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Kaposi’s sarcoma-associated herpesvirus induces mitochondrial fission to evade host immune responses and promote viral production

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Nature Microbiology 2025年 1-20页

作者： Qing Zhu Robert McElroy Janvhi Suresh Machhar Joel Cassel Zihan Zheng Behzad Mansoori Sen Guo Christian Pangilinan Jinghui Liang Dongliang Shen Lu Zhang Qin Liu Maureen E. Murphy Joseph M. Salvino Chengyu Liang Hongrui Guo Andrew V. Kossenkov Dario C. Altieri Paul M. Lieberman Shou-Jiang Gao Pinghui Feng Jikui Song Qiming Liang Jae U. Jung Program in Molecular and Cellular Oncogenesis The Wistar Institute Philadelphia PA USA Department of Molecular Microbiology and Immunology Keck School of Medicine University of Southern California Los Angeles CA USA Program in Genome Regulation and Cell Signaling The Wistar Institute Philadelphia PA USA Cancer Virology Program University of Pittsburgh Medical Center Hillman Cancer Center University of Pittsburgh School of Medicine Pittsburgh PA USA Section of Infection and Immunity Herman Ostrow School of Dentistry Norris Comprehensive Cancer Center University of Southern California Los Angeles CA USA Department of Biochemistry University of California Riverside CA USA Center for Immune-Related Diseases at Shanghai Institute of Immunology Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai China Department of Cancer Biology Department of Infection Biology and Global Center for Pathogen and Human Health Research Lerner Research Institute Cleveland Clinic Cleveland OH USA

Mitochondrial dynamics are pivotal for host immune responses upon infection, yet how viruses manipulate these processes to impair host defence and enhance viral fitness remains unclear. Here we show that Kaposi’s sarcoma-associated herpesvirus (KSHV), an oncogenic virus also known as human herpesvirus 8, encodes Bcl-2 (vBcl-2), which reprogrammes mitochondrial architecture. It binds with NM23-H2, a host nucleoside diphosphate (NDP) kinase, to stimulate GTP loading of the dynamin-related protein (DRP1) GTPase, which triggers mitochondrial fission, inhibits mitochondrial antiviral signalling protein (MAVS) aggregation and impairs interferon responses in cell lines. An NM23-H2-binding-defective vBcl-2 mutant fails to evoke fission, leading to defective virion assembly due to activated MAVS–IFN signalling. Notably, we identify two key interferon-stimulated genes restricting vBcl-2-dependent virion morphogenesis. Using a high-throughput drug screening, we discover an inhibitor targeting vBcl-2–NM23-H2 interaction that blocks virion production in vitro. Our study identifies a mechanism in which KSHV manipulates mitochondrial dynamics to allow for virus assembly and shows that targeting the virus–mitochondria interface represents a potential therapeutic strategy.

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IRE1α governs cytoskeleton remodeling and cell migration through a direct interaction with filamin A (vol 20, pg 942, 2018)

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NATURE cell BIOLOGY 2021年第5期23卷 577-577页

作者： Urra, Hery Henriquez, Daniel R. Canovas, Jose Villarroel-Campos, David Carreras-Sureda, Amado Pulgar, Eduardo Molina, Emiliano Hazari, Younis M. Limia, Celia M. Alvarez-Rojas, Sebastian Figueroa, Ricardo Vidal, Rene L. Rodriguez, Diego A. Rivera, Claudia A. Court, Felipe A. Couve, Andres Qi, Ling Chevet, Eric Akai, Ryoko Iwawaki, Takao Concha, Miguel L. Glavic, Alvaro Gonzalez-Billault, Christian Hetz, Claudio Biomedical Neuroscience Institute Faculty of Medicine University of Chile Santiago Chile Center for Geroscience Brain Health and Metabolism (GERO) Santiago Chile Program of Cellular and Molecular Biology Institute of Biomedical Sciences University of Chile Santiago Chile Program of Anatomy and Developmental Biology Institute of Biomedical Sciences University of Chile Santiago Chile Center for Integrative Biology Faculty of Sciences Universidad Mayor Santiago Chile Department of Neuroscience Faculty of Medicine University of Chile Santiago Chile The Buck Institute for Research in Aging Novato CA USA Department of Immunology and Infectious Diseases Harvard School of Public Health Boston MA USA Department of Biology Faculty of Sciences University of Chile Santiago Chile Center for Genome Regulation Faculty of Sciences University of Chile Santiago Chile Department of Molecular and Integrative Physiology Division of Metabolism Endocrinology and Diabetes The University of Michigan Medical School Ann Arbor MI USA INSERM U1242 Chemistry Oncogenesis Stress and Signaling University of Rennes 1 Rennes France Centre de Lutte contre le Cancer Eugène Marquis Rennes France Division of Cell Medicine Department of Life Science Medical Research Institute Kanazawa Medical University Uchinada Japan

