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1. A community effort to assess and improve drug sensitivity prediction algorithms

Author: Costello, James C, Heiser, Laura M, Georgii, Elisabeth, Gönen, Mehmet, Menden, Michael P, Wang, Nicholas J, Bansal, Mukesh, Ammad-ud-din, Muhammad, Hintsanen, Petteri, Khan, Suleiman A, Mpindi, John-Patrick, Kallioniemi, Olli, Honkela, Antti, Aittokallio, Tero, Wennerberg, Krister, Abbuehl, Jean-Paul, Allen, Jeffrey, Altman, Russ B, Balcome, Shawn, Battle, Alexis, Bender, Andreas, Berger, Bonnie, Bernard, Jonathan, Bhattacharjee, Madhuchhanda, Bhuvaneshwar, Krithika, Bieberich, Andrew A, Boehm, Fred, Califano, Andrea, Chan, Christina, Chen, Beibei, Chen, Ting-Huei, Choi, Jaejoon, Coelho, Luis Pedro, Cokelaer, Thomas, Collins, James C, Creighton, Chad J, Cui, Jike, Dampier, Will, Davisson, V Jo, De Baets, Bernard, Deshpande, Raamesh, DiCamillo, Barbara, Dundar, Murat, Duren, Zhana, Ertel, Adam, Fan, Haoyang, Fang, Hongbin, Gallahan, Dan, Gauba, Robinder, Gottlieb, Assaf, Grau, Michael, Gray, Joe W, Gusev, Yuriy, Ha, Min Jin, Han, Leng, Harris, Michael, Henderson, Nicholas, Hejase, Hussein A, Homicsko, Krisztian, Hou, Jack P, Hwang, Woochang, IJzerman, Adriaan P, Karacali, Bilge, Kaski, Samuel, Keles, Sunduz, Kendziorski, Christina, Kim, Junho, Kim, Min, Kim, Youngchul, Knowles, David A, Koller, Daphne, Lee, Junehawk, Lee, Jae K, Lenselink, Eelke B, Li, Biao, Li, Bin, Li, Jun, Liang, Han, Ma, Jian, Madhavan, Subha, Mooney, Sean, Myers, Chad L, Newton, Michael A, Overington, John P, Pal, Ranadip, Peng, Jian, Pestell, Richard, Prill, Robert J, Qiu, Peng, Rajwa, Bartek, Sadanandam, Anguraj, Saez-Rodriguez, Julio, Sambo, Francesco, Shin, Hyunjin, Singer, Dinah, Song, Jiuzhou, Song, Lei, Sridhar, Arvind, Stock, Michiel, Stolovitzky, Gustavo, Sun, Wei, Ta, Tram, Tadesse, Mahlet, Tan, Ming, Tang, Hao, Theodorescu, Dan, Toffolo, Gianna Maria, Tozeren, Aydin, Trepicchio, William, Varoquaux, Nelle, Vert, Jean-Philippe, Waegeman, Willem, Walter, Thomas, Wan, Qian, Wang, Difei, Wang, Wen, Wang, Yong, Wang, Zhishi, Wegner, Joerg K, Wu, Tongtong, Xia, Tian, Xiao, Guanghua, Xie, Yang, Xu, Yanxun, Yang, Jichen, Yuan, Yuan, Zhang, Shihua, Zhang, Xiang-Sun, Zhao, Junfei, Zuo, Chandler, van Vlijmen, Herman W T, van Westen, Gerard J P, Collins, James J, National Centre for Plasma Science and Technology (NCPST), Dublin City University [Dublin] ( DCU ), Institut Lumière Matière [Villeurbanne] ( ILM ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Mécanique des Contacts et des Structures [Villeurbanne] ( LaMCoS ), Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Centre National de la Recherche Scientifique ( CNRS ), Helsinki Institute for Information Technology, University of Westminster [London] ( UOW ), Stanford Center for BioMedical Informatics Research ( BMIR ), Stanford University [Stanford], DSTO, Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière ( NEMESIS-CRICM ), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière ( CRICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institute for Molecular Bioscience, and ARC Centre of Excellence in Bioinformatics, The University of Queensland, Brisbane, QLD 4072, Nanjing University of Information Science & Technology, Department of Physics [Stockholm], Stockholm University, Chercheur indépendant, Instituto de Engenharia de Sistemas e Computadores ( INESC ), European Bioinformatics Institute [Hinxton] ( EMBL-EBI ), European Molecular Biology Laboratory [Hinxton], Department of Agronomy, Tianjin Agricultural University ( TJAU ), Medicine Faculty, Erciyes University, Faculty of anima Medicine l, Northeast Agricultural University [Harbin], Oxford e-Research Centre [Oxford], University of Oxford [Oxford], Department of Computer Science [Alabama], University of Alabama [Tuscaloosa] ( UA ), Roberval, Université de Technologie de Compiègne ( UTC ), Institut de Mathématiques de Jussieu ( IMJ ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Centre for Inflammation Research, University of Edinburgh-Queen's Medical Research Institute, Division of Medicinal Chemistry, Universiteit Leiden [Leiden], University of Pittsburgh [Pittsburg], University of Pittsburgh, Department of Chemistry and Nano Science, EWHA Womans University ( EWHA ), Institute of Materials Chemistry, Technical University of Vienna [Vienna] ( TU WIEN ), Leiden Academic Center for Drug Research, Peking Univ, Coll Urban & Environm Sci, Lab Earth Surface Proc, Beijing 100871, Peoples R China, Queensland Research Lab, National ICT Australia [Sydney] ( NICTA ), Institut des Systèmes Intelligents et de Robotique ( ISIR ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Centre for Plant Integrative Biology [Nothingham] ( CPIB ), University of Nottingham, UK ( UON ), Department of Electrical and Computer Engineering, University of Utah, SUN Yatsen University, Sidney Kimmel Cancer Center, Jefferson (Philadelphia University + Thomas Jefferson University), Molecular Carcinogenesis [Sutton], Institute of cancer research, Centre d'études et de recherches appliquées à la gestion (Grenoble), Centre d'études et de recherches appliquées à la gestion ( CERAG ), Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Grenoble Alpes ( UGA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Grenoble Alpes ( UGA ), China Meteorological Administration, Equipe de Recherche Interdisciplinaire sur le Tourisme ( IUKB ), Institut Universitaire Kurt Bösch, University of Leeds, Dipartimento di Chimica, Università degli Studi di Roma 'La Sapienza' [Rome], Centre d'élaboration de matériaux et d'études structurales ( CEMES ), Institut National des Sciences Appliquées - Toulouse ( INSA Toulouse ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE, Centre de Bioinformatique ( CBIO ), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University ( PSL ), Computer Graphics Group, Department of Computer Science [Hong Kong], City University of Hong Kong [Hong Kong] ( CUHK ) -City University of Hong Kong [Hong Kong] ( CUHK ), Ingénierie Moléculaire et Physiopathologie Articulaire ( IMoPA ), Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Computing [London], Biomedical Image Analysis Group [London] ( BioMedIA ), Imperial College London-Imperial College London, State Key Laboratory of Virology, Wuhan University [China], MoNOS, Huygens Laboratory, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China ( IMP ), University of Science and Technology Beijing [Beijing] ( USTB ), Laboratoire de Chimie Physique - Matière et Rayonnement ( LCPMR ), Dalian University of Technology, Chalmers University of Technology [Göteborg], Advanced Photon Source [ANL] ( APS ), Argonne National Laboratory [Lemont] ( ANL ) -University of Chicago-US Department of Energy, Beth Israel Deaconess Medical Center, Harvard Medical School [Boston] ( HMS ), Dublin City University [Dublin] (DCU), Helsinki Institute for Information Technology (HIIT), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Aalto University, University of Westminster [London] (UOW), Stanford Center for BioMedical Informatics Research (BMIR), Stanford University, Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière (NEMESIS-CRICM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Bioscience, University of Queensland [Brisbane], Nanjing University of Information Science and Technology (NUIST), Instituto de Engenharia de Sistemas e Computadores (INESC), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Tianjin Agricultural University (TJAU), University of Oxford, University of Alabama [Tuscaloosa] (UA), Roberval (Roberval), Université de Technologie de Compiègne (UTC), University of Edinburgh-Queen's Medical Researche Institute, University of Edinburgh, Universiteit Leiden, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), EWHA Womans University (EWHA), Vienna University of Technology (TU Wien), National ICT Australia [Sydney] (NICTA), Centre for Plant Integrative Biology [Nothingham] (CPIB), University of Nottingham, UK (UON), Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), 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), Centre de Bioinformatique (CBIO), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Computer Graphics Group [Hong Kong], City University of Hong Kong [Hong Kong] (CUHK)-City University of Hong Kong [Hong Kong] (CUHK), Biomedical Image Analysis Group [London] (BioMedIA), Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China (IMP), University of Science and Technology Beijing [Beijing] (USTB), Advanced Photon Source [ANL] (APS), Argonne National Laboratory [Lemont] (ANL)-University of Chicago-US Department of Energy, Harvard Medical School [Boston] (HMS), Aalto University-University of Helsinki, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], MINES ParisTech - École nationale supérieure des mines de Paris, TR11527, Karaçalı, Bilge, and Izmir Institute of Technology. Electronics and Communication Engineering
Subjects: Epigenomics, Proteomics, Biological pathways, Inference, computer.software_genre, Genomic information, Applied Microbiology and Biotechnology, 0302 clinical medicine, Neoplasms, Computational models, Profiling (information science), ta518, [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], ta515, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Computational model, ta213, Genomics, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, Molecular Medicine, Algorithms, Biotechnology, Data integration, Bayesian probability, Biomedical Engineering, Antineoplastic Agents, Bioengineering, Biology, Machine learning, Article, 03 medical and health sciences, Humans, 030304 developmental biology, ta113, ta112, Proteomic Profiling, business.industry, Gene Expression Profiling, Precision medicine, Drug Resistance, Neoplasm, ta5141, Gene expression, Artificial intelligence, business, computer, Forecasting
Abstract: Predicting the best treatment strategy from genomic information is a core goal of precision medicine. Here we focus on predicting drug response based on a cohort of genomic, epigenomic and proteomic profiling data sets measured in human breast cancer cell lines. Through a collaborative effort between the National Cancer Institute (NCI) and the Dialogue on Reverse Engineering Assessment and Methods (DREAM) project, we analyzed a total of 44 drug sensitivity prediction algorithms. The top-performing approaches modeled nonlinear relationships and incorporated biological pathway information. We found that gene expression microarrays consistently provided the best predictive power of the individual profiling data sets; however, performance was increased by including multiple, independent data sets. We discuss the innovations underlying the top-performing methodology, Bayesian multitask MKL, and we provide detailed descriptions of all methods. This study establishes benchmarks for drug sensitivity prediction and identifies approaches that can be leveraged for the development of new methods., MaGNeT grant 5U54CA121852-08; National Institutes of Health, National Cancer Institute (U54 CA 112970); Stand Up To Cancer-American Association for Cancer Research Dream Team Translational Cancer Research (SU2C-AACR-DT0409); Prospect Creek Foundation; Howard Hughes Medical Institute (HHMI); Academy of Finland (Finnish Center of Excellence in Computational Inference Research COIN) (251170--140057)
Published: 2014
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2. Cells Respond to Mechanical Stress by Rapid Disassembly of Caveolae

Author: Graça Raposo, Robert G. Parton, Nobuhiro Morone, Bidisha Sinha, Benoît Vedie, Michele Bastiani, Pierre Nassoy, Pierre Sens, Pauline Gonnord, Richard Ruez, Christophe Lamaze, Ludger Johannes, Radu V. Stan, Gillian Butler-Browne, Daniel Abankwa, Darius Vasco Köster, Indian Institute of Science Education and Research Kolbata (IISER Kolkata), Cell and Developmental Biology [Coventry, UK], Division of Biomedical Sciences [Coventry, UK], Warwick Medical School, University of Warwick [Coventry]-University of Warwick [Coventry]-Warwick Medical School, University of Warwick [Coventry]-University of Warwick [Coventry], Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), 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)-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Center for Microscopy and Microanalysis - University of Queensland, University of Queensland [Brisbane], Darrmouth Medical School, Dartmouth Medical School, Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de biochimie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Compartimentation et dynamique cellulaires (CDC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Department of Ultrastructural Research, National Center of Neurology and Psychiatry, Institute for Molecular Bioscience [Queensland, Australia], Laboratoire de Physico-Chimie Théorique (LPCT), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Photonique, Numérique et Nanosciences (LP2N), Université de Bordeaux (UB)-Institut d'Optique Graduate School (IOGS)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Dartmouth Medical School (DMS), Dartmouth College [Hanover]-Dartmouth College [Hanover], Physico-Chimie-Curie (PCC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Thérapie des maladies du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biochimie, Hô pital Européen Georges Pompidou, Institute for Molecular Bioscience, lp2n-04,lp2n-16, Université Sciences et Technologies - Bordeaux 1 (UB)-Institut d'Optique Graduate School (IOGS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1 (UB)-Institut d'Optique Graduate School (IOGS)-Centre National de la Recherche Scientifique (CNRS), Institut Curie (PIC Division Cellulaire, Polarite et Cancer) Fondation de France Association Francaise contre les Myopathies National Health and Medical Research Council of Australia Australian Research Council NIH Association pour la Recherche sur le Cancer, ANR-06-BLAN-0211,DYNATUBE,Cellular responses to mechanical stress: interplay between membrane tension and membrane dynamics(2006), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Sciences et Technologies - Bordeaux 1-Institut d'Optique Graduate School (IOGS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut d'Optique Graduate School (IOGS)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)
Subjects: ENDOCYTOSIS, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], DEPENDENT ACTIVATION, PROTEIN, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Caveolae, Endocytosis, General Biochemistry, Genetics and Molecular Biology, Article, Cell Line, Mice, 03 medical and health sciences, Adenosine Triphosphate, 0302 clinical medicine, Caveolin, Animals, Humans, Myocyte, SIGNAL-REGULATED KINASE, ComputingMilieux_MISCELLANEOUS, Actin, 030304 developmental biology, Muscle Cells, 0303 health sciences, Biochemistry, Genetics and Molecular Biology(all), MUTATIONS, Myogenesis, Endothelial Cells, IN-VITRO, MUSCLE, MEMBRANE TENSION, ENDOTHELIAL-CELLS, GENE, Actins, Cell biology, Membrane, [PHYS.COND.CM-GEN]Physics [physics]/Condensed Matter [cond-mat]/Other [cond-mat.other], Stress, Mechanical, 030217 neurology & neurosurgery, Cavin
Abstract: The precise role of caveolae, the characteristic plasma membrane invaginations present in many cells, still remains debated. The high density of caveolae in cells experiencing mechanical stress led us to investigate their role in membrane-mediated mechanical response. Acute mechanical stress induced by cell osmotic swelling or by uniaxial stretching results in the immediate disappearance of caveolae, which is associated with a reduced caveolin/Cavin1 interaction, and an increase of free caveolins at the plasma membrane. Tether pulling force measurements in live cells and in plasma membrane spheres demonstrate that caveola flattening and disassembly is the primary actin and ATP-independent cell response which buffers membrane tension surges during mechanical stress. Conversely, stress release leads to complete caveola reassembly in an actin and ATP-dependent process. The absence of a functional caveola reservoir in myotubes from muscular dystrophic patients enhanced membrane fragility under mechanical stress. Our findings support a new role for caveolae as a physiological membrane reservoir that allows cells to quickly accommodate sudden and acute mechanical stresses.
Published: 2011
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3. Structural brain alterations associated with suicidal thoughts and behaviors in young people: results from 21 international studies from the ENIGMA Suicidal Thoughts and Behaviours consortium

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

Author: Couvy-Duchesne, Baptiste, Bottani, Simona, Camenen, Etienne, Fang, Fang, Fikere, Mulusew, Gonzalez-Astudillo, Juliana, Harvey, Joshua, Hassanaly, Ravi, Kassam, Irfahan, Lind, Penelope, Liu, Qianwei, Lu, Yi, Nabais, Marta, Rolland, Thibault, Sidorenko, Julia, Strike, Lachlan, Wright, Margie, Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Bioscience, University of Queensland [Brisbane], Institut du Cerveau = Paris Brain Institute (ICM), 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), Karolinska Institutet [Stockholm], University of Exeter Medical School, University of Exeter, Lee Kong Chian School of Medicine, Nanyang Technological University [Singapour], QIMR Berghofer Medical Research Institute, Queensland Brain Institute, This research was supported by the Australian National Health and Medical Research Council (1078037, 1078901, 1113400, 1161356 and 1107258), the Australian Research Council (FT180100186 and FL180100072), the Sylvia & Charles Viertel Charitable Foundation, the program 'Investissements d’avenir' ANR-10-IAIHU-06 (Agence Nationale de la Recherche-10-IA Institut Hospitalo-Universitaire-6) and reference ANR-19-P3IA-0001 (PRAIRIE 3IA Institute), the European Union H2020 program (project EuroPOND, grant number 666992, the joint NSF/NIH/ANR program 'Collaborative Research in Computational Neuroscience' (project HIPLAY7, grant number ANR-16-NEUC-0001-01), the ICM Big Brain Theory Program (project DYNAMO, project PredictICD), and the Abeona Foundation (project Brain@Scale). BCD is supported by a CJ Martin fellowship (APP1161356)., ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), ANR-16-NEUC-0001,HIPLAY7,Experimental and theoretical investigation of the multi-scale emergence of parametric working memory in prefrontal cortex recurrent networks(2016), European Project: 666992,H2020 Pilier Societal Challenges,H2020-PHC-2015-two-stage,EuroPOND(2016), Couvy-Duchesne, Baptiste, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Experimental and theoretical investigation of the multi-scale emergence of parametric working memory in prefrontal cortex recurrent networks - - HIPLAY72016 - ANR-16-NEUC-0001 - CRCNS - VALID, and Data-driven models for Progression Of Neurological Disease - EuroPOND - - H2020 Pilier Societal Challenges2016-01-01 - 2019-12-31 - 666992 - VALID
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics, PET, [INFO.INFO-DB]Computer Science [cs]/Databases [cs.DB], EEG/MEG, Brain MRI, Wearables, Genetics, [INFO.INFO-DB] Computer Science [cs]/Databases [cs.DB], Electronic health records, Omics, [SDV.GEN] Life Sciences [q-bio]/Genetics, Gene expression, Methylation
Abstract: Recent advances in technology have made possible to quantify fine-grained individual differences at many levels, such as genetic, genomics, organ level, behaviour, clinical. The wealth of data becoming available raises great promises for research on brain disorders as well as normal brain function. To name a few: systematic and agnostic study of disease risk factors (e.g. genetic variants, brain regions), the use of natural experiments (e.g. evaluate the effect of a genetic variant in a human population), and unveiling disease mechanisms across several biological levels (e.g. genetics, cellular gene expression, organ structure and function). However, this data revolution raises many challenges such as data sharing and management, the need for novel analysis methods and software, storage and computing. Here, we sought to provide an overview of some of the main existing human datasets, all accessible to researchers. Our list is far from being exhaustive and our objective is to publicise data sharing initiatives and help researchers find new data sources.
Published: 2022

