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A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1 期刊论文
NATURE, 2020, 577 (7788) : 109-+
作者:  Tao, Panfeng;  Sun, Jinqiao;  Wu, Zheming;  Wang, Shihao;  Wang, Jun;  Li, Wanjin;  Pan, Heling;  Bai, Renkui;  Zhang, Jiahui;  Wang, Ying;  Lee, Pui Y.;  Ying, Wenjing;  Zhou, Qinhua;  Hou, Jia;  Wang, Wenjie;  Sun, Bijun;  Yang, Mi;  Liu, Danru;  Fang, Ran;  Han, Huan;  Yang, Zhaohui;  Huang, Xin;  Li, Haibo;  Deuitch, Natalie;  Zhang, Yuan;  Dissanayake, Dilan;  Haude, Katrina;  McWalter, Kirsty;  Roadhouse, Chelsea;  MacKenzie, Jennifer J.;  Laxer, Ronald M.;  Aksentijevich, Ivona;  Yu, Xiaomin;  Wang, Xiaochuan;  Yuan, Junying;  Zhou, Qing
收藏  |  浏览/下载:23/0  |  提交时间:2020/07/03

Activation of RIPK1 controls TNF-mediated apoptosis, necroptosis and inflammatory pathways(1). Cleavage of human and mouse RIPK1 after residues D324 and D325, respectively, by caspase-8 separates the RIPK1 kinase domain from the intermediate and death domains. The D325A mutation in mouse RIPK1 leads to embryonic lethality during mouse development(2,3). However, the functional importance of blocking caspase-8-mediated cleavage of RIPK1 on RIPK1 activation in humans is unknown. Here we identify two families with variants in RIPK1 (D324V and D324H) that lead to distinct symptoms of recurrent fevers and lymphadenopathy in an autosomaldominant manner. Impaired cleavage of RIPK1 D324 variants by caspase-8 sensitized patients'  peripheral blood mononuclear cells to RIPK1 activation, apoptosis and necroptosis induced by TNF. The patients showed strong RIPK1-dependent activation of inflammatory signalling pathways and overproduction of inflammatory cytokines and chemokines compared with unaffected controls. Furthermore, we show that expression of the RIPK1 mutants D325V or D325H in mouse embryonic fibroblasts confers not only increased sensitivity to RIPK1 activation-mediated apoptosis and necroptosis, but also induction of pro-inflammatory cytokines such as IL-6 and TNF. By contrast, patient-derived fibroblasts showed reduced expression of RIPK1 and downregulated production of reactive oxygen species, resulting in resistance to necroptosis and ferroptosis. Together, these data suggest that human non-cleavable RIPK1 variants promote activation of RIPK1, and lead to an autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory response in peripheral blood mononuclear cells, as well as a compensatory mechanism to protect against several pro-death stimuli in fibroblasts.


