Author: "University of Massachusetts Medical School [Worcester] ( UMASS )" - Searchworks@Jio Institute Digital Library Search Results

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113 results on '"University of Massachusetts Medical School [Worcester] ( UMASS )"'

1. Decreasing CB1 receptor signaling in Kupffer cells improves insulin sensitivity in obese mice

Author: Jie Liu, George Kunos, Nathan J. Coffey, Yuefei Shen, Michael P. Czech, Bin Gao, Sarah M. Nicoloro, Resat Cinar, Grzegorz Godlewski, Zhou Zhou, Tony Jourdan, Myriam Aouadi, Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -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 ), Equipe PADYS (LNC - U1231), Université de Bourgogne ( UB ) -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 ) -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 ), Laboratory of Liver Diseases, National Institutes of Health ( NIH ) -National Institute on Alcohol Abuse and Alcoholism, University of Massachusetts Medical School [Worcester] ( UMASS ), Karolinska Institutet [Stockholm], Lipides - Nutrition - Cancer [Dijon - U1231] (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, 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-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, National Institutes of Health [Bethesda] (NIH)-National Institute on Alcohol Abuse and Alcoholism, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), and université de Bourgogne, LNC
Subjects: 0301 basic medicine, lcsh:Internal medicine, medicine.medical_specialty, Cell type, Cannabinoid receptor, CB(1) receptors, Inflammation, Biology, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Internal medicine, Gene expression, medicine, Kupffer cells, lcsh:RC31-1245, Molecular Biology, Gene, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Cell Biology, [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, Obesity, Insulin receptor, 030104 developmental biology, Endocrinology, siRNA, 030220 oncology & carcinogenesis, biology.protein, medicine.symptom, CB1 receptors
Abstract: International audience; Objective: Obesity-induced accumulation of ectopic fat in the liver is thought to contribute to the development of insulin resistance, and increased activity of hepatic CB1R has been shown to promote both processes. However, lipid accumulation in liver can be experimentally dissociated from insulin resistance under certain conditions, suggesting the involvement of additional mechanisms. Obesity is also associated with pro-inflammatory changes which, in turn, can promote insulin resistance. Kupffer cells (KCs), the liver's resident macrophages, are the major source of pro-inflammatory cytokines in the liver, such as TNF-alpha, which has been shown to inhibit insulin signaling in multiple cell types, including hepatocytes. Here, we sought to identify the role of CB1R in KCs in obesity-induced hepatic insulin resistance.Methods: We used intravenously administered beta-D-glucan-encapsulated siRNA to knock-down CB1R gene expression selectively in KCs.Results: We demonstrate that a robust knock-down of the expression of Cnr1, the gene encoding CB1R, results in improved glucose tolerance and insulin sensitivity in diet-induced obese mice, without affecting hepatic lipid content or body weight. Moreover, Cnr1 knock-down in KCs was associated with a shift from pro-inflammatory M1 to anti-inflammatory M2 cytokine profile and improved insulin signaling as reflected by increased insulin-induced Akt phosphorylation.Conclusion: These findings suggest that CB1R expressed in KCs plays a critical role in obesity-related hepatic insulin resistance via a pro inflammatory mechanism. Published by Elsevier GmbH.
Published: 2017

2. Auditory Hallucinations and the Brain’s Resting-State Networks: Findings and Methodological Observations

Author: Judith M. Ford, Ben Alderson-Day, Remko van Lutterveld, Georg Northoff, Jessica A. Turner, Kelly M. J. Diederen, James M. Shine, Daniel S. Margulies, Charles Fernyhough, Flavie Waters, Guillermo Horga, Renaud Jardri, Simon McCarthy-Jones, Vincent van de Ven, Durham University, University of Cambridge [UK] (CAM), University of California [San Francisco] (UC San Francisco), University of California (UC), Columbia University [New York], The Neuro Bureau [Leipzig], Trinity College Dublin, University of Ottawa [Ottawa], Stanford University, Georgia State University, University System of Georgia (USG), Maastricht University [Maastricht], University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), The University of Western Australia (UWA), Laboratoire Sciences Cognitives et Sciences Affectives - UMR 9193 (SCALab), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), RS: FPN CN 3, Perception, Duke University [Durham], University of California [San Francisco] (UCSF), University of California, University of Ottawa [Ottawa] (uOttawa), Stanford University [Stanford], Sciences Cognitives et Sciences Affectives (SCALab) - UMR 9193 (SCALab), Université de Lille, CNRS, CHU Lille, University of Cambridge [UK] [CAM], University of California [San Francisco] [UC San Francisco], University of Massachusetts Medical School [Worcester] [UMASS], and The University of Western Australia [UWA]
Subjects: Psychosis, Hallucinations, media_common.quotation_subject, Population, perception, Developmental psychology, [SCCO]Cognitive science, default mode network, 03 medical and health sciences, 0302 clinical medicine, Functional neuroimaging, Perception, medicine, Humans, psychosis, education, Default mode network, media_common, education.field_of_study, Resting state fMRI, medicine.diagnostic_test, Functional Neuroimaging, fMRI, Brain, Invited Themed Article, Cognition, medicine.disease, 030227 psychiatry, schizophrenia, Psychiatry and Mental health, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Nerve Net, Psychology, Functional magnetic resonance imaging, 030217 neurology & neurosurgery, Cognitive psychology
Abstract: In recent years, there has been increasing interest in the potential for alterations to the brain's resting-state networks (RSNs) to explain various kinds of psychopathology. RSNs provide an intriguing new explanatory framework for hallucinations, which can occur in different modalities and population groups, but which remain poorly understood. This collaboration from the International Consortium on Hallucination Research (ICHR) reports on the evidence linking resting-state alterations to auditory hallucinations (AH) and provides a critical appraisal of the methodological approaches used in this area. In the report, we describe findings from resting connectivity fMRI in AH (in schizophrenia and nonclinical individuals) and compare them with findings from neurophysiological research, structural MRI, and research on visual hallucinations (VH). In AH, various studies show resting connectivity differences in left-hemisphere auditory and language regions, as well as atypical interaction of the default mode network and RSNs linked to cognitive control and salience. As the latter are also evident in studies of VH, this points to a domain-general mechanism for hallucinations alongside modality-specific changes to RSNs in different sensory regions. However, we also observed high methodological heterogeneity in the current literature, affecting the ability to make clear comparisons between studies. To address this, we provide some methodological recommendations and options for future research on the resting state and hallucinations.
Published: 2016

3. Prediction of homo- and hetero-protein complexes by protein docking and template-based modeling: a CASP-CAPRI experiment

Author: Eichiro Ichiishi, Dmitri Beglov, Bernard Maigret, Gyu Rie Lee, Artem B. Mamonov, Shoshana J. Wodak, Jonathan C. Fuller, Dima Kozakov, Jong Young Joung, Petr Popov, Xiaofeng Yu, Keehyoung Joo, João P. G. L. M. Rodrigues, Anna Vangone, Koen M. Visscher, Xiaoqin Zou, Paul A. Bates, Andriy Kryshtafovych, Shourya S. Roy Burman, Daisuke Kihara, Romina Oliva, Efrat Ben-Zeev, Jeffrey J. Gray, Yang Shen, Li C. Xue, Sameer Velankar, Emilie Neveu, Shruthi Viswanath, Dina Schneidman-Duhovny, Juan Esquivel-Rodríguez, Mieczyslaw Torchala, Amit Roy, Alexandre M. J. J. Bonvin, David R. Hall, Tanggis Bohnuud, Xusi Han, David W. Ritchie, Ron Elber, Daisuke Kuroda, Zhiwei Ma, Joan Segura, Carlos A. Del Carpio, Nicholas A. Marze, Jong Yun Kim, Andrej Sali, Petras J. Kundrotas, Ezgi Karaca, Neil J. Bruce, Chaok Seok, Panagiotis L. Kastritis, Shen You Huang, Ilya A. Vakser, Lim Heo, Sanbo Qin, Raphael A. G. Chaleil, Adrien S. J. Melquiond, Miguel Romero-Durana, Anisah W. Ghoorah, Surendra S. Negi, Andrey Tovchigrechko, Françoise Ochsenbein, Narcis Fernandez-Fuentes, Liming Qiu, Miriam Eisenstein, Mehdi Nellen, Marie-Dominique Devignes, Lenna X. Peterson, Jinchao Yu, Minkyung Baek, Brian G. Pierce, Hasup Lee, Toshiyuki Oda, Rebecca C. Wade, Raphael Guerois, Juan Fernández-Recio, Iain H. Moal, Edrisse Chermak, Sergei Grudinin, Sangwoo Park, Ivan Anishchenko, Chengfei Yan, Thom Vreven, Kentaro Tomii, Bing Xia, Hyung Rae Kim, Chiara Pallara, Jooyoung Lee, Kazunori D. Yamada, Xianjin Xu, Kenichiro Imai, Zhiping Weng, Luigi Cavallo, Tyler M. Borrman, Jianlin Cheng, Marc F. Lensink, Huan-Xiang Zhou, Jilong Li, Gydo C. P. van Zundert, Brian Jiménez-García, Tsukasa Nakamura, Scott E. Mottarella, Sandor Vajda, Institut de Recherche Interdisciplinaire [Villeneuve d'Ascq] ( IRI ), Université de Lille, Sciences et Technologies-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique ( CNRS ), European Molecular Biology Laboratory, European Bioinformatics Institute, Genome Center [UC Davis], University of California at Davis, Research Support Computing [Columbia], University of Missouri-Columbia, Bioinformatics Consortium and Department of Computer Science [Columbia], Department of Bioengineering and Therapeutic Sciences, University of California [San Francisco] ( UCSF ), Department of Pharmaceutical Chemistry, Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, University of California [San Francisco] ( UCSF ) -California Institute for Quantitative Biosciences, GN7 of the National Institute for Bioinformatics (INB) and Biocomputing Unit, Centro Nacional de Biotecnología (CSIC), Institute of Biological, Environmental and Rural Sciences ( IBERS ), Institute for Computational Engineering and Sciences [Austin] ( ICES ), University of Texas at Austin [Austin], Department of Computer Science, Department of Chemistry, Algorithms for Modeling and Simulation of Nanosystems ( NANO-D ), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Laboratoire Jean Kuntzmann ( LJK ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Institut National Polytechnique de Grenoble ( INPG ), Moscow Institute of Physics and Technology [Moscow] ( MIPT ), Seoul National University [Seoul], Florida State University [Tallahassee] ( FSU ), Computational Algorithms for Protein Structures and Interactions ( CAPSID ), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Department of Complex Systems, Artificial Intelligence & Robotics ( LORIA - AIS ), Laboratoire Lorrain de Recherche en Informatique et ses Applications ( LORIA ), Institut National de Recherche en Informatique et en Automatique ( Inria ) -Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ) -Laboratoire Lorrain de Recherche en Informatique et ses Applications ( LORIA ), Institut National de Recherche en Informatique et en Automatique ( Inria ) -Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ), University of Mauritius, Biomolecular Modelling Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, G-INCPM, Weizmann Institute of Science, Chemical Research Support [Rehovot], Sealy Center for Structural Biology and Molecular Biophysics, The University of Texas Medical Branch ( UTMB ), Program in Bioinformatics and Integrative Biology [Worcester], University of Massachusetts Medical School [Worcester] ( UMASS ), 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 ), Bijvoet Center for Biomolecular Research [Utrecht], Utrecht University [Utrecht], Dalton Cardiovascular Research Center [Columbia], Department of Computer Science [Columbia], Informatics Intitute, Department of Biochemistry, University of Missouri, UNIVERSITY OF MISSOURI, Toyota Technological Institute at Chicago [Chicago] ( TTIC ), Department of Biological Sciences, Purdue University, Purdue University [West Lafayette], Department of Computer Science [Purdue], Bioinformatics and Computational Biosciences Branch, Rocky Mountain Laboratories, Molecular and Cellular Modeling Group, Heidelberg Institute of Theoretical Studies, Center for Molecular Biology ( ZMBH ), Universität Heidelberg [Heidelberg], Interdisciplinary Center for Scientiﬁc Computing ( IWR ), Department of Molecular Biosciences [Lawrence], University of Kansas [Lawrence] ( KU ), Computational Biology Research Center ( CBRC ), National Institute of Advanced Industrial Science and Technology ( AIST ), Graduate School of Frontier Sciences, The University of Tokyo, Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center - Centro Nacional de Supercomputacion ( BSC - CNS ), Center for In-Silico Protein Science, Korea Institute for Advanced Study ( KIAS ), Center for Advanced Computation, Department of Biomedical Engineering [Boston], Boston University [Boston] ( BU ), Institute of Biological Diversity, International Pacific Institute of Indiana, Drosophila Genetic Resource Center, Kyoto Institute of Technology, International University of Health and Welfare Hospital ( IUHW Hospital ), International University of Health and Welfare Hospital, Department of Chemical and Biomolecular Engineering [Baltimore], Johns Hopkins University ( JHU ), Program in Molecular Biophysics [Baltimore], King Abdullah University of Science and Technology ( KAUST ), University of Naples, J Craig Venter Institute, Structural Biology Research Center, VIB, 1050 Brussels, Belgium, Institut de Recherche Interdisciplinaire [Villeneuve d'Ascq] (IRI), Université de Lille, Sciences et Technologies-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, University of California [Davis] (UC Davis), University of California (UC)-University of California (UC), University of Missouri [Columbia] (Mizzou), University of Missouri System, University of California [San Francisco] (UC San Francisco), Centro Nacional de Biotecnología [Madrid] (CNB-CSIC), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Institute of Biological, Environmental and Rural Sciences (IBERS), Institute for Computational Engineering and Sciences [Austin] (ICES), Algorithms for Modeling and Simulation of Nanosystems (NANO-D), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Laboratoire Jean Kuntzmann (LJK ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Moscow Institute of Physics and Technology [Moscow] (MIPT), Seoul National University [Seoul] (SNU), Florida State University [Tallahassee] (FSU), Computational Algorithms for Protein Structures and Interactions (CAPSID), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Complex Systems, Artificial Intelligence & Robotics (LORIA - AIS), Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Biomolecular Modelling Laboratory [London], The Francis Crick Institute [London], Weizmann Institute of Science [Rehovot, Israël], The University of Texas Medical Branch (UTMB), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS)-University of Massachusetts System (UMASS), 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), Assemblage moléculaire et intégrité du génome (AMIG), Département Biochimie, Biophysique et Biologie Structurale (B3S), 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), University of Missouri System-University of Missouri System, Toyota Technological Institute at Chicago [Chicago] (TTIC), Department of Biological Sciences [Lafayette IN], Heidelberg Institute for Theoretical Studies (HITS ), Center for Molecular Biology (ZMBH), Universität Heidelberg [Heidelberg] = Heidelberg University, Interdisciplinary Center for Scientiﬁc Computing (IWR), University of Kansas [Lawrence] (KU), Computational Biology Research Center (CBRC), National Institute of Advanced Industrial Science and Technology (AIST), The University of Tokyo (UTokyo), Barcelona Supercomputing Center - Centro Nacional de Supercomputacion (BSC - CNS), Korea Institute for Advanced Study (KIAS), Boston University [Boston] (BU), International University of Health and Welfare Hospital (IUHW Hospital), Johns Hopkins University (JHU), King Abdullah University of Science and Technology (KAUST), University of Naples Federico II = Università degli studi di Napoli Federico II, J. Craig Venter Institute, VIB-VUB Center for Structural Biology [Bruxelles], VIB [Belgium], Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Droit et Santé-Université de Lille, Sciences et Technologies, University of California-University of California, University of California [San Francisco] (UCSF), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), University of Naples Federico II, Barcelona Supercomputing Center, NMR Spectroscopy, and Sub NMR Spectroscopy
Subjects: 0301 basic medicine, Protein Conformation, alpha-Helical, Protein Folding, Computer science, International Cooperation, Amino Acid Motifs, Oligomer state, Homoprotein, DATA-BANK, computer.software_genre, Molecular Docking Simulation, Biochemistry, CAPRI Round 30, DESIGN, Structural Biology, ALIGN, Blind prediction, AFFINITY, Protein interaction, Enginyeria biomèdica [Àrees temàtiques de la UPC], ZDOCK, Oligomer State, computer.file_format, Articles, Protein structure prediction, Proteïnes--Investigació, 3. Good health, WEB SERVER, CASP, Thermodynamics, Data mining, CAPRI, Protein docking, Molecular Biology, Algorithms, INTERFACES, Protein Binding, [ INFO.INFO-MO ] Computer Science [cs]/Modeling and Simulation, Bioinformatics, STRUCTURAL BIOLOGY, Computational biology, Molecular Dynamics Simulation, Article, 03 medical and health sciences, [ INFO.INFO-BI ] Computer Science [cs]/Bioinformatics [q-bio.QM], Heteroprotein, Humans, Protein binding, Macromolecular docking, Protein Interaction Domains and Motifs, Homology modeling, ALGORITHM, Protein-protein docking, Internet, Binding Sites, Models, Statistical, 030102 biochemistry & molecular biology, Bacteria, Sequence Homology, Amino Acid, Computational Biology, Proteins, Protein Data Bank, [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation, Protein Structure, Tertiary, 030104 developmental biology, Structural biology, Docking (molecular), Protein structure, Protein Conformation, beta-Strand, Protein Multimerization, oligomer state, blind prediction, protein interaction, protein docking, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], computer, Software
Abstract: We present the results for CAPRI Round 30, the first joint CASP-CAPRI experiment, which brought together experts from the protein structure prediction and protein–protein docking communities. The Round comprised 25 targets from amongst those submitted for the CASP11 prediction experiment of 2014. The targets included mostly homodimers, a few homotetramers, and two heterodimers, and comprised protein chains that could readily be modeled using templates from the Protein Data Bank. On average 24 CAPRI groups and 7 CASP groups submitted docking predictions for each target, and 12 CAPRI groups per target participated in the CAPRI scoring experiment. In total more than 9500 models were assessed against the 3D structures of the corresponding target complexes. Results show that the prediction of homodimer assemblies by homology modeling techniques and docking calculations is quite successful for targets featuring large enough subunit interfaces to represent stable associations. Targets with ambiguous or inaccurate oligomeric state assignments, often featuring crystal contact-sized interfaces, represented a confounding factor. For those, a much poorer prediction performance was achieved, while nonetheless often providing helpful clues on the correct oligomeric state of the protein. The prediction performance was very poor for genuine tetrameric targets, where the inaccuracy of the homology-built subunit models and the smaller pair-wise interfaces severely limited the ability to derive the correct assembly mode. Our analysis also shows that docking procedures tend to perform better than standard homology modeling techniques and that highly accurate models of the protein components are not always required to identify their association modes with acceptable accuracy. We are most grateful to the PDBe at the European Bioinformatics Institute in Hinxton, UK, for hosting the CAPRI website. Our deepest thanks go to all the structural biologists and to the following structural genomics initiatives: Northeast Structural Genomics Consortium, Joint Center for Structural Genomics, NatPro PSI:Biology, New York Structural Genomics Research Center, Midwest Center for Structural Genomics, Structural Genomics Consortium, for contributing the targets for this joint CASP-CAPRI experiment. MFL acknowledges support from the FRABio FR3688 Research Federation “Structural & Functional Biochemistry of Biomolecular Assemblies.”
Published: 2016

4. Group B Streptococcus Degrades Cyclic-di-AMP to Modulate STING-Dependent Type I Interferon Production

Author: Katherine A. Fitzgerald, Arnaud Firon, Veit Hornung, Patrick Trieu-Cuot, Warrison A. Andrade, Evelyn A. Kurt-Jones, Pierre Alexandre Kaminski, Douglas T. Golenbock, Tobias Schmidt, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS)-University of Massachusetts System (UMASS), Program in Innate Immunity [Worcester], Department of Medicine [Worcester], University of Massachusetts System (UMASS)-University of Massachusetts System (UMASS)-University of Massachusetts Medical School [Worcester] (UMASS), Biologie des Bactéries pathogènes à Gram-positif, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institute of Molecular Medicine [Bonn], Chimie et Biocatalyse, This work was supported by a National Institutes of Health grant (to D.T.G.), Institut Pasteur, and CNRS (to P.T.-C.), the French government’s Investissement d’Avenir program, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' grant ANR-10-LABX-62-IBEID (to P.T.-C.), and Fondation pour la Recherche Médicale grant DEQ20130326538 (to P.T.-C.). W.A.A. was supported by a fellowship from CNPq (Brazil)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, 030106 microbiology, medicine.disease_cause, Microbiology, Article, Streptococcus agalactiae, 03 medical and health sciences, chemistry.chemical_compound, Interferon, interferon-β, Virology, medicine, Extracellular, Ectonucleotidase, Pyrophosphatases, Biotransformation, Immune Evasion, Virulence, biology, Streptococcus, Membrane Proteins, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, eye diseases, c-di-AMP, 030104 developmental biology, chemistry, Cytoplasm, Interferon Type I, Parasitology, Signal transduction, Dinucleoside Phosphates, Bacteria, DNA, medicine.drug, cGAS, ectonucleotidase
Abstract: International audience; Induction of type I interferon (IFN) in response to microbial pathogens depends on a conserved cGAS-STING signaling pathway. The presence of DNA in the cytoplasm activates cGAS, while STING is activated by cyclic dinucleotides (cdNs) produced by cGAS or from bacterial origins. Here, we show that Group B Streptococcus (GBS) induces IFN-β production almost exclusively through cGAS-STING-dependent recognition of bacterial DNA. However, we find that GBS expresses an ectonucleotidase, CdnP, which hydrolyzes extracellular bacterial cyclic-di-AMP. Inactivation of CdnP leads to c-di-AMP accumulation outside the bacteria and increased IFN-β production. Higher IFN-β levels in vivo increase GBS killing by the host. The IFN-β overproduction observed in the absence of CdnP is due to the cumulative effect of DNA sensing by cGAS and STING-dependent sensing of c-di-AMP. These findings describe the importance of a bacterial c-di-AMP ectonucleotidase and suggest a direct bacterial mechanism that dampens activation of the cGAS-STING axis.
Published: 2016

5. Should patients with acute coronary disease be stratified for management according to their risk? Derivation, external validation and outcomes using the updated GRACE risk score

Author: Etienne Puymirat, Pierre Coste, Nicolas Danchin, Tabassome Simon, Kathryn F. Carruthers, Keith A.A. Fox, Phillippe Gabriel Steg, Gordon FitzGerald, Wei Huang, Jacques Monsegu, Frederick A. Anderson, University of Edinburgh, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paris Descartes - Paris 5 (UPD5), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [APHP], Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Université Victor Segalen, Bordeaux, France, Université Paris Diderot - Paris 7 (UPD7), Hôpital d'Instruction des Armées du Val de Grâce, Service de Santé des Armées, Hôpital Bichat - Claude Bernard, 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Galilée, University of Massachusetts Medical School [Worcester] ( UMASS ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Paris Descartes - Paris 5 ( UPD5 ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Plateforme de recherche clinique de l'est parisien ( URCEST-CRCEST ), Hémostase, bio-ingénierie et remodelage cardiovasculaires ( LBPC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris 13 ( UP13 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Galilée, Université Pierre et Marie Curie - Paris 6 ( UPMC ), and Université Paris Diderot - Paris 7 ( UPD7 )
Subjects: Male, Pediatrics, Time Factors, Myocardial Infarction, Blood Pressure, Kaplan-Meier Estimate, Cardiovascular Medicine, 030204 cardiovascular system & hematology, Electrocardiography, 0302 clinical medicine, Risk Factors, ACCIDENT & EMERGENCY MEDICINE, Medicine, Hospital Mortality, 030212 general & internal medicine, Myocardial infarction, 10. No inequality, education.field_of_study, Framingham Risk Score, Age Factors, General Medicine, Middle Aged, [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Survival Rate, Creatinine, Cohort, Female, Risk assessment, Algorithms, medicine.medical_specialty, Acute coronary syndrome, Population, Risk Assessment, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Humans, Acute Coronary Syndrome, Pulse, education, Survival rate, Aged, Killip class, Models, Statistical, business.industry, Research, medicine.disease, Emergency medicine, business
Abstract: International audience; Objectives Risk scores are recommended in guidelines to facilitate the management of patients who present with acute coronary syndromes (ACS). Internationally, such scores are not systematically used because they are not easy to apply and some risk indicators are not available at first presentation. We aimed to derive and externally validate a more accurate version of the Global Registry of Acute Coronary Events (GRACE) risk score for predicting the risk of death or death/myocardial infarction (MI) both acutely and over the longer term. The risk score was designed to be suitable for acute and emergency clinical settings and usable in electronic devices.Design and setting The GRACE risk score (2.0) was derived in 32 037 patients from the GRACE registry (14 countries, 94 hospitals) and validated externally in the French registry of Acute ST-elevation and non-ST-elevation MI (FAST-MI) 2005.Participants Patients presenting with ST-elevation and non-ST elevation ACS and with long-term outcomes.Outcome measures The GRACE Score (2.0) predicts the risk of short-term and long-term mortality, and death/MI, overall and in hospital survivors.Results For key independent risk predictors of death (1 year), non-linear associations (vs linear) were found for age (p
Published: 2014

