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27,765 results on '"Yale School of Medicine"'

1. Long Term Follow Up KET-PD

Author: Fox (Michael J.) Foundation for Parkinson's Research, Yale School of Medicine Center for Brain Mind Health, and Sophie Holmes, Assistant Professor of Psychiatry
Published: 2023

2. Live@Home.Path: Innovating the Clinical Pathway for Home Dwelling Persons With Dementia and Their Families (LIVE)

Author: Haraldsplass Deaconal Hospital, Western Norway University of Applied Sciences, Norwegian Reseach Centre AS (NORCE), Norwegian National Advisory Unit on Ageing and Health, Natioal Association for Public Health, Municipality of Bergen, Municipally of Kristiansund, Municipally of Bærum, The Dignity Centre, Harvard McLean University, Yale School of Medicine, University College, London, University of Leiden, Tohoku University, King's College London, and The University of Hong Kong
Published: 2023

3. Clinical & Community Approaches to Weight Management (CORD 2)

Author: Massachusetts Department of Health, Y-USA, Yale School of Medicine, Harvard School of Public Health (HSPH), and Elsie Taveras, MD, Chief, Division of General Academic Pediatrics
Published: 2021

4. Caretaker Hemodynamic Parameters Validation

Author: University of Virginia, Yale School of Medicine, and Orange County Research Center
Published: 2020

5. A method to study bladder urothelial cellular function in situ

Author: Lu, Ming; Yale School of Medicine, Department of Urology, Chai, Toby C; Yale Department of Urology, Lu, Ming; Yale School of Medicine, Department of Urology, and Chai, Toby C; Yale Department of Urology
Abstract: Objective: The bladder urothelium is comprised of basal, intermediate, and apical urothelial cells. Ability to functionally study an individual urothelial cell while preserving its in situ location would represent an advance in bladder urothelial biology. Materials and Methods: Mice were euthanized and cardiac perfused with phosphate-buffered saline. Bladders were then excised. Urothelial sheets were dissected off the lamina propria using forceps with a microscope (5x magnification). Sheets were stained with H&E. In separate experiments, cell-attached electrophysiology was performed by placing urothelial sheets in Ringer’s bath solution, with either basal or apical surface down. Using 40x magnification, individual urothelial cells from different layers were identified. Potassium currents on these cells were measured in situ using single channel patch-clamp technique.Results: Histology revealed that urothelial sheets were free of lamina propria and smooth muscles. The proportion of apical cells, compared to proportion of intermediate and basal cells, with measureable potassium currents was considerably higher in apical cells (69% of apical versus 16% of intermediate and 18% of basal cells). Of the active patches detected in apical cells, 100% of these patches showed a 43 pS current conductance. For intermediate and basal cells, 75-83% demonstrated a 43 pS current and 17-25% demonstrated a 22 pS current. Single cells, from all 3 layers, could also be individually microdissected completely off the urothelium. Conclusions: A novel approach was developed in which individual urothelial cells within the multi-layered urothelium were identified and functionally studied in situ. Electrophysiologic characterization revealed different phenotype between the cells from different layers. Single cells from an identified layer can be harvested off the urothelium allowing for other studies. This technique allows investigators to study various cellular functions
Published: 2014

6. Does the bladder matter enough to have its own journal?

Author: Chai, Toby C; Department of Urology, Yale School of Medicine, Birder, Lori Ann; Departments of Medicine and Pharmacology, University of Pittsburgh School of Medicine, Chai, Toby C; Department of Urology, Yale School of Medicine, and Birder, Lori Ann; Departments of Medicine and Pharmacology, University of Pittsburgh School of Medicine
Published: 2014

7. How do bacteria localize proteins to the cell pole?

Author: UCL - SSS/DDUV - Institut de Duve, Yale University - Department of Molecular, Cellular and Developmental Biology, Yale School of Medicine - Department of Microbial Pathogenesis, Yale University - Howard Hughes Medical Institute, Laloux, Géraldine, Jacobs-Wagner, Christine, UCL - SSS/DDUV - Institut de Duve, Yale University - Department of Molecular, Cellular and Developmental Biology, Yale School of Medicine - Department of Microbial Pathogenesis, Yale University - Howard Hughes Medical Institute, Laloux, Géraldine, and Jacobs-Wagner, Christine
Abstract: It is now well appreciated that bacterial cells are highly organized, which is far from the initial concept that they are merely bags of randomly distributed macromolecules and chemicals. Central to their spatial organization is the precise positioning of certain proteins in subcellular domains of the cell. In particular, the cell poles - the ends of rod-shaped cells - constitute important platforms for cellular regulation that underlie processes as essential as cell cycle progression, cellular differentiation, virulence, chemotaxis and growth of appendages. Thus, understanding how the polar localization of specific proteins is achieved and regulated is a crucial question in bacterial cell biology. Often, polarly localized proteins are recruited to the poles through their interaction with other proteins or protein complexes that were already located there, in a so-called diffusion-and-capture mechanism. Bacteria are also starting to reveal their secrets on how the initial pole 'recognition' can occur and how this event can be regulated to generate dynamic, reproducible patterns in time (for example, during the cell cycle) and space (for example, at a specific cell pole). Here, we review the major mechanisms that have been described in the literature, with an emphasis on the self-organizing principles. We also present regulation strategies adopted by bacterial cells to obtain complex spatiotemporal patterns of protein localization.
Published: 2014

8. G1-arrested newborn cells are the predominant infectious form of the pathogen Brucella abortus

Author: UNamur - SBIO_URBM (unité de recherche en biologie moléculaire), Yale University - Department of Molecular, Cellular and Developmental Biology, Yale School of Medicine - Department of Microbial Pathogenesis, Yale University - Howard Hughes Medical Institute, Deghelt, Michaël, Mullier, Caroline, Sternon, Jean-François, Francis, Nayla, Laloux, Géraldine, Dotreppe, Delphine, Van der Henst, Charles, Jacobs-Wagner, Christine, Letesson, Jean-Jacques, De Bolle, Xavier, UNamur - SBIO_URBM (unité de recherche en biologie moléculaire), Yale University - Department of Molecular, Cellular and Developmental Biology, Yale School of Medicine - Department of Microbial Pathogenesis, Yale University - Howard Hughes Medical Institute, Deghelt, Michaël, Mullier, Caroline, Sternon, Jean-François, Francis, Nayla, Laloux, Géraldine, Dotreppe, Delphine, Van der Henst, Charles, Jacobs-Wagner, Christine, Letesson, Jean-Jacques, and De Bolle, Xavier
Abstract: Several intracellular pathogens, such as Brucella abortus, display a biphasic infection process starting with a non-proliferative stage of unclear nature. Here, we study the cell cycle of B. abortus at the single-cell level, in culture and during infection of HeLa cells and macrophages. The localization of segregation and replication loci of the two bacterial chromosomes indicates that, immediately after being engulfed by host-cell endocytic vacuoles, most bacterial cells are newborn. These bacterial cells do not initiate DNA replication for the next 4 to 6h, indicating a G1 arrest. Moreover, growth is completely stopped during that time, reflecting a global cell cycle block. Growth and DNA replication resume later, although bacteria still reside within endosomal-like compartments. We hypothesize that the predominance of G1-arrested bacteria in the infectious population, and the bacterial cell cycle arrest following internalization, may constitute a widespread strategy among intracellular pathogens to colonize new proliferation niches.
Published: 2014

9. Spatiotemporal control of PopZ localization through cell cycle-coupled multimerization

Author: Yale University - Department of Molecular, Cellular and Developmental Biology, Yale University - Howard Hughes Medical Institute, Yale School of Medicine - Department of Microbial Pathogenesis, Laloux, Géraldine, Jacobs-Wagner, Christine, Yale University - Department of Molecular, Cellular and Developmental Biology, Yale University - Howard Hughes Medical Institute, Yale School of Medicine - Department of Microbial Pathogenesis, Laloux, Géraldine, and Jacobs-Wagner, Christine
Abstract: Bacterial cell poles constitute defined subcellular domains where numerous proteins localize, often at specific times, to affect various physiological processes. How pole recognition occurs and what governs the timing of protein localization are often unknown. In this paper, we investigate the mechanisms governing the localization of PopZ, a chromosome-anchoring protein whose unipolar to bipolar localization pattern is critical for cell cycle progression in Caulobacter crescentus. We provide evidence that polar localization of PopZ relied on its self-assembly into a higher-order structure (matrix) and that the unipolar to bipolar transition was coupled to the asymmetric distribution of ParA during the translocation of the origin-proximal ParB–parS partition complex. Collectively, our data suggest a model in which a local increase of ParA concentration promotes the assembly of a PopZ matrix precisely when and where this matrix is needed. Such coupling of protein assembly with a cell cycle–associated molecular asymmetry may represent a principle of cellular organization for controlling protein localization in both time and space.
Published: 2013

10. Excess weight and life expectancy after acute myocardial infarction: The obesity paradox reexamined.

Author: Bucholz, Emily M., Beckman, Adam L., Krumholz, Hannah A., Krumholz, Harlan M., and Dr. Bucholz was affiliated with the Yale School of Medicine and Yale School of Public Health during the time that the work was conducted
Abstract: Background: An "obesity paradox" has been described in patients with acute myocardial infarction (AMI), whereby obese and overweight patients have a lower risk of short-term mortality after AMI than normal-weight patients. However, the long-term association of obesity with mortality after AMI remains unknown.Methods: We used data from the Cooperative Cardiovascular Project, a prospective medical record study of Medicare beneficiaries hospitalized with AMI with 17 years of follow-up (N = 124,981), to evaluate the association of higher body mass index (BMI) with short- and long-term survival after AMI. Cox proportional hazards models were used to estimate life expectancy after AMI and the years of potential life lost or gained attributable to excess weight.Results: Approximately 41.5% of patients were classified as normal weight; 38.7%, as overweight; 14.3%, as obese; and 5.5%, as morbidly obese. Normal-weight patients had the highest crude mortality at all follow-up time points, whereas obese patients had the lowest. Adjustment for patient and treatment characteristics reduced this difference, but the survival benefit persisted in overweight and obese patients at all time points. Morbidly obese and normal-weight patients had a comparable risk of death at 17 years. Life expectancy estimates were generally lowest for morbidly obese patients and highest for overweight patients. Differences in life expectancy between BMI groups were most pronounced in younger patients. After adjustment, overweight and obesity were associated with greater life years at all ages; however, morbid obesity was only associated with better survival in patients ≥75 years of age at the time of AMI.Conclusions: Overweight and obesity are associated with improved short- and long-term survival after AMI, which results in moderate gains in life expectancy relative to normal-weight patients. These findings suggest that higher BMI confers a protective advantage over the entire remaining lifespan in older patients with AMI. [ABSTRACT FROM AUTHOR]
Published: 2016
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11. Activation of Transcription Factor PPARgamma In Vivo Protects Against Alloreactive Vascular Remodeling of Human Artery

Author: Kawikova, Ivana, Tai, Yi, Lorber, Marc, Tellides, George, Pober, Jordan, and Bothwell, Alfred
Published: 2007
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12. Noninvasive predictors of clinically significant portal hypertension in NASH cirrhosis: Validation of ANTICIPATE models and development of a lab-based model

Author: Anahita Rabiee, Yanhong Deng, Maria Ciarleglio, Jean L. Chan, Monica Pons, Joan Genesca, Guadalupe Garcia‐Tsao, Institut Català de la Salut, [Rabiee A] Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA. [Deng Y, Ciarleglio M] Department of Biostatistics, School of Public Health, Yale University, New Haven, Connecticut, USA. [Chan JL] Conatus Pharmaceuticals at the time of study conduct, San Diego, California, USA. [Pons M] Unitat Hepàtica, Servei de Medicina Interna, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Genesca J] Unitat Hepàtica, Servei de Medicina Interna, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Centro de Investigacion Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain. [Garcia-Tsao G] Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA. VA-CT Healthcare System, New Haven, Connecticut, USA, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Liver Cirrhosis, Cirrosi hepàtica, Hepatology, enfermedades del sistema digestivo::enfermedades hepáticas::cirrosis hepática [ENFERMEDADES], Digestive System Diseases::Liver Diseases::Liver Cirrhosis [DISEASES], Otros calificadores::/diagnóstico [Otros calificadores], Digestive System Diseases::Liver Diseases::Hypertension, Portal [DISEASES], Portal Pressure, Hipertensió portal - Diagnòstic, enfermedades del sistema digestivo::enfermedades hepáticas::hipertensión portal [ENFERMEDADES], Non-alcoholic Fatty Liver Disease, Hypertension, Portal, Other subheadings::/diagnosis [Other subheadings], Humans, Elasticity Imaging Techniques
Abstract: Noninvasive predictors; Portal hypertension; Cirrhosis Predictores no invasivos; Hipertensión portal; Cirrosis Predictors no invasius; Hipertensió portal; Cirrosi Clinically significant portal hypertension (CSPH), defined as hepatic venous pressure gradient (HVPG) ≥ 10 mm Hg, identifies patients with compensated cirrhosis at a high risk of decompensation. However, HVPG is an invasive and nuanced method. The ANTICIPATE models, which include liver stiffness measurements by transient elastography (TE) and platelet count ± body mass index, are robust noninvasive surrogates of CSPH but required external validation in patients with nonalcoholic steatohepatitis (NASH) cirrhosis. Additionally, TE is not widely available worldwide. The aims of the study were: (1) to externally validate the ANTICIPATE models using baseline data from patients with compensated NASH cirrhosis screened/enrolled in a multicenter international randomized controlled trial; and (2) to develop and externally validate a model using only laboratory values. Regarding aim 1, both ANTICIPATE models showed good calibration and discrimination (area under the curve [AUC] > 0.8) in our cohort (n = 222). Regarding aim 2, a new lab-based model using the Fibrosis-4 index (FIB-4 [age, aspartate aminotransferase, alanine aminotransferase, platelet count]) plus serum albumin was developed. The discrimination in the training cohort (n = 309) was good (AUC of 0.78 [95% confidence interval [CI]:0.72–0.83]). It was then externally validated in a separate cohort of 245 patients with compensated NASH cirrhosis (AUC of 0.8 [95% CI: 0.75–0.86]). Given the difference in the prevalence of CSPH between training (74%) and validation (39%) cohorts, the model required an update of the baseline risk to achieve a good calibration. The updated model was named FIB4+. In conclusion, both ANTICIPATE models performed well in predicting the presence of CSPH in NASH cirrhosis. A model using FIB-4 plus albumin (FIB4+) can be used to predict CSPH where TE is not available. Supported by the Yale Liver Center, National Institutes of Health (P30 DK34989).
Published: 2022

13. Multimodal co-therapy for unaccompanied minors: a qualitative study

Author: Guessoum, Sélim Benjamin, Minassian, Sevan, de Staël, Pauline, Touhami, Fatima, Digiovanni, Madeline, Radjack, Rahmeth, Moro, Marie Rose, Benoit, Laelia, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Psychologie Clinique, Psychopathologie, Psychanalyse (PCPP (URP_4056)), Université Paris Cité (UPCité), Yale School of Medicine [New Haven, Connecticut] (YSM), Child Study Center, Yale School of Medicine, Companhia Energética de São Paulo, CESP, Supported by QUALab , the Qualitative & Mixed Methods Lab, a collaboration between the Yale Child Study Center (New Haven, CT), and CESP, the Centre de recherche en Epidémiologie et Santé des Populations (Paris, France)., and HAL UVSQ, Équipe
Subjects: Psychotherapy, [SDV] Life Sciences [q-bio], Psychiatry and Mental health, Transcultural psychiatry, [SDV]Life Sciences [q-bio], Pediatrics, Perinatology and Child Health, Narrativity, Trauma, Unaccompanied refugee minors, Migration
Abstract: Background Unaccompanied refugee minors—or unaccompanied minors—are children and adolescents who have been separated from parents and other relatives and are not being cared for by an adult. Unaccompanied minors are a vulnerable population, with numerous stressors and complex psychiatric symptoms necessitating specialized mental health care. This study explores patients’ experiences of a Multimodal Co-Therapy for Unaccompanied Minors (MUCTUM), which encompasses cultural, biological, narrative & institutional approaches to care. Methods MUCTUM is a co-therapy program for unaccompanied minors, with a psychiatrist, psychologist, native-language interpreter, and caseworker for each patient. In this qualitative study, we interviewed adolescents about their experiences with MUCTUM and analyzed these semi-structured interviews using a phenomenological framework (Interpretative Phenomenological Analysis). Results Qualitative analysis of 16 interviews discovered that unaccompanied minors felt misunderstood before participating in MUCTUM, describing a sense of strangeness and loneliness in relation to psychiatric symptoms. Several youths experienced triple stigmatization: of being unaccompanied minors, of suffering from psychotrauma, and of being mental health patients. We further describe three overarching domains that inform on MUCTUM support to unaccompanied minors: (1) A safe space for unaccompanied minors; (2) Helpful interventions during therapy; and (3) Narrating one’s story can “set us free” if guided carefully by care providers. Conclusion This study suggests that MUCTUM therapy may efficiently support unaccompanied minors’ mental health by acknowledging their hierarchy of needs. Psychotherapeutic strategies include creating a safe place, providing culturally appropriate care and patient-centered therapy, addressing concrete problems, supporting relationships, and making use of limited reparenting in therapy. Delayed and progressive inquiry about traumatic events may be beneficial. Replication of these findings and their field application is warranted.
Published: 2022

14. FisB relies on homo-oligomerization and lipid binding to catalyze membrane fission in bacteria

Author: Hughson, Frederick M., Landajuela, Ane, Braun, Martha, Rodrigues, Christopher D.A., Martínez-Calvo, Alejandro, Doan, Thierry, Horenkamp, Florian, Andronicos, Anna, Shteyn, Vladimir, Williams, Nathan D., Lin, Chenxiang, Wingreen, Ned S., Rudner, David Z., Karatekin, Erdem, Yale University [New Haven], University of Technology Sydney (UTS), Universidad Carlos III de Madrid [Madrid] (UC3M), Laboratoire d'ingénierie des systèmes macromoléculaires (LISM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), University of California, Department of Cell Biology [New Haven], Yale University School of Medicine-Howard Hughes Medical Institute (HHMI), Princeton University, Harvard Medical School [Boston] (HMS), Yale University School of Medicine, Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of California (UC), Yale School of Medicine [New Haven, Connecticut] (YSM)-Howard Hughes Medical Institute (HHMI), Yale School of Medicine [New Haven, Connecticut] (YSM), and Doan, Thierry
Subjects: Models, Molecular, Fission, Clostridium perfringens, Physiology, Cell Membranes, Bacillus, Pathology and Laboratory Medicine, Biochemistry, Cell membrane, Membrane fission, Microbial Physiology, Medicine and Health Sciences, QD, Bacterial Physiology, Cell Cycle and Cell Division, Biology (General), 06 Biological Sciences, 07 Agricultural and Veterinary Sciences, 11 Medical and Health Sciences, 0303 health sciences, Bacterial Sporulation, General Neuroscience, 030302 biochemistry & molecular biology, Lipids, Bacterial Pathogens, Electrophysiology, Bacillus Subtilis, Membrane, medicine.anatomical_structure, Experimental Organism Systems, Membrane curvature, Medical Microbiology, Cell Processes, Membrane topology, Nucleation, Prokaryotic Models, Cellular Structures and Organelles, Pathogens, General Agricultural and Biological Sciences, Protein Binding, Research Article, QH301-705.5, Green Fluorescent Proteins, Biophysics, Membrane fusion, Biology, Research and Analysis Methods, Microbiology, Membrane Potential, General Biochemistry, Genetics and Molecular Biology, Catalysis, 03 medical and health sciences, Membrane Lipids, Bacterial Proteins, Protein Domains, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Escherichia coli, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Vesicles, Microbial Pathogens, 030304 developmental biology, General Immunology and Microbiology, Bacteria, Lipid microdomain, Cell Membrane, Organisms, Membrane Proteins, Correction, Biology and Life Sciences, Bacteriology, Cell Biology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, QP, Liposomes, Animal Studies, Mutant Proteins, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Protein Multimerization, Membrane Characteristics, Cytokinesis, Developmental Biology
Abstract: Little is known about mechanisms of membrane fission in bacteria despite their requirement for cytokinesis. The only known dedicated membrane fission machinery in bacteria, fission protein B (FisB), is expressed during sporulation in Bacillus subtilis and is required to release the developing spore into the mother cell cytoplasm. Here, we characterized the requirements for FisB-mediated membrane fission. FisB forms mobile clusters of approximately 12 molecules that give way to an immobile cluster at the engulfment pole containing approximately 40 proteins at the time of membrane fission. Analysis of FisB mutants revealed that binding to acidic lipids and homo-oligomerization are both critical for targeting FisB to the engulfment pole and membrane fission. Experiments using artificial membranes and filamentous cells suggest that FisB does not have an intrinsic ability to sense or induce membrane curvature but can bridge membranes. Finally, modeling suggests that homo-oligomerization and trans-interactions with membranes are sufficient to explain FisB accumulation at the membrane neck that connects the engulfment membrane to the rest of the mother cell membrane during late stages of engulfment. Together, our results show that FisB is a robust and unusual membrane fission protein that relies on homo-oligomerization, lipid binding, and the unique membrane topology generated during engulfment for localization and membrane scission, but surprisingly, not on lipid microdomains, negative-curvature lipids, or curvature sensing., Little is known about how membrane fission occurs in bacteria; this study suggests that the membrane fission protein FisB exploits the unique cellular geometry encountered during sporulation to enable its localization to the fission site through a novel mechanism, where it catalyzes membrane scission.
Published: 2021

15. Optimization of Advanced Live-Cell Imaging through Red/Near-Infrared Dye Labeling and Fluorescence Lifetime-Based Strategies

Author: Komuro, Yutaro, Galas, Ludovic, Morozov, Yury, Fahrion, Jennifer, Raoult, Emilie, Lebon, Alexis, Tilot, Amanda, Kikuchi, Shin, Ohno, Nobuhiko, Vaudry, David, Rakic, Pasko, Komuro, Hitoshi, Plate-Forme de Recherche en Imagerie Cellulaire de Haute-Normandie (PRIMACEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-High-tech Research Infrastructures for Life Sciences (HeRacLeS), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Pathologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Lerner Research Institute [Cleveland, OH, USA], Cleveland Clinic, Lebon, Alexis, Department of Neurosciences [Lerner Research Institute, Cleveland Clinic], Cleveland Clinic-Cleveland Clinic, Department of Neuroscience, Yale University School of Medicine, Yale School of Medicine [New Haven, Connecticut] (YSM), Department of Genomic Medicine [Lerner Research Institute, Cleveland Clinic], Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Aichi 444-8787, Japan, National Institute for Physiological Sciences, School of Medicine [Jichi Medical University, Japan], Jichi Medical University [Tochigi-Ken, Japan], Différenciation et communication neuronale et neuroendocrine (DC2N), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Kavli Institute for Neuroscience, Yale School of Medicine, and Yale School of Medicine [New Haven, Connecticut] (YSM)-Yale School of Medicine [New Haven, Connecticut] (YSM)
Subjects: MESH: Photons, [SDV]Life Sciences [q-bio], MESH: Microscopy, Fluorescence, live-cell imaging, law.invention, law, Microscopy, Image Processing, Computer-Assisted, MESH: Microscopy, Confocal, Stimulated emission, Biology (General), MESH: Fluorescein, Spectroscopy, Microscopy, Confocal, STED microscopy, Equipment Design, General Medicine, MESH: Fluorescent Dyes, MESH: Image Processing, Computer-Assisted, Fluorescence, Computer Science Applications, Numerical aperture, STED, [SDV] Life Sciences [q-bio], Chemistry, confocal, Optoelectronics, Fluorescein, MESH: Infrared Rays, FLIM, Photomultiplier, MESH: Cell Line, Tumor, Materials science, QH301-705.5, Infrared Rays, τ separation, MESH: Rhodamines, Article, Catalysis, Inorganic Chemistry, Confocal microscopy, Cell Line, Tumor, fluorescence lifetime, Humans, Physical and Theoretical Chemistry, QD1-999, Molecular Biology, Fluorescent Dyes, Photons, MESH: Humans, Rhodamines, business.industry, MESH: Fluorescence, Organic Chemistry, FLIM-STED, Photon counting, Microscopy, Fluorescence, business, sample preservation, MESH: Equipment Design
Abstract: Fluorescence microscopy is essential for a detailed understanding of cellular processes, however, live-cell preservation during imaging is a matter of debate. In this study, we proposed a guide to optimize advanced light microscopy approaches by reducing light exposure through fluorescence lifetime (τ) exploitation of red/near-infrared dyes. Firstly, we characterized key instrumental elements which revealed that red/near-infrared laser lines with an 86x (Numerical Aperture (NA) = 1.2, water immersion) objective allowed high transmission of fluorescence signals, low irradiance and super-resolution. As a combination of two technologies, i.e., vacuum tubes (e.g., photomultiplier) and semiconductor microelectronics (e.g., avalanche photodiode), type S, X and R of hybrid detectors (HyD-S, HyD-X and HyD-R) were particularly adapted for red/near-infrared photon counting and τ separation. Secondly, we tested and compared lifetime-based imaging including coarse τ separation for confocal microscopy, fitting and phasor plot analysis for fluorescence lifetime microscopy (FLIM), and lifetimes weighting for enhanced stimulated emission depletion (STED) nanoscopy, in light of red/near-infrared multiplexing. Mainly, we showed that the choice of appropriate imaging approach may depend on fluorochrome number, together with their spectral/lifetime characteristics and STED compatibility. Photon-counting mode and sensitivity of HyDs together with phasor plot analysis of fluorescence lifetimes enabled the flexible and fast imaging of multi-labeled living H28 cells. Therefore, a combination of red/near-infrared dyes labeling with lifetime-based strategies offers new perspectives for live-cell imaging by enhancing sample preservation through acquisition time and light exposure reduction.
Published: 2021

16. Structural intermediates in the fusion‐associated transition of vesiculovirus glycoprotein

Author: Aurélie A. Albertini, John K. Rose, Jean Lepault, Stéphane Bressanelli, Linda Buonocore, Elisabetta Boeri-Erba, Hélène Raux, Yves Gaudin, Malika Ouldali, Eduard Baquero, Abbas Abou-Hamdan, Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Institut de biologie structurale ( IBS - UMR 5075 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Yale University School of Medicine, Yale School of Medicine, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Rhabdovirus (RHABDO), Département Virologie (Dpt Viro), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Virologie structurale corrélative par cryo-microscopie électronique et radiocristallographie (VIROEM), Yale School of Medicine [New Haven, Connecticut] (YSM), Interactions et mécanismes d’assemblage des protéines et des peptides (IMAPP), Département Biochimie, Biophysique et Biologie Structurale (B3S), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Models, Molecular, glycoprotein, 0301 basic medicine, Conformational change, Protein Conformation, Viral protein, Dimer, membrane fusion, intermediate structures, Biology, Crystallography, X-Ray, medicine.disease_cause, Antiparallel (biochemistry), Models, Biological, Mass Spectrometry, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, chemistry.chemical_compound, conformational change, Protein structure, Viral Envelope Proteins, medicine, Tomography, Molecular Biology, Glycoproteins, Fusion, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], 030102 biochemistry & molecular biology, General Immunology and Microbiology, General Neuroscience, Lipid bilayer fusion, Articles, Hydrogen-Ion Concentration, Virus Internalization, vesiculovirus, Fusion protein, Microscopy, Electron, 030104 developmental biology, Biochemistry, chemistry, Biophysics, Protein Multimerization, [ SDV.BBM.BS ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM]
Abstract: International audience; Vesiculoviruses enter cells by membrane fusion, driven by a large, low-pH-induced, conformational change in the fusion glycoprotein G that involves transition from a trimeric pre-fusion toward a trimeric post-fusion state via monomeric intermediates. Here, we present the structure of the G fusion protein at intermediate pH for two vesiculoviruses, vesicular stomatitis virus (VSV) and Chandipura virus (CHAV), which is responsible for deadly encephalopathies. First, a CHAV G crystal structure shows two intermediate conformations forming a flat dimer of heterodimers. On virions, electron microscopy (EM) and tomography reveal monomeric spikes similar to one of the crystal conformations. In solution, mass spectrometry shows dimers of G. Finally, mutations at a dimer interface, involving fusion domains associated in an antiparallel manner to form an intermolecular β-sheet, affect G fusion properties. The location of the compensatory mutations restoring fusion activity strongly suggests that this interface is functionally relevant. This work reveals the range of G structural changes and suggests that G monomers can re-associate, through antiparallel interactions between fusion domains, into dimers that play a role at some early stage of the fusion process.
Published: 2017

17. FT-GPI, a highly sensitive and accurate predictor of GPI-anchored proteins, reveals the composition and evolution of the GPI proteome in Plasmodium species

Author: Lena M. Sauer, Rodrigo Canovas, Daniel Roche, Hosam Shams-Eldin, Patrice Ravel, Jacques Colinge, Ralph T. Schwarz, Choukri Ben Mamoun, Eric Rivals, Emmanuel Cornillot, Institut de Biologie Computationnelle (IBC), Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université de Montpellier (UM), Institute for Virology [Marburg], Philipps Universität Marburg = Philipps University of Marburg, Méthodes et Algorithmes pour la Bioinformatique (MAB), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Yale School of Medicine [New Haven, Connecticut] (YSM)
Subjects: GPI-proteome, GPI-anchored protein, Infectious Diseases, FT-GPI, [SDV]Life Sciences [q-bio], Plasmodium falciparum, P. vivax, Parasitology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
Abstract: Background Protozoan parasites are known to attach specific and diverse group of proteins to their plasma membrane via a GPI anchor. In malaria parasites, GPI-anchored proteins (GPI-APs) have been shown to play an important role in host–pathogen interactions and a key function in host cell invasion and immune evasion. Because of their immunogenic properties, some of these proteins have been considered as malaria vaccine candidates. However, identification of all possible GPI-APs encoded by these parasites remains challenging due to their sequence diversity and limitations of the tools used for their characterization. Methods The FT-GPI software was developed to detect GPI-APs based on the presence of a hydrophobic helix at both ends of the premature peptide. FT-GPI was implemented in C ++and applied to study the GPI-proteome of 46 isolates of the order Haemosporida. Using the GPI proteome of Plasmodium falciparum strain 3D7 and Plasmodium vivax strain Sal-1, a heuristic method was defined to select the most sensitive and specific FT-GPI software parameters. Results FT-GPI enabled revision of the GPI-proteome of P. falciparum and P. vivax, including the identification of novel GPI-APs. Orthology- and synteny-based analyses showed that 19 of the 37 GPI-APs found in the order Haemosporida are conserved among Plasmodium species. Our analyses suggest that gene duplication and deletion events may have contributed significantly to the evolution of the GPI proteome, and its composition correlates with speciation. Conclusion FT-GPI-based prediction is a useful tool for mining GPI-APs and gaining further insights into their evolution and sequence diversity. This resource may also help identify new protein candidates for the development of vaccines for malaria and other parasitic diseases.
Published: 2023

18. High-Throughput Monitoring of Single Vesicle Fusion Using Freestanding Membranes and Automated Analysis

Author: Jeff Coleman, Weiming Xu, Feng Li, Frederic Pincet, Sathish Ramakrishnan, James E. Rothman, Andrea Gohlke, Laboratoire de Physique Statistique de l'ENS (LPS), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Yale School of Medicine [New Haven, Connecticut] (YSM), Yale University [New Haven], Parallélisme de Kahn Synchrone ( Parkas), Département d'informatique - ENS Paris (DI-ENS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria), Department of Cell Biology [New Haven], Yale School of Medicine [New Haven, Connecticut] (YSM)-Howard Hughes Medical Institute (HHMI), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Yale University School of Medicine, Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Département d'informatique - ENS Paris (DI-ENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Yale University School of Medicine-Howard Hughes Medical Institute (HHMI), École normale supérieure - Paris (ENS Paris), Département d'informatique de l'École normale supérieure (DI-ENS), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)
Subjects: 0301 basic medicine, lipid mixing, Vesicle fusion, Materials science, Vesicle docking, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Lipid Bilayers, 010402 general chemistry, Membrane Fusion, 01 natural sciences, 03 medical and health sciences, Content release, Electrochemistry, General Materials Science, Lipid bilayer, Spectroscopy, Fusion, Bilayer, Vesicle, Lipid bilayer fusion, Surfaces and Interfaces, Silicon Dioxide, Condensed Matter Physics, 0104 chemical sciences, Kinetics, 030104 developmental biology, Membrane, SNARE, Biophysics, SNARE Proteins, holey silicon substrate, protein mobility
Abstract: International audience; In vivo membrane fusion primarily occurs between highly curved vesicles and planar membranes. A better understanding of fusion entails an accurate in vitro reproduction of the process. To date, supported bilayers have been commonly used to mimic the planar membranes. Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins that induce membrane fusion usually have limited fluidity when embedded in supported bilayers. This alters the kinetics and prevents correct reconstitution of the overall fusion process. Also, observing content release across the membrane is hindered by the lack of a second aqueous compartment. Recently, a step toward resolving these issues was achieved by using membranes spread on holey substrates. The mobility of proteins was preserved but vesicles were prone to bind to the substrate when reaching the edge of the hole, preventing the observation of many fusion events over the suspended membrane. Building on this recent advance, we designed a method for the formation of pore-spanning lipid bilayers containing t-SNARE proteins on Si/SiO2 holey chips, allowing the observation of many individual vesicle fusion events by both lipid mixing and content release. With this setup, proteins embedded in the suspended membrane bounced back when they reached the edge of the hole which ensured vesicles did not bind to the substrate. We observed SNARE-dependent membrane fusion with the freestanding bilayer of about 500 vesicles. The time between vesicle docking and fusion is ∼1 s. We also present a new multimodal open-source software, Fusion Analyzer Software, which is required for fast data analysis.
Published: 2018
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19. Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013