  
Fatty acids and cancer-amplified ZDHHC19 promote STAT3 activation throughS-palmitoylation (vol 573, pg 139, 2019) (Retraction of Vol 573, Pg 139, 2020) 期刊论文
NATURE, 2020, 583 (7814) : 154-154
作者:  Zhang, Hao;  Liu, Chun-Xiao;  Gazibegovic, Sasa;  Xu, Di;  Logan, John A.;  Wang, Guanzhong;  van Loo, Nick;  Bommer, Jouri D. S.;  de Moor, Michiel W. A.;  Car, Diana;  Op Het Veld, Roy L. M.;  van Veldhoven, Petrus J.;  Koelling, Sebastian;  Verheijen, Marcel A.;  Pendharkar, Mihir;  Pennachio, Daniel J.;  Shojaei, Borzoyeh;  Lee, Joon Sue;  Palmstrom, Chris J.;  Bakkers, Erik P. A. M.;  Sarma, S. Das;  Kouwenhoven, Leo P.
收藏  |  浏览/下载:17/0  |  提交时间:2020/07/03
Rapid reconstruction of SARS-CoV-2 using a synthetic genomics platform 期刊论文
NATURE, 2020
作者:  Touat, Mehdi;  Li, Yvonne Y.;  Boynton, Adam N.;  Spurr, Liam F.;  Iorgulescu, J. Bryan;  Bohrson, Craig L.;  Cortes-Ciriano, Isidro;  Birzu, Cristina;  Geduldig, Jack E.;  Pelton, Kristine;  Lim-Fat, Mary Jane;  Pal, Sangita;  Ferrer-Luna, Ruben;  Ramkissoon, Shakti H.;  Dubois, Frank;  Bellamy, Charlotte;  Currimjee, Naomi;  Bonardi, Juliana;  Qian Kenin;  Ho, Patricia;  Malinowski, Seth;  Taquet, Leon;  Jones, Robert E.;  Shetty, Aniket;  Chow, Kin-Hoe;  Sharaf, Radwa;  Pavlick, Dean;  Albacker, Lee A.;  Younan, Nadia;  Baldini, Capucine;  Verreault, Maite;  Giry, Marine;  Guillerm, Erell;  Ammari, Samy;  Beuvon, Frederic;  Mokhtari, Karima;  Alentorn, Agusti;  Dehais, Caroline;  Houillier, Caroline;  Laigle-Donadey, Florence;  Psimaras, Dimitri;  Lee, Eudocia Q.;  Nayak, Lakshmi;  McFaline-Figueroa, J. Ricardo;  Carpentier, Alexandre;  Cornu, Philippe;  Capelle, Laurent;  Mathon, Bertrand;  Barnholtz-Sloan, Jill S.;  Chakravarti, Arnab;  Bi, Wenya Linda;  Chiocca, E. Antonio;  Fehnel, Katie Pricola;  Alexandrescu, Sanda;  Chi, Susan N.;  Haas-Kogan, Daphne;  Batchelor, Tracy T.;  Frampton, Garrett M.;  Alexander, Brian M.;  Huang, Raymond Y.;  Ligon, Azra H.;  Coulet, Florence;  Delattre, Jean-Yves;  Hoang-Xuan, Khe;  Meredith, David M.;  Santagata, Sandro;  Duval, Alex;  Sanson, Marc;  Cherniack, Andrew D.;  Wen, Patrick Y.;  Reardon, David A.;  Marabelle, Aurelien;  Park, Peter J.;  Idbaih, Ahmed;  Beroukhim, Rameen;  Bandopadhayay, Pratiti;  Bielle, Franck;  Ligon, Keith L.
收藏  |  浏览/下载:11/0  |  提交时间:2020/07/03

Reverse genetics has been an indispensable tool to gain insights into viral pathogenesis and vaccine development. The genomes of large RNA viruses, such as those from coronaviruses, are cumbersome to clone and manipulate inEscherichia coliowing to the size and occasional instability of the genome(1-3). Therefore, an alternative rapid and robust reverse-genetics platform for RNA viruses would benefit the research community. Here we show the full functionality of a yeast-based synthetic genomics platform to genetically reconstruct diverse RNA viruses, including members of theCoronaviridae,FlaviviridaeandPneumoviridaefamilies. Viral subgenomic fragments were generated using viral isolates, cloned viral DNA, clinical samples or synthetic DNA, and these fragments were then reassembled in one step inSaccharomyces cerevisiaeusing transformation-associated recombination cloning to maintain the genome as a yeast artificial chromosome. T7 RNA polymerase was then used to generate infectious RNA to rescue viable virus. Using this platform, we were able to engineer and generate chemically synthesized clones of the virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)(4), which has caused the recent pandemic of coronavirus disease (COVID-19), in only a week after receipt of the synthetic DNA fragments. The technical advance that we describe here facilitates rapid responses to emerging viruses as it enables the real-time generation and functional characterization of evolving RNA virus variants during an outbreak.


A yeast-based synthetic genomics platform is used to reconstruct and characterize large RNA viruses from synthetic DNA fragments  this technique will facilitate the rapid analysis of RNA viruses, such as SARS-CoV-2, during an outbreak.