6. Dimeric G-quadruplex motifs determine a large fraction of strong replication origins in vertebrates

Author: Poulet-Benedetti, Jérémy, Tonnerre-Doncarli, Caroline, Valton, Anne-Laure, Laurent, Marc, Gérard, Marie, Barinova, Natalja, Parisis, Nikolaos, Massip, Florian, Picard, Franck, Prioleau, Marie-Noëlle, Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Howard Hughes Medical Institute (HHMI), École des Mines de Paris, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure de Lyon (ENS de 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), massip, florian, and École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL)
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Abstract: International audience; Abstract Replication of vertebrate genomes is tightly regulated to ensure accurate duplication, but our understanding of the interplay between genetic and epigenetic factors in this regulation remains incomplete. Here, we investigated the involvement of three elements enriched at gene promoters and replication origins: guanine-rich motifs potentially forming G-quadruplexes (pG4s), nucleosome-free regions (NFRs), and the histone variant H2A.Z, in the firing of origins of replication. We show that two pG4s on the same DNA strand (dimeric pG4s) are sufficient to induce assembly of an efficient minimal replication origin without inducing transcription, and that dimeric pG4s in replication origins are located in an NFR next to well-positioned nucleosomes enriched in H2A.Z. Thus, our data suggest a crucial role for dimeric pG4s in the organization and duplication of vertebrate genomes.
Published: 2022

7. Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes

Author: Aaron Ciechanover, Eric H. Baehrecke, Josef M. Penninger, Moshe Oren, Marja Jäättelä, Cecília M. P. Rodrigues, Seamus J. Martin, Lorenzo Galluzzi, Dale E. Bredesen, Stuart A. Aaronson, Donald W. Nicholson, Frank Madeo, Mikhail V. Blagosklonny, Gabriel Núñez, Hans-Uwe Simon, Adi Kimchi, Karen H. Vousden, Yoshihide Tsujimoto, David W. Andrews, Simone Fulda, J. Tschopp, John M. Abrams, Hinrich Gronemeyer, Nicolas G. Bazan, Michael O. Hengartner, Richard A. Flavell, Beth Levine, Thomas Rudel, Ilio Vitale, Eugenia Morselli, Rosario Rizzuto, Boris Zhivotovsky, Douglas R. Green, J. M. Hardwick, Maria Castedo, Guido Kroemer, Pierluigi Nicotera, Christoph Borner, David C. Rubinsztein, Junying Yuan, Jan Paul Medema, Oliver Kepp, Carmen Garrido, V De Laurenzi, Jean-Christophe Marine, Richard J. Youle, Hidenori Ichijo, Daniel J. Klionsky, Hamsa Puthalakath, Ute M. Moll, Shigekazu Nagata, R De Maria, Pierre Golstein, Marie-Lise Gougeon, Mohanish Deshmukh, Enrico Lugli, Brian David Dynlacht, Emad S. Alnemri, John A. Cidlowski, Luca Scorrano, Stuart A. Lipton, Hermann Steller, Sally Kornbluth, Gerry Melino, György Hajnóczky, Gabriel A. Rabinovich, Peter Vandenabeele, Gerald M. Cohen, Shazib Pervaiz, Marcus E. Peter, Richard A. Knight, Jochen H. M. Prehn, Sharad Kumar, Klas Blomgren, Walter Malorni, Wafik S. El-Deiry, Patrick Mehlen, Mauro Piacentini, Catherine Brenner, 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), Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department of Cell Biology, University of Texas Southwestern Medical Center [Dallas], Department of Biochemistry and Molecular Biology, Thomas Jefferson University-Sidney Kimmel Cancer Center, Jefferson (Philadelphia University + Thomas Jefferson University)-Jefferson (Philadelphia University + Thomas Jefferson University), Department of Biochemistry and Biomedical Sciences, McMaster University [Hamilton, Ontario], Department of Cancer Biology, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS)-University of Massachusetts System (UMASS), Neuroscience Center of Excellence, LSU Health Sciences Center, Roswell Park Cancer Institute [Buffalo] (RPCI), Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU), Department of Pediatric Oncology, The Queen Silvia Children's Hospital, Institute of Molecular Medicine and Cell Research (ZBMZ), University of Freiburg [Freiburg], Buck Institute for Age Research, Laboratoire de génétique et biologie cellulaire (LGBC), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), National Institutes of Environmental Health Sciences, National Institutes of Health [Bethesda] (NIH), Vascular and Tumor Biology Research Center, Israel Institute of Technology, Toxicology Unit, University of Leicester, Dipartimento di Scienze Biomediche, Università degli studi 'G. d'Annunzio' Chieti-Pescara [Chieti-Pescara] (Ud'A), Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità (ISS), Mediterranean Institute of Oncology, Department of Cell and Developmental Biology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Department of Pathology, New York University School of Medicine, NYU System (NYU)-NYU System (NYU), Hematology-Oncology Division, Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Section of Immunobiology, Yale School of Medicine [New Haven, Connecticut] (YSM), Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), University Children's Hospital, 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), 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), Immunité Antivirale, Biothérapie et Vaccins, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Immunology, St Jude Children's Research Hospital, 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), Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Department of Pharmacology and Molecular Sciences, Johns Hopkins University (JHU), Institute of Molecular Biology, Universität Zürich [Zürich] = University of Zurich (UZH), Graduate School of Medecine, The University of Tokyo (UTokyo), Danish Cancer Society, Institute of Cancer Biology, Department of Molecular Genetics, Weizmann Institute of Science [Rehovot, Israël], Life Sciences Institute and Department of Molecular, Cellular, and Developmental Biology and Biological Chemistry, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Institute of Child Health [London], University College of London [London] (UCL), Duke University School of Medicine, Centre for Cancer Biology, Hanson Institute, Adelaide, Burnham Institute for Medical Research, The Salk Institute for Biological Studies, The Scripps Research Institute [La Jolla, San Diego], University of California [San Diego] (UC San Diego), University of California (UC), Immunotechnology Section, Vaccine Research Center, National Institutes of Health [Bethesda] (NIH)-National Institute of Allergy and Infectious Diseases, Institute of Molecular Biosciences, Karl-Franzens-Universität Graz, Department of Therapeutic Research and Medicines Evaluation, Laboratory for Molecular Cancer Biology, VIB-UGent, Department for Molecular Biology, Universiteit Gent = Ghent University (UGENT), Department of Genetics, Trinity College Dublin, Center for Experimental and Molecular Medicine, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), University of Amsterdam [Amsterdam] (UvA), Apoptosis, Cancer, and Development Laboratory, Centre Léon Bérard [Lyon], Apoptose Cancer et Développement, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Department of Experimental Medicine and Biochemical Sciences, Università degli Studi di Roma Tor Vergata [Roma], Stony Brook University [SUNY] (SBU), State University of New York (SUNY)-State University of New York (SUNY), Department of Molecular Oncology, Göttingen Center of Molecular Biosciences, Faculty of Medicine, Georg-August-University = Georg-August-Universität Göttingen, Fujitsu Laboratories LTD., Fujitsu Laboratories Ltd., Department of Medical Chemistry, Kyoto University-Graduate School of Medicine, Merck & Co. Inc, University of Michigan Medical School [Ann Arbor], Department of Molecular Cell Biology [Rehovot], Institute of Molecular Biotechnology, Austrian Academy of Sciences (OeAW), Department of Physiology, National University of Singapore (NUS)-Yong Loo Lin School of Medicine-Graduate School for Integrative Sciences and Engineering, Singapore-MIT Alliance for Research and Technology (SMART), Massachusetts Institute of Technology (MIT), Duke-NUS Medical School [Singapore], Ben May Department for Cancer Research, University of Chicago-Ben May Department for Cancer Research, Laboratory of Cell Biology, National Institute for Infectious Diseases IRCCS 'L. Spallanzani', Department of Biology, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland (RCSI), Department of Biochemistry, La Trobe University [Melbourne], Laboratorie de Inmunopatologia, Instituto de Biología y Medicina Experimental [Buenos Aires] (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET)-Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), Department of Biomedical Sciences, Università degli Studi di Padova = University of Padua (Unipd), iMed.UL, Universidade de Lisboa = University of Lisbon (ULISBOA), Cambridge Institute for Medical Research (CIMR), University of Cambridge [UK] (CAM), Biocenter, Julius-Maximilians-Universität Würzburg (JMU), Department of Cell Physiology and Metabolism, University of Geneva Medical School, Dulbecco-Telethon Institute, Venetian Institute Molecular Medicine (VIMM), University of Bern, Laboratory of Apoptosis and Cancer Biology, Rockefeller University [New York], Department of Biochemistry [Lausanne], Université de Lausanne = University of Lausanne (UNIL), Department of Medical Genetics, Osaka University Medical School, Department for Molecular Biomedical Research, The Beatson Institute for Cancer Research, University of Glasgow, Biochemistry Section, Surgical Neurology Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Neurological Disorders and Stroke, Department of cell biology, Harvard Medical School [Boston] (HMS), Division of Toxicology, karolinska institute-Institute of Environmental Medicine, Scorrano, Luca, Tschopp, Jean-Marie, 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 ), Mount Sinai School of Medicine, Thomas Jefferson University-Kimmel Cancer Institute, University of Massachusetts Medical School [Worcester] ( UMASS ), Roswell Park Cancer Institute [Buffalo], Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg ( GU ), Institute of Molecular Medicine and Cell Research ( ZBMZ ), Albert-Ludwigs University, Laboratoire de génétique et biologie cellulaire ( LGBC ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -École pratique des hautes études ( EPHE ) -Centre National de la Recherche Scientifique ( CNRS ), National Institutes of Health ( NIH ), Università degli studi 'G. d'Annunzio' Chieti-Pescara [Chieti-Pescara] ( Ud'A ), Istituto Superiore di Sanita [Rome], The University of North Carolina at Chapel Hill, University of Pennsylvania School of Medicine, Yale School of Medicine, Howard Hughes Medical Institute, Howard Hugues Medical Institute, 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 ), 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 ), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), St. Jude Children's Research Hospital, 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 ), Johns Hopkins University ( JHU ), University of Zürich [Zürich] ( UZH ), The University of Tokyo, Weizmann Institute of Science, University College of London [London] ( UCL ), The Scripps Research Institute, University of California [San Diego] ( UC San Diego ), National Institutes of Health ( NIH ) -National Institute of Allergy and Infectious Diseases, University of Graz, Ghent University [Belgium] ( UGENT ), Academic Medical Center [Amsterdam] ( AMC ), University of Amsterdam [Amsterdam] ( UvA ) -University of Amsterdam [Amsterdam] ( UvA ), University of Amsterdam [Amsterdam] ( UvA ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Stony Brook University [The State University of New York] ( SBU ), University of Göttingen, Kyoto University [Kyoto]-Graduate School of Medicine, Merck and Co [Rahway], University of Michigan Medical School, Austrian Academy of Sciences ( OeAW ), National University of Singapore ( NUS ) -Yong Loo Lin School of Medicine-Graduate School for Integrative Sciences and Engineering, Singapore-MIT Alliance, National University of Singapore ( NUS ), Duke-NUS Graduate Medical School, Royal College of Surgeons in Ireland, Instituto de Biología y Medicina Experimental (IBYME- CONICET), Universita degli Studi di Padova = University of Padua = Université de Padoue, University of Lisbon, Cambridge Institute for Medical Research, University of Würzburg, Venetian Institute of Molecular Medicine, The Rockefeller University, Université de Lausanne ( UNIL ), Vib Ghent University, National Institutes of Health ( NIH ) -National Institute of Neurological Disorders and Stroke, Harvard Medical School [Boston] ( HMS ), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Yale University School of Medicine, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), University of California, Karl-Franzens-Universität [Graz, Autriche], Universiteit Gent = Ghent University [Belgium] (UGENT), Georg-August-University [Göttingen], Universita degli Studi di Padova, Universidade de Lisboa (ULISBOA), Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Université de Lausanne (UNIL), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-École pratique des hautes études (EPHE), Peney, Maité, Galluzzi, L, Aaronson, SA, Abrams, J, Alnemri, ES, Kumar, Sharad, and Kroemer, Guido
Subjects: MESH: Cell Death, cytofluorometry, MESH : Microscopy, Fluorescence, ved/biology.organism_classification_rank.species, Cell, MESH: Flow Cytometry, MESH: Microscopy, Fluorescence, Apoptosis, fluorescence microscopy, MESH: Eukaryotic Cells, Annexin V, necrosis, 0302 clinical medicine, Eukaryotic Cells/cytology, Mitochondrial membrane permeabilization, Scanning, MESH : Immunoblotting, Genetics, Cell Death, Flow Cytometry, Guidelines as Topic, Humans, Immunoblotting, Microscopy, Electron, Scanning, Microscopy, Fluorescence, Spectrometry, Fluorescence, 0303 health sciences, Microscopy, MESH : Spectrometry, Fluorescence, MESH: Immunoblotting, MESH: Guidelines as Topic, purl.org/becyt/ford/3.1 [https], Bioquímica y Biología Molecular, 3. Good health, Tunel, Medicina Básica, medicine.anatomical_structure, Eukaryotic Cells, caspases, 030220 oncology & carcinogenesis, purl.org/becyt/ford/3 [https], MESH: Spectrometry, Fluorescence, MESH : Microscopy, Electron, Scanning, Programmed cell death, autophagy, CIENCIAS MÉDICAS Y DE LA SALUD, MESH: Microscopy, Electron, Scanning, MESH : Flow Cytometry, caspase, Computational biology, Biology, Electron, Fluorescence, Article, 03 medical and health sciences, Settore MED/04 - PATOLOGIA GENERALE, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Model organism, ddc:612, mitotic catastrophe, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Guidelines as Topic, 030304 developmental biology, cell death, Oxidative stress, MESH: Humans, ved/biology, Spectrometry, Interpretation (philosophy), MESH: Apoptosis, MESH : Eukaryotic Cells, MESH : Humans, Cell Biology, immunofluorescence microscopy, MESH : Cell Death, Cancer cell, MESH : Apoptosis
Abstract: Cell death is essential for a plethora of physiological processes, and its deregulation characterizes numerous human diseases. Thus, the in-depth investigation of cell death and its mechanisms constitutes a formidable challenge for fundamental and applied biomedical research, and has tremendous implications for the development of novel therapeutic strategies. It is, therefore, of utmost importance to standardize the experimental procedures that identify dying and dead cells in cell cultures and/or in tissues, from model organisms and/or humans, in healthy and/or pathological scenarios. Thus far, dozens of methods have been proposed to quantify cell death-related parameters. However, no guidelines exist regarding their use and interpretation, and nobody has thoroughly annotated the experimental settings for which each of these techniques is most appropriate. Here, we provide a nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls. These guidelines are intended for investigators who study cell death, as well as for reviewers who need to constructively critique scientific reports that deal with cellular demise. Given the difficulties in determining the exact number of cells that have passed the point-of-no-return of the signaling cascades leading to cell death, we emphasize the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells. Fil: Galluzzi, L.. Inserm; Francia. Universite Paris Sud; Francia. Institut Gustave Roussy; Francia Fil: Aaronson, S. A.. Mount Sinai School of Medicine; Estados Unidos Fil: Abrams, J.. University of Texas. Southwestern Medical Center; Estados Unidos Fil: Alnemri, E. S.. Thomas Jefferson University; Estados Unidos Fil: Andrews, D. W.. McMaster University; Canadá Fil: Baehrecke, E. H.. University of Massachussets; Estados Unidos Fil: Bazan, N. G.. Louisiana State University Health Sciences Center; Estados Unidos Fil: Blagosklonny, M. V.. Roswell Park Cancer Institute; Estados Unidos Fil: Blomgren, K.. Universityt of Gothenburg; Suecia. The Queen Silvia Children; Suecia Fil: Borner, C.. Albert-Ludwigs Universität Freiburg; Alemania Fil: Bredesen, E.. Buck Institute for Age Research; Estados Unidos. University of California; Estados Unidos Fil: Brenner, C.. univeristy of Versailles ; Francia Fil: Castedo, M.. Inserm; Francia. Universite Paris Sud; Francia Fil: Cidlowski, J. A.. National Institutes of Health; Estados Unidos Fil: Ciechanover, A.. The Rappaport Faculty of Medicine; Israel Fil: Cohen, G. M.. University of Leicester; Reino Unido Fil: De Laurenzi, V.. Università ‘G. d’Annunzio’ Chieti Pescara; Italia Fil: De Maria, R.. Istituto Superiore di Sanità; Italia. Mediterranean Institute of Oncology; Italia Fil: Deshmukh, M.. University of North Carolina; Estados Unidos Fil: Dynlacht, B. D.. University of New York; Estados Unidos Fil: El Deiry, W. S.. University of Pennsylvania; Estados Unidos Fil: Flavell, R. A.. University of Yale; Estados Unidos Fil: Fulda, S.. University Children; Alemania Fil: Garrido, C.. Inserm; Francia. University of Burgundy; Francia Fil: Golstein, P.. Inserm; Francia. Aix Marseille Université; Francia Fil: Gougeon, M. L.. Instituto Pasteur; Francia Fil: Green, D. R.. St. Jude Children′s Research Hospital; Estados Unidos Fil: Gronemeyer, H.. Institut de Génétique et de Biologie Moléculaire et Cellulaire; Francia. Inserm; Francia Fil: Hajnóczky, G.. Thomas Jefferson University; Estados Unidos Fil: Hardwick, J. M.. Johns Hopkins University; Estados Unidos Fil: Hengartner, M.O.. University Johns Hopkins; Estados Unidos Fil: Ichijo, H.. University of Tokyo; Japón Fil: Jäättelä, M.. Institute of Cancer Biology; Dinamarca Fil: Kepp, O.. Inserm; Francia. Universite Paris Sud; Francia. Institut Gustave Roussy; Francia Fil: Kimchi, A.. Weizmann Institute of Science; Israel Fil: Klionsky, D. J.. University of Michigan; Estados Unidos Fil: Knight, R. A.. University College London; Estados Unidos Fil: Kornbluth, S.. University of Duke; Estados Unidos Fil: Kumar, S.. Hanson Institute; Australia Fil: Levine, B.. Howard Hughes Medical Institute; Estados Unidos. University of Texas; Estados Unidos Fil: Lipton, S. A.. Burnham Institute for Medical Research; Estados Unidos. The Salk Institute for Biological Studies; Estados Unidos. The Scripps Research Institute; Estados Unidos. University of California at San Diego; Estados Unidos Fil: Lugli, E.. National Institutes of Health; Estados Unidos Fil: Madeo, F.. university of Graz; Austria Fil: Malorni, W.. Istituto Superiore di Sanità; Italia Fil: Marine, J. C.. VIB; Bélgica. Ghent University; Bélgica Fil: Martin, S. J.. Trinity College; Irlanda Fil: Medema, J. P.. Academic Medical Center; Países Bajos. University of Amsterdam; Países Bajos Fil: Mehlen, P.. Centre Léon Berard; Francia. Centre National de la Recherche Scientifique; Francia. Universite Lyon 2; Francia Fil: Melino, G.. University of Leicester; Reino Unido. Göttingen Center of Molecular Biosciences; Alemania Fil: Moll, U. M.. Stony Brook University; Estados Unidos. Göttingen Center of Molecular Biosciences; Alemania. University of Göttingen; Alemania Fil: Morselli, E.. Inserm; Francia. Universite Paris Sud; Francia. Institut Gustave Roussy; Francia Fil: Nagata, S.. University of Kyoto; Japón Fil: Nicholson, D. W.. Merck Research Laboratories; Estados Unidos Fil: Nicotera, P.. University of Leicester; Reino Unido Fil: Nuñez, G.. University of Michigan; Estados Unidos Fil: Oren, M.. Weizmann Institute of Science; Israel Fil: Penninger, J.. Institute of Molecular Biotechnology of the Austrian Academy of Science; Austria Fil: Pervaiz, S.. National University of Singapore; Singapur. Duke-NUS Graduate Medical School; Singapur Fil: Peter, M. E.. University of Chicago; Estados Unidos Fil: Piacentini, M.. National Institute for Infectious Diseases IRCCS "L. Spallanzani"; Italia. University of Rome "Tor Vergata"; Italia Fil: Prehn. J. H.. Royal College of Surgeons in Ireland; Irlanda Fil: Puthalakath, H.. La Trobe University; Australia Fil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Rizzuto, R.. Università di Padova; Italia Fil: Rodrigues, C. M.. Universidade de Lisboa; Portugal Fil: Rubinsztein, D. C.. Cambridge Institute for Medical Research; Reino Unido Fil: Rudel, T.. University of Würzburg; Alemania Fil: Scorrano, L.. University of Geneva ; Suiza. Venetian Institute of Molecular Medicine; Italia Fil: Simon, H. U.. University of Bern; Suiza Fil: Steller, H.. Howard Hughes Medical Institute; Estados Unidos. The Rockefeller University; Estados Unidos Fil: Tschoop, J.. University of Lausanne; Suiza Fil: Tsujimoto, Y.. Osaka University Medical School; Japón Fil: Vandenabeele, P.. Ghent University; Bélgica. VIB; Bélgica Fil: Vitale, I.. Inserm; Francia. Universite Paris Sud; Francia. Institut Gustave Roussy; Francia Fil: Vousden, K. H.. The Beatson Institute for Cancer Research; Reino Unido Fil: Youle, J. R.. National Institutes of Health; Estados Unidos Fil: Yuan, J.. Harvard Medical School; Estados Unidos Fil: Zhivotovsky, B.. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia Fil: Kroemer, G.. Inserm; Francia. Universite Paris Sud; Francia. Institut Gustave Roussy; Francia
Published: 2009

8. Psychiatric illness and regression in individuals with Phelan-McDermid syndrome

Author: Alexander Kolevzon, Audrey Thurm, M. Pilar Trelles, Catalina Betancur, Teresa M. Kohlenberg, Brittany McLarney, Betancur, Catalina, Department of Psychiatry [Worcester, MA, USA], University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS)-University of Massachusetts System (UMASS), Seaver Autism Center for Research and Treatment [New York, NY, USA], Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department of Psychiatry [New York, NY, USA], Phelan-McDermid Syndrome Foundation [Osprey, FL, USA], Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neurodevelopmental and Behavioral Phenotyping Service [Bethesda, MD, USA] (Intramural Research Program), National Institute of Environmental Health Sciences [Durham] (NIEHS-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), MPT receives research support from the National Institute of Health National Research Service Award Institutional Training Program (T32) and the Beatrice and Samuel A. Seaver Foundation. AT receives support from the Intramural Research Program of the National Institute of Mental Health (ZICMH002961). AK receives support from the National Institute of Neurological Disorders and Stroke (R01NS105845-01 and U54 NS092090-01) and from the Beatrice and Samuel A. Seaver Foundation., Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Chromosomes, Human, Pair 22, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Chromosome Disorders, 0302 clinical medicine, Intellectual disability, Medicine, SHANK3, Depression (differential diagnoses), 0303 health sciences, Depression, Mental Disorders, Catatonia, Middle Aged, Regression, 3. Good health, Regression, Psychology, Mania, Phenotype, Autism spectrum disorder, Female, medicine.symptom, Chromosome Deletion, Adult, medicine.medical_specialty, Psychosis, Adolescent, Bipolar disorder, Cognitive Neuroscience, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Pathology and Forensic Medicine, lcsh:RC321-571, 03 medical and health sciences, Young Adult, Humans, Psychiatry, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, 030304 developmental biology, business.industry, Research, medicine.disease, Mood, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Pediatrics, Perinatology and Child Health, Phelan-McDermid syndrome, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: Background Phelan-McDermid syndrome (PMS) is a genetic condition characterized by intellectual disability, speech and language deficits, hypotonia, autism spectrum disorder, and epilepsy. PMS is caused by 22q13.33 deletions or mutations affecting SHANK3, which codes for a critical scaffolding protein in excitatory synapses. SHANK3 variants are also known to be associated with an increased risk for regression, as well as for psychiatric disorders, including bipolar disorder and catatonia. This study aimed to further describe these phenomena in PMS and to explore any relationship between psychiatric illness and regression after early childhood. Methods Thirty-eight people with PMS were recruited to this study through the Phelan-McDermid Syndrome Foundation based on caregiver report of distinct development of psychiatric symptoms. Caregivers completed a clinician-administered semi-structured interview focused on eliciting psychiatric symptomatology. Data from the PMS International Registry were used to confirm genetic diagnoses of participants and to provide a larger sample for comparison. Results The mean age of the 38 participants was 24.7 years (range = 13 to 50; SD = 10.06). Females (31 of 38 cases; 82%) and sequence variants (15 of 38 cases; 39%) were over-represented in this sample, compared to base rates in the PMS International Registry. Onset of psychiatric symptoms occurred at a mean age of 15.4 years (range = 7 to 32), with presentations marked by prominent disturbances of mood. Enduring substantial loss of functional skills after onset of psychiatric changes was seen in 25 cases (66%). Symptomst indicative of catatonia occurred in 20 cases (53%). Triggers included infections, changes in hormonal status, and stressful life events. Conclusions This study confirms that individuals with PMS are at risk of developing severe neuropsychiatric illness in adolescence or early adulthood, including bipolar disorder, catatonia, and lasting regression of skills. These findings should increase the awareness of these phenotypes and lead to earlier diagnosis and the implementation of appropriate interventions. Our findings also highlight the importance of genetic testing in the work-up of individuals with intellectual disability and acute psychiatric illness or regression. Future research is needed to clarify the prevalence and nature of psychiatric disorders and regression among larger unbiased samples of individuals with PMS.
Published: 2020