Author: Meghan D. Mooney, Ken Takahashi, Andrea Stewart, Jonathan C Brown, Shireen Sindi, Amany H Refaat, Ruben Castro, Sara Sheikhbahaei, Kyle R. Heuton, Gillian M. Hansen, Chante Karimkhani, Bryan K. Phillips, Ibrahim Abubakar, Yohannes Kinfu, Victoria F Bachman, Konstantinos Stroumpoulis, Megan Coggeshall, Lucía Cuevas-Nasu, Yichong Li, Vineet K. Chadha, Andrew G. M. Bulloch, Takayoshi Ohkubo, Don C. Des Jarlais, Giancarlo Logroscino, Francis Apolinary Mhimbira, Jefferson G Fernandes, Cheng Huang, Ejaz Ahmad Khan, Fortuné Gbètoho Gankpé, Roderick J Hay, Itamar S. Santos, Zanfina Ademi, Fiona J Charlson, Norlinah Mohamed Ibrahim, Anwar Rafay, Andrew L. Thorne-Lyman, Juanita A. Haagsma, Emmanuel A. Ameh, John J. McGrath, Massimo Cirillo, Wubegzier Mekonnen, Holly Hagan, Naohiro Yonemoto, Frida Namnyak Ngalesoni, Dietrich Plass, Matias Trillini, David Phillips, Braden Te Ao, Wanqing Chen, Yun Jin Kim, David Rojas-Rueda, Christina Papachristou, Andrew E. Moran, Richard A. Gosselin, Maziar Moradi-Lakeh, Soraya Seedat, Janet L Leasher, Belinda K Lloyd, Lorenzo Monasta, Bruno F. Sunguya, Eun-Kee Park, Eduardo A. Undurraga, Mohammad A. AlMazroa, Mohammad H. Forouzanfar, Young-Ho Khang, Vasiliki Stathopoulou, Dima M. Qato, James Scott, Ileana Heredia-Pi, Luca Ronfani, Haidong Kan, Tasara T. Mazorodze, Murugesan Raju, Saeid Shahraz, Taavi Tillmann, Wang Wenzhi, Neil Pearce, Eric Y. Tenkorang, Aliya Naheed, Ferrán Catalá-López, Sudan Prasad Neupane, Emily Dansereau, Michael McKee, Derrick A Bennett, Mazeda Hossain, Paul S. F. Yip, Grant Nguyen, Norberto Perico, Miguel Angel Alegretti, Babak Eshrati, Boris Bikbov, Palwasha Anwari, Guoqing Hu, Amelia Bertozzi-Villa, Peter A. Meaney, Farshad Farzadfar, Svetlana Popova, Tara Templin, Hmwe H Kyu, Uche S. Uchendu, Kebede Deribe, Sergey Soshnikov, Nobhojit Roy, Daniel Kim, Ilana N. Ackerman, Homie Razavi, Leslie T. Cooper, Sandra Nolte, David T. Felson, John J Huang, Yang Liu, Fiorella Cavalleri, Adrian Davis, Héctor Gómez Dantés, Klara Dokova, Yuantao Hao, Catalina Medina, Austin E Schumacher, Stan Biryukov, Jane Rowley, Arindam Basu, Jose C. Adsuar, Rosana E. Norman, Yousef Khader, Rafael Alfonso-Cristancho, Sukanta Saha, Simón Barquera, Diego Gonzalez-Medina, Philip B. Mitchell, Lars Barregard, Haidong Wang, Yongmei Li, Ami R. Moore, Marie Ng, Raghib Ali, Peter T. Serina, Lijing L Yan, Ayse Abbasoglu Ozgoren, Ricky Leung, Michelle L. Bell, Tim Driscoll, Azmeraw T. Amare, Farshad Pourmalek, Tea Lallukka, Benjamin O Anderson, Raimundas Lunevicius, Corine Karema, Robert G. Weintraub, Erin C Mullany, Anders Larsson, Glen Mola, Paulo A. Lotufo, Luke Nyakarahuka, Sayed Saidul Alam, Louisa Degenhardt, Hugh R. Taylor, E. Ray Dorsey, Suzanne Polinder, Hilton Lam, Urbano Fra Paleo, David Zonies, Rahman Shiri, Marco A Avila, Alicia Elena Beatriz Lawrynowicz, Katya Anne Shackelford, Lynne Gaffikin, Konstantin Kazanjan, Mark T Mackay, Jasvinder A. Singh, Bryan L. Sykes, Sadaf G. Sepanlou, Chantal Huynh, Rakhi Dandona, Logan Sandar, Lavanya Singh, Dietrich Rothenbacher, Theo Vos, Steven E. Lipshultz, Coen H. Van Gool, Peggy P. Chiang, Mark G. Shrime, Christopher J L Murray, Scott Weichenthal, Jae-Hyun Park, Samia Alhabib, Philimon Gona, Christian Kieling, Yuichiro Yano, Ronny Westerman, Thomas Truelsen, Rajeev Gupta, Megan Bohensky, Abdullatif Husseini, Qing Lan, Luke D. Knibbs, Yousef M. Elshrek, H. Ross Anderson, Guohong Jiang, Madeline L. Moyer, Vinod K. Paul, Wim H. van Brakel, Emin Murat Tuzcu, Kara Estep, Lalit Dandona, Uchechukwu K.A. Sampson, Mohammad Tavakkoli, Ying Jiang, Joseph A Wagner, Mitsuru Mukaigawara, In-Hwan Oh, Siyi Shangguan, Noela M. Prasad, Charles D.A. Wolfe, Borja del Pozo-Cruz, Gokalp Kadri Yentur, Hilda L Harb, Elena Alvarez, Carlos A Castañeda-Orjuela, Mustafa Z. Younis, Herbert C. Duber, Erica Leigh Slepak, George A. Mensah, Knud Juel, Graeme J. Hankey, Natan M. Bornstein, Martha Híjar, Johan Ärnlöv, Mohamed Hsairi, Katherine T. Lofgren, Murray B. Stein, Renata Micha, Luigi Naldi, Margreet ten Have, Bolajoko O. Olusanya, Kyle J Foreman, Kenji Shibuya, F. Gerry R. Fowkes, Abdullah Sulieman Terkawi, Rana J. Asghar, Karen M. Tabb, Kovin Naidoo, Rogelio Pérez-Padilla, Honglei Chen, Antônio Luiz Pinho Ribeiro, Rasmus Havmoeller, Yukito Shinohara, Bongani M. Mayosi, Ernst J Kuipers, Konrad Pesudovs, Mouhanad Hammami, Lee Richardson, Rintaro Mori, Thomas D. Fleming, Pouria Heydarpour, Stephen G. Waller, Nicholas Graetz, Chanda Kulkarni, Peter Brooks, Gulfaraz Khan, Marcel Tanner, Van C. Lansingh, François Alla, Jamie Hancock, Yohannes Adama Melaku, Neeraj Bedi, Anthony D. Woolf, Tariku Jibat Beyene, Amanda W Pain, Eric L. Ding, Narayanaswamy Venketasubramanian, Semaw Ferede Abera, Devina Nand, Odgerel Chimed-Ochir, George D Thurston, Victor Aboyans, Alanur Çavlin, Jefferson Traebert, Michael R. Phillips, Yingfeng Zheng, Baffour Awuah, Carlo Irwin A. Panelo, Selen Begüm Uzun, Muhammad Imran Nisar, Samir Soneji, Veena S. Kulkarni, Mukesh Dherani, Stephen S Lim, Andre Keren, Kingsley N. Ukwaja, Sajjad Ur Rahman, Giuseppe Remuzzi, Kjetil Søreide, Blake Thomson, Samath D Dharmaratne, Christopher D. Blosser, David H. Rothstein, Amanda G. Thrift, Fabrizio Tediosi, Andrew H. Kemp, H. Dean Hosgood, Yoshihiro Kokubo, Miia Kivipelto, Amitava Banerjee, Edgar P. Simard, Reza Malekzadeh, Maggie Lind, Robert P. Dellavalle, Emerito Jose A. Faraon, Lydia S. Atkins, Tom Achoki, Aslam Pervaiz, Peter Scarborough, Hans W. Hoek, Ettore Beghi, Emilie Agardh, Abraham D. Flaxman, Dariush Mozaffarian, Juan R. Sanabria, Muluken Dessalegn, David C. Schwebel, Caitlyn Steiner, Ubai Alsharif, Richard C. Franklin, Gail Davey, Gelin Xu, Reyna A Gutiérrez, Joannie Lortet-Tieulent, Ashish Bhalla, Jost B. Jonas, Paul N. Jensen, Simon I. Hay, Xiaonong Zou, Andre Pascal Kengne, Tolesa Bekele, Brittany Wurtz, Jung-Chen Chang, Joseph Murray, Luciano A. Sposato, Stefan Ma, Summer Lockett Ohno, Charles R. Newton, Bradford D. Gessner, JianLi Wang, Scott B. Patten, Thomas Fürst, Carol Brayne, Christina Fitzmaurice, Peilin Shi, Ted R. Miller, Kinnari S. Murthy, Habib Benzian, Peter W. Gething, Cesar Diaz-Torne, Burcu Kucuk Bicer, Bo Norrving, Carly E Levitz, Adam D M Briggs, Sungroul Kim, Isabela M. Benseñor, John A. Crump, Sergey Petrovich Ermakov, Kalpana Balakrishnan, Awoke Misganaw Temesgen, Marcella Montico, Sanjay Krishnaswami, Kim Moesgaard Iburg, Ann Kristin Knudsen, Sun Ha Jee, Valery L. Feigin, Christine M. Budke, Anne Bulchis, Anand Dayama, Jonathan R. Carapetis, Cyrus Cooper, Teresa Shamah Levy, Ismael R. Campos-Nonato, Nataliya A. Foigt, Beth E. Ebel, Max Petzold, Heresh Amini, Ole Frithjof Norheim, Zulfiqar A Bhutta, Dan Poenaru, Jim van Os, Michele E. Murdoch, Samantha M. Colquhoun, Michael H. Criqui, Giorgia Giussani, Man Mohan Mehndiratta, Thomas N. Williams, Chandrashekhar T Sreeramareddy, Chuanhua Yu, Luis M. Coppola, Thomas J. Montine, Alaa Badawi, Eduardo Bernabé, Melvin Barrientos Marzan, James Leigh, Frédéric B. Piel, Ratilal Lalloo, Panniyammakal Jeemon, Maheswar Satpathy, Hélène Carabin, Corina Benjet, Seyed-Mohammad Fereshtehnejad, Ryan M Barber, Fotis Topouzis, Bin Li, Serge Resnikoff, Taavi Lai, Rachelle Buchbinder, Randah R. Hamadeh, Valeria Caso, Holly E. Erskine, Dragos Virgil Davitoiu, Miltiadis K. Tsilimbaris, Rachel L. Pullan, Ben Schöttker, Rafael Lozano, Damian G Hoy, Fiona M. Blyth, Belinda J. Gabbe, Hebe N. Gouda, Farhad Islami, Atte Meretoja, Christopher Margono, Marissa Iannarone, Ronan A Lyons, Wilkister N. Moturi, Donald H. Silberberg, Alexandra Brazinova, Monica Cortinovis, Deena Alasfoor, Richard Matzopoulos, Jerry Abraham, Francesco Saverio Violante, Monika Sawhney, Dorairaj Prabhakaran, Valentina Colistro, Derek F J Fay, Mamta Swaroop, Nima Hafezi-Nejad, John Nelson Opio, Hanne Christensen, Jun She, Soewarta Kosen, Atsushi Goto, Costas A. Christophi, Jeyaraj D. Pandian, Peter J. Hotez, K. Srinath Reddy, Al Artaman, Peter Allebeck, Jonas Minet Kinge, Graham S Cooke, Dan J. Stein, Kawkab Shishani, Laith J. Abu-Raddad, Katrina F Ortblad, Deborah Jarvis, Arsène Kouablan Adou, Barthelemy Kuate Defo, Alan D. Lopez, G Anil Kumar, K.M. Venkat Narayan, Yong Zhao, Rajiv Chowdhury, Hadi Danawi, George C Patton, Vasiliy Victorovich Vlassov, André Karch, Tommi J. Vasankari, Matthias Endres, Ione Jayce Ceola Schneider, Nelson Alvis-Guzman, Charles N Mock, Katharine J Looker, Bach Xuan Tran, Fernando Perez-Ruiz, Harish Chander Gugnani, Reza Assadi, Hannah Hamavid, Rosario Cárdenas, Mohammed I. Albittar, Sarah Derrett, Mohammad Yahya Saeedi, Traolach S. Brugha, Jan Hendrik Richardus, Alireza Esteghamati, Seok Jun Yoon, Josep Maria Haro, Michael Brainin, Ziad A. Memish, Rupert R A Bourne, Katherine B Gibney, David M. Pereira, Kathryn H. Jacobsen, Luc E. Coffeng, Joshua A. Salomon, Xia Wan, Ian Bolliger, Boris I. Pavlin, Karen Sliwa, Tati S. Warouw, Geoffrey Buckle, Chakib Nejjari, Diego De Leo, Ashkan Afshin, Vinay Nangia, Daniel Pope, Johanna M. Geleijnse, Nikhil Tandon, Kelly Bienhoff, Jed D. Blore, Walid Ammar, D. Allen Roberts, Elisabete Weiderpass, Gregory A. Roth, Manami Inoue, James D. Wilkinson, Hideaki Toyoshima, Soufiane Boufous, Ivy Shiue, Edward J Mills, Leilei Duan, Matthew M Coates, Ganesan Karthikeyan, Alberto Ortiz, Steven van de Vijver, David Carpenter, Suzanne Lyn Barker-Collo, Antony Stevens, Sanjay Basu, Maria Cecilia Bahit, Kaire Innos, Lindsay N. Boyers, Nicholas J K Breitborde, Alize J. Ferrari, Timothy M. Wolock, Simerjot K. Jassal, Mohammad Ali Sahraian, Joanna Moschandreas, Howard J. Hoffman, Hideki Higashi, George M. Ruhago, Karzan Abdulmuhsin Mohammad, Mohammed Basulaiman, D. Alex Quistberg, Justin Beardsley, Marcello Tonelli, Maurice Giroud, Karen Edmond, Norito Kawakami, Mohammad T Mashal, Neeraj Bhala, Carl Abelardo T. Antonio, David Tanne, Abhishek Singh, Kazem Rahimi, Vivekanand Jha, Wagner Marcenes, David J. Margolis, Yara A. Halasa, Zewdie Aderaw Alemu, Carrie Beth Peterson, Edson Serván-Mori, Anil Kaul, Foad Abd-Allah, Marek Majdan, Rahul Gupta, Robyn M. Lucas, Sarah Wulf, Lars Jacob Stovner, Mohsen Naghavi, Vegard Skirbekk, Ulrich Otto Mueller, Pengpeng Ye, Ali H. Mokdad, Dipan Bose, Saleem M Rana, Jeffrey D Stanaway, Abigail Mclain, Timothy J. Steiner, Amira Shaheen, Stein Emil Vollset, Andrea Werdecker, Michele Meltzer, Richie G Poulton, Joseph R. Masci, Inga Dora Sigfusdottir, Daniel Dicker, Maysaa El Sayed Zaki, Shiwei Liu, Julio C. Montañez Hernandez, Valentina Arsić Arsenijević, William Msemburi, Lope H Barrero, Linhong Wang, Soumya Swaminathan, Harvey Whiteford, Michael F. Macintyre, Berrak Bora Basara, Gregory R. Wagner, Paul I. Dargan, Hermann Brenner, Carolyn C. Gotay, Niveen M E Abu-Rmeileh, Nicholas J Kassebaum, Shams Eldin Ali Hassan Khalifa, Neil McGill, Murray, Christopher J. L, Barber, Ryan M., Foreman, Kyle J., Ozgoren, Ayse Abbasoglu, Abd-Allah, Foad, Abera, Semaw F., Aboyans, Victor, Abraham, Jerry P., Abubakar, Ibrahim, Abu-Raddad, Laith J., Abu-Rmeileh, Niveen M., Achoki, Tom, Ackerman, Ilana N., Ademi, Zanfina, Adou, Arsène K., Adsuar, José C., Afshin, Ashkan, Agardh, Emilie E., Alam, Sayed Saidul, Alasfoor, Deena, Albittar, Mohammed I., Alegretti, Miguel A., Alemu, Zewdie A., Alfonso-Cristancho, Rafael, Alhabib, Samia, Ali, Raghib, Alla, Françoi, Allebeck, Peter, Almazroa, Mohammad A., Alsharif, Ubai, Alvarez, Elena, Alvis-Guzman, Nelson, Amare, Azmeraw T., Ameh, Emmanuel A., Amini, Heresh, Ammar, Walid, Anderson, H. Ro, Anderson, Benjamin O., Antonio, Carl Abelardo T., Anwari, Palwasha, Arnlöv, Johan, Arsenijevic, Valentina S. Arsic, Artaman, Al, Asghar, Rana J., Assadi, Reza, Atkins, Lydia S., Avila, Marco A., Awuah, Baffour, Bachman, Victoria F., Badawi, Alaa, Bahit, Maria C., Balakrishnan, Kalpana, Banerjee, Amitava, Barker-Collo, Suzanne L., Barquera, Simon, Barregard, Lar, Barrero, Lope H., Basu, Arindam, Basu, Sanjay, Basulaiman, Mohammed O., Beardsley, Justin, Bedi, Neeraj, Beghi, Ettore, Bekele, Tolesa, Bell, Michelle L., Benjet, Corina, Bennett, Derrick A., Bensenor, Isabela M., Benzian, Habib, Bernabé, Eduardo, Bertozzi-Villa, Amelia, Beyene, Tariku J., Bhala, Neeraj, Bhalla, Ashish, Bhutta, Zulfiqar A., Bienhoff, Kelly, Bikbov, Bori, Biryukov, Stan, Blore, Jed D., Blosser, Christopher D., Blyth, Fiona M., Bohensky, Megan A., Bolliger, Ian W., Başara, Berrak Bora, Bornstein, Natan M., Bose, Dipan, Boufous, Soufiane, Bourne, Rupert R. A., Boyers, Lindsay N., Brainin, Michael, Brayne, Carol E., Brazinova, Alexandra, Breitborde, Nicholas J. K., Brenner, Hermann, Briggs, Adam D., Brooks, Peter M., Brown, Jonathan C., Brugha, Traolach S., Buchbinder, Rachelle, Buckle, Geoffrey C., Budke, Christine M., Bulchis, Anne, Bulloch, Andrew G., Campos-Nonato, Ismael R., Carabin, Hélène, Carapetis, Jonathan R., Cárdenas, Rosario, Carpenter, David O., Caso, Valeria, Castañeda-Orjuela, Carlos A., Castro, Ruben E., Catalá-López, Ferrán, Cavalleri, Fiorella, Çavlin, Alanur, Chadha, Vineet K., Chang, Jung-Chen, Charlson, Fiona J., Chen, Honglei, Chen, Wanqing, Chiang, Peggy P., Chimed-Ochir, Odgerel, Chowdhury, Rajiv, Christensen, Hanne, Christophi, Costas A., Cirillo, Massimo, Coates, Matthew M., Coffeng, Luc E., Coggeshall, Megan S., Colistro, Valentina, Colquhoun, Samantha M., Cooke, Graham S., Cooper, Cyru, Cooper, Leslie T., Coppola, Luis M., Cortinovis, Monica, Criqui, Michael H., Crump, John A., Cuevas-Nasu, Lucia, Danawi, Hadi, Dandona, Lalit, Dandona, Rakhi, Dansereau, Emily, Dargan, Paul I., Davey, Gail, Davis, Adrian, Davitoiu, Dragos V., Dayama, Anand, De Leo, Diego, Degenhardt, Louisa, Del Pozo-Cruz, Borja, Dellavalle, Robert P., Deribe, Kebede, Derrett, Sarah, Des Jarlais, Don C., Dessalegn, Muluken, Dharmaratne, Samath D., Dherani, Mukesh K., Diaz-Torné, Cesar, Dicker, Daniel, Ding, Eric L., Dokova, Klara, Dorsey, E Ray, Driscoll, Tim R., Duan, Leilei, Duber, Herbert C., Ebel, Beth E., Edmond, Karen M., Elshrek, Yousef M., Endres, Matthia, Ermakov, Sergey P., Erskine, Holly E., Eshrati, Babak, Esteghamati, Alireza, Estep, Kara, Faraon, Emerito Jose A., Farzadfar, Farshad, Fay, Derek F., Feigin, Valery L., Felson, David T., Fereshtehnejad, Seyed-Mohammad, Fernandes, Jefferson G., Ferrari, Alize J., Fitzmaurice, Christina, Flaxman, Abraham D., Fleming, Thomas D., Foigt, Nataliya, Forouzanfar, Mohammad H., Fowkes, F Gerry R., Paleo, Urbano Fra., Franklin, Richard C., Fürst, Thoma, Gabbe, Belinda, Gaffikin, Lynne, Gankpé, Fortuné G., Geleijnse, Johanna M., Gessner, Bradford D., Gething, Peter, Gibney, Katherine B., Giroud, Maurice, Giussani, Giorgia, Dantes, Hector Gomez, Gona, Philimon, González-Medina, Diego, Gosselin, Richard A., Gotay, Carolyn C., Goto, Atsushi, Gouda, Hebe N., Graetz, Nichola, Gugnani, Harish C., Gupta, Rahul, Gupta, Rajeev, Gutiérrez, Reyna A., Haagsma, Juanita, Hafezi-Nejad, Nima, Hagan, Holly, Halasa, Yara A., Hamadeh, Randah R., Hamavid, Hannah, Hammami, Mouhanad, Hancock, Jamie, Hankey, Graeme J., Hansen, Gillian M., Hao, Yuantao, Harb, Hilda L., Haro, Josep Maria, Havmoeller, Rasmu, Hay, Simon I., Hay, Roderick J., Heredia-Pi, Ileana B., Heuton, Kyle R., Heydarpour, Pouria, Higashi, Hideki, Hijar, Martha, Hoek, Hans W., Hoffman, Howard J., Hosgood, H Dean, Hossain, Mazeda, Hotez, Peter J., Hoy, Damian G., Hsairi, Mohamed, Hu, Guoqing, Huang, Cheng, Huang, John J., Husseini, Abdullatif, Huynh, Chantal, Iannarone, Marissa L., Iburg, Kim M., Innos, Kaire, Inoue, Manami, Islami, Farhad, Jacobsen, Kathryn H., Jarvis, Deborah L., Jassal, Simerjot K., Jee, Sun Ha, Jeemon, Panniyammakal, Jensen, Paul N., Jha, Vivekanand, Jiang, Guohong, Jiang, Ying, Jonas, Jost B., Juel, Knud, Kan, Haidong, Karch, André, Karema, Corine K., Karimkhani, Chante, Karthikeyan, Ganesan, Kassebaum, Nicholas J., Kaul, Anil, Kawakami, Norito, Kazanjan, Konstantin, Kemp, Andrew H., Kengne, Andre P., Keren, Andre, Khader, Yousef S., Khalifa, Shams Eldin A., Khan, Ejaz A., Khan, Gulfaraz, Khang, Young-Ho, Kieling, Christian, Kim, Daniel, Kim, Sungroul, Kim, Yunjin, Kinfu, Yohanne, Kinge, Jonas M., Kivipelto, Miia, Knibbs, Luke D., Knudsen, Ann Kristin, Kokubo, Yoshihiro, Kosen, Soewarta, Krishnaswami, Sanjay, Defo, Barthelemy Kuate, Bicer, Burcu Kucuk, Kuipers, Ernst J., Kulkarni, Chanda, Kulkarni, Veena S., Kumar, G Anil, Kyu, Hmwe H., Lai, Taavi, Lalloo, Ratilal, Lallukka, Tea, Lam, Hilton, Lan, Qing, Lansingh, Van C., Larsson, Ander, Lawrynowicz, Alicia E. B., Leasher, Janet L., Leigh, Jame, Leung, Ricky, Levitz, Carly E., Li, Bin, Li, Yichong, Li, Yongmei, Lim, Stephen S., Lind, Maggie, Lipshultz, Steven E., Liu, Shiwei, Liu, Yang, Lloyd, Belinda K., Lofgren, Katherine T., Logroscino, Giancarlo, Looker, Katharine J., Lortet-Tieulent, Joannie, Lotufo, Paulo A., Lozano, Rafael, Lucas, Robyn M., Lunevicius, Raimunda, Lyons, Ronan A., Ma, Stefan, Macintyre, Michael F., Mackay, Mark T., Majdan, Marek, Malekzadeh, Reza, Marcenes, Wagner, Margolis, David J., Margono, Christopher, Marzan, Melvin B., Masci, Joseph R., Mashal, Mohammad T., Matzopoulos, Richard, Mayosi, Bongani M., Mazorodze, Tasara T., Mcgill, Neil W., Mcgrath, John J., Mckee, Martin, Mclain, Abigail, Meaney, Peter A., Medina, Catalina, Mehndiratta, Man Mohan, Mekonnen, Wubegzier, Melaku, Yohannes A., Meltzer, Michele, Memish, Ziad A., Mensah, George A., Meretoja, Atte, Mhimbira, Francis A., Micha, Renata, Miller, Ted R., Mills, Edward J., Mitchell, Philip B., Mock, Charles N., Ibrahim, Norlinah Mohamed, Mohammad, Karzan A., Mokdad, Ali H., Mola, Glen L. D., Monasta, Lorenzo, Hernandez, Julio C. Montañez, Montico, Marcella, Montine, Thomas J., Mooney, Meghan D., Moore, Ami R., Moradi-Lakeh, Maziar, Moran, Andrew E., Mori, Rintaro, Moschandreas, Joanna, Moturi, Wilkister N., Moyer, Madeline L., Mozaffarian, Dariush, Msemburi, William T., Mueller, Ulrich O., Mukaigawara, Mitsuru, Mullany, Erin C., Murdoch, Michele E., Murray, Joseph, Murthy, Kinnari S., Naghavi, Mohsen, Naheed, Aliya, Naidoo, Kovin S., Naldi, Luigi, Nand, Devina, Nangia, Vinay, Narayan, K M. Venkat, Nejjari, Chakib, Neupane, Sudan P., Newton, Charles R., Ng, Marie, Ngalesoni, Frida N., Nguyen, Grant, Nisar, Muhammad I., Nolte, Sandra, Norheim, Ole F., Norman, Rosana E., Norrving, Bo, Nyakarahuka, Luke, Oh, In-Hwan, Ohkubo, Takayoshi, Ohno, Summer L., Olusanya, Bolajoko O., Opio, John Nelson, Ortblad, Katrina, Ortiz, Alberto, Pain, Amanda W., Pandian, Jeyaraj D., Panelo, Carlo Irwin A., Papachristou, Christina, Park, Eun-Kee, Park, Jae-Hyun, Patten, Scott B., Patton, George C., Paul, Vinod K., Pavlin, Boris I., Pearce, Neil, Pereira, David M., Perez-Padilla, Rogelio, Perez-Ruiz, Fernando, Perico, Norberto, Pervaiz, Aslam, Pesudovs, Konrad, Peterson, Carrie B., Petzold, Max, Phillips, Michael R., Phillips, Bryan K., Phillips, David E., Piel, Frédéric B., Plass, Dietrich, Poenaru, Dan, Polinder, Suzanne, Pope, Daniel, Popova, Svetlana, Poulton, Richie G., Pourmalek, Farshad, Prabhakaran, Dorairaj, Prasad, Noela M., Pullan, Rachel L., Qato, Dima M., Quistberg, D Alex, Rafay, Anwar, Rahimi, Kazem, Rahman, Sajjad U., Raju, Murugesan, Rana, Saleem M., Razavi, Homie, Reddy, K Srinath, Refaat, Amany, Remuzzi, Giuseppe, Resnikoff, Serge, Ribeiro, Antonio L., Richardson, Lee, Richardus, Jan Hendrik, Roberts, D Allen, Rojas-Rueda, David, Ronfani, Luca, Roth, Gregory A., Rothenbacher, Dietrich, Rothstein, David H., Rowley, Jane T., Roy, Nobhojit, Ruhago, George M., Saeedi, Mohammad Y., Saha, Sukanta, Sahraian, Mohammad Ali, Sampson, Uchechukwu K. A., Sanabria, Juan R., Sandar, Logan, Santos, Itamar S., Satpathy, Maheswar, Sawhney, Monika, Scarborough, Peter, Schneider, Ione J., Schöttker, Ben, Schumacher, Austin E., Schwebel, David C., Scott, James G., Seedat, Soraya, Sepanlou, Sadaf G., Serina, Peter T., Servan-Mori, Edson E., Shackelford, Katya A., Shaheen, Amira, Shahraz, Saeid, Levy, Teresa Shamah, Shangguan, Siyi, She, Jun, Sheikhbahaei, Sara, Shi, Peilin, Shibuya, Kenji, Shinohara, Yukito, Shiri, Rahman, Shishani, Kawkab, Shiue, Ivy, Shrime, Mark G., Sigfusdottir, Inga D., Silberberg, Donald H., Simard, Edgar P., Sindi, Shireen, Singh, Abhishek, Singh, Jasvinder A., Singh, Lavanya, Skirbekk, Vegard, Slepak, Erica Leigh, Sliwa, Karen, Soneji, Samir, Søreide, Kjetil, Soshnikov, Sergey, Sposato, Luciano A., Sreeramareddy, Chandrashekhar T., Stanaway, Jeffrey D., Stathopoulou, Vasiliki, Stein, Dan J., Stein, Murray B., Steiner, Caitlyn, Steiner, Timothy J., Stevens, Antony, Stewart, Andrea, Stovner, Lars J., Stroumpoulis, Konstantino, Sunguya, Bruno F., Swaminathan, Soumya, Swaroop, Mamta, Sykes, Bryan L., Tabb, Karen M., Takahashi, Ken, Tandon, Nikhil, Tanne, David, Tanner, Marcel, Tavakkoli, Mohammad, Taylor, Hugh R., Te Ao, Braden J., Tediosi, Fabrizio, Temesgen, Awoke M., Templin, Tara, Ten Have, Margreet, Tenkorang, Eric Y., Terkawi, Abdullah S., Thomson, Blake, Thorne-Lyman, Andrew L., Thrift, Amanda G., Thurston, George D., Tillmann, Taavi, Tonelli, Marcello, Topouzis, Foti, Toyoshima, Hideaki, Traebert, Jefferson, Tran, Bach X., Trillini, Matia, Truelsen, Thoma, Tsilimbaris, Miltiadi, Tuzcu, Emin M., Uchendu, Uche S., Ukwaja, Kingsley N., Undurraga, Eduardo A., Uzun, Selen B., Van Brakel, Wim H., Van De Vijver, Steven, Van Gool, Coen H., Van Os, Jim, Vasankari, Tommi J., Venketasubramanian, N, Violante, Francesco S., Vlassov, Vasiliy V., Vollset, Stein Emil, Wagner, Gregory R., Wagner, Joseph, Waller, Stephen G., Wan, Xia, Wang, Haidong, Wang, Jianli, Wang, Linhong, Warouw, Tati S., Weichenthal, Scott, Weiderpass, Elisabete, Weintraub, Robert G., Wenzhi, Wang, Werdecker, Andrea, Westerman, Ronny, Whiteford, Harvey A., Wilkinson, James D., Williams, Thomas N., Wolfe, Charles D., Wolock, Timothy M., Woolf, Anthony D., Wulf, Sarah, Wurtz, Brittany, Xu, Gelin, Yan, Lijing L., Yano, Yuichiro, Ye, Pengpeng, Yentür, Gökalp K., Yip, Paul, Yonemoto, Naohiro, Yoon, Seok-Jun, Younis, Mustafa Z., Yu, Chuanhua, Zaki, Maysaa E., Zhao, Yong, Zheng, Yingfeng, Zonies, David, Zou, Xiaonong, Salomon, Joshua A., Lopez, Alan D., Vos, Theo, Medische Sociologie, MUMC+: Hersen en Zenuw Centrum (3), MUMC+: MA Psychiatrie (3), Psychiatrie & Neuropsychologie, Barber, Ryan M, Foreman, Kyle J, Abd Allah, Foad, Abera, Semaw F, Abraham, Jerry P, Abu Raddad, Laith J, Abu Rmeileh, Niveen M, Ackerman, Ilana N, Adou, Arsène K, Adsuar, José C, Agardh, Emilie E, Albittar, Mohammed I, Alegretti, Miguel A, Alemu, Zewdie A, Alfonso Cristancho, Rafael, Almazroa, Mohammad A, Alvis Guzman, Nelson, Amare, Azmeraw T, Ameh, Emmanuel A, Anderson, Benjamin O, Antonio, Carl Abelardo T, Asghar, Rana J, Atkins, Lydia S, Avila, Marco A, Bachman, Victoria F, Bahit, Maria C, Barker Collo, Suzanne L, Barrero, Lope H, Basulaiman, Mohammed O, Bell, Michelle L, Bennett, Derrick A, Bensenor, Isabela M, Bertozzi Villa, Amelia, Beyene, Tariku J, Bhutta, Zulfiqar A, Blore, Jed D, Blosser, Christopher D, Blyth, Fiona M, Bohensky, Megan A, Bolliger, Ian W, Bornstein, Natan M, Bourne, Rupert R. A, Boyers, Lindsay N, Brayne, Carol E, Breitborde, Nicholas J. K, Briggs, Adam D, Brooks, Peter M, Brown, Jonathan C, Brugha, Traolach S, Buckle, Geoffrey C, Budke, Christine M, Bulloch, Andrew G, Campos Nonato, Ismael R, Carapetis, Jonathan R, Carpenter, David O, Castañeda Orjuela, Carlos A, Castro, Ruben E, Catalá López, Ferrán, Chadha, Vineet K, Chang, Jung Chen, Charlson, Fiona J, Chiang, Peggy P, Chimed Ochir, Odgerel, Christophi, Costas A, Coates, Matthew M, Coffeng, Luc E, Coggeshall, Megan S, Colquhoun, Samantha M, Cooke, Graham S, Cooper, Leslie T, Coppola, Luis M, Criqui, Michael H, Crump, John A, Cuevas Nasu, Lucia, Dargan, Paul I, Davitoiu, Dragos V, Del Pozo Cruz, Borja, Dellavalle, Robert P, Jarlais, Don C. De, Dharmaratne, Samath D, Dherani, Mukesh K, Diaz Torné, Cesar, Ding, Eric L, Dorsey, E. 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Dean, Hotez, Peter J, Hoy, Damian G, Huang, John J, Iannarone, Marissa L, Iburg, Kim M, Jacobsen, Kathryn H, Jarvis, Deborah L, Jassal, Simerjot K, Jensen, Paul N, Jonas, Jost B, Karema, Corine K, Kassebaum, Nicholas J, Kemp, Andrew H, Kengne, Andre P, Khader, Yousef S, Khalifa, Shams Eldin A, Khan, Ejaz A, Khang, Young Ho, Kinge, Jonas M, Knibbs, Luke D, Kuipers, Ernst J, Kulkarni, Veena S, Kumar, G. Anil, Kyu, Hmwe H, Lansingh, Van C, Lawrynowicz, Alicia E. B, Leasher, Janet L, Levitz, Carly E, Lim, Stephen S, Lipshultz, Steven E, Lloyd, Belinda K, Lofgren, Katherine T, Looker, Katharine J, Lortet Tieulent, Joannie, Lotufo, Paulo A, Lucas, Robyn M, Lyons, Ronan A, Macintyre, Michael F, Mackay, Mark T, Margolis, David J, Marzan, Melvin B, Masci, Joseph R, Mashal, Mohammad T, Mayosi, Bongani M, Mazorodze, Tasara T, Mcgill, Neil W, Mcgrath, John J, Meaney, Peter A, Melaku, Yohannes A, Memish, Ziad A, Mensah, George A, Mhimbira, Francis A, Miller, Ted R, Mills, Edward J, Mitchell, Philip B, Mock, Charles N, Mohammad, Karzan A, Mokdad, Ali H, Mola, Glen L. D, Montine, Thomas J, Mooney, Meghan D, Moore, Ami R, Moradi Lakeh, Maziar, Moran, Andrew E, Moturi, Wilkister N, Moyer, Madeline L, Msemburi, William T, Mueller, Ulrich O, Mullany, Erin C, Murdoch, Michele E, Murthy, Kinnari S, Naidoo, Kovin S, Narayan, K. M. Venkat, Neupane, Sudan P, Newton, Charles R, Ngalesoni, Frida N, Nisar, Muhammad I, Norheim, Ole F, Norman, Rosana E, Oh, In Hwan, Ohno, Summer L, Olusanya, Bolajoko O, Pain, Amanda W, Pandian, Jeyaraj D, Panelo, Carlo Irwin A, Park, Eun Kee, Park, Jae Hyun, Patten, Scott B, Patton, George C, Paul, Vinod K, Pavlin, Boris I, Pereira, David M, Perez Padilla, Rogelio, Perez Ruiz, Fernando, Peterson, Carrie B, Phillips, Michael R, Phillips, Bryan K, Phillips, David E, Piel, Frédéric B, Poulton, Richie G, Prasad, Noela M, Pullan, Rachel L, Qato, Dima M, Quistberg, D. Alex, Rahman, Sajjad U, Rana, Saleem M, Reddy, K. Srinath, Ribeiro, Antonio L, Roberts, D. Allen, Rojas Rueda, David, Roth, Gregory A, Rothstein, David H, Rowley, Jane T, Ruhago, George M, Saeedi, Mohammad Y, Sampson, Uchechukwu K. A, Sanabria, Juan R, Santos, Itamar S, Schneider, Ione J, Schumacher, Austin E, Schwebel, David C, Scott, James G, Sepanlou, Sadaf G, Serina, Peter T, Servan Mori, Edson E, Shackelford, Katya A, Shrime, Mark G, Sigfusdottir, Inga D, Silberberg, Donald H, Simard, Edgar P, Singh, Jasvinder A, Sposato, Luciano A, Sreeramareddy, Chandrashekhar T, Stanaway, Jeffrey D, Stein, Dan J, Stein, Murray B, Steiner, Timothy J, Stovner, Lars J, Sunguya, Bruno F, Sykes, Bryan L, Tabb, Karen M, Taylor, Hugh R, Ao, Braden J. Te, Temesgen, Awoke M, Tenkorang, Eric Y, Terkawi, Abdullah S, Thorne Lyman, Andrew L, Thrift, Amanda G, Thurston, George D, Tran, Bach X, Tuzcu, Emin M, Uchendu, Uche S, Ukwaja, Kingsley N, Undurraga, Eduardo A, Uzun, Selen B, Van Brakel, Wim H, van Gool, Coen H, Vasankari, Tommi J, Violante, Francesco S, Vlassov, Vasiliy V, Wagner, Gregory R, Waller, Stephen G, Warouw, Tati S, Weintraub, Robert G, Whiteford, Harvey A, Wilkinson, James D, Williams, Thomas N, Wolfe, Charles D, Wolock, Timothy M, Woolf, Anthony D, Yan, Lijing L, Yentür, Gökalp K, Yoon, Seok Jun, Younis, Mustafa Z, Zaki, Maysaa E, Salomon, Joshua A, Lopez, Alan D, Computational Science and Engineering Department [Daresbury] ( STFC ), Science & Technologie Facilities Council, Neuroépidémiologie Tropicale ( NET ), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST ), Université de Limoges ( UNILIM ) -Université de Limoges ( UNILIM ), Service de Chirurgie Thoracique et Vasculaire - Médecine vasculaire [CHU Limoges], CHU Limoges, Weill Cornell Medical College - Qatar, Qatar Foundation - Education City, Doha, Maladies chroniques, santé perçue, et processus d'adaptation ( APEMAC ), Université Paris Descartes - Paris 5 ( UPD5 ) -Université de Lorraine ( UL ), Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques Nancy, Cancéropôle du Grand Est-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Karolinska Institute, karolinska institute, Centro de Estudios Avanzados en Zonas Aridas ( CEAZA ), Ecole Polytechnique Fédérale de Lausanne ( EPFL ), Wisconsin Division of Public Health, Regional Genetic Service, St Mary's Hospital, Manchester, Laboratoire d'Ingénierie des Matériaux ( LIM ), Centre National de la Recherche Scientifique ( CNRS ), Computer Science Department [Bristol], University of Bristol [Bristol], Lawrence Berkeley National Laboratory [Berkeley] ( LBNL ), Samsung Research &Development Institute India - Bangalore (Groupe Samsung) ( SRI-B ), Multimedia Research Center ( MRC ), University of Alberta [Edmonton], Division of Biostatistics ( Biostat - MINNEAPOLIS ), University of Minnesota [Minneapolis], Laboratory of Neurologic Diseases, Mario Negri Institute, Milan, University of Southampton [Southampton], Imperial College London, Neurology Department, Ichilov Medical Center, Department of Public Health and Primary Care, Cambridge University, Interactions, transferts, ruptures artistiques et culturels - EA 6301 ( InTRu ), Université de Tours, Institut Jacques Monod ( IJM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Institute of Parasitology, STAR laboratory, Stanford University [Stanford], Unité de recherche Virologie et Immunologie Moléculaires ( VIM ), Institut National de la Recherche Agronomique ( INRA ), Tennent Institute of Ophthalmology, National University of Singapore ( NUS ), Multidisciplinary Nanotechnology Centre, Swansea University, Department of Computer Sciences [Scheffield], University of Sheffield [Sheffield], Cyprus International Institute for the Environment and Public Health, Harvard School of Public Health, Glasgow Centre for Physical Organic Chemistry, University of Glasgow, King‘s College London, Université Panthéon-Sorbonne - UFR Science Politique ( UP1 UFR11 ), Université Panthéon-Sorbonne ( UP1 ), National Diagnostics Centre ( NDC ), National University of Ireland [Galway] ( NUI Galway ), Arthritis Research UK Epidemiology Unit ( MANCHESTER - Arthritis Research ), University of Manchester [Manchester], CEGOT - Porto, Universidade do Porto [Porto], Advanced Laboratories on Embedded Systems [Roma] ( ALES ), Department of Biology [Miami], University of Miami [Coral Gables], Division of Human Nutrition, Wageningen University and Research Centre [Wageningen] ( WUR ), Spatial Ecology and Epidemiology Group, University of Oxford [Oxford], Department of Civil Engineering [Hamirpur], National Institute of Technology [Hamirpur], GEMMA — Environmental Engineering and Microbiology Research Group, Department of Hydraulic, Maritime and Environmental Engineering, Universitat Politècnica de Catalunya [Barcelona] ( UPC ), Institut National de Recherche et d'Analyse Physico-Chimique ( INRAP ), Institut National de Recherche et d'Analyse Physico-chimique (INRAP-Tunisie), University of Connecticut ( UCONN ), Norwegian Institute for Air Research ( NILU ), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) ( FEMTO-ST ), Université de Franche-Comté ( UFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Ecole Nationale Supérieure de Mécanique et des Microtechniques ( ENSMM ) -Université de Technologie de Belfort-Montbeliard ( UTBM ), Tehran University, Friedrich-Alexander Universität Erlangen-Nürnberg ( FAU ), Secretariat of the Pacific Community, Public Health Division, Sociétés, Acteurs, Gouvernement en Europe ( SAGE ), Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ), School of Physics and Astronomy, Washington State University ( WSU ), Laboratoire de Physique de l'ENS Lyon ( Phys-ENS ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Institut de recherche en informatique de Toulouse ( IRIT ), Institut National Polytechnique [Toulouse] ( INP ) -Université Toulouse 1 Capitole ( UT1 ) -Université Toulouse - Jean Jaurès ( UT2J ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique ( CNRS ), School of Computer Science - China University of Geosciences (China University of Geosciences (East Area)), Université Catholique de Louvain ( UCL ), Div Cyclotron & Radiopharmaceut Sci ( DRDO, INMAS ), Univ New Delhi, University of St Andrews [Scotland], University of Cape Town, Department of Neuroscience, Karolinska Institutet [Stockholm], Institut de Physique Nucléaire d'Orsay ( IPNO ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Computer Science and Engineering [Daejeon] (Chungnam National University), Lawrence University, Gastroenterology & Hepatology, Tata Research Development and Design Center ( TRDDC ), TCS Innovation Labs, Laboratoire MOLTECH-Anjou [Angers] ( MOLTECH ANJOU ), Université d'Angers ( UA ) -Centre National de la Recherche Scientifique ( CNRS ), University of Helsinki [Helsinki], Google Inc [Mountain View], Research at Google, Swedish Defense Research Agency ( FOI ), Centre de Recherche en Information Biomédicale sino-français ( CRIBS ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Southeast University [Jiangsu]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratory of Image Science and Technology [Nanjing] ( LIST ), Southeast University [Jiangsu]-School of Computer Science and Engineering, Laboratoire de glaciologie et géophysique de l'environnement ( LGGE ), Observatoire des Sciences de l'Univers de Grenoble ( OSUG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Centre National de la Recherche Scientifique ( CNRS ), School of Business and Informatics, University of Boras, Department of Mechanical and Automation Engineering ( CAD Laboratory ), The Chinese University of Hong Kong [Hong Kong], Università degli studi di Bari, Heuristique et Diagnostic des Systèmes Complexes [Compiègne] ( Heudiasyc ), Université de Technologie de Compiègne ( UTC ) -Centre National de la Recherche Scientifique ( CNRS ), Department of plant pathology and microbiology - centre for sustainable pest and disease management, Rothamsted Research, RGU, Department of Rheumatology and Connective Tissue Diseases, Medical University of Lublin, Barts and The London School of Medicine and Dentistry, Queen Mary University of London ( QMUL ), Centre d'économie de la Sorbonne ( CES ), Université Panthéon-Sorbonne ( UP1 ) -Centre National de la Recherche Scientifique ( CNRS ), Paris School of Economics ( PSE ), Istituto Dalle Molle di Studi sull'Intelligenza Artificiale ( IDSIA ), Università della Svizzera italiana ( USI ) -Scuola universitaria professionale della Svizzera italiana [Manno] ( SUPSI ), Anaesthetics, Southampton University Hospital, Department of Mathematics, University of Iowa [Iowa City], College of Medicine, Alfaisal University, Saudi Ministry of Health, Institut national des recherches agricoles du Bénin, Centre de Recherches agricoles du Sud, Departments of Epidemiology and Nutrition, Unit of Human Nutrition, Agricultural University of Athens, Department of Animal Science, PennState University [Pennsylvania] ( PSU ), University of Virginia, University of Virginia [Charlottesville], Epidemiology and Biostatistics Unit, Institute for Maternal and Child Health - IRCCS ‘‘Burlo Garofolo', Jet Propulsion Laboratory ( JPL ), NASA-California Institute of Technology ( CALTECH ), Division of Cardiovascular Medicine and Channing Division of Network Medicine, Brigham and Women's Hospital [Boston], Division of Gastroenterology and Hepatology, Department of Immunology, Mayo Clinic, Department of Chemistry, Scientific Computing Research Unit, Department of dermatology, Milano University-Azienda Ospedaleria Ospedali Riuniti di Bergamo, Department of epidemiology and Public Health, Faculty of Medicine, Hong Kong Baptist University ( HKBU ), Département Optique ( OPT ), Université européenne de Bretagne ( UEB ) -Télécom Bretagne-Institut Mines-Télécom [Paris], Department of Neurology Lunds University Hospital Lund, Services répartis, Architectures, MOdélisation, Validation, Administration des Réseaux ( SAMOVAR ), Institut Mines-Télécom [Paris]-Télécom SudParis ( TSP ) -Centre National de la Recherche Scientifique ( CNRS ), Département Réseaux et Services Multimédia Mobiles ( RS2M ), Institut Mines-Télécom [Paris]-Télécom SudParis ( TSP ), Electrical Engineering and Computer Science Department - Case Western Reserve University, Case Western Reserve University [Cleveland], Institut Lumière Matière [Villeurbanne] ( ILM ), Université Claude Bernard Lyon 1 ( UCBL ), World Health Organization, Nordic School of Public Health, The James Hutton Institute, Sero, Sero consulting, Evolutionary Ecology of Infectious Disease Group, Department of Zoology, Horia Hulubei National Institute for Physics and Nuclear Engineering, Dunedin School of Medicine, University of Otago, Department of Physics, Clarendon Laboratory, Center for TeleInFrastruktur ( CTIF ), Aalborg University [Denmark] ( AAU ), Physikalisches Institut [Freiburg], Albert-Ludwigs-Universität Freiburg, Savoirs, Textes, Langage (STL) - UMR 8163 ( STL ), Université de Lille-Centre National de la Recherche Scientifique ( CNRS ), Dept.of Computer Science, Indian Institute of Technology Madras ( IIT Madras ), Istituto Mario Negri Bergamo, Centro Ricerche e Trapianti Villa Camozzi, Universidade Estadual Paulista Júlio de Mesquita ( UNESP ), Department of Public Health, Erasmus MC-University Medical Center Rotterdam, Université Grenoble Alpes - UFR Médecine ( UGA UFRM ), Université Grenoble Alpes ( UGA ), Clinical Epidemiology and Aging Research, German Cancer Research Center, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Symantec, European Microsoft Innovation Center ( EMIC ), Microsoft Corporation [Redmond, Wash.], Laboratoire de Mécanique, Physique et Géosciences ( LMPG ), Université Le Havre Normandie ( ULH ), Normandie Université ( NU ) -Normandie Université ( NU ), Novartis institute for tropical diseases, Institut de Génétique et de Biologie Moléculaire et Cellulaire ( IGBMC ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Departments of Anatomy and Cell Biology, Wayne State University School of Medicine, Departments of Ophthalmology, Departments of Applied Physics [New Haven], Yale University [New Haven], Center for Mathematical Modeling ( CMM ), Universidad de Santiago de Chile [Santiago] ( USACH ), Laboratory for Atmospheric and Space Physics [Boulder] ( LASP ), University of Colorado Boulder [Boulder], University of Occupational and Environmental Health [Kitakyushu] ( UEOH ), Department of Computer Science and Engineering [New Delhi], Indian Institute of Technology Delhi ( IIT Delhi ), Institut de Recherche sur les Phénomènes Hors Equilibre ( IRPHE ), Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ) -Centre National de la Recherche Scientifique ( CNRS ), GlaxoSmithKline, Imperial College London-Clinical Imaging Center, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Yale School of Medicine-Yale School of Medicine-Yale Stem Cell Center, Maclean Building, Benson Lane, Crowmarsh Gifford, Centre for Ecology and Hydrology, Nanoscience Institute ( NEST ), Dipartimento di Fisica, Università di Pisa, Aristotle University of Thessaloniki, Laboratory Of Immune Cell Biology ( LICB ), National Institutes of Health ( NIH ), Institute of Human Genetics, Bonn Universität [Bonn], Occupational Health Unit, Bologna University Hospital-Sant'Orsola-Malpighi Polyclinic, Royal Institute of Technology [Stockholm] ( KTH ), Institut für Informatik [München/Munich] ( LMU ), Ludwig-Maximilians-Universität München, NICTA [Eveleigh], National ICT Australia [Sydney] ( NICTA ), Manchester Academic Health Sciences Centre, Institut d'Histoire et de Philosophie des Sciences et des Techniques ( IHPST ), Université Panthéon-Sorbonne ( UP1 ) -Département d'Etudes Cognitives - ENS Paris ( DEC ), École normale supérieure - Paris ( ENS Paris ) -École normale supérieure - Paris ( ENS Paris ) -Centre National de la Recherche Scientifique ( CNRS ), Ghent University [Belgium] ( UGENT ), German Research Centre for Geosciences - Helmholtz-Centre Potsdam ( GFZ ), Laboratoire de recherche en Hydrodynamique, Énergétique et Environnement Atmosphérique ( LHEEA ), École Centrale de Nantes ( ECN ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Recherche en Génie Civil et Mécanique ( GeM ), Université de Nantes ( UN ) -École Centrale de Nantes ( ECN ) -Centre National de la Recherche Scientifique ( CNRS ), Neurorestoration Group, King‘s College London-Wolfson Centre for Age-related Diseases, Department of Computer Science [KAIST] ( CS ), Korea Advanced Institute of Science and Technology ( KAIST ), Laboratoire de l'Accélérateur Linéaire ( LAL ), Natl Engn Res Ctr Vegetables, Key Lab Biol & Genet Improvement Hort Crops N Chi, Beijing Acad Agr & Forestry Sci, University Hospital Puerta de Hierro, Madrid, Computational Science and Engineering Department [Daresbury] (STFC), Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Weill Cornell Medicine [Qatar], Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université Paris Descartes - Paris 5 (UPD5)-Université de Lorraine (UL), Cancéropôle du Grand Est-Institut National de la Santé et de la Recherche Médicale (INSERM), Centro de Estudios Avanzados en Zonas Aridas (CEAZA), Ecole Polytechnique Fédérale de Lausanne (EPFL), Laboratoire d'Ingénierie des Matériaux (LIM), Centre National de la Recherche Scientifique (CNRS), Lawrence Berkeley National Laboratory [Berkeley] (LBNL), Samsung Research &Development Institute India - Bangalore (Groupe Samsung) (SRI-B), Multimedia Research Center (MRC), University of Alberta, Division of Biostatistics (Biostat - MINNEAPOLIS), University of Minnesota [Twin Cities] (UMN), University of Minnesota System-University of Minnesota System, University of Southampton, University of Cambridge [UK] (CAM), Interactions, transferts, ruptures artistiques et culturels - EA 6301 (InTRu), Université de Tours (UT), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Stanford University, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), National University of Singapore (NUS), Université Paris 1 Panthéon-Sorbonne - UFR Science Politique (UP1 UFR11), Université Paris 1 Panthéon-Sorbonne (UP1), National Diagnostics Centre (NDC), National University of Ireland [Galway] (NUI Galway), Arthritis Research UK Epidemiology Unit (MANCHESTER - Arthritis Research), Universidade do Porto = University of Porto, Advanced Laboratories on Embedded Systems [Roma] (ALES), Wageningen University and Research [Wageningen] (WUR), University of Oxford, Universitat Politècnica de Catalunya [Barcelona] (UPC), Institut National de Recherche et d'Analyse Physico-Chimique (INRAP), University of Connecticut (UCONN), Norwegian Institute for Air Research (NILU), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), University of Tehran, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Sociétés, Acteurs, Gouvernement en Europe (SAGE), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), The George Washington University (GW), Washington State University (WSU), Laboratoire de Physique de l'ENS Lyon (Phys-ENS), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut de recherche en informatique de Toulouse (IRIT), Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Université Catholique de Louvain = Catholic University of Louvain (UCL), Div Cyclotron & Radiopharmaceut Sci (DRDO, INMAS), School of Physics and Astronomy [St Andrews], Tata Research Development and Design Center (TRDDC), MOLTECH-Anjou, Université d'Angers (UA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Swedish Defense Research Agency (FOI), Centre de Recherche en Information Biomédicale sino-français (CRIBS), Université de Rennes (UR)-Southeast University [Jiangsu]-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Image Science and Technology [Nanjing] (LIST), Laboratoire de glaciologie et géophysique de l'environnement (LGGE), Observatoire des Sciences de l'Univers de Grenoble (OSUG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national des sciences de l'Univers (INSU - CNRS)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national des sciences de l'Univers (INSU - CNRS)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Department of Mechanical and Automation Engineering (CAD Laboratory), Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Heuristique et Diagnostic des Systèmes Complexes [Compiègne] (Heudiasyc), Université de Technologie de Compiègne (UTC)-Centre National de la Recherche Scientifique (CNRS), Biotechnology and Biological Sciences Research Council (BBSRC)-Biotechnology and Biological Sciences Research Council (BBSRC), Queen Mary University of London (QMUL), Centre d'économie de la Sorbonne (CES), Université Paris 1 Panthéon-Sorbonne (UP1)-Centre National de la Recherche Scientifique (CNRS), Paris School of Economics (PSE), Université Paris 1 Panthéon-Sorbonne (UP1)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École des hautes études en sciences sociales (EHESS)-École des Ponts ParisTech (ENPC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Istituto Dalle Molle di Studi sull'Intelligenza Artificiale (IDSIA), Università della Svizzera italiana = University of Italian Switzerland (USI)-Scuola universitaria professionale della Svizzera italiana = University of Applied Sciences and Arts of Southern Switzerland [Manno] (SUPSI), Pennsylvania State University (Penn State), Penn State System-Penn State System, Jet Propulsion Laboratory (JPL), NASA-California Institute of Technology (CALTECH), Hong Kong Baptist University (HKBU), Département Optique (OPT), Université européenne de Bretagne - European University of Brittany (UEB)-Télécom Bretagne-Institut Mines-Télécom [Paris] (IMT), Services répartis, Architectures, MOdélisation, Validation, Administration des Réseaux (SAMOVAR), Institut Mines-Télécom [Paris] (IMT)-Télécom SudParis (TSP), Département Réseaux et Services Multimédia Mobiles (TSP - RS2M), University of Melbourne, Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), University of Otago [Dunedin, Nouvelle-Zélande], Center for TeleInFrastruktur (CTIF), Aalborg University [Denmark] (AAU), Savoirs, Textes, Langage (STL) - UMR 8163 (STL), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Indian Institute of Technology Madras (IIT Madras), Universidade Estadual Paulista Júlio de Mesquita Filho = São Paulo State University (UNESP), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), European Microsoft Innovation Center (EMIC), Laboratoire de Mécanique, Physique et Géosciences (LMPG), Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU), Novartis Institute for Tropical Diseases (NITD), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Center for Mathematical Modeling (CMM), Universidad de Chile = University of Chile [Santiago] (UCHILE), Laboratory for Atmospheric and Space Physics [Boulder] (LASP), University of Colorado [Boulder], University of Occupational and Environmental Health [Kitakyushu] (UEOH), Indian Institute of Technology Delhi (IIT Delhi), Institut de Recherche sur les Phénomènes Hors Equilibre (IRPHE), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), Yale University [New Haven]-Yale School of Medicine [New Haven, Connecticut] (YSM), Nanoscience Institute (NEST), University of Pisa - Università di Pisa, Laboratory Of Immune Cell Biology (LICB), National Institutes of Health [Bethesda] (NIH), Rheinische Friedrich-Wilhelms-Universität Bonn, Royal Institute of Technology [Stockholm] (KTH ), Institut für Informatik [München/Munich] (LMU), Ludwig-Maximilians-Universität München (LMU), National ICT Australia [Sydney] (NICTA), Institut d'Histoire et de Philosophie des Sciences et des Techniques (IHPST), Université Paris 1 Panthéon-Sorbonne (UP1)-Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Universiteit Gent = Ghent University (UGENT), German Research Centre for Geosciences - Helmholtz-Centre Potsdam (GFZ), Laboratoire de recherche en Hydrodynamique, Énergétique et Environnement Atmosphérique (LHEEA), École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Génie Civil et Mécanique (GeM), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), Department of Computer Science [KAIST] (CS), Korea Advanced Institute of Science and Technology (KAIST), Kardiyoloji, Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Minnesota [Twin Cities], Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Unité de recherche Virologie et Immunologie Moléculaires (VIM), Université Panthéon-Sorbonne - UFR Science Politique (UP1 UFR11), Université Panthéon-Sorbonne (UP1), Wageningen University and Research Centre [Wageningen] (WUR), Institut National de Recherche et d'Analyse Physico-chimique (Ariana, Tunisie) (INRAP), Université de Franche-Comté (UFC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Technologie de Belfort-Montbeliard (UTBM), George Washington University (GW), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Université Catholique de Louvain (UCL), MOLTECH-ANJOU (MOLTECH-ANJOU), Université d'Angers (UA)-Centre National de la Recherche Scientifique (CNRS), University of Helsinki, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Southeast University [Jiangsu]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Université Panthéon-Sorbonne (UP1)-Centre National de la Recherche Scientifique (CNRS), Università della Svizzera italiana (USI)-Scuola universitaria professionale della Svizzera italiana [Manno] (SUPSI), California Institute of Technology (CALTECH)-NASA, Institut Mines-Télécom [Paris] (IMT)-Télécom SudParis (TSP)-Centre National de la Recherche Scientifique (CNRS), Département Réseaux et Services Multimédia Mobiles (RS2M), Universidade Estadual Paulista Júlio de Mesquita Filho [São José do Rio Preto] (UNESP), Université Grenoble Alpes (UGA), Universidad de Santiago de Chile [Santiago] (USACH), Yale University [New Haven]-Yale University School of Medicine, Université Panthéon-Sorbonne (UP1)-Centre National de la Recherche Scientifique (CNRS)-Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris), Ghent University [Belgium] (UGENT), Université de Nantes - Faculté des Sciences et des Techniques, Grelier, Elisabeth, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Universidade do Porto, Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Université Toulouse 1 Capitole (UT1), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire des Sciences de l'Univers de Grenoble (OSUG), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Università degli studi di Bari Aldo Moro (UNIBA), École des Ponts ParisTech (ENPC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris 1 Panthéon-Sorbonne (UP1)-Centre National de la Recherche Scientifique (CNRS)-École des hautes études en sciences sociales (EHESS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Università della Svizzera italiana = University of Italian Switzerland (USI)-Scuola universitaria professionale della Svizzera italiana [Manno] (SUPSI), Institut Mines-Télécom [Paris] (IMT)-Télécom Bretagne-Université européenne de Bretagne - European University of Brittany (UEB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Universiteit Gent = Ghent University [Belgium] (UGENT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-CHU Limoges-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Centre National de la Recherche Scientifique (CNRS)-Université de Technologie de Belfort-Montbeliard (UTBM), Institut de Chimie du CNRS (INC)-Université d'Angers (UA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-École Centrale de Nantes (ECN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national des sciences de l'Univers (INSU - CNRS)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS), Wolfson Centre for Age-related Diseases-King‘s College London, Cell biology, Public Health, Epidemiology, Health Technology Assessment (HTA), Erasmus MC other, Pathology, and Cardiothoracic Surgery
Subjects: Gerontology, Male, CHANGING RELATION, Nutrition and Disease, MESH : Life Expectancy, MESH : Aged, ECONOMIC-DEVELOPMENT, Poison control, MESH: Global Health, Global Health, Socioeconomic Factor, Communicable Disease, MESH : Chronic Disease, Health Transition, Voeding en Ziekte, Quality-Adjusted Life Year, SELF-RATED HEALTH, MESH : Socioeconomic Factors, Medicine, MESH : Female, MESH: Mortality, Premature, 2. Zero hunger, MESH: Aged, education.field_of_study, MESH: Middle Aged, Mortality rate, Medicine (all), GBD2013 diseases, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, General Medicine, Middle Aged, 3. Good health, MESH : Wounds and Injuries, Epidemiological transition, MESH: Quality-Adjusted Life Years, MESH: Communicable Diseases, NONCOMMUNICABLE DISEASES, Female, Quality-Adjusted Life Years, MESH: Life Expectancy, MESH: Health Transition, Human, MESH: Socioeconomic Factors, ACUTE MYOCARDIAL-INFARCTION, MESH : Male, MORTALITY TRENDS, Population, MESH : Health Transition, Communicable Diseases, Article, Life Expectancy, EUROPEAN-UNION, SDG 3 - Good Health and Well-being, General & Internal Medicine, SYSTEMATIC ANALYSIS, Disability-adjusted life year, Humans, Life Science, MESH : Middle Aged, Mortality, education, Premature, MESH : Mortality, Premature, VLAG, Aged, MESH: Humans, business.industry, Mortality, Premature, MESH: Chronic Disease, MESH : Communicable Diseases, Wounds and Injurie, MESH : Humans, MESH : Quality-Adjusted Life Years, Non-communicable disease, Chronic Disease, Socioeconomic Factors, Wounds and Injuries, medicine.disease, MESH: Male, LOW SOCIOECONOMIC-STATUS, Years of potential life lost, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Wounds and Injuries, Life expectancy, RISK-FACTORS, MESH : Global Health, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Female, Demography
Abstract: Summary Background The Global Burden of Disease Study 2013 (GBD 2013) aims to bring together all available epidemiological data using a coherent measurement framework, standardised estimation methods, and transparent data sources to enable comparisons of health loss over time and across causes, age–sex groups, and countries. The GBD can be used to generate summary measures such as disability-adjusted life-years (DALYs) and healthy life expectancy (HALE) that make possible comparative assessments of broad epidemiological patterns across countries and time. These summary measures can also be used to quantify the component of variation in epidemiology that is related to sociodemographic development. Methods We used the published GBD 2013 data for age-specific mortality, years of life lost due to premature mortality (YLLs), and years lived with disability (YLDs) to calculate DALYs and HALE for 1990, 1995, 2000, 2005, 2010, and 2013 for 188 countries. We calculated HALE using the Sullivan method; 95% uncertainty intervals (UIs) represent uncertainty in age-specific death rates and YLDs per person for each country, age, sex, and year. We estimated DALYs for 306 causes for each country as the sum of YLLs and YLDs; 95% UIs represent uncertainty in YLL and YLD rates. We quantified patterns of the epidemiological transition with a composite indicator of sociodemographic status, which we constructed from income per person, average years of schooling after age 15 years, and the total fertility rate and mean age of the population. We applied hierarchical regression to DALY rates by cause across countries to decompose variance related to the sociodemographic status variable, country, and time. Findings Worldwide, from 1990 to 2013, life expectancy at birth rose by 6·2 years (95% UI 5·6–6·6), from 65·3 years (65·0–65·6) in 1990 to 71·5 years (71·0–71·9) in 2013, HALE at birth rose by 5·4 years (4·9–5·8), from 56·9 years (54·5–59·1) to 62·3 years (59·7–64·8), total DALYs fell by 3·6% (0·3–7·4), and age-standardised DALY rates per 100 000 people fell by 26·7% (24·6–29·1). For communicable, maternal, neonatal, and nutritional disorders, global DALY numbers, crude rates, and age-standardised rates have all declined between 1990 and 2013, whereas for non–communicable diseases, global DALYs have been increasing, DALY rates have remained nearly constant, and age-standardised DALY rates declined during the same period. From 2005 to 2013, the number of DALYs increased for most specific non-communicable diseases, including cardiovascular diseases and neoplasms, in addition to dengue, food-borne trematodes, and leishmaniasis; DALYs decreased for nearly all other causes. By 2013, the five leading causes of DALYs were ischaemic heart disease, lower respiratory infections, cerebrovascular disease, low back and neck pain, and road injuries. Sociodemographic status explained more than 50% of the variance between countries and over time for diarrhoea, lower respiratory infections, and other common infectious diseases; maternal disorders; neonatal disorders; nutritional deficiencies; other communicable, maternal, neonatal, and nutritional diseases; musculoskeletal disorders; and other non-communicable diseases. However, sociodemographic status explained less than 10% of the variance in DALY rates for cardiovascular diseases; chronic respiratory diseases; cirrhosis; diabetes, urogenital, blood, and endocrine diseases; unintentional injuries; and self-harm and interpersonal violence. Predictably, increased sociodemographic status was associated with a shift in burden from YLLs to YLDs, driven by declines in YLLs and increases in YLDs from musculoskeletal disorders, neurological disorders, and mental and substance use disorders. In most country-specific estimates, the increase in life expectancy was greater than that in HALE. Leading causes of DALYs are highly variable across countries. Interpretation Global health is improving. Population growth and ageing have driven up numbers of DALYs, but crude rates have remained relatively constant, showing that progress in health does not mean fewer demands on health systems. The notion of an epidemiological transition—in which increasing sociodemographic status brings structured change in disease burden—is useful, but there is tremendous variation in burden of disease that is not associated with sociodemographic status. This further underscores the need for country-specific assessments of DALYs and HALE to appropriately inform health policy decisions and attendant actions. Funding Bill & Melinda Gates Foundation. BACKGROUND: The Global Burden of Disease Study 2013 (GBD 2013) aims to bring together all available epidemiological data using a coherent measurement framework, standardised estimation methods, and transparent data sources to enable comparisons of health loss over time and across causes, age-sex groups, and countries. The GBD can be used to generate summary measures such as disability-adjusted life-years (DALYs) and healthy life expectancy (HALE) that make possible comparative assessments of broad epidemiological patterns across countries and time. These summary measures can also be used to quantify the component of variation in epidemiology that is related to sociodemographic development. METHODS: We used the published GBD 2013 data for age-specific mortality, years of life lost due to premature mortality (YLLs), and years lived with disability (YLDs) to calculate DALYs and HALE for 1990, 1995, 2000, 2005, 2010, and 2013 for 188 countries. We calculated HALE using the Sullivan method; 95% uncertainty intervals (UIs) represent uncertainty in age-specific death rates and YLDs per person for each country, age, sex, and year. We estimated DALYs for 306 causes for each country as the sum of YLLs and YLDs; 95% UIs represent uncertainty in YLL and YLD rates. We quantified patterns of the epidemiological transition with a composite indicator of sociodemographic status, which we constructed from income per person, average years of schooling after age 15 years, and the total fertility rate and mean age of the population. We applied hierarchical regression to DALY rates by cause across countries to decompose variance related to the sociodemographic status variable, country, and time. FINDINGS: Worldwide, from 1990 to 2013, life expectancy at birth rose by 6·2 years (95% UI 5·6-6·6), from 65·3 years (65·0-65·6) in 1990 to 71·5 years (71·0-71·9) in 2013, HALE at birth rose by 5·4 years (4·9-5·8), from 56·9 years (54·5-59·1) to 62·3 years (59·7-64·8), total DALYs fell by 3·6% (0·3-7·4), and age-standardised DALY rates per 100 000 people fell by 26·7% (24·6-29·1). For communicable, maternal, neonatal, and nutritional disorders, global DALY numbers, crude rates, and age-standardised rates have all declined between 1990 and 2013, whereas for non-communicable diseases, global DALYs have been increasing, DALY rates have remained nearly constant, and age-standardised DALY rates declined during the same period. From 2005 to 2013, the number of DALYs increased for most specific non-communicable diseases, including cardiovascular diseases and neoplasms, in addition to dengue, food-borne trematodes, and leishmaniasis; DALYs decreased for nearly all other causes. By 2013, the five leading causes of DALYs were ischaemic heart disease, lower respiratory infections, cerebrovascular disease, low back and neck pain, and road injuries. Sociodemographic status explained more than 50% of the variance between countries and over time for diarrhoea, lower respiratory infections, and other common infectious diseases; maternal disorders; neonatal disorders; nutritional deficiencies; other communicable, maternal, neonatal, and nutritional diseases; musculoskeletal disorders; and other non-communicable diseases. However, sociodemographic status explained less than 10% of the variance in DALY rates for cardiovascular diseases; chronic respiratory diseases; cirrhosis; diabetes, urogenital, blood, and endocrine diseases; unintentional injuries; and self-harm and interpersonal violence. Predictably, increased sociodemographic status was associated with a shift in burden from YLLs to YLDs, driven by declines in YLLs and increases in YLDs from musculoskeletal disorders, neurological disorders, and mental and substance use disorders. In most country-specific estimates, the increase in life expectancy was greater than that in HALE. Leading causes of DALYs are highly variable across countries. INTERPRETATION: Global health is improving. Population growth and ageing have driven up numbers of DALYs, but crude rates have remained relatively constant, showing that progress in health does not mean fewer demands on health systems. The notion of an epidemiological transition-in which increasing sociodemographic status brings structured change in disease burden-is useful, but there is tremendous variation in burden of disease that is not associated with sociodemographic status. This further underscores the need for country-specific assessments of DALYs and HALE to appropriately inform health policy decisions and attendant actions. FUNDING: Bill & Melinda Gates Foundation.
Published: 2015