  
Late Cretaceous neornithine from Europe illuminates the origins of crown birds 期刊论文
NATURE, 2020, 579 (7799) : 397-+
作者:  Shao, Zhengping;  Flynn, Ryan A.;  Crowe, Jennifer L.;  Zhu, Yimeng;  Liang, Jialiang;  Jiang, Wenxia;  Aryan, Fardin;  Aoude, Patrick;  Bertozzi, Carolyn R.;  Estes, Verna M.;  Lee, Brian J.;  Bhagat, Govind;  Zha, Shan;  Calo, Eliezer
收藏  |  浏览/下载:14/0  |  提交时间:2020/05/13

Our understanding of the earliest stages of crown bird evolution is hindered by an exceedingly sparse avian fossil record from the Mesozoic era. The most ancient phylogenetic divergences among crown birds are known to have occurred in the Cretaceous period(1-3), but stem-lineage representatives of the deepest subclades of crown birds-Palaeognathae (ostriches and kin), Galloanserae (landfowl and waterfowl) and Neoaves (all other extant birds)-are unknown from the Mesozoic era. As a result, key questions related to the ecology(4,5), biogeography(3,6,7) and divergence times(1,8-10) of ancestral crown birds remain unanswered. Here we report a new Mesozoic fossil that occupies a position close to the last common ancestor of Galloanserae and fills a key phylogenetic gap in the early evolutionary history of crown birds(10,11). Asteriornis maastrichtensis, gen. et sp. nov., from the Maastrichtian age of Belgium (66.8-66.7 million years ago), is represented by a nearly complete, three-dimensionally preserved skull and associated postcranial elements. The fossil represents one of the only well-supported crown birds from the Mesozoic era(12), and is the first Mesozoic crown bird with well-represented cranial remains. Asteriornis maastrichtensis exhibits a previously undocumented combination of galliform (landfowl)-like and anseriform (waterfowl)-like features, and its presence alongside a previously reported Ichthyornis-like taxon from the same locality(13) provides direct evidence of the co-occurrence of crown birds and avialan stem birds. Its occurrence in the Northern Hemisphere challenges biogeographical hypotheses of a Gondwanan origin of crown birds(3), and its relatively small size and possible littoral ecology may corroborate proposed ecological filters(4,5,9) that influenced the persistence of crown birds through the end-Cretaceous mass extinction.


A newly discovered fossil from the Cretaceous of Belgium is the oldest modern bird ever found, showing a unique combination of features and suggesting attributes shared by avian survivors of the end-Cretaceous extinction.


  
Asynchronous carbon sink saturation in African and Amazonian tropical forests 期刊论文
NATURE, 2020, 579 (7797) : 80-+
作者:  Wannes Hubau;  Simon L. Lewis;  Oliver L. Phillips;  Kofi Affum-Baffoe;  Hans Beeckman;  Aida Cuní;  -Sanchez;  Armandu K. Daniels;  Corneille E. N. Ewango;  Sophie Fauset;  Jacques M. Mukinzi;  Douglas Sheil;  Bonaventure Sonké;  Martin J. P. Sullivan;  Terry C. H. Sunderland;  Hermann Taedoumg;  Sean C. Thomas;  Lee J. T. White;  Katharine A. Abernethy;  Stephen Adu-Bredu;  Christian A. Amani;  Timothy R. Baker;  Lindsay F. Banin;  Fidè;  le Baya;  Serge K. Begne;  Amy C. Bennett;  Fabrice Benedet;  Robert Bitariho;  Yannick E. Bocko;  Pascal Boeckx;  Patrick Boundja;  Roel J. W. Brienen;  Terry Brncic;  Eric Chezeaux;  George B. Chuyong;  Connie J. Clark;  Murray Collins;  James A. Comiskey;  David A. Coomes;  Greta C. Dargie;  Thales de Haulleville;  Marie Noel Djuikouo Kamdem;  Jean-Louis Doucet;  Adriane Esquivel-Muelbert;  Ted R. Feldpausch;  Alusine Fofanah;  Ernest G. Foli;  Martin Gilpin;  Emanuel Gloor;  Christelle Gonmadje;  Sylvie Gourlet-Fleury;  Jefferson S. Hall;  Alan C. Hamilton;  David J. Harris;  Terese B. Hart;  Mireille B. N. Hockemba;  Annette Hladik;  Suspense A. Ifo;  Kathryn J. Jeffery;  Tommaso Jucker;  Emmanuel Kasongo Yakusu;  Elizabeth Kearsley;  David Kenfack;  Alexander Koch;  Miguel E. Leal;  Aurora Levesley;  Jeremy A. Lindsell;  Janvier Lisingo;  Gabriela Lopez-Gonzalez;  Jon C. Lovett;  Jean-Remy Makana;  Yadvinder Malhi;  Andrew R. Marshall;  Jim Martin;  Emanuel H. Martin;  Faustin M. Mbayu;  Vincent P. Medjibe;  Vianet Mihindou;  Edward T. A. Mitchard;  Sam Moore;  Pantaleo K. T. Munishi;  Natacha Nssi Bengone;  Lucas Ojo;  Fidè;  le Evouna Ondo;  Kelvin S.-H. Peh;  Georgia C. Pickavance;  Axel Dalberg Poulsen;  John R. Poulsen;  Lan Qie;  Jan Reitsma;  Francesco Rovero;  Michael D. Swaine;  Joey Talbot;  James Taplin;  David M. Taylor;  Duncan W. Thomas;  Benjamin Toirambe;  John Tshibamba Mukendi;  Darlington Tuagben;  Peter M. Umunay;  Geertje M. F. van der Heijden;  Hans Verbeeck;  Jason Vleminckx;  Simon Willcock;  Hannsjö;  rg Wö;  ll;  John T. Woods;  Lise Zemagho
收藏  |  浏览/下载:23/0  |  提交时间:2020/05/13