9. Recognition of mRNA Splice Variant and Secretory Granule Epitopes by CD4+ T Cells in Type 1 Diabetes

Author: Perrin Guyer, David Arribas-Layton, Anthony Manganaro, Cate Speake, Sandra Lord, Decio L. Eizirik, Sally C. Kent, Roberto Mallone, Eddie A. James, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Benaroya Research Institute [Seattle] (BRI), Université libre de Bruxelles (ULB), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Mallone, Roberto
Subjects: CD4-Positive T-Lymphocytes, epitope, splice variant, Endocrinology, Diabetes and Metabolism, Secretory Vesicles, Epitopes, T-Lymphocyte, CD4+ T cells, Type 1 diabetes, Diabetes Mellitus, Type 1, Cyclin I, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, Internal Medicine, beta cell stress, Humans, secretory granule, Peptides
Abstract: A recent discovery effort resulted in identification of novel splice variant and secretory granule antigens within the HLA class I peptidome of human islets and documentation of their recognition by CD8+ T cells from peripheral blood and human islets. In the current study, we applied a systematic discovery process to identify novel CD4+ T cell epitopes derived from these candidate antigens. We predicted 145 potential epitopes spanning unique splice junctions and within conventional secretory granule antigens and measured their in vitro binding to DRB1*04:01. We generated HLA class II tetramers for the 35 peptides with detectable binding and used these to assess immunogenicity and isolate T cell clones. Tetramers corresponding to peptides with verified immunogenicity were then used to label T cells specific for these putative epitopes in peripheral blood. T cells that recognize distinct epitopes derived from a cyclin I splice variant, neuroendocrine convertase 2, and urocortin-3 were detected at frequencies that were similar to those of an immunodominant proinsulin epitope. Cells specific for these novel epitopes predominantly exhibited a Th1-like surface phenotype. Among the three epitopes, responses to the cyclin I peptide exhibited a distinct memory profile. Responses to neuroendocrine convertase 2 were detected among pancreatic infiltrating T cells. These results further establish the contribution of unconventional antigens to the loss of tolerance in autoimmune diabetes.
Published: 2022

10. The amyloid precursor protein is a conserved Wnt receptor

Author: Alessia Soldano, Bart De Strooper, Bassem A. Hassan, Lee G. Fradkin, Lydie Boussicault, Heather C. Rice, Marie-Claude Potier, Iveta M. Petrova, Annelies Claeys, Tengyuan Liu, Maya Nicolas, Tingting Zhang, 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), Center for Human Genetics, University of Leuven School of Medicine, SCHOOL of MEDICINE [Louvain], Université Catholique de Louvain = Catholic University of Louvain (UCL)-Université Catholique de Louvain = Catholic University of Louvain (UCL), VIB Center for the Biology of Disease [Louvain, Belgique] (VIB-CBD), Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Gestionnaire, HAL Sorbonne Université 5, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Life Sciences & Biomedicine - Other Topics, DIMERIZATION, brain development, amyloid precursor protein, neuroscience, Amyloid beta-Protein Precursor, Mice, 0302 clinical medicine, DOMAIN, BINDING, cell biology, Receptors, D. melanogaster, Drosophila, alzheimer's disease, mouse, wnt, Amino Acid Sequence, Animals, Brain, Cells, Cultured, Cloning, Molecular, Drosophila Proteins, Drosophila melanogaster, Gene Deletion, Gene Expression Regulation, Humans, Membrane Proteins, Mushroom Bodies, Nerve Tissue Proteins, Neurons, Protein Transport, Receptors, Wnt, Signal Transduction, Amyloid precursor protein, Biology (General), Receptor, 0303 health sciences, Cultured, biology, Chemistry, General Neuroscience, Wnt signaling pathway, General Medicine, Phenotype, Transmembrane protein, Cell biology, ALZHEIMERS-DISEASE, WNT5A, Medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Life Sciences & Biomedicine, POLARITY, Research Article, EXPRESSION, QH301-705.5, Cells, Science, General Biochemistry, Genetics and Molecular Biology, Wnt, 03 medical and health sciences, mental disorders, Extracellular, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Biology, 030304 developmental biology, Science & Technology, General Immunology and Microbiology, Molecular, Cell Biology, ESTABLISHMENT, biology.protein, APP, 030217 neurology & neurosurgery, WNT3A, Cloning, Neuroscience
Abstract: The Amyloid Precursor Protein (APP) and its homologues are transmembrane proteins required for various aspects of neuronal development and activity, whose molecular function is unknown. Specifically, it is unclear whether APP acts as a receptor, and if so what its ligand(s) may be. We show that APP binds the Wnt ligands Wnt3a and Wnt5a and that this binding regulates APP protein levels. Wnt3a binding promotes full-length APP (flAPP) recycling and stability. In contrast, Wnt5a promotes APP targeting to lysosomal compartments and reduces flAPP levels. A conserved Cysteine-Rich Domain (CRD) in the extracellular portion of APP is required for Wnt binding, and deletion of the CRD abrogates the effects of Wnts on flAPP levels and trafficking. Finally, loss of APP results in increased axonal and reduced dendritic growth of mouse embryonic primary cortical neurons. This phenotype can be cell-autonomously rescued by full length, but not CRD-deleted, APP and regulated by Wnt ligands in a CRD-dependent manner. ispartof: ELIFE vol:10 ispartof: location:England status: published
Published: 2021

11. Targeting of the Tec Kinase ITK Drives Resolution of T Cell–Mediated Colitis and Emerges as Potential Therapeutic Option in Ulcerative Colitis

Author: Valérie S. Zimmermann, Markus F. Neurath, Benno Weigmann, Ragheed Al-Saifi, Stefanie Mott, Michael Vieth, Timo Rath, Zoltan Winter, Tina Fraass, Raja Atreya, Avery August, Jeremy Luban, Stefan Wirtz, Lisa Knipfer, Kristina Lechner, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Cornell University [New York], University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Hematopoïèse et Immunothérapie, Institut de Génétique Moléculaire de Montpellier (IGMM), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Subjects: Colon, medicine.medical_treatment, T cell, IBD, Anti-Inflammatory Agents, Apoptosis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Inflammatory bowel disease, Cyclosporine A, Interferon, Animals, Humans, Medicine, Molecular Targeted Therapy, Intestinal Mucosa, Phosphorylation, Colitis, Intraepithelial Lymphocytes, Protein Kinase Inhibitors, Cells, Cultured, Mice, Knockout, Therapeutic Strategies, Hepatology, business.industry, T-cell receptor, Gastroenterology, Protein-Tyrosine Kinases, medicine.disease, 3. Good health, Disease Models, Animal, Cytokine, medicine.anatomical_structure, ITK, Cyclosporine, Cancer research, Cytokines, Colitis, Ulcerative, Tumor necrosis factor alpha, Signal transduction, business, Signal Transduction, medicine.drug
Abstract: International audience; Background & Aims: The molecular checkpoints driving T cell activation and cytokine responses in ulcerative colitis are incompletely understood. Here, we studied the Tec kinase ITK in ulcerative colitis and explored the link between Cyclosporine A (CsA) function and ITK activation. Methods: We analyzed patients with inflammatory bowel disease (n=202) and evaluated ITK expression and activity as well as the functional effects of CsA. Moreover, three independent murine colitis models were used to investigate the functional role of ITK. Finally, the activity of ITK was blocked via pharmacological inhibitors and genetically engineered mice. Readout parameters were mini-endoscopy, histopathology, mucosal T cell apoptosis and cytokine production. Results: We found an expansion of ITK expressing mucosal CD4+ T cells in ulcerative colitis rather than Crohn ́s disease that correlated with disease severity. CsA suppressed activation of ITK in cultured CD4+ T cells and calcineurin-containing microclusters adjacent to the T cell receptor signaling complex. Functionally, the capacity of CsA to suppress activity of experimental colitis was critically dependent on ITK. Moreover, genetic inactivation of Itk via gene targeting or induction of allele-sensitive Itk mutants suppressed experimental colitis in three colitis models, while pharmacological ITK blockers could be used for treatment of established colitis and triggered resolution of inflammation. Hereby, ITK controlled apoptosis and activation of mucosal Th2 and Th17 lymphocytes via NFATc2 signaling pathways. Conclusion: ITK activation was detected in ulcerative colitis and could be downregulated in cultured T cells by CsA administration. Selective targeting of ITK emerges as an attractive approach for treatment of chronic intestinal inflammation and potentially ulcerative colitis by driving resolution of mucosal inflammation
Published: 2021

12. De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder

Author: Jonathan A. Bernstein, Leah J. Rowe, Kimberly Foss, Samin A. Sajan, Kun Xia, Juliane Hoyer, Anita E. Beck, Shayna Svihovec, Vincent Gatinois, Lance H. Rodan, Roksana Sasanfar, Christiane Zweier, Alban Ziegler, Sonal Mahida, Kristin G. Monaghan, Charlotte W. Ockeloen, André Reis, Milen Velinov, Janson White, Evan E. Eichler, Nasim Vasli, Jennifer Friedman, Constance Smith-Hicks, Gilles Morin, Rachel Westman, Sandra Yang, Joshua Scheck, Christian Thiel, John B. Vincent, Deborah A. Nickerson, Michelle E. Ernst, Jacqueline Harris, Natasha Zeid, Bernt Popp, Francesca Mattioli, Zehra Agha, Ellen van Binsbergen, Julian A. Martinez-Agosto, Karen W. Gripp, Gwenaël Le Guyader, Catherine Vincent-Delorme, Lori-Anne Schillaci, Jennefer N. Kohler, Kimberly A. Aldinger, Laurence J. Walsh, Jessica X. Chong, David Geneviève, Rami Abou Jamra, Amy Yang, Cigdem I. Akman, Sha Tang, Ricardo Harripaul, Rick Person, Marleen Simon, Hui Guo, Muhammad Ayub, Laura S. Farach, Patricia Blanchet, Austin Larson, Marie Vincent, Luis Rohena, Michael J. Bamshad, Raheel Qamar, Gregory M. Enns, Joshua Rotenberg, Katelyn Payne, William J. Sunderland, Anne C.-H. Tsai, Annika M. Dries, Michèle Mathieu-Dramard, Dominique Bonneau, Ghayda M. Mirzaa, Bénédicte Gérard, Elise Schaefer, Amélie Piton, Patricia G Wheeler, Division of Medical Genetics [Seattle], University of Washington [Seattle], Détoxication et réparation tissulaire, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Center for Integrative Brain Research [Seattle, WA, USA], University of Washington [Seattle]-Seattle Children's Research Institute, Central South University [Changsha], Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Center for Integrative Brain Research, Ambry Genetics [Aliso Viejo, CA, USA], China Agricultural University (CAU), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Kennedy Krieger Institute [Baltimore], Institute of Human Genetics [Erlangen, Allemagne], Universität Leipzig, Yale University [New Haven], Oregon Health and Science University [Portland] (OHSU), McGovern Medical School [Houston, Texas], Indiana University - Purdue University Indianapolis (IUPUI), Indiana University System, Indiana University [South Bend], The University of Texas at San Antonio (UTSA), New York State Psychiatric Institute, Columbia University [New York], Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], CHU Strasbourg, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University Medical Center [Utrecht], Stanford University School of Medicine [CA, USA], Memorial Hermann Heart and Vascular Institute [Houston, TX, USA], University of Central Florida [Orlando] (UCF), Department of Pediatrics [Univ California San Diego] (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), University of California (UC)-University of California (UC), University of Colorado Anschutz [Aurora], Department of Chemistry and Biochemistry [Bern], University of Bern, Columbia University Irving Medical Center (CUIMC), Signal Processing Lab [Boise - Idaho], Boise State University, University Hospitals Case Medical Center (CLEVELAND - UHCMC), University Hospitals Case Medical Center, Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Psychology [University North Carolina Wilmington], University of North Carolina [Wilmington] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), 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), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'hématologie et immunologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, Institut d'histoire du temps présent (IHTP), Centre National de la Recherche Scientifique (CNRS), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Queen's University [Kingston, Canada], Department of Molecular Genetics [Toronto], University of Toronto, GeneDx [Gaithersburg, MD, USA], Department of Genome Sciences [Seattle] (GS), Department of Pediatrics [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford School of Medicine [Stanford], Stanford University, University of California (UC), COMSATS Institute of Information Technology [Islamabad] (CIIT), Boston Children's Hospital, University of California [Los Angeles] (UCLA), Radboud University Medical Center [Nijmegen], Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Psychiatry, Seattle University [Seattle], 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), Universität Leipzig [Leipzig], Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Department of Pediatrics [san Diego], UC San Diego School of Medicine, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and University of California
Subjects: 0301 basic medicine, Proband, Male, Adolescent, Autism Spectrum Disorder, autism spectrum disorders, Nerve Tissue Proteins, Neuroimaging, 030105 genetics & heredity, Biology, Article, 03 medical and health sciences, Neurodevelopmental disorder, ZNF292, Intellectual disability, mental disorders, Exome Sequencing, medicine, Humans, Genetic Predisposition to Disease, Child, Genetics (clinical), Exome sequencing, Genetics, Zinc finger, next generation sequencing, Genetic heterogeneity, High-Throughput Nucleotide Sequencing, medicine.disease, Phenotype, 3. Good health, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism spectrum disorder, intellectual disability, Neurodevelopmental Disorders, Child, Preschool, next-generation sequencing, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Carrier Proteins, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract: Contains fulltext : 218267.pdf (Publisher’s version ) (Closed access) PURPOSE: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292). METHODS: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships. RESULTS: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment. CONCLUSION: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.
Published: 2019

13. Axonal chemokine-like Orion induces astrocyte infiltration and engulfment during mushroom body neuronal remodeling

Author: Stephan Züchner, Lee G. Fradkin, Ana Boulanger, Jean Maurice Dura, Camille Thinat, Hugues Lortat-Jacob, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), University of Miami [Coral Gables], University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-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)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)
Subjects: 0301 basic medicine, Nervous system, Chemokine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Science, Amino Acid Motifs, General Physics and Astronomy, chemical and pharmacologic phenomena, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Developmental biology, medicine, Animals, Axon, Mushroom Bodies, Neuronal Plasticity, Multidisciplinary, Whole Genome Sequencing, fungi, Membrane Proteins, food and beverages, Chemotaxis, General Chemistry, Axons, Cell biology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, 030104 developmental biology, medicine.anatomical_structure, nervous system, Mutagenesis, Astrocytes, Mushroom bodies, biology.protein, Neuronal development, Drosophila, RNA Interference, Chemokines, Astrocyte, 030217 neurology & neurosurgery, Function (biology), Protein Binding, circulatory and respiratory physiology
Abstract: The remodeling of neurons is a conserved fundamental mechanism underlying nervous system maturation and function. Astrocytes can clear neuronal debris and they have an active role in neuronal remodeling. Developmental axon pruning of Drosophila memory center neurons occurs via a degenerative process mediated by infiltrating astrocytes. However, how astrocytes are recruited to the axons during brain development is unclear. Using an unbiased screen, we identify the gene requirement of orion, encoding for a chemokine-like protein, in the developing mushroom bodies. Functional analysis shows that Orion is necessary for both axonal pruning and removal of axonal debris. Orion performs its functions extracellularly and bears some features common to chemokines, a family of chemoattractant cytokines. We propose that Orion is a neuronal signal that elicits astrocyte infiltration and astrocyte-driven axonal engulfment required during neuronal remodeling in the Drosophila developing brain., Astrocytes can engulf axonal debris in the developing brain. However, the mechanisms regulating astrocyte recruitment to the proper axons is unclear. Here, the authors identify Orion as a signal for astrocyte infiltration and engulfment to the mushroom bodies in the Drosophila developing brain.
Published: 2021

14. Rpgrip1l controls ciliary gating by ensuring the proper amount of Cep290 at the vertebrate transition zone

Author: Hemant Khanna, Christoph Gerhardt, Sylvie Schneider-Maunoury, Christine Vesque, Renate Dildrop, Antonia Wiegering, Laboratoire de Biologie du Développement [Paris] (LBD), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-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), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Morphogénèse du Cerveau des Vertébrés = Morphogenesis of the vertebrate brain (LBD-E10), Institut National de la Santé et de la Recherche Médicale (INSERM)-Laboratoire de Biologie du Développement [Paris] (LBD), Sorbonne Université (SU)-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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Laboratoire de Biologie du Développement [IBPS] (LBD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-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)-Laboratoire de Biologie du Développement [IBPS] (LBD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and HAL-SU, Gestionnaire
Subjects: Axoneme, [SDV]Life Sciences [q-bio], Cell Cycle Proteins, Gating, Ciliopathies, 03 medical and health sciences, Mice, 0302 clinical medicine, Antigens, Neoplasm, biology.animal, Animals, Humans, Cilia, Molecular Biology, 030304 developmental biology, Adaptor Proteins, Signal Transducing, Centrioles, 0303 health sciences, biology, Cilium, Vertebrate, Cell Biology, Articles, Basal Bodies, [SDV] Life Sciences [q-bio], Cytoskeletal Proteins, HEK293 Cells, RPGRIP1L, Mutation, NIH 3T3 Cells, Neuroscience, 030217 neurology & neurosurgery, Signal Transduction
Abstract: International audience; A range of severe human diseases called ciliopathies are caused by the dysfunction of primary cilia. Primary cilia are cytoplasmic protrusions consisting of the basal body (BB), the axoneme and the transition zone (TZ). The BB is a modified mother centriole from which the axoneme, the microtubule-based ciliary scaffold, is formed. At the proximal end of the axoneme, the TZ functions as the ciliary gate governing ciliary protein entry and exit. Since ciliopathies often develop due to mutations in genes encoding proteins that localise to the TZ, the understanding of the mechanisms underlying TZ function is of eminent importance. Here, we show that the ciliopathy protein Rpgrip1l governs ciliary gating by ensuring the proper amount of Cep290 at the vertebrate TZ. Further, we identified the flavonoid eupatilin as a potential agent to tackle ciliopathies caused by mutations in RPGRIP1L as it rescues ciliary gating in the absence of Rpgrip1l.
Published: 2021