20. Safety and activity of anti-mesothelin antibody–drug conjugate anetumab ravtansine in combination with pegylated-liposomal doxorubicin in platinum-resistant ovarian cancer: multicenter, phase Ib dose escalation and expansion study

Author: Alessandro D Santin, Ignace Vergote, Antonio González-Martín, Kathleen Moore, Ana Oaknin, Ignacio Romero, Sami Diab, Larry J Copeland, Bradley J Monk, Robert L Coleman, Thomas J Herzog, Jonathan Siegel, Linda Kasten, Andreas Schlicker, Anke Schulz, Karl Köchert, Annette O Walter, Barrett H Childs, Cem Elbi, Iurie Bulat, Institut Català de la Salut, [Santin AD] Yale School of Medicine, New Haven, CT, USA. [Vergote I] University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium. [González-Martín A] Clinica Universidad de Navarra, Madrid, Spain. [Moore K] University of Oklahoma Health Sciences Center, Oklahoma, OK, USA. [Oaknin A] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Romero I] Instituto Valenciano de Oncología, Valencia, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Science & Technology, Anticossos monoclonals - Ús terapèutic, Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms [DISEASES], BEVACIZUMAB, terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Medicaments antineoplàstics - Ús terapèutic, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Obstetrics & Gynecology, Obstetrics and Gynecology, aminoácidos, péptidos y proteínas::proteínas::proteínas sanguíneas::globulinas séricas::inmunoglobulinas::anticuerpos::inmunoconjugados [COMPUESTOS QUÍMICOS Y DROGAS], Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Serum Globulins::Immunoglobulins::Antibodies::Immunoconjugates [CHEMICALS AND DRUGS], Ovaris - Càncer - Tractament, neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas [ENFERMEDADES], CHEMOTHERAPY, Other subheadings::Other subheadings::/drug therapy [Other subheadings], ovarian cancer, Oncology, Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], TRIAL, WEEKLY PACLITAXEL, TOPOTECAN, Life Sciences & Biomedicine
Abstract: ObjectivesAnetumab ravtansine is an antibody-drug conjugate consisting of a fully human anti-mesothelin monoclonal antibody conjugated to cytotoxic maytansinoid tubulin inhibitor DM4. Mesothelin is highly expressed in ovarian cancer. This phase Ib study determines the safety, pharmacokinetics, and anti-tumor activity of anetumab ravtansine and pegylated liposomal doxorubicin in mesothelin-expressing platinum-resistant ovarian cancer.MethodsAnetumab ravtansine (5.5 or 6.5 mg/kg) and pegylated liposomal doxorubicin (30 mg/m2) were administered intravenously every 3 weeks to 65 patients with platinum-resistant epithelial ovarian cancer. Mesothelin expression was assessed by central immunohistochemistry. Adverse events, tumor response (RECIST 1.1), and progression-free survival were determined. Biomarker samples were assessed by ELISA and next-generation sequencing.ResultsIn dose escalation, nine patients received anetumab ravtansine across two doses (5.5 or 6.5 mg/kg). The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg every 3 weeks and no dose-limiting toxicities were observed. In dose expansion, 56 patients were treated at the maximum tolerated dose. The most common treatment-emergent adverse events of any grade were nausea (47.7%), decreased appetite (43.1%), fatigue (38.5%), diarrhea (32.3%), and corneal disorder (29.2%). In all treated patients the objective response rate was 27.7% (95% CI 17.3% to 40.2%), including one complete (1.5%) and 17 partial responses (26.2%), with median duration of response of 7.6 (95% CI 3.3 to 10.2) months and median progression-free survival of 5.0 (95% CI 3.2 to 6.0) months. In an exploratory analysis of a sub-set of patients (n=19) with high mesothelin expression who received ≤3 prior lines of systemic therapy, the objective response rate was 42.1% (95% CI 20.3% to 66.5%) with a median duration of response of 8.3 (95% CI 4.1 to 12.0) months and median progression-free survival of 8.5 (95% CI 4.0 to 11.4) months.ConclusionsAnetumab ravtansine and pegylated liposomal doxorubicin showed tolerability and promising clinical activity. These results established the dose schedule and the mesothelin-positive target population of this combination for a phase III study in platinum-resistant ovarian cancer.Trial registration numberNCT02751918.
Published: 2022

21. Rare pathogenic variants in WNK3 cause X-linked intellectual disability

Author: Sébastien Küry, Jinwei Zhang, Thomas Besnard, Alfonso Caro-Llopis, Xue Zeng, Stephanie M. Robert, Sunday S. Josiah, Emre Kiziltug, Anne-Sophie Denommé-Pichon, Benjamin Cogné, Adam J. Kundishora, Le T. Hao, Hong Li, Roger E. Stevenson, Raymond J. Louie, Wallid Deb, Erin Torti, Virginie Vignard, Kirsty McWalter, F. Lucy Raymond, Farrah Rajabi, Emmanuelle Ranza, Detelina Grozeva, Stephanie A. Coury, Xavier Blanc, Elise Brischoux-Boucher, Boris Keren, Katrin Õunap, Karit Reinson, Pilvi Ilves, Ingrid M. Wentzensen, Eileen E. Barr, Solveig Heide Guihard, Perrine Charles, Eleanor G. Seaby, Kristin G. Monaghan, Marlène Rio, Yolande van Bever, Marjon van Slegtenhorst, Wendy K. Chung, Ashley Wilson, Delphine Quinquis, Flora Bréhéret, Kyle Retterer, Pierre Lindenbaum, Emmanuel Scalais, Lindsay Rhodes, Katrien Stouffs, Elaine M. Pereira, Sara M. Berger, Sarah S. Milla, Ankita B. Jaykumar, Melanie H. Cobb, Shreyas Panchagnula, Phan Q. Duy, Marie Vincent, Sandra Mercier, Brigitte Gilbert-Dussardier, Xavier Le Guillou, Séverine Audebert-Bellanger, Sylvie Odent, Sébastien Schmitt, Pierre Boisseau, Dominique Bonneau, Annick Toutain, Estelle Colin, Laurent Pasquier, Richard Redon, Arjan Bouman, Jill. A. Rosenfeld, Michael J. Friez, Helena Pérez-Peña, Syed Raza Akhtar Rizvi, Shozeb Haider, Stylianos E. Antonarakis, Charles E. Schwartz, Francisco Martínez, Stéphane Bézieau, Kristopher T. Kahle, Bertrand Isidor, Clinical Genetics, Clinical sciences, Medical Genetics, Reproduction and Genetics, Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), University of Exeter, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), The Greenwood Genetic Center, GeneDx [Gaithersburg, MD, USA], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Genève = University of Geneva (UNIGE), Yale School of Medicine [New Haven, Connecticut] (YSM), This work was granted by the French network of University Hospitals HUGO ('Hôpitaux Universitaires du Grand Ouest'), the French Ministry of Health, and and the Health Regional Agencies from Poitou-Charentes (represented by Frédérique Allaire), Bretagne, Pays de la Loire, and Centre-Val de Loire (HUGODIMS, 2013, RC14_0107). W.K.C. was supported by grants from Simons Foundation Autism Research Initiative, United
Subjects: MESH: Symporters, Exome sequencing, Male, KCC2, Mutation, Missense, MESH: Catalytic Domain, Neurodevelopmental disease, Protein Serine-Threonine Kinases, X-linked intellectual disability, MESH: Brain, WNK3, SDG 3 - Good Health and Well-being, Loss of Function Mutation, Catalytic Domain, MESH: Mental Retardation, X-Linked, Humans, Phosphorylation, MESH: Hemizygote, Genetics (clinical), Hemizygote, MESH: Mutation, Missense, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Phosphorylation, Symporters, Brain, MESH: Loss of Function Mutation, MESH: Protein Serine-Threonine Kinases, MESH: Male, Mental Retardation, X-Linked, Maternal Inheritance, MESH: Maternal Inheritance
Abstract: PURPOSE: WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown. METHOD: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID). RESULTS: We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had identifier with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition. CONCLUSION: Pathogenic WNK3 variants cause a rare form of human X-linked identifier with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.
Published: 2022

22. Advances in the Research of Melatonin in Autism Spectrum Disorders: Literature Review and New Perspectives

Author: Nemat Jaafari, Michel Botbol, Olivier Schischmanoff, George M. Anderson, Sylvie Tordjman, Guillaume Bronsard, Sophie Ribardiere, Solenn Kermarrec, Marianne Barbu-Roth, Eric Bellissant, Claire Fougerou, Julie Vernay-Leconte, David Cohen, Imen Najjar, Remi Fagard, Enas Lagdas, Service Psychiatrie de l'Enfant et de l'Adolescent, CHU Pontchaillou [Rennes]-Centre Hospitalier Guillaume Régnier [Rennes]-CHS (Centre Hospitalier Spécialisé lutte Maladies Mentales), Laboratoire Psychologie de la Perception ( LPP - UMR 8242 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Investigation Clinique [Rennes] ( CIC ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Pharmacologie, CHU Pontchaillou [Rennes], Laboratory of Developmental Neurochemistry, Yale Child Study Center, Department of Laboratory Medicine, Yale School of Medicine, Service de psychiatrie de l'enfant et de l'adolescent, CHU Pitié-Salpêtrière [APHP], CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers ( CHU Poitiers ) -Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Adaptateurs de signalisation en hématologie ( ASIH ), Université Paris 13 ( UP13 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de biochimie et biologie moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne-Université Paris 13 ( UP13 ), Service Hospitalo-Universitaire de Psychiatrie de l'Enfant et de l'Adolescent, Université de Brest ( UBO ), Santé Publique et maladies Chroniques : Qualité de vie Concepts, Usages et Limites, Déterminants ( SPMC ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ), Maison Départementale de l'Adolescent et Centre Médico-Psycho-Pédagogique, Le Corre, Morgane, Laboratoire Psychologie de la Perception (LPP - UMR 8242), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pharmacologie [Rennes], Yale School of Medicine [New Haven, Connecticut] (YSM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Adaptateurs de signalisation en hématologie (ASIH), Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Brest (UBO), Santé Publique et maladies Chroniques : Qualité de vie Concepts, Usages et Limites, Déterminants (SPMC), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Yale University School of Medicine, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris 13 (UP13)-Hôpital Avicenne [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: [ SDV.MHEP.PED ] Life Sciences [q-bio]/Human health and pathology/Pediatrics, melatonin, Review, lcsh:Chemistry, Peripheral oscillators, Pineal gland, 0302 clinical medicine, stereotyped behaviors, lcsh:QH301-705.5, Spectroscopy, 0303 health sciences, Social communication, General Medicine, 3. Good health, Computer Science Applications, medicine.anatomical_structure, Communication Disorders, hormones, hormone substitutes, and hormone antagonists, biological clocks, medicine.drug, circadian rhythm, medicine.medical_specialty, endocrine system, autism spectrum disorders, social communication, Catalysis, Inorganic Chemistry, Melatonin, 03 medical and health sciences, Nonverbal communication, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, medicine, Animals, Humans, Circadian rhythm, Physical and Theoretical Chemistry, Psychiatry, Molecular Biology, 030304 developmental biology, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, business.industry, Organic Chemistry, synchrony, medicine.disease, Social relation, lcsh:Biology (General), lcsh:QD1-999, Child Development Disorders, Pervasive, Autism, business, Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; Abnormalities in melatonin physiology may be involved or closely linked to the pathophysiology and behavioral expression of autistic disorder, given its role in neurodevelopment and reports of sleep-wake rhythm disturbances, decreased nocturnal melatonin production, and beneficial therapeutic effects of melatonin in individuals with autism. In addition, melatonin, as a pineal gland hormone produced from serotonin, is of special interest in autistic disorder given reported alterations in central and peripheral serotonin neurobiology. More specifically, the role of melatonin in the ontogenetic establishment of circadian rhythms and the synchronization of peripheral oscillators opens interesting perspectives to ascertain better the mechanisms underlying the significant relationship found between lower nocturnal melatonin excretion and increased severity of autistic social communication impairments, especially for verbal communication and social imitative play. In this article, first we review the studies on melatonin levels and the treatment studies of melatonin in autistic disorder. Then, we discuss the relationships between melatonin and autistic behavioral impairments with regard to social communication (verbal and non-verbal communication, social interaction), and repetitive behaviors or interests with difficulties adapting to change. In conclusion, we emphasize that randomized clinical trials in autism spectrum disorders are warranted to establish potential therapeutic efficacy of melatonin for social communication impairments and stereotyped behaviors or interests.
Published: 2013

23. Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia

Author: Tamas L. Horvath, Maria Teresa Dell’Anno, Xiao-Bing Gao, Naoki Nakagawa, Anze Testen, Yalan Zhang, Tianliuyun Gao, Mihovil Pletikos, Candace Bichsel, Nenad Sestan, Mingfeng Li, Sirisha Pochareddy, Brett D. Lindenbach, Leonard K. Kaczmarek, Zhen Li, Wenqi Han, Forrest O. Gulden, Fuchen Liu, André M. M. Sousa, Stephen M. Strittmatter, Andrew T.N. Tebbenkamp, Marco Onorati, Steven Lisgo, Jernej Mlakar, Marie Flamand, Mara Popović, Eva S. Anton, Luis Varela, Klara Szigeti-Buck, Ying Zhu, Department of Neuroscience [New Haven], Yale University School of Medicine-Kavli Institute for Neuroscience [New Haven], Department of Cell Biology and Physiology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neuroscience [New Haven], Yale University School of Medicine, Section of Comparative Medicine [New Haven], Institute of Genetic Medicine, Newcastle University [Newcastle], Departments of pharmacology and molecular biophysics and biochemistry [New Haven], University of Ljubljana, Département de Virologie - Department of Virology, Institut Pasteur [Paris], Departments of Internal Medicine, Cellular & Molecular Physiology, Departments of Medicine and Cell Biology & Physiology, Department of Microbial Pathogenesis, Reproductive Neuroscience Unit, Department of Obstetrics and Gynecology and Department of Neurobiology, Yale Program in Integrative Cell Signaling and Neurobiology of Metabolism, Kavli Institute for Neuroscience [New Haven], Departments of Psychiatry and Genetics, This work was supported by grants NS076503, MH103339, MH105972, MH106934, MH060929, NS080388, AG034924, AG047270, DC01919, AI120113, and AI089826 from the NIH, SFARI 307705 from the Simons Foundation, and 15-RMA-YALE-31 from Connecticut Innovations’ Regenerative Medicine Research Fund. The Laboratory of Developmental Biology at the University of Washington, Seattle, and Human Developmental Biology Resource were supported by NIH award number HD0008836 and the Joint MRC/Wellcome Trust grant 099175/Z/12/Z, respectively. Additional support was provided by the Kavli Foundation and the Falk Medical Research Trust., Department of Neuroscience, Yale University School of Medicine, Yale School of Medicine [New Haven, Connecticut] (YSM), Institut Pasteur [Paris] (IP), Kavli Institute for Neuroscience, Yale School of Medicine, and Yale School of Medicine [New Haven, Connecticut] (YSM)-Yale School of Medicine [New Haven, Connecticut] (YSM)
Subjects: Genetics and Molecular Biology (all), Microcephaly, Transcription, Genetic, Neocortex, MESH: Neuroepithelial Cells/ultrastructure, Biochemistry, environment and public health, MESH: Brain/virology, Neural Stem Cells, MESH: Centrosome/drug effects, MESH: Mitochondria/metabolism, lcsh:QH301-705.5, Neurons, MESH: Protein-Serine-Threonine Kinases/metabolism, Zika Virus Infection, Brain, MESH: Neurons/virology, MESH: Neural Stem Cells/virology, MESH: Neural Stem Cells/immunology, Nucleosides, MESH: Zika Virus/physiology, MESH: Virus Replication/drug effects, Neural stem cell, 3. Good health, Cell biology, Neuroepithelial cell, MESH: Brain/pathology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Spinal Cord, MESH: Neocortex/pathology, MESH: Neuroepithelial Cells/immunology, Neuroglia, MESH: Receptor Protein-Tyrosine Kinases/metabolism, Article, General Biochemistry, Genetics and Molecular Biology, MESH: Protein Kinase Inhibitors/pharmacology, 03 medical and health sciences, MESH: Gene Expression Profiling, Fetus, Humans, MESH: Phosphorylation/drug effects, Mitosis, MESH: Neural Stem Cells/ultrastructure, Biochemistry, Genetics and Molecular Biology (all), MESH: Humans, Receptor Protein-Tyrosine Kinases, MESH: Zika Virus/pathogenicity, medicine.disease, Immunity, Innate, MESH: Mitosis/drug effects, 030104 developmental biology, MESH: Neuroprotective Agents/pharmacology, MESH: Mitochondria/drug effects, MESH: Spinal Cord/pathology, MESH: Neuroglia/ultrastructure, 0301 basic medicine, MESH: Fetus/virology, viruses, [SDV]Life Sciences [q-bio], Neuroepithelial Cells, MESH: Zika Virus/ultrastructure, Virus Replication, MESH: Neurons/drug effects, MESH: Neuroepithelial Cells/drug effects, MESH: Zika Virus Infection/pathology, MESH: Neurons/pathology, MESH: Immunity, Innate/drug effects, Phosphorylation, Genetics, Cell Death, MESH: Transcription, Genetic/drug effects, MESH: Neuroglia/virology, MESH: Nucleosides/pharmacology, Mitochondria, Neuroprotective Agents, MESH: Neuroglia/pathology, lipids (amino acids, peptides, and proteins), MESH: Zika Virus Infection/virology, Stem cell, Programmed cell death, MESH: Centrosome/metabolism, MESH: Brain/embryology, Protein Serine-Threonine Kinases, Biology, Proto-Oncogene Proteins, MESH: Microcephaly/pathology, medicine, MESH: Zika Virus/drug effects, Protein Kinase Inhibitors, Centrosome, MESH: Neural Stem Cells/enzymology, Gene Expression Profiling, MESH: Proto-Oncogene Proteins/metabolism, Zika Virus, Axl Receptor Tyrosine Kinase, MESH: Microcephaly/virology, Gene expression profiling, MESH: Cell Death/drug effects, lcsh:Biology (General), MESH: Neuroepithelial Cells/virology
Abstract: SummaryThe mechanisms underlying Zika virus (ZIKV)-related microcephaly and other neurodevelopment defects remain poorly understood. Here, we describe the derivation and characterization, including single-cell RNA-seq, of neocortical and spinal cord neuroepithelial stem (NES) cells to model early human neurodevelopment and ZIKV-related neuropathogenesis. By analyzing human NES cells, organotypic fetal brain slices, and a ZIKV-infected micrencephalic brain, we show that ZIKV infects both neocortical and spinal NES cells as well as their fetal homolog, radial glial cells (RGCs), causing disrupted mitoses, supernumerary centrosomes, structural disorganization, and cell death. ZIKV infection of NES cells and RGCs causes centrosomal depletion and mitochondrial sequestration of phospho-TBK1 during mitosis. We also found that nucleoside analogs inhibit ZIKV replication in NES cells, protecting them from ZIKV-induced pTBK1 relocalization and cell death. We established a model system of human neural stem cells to reveal cellular and molecular mechanisms underlying neurodevelopmental defects associated with ZIKV infection and its potential treatment.
Published: 2016

24. A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis

Author: Richard H. Duerr, Dalin Li, Ming-Hsi Wang, Tariq Ahmad, John D. Rioux, Patrick Sulem, Daniel B. Graham, Steven R. Brant, Severine Vermeire, Mark Tremelling, James Lee, Leena Halme, K. de Lane, Miguel Regueiro, M Parkes, David C. Wilson, Alain Bitton, R. Milgrom, Daniel G. MacArthur, Marijn C. Visschedijk, Sören Mucha, Kenneth Croitoru, Alison Simmons, Mark S. Silverberg, Rinse K. Weersma, Jonas Halfvarson, Daniel L. Rice, J. M. Stempak, Christopher J. Hawkey, Mauro D'Amato, Christopher G. Mathew, Philippe Goyette, Frauke Degenhardt, Daniel F. Gudbjartsson, Mark J. Daly, Kari Stefansson, Beryl B. Cummings, Maarit Lappalainen, Päivi Saavalainen, Paulina Paavola-Sakki, P. Fleshner, Talin Haritunians, Joshua C. Randall, Elaine R. Nimmo, Taru Tukiainen, Christine Stevens, Subra Kugathasan, Monkol Lek, Andre Franke, Kimmo Kontula, Unnur Thorsteinsdottir, Andrew Hart, Martin O. Pollard, Gabrielle Boucher, Natalie J. Prescott, Benjamin M. Neale, Holm H. Uhlig, Carl A. Anderson, Ashwin N. Ananthakrishnan, Luke Jostins, C. Mowatt, Judy H. Cho, B. Newman, A. Nicole Desch, Yang Luo, Dermot P.B. McGovern, Clara Abraham, Ingileif Jonsdottir, Jeffrey C. Barrett, John C. Mansfield, Jean-Paul Achkar, Charlie W. Lees, Martti Färkkilä, Ramnik J. Xavier, S. R. Targan, Manuel A. Rivas, Deborah D. Proctor, Johan Van Limbergen, Nicholas A. Kennedy, Christopher A. Lamb, Jürgen Glas, Vito Annese, Yashoda Sharma, Phil Schumm, Graham A. Heap, Cathryn Edwards, Lotta L. E. Koskinen, Jack Satsangi, Mitja I. Kurki, Aarno Palotie, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA deCODE Genetics, Amgen Inc., 101 Reykjavik, Iceland Research Center, Montreal Heart Institute, Montréal, Québec, Canada H1T1C8 School of Engineering and Natural Sciences, University of Iceland, 101 Reykjavik, Iceland Department of Immunology, Landspitali, the National University Hospital of Iceland, 101 Reykjavik, Iceland Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048 USA Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Stockholm, Sweden BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science, 48903 Bilbao, Spain Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, 71013 San Giovanni Rotondo, Italy Strutture Organizzative Dipartimentali (SOD) Gastroenterologia 2, Azienda Ospedaliero Universitaria (AOU) Careggi, 50134 Florence, Italy Department of Clinical and Experimental Medicine, Translational Research in GastroIntestinal Disorders (TARGID), Katholieke Universiteit (KU) Leuven, Leuven 3000, Belgium Division of Gastroenterology, University Hospital Gasthuisberg, BE-3000 Leuven, Belgium Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, 9713 GZ Groningen, The Netherlands Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, SE 701 82 Örebro, Sweden Department of Medicine, University of Helsinki, 00100 Helsinki, Finland Helsinki University Hospital, 00100 Helsinki, Finland Clinic of Gastroenterology, Helsinki University Hospital, 00100 Helsinki, Finland Research Programs Unit, Immunobiology, and Department of Medical and Clinical Genetics, University of Helsinki, 00014 Helsinki, Finland Department of Transplantation and Liver Surgery, University of Helsinki, 00100 Helsinki, Finland Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, 00100 Helsinki, Finland Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts 02114, USA Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK Graham A. Heap Peninsula College of Medicine and Dentistry, Exeter PL6 8BU, UK Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, 21205, USA Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, 21205, USA Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261, USA Department of Medicine, Inflammatory Bowel Disease Centre, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA Institute for Molecular Medicine Finland, University of Helsinki, 00100 Helsinki, Finland Massachusetts General Hospital, Center for Human Genetic Research, Psychiatric and Neurodevelopmental Genetics Unit, Boston, Massachusetts 02114, USA Research Programs Unit, Immunobiology, University of Helsinki, 00100 Helsinki, Finland Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada H3T 1J4 Department of Gastroenterology, Torbay Hospital, Devon, UK Department of Medicine, St. Mark’s Hospital, Middlesex, UK Nottingham Digestive Disease Centre, Queens Medical Centre, Nottingham, UK Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK Christ Church, University of Oxford, Oxford, UK Gastrointestinal Unit, Wester General Hospital, University of Edinburgh, Edinburgh, UK Newcastle University, Newcastle upon Tyne, UK Inflammatory Bowel Disease Research Group, Addenbrooke’s Hospital, Cambridge, UK Department of Medical and Molecular Genetics, Guy’s Hospital, London, UK Department of Medical and Molecular Genetics, King’s College London School of Medicine, Guy’s Hospital, London, UK Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK Genetic Medicine, Manchester Academic Health Science Centre, Manchester, UK The Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK Gastroenterology & General Medicine, Norfolk and Norwich University Hospital, Norwich, UK Translational Gastroenterology Unit and the Department of Pediatrics, University of Oxford, Oxford, UK Pediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK Child Life and Health, University of Edinburgh, Edinburgh, UK Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA Division of Gastroenterology, Royal Victoria Hospital, Montréal, Québec, Canada Inflammatory Bowel Disease Group, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA, Department of Medicine, Clinicum, Gastroenterologian yksikkö, Immunobiology Research Program, Research Programs Unit, Department of Medical and Clinical Genetics, Medicum, II kirurgian klinikka, Department of Surgery, Institute for Molecular Medicine Finland, Aarno Palotie / Principal Investigator, Immunomics, Kimmo Kontula Research Group, and Genomics of Neurological and Neuropsychiatric Disorders
Subjects: 0301 basic medicine, AAI12, Chemistry(all), SUSCEPTIBILITY LOCI, Science, Population, General Physics and Astronomy, Physics and Astronomy(all), OF-FUNCTION VARIANTS, Inflammatory bowel disease, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, NUMBER, medicine, Ring finger, IMPUTATION, Allele, education, POPULATION, RISK, education.field_of_study, Multidisciplinary, biology, Biochemistry, Genetics and Molecular Biology(all), MUTATIONS, General Chemistry, ASSOCIATION, medicine.disease, Inflammatory Bowel Diseases, Ulcerative colitis, digestive system diseases, 3. Good health, Ubiquitin ligase, Transport protein, Transmembrane domain, 030104 developmental biology, medicine.anatomical_structure, RARE VARIANTS, Immunology, biology.protein, Cancer research, 3111 Biomedicine, INFLAMMATORY-BOWEL-DISEASE
Abstract: To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain. National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) DK064869 DK062432 National Human Genome Research Institute (NHGRI) DK064869 DK043351 HG005923 Crohns and Colitis Foundation 3765 Leona M. & Harry B. Helmsley Charitable Trust 2015PG-IBD001 Amgen 2013583217 CCFA 3765 Cedars-Sinai F. Widjaja Foundation, info:eu-repo/grantAgreement/EC/FP7/305479, European Union DK062413 AI067068 U54DE023789-01 Leona M. and Harry B. Helmsley Charitable Trust Crohn's and Colitis Foundation of America NIH DK062431 U01 DK062429 U01 DK062422 R01 DK092235 U01 DK062420 Medical Research Council, UK MR/J00314X/1 Wellcome Trust WT091310 098051 Inflammatory Bowel Disease Genetic Research Chair at the University of Pittsburgh PO1DK046763
Published: 2016