Structurally intact tropical forests sequestered about half of the global terrestrial carbon uptake over the 1990s and early 2000s, removing about 15 per cent of anthropogenic carbon dioxide emissions(1-3). Climate-driven vegetation models typically predict that this tropical forest '  carbon sink'  will continue for decades(4,5). Here we assess trends in the carbon sink using 244 structurally intact African tropical forests spanning 11 countries, compare them with 321 published plots from Amazonia and investigate the underlying drivers of the trends. The carbon sink in live aboveground biomass in intact African tropical forests has been stable for the three decades to 2015, at 0.66 tonnes of carbon per hectare per year (95 per cent confidence interval 0.53-0.79), in contrast to the long-term decline in Amazonian forests(6). Therefore the carbon sink responses of Earth'  s two largest expanses of tropical forest have diverged. The difference is largely driven by carbon losses from tree mortality, with no detectable multi-decadal trend in Africa and a long-term increase in Amazonia. Both continents show increasing tree growth, consistent with the expected net effect of rising atmospheric carbon dioxide and air temperature(7-9). Despite the past stability of the African carbon sink, our most intensively monitored plots suggest a post-2010 increase in carbon losses, delayed compared to Amazonia, indicating asynchronous carbon sink saturation on the two continents. A statistical model including carbon dioxide, temperature, drought and forest dynamics accounts for the observed trends and indicates a long-term future decline in the African sink, whereas the Amazonian sink continues to weaken rapidly. Overall, the uptake of carbon into Earth'  s intact tropical forests peaked in the 1990s. Given that the global terrestrial carbon sink is increasing in size, independent observations indicating greater recent carbon uptake into the Northern Hemisphere landmass(10) reinforce our conclusion that the intact tropical forest carbon sink has already peaked. This saturation and ongoing decline of the tropical forest carbon sink has consequences for policies intended to stabilize Earth'  s climate.