A Correction to this paper has been published: https://***/10.1038/s41556-021-00673-2.

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Natural variation in the parameters of innate immune cells is preferentially driven by genetic factors (vol 19, pg 302, 2018)

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NATURE IMMUNOLOGY 2018年第6期19卷 645-645页

作者： Patin, Etienne Hasan, Milena Bergstedt, Jacob Rouilly, Vincent Libri, Valentina Urrutia, Alejandra Alanio, Cecile Scepanovic, Petar Hammer, Christian Joensson, Friederike Beitz, Benoit Quach, Helene Lim, Yoong Wearn Hunkapiller, Julie Zepeda, Magge Green, Cherie Piasecka, Barbara Leloup, Claire Rogge, Lars Huetz, Francois Peguillet, Isabelle Lantz, Olivier Fontes, Magnus Di Santo, James P. Thomas, Stephanie Fellay, Jacques Duffy, Darragh Quintana-Murci, Lluis Albert, Matthew L. Unit of Human Evolutionary Genetics Department of Genomes & Genetics Institut Pasteur Paris France CNRS UMR 2000 Paris France Center of Bioinformatics Biostatistics and Integrative Biology Institut Pasteur Paris France Center for Translation Research Institut Pasteur Paris France Department of Automatic Control Lund University Lund Sweden International Group for Data Analysis Institut Pasteur Paris France Laboratory of Dendritic Cell Immunobiology Department of Immunology Institut Pasteur Paris France INSERM U1223 Paris France Department of Cancer Immunology Genentech South San Francisco CA USA School of Life Sciences École Polytechnique Fédérale de Lausanne Lausanne Switzerland Swiss Institute of Bioinformatics Lausanne Switzerland Antibodies in Therapy and Pathology Department of Immunology Institut Pasteur Paris France INSERM U760 Paris France Department of Human Genetics Genentech South San Francisco CA USA Employee Donation Program Genentech South San Francisco CA USA Department of Development Sciences Genentech South San Francisco CA USA Immunoregulation Unit Department of Immunology Institut Pasteur Paris France INSERM U783 Faculté de Médecine Site Necker-Enfants Malades Université Paris Descartes Paris France Lymphocyte Population Biology CNRS URA 1961 Institut Pasteur Paris France Center of Clinical Investigations CIC-BT1428 IGR/Curie Paris France Department of Biopathology Institut Curie Paris France Equipe Labellisée de la Ligue de Lutte Contre le Cancer Institut Curie Paris France INSERM/Institut Curie U932 Paris France Centre for Mathematical Sciences Lund University Lund Sweden Innate Immunity Unit Institut Pasteur Paris France St. Giles Laboratory of Human Genetics of Infectious Diseases Rockefeller Branch Rockefeller University New York NY USA Laboratory of Human Genetics of Infectious Diseases Necker Branch INSERM U1163 Necker Hospital for Sick Children Paris France Paris Descartes University Imagine Insti