25. Role of TLRs and DAMPs in allograft inflammation and transplant outcomes

Author: Daniel R. Goldstein, Steve Chadban, Sophie Brouard, Faouzi Braza, Instituto Gulbenkian de Ciência [Oeiras] (IGC), Fundação Calouste Gulbenkian, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Renal Medicine and Transplantation [Sydney, Australia], Royal Prince Alfred Hospital [Sydney, Australia], Kidney Node [Sydney, Australia] (Charles Perkins Centre), The University of Sydney, Section of Infectious Diseases [New Haven, CT, USA] (Department of Internal Medicine), Yale School of Medicine [New Haven, Connecticut] (YSM), Department of Immunobiology [New Haven, CT, USA] (Yale School of Medicine), Yale University [New Haven], NIH/NIA grant R01AG028082, NHMRC Project Grant funding, the CENTAURE foundation, the IHU-Cesti project and the Nantes Metropole and the Pays de la Loire Region., and Le Bihan, Sylvie
Subjects: 0301 basic medicine, medicine.medical_specialty, Inflammation, Organ transplantation, Article, 03 medical and health sciences, Immunity, medicine, Animals, Humans, HMGB1 Protein, Hyaluronic Acid, Receptor, Innate immune system, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Toll-Like Receptors, Acute kidney injury, Organ Transplantation, medicine.disease, Allografts, Immunity, Innate, 030104 developmental biology, surgical procedures, operative, Nephrology, Immunology, Myeloid Differentiation Factor 88, medicine.symptom, Signal transduction, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction
Abstract: International audience; Graft inflammation impairs the induction of solid organ transplant tolerance and enhances acute and chronic rejection. Elucidating the mechanisms by which inflammation is induced after organ transplantation could lead to novel therapeutics to improve transplant outcomes. In this Review we describe endogenous substances — damage-associated molecular patterns (DAMPs) — that are released after allograft reperfusion and induce inflammation. We also describe innate immune signalling pathways that are activated after solid organ transplantation, with a focus on Toll-like receptors (TLRs) and their signal adaptor, MYD88. Experimental and clinical studies have yielded a large body of evidence that TLRs and MYD88 are instrumental in initiating allograft inflammation and promoting the development of acute and chronic rejection. Ongoing clinical studies are testing TLR inhibition strategies in solid organ transplantation, although avoiding compromising host defence to pathogens is a key challenge. Further elucidation of the mechanisms by which sterile inflammation is induced, maintained and amplified within the allograft has the potential to lead to novel anti-inflammatory treatments that could improve outcomes for solid organ transplant recipients.
Published: 2016

26. Cause-Specific Mortality in HIV-Positive Patients Who Survived Ten Years after Starting Antiretroviral Therapy

Author: Jonathan A C Sterne, Matthias Cavassini, Timothy R. Sterling, Amy C. Justice, Christoph Boesecke, Suzanne M Ingle, Fiona C Lampe, Robert Zangerle, Margaret T May, Victoria Hernando, Heidi M. Crane, Jorg-Janne Vehreschild, Antonella d'Arminio Monforte, Charles Cazanave, Adam Trickey, Colette Smit, José M. Miró, Michael S. Saag, Hasina Samji, Marta Montero, Leah Shepherd, Niels Obel, Sophie Grabar, Michael Gill, Antiretroviral Therapy Cohort Collaboration (ART-CC), University of Bristol [Bristol], Koln University, Köln University, German Centre for Infection Research (DZIF), Partner Site Hamburg, Department of Infectious Diseases [Rigshospitalet], Rigshospitalet [Copenhagen], University of Calgary, University of Washington [Seattle], Rheinische Friedrich-Wilhelms-Universität Bonn, British Columbia Centre for Excellence in HIV/AIDS, St. Paul's Hospital, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Cochin [AP-HP], Université Paris Descartes - Paris 5 (UPD5), Groupe hospitalier Pellegrin, Université de Lausanne (UNIL), UCL Medical School, Università degli studi di Milano [Milano], Stichting HIV Monitoring [Amsterdam], Universiteit van Amsterdam (UvA), University of Alabama [Tuscaloosa] (UA), Instituto Salud Carlos III, Hospital La Fe, Innsbruck Medical University [Austria] (IMU), Yale University School of Medicine, Vanderbilt University [Nashville], Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), German Centre for Infection Research - partner site Hamburg-Lübeck-Borstel-Riems (DZIF), Copenhagen University Hospital-Copenhagen University Hospital, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Università degli Studi di Milano [Milano] (UNIMI), Medical Research Council (Reino Unido), Department for International Development (Reino Unido), Unión Europea, Université de Lausanne = University of Lausanne (UNIL), Università degli Studi di Milano = University of Milan (UNIMI), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Yale School of Medicine [New Haven, Connecticut] (YSM), German Centre for Infection Research ( DZIF ), Department of Infectious Diseases [Copenhagen], Rigshospitalet [Copenhagen]-University of Copenhagen ( KU ), Bonn Universität [Bonn], Institut Pierre Louis d'Epidémiologie et de Santé Publique ( iPLESP ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Paris Descartes - Paris 5 ( UPD5 ), Université de Lausanne ( UNIL ), Universiteit van Amsterdam ( UvA ), University of Alabama [Tuscaloosa] ( UA ), Innsbruck Medical University [Austria] ( IMU ), and Yale School of Medicine
Subjects: 0301 basic medicine, RNA viruses, Male, Pediatrics, Viral Diseases, Cancer Treatment, lcsh:Medicine, HIV Infections, Pathology and Laboratory Medicine, 0302 clinical medicine, Immunodeficiency Viruses, Risk Factors, Medicine and Health Sciences, Medicine, Public and Occupational Health, 030212 general & internal medicine, Young adult, lcsh:Science, [SDV.EE]Life Sciences [q-bio]/Ecology, environment, Multidisciplinary, Transmission (medicine), Mortality rate, Viral Load, Middle Aged, Prognosis, Vaccination and Immunization, 3. Good health, AIDS, Infectious Diseases, Oncology, Medical Microbiology, Viral Pathogens, Cohort, Viruses, Female, Pathogens, Viral load, Cohort study, Research Article, Adult, medicine.medical_specialty, Adolescent, Death Rates, Anti-HIV Agents, Immunology, Antiretroviral Therapy, Microbiology, [ SDV.EE ] Life Sciences [q-bio]/Ecology, environment, 03 medical and health sciences, Young Adult, Acquired immunodeficiency syndrome (AIDS), Antiviral Therapy, Population Metrics, Diagnostic Medicine, Virology, Retroviruses, Humans, Aged, Anti-HIV Agents/pharmacology, Anti-HIV Agents/therapeutic use, Demography, HIV Infections/drug therapy, HIV Infections/mortality, HIV-1/drug effects, HIV-1/physiology, Survival Analysis, Microbial Pathogens, Survival analysis, Population Biology, business.industry, lcsh:R, Lentivirus, Organisms, Biology and Life Sciences, HIV, medicine.disease, 030112 virology, Surgery, People and Places, HIV-1, lcsh:Q, Preventive Medicine, business, Viral Transmission and Infection
Abstract: OBJECTIVES: To estimate mortality rates and prognostic factors in HIV-positive patients who started combination antiretroviral therapy between 1996-1999 and survived for more than ten years. METHODS: We used data from 18 European and North American HIV cohort studies contributing to the Antiretroviral Therapy Cohort Collaboration. We followed up patients from ten years after start of combination antiretroviral therapy. We estimated overall and cause-specific mortality rate ratios for age, sex, transmission through injection drug use, AIDS, CD4 count and HIV-1 RNA. RESULTS: During 50,593 person years 656/13,011 (5%) patients died. Older age, male sex, injecting drug use transmission, AIDS, and low CD4 count and detectable viral replication ten years after starting combination antiretroviral therapy were associated with higher subsequent mortality. CD4 count at ART start did not predict mortality in models adjusted for patient characteristics ten years after start of antiretroviral therapy. The most frequent causes of death (among 340 classified) were non-AIDS cancer, AIDS, cardiovascular, and liver-related disease. Older age was strongly associated with cardiovascular mortality, injecting drug use transmission with non-AIDS infection and liver-related mortality, and low CD4 and detectable viral replication ten years after starting antiretroviral therapy with AIDS mortality. Five-year mortality risk was
Published: 2016

27. Human influence on climate in the 2014 southern England winter floods and their impacts

Author: Chris Huntingford, Alison L. Kay, Simon Wilson, Karsten Haustein, William Ingram, David Wallom, Peter A. Stott, Robert Vautard, Ian Ashpole, Jonathan Miller, S. M. Crooks, Geert Jan van Oldenborgh, Neil Massey, Sarah Sparrow, Jessica Skeggs, Andy Bowery, Rob Lamb, Nathalie Schaller, Richard G. Jones, Tim Legg, Myles R. Allen, Pascal Yiou, Antje Weisheimer, Friederike E. L. Otto, Department of Atmospheric, Oceanic and Planetary Physics [Oxford] (AOPP), University of Oxford, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Computing Laboratory (OUCL), Royal Netherlands Meteorological Institute (KNMI), Max-Planck-Institut für Mathematik in den Naturwissenschaften (MPI-MiS), Max-Planck-Gesellschaft, Laboratoire des Sciences du Climat et de l'Environnement [Gif-sur-Yvette] (LSCE), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Extrèmes : Statistiques, Impacts et Régionalisation (ESTIMR), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre for Ecology and Hydrology (CEH), Natural Environment Research Council (NERC), Centre for Ecology and Hydrology [Wallingford] (CEH), Met Office Hadley Centre for Climate Change (MOHC), United Kingdom Met Office [Exeter], Royal United Hospital, Australian Resources Research Centre, Kensington, Yale School of Medicine [New Haven, Connecticut] (YSM), The MITRE corporation, Department of Atmospheric, Oceanic and Planetary Physics [Oxford] ( AOPP ), University of Oxford [Oxford], Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Computing Laboratory ( OUCL ), Royal Netherlands Meteorological Institute ( KNMI ), Max-Planck-Institut für Mathematik in den Naturwissenschaften, Leipzig ( MPI-MATH ), Max-Planck-Institut, Laboratoire des Sciences du Climat et de l'Environnement [Gif-sur-Yvette] ( LSCE ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Centre for Ecology and Hydrology ( CEH ), Natural Environment Research Council ( NERC ), Centre for Ecology and Hydrology [Wallingford] ( CEH ), Met Office Hadley Centre ( MOHC ), Yale School of Medicine, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), and Yale University School of Medicine
Subjects: [ SDU.OCEAN ] Sciences of the Universe [physics]/Ocean, Atmosphere, 010504 meteorology & atmospheric sciences, Hydrological modelling, 0208 environmental biotechnology, Drainage basin, 02 engineering and technology, Environmental Science (miscellaneous), 01 natural sciences, Meteorology and Climatology, [ SDU.ENVI ] Sciences of the Universe [physics]/Continental interfaces, environment, Precipitation, [SDU.ENVI]Sciences of the Universe [physics]/Continental interfaces, environment, ComputingMilieux_MISCELLANEOUS, 0105 earth and related environmental sciences, [SDU.OCEAN]Sciences of the Universe [physics]/Ocean, Atmosphere, geography, geography.geographical_feature_category, Flood myth, Flooding (psychology), Storm, 6. Clean water, 020801 environmental engineering, 13. Climate action, Climatology, Snowmelt, Environmental science, Climate model, Hydrology, Social Sciences (miscellaneous)
Abstract: A succession of storms reaching Southern England in the winter of 2013/2014 caused severe floods and £451 million insured losses. In a large ensemble of climate model simulations, we find that, as well as increasing the amount of moisture the atmosphere can hold, anthropogenic warming caused a small but significant increase in the number of January days with westerly flow, both of which increased extreme precipitation. Hydrological modelling indicates this increased extreme 30-day-average Thames river flows, and slightly increased daily peak flows, consistent with the understanding of the catchment’s sensitivity to longer-duration precipitation and changes in the role of snowmelt. Consequently, flood risk mapping shows a small increase in properties in the Thames catchment potentially at risk of riverine flooding, with a substantial range of uncertainty, demonstrating the importance of explicit modelling of impacts and relatively subtle changes in weather-related risks when quantifying present-day effects of human influence on climate.
Published: 2016

28. Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex

Author: Derek W. Morris, Carles Soriano-Mas, Tomáš Paus, Henrik Walter, Dick J. Veltman, Yuqi Cheng, Benjamin S. Aribisala, Anna Cattrell, Hilleke E. Hulshoff Pol, Vatche G. Baboyan, Simon E. Fisher, Michael N. Smolka, Saskia P. Hagenaars, Sarah Jurk, Roberto Roiz-Santiañez, Nicholas G. Martin, Lars T. Westlye, Odile A. van den Heuvel, Lucija Abramovic, Jan Egil Nordvik, Guillén Fernández, Jürgen Gallinat, Je Yeon Yun, Benson Mwangi, Ignacio Martínez-Zalacaín, Bernd Kraemer, Gareth J. Barker, José M. Menchón, Marie-Laure Paillère Martinot, Zhen Wang, Jan K. Buitelaar, Jean-Luc Martinot, Herve Lemaitre, Aiden Corvin, Henry Brodaty, Thomas Wolfers, Silvia Brem, Christine Lochner, Derrek P. Hibar, Susanne Walitza, Susana Muñoz Maniega, Premika S.W. Boedhoe, Nathalie Tzourio-Mazoyer, Uli Bromberg, Sonja M C de Zwarte, Dan J. Stein, Mark E. Bastin, Clyde Francks, Tobias U. Hauser, Sinead Kelly, Hugh Garavan, Omar Mothersill, Gary Donohoe, Neda Jahanshad, Greig I. de Zubicaray, Yoshinari Abe, Roel A. Ophoff, Christian Büchel, Esther Walton, Pieter J. Hoekstra, Nils Opel, Gunter Schumann, Jian Xu, Dara M. Cannon, Elena Shumskaya, Ingrid Agartz, Bernhard T. Baune, A. Marten H. Onnink, Tomohiro Nakao, Rosa Ayesa-Arriola, David Mataix-Cols, Sylvane Desrivières, Klaus-Peter Lesch, Paul Pauli, Wei Wen, Nora C. Vetter, Martine Hoogman, Ganesan Venkatasubramanian, Miguel E. Rentería, Ole A. Andreassen, Penny A. Gowland, Ian J. Deary, Patricia J. Conrod, Nicola J. Armstrong, Masaki Fukunaga, Vince D. Calhoun, Volker Arolt, Dimitri Papadopoulos Orfanos, Benedicto Crespo-Facorro, Lachlan T. Strike, Natalie A. Royle, Joanna M. Wardlaw, Sarah E. Medland, Annette Conzelmann, Andrea Gonzalez Suarez, Arun L.W. Bokde, Ryota Hashimoto, Robert Whelan, Michelle Luciano, Pascual Sánchez-Juan, Neeltje E.M. van Haren, Hao Hu, Luise Poustka, Jun Soo Kwon, Hans J. Grabe, Andreas Heinz, Katharina Wittfeld, Michael Gill, Erik G. Jönsson, Frauke Nees, Perminder S. Sachdev, Oliver Gruber, David C. Glahn, Chaim Huyser, Anushree Bose, Herta Flor, Janardhan Y. C. Reddy, Bernd Ittermann, John Blangero, Dennis van der Meer, Andre F. Marquand, Xiufeng Xu, Tulio Guadalupe, Dominik Grotegerd, Jessica A. Turner, Annerine Roos, Tobias Banaschewski, Theo G.M. vanErp, Jean-Paul Fouche, Paul M. Thompson, Alejandro Arias-Vasquez, Christopher D. Whelan, Maria del C. Valdés Hernández, Eric Artiges, Janardhanan C. Narayanaswaamy, Thomas Espeseth, Bernard Mazoyer, Katie L. McMahon, Erlend S. Dørum, Samantha J. Brooks, Samuel R. Mathias, Vincent Frouin, Fleur M. Howells, Barbara Franke, Colm McDonald, Jingjing Zhao, Daniella Vuletic, Nhat Trung Doan, Harald Kugel, Lianne Schmaal, Marcel P. Zwiers, Fabrice Crivello, Anne Uhlmann, Karen A. Mather, René S. Kahn, Roberto Toro, Stefan Ehrlich, Udo Dannlowski, Jair C. Soares, Takashi Nakamae, Margaret J. Wright, RS: MHeNs - R3 - Neuroscience, Psychiatrie & Neuropsychologie, Psychiatry, Anatomy and neurosciences, Amsterdam Neuroscience - Brain Imaging, Child Psychiatry, Other departments, ANS - Complex Trait Genetics, International Max Planck Research School for Language Sciences (IMPRS ), Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Language and Genetics Department [Nijmegen], Yale University [New Haven], Department of Psychiatry and Human Behavior, University of California [Irvine] (UCI), University of California-University of California, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Department of Psychiatry, Graduate School of Medical Science Kyoto Prefectural University of Medicine Kyoto Japan, University Medical Center [Utrecht], KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], University of Oslo (UiO), Department of Human Genetics, Radboud University Medical Center [Nijmegen], Department of Psychiatry, Donders Centre for Neuroscience, Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen], University of Edinburgh, Lagos State University (LASU), Heriot-Watt University [Edinburgh] (HWU), Mental Health Sciences Unit, University College of London [London] (UCL), Adolescent psychopathology and Medicine, CHU Cochin [AP-HP], Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Hospital Sant Joan de Déu [Barcelona], Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), University of Southern California (USC), Department of Child and Adolescent Psychiatry and Psychotherapy [Mannheim], Universität Heidelberg [Heidelberg], Centre for Neuroimaging Sciences, Institute of Psychiatry, King‘s College London, University of Adelaide, The University of Texas Health Science Center at Houston (UTHealth), Texas Biomedical Research Institute [San Antonio, Texas], Discipline of Psychiatry [Dublin], School of Medicine [Dublin], Trinity College Dublin-Trinity College Dublin, VU University Medical Center [Amsterdam], National Institute of Mental Health and Neurosciences [Bagalore, India], Hospital of the University of Pennsylvania, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Dementia Collaborative Research Centre, University of New South Wales [Sydney] (UNSW), Centre for Healthy Brain Ageing, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud university [Nijmegen]-Radboud university [Nijmegen], The Mind Research Network, Department of Electrical and Computer Engineering [Albuquerque] (ECE Department), The University of New Mexico [Albuquerque], Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Institute of Psychiatry, Psychology & Neuroscience, King's College London, Center for disease control, China (Chinese CDC), Center for Disease Control, China, Department of Psychology (Biological Psychology, Clinical Psychology, and Psychotherapy), University of Würzburg, Germany, Tübingen, Würzburg, Germany, Neuropsychiatric Genetics Research Group, Trinity College Dublin, Trinity College Dublin-St. James's Hospital, Groupe d'imagerie neurofonctionnelle (GIN), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), School of Psychology, University of Queensland, University of Queensland [Brisbane], MetaGenoPolis, Institut National de la Recherche Agronomique (INRA), Department of Psychology [Oslo], Faculty of Social Sciences [Oslo], University of Oslo (UiO)-University of Oslo (UiO), sans affiliation, Universität Mannheim [Mannheim], Service NEUROSPIN (NEUROSPIN), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Division of Cerebral Integration National Institute for Physiological Sciences Okazaki Japan, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, University of Calgary, Sir Peter Mansfield Magnetic Resonance Centre [Nottingham], University of Nottingham, UK (UON), Department of Psychiatry and Psychotherapy, HELIOS Klinikum Stralsund Hanseatic-Greifswald University Hospital, Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University [Osaka], University Clinic for Child and Adolescent Psychiatry (UCCAP), University of Zürich [Zürich] (UZH), University Medical Center Groningen [Groningen] (UMCG), Department of Medicine, Clinical Pharmacology Unit, Karolinska University Hospital [Stockholm], Brain Centre Rudolf Magnus [Utrecht], MetaCase [Jyväskylä], Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center, Goettingen 37075, Germany, Department of Psychiatry & Behavioral Science Seoul National University College of Medicine Seoul Republic of Korea, Université de Cergy Pontoise (UCP), Université Paris-Seine, Institute of Human Genetics, Rheinische Friedrich-Wilhelms-Universität Bonn, Medstar Research Institute, Neuroimagerie en psychiatrie (U1000), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), IFR de Neuroimagerie Fonctionnelle (IFR 49), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia, Department of Life Sciences, Imperial College London, Centre for Advanced Imaging, Queensland Institute of Medical Research, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Universitat de Barcelona (UB), National University of Ireland [Galway] (NUI Galway), Climate Change Unit [Ispra], JRC Institute for Environment and Sustainability (IES), European Commission - Joint Research Centre [Ispra] (JRC)-European Commission - Joint Research Centre [Ispra] (JRC), Sunnaas Rehabilitation Hospital HT Nesodden Norway, University Medical Center [Utrecht]-Brain Center Rudolf Magnus, McConnell Brain Imaging Centre (MNI), Montreal Neurological Institute and Hospital, McGill University-McGill University, Texas A&M University [College Station], QIMR Berghofer Medical Research Institute, Universiteit van Amsterdam (UvA), Centre for Healthy Brain Ageing [Sydney], The University of Sydney, CIBER de Enfermedades Neurodegenerativas (CIBERNED), Göttingen Zentrum Geowissenschaften, Georg-August-Universität Göttingen, Technische Universität Dresden (TUD), Instituto de Geociências, Universidade de Brasília, Magnetic Resonance Imaging, Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa, Centre for Advanced Imaging, University of Queensland, Brisbane 4072, Australia, School of Psychology, University of Queensland, Brisbane 4072, Australia, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], University of York [York, UK], Centre for Cognitive Ageing & Cognitive Epidemiology, Department of Anatomy & Neurosciences, VU University Medical Center, Amsterdam, The Netherlands, University of Twente [Netherlands], Berlin School of Mind and Brain [Berlin], Humboldt Universität zu Berlin, Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Department of Computational and Applied Mathematics [Houston], Rice University [Houston], Department of Physics [Kowloon], Hong Kong University of Science and Technology (HKUST), University College Dublin [Dublin] (UCD), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Greifswald University Hospital, University of Missouri [Columbia], University of Missouri System, Mechanics surfaces and materials processing (MSMP), École Nationale Supérieure d'Arts et Métiers (ENSAM), Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM), Department of Genetics, North Carolina State University [Raleigh] (NC State), University of North Carolina System (UNC)-University of North Carolina System (UNC), Dpt of Psychiatry [New Haven], Yale University School of Medicine, University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Radboud University [Nijmegen], Radboud University [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud University [Nijmegen]-Radboud University Medical Center [Nijmegen], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universität Heidelberg [Heidelberg] = Heidelberg University, Texas Biomedical Research Institute [San Antonio, TX], University of Pennsylvania-University of Pennsylvania, Radboud University [Nijmegen]-Radboud University [Nijmegen], [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Sans affiliation, Universität Mannheim, Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Universität Zürich [Zürich] = University of Zurich (UZH), Seoul National University [Seoul] (SNU), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), Georg-August-University = Georg-August-Universität Göttingen, Technische Universität Dresden = Dresden University of Technology (TU Dresden), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), University of Twente, Humboldt University Of Berlin, Centre épigénétique et destin cellulaire (EDC), Department of Physics [Hong Kong University of Science and Technology], University of Missouri [Columbia] (Mizzou), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Yale School of Medicine [New Haven, Connecticut] (YSM), Hal, GIN, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen], Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), Georg-August-University [Göttingen], Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Humboldt-Universität zu Berlin, International Max Planck Research School for Language Sciences ( IMPRS ), Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen 6525 XD, The Netherlands, Department of Psychiatry Yale School of Medicine New Haven USA, University of California [Irvine] ( UCI ), Laboratory of Neuro Imaging, David Geffen School of Medicine, University of California, Los Angeles, California, USA, Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands, University of Oslo ( UiO ) -Institute of Clinical Medicine-Oslo University Hospital, NORMENT - KG Jebsen Centre, Institute of Clinical Medicine, University of Oslo, Oslo N-0316, Norway, Donders Centre for Neuroscience, Radboud University Nijmegen Medical Centre, Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration, Department of Neuroimaging Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK, Department of Computer Science, Lagos State University, Lagos, Nigeria, Brain Research Imaging Centre, University of Edinburgh, Edinburgh EH4 2XU, UK, Heriot-Watt University [Edinburgh] ( HWU ), University College of London [London] ( UCL ), Centro de Investigación Biomédica en Red de Salud Mental ( CIBERSAM ), Cibersam (Centro Investigación Biomédica en Red Salud Mental), Madrid 28029, Spain, Imaging Genetics Center, Mark & Mary Stevens Neuroimaging & Informatics Institute, University of Southern California, Marina del Rey, CA, USA, The University of Adelaide, University of Texas Health Science Center, San Antonio, Texas 78229, USA, Texas Biomedical Research Institute, San Antonio, Texas 78245, USA, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, India, Hospital of the University of Pennsylvania, University of New South Wales [Sydney] ( UNSW ), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] ( UKE ), The Mind Research Network & LBERI, Albuquerque, New Mexico 87106, USA, Department of ECE, University of New Mexico, Albuquerque, New Mexico 87131, USA, National Institutes of Health ( NIH ) -National Institute of Mental Health (NIMH), King's College, Center for disease control, China ( Chinese CDC ), GIN - IMN UMR 5293 CNRS CEA Université de Bordeaux, Institut des Maladies Neurodégénératives [Bordeaux] ( IMN ), Université de Bordeaux ( UB ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Bordeaux ( UB ) -Centre National de la Recherche Scientifique ( CNRS ), Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK, MRC- SGDP Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK, Institut Armand Frappier ( INRS-IAF ), Institut National de la Recherche Scientifique [Québec] ( INRS ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut Armand Frappier, NORMENT - KG Jebsen Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo 0424, Norway, Institut national de la recherche agronomique [Jouy en Josas] ( INRA Jouy en Josas ), Department of Psychology, University of Oslo, Oslo 0373, Norway, Service NEUROSPIN ( NEUROSPIN ), Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Charite-Universitatsmedizin Berlin [Berlin], University of Nottingham, UK ( UON ), University Medicine Greifswald,-HELIOS Hospital Stralsund, Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Osaka 565-0871, Japan, (UCCAP) University of Zurich Zurich Switzerland, University Medical Center Groningen, University of Groningen, Karolinska University Hospital (Solna), Université de Cergy Pontoise ( UCP ), Bonn Universität [Bonn], Institut de Physique Nucléaire d'Orsay ( IPNO ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Centre National de la Recherche Scientifique ( CNRS ), Neuroimagerie en psychiatrie ( U1000 ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), IFR de Neuroimagerie Fonctionnelle ( IFR 49 ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] ( IDIBELL ), Universitat de Barcelona ( UB ), National University of Ireland [Galway] ( NUI Galway ), JRC Institute for Environment and Sustainability ( IES ), European Commission - Joint Research Centre [Ispra] ( JRC ) -European Commission - Joint Research Centre [Ispra] ( JRC ), University Medical Center Utrecht-Brain Center Rudolf Magnus, McConnell Brain Imaging Centre ( MNI ), Montreal Neurological Institute [Montréal], Universiteit van Amsterdam ( UvA ), The University of Sydney [Sydney], Department of Psychiatry, Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam 1081 HL, The Netherlands, Technische Universität Dresden ( TUD ), Génétique humaine et Fonctions cognitives - Human Genetics and Cognitive Functions, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Centre épigénétique et destin cellulaire ( EDC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Hong Kong University of Science and Technology ( HKUST ), University College Dublin [Dublin] ( UCD ), German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, Greifswald 17487, Germany, Department of Psychiatry, University Medicine Greifswald, Greifswald 17489, Germany, University of Missouri-Columbia, Mechanics surfaces and materials processing ( MSMP ), North Carolina State University [Raleigh] ( NCSU ), and Yale School of Medicine
Subjects: Male, Aging, Planum temporale, Caudate nucleus, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], Subcortical brain asymmetry, Functional Laterality, Behavioral Neuroscience, 0302 clinical medicine, pathology [Aging], ddc:150, 130 000 Cognitive Neurology & Memory, Basal ganglia, YOUNG-ADULTS, Brain asymmetry, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Handedness, Original Research, Sex Characteristics, Age, Enigma, Heritability, Meta-analysis, Sex, Putamen, 05 social sciences, Brain, Human brain, Organ Size, Middle Aged, Magnetic Resonance Imaging, AMYGDALA VOLUME, Psychiatry and Mental health, genetics [Functional Laterality], Globus pallidus, medicine.anatomical_structure, Neurology, BASAL GANGLIA VOLUMES, Radiology Nuclear Medicine and imaging, genetics [Aging], [ SCCO.NEUR ] Cognitive science/Neuroscience, CAUDATE-NUCLEUS, Female, Psychology, Sex characteristics, MRI, Neuroinformatics, Adult, Adolescent, Cognitive Neuroscience, Clinical Neurology, BF, HAND PREFERENCE, 050105 experimental psychology, 150 000 MR Techniques in Brain Function, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, Quantitative Trait, Heritable, Meta-Analysis as Topic, medicine, Journal Article, Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, diagnostic imaging [Brain], Aged, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], [SCCO.NEUR]Cognitive science/Neuroscience, TOURETTE-SYNDROME, [SCCO.NEUR] Cognitive science/Neuroscience, PLANUM TEMPORALE, NORMAL INDIVIDUALS, HEMISPHERIC-DIFFERENCES, nervous system, RC0321, Neurology (clinical), Neuroscience, anatomy & histology [Brain], 030217 neurology & neurosurgery
Abstract: The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders. Electronic supplementary material The online version of this article (doi:10.1007/s11682-016-9629-z) contains supplementary material, which is available to authorized users.
Published: 2016

29. Chitin Particles Are Multifaceted Immune Adjuvants

Author: Carla A. Da Silva, Jack A. Elias, Pierre Pochard, Chun Geun Lee, Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Immunobiology, Yale School of Medicine [New Haven, Connecticut] (YSM), Animal, Food and Health Sciences, Commonwealth Scientific and Industrial Research Organisation [Canberra] (CSIRO), Laboratoire d'Informatique Paris Descartes (LIPADE - EA 2517), Université Paris Descartes - Paris 5 (UPD5), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Yale University School of Medicine, CEA-Institut de génomique-genoscope, Yale School of Medicine, Commonwealth Scientific and Industrial Research Organisation, and Michel, Geneviève
Subjects: MESH: Interleukin-17, medicine.medical_treatment, Chitin, MESH: Adjuvants, Immunologic, Adaptive Immunity, Lymphocyte Activation, Critical Care and Intensive Care Medicine, MESH: Chitin, Mice, chemistry.chemical_compound, 0302 clinical medicine, MESH: Animals, Lung, chemistry.chemical_classification, Immunity, Cellular, 0303 health sciences, Interleukin-17, MESH: Toll-Like Receptor 2, respiratory system, 3. Good health, [SDV.IMM]Life Sciences [q-bio]/Immunology, Adjuvant, Pulmonary and Respiratory Medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, macromolecular substances, Biology, Polysaccharide, MESH: Immunity, Cellular, Microbiology, 03 medical and health sciences, Th2 Cells, Immune system, Adjuvants, Immunologic, MESH: Mice, Inbred C57BL, MESH: Th2 Cells, In vivo, Intensive care, medicine, Animals, MESH: Lung, MESH: Lymphocyte Activation, MESH: Mice, 030304 developmental biology, fungi, Th1 Cells, Toll-Like Receptor 2, A. Asthma and Allergy, Mice, Inbred C57BL, carbohydrates (lipids), Disease Models, Animal, Ovalbumin, MESH: Th1 Cells, chemistry, biology.protein, MESH: Disease Models, Animal, MESH: Adaptive Immunity, Ex vivo, 030215 immunology
Abstract: International audience; Chitin is a ubiquitous polysaccharide in fungi, insects, allergens, and parasites that is released at sites of infection. Its role in the generation of tissue inflammation, however, is not fully understood. We hypothesized that chitin is an important adjuvant for adaptive immunity. Mice were injected with a solution of ovalbumin and chitin. We used in vivo and ex vivo/in vitro approaches to characterize the ability of chitin fragments to foster adaptive immune responses against ovalbumin and compared these responses to those induced by aluminum hydroxide (alum). In vivo, ovalbumin challenge caused an eosinophil-rich pulmonary inflammatory response, Th2 cytokine elaboration, IgE induction, and mucus metaplasia in mice that had been sensitized with ovalbumin plus chitin or ovalbumin plus alum. Toll-like receptor-2, MyD88, and IL-17A played critical roles in the chitin-induced responses, and MyD88 and IL-17A played critical roles in the alum-induced responses. In vitro, CD4(+) T cells from mice sensitized with ovalbumin plus chitin were incubated with ovalbumin-stimulated bone marrow-derived dendritic cells. In these experiments, CD4(+) T-cell proliferation, IL-5, IL-13, IFN-γ, and IL-17A production were appreciated. Toll-like receptor-2, MyD88, and IL-17A played critical roles in these in vitro adjuvant properties of chitin. TLR-2 was required for cell proliferation, whereas IL-17 and TLR-2 were required for cytokine elaboration. IL-17A also inhibited the generation of adaptive Th1 responses. These studies demonstrate that chitin is a potent multifaceted adjuvant that induces adaptive Th2, Th1, and Th17 immune responses. They also demonstrate that the adjuvant properties of chitin are mediated by a pathway(s) that involves and is regulated by TLR-2, MyD88, and IL-17A.
Published: 2010

30. The radiologically isolated syndrome: revised diagnostic criteria

Author: Lebrun-Frénay, Christine, Okuda, Darin, Siva, Aksel, Landes-Chateau, Cassandre, Azevedo, Christina, Mondot, Lydiane, Carra-Dallière, Clarisse, Zephir, Helene, Louapre, Celine, Durand-Dubief, Françoise, Le Page, Emmanuelle, Bensa, Caroline, Ruet, Aurélie, Ciron, Jonathan, Laplaud, David, Casez, Olivier, Mathey, Guillaume, de Seze, Jerome, Zeydan, Burcu, Makhani, Naila, Tutuncu, Melih, Levraut, Michael, Cohen, Mikael, Thouvenot, Eric, Pelletier, Daniel, Kantarci, Orhun, Sehaki, Sabrina, Devys-Meyer, Nathalie, Bereau, Mathieu, Cappe, Chrystelle, Brochet, Bruno, Ouallet, Jean-Christophe, Kounkou, Katy-Kim, Defer, Gilles, Branger, Pierre, Taithe, Frédéric, Dumont, Emilie, Lescieux, Edwige, Fromont, Agnès, Protin, Alexia, Kane, Maty Diop, Hautecoeur, Patrick, Outteryck, Olivier, Vermersch, Patrick, Boucher, Julie, Petit, Julie, Kasonde, Irène Tabellah, de Vilmarrest, Aymeric, Magy, Laurent, Nicol, Marie, Malbezin, Muriel, Olaiz, Javier, Rigaud-Bully, Claire, Debard, Nadine, Cotton, Sandra Vukusic François, Ionescu, Iuliana, Abdelalli, Amalle, Pelletier, Jean, Audoin, Bertrand, Maarouf, Adil, Di Lelio, Bernadette, Ayrignac, Xavier, Labauge, Pierre, Pinna, Frédéric, Guillemin, Francis, Debouverie, Marc, Ziegler, Amandine, Wiertlevski, Sandrine, Bresch, Saskia, Callier, Céline, David, Elodie, Castelnovo, Giovanni, Papeix, Caroline, Maillart, Elisabeth, Lubetzki, Catherine, Zehrouni, Karima, Fontaine, Bertrand, Giannesini, Claire, Hodel, Jérôme, Wahab, Abir, Zedet, Mickaël, Fagniez, Ombeline, Laage, Clémence, Pottier, Corinne, Slesari, Iuliana, Sampaio, Mathilde, Rabois, Emilie, Castex, Cédric, Hebant, Benjamin, Guillaume, Maxime, Vimont, Christine, Gout, Olivier, Guegen, Antoine, Michel, Laure, Muraz, Romain, Le Port, Damien, Leray, Emmanuelle, Henry, Carole, de Broucker, Thomas, Collongues, Nicolas, Berthe, Carole, Biotti, Damien, Freitas, Noellie, Visneux, Vincent, Forestier, Mélanie, Beltran, Stéphane, Meunier, Géraldine, Servan, Jérôme, Pico, Fernando, Chatagner, Virginie, Radji, Fatai, Morel, Nathalie, Grosset-Jeannin, Deborah, Ungureanu, Aurelian, Boyer, Latine, Suchet, Laurent, Lebrun-Frenay, Christine, Centre Hospitalier Universitaire de Nice (CHU Nice), Université Côte d'Azur (UCA), Unité de Recherche Clinique de la Côte d’Azur (URRIS UR2CA), Centre Hospitalier Universitaire de Nice (CHU Nice)-Université Côte d'Azur (UCA), University of Texas Southwestern Medical Center [Dallas], Cerrahpasa Faculty of Medicine, Istanbul University, University of Southern California (USC), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Lille, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale (U1215 Inserm - UB), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CIC Plurithématique de Nantes, Institut National de la Santé et de la Recherche Médicale (INSERM)-Ministère des Affaires sociales et de la Santé-Direction générale de l'offre de soins (DGOS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Translational Research in Autoimmunity and Inflammation Group (TIMC-T-RAIG), Translational Innovation in Medicine and Complexity / Recherche Translationnelle et Innovation en Médecine et Complexité - UMR 5525 (TIMC ), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Adaptation, mesure et évaluation en santé. Approches interdisciplinaires (APEMAC), Université de Lorraine (UL), CHU Strasbourg, CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], Mayo Clinic [Rochester], Yale School of Medicine [New Haven, Connecticut] (YSM), Service de Neurologie [CHU Nimes] (Pôle NIRR), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and None
Subjects: [SCCO.NEUR]Cognitive science/Neuroscience, diagnostic criteria, radiologically isolated syndrome, Neurology (clinical), prognosis, multiple sclerosis, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MRI
Abstract: The radiologically isolated syndrome (RIS) was defined in 2009 as the presence of asymptomatic, incidentally identified demyelinating-appearing white matter lesions in the CNS within individuals lacking symptoms typical of multiple sclerosis (MS). The RIS criteria have been validated and predict the transition to symptomatic MS reliably. The performance of RIS criteria that require fewer MRI lesions is unknown. 2009-RIS subjects, by definition, fulfil three to four of four criteria for 2005 dissemination in space (DIS) and subjects fulfilling only one or two lesions in at least one 2017 DIS location were identified within 37 prospective databases. Univariate and multivariate Cox regression models were used to identify predictors of a first clinical event. Performances of different groups were calculated. Seven hundred and forty-seven subjects (72.2% female, mean age 37.7 ± 12.3 years at the index MRI) were included. The mean clinical follow-up time was 46.8 ± 45.4 months. All subjects had focal T2 hyperintensities suggestive of inflammatory demyelination on MRI; 251 (33.6%) fulfilled one or two 2017 DIS criteria (designated as Groups 1 and 2, respectively), and 496 (66.4%) fulfilled three or four 2005 DIS criteria representing 2009-RIS subjects. Group 1 and 2 subjects were younger than the 2009-RIS group and were more likely to develop new T2 lesions over time (P < 0.001). Groups 1 and 2 were similar regarding survival distribution and risk factors for transition to MS. At 5 years, the cumulative probability for a clinical event was 29.0% for Groups 1 and 2 compared to 38.7% for 2009-RIS (P = 0.0241). The presence of spinal cord lesions on the index scan and CSF-restricted oligoclonal bands in Groups 1–2 increased the risk of symptomatic MS evolution at 5 years to 38%, comparable to the risk of development in the 2009-RIS group. The presence of new T2 or gadolinium-enhancing lesions on follow-up scans independently increased the risk of presenting with a clinical event (P < 0.001). The 2009-RIS subjects or Groups 1 and 2 with at least two of the risk factors for a clinical event demonstrated better sensitivity (86.0%), negative predictive value (73.1%), accuracy (59.8%) and area under the curve (60.7%) compared to other criteria studied. This large prospective cohort brings Class I evidence that subjects with fewer lesions than required in the 2009 RIS criteria evolve directly to a first clinical event at a similar rate when additional risk factors are present. Our results provide a rationale for revisions to existing RIS diagnostic criteria.
Published: 2023

31. IFT81, encoding an IFT-B core protein, as a very rare cause of a ciliopathy phenotype

Author: Josseline Kaplan, Tania Attié-Bitach, Meriem Garfa-Traore, Michael Taschner, Esben Lorentzen, Catherine Caillaud, Markus Schueler, Hanan M. Fathy, Xavier Gérard, Valérie Cormier-Daire, Heon Yung Gee, Nathalie Boddaert, Richard P. Lifton, Jonathan D. Porath, Jennifer A. Lawson, Jan Halbritter, Daniela A. Braun, Sophie Saunier, Friedhelm Hildebrandt, Philippe Bastin, Sophie Thomas, Edgar A. Otto, Jean-Michel Rozet, Isabelle Perrault, Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Division of Nephrology, Boston Children's Hospital, University Clinic, Leipzig, Pediatric Nephrology Unit, University of Alexandria, Service de Radiologie et imagerie médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Max Planck Institute for Biochemistry, Max-Planck-Institut, Yale School of Medicine, University of Michigan [Ann Arbor], Biologie Cellulaire des Trypanosomes, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), CHU Necker - Enfants Malades [AP-HP], Howard Hughes Medical Institute [Chevy Chase] ( HHMI ), Howard Hugues Medical Institute, This work was further supported by grants from the following funding agencies: the National Institutes of Health (NIH) to FH (DK068308), the ‘Agence Nationale de la Recherche’ (ANR) to SS and TA (20100BLAN112202, ANR-10-IAHY-01), the ‘Fondation pour la Recherche Médicale’ to SS (DEQ20130326532), the ‘Institut National de la Santé et de la Recherche Médicale’ (INSERM), the ‘Imagine Institute’, the ‘Association Retina France’ and PHRC GENPHENACL to JMR and JK. FH is an Investigator of the Howard Hughes Medical Institute (HHMI) and a Warren E Grupe Professor. The authors declare that they have no competing financial interests., ANR : IAHY, ANR-10-IAHY-01, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Alexandria University [Alexandrie], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Max-Planck-Institut für Biochemie = Max Planck Institute of Biochemistry (MPIB), Max-Planck-Gesellschaft, Yale School of Medicine [New Haven, Connecticut] (YSM), University of Michigan System, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), Lassailly-Bondaz, Anne, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Max Planck Institute of Biochemistry (MPIB), Yale University School of Medicine, and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: Candidate gene, Muscle Proteins, Biology, medicine.disease_cause, Eye, Kidney, Ciliopathies, Intraflagellar transport, Nephronophthisis, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, GLI2, medicine, Genetics, Humans, Molecular genetics, Cilia, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Genetics (clinical), Mutation, Renal Medicine, Cilium, New Loci, Sequence Analysis, DNA, medicine.disease, Ciliopathy, Ophthalmology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, sense organs
Abstract: International audience; Background Bidirectional intraflagellar transport (IFT) consists of two major protein complexes, IFT-A and IFT-B. In contrast to the IFT-B complex, all components of IFT-A have recently been linked to human ciliopathies when defective. We therefore hypothesised that mutations in additional IFT-B encoding genes can be found in patients with multisystemic ciliopathies. Methods We screened 1628 individuals with renoocular ciliopathies by targeted next-generation sequencing of ciliary candidate genes, including all IFT-B encoding genes. Results Consequently, we identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly. Further, we detected a loss-of-stop mutation with extension of the deduced protein by 10 amino acids in an individual with neuronal ceroid lipofuscinosis-1. This proband presented with retinal dystrophy and brain lesions including cerebellar atrophy, a phenotype to which the IFT81 variant might contribute. Cultured fibroblasts of this latter affected individual showed a significant decrease in ciliated cell abundance compared with controls and increased expression of the transcription factor GLI2 suggesting deranged sonic hedgehog signalling. Conclusions This work describes identification of mutations of IFT81 in individuals with symptoms consistent with the clinical spectrum of ciliopathies. It might represent the rare case of a core IFT-B complex protein found associated with human disease. Our data further suggest that defects in the IFT-B core are an exceedingly rare finding, probably due to its indispensable role for ciliary assembly in development.
Published: 2015