5. Parsimonious model for mass-univariate vertexwise analysis

Author: Baptiste Couvy-Duchesne, Futao Zhang, Kathryn E. Kemper, Julia Sidorenko, Naomi R. Wray, Peter M. Visscher, Olivier Colliot, Jian Yang, Colliot, Olivier, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Experimental and theoretical investigation of the multi-scale emergence of parametric working memory in prefrontal cortex recurrent networks - - HIPLAY72016 - ANR-16-NEUC-0001 - CRCNS - VALID, Data-driven models for Progression Of Neurological Disease - EuroPOND - - H2020 Pilier Societal Challenges2016-01-01 - 2019-12-31 - 666992 - VALID, Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Bioscience, University of Queensland [Brisbane], Westlake University [Zhejiang], ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), ANR-16-NEUC-0001,HIPLAY7,Experimental and theoretical investigation of the multi-scale emergence of parametric working memory in prefrontal cortex recurrent networks(2016), and European Project: 666992,H2020 Pilier Societal Challenges,H2020-PHC-2015-two-stage,EuroPOND(2016)
Subjects: Linear mixed model, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Structural brain MRI, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [INFO.INFO-IM] Computer Science [cs]/Medical Imaging, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Association, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, [INFO.INFO-CV] Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Vertex-wise processing, [INFO.INFO-TI] Computer Science [cs]/Image Processing [eess.IV], [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Radiology, Nuclear Medicine and imaging, Brain mapping, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, [SPI.SIGNAL] Engineering Sciences [physics]/Signal and Image processing
Abstract: International audience; Purpose: Covariance between gray-matter measurements can reflect structural or functional brain networks though it has also been shown to be influenced by confounding factors (e.g., age, head size, and scanner), which could lead to lower mapping precision (increased size of associated clusters) and create distal false positives associations in mass-univariate vertexwise analyses. Approach: We evaluated this concern by performing state-of-the-art mass-univariate analyses (general linear model, GLM) on traits simulated from real vertex-wise gray matter data (including cortical and subcortical thickness and surface area). We contrasted the results with those from linear mixed models (LMMs), which have been shown to overcome similar issues in omics association studies. Results: We showed that when performed on a large sample (N ¼ 8662, UK Biobank), GLMs yielded greatly inflated false positive rate (cluster false discovery rate >0.6). We showed that LMMs resulted in more parsimonious results: smaller clusters and reduced false positive rate but at a cost of increased computation. Next, we performed mass-univariate association analyses on five real UKB traits (age, sex, BMI, fluid intelligence, and smoking status) and LMM yielded fewer and more localized associations. We identified 19 significant clusters displaying small associations with age, sex, and BMI, which suggest a complex architecture of at least dozens of associated areas with those phenotypes. Conclusions: The published literature could contain a large proportion of redundant (possibly confounded) associations that are largely prevented using LMMs. The parsimony of LMMs results from controlling for the joint effect of all vertices, which prevents local and distal redundant associations from reaching significance.
Published: 2022
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6. MRI field strength predicts Alzheimer's disease: a case example of bias in the ADNI data set

Author: Elina Thibeau-Sutre, Baptiste Couvy-Duchesne, Didier Dormont, Olivier Colliot, Ninon Burgos, THIBEAU-SUTRE, Elina, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Bioscience, University of Queensland [Brisbane], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), The research leading to these results has received funding from the French government under man-agement of Agence Nationale de la Recherche as part of the 'Investissements d’avenir' program, reference ANR-19-P3IA-0001 (PRAIRIE 3IA Institute) and reference ANR-10-IAIHU-06 (Agence Nationale de la Recherche-10-IA Institut Hospitalo-Universitaire-6). BCD is supported by the NHMRC (app1161356)., and ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019)
Subjects: [INFO.INFO-AI] Computer Science [cs]/Artificial Intelligence [cs.AI], Bias, Alzheimer, ADNI, [INFO.INFO-IM] Computer Science [cs]/Medical Imaging, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Neuroimaging, Deep learning, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI]
Abstract: International audience; The Alzheimer's Disease Neuroimaging Initiative (ADNI) data set has been extensively used for the prediction of the progression of prodromal patients to Alzheimer's disease dementia. However, the deep learning community is not always aware of the biases that may contaminate neuroimaging data sets, which may lead to flawed results. In this case example, we demonstrated how ignoring the magnetic resonance (MR) field strength can bias performance of deep learning prediction when using MR images as input. Finally, we discussed options to overcome this problem.
Published: 2022
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7. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author: Tove Fall, Anubha Mahajan, Dmitry Shungin, B. Balkau, Gerjan Navis, A. Metspalu, Anneli Pouta, Andrew A. Hicks, Ilja M. Nolte, Ian Ford, Aroon D. Hingorani, Stefan R Bornstein, Anuj Goel, Rona J. Strawbridge, Niek Verweij, Sarah H. Wild, Patricia B. Munroe, T.B. Harris, Jaana Lindström, Johnson Pcd., Nita G. Forouhi, Pierre Meneton, Patricia A. Peyser, Sarin A-P., Andrea Ganna, Timothy M. Frayling, Patrik K. E. Magnusson, Joanne M. Meyer, Yongmei Liu, Jeanette M. Stafford, Christian Herder, L Zudina, Maria G. Stathopoulou, May E. Montasser, Nicholas D. Hastie, Inês Barroso, Schwarz Peh., James B. Meigs, Perttu Salo, George Davey Smith, Gonneke Willemsen, Christopher J. Groves, Erik P A Van Iperen, M. A. Province, Veikko Salomaa, Naveed Sattar, Serena Sanna, Maria Dimitriou, Joop Jukema, Ulrika Krus, Albert V. Smith, Markku Laakso, James F. Wilson, George Nicholson, Loic Yengo, Tatijana Zemunik, Per Eriksson, Harold Snieder, Peter P. Pramstaller, Claudia Langenberg, R. Rauramaa, Alan R. Shuldiner, Pau Navarro, Veronique Vitart, Ross M. Fraser, Aaron Isaacs, C. Lecoeur, Jesper R. Gådin, Jackie F. Price, Letizia Marullo, L.F. Bielak, Sirkka Keinänen-Kiukaanniemi, Amélie Bonnefond, Michael Stumvoll, Alessia Faggian, Anke Tönjes, Tomohiro Tanaka, Wieland Kiess, Harry Campbell, Josée Dupuis, David Altshuler, João Fadista, Winfried März, G K Hovingh, Thomas Illig, Toby Johnson, H Grallert, Kari Stefansson, Reedik Mägi, Palmer Cna., de Geus Ejcn., Martina Müller-Nurasyid, Karen Kapur, Philippe Froguel, Dorret I. Boomsma, Anders Franco-Cereceda, Marcus E. Kleber, Boehnke M, Olga D. Carlson, Ozren Polasek, Andrew P. Morris, Alex S. F. Doney, Najaf Amin, Sara M. Willems, Vilmundur Gudnason, Jose C. Florez, Jeffery R. O'Connell, Nancy L. Pedersen, T. Saaristo, Wolffenbuttel Bhr., M. I. J. Uusitupa, Longda Jiang, Iva Miljkovic, James S. Pankow, Caroline Hayward, Hugh Watkins, Vasiliki Lagou, Johanna Kuusisto, Jaakko Tuomilehto, Alan F. Wright, Josephine M. Egan, Perry Jrb., C M van Duijn, Valeriya Lyssenko, Leif Groop, Stefania Bandinelli, Nigel W. Rayner, Tõnu Esko, Stela McLachlan, Momoko Horikoshi, Eric Boerwinkle, Rick Jansen, Richard N. Bergman, Gudmar Thorleifsson, Lyle J. Palmer, Vilmantas Giedraitis, Peter Kovacs, Nicholas J. Wareham, Luigi Ferrucci, N J Timpson, D Rybin, Anne U. Jackson, Tiinamaija Tuomi, Gonçalo R. Abecasis, Harst Pvd., Meena Kumari, Albert Hofman, Chiara Scapoli, Evelin Mihailov, Josine L. Min, Anders Hamsten, Hottenga J-J., Loos Rjf., Lars Lind, Ulf de Faire, Jaakko Kaprio, Guo Li, Beate St Pourcain, C Gieger, Amanda J. Bennett, Anna Ulrich, Nabila Bouatia-Naji, Satu Männistö, Antigone S. Dimas, Jarvelin M-R., Günther Silbernagel, F Karpe, A. Körner, David S. Siscovick, M Blüher, Rebecca J. Webster, Erik Ingelsson, Susan Campbell, Mika Kivimäki, Laura J. Rasmussen-Torvik, Heikki A. Koistinen, Sophie Visvikis-Siest, Bernhard O. Boehm, Inga Prokopenko, Ping An, Emmanouil T. Dermitzakis, Cecilia M. Lindgren, Kardia Slr., Richa Saxena, Igor Rudan, Richard M. Watanabe, Jian'an Luan, Marika Kaakinen, Shin S-Y., George Dedoussis, Panagiotis Deloukas, Mark I. McCarthy, Barbara Thorand, B.W.J.H. Penninx, Peter Vollenweider, Paul W. Franks, Leena Kinnunen, Markus Perola, Yvonne Boettcher, Timo A. Lakka, Nicole Soranzo, Stavroula Kanoni, Bakker Sjl., Winkelmann Br, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institute of Genomics [Tartu, Estonia], University of Tartu, Vrije Universiteit Amsterdam [Amsterdam] (VU), Vrije Universiteit Medical Centre (VUMC), Helmholtz-Zentrum München (HZM), University of Cambridge [UK] (CAM), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Università degli Studi di Ferrara (UniFE), Boston University [Boston] (BU), VU University Medical Center [Amsterdam], University of Bristol [Bristol], Biomedical Sciences Research Centre Alexander Fleming [Vari, Greece] (BSRC), Imperial College London, Karolinska Institutet [Stockholm], Institute for Molecular Bioscience, University of Queensland [Brisbane], Statens Serum Institut [Copenhagen], Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Cardiovascular Research Institute Maastricht (CARIM), Maastricht University [Maastricht], MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, National Institute on Aging [Baltimore, MD, USA] (NIH), University of Michigan [Ann Arbor], University of Michigan System, University of Maryland School of Medicine, University of Maryland System, The University of Western Australia (UWA), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Wake Forest University, National Institute for Health and Welfare [Helsinki], The Wellcome Trust Sanger Institute [Cambridge], University of Iceland [Reykjavik], University of Washington [Seattle], University of Groningen [Groningen], University of Glasgow, William Harvey Research Institute, Barts and the London Medical School, Université de Lausanne (UNIL), deCODE genetics [Reykjavik], Northwestern University Feinberg School of Medicine, Uppsala Universitet [Uppsala], University of Edinburgh, Medical Faculty [Mannheim], University of Graz, Ludwig-Maximilians-Universität München (LMU), Johannes Gutenberg - Universität Mainz (JGU), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Umeå University, Skane University Hospital [Malmo], Lund University [Lund], RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche [Roma] (CNR), University Medical Center Groningen [Groningen] (UMCG), Universität Leipzig [Leipzig], Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Split, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), University of Eastern Finland, Harokopio University of Athens, European Academy Bozen/Bolzano (EURAC), University of Kuopio, German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Ninewells Hospital and Medical School [Dundee], University College of London [London] (UCL), University of Essex, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], University of Helsinki, Leiden University Medical Center (LUMC), Institute of Cardiovascular and Medical Sciences [Glasgow], University of Oulu, The University of Texas Health Science Center at Houston (UTHealth), University of Minnesota Medical School, University of Minnesota System, Keck School of Medicine [Los Angeles], University of Southern California (USC), Amsterdam UMC, University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Lee Kong Chian School of Medicine, Nanyang Technological University (NTU), Universität Heidelberg [Heidelberg], King Abdulaziz University, Pirkanmaa Hospital District, Tampere University Hospital, Cedars-Sinai Medical Center, Danube University Krems, Harvard School of Public Health, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Hannover Medical School [Hannover] (MHH), Universität zu Lübeck [Lübeck], University of Exeter, Regeneron Pharmaceuticals [Tarrytown], University of Adelaide, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Harvard T.H. Chan School of Public Health, John Radcliffe Hospital [Oxford University Hospital], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Université de Genève (UNIGE), Big Data Institute, University of Surrey (UNIS), University of Bergen (UiB), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford Cardiovascular Institute, University of Liverpool, University of Manchester [Manchester], Institute of Biochemistry and Genetics of Ufa Scientific Centre, Russian Academy of Sciences [Moscow] (RAS), Experimental Vascular Medicine, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, SIEST, Sofia, PreciDIAB Institute, the holistic approach of personal diabets care - - PreciDIAB2018 - ANR-18-IBHU-0001 - IBHU - VALID, Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging - DYNAHEALTH - - H20202015-04-01 - 2019-03-31 - 633595 - VALID, Beyond the Genetics of Addiction - ADDICTION - - EC:FP7:ERC2011-12-01 - 2017-05-31 - 284167 - VALID, Rise of scientific excellence and collaboration for implementing personalised medicine in Estonia - ePerMed - - H20202016-01-01 - 2018-12-31 - 692145 - VALID, University of Oxford, Helmholtz Zentrum München = German Research Center for Environmental Health, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Università degli Studi di Ferrara = University of Ferrara (UniFE), Université de Lausanne = University of Lausanne (UNIL), Karl-Franzens-Universität Graz, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Amsterdam UMC - Amsterdam University Medical Center, Nanyang Technological University [Singapour], Universität zu Lübeck = University of Lübeck [Lübeck], Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Université de Genève = University of Geneva (UNIGE), ANR-18-IBHU-0001,PreciDIAB,PreciDIAB Institute, the holistic approach of personal diabets care(2018), European Project: 633595,H2020,H2020-PHC-2014-two-stage,DYNAHEALTH(2015), European Project: 284167,EC:FP7:ERC,ERC-2011-StG_20101124,ADDICTION(2011), European Project: 692145,H2020,H2020-TWINN-2015,ePerMed(2016), Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Functional Genomics, APH - Mental Health, Sociology and Social Gerontology, APH - Methodology, Hottenga, Jouke- Jan [0000-0002-5668-2368], Bouatia-Naji, Nabila [0000-0001-5424-2134], Jansen, Rick [0000-0002-3333-6737], Min, Josine L. [0000-0003-4456-9824], Faggian, Alessia [0000-0002-3799-9722], Bonnefond, Amélie [0000-0001-9976-3005], Isaacs, Aaron [0000-0001-5037-4834], Willems, Sara M. [0000-0002-6803-3007], Navarro, Pau [0000-0001-5576-8584], Jackson, Anne U. [0000-0002-9672-2547], Bielak, Lawrence F. [0000-0002-3443-8030], Saxena, Richa [0000-0003-2233-1065], Smith, Albert V. [0000-0003-1942-5845], Verweij, Niek [0000-0002-4303-7685], Goel, Anuj [0000-0003-2307-4021], Johnson, Paul C. D. [0000-0001-6663-7520], Strawbridge, Rona J. [0000-0001-8506-3585], Fall, Tove [0000-0003-2071-5866], Fraser, Ross M. [0000-0003-0488-2592], Kanoni, Stavroula [0000-0002-1691-9615], Giedraitis, Vilmantas [0000-0003-3423-2021], Kleber, Marcus E. [0000-0003-0663-7275], Müller-Nurasyid, Martina [0000-0003-3793-5910], Luan, Jian’an [0000-0003-3137-6337], Sanna, Serena [0000-0002-3768-1749], Nolte, Ilja M. [0000-0001-5047-4077], Zemunik, Tatijana [0000-0001-8120-2891], Kovacs, Peter [0000-0002-0290-5423], Wild, Sarah H. [0000-0001-7824-2569], McLachlan, Stela [0000-0003-0480-6143], Egan, Josephine [0000-0002-8945-0053], Hicks, Andrew A. [0000-0001-6320-0411], Thorand, Barbara [0000-0002-8416-6440], Hingorani, Aroon [0000-0001-8365-0081], Kivimaki, Mika [0000-0002-4699-5627], Koistinen, Heikki A. [0000-0001-7870-070X], Bakker, Stephan J. L. [0000-0003-3356-6791], Palmer, Colin N. A. [0000-0002-6415-6560], Jukema, J. Wouter [0000-0002-3246-8359], Sattar, Naveed [0000-0002-1604-2593], Snieder, Harold [0000-0003-1949-2298], Magnusson, Patrik K. [0000-0002-7315-7899], Blüher, Matthias [0000-0003-0208-2065], Wolffenbuttel, Bruce H. R. [0000-0001-9262-6921], Abecasis, Goncalo R. [0000-0003-1509-1825], Meigs, James B. [0000-0002-2439-2657], Wilson, James F. [0000-0001-5751-9178], Schwarz, Peter E. H. [0000-0001-6317-7880], Boehm, Bernhard O. [0000-0002-2706-7710], Metspalu, Andres [0000-0002-3718-796X], Deloukas, Panos [0000-0001-9251-070X], Körner, Antje [0000-0001-6001-0356], Wareham, Nicholas J. [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Männistö, Satu [0000-0002-8668-3046], Franks, Paul W. [0000-0002-0520-7604], Hayward, Caroline [0000-0002-9405-9550], Vitart, Veronique [0000-0002-4991-3797], Kaprio, Jaakko [0000-0002-3716-2455], Visvikis-Siest, Sophie [0000-0001-8104-8425], Altshuler, David [0000-0002-7250-4107], Rudan, Igor [0000-0001-6993-6884], van Duijn, Cornelia M. [0000-0002-2374-9204], Pramstaller, Peter P. [0000-0002-9831-8302], Boehnke, Michael [0000-0002-6442-7754], Frayling, Timothy M. [0000-0001-8362-2603], Peyser, Patricia A. [0000-0002-9717-8459], Harst, Pim van der [0000-0002-2713-686X], Smith, George Davey [0000-0002-1407-8314], Forouhi, Nita G. [0000-0002-5041-248X], Loos, Ruth J. F. [0000-0002-8532-5087], Salomaa, Veikko [0000-0001-7563-5324], Soranzo, Nicole [0000-0003-1095-3852], Boomsma, Dorret I. [0000-0002-7099-7972], Groop, Leif [0000-0002-0187-3263], Tuomi, Tiinamaija [0000-0002-8306-6202], Munroe, Patricia B. [0000-0002-4176-2947], Gudnason, Vilmundur [0000-0001-5696-0084], Lecoeur, Cecile [0000-0003-0075-6417], Jarvelin, Marjo-Riitta [0000-0002-2149-0630], Stefansson, Kari [0000-0003-1676-864X], Dermitzakis, Emmanouil T. [0000-0002-9302-6490], Lindgren, Cecilia M. [0000-0002-4903-9374], Froguel, Philippe [0000-0003-2972-0784], Kaakinen, Marika A. [0000-0002-9228-0462], Watanabe, Richard M. [0000-0003-1015-0531], Ingelsson, Erik [0000-0003-2256-6972], Dupuis, Josée [0000-0003-2871-3603], Barroso, Inês [0000-0001-5800-4520], Apollo - University of Cambridge Repository, Epidemiology, University Hospital Mannheim | Universitätsmedizin Mannheim, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Universität Leipzig, Universiteit Leiden, Universität Heidelberg [Heidelberg] = Heidelberg University, Karl-Franzens-Universität [Graz, Autriche], Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, General practice, APH - Digital Health, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Value, Affordability and Sustainability (VALUE), Cardiovascular Centre (CVC), Hottenga, Jouke-Jan [0000-0002-5668-2368], Min, Josine L [0000-0003-4456-9824], Willems, Sara M [0000-0002-6803-3007], Jackson, Anne U [0000-0002-9672-2547], Bielak, Lawrence F [0000-0002-3443-8030], Smith, Albert V [0000-0003-1942-5845], Johnson, Paul CD [0000-0001-6663-7520], Strawbridge, Rona J [0000-0001-8506-3585], Fraser, Ross M [0000-0003-0488-2592], Kleber, Marcus E [0000-0003-0663-7275], Luan, Jian'an [0000-0003-3137-6337], Nolte, Ilja M [0000-0001-5047-4077], Wild, Sarah H [0000-0001-7824-2569], Hicks, Andrew A [0000-0001-6320-0411], Koistinen, Heikki A [0000-0001-7870-070X], Bakker, Stephan JL [0000-0003-3356-6791], Palmer, Colin NA [0000-0002-6415-6560], Jukema, J Wouter [0000-0002-3246-8359], Magnusson, Patrik K [0000-0002-7315-7899], Wolffenbuttel, Bruce HR [0000-0001-9262-6921], Abecasis, Goncalo R [0000-0003-1509-1825], Meigs, James B [0000-0002-2439-2657], Wilson, James F [0000-0001-5751-9178], Schwarz, Peter EH [0000-0001-6317-7880], Boehm, Bernhard O [0000-0002-2706-7710], Wareham, Nicholas J [0000-0003-1422-2993], Franks, Paul W [0000-0002-0520-7604], van Duijn, Cornelia M [0000-0002-2374-9204], Pramstaller, Peter P [0000-0002-9831-8302], Frayling, Timothy M [0000-0001-8362-2603], Peyser, Patricia A [0000-0002-9717-8459], Forouhi, Nita G [0000-0002-5041-248X], Loos, Ruth JF [0000-0002-8532-5087], Boomsma, Dorret I [0000-0002-7099-7972], Munroe, Patricia B [0000-0002-4176-2947], Dermitzakis, Emmanouil T [0000-0002-9302-6490], Lindgren, Cecilia M [0000-0002-4903-9374], Kaakinen, Marika A [0000-0002-9228-0462], Watanabe, Richard M [0000-0003-1015-0531], Tampere University, Tays Research Services, Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), Fysiologie, RS: FHML MaCSBio, and RS: Carim - B01 Blood proteins & engineering
Subjects: Male, Anorexia Nervosa, medicine.medical_treatment, 45/43, Insulin Resistance/genetics, SUSCEPTIBILITY, Quantitative trait, Impaired glucose tolerance, 0302 clinical medicine, Architecture, LS2_1, IMPUTATION, Insulin, ComputingMilieux_MISCELLANEOUS, Fasting, Publisher Correction, 3. Good health, [SDV] Life Sciences [q-bio], Kruppel-Like Transcription Factors/blood, Endokrinologi och diabetes, Science & Technology - Other Topics, Adult, Blood Glucose, European Continental Ancestry Group, Female, Gene Expression, Genetic Loci, Genome-Wide Association Study, Glucose Intolerance, Humans, Insulin Receptor Substrate Proteins, Insulin Resistance, Kruppel-Like Transcription Factors, Middle Aged, Phenotype, Sex Characteristics, Sex Factors, Waist-Hip Ratio, Sex characteristics, medicine.medical_specialty, Science, 631/208/205/2138, Endocrinology and Diabetes, General Biochemistry, Genetics and Molecular Biology, White People, Gender-differences, 03 medical and health sciences, SDG 3 - Good Health and Well-being, 692/53/2421, GLYCEMIC TRAITS, GENOME-WIDE ASSOCIATION, Glycemic, GENDER-DIFFERENCES, Science & Technology, IDENTIFICATION, 692/699/2743/2815, Blood Glucose/metabolism, Diagnostic markers, medicine.disease, Anorexia Nervosa/blood, 030104 developmental biology, Endocrinology, Glucose, Insulin/blood, Anorexia Nervosa/ethnology, Anorexia Nervosa/genetics, Anorexia Nervosa/physiopathology, Fasting/blood, Glucose Intolerance/blood, Glucose Intolerance/ethnology, Glucose Intolerance/genetics, Glucose Intolerance/physiopathology, Insulin Receptor Substrate Proteins/blood, Insulin Receptor Substrate Proteins/genetics, Kruppel-Like Transcription Factors/genetics, 0301 basic medicine, Identification, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Genome-wide association studies, Waist–hip ratio, LS4_5, RISK, ARCHITECTURE, Multidisciplinary, article, Type 2 diabetes, Multidisciplinary Sciences, MENDELIAN RANDOMIZATION, Pre-diabetes, Medical Genetics, Risk, PATHOPHYSIOLOGY, 030209 endocrinology & metabolism, 3121 Internal medicine, 692/163/2743/137/773, NO, Insulin resistance, Internal medicine, Diabetes mellitus, medicine, Mendelian randomization, 631/208/480, Medicinsk genetik, business.industry, General Chemistry, Impaired fasting glucose, business
Abstract: Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes., Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.
Published: 2021
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8. Association and prediction of phenotypic traits from neuroimaging data using a multi-component mixed model excluding the target vertex