  
A lysosomal switch triggers proteostasis renewal in the immortal C. elegans germ lineage (vol 551, pg 629, 2017) 期刊论文
NATURE, 2020, 580 (7802) : E5-E5
作者:  Lu, Zhihao;  Zou, Jianling;  Li, Shuang;  Topper, Michael J.;  Tao, Yong;  Zhang, Hao;  Jiao, Xi;  Xie, Wenbing;  Kong, Xiangqian;  Vaz, Michelle;  Li, Huili;  Cai, Yi;  Xia, Limin;  Huang, Peng;  Rodgers, Kristen;  Lee, Beverly;  Riemer, Joanne B.;  Day, Chi-Ping;  Yen, Ray-Whay Chiu;  Cui, Ying;  Wang, Yujiao;  Wang, Yanni;  Zhang, Weiqiang;  Easwaran, Hariharan;  Hulbert, Alicia;  Kim, KiBem;  Juergens, Rosalyn A.;  Yang, Stephen C.;  Battafarano, Richard J.;  Bush, Errol L.;  Broderick, Stephen R.;  Cattaneo, Stephen M.;  Brahmer, Julie R.;  Rudin, Charles M.;  Wrangle, John;  Mei, Yuping;  Kim, Young J.;  Zhang, Bin;  Wang, Ken Kang-Hsin;  Forde, Patrick M.;  Margolick, Joseph B.;  Nelkin, Barry D.;  Zahnow, Cynthia A.;  Pardoll, Drew M.;  Housseau, Franck;  Baylin, Stephen B.;  Shen, Lin;  Brock, Malcolm V.
收藏  |  浏览/下载:26/0  |  提交时间:2020/07/03
Nightside condensation of iron in an ultrahot giant exoplanet 期刊论文
NATURE, 2020, 580 (7805) : 597-+
作者:  Lu, Zhihao;  Zou, Jianling;  Li, Shuang;  Topper, Michael J.;  Tao, Yong;  Zhang, Hao;  Jiao, Xi;  Xie, Wenbing;  Kong, Xiangqian;  Vaz, Michelle;  Li, Huili;  Cai, Yi;  Xia, Limin;  Huang, Peng;  Rodgers, Kristen;  Lee, Beverly;  Riemer, Joanne B.;  Day, Chi-Ping;  Yen, Ray-Whay Chiu;  Cui, Ying;  Wang, Yujiao;  Wang, Yanni;  Zhang, Weiqiang;  Easwaran, Hariharan;  Hulbert, Alicia;  Kim, KiBem;  Juergens, Rosalyn A.;  Yang, Stephen C.;  Battafarano, Richard J.;  Bush, Errol L.;  Broderick, Stephen R.;  Cattaneo, Stephen M.;  Brahmer, Julie R.;  Rudin, Charles M.;  Wrangle, John;  Mei, Yuping;  Kim, Young J.;  Zhang, Bin;  Wang, Ken Kang-Hsin;  Forde, Patrick M.;  Margolick, Joseph B.;  Nelkin, Barry D.;  Zahnow, Cynthia A.;  Pardoll, Drew M.;  Housseau, Franck;  Baylin, Stephen B.;  Shen, Lin;  Brock, Malcolm V.
收藏  |  浏览/下载:57/0  |  提交时间:2020/07/03

Ultrahot giant exoplanets receive thousands of times Earth'  s insolation(1,2). Their high-temperature atmospheres (greater than 2,000 kelvin) are ideal laboratories for studying extreme planetary climates and chemistry(3-5). Daysides are predicted to be cloud-free, dominated by atomic species(6) and much hotter than nightsides(5,7,8). Atoms are expected to recombine into molecules over the nightside(9), resulting in different day and night chemistries. Although metallic elements and a large temperature contrast have been observed(10-14), no chemical gradient has been measured across the surface of such an exoplanet. Different atmospheric chemistry between the day-to-night ('  evening'  ) and night-to-day ('  morning'  ) terminators could, however, be revealed as an asymmetric absorption signature during transit(4,7,15). Here we report the detection of an asymmetric atmospheric signature in the ultrahot exoplanet WASP-76b. We spectrally and temporally resolve this signature using a combination of high-dispersion spectroscopy with a large photon-collecting area. The absorption signal, attributed to neutral iron, is blueshifted by -11 +/- 0.7 kilometres per second on the trailing limb, which can be explained by a combination of planetary rotation and wind blowing from the hot dayside(16). In contrast, no signal arises from the nightside close to the morning terminator, showing that atomic iron is not absorbing starlight there. We conclude that iron must therefore condense during its journey across the nightside.


Absorption lines of iron in the dayside atmosphere of an ultrahot giant exoplanet disappear after travelling across the nightside, showing that the iron has condensed during its travel.


  
Microbiome analyses of blood and tissues suggest cancer diagnostic approach 期刊论文
NATURE, 2020, 579 (7800) : 567-+
作者:  Shao, Zhengping;  Flynn, Ryan A.;  Crowe, Jennifer L.;  Zhu, Yimeng;  Liang, Jialiang;  Jiang, Wenxia;  Aryan, Fardin;  Aoude, Patrick;  Bertozzi, Carolyn R.;  Estes, Verna M.;  Lee, Brian J.;  Bhagat, Govind;  Zha, Shan;  Calo, Eliezer
收藏  |  浏览/下载:54/0  |  提交时间:2020/07/03

Microbial nucleic acids are detected in samples of tissues and blood from more than 10,000 patients with cancer, and machine learning is used to show that these can be used to discriminate between and among different types of cancer, suggesting a new microbiome-based diagnostic approach.