32. Common genetic variants influence human subcortical brain structures

Author: Hibar, Derrek P, Stein, Jason L, Aribisala, Benjamin S, de Zubicaray, Greig I, Dillman, Allissa, Duggirala, Ravi, Dyer, Thomas D, Erk, Susanne, Fedko, Iryna O, Ferrucci, Luigi, Foroud, Tatiana M, Fox, Peter T, Fukunaga, Masaki, Armstrong, Nicola J, Gibbs, J Raphael, Göring, Harald H H, Green, Robert C, Guelfi, Sebastian, Hansell, Narelle K, Hartman, Catharina A, Hegenscheid, Katrin, Heinz, Andreas, Hernandez, Dena G, Heslenfeld, Dirk J, Bernard, Manon, Hoekstra, Pieter J, Holsboer, Florian, Homuth, Georg, Hottenga, Jouke-Jan, Ikeda, Masashi, Jack, Clifford R, Jenkinson, Mark, Johnson, Robert, Kanai, Ryota, Keil, Maria, Bohlken, Marc M, Kent, Jack W, Kochunov, Peter, Kwok, John B, Lawrie, Stephen M, Liu, Xinmin, Longo, Dan L, McMahon, Katie L, Meisenzahl, Eva, Melle, Ingrid, Mohnke, Sebastian, Boks, Marco P, Montgomery, Grant W, Mostert, Jeanette C, Mühleisen, Thomas W, Nalls, Michael A, Nichols, Thomas E, Nilsson, Lars G, Nöthen, Markus M, Ohi, Kazutaka, Olvera, Rene L, Perez-Iglesias, Rocio, Bralten, Janita, Pike, G Bruce, Potkin, Steven G, Reinvang, Ivar, Reppermund, Simone, Rietschel, Marcella, Romanczuk-Seiferth, Nina, Rosen, Glenn D, Rujescu, Dan, Schnell, Knut, Schofield, Peter R, Brown, Andrew A, Smith, Colin, Steen, Vidar M, Sussmann, Jessika E, Thalamuthu, Anbupalam, Toga, Arthur W, Traynor, Bryan J, Troncoso, Juan, Turner, Jessica A, Valdés Hernández, Maria C, van 't Ent, Dennis, Chakravarty, M Mallar, van der Brug, Marcel, van der Wee, Nic J A, van Tol, Marie-Jose, Veltman, Dick J, Wassink, Thomas H, Westman, Eric, Zielke, Ronald H, Zonderman, Alan B, Ashbrook, David G, Hager, Reinmar, Chen, Qiang, Lu, Lu, McMahon, Francis J, Morris, Derek W, Williams, Robert W, Brunner, Han G, Buckner, Randy L, Buitelaar, Jan K, Cahn, Wiepke, Calhoun, Vince D, Cavalleri, Gianpiero L, Ching, Christopher R K, Crespo-Facorro, Benedicto, Dale, Anders M, Davies, Gareth E, Delanty, Norman, Depondt, Chantal, Djurovic, Srdjan, Drevets, Wayne C, Espeseth, Thomas, Gollub, Randy L, Ho, Beng-Choon, Renteria, Miguel E, Cuellar-Partida, Gabriel, Hoffmann, Wolfgang, Hosten, Norbert, Kahn, René S, Le Hellard, Stephanie, Meyer-Lindenberg, Andreas, Müller-Myhsok, Bertram, Nauck, Matthias, Nyberg, Lars, Pandolfo, Massimo, Penninx, Brenda W J H, den Braber, Anouk, Roffman, Joshua L, Sisodiya, Sanjay M, Smoller, Jordan W, van Bokhoven, Hans, van Haren, Neeltje E M, Völzke, Henry, Walter, Henrik, Weiner, Michael W, Wen, Wei, White, Tonya, Giddaluru, Sudheer, Agartz, Ingrid, Andreassen, Ole A, Blangero, John, Boomsma, Dorret I, Brouwer, Rachel M, Cannon, Dara M, Cookson, Mark R, de Geus, Eco J C, Deary, Ian J, Donohoe, Gary, Goldman, Aaron L, Fernández, Guillén, Fisher, Simon E, Francks, Clyde, Glahn, David C, Grabe, Hans J, Gruber, Oliver, Hardy, John, Hashimoto, Ryota, Hulshoff Pol, Hilleke E, Jönsson, Erik G, Grimm, Oliver, Kloszewska, Iwona, Lovestone, Simon, Mattay, Venkata S, Mecocci, Patrizia, McDonald, Colm, McIntosh, Andrew M, Ophoff, Roel A, Paus, Tomas, Pausova, Zdenka, Ryten, Mina, Guadalupe, Tulio, Sachdev, Perminder S, Saykin, Andrew J, Simmons, Andy, Singleton, Andrew, Soininen, Hilkka, Wardlaw, Joanna M, Weale, Michael E, Weinberger, Daniel R, Adams, Hieab H H, Launer, Lenore J, Hass, Johanna, Seiler, Stephan, Schmidt, Reinhold, Chauhan, Ganesh, Satizabal, Claudia L, Becker, James T, Yanek, Lisa, van der Lee, Sven J, Ebling, Maritza, Fischl, Bruce, Longstreth, W. T., Woldehawariat, Girma, Greve, Douglas, Schmidt, Helena, Nyquist, Paul, Vinke, Louis N, van Duijn, Cornelia M, Xue, Luting, Mazoyer, Bernard, Bis, Joshua C, Gudnason, Vilmundur, Seshadri, Sudha, Holmes, Avram J, Ikram, M Arfan, Initiative, Alzheimer’s Disease Neuroimaging, Consortium, CHARGE, EPIGEN, IMAGEN, SYS, Martin, Nicholas G, Wright, Margaret J, Schumann, Gunter, Franke, Barbara, Hoogman, Martine, Thompson, Paul M, Medland, Sarah E, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jagust, William, Trojanowki, John Q, Beckett, Laurel, Arias-Vasquez, Alejandro, Janowitz, Deborah, Morris, John, Shaw, Leslie M, Khachaturian, Zaven, Sorensen, Greg, Carrillo, Maria, Kuller, Lew, Raichle, Marc, Paul, Steven, Jia, Tianye, Davies, Peter, Fillit, Howard, Hefti, Franz, Holtzman, Davie, Mesulman, M Marcel, Potter, William, Snyder, Peter, Schwartz, Adam, Montine, Tom, Kim, Sungeun, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Jiminez, Gus, Harvey, Danielle, Klein, Marieke, Bernstein, Matthew, Fox, Nick, Thompson, Paul, Schuff, Norbert, DeCarli, Charles, Borowski, Bret, Gunter, Jeff, Senjem, Matt, Kraemer, Bernd, Vemuri, Prashanthi, Jones, David, Kantarci, Kejal, Ward, Chad, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Lee, Phil H, Landau, Susan, Cairns, Nigel J, Householder, Erin, Taylor-Reinwald, Lisa, Trojanowki, J. Q., Shaw, Les, Lee, Virginia M Y, Korecka, Magdalena, Figurski, Michal, Olde Loohuis, Loes M, Crawford, Karen, Neu, Scott, Potkin, Steven, Shen, Li, Faber, Kelley, Nho, Kwangsik, Luciano, Michelle, Thal, Leon, Frank, Richard, Snyder, Peter J, Buckholtz, Neil, Macare, Christine, Albert, Marilyn, Hsiao, John, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Carter, Raina, Dolen, Sara, Gutman, Boris A, Schneider, Lon S, Mather, Karen A, Pawluczyk, Sonia, Beccera, Mauricio, Teodoro, Liberty, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Fleisher, Adam, Heidebrink, Judith L, Lord, Joanne L, Desrivières, Sylvane, Mattheisen, Manuel, Mason, Sara S, Albers, Colleen S, Knopman, David, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Rountree, Susan, Dang, Mimi, Stern, Yaakov, Milaneschi, Yuri, Honig, Lawrence S, Bell, Karen L, Ances, Beau, Morris, John C, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, Oliver, Angela, Marson, Daniel, Griffith, Randall, Clark, David, Geldmacher, David, Brockington, John, Roberson, Erik, Grossman, Hillel, Mitsis, Effie, deToledo-Morrell, Leyla, Shah, Raj C, Papmeyer, Martina, Duara, Ranjan, Varon, Daniel, Greig, Maria T, Roberts, Peggy, Onyike, Chiadi, D'Agostino, Daniel, Kielb, Stephanie, Galvin, James E, Pogorelec, Dana M, Ramasamy, Adaikalavan, Cerbone, Brittany, Michel, Christina A, Rusinek, Henry, de Leon, Mony J, Glodzik, Lidia, De Santi, Susan, Doraiswamy, P Murali, Petrella, Jeffrey R, Wong, Terence Z, Arnold, Steven E, Risacher, Shannon L, Karlawish, Jason H, Wolk, David, Smith, Charles D, Jicha, Greg, Hardy, Peter, Sinha, Partha, Oates, Elizabeth, Conrad, Gary, Lopez, Oscar L, Oakley, MaryAnn, Roiz-Santiañez, Roberto, Simpson, Donna M, Porsteinsson, Anton P, Goldstein, Bonnie S, Martin, Kim, Makino, Kelly M, Ismail, M Saleem, Brand, Connie, Mulnard, Ruth A, Thai, Gaby, Mc-Adams-Ortiz, Catherine, Rose, Emma J, Womack, Kyle, Mathews, Dana, Quiceno, Mary, Diaz-Arrastia, Ramon, King, Richard, Weiner, Myron, Martin-Cook, Kristen, DeVous, Michael, Levey, Allan I, Lah, James J, Salami, Alireza, Cellar, Janet S, Burns, Jeffrey M, Anderson, Heather S, Swerdlow, Russell H, Apostolova, Liana, Tingus, Kathleen, Woo, Ellen, Silverman, Daniel H S, Lu, Po H, Bartzokis, George, Sämann, Philipp G, Graff-Radford, Neill R, Parfitt, Francine, Kendall, Tracy, Johnson, Heather, Farlow, Martin R, Hake, Ann Marie, Matthews, Brandy R, Herring, Scott, Hunt, Cynthia, van Dyck, Christopher H, Jahanshad, Neda, Schmaal, Lianne, Carson, Richard E, MacAvoy, Martha G, Chertkow, Howard, Bergman, Howard, Hosein, Chris, Black, Sandra, Stefanovic, Bojana, Caldwell, Curtis, Hsiung, Yuek Robin, Feldman, Howard, Schork, Andrew J, Mudge, Benita, Assaly, Michele, Kertesz, Andrew, Rogers, John, Trost, Dick, Bernick, Charles, Munic, Donna, Kerwin, Diana, Mesulam, Marek-Marsel, Lipowski, Kristine, Shin, Jean, Wu, Chuang-Kuo, Johnson, Nancy, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Turner, Raymond Scott, Johnson, Kathleen, Reynolds, Brigid, Sperling, Reisa A, Johnson, Keith A, Strike, Lachlan T, Marshall, Gad, Frey, Meghan, Yesavage, Jerome, Taylor, Joy L, Lane, Barton, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan N, Belden, Christine M, Jacobson, Sandra A, Teumer, Alexander, Sirrel, Sherye A, Kowall, Neil, Killiany, Ronald, Budson, Andrew E, Norbash, Alexander, Johnson, Patricia Lynn, Obisesan, Thomas O, Wolday, Saba, Allard, Joanne, Lerner, Alan, van Donkelaar, Marjolein M J, Ogrocki, Paula, Hudson, Leon, Fletcher, Evan, Carmichael, Owen, Olichney, John, Kittur, Smita, Borrie, Michael, Lee, T-Y, Bartha, Rob, van Eijk, Kristel R, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M, Preda, Adrian, Nguyen, Dana, Tariot, Pierre, Reeder, Stephanie, Bates, Vernice, Walters, Raymond K, Capote, Horacio, Rainka, Michelle, Scharre, Douglas W, Kataki, Maria, Adeli, Anahita, Zimmerman, Earl A, Celmins, Dzintra, Brown, Alice D, Pearlson, Godfrey D, Blank, Karen, Westlye, Lars T, Anderson, Karen, Santulli, Robert B, Kitzmiller, Tamar J, Schwartz, Eben S, Sink, Kaycee M, Williamson, Jeff D, Garg, Pradeep, Watkins, Franklin, Ott, Brian R, Querfurth, Henry, Whelan, Christopher D, Tremont, Geoffrey, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J, Miller, Bruce L, Mintzer, Jacobo, Spicer, Kenneth, Bachman, David, Finger, Elizabether, Toro, Roberto, Winkler, Anderson M, Pasternak, Stephen, Rachinsky, Irina, Drost, Dick, Pomara, Nunzio, Hernando, Raymundo, Sarrael, Antero, Schultz, Susan K, Ponto, Laura L Boles, Zwiers, Marcel P, Shim, Hyungsub, Smith, Karen Elizabeth, Relkin, Norman, Chaing, Gloria, Raudin, Lisa, Smith, Amanda, Fargher, Kristin, Raj, Balebail Ashok, Amin, Najaf, Becker, Diane, Alhusaini, Saud, Beiser, Alexa, Debette, Stéphanie, DeStefano, Anita, Hofer, Edith, Hofman, Albert, Niessen, Wiro J, Smith, Albert, Tzourio, Christophe, Vaidya, Dhananjay, Athanasiu, Lavinia, Vernooij, Meike W, Goldstein, David B, Heinzen, Erin L, Shianna, Kevin, Radtke, Rodney, Ottmann, Ruth, Albrecht, Lisa, Andrew, Chris, Arroyo, Mercedes, Artiges, Eric, Ehrlich, Stefan, Aydin, Semiha, Bach, Christine, Banaschewski, Tobias, Barbot, Alexis, Barker, Gareth, Boddaert, Nathalie, Bokde, Arun, Bricaud, Zuleima, Bromberg, Uli, Bruehl, Ruediger, Hakobjan, Marina M H, Büchel, Christian, Cachia, Arnaud, Cattrell, Anna, Conrod, Patricia, Constant, Patrick, Crombag, Hans, Czech, Katharina, Dalley, Jeffrey, Decideur, Benjamin, Desrivieres, Sylvane, Hartberg, Cecilie B, Fadai, Tahmine, Flor, Herta, Frouin, Vincent, Fuchs, Birgit, Gallinat, Jürgen, Garavan, Hugh, Briand, Fanny Gollier, Gowland, Penny, Head, Kay, Heinrichs, Bert, Haukvik, Unn K, Heym, Nadja, Hübner, Thomas, Ihlenfeld, Albrecht, Ireland, James, Ittermann, Bernd, Ivanov, Nikolay, Jones, Jennifer, Klaassen, Arno, Heister, Angelien J G A M, Lalanne, Christophe, Lathrop, Mark, Lanzerath, Dirk, Lemaitre, Hervé, Lüdemann, Katharina, Mallik, Catherine, Mangin, Jean-François, Mann, Karl, Mar, Adam, Hoehn, David, Martinot, Jean-Luc, Massicotte, Jessica, Mennigen, Eva, Mesquita de Carvahlo, Fabiana, Mignon, Xavier, Miranda, Ruben, Müller, Kathrin, Nees, Frauke, Nymberg, Charlotte, Paillere, Marie-Laure, Wittfeld, Katharina, Kasperaviciute, Dalia, Pena-Oliver, Yolanda, Poline, Jean-Baptiste, Poustka, Luise, Rapp, Michael, Reed, Laurence, Robert, Gabriel, Reuter, Jan, Liewald, David C M, Ripke, Stephan, Ripley, Tamzin, Robbins, Trevor, Rodehacke, Sarah, Romanowski, Alexander, Ruggeri, Barbara, Schilling, Christina, Schmäl, Christine, Schmidt, Dirk, Lopez, Lorna M, Schneider, Sophia, Schroeder, Markus, Schubert, Florian, Schwartz, Yannick, Smolka, Michael, Sommer, Wolfgang, Spanagel, Rainer, Speiser, Claudia, Spranger, Tade, Stedman, Alicia, Makkinje, Remco R R, Steiner, Sabina, Stephens, Dai, Strache, Nicole, Ströhle, Andreas, Struve, Maren, Subramaniam, Naresh, Theobald, David, Topper, Lauren, Vollstaedt-Klein, Sabine, Walaszek, Bernadeta, Matarin, Mar, Weiß, Katharina, Werts, Helen, Whelan, Robert, Williams, Steve, Yacubian, Juliana, Ziesch, Veronika, Zilbovicius, Monica, Wong, C Peng, Lubbe, Steven, Naber, Marlies A M, Martinez-Medina, Lourdes, Kepa, Agnes, Fernandes, Alinda, Tahmasebi, Amir, Abrahamowicz, Michal, Gaudet, Daniel, Leonard, Gabriel, Perron, Michel, Richer, Louis, Seguin, Jean, McKay, D Reese, Veillette, Suzanne, Needham, Margaret, Nugent, Allison C, Pütz, Benno, Abramovic, Lucija, Royle, Natalie A, Sprooten, Emma, Trabzuni, Daniah, van der Marel, Saskia S L, van Hulzen, Kimm J E, Walton, Esther, Wolf, Christiane, Almasy, Laura, Ames, David, Andersson, Micael, Arepalli, Sampath, Assareh, Amelia A, Bastin, Mark E, Brodaty, Henry, Bulayeva, Kazima B, Carless, Melanie A, Cichon, Sven, Corvin, Aiden, Curran, Joanne E, Czisch, Michael, MUMC+: DA Klinische Genetica (5), RS: GROW - Developmental Biology, RS: GROW - R4 - Reproductive and Perinatal Medicine, Université de Montréal. Faculté de médecine. Département de psychiatrie et d'addictologie, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), QIMR Berghofer Medical Research Institute, Department of Psychiatry, Donders Centre for Neuroscience, Radboud University [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud University [Nijmegen]-Radboud University Medical Center [Nijmegen], Department of Human Genetics, Radboud University Medical Center [Nijmegen], Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, PRES Sorbonne Paris Cité, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Greifswald University Hospital, University Medical Center [Utrecht], European Commission, University of Edinburgh, Lagos State University (LASU), Heriot-Watt University [Edinburgh] (HWU), Unité d'expérimentation sur les Ruminants de Theix, Institut National de la Recherche Agronomique (INRA), Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], University of Oslo (UiO), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], School of Technical Physics, Xidian University, Dept. of Mechanical Engineering, McMaster University [Hamilton, Ontario], Biological Psychology, Neuroscience Campus Amsterdam & EMGO Institute for Health and Care Research, VU University & VU Medical Center, Amsterdam 1081 BT, The Netherlands, Haukeland University Hospital, University of Bergen (UiB), Physicochimie des Processus de Combustion et de l’Atmosphère - UMR 8522 (PC2A), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Universität Heidelberg [Heidelberg] = Heidelberg University, Language and Genetics Department [Nijmegen], Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, International Max Planck Research School for Language Sciences (IMPRS ), Georgia Institute of Technology [Atlanta], National Institutes of Health [Bethesda] (NIH), Yale University [New Haven], Massachusetts General Hospital [Boston], Mental Health Sciences Unit, University College of London [London] (UCL), Beijing Normal University (BNU), Indiana University School of Medicine, Indiana University System, Indiana Alzheimer Disease Center, Indiana University System-Indiana University System, Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center, Goettingen 37075, Germany, Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen, University of California (UC), Medstar Research Institute, Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia, Department of Genomics, Life and Brain Center, Universität Bonn = University of Bonn, Institute of Human Genetics, Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University [Aarhus], VU University Medical Center [Amsterdam], Respiratory Epidemiology and Public Health, Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-MRC-HPA Centre for Environment and Health, Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Institut Parisien de Chimie Moléculaire (IPCM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Umeå Centre for Functional Brain Imaging (UFBI), Umeå University, Umeå 901 87, Sweden, Aging Research Center [Karolinska Institutet] (ARC ), Stockholm University-Karolinska Institutet [Stockholm], Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Department of Neurosciences [Univ California San Diego] (Neuro - UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), Department of Cognitive Sciences [Univ California San Diego] (CogSci - UC San Diego), The Hospital for sick children [Toronto] (SickKids), Queensland Institute of Medical Research, School of Psychology, University of Queensland, Brisbane 4072, Australia, University of Queensland [Brisbane], Centre for Advanced Imaging, University of Queensland, Brisbane 4072, Australia, Department of Genomics of Common Disease, Imperial College London, Department of Psychology [Oslo], Faculty of Social Sciences [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Deutsche Bundesbank, Department of Neurology and Neurosurgery [Montreal], McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), MetaGenoPolis, Department of Psychiatric Research and Development, Diakonhjemmet Hospital, Oslo 0319, Norway, UCL Institute of Neurology and Epilepsy Society, Department of Medicine, Clinical And Experimental Epilepsy, Dpt of Psychiatry [New Haven], Yale School of Medicine [New Haven, Connecticut] (YSM), Hartford Hospital, Neuropsychiatric Genetics Research Group and Department of Psychiatry, Trinity College Institute of Psychiatry, Trinity College Dublin, Dublin 2, Ireland, Institute of Food & Health, University College Dublin, University College Dublin [Dublin] (UCD), Statistical Genetics Group, State Key Laboratory of Lead Compound Research, WuXi AppTec, Co., Ltd, Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL, Institute of Neurology [London], Department of Genetics, King Faisal Specialist Hospital and Research Centre (KFSH & RC), Centre épigénétique et destin cellulaire (EDC), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Dundee Technopole, CXR Biosciences Ltd, Ninewells Hospital and Medical School, Biomedical Research Centre, University of Dundee, Southwest Foundation for Biomedical Research, Department of Psychiatry and National Ageing Research Institute, University of Melbourne, Department of Clinical Genetics, Department of Medical Parasitology and Mycology, School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-Tehran University of Medical Siences, Centre for Healthy Brain Ageing, University of New South Wales [Sydney] (UNSW), Dementia Collaborative Research Centre, N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Texas Biomedical Research Institute [San Antonio, TX], Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Division of Medical Genetics, University of Basel (Unibas), Trinity College Dublin-St. James's Hospital, Neuropsychiatric Genetics Research Group, Trinity College Dublin, Department of Materials Science & Metallurgy, University of Cambridge [UK] (CAM), Bijvoet Center of Biomolecular Research [Utrecht], Utrecht University [Utrecht], School of Psychology, University of Queensland, Laboratory of Neurogenetics, The University of Texas Health Science Center at Houston (UTHealth), Department of Genomics, Department of Medical and Molecular Genetics, South Texas Veterans Health Care System, San Antonio, Texas 78229, USA, Biofunctional Imaging, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan, Public Health Genomics Unit, Department of Biomolecular Engineering, Rheinische Friedrich-Wilhelms-Universität Bonn, Estación Experimental de Pastos y Forrajes 'Indio Hatuey', University Medical Center Groningen [Groningen] (UMCG), Neuronal Plasticity / Mouse Behaviour, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Department of Psychiatry, Fujita Health University School of Medicine, Toyoake 470-1192, Japan, Department of Radiology, Mayo Clinic, Department of Clinical Neurology [Oxford], University of Oxford-FMRIB Centre- John Radcliffe Hospital [Oxford University Hospital], University of Maryland School of Medicine, University of Maryland System, University of Sussex, Institute of Cognitive Neuroscience, United Kingdom Met Office [Exeter], University of Maryland [Baltimore County] (UMBC), University of Maryland System-University of Maryland System-University of Maryland School of Medicine, Department of Civil and Structural Engineering, The Hong Kong Polytechnic University [Hong Kong] (POLYU)-The Hong Kong Polytechnic University [Hong Kong] (POLYU), Columbia University Irving Medical Center (CUIMC), Lymphocyte Cell Biology Unit, Laboratory of Genetics, Centre for Advanced Imaging, Psychiatry and Psychotherapy, KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Division of Mental Health and Addiction, Oslo University Hospital [Oslo], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Genetic Epidemiology Unit, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Statistics [Warwick], University of Warwick [Coventry], Osaka University [Osaka], Institute of Psychiatry, King’s College London, London SE5 8AF, UK, University of Calgary, Psychiatry and Human Behavior, University of California, Irvine, California 92617, USA, University of California [Irvine] (UC Irvine), Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], University Hospital Mannheim | Universitätsmedizin Mannheim-University Hospital Mannheim | Universitätsmedizin Mannheim, Space and Naval Warfare Systems Center, Klinik für Psychiatrie, Martin-Luther-University Halle-Wittenberg, Department of Psychiatry, Division of Medical Psychology, Genetics of Mental Illness and Brain Function, Neuroscience Research Australia, Développement et amélioration des plantes (UMR DAP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney 2052, Australia, Laboratory of Neuro Imaging [Los Angeles] (LONI), Departamento de Física Aplicada, Universidade de Vigo, Georgia State University, University System of Georgia (USG), Genentech, Inc. [San Francisco], Psychiatry and Leiden Institute for Brain and Cognition, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Universiteit Leiden, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Department of Neurobiology, Care Sciences and Society, Karolinska Institutet [Stockholm], University of Manchester [Manchester], The University of Tennessee Health Science Center [Memphis] (UTHSC), iangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College of Nantong University, Nantong 226001, China, Centre for Ultrahigh Bandwidth Devices for Optical Systems (CUDOS), Macquarie University, Cognitive Neuroscience Laboratory (CNL), Harvard University, Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud University [Nijmegen]-Radboud University [Nijmegen], Icahn School of Medicine at Mount Sinai [New York] (MSSM), The Mind Research Network, Department of Electrical and Computer Engineering [Albuquerque] (ECE Department), The University of New Mexico [Albuquerque], Division of Molecular and Cellular Therapeutics, Scottish Association for Marine Science (SAMS), Structural Biology Laboratory, Department of Chemistry, University of York, Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, Department of Neurology, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Deparment of Medical Genetics, Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Psychiatry, University of Iowa, University of Iowa [Iowa City], Institute for Community Medicine, Department Epidemiology of Health Care and Community Health, Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig-Universität Leipzig, Institute of Clinical Chemistry and Laboratory Medicine, Department of Health Science, Division of Health and Rehabilitation, Luleå University of Technology (LUT), Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Psychiatric and Neurodevelopmental Genetics Unit, 849 Department of Human Genetics, Institute for Community Medicine, Institute for Energy Systems and Thermodynamics, Renyi Institute, Neuropsychiatric Institute, Prince of Wales Hospital, Randwick, NSW, Department of Child and Adolescent Psychiatry, Erasmus University Medical Centre, Rotterdam 3000 CB, The Netherlands, Department of Radiology, Erasmus University Medical Centre, Rotterdam 3015 CN, The Netherlands, Vrije Universiteit Amsterdam [Amsterdam] (VU), Cell Biology and Gene Expression Section, National Institute of Health, Bethesda, Dept of Psychology, Laboratoire de Recherche Magellan, Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Institut d'Administration des Entreprises (IAE) - Lyon, Institut de Socio-économie des Entreprises et des ORganisations (ISEOR), Institut de socio-économie des entreprises et des organisations, Department of Psychiatry and Psychotherapy, HELIOS Klinikum Stralsund Hanseatic-Greifswald University Hospital, Laboratoire d'Informatique de Grenoble (LIG), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Centre for Allergy Research, Department of Medicine, Clinical Pharmacology Unit, Karolinska University Hospital [Stockholm], Medical University of Łódź (MUL), Psychiatry Institute, Department of Health and Human Services, Institute of Gerontology and Geriatrics, Università degli Studi di Perugia = University of Perugia (UNIPG), Commonwealth Scientific and Industrial Research Organisation [Canberra] (CSIRO), Australian Centre for Research into Injury in Sport and its Prevention, Monash University [Clayton], University Medical Center [Utrecht]-Brain Center Rudolf Magnus, School of Psychology [Nottingham], University of Nottingham, UK (UON), McConnell Brain Imaging Centre (MNI), SickKids - The Hospital for sick children, European Centre for Medium-Range Weather Forecasts (ECMWF), University of Eastern Finland, Centre for Population Health Sciences, Lieber Institute for Brain Development [Baltimore] (LIBD), Johns Hopkins University (JHU), Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Graz 8010, Austria, Austrian Institute of Technology [Vienna] (AIT), INSERM Research Center for Epidemiology and Biostatistics (U897) Team Neuroepidemiology, Bordeaux, France College of Health Sciences, University of Bordeaux, Bordeaux, France, INSERM, Neuroepidemiology U708, Bordeaux, France, Karlsruhe Institute of Technology (KIT), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Harvard Medical School [Boston] (HMS), Computer Science and Artificial Intelligence Laboratory [Cambridge] (CSAIL), Massachusetts Institute of Technology (MIT), University of Washington [Seattle], Department of Physics [Stockholm], Stockholm University, Center for Medical Systems Biology, Netherlands Genomics Initiative, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Boston University [Boston] (BU), Groupe d'Imagerie Neurofonctionnelle (GIN - UMR 5296), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Faculty of Medicine, University of Iceland [Reykjavik], Icelandic Heart Association, Kopavogur, Iceland., Boston University School of Medicine (BUSM), Laboratoire d'Ingénierie des Matériaux de Bretagne (LIMATB), Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université de Brest (UBO), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of California-University of California, Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen], Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Gènes, Synapses et Cognition, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), UE 1354 Unité d'expérimentation sur les Ruminants de Theix, Institut National de la Recherche Agronomique (INRA)-Physiologie Animale et Systèmes d'Elevage (PHASE), Institut National de la Recherche Agronomique (INRA)-Unité d'expérimentation sur les Ruminants de Theix (UE RT), Radboud university [Nijmegen], McGill University, University of Bergen (UIB), Universität Heidelberg [Heidelberg], Beijing Normal University, University of California, University of Bonn, Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Department of Neurosciences [San Diego], Department of Cognitive Sciences [San Diego], The Hospital for Sick Children, University of Toronto, Toronto M5G 1X8, Canada, McGill University-McGill University, US 1367 MetaGénoPolis, Institut National de la Recherche Agronomique (INRA)-Département Microbiologie et Chaîne Alimentaire (MICA), Institut National de la Recherche Agronomique (INRA)-MetaGénoPolis (MGP), Yale University School of Medicine, King Faisal Specialist Hospital and Research Centre, Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Texas Biomedical Research Institute [San Antonio, Texas], Bijvoet Center of Biomolecular Research, Academic Unit for Psychiatry of Old Age, University of Melbourne, Melbourne 3101, Australia, Department of Genomics, Life & Brain Center, University of Bonn, Bonn D-53127, Germany, University of Oxford [Oxford]-FMRIB Centre- John Radcliffe Hospital [Oxford University Hospital], School of Psychology, University of Sussex, Brighton BN1 9QH, UK, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Department of Neurology [University of Calgary], Department of Clinical Neuroscience [University of Calgary], University of California [Irvine] (UCI), Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Recherche Agronomique (INRA)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Universidate de Vigo, Harvard University [Cambridge], Radboud university [Nijmegen]-Radboud university [Nijmegen], Université Libre de Bruxelles [Bruxelles] (ULB)-Hôpital Erasme (Bruxelles), Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], Centre de Recherche Magellan, Institut d'Administration des Entreprises (IAE) - Lyon-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon, Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Università degli Studi di Perugia (UNIPG), Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Service NEUROSPIN (NEUROSPIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université de Bretagne Sud (UBS)-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO), The Alzheimer’s Disease Neuroimaging Initiative, The CHARGE Consortium, EPIGEN, IMAGEN, SYS, Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen], Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), FMRIB Centre- John Radcliffe Hospital [Oxford University Hospital]-University of Oxford [Oxford], Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris], Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), University of Oxford [Oxford]- John Radcliffe Hospital [Oxford University Hospital]-FMRIB Centre, Neurology, Psychiatry, Anatomy and neurosciences, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Biological Psychology, Cognitive Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Neuroscience Campus Amsterdam - Brain Imaging Technology, EMGO+ - Mental Health, Child and Adolescent Psychiatry / Psychology, Epidemiology, Radiology & Nuclear Medicine, Laboratory of Neuro Imaging, David Geffen School of Medicine, University of California, Los Angeles, California, USA, Donders Centre for Neuroscience, Radboud University Nijmegen Medical Centre, MRC- SGDP Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK, Génétique humaine et Fonctions cognitives - Human Genetics and Cognitive Functions, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, Greifswald 17487, Germany, Department of Psychiatry, University Medicine Greifswald, Greifswald 17489, Germany, Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands, Brain Research Imaging Centre, University of Edinburgh, Edinburgh EH4 2XU, UK, Department of Computer Science, Lagos State University, Lagos, Nigeria, Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration, Department of Neuroimaging Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK, Heriot-Watt University [Edinburgh] ( HWU ), Institut National de la Recherche Agronomique ( INRA ) -Physiologie Animale et Systèmes d'Elevage ( PHASE ) -Unité d'expérimentation sur les Ruminants de Theix ( UE RT ), Department of Human Genetics, Radboud university medical center, Nijmegen 6500 HB, The Netherlands, Department of Cognitive Neuroscience, Radboud university medical center, Nijmegen 6500 HB, The Netherlands, NORMENT - KG Jebsen Centre, Institute of Clinical Medicine, University of Oslo, Oslo N-0316, Norway, NORMENT - KG Jebsen Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo 0424, Norway, Montreal Neurological Institute [Montréal], NORMENT - KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway, Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen 5021, Norway, Physicochimie des Processus de Combustion et de l’Atmosphère - UMR 8522 ( PC2A ), Université de Lille-Centre National de la Recherche Scientifique ( CNRS ), Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen 6525 XD, The Netherlands, International Max Planck Research School for Language Sciences, Nijmegen 6525 XD, The Netherlands, Human Genetics Branch and Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health Intramural Research Program, Bethesda, Maryland 20892, USA, Department of Psychology, Yale University, New Haven, Connecticut 06511, USA, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02115, USA, University College of London [London] ( UCL ), Center for Neuroimaging, Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA, Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA, Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA, Center for Neurobehavioral Genetics, University of California, Los Angeles, California 90095, USA, Université de Bonn, Department of Psychiatry, Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam 1081 HL, The Netherlands, Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh EH10 5HF, UK, Imperial College London-School of public health-MRC-HPA Centre for Environment and Health, Cibersam (Centro Investigación Biomédica en Red Salud Mental), Madrid 28029, Spain, Institut Parisien de Chimie Moléculaire ( IPCM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Aging Research Center [Karolinska Institutet] ( ARC ), Max Planck Institute of Psychiatry, Munich 80804, Germany, Multimodal Imaging Laboratory, Department of Neurosciences, University of California, San Diego, California 92093, USA, Department of Cognitive Sciences, University of California, San Diego, California 92161, USA, Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia, Department of Psychology, University of Oslo, Oslo 0373, Norway, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal H3A 2B4, Canada, Molecular and Cellular Therapeutics, The Royal College of Surgeons, Dublin 2, Ireland, Institut National de la Recherche Agronomique ( INRA ) -MetaGénoPolis ( MGP ) -Microbiologie et Chaîne Alimentaire ( MICA ), UCL Institute of Neurology, London, United Kingdom and Epilepsy Society, London WC1N 3BG, UK, Department of Medicine, Imperial College London, London W12 0NN, UK, Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK, Yale School of Medicine, Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital, Hartford, Connecticut 06106, USA, University College Dublin [Dublin] ( UCD ), Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK, Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia, Centre épigénétique et destin cellulaire ( EDC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), School of public health-Tehran University of Medical Siences, University of New South Wales [Sydney] ( UNSW ), Texas Biomedical Research Institute, San Antonio, Texas 78245, USA, Institute of Neuroscience and Medicine ( INM-1 ), University of Basel ( Unibas ), Cambridge University, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA, University of Texas Health Science Center, San Antonio, Texas 78229, USA, Clinical Research Branch, National Institute on Aging, Baltimore, Maryland 20892, USA, Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald 17475, Germany, University Medical Center Groningen, University of Groningen, University of Greifswald, Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA, NICHD Brain and Tissue Bank for Developmental Disorders, University of Maryland Medical School, Baltimore, Maryland 21201, USA, nstitute of Cognitive Neuroscience, University College London, London WC1N 3AR, UK, Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland, Baltimore, Maryland 21201, USA, Department of Pathology and Cell Biology, Columbia University Medical Center, New York 10032, USA, Lymphocyte Cell Biology Unit, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA, University of Oslo ( UiO ) -Institute of Clinical Medicine-Oslo University Hospital, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo ( UiO ) -European Network of Bipolar Research Expert Centers (ENBREC) Group, Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, CCM, Berlin 10117, Germany, Erasmus MC, Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIH), Bethesda, Maryland, USA, Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA, Central Institute of Mental Health, UMR 1098 Développement et Amélioration des Plantes, Institut National de la Recherche Agronomique ( INRA ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -MontpellierSupAgro ( MontpellierSupAgro ) -Génétique et amélioration des plantes ( G.A.P. ) -Développement et Amélioration des Plantes ( DAP ), Laboratory of Neuro Imaging [Los Angeles] ( LONI ), University of California at Los Angeles [Los Angeles] ( UCLA ), Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK, Genentech, South San Francisco, California 94080, USA, Psychiatry and Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands, LUMC, Carver College of Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm SE-141 83, Sweden, Behavioral Epidemiology Section, National Institute on Aging Intramural Research Program, Baltimore, Maryland 20892, USA, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK, Center for Integrative and Translational Genomics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA, Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA, Centre Interlangues - Texte, Image, Langage ( TIL ), Université de Bourgogne ( UB ), Centre for Ultrahigh Bandwidth Devices for Optical Systems ( CUDOS ), Icahn School of Medicine at Mount Sinai [New York], The Mind Research Network & LBERI, Albuquerque, New Mexico 87106, USA, Department of ECE, University of New Mexico, Albuquerque, New Mexico 87131, USA, Scottish Association for Marine Science ( SAMS ), Department of Neurology, Hopital Erasme, Universite Libre de Bruxelles, Brussels 1070, Belgium, National Institutes of Health ( NIH ) -National Institute of Mental Health (NIMH), Harvard Medical School [Boston] ( HMS ) -Massachusetts General Hospital [Boston], Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242, USA, Luleå University of Technology ( LUT ), Broad Institute of MIT and Harvard, Massachusetts General Hospital, Vrije Universiteit Amsterdam [Amsterdam] ( VU ), Université Jean Moulin - Lyon III-Institut d'Administration des Entreprises (IAE) - Lyon, Institut de Socio-économie des Entreprises et des ORganisations ( ISEOR ), University Medicine Greifswald,-HELIOS Hospital Stralsund, Laboratoire d'Informatique de Grenoble ( LIG ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut National Polytechnique de Grenoble ( INPG ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Osaka 565-0871, Japan, Karolinska University Hospital (Solna), Medical University of Łódź ( MUL ), National Institutes of Health ( NIH ), University of Perugia, Commonwealth Scientific and Industrial Research Organisation, University Medical Center Utrecht-Brain Center Rudolf Magnus, University of Nottingham, UK ( UON ), McConnell Brain Imaging Centre ( MNI ), The Hospital for sick children [Toronto] ( SickKids ), Department of Medical and Molecular Genetics, King’s College London, London SE1 9RT, UK, European Centre for Medium-Range Weather Forecasts ( ECMWF ), Lieber Institute for Brain Development, Baltimore, Maryland 21205, USA, Departments of Psychiatry, Neurology, Neuroscience and the Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique ( CNRS ), Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, Austrian Institute of Technology [Vienna] ( AIT ), Karlsruhe Institute of Technology ( KIT ), General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA, Department of Radiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA, Computer Science and Artificial Intelligence Laboratory [Cambridge] ( CSAIL ), Massachusetts Institute of Technology ( MIT ), Department of Epidemiology, University of Washington, Seattle, Washington, USA, Department of Neurology, University of Washington, Seattle, Washington, USA, Department of Physics, Stockholm University ( Department of Physics, Stockholm University ), Université de Lille, Sciences Humaines et Sociales, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA, Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands, Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA, Groupe d'Imagerie Neurofonctionnelle ( GIN - UMR 5296 ), Service NEUROSPIN ( NEUROSPIN ), Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université de Bordeaux ( UB ), Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA, Faculty of Medicine, University of Iceland, Reykjavik, Iceland, Department of Neurology, Boston University School of Medicine, Framingham Heart Study, Boston, MA, Department of Neurology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands, Laboratoire d'Ingénierie des Matériaux de Bretagne ( LIMATB ), Université de Bretagne Sud ( UBS ) -Institut Brestois du Numérique et des Mathématiques ( IBNM ), Université de Brest ( UBO ) -Université de Brest ( UBO ) -Université de Brest ( UBO ), King's College, Department of Psychiatry, Radboud university medical center, Nijmegen 6500 HB, The Netherlands, and Broad Institute of © 2012 Nature America, Inc. All rights reserved. Nature Ge N etics aDV a NCE ONLINE PUBLIC a TION 7 l e t t e r s Harvard and MIT, Cambridge, Massachusetts, US
Subjects: CHROMATIN, Male, Netherlands Twin Register (NTR), Aging, Identification, nervous-system, human geography, SEGMENTATION, Caudate nucleus, Apoptosis, Expression, Genome-wide association study, Striatum, Hippocampal formation, Hippocampus, BASAL GANGLIA, 130 000 Cognitive Neurology & Memory, Basal ganglia, genetics [Gene Expression Regulation, Developmental], Hippocampal, Child, anatomy & histology [Skull], Aged, 80 and over, Genetics, Sex Characteristics, KINECTIN, Genome-wide association, Multidisciplinary, Putamen, Brain, Gene Expression Regulation, Developmental, blood, brain, disease incidence, genetic variation, neurology, Organ Size, Human brain, Middle Aged, organization, Magnetic Resonance Imaging, genetics [Genetic Variation], Chromatin, Dynamics, genetics [Membrane Proteins], medicine.anatomical_structure, genetics [Aging], Anatomy & histology, [ SCCO.NEUR ] Cognitive science/Neuroscience, Female, ddc:500, anatomy & histology [Caudate Nucleus], Neuroinformatics, EXPRESSION, Adult, Adolescent, Evolution, anatomy & histology [Hippocampus], ORGANIZATION, genetics [Genetic Loci], Biology, Article, Young Adult, SDG 3 - Good Health and Well-being, Journal Article, medicine, Humans, GENOME-WIDE ASSOCIATION, General, genetics [Apoptosis], Kinectin, Aged, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], HIPPOCAMPAL, IDENTIFICATION, genetics [Organ Size], [SCCO.NEUR]Cognitive science/Neuroscience, Skull, segmentation, Genetic Variation, Membrane Proteins, NERVOUS-SYSTEM, anatomy & histology [Putamen], Genetic Loci, KTN1 protein, human, Caudate Nucleus, anatomy & histology [Brain], Neuroscience, Genome-Wide Association Study
Abstract: Contains fulltext : 144426.pdf (Publisher’s version ) (Closed access) Contains fulltext : 144426pre.pdf (Author’s version preprint ) (Open Access) The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 x 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction. 6 p.
Published: 2015