15. Decline in subarachnoid haemorrhage volumes associated with the first wave of the COVID-19 pandemic

Author: Ajit S. Puri, Allan Taylor, Huynh Le Vu, Tatemi Todaka, Teddy Y. Wu, Octavio M. Pontes-Neto, Eytan Raz, Pedro Lylyk, Jasmine Johann, Roberta Novakovic, Hormuzdiyar H. Dasenbrock, Francisco Mont’Alverne, Nobuyuki Sakai, Melanie Walker, Hugh Stephen Winters, Ossama Mansour, Yohei Takenobu, Gregory Walker, Miki Fujimura, Saif Bushnaq, Odysseas Kargiotis, Nabeel Herial, Markus A Möhlenbruch, Malveeka Sharma, Hiroshi Tokimura, Maxim Mokin, Jean Raymond, Michael D. Hill, Amal Abou-Hamden, Leonardo Renieri, Serdar Geyik, Yuri Sugiura, Luisa Fonseca, Roberto Crosa, Fabricio O Lima, Ameer E Hassan, Viet Quy Nguyen, Jane G. Morris, Steven W. Hetts, Jawad F. Kirmani, Matthew S. Tenser, Muhammad M. Qureshi, Gianmarco Bernava, Mahmoud H Mohammaden, Verónica V. Olavarría, Jun Deguchi, André Beer-Furlan, Steve M. Cordina, Hiroshi Yamagami, Mohamad Abdalkader, Toshiyuki Fujinaka, Clifford J. Eskey, Rotem Sivan-Hoffmann, Hao Zhang, Anirudh Kulkarni, Brendan Steinfort, Özlem Aykaç, Barbara Voetsch, Alex Brehm, Italo Linfante, Wenguo Huang, Omer Eker, M. Luis Silva, Pascal Jabbour, Lissa Peeling, Mollie McDermott, Pascale Lavoie, Kazutaka Sonoda, Thomas Devlin, Alicia C. Castonguay, Jin Soo Lee, Diogo C Haussen, Dileep R. Yavagal, Thanh N. Nguyen, Umair Rashid, Vasu Saini, Raghid Kikano, Hiroyuki Hashimoto, Masaaki Uno, Saima Ahmad, Artem Kaliaev, Eiji Hagashi, Ajay K. Wakhloo, Romain Bourcier, Ryoo Yamamoto, Jesse M. Thon, Georgios Tsivgoulis, Dorothea Altschul, Achmad Fidaus Sani, Satoshi Yamada, Varsha Singh, David S Liebeskind, Tatsuo Amano, Anchalee Churojana, Juan F. Arenillas, Junichi Iida, Charles C. Matouk, Nobuyuki Ohara, Osama O. Zaidat, Mario Martínez-Galdámez, Chandril Chugh, Don Frei, Vanessa Chalumeau, Brijesh P Mehta, Marios Psychogios, Anna Luisa Kühn, Leticia C Rebello, Xianjin Shang, Hosam Al-Jehani, Hiroki Fukuda, Hong Gee Roh, Gisele Sampaio Silva, Rakesh Khatri, Kenichi Todo, Amal Al Hashmi, Alex Bou Chebl, Sunil A Sheth, Zhongming Qiu, Oriana Cornett, Zhengzhou Yuan, Wazim Izzath, Hesham Masoud, Rodrigo Rivera, Michel Piotin, Vikram Huded, Mamoru Murakami, Mohamed Teleb, Viktor Szeder, Ruchir Shah, Dheeraj Gandhi, John Thornton, Michael Chen, Vitor Mendes Pereira, Nadia Hammami, Alice Ma, Anna M. Cervantes-Arslanian, James E. Siegler, Seby John, Carlos Ynigo Lopez, Mudassir Farooqui, David Ozretić, Takuya Kanamaru, Romain Guile, Daisuke Watanabe, Kosuke Miyake, Alejandro Rodriguez Vasquez, Patrick Nicholson, Yuki Yamamoto, William J. Mack, Naoto Kimura, Simon Mathew John, Robert Fahed, Yuji Matsumaru, David Y. Chung, Rishi Gupta, Ryuhei Kono, Michael Frankel, Victor S. Lopez Rivera, Johanna T. Fifi, Raul G Nogueira, Paolo Machi, Tudor G. Jovin, Jordi Blasco, Emma Griffin, Salvatore Mangiafico, Masafumi Morimoto, Jun Luo, Santiago Ortega-Gutierrez, Monika Killer-Oberpfalzer, Daniel Giansante Abud, Syed I. Hussain, Fawaz Al-Mufti, Yusuke Sugimura, Atilla Özcan Özdemir, Stephan A. Mayer, Sumeet Multani, Adel Alhazzani, Alhamza R Al-Bayati, Michael Kelly, Lee A Birnbaum, Shadi Yaghi, Jeyaraj D Pandian, Ji Man Hong, Junsuke Shimbo, Johnny Ho-Yin Wong, Elena A. Cora, Laura Mechtouff, Pedro S.C. Magalhães, Pablo M. Lavados, Yuichi Murayama, Dong Hun Shin, Simon Nagel, Ken Wong, Jose Antonio Fiorot, Jeremy Payne, Randall C. Edgell, Adrienne Weeks, CarMeN, laboratoire, Department of Neurology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Emory University School of Medicine, Emory University [Atlanta, GA], Boston University School of Medicine (BUSM), Boston University [Boston] (BU), National Hospital Organization Osaka National Hospital [Japon] (NHO Osaka National Hospital), Alexandria University [Alexandrie], Boston Medical Center [Boston, MA, USA] (BMC), Xinqiao Hospital [Chongqing, China] (XH), University of Cape Town, La Sagrada Familia Clinic/Clínica La Sagrada Familia [Buenos Aires, Argentina] (LSFC), Hospices Civils de Lyon (HCL), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Hospital General de Fortaleza [Fortaleza, Brazil] (HGF), Nottingham University Hospitals NHS Trust [UK], Kobe City Medical Center General Hospital [Kobe, Hyogo, Japan] (KCMCGH), Azienda Ospedaliero-Universitaria Careggi [Firenze, Toscana, Italy] (AOUC), University Hospital Centre Zagreb, Partenaires INRAE, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service de Neuroradiologie [CHU de Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cleveland Clinic Abu Dhabi [Abou Dabi, Émirats arabes unis], Hôpital de Beaumont [Dublin, Ireland] (HB), Hospital-Estadual Central [Vitoria, Brazil] (HEC), Instituto de NeuroCirugía Asenjo, Institut national de neurologie Mongi-Ben Hamida [Tunis], Hue Central Hospital [Thua Thien Hue, Vietnam] (HCH), University of California [San Francisco] (UC San Francisco), University of California (UC), Centre hospitalier universitaire de Nantes (CHU Nantes), Washington University School of Medicine (WUSM), University of Washington [Seattle], Englewood Hospital and Medical Center [Englewood], Jefferson (Philadelphia University + Thomas Jefferson University), Westchester Medical Center [Valhalla, New York, USA] (WMC), Eskisehir Osmangazi University, University of Maryland School of Medicine, University of Maryland System, MAX Superspecialty Hospital [Saket, New Delhi, India] (MSH), Yale School of Medicine [New Haven, Connecticut] (YSM), Université Laval [Québec] (ULaval), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Rush University Medical Center [Chicago], Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), University of Toronto, NH Mazumdar Shah Medical Center [Bangalore, India] (NHMSMC), IMS Tokyo-Katsushika General Hospital [Tokyo, Japan], Gachon University [Seongnam, Korea] (GU), Hospital Municipal Sao Jose [Joinville, Santa Catarina, Brazil] (HMSJ), Lau Medical Center [Beirut, Lebanon] (LMC), University of Iowa [Iowa City], Royal Adelaide Hospital [Adelaide Australia], Kyorin University [Tokyo, Japan], Yokohama Brain and Spine Center [Yokohama, Japan] (YBSC), Dalhousie University [Halifax], Rambam Health Care Campus [Haifa, Israel], Centro Endovascular Neurologico Medica Uruguaya [Montevideo, Uruguay] (CENMU), Heidelberg University Hospital [Heidelberg], Imam Abdulrahman bin Faisal University [Alkhobar, Saudi Arabia] (IAFU), McGovern Medical School [Houston, TX, USA] (McGMS), The University of Texas Health Science Center at Houston (UTHealth), Cooper Medical School of Rowan University [Camden] (CMSRU), Airlangga University [Jawa Timur, Indonesia] (AU), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Geneva University Hospitals and Geneva University, Universidade de São Paulo = University of São Paulo (USP), Beth Israel Lahey Health [Burlington, MA, USA] (BILH), New York University School of Medicine (NYU Grossman School of Medicine), Memorial Neuroscience Institute [Pembroke Pines, FL, USA] (MNI), Iwate Prefectural Central Hospital [Morioka, Iwate, Japan] (IPCH), Japanese Red Cross Musashino Hospital [Tokyo], Ajou University, University of Ottawa [Ottawa], Saga-ken Medical Centre Koseikan [Saga, Japan] (SMCK), University of South Alabama, Konkuk University [Seoul], Royal Free Hospital [London, UK], Hospital Clinico Universitario de Valladolid [Castilla y León, Spain] (HCUV), Universidad de Valladolid [Valladolid] (UVa), Instituto de Ciencia de Materiales de Aragón [Saragoza, España] (ICMA-CSIC), University of Zaragoza - Universidad de Zaragoza [Zaragoza], Hospital Clínic de Barcelona [Catalonia, Spain], Centro Hospitalar Universitário de São João [Porto], Christchurch Hospital [Christchurch, New Zealand] (CH), University Hospital Basel [Basel], University of Southern California (USC), Kohnan Hospital - Sendai [Miyagi, Japan], University of Texas Southwestern Medical Center [Dallas], Nara City Hospital [Nara, Japan] (NCH), Toyonaka Municipal Hospital [Osaka, Japan] (TMH), Kagoshima City Hospita [Kagoshima, Japan] (KCH), Texas Tech University System [Lubbock, TX, USA] (TTUS), University of Saskatchewan [Saskatoon] (U of S), National Institute of Information and Communications Technology [Tokyo, Japan] (NICT), Royal Prince Alfred Hospital [Camperdown, Australia] (RPAH), Banner Desert Medical Center [Mesa, AZ, USA] (BDMC), Japanese Red Cross Matsue Hospital [Shimane, Japan] (JRCMH), Shiroyama Hospital [Osaka, Japan] (SH), Niigata City General Hospital [Niigata, Japan] (NCGH), Sugimura Hospital [Kumamoto, Japan] (SH), Kawasaki Medical School [Kurashiki, Japan] (KMS), Osaka Red Cross Hospital [Osaka, Japan] (ORCH), Université de Tsukuba = University of Tsukuba, Saiseikai Central Hospital [Tokyo, Japan] (SCH), Kinikyo Chuo Hospital - Sapporo [Hokkaido, Japan] (KCHS), NTT Medical Center Tokyo [Tokyo, Japan] (NTTMCT), Yokohama Shintoshi Neurosurgical Hospital [Yokohama, Japan]. (YSNH), Osaka General Medical Center [Osaka, Japan] (OGMC), University of Miami Leonard M. Miller School of Medicine (UMMSM), Bon Secours Mercy Health System [Toledo, OH, USA] (BSMHS), Maoming City Hospital [Guandong, China] (MCH), Miami Cardiac & Vascular Institute [Miami, FL, USA] (MC&VI), Hackensack University Medical Center [Hackensack], David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), University of Tennessee [Chattanooga] (UTC), The University of Texas at San Antonio (UTSA), Mianyang 404 Hospital [Sichuan, China] (M404H), Siriraj Hosital - Mahidol University [Bangkok, Thailand] (SHMU), SUNY Upstate Medical University, State University of New York (SUNY), Royal North Shore Hospital (RNSH), The University of Texas Rio Grande Valley [Harlingen, TX, USA] (UTRGV), Khoula Hospital [Muscat, Oman] (Ministry of Health - KH), University of Michigan [Ann Arbor], University of Michigan System, University of South Florida [Tampa] (USF), Henry Ford Health System [Detroit, MI, USA] (HFHS), Metropolitan Hospital [Piraeus, Greece] (MH), National and Kapodistrian University of Athens (NKUA), Maine Medical Center, Dartmouth Hitchcock Medical Center [Lebanon, NH, USA] (DHMC), Centro Universitário Feevale (BRAZIL), The Valley Hospital [Ridgewood, NJ, USA] (TVH), St Joseph's University Medical Center [Paterson, NJ, USA] (StJUMC), Christian Medical College and Hospital Ludhiana [Punjab, India] (CMCHL), Universidad del Desarrollo, University Graduate School of Medicine [Osaka, Japan], Tokushima University, Universidade Federal de São Paulo, Istanbul Aydin University [İstanbul, Turkey] (IAU), Swedish Medical Center [Englewood, CO, USA] (SMC), Bayhealth Medical Center [Dover, DE, USA] (BMC), Saiseikai Fukuoka General Hospital [Fukuoka, Japan] (SFGH), Osaka Rosai Hospital - Sakai [Osaka, Japan] (ORHS), King Saud University [Riyadh] (KSU), Mount Sinai Health System, University of Calgary, Huzhou University [Zhejiang], The Affiliated Hospital of Southwest Medical University - Luzhou [Sichuan, China] (TAHSMUL), Yijishan Hospital of Wannan Medical College [Wuhu, Anhui, China] (YHWMC), University of Toledo, WellStar Health System [Marietta, GA, USA] (WHS), Institut National de la Recherche Scientifique [Québec] (INRS), Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), SVIN COVID-19 Registry, the Middle East North Africa Stroke and Interventional Neurotherapies Organization (MENA-SINO), Japanese Society of Vascular and Interventional Neurology Society (JVIN), University of California [San Francisco] (UCSF), University of California, Yale University School of Medicine, University of São Paulo (USP), and University of California-University of California
Subjects: [SDV]Life Sciences [q-bio], COVID-19, Subarachnoid Hemorrhage* / diagnostic imaging, 030204 cardiovascular system & hematology, Intracranial Aneurysm* / therapy, lcsh:RC346-429, 0302 clinical medicine, Pandemic, Myocardial infarction, Prospective Studies, Stroke, Original Research, 3. Good health, [SDV] Life Sciences [q-bio], Treatment Outcome, Intracranial Aneurysm* / diagnostic imaging, Cardiology, Subarachnoid haemorrhage, haemorrhage, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Subgroup analysis, subarachnoid, Intracranial Aneurysm* / epidemiology, 03 medical and health sciences, Aneurysm, Internal medicine, medicine, Humans, coil, cardiovascular diseases, Pandemics, lcsh:Neurology. Diseases of the nervous system, Retrospective Studies, business.industry, SARS-CoV-2, Intracranial Aneurysm, Subarachnoid Hemorrhage, medicine.disease, infection, nervous system diseases, Mechanical thrombectomy, Cross-Sectional Studies, aneurysm, Neurology (clinical), Subarachnoid Hemorrhage* / epidemiology, business, 030217 neurology & neurosurgery
Abstract: BackgroundDuring the COVID-19 pandemic, decreased volumes of stroke admissions and mechanical thrombectomy were reported. The study’s objective was to examine whether subarachnoid haemorrhage (SAH) hospitalisations and ruptured aneurysm coiling interventions demonstrated similar declines.MethodsWe conducted a cross-sectional, retrospective, observational study across 6 continents, 37 countries and 140 comprehensive stroke centres. Patients with the diagnosis of SAH, aneurysmal SAH, ruptured aneurysm coiling interventions and COVID-19 were identified by prospective aneurysm databases or by International Classification of Diseases, 10th Revision, codes. The 3-month cumulative volume, monthly volumes for SAH hospitalisations and ruptured aneurysm coiling procedures were compared for the period before (1 year and immediately before) and during the pandemic, defined as 1 March–31 May 2020. The prior 1-year control period (1 March–31 May 2019) was obtained to account for seasonal variation.FindingsThere was a significant decline in SAH hospitalisations, with 2044 admissions in the 3 months immediately before and 1585 admissions during the pandemic, representing a relative decline of 22.5% (95% CI −24.3% to −20.7%, pInterpretationThere was a relative decrease in the volume of SAH hospitalisations, aneurysmal SAH hospitalisations and ruptured aneurysm embolisations during the COVID-19 pandemic. These findings in SAH are consistent with a decrease in other emergencies, such as stroke and myocardial infarction.
Published: 2021

16. The effect of SMN gene dosage on ALS risk and disease severity

Author: Vincenzo Silani, Mamede de Carvalho, Nicola Ticozzi, Joke J.F.A. van Vugt, Kristel R. van Eijk, Patrick Vourc'h, Markus Weber, Wouter van Rheenen, Kevin P. Kenna, Christopher Shaw, Wim Robberecht, Philippe Couratier, Mònica Povedano, Jonathan D. Glass, Pamela J. Shaw, Ramona A. J. Zwamborn, Ammar Al-Chalabi, John Landers, Michael A. Eberle, Michael A. van Es, Xiao Chen, Leonard H. van den Berg, Brendan J. Kenna, Philippe Corcia, Karen E. Morrison, Marc Gotkine, Russell McLaughin, Peter M. Andersen, Matthieu Moisse, Philip Van Damme, Rick A.A. van der Spek, Jesus S. Mora Pardina, Orla Hardiman, Vivian E. Drory, Jan H. Veldink, Nazli Basak, Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Moisse, Matthieu, Zwamborn, Ramona A. J., van Vugt, Joke, van Der Spek, Rick, van Rheenen, Wouter, Kenna, Brendan, Van Eijk, Kristel, Kenna, Kevin, Corcia, Philippe, Couratier, Philippe, Vourc'h, Patrick, Hardiman, Orla, McLaughin, Russell, Gotkine, Marc, Drory, Vivian, Ticozzi, Nicola, Silani, Vincenzo, de Carvalho, Mamede, Mora Pardina, Jesus S., Povedano, Monica, Andersen, Peter M., Weber, Markus, Chen, Xiao, Eberle, Michael A., Al-Chalabi, Ammar, Shaw, Chris, Shaw, Pamela J., Morrison, Karen E., Landers, John E., Glass, Jonathan D., Robberecht, Wim, van Es, Michael, van den Berg, Leonard, Veldink, Jan, Van Damme, Philip, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Université de Leuven, Katholiek Universiteit Leuven, Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), 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 Neurologie [CHU Limoges], CHU Limoges, UMR U 1253, Department of Neurology, The Adelaide and Meath Hospital, Trinity College Dublin, Trinity College, Trinity College Dublin, Tel Aviv Sourasky Medical Center [Te Aviv], Department of Neurology, IRCCS San Raffaele, Milano, Université de Lisbonne, Sant Rafael Hospital, Umeå University Hospital, Umea University Hospital, Illumina Incorporated [San Diego, CA, USA], Maurice Wohl Clinical Neuroscience Institut, King‘s College London, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield [Sheffield], Queen's University [Belfast] (QUB), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Emory University School of Medicine, Emory University [Atlanta, GA], University Hospitals Leuven [Leuven], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), 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), Grelier, Elisabeth, and 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)
Subjects: 0301 basic medicine, Male, Neurologi, Survival of Motor Neuron 2 Protein/genetics, Clinical Neurology, Gene Dosage, SMN1, Bioinformatics, Logistic regression, Severity of Illness Index, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, medicine, Survival of Motor Neuron 1 Protein/genetics, Humans, Amyotrophic lateral sclerosis, Gene, Research Articles, Whole genome sequencing, Science & Technology, Whole Genome Sequencing, business.industry, Project MinE, Amyotrophic Lateral Sclerosis, Neurosciences, Case-control study, Reproducibility of Results, Survival of motor neuron, Amyotrophic Lateral Sclerosis/genetics, medicine.disease, Survival of Motor Neuron 1 Protein, 3. Good health, nervous system diseases, Survival of Motor Neuron 2 Protein, 030104 developmental biology, Neurology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Medicine, Clinical neurology, Neurosciences & Neurology, Neurology (clinical), business, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Research Article
Abstract: Objective: the role of the survival of motor neuron (SMN) gene in amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. A decisive result on this topic is needed, given that treatment options are available now for SMN deficiency. Methods: in this largest multicenter case control study to evaluate the effect of SMN1 and SMN2 copy numbers in ALS, we used whole genome sequencing data from Project MinE data freeze 2. SMN copy numbers of 6,375 patients with ALS and 2,412 controls were called from whole genome sequencing data, and the reliability of the calls was tested with multiplex ligation-dependent probe amplification data. Results: the copy number distribution of SMN1 and SMN2 between cases and controls did not show any statistical differences (binomial multivariate logistic regression SMN1 p = 0.54 and SMN2 p = 0.49). In addition, the copy number of SMN did not associate with patient survival (Royston-Parmar; SMN1 p = 0.78 and SMN2 p = 0.23) or age at onset (Royston-Parmar; SMN1 p = 0.75 and SMN2 p = 0.63). Interpretation: in our well-powered study, there was no association of SMN1 or SMN2 copy numbers with the risk of ALS or ALS disease severity. This suggests that changing SMN protein levels in the physiological range may not modify ALS disease course. This is an important finding in the light of emerging therapies targeted at SMN deficiencies., European Union (EU); Horizon 2020; European Research Council (ERC); Research and Innovation Programme; EScORIAL; IWT; FWO-Vlaanderen; United Kingdom Medical Research Council; Neurodegenerative Disease Research (JPND); Netherlands; ZONMW; BRAIN-MEND; NIH/NINDS; Italian Ministry of Health; Fondazione Regionale per la Ricerca Biomedica Regione Lombardia; Science Foundation Ireland; ALS Liga Belgie; National Lottery of Belgium; KU Leuven Opening the Future Fund; E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders; ALS Foundation Netherlands; PPP Allowance; Motor Neurone Disease Association; National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre; Fondazione Italiana di Ricerca per la SLA - AriSLA; Exomefals; Novals; ALS Association; E-RARE JTC Project Repetomics
Published: 2021

17. A call to action for new global approaches to cardiovascular disease drug solutions

Author: Carolyn S.P. Lam, Grant R Drummond, Calum A. MacRae, Joseph C. Wu, Gemma A. Figtree, Filippo Crea, David G. Harrison, James L. Januzzi, Barbara Casadei, Rebecca H. Ritchie, Maciej Tomaszewski, Faiez Zannad, Robert M. Califf, Frank Misselwitz, Jane E. Freedman, Bronwyn A. Kingwell, Derek J. Hausenloy, Tetsuji Miura, Keith Broadfoot, Junjie Xiao, Joseph A. Hill, Tomasz J. Guzik, Royal North Shore Hospital (RNSH), The University of Sydney, Clinical Committee, National Heart Foundation of Australia, Radcliffe Department of Medicine [Oxford], University of Oxford, Oxford NIHR Biomedical Research Centre, British Heart Foundation Centre of Research Excellence [Oxford, Royaume-Uni] (Oxford BHF-CRE), Verily Life Sciences Inc, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), La Trobe University [Melbourne], University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), University of Glasgow, Vanderbilt University School of Medicine [Nashville], National University of Singapore (NUS), University of Texas Southwestern Medical Center, Massachusetts General Hospital [Boston], CSL Ltd, National Heart Centre Singapore (NHCS), Duke-National University of Singapore Graduate Medical School, Brigham and Women’s Hospital [Boston, MA], Harvard Medical School [Boston] (HMS), Bayer AG, Pharmaceuticals Division, Sapporo Medical University, Monash Institute of Pharmaceutical Sciences [Parkville] (MIPS), Faculty of Pharmacy and Pharmaceutical Sciences - Monash University [Parkville], Monash university-Monash university, Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], Stanford Cardiovascular Institute, University of Shanghai [Shanghai], 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 ), BOZEC, Erwan, British Heart Foundation Centre of Research Excellence, University of Cambridge, CSL Limited, and Duke-NUS Medical School [Singapore]
Subjects: Drug, Arterial disease, Therapeutic target, media_common.quotation_subject, precision medicine, heart failure, Heart failure, Disease, 030204 cardiovascular system & hematology, Cardiovascular, drug discovery, 03 medical and health sciences, pharmacotherapy, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Physiology (medical), therapeutics, Medicine, Humans, 030212 general & internal medicine, organoids, 030304 developmental biology, media_common, 0303 health sciences, Multi-omics, business.industry, Drug discovery, cardiovascular, Precision medicine, Atherosclerosis, Pharmacotherapy, drug therapy, Call to action, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Organoids, Incentive, Risk analysis (engineering), Pharmaceutical Preparations, Cardiovascular Diseases, Settore MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, cardiovascular system, atherosclerosis, Cardiology and Cardiovascular Medicine, business, Product identification, Biomarkers
Abstract: Whilst we continue to wrestle with the immense challenge of implementing equitable access to established evidence-based treatments, substantial gaps remain in our pharmacotherapy armament for common forms of cardiovascular disease including coronary and peripheral arterial disease, heart failure, hypertension, and arrhythmia. We need to continue to invest in the development of new approaches for the discovery, rigorous assessment, and implementation of new therapies. Currently, the time and cost to progress from lead compound/product identification to the clinic, and the success rate in getting there reduces the incentive for industry to invest, despite the enormous burden of disease and potential size of market. There are tremendous opportunities with improved phenotyping of patients currently batched together in syndromic ‘buckets’. Use of advanced imaging and molecular markers may allow stratification of patients in a manner more aligned to biological mechanisms that can, in turn, be targeted by specific approaches developed using high-throughput molecular technologies. Unbiased ‘omic’ approaches enhance the possibility of discovering completely new mechanisms in such groups. Furthermore, advances in drug discovery platforms, and models to study efficacy and toxicity more relevant to the human disease, are valuable. Re-imagining the relationships among discovery, translation, evaluation, and implementation will help reverse the trend away from investment in the cardiovascular space, establishing innovative platforms and approaches across the full spectrum of therapeutic development.
Published: 2021

18. Editorial: Immunology of Vitiligo

Author: Julien Seneschal, John E. Harris, I. Caroline Le Poole, Thierry Passeron, Reinhart Speeckaert, Katia Boniface, Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-André, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Northwestern University Medical School [Chicago], Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), Ghent University Hospital, Admin, Oskar, Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Immunology, Adaptive immunity, Vitiligo, Translational research, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Immunology and Allergy, Medicine, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Innate immunity, 0303 health sciences, Innate immune system, business.industry, RC581-607, medicine.disease, Acquired immune system, Oxidative stress, 030220 oncology & carcinogenesis, Melanocytes, Immunologic diseases. Allergy, business, Tolerance
Abstract: International audience; No abstract available
Published: 2021

19. Axon-secreted chemokine-like Orion is a signal for astrocyte infiltration during neuronal remodeling

Author: Ana Boulanger, Stephan Züchner, Hugues Lortat-Jacob, Jean-Maurice Dura, Lee G. Fradkin, Camille Thinat, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-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)-Université Grenoble Alpes (UGA), University of Miami, University of Massachusetts Medical School [Worcester] (UMASS), and University of Massachusetts System (UMASS)
Subjects: Nervous system, 0303 health sciences, Chemokine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Cell, Chemotaxis, Biology, medicine.disease, Cell biology, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, nervous system, medicine, biology.protein, Neuron, Axon, Infiltration (medical), 030217 neurology & neurosurgery, 030304 developmental biology, Astrocyte
Abstract: SummaryThe remodeling of neurons is a conserved fundamental mechanism underlying nervous system maturation and function. Glial cells are known to clear neuronal debris but also to have an active role in the remodeling process. Developmental axon pruning ofDrosophilamemory center neurons occurs by a degenerative process mediated by infiltrating astrocytes. However, how these glial processes are recruited by the axons is unknown. In an unbiased screen, we identified a new gene (orion) which is necessary for both the pruning of some axons and removal of the resulting debris. Orion is secreted from the neurons and bears some features common to the chemokines, a family of chemoattractant cytokines. Thus, chemokine involvement in neuron/glial cell interaction is an evolutionarily ancient mechanism. We propose that Orion is the neuronal signal that elicits astrocyte infiltration required for developmental neuronal remodeling.
Published: 2020

20. PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment

Author: KLEINEIDAM, Luca, Chouraki, Vincent, Próchnicki, Tomasz, van der Lee, Sven, Madrid‑Márquez, Laura, Wagner-Thelen, Holger, Karaca, Ilker, WEINHOLD, Leonie, Wolfsgruber, Steffen, Boland, Anne, Martino Adami, Pamela, Lewczuk, Piotr, POPP, Julius, Brosseron, Frederic, Jansen, Iris, HULSMAN, Marc, Kornhuber, Johannes, Peters, Oliver, Berr, Claudine, Heun, Reinhard, Frölich, Lutz, Tzourio, Christophe, Dartigues, Jean-François, Hüll, Michael, Espinosa, Ana, Hernández, Isabel, de Rojas, Itziar, ORELLANA, Adelina, VALERO, Sergi, STRINGA, Najada, Van Schoor, Natasja, Huisman, Martijn, Scheltens, Philip, For The Alzheimer'S Disease Neuroimaging Initiative, (ADNI), Rüther, Eckart, Deleuze, Jean-François, Wiltfang, Jens, Tarraga, Lluis, Schmid, Matthias, Scherer, Martin, Riedel-Heller, Steffi, Heneka, Michael, Amouyel, Philippe, Jessen, Frank, Boada, Merce, Maier, Wolfgang, Schneider, Anja, González‑Pérez, Antonio, van der Flier, Wiesje, Wagner, Michael, Lambert, Jean-Charles, Holstege, Henne, Saez, Mª Eugenia, Latz, Eicke, Ruiz, Agustin, Ramirez, Alfredo, University Hospital Bonn, Universität zu Köln, German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), 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 Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Epidémiologie et de Santé Publique [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Amsterdam UMC, Vrije Universiteit Amsterdam [Amsterdam] (VU), Centro andaluz de estudios bioinformáticos - Andalusian Bioinformatics Research Centre [Sevilla] (CAEBi), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), 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), Universitätsklinikum Erlangen [Erlangen], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), University of Bialystok, Lausanne University Hospital, University hospital of Zurich [Zurich], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Universität Heidelberg [Heidelberg], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Albert-Ludwigs-Universität Freiburg, Universitat Internacional de Catalunya [Barcelona] (UIC), Instituto de Salud Carlos III [Madrid] (ISC), University Medical Center Göttingen (UMG), Universidade de Aveiro, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Universität Leipzig [Leipzig], University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU), Open Access funding provided by Projekt DEAL. This publication was funded in part by the German Federal Ministry of Education and Research (BMBF) (grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434, grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716, 01ET1006B). Analyses were also funded by the German Federal Ministry of Education and Research (BMBF 01EA1410A) within the project 'Diet-Body-Brain: from epidemiology to evidence-based communication'. Part of the work was funded by the JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A). Part of the analysis was funded by the German Research Foundation (DFG) grant: RA 1971/6-1 to Alfredo Ramirez. Research of the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case–control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). Data collection and sharing for this project were funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation, Araclon Biotech, BioClinica, Inc., Biogen, Bristol-Myers Squibb Company, CereSpir, Inc., Cogstate, Eisai Inc., ElanPharmaceuticals, Inc., Eli Lilly and Company, EuroImmun, F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc., Fujirebio, GE Healthcare, IXICO Ltd., Janssen Alzheimer Immunotherapy Research and Development, LLC., Johnson and Johnson Pharmaceutical Research and Development LLC., Lumosity, Lundbeck, Merck and Co., Inc., Meso Scale Diagnostics, LLC., NeuroRx Research, Neurotrack Technologies, Novartis Pharmaceuticals Corporation, Pfizer Inc., Piramal Imaging, Servier, Takeda Pharmaceutical Company, and transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for NeuroImaging at the University of Southern California. The Three-City Study genotyping and analysis was funded by the GENMED Labex, the Joint Programming Initiative on Neurodegenerative Diseases Research (JPND, PERADES project), the Institute Pasteur de Lille, the University of Lille, and the Nord-Pas de Calais Regional Council. This work also benefited from the Lille Métropole Communauté Urbaine Council, the French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to Alzheimer’s disease). In addition, the Three-City Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. Additional funding for the 3C Study was also obtained from the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Fondation de France and the joint French Ministry of Research/INSERM 'Cohortes et collections de données biologiques' programme. Lille Génopôle received an unconditional grant from Eisai. Fundacio ACE cohort receives support from the Innovative Medicines Initiative 2 Joint Undertaking which receives support from the European Union’s Horizon 2020 research and innovation programme (ADAPTED Grant No. 115975). A. Ruiz’s research is also supported by Instituto de Salud Carlos III (ISCIII) grants PI13/02434, PI16/01861, and PI19/01301. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-'Una manera de Hacer Europa'), by Fundación bancaria 'La Caixa' and Grifols SA (GR@ACE project). For the Longitudinal Aging Study Amsterdam (LASA) supports was largely obtained from a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care. The data collection in 2012–2013 was financially supported by the Netherlands Organization for Scientific Research (NWO) in the framework of the project 'New Cohorts of young old in the twenty-first century' (File Number 480-10-014). Genotyping using Axiom-NL array was financially supported by EMGO+ Research Institute. PL was supported by the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no 115372, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution. JW is supported by an Ilídio Pinho professorship and iBiMED (UID/BIM/04501/2013), at the University of Aveiro, Portugal. JP was supported by a grant from the Swiss National Science Foundation (320030L_141179)., Universität zu Köln = University of Cologne, Amsterdam UMC - Amsterdam University Medical Center, Universität Heidelberg [Heidelberg] = Heidelberg University, Universität Leipzig, Alzheimer's Disease Neuroimaging Initiative (ADNI), Kleineidam, L., Karaca, I., Heneka, M.T., Maier, W., Schneider, A., Wagner, M., Chouraki, V., Amouyel, P., Lambert, J.C., Próchnicki, T., Latz, E., van der Lee, S.J., Jansen, I.E., Hulsman, M., Scheltens, P., van der Flier, W.M., Holstege, H., Madrid-Márquez, L., González-Pérez, A., Sáez, M.E., Wagner-Thelen, H., Martino Adami, P.V., Jessen, F., Ramirez, A., Weinhold, L., Schmid, M., Wolfsgruber, S., Brosseron, F., Boland, A., Deleuze, J.F., Lewczuk, P., Kornhuber, J., Popp, J., Peters, O., Berr, C., Heun, R., Frölich, L., Tzourio, C., Dartigues, J.F., Hüll, M., Espinosa, A., Hernández, I., de Rojas, I., Orellana, A., Valero, S., Ruiz, A., Tarraga, L., Boada, M., Stringa, N., van Schoor, N.M., Huisman, M., Rüther, E., Wiltfang, J., Scherer, M., Riedel-Heller, S., Neurology, Human genetics, Epidemiology and Data Science, APH - Aging & Later Life, APH - Societal Participation & Health, Amsterdam Neuroscience - Complex Trait Genetics, APH - Personalized Medicine, APH - Methodology, Sociology, and The Social Context of Aging (SoCA)
Subjects: Apolipoprotein E, Male, pathology [Cognitive Dysfunction], Cognitive decline, genetics [Alzheimer Disease], Disease, SEPIA, pathology [Alzheimer Disease], 0302 clinical medicine, Cognition, genetics [Amyloid beta-Peptides], Medicine, Aged, 80 and over, 0303 health sciences, education.field_of_study, Microglia, physiology [Cognition], Middle Aged, medicine.anatomical_structure, Disease Progression, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], analysis [Biomarkers], Alzheimer’s disease, Amyloid, Phospholipase C gamma 2, Population, tau Proteins, Pathology and Forensic Medicine, PLCG2, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Alzheimer Disease, Humans, Cognitive Dysfunction, ddc:610, education, Mild cognitive impairment, HEALTHY, 030304 developmental biology, Aged, metabolism [Phospholipase C gamma], Original Paper, Amyloid beta-Peptides, TREM2, business.industry, Phospholipase C gamma, genetics [Cognitive Dysfunction], metabolism [tau Proteins], cerebrospinal fluid [tau Proteins], [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Immunology, Neurology (clinical), business, 030217 neurology & neurosurgery, Biomarkers
Abstract: A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer’s disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and Aβ1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.
Published: 2020

