than four decades ago. Her discovery was significant because it allowed scientists to establish that ancient human ancestors walked upright before evolving a big brain. Lucy was a member of Australopithecus afarensis, an early human species that lived in Africa between about 4 million and 3 million years ago. The earliest humans climbed trees and walked on the ground. Lucy walked upright and occasionally used her long, dangling arms to climb trees. She was a young adult when she died. This Aug. 14, 2007, file photo shows a three-dimensional model of the early human ancestor, Australopithecus afarensis, known as Lucy, on display at the Houston Museum of Natural Science. It's a scientific estimation of what Lucy may have looked like in life. A new study based on an analysis of Lucy's fossil by the University of Texas at Austin suggests she died after falling from a tree. Several scientists, including Lucy's discoverer, reject that she plunged to her death from a tree. (AP Photo/Pat Sullivan, File) Tim White, a paleoanthropologist at the University of California, Berkeley, called the study's conclusion a "misdiagnosis." The Texas researchers "appear to have focused only on the cracks that they could attribute to an imagined fall, ignoring the additional abundant cracks," White said in an email. The split highlights the difficulty of pinpointing a cause of death from fossilized remains. Scientists rarely know how early humans died because skeletons are incomplete and bones tend to get crushed under sand and rocks. Over the years, Lucy's discoverer Donald Johanson has tried to solve the mystery. Lucy's skeleton, which is 40 percent complete, was recovered in Ethiopia in what was an ancient lake near fossilized remains of crocodiles, turtle eggs and crab claws. This undated image provided by the University of Texas at Austin shows the skeleton of Lucy, a fossil specimen of an early human ancestor, Australopithecus afarensis. A new study based on an analysis of Lucy's fossil by the university suggests she died after falling from a tree. Several scientists, including Lucy's discoverer, reject that she plunged to her death from a tree. (University of Texas at Austin via AP) "There's no definitive proof of how she died," said Johanson of Arizona State University. The Texas team examined Lucy's bones and used high-tech imaging. Kappelman said the scans revealed multiple broken bones and no signs of healing, suggesting the injuries occurred around the time of death. He reconstructed her final moments: The 3-foot-6-inch (1.06-meter) Lucy fell from at least 40 feet and hit the ground at 35 mph. She landed on her feet before twisting and falling. Such an impact would have caused internal organ damage. Fractures on her upper arms suggest she tried to break her fall. Kappelman theorized that Lucy's walking ability may have caused her to be less adept at climbing trees, making her more vulnerable to falling from heights. UT Austin professor John Kappelman with 3-D printouts of Lucy's skeleton illustrating the compressive fractures in her right humerus that she suffered at the time of her death 3.18 million years ago Credit: Marsha Miller Not everyone agrees that her tree-climbing skills were lacking. Other scientists point out that there have been documented falls by chimpanzees and orangutans, which spend more time in trees than Lucy's species. "Without a time machine, how can one know that she didn't just get unlucky and fall?" William Harcourt-Smith of the American Museum of Natural History said in an email. This undated photo provided by the University of Texas at Austin shows the distal radius - a wrist bone - of Lucy, a fossil specimen of an early human ancestor, Australopithecus afarensis, undergoing computed tomographic scanning at the university in Austin, Texas. A new study based on an analysis of Lucy's fossil by the university suggests she died after falling from a tree. Several scientists, including Lucy's discoverer, reject that she plunged to her death from a tree. (Marsha Miller/University of Texas at Austin via AP) <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Gamma-ray bursts (GRBs) are the most luminous transients in the universe and are utilized as probes of early stars, gravitational wave counterparts and collisionless shock physics. In spite of studies on polarimetry of GRBs in individual wavelengths that characterized intriguing properties of prompt emission and afterglow, no coordinated multi-wavelength measurements have yet been performed. Here we report the first coordinated simultaneous polarimetry in the optical and radio bands for the afterglow associated with the typical long GRB 191221B. Our observations successfully caught the radio emission, which is not affected by synchrotron self-absorption, and show that the emission is depolarized in the radio band compared with the optical one. Our simultaneous polarization angle measurement and temporal polarization monitoring indicate the existence of cool electrons that increase the estimate of jet kinetic energy by a factor of more than 4 for this GRB afterglow. Further coordinated multi-wavelength polarimetric campaigns would improve our understanding of the total jet energies and magnetic field configurations in the emission regions of various types of GRBs, which are required to comprehend the mass scales of their progenitor systems and the physics of collisionless shocks. Main Gamma-ray burst (GRB) 191221B was detected on 21 December 2019, 20:39:13 UT, and its X-ray afterglow was rapidly identified by the Neil Gehrels Swift Observatory 1 . The optical afterglow was discovered by the MASTER auto-detection system 2 . Optical polarization with a possible time evolution in the early afterglow phase was also detected by the Southern African Large Telescope (SALT) and Very Large Telescope (VLT) (Extended Data Table 1 ) 3 . The redshift was measured as z = 1.148 based on metal absorption lines in the optical afterglow observed by VLT/X-shooter 4 . The isotropic equivalent energy of E γ ,iso = (3.6 ± 0.4) × 10 53 erg and the rest-frame peak energy of the time-integrated spectrum \${E}_{{{{\\rm{peak}}}}}^{{{{\\rm{src}}}}}=810\\pm 65\$ keV were derived by the Konus–Wind observation (with the standard cosmological parameters, the Hubble constant H 0 = 67.3 km s −1 Mpc −1 , the matter density parameter Ω M = 0.315 and the dark energy density parameter Ω Λ = 0.685) 5 . The duration of the prompt emission in the 15–350 keV band is 48.0 ± 16.0 s (ref. 6 ). These prompt emission properties obey the empirical \${E}_{{{{\\rm{peak}}}}}^{{{{\\rm{src}}}}}-{E}_{\\gamma ,{{{\\rm{iso}}}}}\$ correlation (Extended Data Fig. 1 ) and indicate that GRB 191221B is one of the typical long GRBs. The first semi-simultaneous polarimetry for the afterglow between millimetre and optical bands was conducted at 2.5 days after the burst by using Atacama Large Millimetre/submillimetre Array (ALMA) and VLT (Fig. 1 ). The VLT observation measured a linear polarization degree (PD) of 1.3 ± 0.2% (here we employed the systematic errors of 0.1% reported by ref. 7 and the range with 3 σ confidence level is 0.9−1.8%) with a polarization angle (PA) of 61.6 ± 6.3° at the R band. Hereafter, we note 1 σ errors for our measurements without special notification. The low dust extinction and Serkowski law 8 show an intrinsic origin of the polarization ( Methods , Extended Data Figs. 2 – 4 and Extended Data Table 2 ). The PD is consistent with other optical afterglows (an average of 1.6% across 84 polarimetric measurements) 9 . The ALMA observation put the upper limit on PD of 0.6% with a 3 σ confidence level at 97.5 GHz. The detection in Stokes U maps and non-detection in Stokes Q maps (Extended Data Fig. 5 ) constrained the range of PA to be 37.7−52.3° with a 1 σ confidence level. Therefore, this simultaneous polarimetry between optical and radio bands indicates depolarization in the radio band. The significantly low upper limit is also consistent with the first detection of linear polarization in the GRB radio afterglow (that is, 0.2% for the low-luminosity GRB 171205A) 10 . Fig. 1: Spectral flux distribution and polarization spectrum of GRB 191221B afterglow at 2.5 days. a , Spectral flux distribution (red points). The black dotted line is the forward shock model fit to the observed data. b , PDs at 97.5 GHz (3 σ upper limit) and optical R band (red points), and polarization spectrum of the simple one-zone model (grey dashed line), the plasma-scale magnetic field model (purple dash-dotted line) and the cool electron model (green solid line). c , PAs at 97.5 GHz (1 σ range) and optical R band (red points). The observed difference of PAs with ~90% confidence level (that is, 16.6 ± 9.6°) supports the cool electron model. The plasma-scale magnetic field model predicts a constant PA over the frequencies (for example, purple dash-dotted line). All error bars represent 1 σ uncertainties. Full size image The synchrotron self-absorption (SSA) effect, which suppresses polarization below the SSA frequency ( ν a ), is not a reliable explanation for the observed depolarization. ALMA observations at 97.5 GHz, 145 GHz and 203 GHz (Fig. 2 , Table 1 and Extended Data Table 3 ) show that the light curve at the 97.5 GHz band exhibited a broken power-law evolution with power-law indices of α = 0.26 ± 0.02 (before the break) and α = −1.62 ± 0.13 (after the break), and a break time at 3.77 ± 0.35 days, where and hereafter we describe the temporal and spectral properties of the flux density as F ν ∝ t α ν β ( t and v are time since the burst in days and frequency). The multi-frequency measurements (Fig. 3 ) showed that the spectral slope changed from positive power-law index of β ≈ 0.602 ± 0.007 at 1.5 days and β ≈ 0.32 ± 0.15 at 2.5 days to a negative one ( β ≈ −0.7) at 9.5 and 18.4 days. These spectral slopes are in disagreement with the SSA effect which leads to β = 2 (refs. 11 , 12 ). Fig. 2: Radio afterglow light curve of GRB 191221BA with the simultaneous optical (R band) polarimetric observation. The red dashed line indicates the best fitted smoothly connected broken", "role": "user" }, { "content": "Gamma-ray bursts are the most luminous explosions in the universe, allowing astronomers to observe intense gamma rays in short durations. Gamma-ray bursts are classified as either short or long, with long gamma-ray bursts being the result of massive stars dying out. They provide hidden clues about the evolution of the universe. Gamma-ray bursts emit gamma rays as well as radio waves, optical lights, and X-rays. When the conversion of explosion energy to emitted energy (i.e., the conversion efficiency) is high, the total explosion energy can be calculated by simply adding all the emitted energy. But when the conversion efficiency is low or unknown, measuring the emitted energy alone is not enough. Now, a team of astrophysicists has succeeded in measuring a gamma-ray burst's hidden energy by using light polarization. The team was led by Dr. Yuji Urata from the National Central University in Taiwan and MITOS Science CO., LTD and Professor Kenji Toma from Tohoku University's Frontier Research Institute for Interdisciplinary Sciences (FRIS). Details of their findings were published in the journal Nature Astronomy on December 8, 2022. When an electromagnetic wave is polarized, it means that the oscillation of that wave flows in one direction. While light emitted from stars is not polarized, the reflection of that light is. Many everyday items such as sunglasses and light shields utilize polarization to block out the glare of lights traveling in a uniform direction. Measuring the degree of polarization is referred to as polarimetry. In astrophysical observations, measuring a celestial object's polarimetry is not as easy as measuring its brightness. But it offers valuable information on the physical conditions of objects. The team looked at a gamma-ray burst that occurred on December 21, 2019 (GRB191221B). Using the Very Large Telescope of the European Southern Observatory and Atacama Large Millimeter/submillimeter Array—some of the world's most advanced optical and radio telescopes—they calculated the polarimetry of fast-fading emissions from GRB191221B. They then successfully measured the optical and radio polarizations simultaneously, finding the radio polarization degree to be significantly lower than the optical one. \"This difference in polarization at the two wavelengths reveals detailed physical conditions of the gamma-ray burst's emission region,\" said Toma. \"In particular, it allowed us to measure the previously unmeasurable hidden energy.\" When accounting for the hidden energy, the team revealed that the total energy was about 3.5 times bigger than previous estimates. With the explosion energy representing the gravitational energy of the progenitor star, being able to measure this figure has important ramifications for determining stars' masses. \"Knowing the measurements of the progenitor star's true masses will help in understanding the evolutionary history of the universe,\" added Toma. \"The first stars in the universe could be discovered if we can detect their long gamma-ray bursts.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Gamma-ray bursts (GRBs) are the most luminous transients in the universe and are utilized as probes of early stars, gravitational wave counterparts and collisionless shock physics. In spite of studies on polarimetry of GRBs in individual wavelengths that characterized intriguing properties of prompt emission and afterglow, no coordinated multi-wavelength measurements have yet been performed. Here we report the first coordinated simultaneous polarimetry in the optical and radio bands for the afterglow associated with the typical long GRB 191221B. Our observations successfully caught the radio emission, which is not affected by synchrotron self-absorption, and show that the emission is depolarized in the radio band compared with the optical one. Our simultaneous polarization angle measurement and temporal polarization monitoring indicate the existence of cool electrons that increase the estimate of jet kinetic energy by a factor of more than 4 for this GRB afterglow. Further coordinated multi-wavelength polarimetric campaigns would improve our understanding of the total jet energies and magnetic field configurations in the emission regions of various types of GRBs, which are required to comprehend the mass scales of their progenitor systems and the physics of collisionless shocks. Main Gamma-ray burst (GRB) 191221B was detected on 21 December 2019, 20:39:13 UT, and its X-ray afterglow was rapidly identified by the Neil Gehrels Swift Observatory 1 . The optical afterglow was discovered by the MASTER auto-detection system 2 . Optical polarization with a possible time evolution in the early afterglow phase was also detected by the Southern African Large Telescope (SALT) and Very Large Telescope (VLT) (Extended Data Table 1 ) 3 . The redshift was measured as z = 1.148 based on metal absorption lines in the optical afterglow observed by VLT/X-shooter 4 . The isotropic equivalent energy of E γ ,iso = (3.6 ± 0.4) × 10 53 erg and the rest-frame peak energy of the time-integrated spectrum ${E}_{{{{\rm{peak}}}}}^{{{{\rm{src}}}}}=810\pm 65$ keV were derived by the Konus–Wind observation (with the standard cosmological parameters, the Hubble constant H 0 = 67.3 km s −1 Mpc −1 , the matter density parameter Ω M = 0.315 and the dark energy density parameter Ω Λ = 0.685) 5 . The duration of the prompt emission in the 15–350 keV band is 48.0 ± 16.0 s (ref. 6 ). These prompt emission properties obey the empirical ${E}_{{{{\rm{peak}}}}}^{{{{\rm{src}}}}}-{E}_{\gamma ,{{{\rm{iso}}}}}$ correlation (Extended Data Fig. 1 ) and indicate that GRB 191221B is one of the typical long GRBs. The first semi-simultaneous polarimetry for the afterglow between millimetre and optical bands was conducted at 2.5 days after the burst by using Atacama Large Millimetre/submillimetre Array (ALMA) and VLT (Fig. 1 ). The VLT observation measured a linear polarization degree (PD) of 1.3 ± 0.2% (here we employed the systematic errors of 0.1% reported by ref. 7 and the range with 3 σ confidence level is 0.9−1.8%) with a polarization angle (PA) of 61.6 ± 6.3° at the R band. Hereafter, we note 1 σ errors for our measurements without special notification. The low dust extinction and Serkowski law 8 show an intrinsic origin of the polarization ( Methods , Extended Data Figs. 2 – 4 and Extended Data Table 2 ). The PD is consistent with other optical afterglows (an average of 1.6% across 84 polarimetric measurements) 9 . The ALMA observation put the upper limit on PD of 0.6% with a 3 σ confidence level at 97.5 GHz. The detection in Stokes U maps and non-detection in Stokes Q maps (Extended Data Fig. 5 ) constrained the range of PA to be 37.7−52.3° with a 1 σ confidence level. Therefore, this simultaneous polarimetry between optical and radio bands indicates depolarization in the radio band. The significantly low upper limit is also consistent with the first detection of linear polarization in the GRB radio afterglow (that is, 0.2% for the low-luminosity GRB 171205A) 10 . Fig. 1: Spectral flux distribution and polarization spectrum of GRB 191221B afterglow at 2.5 days. a , Spectral flux distribution (red points). The black dotted line is the forward shock model fit to the observed data. b , PDs at 97.5 GHz (3 σ upper limit) and optical R band (red points), and polarization spectrum of the simple one-zone model (grey dashed line), the plasma-scale magnetic field model (purple dash-dotted line) and the cool electron model (green solid line). c , PAs at 97.5 GHz (1 σ range) and optical R band (red points). The observed difference of PAs with ~90% confidence level (that is, 16.6 ± 9.6°) supports the cool electron model. The plasma-scale magnetic field model predicts a constant PA over the frequencies (for example, purple dash-dotted line). All error bars represent 1 σ uncertainties. Full size image The synchrotron self-absorption (SSA) effect, which suppresses polarization below the SSA frequency ( ν a ), is not a reliable explanation for the observed depolarization. ALMA observations at 97.5 GHz, 145 GHz and 203 GHz (Fig. 2 , Table 1 and Extended Data Table 3 ) show that the light curve at the 97.5 GHz band exhibited a broken power-law evolution with power-law indices of α = 0.26 ± 0.02 (before the break) and α = −1.62 ± 0.13 (after the break), and a break time at 3.77 ± 0.35 days, where and hereafter we describe the temporal and spectral properties of the flux density as F ν ∝ t α ν β ( t and v are time since the burst in days and frequency). The multi-frequency measurements (Fig. 3 ) showed that the spectral slope changed from positive power-law index of β ≈ 0.602 ± 0.007 at 1.5 days and β ≈ 0.32 ± 0.15 at 2.5 days to a negative one ( β ≈ −0.7) at 9.5 and 18.4 days. These spectral slopes are in disagreement with the SSA effect which leads to β = 2 (refs. 11 , 12 ). Fig. 2: Radio afterglow light curve of GRB 191221BA with the simultaneous optical (R band) polarimetric observation. The red dashed line indicates the best fitted smoothly connected broken<|im_end|> <|im_start|>assistant Gamma-ray bursts are the most luminous explosions in the universe, allowing astronomers to observe intense gamma rays in short durations. Gamma-ray bursts are classified as either short or long, with long gamma-ray bursts being the result of massive stars dying out. They provide hidden clues about the evolution of the universe. Gamma-ray bursts emit gamma rays as well as radio waves, optical lights, and X-rays. When the conversion of explosion energy to emitted energy (i.e., the conversion efficiency) is high, the total explosion energy can be calculated by simply adding all the emitted energy. But when the conversion efficiency is low or unknown, measuring the emitted energy alone is not enough. Now, a team of astrophysicists has succeeded in measuring a gamma-ray burst's hidden energy by using light polarization. The team was led by Dr. Yuji Urata from the National Central University in Taiwan and MITOS Science CO., LTD and Professor Kenji Toma from Tohoku University's Frontier Research Institute for Interdisciplinary Sciences (FRIS). Details of their findings were published in the journal Nature Astronomy on December 8, 2022. When an electromagnetic wave is polarized, it means that the oscillation of that wave flows in one direction. While light emitted from stars is not polarized, the reflection of that light is. Many everyday items such as sunglasses and light shields utilize polarization to block out the glare of lights traveling in a uniform direction. Measuring the degree of polarization is referred to as polarimetry. In astrophysical observations, measuring a celestial object's polarimetry is not as easy as measuring its brightness. But it offers valuable information on the physical conditions of objects. The team looked at a gamma-ray burst that occurred on December 21, 2019 (GRB191221B). Using the Very Large Telescope of the European Southern Observatory and Atacama Large Millimeter/submillimeter Array—some of the world's most advanced optical and radio telescopes—they calculated the polarimetry of fast-fading emissions from GRB191221B. They then successfully measured the optical and radio polarizations simultaneously, finding the radio polarization degree to be significantly lower than the optical one. "This difference in polarization at the two wavelengths reveals detailed physical conditions of the gamma-ray burst's emission region," said Toma. "In particular, it allowed us to measure the previously unmeasurable hidden energy." When accounting for the hidden energy, the team revealed that the total energy was about 3.5 times bigger than previous estimates. With the explosion energy representing the gravitational energy of the progenitor star, being able to measure this figure has important ramifications for determining stars' masses. "Knowing the measurements of the progenitor star's true masses will help in understanding the evolutionary history of the universe," added Toma. "The first stars in the universe could be discovered if we can detect their long gamma-ray bursts." <|im_end|>

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2,158

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Coronal mass ejections (CMEs) are episodic eruptions of solar plasma and magnetic flux that travel out through the solar system, driving extreme space weather. Interpretation of CME observations and their interaction with the solar wind typically assumes CMEs are coherent, almost solid-like objects. We show that supersonic radial propagation of CMEs away from the Sun results in geometric expansion of CME plasma parcels at a speed faster than the local wave speed. Thus information cannot propagate across the CME. Comparing our results with observed properties of over 400 CMEs, we show that CMEs cease to be coherent magnetohydrodynamic structures within 0.3 AU of the Sun. This suggests Earth-directed CMEs are less like billiard balls and more like dust clouds, with apparent coherence only due to similar initial conditions and quasi homogeneity of the medium through which they travel. The incoherence of CMEs suggests interpretation of CME observations requires accurate reconstruction of the ambient solar wind with which they interact, and that simple assumptions about the shape of the CMEs are likely to be invalid when significant spatial/temporal gradients in ambient solar wind conditions are present. Introduction Coronal mass ejections (CMEs) are large, episodic eruptions of coronal plasma and magnetic flux that are ejected out into the heliosphere at speeds typically 1 ranging from 300–2000 km s −1 . They are of great interest both for their central role in extreme space weather 2 , 3 and in the solar cycle evolution of the coronal magnetic field 4 , 5 . In situ spacecraft observations of CMEs show that around a third to a half of all CMEs contain a magnetic flux-rope structure and low plasma beta 6 , 7 . These “magnetic clouds” are generally assumed to be (quasi-) coherent magnetohydrodynamic (MHD) structures, wherein the magnetic pressure and curvature forces act, to a greater or lesser extent, to resist deformation by external forces such as solar wind speed shear. This, in principle, enables a magnetic cloud to evolve as a single cohesive body. For example: Observations of CME-CME interactions in the heliosphere 8 have been interpreted as elastic or even super-elastic collisions 9 , suggesting the CMEs are solid-like, coherent structures. Non-radial deflection of CME trajectories, possibly by interaction with coronal hole magnetic flux, has been observed 10 , 11 , 12 . While this has largely been interpreted as centre-of-mass deflection, which would require the CME to behave as a coherent structure, distortion of the CME shape could equally explain the available observations. Methods for tracking CMEs through the corona and heliosphere assume the CME front remains quasi-spherical (or some other simple shape) 13 , 14 , 15 , 16 , implying the CME front remains a coherent structure throughout the heliosphere. There is observational evidence, however, for significant disruption of CME structure by solar wind inhomogeneity 17 . Numerous studies (including some by the authors of present paper) either explicitly or implicitly assume that single-point in situ measurements of a magnetic cloud are representative of its global structure 7 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , implying a large degree of coherence of CMEs. Single- 25 and multi-point 26 , 27 observations, even at relatively modest spacecraft separations, often reveal this picture to be far too simplistic, with evidence of CME distortion by the ambient solar wind. Numerical MHD models provide a complementary means to test the coherence of CMEs. There have been a number of numerical experiments investigating interaction of CMEs both with a structured solar wind and other CMEs, which often reveal significant distortion of CME structure 28 , 29 , 30 , 31 , 32 , 33 . Interpretation of the results, however, has largely focussed on the issue of force balance, with internal magnetic pressure/curvature from the magnetic flux-rope unable to resist distortion from interaction with external solar wind structures. Here, we investigate a fundamental physical limit on a CME’s ability to act as a coherent magnetohydrodynamic structure; namely the inability of information to propagate within a CME. We use a simple analytical model for CME evolution in the heliosphere to calculate the Alfvén wave speed [ V A ] within the CME at a range of heliocentric distances. We also estimate the geometric speed of separation of plasma parcels [ V G ] within the CME that results from purely radial heliocentric propagation. For a range of CME parameters, we determine the heliocentric distance at which V G exceeds V A and hence information can no longer propagate within the CME. Methodology The geometric and dynamic effects of CME propagation are investigated using a simple analytical model, closely following Owens, et al . 21 , which agrees well with numerical MHD simulations of CME evolution 34 . In summary, CMEs are assumed to initially take the form of a circular cross-section, force-free flux rope in the low corona and subsequently be deformed by a combination of CME-centred self-expansion and heliocentric radial propagation. The internally-driven self-expansion is limited to the heliocentric radial direction, so that the CME maintains constant angular width, as is commonly observed 1 . Figure 1 shows snapshots of the resulting CME cross section at increasing times (in arbitrary units), using typical CME parameters: an initial (at time t = 0) circular cross-section of radius 1 solar radii [ r S ] at a height of 2 r S gives a CME angular extent with respect to the Sun of approximately 60°; a constant CME transit speed [ V TR ] of 600 km s −1 and a constant internally-driven expansion speed [ V EX ] of 90 km s −1 35 . The CME rapidly “pancakes” due to radial propagation in spherical geometry 34 , 36 . The change in CME cross-sectional area, computed by numerically integrating the analytical model, is shown in Fig. 2a . By 1 AU, the cross-sectional area of the CME is approximately 3000 times its initial value. Figure 1 An analytical model for the cross-sectional area", "role": "user" }, { "content": "Long-term power cuts, destruction of electronic devices and increased cancer risk for aeroplane passengers are all potential effects of the Earth being hit by a powerful solar eruption. Yet, new research has found space scientists have their work cut out to predict when these coronal mass ejections (CMEs) are on a collision course with Earth. A study of CMEs by scientists at the University of Reading has found they have cloud-like structures. This means they are more influenced by solar wind, through which they pass to reach Earth, making their movements much harder to predict than if they were single bubble-like entities as was previously thought. CMEs are huge blasts of solar plasma and magnetic fields from the sun's atmosphere that can reach Earth in one to three days. A direct hit could have catastrophic consequences, as CMEs are capable of damaging satellites, destroying electronic devices and potentially exposing people at high altitude, such as astronauts and aviation crew and passengers, to cancer-causing radiation. They occur frequently, but predicting which ones will impact Earth and how severely is difficult. Clouds not bubbles Professor Mathew Owens said: \"Up until now, it has been assumed CMEs move like bubbles through space, and respond to forces as single objects. We have found they are more like an expanding dust cloud or sneeze, made up of individual plasma parcels all doing their own thing. \"This means that trying to predict the shape and movement of CMEs as they pass through the solar wind becomes extremely difficult. Therefore if we want to protect ourselves from solar eruptions, we need to understand more about the solar wind.\" The new study, published in Nature Scientific Reports on Friday 23 June, looks in detail for the first time at how CMEs behave as they make their way through space, and how they interact with external forces like solar wind. The Reading scientists took a cross section of a CME to examine its structure more closely. They found that a CME quickly reaches the point at which the speed of its expansion exceeds the speed at which information can travel within the CME. At this point, it ceases to be a coherent structure, so any distortion to one part of the cloud caused by external forces does not affect it as a whole. Space weather threat Scientists are constantly monitoring the sun to track solar wind and extreme space weather. The Reading team recommends that information about solar wind should be incorporated into CME observations to ensure we are fully aware of the threat they pose to Earth. A previous study by University of Reading scientists found a shift in solar activity, expected to occur by the middle of the century, could make us more vulnerable to CMEs, as well as concentrating the Northern Lights around the poles – out of view of Great Britain. In 2011, the threat of space weather was added to the Government National Risk Register of Civil Emergencies. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Coronal mass ejections (CMEs) are episodic eruptions of solar plasma and magnetic flux that travel out through the solar system, driving extreme space weather. Interpretation of CME observations and their interaction with the solar wind typically assumes CMEs are coherent, almost solid-like objects. We show that supersonic radial propagation of CMEs away from the Sun results in geometric expansion of CME plasma parcels at a speed faster than the local wave speed. Thus information cannot propagate across the CME. Comparing our results with observed properties of over 400 CMEs, we show that CMEs cease to be coherent magnetohydrodynamic structures within 0.3 AU of the Sun. This suggests Earth-directed CMEs are less like billiard balls and more like dust clouds, with apparent coherence only due to similar initial conditions and quasi homogeneity of the medium through which they travel. The incoherence of CMEs suggests interpretation of CME observations requires accurate reconstruction of the ambient solar wind with which they interact, and that simple assumptions about the shape of the CMEs are likely to be invalid when significant spatial/temporal gradients in ambient solar wind conditions are present. Introduction Coronal mass ejections (CMEs) are large, episodic eruptions of coronal plasma and magnetic flux that are ejected out into the heliosphere at speeds typically 1 ranging from 300–2000 km s −1 . They are of great interest both for their central role in extreme space weather 2 , 3 and in the solar cycle evolution of the coronal magnetic field 4 , 5 . In situ spacecraft observations of CMEs show that around a third to a half of all CMEs contain a magnetic flux-rope structure and low plasma beta 6 , 7 . These “magnetic clouds” are generally assumed to be (quasi-) coherent magnetohydrodynamic (MHD) structures, wherein the magnetic pressure and curvature forces act, to a greater or lesser extent, to resist deformation by external forces such as solar wind speed shear. This, in principle, enables a magnetic cloud to evolve as a single cohesive body. For example: Observations of CME-CME interactions in the heliosphere 8 have been interpreted as elastic or even super-elastic collisions 9 , suggesting the CMEs are solid-like, coherent structures. Non-radial deflection of CME trajectories, possibly by interaction with coronal hole magnetic flux, has been observed 10 , 11 , 12 . While this has largely been interpreted as centre-of-mass deflection, which would require the CME to behave as a coherent structure, distortion of the CME shape could equally explain the available observations. Methods for tracking CMEs through the corona and heliosphere assume the CME front remains quasi-spherical (or some other simple shape) 13 , 14 , 15 , 16 , implying the CME front remains a coherent structure throughout the heliosphere. There is observational evidence, however, for significant disruption of CME structure by solar wind inhomogeneity 17 . Numerous studies (including some by the authors of present paper) either explicitly or implicitly assume that single-point in situ measurements of a magnetic cloud are representative of its global structure 7 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , implying a large degree of coherence of CMEs. Single- 25 and multi-point 26 , 27 observations, even at relatively modest spacecraft separations, often reveal this picture to be far too simplistic, with evidence of CME distortion by the ambient solar wind. Numerical MHD models provide a complementary means to test the coherence of CMEs. There have been a number of numerical experiments investigating interaction of CMEs both with a structured solar wind and other CMEs, which often reveal significant distortion of CME structure 28 , 29 , 30 , 31 , 32 , 33 . Interpretation of the results, however, has largely focussed on the issue of force balance, with internal magnetic pressure/curvature from the magnetic flux-rope unable to resist distortion from interaction with external solar wind structures. Here, we investigate a fundamental physical limit on a CME’s ability to act as a coherent magnetohydrodynamic structure; namely the inability of information to propagate within a CME. We use a simple analytical model for CME evolution in the heliosphere to calculate the Alfvén wave speed [ V A ] within the CME at a range of heliocentric distances. We also estimate the geometric speed of separation of plasma parcels [ V G ] within the CME that results from purely radial heliocentric propagation. For a range of CME parameters, we determine the heliocentric distance at which V G exceeds V A and hence information can no longer propagate within the CME. Methodology The geometric and dynamic effects of CME propagation are investigated using a simple analytical model, closely following Owens, et al . 21 , which agrees well with numerical MHD simulations of CME evolution 34 . In summary, CMEs are assumed to initially take the form of a circular cross-section, force-free flux rope in the low corona and subsequently be deformed by a combination of CME-centred self-expansion and heliocentric radial propagation. The internally-driven self-expansion is limited to the heliocentric radial direction, so that the CME maintains constant angular width, as is commonly observed 1 . Figure 1 shows snapshots of the resulting CME cross section at increasing times (in arbitrary units), using typical CME parameters: an initial (at time t = 0) circular cross-section of radius 1 solar radii [ r S ] at a height of 2 r S gives a CME angular extent with respect to the Sun of approximately 60°; a constant CME transit speed [ V TR ] of 600 km s −1 and a constant internally-driven expansion speed [ V EX ] of 90 km s −1 35 . The CME rapidly “pancakes” due to radial propagation in spherical geometry 34 , 36 . The change in CME cross-sectional area, computed by numerically integrating the analytical model, is shown in Fig. 2a . By 1 AU, the cross-sectional area of the CME is approximately 3000 times its initial value. Figure 1 An analytical model for the cross-sectional area<|im_end|> <|im_start|>assistant Long-term power cuts, destruction of electronic devices and increased cancer risk for aeroplane passengers are all potential effects of the Earth being hit by a powerful solar eruption. Yet, new research has found space scientists have their work cut out to predict when these coronal mass ejections (CMEs) are on a collision course with Earth. A study of CMEs by scientists at the University of Reading has found they have cloud-like structures. This means they are more influenced by solar wind, through which they pass to reach Earth, making their movements much harder to predict than if they were single bubble-like entities as was previously thought. CMEs are huge blasts of solar plasma and magnetic fields from the sun's atmosphere that can reach Earth in one to three days. A direct hit could have catastrophic consequences, as CMEs are capable of damaging satellites, destroying electronic devices and potentially exposing people at high altitude, such as astronauts and aviation crew and passengers, to cancer-causing radiation. They occur frequently, but predicting which ones will impact Earth and how severely is difficult. Clouds not bubbles Professor Mathew Owens said: "Up until now, it has been assumed CMEs move like bubbles through space, and respond to forces as single objects. We have found they are more like an expanding dust cloud or sneeze, made up of individual plasma parcels all doing their own thing. "This means that trying to predict the shape and movement of CMEs as they pass through the solar wind becomes extremely difficult. Therefore if we want to protect ourselves from solar eruptions, we need to understand more about the solar wind." The new study, published in Nature Scientific Reports on Friday 23 June, looks in detail for the first time at how CMEs behave as they make their way through space, and how they interact with external forces like solar wind. The Reading scientists took a cross section of a CME to examine its structure more closely. They found that a CME quickly reaches the point at which the speed of its expansion exceeds the speed at which information can travel within the CME. At this point, it ceases to be a coherent structure, so any distortion to one part of the cloud caused by external forces does not affect it as a whole. Space weather threat Scientists are constantly monitoring the sun to track solar wind and extreme space weather. The Reading team recommends that information about solar wind should be incorporated into CME observations to ensure we are fully aware of the threat they pose to Earth. A previous study by University of Reading scientists found a shift in solar activity, expected to occur by the middle of the century, could make us more vulnerable to CMEs, as well as concentrating the Northern Lights around the poles – out of view of Great Britain. In 2011, the threat of space weather was added to the Government National Risk Register of Civil Emergencies. <|im_end|>