33. Autism as a disorder of biological and behavioral rhythms: toward new therapeutic perspectives

Author: Tordjman, Sylvie, Davlantis, Katherine S, Georgieff, Nicolas, Geoffray, Marie-Maude, Speranza, Mario, Anderson, George M, Xavier, Jean, Botbol, Michel, Oriol, Cécile, Bellissant, Eric, Vernay-Leconte, Julie, Fougerou, Claire, Hespel, Anne, Tavenard, Aude, Cohen, David, Kermarrec, Solenn, Coulon, Nathalie, Bonnot, Olivier, Dawson, Geraldine, Service Psychiatrie de l'Enfant et de l'Adolescent, CHU Pontchaillou [Rennes]-Centre Hospitalier Guillaume Régnier [Rennes]-CHS (Centre Hospitalier Spécialisé lutte Maladies Mentales), Audition (Psychophysique, Modélisation, Neurosciences) (APMN), Laboratoire des systèmes perceptifs (LSP), Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Département d'Etudes Cognitives - ENS Paris (DEC), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Centre Hospitalier le Vinatier [Bron], Centre Hospitalier de Versailles André Mignot (CHV), Yale University School of Medicine, Laboratoire de Psychologie et Neurosciences Cognitives (LPNCog / UMR 8189), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Service Hospitalo-Universitaire de Psychiatrie de l'Enfant et de l'Adolescent, Université de Brest (UBO), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pharmacologie [Rennes], CHU Pontchaillou [Rennes], École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Yale School of Medicine [New Haven, Connecticut] (YSM), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Audition (Psychophysique, Modélisation, Neurosciences) ( APMN ), Laboratoire des systèmes perceptifs, Département d'Etudes Cognitives - ENS Paris ( DEC ), École normale supérieure - Paris ( ENS Paris ) -École normale supérieure - Paris ( ENS Paris ) -Centre National de la Recherche Scientifique ( CNRS ) -Département d'Etudes Cognitives - ENS Paris ( DEC ), École normale supérieure - Paris ( ENS Paris ) -École normale supérieure - Paris ( ENS Paris ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier de Versailles (CHV), Yale School of Medicine, Laboratoire de Psychologie et Neurosciences Cognitives ( LPNCog ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Brest ( UBO ), Centre d'Investigation Clinique [Rennes] ( CIC ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Pharmacologie, and Jonchère, Laurent
Subjects: [SDV] Life Sciences [q-bio], emotional and relational rhythms, biological rhythms, [ SDV ] Life Sciences [q-bio], Early Start Denver Model, [SDV]Life Sciences [q-bio], therapeutics, melatonin, autism spectrum disorder, Review Article, synchronization of rhythms, Pediatrics, motor
Abstract: International audience; There is a growing interest in the role of biological and behavioral rhythms in typical and atypical development. Recent studies in cognitive and developmental psychology have highlighted the importance of rhythmicity and synchrony of motor, emotional, and interpersonal rhythms in early development of social communication. The synchronization of rhythms allows tuning and adaptation to the external environment. The role of melatonin in the ontogenetic establishment of circadian rhythms and the synchronization of the circadian clocks network suggests that this hormone might be also involved in the synchrony of motor, emotional, and interpersonal rhythms. Autism provides a challenging model of physiological and behavioral rhythm disturbances and their possible effects on the development of social communication impairments and repetitive behaviors and interests. This article situates autism as a disorder of biological and behavioral rhythms and reviews the recent literature on the role of rhythmicity and synchrony of rhythms in child development. Finally, the hypothesis is developed that an integrated approach focusing on biological, motor, emotional, and interpersonal rhythms may open interesting therapeutic perspectives for children with autism. More specifically, promising avenues are discussed for potential therapeutic benefits in autism spectrum disorder of melatonin combined with developmental behavioral interventions that emphasize synchrony, such as the Early Start Denver Model.
Published: 2015

34. New genetic loci link adipose and insulin biology to body fat distribution

Author: Shungin, Dmitry, Winkler, Thomas W, Workalemahu, Tsegaselassie, Hartman, Catharina A, Duncan, Emma L, Ntzani, Evangelia E, Oei, Ling, Albagha, Omar M E, Amin, Najaf, Kemp, John P, Koller, Daniel L, Li, Guo, Liu, Ching-Ti, Minster, Ryan L, Hassinen, Maija, Moayyeri, Alireza, Vandenput, Liesbeth, Willner, Dana, Xiao, Su-Mei, Yerges-Armstrong, Laura M, Zheng, Hou-Feng, Alonso, Nerea, Eriksson, Joel, Kammerer, Candace M, Kaptoge, Stephen K, Hayward, Caroline, Leo, Paul J, Thorleifsson, Gudmar, Wilson, Scott G, Wilson, James F, Aalto, Ville, Alen, Markku, Aragaki, Aaron K, Aspelund, Thor, Center, Jacqueline R, Dailiana, Zoe, Heikkilä, Kauko, Duggan, David J, Garcia, Melissa, Garcia-Giralt, Natàlia, Giroux, Sylvie, Hallmans, Göran, Hocking, Lynne J, Husted, Lise Bjerre, Jameson, Karen A, Khusainova, Rita, Kim, Ghi Su, Herzig, Karl-Heinz, Kooperberg, Charles, Koromila, Theodora, Kruk, Marcin, Laaksonen, Marika, Lacroix, Andrea Z, Lee, Seung Hun, Leung, Ping C, Lewis, Joshua R, Masi, Laura, Mencej-Bedrac, Simona, Helmer, Quinta, Nguyen, Tuan V, Nogues, Xavier, Patel, Millan S, Prezelj, Janez, Rose, Lynda M, Scollen, Serena, Siggeirsdottir, Kristin, Smith, Albert V, Svensson, Olle, Trompet, Stella, Hillege, Hans L, Trummer, Olivia, van Schoor, Natasja M, Woo, Jean, Zhu, Kun, Balcells, Susana, Brandi, Maria Luisa, Buckley, Brendan M, Cheng, Sulin, Christiansen, Claus, Cooper, Cyrus, Holmen, Oddgeir, Dedoussis, George, Ford, Ian, Frost, Morten, Goltzman, David, González-Macías, Jesús, Kähönen, Mika, Karlsson, Magnus, Khusnutdinova, Elza, Koh, Jung-Min, Kollia, Panagoula, Hunt, Steven C, Langdahl, Bente Lomholt, Leslie, William D, Lips, Paul, Ljunggren, Östen, Lorenc, Roman S, Marc, Janja, Mellström, Dan, Obermayer-Pietsch, Barbara, Olmos, José M, Pettersson-Kymmer, Ulrika, Isaacs, Aaron, Reid, David M, Riancho, José A, Ridker, Paul M, Rousseau, François, Slagboom, P Eline, Tang, Nelson L S, Urreizti, Roser, Van Hul, Wim, Viikari, Jorma, Zarrabeitia, María T, Wu, Joseph M W, Ittermann, Till, Aulchenko, Yurii S, Castano-Betancourt, Martha, Grundberg, Elin, Herrera, Lizbeth, Ingvarsson, Thorvaldur, Johannsdottir, Hrefna, Kwan, Tony, Li, Rui, Luben, Robert, Medina-Gómez, Carolina, James, Alan L, Palsson, Stefan Th, Reppe, Sjur, Rotter, Jerome I, Sigurdsson, Gunnar, van Meurs, Joyce B J, Verlaan, Dominique, Williams, Frances M K, Wood, Andrew R, Zhou, Yanhua, Gautvik, Kaare M, Johansson, Ingegerd, Pastinen, Tomi, Raychaudhuri, Soumya, Cauley, Jane A, Chasman, Daniel I, Clark, Graeme R, Cummings, Steven R, Danoy, Patrick, Dennison, Elaine M, Eastell, Richard, Eisman, John A, Juliusdottir, Thorhildur, Gudnason, Vilmundur, Hofman, Albert, Jackson, Rebecca D, Jones, Graeme, Jukema, J Wouter, Khaw, Kay-Tee, Lehtimäki, Terho, Liu, Yongmei, Lorentzon, Mattias, McCloskey, Eugene, Kalafati, Ioanna-Panagiota, Mitchell, Braxton D, Nandakumar, Kannabiran, Nicholson, Geoffrey C, Oostra, Ben A, Peacock, Munro, Pols, Huibert A P, Prince, Richard L, Raitakari, Olli, Reid, Ian R, Robbins, John, Kinnunen, Leena, Sambrook, Philip N, Sham, Pak Chung, Shuldiner, Alan R, Tylavsky, Frances A, van Duijn, Cornelia M, Wareham, Nick J, Cupples, L Adrienne, Econs, Michael J, Evans, David M, Harris, Tamara B, Koenig, Wolfgang, Kung, Annie Wai Chee, Psaty, Bruce M, Reeve, Jonathan, Spector, Timothy D, Streeten, Elizabeth A, Zillikens, M Carola, Thorsteinsdottir, Unnur, Ohlsson, Claes, Karasik, David, Richards, J Brent, Kooner, Ishminder K, Brown, Matthew A, Stefansson, Kari, Uitterlinden, André G, Ralston, Stuart H, Ioannidis, John P A, Kiel, Douglas P, Rivadeneira, Fernando, Sandholm, Niina, Salem, Rany M, McKnight, Amy Jayne, Kratzer, Wolfgang, Brennan, Eoin P, Forsblom, Carol, Isakova, Tamara, McKay, Gareth J, Williams, Winfred W, Sadlier, Denise M, Mäkinen, Ville-Petteri, Swan, Elizabeth J, Palmer, Cameron, Boright, Andrew P, Lamina, Claudia, Ahlqvist, Emma, Deshmukh, Harshal A, Keller, Benjamin J, Huang, Huateng, Ahola, Aila, Fagerholm, Emma, Gordin, Daniel, Harjutsalo, Valma, He, Bing, Heikkilä, Outi, Buchkovich, Martin L, Leander, Karin, Hietala, Kustaa, Kytö, Janne, Lahermo, Päivi, Lehto, Markku, Österholm, Anne-May, Parkkonen, Maija, Pitkäniemi, Janne, Rosengård-Bärlund, Milla, Saraheimo, Markku, Sarti, Cinzia, Lee, Nanette R, Söderlund, Jenny, Soro-Paavonen, Aino, Syreeni, Anna, Thorn, Lena M, Tikkanen, Heikki, Tolonen, Nina, Tryggvason, Karl, Tuomilehto, Jaakko, Wadén, Johan, Gill, Geoffrey V, Lichtner, Peter, Prior, Sarah, Guiducci, Candace, Mirel, Daniel B, Taylor, Andrew, Hosseini, Mohsen, Parving, Hans-Henrik, Rossing, Peter, Tarnow, Lise, Ladenvall, Claes, Alhenc-Gelas, François, Lind, Lars, Lefebvre, Pierre, Rigalleau, Vincent, Roussel, Ronan, Tregouet, David-Alexandre, Maestroni, Anna, Maestroni, Silvia, Falhammar, Henrik, Gu, Tianwei, Möllsten, Anna, Cimponeriu, Dan, Lindström, Jaana, Mihai, Ioana, Mota, Maria, Mota, Eugen, Serafinceanu, Cristian, Stavarachi, Monica, Hanson, Robert L, Nelson, Robert G, Kretzler, Matthias, Colhoun, Helen M, Panduru, Nicolae Mircea, Lobbens, Stéphane, Gu, Harvest F, Brismar, Kerstin, Zerbini, Gianpaolo, Hadjadj, Samy, Marre, Michel, Groop, Leif, Lajer, Maria, Bull, Shelley B, Waggott, Daryl, Paterson, Andrew D, Savage, David A, Bain, Stephen C, Martin, Finian, Hirschhorn, Joel N, Godson, Catherine, Florez, Jose C, Groop, Per-Henrik, Maxwell, Alexander P, Willer, Cristen J, Schmidt, Ellen M, Mach, François, Sengupta, Sebanti, Peloso, Gina M, Gustafsson, Stefan, Kanoni, Stavroula, Ganna, Andrea, Chen, Jin, Mora, Samia, Beckmann, Jacques S, Bragg-Gresham, Jennifer L, Magnusson, Patrik Ke, Chang, Hsing-Yi, Demirkan, Ayşe, Den Hertog, Heleen M, Do, Ron, Donnelly, Louise A, Ehret, Georg B, Esko, Tõnu, Feitosa, Mary F, Ferreira, Teresa, Fischer, Krista, Mahajan, Anubha, Fontanillas, Pierre, Fraser, Ross M, Freitag, Daniel F, Gurdasani, Deepti, Hyppönen, Elina, Jackson, Anne U, Johansson, Åsa, Johnson, Toby, Heard-Costa, Nancy L, McArdle, Wendy L, Kaakinen, Marika, Kettunen, Johannes, Kleber, Marcus E, Li, Xiaohui, Luan, Jian'an, Lyytikäinen, Leo-Pekka, Magnusson, Patrik K E, Mangino, Massimo, Mihailov, Evelin, Montasser, May E, Menni, Cristina, Müller-Nurasyid, Martina, Nolte, Ilja M, O'Connell, Jeffrey R, Palmer, Cameron D, Perola, Markus, Petersen, Ann-Kristin, Sanna, Serena, Saxena, Richa, Service, Susan K, Shah, Sonia, Merger, Sigrun, Sidore, Carlo, Song, Ci, Strawbridge, Rona J, Surakka, Ida, Tanaka, Toshiko, Teslovich, Tanya M, Van den Herik, Evita G, Voight, Benjamin F, Volcik, Kelly A, Waite, Lindsay L, Wong, Andrew, Wu, Ying, Zhang, Weihua, Absher, Devin, Asiki, Gershim, Barroso, Inês, Been, Latonya F, Bolton, Jennifer L, Milani, Lili, Bonnycastle, Lori L, Brambilla, Paolo, Burnett, Mary S, Cesana, Giancarlo, Dimitriou, Maria, Doney, Alex S F, Döring, Angela, Elliott, Paul, Epstein, Stephen E, Eyjolfsson, Gudmundur Ingi, Mills, Rebecca, Gigante, Bruna, Goodarzi, Mark O, Grallert, Harald, Gravito, Martha L, Groves, Christopher J, Hartikainen, Anna-Liisa, Hernandez, Dena, Hicks, Andrew A, Holm, Hilma, Hung, Yi-Jen, Illig, Thomas, Jones, Michelle R, Kaleebu, Pontiano, Kastelein, John J P, Kim, Eric, Klopp, Norman, Komulainen, Pirjo, Monda, Keri L, Kumari, Meena, Langenberg, Claudia, Lin, Shih-Yi, Loos, Ruth J F, Meisinger, Christa, Mooijaart, Simon P, Müller, Gabrielle, Nagaraja, Ramaiah, Narisu, Narisu, Nieminen, Tuomo V M, Nsubuga, Rebecca N, Olafsson, Isleifur, Ong, Ken K, Palotie, Aarno, Papamarkou, Theodore, Pomilla, Cristina, Mühleisen, Thomas W, Pouta, Anneli, Rader, Daniel J, Reilly, Muredach P, Rudan, Igor, Ruokonen, Aimo, Samani, Nilesh, Scharnagl, Hubert, Seeley, Janet, Roman, Tamara S, Mulas, Antonella, Silander, Kaisa, Stančáková, Alena, Stirrups, Kathleen, Swift, Amy J, Tiret, Laurence, Uitterlinden, Andre G, van Pelt, L Joost, Vedantam, Sailaja, Wainwright, Nicholas, Wijmenga, Cisca, Müller, Gabriele, Wild, Sarah H, Willemsen, Gonneke, Wilsgaard, Tom, Young, Elizabeth H, Zhao, Jing Hua, Adair, Linda S, Arveiler, Dominique, Assimes, Themistocles L, Bandinelli, Stefania, Bennett, Franklyn, Bochud, Murielle, Boehm, Bernhard O, Boomsma, Dorret I, Borecki, Ingrid B, Bornstein, Stefan R, Bovet, Pascal, Burnier, Michel, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C, Chen, Yii-Der Ida, Collins, Francis S, Cooper, Richard S, Danesh, John, de Faire, Ulf, Feranil, Alan B, Ferrières, Jean, Ferrucci, Luigi, Nalls, Michael A, Freimer, Nelson B, Gieger, Christian, Groop, Leif C, Gyllensten, Ulf, Hamsten, Anders, Hingorani, Aroon, Hovingh, G Kees, Hsiung, Chao Agnes, Humphries, Steve E, Hveem, Kristian, Iribarren, Carlos, Järvelin, Marjo-Riitta, Jula, Antti, Kaprio, Jaakko, Glorioso, Nicola, Kesäniemi, Antero, Kivimaki, Mika, Kooner, Jaspal S, Koudstaal, Peter J, Krauss, Ronald M, Kuh, Diana, Kuusisto, Johanna, Kyvik, Kirsten O, Laakso, Markku, Lakka, Timo A, Lindgren, Cecilia M, Martin, Nicholas G, März, Winfried, McCarthy, Mark I, McKenzie, Colin A, Meneton, Pierre, Metspalu, Andres, Moilanen, Leena, Morris, Andrew D, Olden, Matthias, Munroe, Patricia B, Njølstad, Inger, Pedersen, Nancy L, Power, Chris, Pramstaller, Peter P, Price, Jackie F, Quertermous, Thomas, Rauramaa, Rainer, Saleheen, Danish, Rayner, Nigel W, Salomaa, Veikko, Sanghera, Dharambir K, Saramies, Jouko, Schwarz, Peter E H, Sheu, Wayne H-H, Siegbahn, Agneta, Spector, Tim D, Strachan, David P, Drong, Alexander W, Renstrom, Frida, Tayo, Bamidele O, Tremoli, Elena, Uusitupa, Matti, Vollenweider, Peter, Wallentin, Lars, Wareham, Nicholas J, Whitfield, John B, Wolffenbuttel, Bruce H R, Ried, Janina S, Ordovas, Jose M, Boerwinkle, Eric, Palmer, Colin N A, Franks, Paul W, Ripatti, Samuli, Sandhu, Manjinder S, Robertson, Neil R, Rich, Stephen S, Boehnke, Michael, Deloukas, Panos, Kathiresan, Sekar, Mohlke, Karen L, Ingelsson, Erik, Abecasis, Gonçalo R, Abecasis, Gonçalo, Caulfield, Mark, Chasman, Dan, Ehret, Georg, Johnson, Andrew, Johnson, Louise, Larson, Martin, Levy, Daniel, Munroe, Patricia, Newton-Cheh, Christopher, O'Reilly, Paul, Palmas, Walter, Psaty, Bruce, Rice, Kenneth, Smith, Albert, Snider, Harold, Tobin, Martin, Van Duijn, Cornelia, Verwoert, Germaine, Rice, Kenneth M, Johnson, Andrew D, Tobin, Martin D, Verwoert, Germaine C, Hwang, Shih-Jen, Pihur, Vasyl, Scholtens, Salome, O'Reilly, Paul F, Teumer, Alexander, Glazer, Nicole L, Launer, Lenore, Aulchenko, Yurii, Heath, Simon, Sennblad, Bengt, Sõber, Siim, Parsa, Afshin, Arora, Pankaj, Dehghan, Abbas, Zhang, Feng, Lucas, Gavin, Peden, John F, Seufferlein, Thomas, Igl, Wilmar, Milaneschi, Yuri, Parker, Alex N, Fava, Cristiano, Fox, Ervin R, Sitlani, Colleen M, Go, Min Jin, van der Harst, Pim, Kao, Wen Hong Linda, Sjögren, Marketa, Vinay, D. G., Alexander, Myriam, Tabara, Yasuharu, Shaw-Hawkins, Sue, Whincup, Peter H, Smith, Albert Vernon, Shi, Gang, Tayo, Bamidele, Seielstad, Mark, Sim, Xueling, Nguyen, Khanh-Dung Hoang, Matullo, Giuseppe, Gaunt, Tom R, Onland-Moret, N Charlotte, Cooper, Matthew N, Platou, Carl G P, Org, Elin, Hardy, Rebecca, Dahgam, Santosh, Palmen, Jutta, Vitart, Veronique, Braund, Peter S, Kuznetsova, Tatiana, Stringham, Heather M, Uiterwaal, Cuno S P M, Adeyemo, Adebowale, Ludwig, Barbara, Tomaszewski, Maciej, Tzoulaki, Ioanna, Palmer, Nicholette D, Sundström, Johan, Chang, Yen-Pei C, Steinle, Nanette I, Grobbee, Diederick E, Arking, Dan E, Kardia, Sharon L, Morrison, Alanna C, Najjar, Samer, Swertz, Morris A, Hadley, David, Brown, Morris J, Connell, John M, Hingorani, Aroon D, Day, Ian N M, Lawlor, Debbie A, Beilby, John P, Lawrence, Robert W, Clarke, Robert, Collins, Rory, Hopewell, Jemma C, Ongen, Halit, Dreisbach, Albert W, Li, Yali, Young, J. 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Zgaga, L., Zygmunt, M., Arnold, AM., Buring, JE., Crisponi, L., Demerath, EW., Hunter, DJ., Schlessinger, D., Murray, A., Murabito, JM., Visser, JA., Lunetta, KL., Elks, CE., Cousminer, DL., Feenstra, B., Lin, P., van Wingerden SW., Smith, EN., Warrington, NM., Alavere, H., Barroso, I., Berenson, GS., Blackburn, H., Busonero, F., Chen, W., Couper, D., Easton, DF., Foroud, T., Geller, F., Hernandez, DG., Kilpeläinen, TO., Li, S., Melbye, M., Murray, JC., Murray, SS., Nelis, M., Ness, AR., Northstone, K., Pennell, CE., Pharoah, P., Rafnar, T., Rice, JP., Ring, SM., Schork, NJ., Segrè, AV., Sovio, U., Srinivasan, SR., Tammesoo, ML., Tyrer, J., Weedon, MN., Wichmann, H., Young, L., Zhuang, WV., Bierut, LJ., Boyd, HA., Department of Clinical Sciences, Lund University [Lund], Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Department of Odontology, Umeå University, Signalisation et Transports Ioniques Membranaires (STIM), Université de Poitiers-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Department of Medical Sciences, Center for Biological Sequence Analysis [Lyngby], Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Laboratory of Image Science and Technology [Nanjing] (LIST), Southeast University [Jiangsu]-School of Computer Science and Engineering, Limnology, Ecology, Estonian Genome and Medicine, University of Tartu, Institute of Molecular and Cell Biology, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Department of Medical Genetics, Université de Lausanne = University of Lausanne (UNIL), Institute of Medical Informatics, Biometry and Epidemiology, Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Genetic Epidemiology Unit, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Space Sciences Laboratory [Berkeley] (SSL), University of California [Berkeley] (UC Berkeley), University of California (UC)-University of California (UC), Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Division of Statistical Genomics, Washington University School of Medicine, King‘s College London, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, Molecular Genetics Section, University of Groningen [Groningen]-University Medical Centre Groningen, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Geriatric Rehabilitation Unit, Azienda Sanitaria Firenze, Department of Pharmacy Sciences, Creighton University Medical Center, Medical Department III, Universität Leipzig, Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Department of Epidemiology, Erasmus Medical Centre, Netherlands Genomics Initiative (NGI), Netherlands Genomics Initiative, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Department of Public Health and Clinical Medicine, Medstar Research Institute, Genetics and Pathology, Finnish Institute of Occupational Health, Epidemiology, University Medical Centre Groningen, Departments of Microbiology & Molecular Genetics and Molecular Biology & Biochemistry, University of California [Irvine] (UC Irvine), Department of Odontology, Cariology, Institute of Human Genetics, Helmholtz Zentrum München = German Research Center for Environmental Health, Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Division of Cardiology, Geneva University Hospital (HUG), Department of Psychiatry and Psychotherapy, Rheinische Friedrich-Wilhelms-Universität Bonn, Department of Physics, Indian Institute of Technology Kanpur (IIT Kanpur), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Department of Genomics, Life and Brain Center, Universität Bonn = University of Bonn, Anaesthesia and Intensive care, Royal Aberdeen Childrens Hospital, UCL Institute of neurology, UCL Institute of Neurology, Human Genetics, The Wellcome Trust Sanger Institute [Cambridge], Departments of Epidemiology and Nutrition, Harvard School of Public Health, Institute of Experimental Medicine, Czech Academy of Sciences [Prague] (CAS), Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University Hospital, Department of Genetics, University of Groningen [Groningen], deCODE Genetics, deCODE genetics [Reykjavik], Pediatric Pulmonology, Allergology & Epidemiology, University of Groningen [Groningen]-University Medical Center Groningen [Groningen] (UMCG)-Beatrix Children's Hospital-Groningen Research Institute for Asthma and COPD, Department of Nutrition-Dietetics, Harokopio University of Athens, Yale School of Medicine [New Haven, Connecticut] (YSM), National Heart and Lung Institute (NHLI), Imperial College London, Queensland Institute of Medical Research, Concord Hospital, Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Dept. Atherosclerose, Kidney Center, University Medical Center Groningen [Groningen] (UMCG), Department of Public Health & Primary Care, University of Cambridge [UK] (CAM), Department of cardiology, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, Department of Internal Medicine, University of Pisa - Università di Pisa, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Health Sciences Research Institute, Warwick, Department of Nephrology, University Medical Center, University of Groningen, Institute of Genetic Epidemiology, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland [Reykjavik], Executive Board, Polycystic Kidney Disease Charity (PKD Charity)-Ciliopathy Alliance-International Alliance, Department of Zoology, University of Otago [Dunedin, Nouvelle-Zélande], Institute for Community Medicine, Department Epidemiology of Health Care and Community Health, Universität Greifswald - University of Greifswald, Interfaculty Institute for Genetics and Functional Genomics, 5 University Street, Centre for Paediatric Epidemiology and Biostatistics, University College of London [London] (UCL), MRC Centre for Epidemiology of Child Health, UCL Institute of Child Health, Unit for Molecular Epidemiology, Institute of Health Sciences and Biocenter Oulu, University of Oulu, Department of Epidemiology and Biostatistics, Department of Life Course and Services, National Institute for Health and Welfare [Helsinki], Department of Epidemiology and Public Health, Queen's University [Belfast] (QUB), Interdisciplinary Center of Clinical Research, Department of Physiology, University of Eastern Finland-Institute of Biomedicine, University of Hawai‘i [Mānoa] (UHM), Department of Clinical Chemistry, University of Tampere [Finland]-Tampere University Hospital, Chronic Disease Epidemiology and Prevention Unit, Université Laval [Québec] (ULaval), Centre for Bone and Arthritis Research, University of Gothenburg (GU)-Institute of Medicine, Interdisciplinary Center for Psychiatric Epidemiology, Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, The Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Department of Clinical Physiology, Turku University Hospital (TYKS), Brigham and Women's Hospital [Boston], Department of Chronic Disease Prevention, Department of Cardiovascular Sciences [Leicester], University of Leicester, Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Maastricht University [Maastricht], Institute of Social and Preventive Medicine, Lausanne University Hospital, Carl Gustav Carus University Hospital, Recherches en Psychopathologie, nouveaux symptômes et lien social (EA 4050), Université de Poitiers-Université de Brest (UBO)-Université Catholique de l'Ouest (UCO)-Université de Rennes 2 (UR2), Institut de biologie de Lille - UMS 3702 (IBL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), HELIOS Klinikum Stralsund Hanseatic-Greifswald University Hospital, Department of child and adolescent psychiatry, Institute for Medical Informatics, Biometry, and Epidemiology, MRC National Survey of Health and Development, MRC Unit for Lifelong Health and Ageing, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Karl-Franzens-Universität Graz, Peter MacCallum Cancer Center, Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen, Department of Pediatrics, Augusta University - Medical College of Georgia, University System of Georgia (USG)-University System of Georgia (USG), Department of Public Health, South Ostrobothnia Central Hospital, Department of Clinical and Preventive Medicine, Danube-University Krems, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), Institute of Public Health and Clinical Nutrition, University of Eastern Finland, MRC epidemiology Unit, Institute of Epidemiology, Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Department of Oncology, Queensland Brain Institute, University of Queensland [Brisbane], Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital [Boston], Divisions of Genetics and Endocrinology and Program in Genomics, Boston Children's Hospital, Metabolism Initiative and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, Metabolic Disease Group, University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Department of Epidemiology and Preventive Medicine, Regensburg University Medical Center, Epidemiology Unit, Addenbrooke's Hospital-Medical Research Council (MRC), Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Endocrinology and Metabolism, The Churchill Hospital-Oxford Centre for Diabetes, Landsteiner Laboratory, Clinical Haematology, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Lund University Diabetes Centre-Lund University [Lund], Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Université de Poitiers, Technical University of Denmark [Lyngby] (DTU), Université de Lausanne (UNIL), Universität Duisburg-Essen [Essen], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), University of California [Berkeley], University of California-University of California, Génomique Intégrative et Modélisation des Maladies Métaboliques (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Universität Leipzig [Leipzig], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), University of California [Irvine] (UCI), German Research Center for Environmental Health, University of Bonn, Czech Academy of Sciences [Prague] (ASCR), Yale University School of Medicine, University of Oxford [Oxford], German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), Laval University, Laval University [Québec], Turku University Hospital, Lausanne university hospital, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), University of Helsinki-University of Helsinki, Helmholtz-Zentrum München (HZM), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), Internal Medicine, Child and Adolescent Psychiatry / Psychology, Clinical Genetics, Medical Informatics, Obstetrics & Gynecology, Lund University [Lund]-Lund University Diabetes Centre, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institute of Medicine-University of Gothenburg (GU), Signalisation et Transports Ioniques Membranaires ( STIM ), Université de Poitiers-Centre National de la Recherche Scientifique ( CNRS ), Technical University of Denmark [Lyngby] ( DTU ), Laboratory of Image Science and Technology [Nanjing] ( LIST ), Department of Medical Epidemiology and Biostatistics ( MEB ), University of Lausanne, Centre d'Immunologie de Marseille - Luminy ( CIML ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Erasmus MC, Space Sciences Laboratory [Berkeley] ( SSL ), Génomique Intégrative et Modélisation des Maladies Métaboliques ( EGID ), Université de Lille-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Pasteur de Lille, Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), University of Leipzig, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institute of Epidemiology [Neuherberg] ( EPI ), University of California [Irvine] ( UCI ), Génétique des maladies multifactorielles ( GMM ), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique ( CNRS ), Geneva University Hospital ( HUG ), Bonn Universität [Bonn], Indian Institute of Technology Kanpur ( IIT Kanpur ), The University of North Carolina at Chapel Hill, Université de Bonn, Wellcome Trust Sanger Institute, Harvard University School of Public Health, Czech Academy of Sciences [Prague] ( ASCR ), deCODE genetics, University of Groningen [Groningen]-University Medical Center Groningen-Beatrix Children's Hospital-Groningen Research Institute for Asthma and COPD, Yale School of Medicine, National Heart and Lung Institute ( NHLI ), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, University Medical Center Groningen, University of Cambridge [UK] ( CAM ), Wellcome Trust Centre for Human Genetics, University of Pisa [Pisa], University of Cambridge [UK] ( CAM ) -Institute of Metabolic Science, German Research Center for Environmental Health-Helmholtz-Zentrum München ( HZM ), University of Otago, University of Greifswald, University College of London [London] ( UCL ), National Institute for Health and Welfare, Queen's University [Belfast] ( QUB ), University of Hawaii at Manoa ( UHM ), University of Gothenburg ( GU ) -Institute of Medicine, Recherches en Psychopathologie, nouveaux symptômes et lien social ( EA 4050 ), Université de Poitiers-Université de Brest ( UBO ) -Université Catholique de l'Ouest-Université de Rennes 2 ( UR2 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ), Institut de biologie de Lille - IBL ( IBLI ), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), University Medicine Greifswald,-HELIOS Hospital Stralsund, Finland Institute for Molecular Medicine ( FIMM ), Georgia Prevention Institute, Netherlands Consortium for Healthy Aging, Helmholtz-Zentrum München ( HZM ), National Institutes of Health ( NIH ) -National Cancer Institute ( NIH ), Massachusetts General Hospital, Children's Hospital, Boston, Broad Institute, Cambridge, MA, The University of North Carolina at Chapel Hill-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, Shungin D, Winkler TW, Adipogen, Consortium, Cardiogramplusc4d, Consortium, Ckdgen, Consortium, Gefos, Consortium, Genie, Consortium, Glgc, Icbp, International, Endogene Consortium, Lifelines, Cohort Study, Magic, Investigator, Muther, Consortium, Consortium, Page, ReproGen Consortium, Amouyel P, D'Adamo, ADAMO PIO, Gasparini, Paolo, Shungin, Dmitry, Winkler, Thomas W, Croteau-Chonka, Damien C, Ferreira, Teresa, Hypponen, Elina, Mohlke, Karen L, ADIPOGEN Consortium, Int Endogene Consortium, Lee Kong Chian School of Medicine (LKCMedicine), Epidemiologie, RS: CARIM - R3.02 - Hypertension and target organ damage, Université de Tours-Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Groningen Kidney Center (GKC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Shungin, D, Winkler, T, Croteau Chonka, D, Ferreira, T, Locke, A, Mägi, R, Strawbridge, R, Pers, T, Fischer, K, Justice, A, Workalemahu, T, Wu, J, Buchkovich, M, Heard Costa, N, Roman, T, Drong, A, Song, C, Gustafsson, S, Day, F, Esko, T, Fall, T, Kutalik, Z, Luan, J, Randall, J, Scherag, A, Vedantam, S, Wood, A, Chen, J, Fehrmann, R, Karjalainen, J, Kahali, B, Liu, C, Schmidt, E, Absher, D, Amin, N, Anderson, D, Beekman, M, Bragg Gresham, J, Buyske, S, Demirkan, A, Ehret, G, Feitosa, M, Goel, A, Jackson, A, Johnson, T, Kleber, M, Kristiansson, K, Mangino, M, Leach, I, Medina Gomez, C, Palmer, C, Pasko, D, Pechlivanis, S, Peters, M, Prokopenko, I, Stanca'Kova', A, Sung, Y, Tanaka, T, Teumer, A, Van Vliet Ostaptchouk, J, Yengo, L, Zhang, W, Albrecht, E, Ärnlöv, J, Arscott, G, Bandinelli, S, Barrett, A, Bellis, C, Bennett, A, Berne, C, Blüher, M, Böhringer, S, Bonnet, F, Böttcher, Y, Bruinenberg, M, Carba, D, Caspersen, I, Clarke, R, Daw, E, Deelen, J, Deelman, E, Delgado, G, Doney, A, Eklund, N, Erdos, M, Estrada, K, Eury, E, Friedrich, N, Garcia, M, Giedraitis, V, Gigante, B, Go, A, Golay, A, Grallert, H, Grammer, T, Gräsler, J, Grewal, J, Groves, C, Haller, T, Hallmans, G, Hartman, C, Hassinen, M, Hayward, C, Heikkilä, K, Herzig, K, Helmer, Q, Hillege, H, Holmen, O, Hunt, S, Isaacs, A, Ittermann, T, James, A, Johansson, I, Juliusdottir, T, Kalafati, I, Kinnunen, L, Koenig, W, Kooner, I, Kratzer, W, Lamina, C, Leander, K, Lee, N, Lichtner, P, Lind, L, Lindström, J, Lobbens, S, Lorentzon, M, Mach, F, Magnusson, P, Mahajan, A, Mcardle, W, Menni, C, Merger, S, Mihailov, E, Milani, L, Mills, R, Moayyeri, A, Monda, K, Mooijaart, S, Mühleisen, T, Mulas, A, Müller, G, Müller Nurasyid, M, Nagaraja, R, Nalls, M, Narisu, N, Glorioso, N, Nolte, I, Olden, M, Rayner, N, Renstrom, F, Ried, J, Robertson, N, Rose, L, Sanna, S, Scharnagl, H, Scholtens, S, Sennblad, B, Seufferlein, T, Sitlani, C, Smith, A, Stirrups, K, Stringham, H, Sundström, J, Swertz, M, Swift, A, Syvänen, A, Tayo, B, Thorand, B, Thorleifsson, G, Tomaschitz, A, Troffa, C, Van Oort, F, Verweij, N, Vonk, J, Waite, L, Wennauer, R, Wilsgaard, T, Wojczynski, M, Wong, A, Zhang, Q, Zhao, J, Brennan, E, Choi, M, Eriksson, P, Folkersen, L, Franco Cereceda, A, Gharavi, A, Hedman, A, Hivert, M, Huang, J, Kanoni, S, Karpe, F, Keildson, S, Kiryluk, K, Liang, L, Lifton, R, Ma, B, Mcknight, A, Mcpherson, R, Metspalu, A, Min, J, Moffatt, M, Montgomery, G, Murabito, J, Nicholson, G, Nyholt, D, Olsson, C, Perry, J, Reinmaa, E, Salem, R, Sandholm, N, Schadt, E, Scott, R, Stolk, L, Vallejo, E, Westra, H, Zondervan, K, Amouyel, P, Arveiler, D, Bakker, S, Beilby, J, Bergman, R, Blangero, J, Brown, M, Burnier, M, Campbell, H, Chakravarti, A, Chines, P, Claudi Boehm, S, Collins, F, Crawford, D, Danesh, J, De Faire, U, De Geus, E, Dörr, M, Erbel, R, Eriksson, J, Farrall, M, Ferrannini, E, Ferrières, J, Forouhi, N, Forrester, T, Franco, O, Gansevoort, R, Gieger, C, Gudnason, V, Haiman, C, Harris, T, Hattersley, A, Heliövaara, M, Hicks, A, Hingorani, A, Hoffmann, W, Hofman, A, Homuth, G, Humphries, S, Hyppönen, E, Illig, T, Jarvelin, M, Johansen, B, Jousilahti, P, Jula, A, Kaprio, J, Kee, F, Keinanen Kiukaanniemi, S, Kooner, J, Kooperberg, C, Kovacs, P, Kraja, A, Kumari, M, Kuulasmaa, K, Kuusisto, J, Lakka, T, Langenberg, C, Le Marchand, L, Lehtimäki, T, Lyssenko, V, Männistö, S, Marette, A, Matise, T, Mckenzie, C, Mcknight, B, Musk, A, Möhlenkamp, S, Morris, A, Nelis, M, Ohlsson, C, Oldehinkel, A, Ong, K, Palmer, L, Penninx, B, Peters, A, Pramstaller, P, Raitakari, O, Rankinen, T, Rao, D, Rice, T, Ridker, P, Ritchie, M, Rudan, I, Salomaa, V, Samani, N, Saramies, J, Sarzynski, M, Schwarz, P, Shuldiner, A, Staessen, J, Steinthorsdottir, V, Stolk, R, Strauch, K, Tönjes, A, Tremblay, A, Tremoli, E, Vohl, M, Völker, U, Vollenweider, P, Wilson, J, Witteman, J, Adair, L, Bochud, M, Boehm, B, Bornstein, S, Bouchard, C, Cauchi, S, Caulfield, M, Chambers, J, Chasman, D, Cooper, R, Dedoussis, G, Ferrucci, L, Froguel, P, Grabe, H, Hamsten, A, Hui, J, Hveem, K, Jöckel, K, Kivimaki, M, Kuh, D, Laakso, M, Liu, Y, März, W, Munroe, P, Njolstad, I, Oostra, B, Pedersen, N, Perola, M, Pe'Russe, L, Peters, U, Power, C, Quertermous, T, Rauramaa, R, Rivadeneira, F, Saaristo, T, Saleheen, D, Sinisalo, J, Slagboom, P, Snieder, H, Spector, T, Thorsteinsdottir, U, Stumvoll, M, Tuomilehto, J, Uitterlinden, A, Uusitupa, M, Van Der Harst, P, Veronesi, G, Walker, M, Wareham, N, Watkins, H, Wichmann, H, Abecasis, G, Assimes, T, Berndt, S, Boehnke, M, Borecki, I, Deloukas, P, Franke, L, Frayling, T, Groop, L, Hunter, D, Kaplan, R, O'Connell, J, Qi, L, Schlessinger, D, Strachan, D, Stefansson, K, Van Duijn, C, Willer, C, Visscher, P, Yang, J, Hirschhorn, J, Zillikens, M, Mccarthy, M, Speliotes, E, North, K, Fox, C, Barroso, I, Franks, P, Ingelsson, E, Heid, I, Loos, R, Cupples, L, Lindgren, C, Mohlke, K, Dastani, Z, Timpson, N, Yuan, X, Henneman, P, Kizer, J, Lyytikainen, L, Fuchsberger, C, Small, K, Coassin, S, Lohman, K, Pankow, J, Uh, H, Wu, Y, Bidulescu, A, Rasmussen Torvik, L, Greenwood, C, Ladouceur, M, Grimsby, J, Manning, A, Mooser, V, Kapur, K, Frants, R, Willemsvan vanDijk, K, Willems, S, Psaty, B, Tracy, R, Brody, J, Chen, I, Viikari, J, Kähönen, M, Evans, D, St Pourcain, B, Sattar, N, Carlson, O, Egan, J, van Heemst, D, Kedenko, L, Nuotio, M, Loo, B, Kanaya, A, Haun, M, Klopp, N, Katsareli, E, Couper, D, Duncan, B, Kloppenburg, M, Borja, J, Musani, S, Guo, X, Semple, R, Teslovich, T, Allison, M, Redline, S, Buxbaum, S, Meulenbelt, I, Ballantyne, C, Hu, F, Paulweber, B, Florez, J, Smith, G, Siscovick, D, Kronenberg, F, van Duijn, C, Waterworth, D, Meigs, J, Dupuis, J, Richards, J, Willenborg, C, Thompson, J, Erdmann, J, Goldstein, B, König, I, Cazier, J, Johansson, Å, Hall, A, Lee, J, Grundberg, E, Havulinna, A, Ho, W, Hopewell, J, Eriksson, N, Lundmark, P, Lyytikäinen, L, Rafelt, S, Tikkanen, E, Van Zuydam, N, Voight, B, Ziegler, A, Altshuler, D, Balmforth, A, Braund, P, Burgdorf, C, Cox, D, Dimitriou, M, Do, R, El Mokhtari, N, Fontanillas, P, Hager, J, Han, B, Kang, H, Kessler, T, Knowles, J, Kolovou, G, Langford, C, Lokki, M, Lundmark, A, Meisinger, C, Melander, O, Maouche, S, Nikus, K, Peden, J, Rasheed, A, Rosinger, S, Rubin, D, Rumpf, M, Schäfer, A, Sivananthan, M, Stewart, A, Tan, S, Thorgeirsson, G, van der Schoot, C, Wagner, P, Wells, G, Wild, P, Yang, T, Basart, H, Boerwinkle, E, Brambilla, P, Cambien, F, Cupples, A, de Faire, U, Dehghan, A, Diemert, P, Epstein, S, Evans, A, Ferrario, M, Gauguier, D, Goodall, A, Hazen, S, Holm, H, Iribarren, C, Jang, Y, Kim, H, Laaksonen, R, Ouwehand, W, Parish, S, Park, J, Rader, D, Shah, S, Stark, K, Trégouët, D, Virtamo, J, Wallentin, L, Zimmermann, M, Nieminen, M, Hengstenberg, C, Sandhu, M, Pastinen, T, Hovingh, G, Zalloua, P, Siegbahn, A, Schreiber, S, Ripatti, S, Blankenberg, S, O'Donnell, C, Reilly, M, Collins, R, Kathiresan, S, Roberts, R, Schunkert, H, Pattaro, C, Köttgen, A, Garnaas, M, Böger, C, Chen, M, Tin, A, Taliun, D, Li, M, Gao, X, Gorski, M, Yang, Q, Hundertmark, C, Foster, M, O'Seaghdha, C, Glazer, N, Struchalin, M, Li, G, Johnson, A, Gierman, H, Hwang, S, Atkinson, E, Cornelis, M, Chouraki, V, Holliday, E, Sorice, R, Deshmukh, H, Ulivi, S, Chu, A, Murgia, F, Trompet, S, Imboden, M, Kollerits, B, Pistis, G, Launer, L, Aspelund, T, Eiriksdottir, G, Mitchell, B, Schmidt, H, Cavalieri, M, Rao, M, de Andrade, M, Turner, S, Ding, J, Andrews, J, Freedman, B, Döring, A, Kolcic, I, Zemunik, T, Boban, M, Minelli, C, Wheeler, H, Igl, W, Zaboli, G, Wild, S, Wright, A, Ellinghaus, D, Nöthlings, U, Jacobs, G, Biffar, R, Endlich, K, Ernst, F, Kroemer, H, Nauck, M, Stracke, S, Völzke, H, Aulchenko, Y, Polasek, O, Hastie, N, Vitart, V, Helmer, C, Wang, J, Ruggiero, D, Bergmann, S, Nikopensius, T, Province, M, Ketkar, S, Colhoun, H, Robino, A, Giulianini, F, Krämer, B, Portas, L, Ford, I, Buckley, B, Adam, M, Thun, G, Sala, C, Metzger, M, Mitchell, P, Ciullo, M, Kim, S, Gasparini, P, Pirastu, M, Jukema, J, Probst Hensch, N, Toniolo, D, Coresh, J, Schmidt, R, Kardia, S, Curhan, G, Gyllensten, U, Franke, A, Rettig, R, Parsa, A, Goessling, W, Kao, W, de Boer, I, Peralta, C, Akylbekova, E, Kramer, H, van der Harst, P, Arking, D, Franceschini, N, Hernandez, D, Townsend, R, Lumley, T, Kestenbaum, B, Haritunians, T, Waeber, G, Lu, X, Leak, T, Aasarød, K, Skorpen, F, Baumert, J, Devuyst, O, Mychaleckyj, J, Hallan, S, Navis, G, Shlipak, M, Bull, S, Paterson, A, Rotter, J, Beckmann, J, Dreisbach, A, Styrkarsdottir, U, Evangelou, E, Hsu, Y, Duncan, E, Ntzani, E, Oei, L, Albagha, O, Kemp, J, Koller, D, Minster, R, Vandenput, L, Willner, D, Xiao, S, Yerges Armstrong, L, Zheng, H, Alonso, N, Kammerer, C, Kaptoge, S, Leo, P, Wilson, S, Aalto, V, Alen, M, Aragaki, A, Center, J, Dailiana, Z, Duggan, D, Garcia Giralt, N, Giroux, S, Hocking, L, Husted, L, Jameson, K, Khusainova, R, Kim, G, Koromila, T, Kruk, M, Laaksonen, M, Lacroix, A, Lee, S, Leung, P, Lewis, J, Masi, L, Mencej Bedrac, S, Nguyen, T, Nogues, X, Patel, M, Prezelj, J, Scollen, S, Siggeirsdottir, K, Svensson, O, Trummer, O, van Schoor, N, Woo, J, Zhu, K, Balcells, S, Brandi, M, Cheng, S, Christiansen, C, Cooper, C, Frost, M, Goltzman, D, González Macías, J, Karlsson, M, Khusnutdinova, E, Koh, J, Kollia, P, Langdahl, B, Leslie, W, Lips, P, Ljunggren, Ö, Lorenc, R, Marc, J, Mellström, D, Obermayer Pietsch, B, Olmos, J, Pettersson Kymmer, U, Reid, D, Riancho, J, Rousseau, F, Tang, N, Urreizti, R, Van Hul, W, Zarrabeitia, M, Castano Betancourt, M, Herrera, L, Ingvarsson, T, Johannsdottir, H, Kwan, T, Li, R, Luben, R, Medina Gómez, C, Palsson, S, Reppe, S, Sigurdsson, G, van Meurs, J, Verlaan, D, Williams, F, Zhou, Y, Gautvik, K, Raychaudhuri, S, Cauley, J, Clark, G, Cummings, S, Danoy, P, Dennison, E, Eastell, R, Eisman, J, Jackson, R, Jones, G, Khaw, K, Mccloskey, E, Nandakumar, K, Peacock, M, Pols, H, Prince, R, Reid, I, Robbins, J, Sambrook, P, Sham, P, Tylavsky, F, Econs, M, Kung, A, Reeve, J, Streeten, E, Karasik, D, Ralston, S, Ioannidis, J, Kiel, D, Forsblom, C, Isakova, T, Mckay, G, Williams, W, Sadlier, D, Mäkinen, V, Swan, E, Boright, A, Ahlqvist, E, Keller, B, Huang, H, Ahola, A, Fagerholm, E, Gordin, D, Harjutsalo, V, He, B, Heikkilä, O, Hietala, K, Kytö, J, Lahermo, P, Lehto, M, Österholm, A, Parkkonen, M, Pitkäniemi, J, Rosengård Bärlund, M, Saraheimo, M, Sarti, C, Söderlund, J, Soro 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Kaleebu, P, Kastelein, J, Kim, E, Komulainen, P, Lin, S, Nieminen, T, Nsubuga, R, Olafsson, I, Palotie, A, Papamarkou, T, Pomilla, C, Pouta, A, Ruokonen, A, Seeley, J, Silander, K, Stančáková, A, Tiret, L, van Pelt, L, Wainwright, N, Wijmenga, C, Willemsen, G, Young, E, Bennett, F, Boomsma, D, Bovet, P, Chen, Y, Feranil, A, Freimer, N, Hsiung, C, Järvelin, M, Kesäniemi, A, Koudstaal, P, Krauss, R, Kyvik, K, Martin, N, Meneton, P, Moilanen, L, Njølstad, I, Price, J, Sanghera, D, Sheu, W, Whitfield, J, Wolffenbuttel, B, Ordovas, J, Rich, S, Johnson, L, Larson, M, Levy, D, Newton Cheh, C, O'Reilly, P, Palmas, W, Rice, K, Snider, H, Tobin, M, Verwoert, G, Pihur, V, Heath, S, Sõber, S, Arora, P, Zhang, F, Lucas, G, Milaneschi, Y, Parker, A, Fava, C, Fox, E, Go, M, Sjögren, M, Vinay, D, Alexander, M, Tabara, Y, Shaw Hawkins, S, Whincup, P, Shi, G, Seielstad, M, Sim, X, Nguyen, K, Matullo, G, Gaunt, T, Onland Moret, N, Cooper, M, Platou, C, Org, E, Hardy, R, Dahgam, S, Palmen, J, Kuznetsova, T, Uiterwaal, C, Adeyemo, A, Ludwig, B, Tomaszewski, M, Tzoulaki, I, Palmer, N, Chang, Y, Steinle, N, Grobbee, D, Morrison, A, Najjar, S, Hadley, D, Connell, J, Day, I, Lawlor, D, Lawrence, R, Ongen, H, Li, Y, Young, J, Bis, J, Chaturvedi, N, Islam, M, Jafar, T, Kulkarni, S, Grässler, J, Howard, P, Guarrera, S, Ricceri, F, Emilsson, V, Plump, A, Weder, A, Sun, Y, Scott, L, Peltonen, L, Vartiainen, E, Brand, S, Wang, T, Burton, P, Artigas, M, Dong, Y, Wang, X, Zhu, H, Rudock, M, Heckbert, S, Smith, N, Wiggins, K, Doumatey, A, Shriner, D, Veldre, G, Viigimaa, M, Kinra, S, Prabhakaran, D, Tripathy, V, Langefeld, C, Rosengren, A, Thelle, D, Corsi, A, Singleton, A, Hilton, G, Salako, T, Iwai, N, Kita, Y, Ogihara, T, Ohkubo, T, Okamura, T, Ueshima, H, Umemura, S, Eyheramendy, S, Meitinger, T, Cho, Y, Scott, J, Sehmi, J, Hedblad, B, Nilsson, P, Stanèáková, A, Raffel, L, Yao, J, Schwartz, S, Ikram, M, Longstreth W., J, Mosley, T, Seshadri, S, Shrine, N, Wain, L, Morken, M, Laitinen, J, Zitting, P, Cooper, J, van Gilst, W, Janipalli, C, Mani, K, Yajnik, C, Mattace Raso, F, Lakatta, E, Orru, M, Scuteri, A, Ala Korpela, M, Kangas, A, Soininen, P, Tukiainen, T, Würtz, P, Ong, R, Galan, P, Hercberg, S, Lathrop, M, Zelenika, D, Zhai, G, Meschia, J, Sharma, P, Terzic, J, Kumar, M, Denniff, M, Zukowska Szczechowska, E, Wagenknecht, L, Fowkes, F, Charchar, F, Rotimi, C, Bots, M, Brand, E, Talmud, P, Nyberg, F, Laan, M, van der Schouw, Y, Casas, J, Vineis, P, Ganesh, S, Wong, T, Tai, E, Morris, R, Dominiczak, A, Marmot, M, Miki, T, Chandak, G, Zhu, X, Elosua, R, Soranzo, N, Sijbrands, E, Uda, M, Vasan, R, Anderson, C, Gordon, S, Guo, Q, Henders, A, Lambert, A, Kraft, P, Kennedy, S, Macgregor, S, Missmer, S, Painter, J, Roseman, F, Treloar, S, Wallace, L, Alizadeh, B, de Boer, R, Boezen, H, van der Klauw, M, Ormel, J, Postma, D, Rosmalen, J, Slaets, J, Lagou, V, Welch, R, Wheeler, E, Rehnberg, E, Lecoeur, C, Johnson, P, Hottenga, J, Salo, P, Bielak, L, Zhao, W, Horikoshi, M, Navarro, P, Chen, H, Rybin, D, Song, K, An, P, Marullo, L, Jansen, H, Edkins, S, Varga, T, Oksa, H, Antonella, M, Kong, A, Herder, C, Antti, J, Miljkovic, I, Atalay, M, Kiess, W, Smit, J, Campbell, S, Fowkes, G, Rathmann, W, Maerz, W, Watanabe, R, de Geus, E, Toenjes, A, Peyser, P, Körner, A, Cucca, F, Balkau, B, Bouatia Naji, N, Ahmadi, K, Ainali, C, Bataille, V, Bell, J, Buil, A, Dermitzakis, E, Dimas, A, Durbin, R, Glass, D, Hassanali, N, Hedman, Å, Ingle, C, Knowles, D, Krestyaninova, M, Lowe, C, Meduri, E, di Meglio, P, Montgomery, S, Nestle, F, Nica, A, Nisbet, J, O'Rahilly, S, Parts, L, Potter, S, Sekowska, M, Shin, S, Surdulescu, G, Travers, M, Tsaprouni, L, Tsoka, S, Wilk, A, Higashio, J, Williams, R, Nato, A, Ambite, J, Manolio, T, Hindorff, L, Heiss, G, Taylor, K, Avery, C, Graff, M, Lin, D, Quibrera, M, Cochran, B, Kao, L, Umans, J, Cole, S, Maccluer, J, Person, S, Gross, M, Fornage, M, Durda, P, Jenny, N, Patsy, B, Arnold, A, Buzkova, P, Haines, J, Murdock, D, Glenn, K, Brown Gentry, K, Thornton Wells, T, Dumitrescu, L, Jeff, J, Bush, W, Mitchell, S, Goodloe, R, Boston, J, Malinowski, J, Restrepo, N, Oetjens, M, Fowke, J, Zheng, W, Spencer, K, Pendergrass, S, Wilkens, L, Park, L, Tiirikainen, M, Kolonel, L, Lim, U, Cheng, I, Wang, H, Shohet, R, Stram, D, Henderson, B, Monroe, K, Schumacher, F, Anderson, G, Carlson, C, Prentice, R, Wu, C, Carty, C, Gong, J, Rosse, S, Young, A, Haessler, J, Kocarnik, J, Lin, Y, Kuller, L, He, C, Sulem, P, Barbalic, M, Broer, L, Byrne, E, Gudbjartsson, D, Mcardle, P, Porcu, E, van Wingerden, S, Zhuang, W, Lauc, L, Broekmans, F, Burri, A, Chanock, S, Chen, C, Corre, T, Coviello, A, D'Adamo, P, Davies, G, Deary, I, Ebrahim, S, Fauser, B, Ferreli, L, Folsom, A, Hall, P, Hankinson, S, Hass, M, Heath, A, Janssens, A, Keyzer, J, Lahti, J, Lai, S, Laisk, T, Laven, J, Liu, J, Lopez, L, Louwers, Y, Marongiu, M, Klaric, I, Masciullo, C, Medland, S, Melzer, D, Newman, A, Paré, G, Peeters, P, Pop, V, Räikkönen, K, Salumets, A, Smith, J, Stacey, S, Starr, J, Stathopoulou, M, Tenesa, A, Tryggvadottir, L, Tsui, K, van Dam, R, van Gils, C, van Nierop, P, Vink, J, Voorhuis, M, Wallaschofski, H, Widen, E, Wijnands van Gent, C, Zgaga, L, Zygmunt, M, Buring, J, Crisponi, L, Demerath, E, Murray, A, Visser, J, Lunetta, K, Elks, C, Cousminer, D, Feenstra, B, Lin, P, Smith, E, Warrington, N, Alavere, H, Berenson, G, Blackburn, H, Busonero, F, Chen, W, Easton, D, Foroud, T, Geller, F, Kilpeläinen, T, Li, S, Melbye, M, Murray, J, Murray, S, Ness, A, Northstone, K, Pennell, C, Pharoah, P, Rafnar, T, Rice, J, Ring, S, Schork, N, Segrè, A, Sovio, U, Srinivasan, S, Tammesoo, M, Tyrer, J, Weedon, M, Young, L, Bierut, L, Boyd, H, Psychiatry, NCA - Neurobiology of mental health, and EMGO - Lifestyle, overweight and diabetes
Subjects: Adipose Tissue/metabolism, Male, genetic association, subcutaneous fat, Transcription, Genetic, Adipocytes, Adipogenesis, Adipose Tissue, Age Factors, Body Mass Index, Continental Population Groups, Epigenesis, Genetic, Europe, Female, Genome, Human, Humans, Insulin, Insulin Resistance, Models, Biological, Neovascularization, Physiologic, Obesity, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Sex Characteristics, Waist-Hip Ratio, Body Fat Distribution, Genome-Wide Association Study, Multidisciplinary, Insulin Resistance/genetics, Genome-wide association study, Continental Population Groups/genetics, genetic analysis, heritability, gene cluster, Science::Biological sciences::Human anatomy and physiology [DRNTU], 0302 clinical medicine, high density lipoprotein cholesterol, Models, genetics [Insulin Resistance], histone modification, Age Factor, insulin receptor, 0303 health sciences, Adipocyte, Human/genetics, CARDIOGRAMplusC4D Consortium, ADIPOGENIC DIFFERENTIATION, genetic correlation, body fat, Continental Population Group, priority journal, 5 trisphosphate 3 phosphatase, GEFOS Consortium, meta analysis (topic), Science & Technology - Other Topics, ddc:500, transcription regulation, Adipogenesis/genetics, Single Nucleotide/genetics, Human, medicine.medical_specialty, Waist, phosphatidylinositol 3, European, ta3111, genetic regulation, Article, developmental biology, 03 medical and health sciences, MAGIC Investigators, transcription initiation site, SDG 3 - Good Health and Well-being, Genetic, genomics, GLYCEMIC TRAITS, genetics [Continental Population Groups], Polymorphism, GENOME-WIDE ASSOCIATION, Physiologic, genetics [Adipogenesis], Adipocytes/metabolism, Europe/ethnology, Genome, Human/genetics, Insulin/metabolism, Neovascularization, Physiologic/genetics, Obesity/genetics, Polymorphism, Single Nucleotide/genetics, Quantitative Trait Loci/genetics, Transcription, Genetic/genetics, Genetic/genetics, Adipogenesi, Science & Technology, adiponectin, [ SDV ] Life Sciences [q-bio], vasculotropin, genetics [Quantitative Trait Loci], ta1184, Racial Groups, ta1182, gene mapping, ta3121, triacylglycerol blood level, medicine.disease, Biological, major clinical study, amino acid sequence, metabolism [Insulin], Endocrinology, metabolism [Adipocytes], genetic loci, insulin, body fat, GLGC, International Endogene Consortium, metabolism [Adipose Tissue], Body mass index, HUMAN HEIGHT, Epigenesis, LifeLines Cohort Study, ReproGen Consortium, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, tissue level, Physiologic/genetics, [SDV]Life Sciences [q-bio], Medizin, Adipose tissue, low density lipoprotein cholesterol, PAGE Consortium, COMMON SNPS, angiogenesis, Waist–hip ratio, genetics [Obesity], MESH: Adipocytes/metabolism Adipogenesis/genetics Adipose Tissue/metabolism* Age Factors Body Fat Distribution* Body Mass Index Continental Population Groups/genetics Epigenesis, Genetic Europe/ethnology Female Genome, Human/genetics Genome-Wide Association Study* Humans Insulin/metabolism* Insulin Resistance/genetics Male Models, Biological Neovascularization, Physiologic/genetics Obesity/genetics Polymorphism, Single Nucleotide/genetics Quantitative Trait Loci/genetics* Sex Characteristics Transcription, Genetic/genetics Waist-Hip Ratio, single nucleotide polymorphism, fat, genetic variability, molecular biology, body mass index (BMI), ethnology [Europe], peroxisome proliferator activated receptor, 2. Zero hunger, Genetics, Genome, Single Nucleotide, waist circumference, insulin, phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase, triacylglycerol, vasculotropin, developmental biology, gene expression, genome, numerical model, adipocyte, adipose tissue, body fat distribution, body mass, female, gene locus, gene structure, hip circumference, human, insulin resistance, lipoprotein blood level, male, obesity, protein protein interaction, sex difference, waist hip ratio, Multidisciplinary Sciences, genetics [Transcription, Genetic], genetics [Polymorphism, Single Nucleotide], ADIPOGen Consortium, genetics [Neovascularization, Physiologic], Transcription, SUSCEPTIBILITY LOCI, General Science & Technology, ICBP, 030209 endocrinology & metabolism, Biology, adipocyte, MESH : Adipocytes/metabolism Adipogenesis/genetics Adipose Tissue/metabolism* Age Factors Body Fat Distribution* Body Mass Index Continental Population Groups/genetics Epigenesis, Genetic Europe/ethnology Female Genome, Human/genetics Genome-Wide Association Study* Humans Insulin/metabolism* Insulin Resistance/genetics Male Models, Biological Neovascularization, Physiologic/genetics Obesity/genetics Polymorphism, Single Nucleotide/genetics Quantitative Trait Loci/genetics* Sex Characteristics Transcription, Genetic/genetics Waist-Hip Ratio, MESENCHYMAL STEM-CELLS, GENIE Consortium, SEXUAL-DIMORPHISM, Insulin resistance, Internal medicine, medicine, genetics [Genome, Human], ABDOMINAL ADIPOSITY, Neovascularization, 030304 developmental biology, FALSE DISCOVERY, CKDGen Consortium, Sex Characteristic, MuTHER Consortium, numerical model
Abstract: Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P
Published: 2015