The quantification and characterization of circulating immune cells provide key indicators of human health and disease. To identify the relative effects of environmental and genetic factors on variation in the parameters of innate and adaptive immune cells in homeostatic conditions, we combined standardized flow cytometry of blood leukocytes and genome-wide DNA genotyping of 1,000 healthy, unrelated people of Western European ancestry. We found that smoking, together with age, sex and latent infection with cytomegalovirus, were the main non-genetic factors that affected variation in parameters of human immune cells. genome-wide association studies of 166 immunophenotypes identified 15 loci that showed enrichment for disease-associated variants. Finally, we demonstrated that the parameters of innate cells were more strongly controlled by genetic variation than were those of adaptive cells, which were driven by mainly environmental exposure. Our data establish a resource that will generate new hypotheses in immunology and highlight the role of innate immunity in susceptibility to common autoimmune diseases.

关键词： Activated Lymphocyte Genetic factors Immunity Nonspecific Immune cell Variation

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The Tastemakers: Semonyx Targets Taste Receptors

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CHEMISTRY & BIOLOGY 2009年第11期16卷 1123-1124页

作者： Wolfson, Wendy Main Text Our society is awash with cheap food high in calories and salt. Currently over two thirds of Americans are overweight with a third considered obese. Consumer advocacy groups are lobbying food manufacturers to market healthier foods and drinks even pushing taxes on sugary sodas. But genomics advances could indirectly save our cookies as molecular biology meets taste perception. Unfortunately stripping the sugar fat and salt also strips away taste. But genomics advances could indirectly save our cookies as molecular biology meets taste perception. Companies like San Diego-based Semonyx (http://***) are using drug discovery techniques to engineer a new generation of taste enhancers that can fool our tastebuds. Senomyx targets G protein-coupled receptors for sweet bitter and savory tastes and ion channels for saltiness. In addition the company is developing bitter blockers and menthol cooling agents. “I think there is great interest in big food and fragrance companies and entrepreneurial companies like Senomyx and Redpoint to try to find technological ways to make food healthier.” said Gary Beauchamp Ph.D. director of the Monell Chemical Senses Center. “The trouble is that if you look at the history of public health organizations telling you to eat a healthier diet the results are not very encouraging.” Good Taste Is a Matter of Perception Humans can taste five different tastes: sweet sour bitter salty and umami (savory). It has long been known that taste is linked to sense of smell. Research groups continue to explore the function of distinct taste receptors on the tongue and on the lining of the gut. The human sweet receptor is comprised of two proteins T1R2 and T1R3 expressed on the surface of particular taste receptor cells. Savory taste receptors consist of T1R1 and T1R3 proteins. The selectivity of these heterodimeric receptors for sweet or savory is determined by the combination of receptor subunits. The T1R3 protein is used by both the sweet and savory taste recepto

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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits (vol 50, pg 1412, 2018)

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NATURE GENETICS 2018年第12期50卷 1755-1755页