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1,948

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Heat-flow sensing is expected to be an important technological component of smart thermal management in the future. Conventionally, the thermoelectric (TE) conversion technique, which is based on the Seebeck effect, has been used to measure a heat flow by converting the flow into electric voltage. However, for ubiquitous heat-flow visualization, thin and flexible sensors with extremely low thermal resistance are highly desired. Recently, another type of TE effect, the longitudinal spin Seebeck effect (LSSE), has aroused great interest because the LSSE potentially offers favourable features for TE applications such as simple thin-film device structures. Here we demonstrate an LSSE-based flexible TE sheet that is especially suitable for a heat-flow sensing application. This TE sheet contained a Ni 0.2 Zn 0.3 Fe 2.5 O 4 film which was formed on a flexible plastic sheet using a spray-coating method known as “ferrite plating”. The experimental results suggest that the ferrite-plated film, which has a columnar crystal structure aligned perpendicular to the film plane, functions as a unique one-dimensional spin-current conductor suitable for bendable LSSE-based sensors. This newly developed thin TE sheet may be attached to differently shaped heat sources without obstructing an innate heat flux, paving the way to versatile heat-flow measurements and management. Introduction As efficient energy utilization is becoming a crucially important issue for sustainable future, a heat management technique to optimally control the flow of omnipresent thermal energy is currently of great interest. To realize smart thermal management with real-time controllability, there has been a growing demand for visualizing the flow of heat in various places such as industrial facilities and large-scale data centres. The thermoelectric (TE) conversion technique 1 , 2 , 3 , which directly converts a thermal gradient into an electric current, is one of the most powerful methods utilized to sense a heat flow as a voltage signal. In fact, heat-flow sensors based on the Seebeck effect 4 , which have thermopile structures consisting of π-structured thermocouples, are commercially available and used for various purposes such as the evaluation of materials. To further extend heat-flow-sensing capabilities to other widespread applications, however, such conventional devices face certain challenges. First, because Seebeck-based TE devices exhibit a relatively high heat resistance, the introduction of these devices into a heat-flow environment inevitably obstructs the heat flux and alters the distribution of the heat flow. Therefore, it is difficult to correctly evaluate the innate heat flux which we actually want to determine. Second, most of the commercially available heat-flow sensors are rigid and not easily applied to curved or uneven surfaces, making it difficult to monitor the heat flux around irregularly shaped heat sources. Because conventional TE devices, in which thermocouples are connected electrically in series, are intrinsically vulnerable to bending stresses, materials and structures for flexible TE devices have been extensively studied 5 , 6 , 7 . For such sensing applications, an emerging research field, spin caloritronics 8 , 9 , will provide new device-design opportunities. For example, TE devices based on the anomalous Nernst effect (ANE), which exhibit transverse TE voltage in ferromagnetic metals (FM), can be suitably utilized for sensing purposes 9 , 10 , 11 , 12 , 13 . In this work, we present another promising approach to realizing flexible heat flow sensors using the longitudinal spin Seebeck effect (LSSE) 14 , 15 , 16 , 17 , 18 . First reported in 2010, the LSSE offers an unconventional method to design TE devices by making use of a physical quantity called a spin current. The LSSE devices, typically composed of a ferromagnetic insulator (FI) and a normal metallic film (NM), have gained attention because of the simple device structure and novel scaling capability, leading to novel TE devices 16 . The LSSE also has potential to realize practical sensing applications. It is recently reported that FI/NM multilayer structure unexpectedly exhibit significantly enhanced LSSE signal 19 , which may lead to high-sensitive heat-flow sensors. Furthermore, combination of the LSSE and ANE is also a quite hopeful approach. In hybrid TE devices consisting of FI and FM layers, both the LSSE and ANE can constructively contribute to the output voltage, leading to largely enhanced TE signals 20 , 21 . To pave the way for practical sensing applications using the LSSE, here we have demonstrated LSSE-based heat-flow sensing sheets. The concept of the LSSE-based flexible TE sheet is schematically depicted in Fig. 1 . The sheet consists of a magnetic (ferro- or ferrimagnetic) film with in-plane magnetization M and a metallic film formed on a flexible substrate. When a heat flux q flows through the TE sheet perpendicularly to the film plane, a spin current density j s is induced by q via the LSSE. The value of j s is proportional to q (| j s | ∝ q ). Then, j s is converted into an electric field in the transverse direction via the inverse spin Hall effect (ISHE) 22 , 23 : Figure 1 Concept of TE sheet for heat-flow sensing based on the LSSE. The LSSE-based TE sheet consists of a metallic film and a magnetic (ferro- or ferrimagnetic) film formed on a flexible substrate. When a heat flux q flows through the TE sheet, a spin current j s is induced and injected from the ferrite film into the metallic film by the LSSE. Then the j s is finally converted into an electric voltage V as a result of the inverse spin Hall effect (ISHE) in the metallic film. The thin and simple bilayer structure of the TE sheet allows us to design novel heat-flow sensors with low thermal resistance and a flexible shape. Full size image In the above equation, θ SH and ρ represent the spin-Hall angle and resistivity of the metallic film, respectively. Therefore, the voltage signal V between the two ends of the TE sheet can be employed to evaluate the heat flux q penetrating through the sheet, because V is proportional to q ( V = E ISHE l ∝ q ). Here,", "role": "user" }, { "content": "A thermoelectric (TE) device using cutting edge thermoelectric conversion technology has been created by a team comprising NEC Corporation, NEC TOKIN Corporation and Tohoku University. The new technology, known as the spin Seebeck effect, has conversion efficiency 10 times higher than the conventional method. Thermoelectric conversion technology that converts energy abandoned as waste heat back to electric power could potentially save energy and reduce greenhouse gas emissions. Although conventional spin Seebeck thermoelectric devices have the advantage of low manufacturing costs and high versatility and durability, their energy conversion efficiency is inferior. \"We have improved the conversion efficiency of this spin Seebeck thermoelectric device by more than 10 times because of its newly developed material and device structure,\" says Soichi Tsumura, General Manager, IoT Device Research Laboratories, NEC Corporation. \"Furthermore, devices made of flexible material, such as resin, have been achieved using a manufacturing process that does not require high-temperature heat treatment.\" \"The conversion efficiency of this new spin thermoelectric device has been improved by almost one million times when compared to the earliest device, and has taken an important step towards practical use as a generator element. The achievement of practical use as a heat flux sensor is also in sight,\" says Tsumura. Devices with bending resistance and low heat treatment temperature achieved by new deposition technology.New deposition technology fabricates a fine ferrite film for spin Seebeck thermoelectric devices at 90°C, much lower than the 700°C used with the conventional method. Owing to the decrease in heat treatment temperature, elements can be created on the surface of plastic film, etc., and flexible devices of various shapes are created. Credit: NEC Corporation The three parties aim to further the research and development of technologies to generate electricity from the large amount of waste heat emitted by things such as plants, data centers and vehicles. These results were achieved as part of the \"Saitoh Spin Quantum Rectification Project\" led by Tohoku University Professor Eiji Saitoh. It is funded by the Exploratory Research for Advanced Technology (ERATO) program of the Japan Science and Technology Agency (JST). ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Heat-flow sensing is expected to be an important technological component of smart thermal management in the future. Conventionally, the thermoelectric (TE) conversion technique, which is based on the Seebeck effect, has been used to measure a heat flow by converting the flow into electric voltage. However, for ubiquitous heat-flow visualization, thin and flexible sensors with extremely low thermal resistance are highly desired. Recently, another type of TE effect, the longitudinal spin Seebeck effect (LSSE), has aroused great interest because the LSSE potentially offers favourable features for TE applications such as simple thin-film device structures. Here we demonstrate an LSSE-based flexible TE sheet that is especially suitable for a heat-flow sensing application. This TE sheet contained a Ni 0.2 Zn 0.3 Fe 2.5 O 4 film which was formed on a flexible plastic sheet using a spray-coating method known as “ferrite plating”. The experimental results suggest that the ferrite-plated film, which has a columnar crystal structure aligned perpendicular to the film plane, functions as a unique one-dimensional spin-current conductor suitable for bendable LSSE-based sensors. This newly developed thin TE sheet may be attached to differently shaped heat sources without obstructing an innate heat flux, paving the way to versatile heat-flow measurements and management. Introduction As efficient energy utilization is becoming a crucially important issue for sustainable future, a heat management technique to optimally control the flow of omnipresent thermal energy is currently of great interest. To realize smart thermal management with real-time controllability, there has been a growing demand for visualizing the flow of heat in various places such as industrial facilities and large-scale data centres. The thermoelectric (TE) conversion technique 1 , 2 , 3 , which directly converts a thermal gradient into an electric current, is one of the most powerful methods utilized to sense a heat flow as a voltage signal. In fact, heat-flow sensors based on the Seebeck effect 4 , which have thermopile structures consisting of π-structured thermocouples, are commercially available and used for various purposes such as the evaluation of materials. To further extend heat-flow-sensing capabilities to other widespread applications, however, such conventional devices face certain challenges. First, because Seebeck-based TE devices exhibit a relatively high heat resistance, the introduction of these devices into a heat-flow environment inevitably obstructs the heat flux and alters the distribution of the heat flow. Therefore, it is difficult to correctly evaluate the innate heat flux which we actually want to determine. Second, most of the commercially available heat-flow sensors are rigid and not easily applied to curved or uneven surfaces, making it difficult to monitor the heat flux around irregularly shaped heat sources. Because conventional TE devices, in which thermocouples are connected electrically in series, are intrinsically vulnerable to bending stresses, materials and structures for flexible TE devices have been extensively studied 5 , 6 , 7 . For such sensing applications, an emerging research field, spin caloritronics 8 , 9 , will provide new device-design opportunities. For example, TE devices based on the anomalous Nernst effect (ANE), which exhibit transverse TE voltage in ferromagnetic metals (FM), can be suitably utilized for sensing purposes 9 , 10 , 11 , 12 , 13 . In this work, we present another promising approach to realizing flexible heat flow sensors using the longitudinal spin Seebeck effect (LSSE) 14 , 15 , 16 , 17 , 18 . First reported in 2010, the LSSE offers an unconventional method to design TE devices by making use of a physical quantity called a spin current. The LSSE devices, typically composed of a ferromagnetic insulator (FI) and a normal metallic film (NM), have gained attention because of the simple device structure and novel scaling capability, leading to novel TE devices 16 . The LSSE also has potential to realize practical sensing applications. It is recently reported that FI/NM multilayer structure unexpectedly exhibit significantly enhanced LSSE signal 19 , which may lead to high-sensitive heat-flow sensors. Furthermore, combination of the LSSE and ANE is also a quite hopeful approach. In hybrid TE devices consisting of FI and FM layers, both the LSSE and ANE can constructively contribute to the output voltage, leading to largely enhanced TE signals 20 , 21 . To pave the way for practical sensing applications using the LSSE, here we have demonstrated LSSE-based heat-flow sensing sheets. The concept of the LSSE-based flexible TE sheet is schematically depicted in Fig. 1 . The sheet consists of a magnetic (ferro- or ferrimagnetic) film with in-plane magnetization M and a metallic film formed on a flexible substrate. When a heat flux q flows through the TE sheet perpendicularly to the film plane, a spin current density j s is induced by q via the LSSE. The value of j s is proportional to q (| j s | ∝ q ). Then, j s is converted into an electric field in the transverse direction via the inverse spin Hall effect (ISHE) 22 , 23 : Figure 1 Concept of TE sheet for heat-flow sensing based on the LSSE. The LSSE-based TE sheet consists of a metallic film and a magnetic (ferro- or ferrimagnetic) film formed on a flexible substrate. When a heat flux q flows through the TE sheet, a spin current j s is induced and injected from the ferrite film into the metallic film by the LSSE. Then the j s is finally converted into an electric voltage V as a result of the inverse spin Hall effect (ISHE) in the metallic film. The thin and simple bilayer structure of the TE sheet allows us to design novel heat-flow sensors with low thermal resistance and a flexible shape. Full size image In the above equation, θ SH and ρ represent the spin-Hall angle and resistivity of the metallic film, respectively. Therefore, the voltage signal V between the two ends of the TE sheet can be employed to evaluate the heat flux q penetrating through the sheet, because V is proportional to q ( V = E ISHE l ∝ q ). Here,<|im_end|> <|im_start|>assistant A thermoelectric (TE) device using cutting edge thermoelectric conversion technology has been created by a team comprising NEC Corporation, NEC TOKIN Corporation and Tohoku University. The new technology, known as the spin Seebeck effect, has conversion efficiency 10 times higher than the conventional method. Thermoelectric conversion technology that converts energy abandoned as waste heat back to electric power could potentially save energy and reduce greenhouse gas emissions. Although conventional spin Seebeck thermoelectric devices have the advantage of low manufacturing costs and high versatility and durability, their energy conversion efficiency is inferior. "We have improved the conversion efficiency of this spin Seebeck thermoelectric device by more than 10 times because of its newly developed material and device structure," says Soichi Tsumura, General Manager, IoT Device Research Laboratories, NEC Corporation. "Furthermore, devices made of flexible material, such as resin, have been achieved using a manufacturing process that does not require high-temperature heat treatment." "The conversion efficiency of this new spin thermoelectric device has been improved by almost one million times when compared to the earliest device, and has taken an important step towards practical use as a generator element. The achievement of practical use as a heat flux sensor is also in sight," says Tsumura. Devices with bending resistance and low heat treatment temperature achieved by new deposition technology.New deposition technology fabricates a fine ferrite film for spin Seebeck thermoelectric devices at 90°C, much lower than the 700°C used with the conventional method. Owing to the decrease in heat treatment temperature, elements can be created on the surface of plastic film, etc., and flexible devices of various shapes are created. Credit: NEC Corporation The three parties aim to further the research and development of technologies to generate electricity from the large amount of waste heat emitted by things such as plants, data centers and vehicles. These results were achieved as part of the "Saitoh Spin Quantum Rectification Project" led by Tohoku University Professor Eiji Saitoh. It is funded by the Exploratory Research for Advanced Technology (ERATO) program of the Japan Science and Technology Agency (JST). <|im_end|>