35. Criteria for preclinical models of cholangiocarcinoma:scientific and medical relevance

Author: Calvisi, Diego, Boulter, Luke, Vaquero, Javier, Saborowski, Anna, Fabris, Luca, Rodrigues, Pedro, Coulouarn, Cédric, Castro, Rui, Segatto, Oreste, Raggi, Chiara, van der Laan, Luc, Carpino, Guido, Goeppert, Benjamin, Roessler, Stephanie, Kendall, Timothy, Evert, Matthias, Gonzalez-Sanchez, Ester, Valle, Juan, Vogel, Arndt, Bridgewater, John, Borad, Mitesh, Gores, Gregory, Roberts, Lewis, Marin, Jose, Andersen, Jesper, Alvaro, Domenico, Forner, Alejandro, Banales, Jesus, Cardinale, Vincenzo, Macias, Rocio, Vicent, Silve, Chen, Xin, Braconi, Chiara, Verstegen, Monique, Fouassier, Laura, Scheiter, Alexander, Selaru, Florin, Evert, Katja, Utpatel, Kirsten, Broutier, Laura, Cadamuro, Massimiliano, Huch, Meritxell, Goldin, Robert, Gradilone, Sergio, Saito, Yoshimasa, University of Regensburg, University of Edinburgh, Instituto de Salud Carlos III [Madrid] (ISC), Hannover Medical School [Hannover] (MHH), Yale School of Medicine [New Haven, Connecticut] (YSM), University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Universidade de Lisboa, Università degli Studi di Firenze = University of Florence (UniFI), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Università degli Studi di Roma 'Foro Italico', Heidelberg University Hospital [Heidelberg], University of Barcelona, Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Liver Unit, Clínica Universitaria, CIBER-EHD, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), The Christie NHS Foundation Trust [Manchester, Royaume-Uni], University of Manchester [Manchester], University College of London [London] (UCL), Mayo Clinic, Mayo Clinic [Rochester], Universidad de Salamanca, University of Copenhagen = Københavns Universitet (UCPH), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA), University of California [San Francisco] (UC San Francisco), University of California (UC), University of Glasgow, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), The authors thank the European Network for the Study of Cholangiocarcinoma (ENS-CCA) and the European H2020 COST Action CA18122. The authors also acknowledge the valuable contributions of the external advisory panel. C.C. is supported by Inserm, Université de Rennes 1 and by a grant from the French Ministry of Health and the French National Cancer Institute (PRT-K20-136), CHU Rennes, CLCC Eugène Marquis, Rennes. M.M.A.V. and L.J.W.v.d.L. are supported by Medical Delta Regenerative Medicine 4D (Generating complex tissues with stem cells and printing technology) and TKI-LSH grant EMC-LSH19002. S.R. is supported by the German Research Foundation (DFG, project no. 314905040 and no. 493697503) and by German Cancer Aid (Deutsche Krebshilfe, project no. 70113922). S.V. is supported by Ministerio de Ciencia, Innovación y Universidades, Convocatoria 2019 para incentivar la Incorporación Estable de Doctores (IED2019-001007-I), by FEDER/Ministerio de Ciencia, Innovación y Universidades – Agencia Estatal de Investigación (PID2020‐116344‐RB‐100) and by the Government of Navarra-Health Research Department (58, and 2018). J.V. is funded by Ministerio de Ciencia e Innovación, part of Agencia Estatal de Investigación (AEI), through the Retos Investigación grant number PID2019-108651RJ-I00/DOI 10.13039/501100011033. The authors thank CERCA Programme/Generalitat de Catalunya for institutional support. R.I.R.M. and J.J.G.M. are supported by Instituto de Salud Carlos III, Spain (PI20/00189, PI19/00819) co-funded by the European Union. L. Fouassier belongs to a team supported by the Fondation pour la Recherche Médicale (Equipe FRM 2020 no. EQU202003010517) and is supported by Inserm and Sorbonne Université, INCa and ITMO Cancer of Aviesan within the framework of the 2021–2030 Cancer Control Strategy, on funds administered by Inserm.
Subjects: Hepatology, [SDV]Life Sciences [q-bio], Gastroenterology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology
Abstract: International audience; Cholangiocarcinoma (CCA) is a rare malignancy that develops at any point along the biliary tree. CCA has a poor prognosis, its clinical management remains challenging, and effective treatments are lacking. Therefore, preclinical research is of pivotal importance and necessary to acquire a deeper understanding of CCA and improve therapeutic outcomes. Preclinical research involves developing and managing complementary experimental models, from in vitro assays using primary cells or cell lines cultured in 2D or 3D to in vivo models with engrafted material, chemically induced CCA or genetically engineered models. All are valuable tools with well-defined advantages and limitations. The choice of a preclinical model is guided by the question(s) to be addressed; ideally, results should be recapitulated in independent approaches. In this Consensus Statement, a task force of 45 experts in CCA molecular and cellular biology and clinicians, including pathologists, from ten countries provides recommendations on the minimal criteria for preclinical models to provide a uniform approach. These recommendations are based on two rounds of questionnaires completed by 35 (first round) and 45 (second round) experts to reach a consensus with 13 statements. An agreement was defined when at least 90% of the participants voting anonymously agreed with a statement. The ultimate goal was to transfer basic laboratory research to the clinics through increased disease understanding and to develop clinical biomarkers and innovative therapies for patients with CCA.
Published: 2023

36. Screening for asymptomatic carotid stenosis in patients with non-valvular atrial fibrillation

Author: Kosmas I. Paraskevas, Hans-Henning Eckstein, Armando Mansilha, Jean-Baptiste Ricco, George Geroulakos, Vincenzo Di Lazzaro, Tatjana Rundek, Gaetano Lanza, Gustav Fraedrich, Alexei S. Svetlikov, Jasjit S. Suri, Clark J. Zeebregts, Alun H. Davies, Laura Capoccia, Robert M. Proczka, Piotr Myrcha, Pier Luigi Antignani, Jose Fernandes e Fernandes, J. David Spence, Alan Dardik, Mateja K. Jezovnik, Michael Knoflach, George S. Lavenson, Stavros K. Kakkos, Arkadiusz Jawien, Mauro Silvestrini, Aleš Blinc, Francesco Spinelli, Francesco Stilo, Piotr Musiałek, Sherif Sultan, Guillaume Goudot, Christos D. Liapis, Luca Saba, Gianluca Faggioli, Rodolfo Pini, Pavel Poredos, Dimitri P. Mikhailidis, Peter Gloviczki, Andrew N. Nicolaides, Man, Biomaterials and Microbes (MBM), Repositório da Universidade de Lisboa, Goudot, Guillaume, Central Clinic of Athens SA [Athens, Greece] (2CA), Klinikums rechts der Isar, Universidade do Porto = University of Porto, Centre hospitalier universitaire de Poitiers (CHU Poitiers), University General Hospital ' Attikon ' [Athens, Greece], National and Kapodistrian University of Athens (NKUA), Università Campus Bio-Medico di Roma / University Campus Bio-Medico of Rome ( UCBM), University of Miami, IRCSS MultiMedica Hospital [Castellanza, Italy] (2MH), Leopold Franzens Universität Innsbruck - University of Innsbruck, North-Western Scientific Clinical Center of Federal Medical Biological Agency [St. Petersburg, Russia] (NWS2CFMBA), Stroke Diagnosis and Monitoring Division [Roseville, CA, USA] (DMD/AtheroPointTM), University Medical Center Groningen [Groningen] (UMCG), Imperial College London, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Medicover Hospital [Warsaw, Poland] (MH), Medical University of Warsaw - Poland, Nuova Villa Claudia [Rome, Italy] (NVC), Universidade de Lisboa = University of Lisbon (ULISBOA), Robarts Research Institute [Canada], University of Western Ontario (UWO), Department of Neuroscience, Yale University School of Medicine, Yale School of Medicine [New Haven, Connecticut] (YSM), University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), Uniformed Services University of the Health Sciences (USUHS), General University Hospital of Patras, Nicolaus Copernicus University [Toruń], Polytechnic University of Marche [Ancona, Italy] / Università Politecnica delle Marche [Ancona, Italia], University Medical Centre Ljubljana [Ljubljana, Slovenia] (UMCL), Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), University Hospital Galway, Université Paris Cité (UPCité), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Athens Vascular Research Center [Athens, Greece] (AVRC), Università degli Studi di Cagliari = University of Cagliari (UniCa), Alma Mater Studiorum University of Bologna (UNIBO), University College of London [London] (UCL), Mayo Clinic [Rochester], and University of Nicosia
Subjects: Stroke, [SDV] Life Sciences [q-bio], Ischemic Attack, Transient, [SDV]Life Sciences [q-bio], Atrial Fibrillation, Humans, Carotid Stenosis, Cardiology and Cardiovascular Medicine
Abstract: © 2022 Elsevier B.V. All rights reserved., Jolobe supports that screening for asymptomatic carotid stenosis (AsxCS) should be extended to patients with non-valvular atrial fibrillation (NVAF). Indeed, a 2021 meta-analysis (n = 20 studies; 49,070 patients) demonstrated that the pooled prevalence of >50% AsxCS inpatients with NVAF was 12.4% (range: 4.4–24.3%). Although this issue was not discussed in our manuscript, the optimal management of patients presenting with a recent transient ischemic attack [TIA]/ischemic stroke with an ipsilateral 50–99% carotid stenosis and concomitant NVAF was addressed by the 2023 European Society for Vascular Surgery (ESVS) carotid guidelines. It was recognized that although no guidelines have provided recommendations regarding the management of these patients, a pragmatic approach is warranted.
Published: 2023

37. Implementing clinical trial data sharing requires training a new generation of biomedical researchers

Author: Ulrich Mansmann, Clara Locher, Fabian Prasser, Tracey Weissgerber, Ulrich Sax, Martin Posch, Evelyne Decullier, Ioana A. Cristea, Thomas P. A. Debray, Leonhard Held, David Moher, John P. A. Ioannidis, Joseph S. Ross, Christian Ohmann, Florian Naudet, Ludwig-Maximilians-Universität München (LMU), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Medizinische Universität Wien = Medical University of Vienna, Hospices Civils de Lyon (HCL), Università degli Studi di Padova = University of Padua (Unipd), Universiteit Utrecht, Universität Zürich [Zürich] = University of Zurich (UZH), University of Ottawa [Ottawa], Stanford University, Yale School of Medicine [New Haven, Connecticut] (YSM), European Clinical Research Infrastructures Network [Dusseldorf] (ECRIN), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), CHU Pontchaillou [Rennes], and Yale University
Subjects: Clinical trials, training, data sharing, [SDV]Life Sciences [q-bio], open science, General Medicine, individual patient data, General Biochemistry, Genetics and Molecular Biology
Abstract: International audience; Data sharing enhances the value of medical research and builds trust in clinical trials, but more biomedical researchers need to be trained in these approaches, which include meta-research, data science and ethical, legal and social issues.
Published: 2023

38. Phase 1/2 study of intratumoral G100 (TLR4 agonist) with or without pembrolizumab in follicular lymphoma

Author: Ahmad S. Halwani, Carlos Panizo, Iris Isufi, Alex F. Herrera, Craig Y. Okada, Elizabeth H. Cull, Bela Kis, Jorge M. Chaves, Nancy L. Bartlett, Weiyun Ai, Luis de la Cruz-Merino, Locke J. Bryan, Roch Houot, Kim Linton, Javier Briones, Ian Chau, Gottfried R. von Keudell, Hailing Lu, Adam Yakovich, Michael Chen, ter Meulen JH, Sergey Yurasov, Frank J. Hsu, Christopher R. Flowers, University of Utah, Clínica Universidad de Navarra [Pamplona], Universidad de Navarra [Pamplona] (UNAV), Yale University School of Medicine, H. Lee Moffitt Cancer Center and Research Institute, North-West University [Potchefstroom] (NWU), University of California [San Francisco] (UCSF), University of California, University of Sevilla, Augusta University, University System of Georgia (USG), CHU Pontchaillou [Rennes], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Manchester University NHS Foundation Trust (MFT), Memorial Sloan Kettering Cancer Center (MSKCC), The University of Texas M.D. Anderson Cancer Center [Houston], Emory University [Atlanta, GA], Immune Design Corp., Yale School of Medicine [New Haven, Connecticut] (YSM), University of California [San Francisco] (UC San Francisco), University of California (UC), Universidad de Sevilla / University of Sevilla, and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: 0303 health sciences, Cancer Research, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hematology, Antibodies, Monoclonal, Humanized, 3. Good health, Toll-Like Receptor 4, 03 medical and health sciences, 0302 clinical medicine, follicular lymphoma, Oncology, glucopyranosyl lipid A, 030220 oncology & carcinogenesis, Antineoplastic Combined Chemotherapy Protocols, Humans, TLR4, immunotherapy, pembrolizumab, Lymphoma, Follicular, 030304 developmental biology
Abstract: International audience; Intratumoral injection of G100, a toll-like receptor 4 (TLR4) agonist, was shown pre-clinically to stimulate anti-tumor immune responses and tumor regression. This open-label, multicenter, phase 1/2 trial evaluated the safety, tolerability, and preliminary efficacy of intratumoral G100 injections following localized low-dose radiation in patients with follicular lymphoma (ClinicalTrials.gov #NCT02501473). The study was comprised of a G100 dose escalation (5 or 10 mu g/dose, or 20 mu g/dose for large tumors); a randomized component comparing G100 to G100 plus pembrolizumab; and G100 20 mu g/dose expansion. Adverse events grade >= 3 were uncommon in patients treated with G100, and no unexpected toxicities were observed when combined with pembrolizumab. G100 20 mu g (n = 18) resulted in an overall response rate of 33.3% and abscopal tumor regression in 72.2% of patients. This early-phase study provides a foundation for combining an intratumoral TLR4 agonist with agents to produce immune-mediated responses in follicular lymphoma with limited added toxicity.
Published: 2021

39. Membrane-remodeling protein ESCRT-III homologs incarnate the evolution and morphogenesis of multicellular magnetotactic bacteria

Author: Wenyan Zhang, Jianwei Chen, Jie Dai, Shiwei Zhu, Hugo Le Guenno, Artemis Kosta, Hongmiao Pan, Xin-Xin Qian, Claire-Lise Santini, Nicolas Menguy, Xuegong Li, Yiran Chen, Jia Liu, Kaixuan Cui, Yicong Zhao, Guilin Liu, Eric Durand, Wei-Jia Zhang, Alain Roussel, Tian Xiao, Long-Fei Wu, Helmholtz-Zentrum Geesthacht (GKSS), Ming Hsieh Department of Electrical Engineering [Los Angeles], USC Viterbi School of Engineering, University of Southern California (USC)-University of Southern California (USC), Research Center for Proteome Analysis Key Lab of Proteomics, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Chinese Academy of Sciences [Beijing] (CAS), Yale School of Medicine [New Haven, Connecticut] (YSM), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CAS Key Laboratory of Marine Ecology and Environmental Science (KLMEES), CAS Institute of Oceanology (IOCAS), Chinese Academy of Sciences [Beijing] (CAS)-Chinese Academy of Sciences [Beijing] (CAS), Laboratoire de chimie bactérienne (LCB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de recherche pour le développement [IRD] : UR206-Centre National de la Recherche Scientifique (CNRS), International Associated Laboratory of Evolution and Development of Magnetotactic Multicellular Organisms ( LIA-MagMC), Chinese Academy of Sciences [Beijing] (CAS)-Centre National de la Recherche Scientifique (CNRS), Xi'an Jiaotong University (Xjtu), Endothélium, valvulopathies et insuffisance cardiaque (EnVI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Architecture et fonction des macromolécules biologiques (AFMB), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE]
Abstract: Endosomal sorting complex required transport (ESCRT) III proteins are essential for membrane remodeling and repair across all domains of life. Eukaryotic ESCRT-III and the cyanobacterial homologs PspA and Vipp1/Imm30 remodel membrane into vesicles, rings, filaments and tubular rods structures. Here our microscopy analysis showed that multicellular bacteria, referred to as magnetoglobules, possess multiple compartments including magnetosome organelles, polyphosphate granules, vesicles, rings, tubular rods, filaments and MVB-like structures. Therefore, membrane remodeling protein PspA might be required for the formation of these compartments, and contribute to the morphogenesis and evolution of multicellularity. To assess these hypotheses, we sequenced nine genomes of magnetoglobules and found a significant genome expansion compared to unicellular magnetotactic bacteria. Moreover, PspA was ubiquitous in magnetoglobules and formed a distinct clade on the tree of eubacterial and archaeal ESCRT-III. The phylogenetic feature suggested the evolution of magnetoglobules from a unicellular ancestor of deltaproteobacterium. Hetero-expression of ellipsoidal magnetoglobulepspA2gene alone inEscherichia coliresulted in intracellular membrane aggregation. GFP fusion labeling revealed polar location of PspA2 in rod-shaped unicells and regular interval location in filamentous cells. Cryo-electron tomography analysis showed filament bundle, membrane sacculus, vesicles and MVB-like structure in the cells expressing PspA2. Moreover, electron-dense area with a similar distribution as GFP-PspA2 foci in filamentous cells changed the inward orientation of the septum, which might interfere with the cell division. Collectively, these results show the membrane remodeling function of magnetoglobule PspA proteins, which may contribute to morphogenesis and the evolution of multicellularity of magnetotactic bacteria.
Published: 2022

40. The H19/let-7 double-negative feedback loop contributes to glucose metabolism in muscle cells

Author: Gordon G. Carmichael, Yuan Gao, Jichun Zhou, Michael J. Jurczak, Lihua Yang, Michael Roden, Hugh S. Taylor, Fuju Wu, Xiao-Bo Zhou, Luisa Dandolo, Lei Yan, Yingqun Huang, Martin Mueller, Hui-Young Lee, Julia Szendroedi, Clare A. Flannery, Gerald I. Shulman, Bos, Mireille, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University [New Haven]-Yale School of Medicine [New Haven, Connecticut] (YSM), Department of Gynecology and Obstetrics, Chinese PLA General Hospital, Department of Obstetrics and Gynecology, Jilin University (JLU), Department of Surgical Oncology, Zhejiang University School of Medicine-Affiliated Sir Run Run Shaw Hospital, Shandong Provincial Hospital Affiliated to Shandong University, Howard Hughes Medical Institute (HHMI), Departments of Internal Medicine, Cellular & Molecular Physiology, Yale School of Medicine [New Haven, Connecticut] (YSM), Obstetrics and Gynecology Department, Tangshan Gongren Hospital, Analytical, Environmental and Geo- Chemistry, Vrije Universiteit Brussel (VUB), Department of Immunology and Pathogenic Biology, Xi'an Jiaotong University (Xjtu), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute for Clinical Diabetology, German Diabetes Center-Leibniz Center for Diabetes Research, Department of Metabolic Diseases, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], 3Department of Genetics and Developmental Biology, University of Connecticut (UCONN), Albert McKern Scholar Award [R01 DK-40936 to Y.H.,U24 DK-059635 to G.I.S., R01 HD072418 to G.G.C.].Funding for open access charge: NIH [R01 HD072418]., Yale University School of Medicine, Yale School of Medicine-Yale School of Medicine-Yale Stem Cell Center, Jilin University ( JLU ), Howard Hugues Medical Institute, Department of Analytical and Environmental Chemistry, Vrije Universiteit [Brussel] ( VUB ), Xi'an Jiaotong University ( Xjtu ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Heinrich-Heine-Universität Düsseldorf [Düsseldorf], University of Connecticut Health Center, Yale University [New Haven]-Yale University School of Medicine, and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, medicine.medical_specialty, Glucose uptake, medicine.medical_treatment, Muscle Fibers, Skeletal, Down-Regulation, 610 Medicine & health, Biology, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Hyperinsulinism, Internal medicine, Genetics, medicine, Hyperinsulinemia, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, Insulin, Myocyte, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Muscle, Skeletal, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Feedback, Physiological, 0303 health sciences, RNA-Binding Proteins, medicine.disease, female genital diseases and pregnancy complications, 3. Good health, Mice, Inbred C57BL, MicroRNAs, Insulin receptor, Glucose, Endocrinology, 030220 oncology & carcinogenesis, embryonic structures, Trans-Activators, biology.protein, RNA, Long Noncoding, Blood sugar regulation, Signal Transduction
Abstract: International audience; The H19 lncRNA has been implicated in develop-ment and growth control and is associated with human genetic disorders and cancer. Acting as a molecular sponge, H19 inhibits microRNA (miRNA) let-7. Here we report that H19 is significantly de-creased in muscle of human subjects with type-2 di-abetes and insulin resistant rodents. This decrease leads to increased bioavailability of let-7, causing diminished expression of let-7 targets, which is re-capitulated in vitro where H19 depletion results in impaired insulin signaling and decreased glucose uptake. Furthermore, acute hyperinsulinemia down-regulates H19, a phenomenon that occurs through PI3K/AKT-dependent phosphorylation of the miRNA processing factor KSRP, which promotes biogen-esis of let-7 and its mediated H19 destabilization. Our results reveal a previously undescribed double-negative feedback loop between sponge lncRNA and target miRNA that contributes to glucose regulation in muscle cells.
Published: 2014

41. Heat shock factor 2 is a stress-responsive mediator of neuronal migration defects in models of fetal alcohol syndrome

Author: Federico Miozzo, Rachid El Fatimy, Illiasse Massaoudi, Ryma Abane, Kazue Hashimoto-Torii, Pasko Rakic, Liliana Paslaru, Aurélie de Thonel, Délara Sabéran-Djoneidi, Valérie Mezger, Anne Le Mouël, Elisabeth Christians, Leslie Schwendimann, Pierre Gressens, Centre épigénétique et destin cellulaire ( EDC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Diderot - Paris 7 ( UPD7 ), ED 387 iViv, Université Pierre et Marie Curie - Paris 6 ( UPMC ), Neuroprotection du Cerveau en Développement ( PROTECT ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Département de Médecine Générale, Physiologie de la Nutrition et Toxicologie (NUTox) (U866, Lipides et nutrition, équipe 7) ( NUTox ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Fundeni Hospital, Yale University School of Medicine, Yale School of Medicine, Laboratoire de Biologie du Développement de Villefranche sur mer ( LBDV ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7), Université Pierre et Marie Curie - Paris 6 (UPMC), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie de la Nutrition et Toxicologie (NUTox) (U866, Lipides et nutrition, équipe 7) (NUTox), Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de Biologie du Développement de Villefranche sur mer (LBDV), Observatoire océanologique de Villefranche-sur-mer (OOVM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre épigénétique et destin cellulaire (EDC), Yale School of Medicine [New Haven, Connecticut] (YSM), HAL UPMC, Gestionnaire, and Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Mice, 0302 clinical medicine, radial neuronal migration, Heat Shock Transcription Factors, HSF1, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Research Articles, Heat-Shock Proteins, ComputingMilieux_MISCELLANEOUS, Regulation of gene expression, Cerebral Cortex, Mice, Knockout, 0303 health sciences, [SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Cell biology, heat shock factors, DNA-Binding Proteins, [SDV.TOX] Life Sciences [q-bio]/Toxicology, medicine.anatomical_structure, Cerebral cortex, Fetal Alcohol Spectrum Disorders, [SDV.TOX]Life Sciences [q-bio]/Toxicology, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Molecular Medicine, transcription, Protein Binding, Doublecortin Protein, Fetal alcohol syndrome, Biology, 03 medical and health sciences, Mediator, Stress, Physiological, Heat shock protein, [SDV.BDD] Life Sciences [q-bio]/Development Biology, medicine, Animals, [ SDV.BDD ] Life Sciences [q-bio]/Development Biology, microtubule‐associated proteins, Transcription factor, 030304 developmental biology, microtubule-associated proteins, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, Heat shock factor, Disease Models, Animal, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Gene Expression Regulation, Immunology, fetal alcohol syndrome, 030217 neurology & neurosurgery, Malformations of Cortical Development, Group II, Transcription Factors, Neuroscience
Abstract: Fetal alcohol spectrum disorder (FASD) is a frequent cause of mental retardation. However, the molecular mechanisms underlying brain development defects induced by maternal alcohol consumption during pregnancy are unclear. We used normal and Hsf2-deficient mice and cell systems to uncover a pivotal role for heat shock factor 2 (HSF2) in radial neuronal migration defects in the cortex, a hallmark of fetal alcohol exposure. Upon fetal alcohol exposure, HSF2 is essential for the triggering of HSF1 activation, which is accompanied by distinctive post-translational modifications, and HSF2 steers the formation of atypical alcohol-specific HSF1–HSF2 heterocomplexes. This perturbs the in vivo binding of HSF2 to heat shock elements (HSEs) in genes that control neuronal migration in normal conditions, such as p35 or the MAPs (microtubule-associated proteins, such as Dclk1 and Dcx), and alters their expression. In the absence of HSF2, migration defects as well as alterations in gene expression are reduced. Thus, HSF2, as a sensor for alcohol stress in the fetal brain, acts as a mediator of the neuronal migration defects associated with FASD. Subject Categories Development & Differentiation; Neuroscience
Published: 2014