作者： Evangelou, Evangelos Warren, Helen R. Mosen-Ansorena, David Mifsud, Borbala Pazoki, Raha Gao, He Ntritsos, Georgios Dimou, Niki Cabrera, Claudia P. Karaman, Ibrahim Fu Liang Ng Evangelou, Marina Witkowska, Katarzyna Tzanis, Evan Hellwege, Jacklyn N. Giri, Ayush Edwards, Digna R. Velez Sun, Yan V. Cho, Kelly Gaziano, J. Michael Wilson, Peter W. F. Tsao, Philip S. Kovesdy, Csaba P. Esko, Tonu Magi, Reedik Milani, Lili Almgren, Peter Boutin, Thibaud Debette, Stephanie Ding, Jun Giulianini, Franco Holliday, Elizabeth G. Jackson, Anne U. Li-Gao, Ruifang Lin, Wei-Yu Luan, Jian'an Mangino, Massimo Oldmeadow, Christopher Prins, Bram Peter Qian, Yong Sargurupremraj, Muralidharan Shah, Nabi Surendran, Praveen Theriault, Sebastien Verweij, Niek Willems, Sara M. Zhao, Jing-Hua Amouyel, Philippe Connell, John de Mutsert, Renee Doney, Alex S. F. Farrall, Martin Menni, Cristina Morris, Andrew D. Noordam, Raymond Pare, Guillaume Poulter, Neil R. Shields, Denis C. Stanton, Alice Thom, Simon Abecasis, Goncalo Amin, Najaf Arking, Dan E. Ayers, Kristin L. Barbieri, Caterina M. Batini, Chiara Bis, Joshua C. Blake, Tineka Bochud, Murielle Boehnke, Michael Boerwinkle, Eric Boomsma, Dorret I. Bottinger, Erwin P. Braund, Peter S. Brumat, Marco Campbell, Archie Campbell, Harry Chakravarti, Aravinda Chambers, John C. Chauhan, Ganesh Ciullo, Marina Cocca, Massimiliano Collins, Francis Cordell, Heather J. Davies, Gail de Borst, Martin H. de Geus, Eco J. Deary, Ian J. Deelen, Joris Del Greco, Fabiola M. Demirkale, Cumhur Yusuf Dorr, Marcus Ehret, Georg B. Elosua, Roberto Enroth, Stefan Erzurumluoglu, A. Mesut Ferreira, Teresa Franberg, Mattias Franco, Oscar H. Gandin, Ilaria Gasparini, Paolo Giedraitis, Vilmantas Gieger, Christian Girotto, Giorgia Goel, Anuj Gow, Alan J. Gudnason, Vilmundur Guo, Xiuqing Gyllensten, Ulf Hamsten, Anders Harris, Tamara B. Harris, Sarah E. Hartman, Catharina A. Havulinna, Aki S. Hicks, Andrew A. Hofer, Edith Hofman, Albert Hottenga, Jouke-Jan Huffman, Jennifer E. Hwang, Shih-Jen Ingelsson, Erik James, Alan Jansen Department of Epidemiology and Biostatistics Imperial College London London UK Department of Hygiene and Epidemiology University of Ioannina Medical School Ioannina Greece William Harvey Research Institute Barts and The London School of Medicine and Dentistry Queen Mary University of London London UK National Institute for Health Research Barts Cardiovascular Biomedical Research Center Queen Mary University of London London UK MRC-PHE Centre for Environment and Health Imperial College London London UK Department of Mathematics Imperial College London London UK Division of Epidemiology Department of Medicine Institute for Medicine and Public Health Vanderbilt Genetics Institute Vanderbilt University Medical Center Tennessee Valley Healthcare System (626)/Vanderbilt University Nashville TN USA Vanderbilt Genetics Institute Vanderbilt Epidemiology Center Department of Obstetrics and Gynecology Vanderbilt University Medical Center Tennessee Valley Health Systems VA Nashville TN USA Department of Epidemiology Emory University Rollins School of Public Health Atlanta GA USA Department of Biomedical Informatics Emory University School of Medicine Atlanta GA USA Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC) VA Boston Healthcare System Boston MA USA Division of Aging Department of Medicine Brigham and Women’s Hospital Department of Medicine Harvard Medical School Boston MA USA Atlanta VAMC and Emory Clinical Cardiovascular Research Institute Atlanta GA USA VA Palo Alto Health Care System Division of Cardiovascular Medicine Stanford University School of Medicine Stanford CA USA Nephrology Section Memphis VA Medical Center and University of Tennessee Health Science Center Memphis TN USA Estonian Genome Center University of Tartu Tartu Estonia Program in Medical and Population Genetics Broad Institute of Harvard and MIT Cambridge MA USA Department Clinical Sciences Malmö Lund University Malmö Sweden MRC Human Genetics Un

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

关键词： Cardiovascular diseases genome informatics genome-wide association studies

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LifeTime and improving European healthcare through cell-based interceptive medicine (vol 587, pg 377, 2020)

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NATURE 2021年第7852期592卷 E8-E8页