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1,746

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The character and health of ecosystems worldwide is tightly coupled to changes in Earth’s climate. Theory suggests that ecosystem resilience—the ability of ecosystems to resist and recover from external shocks such as droughts and fires—can be inferred from their natural variability. Here, we quantify vegetation resilience globally with complementary metrics based on two independent long-term satellite records. We first empirically confirm that the recovery rates from large perturbations can be closely approximated from internal vegetation variability across vegetation types and climate zones. On the basis of this empirical relationship, we quantify vegetation resilience continuously and globally from 1992 to 2017. Long-term vegetation resilience trends are spatially heterogeneous, with overall increasing resilience in the tropics and decreasing resilience at higher latitudes. Shorter-term trends, however, reveal a marked shift towards a global decline in vegetation resilience since the early 2000s, particularly in the equatorial rainforest belt. Main Natural ecosystems are severely threatened by climate change and biodiversity loss; the Amazon, African and southeast Asian rainforests are key examples that have attracted substantial recent attention 1 , 2 , 3 . These tropical vegetation systems have been inferred to exhibit multistability for broad ranges of mean annual precipitation 4 , 5 ; within the same precipitation ranges, both the rainforest state and an alternative savannah state are simultaneously stable. This implies that, even absent long-term changes in local or regional precipitation, transitions from the current rainforest state to the savannah state are possible and may be triggered by external perturbations such as droughts, forest fires and deforestation 6 . Although ecosystem transitions in tropical rainforests have received widespread attention, the risk of transitions to alternative ecosystem states appears to be a global characteristic that extends to high-latitude 7 , 8 and dryland ecosystems 9 . Given that ecosystem transitions could turn net carbon sinks into carbon sources 3 and the tremendous potential of vegetation to reduce atmospheric carbon dioxide concentrations 10 , the mitigation of anthropogenic climate change and the maintenance of global biodiversity are strongly dependent on the resilience of vegetation systems worldwide. Ecosystem resilience is typically defined as the capacity to resist and recover from external disturbances 11 , 12 , 13 . Unfortunately, this definition only allows for the empirical measurement of resilience either in controlled experiments (by applying an artificial disturbance) or by waiting for occurrences of large external disturbances to natural vegetation systems. Due to the scarcity of suitably strong external perturbations, it is difficult to quantify the resilience of natural ecosystems at a global scale, and in particular to investigate resilience changes over time. Theoretically, the fluctuation–dissipation theorem (FDT) from statistical mechanics 14 , 15 , 16 , 17 suggests that for specific classes of systems, the response to external perturbations can be expressed in terms of the characteristics of natural fluctuations around the equilibrium state. In other words, the FDT states that the rate at which a system will return to equilibrium following an external disturbance can be determined from its internal natural fluctuations. The tremendous practical value of the FDT comes from the fact that, if it can be shown to hold for a given system, the response to external perturbations can be predicted on the basis of the internal variability of the system in question. Evidence that the FDT holds has been revealed in several real-world systems 17 , ranging from financial market data 18 , 19 to atmospheric and climate dynamics 20 , 21 . Several studies have suggested that the lag-one autocorrelation (AC1)—a measure of how strongly correlated neighbouring time spans of a given time series are—and variance of a system can be used as measures of vegetation resilience 1 , 22 , 23 , 24 , 25 , 26 , 27 . The variability of natural fluctuations can be estimated in terms of the variance 22 , 27 , 28 , while the strength of the system’s memory can be measured using the AC1 1 , 23 , 24 , 25 , 28 . Low-dimensional dynamical system frameworks and designed experiments justify this choice by showing that variance and AC1 increase as the system approaches a critical threshold beyond which a bifurcation-induced transition—a jump to an alternative stable state—occurs, which is interpreted as a loss of resilience 29 , 30 . The increase in AC1 together with a corresponding increase in variance have been termed early-warning signals for critical transitions; the underlying change in dynamics is referred to as ‘critical slowing down’ 22 , 28 . It has been shown that early-warning signals can be identified before abrupt climate transitions evidenced in palaeoclimate records 31 , 32 , 33 as well as in ecosystem 28 and climate 34 , 35 model simulations. However, although the AC1 and variance have been used to quantify the stability or resilience of different systems, their actual suitability as measures of ecosystem, and in particular vegetation, resilience has not been confirmed outside of controlled and model-based experiments 36 , 37 , and in particular not based on empirical evidence. In this article, we use empirical remotely sensed vegetation data to test for the correspondence between theoretical vegetation resilience—AC1 and variance—and the rates of recovery from perturbations. We first use large perturbations to derive empirical recovery rates for diverse landscapes, vegetation types and climate zones using two independent vegetation datasets based on optical (advanced very-high-resolution radiometer (AVHRR) normalized difference vegetation index (NDVI), 1981–2015 38 ) and passive microwave (vegetation optical depth (VOD), 1992–2017 39 ) data; these data measure changes in vegetation with different methods and thus provide complementary information for our analysis. We then show that for VOD, the empirically estimated recovery rates from large external perturbations are indeed closely related to the continuously measurable response to small natural fluctuations, quantified here by AC1 and variance. We further show that the AC1 and variance of NDVI are not well matched to empirically estimated recovery rates from large disturbances and conclude that VOD is a more suitable basis for measuring vegetation resilience. We emphasize that while", "role": "user" }, { "content": "A natural habitat's ability to withstand and recover from damage can be empirically monitored from space—and the method may prove important during upcoming decades of climate and land-use change. The first study to empirically document that vegetation resilience can be measured from space is published today in Nature Climate Change by a research team from the University of Potsdam, the Potsdam Institute for Climate Impact Research (PIK), the Technical University of Munich (TUM) and the University of Exeter. The method will likely be important for future assessments of declines in vegetation resilience due to anthropogenic climate change and unsustainable resource management. \"New ways of handling large data sets make it possible to check on widely held theories and assumptions about how ecosystems function,\" said lead author Taylor Smith, from the University of Potsdam. \"Our work empirically confirms of one of those theories—that it is possible to measure how resilient vegetation is to outside pressure with a straightforward mathematical model.\" The study used observational data to estimate the variability of global vegetation as well as the speed of recovery after large losses in vegetation. By analyzing different satellite products since 1992, the group shows that simple metrics can be used to estimate the resilience of ecosystems to large shocks—even where large losses of vegetation haven't happened yet. \"So far it has been difficult to reliably measure vegetation resilience at a global scale,\" said co-author Niklas Boers, TUM, PIK and Exeter's Global Systems Institute. \"We used powerful mathematical results to overcome this problem. This allows us to continuously measure changes in vegetation resilience at any place on the Earth's surface. We provide a solid, empirically confirmed framework for monitoring vegetation resilience from space.\" The work further reveals that in many regions, global vegetation has lost resilience over the last two decades, meaning vegetation has become more vulnerable and takes longer to regain its natural equilibrium after disturbances. \"Vegetation resilience can be thought of as the ability to recover from large shocks such as droughts or fires. We find very different long-term trends in resilience—depending on climate zone and vegetation type—but overall, declines in vegetation resilience have become more common during the last two decades,\" said Smith. The analysis shows that on average, vegetation initially gained resilience globally during the '90s. Then a shift took place with a more pronounced resilience loss since the early 2000s. The finding indicates that especially tropical rainforests and Siberian Boreal forests have grown more vulnerable to events like wildfires, pests, human disturbances, and natural catastrophes. Numerous factors might contribute to this shift, such as natural variability, anthropogenic climate change, increasing human land use and deforestation, and a higher frequency of droughts and wildfires. \"We urgently need to intensify our efforts to detect potential changes in vegetation resilience and to understand the underlying drivers,\" said Boers. \"We expect anthropogenic global heating as well as land-use change to play an important role, but many processes aren't well understood, making it difficult to predict the fate of natural vegetation systems in the coming decades.\" Smith added: \"Satellite data can play a crucial role here, particularly in continuously monitoring the health of vegetation and other ecosystems.\" The study is part of the TiPES project, an EU Horizon 2020 interdisciplinary climate science project on tipping points in the Earth system. Eighteen partner institutions work together in more than 10 countries. TiPES is coordinated and led by The Niels Bohr Institute at the University of Copenhagen, Denmark and the Potsdam Institute for Climate Impact Research, Germany. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The character and health of ecosystems worldwide is tightly coupled to changes in Earth’s climate. Theory suggests that ecosystem resilience—the ability of ecosystems to resist and recover from external shocks such as droughts and fires—can be inferred from their natural variability. Here, we quantify vegetation resilience globally with complementary metrics based on two independent long-term satellite records. We first empirically confirm that the recovery rates from large perturbations can be closely approximated from internal vegetation variability across vegetation types and climate zones. On the basis of this empirical relationship, we quantify vegetation resilience continuously and globally from 1992 to 2017. Long-term vegetation resilience trends are spatially heterogeneous, with overall increasing resilience in the tropics and decreasing resilience at higher latitudes. Shorter-term trends, however, reveal a marked shift towards a global decline in vegetation resilience since the early 2000s, particularly in the equatorial rainforest belt. Main Natural ecosystems are severely threatened by climate change and biodiversity loss; the Amazon, African and southeast Asian rainforests are key examples that have attracted substantial recent attention 1 , 2 , 3 . These tropical vegetation systems have been inferred to exhibit multistability for broad ranges of mean annual precipitation 4 , 5 ; within the same precipitation ranges, both the rainforest state and an alternative savannah state are simultaneously stable. This implies that, even absent long-term changes in local or regional precipitation, transitions from the current rainforest state to the savannah state are possible and may be triggered by external perturbations such as droughts, forest fires and deforestation 6 . Although ecosystem transitions in tropical rainforests have received widespread attention, the risk of transitions to alternative ecosystem states appears to be a global characteristic that extends to high-latitude 7 , 8 and dryland ecosystems 9 . Given that ecosystem transitions could turn net carbon sinks into carbon sources 3 and the tremendous potential of vegetation to reduce atmospheric carbon dioxide concentrations 10 , the mitigation of anthropogenic climate change and the maintenance of global biodiversity are strongly dependent on the resilience of vegetation systems worldwide. Ecosystem resilience is typically defined as the capacity to resist and recover from external disturbances 11 , 12 , 13 . Unfortunately, this definition only allows for the empirical measurement of resilience either in controlled experiments (by applying an artificial disturbance) or by waiting for occurrences of large external disturbances to natural vegetation systems. Due to the scarcity of suitably strong external perturbations, it is difficult to quantify the resilience of natural ecosystems at a global scale, and in particular to investigate resilience changes over time. Theoretically, the fluctuation–dissipation theorem (FDT) from statistical mechanics 14 , 15 , 16 , 17 suggests that for specific classes of systems, the response to external perturbations can be expressed in terms of the characteristics of natural fluctuations around the equilibrium state. In other words, the FDT states that the rate at which a system will return to equilibrium following an external disturbance can be determined from its internal natural fluctuations. The tremendous practical value of the FDT comes from the fact that, if it can be shown to hold for a given system, the response to external perturbations can be predicted on the basis of the internal variability of the system in question. Evidence that the FDT holds has been revealed in several real-world systems 17 , ranging from financial market data 18 , 19 to atmospheric and climate dynamics 20 , 21 . Several studies have suggested that the lag-one autocorrelation (AC1)—a measure of how strongly correlated neighbouring time spans of a given time series are—and variance of a system can be used as measures of vegetation resilience 1 , 22 , 23 , 24 , 25 , 26 , 27 . The variability of natural fluctuations can be estimated in terms of the variance 22 , 27 , 28 , while the strength of the system’s memory can be measured using the AC1 1 , 23 , 24 , 25 , 28 . Low-dimensional dynamical system frameworks and designed experiments justify this choice by showing that variance and AC1 increase as the system approaches a critical threshold beyond which a bifurcation-induced transition—a jump to an alternative stable state—occurs, which is interpreted as a loss of resilience 29 , 30 . The increase in AC1 together with a corresponding increase in variance have been termed early-warning signals for critical transitions; the underlying change in dynamics is referred to as ‘critical slowing down’ 22 , 28 . It has been shown that early-warning signals can be identified before abrupt climate transitions evidenced in palaeoclimate records 31 , 32 , 33 as well as in ecosystem 28 and climate 34 , 35 model simulations. However, although the AC1 and variance have been used to quantify the stability or resilience of different systems, their actual suitability as measures of ecosystem, and in particular vegetation, resilience has not been confirmed outside of controlled and model-based experiments 36 , 37 , and in particular not based on empirical evidence. In this article, we use empirical remotely sensed vegetation data to test for the correspondence between theoretical vegetation resilience—AC1 and variance—and the rates of recovery from perturbations. We first use large perturbations to derive empirical recovery rates for diverse landscapes, vegetation types and climate zones using two independent vegetation datasets based on optical (advanced very-high-resolution radiometer (AVHRR) normalized difference vegetation index (NDVI), 1981–2015 38 ) and passive microwave (vegetation optical depth (VOD), 1992–2017 39 ) data; these data measure changes in vegetation with different methods and thus provide complementary information for our analysis. We then show that for VOD, the empirically estimated recovery rates from large external perturbations are indeed closely related to the continuously measurable response to small natural fluctuations, quantified here by AC1 and variance. We further show that the AC1 and variance of NDVI are not well matched to empirically estimated recovery rates from large disturbances and conclude that VOD is a more suitable basis for measuring vegetation resilience. We emphasize that while<|im_end|> <|im_start|>assistant A natural habitat's ability to withstand and recover from damage can be empirically monitored from space—and the method may prove important during upcoming decades of climate and land-use change. The first study to empirically document that vegetation resilience can be measured from space is published today in Nature Climate Change by a research team from the University of Potsdam, the Potsdam Institute for Climate Impact Research (PIK), the Technical University of Munich (TUM) and the University of Exeter. The method will likely be important for future assessments of declines in vegetation resilience due to anthropogenic climate change and unsustainable resource management. "New ways of handling large data sets make it possible to check on widely held theories and assumptions about how ecosystems function," said lead author Taylor Smith, from the University of Potsdam. "Our work empirically confirms of one of those theories—that it is possible to measure how resilient vegetation is to outside pressure with a straightforward mathematical model." The study used observational data to estimate the variability of global vegetation as well as the speed of recovery after large losses in vegetation. By analyzing different satellite products since 1992, the group shows that simple metrics can be used to estimate the resilience of ecosystems to large shocks—even where large losses of vegetation haven't happened yet. "So far it has been difficult to reliably measure vegetation resilience at a global scale," said co-author Niklas Boers, TUM, PIK and Exeter's Global Systems Institute. "We used powerful mathematical results to overcome this problem. This allows us to continuously measure changes in vegetation resilience at any place on the Earth's surface. We provide a solid, empirically confirmed framework for monitoring vegetation resilience from space." The work further reveals that in many regions, global vegetation has lost resilience over the last two decades, meaning vegetation has become more vulnerable and takes longer to regain its natural equilibrium after disturbances. "Vegetation resilience can be thought of as the ability to recover from large shocks such as droughts or fires. We find very different long-term trends in resilience—depending on climate zone and vegetation type—but overall, declines in vegetation resilience have become more common during the last two decades," said Smith. The analysis shows that on average, vegetation initially gained resilience globally during the '90s. Then a shift took place with a more pronounced resilience loss since the early 2000s. The finding indicates that especially tropical rainforests and Siberian Boreal forests have grown more vulnerable to events like wildfires, pests, human disturbances, and natural catastrophes. Numerous factors might contribute to this shift, such as natural variability, anthropogenic climate change, increasing human land use and deforestation, and a higher frequency of droughts and wildfires. "We urgently need to intensify our efforts to detect potential changes in vegetation resilience and to understand the underlying drivers," said Boers. "We expect anthropogenic global heating as well as land-use change to play an important role, but many processes aren't well understood, making it difficult to predict the fate of natural vegetation systems in the coming decades." Smith added: "Satellite data can play a crucial role here, particularly in continuously monitoring the health of vegetation and other ecosystems." The study is part of the TiPES project, an EU Horizon 2020 interdisciplinary climate science project on tipping points in the Earth system. Eighteen partner institutions work together in more than 10 countries. TiPES is coordinated and led by The Niels Bohr Institute at the University of Copenhagen, Denmark and the Potsdam Institute for Climate Impact Research, Germany. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Population scale sweeps of viral pathogens, such as SARS-CoV-2, require high intensity testing for effective management. Here, we describe “Systematic Parallel Analysis of RNA coupled to Sequencing for Covid-19 screening” (C19-SPAR-Seq), a multiplexed, scalable, readily automated platform for SARS-CoV-2 detection that is capable of analyzing tens of thousands of patient samples in a single run. To address strict requirements for control of assay parameters and output demanded by clinical diagnostics, we employ a control-based Precision-Recall and Receiver Operator Characteristics (coPR) analysis to assign run-specific quality control metrics. C19-SPAR-Seq coupled to coPR on a trial cohort of several hundred patients performs with a specificity of 100% and sensitivity of 91% on samples with low viral loads, and a sensitivity of >95% on high viral loads associated with disease onset and peak transmissibility. This study establishes the feasibility of employing C19-SPAR-Seq for the large-scale monitoring of SARS-CoV-2 and other pathogens. Introduction Viral pathogens, such as SARS-CoV-2, that incorporate large numbers of asymptomatic or mild symptom patients present unique challenges for public health agencies trying to manage both travel and local spread. Physical distancing is the current major strategy to suppress spread of the disease, but with enormous socio-economic costs. However, modeling and studies in isolated jurisdictions suggest that active population surveillance through systematic molecular diagnostics, combined with contact tracing and focused quarantining can significantly suppress disease spread 1 , 2 , 3 and has significantly impacted disease transmission rates, the number of infected people, and prevented saturation of the healthcare system 4 , 5 , 6 , 7 . However, reliable systems allowing for parallel testing of tens of thousands to hundreds of thousands of patients in larger urban environments have not yet been employed. Here we describe “COVID-19 screening using Systematic Parallel Analysis of RNA coupled to Sequencing” (C19-SPAR-Seq), which is a next generation sequencing (NGS)-based platform 8 for analyzing tens of thousands of COVID-19 patient samples in a single instrument run. To enable NGS-based diagnostics we employed large numbers of control samples embedded in each run coupled to control-based Precision-Recall and predictive Receiver Operator Characteristics (coPR) analysis that assigns run-specific thresholds and quality control metrics. C19-SPAR-Seq coupled to coPR on a trial cohort of over 600 patients performed with a specificity of 100% and sensitivity of 91% on samples with low viral loads versus >95% on samples with the higher viral loads associated with disease onset and peak transmissibility. Our study thus establishes the feasibility of employing C19-SPAR-Seq for the large-scale monitoring of SARS-CoV-2 and other pathogens. Results Multiplex detection of SARS-CoV-2 using C19-SPAR-Seq The current gold standard diagnostic for SARS-CoV-2 is Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR), which is not readily adaptable to large-scale population testing 9 . To establish a population-scale testing platform we designed a SPAR-Seq multiplex primer mix v1 that targets RNA-dependent RNA polymerase ( RdRP ), Envelope ( E ), Nucleocapsid ( N ), and two regions of the Spike ( S ) gene that correspond to the receptor-binding domain (RBD) and the polybasic cleavage site (PBS) (Fig. 1a , Supplementary Table 1 and Supplementary Data 1 ). The latter two are SARS-CoV-2-specific regions that capture five key residues necessary for ACE2 receptor binding ( Srbd ) and the furin cleavage site ( Spbs ) that is critical for viral infectivity 10 , 11 . Thus, the RdRP-specific primers could produce an amplicon from SARS-CoV-1 that can be readily distinguished based on sequence analysis, while the Spike-specific primers, targeting the RBD and Polybasic site regions, would distinguish a SARS-CoV-2 infection. For quality control, we targeted Peptidylprolyl Isomerase B ( PPIB ). Current standard testing strategies for viral pathogens employ gene-specific primers in “all-in-one” qRT-PCR reactions that could in principle be adapted to incorporate barcodes into gene-specific primers. However, to allow for rapid adaptation to test for novel and multiple pathogens, and/or profiling host responses we used a generic oligo-dT and random hexamer primed reverse transcription step followed by multiplex PCR and barcoding in a rapid, readily automated format we call “COVID-19 screening using Systematic Parallel Analysis of RNA coupled to Sequencing” or C19-SPAR-Seq (Fig. 1b , Supplementary Table 1 and Supplementary Data 1 ). Although cost is often cited as a concern for NGS-based testing, our platform is cost effective with retail material costs ranging from USD ~$9 to $6 for 500 versus 10,000 sample batch sizes, respectively (Supplementary Data 2 ). Fig. 1: Application of C19-SPAR-Seq to detect SARS-CoV-2. a Schematic representation of the SARS-CoV-2 with the five regions targeted for multiplex C19-SPAR-Seq indicated: RdRP (purple), S receptor-binding domain ( Srbd ) (red), S polybasic cleavage site ( Spbs ) (light red), E (yellow), and N (orange). b Schematic of the C19-SPAR-Seq strategy for detecting SARS-CoV-2. cDNA is synthesized using reverse transcriptase (RT) from RNA extracted from clinical samples, subjected to multiplex PCR, then barcoded, pooled, and analyzed by next generation sequencing (NGS). c Analysis of archival NASOP swab eluents by C19-SPAR-Seq. A Proof-of-Concept (PoC) cohort ( n = 19) was analyzed by C19-SPAR-Seq and read numbers for each of the indicated amplicons are presented in a heatmap. Control samples (HEK293T, synthetic SARS-CoV-2 RNA) are represented in the left panel, while the right panel shows unsupervised 2D hierarchical clustering of results from negative (blue) and positive (red) patients. Full size image To assess C19-SPAR-Seq performance, we assembled a proof-of-concept (PoC) cohort of 19 archival Nasopharyngeal (NASOP) swab eluents from the Toronto University Health Network-Mount Sinai Hospital clinical diagnostics lab (Supplementary Data 3 ), 17 of which were positive for SARS-CoV-2. Viral load in these archival samples was quantified using the clinically approved TaqMan-based SARS-CoV-2 RT-qPCR detection kit (‘BGI’, see the “Methods” section), which identified five SARS-CoV-2 low (Ct > 25), seven SARS-CoV-2 medium (Ct between 20 and 25), and five SARS-CoV-2 high (Ct < 20) patients (Supplementary Data 3 ). After confirming the efficiency of multiplex v1 primer pairs using a SARS-CoV-2 high sample (LTRI-18, Ct < 20; Supplementary Fig. 1 ), we performed C19-SPAR-Seq using HEK293T RNA as a negative control (", "role": "user" }, { "content": "A robotics platform designed by Toronto researchers to screen thousands of COVID-19 samples at once has the potential to revolutionize how labs track the spread of viruses and other pathogens, according to new findings. The study, out Wednesday in Nature Communications, found that the next-generation, ultra-high-throughput sequencing platform, called C19-SPAR-Seq, designed by researchers from the Lunenfeld-Tanenbaum Research Institute (LTRI) at Sinai Health, has a sensitivity rate greater than 95 percent in positive cases during peak onset. \"Identifying positive samples quickly and accurately is critical in beating this pandemic,\" said Dr. Jeff Wrana, senior investigator at the LTRI and professor in the Department of Molecular Genetics at the University of Toronto. \"With new and potentially dangerous variants now circulating, this is a platform that is scalable, automated and capable of analyzing thousands of COVID-19 patient samples in a single instrument run.\" Wrana and fellow LTRI senior investigator Dr. Laurence Pelletier, in collaboration with University of Toronto professor Dr. Ben Blencowe, credit a strong team of eager trainees who shifted from other areas of research to help develop and validate the platform, allowing for the team to go from concept to published paper in under 12 months. \"The co-operation of the Mount Sinai Hospital clinical diagnostic lab was the other key ingredient to our success,\" said Pelletier. \"To date the shared microbiology lab, headed by Dr. Tony Mazzulli, has provided access to thousands of samples.\" In late 2020, the team pivoted again to use the robotics platform to screen thousands of positive samples for variants by rapidly sequencing fingerprint regions of the viral genome to look for key mutations. \"It has been an absolute pleasure to work with Dr. Jeff Wrana and his team at the LTRI,\" said Dr. Mazzulli, microbiologist-in-chief for Sinai Health and University Health Network (UHN). \"His novel SPAR-Seq System is cutting-edge technology and his team's ability to sequence COVID-19 samples in real time has tremendous potential for impacting our understanding of the epidemiology and spread of novel mutants in the province.\" The platform is also cost-effective. The study notes it only costs about $8 USD per test when running thousands of samples at once, as the cost per sample decreases due to economies of scale. \"It's extremely reliable and readily adaptable,\" said Javier Hernandez, a junior researcher in the Wrana lab who co-led the study with Drs. Marie-Ming Aynaud and Seda Barutcu. \"The turnaround is approximately 24 hours. It's very simple as we've automated practically every step in the process. For me, it's been a very exciting thing to see my work make a difference.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Population scale sweeps of viral pathogens, such as SARS-CoV-2, require high intensity testing for effective management. Here, we describe “Systematic Parallel Analysis of RNA coupled to Sequencing for Covid-19 screening” (C19-SPAR-Seq), a multiplexed, scalable, readily automated platform for SARS-CoV-2 detection that is capable of analyzing tens of thousands of patient samples in a single run. To address strict requirements for control of assay parameters and output demanded by clinical diagnostics, we employ a control-based Precision-Recall and Receiver Operator Characteristics (coPR) analysis to assign run-specific quality control metrics. C19-SPAR-Seq coupled to coPR on a trial cohort of several hundred patients performs with a specificity of 100% and sensitivity of 91% on samples with low viral loads, and a sensitivity of >95% on high viral loads associated with disease onset and peak transmissibility. This study establishes the feasibility of employing C19-SPAR-Seq for the large-scale monitoring of SARS-CoV-2 and other pathogens. Introduction Viral pathogens, such as SARS-CoV-2, that incorporate large numbers of asymptomatic or mild symptom patients present unique challenges for public health agencies trying to manage both travel and local spread. Physical distancing is the current major strategy to suppress spread of the disease, but with enormous socio-economic costs. However, modeling and studies in isolated jurisdictions suggest that active population surveillance through systematic molecular diagnostics, combined with contact tracing and focused quarantining can significantly suppress disease spread 1 , 2 , 3 and has significantly impacted disease transmission rates, the number of infected people, and prevented saturation of the healthcare system 4 , 5 , 6 , 7 . However, reliable systems allowing for parallel testing of tens of thousands to hundreds of thousands of patients in larger urban environments have not yet been employed. Here we describe “COVID-19 screening using Systematic Parallel Analysis of RNA coupled to Sequencing” (C19-SPAR-Seq), which is a next generation sequencing (NGS)-based platform 8 for analyzing tens of thousands of COVID-19 patient samples in a single instrument run. To enable NGS-based diagnostics we employed large numbers of control samples embedded in each run coupled to control-based Precision-Recall and predictive Receiver Operator Characteristics (coPR) analysis that assigns run-specific thresholds and quality control metrics. C19-SPAR-Seq coupled to coPR on a trial cohort of over 600 patients performed with a specificity of 100% and sensitivity of 91% on samples with low viral loads versus >95% on samples with the higher viral loads associated with disease onset and peak transmissibility. Our study thus establishes the feasibility of employing C19-SPAR-Seq for the large-scale monitoring of SARS-CoV-2 and other pathogens. Results Multiplex detection of SARS-CoV-2 using C19-SPAR-Seq The current gold standard diagnostic for SARS-CoV-2 is Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR), which is not readily adaptable to large-scale population testing 9 . To establish a population-scale testing platform we designed a SPAR-Seq multiplex primer mix v1 that targets RNA-dependent RNA polymerase ( RdRP ), Envelope ( E ), Nucleocapsid ( N ), and two regions of the Spike ( S ) gene that correspond to the receptor-binding domain (RBD) and the polybasic cleavage site (PBS) (Fig. 1a , Supplementary Table 1 and Supplementary Data 1 ). The latter two are SARS-CoV-2-specific regions that capture five key residues necessary for ACE2 receptor binding ( Srbd ) and the furin cleavage site ( Spbs ) that is critical for viral infectivity 10 , 11 . Thus, the RdRP-specific primers could produce an amplicon from SARS-CoV-1 that can be readily distinguished based on sequence analysis, while the Spike-specific primers, targeting the RBD and Polybasic site regions, would distinguish a SARS-CoV-2 infection. For quality control, we targeted Peptidylprolyl Isomerase B ( PPIB ). Current standard testing strategies for viral pathogens employ gene-specific primers in “all-in-one” qRT-PCR reactions that could in principle be adapted to incorporate barcodes into gene-specific primers. However, to allow for rapid adaptation to test for novel and multiple pathogens, and/or profiling host responses we used a generic oligo-dT and random hexamer primed reverse transcription step followed by multiplex PCR and barcoding in a rapid, readily automated format we call “COVID-19 screening using Systematic Parallel Analysis of RNA coupled to Sequencing” or C19-SPAR-Seq (Fig. 1b , Supplementary Table 1 and Supplementary Data 1 ). Although cost is often cited as a concern for NGS-based testing, our platform is cost effective with retail material costs ranging from USD ~$9 to $6 for 500 versus 10,000 sample batch sizes, respectively (Supplementary Data 2 ). Fig. 1: Application of C19-SPAR-Seq to detect SARS-CoV-2. a Schematic representation of the SARS-CoV-2 with the five regions targeted for multiplex C19-SPAR-Seq indicated: RdRP (purple), S receptor-binding domain ( Srbd ) (red), S polybasic cleavage site ( Spbs ) (light red), E (yellow), and N (orange). b Schematic of the C19-SPAR-Seq strategy for detecting SARS-CoV-2. cDNA is synthesized using reverse transcriptase (RT) from RNA extracted from clinical samples, subjected to multiplex PCR, then barcoded, pooled, and analyzed by next generation sequencing (NGS). c Analysis of archival NASOP swab eluents by C19-SPAR-Seq. A Proof-of-Concept (PoC) cohort ( n = 19) was analyzed by C19-SPAR-Seq and read numbers for each of the indicated amplicons are presented in a heatmap. Control samples (HEK293T, synthetic SARS-CoV-2 RNA) are represented in the left panel, while the right panel shows unsupervised 2D hierarchical clustering of results from negative (blue) and positive (red) patients. Full size image To assess C19-SPAR-Seq performance, we assembled a proof-of-concept (PoC) cohort of 19 archival Nasopharyngeal (NASOP) swab eluents from the Toronto University Health Network-Mount Sinai Hospital clinical diagnostics lab (Supplementary Data 3 ), 17 of which were positive for SARS-CoV-2. Viral load in these archival samples was quantified using the clinically approved TaqMan-based SARS-CoV-2 RT-qPCR detection kit (‘BGI’, see the “Methods” section), which identified five SARS-CoV-2 low (Ct > 25), seven SARS-CoV-2 medium (Ct between 20 and 25), and five SARS-CoV-2 high (Ct < 20) patients (Supplementary Data 3 ). After confirming the efficiency of multiplex v1 primer pairs using a SARS-CoV-2 high sample (LTRI-18, Ct < 20; Supplementary Fig. 1 ), we performed C19-SPAR-Seq using HEK293T RNA as a negative control (<|im_end|> <|im_start|>assistant A robotics platform designed by Toronto researchers to screen thousands of COVID-19 samples at once has the potential to revolutionize how labs track the spread of viruses and other pathogens, according to new findings. The study, out Wednesday in Nature Communications, found that the next-generation, ultra-high-throughput sequencing platform, called C19-SPAR-Seq, designed by researchers from the Lunenfeld-Tanenbaum Research Institute (LTRI) at Sinai Health, has a sensitivity rate greater than 95 percent in positive cases during peak onset. "Identifying positive samples quickly and accurately is critical in beating this pandemic," said Dr. Jeff Wrana, senior investigator at the LTRI and professor in the Department of Molecular Genetics at the University of Toronto. "With new and potentially dangerous variants now circulating, this is a platform that is scalable, automated and capable of analyzing thousands of COVID-19 patient samples in a single instrument run." Wrana and fellow LTRI senior investigator Dr. Laurence Pelletier, in collaboration with University of Toronto professor Dr. Ben Blencowe, credit a strong team of eager trainees who shifted from other areas of research to help develop and validate the platform, allowing for the team to go from concept to published paper in under 12 months. "The co-operation of the Mount Sinai Hospital clinical diagnostic lab was the other key ingredient to our success," said Pelletier. "To date the shared microbiology lab, headed by Dr. Tony Mazzulli, has provided access to thousands of samples." In late 2020, the team pivoted again to use the robotics platform to screen thousands of positive samples for variants by rapidly sequencing fingerprint regions of the viral genome to look for key mutations. "It has been an absolute pleasure to work with Dr. Jeff Wrana and his team at the LTRI," said Dr. Mazzulli, microbiologist-in-chief for Sinai Health and University Health Network (UHN). "His novel SPAR-Seq System is cutting-edge technology and his team's ability to sequence COVID-19 samples in real time has tremendous potential for impacting our understanding of the epidemiology and spread of novel mutants in the province." The platform is also cost-effective. The study notes it only costs about $8 USD per test when running thousands of samples at once, as the cost per sample decreases due to economies of scale. "It's extremely reliable and readily adaptable," said Javier Hernandez, a junior researcher in the Wrana lab who co-led the study with Drs. Marie-Ming Aynaud and Seda Barutcu. "The turnaround is approximately 24 hours. It's very simple as we've automated practically every step in the process. For me, it's been a very exciting thing to see my work make a difference." <|im_end|>