Author: Julia Sidorenko, Kathryn E. Kemper, Jian Yang, Olivier Colliot, Naomi R. Wray, Baptiste Couvy-Duchesne, Futao Zhang, Peter M. Visscher, Institute for Molecular Bioscience, University of Queensland [Brisbane], Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), 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), Institute for Advanced Research (IFAR), Wenzhou Medical University [Wenzhou, China] (WMU), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), Couvy-Duchesne, Baptiste, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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], 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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: General linear model, Mixed model, [STAT.ME] Statistics [stat]/Methodology [stat.ME], business.industry, [INFO.INFO-IM] Computer Science [cs]/Medical Imaging, Pattern recognition, 02 engineering and technology, Biology, 021001 nanoscience & nanotechnology, 01 natural sciences, 010309 optics, Correlation, Neuroimaging, Sample size determination, 0103 physical sciences, False positive paradox, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], False positive rate, Artificial intelligence, 0210 nano-technology, business, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Genetic association
Abstract: International audience; Mass-univariate association analyses aim at mapping the brain regions associated with a trait/disorder. The correlation between vertices may cause a true association to spread locally (cluster of association) or distally (false positive cluster). We previously showed that controlling for all vertices in the model (using a linear mixed model: LMM), could greatly reduce the probability of false positive and improve mapping precision. Here, we investigated a new LMM called MOMENT which reduces false positive rate in methylome-wide association studies. Compared to LMM, MOMENT had enhanced power and mapping precision but failed at reducing the rates of false positives clusters.The increasing sample sizes from neuroimaging studies should allow detection of image measures are associated with phenotypic traits with smaller effect sizes, which will advance progress in the mapping of the brain regions associated with traits and diseases [1]. The UK Biobank (UKB) is one of the best example of this new generation of samples [2]. Multimodal Brain MRI collection is currently ongoing, with tens of thousands of individuals already imaged out of a target of 100,000 [2]. The large sample size, together with the breadth of phenotyping (incl. self-reports, in lab assessments, prescription and medical history), should allow new insights into the factors contributing to brain differences between older adults.
Published: 2021
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9. De novo missense variants in LMBRD2 are associated with developmental and motor delays, brain structure abnormalities and dysmorphic features

Author: Benjamin Navet, Renee Perrier, Kiyotaka Tomiwa, Alexander Pepler, Hui Xi, Adele Schneider, Xiao Mao, Ryan J. Taft, Paul Rollier, Alban Ziegler, Roberto Colombo, Noriko Miyake, Emmanuel Scalais, Katrien Stouffs, Estelle Colin, Denise L. Perry, Adeline Vanderver, Nobuhiko Okamoto, Magalie Barth, Li Shu, Elizabeth Wohler, Louise Amlie-Wolf, Hainan Zhang, Alessandro Serretti, Naomichi Matsumoto, Dominique Bonneau, Hua Wang, Omar Sherbini, Alka Malhotra, Nara Sobreira, Alessandra Ferrarini, Malhotra A., Ziegler A., Shu L., Perrier R., Amlie-Wolf L., Wohler E., Lygia De MacEna Sobreira N., Colin E., Vanderver A., Sherbini O., Stouffs K., Scalais E., Serretti A., Barth M., Navet B., Rollier P., Xi H., Wang H., Zhang H., Perry D.L., Ferrarini A., Colombo R., Pepler A., Schneider A., Tomiwa K., Okamoto N., Matsumoto N., Miyake N., Taft R., Mao X., Bonneau D., Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hunan Agricultural University [Changsha], Department of Neurology, Children's National Medical Center, Universitair Ziekenhuis Brussel, Centre Hospitalier de Luxembourg [Luxembourg] (CHL), Institute of Psychiatry, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Réseau Maladies Métaboliques, Hôpitaux Universitaires du Grand Ouest, Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), 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), CHU Pontchaillou [Rennes], Shandong University, Nanjing University of Science and Technology (NJUST), Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Università degli Studi di Brescia [Brescia], Genetics Division, Einstein Medical Center, Gifu University Graduate School of Medicine, Yokohama City University School of Medecine (YCUSM), Yokohama University School of Medecine, Institute for Molecular Bioscience, University of Queensland [Brisbane], Clinical sciences, Medical Genetics, Reproduction and Genetics, and Faculty of Law and Criminology
Subjects: 0301 basic medicine, gain of function mutation, Microcephaly, [SDV]Life Sciences [q-bio], Population, Biology, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Genetics, medicine, Missense mutation, education, Exome, Allele frequency, Genetics (clinical), Exome sequencing, ComputingMilieux_MISCELLANEOUS, education.field_of_study, mutation, missense, medicine.disease, 030104 developmental biology, genetics, medical, 030217 neurology & neurosurgery
Abstract: ObjectiveTo determine the potential disease association between variants in LMBRD2 and complex multisystem neurological and developmental delay phenotypes.MethodsHere we describe a series of de novo missense variants in LMBRD2 in 10 unrelated individuals with overlapping features. Exome sequencing or genome sequencing was performed on all individuals, and the cohort was assembled through GeneMatcher.ResultsLMBRD2 encodes an evolutionary ancient and widely expressed transmembrane protein with no known disease association, although two paralogues are involved in developmental and metabolic disorders. Exome or genome sequencing revealed rare de novo LMBRD2 missense variants in 10 individuals with developmental delay, intellectual disability, thin corpus callosum, microcephaly and seizures. We identified five unique variants and two recurrent variants, c.1448G>A (p.Arg483His) in three cases and c.367T>C (p.Trp123Arg) in two cases. All variants are absent from population allele frequency databases, and most are predicted to be deleterious by multiple in silico damage-prediction algorithms.ConclusionThese findings indicate that rare de novo variants in LMBRD2 can lead to a previously unrecognised early-onset neurodevelopmental disorder. Further investigation of individuals harbouring LMBRD2 variants may lead to a better understanding of the function of this ubiquitously expressed gene.
Published: 2021
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10. Exploratory analysis of the genetics of impulse control disorders in Parkinson's disease using genetic risk scores

Author: Samir Bekadar, Johann Faouzi, Jean-Christophe Corvol, Olivier Colliot, Baptiste Couvy-Duchesne, Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Bioscience, University of Queensland [Brisbane], Institut du Cerveau = Paris Brain Institute (ICM), 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), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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], 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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), Faouzi, Johann, and PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID
Subjects: 0301 basic medicine, Adult, Male, Genome-wide association study, Disease, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Risk Factors, Medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Depression (differential diagnoses), Genetic association, Aged, Genetics, Aged, 80 and over, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], business.industry, Parkinson Disease, Impulse control disorders, Middle Aged, 3. Good health, Disruptive, Impulse Control, and Conduct Disorders, 030104 developmental biology, Bonferroni correction, Neurology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Sample size determination, Parkinson''s disease, Multiple comparisons problem, Cohort, [SDV.GEN.GPO] Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], symbols, Female, Genetic risk scores, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: International audience; Objective: To study the association between impulse control disorders (ICDs) in Parkinsons disease (PD) and genetic risk scores (GRS) for 40 known or putative risk factors (e.g. depression, personality traits). Background: In absence of published genome-wide association studies (GWAS), little is known about the genetics of ICDs in PD. GRS of related phenotypes, for which large GWAS are available, may help shed light on the genetic contributors of ICDs in PD. Methods: We searched for GWAS on European ancestry populations with summary statistics publicly available for a broad range of phenotypes, including other psychiatric disorders, personality traits, and simple phenotypes. We separately tested their predictive ability in two of the largest PD cohorts with clinical and genetic available: the Parkinsons Progression Markers Initiative database (N = 368, 33% female, age range = [33 − 84]) and the Drug Interaction With Genes in Parkinsons Disease study (N = 373, 40% female, age range = [29 − 85]). Results: We considered 40 known or putative risk factors for ICDs in PD for which large GWAS had been published. After Bonferroni correction for multiple comparisons, no GRS or the combination of the 40 GRS were significantly associated with ICDs from the analyses in each cohort separately and from the meta-analysis. Conclusion: Albeit unsuccessful, our approach will gain power in the coming years with increasing availability of genotypes in clinical cohorts of PD, but also from future increase in GWAS sample sizes of the phenotypes we considered. Our approach may be applied to other complex disorders, for which GWAS are not available or limited.
Published: 2021
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11. Ensemble Learning of Convolutional Neural Network, Support Vector Machine, and Best Linear Unbiased Predictor for Brain Age Prediction: ARAMIS Contribution to the Predictive Analytics Competition 2019 Challenge

Author: Couvy-Duchesne, Baptiste, Faouzi, Johann, Martin, Benoît, Thibeau-Sutre, Elina, Wild, Adam, Ansart, Manon, Durrleman, Stanley, Dormont, Didier, Burgos, Ninon, Colliot, Olivier, Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau 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], 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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), Institute for Molecular Bioscience, University of Queensland [Brisbane], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The research leading to these results has received funding from the program Investissements d’avenir ANR-10-IAIHU-06 (Agence Nationale de la Recherche-10-IA InstitutHospitalo-Universitaire-6) and reference ANR-19-P3IA-0001 (PRAIRIE 3IA Institute), from the European Union H2020program (project EuroPOND, Grant No. 666992, from the joint NSF/NIH/ANR program Collaborative Research in Computational Neuroscience (project HIPLAY7, Grant No. ANR-16-NEUC-0001-01), from the ICM Big Brain Theory Program (project DYNAMO, project PredictICD), from the European Research Council (to SD project LEASP, Grant No. 678304), and from the Abeona Foundation (project Brain@Scale). Baptiste Couvy-Duchesne was supported by a CJ Martin Fellowship funded by the NHMRC (1161356)., ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), ANR-16-NEUC-0001,HIPLAY7,Experimental and theoretical investigation of the multi-scale emergence of parametric working memory in prefrontal cortex recurrent networks(2016), European Project: 678304,H2020 ERC,ERC-2015-STG,LEASP(2016), European Project: 666992,H2020 Pilier Societal Challenges,H2020-PHC-2015-two-stage,EuroPOND(2016), Couvy-Duchesne, Baptiste, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Experimental and theoretical investigation of the multi-scale emergence of parametric working memory in prefrontal cortex recurrent networks - - HIPLAY72016 - ANR-16-NEUC-0001 - CRCNS - VALID, Learning spatiotemporal patterns in longitudinal image data sets of the aging brain - LEASP - - H2020 ERC2016-09-01 - 2021-08-31 - 678304 - VALID, Data-driven models for Progression Of Neurological Disease - EuroPOND - - H2020 Pilier Societal Challenges2016-01-01 - 2019-12-31 - 666992 - VALID, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), and 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)
Subjects: Psychiatry, [INFO.INFO-AI] Computer Science [cs]/Artificial Intelligence [cs.AI], [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Deep learning, Brain age, [STAT.ML] Statistics [stat]/Machine Learning [stat.ML], Statistical learning, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], [INFO.INFO-CV] Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], [STAT.ML]Statistics [stat]/Machine Learning [stat.ML], Ensemble learning, Machine learning, Original Research, MRI
Abstract: International audience; We ranked third in the Predictive Analytics Competition (PAC) 2019 challenge by achieving a mean absolute error (MAE) of 3.33 years in predicting age from T1-weighted MRI brain images. Our approach combined seven algorithms that allow generating predictions when the number of features exceeds the number of observations, in particular, two versions of best linear unbiased predictor (BLUP), support vector machine (SVM), two shallow convolutional neural networks (CNNs), and the famous ResNet and Inception V1. Ensemble learning was derived from estimating weights via linear regression in a hold-out subset of the training sample. We further evaluated and identified factors that could influence prediction accuracy: choice of algorithm, ensemble learning, and features used as input/MRI image processing. Our prediction error was correlated with age, and absolute error was greater for older participants, suggesting to increase the training sample for this subgroup. Our results may be used to guide researchers to build age predictors on healthy individuals, which can be used in research and in the clinics as non-specific predictors of disease status.
Published: 2020
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12. A unified framework for association and prediction from vertex-wise grey-matter structure