作者： Rajewsky, Nikolaus Almouzni, Genevieve Gorski, Stanislaw A. Aerts, Stein Amit, Ido Bertero, Michela G. Bock, Christoph Bredenoord, Annelien L. Cavalli, Giacomo Chiocca, Susanna Clevers, Hans De Strooper, Bart Eggert, Angelika Ellenberg, Jan Fernandez, Xose M. Figlerowicz, Marek Gasser, Susan M. Hubner, Norbert Kjems, Jorgen Knoblich, Jurgen A. Krabbe, Grietje Lichter, Peter Linnarsson, Sten Marine, Jean-Christophe Marioni, John C. Marti-Renom, Marc A. Netea, Mihai G. Nickel, Dorthe Nollmann, Marcelo Novak, Halina R. Parkinson, Helen Piccolo, Stefano Pinheiro, Ines Pombo, Ana Popp, Christian Reik, Wolf Roman-Roman, Sergio Rosenstiel, Philip Schultze, Joachim L. Stegle, Oliver Tanay, Amos Testa, Giuseppe Thanos, Dimitris Theis, Fabian J. Torres-Padilla, Maria-Elena Valencia, Alfonso Vallot, Celine van Oudenaarden, Alexander Vidal, Marie Voet, Thierry Berlin Institute for Medical Systems Biology Max Delbrück Center for Molecular Medicine in the Helmholtz Association Berlin Germany Charité-Universitätsmedizin Berlin Germany Berlin Institute of Health (BIH) Berlin Germany German Center for Cardiovascular Research (DZHK) Partner Site Berlin Berlin Germany Institute for Biology Humboldt University of Berlin Berlin Germany Cardiovascular and Metabolic Sciences Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) Berlin Germany Department of Pediatric Oncology/Hematology Charité-Universitätsmedizin Berlin Berlin Germany Institut Curie CNRS PSL Research University Sorbonne Université Nuclear Dynamics Unit Equipe Labellisée Ligue contre le cancer Paris France VIB Center for Brain and Disease Research Leuven Belgium Department of Human Genetics KU Leuven Leuven Belgium Department of Neurosciences KU Leuven Leuven Belgium UK Dementia Research Institute at UCL University College London London UK Wellcome Sanger Institute Wellcome Genome Campus Cambridge UK Department of Immunology Weizmann Institute of Science Rehovot Israel Centre for Genomic Regulation (CRG) Barcelona Institute of Science and Technology Barcelona Spain CNAG-CRG Centre for Genomic Regulation Barcelona Institute of Science and Technology Barcelona Spain Universitat Pompeu Fabra Barcelona Spain ICREA Barcelona Spain CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Vienna Austria Department of Laboratory Medicine Medical University of Vienna Vienna Austria Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases Vienna Austria Department of Medical Humanities Julius Center for Health Sciences and Primary Care University Medical Center Utrecht Utrecht The Netherlands Institute of Human Genetics UMR 9002 CNRS and University of Montpellier Montpellier France Department of Experimental Oncology IEO European Institute of Oncology IRCCS Milan Italy Department of Oncology and Hemato

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Author Correction: The power of genetic diversity in genome-wide association studies of lipids

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Nature 2023年第7965期618卷 E19-E20页