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2,162

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Colorectal Peritoneal metastases (CPM) develop in 15% of colorectal cancers. Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS & HIPEC) is the current standard of care in selected patients with limited resectable CPM. Despite selection using known prognostic factors survival is varied and morbidity and mortality are relatively high. There is a need to improve patient selection and a paucity of research concerning the biology of isolated CPM. We aimed to determine the biology associated with transition from primary CRC to CPM and of patients with CPM not responding to treatment with CRS & HIPEC, to identify those suitable for treatment with CRS & HIPEC and to identify targets for existing repurposed or novel treatment strategies. A cohort of patients with CPM treated with CRS & HIPEC was recruited and divided according to prognosis. Molecular profiling of the transcriptome (n = 25), epigenome (n = 24) and genome (n = 21) of CPM and matched primary CRC was performed. CPM were characterised by frequent Wnt/ β catenin negative regulator mutations, TET2 mutations, mismatch repair mutations and high tumour mutational burden. Here we show the molecular features associated with CPM development and associated with not responding to CRS & HIPEC. Potential applications include improving patient selection for treatment with CRS & HIPEC and in future research into novel and personalised treatments targeting the molecular features identified here. Background Little is known about the biology of isolated colorectal peritoneal metastasis (CPM), which although a relatively rare phenomenon is one with a high mortality rate 1 . Understanding tumour biology may identify which patients with primary colorectal cancer (CRC) are at risk of developing CPM, and which are suitable for treatment with cytoreductive surgery and heated intra-peritoneal chemotherapy (CRS & HIPEC). CRS & HIPEC (usually using an agent such as mitomycin C or more recently, oxaliplatin) aims to achieve macroscopic tumour resection with multiple visceral and peritoneal resections and ablation of microscopic disease. Five-year survival however varies widely, and morbidity and mortality are relatively high 2 . There is a need therefore to improve patient selection, allowing alternative existing or novel treatment strategies to be used for patients unlikely to respond. Primary CRC research has identified markers of response to specific treatments, for example KRAS mutation in selection for anti-EGFR mAb therapy 3 . Gene expression signatures have been developed and are in clinical use for prognostication and therapeutic stratification in breast cancer 4 , 5 , 6 , 7 . Gene expression profiling in primary CRC has identified signatures associated with the development of metastasis 6 . One small study combining a small number of CPM with a larger cohort of appendix adenocarcinoma identified a signature predictive of reduced overall survival (OS) following CRS & HIPEC; these are however two biologically distinct tumours, appendix having significantly improved prognosis 7 . The dysregulation of methylation is a key step in tumorigenesis CpG island promoter methylation (CIMP) appears to be stable between matched primary CRC and hepatic metastasis suggesting an epigenetic methylation programme is established prior to the development of metastasis 8 , 9 , 10 . Hypermethylation of KRAS, Wnt modulators, tumour suppressor genes, CIMP and hypomethylation of oncogenes are associated with an unfavourable response to chemotherapy and anti-EGFR antibodies as well as tumour recurrence and reduced OS in primary and metastatic CRC 11 , 12 , 13 , 14 , 15 , 16 . Chromosomal instability is ubiquitous in cancer, increased copy number alteration, indicative of chromosomal instability is found in metastatic CRC 17 , 18 . Lopez-Garcia et al. 19 demonstrated that the evolution of chromosomal instability is depending on cellular tolerance, either via dysregulation of TP53 or via alternate escape mechanisms such as dysfunction of BCL9L regulated caspase signalling. CRC metastatic drivers are less clearly defined, apart from TP53 which is well characterised as being present in metastatic cancer 20 . Some studies have found mutations exclusive to metastatic sites 21 , 22 , whereas others found similar patterns of mutation between primary and metastasis 23 . Studies have examined the somatic mutations in CPM and their prognostic implications. These studies are limited to individual or small panels of mutations routinely tested for in clinical practice with limited evidence to suggest which genes should be included in panel sequencing in CPM. Schneider et al. examined the KRAS and BRAF mutation status of patients with CPM who underwent CRS & HIPEC 24 . They found mutations of RAS/RAF were associated with reduced OS independent of the use of targeted anti-EGFR treatment 24 . Sasaki et al. examined the KRAS, BRAF and PIK3CA mutation status of patients with metastatic CRC, with or without CPM 25 . They found the incidence of BRAF mutation was significantly associated with the presence of CPM but not with prognosis 25 . The landscape of metastatic colorectal cancer was studied by the MSK-IMPACT 20 group which undertook panel based sequencing of 1134 metastatic colorectal cancers. Of these 39 patients were defined as “peritoneal” malignancy, it is unclear whether these were isolated peritoneal metastasis. Only 14 of these patients had metasectomy. 7 of these had peritonectomy suggesting isolated disease suitable for resection. These tumours were also not studied with matched primary tumour of origin. There is a need to improve the outcomes for patients with CPM and significant variation in survival despite patient selection for treatment using known prognostic factors. There is a paucity of knowledge concerning CPM tumour biology. Understanding tumour biology will identify patients with primary CRC at risk of developing CPM, those suitable for treatment with CRS & HIPEC or alternative existing and novel treatment strategies. This study aims to determine the landscape of gene expression, methylation, and somatic mutation profile associated with the transition from primary CRC to isolated CPM and determine the association between these and prognosis following CRS & HIPEC in order to identify therapeutic targets. Methods Patient cohorts This study obtained ethical approval from the North West Haydock Research Ethics Committee, (15/NW/0079), project ID (17/283). Participants gave informed consent. All experiments", "role": "user" }, { "content": "A new study from the University of Birmingham has found that 50% of patients with a rare type of cancer that has spread into the lining of their abdomen may be suitable for immunotherapy treatment. Unfortunately for around 1% of bowel cancer patients, their cancer spreads to the lining of their abdomen (peritoneal cavity) - known as colorectal peritoneal metastasis (CPM). This type of spread in bowel cancer patients carries a very poor prognosis and so most patients do not survive beyond 12 months from diagnosis. Patients with CPM have a limited survival rate with the best available treatments. Conventional chemotherapy is ineffective, and current treatment consists of extensive surgery which does not always work. This first of its kind study funded by Good Hope Hospital Charity, found that understanding the tumor biology may identify which patients with bowel cancer are at risk of developing CPM. Results published in Scientific Reports show that by identifying the specific tumor biology of this groups of patients, they carry a specific mutation that makes them sensitive to immunotherapy. Lead author, Professor Andrew Beggs from the University of Birmingham's Institute of Cancer and Genomic Sciences, said: \"We have found that approximately 50% of patients with CPM have a type of genetic change, called hypermutation. This means they may be sensitive to immunotherapy as this type of treatment has good results in other patient groups with hypermutations. \"We also found potential sensitivity to a drug called a Porcupine inhibitor, based on another genetic marker identified in these patients. \"This is the first study of its kind in the world for patients with CPM, and our results have shown this could provide a potentially curative option for patients given the responses we have seen to immunotherapy in other cancers.\" Researchers will now look to set up an international clinical trial to examine the use of immunotherapy for patients with CPM. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Colorectal Peritoneal metastases (CPM) develop in 15% of colorectal cancers. Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS & HIPEC) is the current standard of care in selected patients with limited resectable CPM. Despite selection using known prognostic factors survival is varied and morbidity and mortality are relatively high. There is a need to improve patient selection and a paucity of research concerning the biology of isolated CPM. We aimed to determine the biology associated with transition from primary CRC to CPM and of patients with CPM not responding to treatment with CRS & HIPEC, to identify those suitable for treatment with CRS & HIPEC and to identify targets for existing repurposed or novel treatment strategies. A cohort of patients with CPM treated with CRS & HIPEC was recruited and divided according to prognosis. Molecular profiling of the transcriptome (n = 25), epigenome (n = 24) and genome (n = 21) of CPM and matched primary CRC was performed. CPM were characterised by frequent Wnt/ β catenin negative regulator mutations, TET2 mutations, mismatch repair mutations and high tumour mutational burden. Here we show the molecular features associated with CPM development and associated with not responding to CRS & HIPEC. Potential applications include improving patient selection for treatment with CRS & HIPEC and in future research into novel and personalised treatments targeting the molecular features identified here. Background Little is known about the biology of isolated colorectal peritoneal metastasis (CPM), which although a relatively rare phenomenon is one with a high mortality rate 1 . Understanding tumour biology may identify which patients with primary colorectal cancer (CRC) are at risk of developing CPM, and which are suitable for treatment with cytoreductive surgery and heated intra-peritoneal chemotherapy (CRS & HIPEC). CRS & HIPEC (usually using an agent such as mitomycin C or more recently, oxaliplatin) aims to achieve macroscopic tumour resection with multiple visceral and peritoneal resections and ablation of microscopic disease. Five-year survival however varies widely, and morbidity and mortality are relatively high 2 . There is a need therefore to improve patient selection, allowing alternative existing or novel treatment strategies to be used for patients unlikely to respond. Primary CRC research has identified markers of response to specific treatments, for example KRAS mutation in selection for anti-EGFR mAb therapy 3 . Gene expression signatures have been developed and are in clinical use for prognostication and therapeutic stratification in breast cancer 4 , 5 , 6 , 7 . Gene expression profiling in primary CRC has identified signatures associated with the development of metastasis 6 . One small study combining a small number of CPM with a larger cohort of appendix adenocarcinoma identified a signature predictive of reduced overall survival (OS) following CRS & HIPEC; these are however two biologically distinct tumours, appendix having significantly improved prognosis 7 . The dysregulation of methylation is a key step in tumorigenesis CpG island promoter methylation (CIMP) appears to be stable between matched primary CRC and hepatic metastasis suggesting an epigenetic methylation programme is established prior to the development of metastasis 8 , 9 , 10 . Hypermethylation of KRAS, Wnt modulators, tumour suppressor genes, CIMP and hypomethylation of oncogenes are associated with an unfavourable response to chemotherapy and anti-EGFR antibodies as well as tumour recurrence and reduced OS in primary and metastatic CRC 11 , 12 , 13 , 14 , 15 , 16 . Chromosomal instability is ubiquitous in cancer, increased copy number alteration, indicative of chromosomal instability is found in metastatic CRC 17 , 18 . Lopez-Garcia et al. 19 demonstrated that the evolution of chromosomal instability is depending on cellular tolerance, either via dysregulation of TP53 or via alternate escape mechanisms such as dysfunction of BCL9L regulated caspase signalling. CRC metastatic drivers are less clearly defined, apart from TP53 which is well characterised as being present in metastatic cancer 20 . Some studies have found mutations exclusive to metastatic sites 21 , 22 , whereas others found similar patterns of mutation between primary and metastasis 23 . Studies have examined the somatic mutations in CPM and their prognostic implications. These studies are limited to individual or small panels of mutations routinely tested for in clinical practice with limited evidence to suggest which genes should be included in panel sequencing in CPM. Schneider et al. examined the KRAS and BRAF mutation status of patients with CPM who underwent CRS & HIPEC 24 . They found mutations of RAS/RAF were associated with reduced OS independent of the use of targeted anti-EGFR treatment 24 . Sasaki et al. examined the KRAS, BRAF and PIK3CA mutation status of patients with metastatic CRC, with or without CPM 25 . They found the incidence of BRAF mutation was significantly associated with the presence of CPM but not with prognosis 25 . The landscape of metastatic colorectal cancer was studied by the MSK-IMPACT 20 group which undertook panel based sequencing of 1134 metastatic colorectal cancers. Of these 39 patients were defined as “peritoneal” malignancy, it is unclear whether these were isolated peritoneal metastasis. Only 14 of these patients had metasectomy. 7 of these had peritonectomy suggesting isolated disease suitable for resection. These tumours were also not studied with matched primary tumour of origin. There is a need to improve the outcomes for patients with CPM and significant variation in survival despite patient selection for treatment using known prognostic factors. There is a paucity of knowledge concerning CPM tumour biology. Understanding tumour biology will identify patients with primary CRC at risk of developing CPM, those suitable for treatment with CRS & HIPEC or alternative existing and novel treatment strategies. This study aims to determine the landscape of gene expression, methylation, and somatic mutation profile associated with the transition from primary CRC to isolated CPM and determine the association between these and prognosis following CRS & HIPEC in order to identify therapeutic targets. Methods Patient cohorts This study obtained ethical approval from the North West Haydock Research Ethics Committee, (15/NW/0079), project ID (17/283). Participants gave informed consent. All experiments<|im_end|> <|im_start|>assistant A new study from the University of Birmingham has found that 50% of patients with a rare type of cancer that has spread into the lining of their abdomen may be suitable for immunotherapy treatment. Unfortunately for around 1% of bowel cancer patients, their cancer spreads to the lining of their abdomen (peritoneal cavity) - known as colorectal peritoneal metastasis (CPM). This type of spread in bowel cancer patients carries a very poor prognosis and so most patients do not survive beyond 12 months from diagnosis. Patients with CPM have a limited survival rate with the best available treatments. Conventional chemotherapy is ineffective, and current treatment consists of extensive surgery which does not always work. This first of its kind study funded by Good Hope Hospital Charity, found that understanding the tumor biology may identify which patients with bowel cancer are at risk of developing CPM. Results published in Scientific Reports show that by identifying the specific tumor biology of this groups of patients, they carry a specific mutation that makes them sensitive to immunotherapy. Lead author, Professor Andrew Beggs from the University of Birmingham's Institute of Cancer and Genomic Sciences, said: "We have found that approximately 50% of patients with CPM have a type of genetic change, called hypermutation. This means they may be sensitive to immunotherapy as this type of treatment has good results in other patient groups with hypermutations. "We also found potential sensitivity to a drug called a Porcupine inhibitor, based on another genetic marker identified in these patients. "This is the first study of its kind in the world for patients with CPM, and our results have shown this could provide a potentially curative option for patients given the responses we have seen to immunotherapy in other cancers." Researchers will now look to set up an international clinical trial to examine the use of immunotherapy for patients with CPM. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract We report on dental and mandibular pathology in Labidosaurus hamatus , a 275 million-year-old terrestrial reptile from North America and associate it with bacterial infection in an organism that is characterized by reduced tooth replacement. Analysis of the surface and internal mandibular structure using mechanical and CT-scanning techniques permits the reconstruction of events that led to the pathology and the possible death of the individual. The infection probably occurred as a result of prolonged exposure of the dental pulp cavity to oral bacteria, and this exposure was caused by injury to the tooth in an animal that is characterized by reduced tooth replacement cycles. In these early reptiles, the reduction in tooth replacement is an evolutionary innovation associated with strong implantation and increased oral processing. The dental abscess observed in L . hamatus , the oldest known infection in a terrestrial vertebrate, provides clear evidence of the ancient association between terrestrial vertebrates and their oral bacteria. Access provided by DEAL DE / Springer Compact Clearingstelle Uni Freiburg _ Working on a manuscript? Avoid the common mistakes Introduction The rich fossil record of amniotes (extant reptiles, birds, mammals, and their extinct relatives) extends over the last 315 million years and spans three eras (Reisz 1997 ). Whereas Mesozoic dinosaurs and Cenozoic mammals often show evidence of pathology (Lucas and Schoch 1987 ; Rothschild 1997 ; Tanke and Rothschild 2002 ; Witzmann et al. 2008 ), including bite marks, healed scars, infections, and tumors, they are poorly documented in Paleozoic amniotes (Reisz 1980 ; Johnson 1988 ; Reisz and Tsuji 2006 ; Huttenlocker et al. 2010 ), the first vertebrates to diversify extensively on land. The pathology reported here was discovered in the anterior part of the lower jaw (Fig. 1 ) in the largest and presumably oldest known individual of Labidosaurus hamatus , a member of the late Paleozoic group Captorhinidae (Modesto et al. 2007 ). Captorhinids were the first reptiles to diversify rapidly and disperse globally during the Paleozoic (Müller et al. 2007 ). They range in size from 25 cm in total length in late Carboniferous (Müller and Reisz 2005 ) and Early Permian (Heaton and Reisz 1980 ) forms, and achieve total lengths up to 2.5 m in some of the Middle and Late Permian species (Dodick and Modesto 1995 ; O'Keefe et al. 2005 ). During the Early Permian, members of this clade were the most commonly occurring reptiles in the fossil record. Fig. 1 Evidence of dental and mandibular pathology in L. hamatus , a basal reptile from the Lower Permian of Oklahoma. a Skull reconstruction in right lateral view, modified from Ref. 4. Shaded area represents region of the lower jaw shown in b and c . b CMNH 76876, a right hemimandible in lateral, occlusal, and medial views. c Longitudinal CT scans of the mandible shown in b , illustrating the internal changes that occurred in the anterior region of the jaw as a consequence of the infection. Only one ( t2 ) of the three anterior teeth was functional at the time this individual died. Remnants of the first ( rt1 ) and third ( rt3 ) teeth are visible in the CT scan, and were encapsulated into the mandible by dentary bone, probably after they were broken. Tooth sockets at positions 1 ( tp1 ) and 3 ( tp3 ) have been filled with bone. The direction of infection extends posteriorly from the first tooth position to the fourth open tooth position ( ots4 ) and to the lingual and labial abscesses. It is at the level where the pulp cavity of the teeth would have been in the living organism. Scale bar = 10 mm Full size image The more derived captorhinids evolved dental and cranial specializations as part of their adaptation to omnivory and high-fiber herbivory (Reisz and Sues 2000 ). In particular they modified their dentition by attaching them very strongly to the jaws through ankylosis, and by changing dramatically the pattern of tooth replacement. The normal pattern of tooth replacement seen in most other Paleozoic tetrapods is characterized by teeth that are relatively loosely attached to the jaw bones, and continuous waves of new teeth erupting at specific tooth positions or sockets, with older teeth being partly resorbed and then shed as the new teeth erupt in the same socket (polyphyodonty). This pattern of tooth replacement is also present in extant tetrapods, including amphibians and most squamates (Edmund 1960 ). Thus, several teeth in any jaw in certain extant and fossil tetrapods can always be seen in the process of being replaced, with two teeth being present in a single tooth position: the crown of a partially resorbed older tooth from an older wave of replacement and another small tooth from the next wave of replacement growing at the base and slightly lingual to the older tooth (polyphyodonty). With continued resorption, the tooth of the previous wave of replacement is eventually shed and the younger tooth grows into full function in that tooth position (Edmund 1960 ). However, in the clade that includes captorhinids like Captorhinus , Labidosaurus , and Moradisaurinae (Fig. 2 ), the change in the pattern of dental development resulted in a dramatic decrease in tooth replacement waves, with older teeth being removed only occasionally, and by erosion, while new teeth did not erupt in the same tooth position as the older teeth. This highly modified pattern can be best seen in Captorhinus aguti , a species that developed multiple tooth rows (Bolt and DeMar 1975 ). The development of multiple tooth rows occurred by the eruption of a new series of teeth lingual to the older tooth row, with the wave of eruption extending mesially along the jaw. The older tooth row was not replaced, and instead, an additional row was added. Only the oldest tooth from an older series appears to be occasionally replaced, and only when it appears to be in the way of the new wave (de Ricqles and Bolt", "role": "user" }, { "content": "A reptile that lived 275-million years ago in what is now Oklahoma is giving paleontologists a glimpse of the oldest known toothache. Led by Professor Robert Reisz, the chair of the Department of Biology at the University of Toronto Mississauga, scientists found evidence of bone damage due to oral infection in Paleozoic reptiles as they adapted to living on land. Their findings, published online in the journal Naturwissenschaften – The Nature of Science, predate the previous record for oral and dental disease in a terrestrial vertebrate by nearly 200 million years. \"Not only does this fossil extend our understanding of dental disease, it reveals the advantages and disadvantages that certain creatures faced as their teeth evolved to feed on both meat and plants,\" says Reisz. \"In this case, as with humans, it may have increased their susceptibility to oral infections.\" The researchers investigated the jaws of several well-preserved specimens of Labidosaurus hamatus, a 275-million-year-old terrestrial reptile from North America. One specimen stood out because of missing teeth and associated erosion of the jaw bone. With the aid of CT-scanning, Reisz and colleagues found evidence of a massive infection. This resulted in the loss of several teeth, as well as bone destruction in the jaw in the form of an abscess and internal loss of bone tissue. As the ancestors of advanced reptiles adapted to life on land, many evolved dental and cranial specializations to feed more efficiently on other animals and to incorporate high-fiber plant leaves and stems into their diet. The primitive dental pattern in which teeth were loosely attached to the jaws and continuously replaced, changed in some animals. Teeth became strongly attached to the jaw, with little or no tooth replacement. This was clearly advantageous to some early reptiles, allowing them to chew their food and thus improve nutrient absorption. The abundance and global distribution of Labidosauris and its kin suggest that it was an evolutionary success. However, Reisz and his colleagues suggest that as this reptile lost the ability to replace teeth, the likelihood of infections of the jaw, resulting from damage to the teeth, increased substantially. This is because prolonged exposure of the dental pulp cavity of heavily worn or damaged teeth to oral bacteria was much greater than in other animals that quickly replaced their teeth. Reisz notes that human susceptibility to oral infection has some parallels to those of ancient reptiles that evolved to eat a diet incorporating plants in addition to meat. \"Our findings suggest that our own human system of having just two sets of teeth, baby and permanent, although of obvious advantage because of its ability to chew and process many different types of food, is more susceptible to infection than that of our distant ancestors that had a continuous cycle of tooth replacement.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract We report on dental and mandibular pathology in Labidosaurus hamatus , a 275 million-year-old terrestrial reptile from North America and associate it with bacterial infection in an organism that is characterized by reduced tooth replacement. Analysis of the surface and internal mandibular structure using mechanical and CT-scanning techniques permits the reconstruction of events that led to the pathology and the possible death of the individual. The infection probably occurred as a result of prolonged exposure of the dental pulp cavity to oral bacteria, and this exposure was caused by injury to the tooth in an animal that is characterized by reduced tooth replacement cycles. In these early reptiles, the reduction in tooth replacement is an evolutionary innovation associated with strong implantation and increased oral processing. The dental abscess observed in L . hamatus , the oldest known infection in a terrestrial vertebrate, provides clear evidence of the ancient association between terrestrial vertebrates and their oral bacteria. Access provided by DEAL DE / Springer Compact Clearingstelle Uni Freiburg _ Working on a manuscript? Avoid the common mistakes Introduction The rich fossil record of amniotes (extant reptiles, birds, mammals, and their extinct relatives) extends over the last 315 million years and spans three eras (Reisz 1997 ). Whereas Mesozoic dinosaurs and Cenozoic mammals often show evidence of pathology (Lucas and Schoch 1987 ; Rothschild 1997 ; Tanke and Rothschild 2002 ; Witzmann et al. 2008 ), including bite marks, healed scars, infections, and tumors, they are poorly documented in Paleozoic amniotes (Reisz 1980 ; Johnson 1988 ; Reisz and Tsuji 2006 ; Huttenlocker et al. 2010 ), the first vertebrates to diversify extensively on land. The pathology reported here was discovered in the anterior part of the lower jaw (Fig. 1 ) in the largest and presumably oldest known individual of Labidosaurus hamatus , a member of the late Paleozoic group Captorhinidae (Modesto et al. 2007 ). Captorhinids were the first reptiles to diversify rapidly and disperse globally during the Paleozoic (Müller et al. 2007 ). They range in size from 25 cm in total length in late Carboniferous (Müller and Reisz 2005 ) and Early Permian (Heaton and Reisz 1980 ) forms, and achieve total lengths up to 2.5 m in some of the Middle and Late Permian species (Dodick and Modesto 1995 ; O'Keefe et al. 2005 ). During the Early Permian, members of this clade were the most commonly occurring reptiles in the fossil record. Fig. 1 Evidence of dental and mandibular pathology in L. hamatus , a basal reptile from the Lower Permian of Oklahoma. a Skull reconstruction in right lateral view, modified from Ref. 4. Shaded area represents region of the lower jaw shown in b and c . b CMNH 76876, a right hemimandible in lateral, occlusal, and medial views. c Longitudinal CT scans of the mandible shown in b , illustrating the internal changes that occurred in the anterior region of the jaw as a consequence of the infection. Only one ( t2 ) of the three anterior teeth was functional at the time this individual died. Remnants of the first ( rt1 ) and third ( rt3 ) teeth are visible in the CT scan, and were encapsulated into the mandible by dentary bone, probably after they were broken. Tooth sockets at positions 1 ( tp1 ) and 3 ( tp3 ) have been filled with bone. The direction of infection extends posteriorly from the first tooth position to the fourth open tooth position ( ots4 ) and to the lingual and labial abscesses. It is at the level where the pulp cavity of the teeth would have been in the living organism. Scale bar = 10 mm Full size image The more derived captorhinids evolved dental and cranial specializations as part of their adaptation to omnivory and high-fiber herbivory (Reisz and Sues 2000 ). In particular they modified their dentition by attaching them very strongly to the jaws through ankylosis, and by changing dramatically the pattern of tooth replacement. The normal pattern of tooth replacement seen in most other Paleozoic tetrapods is characterized by teeth that are relatively loosely attached to the jaw bones, and continuous waves of new teeth erupting at specific tooth positions or sockets, with older teeth being partly resorbed and then shed as the new teeth erupt in the same socket (polyphyodonty). This pattern of tooth replacement is also present in extant tetrapods, including amphibians and most squamates (Edmund 1960 ). Thus, several teeth in any jaw in certain extant and fossil tetrapods can always be seen in the process of being replaced, with two teeth being present in a single tooth position: the crown of a partially resorbed older tooth from an older wave of replacement and another small tooth from the next wave of replacement growing at the base and slightly lingual to the older tooth (polyphyodonty). With continued resorption, the tooth of the previous wave of replacement is eventually shed and the younger tooth grows into full function in that tooth position (Edmund 1960 ). However, in the clade that includes captorhinids like Captorhinus , Labidosaurus , and Moradisaurinae (Fig. 2 ), the change in the pattern of dental development resulted in a dramatic decrease in tooth replacement waves, with older teeth being removed only occasionally, and by erosion, while new teeth did not erupt in the same tooth position as the older teeth. This highly modified pattern can be best seen in Captorhinus aguti , a species that developed multiple tooth rows (Bolt and DeMar 1975 ). The development of multiple tooth rows occurred by the eruption of a new series of teeth lingual to the older tooth row, with the wave of eruption extending mesially along the jaw. The older tooth row was not replaced, and instead, an additional row was added. Only the oldest tooth from an older series appears to be occasionally replaced, and only when it appears to be in the way of the new wave (de Ricqles and Bolt<|im_end|> <|im_start|>assistant A reptile that lived 275-million years ago in what is now Oklahoma is giving paleontologists a glimpse of the oldest known toothache. Led by Professor Robert Reisz, the chair of the Department of Biology at the University of Toronto Mississauga, scientists found evidence of bone damage due to oral infection in Paleozoic reptiles as they adapted to living on land. Their findings, published online in the journal Naturwissenschaften – The Nature of Science, predate the previous record for oral and dental disease in a terrestrial vertebrate by nearly 200 million years. "Not only does this fossil extend our understanding of dental disease, it reveals the advantages and disadvantages that certain creatures faced as their teeth evolved to feed on both meat and plants," says Reisz. "In this case, as with humans, it may have increased their susceptibility to oral infections." The researchers investigated the jaws of several well-preserved specimens of Labidosaurus hamatus, a 275-million-year-old terrestrial reptile from North America. One specimen stood out because of missing teeth and associated erosion of the jaw bone. With the aid of CT-scanning, Reisz and colleagues found evidence of a massive infection. This resulted in the loss of several teeth, as well as bone destruction in the jaw in the form of an abscess and internal loss of bone tissue. As the ancestors of advanced reptiles adapted to life on land, many evolved dental and cranial specializations to feed more efficiently on other animals and to incorporate high-fiber plant leaves and stems into their diet. The primitive dental pattern in which teeth were loosely attached to the jaws and continuously replaced, changed in some animals. Teeth became strongly attached to the jaw, with little or no tooth replacement. This was clearly advantageous to some early reptiles, allowing them to chew their food and thus improve nutrient absorption. The abundance and global distribution of Labidosauris and its kin suggest that it was an evolutionary success. However, Reisz and his colleagues suggest that as this reptile lost the ability to replace teeth, the likelihood of infections of the jaw, resulting from damage to the teeth, increased substantially. This is because prolonged exposure of the dental pulp cavity of heavily worn or damaged teeth to oral bacteria was much greater than in other animals that quickly replaced their teeth. Reisz notes that human susceptibility to oral infection has some parallels to those of ancient reptiles that evolved to eat a diet incorporating plants in addition to meat. "Our findings suggest that our own human system of having just two sets of teeth, baby and permanent, although of obvious advantage because of its ability to chew and process many different types of food, is more susceptible to infection than that of our distant ancestors that had a continuous cycle of tooth replacement." <|im_end|>