Systematic characterization of the cancer microbiome provides the opportunity to develop techniques that exploit non-human, microorganism-derived molecules in the diagnosis of a major human disease. Following recent demonstrations that some types of cancer show substantial microbial contributions(1-10), we re-examined whole-genome and whole-transcriptome sequencing studies in The Cancer Genome Atlas(11) (TCGA) of 33 types of cancer from treatment-naive patients (a total of 18,116 samples) for microbial reads, and found unique microbial signatures in tissue and blood within and between most major types of cancer. These TCGA blood signatures remained predictive when applied to patients with stage Ia-IIc cancer and cancers lacking any genomic alterations currently measured on two commercial-grade cell-free tumour DNA platforms, despite the use of very stringent decontamination analyses that discarded up to 92.3% of total sequence data. In addition, we could discriminate among samples from healthy, cancer-free individuals (n = 69) and those from patients with multiple types of cancer (prostate, lung, and melanoma  100 samples in total) solely using plasma-derived, cell-free microbial nucleic acids. This potential microbiome-based oncology diagnostic tool warrants further exploration.


  
Premature mortality related to United States cross-state air pollution 期刊论文
NATURE, 2020, 578 (7794) : 261-+
作者:  Helmink, Beth A.;  Reddy, Sangeetha M.;  Gao, Jianjun;  Zhang, Shaojun;  Basar, Rafet;  Thakur, Rohit;  Yizhak, Keren;  Sade-Feldman, Moshe;  Blando, Jorge;  Han, Guangchun;  Gopalakrishnan, Vancheswaran;  Xi, Yuanxin;  Zhao, Hao;  Amaria, Rodabe N.;  Tawbi, Hussein A.;  Cogdill, Alex P.;  Liu, Wenbin;  LeBleu, Valerie S.;  Kugeratski, Fernanda G.;  Patel, Sapna;  Davies, Michael A.;  Hwu, Patrick;  Lee, Jeffrey E.;  Gershenwald, Jeffrey E.;  Lucci, Anthony;  Arora, Reetakshi;  Woodman, Scott;  Keung, Emily Z.;  Gaudreau, Pierre-Olivier;  Reuben, Alexandre;  Spencer, Christine N.;  Burton, Elizabeth M.;  Haydu, Lauren E.;  Lazar, Alexander J.;  Zapassodi, Roberta;  Hudgens, Courtney W.;  Ledesma, Deborah A.;  Ong, SuFey;  Bailey, Michael;  Warren, Sarah;  Rao, Disha;  Krijgsman, Oscar;  Rozeman, Elisa A.;  Peeper, Daniel;  Blank, Christian U.;  Schumacher, Ton N.;  Butterfield, Lisa H.;  Zelazowska, Monika A.;  McBride, Kevin M.;  Kalluri, Raghu;  Allison, James;  Petitprez, Florent;  Fridman, Wolf Herman;  Sautes-Fridman, Catherine;  Hacohen, Nir;  Rezvani, Katayoun;  Sharma, Padmanee;  Tetzlaff, Michael T.;  Wang, Linghua;  Wargo, Jennifer A.
收藏  |  浏览/下载:37/0  |  提交时间:2020/05/13

Outdoor air pollution adversely affects human health and is estimated to be responsible for five to ten per cent of the total annual premature mortality in the contiguous United States(1-3). Combustion emissions from a variety of sources, such as power generation or road traffic, make a large contribution to harmful air pollutants such as ozone and fine particulate matter (PM2.5)(4). Efforts to mitigate air pollution have focused mainly on the relationship between local emission sources and local air quality(2). Air quality can also be affected by distant emission sources, however, including emissions from neighbouring federal states(5,6). This cross-state exchange of pollution poses additional regulatory challenges. Here we quantify the exchange of air pollution among the contiguous United States, and assess its impact on premature mortality that is linked to increased human exposure to PM2.5 and ozone from seven emission sectors for 2005 to 2018. On average, we find that 41 to 53 per cent of air-quality-related premature mortality resulting from a state'  s emissions occurs outside that state. We also find variations in the cross-state contributions of different emission sectors and chemical species to premature mortality, and changes in these variations over time. Emissions from electric power generation have the greatest cross-state impacts as a fraction of their total impacts, whereas commercial/residential emissions have the smallest. However, reductions in emissions from electric power generation since 2005 have meant that, by 2018, cross-state premature mortality associated with the commercial/residential sector was twice that associated with power generation. In terms of the chemical species emitted, nitrogen oxides and sulfur dioxide emissions caused the most cross-state premature deaths in 2005, but by 2018 primary PM2.5 emissions led to cross-state premature deaths equal to three times those associated with sulfur dioxide emissions. These reported shifts in emission sectors and emission species that contribute to premature mortality may help to guide improvements to air quality in the contiguous United States.