21. A RUNX2 stabilization pathway mediates physiologic and pathologic bone formation

Author: Jae-Hyuck Shim, Julia F. Charles, Matthew B. Greenblatt, Yeon Suk Yang, Paul B. Yu, Takeshi Takarada, Xianpeng Ge, Hyunho Chun, Wei Gu, Jung-Min Kim, Minkyung Song, Teresa Dinter, Na Li, Odile Filhol-Cochet, Seoyeon Bok, Kwang Hwan Park, Ning Kon, Ren Xu, Brigitte Boldyreff, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Yonsei University College of Medicine [Séoul, Corée du Sud], Xiamen University, Sungkyunkwan University [Suwon] (SKKU), Korea Advanced Institute of Science and Technology (KAIST), Weill Medical College of Cornell University [New York], Harvard Medical School [Boston] (HMS), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Université Grenoble Alpes (UGA), KinaseDetect ApS [Krusa, Danemark], Columbia University College of Physicians and Surgeons, Okayama University Graduate School of Medicine [Okayama, Japon], This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2014R1A6A3A03055719, J.M.K.). M.B.G. holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund, a Basil O’Connor Award from the March of Dimes and is supported by an NIH Director’s Early Independence Award (1DP5OD021351), and a Pershing Square Sohn Cancer Research Prize for Young Investigators. J.H.S holds support from NIAMS of the NIH under R01AR068983, R21AR072836, and R21AR073331, an UMCCTS pilot project program award., Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Bodescot, Myriam
Subjects: 0301 basic medicine, Male, Cellular differentiation, Regulator, General Physics and Astronomy, Core Binding Factor Alpha 1 Subunit, Haploinsufficiency, Ubiquitin-Specific Peptidase 7, 0302 clinical medicine, Osteogenesis, Phosphorylation, lcsh:Science, Casein Kinase II, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Multidisciplinary, Chemistry, Protein Stability, musculoskeletal, neural, and ocular physiology, Bone development, Osteoblast, Cell Differentiation, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Middle Aged, Cell biology, Hindlimb, RUNX2, medicine.anatomical_structure, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 030220 oncology & carcinogenesis, embryonic structures, Female, Stem cell, Casein kinase 2, Cleidocranial Dysplasia, Deubiquitination, Adult, musculoskeletal diseases, endocrine system, Science, Trauma, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, stomatognathic system, medicine, Animals, Humans, RNA, Messenger, Bone, Aged, Osteoblasts, Ossification, Heterotopic, fungi, General Chemistry, Mice, Inbred C57BL, 030104 developmental biology, [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], lcsh:Q, Gene Deletion
Abstract: The osteoblast differentiation capacity of skeletal stem cells (SSCs) must be tightly regulated, as inadequate bone formation results in low bone mass and skeletal fragility, and over-exuberant osteogenesis results in heterotopic ossification (HO) of soft tissues. RUNX2 is essential for tuning this balance, but the mechanisms of posttranslational control of RUNX2 remain to be fully elucidated. Here, we identify that a CK2/HAUSP pathway is a key regulator of RUNX2 stability, as Casein kinase 2 (CK2) phosphorylates RUNX2, recruiting the deubiquitinase herpesvirus-associated ubiquitin-specific protease (HAUSP), which stabilizes RUNX2 by diverting it away from ubiquitin-dependent proteasomal degradation. This pathway is important for both the commitment of SSCs to osteoprogenitors and their subsequent maturation. This CK2/HAUSP/RUNX2 pathway is also necessary for HO, as its inhibition blocked HO in multiple models. Collectively, active deubiquitination of RUNX2 is required for bone formation and this CK2/HAUSP deubiquitination pathway offers therapeutic opportunities for disorders of inappropriate mineralization., Runx2 is essential for tuning the generation of bone from skeletal stem cells (SSCs). Here, the authors demonstrate that the CK2/HAUSP pathway stabilizes RUNX2 protein thereby regulating the commitment of SSCs to osteoprogenitors as well as their subsequent maturation, and that inhibition of this pathway can block heterotopic ossification.
Published: 2020

22. Molecular and functional characterization of the SBP-box transcription factor SPL-CNR in tomato fruit ripening and cell death

Author: Yiguo Hong, Huizhong Wang, Xinlian Zhang, Pengcheng Zhang, Tongfei Lai, Philippe Gallusci, Yule Liu, Mahmut Tör, Ying Wang, Chunyang Li, Mingfei Jin, Bishun Ye, Mei Gu, Yingying Zhou, Weiwei Chen, Andrew M. Blanks, Xiaohong Wang, Hangzhou Normal University, University of Science and Technology of China [Hefei] (USTC), University of Warwick, The University of Texas M.D. Anderson Cancer Center [Houston], Institute of Refrigeration and Cryogenics, Shanghai Jiao Tong University [Shanghai], Tsinghua University [Beijing] (THU), Ecophysiologie et Génomique Fonctionnelle de la Vigne (UMR EGFV), Université de Bordeaux (UB)-Institut des Sciences de la Vigne et du Vin (ISVV)-Ecole Nationale Supérieure des Sciences Agronomiques de Bordeaux-Aquitaine (Bordeaux Sciences Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Massachusetts Medical School [Worcester] (UMASS), and University of Massachusetts System (UMASS)
Subjects: 0106 biological sciences, 0301 basic medicine, Cell death, Physiology, Mutant, SlSPL-CNR, Plant Science, Biology, 01 natural sciences, 03 medical and health sciences, Solanum lycopersicum, Gene Expression Regulation, Plant, Gene silencing, NLS, Gene, Transcription factor, Plant Proteins, Zinc finger, AcademicSubjects/SCI01210, tomato (Solanum lycopersicum) fruit ripening, food and beverages, Ripening, Ethylenes, Colourless non-ripening, nuclear localization signal, Research Papers, Cell biology, 030104 developmental biology, Fruit, [SDE]Environmental Sciences, cardiovascular system, Growth and Development, SlSnRK1, zinc-finger motif, Nuclear localization sequence, Transcription Factors, 010606 plant biology & botany, circulatory and respiratory physiology
Abstract: SlSPL-CNR, an SBP-box transcription factor (TF) gene residing at the epimutant Colourless non-ripening (Cnr) locus, is involved in tomato ripening. This epimutant provides a unique model to investigate the (epi)genetic basis of fruit ripening. Here we report that SlSPL-CNR is a nucleus-localized protein with a distinct monopartite nuclear localization signal (NLS). It consists of four consecutive residues ‘ 30KRKR33’ at the N-terminus of the protein. Mutation of the NLS abolishes SlSPL-CNR’s ability to localize in the nucleus. SlSPL-CNR comprises two zinc-finger motifs (ZFMs) within the C-terminal SBP-box domain. Both ZFMs contribute to zinc-binding activity. SlSPL-CNR can induce cell death in tomato and tobacco, dependent on its nuclear localization. However, the two ZFMs have differential impacts on SlSPL-CNR’s induction of severe necrosis or mild necrotic ringspot. NLS and ZFM mutants cannot complement Cnr fruits to ripen. SlSPL-CNR interacts with SlSnRK1. Virus-induced SlSnRK1 silencing leads to reduction in expression of ripening-related genes and inhibits ripening in tomato. We conclude that SlSPL-CNR is a multifunctional protein that consists of a distinct monopartite NLS, binds to zinc, and interacts with SlSnRK1 to affect cell death and tomato fruit ripening., The tomato transcription factor SlSPL-CNR is a multi-functional protein that has a role in fruit ripening and is capable of triggering cell death.
Published: 2020

23. Genetic Susceptibility, Diet Quality, and Two-Step Progression in Drusen Size

Author: Johanna M. Seddon, Bénédicte M. J. Merle, Bernard Rosner, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Harvard Medical School [Boston] (HMS), University of Massachusetts Medical School [Worcester] (UMASS), and University of Massachusetts System (UMASS)
Subjects: 0301 basic medicine, Male, Vascular Endothelial Growth Factor A, Mediterranean diet, Physiology, AMD, Diet, Mediterranean, LEHA, Macular Degeneration, 0302 clinical medicine, Photography, genetics, HSP110 Heat-Shock Proteins, 2. Zero hunger, Aged, 80 and over, Hazard ratio, Nuclear Proteins, Complement C3, High-Temperature Requirement A Serine Peptidase 1, Middle Aged, 3. Good health, nutrition, drusen progression, Complement Factor H, Disease Progression, Female, Retinal Drusen, Drusen, Biology, Lower risk, Retina, 03 medical and health sciences, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Alleles, Aged, Tissue Inhibitor of Metalloproteinase-3, Proportional hazards model, Proteins, mediterranean diet, Stepwise regression, medicine.disease, Confidence interval, eye diseases, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030221 ophthalmology & optometry, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, sense organs, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Follow-Up Studies
Abstract: International audience; Purpose: To investigate the relationship of growth in drusen size with genetic susceptibility and adherence to the alternate Mediterranean diet.Methods: Participants in this analysis had complete ocular, genetic, and dietary data with mean follow-up time of 10.2 years in the Age-Related Eye Disease database. Maximal drusen size was graded on an ordinal scale and two-step progression was determined. A genetic risk score using variants associated with advanced AMD and derived from a stepwise regression model yielded 11 variants in 8 genes. Adherence to the alternate Mediterranean diet was assessed using a nine-component score based on intake of vegetables, fruits, legumes, whole cereals, fish, meat, nuts, alcohol, and monounsaturated-to-saturated fatty acids ratio. Multivariate Cox proportional hazards models were used.Results: Among 3023 eligible eyes, 19% had drusen growth. In the stepwise selection, common and rare risk alleles for CFH Y402H, CFH rs1410996, CFH R1210C, C3 R102G, C3 K155Q, and ARMS2/HTRA1, as well as VEGF-A, TIMP3, NPLOC4, and HSPH1 variants were significantly associated with 2-step progression in drusen size, and the C2 E318D protective allele conferred decreased risk, adjusting for other covariates. A higher genetic risk score conferred a higher risk (hazard ratio per 1-unit increase, 2.68; 95% confidence interval, 2.23–3.23; P < 0.001), and a medium/high adherence to alternate Mediterranean diet score (4–9) tended to lower risk (hazard ratio, 0.83; 95% confidence interval, 0.68–0.99; P = 0.049), adjusting for all covariates.Conclusions: Genetic susceptibility was independently related to drusen growth. A Mediterranean-style diet with healthful nutrient-rich foods (fruits, vegetables, legumes and fish), may reduce enlargement of drusen, the hallmark of AMD.
Published: 2020

24. HTT is a repressor of ABL activity required for APP induced axonal growth

Author: Lee G. Fradkin, Jean-Maurice Dura, Brittany S. Leger, Ana Boulanger, Germain U. Busto, Claire Marquilly, James A. Walker, Edward Giniger, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), St James University Hospital, Massachusetts General Hospital [Boston], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), and ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010)
Subjects: Huntingtin, Mutant, Axonal Transport, 0302 clinical medicine, Animal Cells, Fluorescence Resonance Energy Transfer, Amyloid precursor protein, Axon, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Neurons, Huntingtin Protein, 0303 health sciences, ABL, Effector, Drosophila Melanogaster, Eukaryota, Polyglutamine tract, 3. Good health, Cell biology, Phenotypes, Huntington Disease, Spectrophotometry, Hyperexpression Techniques, Cellular Types, HTT, Embryonic Development, Repressor, 03 medical and health sciences, Alzheimer Disease, Memory, Genetics, Humans, Molecular Biology Techniques, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Mushroom Bodies, Molecular Biology Assays and Analysis Techniques, fungi, Organisms, Biology and Life Sciences, Invertebrates, nervous system, Mutation, Nerve Degeneration, Animal Studies, FRET, Acyltransferases, 030217 neurology & neurosurgery, Appl signaling, Neuroscience, Cloning, Developmental Biology, Cancer Research, Life Cycles, [SDV]Life Sciences [q-bio], QH426-470, Fluorophotometry, axonal growth, Amyloid beta-Protein Precursor, Nerve Fibers, Spectrum Analysis Techniques, Larvae, hemic and lymphatic diseases, Drosophila Proteins, Genetics (clinical), biology, Chemistry, Animal Models, Insects, medicine.anatomical_structure, Experimental Organism Systems, Mushroom bodies, Drosophila, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Drosophila melanogaster, Signal transduction, Signal Transduction, Research Article, congenital, hereditary, and neonatal diseases and abnormalities, animal structures, Arthropoda, Research and Analysis Methods, Model Organisms, mental disorders, Gene Expression and Vector Techniques, medicine, Animals, Learning, Kinase activity, 030304 developmental biology, Cell Biology, biology.organism_classification, mushroom body, Axons, Cellular Neuroscience, biology.protein, Zoology, Entomology
Abstract: Huntington’s disease is a progressive autosomal dominant neurodegenerative disorder caused by the expansion of a polyglutamine tract at the N-terminus of a large cytoplasmic protein. The Drosophila huntingtin (htt) gene is widely expressed during all developmental stages from embryos to adults. However, Drosophila htt mutant individuals are viable with no obvious developmental defects. We asked if such defects could be detected in htt mutants in a background that had been genetically sensitized to reveal cryptic developmental functions. Amyloid precursor protein (APP) is linked to Alzheimer’s disease. Appl is the Drosophila APP ortholog and Appl signaling modulates axon outgrowth in the mushroom bodies (MBs), the learning and memory center in the fly, in part by recruiting Abl tyrosine kinase. Here, we find that htt mutations suppress axon outgrowth defects of αβ neurons in Appl mutant MB by derepressing the activity of Abl. We show that Abl is required in MB αβ neurons for their axon outgrowth. Importantly, both Abl overexpression and lack of expression produce similar phenotypes in the MBs, indicating the necessity of tightly regulating Abl activity. We find that Htt behaves genetically as a repressor of Abl activity, and consistent with this, in vivo FRET-based measurements reveal a significant increase in Abl kinase activity in the MBs when Htt levels are reduced. Thus, Appl and Htt have essential but opposing roles in MB development, promoting and suppressing Abl kinase activity, respectively, to maintain the appropriate intermediate level necessary for axon growth., Author summary Understanding the normal physiological roles of proteins involved in neurodegenerative diseases can provide significant insight into disease mechanisms. Drosophila offers a powerful system in which to ask these fundamental questions. Both Htt, related to Huntington’s disease, and Appl, related to Alzheimer’s disease, have well-conserved single orthologs in the fly genome. Appl has been shown to be a conserved modulator of a Wnt-PCP signaling pathway required for axon outgrowth in the mushroom body (MB) in the Drosophila brain. However, roles for Htt in fly brain development have not been reported. Unexpectedly, we found that htt mutations suppress the axon outgrowth defects of Appl mutants in the MB, indicating a link between these two neurodegenerative proteins and a cryptic role of Htt during development. Abl tyrosine kinase is a downstream effector of the Appl receptor, and we show here that Abl is also required for MB axon outgrowth. Importantly, Abl activity must be tightly regulated as evidenced by our observations that both under and overexpression of Abl result in similar axonal defects. We demonstrate that Htt is an inhibitor of Abl activity and provide evidence that the phenotypic rescue of αβ axons in Appl mutants by reducing htt is mediated by the restoration of proper levels of Abl signaling. These data, therefore, suggest that Appl and Htt act antagonistically to maintain an optimal balance of activation and inhibition of Abl, and thereby promote the growth of MB αβ axons.
Published: 2019

25. Tethering of vesicles to the Golgi by GMAP210 controls LAT delivery to the immune synapse

Author: Mathieu Maurin, Gregory J. Pazour, Rosa M. Ríos, Andrés Ernesto Zucchetti, Mabel San Roman-Jouve, Michael W. Stuck, Jean-Marie Carpier, Claire Hivroz, Stéphanie Dogniaux, Laurence Bataille, Cosima T. Baldari, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Immunobiology [New Haven, CT, USA] (Yale School of Medicine), Yale University [New Haven], Program in Molecular Medicine [Worcester, MA, USA], University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS)-University of Massachusetts System (UMASS), Cell Dynamics and Signaling Department [Seville, Spain] (CABIMER-CSIC/US/UPO), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Department of Life Sciences [Siena, Italy], Università degli Studi di Siena = University of Siena (UNISI), P. Le Baccon from PICT-IBiSA@Pasteur microscopy facility (Institut Curie, Paris), the PICT-IBiSA, member of the France-BioImaging National Research infrastructure, supported by French National Research Agency through the Investments for the Future program (France-BioImaging, ANR-10-INSB-04) and the CelTisPhyBio Labex (No. ANR-10-LBX-0038) part of the IDEX PSL (No. ANR-10-IDEX-0001-02 PSL), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), Agence Nationale de la Recherche (France), Institut Curie, Centre National de la Recherche Scientifique (France), Association de la Recherche Contre le Cancer (France), Fondazione Telethon, Institut National de la Santé et de la Recherche Médicale (France), Fondation pour la Recherche Médicale, Hivroz, Claire, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, and Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID
Subjects: Male, 0301 basic medicine, T-Lymphocytes, viruses, [SDV]Life Sciences [q-bio], Golgi Apparatus, General Physics and Astronomy, Membrane trafficking, 02 engineering and technology, Immunological synapse, R-SNARE Proteins, lcsh:Science, skin and connective tissue diseases, Multidisciplinary, Chemistry, Tethering, Cilium, Vesicle, Nuclear Proteins, 021001 nanoscience & nanotechnology, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], Vesicular transport protein, medicine.anatomical_structure, symbols, Imaging the immune system, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, SNARE Proteins, 0210 nano-technology, Signal Transduction, [SDV.IMM] Life Sciences [q-bio]/Immunology, Science, T cell, T cells, chemical and pharmacologic phenomena, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, symbols.namesake, medicine, Humans, Transport Vesicles, Lymphocyte activation, Adaptor Proteins, Signal Transducing, Membrane Proteins, General Chemistry, Golgi apparatus, biochemical phenomena, metabolism, and nutrition, Cytoskeletal Proteins, 030104 developmental biology, Gene Expression Regulation, Leukocytes, Mononuclear, lcsh:Q, Ectopic expression, sense organs
Abstract: The T cell immune synapse is a site of intense vesicular trafficking. Here we show that the golgin GMAP210, known to capture vesicles and organize membrane traffic at the Golgi, is involved in the vesicular transport of LAT to the immune synapse. Upon activation, more GMAP210 interact with LAT-containing vesicles and go together with LAT to the immune synapse. Regulating LAT recruitment and LAT-dependent signaling, GMAP210 controls T cell activation. Using a rerouting and capture assay, we show that GMAP210 captures VAMP7-decorated vesicles. Overexpressing different domains of GMAP210, we also show that GMAP210 allows their specific delivery to the immune synapse by tethering LAT-vesicles to the Golgi. Finally, in a model of ectopic expression of LAT in ciliated cells, we show that GMAP210 tethering activity controls the delivery of LAT to the cilium. Hence, our results reveal a function for the golgin GMAP210 conveying specific vesicles to the immune synapse., P. Le Baccon from PICT-IBiSA@Pasteur microscopy facility (Institut Curie, Paris), the PICT-IBiSA, member of the France-BioImaging National Research infrastructure, supported by French National Research Agency through the Investments for the Future program (France-BioImaging, ANR-10-INSB-04) and the CelTisPhyBio Labex (No. ANR-10-LBX-0038) part of the IDEX PSL (No. ANR-10-IDEX-0001-02 PSL), L. Sengmanivong and all the staff from the Nikon Imaging Center (Institut Curie-CNRS, Paris), Damarys Loew, Florent Dingli et Guillaume Arras from the Institut Curie Mass Spectrometry, and Proteomics facility (LSMP), S. Moutel from Antibody platform (Institut Curie, Paris), B. Malissen, and R. Roncagalli (CIML, Marseille, France) for giving us the LAT-TST constructs. Alexandre Benmerah (INSERM UMR-1163, Laboratory of Inherited Kidney Diseases, Institut Imagine, Paris, France) for discussion and protocols, Ana-Maria Lennon-Duménil and Michel Bornens (Institut Curie, Paris) for critical reading of our manuscript. Bertsy GOIC for the graphic design and scientific discussions. A.E.Z. received a grant from l’Association pour la Recherche contre le Cancer (ARC), J.- M.C. received grants from La Ligue Nationale Contre le Cancer and Fondation pour la Recherche Médicale. C.T.B. received a grant from Fondazione Telethon—Italy (Grant GGP1102). Work was supported by funds from Institut Curie, INSERM, ANR (ANR-13- BSV2-0018 NeuroImmunoSynapse, ANR-10-IDEX-0001-02 PSL* and ANR-11-LABX0043), the Fondation pour la Recherche Médicale (FRM, FRM DEQ20140329513”).
Published: 2019

26. α1AMPK deletion in myelomonocytic cells induces a pro-inflammatory phenotype and enhances angiotensin II-induced vascular dysfunction