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1109, 430, 315, 1057, 29827, 38618, 430, 1047, 264, 19815, 11008, 315, 26588, 14039, 1210, 220, 128257, 198 ]

1,920

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract In plants, pathogen attack can induce an immune response known as systemic acquired resistance that protects against a broad spectrum of pathogens. In the search for safer agrochemicals, silica nanoparticles (SiO 2 NPs; food additive E551) have recently been proposed as a new tool. However, initial results are controversial, and the molecular mechanisms of SiO 2 NP-induced disease resistance are unknown. Here we show that SiO 2 NPs, as well as soluble Si(OH) 4 , can induce systemic acquired resistance in a dose-dependent manner, which involves the defence hormone salicylic acid. Nanoparticle uptake and action occurred exclusively through the stomata (leaf pores facilitating gas exchange) and involved extracellular adsorption in the air spaces in the spongy mesophyll of the leaf. In contrast to the treatment with SiO 2 NPs, the induction of systemic acquired resistance by Si(OH) 4 was problematic since high Si(OH) 4 concentrations caused stress. We conclude that SiO 2 NPs have the potential to serve as an inexpensive, highly efficient, safe and sustainable alternative for plant disease protection. Main Nanoagrochemicals are a promising tool to improve crop yield and thus global food security 1 . Silica nanoparticles (SiO 2 NPs) have been proposed for the controlled nanodelivery of silicon (Si) and other active ingredients to plants, but they have never been systematically tested for this purpose. Si from orthosilicic acid (Si(OH) 4 , also known as monosilicic acid)—the hydrolytic degradation product of SiO 2 NPs—is the only known form of Si bioavailable for plants, and it is ubiquitous in soil pore water 2 , 3 , 4 . Si(OH) 4 can promote plant growth and plant resistance against biotic and abiotic stresses 3 , 5 , thereby protecting plants against pathogen attacks or agricultural damages related to severe climate conditions 3 , 6 , 7 . The uptake and movement of SiO 2 NPs as well as other engineered nanomaterials in plants have been intensively studied in the past decade 7 , 8 , 9 , 10 . However, it is uncertain how the nanoparticles interact with leaves at the subcellular level. Direct evidence by nanometre-resolution imaging for the entrance of intact nanoparticles into leaves, or the intercellular movement of SiO 2 NPs within leaves, is mostly missing 10 . It is also not known whether SiO 2 NPs can induce resistance in plants, whether their performance differs from dissolved Si species and which molecular pathways they may induce. To fend off potential pathogens, plants have evolved disease resistance mechanisms that share mechanistic principles with the innate immunity of animals 11 . An especially interesting form of plant disease resistance is the so-called induced resistance in which the disease resistance of the plant can be enhanced by previous exposure to beneficial rhizosphere microorganisms, avirulent and virulent pathogens, or specific resistance-inducing chemical compounds 12 , 13 , 14 . A hallmark of induced resistance is its activity against a broad spectrum of pathogens. While the induction of plant disease resistance using chemical compounds is relatively well understood 12 , the benefit of using slow nano-enabled delivery systems for the same purpose has not been investigated via systematic experiments 1 , 7 . A special form of induced resistance is systemic acquired resistance (SAR) that is characterized by the spread of locally induced disease resistance to the whole plant 15 , 16 . SAR is induced in all plant parts after locally challenging the plant with a pathogen or by the local application of so-called resistance-inducing compounds. Both these treatments induce signal transduction pathways that lead to the production of signals moving to distant tissues 14 . A key signalling compound that contributes to SAR is the plant hormone salicylic acid (SA) that is responsible for the activation of pathogenesis-related (PR) genes 16 , 17 . Other factors include, for example, nitric oxide and reactive oxygen species 18 , 19 . The fact that SAR can be activated by the application of resistance-inducing compounds 12 , 13 makes SAR an attractive alternative strategy for controlling crop pests without the need for using irreversible genetic modifications or environmentally problematic pesticides. SAR-inducing compounds such as benzothiadiazole successfully enhance disease resistance, but also reduce crop yields 20 , 21 . Interestingly, Si-based compounds also seem to have the capacity to induce disease resistance via a broad range of different and partially still unknown mechanisms, including the mechanical reinforcement of defensive structures of the plant architecture, most notably the cell wall 3 , 22 , but also the activation of biochemical defences 3 , 23 . For example, biochemically, root-applied Si led to a broad-spectrum resistance against powdery mildew pathogen by increasing the activity of defence-related enzymes in leaves 24 . It is important to note that the protective effect of Si seems to have—in contrast to other biostimulants such as benzothiadiazole—no negative effects on the growth and yield of plants 3 , 25 . All this makes Si an attractive candidate to strengthen plant stress tolerance. Initial studies found that SiO 2 NPs may induce stress tolerance similar to conventional Si products, but a clear mechanistic understanding of the underlying processes is still lacking 7 , 8 , 26 , 27 . In this Article, we demonstrate the potential of SiO 2 NPs in inducing local and systemic disease resistance in the widely used model plant Arabidopsis thaliana against the bacterial pathogen Pseudomonas syringae . Silicic acid was assessed in parallel to disentangle the potential differences in the mode of action of dissolved Si species compared with SiO 2 NPs. We assessed the role of SA and reactive-oxygen-species defence-related genes, established the therapeutic concentration range of SiO 2 NPs to induce the desired beneficial effects in plants, compared the laboratory setup (infiltration of selected leaves) with the more realistic spray application and visualized the nanoparticle–leaf interactions using transmission electron microscopy (TEM), with important implications for future strategies to apply nanoscale active ingredients for slow release in leaves. SiO 2 NPs and subcellular distribution within the leaf The SiO 2 NP suspensions", "role": "user" }, { "content": "Researchers at the Adolphe Merkle Institute and the Department of Biology at the University of Fribourg have discovered how certain silica nanoparticles could act as a traceless, degradable, and highly efficient treatment against some plant pathogens. One of the biggest challenges facing agriculture today is the extensive use of fertilizers and pesticides. With an increasing number of products banned or considered dangerous for human and animal health, the need for substitutes is acute. One approach is to stimulate plants' own immune response to pathogen attacks. Silicic acid, which naturally occurs in soil, is known to provoke such responses in plants, and amorphous silica nanoparticles can release this substance in small amounts. These nanoparticles, which are also naturally present in many food crops such as cereals, are more common than most people think. They are part of food grade silica (SiO2), otherwise known as E551 on labels and packaging, and used for decades in a variety of products such as table salt, pills, or protein powders to avoid clumping. Increased resistance With this in mind, the Fribourg-based researchers aimed to create an environmentally safe nano-agrochemical for the targeted delivery of silicic acid and to stimulate plant defense. They synthesized silica nanoparticles with similar properties to those found in plants. To test their efficiency, they applied the nanoparticles on Arabidopsis thaliana (thale cress), a widely used plant model, infected with the bacterial pest Pseudomonas syringae, another model organism. The results showed that their nanoparticles can boost resistance against the bacteria in a dose-dependent manner by stimulating the plant's defense hormone, salicylic acid (which is also the active ingredient in aspirin). The researchers also investigated the interactions of the nanoparticles with plant leaves. They were able to show that nanoparticle uptake and action occurred exclusively through the leaf pores (stomata) that allow the plants to breathe. The nanoparticles did not distribute further in the plants, and the particles degrade without leaving a trace in the presence of water, an important consideration for environmental and food safety. Compared to free silicic acid, which is already used in crop protection, the silica nanoparticles caused less stress to the plants and to other soil microorganisms due to the slow release of the silicic acid. The study, published in the top-ranking journal Nature Nanotechnology, shows that silica nanoparticles could serve as an inexpensive, highly efficient, safe, and sustainable alternative for plant disease protection. Future research could extend the investigations to a broader spectrum of plant pathogens according to the researchers such as other bacteria, insects, or viruses. They emphasize though that before any broad application of nanoparticles as nano-biostimulants and -fertilizers, a thorough analysis is needed to assess the potential long-term fate of silica nanoparticles in the environment. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract In plants, pathogen attack can induce an immune response known as systemic acquired resistance that protects against a broad spectrum of pathogens. In the search for safer agrochemicals, silica nanoparticles (SiO 2 NPs; food additive E551) have recently been proposed as a new tool. However, initial results are controversial, and the molecular mechanisms of SiO 2 NP-induced disease resistance are unknown. Here we show that SiO 2 NPs, as well as soluble Si(OH) 4 , can induce systemic acquired resistance in a dose-dependent manner, which involves the defence hormone salicylic acid. Nanoparticle uptake and action occurred exclusively through the stomata (leaf pores facilitating gas exchange) and involved extracellular adsorption in the air spaces in the spongy mesophyll of the leaf. In contrast to the treatment with SiO 2 NPs, the induction of systemic acquired resistance by Si(OH) 4 was problematic since high Si(OH) 4 concentrations caused stress. We conclude that SiO 2 NPs have the potential to serve as an inexpensive, highly efficient, safe and sustainable alternative for plant disease protection. Main Nanoagrochemicals are a promising tool to improve crop yield and thus global food security 1 . Silica nanoparticles (SiO 2 NPs) have been proposed for the controlled nanodelivery of silicon (Si) and other active ingredients to plants, but they have never been systematically tested for this purpose. Si from orthosilicic acid (Si(OH) 4 , also known as monosilicic acid)—the hydrolytic degradation product of SiO 2 NPs—is the only known form of Si bioavailable for plants, and it is ubiquitous in soil pore water 2 , 3 , 4 . Si(OH) 4 can promote plant growth and plant resistance against biotic and abiotic stresses 3 , 5 , thereby protecting plants against pathogen attacks or agricultural damages related to severe climate conditions 3 , 6 , 7 . The uptake and movement of SiO 2 NPs as well as other engineered nanomaterials in plants have been intensively studied in the past decade 7 , 8 , 9 , 10 . However, it is uncertain how the nanoparticles interact with leaves at the subcellular level. Direct evidence by nanometre-resolution imaging for the entrance of intact nanoparticles into leaves, or the intercellular movement of SiO 2 NPs within leaves, is mostly missing 10 . It is also not known whether SiO 2 NPs can induce resistance in plants, whether their performance differs from dissolved Si species and which molecular pathways they may induce. To fend off potential pathogens, plants have evolved disease resistance mechanisms that share mechanistic principles with the innate immunity of animals 11 . An especially interesting form of plant disease resistance is the so-called induced resistance in which the disease resistance of the plant can be enhanced by previous exposure to beneficial rhizosphere microorganisms, avirulent and virulent pathogens, or specific resistance-inducing chemical compounds 12 , 13 , 14 . A hallmark of induced resistance is its activity against a broad spectrum of pathogens. While the induction of plant disease resistance using chemical compounds is relatively well understood 12 , the benefit of using slow nano-enabled delivery systems for the same purpose has not been investigated via systematic experiments 1 , 7 . A special form of induced resistance is systemic acquired resistance (SAR) that is characterized by the spread of locally induced disease resistance to the whole plant 15 , 16 . SAR is induced in all plant parts after locally challenging the plant with a pathogen or by the local application of so-called resistance-inducing compounds. Both these treatments induce signal transduction pathways that lead to the production of signals moving to distant tissues 14 . A key signalling compound that contributes to SAR is the plant hormone salicylic acid (SA) that is responsible for the activation of pathogenesis-related (PR) genes 16 , 17 . Other factors include, for example, nitric oxide and reactive oxygen species 18 , 19 . The fact that SAR can be activated by the application of resistance-inducing compounds 12 , 13 makes SAR an attractive alternative strategy for controlling crop pests without the need for using irreversible genetic modifications or environmentally problematic pesticides. SAR-inducing compounds such as benzothiadiazole successfully enhance disease resistance, but also reduce crop yields 20 , 21 . Interestingly, Si-based compounds also seem to have the capacity to induce disease resistance via a broad range of different and partially still unknown mechanisms, including the mechanical reinforcement of defensive structures of the plant architecture, most notably the cell wall 3 , 22 , but also the activation of biochemical defences 3 , 23 . For example, biochemically, root-applied Si led to a broad-spectrum resistance against powdery mildew pathogen by increasing the activity of defence-related enzymes in leaves 24 . It is important to note that the protective effect of Si seems to have—in contrast to other biostimulants such as benzothiadiazole—no negative effects on the growth and yield of plants 3 , 25 . All this makes Si an attractive candidate to strengthen plant stress tolerance. Initial studies found that SiO 2 NPs may induce stress tolerance similar to conventional Si products, but a clear mechanistic understanding of the underlying processes is still lacking 7 , 8 , 26 , 27 . In this Article, we demonstrate the potential of SiO 2 NPs in inducing local and systemic disease resistance in the widely used model plant Arabidopsis thaliana against the bacterial pathogen Pseudomonas syringae . Silicic acid was assessed in parallel to disentangle the potential differences in the mode of action of dissolved Si species compared with SiO 2 NPs. We assessed the role of SA and reactive-oxygen-species defence-related genes, established the therapeutic concentration range of SiO 2 NPs to induce the desired beneficial effects in plants, compared the laboratory setup (infiltration of selected leaves) with the more realistic spray application and visualized the nanoparticle–leaf interactions using transmission electron microscopy (TEM), with important implications for future strategies to apply nanoscale active ingredients for slow release in leaves. SiO 2 NPs and subcellular distribution within the leaf The SiO 2 NP suspensions<|im_end|> <|im_start|>assistant Researchers at the Adolphe Merkle Institute and the Department of Biology at the University of Fribourg have discovered how certain silica nanoparticles could act as a traceless, degradable, and highly efficient treatment against some plant pathogens. One of the biggest challenges facing agriculture today is the extensive use of fertilizers and pesticides. With an increasing number of products banned or considered dangerous for human and animal health, the need for substitutes is acute. One approach is to stimulate plants' own immune response to pathogen attacks. Silicic acid, which naturally occurs in soil, is known to provoke such responses in plants, and amorphous silica nanoparticles can release this substance in small amounts. These nanoparticles, which are also naturally present in many food crops such as cereals, are more common than most people think. They are part of food grade silica (SiO2), otherwise known as E551 on labels and packaging, and used for decades in a variety of products such as table salt, pills, or protein powders to avoid clumping. Increased resistance With this in mind, the Fribourg-based researchers aimed to create an environmentally safe nano-agrochemical for the targeted delivery of silicic acid and to stimulate plant defense. They synthesized silica nanoparticles with similar properties to those found in plants. To test their efficiency, they applied the nanoparticles on Arabidopsis thaliana (thale cress), a widely used plant model, infected with the bacterial pest Pseudomonas syringae, another model organism. The results showed that their nanoparticles can boost resistance against the bacteria in a dose-dependent manner by stimulating the plant's defense hormone, salicylic acid (which is also the active ingredient in aspirin). The researchers also investigated the interactions of the nanoparticles with plant leaves. They were able to show that nanoparticle uptake and action occurred exclusively through the leaf pores (stomata) that allow the plants to breathe. The nanoparticles did not distribute further in the plants, and the particles degrade without leaving a trace in the presence of water, an important consideration for environmental and food safety. Compared to free silicic acid, which is already used in crop protection, the silica nanoparticles caused less stress to the plants and to other soil microorganisms due to the slow release of the silicic acid. The study, published in the top-ranking journal Nature Nanotechnology, shows that silica nanoparticles could serve as an inexpensive, highly efficient, safe, and sustainable alternative for plant disease protection. Future research could extend the investigations to a broader spectrum of plant pathogens according to the researchers such as other bacteria, insects, or viruses. They emphasize though that before any broad application of nanoparticles as nano-biostimulants and -fertilizers, a thorough analysis is needed to assess the potential long-term fate of silica nanoparticles in the environment. <|im_end|>