Author: Peter M. Visscher, Baptiste Couvy-Duchesne, Olivier Colliot, Kathryn E. Kemper, Jian Yang, Zhili Zheng, Margaret J. Wright, Loic Yengo, Futao Zhang, Naomi R. Wray, Lachlan T. Strike, Yan Holtz, Institute for Molecular Bioscience, University of Queensland [Brisbane], 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], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Queensland Brain Institute, Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM), National Council for Scientific Research = Conseil national de la recherche scientifique du Liban [Lebanon] (CNRS-L), Institute for Advanced Research (IFAR), Wenzhou Medical University [Wenzhou, China] (WMU), This research was supported by the Australian National Health and Medical Research Council (1078037, 1078901, 1113400, 1161356 and 1107258), the Australian Research Council (FT180100186 and FL180100072), the Sylvia & Charles Viertel Charitable Foundation, as well as the Agence Nationale de la Recherche as part of the 'Investissements d'avenir' program, reference ANR-19-P3IA-0001 (PRAIRIE 3IA Institute) and reference ANR-2910-IAIHU-06 (Agence Nationale de la Recherche-10-IA Institut Hospitalo-Universitaire-6), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), 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), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Databases, Factual, [SDV]Life Sciences [q-bio], Body fat percentage, Correlation, 0302 clinical medicine, [STAT.ML]Statistics [stat]/Machine Learning [stat.ML], Statistics, Body Size, Gray Matter, Mixed models, Research Articles, 2. Zero hunger, Aged, 80 and over, [STAT.AP]Statistics [stat]/Applications [stat.AP], Human Connectome Project, Radiological and Ultrasound Technology, 05 social sciences, Age Factors, Middle Aged, Random effects model, Magnetic Resonance Imaging, [STAT]Statistics [stat], Phenotype, Neurology, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Anatomy, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Research Article, Mixed model, Neuroimaging, Bivariate analysis, Grey-matter correlation, Biology, 050105 experimental psychology, Association, 03 medical and health sciences, Sex Factors, Region of interest, Connectome, Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, Morphometricity, Aged, grey‐matter correlation, Brain MRI, Neurology (clinical), Prediction, Body mass index, 030217 neurology & neurosurgery
Abstract: The recent availability of large‐scale neuroimaging cohorts facilitates deeper characterisation of the relationship between phenotypic and brain architecture variation in humans. Here, we investigate the association (previously coined morphometricity) of a phenotype with all 652,283 vertex‐wise measures of cortical and subcortical morphology in a large data set from the UK Biobank (UKB; N = 9,497 for discovery, N = 4,323 for replication) and the Human Connectome Project (N = 1,110). We used a linear mixed model with the brain measures of individuals fitted as random effects with covariance relationships estimated from the imaging data. We tested 167 behavioural, cognitive, psychiatric or lifestyle phenotypes and found significant morphometricity for 58 phenotypes (spanning substance use, blood assay results, education or income level, diet, depression, and cognition domains), 23 of which replicated in the UKB replication set or the HCP. We then extended the model for a bivariate analysis to estimate grey‐matter correlation between phenotypes, which revealed that body size (i.e., height, weight, BMI, waist and hip circumference, body fat percentage) could account for a substantial proportion of the morphometricity (confirmed using a conditional analysis), providing possible insight into previous MRI case–control results for psychiatric disorders where case status is associated with body mass index. Our LMM framework also allowed to predict some of the associated phenotypes from the vertex‐wise measures, in two independent samples. Finally, we demonstrated additional new applications of our approach (a) region of interest (ROI) analysis that retain the vertex‐wise complexity; (b) comparison of the information retained by different MRI processings., This manuscript introduces a set of analyses, that rely on linear mixed models to perform association and prediction, while being suited to tackle the challenges of big‐data in neuroimaging. Our framework allows estimating new sample characteristics such as the total association (morphometricity) between a phenotype and vertex‐wise brain data or grey‐matter correlations that quantify how much phenotypes may be similarly associated with grey‐matter. In addition, it offers to build performant brain‐based predictors that do not require hyper‐parameter estimation.
Published: 2020
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13. Linear Mixed Models Minimise False Positive Rate and Enhance Precision of Mass Univariate Vertex-Wise Analyse of Grey-Matter

Author: Julia Sidorenko, Naomi R. Wray, Peter M. Visscher, Jian Yang, Kathryn E. Kemper, Futao Zhang, Baptiste Couvy-Duchesne, Olivier Colliot, Institute for Molecular Bioscience, University of Queensland [Brisbane], Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau 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], 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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), Sorbonne Université (SU), Institute for Advanced Research (IFAR), Wenzhou Medical University [Wenzhou, China] (WMU), PNRIA, ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), and 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)
Subjects: Vertex (graph theory), Simulations, 0303 health sciences, Mass univariate vertex-wise analyses, [SDV]Life Sciences [q-bio], Linear model, Univariate, Grey-matter, Precision, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Generalized linear mixed model, Statistical power, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Bonferroni correction, Statistics, Multiple comparisons problem, symbols, False positive rate, False positive, 030217 neurology & neurosurgery, 030304 developmental biology, Mathematics
Abstract: International audience; We evaluated the statistical power, family wise error rate (FWER) and precision of several competing methods that perform mass-univariate vertex-wise analyses of grey-matter (thickness and surface area). In particular, we compared several generalised linear models (GLMs, current state of the art) to linear mixed models (LMMs) that have proven superior in genomics. We used phenotypes simulated from real vertex-wise data and a large sample size (N=8,662) which may soon become the norm in neuroimaging. No method ensured a FWER
Published: 2020

14. Bilateral hypoglossal nerve stimulation for treatment of adult obstructive sleep apnoea

Author: Valérie Attali, Maree Barnes, Peter R. Eastwood, Chloé Bertolus, N. Meslier, Carsten E. Palme, Xuân Lan Nguyên, John R. Wheatley, Matthew C. Campbell, Boris Pételle, Stuart G. MacKay, Laurent Laccourreye, Richard Lewis, David R. Hillman, Jennifer H. Walsh, Guillaume Raux, Frédéric Gagnadoux, Alain Bizon, Andrew Jones, Sandrine Launois, Kathleen J. Maddison, K. Denoncin, Institute for Molecular Bioscience, University of Queensland [Brisbane], Ocular Genetics Unit, Smurfit Institute of Genetics, Kansas State University, Stress Oxydant et Pathologies Métaboliques (SOPAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Cytokines : structure, signalisation et prolifération tumorale, de Duve Institute, Université Catholique de Louvain = Catholic University of Louvain (UCL), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service des Pathologies du sommeil [CHU Pitié-Salpêtrière], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Pulmonary and Respiratory Medicine, Sleep Medicine, Adult, Hypoglossal Nerve, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Polysomnography, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 03 medical and health sciences, 0302 clinical medicine, Quality of life, medicine, Humans, Prospective cohort study, Neurostimulation, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, Sleep Apnea, Obstructive, business.industry, [SDV.BA]Life Sciences [q-bio]/Animal biology, Sleep apnea, Original Articles, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, medicine.disease, Electric Stimulation, 3. Good health, Obstructive sleep apnea, 030228 respiratory system, Anesthesia, Complication, business, Airway, Hypoglossal nerve, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery
Abstract: Background and aim Hypoglossal nerve stimulation (HNS) decreases obstructive sleep apnoea (OSA) severity via genioglossus muscle activation and decreased upper airway collapsibility. This study assessed the safety and effectiveness at 6 months post-implantation of a novel device delivering bilateral HNS via a small implanted electrode activated by a unit worn externally, to treat OSA: the Genio™ system. Methods This prospective, open-label, non-randomised, single-arm treatment study was conducted at eight centres in three countries (Australia, France and the UK). Primary outcomes were incidence of device-related serious adverse events and change in the apnoea–hypopnoea index (AHI). The secondary outcome was the change in the 4% oxygen desaturation index (ODI). Additional outcomes included measures of sleepiness, quality of life, snoring and device use. This trial was registered with ClinicalTrials.gov, number NCT03048604. Results 22 out of 27 implanted participants (63% male, aged 55.9±12.0 years, body mass index (BMI) 27.4±3.0 kg·m−2) completed the protocol. At 6 months BMI was unchanged (p=0.85); AHI decreased from 23.7±12.2 to 12.9±10.1 events·h−1, a mean change of 10.8 events·h−1 (p5 days per week, and 77% reported use for >5 h per night. No device-related serious adverse events occurred during the 6-month post-implantation period. Conclusions Bilateral HNS using the Genio™ system reduces OSA severity and improves quality of life without device-related complications. The results are comparable with previously published HNS systems despite minimal implanted components and a simple stimulation algorithm., A new method of hypoglossal nerve stimulation to treat sleep apnoea does so bilaterally via an implanted neurostimulator activated externally. Its simplicity and relative non-invasiveness have not compromised its effectiveness relative to older methods. http://bit.ly/2lDCeif
Published: 2020
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15. Comparison and validation of seven white matter hyperintensities segmentation software in elderly patients

Author: Vanderbecq, Quentin, Xu, Eric, Stroër, Sebastian, Couvy-Duchesne, Baptiste, Diaz-Melo, Mauricio, Dormont, Didier, Colliot, Olivier, Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Institute for Molecular Bioscience, University of Queensland [Brisbane], Service Expérimentation et Développement [Paris] (SED), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), ANR-19-P3IA-0001 - PRAIRIE IA - Paris Artificial Intelligence Research Institute (2019), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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], 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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), Colliot, Olivier, and PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID
Subjects: Artificial intelligence, WMH, White Mater Hyperintensities, White Mater Hyperintensities, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [INFO.INFO-IM] Computer Science [cs]/Medical Imaging, WM, White Matter, lcsh:Computer applications to medicine. Medical informatics, lcsh:RC346-429, DSC, [INFO.INFO-CV] Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Segmentation, DSC, Dice similarity coefficient, Alzheimer Disease, Image Processing, Computer-Assisted, ADNI, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Humans, White matter hyperintensity, Cognitive Dysfunction, WM, lcsh:Neurology. Diseases of the nervous system, ComputingMilieux_MISCELLANEOUS, [SPI.SIGNAL] Engineering Sciences [physics]/Signal and Image processing, Aged, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Alzheimer's Disease Neuroimaging Initiative, Dice similarity coefficient, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Regular Article, Magnetic Resonance Imaging, WMH, White Matter, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, ADNI, Alzheimer's Disease Neuroimaging Initiative, [INFO.INFO-TI] Computer Science [cs]/Image Processing [eess.IV], [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], lcsh:R858-859.7, Dementia, Microvascular, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Algorithms, Software
Abstract: Highlights: • The comparison used 207 images from both research and clinical datasets. • When retrained, NicMSlesion, a convolutional network, was the most accurate. • Performance of this deep learning method severely dropped on clinical routine data. • On clinical routine data, regression and clustering methods were the top-ranked methods. • SLS was the most robust to artifacted images, and BIANCA to scanners variability., Background Manual segmentation is currently the gold standard to assess white matter hyperintensities (WMH), but it is time consuming and subject to intra and inter-operator variability. Purpose To compare automatic methods to segment white matter hyperintensities (WMH) in the elderly in order to assist radiologist and researchers in selecting the most relevant method for application on clinical or research data. Material and Methods We studied a research dataset composed of 147 patients, including 97 patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) 2 database and 50 patients from ADNI 3 and a clinical routine dataset comprising 60 patients referred for cognitive impairment at the Pitié-Salpêtrière hospital (imaged using four different MRI machines). We used manual segmentation as the gold standard reference. Both manual and automatic segmentations were performed using FLAIR MRI. We compared seven freely available methods that produce segmentation mask and are usable by a radiologist without a strong knowledge of computer programming: LGA (Schmidt et al., 2012), LPA (Schmidt, 2017), BIANCA (Griffanti et al., 2016), UBO detector (Jiang et al., 2018), W2MHS (Ithapu et al., 2014), nicMSlesion (with and without retraining) (Valverde et al., 2019, Valverde et al., 2017). The primary outcome for assessing segmentation accuracy was the Dice similarity coefficient (DSC) between the manual and the automatic segmentation software. Secondary outcomes included five other metrics. Results A deep learning approach, NicMSlesion, retrained on data from the research dataset ADNI, performed best on this research dataset (DSC: 0.595) and its DSC was significantly higher than that of all others. However, it ranked fifth on the clinical routine dataset and its performance severely dropped on data with artifacts. On the clinical routine dataset, the three top-ranked methods were LPA, SLS and BIANCA. Their performance did not differ significantly but was significantly higher than that of other methods. Conclusion This work provides an objective comparison of methods for WMH segmentation. Results can be used by radiologists to select a tool.
Published: 2020
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16. Chemical synthesis and structure elucidation of bovine {kappa}-casein (1-44)

Author: Alewood, Paul [Institute for Molecular Bioscience, University of Queensland, St. Lucia, Qld 4072 (Australia)]
Published: 2006
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17. The PCNA-associated factor KIAA0101/p15{sup PAF} binds the potential tumor suppressor product p33ING1b

Author: Wicking, Carol [Institute for Molecular Bioscience, University of Queensland, St Lucia, Brisbane, Queensland 4072 (Australia)]
Published: 2006
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18. Caveolae: The FAQs

Author: Anne K. Kenworthy, Christophe Lamaze, Anne Camus, Richard Lundmark, Soazig Le Lay, William C. Sessa, Stéphane Vassilopoulos, Ivan R. Nabi, Miguel A. del Pozo, Cédric M. Blouin, Robert G. Parton, Institute for Molecular Bioscience [Queensland, Australia], University of Queensland [Brisbane], Centre for Microscopy and Microanalysis [Queensland, Australia], Mechanoadaptation & Caveolae Biology Lab [Madrid, Spain] (Cell & Developmental Biology Area), Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Centre de recherche en myologie, Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Department of Cellular and Physiological Sciences [Vancouver, BC, Canada] (Life Sciences Institute), University of British Columbia (UBC)-Life Sciences Institute [Vancouver, BC, Canada], Stress Oxydant et Pathologies Métaboliques (SOPAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Integrative Medical Biology [Umeå, Sweden], Umeå University, Center for Membrane and Cell Physiology [Charlottesville, VA, USA] (School of Medicine), University of Virginia [Charlottesville], Regenerative Medicine and Skeleton research lab (RMeS), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Vascular Biology and Therapeutics Program [New Haven, CT, USA] (Department of Pharmacology), Yale University School of Medicine, Centro Nacional de Investigaciones Cardiovasculares Carlos III [Madrid, Spain] (CNIC), Instituto de Salud Carlos III [Madrid] (ISC)-Instituto de Salud Carlos III [Madrid] (ISC), Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-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), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC), Centre de recherche en Myologie – U974 SU-INSERM, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Jehan, Frederic, University of Virginia, Regenerative Medicine and Skeleton (RMeS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Yale School of Medicine [New Haven, Connecticut] (YSM)
Subjects: muscular dystrophy, lipodystrophy, [SDV]Life Sciences [q-bio], [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], cavins, Biology, Caveolae, Biochemistry, Article, 03 medical and health sciences, 0302 clinical medicine, Structural Biology, Genetics, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, endocytosis, Molecular Biology, membrane, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, caveolins, 0303 health sciences, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, EHD2, Cell Biology, Cell biology, Cell and molecular biology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, cell membrane, 030217 neurology & neurosurgery
Abstract: International audience; At the first EMBO conference dedicated to caveolae held in Le Pouliguen, France, May 12-16 (http://meetings.embo.org.gate2.inist.fr/event/19-caveolae), round-table discussions were used to address some of the long-standing issues in the field and to decide upon a consensus view regarding key aspects of caveola biology. Here we summarise some of the frequently asked questions (FAQs) posed by cell biologists about caveolae and provide some brief consensual answers based on these discussions. This article is protected by copyright. All rights reserved.
Published: 2019
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19. Fluoroquinolone-derived fluorescent probes for studies of bacterial penetration and efflux