Author: Marc Foretz, Moritz Brandt, Eberhard Schulz, Philip Wenzel, Matthias Oelze, John F. Keaney, Swenja Kröller-Schön, Thomas Münzel, Benoit Viollet, Thomas Jansen, Andreas Daiber, Sebastian Steven, Jeremy Lagrange, Miroslava Kvandova, Sanela Kalinovic, Tanja Schönfelder, Johannes Gutenberg - Universität Mainz (JGU), 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), Université Paris Descartes - Paris 5 (UPD5), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), and Johannes Gutenberg - University of Mainz (JGU)
Subjects: MESH: Signal Transduction, 0301 basic medicine, CCR2, Physiology, medicine.medical_treatment, MESH: Aortic Diseases, AMP-Activated Protein Kinases, 030204 cardiovascular system & hematology, MESH: Mice, Knockout, 0302 clinical medicine, MESH: Animals, MESH: AMP-Activated Protein Kinases, Aorta, Cells, Cultured, Mice, Knockout, MESH: Cytokines, MESH: Oxidative Stress, biology, Chemistry, Angiotensin II, MESH: Genetic Predisposition to Disease, MESH: Aorta, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Respiratory burst, Vasodilation, Phenotype, Cytokine, Cytokines, Tumor necrosis factor alpha, MESH: Angiotensin II, Inflammation Mediators, medicine.symptom, Cardiology and Cardiovascular Medicine, Signal Transduction, MESH: Cells, Cultured, MESH: Inflammation Mediators, Aortic Diseases, Inflammation, MESH: Phenotype, MESH: Vasodilation, 03 medical and health sciences, Immune system, MESH: Mice, Inbred C57BL, Physiology (medical), medicine, Animals, Genetic Predisposition to Disease, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Interleukin 6, Macrophages, MESH: Macrophages, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Mice, Inbred C57BL, Disease Models, Animal, Oxidative Stress, 030104 developmental biology, MESH: Gene Deletion, Cancer research, biology.protein, MESH: Disease Models, Animal, Gene Deletion
Abstract: Aims Immune cell function involves energy-dependent processes including growth, proliferation, and cytokine production. Since the AMP-activated protein kinase (AMPK) is a crucial regulator of intracellular energy homeostasis, its expression and activity may also affect innate and adaptive immune cell responses. Therefore, we aimed to investigate the consequences of α1AMPK deletion in myelomonocytic cells on vascular function, inflammation, and hypertension during chronic angiotensin II (ATII) treatment. Methods and results We generated a mouse strain with α1AMPK deletion in lysozyme M+ myelomonocytic cells. Compared to controls, chronic ATII infusion (1 mg/kg/day for 7 days) lead to increased vascular oxidative stress and aggravated endothelial dysfunction in LysM-Cre+ x α1AMPKfl/fl mice. This was accompanied by an increased aortic infiltration of CD11b+F4/80+ macrophages and enhanced pro-inflammatory cytokine release (tumour necrosis factor-alpha, interferon-gamma, and interleukin-6). Mechanistically, we found that increased expression of C-C chemokine receptor 2 (CCR2) in α1AMPK deficient myelomonocytic cells facilitated their recruitment to the vascular wall. In addition, expression of the ATII receptor type 1a and the oxidative burst was increased in these cells, indicating an increased susceptibility towards pro-oxidant stimuli. Conclusions In summary, α1AMPK deletion in myelomonocytic cells aggravates vascular oxidative stress and dysfunction by enhancing their recruitment to the vascular wall and increasing their susceptibility towards pro-oxidant stimuli. Our observations suggest that metabolic control in myelomonocytic cells has profound implications for their inflammatory phenotype and may trigger the development of vascular disease.
Published: 2018

27. The wide utility of rabbits as models of human diseases

Author: Xiang-Peng Kong, Jacques Le Pendu, Selvakumar Subbian, Dennis K. Lanning, Ana M. Lopes, Natalie Ruvoën-Clouet, Katherine L. Knight, Joana Abrantes, Javier González-Gallego, Xuwen Peng, Lbachir BenMohamed, Ana Acacia S. Pinheiro, Michael Vaine, Lorenzo Giacani, Rose G. Mage, Neil D. Christensen, Wessel van der Loo, Shuying Liu, Pedro J. Esteves, María J. Tuñón, Fabiana Neves, Masmudur M. Rahman, Yuxing Chen, Hanna Mari Baldauf, Ana Lemos de Matos, Ruimin Pan, Jia Liu, Laura E. Via, Patrícia de Sousa-Pereira, Jiafen Hu, Shixia Wang, Oliver T. Keppler, Grant McFadden, Shan Lu, Sheila A. Lukehart, Gilla Kaplan, Yukari C. Manabe, CIBIO, InBIO, Research Network in Biodiversity and Evolutionary Biology, Universidade do Porto, Departamento de Biologia, Faculdade de Ciências da Universidade do Porto, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde - CESPU [Gandra, Portugal], Max von Pettenkofer Institute and Gene Center, Ludwig-Maximilians-Universität München (LMU), Laboratory of Cellular and Molecular Immunology, University of California [Irvine] (UCI), University of California-University of California, Department of Molecular Biology and Biochemistry, Institute for Immunology, Department of Medicine, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS)-University of Massachusetts System (UMASS), Departments of Pathology, Microbiology and Immunology, and Comparative Medicine, Pennsylvania State University (Penn State), Penn State System-Penn State System, Institute of Biomedicine (IBIOMED) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of Léon, Departments of Medicine and Global Health, University of Washington [Seattle], Bill & Melinda Gates Foundation [Seattle], Department of Microbiology and Immunology, Loyola University [Chicago], Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, NYU System (NYU)-NYU System (NYU), Host-Pathogen Interactions in the Regulation of Immune Responses (CRCINA-ÉQUIPE 5), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), 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)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-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)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), The Biodesign Institute, Center for Immunotherapy, Vaccines, and Virotherapy, Arizona State University [Tempe] (ASU), University of Arkansas for Medical Sciences (UAMS), Department of Anatomy and Unit for Multidisciplinary Research in Biomedicine (UMIB), Universidade do Porto-Institute of Biomedical Sciences Abel Salazar - ICBAS [Porto, Portugal], Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine [Baltimore], Public Health Research Institute [Newark] (PHRI), Tubercolosis Research Section, Laboratory of Clinical Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases - NIH (National Institutes of Health), Institute of Infectious Disease and Molecular Medicine, Department of Clinical Laboratory Sciences, University of Cape Town, Laboratory of Immune System Biology, Universidade do Porto = University of Porto, University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Universidade do Porto = University of Porto-Institute of Biomedical Sciences Abel Salazar - ICBAS [Porto, Portugal], and Bernardo, Elizabeth
Subjects: 0301 basic medicine, medicine.drug_class, Clinical Biochemistry, lcsh:Medicine, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review Article, Disease, Monoclonal antibody, Biochemistry, Virus, Ocular herpes, lcsh:Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Rabies vaccine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Immunity, medicine, biology.domesticated_animal, lcsh:QD415-436, Molecular Biology, Myxomatosis, biology, lcsh:R, medicine.disease, Virology, 3. Good health, 030104 developmental biology, Molecular Medicine, European rabbit, 030215 immunology, medicine.drug
Abstract: Studies using the European rabbit Oryctolagus cuniculus contributed to elucidating numerous fundamental aspects of antibody structure and diversification mechanisms and continue to be valuable for the development and testing of therapeutic humanized polyclonal and monoclonal antibodies. Additionally, during the last two decades, the use of the European rabbit as an animal model has been increasingly extended to many human diseases. This review documents the continuing wide utility of the rabbit as a reliable disease model for development of therapeutics and vaccines and studies of the cellular and molecular mechanisms underlying many human diseases. Examples include syphilis, tuberculosis, HIV-AIDS, acute hepatic failure and diseases caused by noroviruses, ocular herpes, and papillomaviruses. The use of rabbits for vaccine development studies, which began with Louis Pasteur’s rabies vaccine in 1881, continues today with targets that include the potentially blinding HSV-1 virus infection and HIV-AIDS. Additionally, two highly fatal viral diseases, rabbit hemorrhagic disease and myxomatosis, affect the European rabbit and provide unique models to understand co-evolution between a vertebrate host and viral pathogens., Infectious disease: A leap forward for disease models Rabbits offer a powerful complement to rodents as a model for studying human immunology, disease pathology, and responses to infectious disease. A review from Pedro Esteves at the University of Porto, Portugal, Rose Mage of the National Institute of Allergy and Infectious Disease, Bethesda, USA and colleagues highlights some of the areas of research where rabbits offer an edge over rats and mice. Rabbits have a particularly sophisticated adaptive immune system, which could provide useful insights into human biology and produce valuable research and clinical reagents. They are also excellent models for studying - infectious diseases such as syphilis and tuberculosis, which produce pathology that closely resembles that of human patients. Rabbit-specific infections such as myxomatosis are giving researchers insights into how pathogens and hosts can shape each other’s evolution.
Published: 2018

28. Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes

Author: Michael T. Heneka, Susanne Schmidt, Luc Bousset, Lena Wischhof, Alexandru Odainic, Daniele Bano, Stephanie Schwartz, Cira Dansokho, Jasper Spitzer, Ronald Melki, Hannah Scheiblich, Angelika Griep, Dilek Mercan, Eicke Latz, Frederik Eikens, Universität Bonn = University of Bonn, Dendrite Differenciation Group [DZNE - Bonn], German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Institute of Innate Immunity, Bonn, Centre National de la Recherche Scientifique (CNRS), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-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), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), European Project: 821522,PD-MitoQUANT - H2020-EU.3.1.7. - Innovative Medicines Initiative 2 (IMI2), European Project: (grant No 116060),IMPRiND, University of Bonn, and Université Paris-Saclay-Institut de Biologie François JACOB (JACOB)
Subjects: Male, metabolism [Cytoskeleton], alpha-synuclein, animal diseases, metabolism [Leucine-Rich Repeat Serine-Threonine Protein Kinase-2], genetics [Transcriptome], microglia, Apoptosis, metabolism [Microglia], environment and public health, tunneling nanotubes, chemistry.chemical_compound, 0302 clinical medicine, metabolism [Reactive Oxygen Species], heterocyclic compounds, metabolism [alpha-Synuclein], Cytoskeleton, degradation, Aged, 80 and over, 0303 health sciences, Nanotubes, Microglia, Pattern recognition receptor, pathology [Microglia], LRRK2, metabolism [Cell Membrane Structures], Mitochondria, 3. Good health, Cell biology, ultrastructure [Microglia], medicine.anatomical_structure, alpha-Synuclein, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Intracellular, Cell signaling, metabolism [Actins], Down-Regulation, clearance, Biology, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Fibril, Cell Membrane Structures, General Biochemistry, Genetics and Molecular Biology, genetics [Inflammation], Protein Aggregates, 03 medical and health sciences, Immune system, medicine, Animals, Humans, ddc:610, Aged, pathology [Inflammation], 030304 developmental biology, Inflammation, Synucleinopathies, Alpha-synuclein, synucleinopathies, metabolism [Mitochondria], Actins, nervous system diseases, Mice, Inbred C57BL, nervous system, chemistry, Proteolysis, Reactive Oxygen Species, Transcriptome, 030217 neurology & neurosurgery, cell-to-cell transfer
Abstract: International audience; Microglia are the CNS resident immune cells that react to misfolded proteins through pattern recognition receptor ligation and activation of inflammatory pathways. Here, we studied how microglia handle and cope with $\alpha$-synuclein ($\alpha$-syn) fibrils and their clearance. We found that microglia exposed to $\alpha$-syn establish a cellular network through the formation of F-actin-dependent intercellular connections, which transfer $\alpha$-syn from overloaded microglia to neighboring naive microglia where the $\alpha$-syn cargo got rapidly and effectively degraded. Lowering the $\alpha$-syn burden attenuated the inflammatory profile of microglia and improved their survival. This degradation strategy was compromised in cells carrying the LRRK2 G2019S mutation. We confirmed the intercellular transfer of $\alpha$-syn assemblies in microglia using organotypic slice cultures, 2-photon microscopy, and neuropathology of patients. Together, these data identify a mechanism by which microglia create an ''on-demand'' functional network in order to improve pathogenic $\alpha$-syn clearance.
Published: 2021

29. Development and Validation of a Nomogram for Early Detection of Malignant Gallbladder Lesions

Author: Arie Ariche, Sherry X Yang, Xiujun Cai, Fabrizio Panaro, Leandro Cardoso Barchi, Mingyu Chen, Keita Kai, Tanios Bekaii-Saab, Jian Lin, Jiasheng Cao, Yang Bai, Silvio Nadalin, Vishal Jindal, Antonio Pesce, Riccardo Memeo, Chenhao Tong, Institute of Computing Technology [Beijing] (ICT), Chinese Academy of Sciences [Changchun Branch] (CAS), Zhejiang University, Zhejiang Hospital [Hangzhou], University of Oulu, Woods Hole Oceanographic Institution (WHOI), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Universidade de São Paulo = University of São Paulo (USP), Internal Medicine [Tuebingen, Germany], Tuebingen University [Germany], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), University of Catania [Italy], Service Médico-Chirurgical des Maladies de l'Appareil Digestif et de Transplantation Hépatique, Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hadassah Hebrew University Medical Center [Jerusalem], Saga University [Japon], L'Institut hospitalo-universitaire de Strasbourg (IHU Strasbourg), Institut National de Recherche en Informatique et en Automatique (Inria)-l'Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD)-Les Hôpitaux Universitaires de Strasbourg (HUS)-La Fédération des Crédits Mutuels Centre Est (FCMCE)-L'Association pour la Recherche contre le Cancer (ARC)-La société Karl STORZ, and Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA)
Subjects: Adult, Male, medicine.medical_specialty, Multivariate analysis, genetic structures, CA-19-9 Antigen, Gallbladder masses, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gallbladder cancer (GBC), Logistic regression, Cystectomy, Article, 03 medical and health sciences, Young Adult, 0302 clinical medicine, medicine, Humans, Gallbladder cancer, Early Detection of Cancer, Aged, Retrospective Studies, Aged, 80 and over, business.industry, Gallbladder, Biliary, Gastroenterology, IGBC identification, Cancer, Nomogram, Middle Aged, medicine.disease, Nomograms, medicine.anatomical_structure, ROC Curve, 030220 oncology & carcinogenesis, Radiological weapon, Cohort, Multivariate Analysis, Preoperative Period, 030211 gastroenterology & hepatology, Female, Gallbladder Neoplasms, Radiology, business, Tomography, X-Ray Computed
Abstract: International audience; OBJECTIVES:Preoperative decision-making for differentiating malignant from benign lesions in the gallbladder remains challenging. We aimed to create a diagnostic nomogram to identify gallbladder cancer (GBC), especially for incidental GBC (IGBC), before surgical resection.METHODS:A total of 587 consecutive patients with pathologically confirmed gallbladder lesions from a hospital were randomly assigned to a training cohort (70%) and an internal validation cohort (30%), with 287 patients from other centers as an external validation cohort. Radiological features were developed by the least absolute shrinkage and selection operator logistic regression model. Significant radiological features and independent clinical factors, identified by multivariate analyses, were used to construct a nomogram.RESULTS:A diagnostic nomogram was established by age, CA19.9, and 6 radiological features. The values of area under the curve in the internal and external validation cohorts were up to 0.91 and 0.89, respectively. The calibration curves for probability of GBC showed optimal agreement between nomogram prediction and actual observation. Compared with previous methods, it demonstrated superior sensitivity (91.5%) and accuracy (85.1%) in the diagnosis of GBC. The accuracy using the nomogram was significantly higher in GBC groups compared with that by radiologists in the training cohort (P < 0.001) and similarly in each cohort. Notably, most of the IGBC, which were misdiagnosed as benign lesions, were successfully identified using this nomogram.DISCUSSION:A novel nomogram provides a powerful tool for detecting the presence of cancer in gallbladder masses, with an increase in accuracy and sensitivity. It demonstrates an unprecedented potential for IGBC identification.
Published: 2019

30. Tools for FAIR Neuroimaging Experiment Metadata Annotation with NIDM Experiment

Author: David Keator, Karl Helmer, Camille Maumet, Smruti Padhy, Dorota Jarecka, David Kennedy, Satrajit Ghosh, Jean-Baptiste Poline, University of California [Irvine] (UC Irvine), University of California (UC), Massachusetts General Hospital [Boston], Neuroimagerie: méthodes et applications (Empenn), Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Massachusetts Institute of Technology (MIT), Child and Adolescent NeuroDevelopment Initiative (CANDI), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS)-University of Massachusetts System (UMASS)-Division of Neuroinformatics, McGill University = Université McGill [Montréal, Canada], University of California [Irvine] (UCI), University of California, Empenn, Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Maumet, Camille
Subjects: [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2019

31. Performance Assessment of Linearized OPF-based Distributed Real-time Predictive Control

Author: Rahul Guptal, Mario Paolone, Fabrizio Sossan, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS)-University of Massachusetts System (UMASS), Centre Procédés, Énergies Renouvelables, Systèmes Énergétiques (PERSEE), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), and Ecole Polytechnique Fédérale de Lausanne (EPFL)
Subjects: Distributed control, sensitivity coefficients, 0209 industrial biotechnology, linear optimal power flow, Linear programming, energy storage, Computer science, 020209 energy, [SPI.NRJ]Engineering Sciences [physics]/Electric power, linear programming, 02 engineering and technology, Grid, photovoltaic (PV), photovoltaic, Tracking error, Model predictive control, 020901 industrial engineering & automation, Control theory, Convergence (routing), 0202 electrical engineering, electronic engineering, information engineering, Benchmark (computing), Grid connection, optimal power flow, Sensitivity (control systems)
Abstract: International audience; We consider the problem of controlling heterogeneous controllable resources of a distribution network with the objective of achieving a certain power flow at the grid connection point while respecting local grid constraints. The problem is formulated as a model predictive control (MPC), where a linearized grid model, to retain convexity, based on sensitivity coefficients (SCs) is used to model the grid constraints. We consider and compare the modelling performance of three different update policies for the SCs: when they are updated once per day considering static injections, updated once per day considering point prediction of the nodal injections, and recursively estimated using on-line measurements. Simulations are performed considering the CIGRÉCIGR´CIGRÉ low voltage benchmark network. Performance is evaluated in terms of convergence speed, tracking error, and constraints modeling errors. Further, we perform a sensitivity analysis on the dominant model w.r.t. the length of the predictive horizon and number of controllable units.
Published: 2019

32. Endothelial α1AMPK modulates angiotensin II-mediated vascular inflammation and dysfunction

Author: Andreas Daiber, Marc Foretz, Matthias Oelze, Sabine Kossmann, Philip Wenzel, Thomas Münzel, Jeremy Lagrange, Katie Frenis, John F. Keaney, Eberhard Schulz, Thi Lan P. Tran, Thomas Jansen, Benoit Viollet, Swenja Kröller-Schön, Miroslawa Kvandová, Sanela Kalinovic, Johannes Gutenberg - Universität Mainz (JGU), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), 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), Université Paris Descartes - Paris 5 (UPD5), and Johannes Gutenberg - University of Mainz (JGU)
Subjects: Male, 0301 basic medicine, MESH: Inflammation, Physiology, AMP-Activated Protein Kinases, 030204 cardiovascular system & hematology, medicine.disease_cause, MESH: Mice, Knockout, Antioxidants, Mice, 0302 clinical medicine, MESH: Animals, Endothelial dysfunction, MESH: AMP-Activated Protein Kinases, Vascular inflammation, Mice, Knockout, NADPH oxidase, MESH: Oxidative Stress, biology, MESH: Heme Oxygenase-1, Chemistry, Angiotensin II, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, α1AMPK, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Integrin alpha M, Knockout mouse, MESH: Angiotensin II, MESH: Membrane Proteins, MESH: Endothelium, Vascular, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, 03 medical and health sciences, Downregulation and upregulation, MESH: Mice, Inbred C57BL, Physiology (medical), Internal medicine, medicine, Animals, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Mice, Inflammation, Macrophages, MESH: Antioxidants, Membrane Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH: Male, Mice, Inbred C57BL, Heme oxygenase, Oxidative Stress, 030104 developmental biology, Endocrinology, biology.protein, Endothelium, Vascular, Reactive oxygen species, Heme Oxygenase-1, Oxidative stress
Abstract: International audience; Mice with a global deletion of α1AMPK are characterized by endothelial dysfunction and NADPH oxidase subunit 2 (NOX-2)-mediated vascular oxidative stress. However, the underlying mechanisms are incompletely understood and may involve endothelial NOX-2 upregulation or facilitated vascular infiltration of phagocytic cells. Therefore, the current study was designed to investigate the vascular effects of chronic angiotensin II (AngII) infusion in mice with an endothelial-specific α1AMPK deletion. A mouse strain with endothelial-specific α1AMPK deletion was generated by breeding α1AMPKflox/flox mice with TekCre+ or Cadh5Cre+ mice. Chronic AngII infusion (0.5 mg/kg/day for 7day) caused mild endothelial dysfunction in wild-type mice that was significantly aggravated in endothelial α1AMPK knockout mice. Aortic NOX-2 and CD68 expression were increased, indicating that infiltrating leukocytes may significantly contribute to enhanced vascular oxidative stress. Flow cytometry revealed a higher abundance of aortic CD90.2+ T-cells, CD11b+F4/80+ macrophages and Ly6G-Ly6C+ monocytes. Vascular mRNA expression of monocyte chemoattractant protein 1, CCL5 and vascular cell adhesion molecule 1 was enhanced in AngII-infused mice lacking endothelial α1AMPK, facilitating the recruitment of inflammatory cells to the vessel wall. In addition, AngII-induced upregulation of cytoprotective heme oxygenase 1 (HO-1) was blunted in mice with endothelial α1AMPK deletion, compatible with an impaired antioxidant defense in these animals. In summary, endothelial expressed α1AMPK limits the recruitment of inflammatory cells to the vessel wall and maintains HO-1 mediated antioxidant defense. Both mechanisms reduce vascular oxidative damage and preserve endothelial function during chronic AngII treatment.
Published: 2019

33. Functional Mapping of Regions Involved in the Negative Imprinting of Virion Particle Infectivity and in Target Cell Protection by Interferon-Induced Transmembrane Protein 3 against HIV-1

Author: Lucie Etienne, Julien Burlaud-Gaillard, George Savidis, Andrea Cimarelli, Li Zhong, Philippe Roingeard, Mathilde Delpeuch, Romain Appourchaux, Kevin Tartour, Abraham L. Brass, Interaction hôte pathogène lors de l'infection lentivirale – Host-Pathogen Interaction during Lentiviral Infection (LP2L), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateforme IBISA de Microscopie Electronique [CHRU de Tours] (UNIV Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT), Department of Microbiology and Physiological Systems, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS)-University of Massachusetts System (UMASS), Virus, pseudo-virus: Morphogénèse et Antigénicité, Université de Tours (UT)-EA3856, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-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 National de la Santé et de la Recherche Médicale (INSERM)-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), École normale supérieure - Lyon (ENS 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)-École normale supérieure - Lyon (ENS 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), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)-Université de Tours, and Université de Tours-EA3856
Subjects: Endosome, Immunology, Mutant, Cellular Response to Infection, Context (language use), Endosomes, Biology, Microbiology, Virus, 03 medical and health sciences, Protein Domains, Interferon, Virology, medicine, Humans, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Infectivity, 0303 health sciences, Protein Stability, Tetraspanin 30, Virus Assembly, 030302 biochemistry & molecular biology, Virion, Membrane Proteins, RNA-Binding Proteins, Transmembrane protein, 3. Good health, Cell biology, Cholesterol, HEK293 Cells, Insect Science, Mutation, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, HIV-1, Intracellular, HeLa Cells, medicine.drug
Abstract: The interferon-induced transmembrane proteins (IFITMs) are a family of highly related antiviral factors that affect numerous viruses at two steps: in target cells by sequestering incoming viruses in endosomes and in producing cells by leading to the production of virions that package IFITMs and exhibit decreased infectivity. While most studies have focused on the former, little is known about the regulation of the negative imprinting of virion particle infectivity by IFITMs and about its relationship with target cell protection. Using a panel of IFITM3 mutants against HIV-1, we have explored these issues as well as others related to the biology of IFITM3, in particular virion packaging, stability, the relation to CD63/multivesicular bodies (MVBs), the modulation of cholesterol levels, and the relationship between negative imprinting of virions and target cell protection. The results that we have obtained exclude a role for cholesterol and indicate that CD63 accumulation does not directly relate to an antiviral behavior. We have defined regions that modulate the two antiviral properties of IFITM3 as well as novel domains that modulate protein stability and that, in so doing, influence the extent of its packaging into virions. The results that we have obtained, however, indicate that, even in the context of an IFITM-susceptible virus, IFITM3 packaging is not sufficient for negative imprinting. Finally, while most mutations concomitantly affect target cell protection and negative imprinting, a region in the C-terminal domain (CTD) exhibits a differential behavior, potentially highlighting the regulatory role that this domain may play in the two antiviral activities of IFITM3. IMPORTANCE IFITM proteins have been associated with the sequestration of incoming virions in endosomes (target cell protection) and with the production of virion particles that incorporate IFITMs and exhibit decreased infectivity (negative imprinting of virion infectivity). How the latter is regulated and whether these two antiviral properties are related remain unknown. By examining the behavior of a large panel of IFITM3 mutants against HIV-1, we determined that IFITM3 mutants are essentially packaged into virions proportionally to their intracellular levels of expression. However, even in the context of an IFITM-susceptible virus, IFITM3 packaging is not sufficient for the antiviral effects. Most mutations were found to concomitantly affect both antiviral properties of IFITM3, but one CTD mutant exhibited a divergent behavior, possibly highlighting a novel regulatory role for this domain. These findings thus advance our comprehension of how this class of broad antiviral restriction factors acts.
Published: 2019