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1,922

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Objective To investigate the associations between air pollution and mortality, focusing on associations below current European Union, United States, and World Health Organization standards and guidelines. Design Pooled analysis of eight cohorts. Setting Multicentre project Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE) in six European countries. Participants 325 367 adults from the general population recruited mostly in the 1990s or 2000s with detailed lifestyle data. Stratified Cox proportional hazard models were used to analyse the associations between air pollution and mortality. Western Europe-wide land use regression models were used to characterise residential air pollution concentrations of ambient fine particulate matter (PM 2.5 ), nitrogen dioxide, ozone, and black carbon. Main outcome measures Deaths due to natural causes and cause specific mortality. Results Of 325 367 adults followed-up for an average of 19.5 years, 47 131 deaths were observed. Higher exposure to PM 2.5 , nitrogen dioxide, and black carbon was associated with significantly increased risk of almost all outcomes. An increase of 5 µg/m 3 in PM 2.5 was associated with 13% (95% confidence interval 10.6% to 15.5%) increase in natural deaths; the corresponding figure for a 10 µg/m 3 increase in nitrogen dioxide was 8.6% (7% to 10.2%). Associations with PM 2.5 , nitrogen dioxide, and black carbon remained significant at low concentrations. For participants with exposures below the US standard of 12 µg/m 3 an increase of 5 µg/m 3 in PM 2.5 was associated with 29.6% (14% to 47.4%) increase in natural deaths. Conclusions Our study contributes to the evidence that outdoor air pollution is associated with mortality even at low pollution levels below the current European and North American standards and WHO guideline values. These findings are therefore an important contribution to the debate about revision of air quality limits, guidelines, and standards, and future assessments by the Global Burden of Disease. Introduction Epidemiological cohort studies have consistently found associations between long term exposure to outdoor air pollution and a range of morbidity and mortality endpoints. Concentrations of health relevant regulated pollutants, including fine particles and nitrogen dioxide, have decreased in the past decades in developed countries. Recent evaluations by the World Health Organization and the Global Burden of Disease study have suggested that health effects might persist at these lower concentrations. 1 2 3 However, there is uncertainty about the shape of the concentration-response function at the low end of the air pollution concentration distribution, related to the scarcity of observations at the lowest concentrations. Associations with mortality at low pollution levels in large populations were primarily investigated in a few North American studies, specifically the Canadian census cohort, the Canadian Community Health survey, the US Medicare cohort, and the US National Health Interview Survey study. 4 5 6 7 8 9 10 All the studies found associations below the current annual average US standard of 12 µg/m 3 and WHO guideline value of 10 µg/m 3 for fine particles with an aerodynamic diameter of <2.5 µm (PM 2.5 ), but only two studies were able to adjust for detailed individual lifestyle factors. 7 9 Most of the studies suggested a steeper concentration response function at the lowest levels, but the National Health Interview Survey study 9 suggested little association below about 5 µg/m 3 . Most studies focused primarily on PM 2.5 , whereas increasing evidence shows that pollutants related to local combustion sources, including nitrogen dioxide and black carbon, might be relevant to health. Few studies have assessed the mortality effects of long term exposure to ozone. Within the project Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE) we assessed associations of low level air pollution concentrations with natural and cause specific mortality. Low level air pollution was defined as concentrations below current European Union limit values, US Environmental Protection Agency national ambient air quality standards, or the 2005 WHO air quality guidelines. We investigated PM 2.5 , nitrogen dioxide, ozone, and black carbon at a fine spatial resolution. To have sufficient statistical power to detect associations at low exposure levels, we pooled data from eight European cohorts with information on important individual risk factors, including smoking and body mass index. Methods Study population The eight cohorts were selected from six European countries (see supplementary figure): Sweden (Stockholm county), Denmark (Copenhagen and Aarhus, and nationwide), France (nationwide), the Netherlands (four cities), Germany (Ruhr and Augsburg areas), and Austria (Vorarlberg region). All the cohorts, except the Danish cohort, 11 were previously part of the European Study of Cohorts for Air Pollution Effects (ESCAPE). 12 Not all ESCAPE cohorts were included, either because of relatively high annual air pollution concentrations or because the data could not be pooled. Several of the included cohorts (ie, from Sweden, Denmark, the Netherlands, and Augsburg, Germany) combined multiple original cohorts, termed subcohorts. All cohorts and subcohorts included general population samples and specific subgroups, such as Danish nurses (DNC cohort). Most cohorts were from large cities and surrounding regions. Supplementary appendix section 1 describes the cohorts in more detail. Recruitment of most of the cohorts was in the 1990s or 2000s (supplementary table S1). To pool data, we used a common codebook to harmonise individual and area level covariates and outcome variables between cohorts. Information on covariates was only available at baseline. Assessment of exposure to air pollution We assessed air pollution concentrations at the baseline residential address of the study participants using land use regression models, described in detail elsewhere. 13 Briefly, we estimated 2010 annual mean PM 2.5 , nitrogen dioxide, black carbon, and (warm season) ozone concentrations using the European Environmental Agency AirBase routine monitoring data (PM 2.5 , nitrogen dioxide, and ozone) and ESCAPE monitoring data (black carbon). Predictors were satellite derived and chemical transport model air pollutant estimates at 10×10 km, and fine scale land use and road traffic data. Western Europe-wide models were developed on a 100×100 m grid and were assigned to the participants using their geocoded residential address. The PM 2.5 , nitrogen dioxide, black carbon,", "role": "user" }, { "content": "Long-term exposure to air pollution appears to still be linked to higher mortality despite the existence of air quality standards that restrict levels of pollution, suggests a study published online in The BMJ today. Researchers found evidence of higher death rates amongst people who had been exposed to more air pollution even though the levels were allowed under current official standards. Previous studies have found an association between long term exposure to outdoor air pollution such as those in the form of fine particles in the air (known as particulate matter or PM2.5) and nitrogen dioxide (NO2) and poor health or death. Air pollution concentrations have fallen substantially in Europe since the 1990s, but it is unclear whether there still is a link between pollution and ill health or death at concentrations of pollution that are below current permitted limits. Therefore, an international team of researchers led by the Institute for Risk Assessment Sciences at Utrecht University in the Netherlands, set out to investigate if there was an association between low levels of air pollution concentrations and natural and cause specific deaths. Low level air pollution was defined as concentrations below current limit values as set by the European Union, US Environmental Protection Agency and the World Health Organization (WHO) air quality guidelines. The researchers analysed data on eight groups of people within six European countries—Sweden, Denmark, France, the Netherlands, Germany and Austria—totalling 325,367 adults collectively. Their study, known as the Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE) recruited participants in the 1990s or 2000s. Of the 325,367 participants who were followed up over an almost 20-year period, around 14.5% (47,131 people) died during the study period. Analysis of the results showed that people who had higher exposure to particulate matter (PM2.5), nitrogen dioxide, and black carbon were more likely to die. An increase of 5 µg/m3 (a concentration measure of particulate matter) in PM2.5 was associated with a 13% increase in natural deaths while the corresponding figure for a 10 µg/m3 increase in nitrogen dioxide was 8.6%. Associations with PM2.5 and nitrogen dioxide were largely independent of each other. Moreover, associations with PM2.5, nitrogen dioxide, and black carbon remained significant at low to very low concentrations. For people who were exposed to pollution levels below the US standard of 12 µg/m3, an increase of 5 µg/m3 in PM2.5 was associated with a 29.6% increase in natural deaths. People exposed to nitrogen dioxide at less than half the current EU standard of 40 µg/m3, a 10 µg/m3 increase in nitrogen dioxide was associated with a 9.9% increase in natural deaths. This is an observational study, and as such, can't establish cause. The study also has some limitations, say the authors, such as the fact that it focused on exposure in 2010 which was towards the end of the follow-up period for most participants and, given the downward trend in air pollution, this measure might not exactly reflect the concentrations experienced during follow-up. However, this was a large study from multiple European groups of people with detailed information provided. As such, the authors conclude: \"Our study contributes to the evidence that outdoor air pollution is associated with mortality even at levels below the current European and North American standards and WHO guideline values. \"These findings are therefore an important contribution to the debate about revision of air quality limits, guidelines and standards, and future assessments by the Global Burden of Disease [study].\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Objective To investigate the associations between air pollution and mortality, focusing on associations below current European Union, United States, and World Health Organization standards and guidelines. Design Pooled analysis of eight cohorts. Setting Multicentre project Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE) in six European countries. Participants 325 367 adults from the general population recruited mostly in the 1990s or 2000s with detailed lifestyle data. Stratified Cox proportional hazard models were used to analyse the associations between air pollution and mortality. Western Europe-wide land use regression models were used to characterise residential air pollution concentrations of ambient fine particulate matter (PM 2.5 ), nitrogen dioxide, ozone, and black carbon. Main outcome measures Deaths due to natural causes and cause specific mortality. Results Of 325 367 adults followed-up for an average of 19.5 years, 47 131 deaths were observed. Higher exposure to PM 2.5 , nitrogen dioxide, and black carbon was associated with significantly increased risk of almost all outcomes. An increase of 5 µg/m 3 in PM 2.5 was associated with 13% (95% confidence interval 10.6% to 15.5%) increase in natural deaths; the corresponding figure for a 10 µg/m 3 increase in nitrogen dioxide was 8.6% (7% to 10.2%). Associations with PM 2.5 , nitrogen dioxide, and black carbon remained significant at low concentrations. For participants with exposures below the US standard of 12 µg/m 3 an increase of 5 µg/m 3 in PM 2.5 was associated with 29.6% (14% to 47.4%) increase in natural deaths. Conclusions Our study contributes to the evidence that outdoor air pollution is associated with mortality even at low pollution levels below the current European and North American standards and WHO guideline values. These findings are therefore an important contribution to the debate about revision of air quality limits, guidelines, and standards, and future assessments by the Global Burden of Disease. Introduction Epidemiological cohort studies have consistently found associations between long term exposure to outdoor air pollution and a range of morbidity and mortality endpoints. Concentrations of health relevant regulated pollutants, including fine particles and nitrogen dioxide, have decreased in the past decades in developed countries. Recent evaluations by the World Health Organization and the Global Burden of Disease study have suggested that health effects might persist at these lower concentrations. 1 2 3 However, there is uncertainty about the shape of the concentration-response function at the low end of the air pollution concentration distribution, related to the scarcity of observations at the lowest concentrations. Associations with mortality at low pollution levels in large populations were primarily investigated in a few North American studies, specifically the Canadian census cohort, the Canadian Community Health survey, the US Medicare cohort, and the US National Health Interview Survey study. 4 5 6 7 8 9 10 All the studies found associations below the current annual average US standard of 12 µg/m 3 and WHO guideline value of 10 µg/m 3 for fine particles with an aerodynamic diameter of <2.5 µm (PM 2.5 ), but only two studies were able to adjust for detailed individual lifestyle factors. 7 9 Most of the studies suggested a steeper concentration response function at the lowest levels, but the National Health Interview Survey study 9 suggested little association below about 5 µg/m 3 . Most studies focused primarily on PM 2.5 , whereas increasing evidence shows that pollutants related to local combustion sources, including nitrogen dioxide and black carbon, might be relevant to health. Few studies have assessed the mortality effects of long term exposure to ozone. Within the project Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE) we assessed associations of low level air pollution concentrations with natural and cause specific mortality. Low level air pollution was defined as concentrations below current European Union limit values, US Environmental Protection Agency national ambient air quality standards, or the 2005 WHO air quality guidelines. We investigated PM 2.5 , nitrogen dioxide, ozone, and black carbon at a fine spatial resolution. To have sufficient statistical power to detect associations at low exposure levels, we pooled data from eight European cohorts with information on important individual risk factors, including smoking and body mass index. Methods Study population The eight cohorts were selected from six European countries (see supplementary figure): Sweden (Stockholm county), Denmark (Copenhagen and Aarhus, and nationwide), France (nationwide), the Netherlands (four cities), Germany (Ruhr and Augsburg areas), and Austria (Vorarlberg region). All the cohorts, except the Danish cohort, 11 were previously part of the European Study of Cohorts for Air Pollution Effects (ESCAPE). 12 Not all ESCAPE cohorts were included, either because of relatively high annual air pollution concentrations or because the data could not be pooled. Several of the included cohorts (ie, from Sweden, Denmark, the Netherlands, and Augsburg, Germany) combined multiple original cohorts, termed subcohorts. All cohorts and subcohorts included general population samples and specific subgroups, such as Danish nurses (DNC cohort). Most cohorts were from large cities and surrounding regions. Supplementary appendix section 1 describes the cohorts in more detail. Recruitment of most of the cohorts was in the 1990s or 2000s (supplementary table S1). To pool data, we used a common codebook to harmonise individual and area level covariates and outcome variables between cohorts. Information on covariates was only available at baseline. Assessment of exposure to air pollution We assessed air pollution concentrations at the baseline residential address of the study participants using land use regression models, described in detail elsewhere. 13 Briefly, we estimated 2010 annual mean PM 2.5 , nitrogen dioxide, black carbon, and (warm season) ozone concentrations using the European Environmental Agency AirBase routine monitoring data (PM 2.5 , nitrogen dioxide, and ozone) and ESCAPE monitoring data (black carbon). Predictors were satellite derived and chemical transport model air pollutant estimates at 10×10 km, and fine scale land use and road traffic data. Western Europe-wide models were developed on a 100×100 m grid and were assigned to the participants using their geocoded residential address. The PM 2.5 , nitrogen dioxide, black carbon,<|im_end|> <|im_start|>assistant Long-term exposure to air pollution appears to still be linked to higher mortality despite the existence of air quality standards that restrict levels of pollution, suggests a study published online in The BMJ today. Researchers found evidence of higher death rates amongst people who had been exposed to more air pollution even though the levels were allowed under current official standards. Previous studies have found an association between long term exposure to outdoor air pollution such as those in the form of fine particles in the air (known as particulate matter or PM2.5) and nitrogen dioxide (NO2) and poor health or death. Air pollution concentrations have fallen substantially in Europe since the 1990s, but it is unclear whether there still is a link between pollution and ill health or death at concentrations of pollution that are below current permitted limits. Therefore, an international team of researchers led by the Institute for Risk Assessment Sciences at Utrecht University in the Netherlands, set out to investigate if there was an association between low levels of air pollution concentrations and natural and cause specific deaths. Low level air pollution was defined as concentrations below current limit values as set by the European Union, US Environmental Protection Agency and the World Health Organization (WHO) air quality guidelines. The researchers analysed data on eight groups of people within six European countries—Sweden, Denmark, France, the Netherlands, Germany and Austria—totalling 325,367 adults collectively. Their study, known as the Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE) recruited participants in the 1990s or 2000s. Of the 325,367 participants who were followed up over an almost 20-year period, around 14.5% (47,131 people) died during the study period. Analysis of the results showed that people who had higher exposure to particulate matter (PM2.5), nitrogen dioxide, and black carbon were more likely to die. An increase of 5 µg/m3 (a concentration measure of particulate matter) in PM2.5 was associated with a 13% increase in natural deaths while the corresponding figure for a 10 µg/m3 increase in nitrogen dioxide was 8.6%. Associations with PM2.5 and nitrogen dioxide were largely independent of each other. Moreover, associations with PM2.5, nitrogen dioxide, and black carbon remained significant at low to very low concentrations. For people who were exposed to pollution levels below the US standard of 12 µg/m3, an increase of 5 µg/m3 in PM2.5 was associated with a 29.6% increase in natural deaths. People exposed to nitrogen dioxide at less than half the current EU standard of 40 µg/m3, a 10 µg/m3 increase in nitrogen dioxide was associated with a 9.9% increase in natural deaths. This is an observational study, and as such, can't establish cause. The study also has some limitations, say the authors, such as the fact that it focused on exposure in 2010 which was towards the end of the follow-up period for most participants and, given the downward trend in air pollution, this measure might not exactly reflect the concentrations experienced during follow-up. However, this was a large study from multiple European groups of people with detailed information provided. As such, the authors conclude: "Our study contributes to the evidence that outdoor air pollution is associated with mortality even at levels below the current European and North American standards and WHO guideline values. "These findings are therefore an important contribution to the debate about revision of air quality limits, guidelines and standards, and future assessments by the Global Burden of Disease [study]." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Molecular clock REV-ERBα is central to regulating lung injuries, and decreased REV-ERBα abundance mediates sensitivity to pro-fibrotic insults and exacerbates fibrotic progression. In this study, we determine the role of REV-ERBα in fibrogenesis induced by bleomycin and Influenza A virus (IAV). Bleomycin exposure decreases the abundance of REV-ERBα, and mice dosed with bleomycin at night display exacerbated lung fibrogenesis. Rev-erbα agonist (SR9009) treatment prevents bleomycin induced collagen overexpression in mice. Rev-erbα global heterozygous (Rev-erbα Het) mice infected with IAV showed augmented levels of collagens and lysyl oxidases compared with WT-infected mice. Furthermore, Rev-erbα agonist (GSK4112) prevents collagen and lysyl oxidase overexpression induced by TGFβ in human lung fibroblasts, whereas the Rev-erbα antagonist exacerbates it. Overall, these results indicate that loss of REV-ERBα exacerbates the fibrotic responses by promoting collagen and lysyl oxidase expression, whereas Rev-erbα agonist prevents it. This study provides the potential of Rev-erbα agonists in the treatment of pulmonary fibrosis. Introduction Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease characterized by progressive lung scar tissue formation that is typically accompanied by impaired lung function and difficulty breathing 1 . The onset of pulmonary fibrosis is usually initiated by the dysregulation of tissue repair mechanisms which can be induced by various causes, such as air pollution (asbestos), antineoplastic drugs, and respiratory viral infections such as influenza A virus (IAV) and even coronavirus (SARS-CoV-2) infection 2 , 3 . In previous decades, rigorous basic studies have improved our understanding of pro-fibrotic pathogenesis and developed many candidates for anti-fibrotic therapy. However, there are no effective therapeutics for IPF, and the detailed molecular mechanism of fibrogenesis is still poorly understood 4 , 5 , 6 . Currently, nintedanib and pirfenidone are the only Food and Drug Administration (FDA)-approved drugs for the treatment of pulmonary fibrosis, which only serve to slow the progression of pulmonary fibrosis 7 . Investigating new promising molecular pathways involved in fibrogenic responses is urgently needed, and Rev-erbα has become a promising candidate 8 , 9 . REV-ERBα is a transcriptional repressor that regulates mRNA transcriptions involved in circadian rhythms, metabolism, and inflammatory responses 10 , 11 , 12 , 13 . Oscillations in circadian rhythm are controlled by the competition of two nuclear receptors, REV-ERBα, and retinoic acid-like orphan receptor alpha (RORα) 14 . REV-ERBα inhibits the transcription and translation of circadian locomotor output cycles kaput (CLOCK)/brain and muscle ARNT-like 1 ( BMAL1 , also known as ARNTL ), which will form a heterodimer and bind to E-box and promote the transcription/translation of either core clock molecules or downstream targets 15 . For regulating BMAL1 and CLOCK expression, RORα competes with REV-ERBα to bind with ROR response elements (ROREs) to activate the transcription of BMAL1 and CLOCK 15 forming an auto-feedback system with REV-ERBα and providing stability and precision to molecular clock regulation. Interestingly, the downstream gene targets of E-box include various fibrotic markers such as α-smooth muscle actin (αSMA) and vimentin (VIM) 16 . Moreover, the removal of REV-ERBα has been associated with increased risks of lung inflammation and premature senescence, which has been confirmed by our and others’ previous studies 17 , 18 , 19 . Circadian clock molecules are identified as essential mediators of pulmonary injuries with various causes, such as cigarette smoke (CS) and IAV 20 , 21 , 22 , 23 . Previous studies have described the importance of circadian molecules in key cell subtypes, including club cells, alveolar macrophages, and fibroblasts, in the lung microenvironment in response to injury and inflammatory mediators 8 , 19 , 24 , 25 . Previous findings showed that CS exposure and IAV infection-induced lung injuries are associated with disruption of the circadian clock and impaired lung function, survival rate, and daily ambulatory activity 26 , 27 . Various studies to date demonstrate the fundamental interactions of core clock molecules, such as REV-ERBα or BMAL1, with lung inflammatory responses and the development of chronic obstructive pulmonary disease (COPD) by CS exposure 23 . Currently, only one study has shown that REV - ERBα deficiency in lung fibroblasts exaggerates bleomycin-induced lung fibrogenesis 8 . However, the mechanism and role of REV-ERBα in lung fibrogenesis via collagen synthesis and its regulation during IAV infection are not known. Stabilization of collagen fibers is regulated by lysyl oxidase, a copper-dependent amino oxidase, via crosslinking the extracellular matrix proteins (collagen and elastin), thereby preventing collagen degradation 28 . Our previous study has identified the potential of REV-ERBα in regulating epithelial-mesenchymal transition (EMT) and fibroblast differentiation induced by CS and TGFβ 27 . We, therefore, hypothesize that REV-ERBα is important in regulating fibrotic progression in the lungs, by targeting collagen synthesis and its stabilization pathways. Here we show, the abundance of REV-ERBα is decreased during fibrogenesis, and loss of REV-ERBα augments the fibrotic responses caused by IAV infection. Furthermore, enhanced REV-ERBα activity/abundance will reduce abnormal collagen accumulation by inhibiting the expression of lysyl oxidases during myofibroblast differentiation. Results Dysregulated protein abundance of REV-ERBα, COL1A1 and LOX were observed in IPF patients compared with healthy controls It is well known that excessive extracellular matrix (ECM) protein production occurs during fibrosis and is deposited within the lesion areas. Human lung sections with verified pathology were purchased from Origene Inc. All the healthy controls were within the normal limits with 100% normal area and at least 80% alveoli area, while the IPF samples were composed of at least 40% lesion area (Supplementary Table 1 ). As shown in Fig. 1a , we observed high expression of type 1 collagen (COL1A1) over the injured tissue area and elevated lysyl oxidase (LOX) protein in IPF patients compared with healthy controls. Both COL1A1 and LOX were highly expressed among ECM in the lesion tissues in IPF samples, whereas limited COL1A1 and Lox were expressed in healthy controls. Consistent with previous data, we observed the diminished protein abundance and distribution of REV-ERBα in the fibrotic lesions from IPF samples, whereas REV-ERBα was highly expressed in the nuclei of healthy controls with limited protein abundance observed in the", "role": "user" }, { "content": "Abnormal sleep patterns, like those of night-shift workers, disrupt the body's natural biological clock and have been linked to lung health issues. A new study by University of Rochester Medical Center (URMC) researchers shows how a biological clock molecule, called REV-ERBα, contributes to lung scarring, uncovering new potential drugs and drug targets along the way. Pulmonary fibrosis, or lung scarring, is a serious condition in which connective tissue builds up in the lungs, making them thick and rigid, and causing difficulty breathing. While medications can ease the symptoms of pulmonary fibrosis, none can repair the lung damage caused by this sometimes-fatal disease. The URMC study, published in Nature Communications, confirms a previously-discovered link between the body's biological clock (or circadian rhythm) and lung diseases and uncovers a new mechanism underlying this link. Study authors show that a lack of the circadian rhythm protein, REV-ERBα, contributes to lung scarring in mice by increasing production of collagen, a major component of connective tissue, and lysyl oxidase, which stabilizes connective tissue and makes it more rigid. The team, which was led by Irfan Rahman, Ph.D., Dean's Professor of Environmental Medicine at URMC, found low levels of REV-ERBα and large amounts of collagen and lysyl oxidase in lung samples from patients with pulmonary fibrosis. Inducing lung injury in mice had a similar outcome: reduced REV-ERBα levels and increased levels of collagen, lysyl oxidase, and other markers of fibrosis. As a circadian rhythm protein, REV-ERBα expression normally fluctuates throughout the day, peaking at noon and dipping to its lowest levels at midnight. When the team induced lung injury at night, mice had larger increases in lysyl oxidase and collagen proteins, more extensive lung damage, and lower survival rates compared to mice injured in the morning. Rahman said this could be relevant to night-shift workers who are exposed to lung irritants at work. \"Night-shift work usually occurs during the midnight timeframe when the expression of REV-ERBα is lowest,\" he said. \"Our study suggests there is less protection against lung fibrosis generated from REV-ERBα activation at night.\" When the team induced lung injury in genetically modified mice that express low levels of REV-ERBα, the mice had worse outcomes that appeared to be mediated by increased collagen and lysyl oxidase. After 15 days of infection with influenza A, these mice had greater upregulation of collagen and lysyl oxidase gene expression, worse flu infections, and worse lung injury compared with mice who expressed normal levels of REV-ERBα. Activating REV-ERBα with a drug 14 days after lung injury in mice that express normal levels of REV-ERBα slightly reduced collagen and lysyl oxidase gene expression and improved lung health in the mice, though not significantly. When tested in cell cultures, the REV-ERBα-activating drugs had an anti-fibrotic effect. \"Currently, there are only two drugs approved by the FDA to treat fibrosis, and they only delay the process, they don't cure the disease,\" said study author Qixin Wang, Ph.D., a postdoctoral fellow working in Rahman's lab. \"REV-ERBα-activating drugs could serve as potential therapeutics to help prevent fibrosis and stop the disease process.\" But, he adds, a better REV-ERBα drug or a more direct way to deliver the drug is needed. In their studies, mice treated with the REV-ERBα-activating drug SR9009 lost more weight and had lower survival than untreated mice. While further research is needed, Rahman and Wang believe their findings open new possibilities for developing treatments for all sorts of fibrotic diseases—especially those with a circadian component, like nighttime alcohol consumption causing liver fibrosis. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Molecular clock REV-ERBα is central to regulating lung injuries, and decreased REV-ERBα abundance mediates sensitivity to pro-fibrotic insults and exacerbates fibrotic progression. In this study, we determine the role of REV-ERBα in fibrogenesis induced by bleomycin and Influenza A virus (IAV). Bleomycin exposure decreases the abundance of REV-ERBα, and mice dosed with bleomycin at night display exacerbated lung fibrogenesis. Rev-erbα agonist (SR9009) treatment prevents bleomycin induced collagen overexpression in mice. Rev-erbα global heterozygous (Rev-erbα Het) mice infected with IAV showed augmented levels of collagens and lysyl oxidases compared with WT-infected mice. Furthermore, Rev-erbα agonist (GSK4112) prevents collagen and lysyl oxidase overexpression induced by TGFβ in human lung fibroblasts, whereas the Rev-erbα antagonist exacerbates it. Overall, these results indicate that loss of REV-ERBα exacerbates the fibrotic responses by promoting collagen and lysyl oxidase expression, whereas Rev-erbα agonist prevents it. This study provides the potential of Rev-erbα agonists in the treatment of pulmonary fibrosis. Introduction Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease characterized by progressive lung scar tissue formation that is typically accompanied by impaired lung function and difficulty breathing 1 . The onset of pulmonary fibrosis is usually initiated by the dysregulation of tissue repair mechanisms which can be induced by various causes, such as air pollution (asbestos), antineoplastic drugs, and respiratory viral infections such as influenza A virus (IAV) and even coronavirus (SARS-CoV-2) infection 2 , 3 . In previous decades, rigorous basic studies have improved our understanding of pro-fibrotic pathogenesis and developed many candidates for anti-fibrotic therapy. However, there are no effective therapeutics for IPF, and the detailed molecular mechanism of fibrogenesis is still poorly understood 4 , 5 , 6 . Currently, nintedanib and pirfenidone are the only Food and Drug Administration (FDA)-approved drugs for the treatment of pulmonary fibrosis, which only serve to slow the progression of pulmonary fibrosis 7 . Investigating new promising molecular pathways involved in fibrogenic responses is urgently needed, and Rev-erbα has become a promising candidate 8 , 9 . REV-ERBα is a transcriptional repressor that regulates mRNA transcriptions involved in circadian rhythms, metabolism, and inflammatory responses 10 , 11 , 12 , 13 . Oscillations in circadian rhythm are controlled by the competition of two nuclear receptors, REV-ERBα, and retinoic acid-like orphan receptor alpha (RORα) 14 . REV-ERBα inhibits the transcription and translation of circadian locomotor output cycles kaput (CLOCK)/brain and muscle ARNT-like 1 ( BMAL1 , also known as ARNTL ), which will form a heterodimer and bind to E-box and promote the transcription/translation of either core clock molecules or downstream targets 15 . For regulating BMAL1 and CLOCK expression, RORα competes with REV-ERBα to bind with ROR response elements (ROREs) to activate the transcription of BMAL1 and CLOCK 15 forming an auto-feedback system with REV-ERBα and providing stability and precision to molecular clock regulation. Interestingly, the downstream gene targets of E-box include various fibrotic markers such as α-smooth muscle actin (αSMA) and vimentin (VIM) 16 . Moreover, the removal of REV-ERBα has been associated with increased risks of lung inflammation and premature senescence, which has been confirmed by our and others’ previous studies 17 , 18 , 19 . Circadian clock molecules are identified as essential mediators of pulmonary injuries with various causes, such as cigarette smoke (CS) and IAV 20 , 21 , 22 , 23 . Previous studies have described the importance of circadian molecules in key cell subtypes, including club cells, alveolar macrophages, and fibroblasts, in the lung microenvironment in response to injury and inflammatory mediators 8 , 19 , 24 , 25 . Previous findings showed that CS exposure and IAV infection-induced lung injuries are associated with disruption of the circadian clock and impaired lung function, survival rate, and daily ambulatory activity 26 , 27 . Various studies to date demonstrate the fundamental interactions of core clock molecules, such as REV-ERBα or BMAL1, with lung inflammatory responses and the development of chronic obstructive pulmonary disease (COPD) by CS exposure 23 . Currently, only one study has shown that REV - ERBα deficiency in lung fibroblasts exaggerates bleomycin-induced lung fibrogenesis 8 . However, the mechanism and role of REV-ERBα in lung fibrogenesis via collagen synthesis and its regulation during IAV infection are not known. Stabilization of collagen fibers is regulated by lysyl oxidase, a copper-dependent amino oxidase, via crosslinking the extracellular matrix proteins (collagen and elastin), thereby preventing collagen degradation 28 . Our previous study has identified the potential of REV-ERBα in regulating epithelial-mesenchymal transition (EMT) and fibroblast differentiation induced by CS and TGFβ 27 . We, therefore, hypothesize that REV-ERBα is important in regulating fibrotic progression in the lungs, by targeting collagen synthesis and its stabilization pathways. Here we show, the abundance of REV-ERBα is decreased during fibrogenesis, and loss of REV-ERBα augments the fibrotic responses caused by IAV infection. Furthermore, enhanced REV-ERBα activity/abundance will reduce abnormal collagen accumulation by inhibiting the expression of lysyl oxidases during myofibroblast differentiation. Results Dysregulated protein abundance of REV-ERBα, COL1A1 and LOX were observed in IPF patients compared with healthy controls It is well known that excessive extracellular matrix (ECM) protein production occurs during fibrosis and is deposited within the lesion areas. Human lung sections with verified pathology were purchased from Origene Inc. All the healthy controls were within the normal limits with 100% normal area and at least 80% alveoli area, while the IPF samples were composed of at least 40% lesion area (Supplementary Table 1 ). As shown in Fig. 1a , we observed high expression of type 1 collagen (COL1A1) over the injured tissue area and elevated lysyl oxidase (LOX) protein in IPF patients compared with healthy controls. Both COL1A1 and LOX were highly expressed among ECM in the lesion tissues in IPF samples, whereas limited COL1A1 and Lox were expressed in healthy controls. Consistent with previous data, we observed the diminished protein abundance and distribution of REV-ERBα in the fibrotic lesions from IPF samples, whereas REV-ERBα was highly expressed in the nuclei of healthy controls with limited protein abundance observed in the<|im_end|> <|im_start|>assistant Abnormal sleep patterns, like those of night-shift workers, disrupt the body's natural biological clock and have been linked to lung health issues. A new study by University of Rochester Medical Center (URMC) researchers shows how a biological clock molecule, called REV-ERBα, contributes to lung scarring, uncovering new potential drugs and drug targets along the way. Pulmonary fibrosis, or lung scarring, is a serious condition in which connective tissue builds up in the lungs, making them thick and rigid, and causing difficulty breathing. While medications can ease the symptoms of pulmonary fibrosis, none can repair the lung damage caused by this sometimes-fatal disease. The URMC study, published in Nature Communications, confirms a previously-discovered link between the body's biological clock (or circadian rhythm) and lung diseases and uncovers a new mechanism underlying this link. Study authors show that a lack of the circadian rhythm protein, REV-ERBα, contributes to lung scarring in mice by increasing production of collagen, a major component of connective tissue, and lysyl oxidase, which stabilizes connective tissue and makes it more rigid. The team, which was led by Irfan Rahman, Ph.D., Dean's Professor of Environmental Medicine at URMC, found low levels of REV-ERBα and large amounts of collagen and lysyl oxidase in lung samples from patients with pulmonary fibrosis. Inducing lung injury in mice had a similar outcome: reduced REV-ERBα levels and increased levels of collagen, lysyl oxidase, and other markers of fibrosis. As a circadian rhythm protein, REV-ERBα expression normally fluctuates throughout the day, peaking at noon and dipping to its lowest levels at midnight. When the team induced lung injury at night, mice had larger increases in lysyl oxidase and collagen proteins, more extensive lung damage, and lower survival rates compared to mice injured in the morning. Rahman said this could be relevant to night-shift workers who are exposed to lung irritants at work. "Night-shift work usually occurs during the midnight timeframe when the expression of REV-ERBα is lowest," he said. "Our study suggests there is less protection against lung fibrosis generated from REV-ERBα activation at night." When the team induced lung injury in genetically modified mice that express low levels of REV-ERBα, the mice had worse outcomes that appeared to be mediated by increased collagen and lysyl oxidase. After 15 days of infection with influenza A, these mice had greater upregulation of collagen and lysyl oxidase gene expression, worse flu infections, and worse lung injury compared with mice who expressed normal levels of REV-ERBα. Activating REV-ERBα with a drug 14 days after lung injury in mice that express normal levels of REV-ERBα slightly reduced collagen and lysyl oxidase gene expression and improved lung health in the mice, though not significantly. When tested in cell cultures, the REV-ERBα-activating drugs had an anti-fibrotic effect. "Currently, there are only two drugs approved by the FDA to treat fibrosis, and they only delay the process, they don't cure the disease," said study author Qixin Wang, Ph.D., a postdoctoral fellow working in Rahman's lab. "REV-ERBα-activating drugs could serve as potential therapeutics to help prevent fibrosis and stop the disease process." But, he adds, a better REV-ERBα drug or a more direct way to deliver the drug is needed. In their studies, mice treated with the REV-ERBα-activating drug SR9009 lost more weight and had lower survival than untreated mice. While further research is needed, Rahman and Wang believe their findings open new possibilities for developing treatments for all sorts of fibrotic diseases—especially those with a circadian component, like nighttime alcohol consumption causing liver fibrosis. <|im_end|>

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4725, 13693, 449, 220, 1041, 4, 4725, 3158, 323, 520, 3325, 220, 1490, 4, 453, 588, 14559, 3158, 11, 1418, 279, 6933, 37, 10688, 1051, 24306, 315, 520, 3325, 220, 1272, 4, 93217, 3158, 320, 10254, 67082, 6771, 220, 16, 7609, 1666, 6982, 304, 23966, 13, 220, 16, 64, 1174, 584, 13468, 1579, 7645, 315, 955, 220, 16, 71313, 320, 19924, 16, 32, 16, 8, 927, 279, 15902, 20438, 3158, 323, 32389, 84495, 4010, 36172, 521, 320, 1623, 55, 8, 13128, 304, 6933, 37, 6978, 7863, 449, 9498, 11835, 13, 11995, 26659, 16, 32, 16, 323, 5125, 55, 1051, 7701, 13605, 4315, 80700, 304, 279, 93217, 39881, 304, 6933, 37, 10688, 11, 20444, 7347, 26659, 16, 32, 16, 323, 445, 5241, 1051, 13605, 304, 9498, 11835, 13, 7440, 18620, 449, 3766, 828, 11, 584, 13468, 279, 54182, 13128, 37492, 323, 8141, 315, 66923, 12, 643, 33, 19481, 304, 279, 16178, 4744, 292, 63324, 505, 6933, 37, 10688, 11, 20444, 66923, 12, 643, 33, 19481, 574, 7701, 13605, 304, 279, 97192, 315, 9498, 11835, 449, 7347, 13128, 37492, 13468, 304, 279, 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33, 19481, 12, 9035, 1113, 11217, 1436, 8854, 439, 4754, 9139, 88886, 311, 1520, 5471, 16178, 63412, 323, 3009, 279, 8624, 1920, 1210, 2030, 11, 568, 11621, 11, 264, 2731, 66923, 12, 643, 33, 19481, 5623, 477, 264, 810, 2167, 1648, 311, 6493, 279, 5623, 374, 4460, 13, 763, 872, 7978, 11, 24548, 12020, 449, 279, 66923, 12, 643, 33, 19481, 12, 9035, 1113, 5623, 21550, 7467, 24, 5675, 810, 4785, 323, 1047, 4827, 20237, 1109, 83920, 24548, 13, 6104, 4726, 3495, 374, 4460, 11, 98376, 323, 29346, 4510, 872, 14955, 1825, 502, 24525, 369, 11469, 22972, 369, 682, 21522, 315, 16178, 4744, 292, 19338, 2345, 36046, 1884, 449, 264, 4319, 10272, 3777, 11, 1093, 93744, 13200, 15652, 14718, 26587, 16178, 63412, 13, 220, 128257, 198 ]