Author: Mark E. Cooper, Mark A. T. Blaskovich, M. Rhia L. Stone, Muriel Masi, Jean-Marie Pagès, Wanida Phetsang, rosa, emmanuelle, Institute for Molecular Bioscience, University of Queensland [Brisbane], Membranes et cibles thérapeutiques (MCT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA)
Subjects: Fluorophore, [SDV]Life Sciences [q-bio], Pharmaceutical Science, medicine.disease_cause, 01 natural sciences, Biochemistry, chemistry.chemical_compound, Fluoroquinolone Antibiotic, Drug Discovery, [CHIM] Chemical Sciences, medicine, Fluorescence microscope, [CHIM]Chemical Sciences, Escherichia coli, ComputingMilieux_MISCELLANEOUS, Pharmacology, 010405 organic chemistry, Organic Chemistry, Combinatorial chemistry, Fluorescence, 0104 chemical sciences, 3. Good health, Ciprofloxacin, [SDV] Life Sciences [q-bio], 010404 medicinal & biomolecular chemistry, chemistry, Molecular Medicine, Azide, Efflux, medicine.drug
Abstract: Fluorescent probes derived from the fluoroquinolone antibiotic ciprofloxacin were synthesised using a Cu(i)-catalysed azide-alkyne cycloaddition (CuAAC) to link a ciprofloxacin azide derivative with alkyne-substituted green and blue fluorophores. The azide (2) and fluorophore (3 and 4) derivatives retained antimicrobial activity against Gram-positive and Gram-negative bacteria. The use of confocal fluorescent microscopy showed intracellular penetration, which was substantially enhanced in the presence of carbonyl cyanide 3-chlorophenylhydrazone as an efflux pump inhibitor in Escherichia coli.
Published: 2019
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20. Venomics Reveals Venom Complexity of the Piscivorous Cone Snail, Conus tulipa

Author: Paul F. Alewood, Sébastien Dutertre, Mriga Dutt, Vincent Lavergne, Ai-Hua Jin, Richard J. Lewis, Institute for Molecular Bioscience, University of Queensland [Brisbane], Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Centre Léon Bérard [Lyon]
Subjects: Conantokins, conantokins, net hunting strategy, Pharmaceutical Science, Conus tulipa, Venom, Biology, 01 natural sciences, complex mixtures, Cone snail, Transcriptome, venomics, 03 medical and health sciences, transcriptomics, proteomics, ion channel modulators, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Drug Discovery, Conotoxin, nirvana cabal, lcsh:QH301-705.5, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), 030304 developmental biology, 0303 health sciences, Conus geographus, biology.organism_classification, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, lcsh:Biology (General), intraspecific variation, Evolutionary biology, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Proteome, conotoxin
Abstract: The piscivorous cone snail Conus tulipa has evolved a net-hunting strategy, akin to the deadly Conus geographus, and is considered the second most dangerous cone snail to humans. Here, we present the first venomics study of C. tulipa venom using integrated transcriptomic and proteomic approaches. Parallel transcriptomic analysis of two C. tulipa specimens revealed striking differences in conopeptide expression levels (2.5-fold) between individuals, identifying 522 and 328 conotoxin precursors from 18 known gene superfamilies. Despite broad overlap at the superfamily level, only 86 precursors (11%) were common to both specimens. Conantokins (NMDA antagonists) from the superfamily B1 dominated the transcriptome and proteome of C. tulipa venom, along with superfamilies B2, A, O1, O3, con-ikot-ikot and conopressins, plus novel putative conotoxins precursors T1.3, T6.2, T6.3, T6.4 and T8.1. Thus, C. tulipa venom comprised both paralytic (putative ion channel modulating &alpha, &omega, &mu, &delta, ) and non-paralytic (conantokins, con-ikot-ikots, conopressins) conotoxins. This venomic study confirms the potential for non-paralytic conotoxins to contribute to the net-hunting strategy of C. tulipa.
Published: 2019
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21. Periplasmic Expression of 4/7 α-Conotoxin TxIA Analogs in E. coli Favors Ribbon Isomer Formation – Suggestion of a Binding Mode at the α7 nAChR

Author: Hamdaoui, Yamina, Wu, Xiaosa, Clark, Richard J., Giribaldi, Julien, Anangi, Raveendra, Craik, David, King, Glenn, Dutertre, Sébastien, Kaas, Quentin, Herzig, Volker, Nicke, Annette, Ludwig-Maximilians-Universität München (LMU), Institute for Molecular Bioscience, University of Queensland [Brisbane], Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Pharmacology, 4/7 α-conotoxin, lcsh:Therapeutics. Pharmacology, NMR spectroscopy, molecular modeling, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.TOX]Life Sciences [q-bio]/Toxicology, lcsh:RM1-950, E. coli, recombinant expression, ribbon isomer, Original Research
Abstract: International audience; Peptides derived from animal venoms provide important research tools for biochemical and pharmacological characterization of receptors, ion channels, and transporters. Some venom peptides have been developed into drugs (such as the synthetic ω-conotoxin MVIIA, ziconotide) and several are currently undergoing clinical trials for various clinical indications. Challenges in the development of peptides include their usually limited supply from natural sources, cost-intensive chemical synthesis, and potentially complicated stereoselective disulfide-bond formation in the case of disulfide-rich peptides. In particular, if extended structure-function analysis is performed or incorporation of stable isotopes for NMR studies is required, the comparatively low yields and high costs of synthesized peptides might constitute a limiting factor. Here we investigated the expression of the 4/7 α-conotoxin TxIA, a potent blocker at α3β2 and α7 nicotinic acetylcholine receptors (nAChRs), and three analogs in the form of maltose binding protein fusion proteins in Escherichia coli. Upon purification via nickel affinity chromatography and release of the toxins by protease cleavage, HPLC analysis revealed one major peak with the correct mass for all peptides. The final yield was 1-2 mg of recombinant peptide per liter of bacterial culture. Two-electrode voltage clamp analysis on oocyte-expressed nAChR subtypes demonstrated the functionality of these peptides but also revealed a 30 to 100-fold potency decrease of expressed TxIA compared to chemically synthesized TxIA. NMR spectroscopy analysis of TxIA and two of its analogs confirmed that the decreased activity was due to an alternative disulfide linkage rather than the missing C-terminal amidation, a post-translational modification that is common in α-conotoxins. All peptides preferentially formed in the ribbon conformation rather than the native globular conformation. Interestingly, in the case of the α7 nAChR, but not the α3β2 subtype, the loss of potency could be rescued by an R5D substitution. In conclusion, we demonstrate efficient expression of functional but alternatively folded ribbon TxIA variants in E. coli and provide the first structure-function analysis for a ribbon 4/7-α-conotoxin at α7 and α3β2 nAChRs. Computational analysis based on these data provide evidence for a ribbon α-conotoxin binding mode that might be exploited to design ligands with optimized selectivity.
Published: 2019
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22. Transcriptomic-Proteomic Correlation in the Predation-Evoked Venom of the Cone Snail, Conus imperialis

Author: Paul F. Alewood, Vincent Lavergne, Mriga Dutt, Richard J. Lewis, Sébastien Dutertre, Alun Jones, Ai-Hua Jin, Institute for Molecular Bioscience, University of Queensland [Brisbane], Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Centre Léon Bérard [Lyon]
Subjects: Conus imperialis, Pharmaceutical Science, Venom, Biology, complex mixtures, Cone snail, Transcriptome, 03 medical and health sciences, transcriptomics, proteomics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Drug Discovery, Conotoxin, Stabilizing selection, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), Gene, lcsh:QH301-705.5, 030304 developmental biology, mass spectrometry, 0303 health sciences, cone snail venom, 030302 biochemistry & molecular biology, conopeptide, 454 sequencing, biology.organism_classification, lcsh:Biology (General), iTRAQ, Evolutionary biology, venom transcriptome, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Proteome, conotoxin
Abstract: International audience; Individual variation in animal venom has been linked to geographical location, feeding habit, season, size, and gender. Uniquely, cone snails possess the remarkable ability to change venom composition in response to predatory or defensive stimuli. To date, correlations between the venom gland transcriptome and proteome within and between individual cone snails have not been reported. In this study, we use 454 pyrosequencing and mass spectrometry to decipher the transcriptomes and proteomes of the venom gland and corresponding predation-evoked venom of two specimens of Conus imperialis. Transcriptomic analyses revealed 17 conotoxin gene superfamilies common to both animals, including 5 novel superfamilies and two novel cysteine frameworks. While highly expressed transcripts were common to both specimens, variation of moderately and weakly expressed precursor sequences was surprisingly diverse, with one specimen expressing two unique gene superfamilies and consistently producing more paralogs within each conotoxin gene superfamily. Using a quantitative labelling method, conotoxin variability was compared quantitatively, with highly expressed peptides showing a strong correlation between transcription and translation, whereas peptides expressed at lower levels showed a poor correlation. These results suggest that major transcripts are subject to stabilizing selection, while minor transcripts are subject to diversifying selection.
Published: 2019
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23. Ecological consequences of abrupt temperature changes in anaerobic digesters

Author: Olivier Chapleur, Céline Madigou, Chrystelle Bureau, Laurent Mazéas, Sébastien Déjean, Kim-Anh Lê Cao, Hydrosystèmes et Bioprocédés (UR HBAN), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Institute for Molecular Bioscience, University of Queensland [Brisbane], Institut de Mathématiques de Toulouse UMR5219 (IMT), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Hydrosystèmes et bioprocédés (UR HBAN), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Methanobacterium, General Chemical Engineering, Microorganism, 02 engineering and technology, 010402 general chemistry, Methanization, 7. Clean energy, 01 natural sciences, Industrial and Manufacturing Engineering, 16S sequencing, PLSDA, Temperature increase, [MATH.MATH-ST]Mathematics [math]/Statistics [math.ST], Bioreactor, Environmental Chemistry, Cellulose, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, biology, Ecology, Chemistry, Thermophile, General Chemistry, Methanosarcina, 021001 nanoscience & nanotechnology, biology.organism_classification, 0104 chemical sciences, Anaerobic digestion, Methanoculleus, 13. Climate action, Temperature decrease, 0210 nano-technology, Anaerobic exercise
Abstract: International audience; Temperature is a key parameter of anaerobic digestion. Its modification can have drastic consequences on microbial communities and performances. However it can be an interesting parameter to adjust the productivity, energy efficiency or stability of bioreactors. The objective of this work was to give insights into the consequences of abrupt temperature modifications on the microbiota of anaerobic digestion. Two complementary experiments were performed. A continuously stirred lab-scale bioreactor (5-L) simulated the functioning of a semi-continuous industrial digester. Five batch-fed incubations (1-L) served as replicated experiments. Each experiment was divided into three successive steps: reactors were first operated at 35 degrees C followed by an abrupt increase to 55 degrees C and finally a decrease to 35 degrees C. After the first temperature shock, gas production rate increased temporarily and then fell for 1 month before a new steady-state was reached. When temperature was reset to 35 degrees C in step 3 gas production decreased sharply again. The semi-continuous reactor recovered after 15 days while the batch-fed incubations never recovered. Ecological changes associated to these performance drops and recovery were sought using 16S sequencing of Bacteria and Archaea and multivariate analyses. In brief, Bacteroidales order was rapidly and strongly affected by temperature increase, while Clostridiales became dominant in thermophilic conditions. Several thermotolerant Bacteria were identified as responsible for reactors early recovery, but were outcompeted by a very diverse bacterial population a few weeks after temperature shock. Methanosarcina and Methanobacterium Archaea dominated at 35 degrees C but were slowly replaced by thermophilic Methanoculleus or Methanosarcina at 55 degrees C that were essential to methane production. In step 3, when returning to initial temperature conditions after the thermophilic period, Ruminococcaceae and Methanobacterium appeared to drive digester resilience.
Published: 2018
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24. Analysis of shared heritability in common disorders of the brain