34. Spinal cord involvement in adult-onset metabolic and genetic diseases

Author: Cecilia Marelli, Pierre Labauge, Ettore Salsano, Letterio S. Politi, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Department of Neurology, Children's Hospital [Boston], Boston Children's Hospital, Département de neurologie [Montpellier], and Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM)
Subjects: Adult, Mitochondrial Diseases, Hereditary spastic paraplegia, Genetic counseling, [SDV]Life Sciences [q-bio], Neurogenetics, Bioinformatics, Spinal Cord Diseases, Leukoencephalopathy, 03 medical and health sciences, Myelopathy, 0302 clinical medicine, Metabolic Diseases, myelopathy, Leukoencephalopathies, Humans, Medicine, Age of Onset, hereditary spastic paraplegia, neurogenetics, business.industry, Leukodystrophy, Autosomal dominant trait, medicine.disease, Spinal cord, metabolic disease, 3. Good health, Psychiatry and Mental health, medicine.anatomical_structure, Surgery, Neurology (clinical), business, 030217 neurology & neurosurgery, MRI
Abstract: International audience; In adulthood, spinal cord MRI abnormalities such as T2-weighted hyperintensities and atrophy are commonly associated with a large variety of causes (inflammation, infections, neoplasms, vascular and spondylotic diseases). Occasionally, they can be due to rare metabolic or genetic diseases, in which the spinal cord involvement can be a prominent or even predominant feature, or a secondary one. This review focuses on these rare diseases and associated spinal cord abnormalities, which can provide important but over-ridden clues for the diagnosis. The review was based on a PubMed search (search terms: 'spinal cord' AND 'leukoencephalopathy' OR 'leukodystrophy'; 'spinal cord' AND 'vitamin'), further integrated according to the authors' personal experience and knowledge. The genetic and metabolic diseases of adulthood causing spinal cord signal alterations were identified and classified into four groups: (1) leukodystrophies; (2) deficiency-related metabolic diseases; (3) genetic and acquired toxic/metabolic causes; and (4) mitochondrial diseases. A number of genetic and metabolic diseases of adulthood causing spinal cord atrophy without signal alterations were also identified. Finally, a classification based on spinal MRI findings is presented, as well as indications about the diagnostic work-up and differential diagnosis. Some of these diseases are potentially treatable (especially if promptly recognised), while others are inherited as autosomal dominant trait. Therefore, a timely diagnosis is needed for a timely therapy and genetic counselling. In addition, spinal cord may be the main site of pathology in many of these diseases, suggesting a tempting role for spinal cord abnormalities as surrogate MRI biomarkers.
Published: 2019

35. 5 years of successful inducible transgene expression following locoregional AAV delivery in nonhuman primates with no detectable immunity

Author: Mickaël Guilbaud, Marie Devaux, Célia Couzinié, Johanne Le Duff, Alice Toromanoff, Céline Vandamme, Nicolas Jaulin, Gwladys Gernoux, Thibaut Larcher, Philippe Moullier, Caroline Le Guiner, Oumeya Adjali, UMR 1089, Institut National de la Santé et de la Recherche Médicale (INSERM), UMR1089, Department of Clinical Microbiology, Institue of Clinical Medicine, University of Eastern Finland, Gene Therapy Center, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques (Inserm UMR 1089), 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), Department of Clinical Microbiology [Kuopio, Finland], University of Eastern Finland- Institute of Clinical Medicine [Kuopio, Finland], Développement et Pathologie du Tissu Musculaire (DPTM), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, JAULIN, Nicolas, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), ProdInra, Archive Ouverte, Ecole Nationale Vétérinaire de Nantes-Institut National de la Recherche Agronomique (INRA), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes (UN)
Subjects: [SDV] Life Sciences [q-bio], [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, viruses, [SDV]Life Sciences [q-bio], biochemical phenomena, metabolism, and nutrition, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: 5 years of successful inducible transgene expression following locoregional AAV delivery in nonhuman primates with no detectable immunity
Published: 2019

36. Production of Pseudotyped Particles to Study Highly Pathogenic Coronaviruses in a Biosafety Level 2 Setting

Author: Tiffany Tang, Susan Daniel, Hung-Lun Hsu, Javier A. Jaimes, Lakshmi Nathan, Gary R. Whittaker, Jean K. Millet, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Cornell University [New York], University of Massachusetts Medical School, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS)-University of Massachusetts System (UMASS), and Department of Microbiology and Immunology
Subjects: 0301 basic medicine, cov, General Chemical Engineering, viruses, [SDV]Life Sciences [q-bio], 030106 microbiology, coronavirus, Hemagglutinin (influenza), medicine.disease_cause, Semliki Forest virus, spike protein, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Mice, Viral life cycle, Viral entry, medicine, Animals, Humans, issue 145, Coronavirus, severe acute respiratory syndrome coronavirus, Ebola virus, biology, General Immunology and Microbiology, General Neuroscience, Virion, virus diseases, Containment of Biohazards, Virus Internalization, biology.organism_classification, Virology, Fusion protein, 3. Good health, 030104 developmental biology, HEK293 Cells, cancer Research, Severe acute respiratory syndrome-related coronavirus, Vesicular stomatitis virus, Spike Glycoprotein, Coronavirus, middle east respiratory syndrome coronavirus, biology.protein, pseudovirion, murine leukemia virus, pseudotyped particle
Abstract: International audience; The protocol aims to generate coronavirus (CoV) spike (S) fusion protein pseudotyped particles with a murine leukemia virus (MLV) core and luciferase reporter, using a simple transfection procedure of the widely available HEK-293T cell line. Once formed and released from producer cells, these pseudovirions incorporate a luciferase reporter gene. Since they only contain the heterologous coronavirus spike protein on their surface, the particles behave like their native coronavirus counterparts for entry steps. As such, they are the excellent surrogates of native virions for studying viral entry into host cells. Upon successful entry and infection into target cells, the luciferase reporter gets integrated into the host cell genome and is expressed. Using a simple luciferase assay, transduced cells can be easily quantified. An important advantage of the procedure is that it can be performed in biosafety level 2 (BSL-2) facilities instead of BSL-3 facilities required for work with highly pathogenic coronaviruses such as Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV). Another benefit comes from its versatility as it can be applied to envelope proteins belonging to all three classes of viral fusion proteins, such as the class I influenza hemagglutinin (HA) and Ebola virus glycoprotein (GP), the class II Semliki forest virus E1 protein, or the class III vesicular stomatitis virus G glycoprotein. A limitation of the methodology is that it can only recapitulate virus entry steps mediated by the envelope protein being investigated. For studying other viral life cycle steps, other methods are required. Examples of the many applications these pseudotype particles can be used in include investigation of host cell susceptibility and tropism and testing the effects of virus entry inhibitors to dissect viral entry pathways used.
Published: 2019

37. Mobile health tools for the management of chronic respiratory diseases

Author: Addolorato, Giovanni, Bataller, Ramon, Burra, Patrizia, Castera, Laurent, Cortez Pinto, Helena, Diehl, Anna Mae, Gao, Bin, Gilmore, Sir Ian, Hampe, Jochen, Jürgen, Rehm, Karin, Michael, Krag, Alexander, Leon, David, Leptak, Christopher, Louvet, Alexandre, Lucey, Michael, McClain, Craig, Nagy, Laura, Pageaux, Georges-Philippe, Sanyal, Arun, Schnabl, Bernd, Tiniakos, Dina, Trautwein, Christian, Tsukamoto, Hidekazu, Szabo, Gyongyi, Kamath, Patrick S., Shah, Vijay H., Thursz, Mark, Mathurin, Philippe, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Caen Normandie - UFR Santé (UNICAEN Santé), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Duke University [Durham], University of California [San Diego] (UC San Diego), University of California, Department of Atmospheric Science [Laramie], University of Wyoming (UW), Hôpital Claude Huriez [Lille], CHU Lille, Hôpital Lapeyronie [Montpellier] (CHU), Virginia Commonwealth University (VCU), Rheinisch-Westfälische Technische Hochschule Aachen (RWTH), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Imperial College London, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Ear, Nose and Throat, AII - Inflammatory diseases, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon (MACVIA-LR), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), and Commission Européenne-Commission Européenne-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO)
Subjects: self-management, Patient Empowerment, [SDV]Life Sciences [q-bio], Immunology, Respiratory Tract Diseases, Disease, App store, Allergic rhinitis, 03 medical and health sciences, 0302 clinical medicine, Patient Education as Topic, pa tient empowerment, mental disorders, Immunology and Allergy, Medicine, Humans, Telemetry, Mobile technology, Public Health Surveillance, 030212 general & internal medicine, mHealth, Asthma, allergic rhinitis, business.industry, Patient Selection, chronic rhinosinusitis, Health technology, Disease Management, mobile application, chronic rhinosi nusitis, asthma, medicine.disease, Mobile Applications, patient empowerment, Telemedicine, 3. Good health, 030228 respiratory system, Medical emergency, business, Patient education
Abstract: BACKGROUND: The market of mobile health (mHealth) technology is rapidly evolving, making new mobile technologies potentially available for healthcare systems. Patient empowerment through self-monitoring of symptoms, shared decision making with the physician, and easily accessible education are important features extending the reach of mHealth technology beyond traditional care. METHODS: Two digital distribution platforms (Apple App Store and Google Play Store) were searched for currently available mobile applications (apps) for patients with chronic respiratory diseases (CRDs). A new index (score ranging from 0 to 10) was developed to assess the potential of apps as a tool to empower patients through mobile technology (based on self-monitoring, personalized feedback, and patient education app features). RESULTS: One hundred and twelve apps were retained for analysis and could be classified in 5 categories: Asthma (n = 71), COPD (n = 15), Asthma and COPD (n = 15), Rhinitis and Asthma (n = 5), and Rhinosinusitis (n = 6). Eighty percent were developed by medical technology companies compared to 18% by medical doctors and 2% by pharmaceutical companies. Two-thirds of apps allow disease self-monitoring, whereas over half of apps provide patient feedback through graphs. Sixty percent of apps contain easily accessible patient education material. Only three percent of apps reach a score of ≥7 on the newly designed patient empowerment index. CONCLUSIONS: A variety of apps are available for patients with CRDs of which only few were developed by or jointly with medical doctors. The majority of these apps include self-monitoring tools, but only few also provide personalized feedback, which is needed to adopt these apps into daily care. ispartof: ALLERGY vol:74 issue:7 pages:1292-1306 ispartof: location:Denmark status: published
Published: 2019

38. Dog10K An international sequencing effort to advance studies of canine domestication, phenotypes and health

Author: Ostrander, E.A., Wang, G.-D., Larson, G., Vonholdt, B.M., Davis, B.W., Jagannathan, V., Hitte, C., Wayne, R.K., Zhang, Y.-p., André, C., Axelsson, E., Boyko, A., Forman, O., Frantz, L., Karlsson, E., Kidd, J., Leeb, T., Lindblad-Toh, K., Lohi, H., Lohmueller, K.E., Marques-Bonet, T., Mellersh, C., Savolainen, P., Schnabel, R., Yang, Z., Zhai, W., National Human Genome Research Institute (NHGRI), Chinese Academy of Sciences [Beijing] (CAS), University of Oxford [Oxford], Princeton University, Texas A&M University [College Station], Universität Bern [Bern], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), University of California [Los Angeles] (UCLA), University of California, Uppsala University, Cornell University College of Veterinary Medicine, State University of New York (SUNY), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), University of Michigan Medical School [Ann Arbor], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Helsinki, Institució Catalana de Recerca i Estudis Avançats (ICREA), Animal Health Trust (AHT), University College of London [London] (UCL), Key Laboratory of Zoological Systematics and Evolution, Chinese Academy of Agricultural Sciences (CAAS), Princeton University, PrincetonNational Institutes of Health, NIHChinese Academy of Sciences, CAS 4PalaeogenomicsUniversity of OxfordPrinceton University, PrincetonTexas A and M University, TAMUUniversity of California, Los Angeles, UCLAUniversität Bern, Ub 8IGDRMerck Genome Research InstituteCollege of Natural Resources and Sciences, Humboldt State University, CNRSPrinceton University, PrincetonKungliga Tekniska Högskolan, KTHChinese Academy of Sciences, CASNational Institutes of Health, NIHUniversity of OxfordPrinceton University, PrincetonUniversität Bern, UbHelsingin YliopistoMorris Animal Foundation, MAFVetenskapsrådet, VRYouth Innovation Promotion Association, YIPA152453KYSB20150002National Council for Eurasian and East European Research, NCEEER ERC-2013-StG-337574-UNDEADChinese Academy of Sciences, CAS XDB13000000National Human Genome Research Institute, NHGRINE/K005243/1, ANR-11-INBS-0003, NE/K003259/1National Natural Science Foundation of China, NSFC 31621062, 91731304, ANR-11-INBS-0003,CRB-Anim,Réseau de Centres de Ressources Biologiques pour les animaux domestiques(2011), Biosciences, Veterinary Biosciences, Hannes Tapani Lohi / Principal Investigator, Helsinki One Health (HOH), Doctoral Programme in Clinical Veterinary Medicine, Doctoral Programme in Integrative Life Science, Haartman Institute (-2014), Veterinary Genetics, University of Oxford, Universität Bern [Bern] (UNIBE), 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 ), University of California (UC), College of Veterinary Medicine [Cornell University], Cornell University [New York]-State University of New York (SUNY), and Helsingin yliopisto = Helsingfors universitet = University of Helsinki
Subjects: breed, [SDV]Life Sciences [q-bio], selection, Genomics, Genome-wide association study, Pedigree chart, 610 Medicine & health, Review, Biology, 413 Veterinary science, Genome, Genome-wide association studies, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, evolution, genomics, genome-wide association studies (GWAS), Domestication, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Mammals, 0303 health sciences, Genetic diversity, Multidisciplinary, Molecular Biology & Genetics, 1184 Genetics, developmental biology, physiology, Genetic architecture, Genes, Evolutionary biology, 570 Life sciences, biology, 590 Animals (Zoology), variation, International cooperation, 030217 neurology & neurosurgery
Abstract: Dogs are the most phenotypically diverse mammalian species, and they possess more known heritable disorders than any other non-human mammal. Efforts to catalog and characterize genetic variation across well-chosen populations of canines are necessary to advance our understanding of their evolutionary history and genetic architecture. To date, no organized effort has been undertaken to sequence the world's canid populations. The Dog10K Consortium (http://www.dog10kgenomes.org) is an international collaboration of researchers from across the globe who will generate 20× whole genomes from 10 000 canids in 5 years. This effort will capture the genetic diversity that underlies the phenotypic and geographical variability of modern canids worldwide. Breeds, village dogs, niche populations and extended pedigrees are currently being sequenced, and de novo assemblies of multiple canids are being constructed. This unprecedented dataset will address the genetic underpinnings of domestication, breed formation, aging, behavior and morphological variation. More generally, this effort will advance our understanding of human and canine health. This work was supported by a number of entities including grants from the Breakthrough Project of the Strategic Priority Program of the Chinese Academy of Sciences (CAS) (XDB13000000 to G-DW); the National Natural Science Foundation of China (91731304, 31621062); the Intramural Program of the National Human Genome Research Institute of the National Institutes of Health, USA (to EAO); a CAS international collaborating grant proposal (152453KYSB20150002 to G-DW); the Morris Animal Foundation (to RKW); the Swedish Research Council (to KLT); the European Research Council (ERC-2013-StG-337574-UNDEAD to GL and LF); the Natural Environmental Research Council (NE/K005243/1 and NE/K003259/1 to GL and LF); grant ‘Cani-DNA_CRB’ (ANR-11-INBS-0003) for the French Tissue Bank (to CA and CH); and a Young Innovation Promotion Association Award (to G-DW).
Published: 2019

39. Peptidylarginine Deiminase Inhibitor Cl-Amidine Attenuates Cornification and Interferes with the Regulation of Autophagy in Reconstructed Human Epidermis

Author: Paul R. Thompson, Hidenari Takahara, Laura Cau, Guy Serre, Michel Simon, Marie-Claire Méchin, CCSD, Accord Elsevier, Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), 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), Ibaraki University, University of Massachusetts Medical School [Worcester] (UMASS), and University of Massachusetts System (UMASS)
Subjects: 0301 basic medicine, Keratinocytes, Ornithine, Arginine, Mitochondrion, Biochemistry, chemistry.chemical_compound, 0302 clinical medicine, Protein-Arginine Deiminase Type 3, MESH: Protein-Arginine Deiminase Type 1 / antagonists & inhibitors, Protein-Arginine Deiminase Type 1, MESH: Citrulline / metabolism, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Autophagy / drug effects, MESH: Ornithine / analogs & derivatives, Citrulline, Cells, Cultured, MESH: Protein-Arginine Deiminase Type 3 / metabolism, deimination, MESH: Protein-Arginine Deiminase Type 1 / metabolism, Citrullination, Cell Differentiation, MESH: Cell Differentiation / physiology, Recombinant Proteins, MESH: Keratinocytes, Cell biology, 030220 oncology & carcinogenesis, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Microscopy, Electron, Transmission, MESH: Protein Processing, Post-Translational / physiology, MESH: Cells, Cultured, skin, autophagy, citrullination, MESH: Epidermis / ultrastructure, Primary Cell Culture, Dermatology, MESH: Epidermis / drug effects, Article, MESH: Ornithine / pharmacology, MESH: Primary Cell Culture, 03 medical and health sciences, Downregulation and upregulation, Microscopy, Electron, Transmission, MESH: Arginine / metabolism, Humans, transitional cells, Molecular Biology, Corneocyte, MESH: Humans, Epidermis (botany), keratinocyte differentiation, Autophagy, MESH: Protein Processing, Post-Translational / drug effects, Cell Biology, MESH: Cell Differentiation / drug effects, MESH: Autophagy / physiology, 030104 developmental biology, chemistry, post-translational modification, MESH: Epidermis / physiology, MESH: Protein-Arginine Deiminase Type 3 / antagonists & inhibitors, MESH: Recombinant Proteins / metabolism, Epidermis, Protein Processing, Post-Translational
Abstract: International audience; Deimination, a post-translational modification catalyzed by a family of enzymes called peptidylarginine deiminases (PADs), is the conversion of arginine into citrulline residues in a protein. Deimination has been associated with numerous physiological and pathological processes. Our aim was to study its implication in the homeostasis of human epidermis, where three PADs are expressed, namely PAD1, 2, and 3. Three-dimensional reconstructed human epidermis (RHEs) were treated for 2 days with increased concentrations (0-800 μM) of Cl-amidine, a specific PAD inhibitor. Cl-amidine treatments inhibited deimination in a dose-dependent manner and were not cytotoxic for keratinocytes. At 800 μM , Cl-amidine was shown to reduce deimination by half, alter keratinocyte differentiation, decrease the number of corneocyte layers, significantly increase the number of transitional cells, induce clustering of mitochondria and of heterogeneous vesicles in the cytoplasm of granular keratinocytes, and upregulate the expression of autophagy proteins, including LC3-II, sestrin-2, and p62/SQSTM1. LC3 and PADs were further shown to partially co-localize in the upper epidermis. These results demonstrated that Cl-amidine treatments slow down cornification and alter autophagy in the granular layer. They suggest that PAD1 and/or PAD3 play a role in the constitutive epidermal autophagy process that appears as an important step in cornification.
Published: 2019

40. Interobserver Variability in Applying American Society of Echocardiography/European Association of Cardiovascular Imaging 2016 Guidelines for Estimation of Left Ventricular Filling Pressure

Author: Jeroen J. Bax, Serge C. Harb, Kinan Carlos El Tallawi, Mohammed A. Chamsi-Pasha, Carmen C. Beladan, Saket Sanghai, Sherif F. Nagueh, Roberta Esposito, Steven A. Goldstein, Erwan Donal, Victoria Delgado, Giulia Dolci, Theodore P. Abraham, Frank A. Flachskampf, Patrizio Lancellotti, Arnaud Hubert, Allan L. Klein, Geneviève Derumeaux, Paolo Marino, Otto A. Smiseth, Gerard P. Aurigemma, Laura Ernande, Judy Hung, Thor Edvardsen, Redah Z. Mahmood, James L. Gentry, Alyssa Browning, Maurizio Galderisi, Jiaqiong Xu, Martina Previato, Bogdan A. Popescu, Nagueh, Sherif F., Abraham, Theodore P., Aurigemma, Gerard P., Bax, Jeroen J., Beladan, Carmen, Browning, Alyssa, Chamsi-Pasha, Mohammed A., Delgado, Victoria, Derumeaux, Genevieve, Dolci, Giulia, Donal, Erwan, Edvardsen, Thor, El Tallawi, Kinan Carlo, Ernande, Laura, Esposito, Roberta, Flachskampf, Frank A., Galderisi, Maurizio, Gentry, Jame, Goldstein, Steven A., Harb, Serge C., Hubert, Arnaud, Hung, Judy, Klein, Allan L., Lancellotti, Patrizio, Mahmood, Redah Z., Marino, Paolo, Popescu, Bogdan A., Previato, Martina, Sanghai, Saket R., Smiseth, Otto A., Xu, Jiaqiong, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Leiden University Medical Center (LUMC), Laboratoire Traitement du Signal et de l'Image (LTSI), 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), CHU Pontchaillou [Rennes], University of Oslo (UiO), Uppsala University, Cleveland Clinic, Università degli Studi del Piemonte Orientale - Amedeo Avogadro (UPO), Universiteit Leiden, and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, medicine.medical_specialty, Radiology, Nuclear Medicine and Imaging, Heart Diseases, Heart Ventricles, echocardiography, Doppler, Diastole, 030204 cardiovascular system & hematology, Doppler echocardiography, Ventricular Function, Left, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, diastole, Predictive Value of Tests, Internal medicine, medicine, Ventricular Pressure, echocardiography, human, humans, ComputingMilieux_MISCELLANEOUS, Aged, Estimation, Observer Variation, medicine.diagnostic_test, business.industry, Limits of agreement, Doppler, Reproducibility of Results, Guideline, Middle Aged, Practice Guidelines as Topic, Cardiology, Female, [SDV.IB]Life Sciences [q-bio]/Bioengineering, business, Ventricular filling, Cardiology and Cardiovascular Medicine, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, guideline
Abstract: Background: Assessment of left ventricular (LV) filling pressure is among the important components of a comprehensive echocardiographic report. Previous studies noted wide limits of agreement using 2009 American Society of Echocardiography/European Association of Echocardiography guidelines, but reproducibility of 2016 guidelines update in estimating LV filling pressure is unknown. Methods: Echocardiographic and hemodynamic data were obtained from 50 patients undergoing cardiac catheterization for clinical indications. Clinical and echocardiographic findings but not invasive hemodynamics were provided to 4 groups of observers, including experienced echocardiographers and cardiology fellows. Invasively acquired LV filling pressure was the gold standard. Results: In group I of 8 experienced echocardiographers from the guidelines writing committee, sensitivity for elevated LV filling pressure was 92% for all observers, and specificity was 93±6%. Fleiss κ-value for the agreement in group I was 0.80. In group II of 4 fellows in training, sensitivity was 91±2%, and specificity was 95±2%. Fleiss κ-value for the agreement in group II was 0.94. In group III of 9 experienced echocardiographers who had not participated in drafting the guidelines, sensitivity was 88±5%, and specificity was 91±7%. Fleiss κ-value for the agreement in group III was 0.76. In group IV of 7 other fellows, sensitivity was 91±3%, and specificity was 92±5%. Fleiss κ-value for the agreement in group IV was 0.89. Conclusions: There is a good level of agreement and accuracy in the estimation of LV filling pressure using the American Society of Echocardiography/European Association of Cardiovascular Imaging 2016 recommendations update, irrespective of the experience level of the observer.
Published: 2019

41. The non-canonical SMC protein SmcHD1 antagonises TAD formation and compartmentalisation on the inactive X chromosome

Author: Gdula, Michal R, Nesterova, Tatyana B, Pintacuda, Greta, Godwin, Jonathan, Zhan, Ye, Ozadam, Hakan, McClellan, Michael, Moralli, Daniella, Krueger, Felix, Green, Catherine M, Reik, Wolf, Kriaucionis, Skirmantas, Heard, Edith, Dekker, Job, Brockdorff, Neil, University of Oxford [Oxford], University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), The Wellcome Trust Centre for Human Genetics [Oxford], The Babraham Institute [Cambridge, UK], Institut Curie [Paris], Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Chaire Epigénétique et mémoire cellulaire, Collège de France (CdF (institution)), Gdula, Michal R [0000-0002-8667-7359], Nesterova, Tatyana B [0000-0001-7740-4386], Pintacuda, Greta [0000-0001-5126-2279], Zhan, Ye [0000-0001-9280-1718], Moralli, Daniella [0000-0001-7977-8496], Krueger, Felix [0000-0002-5513-3324], Heard, Edith [0000-0001-8052-7117], Dekker, Job [0000-0001-5631-0698], and Apollo - University of Cambridge Repository
Subjects: Male, Transcriptional Activation, Chromosomal Proteins, Non-Histone, Science, [SDV]Life Sciences [q-bio], Polycomb-Group Proteins, Exons, DNA Methylation, Fibroblasts, Article, Cell Line, Histones, Gene Knockout Techniques, Mice, X Chromosome Inactivation, Animals, Point Mutation, CpG Islands, Female, lcsh:Q, CRISPR-Cas Systems, lcsh:Science, Alleles
Abstract: The inactive X chromosome (Xi) in female mammals adopts an atypical higher-order chromatin structure, manifested as a global loss of local topologically associated domains (TADs), A/B compartments and formation of two mega-domains. Here we demonstrate that the non-canonical SMC family protein, SmcHD1, which is important for gene silencing on Xi, contributes to this unique chromosome architecture. Specifically, allelic mapping of the transcriptome and epigenome in SmcHD1 mutant cells reveals the appearance of sub-megabase domains defined by gene activation, CpG hypermethylation and depletion of Polycomb-mediated H3K27me3. These domains, which correlate with sites of SmcHD1 enrichment on Xi in wild-type cells, additionally adopt features of active X chromosome higher-order chromosome architecture, including A/B compartments and partial restoration of TAD boundaries. Xi chromosome architecture changes also occurred following SmcHD1 knockout in a somatic cell model, but in this case, independent of Xi gene derepression. We conclude that SmcHD1 is a key factor in defining the unique chromosome architecture of Xi., The inactive X chromosome (Xi) has an atypical structure, with global loss of TADs, A/B compartments and formation of mega-domains. Here the authors show that the non-canonical SMC family protein, SmcHD1, important for developmental gene silencing on Xi, antagonises TAD formation and compartmentalization on the Xi in a transcription independent way.
Published: 2018