2,378

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Chemical loss of Arctic ozone due to anthropogenic halogens is driven by temperature, with more loss occurring during cold winters favourable for formation of polar stratospheric clouds (PSCs). We show that a positive, statistically significant rise in the local maxima of PSC formation potential (PFP LM ) for cold winters is apparent in meteorological data collected over the past half century. Output from numerous General Circulation Models (GCMs) also exhibits positive trends in PFP LM over 1950 to 2100, with highest values occurring at end of century, for simulations driven by a large rise in the radiative forcing of climate from greenhouse gases (GHGs). We combine projections of stratospheric halogen loading and humidity with GCM-based forecasts of temperature to suggest that conditions favourable for large, seasonal loss of Arctic column O 3 could persist or even worsen until the end of this century, if future abundances of GHGs continue to steeply rise. Introduction Variations in ozone within the Arctic polar vortex during winter and spring (hereafter: winter) are driven by anthropogenic chemical loss and dynamical resupply 1 , 2 . Chemical loss and dynamical resupply of stratospheric ozone show large inter-annual variability, driven by meteorology. Colder, more isolated vortices are associated with smaller values of total column ozone 3 , 4 , less resupply and larger chemical loss of ozone (due to low temperatures). Colder vortices are caused by a weaker Brewer-Dobson Circulation, reduced planetary-scale wave activity and lower eddy heat flux in the extratropical lower stratosphere 5 . The coldest Arctic winters experience the smallest values of total column ozone, due in part to a larger amount of chemical loss 3 , 4 . Chemical loss of O 3 in the Arctic stratosphere occurs following the activation of chlorine on or within cold sulphate aerosols 6 , 7 and supercooled ternary (H 2 SO 4 -HNO 3 -H 2 O) solution droplets 8 (STS), and on the surfaces of nitric acid trihydrate (NAT) particles 9 or water ice when air is exceptionally cold. When temperatures fall during Arctic winter, STS and NAT particles 10 , 11 , 12 are the first types of PSCs to form. The timescale for chemical processing of chlorine reservoir gases on STS droplets transitions from weeks to days near the temperature at which NAT becomes thermodynamically stable ( T NAT ) 7 , which is governed by the vapour pressure of nitric acid (HNO 3 ) and water (H 2 O) 9 . The volume of air cold enough to allow for the existence of polar stratospheric clouds (PSCs) in the Arctic polar vortex, averaged over an ozone loss season ( V PSC ), exhibits a compact, near-linear relation with chemical loss of column ozone 13 , 14 , 15 , 16 , 17 during recent winters. Rex et al. 13 postulated that the maximum value of V PSC during Arctic winters had risen in a statistically significant manner between 1966 and 2003, and suggested this increase was caused by radiative and dynamical effects of rising levels of greenhouse gases (GHGs). New record values of V PSC were set in the winters of 2005 (ref. 14 ), 2011 (ref. 3 ), 2016 (refs. 18 , 19 ), and 2020 (ref. 20 ). An early evaluation using a general circulation model (GCM) with coupled active chemistry (a chemistry climate model, or CCM) suggested decreases in planetary wave activity reaching the mid-latitude stratosphere due to increased westerly winds in the subtropics, driven by rising levels of GHGs, would lead to stronger, colder Arctic vortices 21 . More recently, a simulation using another CCM suggested that future cooling of the Arctic lower stratosphere during early winter would result from direct radiative cooling driven by GHGs and indirect effects related to declining Arctic sea ice and rising sea surface temperatures 22 . Simulations conducted using a third CCM showed modest cooling (~0.15 K decade −1 ) of the future Arctic stratosphere at 50 hPa also driven by GHGs, with high interannual variability that complicates the assessment of statistical significance 23 . Here we examine trends in the PSC formation potential (PFP), which represents the number of days a volume of air equal to the volume of the polar vortex was exposed to PSC conditions for each Arctic ozone loss season based on T NAT (similar to ref. 24 ). We show that positive, statistically significant trends in the local maxima (LM) of the PFP timeseries (PFP LM , the upper quartile of PFP relative to a trend line) over the past four decades are apparent in data from four meteorological centres. A central component of our analysis is the examination of output from GCMs that provide estimates of stratospheric conditions until the end of this century, with a focus on models that submitted output for the Shared Socioeconomic Pathways SSP5-8.5, SSP3-7.0, SSP2-4.5, and SSP1-2.6 runs of Climate Model Intercomparison Project Phase 6 (CMIP6) 25 . We combine GCM forecasts of PFP with projections of stratospheric halogen loading and stratospheric humidity to evaluate how the chemical loss of Arctic ozone may evolve, as a function of future levels of atmospheric GHGs and stratospheric H 2 O. We find that if the future abundance of GHGs continues to rise steeply as in either the SSP3-7.0 or SSP5-8.5 scenario, then continued growth in the atmospheric conditions favourable for large, seasonal loss of column ozone could persist or even worsen until the end of this century, despite the decline in the abundance of anthropogenic halogens that is expected to occur due to compliance with the Montreal Protocol. Results Chemical loss of ozone Figure 1a shows values of column ozone loss between 380 and 550 K potential temperature (ΔO 3 ) at the end of winter, based on ozonesonde measurements in the Arctic vortex, plotted as a function of PFP (see “Methods” for the detailed definition of PFP). Data values are shown for all of the cold winters that have occurred since the inception of regular ozonesonde launches. The estimates of ΔO", "role": "user" }, { "content": "There is a race going on high in the atmosphere above the Arctic, and the ozone layer that protects Earth from damaging ultraviolet (UV) radiation will lose the race if greenhouse gas emissions aren't reduced quickly enough. A new study from an international team of scientists, including University of Maryland Professor Ross Salawitch, shows that extremely low winter temperatures high in the atmosphere over the arctic are becoming more frequent and more extreme because of climate patterns associated with global warming. The study also shows that those extreme low temperatures are causing reactions among chemicals humans pumped into the air decades ago, leading to greater ozone losses. The new findings call into question the commonly held assumption that ozone loss would grind to a halt in just a few decades following the 2010 global ban on the production of ozone depleting chemicals called chlorofluorocarbons (CFCs) and halons. The study—which was jointly conducted by UMD, the Alfred Wegener Institute's Helmholtz Centre for Polar and Marine Research, and the Finnish Meteorological Institute—was published in the journal Nature Communications on June 23, 2021. \"We're in a kind of race between the slow and steady decline in CFCs, which take 50 to 100 years to go away, and climate change, which is causing polar vortex temperature extremes to become colder at a rapid pace,\" said Ross Salawitch, who is a professor in the UMD Department of Atmospheric and Oceanic Science, the Department of Chemistry and Biochemistry, and the Earth System Science Interdisciplinary Center. \"The increasingly cold temperatures create conditions that promote ozone depletion by CFCs. So, even though these compounds are slowly going away, Arctic ozone depletion is on the rise as the climate changes.\" New data from the study showed the lowest Arctic polar vortex temperatures and the highest ozone losses on record in 2020, beating the previous records set nine years ago in 2011. The polar vortex is a relatively self-contained, low-pressure system that forms in the stratosphere—at an altitude of about 12 to 50 kilometers (7.5 to 31 miles)—over the Arctic every autumn and stays for varying durations throughout the winter to spring. The pattern of warm and cold winter temperatures in the polar vortex is very irregular, so not every winter is extremely cold. But the trend toward more frequent and more extreme low temperatures in the polar vortex concerns the researchers, because those conditions promote the formation of clouds, and that promotes ozone loss in the polar stratosphere. Most of the chlorine and a significant amount of the bromine in the stratosphere comes from the breakdown of CFCs, halons and other ozone-depleting substances. Normally within the Arctic polar vortex the chlorine is non-reactive, but clouds provide the right conditions for the chlorine to change form and react with bromine and sunlight to destroy ozone. Despite drastic reduction of the industrial production of CFCs and halons since the Montreal Protocol in 1987 and the global ban that followed in 2010, these long-lasting compounds are still abundant in the atmosphere. According to the World Meteorological Organization, atmospheric chlorine and bromine produced by humans is not expected to fall below 50% of their highest levels until the end of this century. To determine what this situation means for the future, the researchers projected ozone loss out to the year 2100 based on the long-term temperature trend in the polar vortex and the expected decline in chlorine and bromine compounds. They based their predictions on the output from 53 top climate models used by the Intergovernmental Panel on Climate Change. \"All but one of the climate models we looked at show that exceptionally cold winters in the polar vortex will get colder over time,\" Salawitch said. \"And the more greenhouse gas emissions there are, the steeper the trend, which means greater ozone depletion.\" Combining these projections with analyses of meteorological data from the past 56 years, the researchers confirmed that the Arctic is already experiencing a significant trend toward lower stratospheric temperatures and associated increases in ozone losses. What's more, their observations reveal that these trends are occurring at rate consistent with the fastest climate models. \"We have been saying that a train is coming for a number of years now,\" said Salawitch, pointing to research papers he published in 2004 and 2006 that showed extreme winters in the Arctic were becoming colder. \"We've now seen the train whizzing by with record ozone loss in 2011 and now in 2020. So, this paper is really a wake-up call that something is happening in the atmosphere that's really important for ozone, and it looks like greenhouse gases are driving it.\" Salawitch and his colleagues do not yet fully understand how increasing greenhouse gas emissions and the associated changes to global climate are causing the extreme cold winters in the stratospheric layer of the polar vortex. But some of the underlying mechanisms are understood. Global warming occurs in part because greenhouse gases trap heat closer to Earth's surface, which allows cooling of the upper layers in the stratosphere, where the ozone layer is located. Warming at the surface causes changes to prevailing wind patterns, and the researchers suggest that these changes also produce lower temperatures in the polar vortex. The researchers also note that recent years have seen a rapid increase in methane, a more powerful greenhouse gas than carbon dioxide, in the lower atmosphere. As this gas travels to the stratosphere, it increases humidity, which also leads to conditions that promote ozone-destroying chemical reactions in the Arctic. Because ozone filters much of the sun's potentially harmful UV radiation, a depleted ozone layer over the Arctic can result in more UV radiation reaching the surface of the Earth over Europe, North America and Asia when the polar vortex dips south. But there is hope for avoiding future ozone depletion, according to the researchers. Their study shows that substantial reductions in greenhouse gas emissions over the coming decades could lead to a steady decline in conditions that favor large ozone loss in the Arctic stratosphere. The research paper, Climate change favours large seasonal loss of Arctic ozone, Peter von der Gathen, Rigel Kivi, Ingo Wohltmann, Ross J. Salawitch, Markus Rex, was published in the journal Nature Communications on June 23, 2021. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Chemical loss of Arctic ozone due to anthropogenic halogens is driven by temperature, with more loss occurring during cold winters favourable for formation of polar stratospheric clouds (PSCs). We show that a positive, statistically significant rise in the local maxima of PSC formation potential (PFP LM ) for cold winters is apparent in meteorological data collected over the past half century. Output from numerous General Circulation Models (GCMs) also exhibits positive trends in PFP LM over 1950 to 2100, with highest values occurring at end of century, for simulations driven by a large rise in the radiative forcing of climate from greenhouse gases (GHGs). We combine projections of stratospheric halogen loading and humidity with GCM-based forecasts of temperature to suggest that conditions favourable for large, seasonal loss of Arctic column O 3 could persist or even worsen until the end of this century, if future abundances of GHGs continue to steeply rise. Introduction Variations in ozone within the Arctic polar vortex during winter and spring (hereafter: winter) are driven by anthropogenic chemical loss and dynamical resupply 1 , 2 . Chemical loss and dynamical resupply of stratospheric ozone show large inter-annual variability, driven by meteorology. Colder, more isolated vortices are associated with smaller values of total column ozone 3 , 4 , less resupply and larger chemical loss of ozone (due to low temperatures). Colder vortices are caused by a weaker Brewer-Dobson Circulation, reduced planetary-scale wave activity and lower eddy heat flux in the extratropical lower stratosphere 5 . The coldest Arctic winters experience the smallest values of total column ozone, due in part to a larger amount of chemical loss 3 , 4 . Chemical loss of O 3 in the Arctic stratosphere occurs following the activation of chlorine on or within cold sulphate aerosols 6 , 7 and supercooled ternary (H 2 SO 4 -HNO 3 -H 2 O) solution droplets 8 (STS), and on the surfaces of nitric acid trihydrate (NAT) particles 9 or water ice when air is exceptionally cold. When temperatures fall during Arctic winter, STS and NAT particles 10 , 11 , 12 are the first types of PSCs to form. The timescale for chemical processing of chlorine reservoir gases on STS droplets transitions from weeks to days near the temperature at which NAT becomes thermodynamically stable ( T NAT ) 7 , which is governed by the vapour pressure of nitric acid (HNO 3 ) and water (H 2 O) 9 . The volume of air cold enough to allow for the existence of polar stratospheric clouds (PSCs) in the Arctic polar vortex, averaged over an ozone loss season ( V PSC ), exhibits a compact, near-linear relation with chemical loss of column ozone 13 , 14 , 15 , 16 , 17 during recent winters. Rex et al. 13 postulated that the maximum value of V PSC during Arctic winters had risen in a statistically significant manner between 1966 and 2003, and suggested this increase was caused by radiative and dynamical effects of rising levels of greenhouse gases (GHGs). New record values of V PSC were set in the winters of 2005 (ref. 14 ), 2011 (ref. 3 ), 2016 (refs. 18 , 19 ), and 2020 (ref. 20 ). An early evaluation using a general circulation model (GCM) with coupled active chemistry (a chemistry climate model, or CCM) suggested decreases in planetary wave activity reaching the mid-latitude stratosphere due to increased westerly winds in the subtropics, driven by rising levels of GHGs, would lead to stronger, colder Arctic vortices 21 . More recently, a simulation using another CCM suggested that future cooling of the Arctic lower stratosphere during early winter would result from direct radiative cooling driven by GHGs and indirect effects related to declining Arctic sea ice and rising sea surface temperatures 22 . Simulations conducted using a third CCM showed modest cooling (~0.15 K decade −1 ) of the future Arctic stratosphere at 50 hPa also driven by GHGs, with high interannual variability that complicates the assessment of statistical significance 23 . Here we examine trends in the PSC formation potential (PFP), which represents the number of days a volume of air equal to the volume of the polar vortex was exposed to PSC conditions for each Arctic ozone loss season based on T NAT (similar to ref. 24 ). We show that positive, statistically significant trends in the local maxima (LM) of the PFP timeseries (PFP LM , the upper quartile of PFP relative to a trend line) over the past four decades are apparent in data from four meteorological centres. A central component of our analysis is the examination of output from GCMs that provide estimates of stratospheric conditions until the end of this century, with a focus on models that submitted output for the Shared Socioeconomic Pathways SSP5-8.5, SSP3-7.0, SSP2-4.5, and SSP1-2.6 runs of Climate Model Intercomparison Project Phase 6 (CMIP6) 25 . We combine GCM forecasts of PFP with projections of stratospheric halogen loading and stratospheric humidity to evaluate how the chemical loss of Arctic ozone may evolve, as a function of future levels of atmospheric GHGs and stratospheric H 2 O. We find that if the future abundance of GHGs continues to rise steeply as in either the SSP3-7.0 or SSP5-8.5 scenario, then continued growth in the atmospheric conditions favourable for large, seasonal loss of column ozone could persist or even worsen until the end of this century, despite the decline in the abundance of anthropogenic halogens that is expected to occur due to compliance with the Montreal Protocol. Results Chemical loss of ozone Figure 1a shows values of column ozone loss between 380 and 550 K potential temperature (ΔO 3 ) at the end of winter, based on ozonesonde measurements in the Arctic vortex, plotted as a function of PFP (see “Methods” for the detailed definition of PFP). Data values are shown for all of the cold winters that have occurred since the inception of regular ozonesonde launches. The estimates of ΔO<|im_end|> <|im_start|>assistant There is a race going on high in the atmosphere above the Arctic, and the ozone layer that protects Earth from damaging ultraviolet (UV) radiation will lose the race if greenhouse gas emissions aren't reduced quickly enough. A new study from an international team of scientists, including University of Maryland Professor Ross Salawitch, shows that extremely low winter temperatures high in the atmosphere over the arctic are becoming more frequent and more extreme because of climate patterns associated with global warming. The study also shows that those extreme low temperatures are causing reactions among chemicals humans pumped into the air decades ago, leading to greater ozone losses. The new findings call into question the commonly held assumption that ozone loss would grind to a halt in just a few decades following the 2010 global ban on the production of ozone depleting chemicals called chlorofluorocarbons (CFCs) and halons. The study—which was jointly conducted by UMD, the Alfred Wegener Institute's Helmholtz Centre for Polar and Marine Research, and the Finnish Meteorological Institute—was published in the journal Nature Communications on June 23, 2021. "We're in a kind of race between the slow and steady decline in CFCs, which take 50 to 100 years to go away, and climate change, which is causing polar vortex temperature extremes to become colder at a rapid pace," said Ross Salawitch, who is a professor in the UMD Department of Atmospheric and Oceanic Science, the Department of Chemistry and Biochemistry, and the Earth System Science Interdisciplinary Center. "The increasingly cold temperatures create conditions that promote ozone depletion by CFCs. So, even though these compounds are slowly going away, Arctic ozone depletion is on the rise as the climate changes." New data from the study showed the lowest Arctic polar vortex temperatures and the highest ozone losses on record in 2020, beating the previous records set nine years ago in 2011. The polar vortex is a relatively self-contained, low-pressure system that forms in the stratosphere—at an altitude of about 12 to 50 kilometers (7.5 to 31 miles)—over the Arctic every autumn and stays for varying durations throughout the winter to spring. The pattern of warm and cold winter temperatures in the polar vortex is very irregular, so not every winter is extremely cold. But the trend toward more frequent and more extreme low temperatures in the polar vortex concerns the researchers, because those conditions promote the formation of clouds, and that promotes ozone loss in the polar stratosphere. Most of the chlorine and a significant amount of the bromine in the stratosphere comes from the breakdown of CFCs, halons and other ozone-depleting substances. Normally within the Arctic polar vortex the chlorine is non-reactive, but clouds provide the right conditions for the chlorine to change form and react with bromine and sunlight to destroy ozone. Despite drastic reduction of the industrial production of CFCs and halons since the Montreal Protocol in 1987 and the global ban that followed in 2010, these long-lasting compounds are still abundant in the atmosphere. According to the World Meteorological Organization, atmospheric chlorine and bromine produced by humans is not expected to fall below 50% of their highest levels until the end of this century. To determine what this situation means for the future, the researchers projected ozone loss out to the year 2100 based on the long-term temperature trend in the polar vortex and the expected decline in chlorine and bromine compounds. They based their predictions on the output from 53 top climate models used by the Intergovernmental Panel on Climate Change. "All but one of the climate models we looked at show that exceptionally cold winters in the polar vortex will get colder over time," Salawitch said. "And the more greenhouse gas emissions there are, the steeper the trend, which means greater ozone depletion." Combining these projections with analyses of meteorological data from the past 56 years, the researchers confirmed that the Arctic is already experiencing a significant trend toward lower stratospheric temperatures and associated increases in ozone losses. What's more, their observations reveal that these trends are occurring at rate consistent with the fastest climate models. "We have been saying that a train is coming for a number of years now," said Salawitch, pointing to research papers he published in 2004 and 2006 that showed extreme winters in the Arctic were becoming colder. "We've now seen the train whizzing by with record ozone loss in 2011 and now in 2020. So, this paper is really a wake-up call that something is happening in the atmosphere that's really important for ozone, and it looks like greenhouse gases are driving it." Salawitch and his colleagues do not yet fully understand how increasing greenhouse gas emissions and the associated changes to global climate are causing the extreme cold winters in the stratospheric layer of the polar vortex. But some of the underlying mechanisms are understood. Global warming occurs in part because greenhouse gases trap heat closer to Earth's surface, which allows cooling of the upper layers in the stratosphere, where the ozone layer is located. Warming at the surface causes changes to prevailing wind patterns, and the researchers suggest that these changes also produce lower temperatures in the polar vortex. The researchers also note that recent years have seen a rapid increase in methane, a more powerful greenhouse gas than carbon dioxide, in the lower atmosphere. As this gas travels to the stratosphere, it increases humidity, which also leads to conditions that promote ozone-destroying chemical reactions in the Arctic. Because ozone filters much of the sun's potentially harmful UV radiation, a depleted ozone layer over the Arctic can result in more UV radiation reaching the surface of the Earth over Europe, North America and Asia when the polar vortex dips south. But there is hope for avoiding future ozone depletion, according to the researchers. Their study shows that substantial reductions in greenhouse gas emissions over the coming decades could lead to a steady decline in conditions that favor large ozone loss in the Arctic stratosphere. The research paper, Climate change favours large seasonal loss of Arctic ozone, Peter von der Gathen, Rigel Kivi, Ingo Wohltmann, Ross J. Salawitch, Markus Rex, was published in the journal Nature Communications on June 23, 2021. <|im_end|>