Author: Brainstorm Consortium, Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K, Walters, Raymond K, Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J, Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A, Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H, Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-François, Duron, Emmanuelle, Vardarajan, Badri N, Reitz, Christiane, Goate, Alison M, Huentelman, Matthew J, Kamboh, M Ilyas, Larson, Eric B, Rogaeva, Ekaterina, St George-Hyslop, Peter, Hakonarson, Hakon, Kukull, Walter A, Farrer, Lindsay A, Barnes, Lisa L, Beach, Thomas G, Demirci, F Yesim, Head, Elizabeth, Hulette, Christine M, Jicha, Gregory A, Kauwe, John SK, Kaye, Jeffrey A, Leverenz, James B, Levey, Allan I, Lieberman, Andrew P, Pankratz, Vernon S, Poon, Wayne W, Quinn, Joseph F, Saykin, Andrew J, Schneider, Lon S, Smith, Amanda G, Sonnen, Joshua A, Stern, Robert A, Van Deerlin, Vivianna M, Van Eldik, Linda J, Harold, Denise, Russo, Giancarlo, Rubinsztein, David C, Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C, Hampel, Harald, Owen, Michael J, Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M, Rossor, Martin, Lupton, Michelle K, Hoffmann, Per, Kornhuber, Johannes, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C, Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, Van Der Lee, Sven J, De Jager, Philip L, Geschwind, Daniel H, Riemenschneider, Matthias, Riedel-Heller, Steffi, Rotter, Jerome I, Ransmayr, Gerhard, Hyman, Bradley T, Cruchaga, Carlos, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, Cuenca-Leon, Ester, Furlotte, Nicholas, Kurth, Tobias, Ligthart, Lannie, Terwindt, Gisela M, Freilinger, Tobias, Ran, Caroline, Gordon, Scott D, Borck, Guntram, Adams, Hieab HH, Lehtimäki, Terho, Wedenoja, Juho, Buring, Julie E, Schürks, Markus, Hrafnsdottir, Maria, Hottenga, Jouke-Jan, Penninx, Brenda, Artto, Ville, Kaunisto, Mari, Vepsäläinen, Salli, Martin, Nicholas G, Montgomery, Grant W, Kurki, Mitja I, Hämäläinen, Eija, Huang, Hailiang, Huang, Jie, Sandor, Cynthia, Webber, Caleb, Muller-Myhsok, Bertram, Schreiber, Stefan, Salomaa, Veikko, Loehrer, Elizabeth, Göbel, Hartmut, Macaya, Alfons, Pozo-Rosich, Patricia, Hansen, Thomas, Werge, Thomas, Kaprio, Jaakko, Metspalu, Andres, Kubisch, Christian, Ferrari, Michel D, Belin, Andrea C, Van Den Maagdenberg, Arn MJM, Zwart, John-Anker, Boomsma, Dorret, Eriksson, Nicholas, Olesen, Jes, Chasman, Daniel I, Nyholt, Dale R, Avbersek, Andreja, Baum, Larry, Berkovic, Samuel, Bradfield, Jonathan, Buono, Russell J, Catarino, Claudia B, Cossette, Patrick, De Jonghe, Peter, Depondt, Chantal, Dlugos, Dennis, Ferraro, Thomas N, French, Jacqueline, Hjalgrim, Helle, Jamnadas-Khoda, Jennifer, Kälviäinen, Reetta, Kunz, Wolfram S, Lerche, Holger, Leu, Costin, Lindhout, Dick, Lo, Warren, Lowenstein, Daniel, McCormack, Mark, Møller, Rikke S, Molloy, Anne, Ng, Ping-Wing, Oliver, Karen, Privitera, Michael, Radtke, Rodney, Ruppert, Ann-Kathrin, Sander, Thomas, Schachter, Steven, Schankin, Christoph, Scheffer, Ingrid, Schoch, Susanne, Sisodiya, Sanjay M, Smith, Philip, Sperling, Michael, Striano, Pasquale, Surges, Rainer, Thomas, G Neil, Visscher, Frank, Whelan, Christopher D, Zara, Federico, Heinzen, Erin L, Marson, Anthony, Becker, Felicitas, Stroink, Hans, Zimprich, Fritz, Gasser, Thomas, Gibbs, Raphael, Heutink, Peter, Martinez, Maria, Morris, Huw R, Sharma, Manu, Ryten, Mina, Mok, Kin Y, Pulit, Sara, Bevan, Steve, Holliday, Elizabeth, Attia, John, Battey, Thomas, Boncoraglio, Giorgio, Thijs, Vincent, Chen, Wei-Min, Mitchell, Braxton, Rothwell, Peter, Sharma, Pankaj, Sudlow, Cathie, Vicente, Astrid, Markus, Hugh, Kourkoulis, Christina, Pera, Joana, Raffeld, Miriam, Silliman, Scott, Boraska Perica, Vesna, Thornton, Laura M, Huckins, Laura M, William Rayner, N, Lewis, Cathryn M, Gratacos, Monica, Rybakowski, Filip, Keski-Rahkonen, Anna, Raevuori, Anu, Hudson, James I, Reichborn-Kjennerud, Ted, Monteleone, Palmiero, Karwautz, Andreas, Mannik, Katrin, Baker, Jessica H, O'Toole, Julie K, Trace, Sara E, Davis, Oliver SP, Helder, Sietske G, Ehrlich, Stefan, Herpertz-Dahlmann, Beate, Danner, Unna N, Van Elburg, Annemarie A, Clementi, Maurizio, Forzan, Monica, Docampo, Elisa, Lissowska, Jolanta, Hauser, Joanna, Tortorella, Alfonso, Maj, Mario, Gonidakis, Fragiskos, Tziouvas, Konstantinos, Papezova, Hana, Yilmaz, Zeynep, Wagner, Gudrun, Cohen-Woods, Sarah, Herms, Stefan, Julià, Antonio, Rabionet, Raquel, Dick, Danielle M, Ripatti, Samuli, Andreassen, Ole A, Espeseth, Thomas, Lundervold, Astri J, Steen, Vidar M, Pinto, Dalila, Scherer, Stephen W, Aschauer, Harald, Schosser, Alexandra, Alfredsson, Lars, Padyukov, Leonid, Halmi, Katherine A, Mitchell, James, Strober, Michael, Bergen, Andrew W, Kaye, Walter, Szatkiewicz, Jin Peng, Cormand, Bru, Ramos-Quiroga, Josep Antoni, Sánchez-Mora, Cristina, Ribasés, Marta, Casas, Miguel, Hervas, Amaia, Arranz, Maria Jesús, Haavik, Jan, Zayats, Tetyana, Johansson, Stefan, Williams, Nigel, Dempfle, Astrid, Rothenberger, Aribert, Kuntsi, Jonna, Oades, Robert D, Banaschewski, Tobias, Franke, Barbara, Buitelaar, Jan K, Arias Vasquez, Alejandro, Doyle, Alysa E, Reif, Andreas, Lesch, Klaus-Peter, Freitag, Christine, Rivero, Olga, Palmason, Haukur, Romanos, Marcel, Langley, Kate, Rietschel, Marcella, Witt, Stephanie H, Dalsgaard, Soeren, Børglum, Anders D, Waldman, Irwin, Wilmot, Beth, Molly, Nikolas, Bau, Claiton HD, Crosbie, Jennifer, Schachar, Russell, Loo, Sandra K, McGough, James J, Grevet, Eugenio H, Medland, Sarah E, Robinson, Elise, Weiss, Lauren A, Bacchelli, Elena, Bailey, Anthony, Bal, Vanessa, Battaglia, Agatino, Betancur, Catalina, Bolton, Patrick, Cantor, Rita, Celestino-Soper, Patrícia, Dawson, Geraldine, De Rubeis, Silvia, Duque, Frederico, Green, Andrew, Klauck, Sabine M, Leboyer, Marion, Levitt, Pat, Maestrini, Elena, Mane, Shrikant, De-Luca, Daniel Moreno, Parr, Jeremy, Regan, Regina, Reichenberg, Abraham, Sandin, Sven, Vorstman, Jacob, Wassink, Thomas, Wijsman, Ellen, Cook, Edwin, Santangelo, Susan, Delorme, Richard, Rogé, Bernadette, Magalhaes, Tiago, Arking, Dan, Schulze, Thomas G, Thompson, Robert C, Strohmaier, Jana, Matthews, Keith, Melle, Ingrid, Morris, Derek, Blackwood, Douglas, McIntosh, Andrew, Bergen, Sarah E, Schalling, Martin, Jamain, Stéphane, Maaser, Anna, Fischer, Sascha B, Reinbold, Céline S, Fullerton, Janice M, Guzman-Parra, José, Mayoral, Fermin, Schofield, Peter R, Cichon, Sven, Mühleisen, Thomas W, Degenhardt, Franziska, Schumacher, Johannes, Bauer, Michael, Mitchell, Philip B, Gershon, Elliot S, Rice, John, Potash, James B, Zandi, Peter P, Craddock, Nick, Ferrier, I Nicol, Alda, Martin, Rouleau, Guy A, Turecki, Gustavo, Ophoff, Roel, Pato, Carlos, Anjorin, Adebayo, Stahl, Eli, Leber, Markus, Czerski, Piotr M, Cruceanu, Cristiana, Jones, Ian R, Posthuma, Danielle, Andlauer, Till FM, Forstner, Andreas J, Streit, Fabian, Baune, Bernhard T, Air, Tracy, Sinnamon, Grant, Wray, Naomi R, MacIntyre, Donald J, Porteous, David, Homuth, Georg, Rivera, Margarita, Grove, Jakob, Middeldorp, Christel M, Hickie, Ian, Pergadia, Michele, Mehta, Divya, Smit, Johannes H, Jansen, Rick, De Geus, Eco, Dunn, Erin, Li, Qingqin S, Nauck, Matthias, Schoevers, Robert A, Beekman, Aartjan Tf, Knowles, James A, Viktorin, Alexander, Arnold, Paul, Barr, Cathy L, Bedoya-Berrio, Gabriel, Bienvenu, O Joseph, Brentani, Helena, Burton, Christie, Camarena, Beatriz, Cappi, Carolina, Cath, Danielle, Cavallini, Maria, Cusi, Daniele, Darrow, Sabrina, Denys, Damiaan, Derks, Eske M, Dietrich, Andrea, Fernandez, Thomas, Figee, Martijn, Freimer, Nelson, Gerber, Gloria, Grados, Marco, Greenberg, Erica, Hanna, Gregory L, Hartmann, Andreas, Hirschtritt, Matthew E, Hoekstra, Pieter J, Huang, Alden, Huyser, Chaim, Illmann, Cornelia, Jenike, Michael, Kuperman, Samuel, Leventhal, Bennett, Lochner, Christine, Lyon, Gholson J, Macciardi, Fabio, Madruga-Garrido, Marcos, Malaty, Irene A, Maras, Athanasios, McGrath, Lauren, Miguel, Eurípedes C, Mir, Pablo, Nestadt, Gerald, Nicolini, Humberto, Okun, Michael S, Pakstis, Andrew, Paschou, Peristera, Piacentini, John, Pittenger, Christopher, Plessen, Kerstin, Ramensky, Vasily, Ramos, Eliana M, Reus, Victor, Richter, Margaret A, Riddle, Mark A, Robertson, Mary M, Roessner, Veit, Rosário, Maria, Samuels, Jack F, Sandor, Paul, Stein, Dan J, Tsetsos, Fotis, Van Nieuwerburgh, Filip, Weatherall, Sarah, Wendland, Jens R, Wolanczyk, Tomasz, Worbe, Yulia, Zai, Gwyneth, Goes, Fernando S, McLaughlin, Nicole, Nestadt, Paul S, Grabe, Hans-Jorgen, Depienne, Christel, Konkashbaev, Anuar, Lanzagorta, Nuria, Valencia-Duarte, Ana, Bramon, Elvira, Buccola, Nancy, Cahn, Wiepke, Cairns, Murray, Chong, Siow A, Cohen, David, Crespo-Facorro, Benedicto, Crowley, James, Davidson, Michael, DeLisi, Lynn, Dinan, Timothy, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Haan, Lieuwe, Hougaard, David, Karachanak-Yankova, Sena, Khrunin, Andrey, Klovins, Janis, Kučinskas, Vaidutis, Lee Chee Keong, Jimmy, Limborska, Svetlana, Loughland, Carmel, Lönnqvist, Jouko, Maher, Brion, Mattheisen, Manuel, McDonald, Colm, Murphy, Kieran C, Nenadic, Igor, Van Os, Jim, Pantelis, Christos, Pato, Michele, Petryshen, Tracey, Quested, Digby, Roussos, Panos, Sanders, Alan R, Schall, Ulrich, Schwab, Sibylle G, Sim, Kang, So, Hon-Cheong, Stögmann, Elisabeth, Subramaniam, Mythily, Toncheva, Draga, Waddington, John, Walters, James, Weiser, Mark, Cheng, Wei, Cloninger, Robert, Curtis, David, Gejman, Pablo V, Henskens, Frans, Mattingsdal, Morten, Oh, Sang-Yun, Scott, Rodney, Webb, Bradley, Breen, Gerome, Churchhouse, Claire, Bulik, Cynthia M, Daly, Mark, Dichgans, Martin, Faraone, Stephen V, Guerreiro, Rita, Holmans, Peter, Kendler, Kenneth S, Koeleman, Bobby, Mathews, Carol A, Price, Alkes, Scharf, Jeremiah, Sklar, Pamela, Williams, Julie, Wood, Nicholas W, Cotsapas, Chris, Palotie, Aarno, Smoller, Jordan W, Sullivan, Patrick, Rosand, Jonathan, Corvin, Aiden, Neale, Benjamin M, Schott, Jonathan M, Anney, Richard, Elia, Josephine, Grigoroiu-Serbanescu, Maria, Edenberg, Howard J, Murray, Robin, 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], UK Dementia Research Institute (UK DRI), University College of London [London] (UCL), School of Psychology [Cardiff University], Cardiff University, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität [München]-Ludwig Maximilian University [Munich] (LMU), New Jersey Institute of Technology [Newark] (NJIT), 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), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), 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), Laboratoire de Biotechnologie et Microbiologie Appliquée (LBMA), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA), 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), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), 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), Gériatrie générale et aigüe [Paris], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Columbia University [New York], Dpt of Neuroscience [New York], Icahn School of Medicine at Mount Sinai [New York] (MSSM), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), University of Washington [Seattle], Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Children’s Hospital of Philadelphia (CHOP ), University of Kentucky (UK), School of medicine, Duke University [Durham], College of medicine, Brigham Young University (BYU), Oregon Health and Science University [Portland] (OHSU), Cleveland Clinic, Department of Neurology, Emory University [Atlanta, GA], Medical School, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Health sciences center, The University of New Mexico [Albuquerque], Institute for Memory Impairments and Neurological Disorders [Irvine], University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Indiana University - Purdue University Indianapolis (IUPUI), Indiana University System, Keck School of Medicine [Los Angeles], University of Southern California (USC), University of South Florida [Tampa] (USF), University of Utah School of Medicine [Salt Lake City], Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Perelman School of Medicine, University of Pennsylvania, Dublin City University [Dublin] (DCU), Functional Genomics Center Zurich, Universität Zürich [Zürich] = University of Zurich (UZH)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Cambridge Institute for Medical Research (CIMR), University of Cambridge [UK] (CAM), Aristotle University of Thessaloniki, Maurice Wohl Clinical Neuroscience Institut, King‘s College London, Dementia Research Centre [London] (DRC), Groupe de recherche clinique Alzheimer Precision Medicine (GRC 21 - APM), Sorbonne Université (SU), MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council-Cardiff University, MRC Prion Unit [London], Queen's University [Belfast] (QUB), School of Life Sciences, University of Nottingham, UK (UON), Rheinische Friedrich-Wilhelms-Universität Bonn, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), QIMR Berghofer Medical Research Institute, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), School of Medicine [Dublin], Trinity College Dublin, Department of Medicine, University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), School of Public Health [Boston], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Columbia University Medical Center (CUMC), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), Saarland University [Saarbrücken], Universität Leipzig, School of Medicine [Los Angeles], Johannes Kepler Universität Linz - Johannes Kepler University Linz [Autriche] (JKU), Department of Neurology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], School of Medecine, Washington University in Saint Louis (WUSTL), Oslo University Hospital [Oslo], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, 23andMe Inc., Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Biological Psychology [Amsterdam], Vrije Universiteit Amsterdam [Amsterdam] (VU), Leiden University Medical Center (LUMC), Universiteit Leiden, University-Hospital Munich-Großhadern [München], Karolinska Institutet [Stockholm], Universität Ulm - Ulm University [Ulm, Allemagne], Faculty of Medicine and Life Sciences [Tampere], University of Tampere [Finland], Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Landspitali National University Hospital of Iceland, VU University Medical Center [Amsterdam], Boston VA Research Institute (BVARI), Department of Physiology, Anatomy and Genetics [Oxford], University of Oxford, Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Christian-Albrechts-Universität zu Kiel (CAU), Institute of Clinical Molecular Biology, Kiel University, National Institute for Health and Welfare [Helsinki], Harvard T.H. Chan School of Public Health, Universitat Autònoma de Barcelona (UAB), Vall d'Hebron University Hospital [Barcelona], University of Tartu, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Center for Human and Clinical Genetics, Universiteit Leiden-Universiteit Leiden, University of Copenhagen = Københavns Universitet (UCPH), Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology [Brisbane] (QUT), Discipline of Psychiatry [Dublin], Trinity College Dublin-Trinity College Dublin, Institute of Neurology [London], The University of Hong Kong (HKU), University of Melbourne, Cooper Medical School of Rowan University [Camden] (CMSRU), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), University of Antwerp (UA), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), New York University School of Medicine (NYU), New York University School of Medicine, NYU System (NYU)-NYU System (NYU), University of Eastern Finland, Universitätsklinikum Bonn (UKB), Hertie Institute for Clinical Brain Research [Tubingen], University of Tübingen, NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, University Medical Center [Utrecht], Ohio State University [Columbus] (OSU), University of California [San Francisco] (UC San Francisco), University of California (UC), Royal College of Surgeons in Ireland (RCSI), University of Southern Denmark (SDU), United Christian Hospital [Hong Kong] (UCH), University of Cincinnati (UC), University of Cologne, Inselspital Bern, University of Wales, Jefferson University Hospitals, University of Liverpool, Medizinische Universität Wien = Medical University of Vienna, National Institutes of Health [Bethesda] (NIH), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Institut de Recherche en Santé Digestive (IRSD ), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Lincoln, University of Newcastle [Callaghan, Australia] (UoN), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Virginia, University of Maryland [Baltimore County] (UMBC), University of Maryland System, Royal Holloway [University of London] (RHUL), University of Edinburgh, Universidade de Lisboa = University of Lisbon (ULISBOA), Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), University of Split, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), McLean Hospital [Belmont, Ma.], Norwegian Institute of Public Health [Oslo] (NIPH), Università degli Studi di Salerno = University of Salerno (UNISA), University of Bristol [Bristol], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Utrecht University [Utrecht], Azienda Ospedaliera di Padova, Université de Liège, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Università degli Studi di Perugia = University of Perugia (UNIPG), Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli, National and Kapodistrian University of Athens (NKUA), Charles University [Prague] (CU), SURFACES, Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Flinders University [Adelaide, Australia], Virginia Commonwealth University (VCU), University of Oslo (UiO), University of Bergen (UiB), Weill Medical College of Cornell University [New York], University of North Dakota [Grand Forks] (UND), Oregon Research Institute (ORI), University of California [San Diego] (UC San Diego), Universitat de Barcelona (UB), Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Hospital Universitario Mutua de Terrassa, School of Computer Science and Communication [Stockholm], Royal Institute of Technology [Stockholm] (KTH ), Jefferson (Philadelphia University + Thomas Jefferson University), University Medical Center Göttingen (UMG), Universität Heidelberg [Heidelberg] = Heidelberg University, Radboud University Medical Center [Nijmegen], Universitätsklinikum Frankfurt, Maastricht University [Maastricht], Institute of Psychological Medicine and Clinical Neurosciences, Aarhus University [Aarhus], University of Iowa [Iowa City], Universidade Federal do Rio Grande do Sul [Porto Alegre] (UFRGS), The Hospital for sick children [Toronto] (SickKids), Hospital de Clínicas de Porto Alegre (HCPA), Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), University of British Columbia (UBC), IRCCS Fondazione Stella Maris [Pisa], 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), 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), Universidade de Coimbra [Coimbra], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Our Lady's Children's Hospital Crumlin (OLCHC), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Children’s Hospital Los Angeles [Los Angeles], Yale University [New Haven], Brown University, Institute of Neuroscience [Newcastle] (ION), Newcastle University [Newcastle], Department of Medical Epidemiology and Biostatistics (MEB), Division of Medical Genetics [Seattle], University of Illinois [Chicago] (UIC), University of Illinois System, Maine Medical Center Research Institute (MMCRI), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre d’Etudes et de Recherches en Psychopathologie et Psychologie de la Santé (CERPPS), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Toulouse Mind & Brain Institut (TMBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Johns Hopkins University School of Medicine [Baltimore], Ludwig Maximilian University [Munich] (LMU), University of Michigan System, Department of Genetic Epidemiology in Psychiatry [Mannhein], Universität Heidelberg [Heidelberg] = Heidelberg University-Central Institute of Mental Health Mannheim, University of Dundee, National University of Ireland [Galway] (NUI Galway), University Hospital Basel [Basel], Neuroscience Research Australia (NeuRA), Forschungszentrum Jülich GmbH | Centre de recherche de Juliers, Helmholtz-Gemeinschaft = Helmholtz Association, UNSW Faculty of Medicine [Sydney], University of New South Wales [Sydney] (UNSW), University of Chicago, Johns Hopkins University (JHU), Johns Hopkins Bloomberg School of Public Health [Baltimore], Dalhousie University [Halifax], Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], State University of New York (SUNY), University Hospital of Cologne [Cologne], University of Adelaide, James Cook University (JCU), Institute for Molecular Bioscience, University of Queensland [Brisbane], Greifswald University Hospital, The University of Sydney, University Medical Center Groningen [Groningen] (UMCG), University of Calgary, University Health Network, Universidad de Antioquia = University of Antioquia [Medellín, Colombia], Universidade de São Paulo = University of São Paulo (USP), Ospedale San Raffaele, University of Amsterdam [Amsterdam] (UvA), University of Groningen [Groningen], Yale School of Medicine [New Haven, Connecticut] (YSM), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Cape Town, Cold Spring Harbor Laboratory (CSHL), Universidad de Sevilla / University of Sevilla, University of Florida [Gainesville] (UF), University of Denver, Purdue University [West Lafayette], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Moscow Institute of Physics and Technology [Moscow] (MIPT), Sunnybrook Health Sciences Centre, Federal Institute of São Paulo (IFSP), Democritus University of Thrace (DUTH), Universiteit Gent = Ghent University (UGENT), Medical University of Warsaw - Poland, Sorbonne Université - Faculté de Médecine - Département d'Enseignement et de Recherche en Médecine Générale, Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Institute of Mental Health [Singapore], Universidad de Cantabria [Santander], Tel Aviv University (TAU), University College Cork (UCC), University of Rochester [USA], Statens Serum Institut [Copenhagen], Софийски университет = Sofia University, Russian Academy of Sciences [Moscow] (RAS), Latvian Biomedical Research and Study Centre [Rīga], Vilnius University [Vilnius], Nanyang Technological University [Singapour], Department of Life Sciences, Imperial College London, Jena University Hospital [Jena], Oxford University Hospitals NHS Trust, Schizophrenia Research Institute [Sydney], Faculty of Science, Medicine and Health [Wollongong], University of Wollongong [Australia], City University of Hong Kong [Hong Kong] (CUHK), Lawrence Berkeley National Laboratory [Berkeley] (LBNL), This work was supported by grants 1R01MH10764901 and 5U01MH09443203 from the National Institute of Mental Health, as well as the Orion Farmos Research Foundation (V.A.) and the Fannie and John Hertz Foundation (H.K.F.). Consortium specific funding is detailed in the supplementary materials ('Study-specific acknowledgments')., Brainstorm Consortium, University of Kentucky, University of California [Irvine] (UCI), University of California-University of California, University of Pennsylvania [Philadelphia], Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universität Leipzig [Leipzig], Johannes Kepler University Linz [Linz] (JKU), University of Helsinki-University of Helsinki, University of Helsinki, University of Oxford [Oxford], University of Copenhagen = Københavns Universitet (KU), University of California [San Francisco] (UCSF), University of California, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Newcastle [Australia] (UoN), University of Virginia [Charlottesville], Universidade de Lisboa (ULISBOA), Università degli Studi di Salerno (UNISA), Rheinisch-Westfälische Technische Hochschule Aachen (RWTH), Università degli Studi di Perugia (UNIPG), Università degli studi della Campania 'Luigi Vanvitelli', Universität Heidelberg [Heidelberg], Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Universität Heidelberg [Heidelberg]-Central Institute of Mental Health Mannheim, VU University Amsterdam, Universidade de São Paulo (USP), Yale University School of Medicine, Universidad de Sevilla, Universiteit Gent = Ghent University [Belgium] (UGENT), Service de Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière] (SPEA), Tel Aviv University [Tel Aviv], University of Sofia, Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K., Walters, Raymond K., Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J., Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A., Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H., Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-Françoi, Duron, Emmanuelle, Vardarajan, Badri N., Reitz, Christiane, Goate, Alison M., Huentelman, Matthew J., Ilyas Kamboh, M., Larson, Eric B., Rogaeva, Ekaterina, George-Hyslop, Peter St, Hakonarson, Hakon, Kukull, Walter A., Farrer, Lindsay A., Barnes, Lisa L., Beach, Thomas G., Yesim Demirci, F., Head, Elizabeth, Hulette, Christine M., Jicha, Gregory A., Kauwe, John S.K., Kaye, Jeffrey A., Leverenz, James B., Levey, Allan I., Lieberman, Andrew P., Pankratz, Vernon S., Poon, Wayne W., Quinn, Joseph F., Saykin, Andrew J., Schneider, Lon S., Smith, Amanda G., Sonnen, Joshua A., Stern, Robert A., Van Deerlin, Vivianna M., Van Eldik, Linda J., Harold, Denise, Russo, Giancarlo, Rubinsztein, David C., Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C., Hampel, Harald, Owen, Michael J., Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M., Rossor, Martin, Lupton, Michelle K., Hoffmann, Per, Kornhuber, Johanne, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C., Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, Van Der Lee, Sven J., De Jager, Philip L., Geschwind, Daniel H., Riemenschneider, Matthia, Riedel-Heller, Steffi, Rotter, Jerome I., Ransmayr, Gerhard, Hyman, Bradley T., Cruchaga, Carlo, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, Cuenca-Leon, Ester, Furlotte, Nichola, Kurth, Tobia, Ligthart, Lannie, Terwindt, Gisela M., Freilinger, Tobia, Ran, Caroline, Gordon, Scott D., Borck, Guntram, Adams, Hieab H.H., Lehtimäki, Terho, Wedenoja, Juho, Buring, Julie E., Schürks, Marku, Hrafnsdottir, Maria, Hottenga, Jouke-Jan, Penninx, Brenda, Artto, Ville, Kaunisto, Mari, Vepsäläinen, Salli, Martin, Nicholas G., Montgomery, Grant W., Kurki, Mitja I., Hämäläinen, Eija, Huang, Hailiang, Huang, Jie, Sandor, Cynthia, Webber, Caleb, Muller-Myhsok, Bertram, Schreiber, Stefan, Salomaa, Veikko, Loehrer, Elizabeth, Göbel, Hartmut, Macaya, Alfon, Pozo-Rosich, Patricia, Hansen, Thoma, Werge, Thoma, Kaprio, Jaakko, Metspalu, Andre, Kubisch, Christian, Ferrari, Michel D., Belin, Andrea C., Van Den Maagdenberg, Arn M. J. M., Zwart, John-Anker, Boomsma, Dorret, Eriksson, Nichola, Olesen, Je, Chasman, Daniel I., Nyholt, Dale R., Avbersek, Andreja, Baum, Larry, Berkovic, Samuel, Bradfield, Jonathan, Buono, Russell, Catarino, Claudia B., Cossette, Patrick, De Jonghe, Peter, Depondt, Chantal, Dlugos, Denni, Ferraro, Thomas N., French, Jacqueline, Hjalgrim, Helle, Jamnadas-Khoda, Jennifer, Kälviäinen, Reetta, Kunz, Wolfram S., Lerche, Holger, Leu, Costin, Lindhout, Dick, Lo, Warren, Lowenstein, Daniel, McCormack, Mark, Møller, Rikke S., Molloy, Anne, Ng, Ping-Wing, Oliver, Karen, Privitera, Michael, Radtke, Rodney, Ruppert, Ann-Kathrin, Sander, Thoma, Schachter, Steven, Schankin, Christoph, Scheffer, Ingrid, Schoch, Susanne, Sisodiya, Sanjay M., Smith, Philip, Sperling, Michael, Striano, Pasquale, Surges, Rainer, Neil Thomas, G., Visscher, Frank, Whelan, Christopher D., Zara, Federico, Heinzen, Erin L., Marson, Anthony, Becker, Felicita, Stroink, Han, Zimprich, Fritz, Gasser, Thoma, Gibbs, Raphael, Heutink, Peter, Martinez, Maria, Morris, Huw R., Sharma, Manu, Ryten, Mina, Mok, Kin Y., Pulit, Sara, Bevan, Steve, Holliday, Elizabeth, Attia, John, Battey, Thoma, Boncoraglio, Giorgio, Thijs, Vincent, Chen, Wei-Min, Mitchell, Braxton, Rothwell, Peter, Sharma, Pankaj, Sudlow, Cathie, Vicente, Astrid, Markus, Hugh, Kourkoulis, Christina, Pera, Joana, Raffeld, Miriam, Silliman, Scott, Perica, Vesna Boraska, Thornton, Laura M., Huckins, Laura M., William Rayner, N., Lewis, Cathryn M., Gratacos, Monica, Rybakowski, Filip, Keski-Rahkonen, Anna, Raevuori, Anu, Hudson, James I., Reichborn-Kjennerud, Ted, Monteleone, Palmiero, Karwautz, Andrea, Mannik, Katrin, Baker, Jessica H., O'Toole, Julie K., Trace, Sara E., Davis, Oliver S. P., Helder, Sietske G., Ehrlich, Stefan, Herpertz-Dahlmann, Beate, Danner, Unna N., Van Elburg, Annemarie A., Clementi, Maurizio, Forzan, Monica, Docampo, Elisa, Lissowska, Jolanta, Hauser, Joanna, Tortorella, Alfonso, Maj, Mario, Gonidakis, Fragisko, Tziouvas, Konstantino, Papezova, Hana, Yilmaz, Zeynep, Wagner, Gudrun, Cohen-Woods, Sarah, Herms, Stefan, Julia, Antonio, Rabionet, Raquel, Dick, Danielle M., Ripatti, Samuli, Andreassen, Ole A., Espeseth, Thoma, Lundervold, Astri J., Steen, Vidar M., Pinto, Dalila, Scherer, Stephen W., Aschauer, Harald, Schosser, Alexandra, Alfredsson, Lar, Padyukov, Leonid, Halmi, Katherine A., Mitchell, Jame, Strober, Michael, Bergen, Andrew W., Kaye, Walter, Szatkiewicz, Jin Peng, Cormand, Bru, Ramos-Quiroga, Josep Antoni, Sánchez-Mora, Cristina, Ribasés, Marta, Casas, Miguel, Hervas, Amaia, Arranz, Maria Jesú, Haavik, Jan, Zayats, Tetyana, Johansson, Stefan, Williams, Nigel, Dempfle, Astrid, Rothenberger, Aribert, Kuntsi, Jonna, Oades, Robert D., Banaschewski, Tobia, Franke, Barbara, Buitelaar, Jan K., Vasquez, Alejandro Aria, Doyle, Alysa E., Reif, Andrea, Lesch, Klaus-Peter, Freitag, Christine, Rivero, Olga, Palmason, Haukur, Romanos, Marcel, Langley, Kate, Rietschel, Marcella, Witt, Stephanie H., Dalsgaard, Soeren, Børglum, Anders D., Waldman, Irwin, Wilmot, Beth, Molly, Nikola, Bau, Claiton H.D., Crosbie, Jennifer, Schachar, Russell, Loo, Sandra K., McGough, James J., Grevet, Eugenio H., Medland, Sarah E., Robinson, Elise, Weiss, Lauren A., Bacchelli, Elena, Bailey, Anthony, Bal, Vanessa, Battaglia, Agatino, Betancur, Catalina, Bolton, Patrick, Cantor, Rita, Celestino-Soper, Patrícia, Dawson, Geraldine, De Rubeis, Silvia, Duque, Frederico, Green, Andrew, Klauck, Sabine M., Leboyer, Marion, Levitt, Pat, Maestrini, Elena, Mane, Shrikant, Moreno-De-Luca, Daniel, Parr, Jeremy, Regan, Regina, Reichenberg, Abraham, Sandin, Sven, Vorstman, Jacob, Wassink, Thoma, Wijsman, Ellen, Cook, Edwin, Santangelo, Susan, Delorme, Richard, Roge, Bernadette, Magalhaes, Tiago, Arking, Dan, Schulze, Thomas G., Thompson, Robert C., Strohmaier, Jana, Matthews, Keith, Melle, Ingrid, Morris, Derek, Blackwood, Dougla, McIntosh, Andrew, Bergen, Sarah E., Schalling, Martin, Jamain, Stéphane, Maaser, Anna, Fischer, Sascha B., Reinbold, Céline S., Fullerton, Janice M., Guzman-Parra, José, Mayoral, Fermin, Schofield, Peter R., Cichon, Sven, Mühleisen, Thomas W., Degenhardt, Franziska, Schumacher, Johanne, Bauer, Michael, Mitchell, Philip B., Gershon, Elliot S., Rice, John, Potash, James B., Zandi, Peter P., Craddock, Nick, Nicol Ferrier, I., Alda, Martin, Rouleau, Guy A., Turecki, Gustavo, Ophoff, Roel, Pato, Carlo, Anjorin, Adebayo, Stahl, Eli, Leber, Marku, Czerski, Piotr M., Cruceanu, Cristiana, Jones, Ian R., Posthuma, Danielle, Andlauer, Till F.M., Forstner, Andreas J., Streit, Fabian, Baune, Bernhard T., Air, Tracy, Sinnamon, Grant, Wray, Naomi R., MacIntyre, Donald J., Porteous, David, Homuth, Georg, Rivera, Margarita, Grove, Jakob, Middeldorp, Christel M., Hickie, Ian, Pergadia, Michele, Mehta, Divya, Smit, Johannes H., Jansen, Rick, De Geus, Eco, Dunn, Erin, Li, Qingqin S., Nauck, Matthia, Schoevers, Robert A., Beekman, Aartjan TF, Knowles, James A., Viktorin, Alexander, Arnold, Paul, Barr, Cathy L., Bedoya-Berrio, Gabriel, Joseph Bienvenu, O., Brentani, Helena, Burton, Christie, Camarena, Beatriz, Cappi, Carolina, Cath, Danielle, Cavallini, Maria, Cusi, Daniele, Darrow, Sabrina, Denys, Damiaan, Derks, Eske M., Dietrich, Andrea, Fernandez, Thoma, Figee, Martijn, Freimer, Nelson, Gerber, Gloria, Grados, Marco, Greenberg, Erica, Hanna, Gregory L., Hartmann, Andrea, Hirschtritt, Matthew E., Hoekstra, Pieter J., Huang, Alden, Huyser, Chaim, Illmann, Cornelia, Jenike, Michael, Kuperman, Samuel, Leventhal, Bennett, Lochner, Christine, Lyon, Gholson J., Macciardi, Fabio, Madruga-Garrido, Marco, Malaty, Irene A., Maras, Athanasio, McGrath, Lauren, Miguel, Eurípedes C., Mir, Pablo, Nestadt, Gerald, Nicolini, Humberto, Okun, Michael S., Pakstis, Andrew, Paschou, Peristera, Piacentini, John, Pittenger, Christopher, Plessen, Kerstin, Ramensky, Vasily, Ramos, Eliana M., Reus, Victor, Richter, Margaret A., Riddle, Mark A., Robertson, Mary M., Roessner, Veit, Rosário, Maria, Samuels, Jack F., Sandor, Paul, Stein, Dan J., Tsetsos, Foti, Van Nieuwerburgh, Filip, Weatherall, Sarah, Wendland, Jens R., Wolanczyk, Tomasz, Worbe, Yulia, Zai, Gwyneth, Goes, Fernando S., McLaughlin, Nicole, Nestadt, Paul S., Grabe, Hans-Jorgen, Depienne, Christel, Konkashbaev, Anuar, Lanzagorta, Nuria, Valencia-Duarte, Ana, Bramon, Elvira, Buccola, Nancy, Cahn, Wiepke, Cairns, Murray, Chong, Siow A., Cohen, David, Crespo-Facorro, Benedicto, Crowley, Jame, Davidson, Michael, DeLisi, Lynn, Dinan, Timothy, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Haan, Lieuwe, Hougaard, David, Karachanak-Yankova, Sena, Khrunin, Andrey, Klovins, Jani, Kučinskas, Vaiduti, Keong, Jimmy Lee Chee, Limborska, Svetlana, Loughland, Carmel, Lönnqvist, Jouko, Maher, Brion, Mattheisen, Manuel, McDonald, Colm, Murphy, Kieran C., Nenadic, Igor, Van Os, Jim, Pantelis, Christo, Pato, Michele, Petryshen, Tracey, Quested, Digby, Roussos, Pano, Sanders, Alan R., Schall, Ulrich, Schwab, Sibylle G., Sim, Kang, So, Hon-Cheong, Stögmann, Elisabeth, Subramaniam, Mythily, Toncheva, Draga, Waddington, John, Walters, Jame, Weiser, Mark, Cheng, Wei, Cloninger, Robert, Curtis, David, Gejman, Pablo V., Henskens, Fran, Mattingsdal, Morten, Oh, Sang-Yun, Scott, Rodney, Webb, Bradley, Breen, Gerome, Churchhouse, Claire, Bulik, Cynthia M., Daly, Mark, Dichgans, Martin, Faraone, Stephen V., Guerreiro, Rita, Holmans, Peter, Kendler, Kenneth S., Koeleman, Bobby, Mathews, Carol A., Price, Alke, Scharf, Jeremiah, Sklar, Pamela, Williams, Julie, Wood, Nicholas W., Cotsapas, Chri, Palotie, Aarno, Smoller, Jordan W., Sullivan, Patrick, Rosand, Jonathan, Corvin, Aiden, Neale, Benjamin M., Epidemiology, Radiology & Nuclear Medicine, Anttila, V, Bulik-Sullivan, B, Finucane, H, Walters, R, Bras, J, Duncan, L, Escott-Price, V, Falcone, G, Gormley, P, Malik, R, Patsopoulos, N, Ripke, S, Wei, Z, Yu, D, Lee, P, Turley, P, Grenier-Boley, B, Chouraki, V, Kamatani, Y, Berr, C, Letenneur, L, Hannequin, D, Amouyel, P, Boland, A, Deleuze, J, Duron, E, Vardarajan, B, Reitz, C, Goate, A, Huentelman, M, Ilyas Kamboh, M, Larson, E, Rogaeva, E, George-Hyslop, P, Hakonarson, H, Kukull, W, Farrer, L, Barnes, L, Beach, T, Yesim Demirci, F, Head, E, Hulette, C, Jicha, G, Kauwe, J, Kaye, J, Leverenz, J, Levey, A, Lieberman, A, Pankratz, V, Poon, W, Quinn, J, Saykin, A, Schneider, L, Smith, A, Sonnen, J, Stern, R, Van Deerlin, V, Van Eldik, L, Harold, D, Russo, G, Rubinsztein, D, Bayer, A, Tsolaki, M, Proitsi, P, Fox, N, Hampel, H, Owen, M, Mead, S, Passmore, P, Morgan, K, Nöthen, M, Rossor, M, Lupton, M, Hoffmann, P, Kornhuber, J, Lawlor, B, Mcquillin, A, Al-Chalabi, A, Bis, J, Ruiz, A, Boada, M, Seshadri, S, Beiser, A, Rice, K, Van Der Lee, S, De Jager, P, Geschwind, D, Riemenschneider, M, Riedel-Heller, S, Rotter, J, Ransmayr, G, Hyman, B, Cruchaga, C, Alegret, M, Winsvold, B, Palta, P, Farh, K, Cuenca-Leon, E, Furlotte, N, Kurth, T, Ligthart, L, Terwindt, G, Freilinger, T, Ran, C, Gordon, S, Borck, G, Adams, H, Lehtimäki, T, Wedenoja, J, Buring, J, Schürks, M, Hrafnsdottir, M, Hottenga, J, Penninx, B, Artto, V, Kaunisto, M, Vepsäläinen, S, Martin, N, Montgomery, G, Kurki, M, Hämäläinen, E, Huang, H, Huang, J, Sandor, C, Webber, C, Muller-Myhsok, B, Schreiber, S, Salomaa, V, Loehrer, E, Göbel, H, Macaya, A, Pozo-Rosich, P, Hansen, T, Werge, T, Kaprio, J, Metspalu, A, Kubisch, C, Ferrari, M, Belin, A, Van Den Maagdenberg, A, Zwart, J, Boomsma, D, Eriksson, N, Olesen, J, Chasman, D, Nyholt, D, Avbersek, A, Baum, L, Berkovic, S, Bradfield, J, Buono, R, Catarino, C, Cossette, P, De Jonghe, P, Depondt, C, Dlugos, D, Ferraro, T, French, J, Hjalgrim, H, Jamnadas-Khoda, J, Kälviäinen, R, Kunz, W, Lerche, H, Leu, C, Lindhout, D, Lo, W, Lowenstein, D, Mccormack, M, Møller, R, Molloy, A, Ng, P, Oliver, K, Privitera, M, Radtke, R, Ruppert, A, Sander, T, Schachter, S, Schankin, C, Scheffer, I, Schoch, S, Sisodiya, S, Smith, P, Sperling, M, Striano, P, Surges, R, Neil Thomas, G, Visscher, F, Whelan, C, Zara, F, Heinzen, E, Marson, A, Becker, F, Stroink, H, Zimprich, F, Gasser, T, Gibbs, R, Heutink, P, Martinez, M, Morris, H, Sharma, M, Ryten, M, Mok, K, Pulit, S, Bevan, S, Holliday, E, Attia, J, Battey, T, Boncoraglio, G, Thijs, V, Chen, W, Mitchell, B, Rothwell, P, Sharma, P, Sudlow, C, Vicente, A, Markus, H, Kourkoulis, C, Pera, J, Raffeld, M, Silliman, S, Perica, V, Thornton, L, Huckins, L, William Rayner, N, Lewis, C, Gratacos, M, Rybakowski, F, Keski-Rahkonen, A, Raevuori, A, Hudson, J, Reichborn-Kjennerud, T, Monteleone, P, Karwautz, A, Mannik, K, Baker, J, O'Toole, J, Trace, S, Davis, O, Helder, S, Ehrlich, S, Herpertz-Dahlmann, B, Danner, U, Van Elburg, A, Clementi, M, Forzan, M, Docampo, E, Lissowska, J, Hauser, J, Tortorella, A, Maj, M, Gonidakis, F, Tziouvas, K, Papezova, H, Yilmaz, Z, Wagner, G, Cohen-Woods, S, Herms, S, Julia, A, Rabionet, R, Dick, D, Ripatti, S, Andreassen, O, Espeseth, T, Lundervold, A, Steen, V, Pinto, D, Scherer, S, Aschauer, H, Schosser, A, Alfredsson, L, Padyukov, L, Halmi, K, Mitchell, J, Strober, M, Bergen, A, Kaye, W, Szatkiewicz, J, Cormand, B, Ramos-Quiroga, J, Sánchez-Mora, C, Ribasés, M, Casas, M, Hervas, A, Arranz, M, Haavik, J, Zayats, T, Johansson, S, Williams, N, Dempfle, A, Rothenberger, A, Kuntsi, J, Oades, R, Banaschewski, T, Franke, B, Buitelaar, J, Vasquez, A, Doyle, A, Reif, A, Lesch, K, Freitag, C, Rivero, O, Palmason, H, Romanos, M, Langley, K, Rietschel, M, Witt, S, Dalsgaard, S, Børglum, A, Waldman, I, Wilmot, B, Molly, N, Bau, C, Crosbie, J, Schachar, R, Loo, S, Mcgough, J, Grevet, E, Medland, S, Robinson, E, Weiss, L, Bacchelli, E, Bailey, A, Bal, V, Battaglia, A, Betancur, C, Bolton, P, Cantor, R, Celestino-Soper, P, Dawson, G, De Rubeis, S, Duque, F, Green, A, Klauck, S, Leboyer, M, Levitt, P, Maestrini, E, Mane, S, Moreno-De-Luca, D, Parr, J, Regan, R, Reichenberg, A, Sandin, S, Vorstman, J, Wassink, T, Wijsman, E, Cook, E, Santangelo, S, Delorme, R, Roge, B, Magalhaes, T, Arking, D, Schulze, T, Thompson, R, Strohmaier, J, Matthews, K, Melle, I, Morris, D, Blackwood, D, Mcintosh, A, Bergen, S, Schalling, M, Jamain, S, Maaser, A, Fischer, S, Reinbold, C, Fullerton, J, Guzman-Parra, J, Mayoral, F, Schofield, P, Cichon, S, Mühleisen, T, Degenhardt, F, Schumacher, J, Bauer, M, Mitchell, P, Gershon, E, Rice, J, Potash, J, Zandi, P, Craddock, N, Nicol Ferrier, I, Alda, M, Rouleau, G, Turecki, G, Ophoff, R, Pato, C, Anjorin, A, Stahl, E, Leber, M, Czerski, P, Cruceanu, C, Jones, I, Posthuma, D, Andlauer, T, Forstner, A, Streit, F, Baune, B, Air, T, Sinnamon, G, Wray, N, Macintyre, D, Porteous, D, Homuth, G, Rivera, M, Grove, J, Middeldorp, C, Hickie, I, Pergadia, M, Mehta, D, Smit, J, Jansen, R, De Geus, E, Dunn, E, Li, Q, Nauck, M, Schoevers, R, Beekman, A, Knowles, J, Viktorin, A, Arnold, P, Barr, C, Bedoya-Berrio, G, Joseph Bienvenu, O, Brentani, H, Burton, C, Camarena, B, Cappi, C, Cath, D, Cavallini, M, Cusi, D, Darrow, S, Denys, D, Derks, E, Dietrich, A, Fernandez, T, Figee, M, Freimer, N, Gerber, G, Grados, M, Greenberg, E, Hanna, G, Hartmann, A, Hirschtritt, M, Hoekstra, P, Huang, A, Huyser, C, Illmann, C, Jenike, M, Kuperman, S, Leventhal, B, Lochner, C, Lyon, G, Macciardi, F, Madruga-Garrido, M, Malaty, I, Maras, A, Mcgrath, L, Miguel, E, Mir, P, Nestadt, G, Nicolini, H, Okun, M, Pakstis, A, Paschou, P, Piacentini, J, Pittenger, C, Plessen, K, Ramensky, V, Ramos, E, Reus, V, Richter, M, Riddle, M, Robertson, M, Roessner, V, Rosário, M, Samuels, J, Sandor, P, Stein, D, Tsetsos, F, Van Nieuwerburgh, F, Weatherall, S, Wendland, J, Wolanczyk, T, Worbe, Y, Zai, G, Goes, F, Mclaughlin, N, Nestadt, P, Grabe, H, Depienne, C, Konkashbaev, A, Lanzagorta, N, Valencia-Duarte, A, Bramon, E, Buccola, N, Cahn, W, Cairns, M, Chong, S, Cohen, D, Crespo-Facorro, B, Crowley, J, Davidson, M, Delisi, L, Dinan, T, Donohoe, G, Drapeau, E, Duan, J, Haan, L, Hougaard, D, Karachanak-Yankova, S, Khrunin, A, Klovins, J, Kučinskas, V, Keong, J, Limborska, S, Loughland, C, Lönnqvist, J, Maher, B, Mattheisen, M, Mcdonald, C, Murphy, K, Nenadic, I, Van Os, J, Pantelis, C, Pato, M, Petryshen, T, Quested, D, Roussos, P, Sanders, A, Schall, U, Schwab, S, Sim, K, So, H, Stögmann, E, Subramaniam, M, Toncheva, D, Waddington, J, Walters, J, Weiser, M, Cheng, W, Cloninger, R, Curtis, D, Gejman, P, Henskens, F, Mattingsdal, M, Oh, S, Scott, R, Webb, B, Breen, G, Churchhouse, C, Bulik, C, Daly, M, Dichgans, M, Faraone, S, Guerreiro, R, Holmans, P, Kendler, K, Koeleman, B, Mathews, C, Price, A, Scharf, J, Sklar, P, Williams, J, Wood, N, Cotsapas, C, Palotie, A, Smoller, J, Sullivan, P, Rosand, J, Corvin, A, Neale, B, Kauwe, John S. K., Mcquillin, Andrew, Adams, Hieab H. H., Mccormack, Mark, Bau, Claiton H. D., Mcgough, James J., Mcintosh, Andrew, Andlauer, Till F. M., Macintyre, Donald J., Mcgrath, Lauren, Mclaughlin, Nicole, Delisi, Lynn, Mcdonald, Colm, Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), RIKEN Center for Integrative Medical Science, Neuropsychiatrie : recherche épidémiologique et clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), University of South Florida (USF), University of Zürich [Zürich] (UZH)-Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), Alzheimer Precision Medicine GRC n°21 (APM), CHU Pitié-Salpêtrière [APHP], Cardiff University-Medical Research Council, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Johannes Kepler University Linz [linz] (JKU), Washington University in St Louis, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Universitat Autònoma de Barcelona [Barcelona] (UAB), Hôpital Erasme (Bruxelles), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Jagiellonian University [Krakow] (UJ), Technische Universität Dresden (TUD), National and Kapodistrian University of Athens = University of Athens (NKUA | UoA), Charles University [Prague], Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), University of Bergen (UIB), University Medicine Goettingen, Università di Bologna [Bologna] (UNIBO), Forschungszentrum Jülich GmbH, UNSW Medicine [Sydney], McGill University, Universidad de Antioquia, University of Florida [Gainesville], Universiteit Gent [Ghent], Service Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], University of Wollongong, Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 APM), Anttila, Verneri [0000-0002-0073-4675], Finucane, Hilary K [0000-0003-3864-9828], Walters, Raymond K [0000-0001-8422-6530], Duncan, Laramie [0000-0003-1131-661X], Escott-Price, Valentina [0000-0003-1784-5483], Falcone, Guido J [0000-0002-6407-0302], Gormley, Padhraig [0000-0002-8908-6968], Malik, Rainer [0000-0001-9212-2520], Ripke, Stephan [0000-0003-3622-835X], Wei, Zhi [0000-0001-6059-4267], Yu, Dongmei [0000-0001-7901-4365], Lee, Phil H [0000-0003-1770-3100], Breen, Gerome [0000-0003-2053-1792], Bulik, Cynthia M [0000-0001-7772-3264], Daly, Mark [0000-0002-0949-8752], Dichgans, Martin [0000-0002-0654-387X], Faraone, Stephen V [0000-0002-9217-3982], Holmans, Peter [0000-0003-0870-9412], Koeleman, Bobby [0000-0001-7749-182X], Mathews, Carol A [0000-0003-2208-7058], Sklar, Pamela [0000-0001-9715-4943], Williams, Julie [0000-0002-4069-0259], Wood, Nicholas W [0000-0002-9500-3348], Cotsapas, Chris [0000-0002-7772-5910], Smoller, Jordan W [0000-0002-0381-6334], Sullivan, Patrick [0000-0002-6619-873X], Rosand, Jonathan [0000-0002-1014-9138], Corvin, Aiden [0000-0001-6717-4089], Neale, Benjamin M [0000-0003-1513-6077], and Apollo - University of Cambridge Repository
Subjects: Etiology, [SDV]Life Sciences [q-bio], MESH: Brain Diseases, body-mass index, genetics [Mental Disorders], Disorders of the Brain, Risks factors, classification [Mental Disorders], MESH: Quantitative Trait, Heritable, MESH: Risk Factors, Risk Factors, MESH: Genetic Variation, alzheimers-disease, 610 Medicine & health, bipolar disorder, Brain Diseases, deficit hyperactivity disorder, Multidisciplinary, Mental Disorders, genetics [Brain Diseases], Brain Disease, Brain, Genetic Variation, Genome-Wide Association Study, Humans, Phenotype, Quantitative Trait, Heritable, Psychiatric Disorders, anorexia-nervosa, Mental Disorder, Psychiatric Genomics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], long-term survival, Engineering sciences. Technology, Human, General Science & Technology, population-based twin, diagnosis [Mental Disorders], MESH: Phenotype, Neurological Disorders, Quantitative Trait, MD Multidisciplinary, MESH: Mental Disorders, diagnosis [Brain Diseases], Heritable, genetic correlations, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, major depressive disorder, Risk Factor, Brain Diseases/classification, Brain Diseases/diagnosis, Brain Diseases/genetics, Mental Disorders/classification, Mental Disorders/diagnosis, Mental Disorders/genetics, classification [Brain Diseases], Perturbações do Desenvolvimento Infantil e Saúde Mental, ddc:320, MESH: Genome-Wide Association Study, genome-wide association, Brainstorm Consortium, Genetic Factors, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities’ assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer’s disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important “scaffolding” to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders.
Published: 2018
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25. Construction of $\Phi^4_3$ diagrams for pedestrians