42. The DNA Damage Response Regulates RAG1/2 Expression in Pre–B Cells through ATM-FOXO1 Signaling

Author: Jeroen E. J. Guikema, Timon A. Bloedjes, Carel J. M. van Noesel, Carol E. Schrader, Katarina Ochodnicka-Mackovicova, Richard J. Bende, Amélie van der Veen, Alexander M. de Bruin, Rudi W. Hendriks, Mahnoush Bahjat, Harmen van Andel, Chiel Maas, Els Verhoeyen, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS 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)-École normale supérieure - Lyon (ENS 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), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Pulmonary Medicine, Graduate School, Pathology, Other departments, Amsterdam institute for Infection and Immunity, and Cancer Center Amsterdam
Subjects: 0301 basic medicine, Precursor Cells, DNA damage, Cells, Immunology, chemical and pharmacologic phenomena, Ataxia Telangiectasia Mutated Proteins, Genotoxic Stress, Biology, Recombination-activating gene, 03 medical and health sciences, 0302 clinical medicine, RAG2, Humans, Immunology and Allergy, Enhancer, Cells, Cultured, B-Lymphoid, Homeodomain Proteins, Cultured, Forkhead Box Protein O1, Precursor Cells, B-Lymphoid, HEK 293 cells, T-cell receptor, Nuclear Proteins, hemic and immune systems, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Molecular biology, DNA-Binding Proteins, HEK293 Cells, 030104 developmental biology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Signal transduction, DNA Damage, Signal Transduction, 030215 immunology
Abstract: The recombination activating gene (RAG) 1 and RAG2 protein complex introduces DNA breaks at Tcr and Ig gene segments that are required for V(D)J recombination in developing lymphocytes. Proper regulation of RAG1/2 expression safeguards the ordered assembly of Ag receptors and the development of lymphocytes, while minimizing the risk for collateral damage. The ataxia telangiectasia mutated (ATM) kinase is involved in the repair of RAG1/2-mediated DNA breaks and prevents their propagation. The simultaneous occurrence of RAG1/2-dependent and -independent DNA breaks in developing lymphocytes exposed to genotoxic stress increases the risk for aberrant recombinations. In this study, we assessed the effect of genotoxic stress on RAG1/2 expression in pre–B cells and show that activation of the DNA damage response resulted in the rapid ATM-dependent downregulation of RAG1/2 mRNA and protein expression. We show that DNA damage led to the loss of FOXO1 binding to the enhancer region of the RAG1/2 locus (Erag) and provoked FOXO1 cleavage. We also show that DNA damage caused by RAG1/2 activity in pre–B cells was able to downmodulate RAG1/2 expression and activity, confirming the existence of a negative feedback regulatory mechanism. Our data suggest that pre–B cells are endowed with a protective mechanism that reduces the risk for aberrant recombinations and chromosomal translocations when exposed to DNA damage, involving the ATM-dependent regulation of FOXO1 binding to the Erag enhancer region.
Published: 2016

43. Kinetic effects on the currents determining the stability of a magnetic island in tokamaks

Author: A. Bergmann, A. G. Peeters, William Hornsby, Emanuele Poli, David Zarzoso, Mattia Siccinio, F. J. Casson, Department of Cancer Biology, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS)-University of Massachusetts System (UMASS), EURATOM/CCFE Fusion Association, Culham Science Centre [Abingdon], Physique des interactions ioniques et moléculaires (PIIM), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [PHYS]Physics [physics], Physics, Physics and Astronomy (miscellaneous), Condensed matter physics, Ion current, Electron, Condensed Matter Physics, Polarization (waves), 01 natural sciences, Instability, Flattening, 010305 fluids & plasmas, Physics::Plasma Physics, 0103 physical sciences, Electron temperature, Diamagnetism, 010306 general physics, Adiabatic process
Abstract: International audience; The role of the bootstrap and polarization currents for the stability of ă neoclassical tearing modes is investigated employing both a drift ă kinetic and a gyrokinetic approach. The adiabatic response of the ions ă around the island separatrix implies, for island widths below or around ă the ion thermal banana width, density flattening for islands rotating at ă the ion diamagnetic frequency, while for islands rotating at the ă electron diamagnetic frequency the density is unperturbed and the only ă contribution to the neoclassical drive arises from electron temperature ă flattening. As for the polarization current, the full inclusion of ă finite orbit width effects in the calculation of the potential ă developing in a rotating island leads to a smoothing of the ă discontinuous derivatives exhibited by the analytic potential on which ă the polarization term used in the modeling is based. This leads to a ă reduction of the polarization-current contribution with respect to the ă analytic estimate, in line with other studies. Other contributions to ă the perpendicular ion current, related to the response of the particles ă around the island separatrix, are found to compete or even dominate the ă polarization-current term for realistic island rotation frequencies.
Published: 2016

44. Cannabis use is associated with reduced prevalence of progressive stages of alcoholic liver disease

Author: Tokunbo Ajayi, Terence N. Bukong, Kelechi Lauretta Adejumo, Nnaemeka Onyeakusi, Ogooluwa A. Ojelabi, Akintunde M Akinjero, Samson Alliu, Oluwole Adegbala, Adeyinka Charles Adejumo, North Shore Medical Center, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Howard County General Hospital, Englewood Hospital and Medical Center, University of Massachusetts [Lowell] (UMass Lowell), Maimonides Medical Center, BronxCare Health System, Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), and Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP)
Subjects: 0301 basic medicine, Adult, Male, cannabis, medicine.medical_specialty, Alcoholic liver disease, Cirrhosis, Carcinoma, Hepatocellular, Adolescent, Databases, Factual, [SDV]Life Sciences [q-bio], Marijuana Smoking, 03 medical and health sciences, Liver disease, Young Adult, 0302 clinical medicine, Internal medicine, medicine, Prevalence, Humans, Liver Diseases, Alcoholic, Effects of cannabis, drug abuse, Hepatology, biology, business.industry, alcohol, Liver Neoplasms, Odds ratio, Middle Aged, Protective Factors, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, medicine.disease, biology.organism_classification, United States, 3. Good health, Substance abuse, Alcoholism, 030104 developmental biology, Disease Progression, Regression Analysis, 030211 gastroenterology & hepatology, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cannabis, Steatohepatitis, business, liver disease
Abstract: International audience; BACKGROUND:Abusive alcohol use has well-established health risks including causing liver disease (ALD) characterized by alcoholic steatosis (AS), steatohepatitis (AH), fibrosis, cirrhosis (AC) and hepatocellular carcinoma (HCC). Strikingly, a significant number of individuals who abuse alcohol also use Cannabis, which has seen increased legalization globally. While cannabis has demonstrated anti-inflammatory properties, its combined use with alcohol and the development of liver disease remain unclear.AIM:The aim of this study was to determine the effects of cannabis use on the incidence of liver disease in individuals who abuse alcohol.METHODS:We analysed the 2014 Healthcare Cost and Utilization Project-Nationwide Inpatient Sample (NIS) discharge records of patients 18 years and older, who had a past or current history of abusive alcohol use (n = 319 514). Using the International Classification of Disease, Ninth Edition codes, we studied the four distinct phases of progressive ALD with respect to three cannabis exposure groups: non-cannabis users (90.39%), non-dependent cannabis users (8.26%) and dependent cannabis users (1.36%). We accounted for the complex survey sampling methodology and estimated the adjusted odds ratio (AOR) for developing AS, AH, AC and HCC with respect to cannabis use (SAS 9.4).RESULTS:Our study revealed that among alcohol users, individuals who additionally use cannabis (dependent and non-dependent cannabis use) showed significantly lower odds of developing AS, AH, AC and HCC (AOR: 0.55 [0.48-0.64], 0.57 [0.53-0.61], 0.45 [0.43-0.48] and 0.62 [0.51-0.76]). Furthermore, dependent users had significantly lower odds than non-dependent users for developing liver disease.CONCLUSIONS:Our findings suggest that cannabis use is associated with a reduced incidence of liver disease in alcoholics.
Published: 2018

45. Reconfiguration of a Multi-oscillator Network by Light in the Drosophila Circadian Clock

Author: Wilson Mena, François Rouyer, Abhishek Chatterjee, Patrick Emery, Béatrice Martin, Angélique Lamaze, Elisabeth Chélot, Sebastian Kadener, Paul E. Hardin, Joydeep De, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Department of Biology and Center for Biological Clocks Research, Brandeis University, University of Massachusetts Medical School [Worcester] (UMASS), and University of Massachusetts System (UMASS)
Subjects: Male, 0301 basic medicine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Circadian clock, Synchronizing, Context (language use), Biology, Article, General Biochemistry, Genetics and Molecular Biology, morning and evening oscillators, 03 medical and health sciences, Pigment dispersing factor, Circadian Clocks, circadian clock, Biological neural network, Animals, Circadian rhythm, hormone receptor-like in 38, Sensory cue, Neurons, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Brain, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Circadian Rhythm, Coupling (electronics), rest-activity rhythms, Drosophila melanogaster, 030104 developmental biology, pigment-dispersing factor, visual system, Drosophila, General Agricultural and Biological Sciences, light, Neuroscience, posterior dorsal neurons 1, oscillator coupling
Abstract: International audience; The brain clock that drives circadian rhythms of locomotor activity relies on a multi-oscillator neuronal network. In addition to synchronizing the clock with day-night cycles, light also reformats the clock-driven daily activity pattern. How changes in lighting conditions modify the contribution of the different oscillators to remodel the daily activity pattern remains largely unknown. Our data in Drosophila indicate that light readjusts the interactions between oscillators through two different modes. We show that a morning s-LNv > DN1p circuit works in series, whereas two parallel evening circuits are contributed by LNds and other DN1ps. Based on the photic context, the master pacemaker in the s-LNv neurons swaps its enslaved partner-oscillator-LNd in the presence of light or DN1p in the absence of light-to always link up with the most influential phase-determining oscillator. When exposure to light further increases, the light-activated LNd pacemaker becomes independent by decoupling from the s-LNvs. The calibration of coupling by light is layered on a clock-independent network interaction wherein light upregulates the expression of the PDF neuropeptide in the s-LNvs, which inhibits the behavioral output of the DN1p evening oscillator. Thus, light modifies inter-oscillator coupling and clock-independent output-gating to achieve flexibility in the network. It is likely that the light-induced changes in the Drosophila brain circadian network could reveal general principles of adapting to varying environmental cues in any neuronal multi-oscillator system.
Published: 2018

46. Proceedings of Shape Modeling International (SMI) 2018 - Special Issue of Computers & Graphics Vol. 74. Jun 2018, Lisbon, Portugal, Elsevier, pp.33-243, 2018

Author: Gomes, Abel, Hahmann, Stefanie, Kalogerakis, Evangelos, University of Beira Interior [Portugal] (UBI), Intuitive Modeling and Animation for Interactive Graphics & Narrative Environments (IMAGINE ), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Laboratoire Jean Kuntzmann (LJK ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), University of Massachusetts Medical School [Worcester] (UMASS), and University of Massachusetts System (UMASS)
Subjects: ComputingMilieux_MISCELLANEOUS, [INFO.INFO-GR]Computer Science [cs]/Graphics [cs.GR]
Abstract: International audience
Published: 2018

47. Measurement invariance and general population reference values of the PROMIS Profile 29 in the UK, France, and Germany

Author: Joël Coste, A. Leplege, Felix Fischer, Chris Gibbons, Jose M Valderas, Matthias Rose, Unité de Biostatistique et Epidémiologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Hôpital Saint-Vincent de Paul-Université Paris Descartes - Paris 5 (UPD5), Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université de Lorraine (UL), Division Public Health and Primary Health Care [Oxford], University of Oxford [Oxford], Recherches Epistémologiques et Historiques sur les Sciences Exactes et les Institutions Scientifiques (REHSEIS), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University of Cambridge [UK] (CAM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Saint-Vincent de Paul-Université Paris Descartes - Paris 5 (UPD5), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Recherches Epistémologiques et Historiques sur les Sciences Exactes et les Institutions Scientifiques (REHSEIS (UMR_7596)), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)
Subjects: Adult, Male, Adolescent, Population, Item response theory, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Reference Values, Germany, Surveys and Questionnaires, Linear regression, Statistics, Humans, Cross-cultural equivalence, Measurement invariance, Patient Reported Outcome Measures, 030212 general & internal medicine, Imputation (statistics), education, ComputingMilieux_MISCELLANEOUS, Aged, education.field_of_study, Patient-reported outcomes, General population reference, 030503 health policy & services, Comparability, Public Health, Environmental and Occupational Health, Middle Aged, United Kingdom, Confirmatory factor analysis, 3. Good health, Quantile regression, Plausible value imputation, Quality of Life, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, Self Report, Self-reported health, Factor Analysis, Statistical, 0305 other medical science, Psychology
Abstract: International audience; Purpose: Comparability of patient-reported outcome measures over different languages is essential to allow cross-national research. We investigate the comparability of the PROMIS Profile 29, a generic health-related quality of life measure, in general population samples in the UK, France, and Germany and present general population reference values.Methods: A web-based survey was simultaneously conducted in the UK (n = 1509), France (1501), and Germany (1502). Along with the PROMIS Profile 29, we collected sociodemographic information as well as the EQ-5D. We tested measurement invariance by means of multigroup confirmatory factor analysis (CFA). Differences in the health-related quality of life between countries were modeled by linear regression analysis. We present general population reference data for the included PROMIS domains utilizing plausible value imputation and quantile regression.Results: Multigroup CFA of the PROMIS Profile 29 showed that factor means are insensitive to potential measurement bias except in one item. We observed significant differences in patient-reported health between countries, which could be partially explained by the differences in overall ratings of health. The physical function and pain interference scales showed considerable floor effects in the normal population in all countries.Conclusions: Scores derived from the PROMIS Profile 29 are largely comparable across the UK, France, and Germany. Due to the use of plausible value imputation, the presented general population reference values can be compared to data collected with other PROMIS short forms or computer-adaptive tests.
Published: 2018

48. Fragment-Based Discovery of a Regulatory Site in Thioredoxin Glutathione Reductase Acting as 'doorstop' for NADPH Entry

Author: Adriana E. Miele, Andrea Bellelli, Qing Cheng, F. Fata, Francesco Angelucci, Wendy A. Lea, I. Silvestri, Rodolfo Ippoliti, Anton Simeonov, Elias S.J. Arnér, Matteo Ardini, Pavel A. Petukhov, Gregory R. J. Thatcher, David L. Williams, Haining Lyu, Ajit Jadhav, Giovanna Boumis, Department of Biochemical Sciences 'Rossi Fanelli', Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Program in Gene Function and Expression, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS)-University of Massachusetts System (UMASS), Dipartimento di Biologia di Base ed Applicata, Università degli Studi dell'Aquila (UNIVAQ), Civil Aviation University of China (CHINA), Civil Aviation University of China (CAUC), Department of Radiology, University of Michigan [Ann Arbor], and University of Michigan System-University of Michigan System
Subjects: Models, Molecular, 0301 basic medicine, Regulatory site, Reductase, Crystallography, X-Ray, Biochemistry, Article, Cofactor, Mice, 03 medical and health sciences, 0302 clinical medicine, biochemistry, molecular medicine, Multienzyme Complexes, Drug Discovery, Animals, Humans, NADH, NADPH Oxidoreductases, Enzyme Inhibitors, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], ComputingMilieux_MISCELLANEOUS, Anthelmintics, chemistry.chemical_classification, biology, Chemistry, Drug discovery, Schistosoma mansoni, General Medicine, Schistosomiasis mansoni, 3. Good health, 030104 developmental biology, Enzyme, Docking (molecular), 030220 oncology & carcinogenesis, biology.protein, Molecular Medicine, NAD+ kinase, Thioredoxin, NADP
Abstract: Members of the FAD/NAD-linked reductase family are recognized as crucial targets in drug development for cancers, inflammatory disorders, and infectious diseases. However, individual FAD/NAD reductases are difficult to inhibit in a selective manner with off-target inhibition reducing usefulness of identified compounds. Thioredoxin glutathione reductase (TGR), a high molecular weight thioredoxin reductase-like enzyme, has emerged as a promising drug target for the treatment of schistosomiasis, a parasitosis afflicting more than 200 million people. Taking advantage of small molecules selected from a high-throughput screen and using X-ray crystallography, functional assays, and docking studies, we identify a critical secondary site of the enzyme. Compounds binding at this site interfere with well-known and conserved conformational changes associated with NADPH reduction, acting as a doorstop for cofactor entry. They selectively inhibit TGR from Schistosoma mansoni and are active against parasites in culture. Since many members of the FAD/NAD-linked reductase family have similar catalytic mechanisms, the unique mechanism of inhibition identified in this study for TGR broadly opens new routes to selectively inhibit homologous enzymes of central importance in numerous diseases.
Published: 2018

49. ETV4 transcription factor and MMP13 metalloprotease are interplaying actors of breast tumorigenesis

Author: Dumortier, Mandy, Ladam, Franck, Damour, Isabelle, Vacher, Sophie, Bièche, Ivan, Marchand, Nathalie, De Launoit, Yvan, Tulasne, David, Chotteau-Lelièvre, Anne, de Launoit, Yvan, Mécanismes de la Tumorigénèse et Thérapies Ciblées - UMR 8161 (M3T), 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), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Institut Curie [Paris], 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), This work was supported by the Centre national de la recherche scientifique (CNRS), the Institut Pasteur de Lille, and Institut National de la Santé et de la Recherche Médicale (INSERM), as well as by grants from the Ligue contre le Cancer, comité Aisne and the Association pour la Recherche sur le Cancer., We thank Martine Duterque-Coquillaud, Anne Flourens, and Antonino Bongiovanni for their precious help in IHC experiments. We thank the Microscopy-Imaging-Cytometry Facility of the BioImaging Center Lille Nord-de-France for access to instruments and technical advice., Mécanismes de tumorigenèse et thérapies ciblées, Mécanismes de la Tumorigénèse et Thérapies Ciblées (M3T) - UMR 8161 (M3T), Institut Curie, 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), Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS), and Département de Génétique [Institut Curie, Paris] (Unité de Pharmacogénomique)
Subjects: Carcinogenesis, [SDV]Life Sciences [q-bio], Mice, Breast cancer, MESH: Aged, 80 and over, Cell Movement, MESH: Animals, ComputingMilieux_MISCELLANEOUS, MESH: Breast Neoplasms/pathology, Aged, 80 and over, MESH: Carcinogenesis/genetics, MESH: Aged, MESH: Middle Aged, MESH: Cell Movement/genetics, MMP13, MESH: Gene Expression Regulation, Neoplastic, Middle Aged, Prognosis, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, MESH: Neoplasm Invasiveness/genetics, MESH: Breast Neoplasms/genetics, Gene Expression Regulation, Neoplastic, [SDV] Life Sciences [q-bio], MESH: Proto-Oncogene Proteins/genetics, Female, Adenovirus E1A Proteins, MESH: Matrix Metalloproteinase 13/genetics, Research Article, Adult, MESH: Xenograft Model Antitumor Assays, MESH: Cell Line, Tumor, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, MESH: Prognosis, Cell Line, Tumor, Proto-Oncogene Proteins, Matrix Metalloproteinase 13, Animals, Humans, Neoplasm Invasiveness, MESH: Mice, Aged, Cell Proliferation, MESH: Humans, Proto-Oncogene Proteins c-ets, ETV4, MESH: Cell Proliferation/genetics, MESH: Adult, Xenograft Model Antitumor Assays, Tumorigenesis, MESH: Adenovirus E1A Proteins/genetics, MESH: Neoplasm Invasiveness/pathology, Transcription factor, MESH: Female
Abstract: Background The ETS transcription factor ETV4 is involved in the main steps of organogenesis and is also a significant mediator of tumorigenesis and metastasis, such as in breast cancer. Indeed, ETV4 is overexpressed in breast tumors and is associated with distant metastasis and poor prognosis. However, the cellular and molecular events regulated by this factor are still misunderstood. In mammary epithelial cells, ETV4 controls the expression of many genes, MMP13 among them. The aim of this study was to understand the function of MMP13 during ETV4-driven tumorigenesis. Methods Different constructs of the MMP13 gene promoter were used to study the direct regulation of MMP13 by ETV4. Moreover, cell proliferation, migration, invasion, anchorage-independent growth, and in vivo tumorigenicity were assayed using models of mammary epithelial and cancer cells in which the expression of MMP13 and/or ETV4 is modulated. Importantly, the expression of MMP13 and ETV4 messenger RNA was characterized in 456 breast cancer samples. Results Our results revealed that ETV4 promotes proliferation, migration, invasion, and anchorage-independent growth of the MMT mouse mammary tumorigenic cell line. By investigating molecular events downstream of ETV4, we found that MMP13, an extracellular metalloprotease, was an ETV4 target gene. By overexpressing or repressing MMP13, we showed that this metalloprotease contributes to proliferation, migration, and anchorage-independent clonogenicity. Furthermore, we demonstrated that MMP13 inhibition disturbs proliferation, migration, and invasion induced by ETV4 and participates to ETV4-induced tumor formation in immunodeficient mice. Finally, ETV4 and MMP13 co-overexpression is associated with poor prognosis in breast cancer. Conclusion MMP13 potentiates the effects of the ETV4 oncogene during breast cancer genesis and progression. Electronic supplementary material The online version of this article (10.1186/s13058-018-0992-0) contains supplementary material, which is available to authorized users.
Published: 2018

50. An ADMM-Based Coordination and Control Strategy for PV and Storage to Dispatch Stochastic Prosumers: Theory and Experimental Validation

Author: Colin N. Jones, Rahul Kumar Gupta, Enrica Scolari, Mario Paolone, Luca Fabietti, Fabrizio Sossan, Emil Namor, Sossan, Fabrizio, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS)-University of Massachusetts System (UMASS), Centre Procédés, Énergies Renouvelables, Systèmes Énergétiques (PERSEE), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Ecole Polytechnique Fédérale de Lausanne (EPFL), Swedish Meteorological and Hydrological Institute (SMHI), Distributed Energy Systems Laboratory, Swiss Federal Institute of Technology (EPFL), Paolone, Mario, and Rehtanz, Christian
Subjects: Distributed control, Energy storage systems, Computer science, 020209 energy, Automatic frequency control, Systems and Control (eess.SY), PV, 02 engineering and technology, 7. Clean energy, Electrical Engineering and Systems Science - Systems and Control, Energy storage, storage, Setpoint, Peak demand, Control theory, FOS: Electrical engineering, electronic engineering, information engineering, 0202 electrical engineering, electronic engineering, information engineering, ComputingMilieux_MISCELLANEOUS, Photovoltaic (PV), business.industry, [SPI.NRJ]Engineering Sciences [physics]/Electric power, Photovoltaic system, Power (physics), Model predictive control, Distributed generation, ADMM, business, Photovoltaic, [SPI.NRJ] Engineering Sciences [physics]/Electric power
Abstract: This paper describes a two-layer control and coordination framework for distributed energy resources. The lower layer is a real-time model predictive control (MPC) executed at 10 s resolution to achieve fine tuning of a given energy set-point. The upper layer is a slower MPC coordination mechanism based on distributed optimization, and solved with the alternating direction method of multipliers (ADMM) at 5 minutes resolution. It is needed to coordinate the power flow among the controllable resources such that enough power is available in real-time to achieve a pre-established energy trajectory in the long term. Although the formulation is generic, it is developed for the case of a battery system and a curtailable PV facility to dispatch stochastic prosumption according to a trajectory at 5 minutes resolution established the day before the operation. The proposed method is experimentally validated in a real-life setup to dispatch the operation of a building with rooftop PV generation (i.e., 101 kW average load, 350 kW peak demand, 82 kW peak PV generation) by controlling a 560 kWh/720 kVA battery and a 13 kW peak curtailable PV facility., 7 pages, 4 figures, 4 tables, to be presented at the 20th Power Systems Computation Conference, June 11-15, 2018, Dublin, Ireland
Published: 2018

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