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2,676

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Chimeric antigen receptor T cells (CAR-T cells) have emerged as a powerful treatment option for individuals with B cell malignancies but have yet to achieve success in treating acute myeloid leukemia (AML) due to a lack of safe targets. Here we leveraged an atlas of publicly available RNA-sequencing data of over 500,000 single cells from 15 individuals with AML and tissue from 9 healthy individuals for prediction of target antigens that are expressed on malignant cells but lacking on healthy cells, including T cells. Aided by this high-resolution, single-cell expression approach, we computationally identify colony-stimulating factor 1 receptor and cluster of differentiation 86 as targets for CAR-T cell therapy in AML. Functional validation of these established CAR-T cells shows robust in vitro and in vivo efficacy in cell line- and human-derived AML models with minimal off-target toxicity toward relevant healthy human tissues. This provides a strong rationale for further clinical development. Main Chimeric antigen receptor T cells (CAR-T cells) are human-derived effector cells that are genetically engineered to therapeutically target a specific epitope on malignant cells 1 . CAR-T cells targeting the B cell lineage antigens cluster of differentiation 19 (CD19) or B cell maturation antigen (BCMA) have shown clinical efficacy in heavily pretreated individuals suffering from different B cell malignancies, such as B cell lymphoma, B cell acute lymphoblastic leukemia and multiple myeloma 2 , 3 , 4 . However, CAR-T cells targeting non-B cell-associated epitopes have yet to show similar response rates 5 . For instance, in myeloid malignancies, such as acute myeloid leukemia (AML), common target structures are often coexpressed on vital tissues, such as endothelial cells or hematopoietic stem and progenitor cells (HSPCs), increasing the risk for on-target off-tumor toxicity 6 , 7 . Identifying safe target structures is thus pivotal to translate the vast potential of CAR-T cell therapy to myeloid neoplasms. AML is the most common acute leukemia in adults, and its molecular heterogeneity has complicated the successful development of new therapeutic agents 8 . Despite upfront curative intent in most individuals with combinatorial chemotherapy, disease relapse is frequent, occurring in over 50% of treated individuals 9 . After relapse, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative approach; but even then, long-term survival probabilities are below 20%. Therefore, innovative treatment options represent a high unmet medical need. Currently, CAR-T cells targeting AML-associated target antigens CD33 and interleukin-3 receptor-α (IL3RA, CD123) are undergoing clinical investigation. Due to preclinical evidence of off-tumor toxicity toward HSPCs, most clinical trials are evaluating the potential of anti-CD123 or anti-CD33 CAR-T cells as a bridge-to-transplant regimen before allo-HSCT. Early reports of these trials have shown only limited therapeutic efficacy 10 , 11 , 12 . Yet, more complete results of these clinical studies in AML are eagerly awaited. Meanwhile, other targets, such as CD70, C-type lectin-like molecule-1, FMS-like tyrosine kinase-3 (FLT3), CD44 variant 6 (CD44v6), sialic acid-binding Ig-like lectin-6 (Siglec-6) or CD117, have been tested in preclinical studies as alternative CAR targets 13 , 14 , 15 , 16 , 17 . However, clinical validation is pending, and expression profiles of most of the targets raise at least some uncertainties regarding their clinical safety and efficacy. Newly developed CAR-T cells are often directed to target structures that have already been used for antibody therapy. By contrast, unbiased de novo target screenings for CAR-T cell therapy have rarely been conducted 18 . In addition, until recently, off-tumor antigen projections could only leverage bulk sequencing data, missing detailed information about cell-type-specific target antigen expression patterns. Conveniently, the revolution in single-cell technologies in the last decade has generated massive single-cell expression datasets that provide precise information about the transcriptomic anatomy of healthy and malignant cells 19 , a mostly untapped resource for therapeutic development, at least in the context of de novo antigen predictions and CAR-T cell development. These advancements allow in-depth on- and off-tumor antigen prediction 20 , offering unique insights into healthy and malignant cells at an unmatched resolution. We thus developed a single-cell RNA-sequencing (scRNA-seq)-based approach specifically tailored to identify promising antigens for CAR-T cell therapy on a discovery AML cohort of 15 individuals 21 . We generated a transcriptomic atlas from publicly available datasets, consisting of over 28,000 healthy and malignant bone marrow cells from these individuals and over 500,000 healthy cells from nine of the most vital human tissues. We screened these data for cell surface antigens expressed on malignant cells with minimal coexpression on healthy cells, including T cells. With rigorous cutoffs, we identified two unrecognized targets for CAR-T cells in AML: colony-stimulating factor 1 receptor (CSF1R) and CD86. We developed CAR-T cells against both targets and tested their efficacy in vitro and in vivo in cell lines and human-derived models, including primary AML blasts. We assessed the safety of these CAR-T cells in vitro using advanced primary cell cultures for target-expressing cell types, demonstrating a better discriminatory capacity than established anti-CD33 CAR-T cells. In addition, we used several in vivo models to mitigate safety concerns. Our results illustrate the translational potential of an unbiased scRNA-seq-based screening approach and lay the basis for clinical development of our CAR candidates. Results Development of scRNA-seq-based screening algorithm We created an unbiased scRNA-seq-based discovery approach for identification of CAR targets. To ensure CAR efficacy, a suitable candidate is (1) overexpressed in malignant cells and (2) located on the cell surface. In terms of CAR safety, the candidate should (3) not be expressed on T cells and (4) show minimal expression across vital, healthy tissues (Fig. 1a ). Applying our approach to AML, we used publicly available scRNA-seq data from 15 individuals with AML 21 . From these, a total of 28,404 sequenced healthy and malignant bone marrow cells passed quality control (Fig. 1b,c ; see Methods for a detailed description of quality control steps). For maximal CAR efficacy, we sought to identify candidates with higher expression on malignant HSPC-like cells (herein termed hematopoietic stem cell (HSC)-like and progenitor (Prog)-like) than on healthy cells. Differential gene expression", "role": "user" }, { "content": "Unlike other forms of blood cancer, acute myeloid leukemia (AML) cannot currently be treated with CAR-T cell immunotherapy. The reason is that specific molecular targets with which certain immune cells could specifically target AML cells are lacking, which would permit the immune system to attack cancer. Two research teams of Professor Dr. Sebastian Kobold with Dr. Adrian Gottschlich from the Division of Clinical Pharmacology at LMU University Hospital Munich and Dr. Carsten Marr with Moritz Thomas from the Institute of AI for Health at Helmholtz Munich have now succeeded in discovering such targets. The results have now been published in the journal Nature Biotechnology. AML—one of several forms of leukemia (\"blood cancer\")—is a treacherous disease. Five years after the initial diagnosis, only one-third of patients are still alive. Up to 85 percent of patients appear to be cured after intensive chemotherapy. However, in more than half of them, the disease returns within one to two years because the chemotherapy has not destroyed all leukemia cells. In the event of a relapse, a stem cell transplant is the only hope for cure for a patient. But even then, the long-term probability of survival is less than 20 percent. New treatment options are therefore urgently needed. CAR-T cell therapy is an innovative therapy. CAR-T stands for \"chimeric antigen receptor in T cells.\" T cells are cells of the immune system. Cancer cells evade their \"normal\" attempts to attack them by using various molecular tricks. Thus, T cells no longer recognize their opponents, the cancer cells. During CAR-T cell therapy, T cells are first removed from the patients and then genetically engineered to produce a specific protein (CAR) on their surface. When these CAR-T cells are injected back into the patient's body, these will only engage their target: CD19, which ensures that they recognize the patient's cancer cells and bind to them in a targeted manner. The cancer cells consequently die. New targets However, the approved CAR-T cells against CD19 are not suitable for AML, because CD19 is (usually) not present on the surface of AML cells. Clinical results with CAR-T cells directed against other surface molecules of AML cells have been sobering so far, according to scientists. This is because CAR-T cells were unable to distinguish between healthy and degenerated cells—with correspondingly induced significant side effects. The physician Sebastian Kobold and the physicist Carsten Marr, together with colleagues from the LMU University Hospital Munich and the Institute of AI for Health at Helmholtz Munich, set out to find alternative molecules that would ideally be found exclusively on the surface of AML cells. With the help of extensive bioinformatic analyses and the integration of expression data from more than half a million individual cells, two candidates finally crystallized out of 25,000 potential cell surface molecules. These are known as CSF1R and CD86. \"Such an analysis would not have been possible a few years ago, since the required single-cell data has been generated only very recently,\" says Marr, who led the AI-assisted analysis in the study at Helmholtz Munich. The researchers produced CAR-T cells in the laboratory of the LMU University Hospital Munich that precisely target these molecules. The cells were then tested on different AML models, including AML cells from patients. The results, according to Kobold are promising: \"On the one hand, these CAR-T cells are effective against AML, but on the other hand, they hardly destroy healthy cells.\" The study impressively demonstrates how the synergy of interdisciplinary research groups can lead to breakthroughs in health research to treat patients in the best possible way. The researchers' next goal: They want to develop GMP (good manufacturing practice)-capable processes to produce CAR-T cells that can then also be used in clinical trials with AML patients. This is to take place within the framework of the \"Bavarian Cell Therapy Catalyst,\" which is supported by the Bavarian Research Foundation. Kobold expects the first tests with patients in two to three years. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Chimeric antigen receptor T cells (CAR-T cells) have emerged as a powerful treatment option for individuals with B cell malignancies but have yet to achieve success in treating acute myeloid leukemia (AML) due to a lack of safe targets. Here we leveraged an atlas of publicly available RNA-sequencing data of over 500,000 single cells from 15 individuals with AML and tissue from 9 healthy individuals for prediction of target antigens that are expressed on malignant cells but lacking on healthy cells, including T cells. Aided by this high-resolution, single-cell expression approach, we computationally identify colony-stimulating factor 1 receptor and cluster of differentiation 86 as targets for CAR-T cell therapy in AML. Functional validation of these established CAR-T cells shows robust in vitro and in vivo efficacy in cell line- and human-derived AML models with minimal off-target toxicity toward relevant healthy human tissues. This provides a strong rationale for further clinical development. Main Chimeric antigen receptor T cells (CAR-T cells) are human-derived effector cells that are genetically engineered to therapeutically target a specific epitope on malignant cells 1 . CAR-T cells targeting the B cell lineage antigens cluster of differentiation 19 (CD19) or B cell maturation antigen (BCMA) have shown clinical efficacy in heavily pretreated individuals suffering from different B cell malignancies, such as B cell lymphoma, B cell acute lymphoblastic leukemia and multiple myeloma 2 , 3 , 4 . However, CAR-T cells targeting non-B cell-associated epitopes have yet to show similar response rates 5 . For instance, in myeloid malignancies, such as acute myeloid leukemia (AML), common target structures are often coexpressed on vital tissues, such as endothelial cells or hematopoietic stem and progenitor cells (HSPCs), increasing the risk for on-target off-tumor toxicity 6 , 7 . Identifying safe target structures is thus pivotal to translate the vast potential of CAR-T cell therapy to myeloid neoplasms. AML is the most common acute leukemia in adults, and its molecular heterogeneity has complicated the successful development of new therapeutic agents 8 . Despite upfront curative intent in most individuals with combinatorial chemotherapy, disease relapse is frequent, occurring in over 50% of treated individuals 9 . After relapse, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative approach; but even then, long-term survival probabilities are below 20%. Therefore, innovative treatment options represent a high unmet medical need. Currently, CAR-T cells targeting AML-associated target antigens CD33 and interleukin-3 receptor-α (IL3RA, CD123) are undergoing clinical investigation. Due to preclinical evidence of off-tumor toxicity toward HSPCs, most clinical trials are evaluating the potential of anti-CD123 or anti-CD33 CAR-T cells as a bridge-to-transplant regimen before allo-HSCT. Early reports of these trials have shown only limited therapeutic efficacy 10 , 11 , 12 . Yet, more complete results of these clinical studies in AML are eagerly awaited. Meanwhile, other targets, such as CD70, C-type lectin-like molecule-1, FMS-like tyrosine kinase-3 (FLT3), CD44 variant 6 (CD44v6), sialic acid-binding Ig-like lectin-6 (Siglec-6) or CD117, have been tested in preclinical studies as alternative CAR targets 13 , 14 , 15 , 16 , 17 . However, clinical validation is pending, and expression profiles of most of the targets raise at least some uncertainties regarding their clinical safety and efficacy. Newly developed CAR-T cells are often directed to target structures that have already been used for antibody therapy. By contrast, unbiased de novo target screenings for CAR-T cell therapy have rarely been conducted 18 . In addition, until recently, off-tumor antigen projections could only leverage bulk sequencing data, missing detailed information about cell-type-specific target antigen expression patterns. Conveniently, the revolution in single-cell technologies in the last decade has generated massive single-cell expression datasets that provide precise information about the transcriptomic anatomy of healthy and malignant cells 19 , a mostly untapped resource for therapeutic development, at least in the context of de novo antigen predictions and CAR-T cell development. These advancements allow in-depth on- and off-tumor antigen prediction 20 , offering unique insights into healthy and malignant cells at an unmatched resolution. We thus developed a single-cell RNA-sequencing (scRNA-seq)-based approach specifically tailored to identify promising antigens for CAR-T cell therapy on a discovery AML cohort of 15 individuals 21 . We generated a transcriptomic atlas from publicly available datasets, consisting of over 28,000 healthy and malignant bone marrow cells from these individuals and over 500,000 healthy cells from nine of the most vital human tissues. We screened these data for cell surface antigens expressed on malignant cells with minimal coexpression on healthy cells, including T cells. With rigorous cutoffs, we identified two unrecognized targets for CAR-T cells in AML: colony-stimulating factor 1 receptor (CSF1R) and CD86. We developed CAR-T cells against both targets and tested their efficacy in vitro and in vivo in cell lines and human-derived models, including primary AML blasts. We assessed the safety of these CAR-T cells in vitro using advanced primary cell cultures for target-expressing cell types, demonstrating a better discriminatory capacity than established anti-CD33 CAR-T cells. In addition, we used several in vivo models to mitigate safety concerns. Our results illustrate the translational potential of an unbiased scRNA-seq-based screening approach and lay the basis for clinical development of our CAR candidates. Results Development of scRNA-seq-based screening algorithm We created an unbiased scRNA-seq-based discovery approach for identification of CAR targets. To ensure CAR efficacy, a suitable candidate is (1) overexpressed in malignant cells and (2) located on the cell surface. In terms of CAR safety, the candidate should (3) not be expressed on T cells and (4) show minimal expression across vital, healthy tissues (Fig. 1a ). Applying our approach to AML, we used publicly available scRNA-seq data from 15 individuals with AML 21 . From these, a total of 28,404 sequenced healthy and malignant bone marrow cells passed quality control (Fig. 1b,c ; see Methods for a detailed description of quality control steps). For maximal CAR efficacy, we sought to identify candidates with higher expression on malignant HSPC-like cells (herein termed hematopoietic stem cell (HSC)-like and progenitor (Prog)-like) than on healthy cells. Differential gene expression<|im_end|> <|im_start|>assistant Unlike other forms of blood cancer, acute myeloid leukemia (AML) cannot currently be treated with CAR-T cell immunotherapy. The reason is that specific molecular targets with which certain immune cells could specifically target AML cells are lacking, which would permit the immune system to attack cancer. Two research teams of Professor Dr. Sebastian Kobold with Dr. Adrian Gottschlich from the Division of Clinical Pharmacology at LMU University Hospital Munich and Dr. Carsten Marr with Moritz Thomas from the Institute of AI for Health at Helmholtz Munich have now succeeded in discovering such targets. The results have now been published in the journal Nature Biotechnology. AML—one of several forms of leukemia ("blood cancer")—is a treacherous disease. Five years after the initial diagnosis, only one-third of patients are still alive. Up to 85 percent of patients appear to be cured after intensive chemotherapy. However, in more than half of them, the disease returns within one to two years because the chemotherapy has not destroyed all leukemia cells. In the event of a relapse, a stem cell transplant is the only hope for cure for a patient. But even then, the long-term probability of survival is less than 20 percent. New treatment options are therefore urgently needed. CAR-T cell therapy is an innovative therapy. CAR-T stands for "chimeric antigen receptor in T cells." T cells are cells of the immune system. Cancer cells evade their "normal" attempts to attack them by using various molecular tricks. Thus, T cells no longer recognize their opponents, the cancer cells. During CAR-T cell therapy, T cells are first removed from the patients and then genetically engineered to produce a specific protein (CAR) on their surface. When these CAR-T cells are injected back into the patient's body, these will only engage their target: CD19, which ensures that they recognize the patient's cancer cells and bind to them in a targeted manner. The cancer cells consequently die. New targets However, the approved CAR-T cells against CD19 are not suitable for AML, because CD19 is (usually) not present on the surface of AML cells. Clinical results with CAR-T cells directed against other surface molecules of AML cells have been sobering so far, according to scientists. This is because CAR-T cells were unable to distinguish between healthy and degenerated cells—with correspondingly induced significant side effects. The physician Sebastian Kobold and the physicist Carsten Marr, together with colleagues from the LMU University Hospital Munich and the Institute of AI for Health at Helmholtz Munich, set out to find alternative molecules that would ideally be found exclusively on the surface of AML cells. With the help of extensive bioinformatic analyses and the integration of expression data from more than half a million individual cells, two candidates finally crystallized out of 25,000 potential cell surface molecules. These are known as CSF1R and CD86. "Such an analysis would not have been possible a few years ago, since the required single-cell data has been generated only very recently," says Marr, who led the AI-assisted analysis in the study at Helmholtz Munich. The researchers produced CAR-T cells in the laboratory of the LMU University Hospital Munich that precisely target these molecules. The cells were then tested on different AML models, including AML cells from patients. The results, according to Kobold are promising: "On the one hand, these CAR-T cells are effective against AML, but on the other hand, they hardly destroy healthy cells." The study impressively demonstrates how the synergy of interdisciplinary research groups can lead to breakthroughs in health research to treat patients in the best possible way. The researchers' next goal: They want to develop GMP (good manufacturing practice)-capable processes to produce CAR-T cells that can then also be used in clinical trials with AML patients. This is to take place within the framework of the "Bavarian Cell Therapy Catalyst," which is supported by the Bavarian Research Foundation. Kobold expects the first tests with patients in two to three years. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Carry-over effects refer to processes that occur in one season and influence fitness in the following. In birds, two costly activities, namely reproduction and moult, are restricted to a small time window, and sometimes overlap. Thus, colour in newly moulted feathers is likely to be affected by the costs of reproduction. Using models of bird vision we investigated male colour change in a free-living population of blue tits ( Cyanistes caeruleus ) in three sampling occasions: spring 1, winter and spring 2. We related crown, tail, breast and cheek feather colouration after the moult (winter) to the intensity of infections by blood parasites during reproduction (spring 1). In the following spring (spring 2), we explored mating patterns with respect to changes in feather colour (springs 1 vs. 2). Males that were less intensely infected by the malaria parasite Plasmodium while breeding showed purer white cheek feathers in winter, which may indicate higher feather quality. Increased brightness in the white cheek was associated with better body condition during reproduction. In the following season, males with brighter cheeks paired with females that had noticeably brighter cheek patches compared to the male’s previous mate. These results suggest that the conditions experienced during reproduction are likely to affect moult and thus feather colouration, at least in the white patch. High quality individuals may allocate resources efficiently during reproduction increasing future reproductive success through variation in mating patterns. Carry-over effects from reproduction might extend not only to the non-breeding phase, but also to the following breeding season. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction A central tenet of life-history theory is that resources allocated to current reproduction are traded-off against self-maintenance and future reproductive output (Stearns 1992 ; Metcalfe and Monaghan 2001 ). In birds, a growing body of research has investigated the mechanisms behind the costs of reproduction (reviewed in Harshman and Zera 2007 ; Blount et al. 2016 ), and the costs per se, which can come as a reduction in survival (Santos and Nakagawa 2012 ), for example, through accelerated ageing (Bize et al. 2009 ; Badás et al. 2015 ). Others have focused on the downstream effects of non-breeding season processes on reproduction, commonly known as ‘carry-over effects’ (Gunnarsson et al. 2006 ; Robb et al. 2008 ; Sorensen et al. 2009 ). However, few studies have explored the effects of reproduction on the subsequent non-reproductive season, when reproductive activities, in fact, could influence the outcome during the following breeding event (Dreiss and Roulin 2010 ; Harrison et al. 2011 ). Reproduction can exert changes in the individual’s post-breeding activities such as the moult. Moulting is an energetically demanding process (Griggio et al. 2009 ), because it encompasses physiological (i.e. altering multiple stress response pathways, Merino and Barbosa 1997 ) and metabolic costs (an increase in 30% of metabolic rate) (Cyr et al. 2008 ). Many birds initiate the post-nuptial moult while still raising young (Jenni and Winkler 1994 ), but because these activities are highly demanding, they should be separate in time. Indeed, passerines that were already moulting while breeding had reduced fledgling success (Sanz 1999 ; Hemborg et al. 2001 ; Morales et al. 2007 ). Delayed reproduction can compromise the time allocated for moulting, thus reducing feather quality, as has been reported in starlings ( Sturnus vulgaris ) (Dawson et al. 2000 ). Furthermore, Nilsson and Svensson ( 1996 ) showed that blue tits ( Cyanistes caeruleus ) that delayed moult had higher thermoregulatory costs in the following winter, and this resulted in reduced over-winter survival and breeding success the following year. Thus, the effects in feather synthesis become evident when reproductive effort exceeds what individuals were prepared to sustain. Additional information is needed on whether the individual’s status during reproduction has an important bearing on feather quality. Data on recently moulted birds in free-living populations are scarce because re-trapping the same individuals repeatedly is difficult (Dawson et al. 2000 ). The costs of reproduction on feather quality could be assessed through colouration, because colours are incorporated to new feathers during moult (Hill and McGraw 2006 ). In fact, because plumage colours are produced through different metabolic pathways depending on its nature (structural or pigmentary), they are subject to different constraints that may convey information to prospecting mates (Hill 2006a ). For example, in eiders ( Somateria mollisima ), it has been suggested that reproductive females with reduced lymphocyte levels may suffer from infections in their following moult, which could reduce the reflectance of the white plumage bands (Hanssen et al. 2006 ). In blue tits, experimentally increasing reproductive effort produced changes in feather colouration in two ornaments in the year following manipulation: the yellow breast and the blue crown (Doutrelant et al. 2012 ). Other mechanisms, such as soiling (Fitzpatrick 1998 ) or feather degrading bacteria (Shawkey et al. 2007 ) can also explain changes in colour during the season, but to date, no study has evaluated these changes with respect to parasitic infections. Because reproduction can affect immunocompetence (Hanssen et al. 2003 ), it is common that bird populations in temperate regions suffer from chronic blood parasite infections with relapses during the breeding season (Valkiūnas 2005 ). The negative effects that these parasites exert on the host are well known (Merino et al. 2000 ; Martínez-de la Puente et al. 2010 ; Asghar et al. 2015 ); however, more studies are needed to explore the effects of parasitic infections during the breeding season on subsequent feather colouration. Strong immune responses (i.e. against parasitic infections) may have negative effects on the moult, decreasing the amount of resources available and resulting in a delayed onset of post-nuptial moult (Sanz et al. 2004 , but see Moreno et al. 2001 ). Indeed, experimental studies have shown that certain aspects of structural colouration can signal food stress (Siefferman and Hill 2005 ) or acute parasite infection during the moult (Doucet and Montgomerie 2003 ). Similarly, many studies have related dull", "role": "user" }, { "content": "Male blue tits with white cheeks are healthier and more likely to mate with higher quality partners than their counterparts with duller cheek feathers. Having purer white cheeks also indicates that a blue tit was better able to overcome an infection with parasites during the previous year. This is according to Elisa Pérez Badás of the Museo Nacional de Ciencias Naturales in Spain. She is lead author of a study published in Springer's journal The Science of Nature. Previous research has shown that the food consumed by a bird, as well as its general well-being, can influence the colour of its feathers. Scientists also know that hardships suffered by birds in one season can be carried over into the next. In this study, Badás and her research team wanted to test whether difficulties encountered by the blue tit (Cyanistes caeruleus) during the breeding season might influence the precise intensity of the new blue, white and yellow feathers growing once these birds have moulted. In the life cycle of this small bird, which is widespread in forests in Europe and Western Asia, moulting only happens once the breeding season is completed. Therefore, the birds show off their new plumage until the end of the next breeding season. To prove their assumptions, the research team monitored a population of blue tits living in a forest in central Spain over the course of two breeding seasons. In the first season, the researchers caught the birds and took blood samples to detect whether the blue tits suffered from parasitic infections. The team also used a spectrophotometer to gauge the spectrum of colour of the birds' feathers. These results were compared with the hues, levels of saturation and luminance that blue tits are known to see. In the following season, the researchers noted the birds' mating patterns, and how these were influenced by changes that might have occurred in particular birds' feather colours. Overall, the researchers found that males in a better physical condition (males that weighed more) during the highly demanding nestling provisioning stage sported brighter, whiter cheeks. Those who were not infected much by the malaria parasite Plasmodium while breeding also showed purer white cheek feathers in winter. According to Pérez Badás, this indicates that their feathers were of a better quality, and that intense parasitic infections can have an effect on a bird's life cycle. \"In the following season, those males with brighter cheeks paired with females that had noticeably brighter cheek patches compared to the male's previous mate,\" adds Badás. The results therefore suggest that the conditions that male blue tits experienced during reproduction are likely to affect moult and thus feather colouration, at least in their white facial feathers. This, in turn, enables the stronger males to find brighter females than the partners they paired with in the previous spring. \"Members of the same species were quite able to pick up such colour differences,\" notes Badás. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Carry-over effects refer to processes that occur in one season and influence fitness in the following. In birds, two costly activities, namely reproduction and moult, are restricted to a small time window, and sometimes overlap. Thus, colour in newly moulted feathers is likely to be affected by the costs of reproduction. Using models of bird vision we investigated male colour change in a free-living population of blue tits ( Cyanistes caeruleus ) in three sampling occasions: spring 1, winter and spring 2. We related crown, tail, breast and cheek feather colouration after the moult (winter) to the intensity of infections by blood parasites during reproduction (spring 1). In the following spring (spring 2), we explored mating patterns with respect to changes in feather colour (springs 1 vs. 2). Males that were less intensely infected by the malaria parasite Plasmodium while breeding showed purer white cheek feathers in winter, which may indicate higher feather quality. Increased brightness in the white cheek was associated with better body condition during reproduction. In the following season, males with brighter cheeks paired with females that had noticeably brighter cheek patches compared to the male’s previous mate. These results suggest that the conditions experienced during reproduction are likely to affect moult and thus feather colouration, at least in the white patch. High quality individuals may allocate resources efficiently during reproduction increasing future reproductive success through variation in mating patterns. Carry-over effects from reproduction might extend not only to the non-breeding phase, but also to the following breeding season. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction A central tenet of life-history theory is that resources allocated to current reproduction are traded-off against self-maintenance and future reproductive output (Stearns 1992 ; Metcalfe and Monaghan 2001 ). In birds, a growing body of research has investigated the mechanisms behind the costs of reproduction (reviewed in Harshman and Zera 2007 ; Blount et al. 2016 ), and the costs per se, which can come as a reduction in survival (Santos and Nakagawa 2012 ), for example, through accelerated ageing (Bize et al. 2009 ; Badás et al. 2015 ). Others have focused on the downstream effects of non-breeding season processes on reproduction, commonly known as ‘carry-over effects’ (Gunnarsson et al. 2006 ; Robb et al. 2008 ; Sorensen et al. 2009 ). However, few studies have explored the effects of reproduction on the subsequent non-reproductive season, when reproductive activities, in fact, could influence the outcome during the following breeding event (Dreiss and Roulin 2010 ; Harrison et al. 2011 ). Reproduction can exert changes in the individual’s post-breeding activities such as the moult. Moulting is an energetically demanding process (Griggio et al. 2009 ), because it encompasses physiological (i.e. altering multiple stress response pathways, Merino and Barbosa 1997 ) and metabolic costs (an increase in 30% of metabolic rate) (Cyr et al. 2008 ). Many birds initiate the post-nuptial moult while still raising young (Jenni and Winkler 1994 ), but because these activities are highly demanding, they should be separate in time. Indeed, passerines that were already moulting while breeding had reduced fledgling success (Sanz 1999 ; Hemborg et al. 2001 ; Morales et al. 2007 ). Delayed reproduction can compromise the time allocated for moulting, thus reducing feather quality, as has been reported in starlings ( Sturnus vulgaris ) (Dawson et al. 2000 ). Furthermore, Nilsson and Svensson ( 1996 ) showed that blue tits ( Cyanistes caeruleus ) that delayed moult had higher thermoregulatory costs in the following winter, and this resulted in reduced over-winter survival and breeding success the following year. Thus, the effects in feather synthesis become evident when reproductive effort exceeds what individuals were prepared to sustain. Additional information is needed on whether the individual’s status during reproduction has an important bearing on feather quality. Data on recently moulted birds in free-living populations are scarce because re-trapping the same individuals repeatedly is difficult (Dawson et al. 2000 ). The costs of reproduction on feather quality could be assessed through colouration, because colours are incorporated to new feathers during moult (Hill and McGraw 2006 ). In fact, because plumage colours are produced through different metabolic pathways depending on its nature (structural or pigmentary), they are subject to different constraints that may convey information to prospecting mates (Hill 2006a ). For example, in eiders ( Somateria mollisima ), it has been suggested that reproductive females with reduced lymphocyte levels may suffer from infections in their following moult, which could reduce the reflectance of the white plumage bands (Hanssen et al. 2006 ). In blue tits, experimentally increasing reproductive effort produced changes in feather colouration in two ornaments in the year following manipulation: the yellow breast and the blue crown (Doutrelant et al. 2012 ). Other mechanisms, such as soiling (Fitzpatrick 1998 ) or feather degrading bacteria (Shawkey et al. 2007 ) can also explain changes in colour during the season, but to date, no study has evaluated these changes with respect to parasitic infections. Because reproduction can affect immunocompetence (Hanssen et al. 2003 ), it is common that bird populations in temperate regions suffer from chronic blood parasite infections with relapses during the breeding season (Valkiūnas 2005 ). The negative effects that these parasites exert on the host are well known (Merino et al. 2000 ; Martínez-de la Puente et al. 2010 ; Asghar et al. 2015 ); however, more studies are needed to explore the effects of parasitic infections during the breeding season on subsequent feather colouration. Strong immune responses (i.e. against parasitic infections) may have negative effects on the moult, decreasing the amount of resources available and resulting in a delayed onset of post-nuptial moult (Sanz et al. 2004 , but see Moreno et al. 2001 ). Indeed, experimental studies have shown that certain aspects of structural colouration can signal food stress (Siefferman and Hill 2005 ) or acute parasite infection during the moult (Doucet and Montgomerie 2003 ). Similarly, many studies have related dull<|im_end|> <|im_start|>assistant Male blue tits with white cheeks are healthier and more likely to mate with higher quality partners than their counterparts with duller cheek feathers. Having purer white cheeks also indicates that a blue tit was better able to overcome an infection with parasites during the previous year. This is according to Elisa Pérez Badás of the Museo Nacional de Ciencias Naturales in Spain. She is lead author of a study published in Springer's journal The Science of Nature. Previous research has shown that the food consumed by a bird, as well as its general well-being, can influence the colour of its feathers. Scientists also know that hardships suffered by birds in one season can be carried over into the next. In this study, Badás and her research team wanted to test whether difficulties encountered by the blue tit (Cyanistes caeruleus) during the breeding season might influence the precise intensity of the new blue, white and yellow feathers growing once these birds have moulted. In the life cycle of this small bird, which is widespread in forests in Europe and Western Asia, moulting only happens once the breeding season is completed. Therefore, the birds show off their new plumage until the end of the next breeding season. To prove their assumptions, the research team monitored a population of blue tits living in a forest in central Spain over the course of two breeding seasons. In the first season, the researchers caught the birds and took blood samples to detect whether the blue tits suffered from parasitic infections. The team also used a spectrophotometer to gauge the spectrum of colour of the birds' feathers. These results were compared with the hues, levels of saturation and luminance that blue tits are known to see. In the following season, the researchers noted the birds' mating patterns, and how these were influenced by changes that might have occurred in particular birds' feather colours. Overall, the researchers found that males in a better physical condition (males that weighed more) during the highly demanding nestling provisioning stage sported brighter, whiter cheeks. Those who were not infected much by the malaria parasite Plasmodium while breeding also showed purer white cheek feathers in winter. According to Pérez Badás, this indicates that their feathers were of a better quality, and that intense parasitic infections can have an effect on a bird's life cycle. "In the following season, those males with brighter cheeks paired with females that had noticeably brighter cheek patches compared to the male's previous mate," adds Badás. The results therefore suggest that the conditions that male blue tits experienced during reproduction are likely to affect moult and thus feather colouration, at least in their white facial feathers. This, in turn, enables the stronger males to find brighter females than the partners they paired with in the previous spring. "Members of the same species were quite able to pick up such colour differences," notes Badás. <|im_end|>

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2,019