作者： Sarah E Graham Shoa L Clarke Kuan-Han H Wu Stavroula Kanoni Greg J M Zajac Shweta Ramdas Ida Surakka Ioanna Ntalla Sailaja Vedantam Thomas W Winkler Adam E Locke Eirini Marouli Mi Yeong Hwang Sohee Han Akira Narita Ananyo Choudhury Amy R Bentley Kenneth Ekoru Anurag Verma Bhavi Trivedi Hilary C Martin Karen A Hunt Qin Hui Derek Klarin Xiang Zhu Gudmar Thorleifsson Anna Helgadottir Daniel F Gudbjartsson Hilma Holm Isleifur Olafsson Masato Akiyama Saori Sakaue Chikashi Terao Masahiro Kanai Wei Zhou Ben M Brumpton Humaira Rasheed Sanni E Ruotsalainen Aki S Havulinna Yogasudha Veturi QiPing Feng Elisabeth A Rosenthal Todd Lingren Jennifer Allen Pacheco Sarah A Pendergrass Jeffrey Haessler Franco Giulianini Yuki Bradford Jason E Miller Archie Campbell Kuang Lin Iona Y Millwood George Hindy Asif Rasheed Jessica D Faul Wei Zhao David R Weir Constance Turman Hongyan Huang Mariaelisa Graff Anubha Mahajan Michael R Brown Weihua Zhang Ketian Yu Ellen M Schmidt Anita Pandit Stefan Gustafsson Xianyong Yin Jian'an Luan Jing-Hua Zhao Fumihiko Matsuda Hye-Mi Jang Kyungheon Yoon Carolina Medina-Gomez Achilleas Pitsillides Jouke Jan Hottenga Gonneke Willemsen Andrew R Wood Yingji Ji Zishan Gao Simon Haworth Ruth E Mitchell Jin Fang Chai Mette Aadahl Jie Yao Ani Manichaikul Helen R Warren Julia Ramirez Jette Bork-Jensen Line L Kårhus Anuj Goel Maria Sabater-Lleal Raymond Noordam Carlo Sidore Edoardo Fiorillo Aaron F McDaid Pedro Marques-Vidal Matthias Wielscher Stella Trompet Naveed Sattar Line T Møllehave Betina H Thuesen Matthias Munz Lingyao Zeng Jianfeng Huang Bin Yang Alaitz Poveda Azra Kurbasic Claudia Lamina Lukas Forer Markus Scholz Tessel E Galesloot Jonathan P Bradfield E Warwick Daw Joseph M Zmuda Jonathan S Mitchell Christian Fuchsberger Henry Christensen Jennifer A Brody Mary F Feitosa Mary K Wojczynski Michael Preuss Massimo Mangino Paraskevi Christofidou Niek Verweij Jan W Benjamins Jorgen Engmann Rachel L Kember Roderick C Slieker Ken Sin Lo Nuno R Zilhao Phuong Le Marcus E Kleber Graciela E Delgado Shaofeng Huo Dai Department of Internal Medicine Division of Cardiology University of Michigan Ann Arbor MI USA. VA Palo Alto Health Care System Palo Alto CA USA. Department of Medicine Division of Cardiovascular Medicine Stanford University School of Medicine Stanford CA USA. Department of Computational Medicine and Bioinformatics University of Michigan Ann Arbor MI USA. William Harvey Research Institute Barts and the London School of Medicine and Dentistry Queen Mary University of London London UK. Department of Biostatistics and Center for Statistics Genetics University of Michigan Ann Arbor MI USA. Department of Genetics Perelman School of Medicine University of Pennsylvania Philadelphia PA USA. Clinical Pharmacology William Harvey Research Institute Barts and The London School of Medicine and Dentistry Queen Mary University of London London UK. Endocrinology Boston Children's Hospital Boston MA USA. Medical and Population Genetics Broad Institute Cambridge MA USA. Department of Genetic Epidemiology University of Regensburg Regensburg Germany. McDonnell Genome Institute and Department of Medicine Washington University St Louis MO USA. Department of Precision Medicine Division of Genome Science National Institute of Health Cheongju-si South Korea. Tohoku Medical Megabank Organization Tohoku University Sendai Japan. Sydney Brenner Institute for Molecular Bioscience Faculty of Health Sciences University of the Witwatersrand Johannesburg South Africa. Center for Research on Genomics and Global Health National Human Genome Research Institute National Institutes of Health Bethesda MD USA. Blizard Institute Barts and the London School of Medicine and Dentistry Queen Mary University of London London UK. Wellcome Sanger Institute Hinxton UK. Department of Epidemiology Emory University Rollins School of Public Health Atlanta GA USA. Atlanta VA Health Care System Decatur GA USA. Malcolm Randall VA Medical Center Gainesville FL USA. Division of Vascular Sur

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