Author: Mourrat, Jean-Christophe, Weber, Hendrik, Xu, Weijun, Unité de Mathématiques Pures et Appliquées (UMPA-ENSL), École normale supérieure de Lyon (ENS de Lyon)-Centre National de la Recherche Scientifique (CNRS), Warwick Mathematics Institute (WMI), University of Warwick [Coventry], Institute for Molecular Bioscience, University of Queensland [Brisbane], ANR-15-CE40-0020,LSD,Modèles stochastiques en grande dimension pour la physique statistique hors équilibre(2015), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon), Mourrat, Jean-Christophe, and Défi de tous les savoirs - Modèles stochastiques en grande dimension pour la physique statistique hors équilibre - - LSD2015 - ANR-15-CE40-0020 - AAPG2015 - VALID
Subjects: [MATH.MATH-PR]Mathematics [math]/Probability [math.PR], [MATH.MATH-PR] Mathematics [math]/Probability [math.PR], [PHYS.MPHY]Physics [physics]/Mathematical Physics [math-ph], [PHYS.MPHY] Physics [physics]/Mathematical Physics [math-ph], Mathematics - Probability, Mathematical Physics, 81T18, 81T08, 60H15
Abstract: We aim to give a pedagogic and essentially self-contained presentation of the construction of various stochastic objects appearing in the dynamical $\Phi^4_3$ model. The construction presented here is based on the use of paraproducts. The emphasis is on describing the stochastic objects themselves rather than introducing a solution theory for the equation., Comment: 39 pages
Published: 2017