  
Neuronal programming by microbiota regulates intestinal physiology 期刊论文
NATURE, 2020, 578 (7794) : 284-+
作者:  Li, Yilong;  Roberts, Nicola D.;  Wala, Jeremiah A.;  Shapira, Ofer;  Schumacher, Steven E.;  Kumar, Kiran;  Khurana, Ekta;  Waszak, Sebastian;  Korbel, Jan O.;  Haber, James E.;  Imielinski, Marcin;  Weischenfeldt, Joachim;  Beroukhim, Rameen;  Campbell, Peter J.;  Akdemir, Kadir C.;  Alvarez, Eva G.;  Baez-Ortega, Adrian;  Boutros, Paul C.;  Bowtell, David D. L.;  Brors, Benedikt;  Burns, Kathleen H.;  Chan, Kin;  Chen, Ken;  Cortes-Ciriano, Isidro;  Dueso-Barroso, Ana;  Dunford, Andrew J.;  Edwards, Paul A.;  Estivill, Xavier;  Etemadmoghadam, Dariush;  Feuerbach, Lars;  Fink, J. Lynn;  Frenkel-Morgenstern, Milana;  Garsed, Dale W.;  Gerstein, Mark;  Gordenin, Dmitry A.;  Haan, David;  Hess, Julian M.;  Hutter, Barbara;  Jones, David T. W.;  Ju, Young Seok;  Kazanov, Marat D.;  Klimczak, Leszek J.;  Koh, Youngil;  Lee, Eunjung Alice;  Lee, Jake June-Koo;  Lynch, Andy G.;  Macintyre, Geoff;  Markowetz, Florian;  Martincorena, Inigo;  Martinez-Fundichely, Alexander;  Meyerson, Matthew;  Miyano, Satoru;  Nakagawa, Hidewaki;  Navarro, Fabio C. P.;  Ossowski, Stephan;  Park, Peter J.;  Pearson, John, V;  Puiggros, Montserrat;  Rippe, Karsten;  Roberts, Steven A.;  Rodriguez-Martin, Bernardo;  Scully, Ralph;  Shackleton, Mark;  Sidiropoulos, Nikos;  Sieverling, Lina;  Stewart, Chip;  Torrents, David;  Tubio, Jose M. C.;  Villasante, Izar;  Waddell, Nicola;  Yang, Lixing;  Yao, Xiaotong;  Yoon, Sung-Soo;  Zamora, Jorge;  Zhang, Cheng-Zhong
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Neural control of the function of visceral organs is essential for homeostasis and health. Intestinal peristalsis is critical for digestive physiology and host defence, and is often dysregulated in gastrointestinal disorders(1). Luminal factors, such as diet and microbiota, regulate neurogenic programs of gut motility(2-5), but the underlying molecular mechanisms remain unclear. Here we show that the transcription factor aryl hydrocarbon receptor (AHR) functions as a biosensor in intestinal neural circuits, linking their functional output to the microbial environment of the gut lumen. Using nuclear RNA sequencing of mouse enteric neurons that represent distinct intestinal segments and microbiota states, we demonstrate that the intrinsic neural networks of the colon exhibit unique transcriptional profiles that are controlled by the combined effects of host genetic programs and microbial colonization. Microbiota-induced expression of AHR in neurons of the distal gastrointestinal tract enables these neurons to respond to the luminal environment and to induce expression of neuron-specific effector mechanisms. Neuron-specific deletion of Ahr, or constitutive overexpression of its negative feedback regulator CYP1A1, results in reduced peristaltic activity of the colon, similar to that observed in microbiota-depleted mice. Finally, expression of Ahr in the enteric neurons of mice treated with antibiotics partially restores intestinal motility. Together, our experiments identify AHR signalling in enteric neurons as a regulatory node that integrates the luminal environment with the physiological output of intestinal neural circuits to maintain gut homeostasis and health.


In a mouse model, aryl hydrocarbon receptor signalling in enteric neurons is revealed as a mechanism that helps to maintain gut homeostasis by integrating the luminal environment with the physiology of intestinal neural circuits.