42. Role of the major determinant of polar flagellation FlhG in the endoflagella‐containing spirochete Leptospira

Author: Gerald L. Murray, Célia Fontana, Jun Liu, Hugo Varet, Ben Adler, Ruben Halifa, Mathieu Picardeau, David R. Hendrixson, Shuaiqi Guo, Alejandro Buschiazzo, Jean Yves Coppée, Lenka Fule, Odile Sismeiro, Rachel Legendre, Biologie des Spirochètes / Biology of Spirochetes, Institut Pasteur [Paris], Integrative Microbiology of Zoonotic Agents [Paris and Montevideo] (IMiZA), Institut Pasteur de Montevideo, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut Pasteur [Paris], Université de Paris (UP), Boehringer Ingelheim Pharma GmbH & Co. KG, Pôle Biomics (C2RT), Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris]-Institut Pasteur [Paris], Transcriptome et Epigénome (PF2), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Monash University [Clayton], University of Texas Southwestern Medical Center, Réseau International des Instituts Pasteur (RIIP), Yale University School of Medicine, This research was supported by ANR LEPTOMOVE (18-CE15-0027-01) and the Pasteur International Unit « Integrative Microbiology of Zoonotic Agents » (IMiZA) to MP, NIH R01AI065539 to DRH, and NIAID R01AI087946 to JL. This work is part of the PhD of Lenka Fule., We thank Olivier Gorgette (UBI platform, Institut Pasteur, Paris, France) and Ariel Mechaly (Plateforme de Cristallographie, Institut Pasteur, Paris, France) for help in electron microscopy and protein structure analysis, respectively. We thank Christophe Becavin for RNA-seq analysis, Sébastien Le Hu Nghia for genetic studies and Meng Shao and Qin Gong for their assistance in cryo-ET sample preparation and segmentation. We also thank David Šmajs for the gift of Borrelia DNA, ANR-18-CE15-0027,LEPTOMOVE,Mécanismes moléculaires de la motilité chez les spirochètes: le modèle de l'endoflagelle des leptospires(2018), Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut Pasteur [Paris] (IP), Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), and Yale School of Medicine [New Haven, Connecticut] (YSM)
Subjects: endoflagellum, [SDV]Life Sciences [q-bio], Mutant, Virulence, Flagellum, Microbiology, 03 medical and health sciences, Bacterial Proteins, Leptospira, Humans, Leptospirosis, spirochetes, Molecular Biology, Pathogen, Monomeric GTP-Binding Proteins, 030304 developmental biology, 0303 health sciences, biology, 030306 microbiology, Gene Expression Profiling, Cryoelectron Microscopy, Genetic Complementation Test, Gene Expression Regulation, Bacterial, Periplasmic space, biology.organism_classification, Complementation, motility, Flagella, Spirochaetales, Mutation, FlhG, Bacteria
Abstract: International audience; Spirochetes can be distinguished from other bacteria by their spiral-shaped morphology and subpolar periplasmic flagella. This study focused on FlhF and FlhG, which control the spatial and numerical regulation of flagella in many exoflagellated bacteria, in the spirochete Leptospira. In contrast to flhF which seems to be essential in Leptospira, we demonstrated that flhG- mutants in both the saprophyte L. biflexa and the pathogen L. interrogans were less motile than the wild-type strains in gel-like environments but not hyperflagellated as reported previously in other bacteria. Cryo-electron tomography revealed that the distance between the flagellar basal body and the tip of the cell decreased significantly in the flhG- mutant in comparison to wild-type and complemented strains. Additionally, comparative transcriptome analyses of L. biflexa flhG- and wild-type strains showed that FlhG acts as a negative regulator of transcription of some flagellar genes. We found that the L. interrogans flhG- mutant was attenuated for virulence in the hamster model. Cross-species complementation also showed that flhG is not interchangeable between species. Our results indicate that FlhF and FlhG in Leptospira contribute to governing cell motility but our data support the hypothesis that FlhF and FlhG function differently in each bacterial species, including among spirochetes.
Published: 2021

43. Mediators of the improvement in heart failure outcomes with empagliflozin in the EMPA‐REG OUTCOME trial

Author: Anne Pernille Ofstad, Afshin Salsali, Erich Bluhmki, Martin Schumacher, Christoph Wanner, John M. Lachin, Silvio E. Inzucchi, Stefan Hantel, Kristin Ohneberg, Jyothis T. George, Claudia Schmoor, David Fitchett, Faiez Zannad, Bernard Zinman, St. Michael's Hospital, Yale University School of Medicine, Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], University Hospital of Würzburg, University of Freiburg [Freiburg], Clinical Trials Center, Freiburg University Medical Center, Boehringer Ingelheim Norway KS, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Boehringer Ingelheim International GmbH, Biostatistics Center, The George Washington University, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), This analysis was funded by Boehringer Ingelheim. TheEMPA-REG OUTCOME trial was funded by BoehringerIngelheim and Eli Lilly., Yale School of Medicine [New Haven, Connecticut] (YSM), Universitäts Klinikum Freiburg = University Medical Center Freiburg (Uniklinik), and BOZEC, Erwan
Subjects: medicine.medical_specialty, Population, Empagliflozin, Renal function, 030204 cardiovascular system & hematology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Glucosides, Diabetes mellitus, Internal medicine, Heart rate, medicine, Diseases of the circulatory (Cardiovascular) system, Humans, 030212 general & internal medicine, Benzhydryl Compounds, education, Heart Failure, education.field_of_study, business.industry, Proportional hazards model, Diabetes, SGLT2 inhibitor, Original Articles, medicine.disease, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Diabetes Mellitus, Type 2, chemistry, RC666-701, Heart failure, Cardiology, Mediation analysis, Uric acid, Original Article, Cardiology and Cardiovascular Medicine, business
Abstract: International audience; Aims: In the EMPA-REG OUTCOME trial, empagliflozin reduced risk of death from heart failure (HF) or hospitalization for heart failure (HHF) versus placebo in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular (CV) disease. We evaluated post hoc the degree to which covariates mediated the effects of empagliflozin on HHF or HF death.Methods and results: A mediator had to fulfil the following criteria: (i) affected by active treatment, (ii) associated with the outcome, and finally (iii) adjustment for it results in a reduced treatment effect compared with unadjusted analysis. Potential mediators were calculated as change from baseline or updated mean and evaluated in univariable analyses as time-dependent covariates in Cox regression of time to HHF or HF death; those with the largest mediating effects were then included in a multivariable analysis. Increases in heart rate, log urine albumin-to-creatinine ratio (UACR), waist circumference, and uric acid were associated with increased risk of HHF or HF death; increases in high-density lipoprotein cholesterol, estimated glomerular filtration rate, haematocrit, haemoglobin, and albumin were associated with reduced risk of HHF or HF death. In univariable analyses, change from baseline in haematocrit, haemoglobin, albumin, uric acid, and logUACR mediated 51%, 54%, 23%, 24%, and 27% of the risk reduction with empagliflozin versus placebo, respectively. Multivariable analysis including haemoglobin, logUACR, and uric acid mediated 85% of risk reduction with similar results when updated means were evaluated.Conclusions: Changes in haematocrit and haemoglobin were the most important mediators of the reduction in HHF and death from HF in patients with T2DM and established CV disease treated with empagliflozin. Albumin, uric acid, and logUACR had smaller mediating effects in this population.
Published: 2021

44. Expanding SPTAN1 monoallelic variant associated disorders: From epileptic encephalopathy to pure spastic paraplegia and ataxia

Author: Heba Morsy, Mehdi Benkirane, Elisa Cali, Clarissa Rocca, Kristina Zhelcheska, Valentina Cipriani, Evangelia Galanaki, Reza Maroofian, Stephanie Efthymiou, David Murphy, Mary O’Driscoll, Mohnish Suri, Siddharth Banka, Jill Clayton-Smith, Thomas Wright, Melody Redman, Jennifer A. Bassetti, Mathilde Nizon, Benjamin Cogne, Rami Abu Jamra, Tobias Bartolomaeus, Marion Heruth, Ilona Krey, Janina Gburek-Augustat, Dagmar Wieczorek, Felix Gattermann, Meriel Mcentagart, Alice Goldenberg, Lucie Guyant-Marechal, Hector Garcia-Moreno, Paola Giunti, Brigitte Chabrol, Severine Bacrot, Roger Buissonnière, Virginie Magry, Vykuntaraju K. Gowda, Varunvenkat M. Srinivasan, Béla Melegh, András Szabó, Katalin Sümegi, Mireille Cossée, Monica Ziff, Russell Butterfield, David Hunt, Georgina Bird-Lieberman, Michael Hanna, Michel Koenig, Michael Stankewich, Jana Vandrovcova, Henry Houlden, J.C. Ambrose, P. Arumugam, E.L. Baple, M. Bleda, F. Boardman-Pretty, J.M. Boissiere, C.R. Boustred, H. Brittain, M.J. Caulfield, G.C. Chan, C.E.H. Craig, L.C. Daugherty, A. de Burca, A. Devereau, G. Elgar, R.E. Foulger, T. Fowler, P. Furió-Tarí, J.M. Hackett, D. Halai, A. Hamblin, S. Henderson, J.E. Holman, T.J.P. Hubbard, K. Ibáñez, R. Jackson, L.J. Jones, D. Kasperaviciute, M. Kayikci, L. Lahnstein, K. Lawson, S.E.A. Leigh, I.U.S. Leong, F.J. Lopez, F. Maleady-Crowe, J. Mason, E.M. McDonagh, L. Moutsianas, M. Mueller, N. Murugaesu, A.C. Need, C.A. Odhams, C. Patch, D. Perez-Gil, D. Polychronopoulos, J. Pullinger, T. Rahim, A. Rendon, P. Riesgo-Ferreiro, T. Rogers, M. Ryten, K. Savage, K. Sawant, R.H. Scott, A. Siddiq, A. Sieghart, D. Smedley, K.R. Smith, A. Sosinsky, W. Spooner, H.E. Stevens, A. Stuckey, R. Sultana, E.R.A. Thomas, S.R. Thompson, C. Tregidgo, A. Tucci, E. Walsh, S.A. Watters, M.J. Welland, E. Williams, K. Witkowska, S.M. Wood, M. Zarowiecki, UCL, Institute of Neurology [London], Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), William Harvey Research Institute, Barts and the London Medical School, Birmingham Women’s and Children’s Hospitals NHS Foundation Trust, Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], Manchester University NHS Foundation Trust (MFT), Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Weill Cornell Medicine [New York], unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), University Hospital Leipzig, University Hospital Düsseldorf, St George’s University Hospitals, Département de génétique [CHU Rouen] (Centre Normandie de Génomique et de Médecine Personnalisée), CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Service de pédiatrie et neurologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), University College London Hospitals NHS Foundation Trust [London, UK] (UCLH), Centre Hospitalier de Versailles André Mignot (CHV), Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, Auteur indépendant, University of Pécs Medical School (UP MS), University of Pecs, Great Ormond Street Hospital for Children NHS Foundation Trust [London, UK] (GOSHC), University of Utah School of Medicine [Salt Lake City], Princess Anne Hospital [Southampton, UK] (PAH), University of Southampton, University Hospital Southampton NHS Foundation Trust, Department of Pathology [Yale], Yale School of Medicine [New Haven, Connecticut] (YSM), H.M., J.V., and H.H. are supported by an Medical Research Council strategic award, MR/S005021/1, to establish International Centre for Genomic Medicine in Neuromuscular Diseases. H.M. is supported by Wellcome Trust grant 220906/Z/20/Z. H.H. is funded by the Medical Research Council (MR/S01165X/1, MR/S005021/1, G0601943), NIHR University College London Hospitals Biomedical Research Centre, Rosetree Trust UK, Ataxia UK, Multiple System Atrophy Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK, and Multiple System Atrophy Trust. R.But. is supported by the Penelope Rare and Undiagnosed Disease Program at the University of Utah with funding from the Center for Genomic Medicine and with support from Matt Velinder (Department of Human Genetics, University of Utah) and Rong Mao and Pinar Bayrak-Toydemir (ARUP Laboratories). B.M. is supported by NKFIH K138669. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health and Care Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded the research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. This study makes use of data generated by the DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) community. A full list of centers which contributed to the generation of the data is available at https://deciphergenomics.org/about/stats and via email from contact@deciphergenomics.org. Funding for the DECIPHER project was provided by Wellcome. We are thankful to the Deciphering Developmental Disorders Study for the invaluable collaboration. The Deciphering Developmental Disorders Study (Cambridge South Research Ethics Committee approval 10/H0305/83 and the Republic of Ireland Research Ethics Committee GEN/284/12) presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and Department of Health and the Wellcome Trust Sanger Institute (grant number WT098051), MORNET, Dominique, Nottingham University Hospitals NHS Trust (NUH), Weill Cornell Medicine [Cornell University], and Cornell University [New York]
Subjects: [SDV] Life Sciences [q-bio], Developmental delay, [SDV]Life Sciences [q-bio], Hereditary spastic paraplegia, Genetics (clinical), Hereditary ataxia, SPTAN1, Developmental epileptic encephalopathy
Abstract: On behalf of Queen Square Genomics On behalf of Genomics England Research Consortium; International audience; Purpose: Nonerythrocytic αII-spectrin (SPTAN1) variants have been previously associated with intellectual disability and epilepsy. We conducted this study to delineate the phenotypic spectrum of SPTAN1 variants.Methods: We carried out SPTAN1 gene enrichment analysis in the rare disease component of the 100,000 Genomes Project and screened 100,000 Genomes Project, DECIPHER database, and GeneMatcher to identify individuals with SPTAN1 variants. Functional studies were performed on fibroblasts from 2 patients.Results: Statistically significant enrichment of rare (minor allele frequency < 1 × 10-5) probably damaging SPTAN1 variants was identified in families with hereditary ataxia (HA) or hereditary spastic paraplegia (HSP) (12/1142 cases vs 52/23,847 controls, p = 2.8 × 10-5). We identified 31 individuals carrying SPTAN1 heterozygous variants or deletions. A total of 10 patients presented with pure or complex HSP/HA. The remaining 21 patients had developmental delay and seizures. Irregular αII-spectrin aggregation was noted in fibroblasts derived from 2 patients with p.(Arg19Trp) and p.(Glu2207del) variants.Conclusion: We found that SPTAN1 is a genetic cause of neurodevelopmental disorder, which we classified into 3 distinct subgroups. The first comprises developmental epileptic encephalopathy. The second group exhibits milder phenotypes of developmental delay with or without seizures. The final group accounts for patients with pure or complex HSP/HA.
Published: 2022

45. Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study

Author: Kevin J. Harrington, Barbara Burtness, Richard Greil, Denis Soulières, Makoto Tahara, Gilberto de Castro, Amanda Psyrri, Irene Brana, Neus Basté, Prakash Neupane, Åse Bratland, Thorsten Fuereder, Brett G.M. Hughes, Ricard Mesia, Nuttapong Ngamphaiboon, Tamara Rordorf, Wan Zamaniah Wan Ishak, Jianxin Lin, Burak Gumuscu, Ramona F. Swaby, Danny Rischin, Institut Català de la Salut, [Harrington KJ] The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, National Institute of Health Research Biomedical Research Centre, London, United Kingdom. [Burtness B] Yale Cancer Center and Yale School of Medicine, New Haven, CT. [Greil R] Salzburg Cancer Research Institute-Center for Clinical Cancer and Immunology Trials, Salzburg, Austria. Paracelsus Medical University Hospital, and Cancer Cluster Salzburg, Salzburg, Austria. [Soulières D] Centre Hospitalier de l’Université de Montréal, Montréal, QC, Canada. [Tahara M] National Cancer Center Hospital East, Kashiwa, Japan. [de Castro G Jr] Instituto do Cancer do Estado de Sao Paulo, Sao Paulo, Brazil. [Brana I, Basté N] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Cancer Research, Anticossos monoclonals - Ús terapèutic, terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Other subheadings::Other subheadings::/drug therapy [Other subheadings], Neck cancer, Cap - Càncer - Tractament, Quimioteràpia combinada, Càncer de coll, Head cancer, Coll - Càncer - Tractament, Oncology, Neoplasms::Neoplasms by Site::Head and Neck Neoplasms [DISEASES], Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Quimioteràpia, neoplasias::neoplasias por localización::neoplasias de cabeza y cuello [ENFERMEDADES], Chemotherapy, Monoclonal antibodies, Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies::Antibodies, Monoclonal [CHEMICALS AND DRUGS], Càncer de cap, Anticossos monoclonals, aminoácidos, péptidos y proteínas::proteínas::proteínas sanguíneas::inmunoproteínas::inmunoglobulinas::anticuerpos::anticuerpos monoclonales [COMPUESTOS QUÍMICOS Y DROGAS]
Abstract: PURPOSE Pembrolizumab and pembrolizumab-chemotherapy demonstrated efficacy in recurrent/metastatic head and neck squamous cell carcinoma in KEYNOTE-048. Post hoc analysis of long-term efficacy and progression-free survival on next-line therapy (PFS2) is presented. METHODS Patients were randomly assigned (1:1:1) to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Efficacy was evaluated in programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20, CPS ≥ 1, and total populations, with no multiplicity or alpha adjustment. RESULTS The median study follow-up was 45.0 months (interquartile range, 41.0-49.2; n = 882). At data cutoff (February 18, 2020), overall survival improved with pembrolizumab in the PD-L1 CPS ≥ 20 (hazard ratio [HR], 0.61; 95% CI, 0.46 to 0.81) and CPS ≥ 1 populations (HR, 0.74; 95% CI, 0.61 to 0.89) and was noninferior in the total population (HR, 0.81; 95% CI, 0.68 to 0.97). Overall survival improved with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.62; 95% CI, 0.46 to 0.84), CPS ≥ 1 (HR, 0.64; 95% CI, 0.53 to 0.78), and total (HR, 0.71; 95% CI, 0.59 to 0.85) populations. The objective response rate on second-course pembrolizumab was 27.3% (3 of 11). PFS2 improved with pembrolizumab in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.84) and CPS ≥ 1 (HR, 0.79; 95% CI, 0.66 to 0.95) populations and with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.86), CPS ≥ 1 (HR, 0.66; 95% CI, 0.55 to 0.81), and total (HR, 0.73; 95% CI, 0.61 to 0.88) populations. PFS2 was similar after pembrolizumab and longer after pembrolizumab-chemotherapy on next-line taxanes and shorter after pembrolizumab and similar after pembrolizumab-chemotherapy on next-line nontaxanes. CONCLUSION With a 4-year follow-up, first-line pembrolizumab and pembrolizumab-chemotherapy continued to demonstrate survival benefit versus cetuximab-chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma. Patients responded well to subsequent treatment after pembrolizumab-based therapy.
Published: 2022

46. Why do guidelines recommend screening for abdominal aortic aneurysms, but not for asymptomatic carotid stenosis? A plea for a randomized controlled trial

Author: Kosmas I. Paraskevas, J. David Spence, Dimitri P. Mikhailidis, Pier Luigi Antignani, Peter Gloviczki, Hans-Henning Eckstein, Francesco Spinelli, Francesco Stilo, Luca Saba, Pavel Poredos, Alan Dardik, Christos D. Liapis, Armando Mansilha, Gianluca Faggioli, Rodolfo Pini, Mateja K. Jezovnik, Sherif Sultan, Piotr Musiałek, Guillaume Goudot, George S. Lavenson, Arkadiusz Jawien, Aleš Blinc, Piotr Myrcha, Jose Fernandes e Fernandes, George Geroulakos, Stavros K. Kakkos, Michael Knoflach, Robert M. Proczka, Laura Capoccia, Tatjana Rundek, Alexei S. Svetlikov, Mauro Silvestrini, Jean-Baptiste Ricco, Alun H. Davies, Vincenzo Di Lazzaro, Jasjit S. Suri, Gaetano Lanza, Gustav Fraedrich, Clark J. Zeebregts, Andrew N. Nicolaides, Central Clinic of Athens SA [Athens, Greece] (2CA), Robarts Research Institute [Canada], University of Western Ontario (UWO), Royal Free Hospital [London, UK], University College of London [London] (UCL), Nuova Villa Claudia [Rome, Italy] (NVC), Mayo Clinic [Rochester], Klinikums rechts der Isar, Università Campus Bio-Medico di Roma / University Campus Bio-Medico of Rome ( UCBM), Università degli Studi di Cagliari = University of Cagliari (UniCa), University Medical Centre Ljubljana [Ljubljana, Slovenia] (UMCL), Department of Neuroscience, Yale University School of Medicine, Yale School of Medicine [New Haven, Connecticut] (YSM), Athens Vascular Research Center [Athens, Greece] (AVRC), Universidade do Porto = University of Porto, Hospital de S. João [Porto, Portugal] (HSJ), Alma Mater Studiorum University of Bologna (UNIBO), Policlinico S. Orsola-malpighi, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO)-Servizio sanitario regionale Emilia-Romagna, The University of Texas Health Science Center at Houston (UTHealth), University Hospital Galway, Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Université Paris Cité (UPCité), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Uniformed Services University of the Health Sciences (USUHS), Nicolaus Copernicus University [Toruń], Medical University of Warsaw - Poland, Universidade de Lisboa = University of Lisbon (ULISBOA), University General Hospital ' Attikon ' [Athens, Greece], National and Kapodistrian University of Athens (NKUA), General University Hospital of Patras, Leopold Franzens Universität Innsbruck - University of Innsbruck, Medicover Hospital [Warsaw, Poland] (MH), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), University of Miami, North-Western Scientific Clinical Center of Federal Medical Biological Agency [St. Petersburg, Russia] (NWS2CFMBA), Polytechnic University of Marche [Ancona, Italy] / Università Politecnica delle Marche [Ancona, Italia], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Imperial College London, Atheropoint LLC Company [Roseville, CA, USA], IRCSS MultiMedica Hospital [Castellanza, Italy] (2MH), University Medical Center Groningen [Groningen] (UMCG), University of Nicosia, Goudot, Guillaume, and Repositório da Universidade de Lisboa
Subjects: Endarterectomy, Carotid, Carotid plaque burden, [SDV]Life Sciences [q-bio], Stroke, Guidelines, [SDV] Life Sciences [q-bio], Asymptomatic carotid atherosclerosis, Risk Factors, Asymptomatic Diseases, Carotid stenosis, Screening, Humans, Mass Screening, Cardiology and Cardiovascular Medicine, Aortic Aneurysm, Abdominal, Randomized Controlled Trials as Topic
Abstract: © 2022 Elsevier B.V. All rights reserved., ackground: Current guidelines do not recommend screening for asymptomatic carotid artery stenosis (AsxCS). The rationale behind this recommendation is that detection of AsxCS may lead to an unnecessary carotid intervention. In contrast, screening for abdominal aortic aneurysms is strongly recommended. Methods: A critical analysis of the literature was performed to evaluate the implications of detecting AsxCS. Results: Patients with AsxCS are at high risk for future stroke, myocardial infarction and vascular death. Population-wide screening for AsxCS should not be recommended. Additionally, screening of high-risk individuals for AsxCS with the purpose of identifying candidates for a carotid intervention is inappropriate. Instead, selective screening for AsxCS should be considered and should be viewed as an opportunity to identify individuals at high risk for atherosclerotic cardiovascular disease and future cardiovascular events for the timely initiation of intensive medical therapy and risk factor modification. Conclusions: Although mass screening should not be recommended, there are several arguments suggesting that selective screening for AsxCS should be considered. The rationale supporting such selective screening is to optimize risk factor control and to initiate intensive medical therapy for prevention of future cardiovascular events, rather than to identify candidates for an intervention.
Published: 2022

47. Structural brain alterations associated with suicidal thoughts and behaviors in young people: results from 21 international studies from the ENIGMA Suicidal Thoughts and Behaviours consortium

Author: van Velzen, Laura, Dauvermann, Maria, Colic, Lejla, Villa, Luca, Savage, Hannah, Toenders, Yara, Zhu, Alyssa, Bright, Joanna, Campos, Adrián, Salminen, Lauren, Ambrogi, Sonia, Ayesa-Arriola, Rosa, Banaj, Nerisa, Başgöze, Zeynep, Bauer, Jochen, Blair, Karina, Blair, Robert James, Brosch, Katharina, Cheng, Yuqi, Colle, Romain, Connolly, Colm, Corruble, Emmanuelle, Couvy-Duchesne, Baptiste, Crespo-Facorro, Benedicto, Cullen, Kathryn, Dannlowski, Udo, Davey, Christopher, Dohm, Katharina, Fullerton, Janice, Gonul, Ali Saffet, Gotlib, Ian, Grotegerd, Dominik, Hahn, Tim, Harrison, Ben, He, Mengxin, Hickie, Ian, Ho, Tiffany, Iorfino, Frank, Jansen, Andreas, Jollant, Fabrice, Kircher, Tilo, Klimes-Dougan, Bonnie, Klug, Melissa, Leehr, Elisabeth, Lippard, Elizabeth, Mclaughlin, Katie, Meinert, Susanne, Miller, Adam Bryant, Mitchell, Philip, Mwangi, Benson, Nenadić, Igor, Ojha, Amar, Overs, Bronwyn, Pfarr, Julia-Katharina, Piras, Fabrizio, Ringwald, Kai, Roberts, Gloria, Romer, Georg, Sanches, Marsal, Sheridan, Margaret, Soares, Jair, Spalletta, Gianfranco, Stein, Frederike, Teresi, Giana, Tordesillas-Gutiérrez, Diana, Uyar-Demir, Aslihan, van der Wee, Nic, van der Werff, Steven, Vermeiren, Robert, Winter, Alexandra, Wu, Mon-Ju, Yang, Tony, Thompson, Paul, Rentería, Miguel, Jahanshad, Neda, Blumberg, Hilary, van Harmelen, Anne-Laura, Schmaal, Lianne, Instituto de Investigación Marqués de Valdecilla, German Research Foundation, National Institutes of Health (US), European Commission, van Velzen, Laura S [0000-0002-6003-5227], Dauvermann, Maria R [0000-0002-2873-8512], Villa, Luca M [0000-0001-5091-6410], Toenders, Yara J [0000-0002-4117-1143], Campos, Adrián I [0000-0003-3468-8619], Ambrogi, Sonia [0000-0002-2897-358X], Ayesa-Arriola, Rosa [0000-0003-0570-5352], Başgöze, Zeynep [0000-0002-0306-4849], Bauer, Jochen [0000-0001-9345-2126], Brosch, Katharina [0000-0002-0526-8095], Connolly, Colm G [0000-0002-4051-3682], Cullen, Kathryn R [0000-0001-9631-3770], Dannlowski, Udo [0000-0001-7117-2908], Davey, Christopher G [0000-0003-1431-3852], Fullerton, Janice M [0000-0003-4014-4490], Gonul, Ali Saffet [0000-0003-3522-1359], Hahn, Tim [0000-0001-6541-3795], He, Mengxin [0000-0003-2714-3565], Hickie, Ian B [0000-0001-8832-9895], Ho, Tiffany C [0000-0002-4500-6364], Ojha, Amar [0000-0002-1038-0225], Overs, Bronwyn J [0000-0002-7138-5556], Piras, Fabrizio [0000-0003-3566-5494], Ringwald, Kai G [0000-0001-5886-6745], Sanches, Marsal [0000-0002-6993-6822], Soares, Jair C [0000-0002-5466-5628], Spalletta, Gianfranco [0000-0002-7432-4249], Tordesillas-Gutiérrez, Diana [0000-0003-1458-3932], Uyar-Demir, Aslihan [0000-0002-0856-4260], Winter, Alexandra [0000-0003-3759-1425], Wu, Mon-Ju [0000-0002-0540-8027], Rentería, Miguel E [0000-0003-4626-7248], Blumberg, Hilary P [0000-0002-6363-4698], Apollo - University of Cambridge Repository, Neurology, Developmental Neuroscience in Society, University of Melbourne, University of Cambridge [UK] (CAM), Yale School of Medicine [New Haven, Connecticut] (YSM), University of Southern California (USC), University of Queensland [Brisbane], Fondazione Santa Lucia [IRCCS], Clinical and Behavioral Neurology [IRCCS Santa Lucia], Universidad de Cantabria [Santander], University of Minnesota Medical School, University of Minnesota System, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Boys Town National Research Hospital [Omaha], Philipps Universität Marburg = Philipps University of Marburg, Kunming Medical University (KMU), Université Paris-Saclay, Florida State University [Tallahassee] (FSU), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Bioscience, Universidad de Sevilla / University of Sevilla, University of New South Wales [Kensington], Ege University [Izmir], Stanford University, The University of Sydney, University of Texas at Austin [Austin], Harvard University, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), University of Pittsburgh Medical Center [Pittsburgh, PA, États-Unis] (UPMC), Neuroscience Research Australia (NeuRA), Hospital Universitario Marqués de Valdecilla [Santander], Leiden University Medical Center (LUMC), Universiteit Leiden, University of California [San Francisco] (UC San Francisco), University of California (UC), and Keck School of Medicine [Los Angeles]
Subjects: Cortical Thickness, History, Adolescent, Volume, Mood Disorders, [SCCO.NEUR]Cognitive science/Neuroscience, Brain, Suicide, Attempted, Neuroimaging, Adolescents, Reliability, Suicidal Ideation, Sample, Regions, Cellular and Molecular Neuroscience, Psychiatry and Mental health, SDG 3 - Good Health and Well-being, Bipolar, Adults, Humans, Molecular Biology, Gray
Abstract: Funder: MQ Brighter Futures Award MQBFC/2 and the U.S. National Institute of Mental Health under Award Number R01MH117601. National Suicide Prevention Research Fund, managed by Suicide Prevention Australia, Funder: MQ Brighter Futures Award MQBFC/2. Interdisziplinäres Zentrum für Klinische Forschung, UKJ, Funder: Italian Ministry of Health grant RC17-18-19-20-21/A, Funder: Instituto de Salud Carlos III through the projects PI14/00639, PI14/00918 and PI17/01056 (Co-funded by European Regional Development Fund/European Social Fund "Investing in your future") and Fundación Instituto de Investigación Marqués de Valdecilla (NCT0235832 and NCT02534363), Funder: National Institute of Mental Health (K23MH090421), the National Alliance for Research on Schizophrenia and Depression, the University of Minnesota Graduate School, the Minnesota Medical Foundation, and the Biotechnology Research Center (P41 RR008079 to the Center for Magnetic Resonance Research), University of Minnesota, and the Deborah E. Powell Center for Women’s Health Seed Grant, University of Minnesota, Funder: Medical Leader Foundation of Yunnan Province (L2019011) and Famous Doctors Project of Yunnan Province Plan (YNWR-MY-2018-041), Funder: CJ Martin Fellowship (NHMRC app 1161356). “Investissements d’avenir” ANR-10-IAIHU-06, Funder: German Research Foundation (DFG, grant FOR2107-DA1151/5-1 and DA1151/5-2 to UD, and DFG grants HA7070/2-2, HA7070/3, HA7070/4 to TH), Funder: Australian National Health and Medical Research Council of Australia (NHMRC) Project Grants 1024570 NHMRC Career Development Fellowships (1061757), Funder: Medical Faculty Münster, Innovative Medizinische Forschung (Grant IMF KO 1218 06), Funder: Australian National Medical and Health Research Council (Program Grant 1037196 and Investigator Grant 1177991 to PBM, Project Grant 1066177 to JMF), the Lansdowne Foundation, Good Talk and the Keith Pettigrew Family Bequest (PM) Janette Mary O’Neil Research Fellowship. IHG is supported in part by R37MH101495, Funder: Australian National Health and Medical Research Council of Australia (NHMRC) Project Grants 1064643 (principal investigator, BJH) NHMRC Career Development Fellowships (1124472), Funder: National Institute of Mental Health (K01MH106805). Klingenstein Third Generation Foundation, the National Institute of Mental Health (K01MH117442), the Stanford Maternal Child Health Research Institute, and the Stanford Center for Cognitive and Neurobiological Imaging. TCH receives partial support from the Ray and Dagmar Dolby Family Fund, Funder: German Research Foundation (DFG, grant FOR2107-JA 1890/7-1 and JA 1890/7-2 to AJ, and DFG, grant FOR2107-KI588/14-1 and FOR2107-KI588/14-2 to TK), Funder: NIAAA (K01AA027573, R21AA027884) and the American Foundation for Suicide Prevention, Funder: National Institute of Mental Health (R01-MH103291), Funder: National Center for Complementary and Integrative Health (NCCIH) R21AT009173 and R61AT009864 National Center for Advancing Translational Sciences (CTSI), National Institutes of Health, through UCSF-CTSI UL1TR001872 American Foundation for Suicide Prevention (AFSP) SRG-1-141-18 UCSF Research Evaluation and Allocation Committee (REAC) and J. Jacobson Fund to TTY; by the National Institute of Mental Health (NIMH) R01MH085734 and the Brain and Behavior Research Foundation (formerly NARSAD), Funder: MQ Brighter Futures Award MQBFC/2 R61MH111929RC1MH088366, R01MH070902, R01MH069747, American Foundation for Suicide Prevention, International Bipolar Foundation, Brain and Behavior Research Foundation, For the Love of Travis Foundation and Women’s Health Research at Yale, Funder: MQ Brighter Futures Award MQBFC/2 Social Safety and Resilience programme of Leiden University, Funder: MQ Brighter Futures Award MQBFC/2 National Institute of Mental Health under Award Number R01MH117601 NHMRC Career Development Fellowship (1140764), Identifying brain alterations associated with suicidal thoughts and behaviors (STBs) in young people is critical to understanding their development and improving early intervention and prevention. The ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium analyzed neuroimaging data harmonized across sites to examine brain morphology associated with STBs in youth. We performed analyses in three separate stages, in samples ranging from most to least homogeneous in terms of suicide assessment instrument and mental disorder. First, in a sample of 577 young people with mood disorders, in which STBs were assessed with the Columbia Suicide Severity Rating Scale (C-SSRS). Second, in a sample of young people with mood disorders, in which STB were assessed using different instruments, MRI metrics were compared among healthy controls without STBs (HC; N = 519), clinical controls with a mood disorder but without STBs (CC; N = 246) and young people with current suicidal ideation (N = 223). In separate analyses, MRI metrics were compared among HCs (N = 253), CCs (N = 217), and suicide attempters (N = 64). Third, in a larger transdiagnostic sample with various assessment instruments (HC = 606; CC = 419; Ideation = 289; HC = 253; CC = 432; Attempt=91). In the homogeneous C-SSRS sample, surface area of the frontal pole was lower in young people with mood disorders and a history of actual suicide attempts (N = 163) than those without a lifetime suicide attempt (N = 323; FDR-p = 0.035, Cohen's d = 0.34). No associations with suicidal ideation were found. When examining more heterogeneous samples, we did not observe significant associations. Lower frontal pole surface area may represent a vulnerability for a (non-interrupted and non-aborted) suicide attempt; however, more research is needed to understand the nature of its relationship to suicide risk.
Published: 2022

48. Semaphorin 3C is a novel adipokine linked to extracellular matrix composition

Author: Vanessa Pellegrinelli, Joan Tordjman, Erik Näslund, Anne Bouloumié, Niklas Mejhert, P. Lång, Vladimir Stich, Nathalie Viguerie, Catherine-Ines Kolditz, Dominique Langin, Jean Galitzky, Ingrid Dahlman, D Lacasa, Mikael Rydén, Paul Trayhurn, Karine Clément, Daniel Esteve, Florian Wilfling, Department of Medicine, Lipid Laboratory (NOVUM), Karolinska Institutet [Stockholm], Department of Cell Biology [New Haven], Yale University School of Medicine-Howard Hughes Medical Institute (HHMI), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Division of Surgery, Department of Clinical Sciences, Karolinska Institutet [Stockholm]-Danderyd Hospital, Obesity Biology Unit, University of Liverpool, Clore Laboratory, University of Buckingham, Department of Sports Medicine, Charles University [Prague] (CU), Department of Laboratory Medicine, Laboratoire de Biochimie [Purpan IFB], CHU Toulouse [Toulouse], Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Simon, Marie Francoise, Yale School of Medicine [New Haven, Connecticut] (YSM)-Howard Hughes Medical Institute (HHMI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Karolinska Institutet [Stockholm]-Danderyds sjukhus = Danderyd University Hospital, Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Department of Medicine, Lipid Laboratory ( NOVUM ), Yale School of Medicine-Howard Hugues Medical Institute, Institut des Maladies Métaboliques et Cardiovasculaires ( I2MC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut Cardiométabolisme et Nutrition, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Charles University [Prague], Université Toulouse III - Paul Sabatier ( UPS ), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: medicine.medical_specialty, Adipose Tissue, White, Endocrinology, Diabetes and Metabolism, Fluorescent Antibody Technique, Adipose tissue, Adipokine, Enzyme-Linked Immunosorbent Assay, 030209 endocrinology & metabolism, Semaphorins, White adipose tissue, Biology, Extracellular matrix, 03 medical and health sciences, 0302 clinical medicine, Adipokines, Semaphorin, Fibrosis, Internal medicine, Internal Medicine, medicine, Humans, Secretion, Cells, Cultured, 030304 developmental biology, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, Microscopy, Confocal, food and beverages, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Immunohistochemistry, Extracellular Matrix, Endocrinology, Function (biology)
Abstract: International audience; AIMS/HYPOTHESIS: Alterations in white adipose tissue (WAT) function, including changes in protein (adipokine) secretion and extracellular matrix (ECM) composition, promote an insulin-resistant state. We set out to identify novel adipokines regulated by body fat mass in human subcutaneous WAT with potential roles in adipose function. METHODS: Adipose transcriptome data and secretome profiles from conditions with increased/decreased WAT mass were combined. WAT donors were predominantly women. In vitro effects were assessed using recombinant protein. Results were confirmed by quantitative PCR/ELISA, metabolic assays and immunochemistry in human WAT and adipocytes. RESULTS: We identified a hitherto uncharacterised adipokine, semaphorin 3C (SEMA3C), the expression of which correlated significantly with body weight, insulin resistance (HOMA of insulin resistance [HOMAIR], and the rate constant for the insulin tolerance test [KITT]) and adipose tissue morphology (hypertrophy vs hyperplasia). SEMA3C was primarily found in mature adipocytes and had no direct effect on human adipocyte differentiation, lipolysis, glucose transport or the expression of β-oxidation genes. This could in part be explained by the significant downregulation of its cognate receptors during adipogenesis. In contrast, in pre-adipocytes, SEMA3C increased the production/secretion of several ECM components (fibronectin, elastin and collagen I) and matricellular factors (connective tissue growth factor, IL6 and transforming growth factor-β1). Furthermore, the expression of SEMA3C in human WAT correlated positively with the degree of fibrosis in WAT. CONCLUSIONS/INTERPRETATION: SEMA3C is a novel adipokine regulated by weight changes. The correlation with WAT hypertrophy and fibrosis in vivo, as well as its effects on ECM production in human pre-adipocytes in vitro, together suggest that SEMA3C constitutes an adipocyte-derived paracrine signal that influences ECM composition and may play a pathophysiological role in human WAT.
Published: 2013

49. Targeting the Intracellular Environment in Cystic Fibrosis: Restoring Autophagy as a Novel Strategy to Circumvent the CFTR Defect

Author: Maria Chiara Maiuri, Valeria Raia, Guido Kroemer, Luigi Maiuri, Emanuela M. Bruscia, Speranza Esposito, Valeria Rachela Villella, San Raffaele Scientific Institute, Vita-Salute San Raffaele University and Center for Translational Genomics and Bioinformatics, Yale University School of Medicine, Università degli studi di Napoli Federico II, Apoptose, cancer et immunité (U848), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Institut Gustave Roussy (IGR), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biologie [CHU HEGP], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Università degli Studi di Foggia - University of Foggia, HAL UPMC, Gestionnaire, Yale School of Medicine [New Haven, Connecticut] (YSM), University of Naples Federico II = Università degli studi di Napoli Federico II, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Università degli Studi di Foggia = University of Foggia (Unifg), Villella, Vr, Esposito, S, Bruscia, Em, Maiuri, MARIA CHIARA, Raia, Valeria, Kroemer, G, Maiuri, L., Yale School of Medicine, Apoptose, cancer et immunité ( U848 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut Gustave Roussy ( IGR ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), and Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE)
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, autophagy, Mutant, proteostasis regulators, Review Article, Cystic fibrosis, cystic fibrosis, 03 medical and health sciences, 0302 clinical medicine, medicine, Pharmacology (medical), CFTR, 030304 developmental biology, Pharmacology, 0303 health sciences, biology, lcsh:RM1-950, Autophagy, BECN1, Potentiator, respiratory system, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, medicine.disease, Cystic fibrosis transmembrane conductance regulator, digestive system diseases, 3. Good health, Cell biology, respiratory tract diseases, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, lcsh:Therapeutics. Pharmacology, [ SDV.SP ] Life Sciences [q-bio]/Pharmaceutical sciences, Proteostasis, Immunology, biology.protein, 030217 neurology & neurosurgery, Intracellular
Abstract: Cystic fibrosis (CF) patients harboring the most common deletion mutation of the cystic fibrosis transmembrane conductance regulator (CFTR), F508del, are poor responders to potentiators of CFTR channel activity which can be used to treat a small subset of CF patients who genetically carry plasma membrane-resident CFTR mutants. The misfolded F508del-CFTR protein is unstable in the plasma membrane even if rescued by pharmacological agents that prevent its intracellular retention and degradation. CF is a conformational disease in which defective CFTR induces an impressive derangement of general proteostasis resulting from disabled autophagy. In this review, we discuss how rescuing Beclin 1 (BECN1), a major player of autophagosome formation, either by means of direct gene transfer or indirectly by administration of proteostasis regulators, could stabilize F508del-CFTR at the plasma membrane. We focus on the relationship between the improvement of peripheral proteostasis and CFTR plasma membrane stability in F508del-CFTR homozygous bronchial epithelia or mouse lungs. Moreover, this article reviews recent preclinical evidence indicating that targeting the intracellular environment surrounding the misfolded mutant CFTR instead of protein itself could constitute an attractive therapeutic option to sensitize patients carrying the F508del-CFTR mutation to the beneficial action of CFTR potentiators on lung inflammation.
Published: 2013

50. CD4+ T cells that help B cells – a proposal for uniform nomenclature

Author: Stuart G. Tangye, Nicolas Fazilleau, Joe Craft, Stephanie C. Eisenbarth, Carola G. Vinuesa, Dirk Baumjohann, Cindy S. Ma, Michelle A. Linterman, Yale School of Medicine [New Haven, Connecticut] (YSM), Medizinische Klinik und Poliklinik III [Bonn, Germany], Universitätsklinikum Bonn (UKB), University of Bonn, Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Garvan Institute of medical research, University of New South Wales [Sydney] (UNSW), Australian National University (ANU), The Babraham Institute [Cambridge, UK], ANR-16-CE15-0019,Ig-MemImpact,Rôle de la classe des Ig / BCR dans les interactions cellulaires supportant la mémoire immune et impact immunopathologique(2016), ANR-16-CE15-0002,MEMO-SIGN,IMPACT DE LA FORMULATION VACCINALE SUR LA COMPOSITION DES COMPARTMENTS LYMPHOCYTAIRES A MEMOIRE TFH ET B(2016), Benson-Rumiz, Alicia, Rôle de la classe des Ig / BCR dans les interactions cellulaires supportant la mémoire immune et impact immunopathologique - - Ig-MemImpact2016 - ANR-16-CE15-0019 - AAPG2016 - VALID, and IMPACT DE LA FORMULATION VACCINALE SUR LA COMPOSITION DES COMPARTMENTS LYMPHOCYTAIRES A MEMOIRE TFH ET B - - MEMO-SIGN2016 - ANR-16-CE15-0002 - AAPG2016 - VALID
Subjects: MESH: Cell Differentiation, Immunology, Cell, Biology, Lymphocyte Activation, Article, Chemokine receptor, Immune system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, medicine, Immunology and Allergy, MESH: Immunity, Humoral, MESH: T-Lymphocytes, Helper-Inducer, MESH: Lymphocyte Activation, B cell, B-Lymphocytes, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Cell Differentiation, T-Lymphocytes, Helper-Inducer, Germinal Center, BCL6, Isotype, Immunity, Humoral, medicine.anatomical_structure, Humoral immunity, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, biology.protein, MESH: Germinal Center, Antibody, MESH: B-Lymphocytes, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; T follicular helper (Tfh) cells cognately guide differentiation of antigen-primed B cells in secondary lymphoid tissues. 'Tfh-like' populations not expressing the canonical Tfh cell transcription factor BCL6 have also been described, which can aid particular aspects of B cell differentiation. Tfh and Tfh-like cells are essential for protective and pathological humoral immunity. These CD4+ T cells that help B cells are polarized to produce diverse combinations of cytokines and chemokine receptors and can be grouped into distinct subsets that promote antibodies of different isotype, affinity, and duration, according to the nature of immune challenge. However, unified nomenclature to describe the distinct functional Tfh and Tfh-like cells does not exist. While explicitly acknowledging cellular plasticity, we propose categorizing these cell states into three groups based on phenotype and function, paired with their anatomical site of action.
Published: 2021

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