26. Reduced Activity of SRY and its Target Enhancer Sox9-TESCO in a Mouse Species with X*Y Sex Reversal

Author: Ee Ting Ng, Alexander E. Quinn, Peter Koopman, Liang Zhao, Frédéric Veyrunes, Institute for Molecular Bioscience, University of Queensland [Brisbane], Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UR226, Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, Transcriptional Activation, health care facilities, manpower, and services, SOX9, Article, Evolution, Molecular, 03 medical and health sciences, Mice, Genes, Reporter, parasitic diseases, Animals, Humans, Amino Acid Sequence, Enhancer, Gene, health care economics and organizations, X chromosome, Genetics, Multidisciplinary, biology, Base Sequence, Models, Genetic, Protein Stability, Chromosome, Mus minutoides, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, SOX9 Transcription Factor, social sciences, Sex reversal, Sex Determination Processes, biology.organism_classification, Molecular biology, Sex-Determining Region Y Protein, 030104 developmental biology, Testis determining factor, Enhancer Elements, Genetic, HEK293 Cells, Haplotypes, population characteristics, Female, Peptides, geographic locations
Abstract: In most eutherian mammals, sex determination is governed by the Y-linked gene Sry, but in African pygmy mice Mus minutoides, Sry action is overridden by a variant X chromosome (X*), yielding X*Y females. We hypothesized that X*Y sex reversal may be underpinned not only by neomorphic X chromosome functionality, but also by a compromised Sry pathway. Here, we show that neither M. minutoides SRY nor its target, the Sox9-TESCO enhancer, had appreciable transcriptional activity in in vitro assays, correlating with sequence degradation compared to Mus musculus counterparts. However, M. minutoides SRY activated its cognate TESCO to a moderate degree, and can clearly engage the male pathway in M. minutoides in the wild, indicating that SRY and TESCO may have co-evolved in M. minutoides to retain function above a threshold level. We suggest that weakening of the SRY/TESCO nexus may have facilitated the rise and spread of a variant X* chromosome carrying female-inducing modifier gene(s).
Published: 2017
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27. Relationship between salivary/pancreatic amylase and body mass index: a systems biology approach

Author: Amélie, Bonnefond, Loïc, Yengo, Aurélie, Dechaume, Mickaël, Canouil, Maxime, Castelain, Estelle, Roger, Frédéric, Allegaert, Robert, Caiazzo, Violeta, Raverdy, Marie, Pigeyre, Abdelilah, Arredouani, Jean-Michel, Borys, Claire, Lévy-Marchal, Jacques, Weill, Ronan, Roussel, Beverley, Balkau, Michel, Marre, François, Pattou, Thierry, Brousseau, Philippe, Froguel, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Bioscience, University of Queensland [Brisbane], Recherche translationnelle sur le diabète - U 1190 (RTD), 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), Département de chirurgie endocrinienne [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Association Fleurbaix Laventie Ville Santé (FLVS), Service d'Epidémiologie clinique [Lille] (CIE 05 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'endocrinologie pédiatrique [Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sorbonne Paris Cité (USPC), Service d'endocrinologie, diabétologie et nutrition [CHU Bichat], 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), DHU FIRE Centre de compétence des maladies pulmonaires rares, Épidémiologie et recherches translationnelles sur les maladies rénales et cardiovasculaires (EPREC) (U1018 (Équipe 5)), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Biochimie Automatisée [Lille] (UF Analyses automatisée de Biochimie), Department of Genomics of Common Disease [London, UK], Imperial College London-Hammersmith Hospital NHS Imperial College Healthcare, ANR-10-LABX-0046,EGID,EGID Diabetes Pole(2010), ANR-10-EQPX-0007,LIGAN PM,Plate forme Lilloise de séquençage du génome humain pour une médecine personnalisée(2010), Génomique Intégrative et Modélisation des Maladies Métaboliques ( EGID ), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -Centre National de la Recherche Scientifique ( CNRS ), Recherche translationelle sur le diabète ( EGID ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -Institut Européen de Génomique du Diabète - EGID, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Fleurbaix Laventie Ville Santé Association ( FLVS ASSOCIATION ), Association Fleurbaix Laventie Ville Santé, Service d'Epidémiologie clinique [Lille] ( CIE 05 Inserm ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AP-HP Hôpital universitaire Robert-Debré [Paris], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Sorbonne Paris Cité ( USPC ), Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Epidémiologie rénale et cardiovasculaire ( Equipe 5 : EpReC ), Centre de recherche en épidémiologie et santé des populations ( CESP ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Biochimie Automatisée [Lille] ( UF Analyses automatisée de Biochimie ), Imperial College London-Hammersmith Hospital, ANR-10-LABX-0046/10-LABX-0046,EGID,EGID Diabetes Pole ( 2010 ), ANR-10-EQPX-07-01 ,[LIGAN-PM],ANR Equipex 2010 session, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Fleurbaix Laventie Ville Santé Association (FLVS ASSOCIATION), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hammersmith Hospital NHS Imperial College Healthcare-Imperial College London, BMC, BMC, EGID Diabetes Pole - - EGID2010 - ANR-10-LABX-0046 - LABX - VALID, and Plate forme Lilloise de séquençage du génome humain pour une médecine personnalisée - - LIGAN PM2010 - ANR-10-EQPX-0007 - EQPX - VALID
Subjects: Male, HOMEOSTASIS, AMY1A/AMY2A, [SDV]Life Sciences [q-bio], CHILDREN, Pancreatic alpha-Amylases, VARIANTS, Copy number variant, Medicine, General & Internal, General & Internal Medicine, Humans, Longitudinal Studies, Child, AMY1, Body mass index, COPY NUMBER VARIATION, Medicine(all), Science & Technology, [ SDV ] Life Sciences [q-bio], Systems Biology, Salivary/Pancreatic amylase, Starch, ASSOCIATION, 11 Medical And Health Sciences, GENE, [SDV] Life Sciences [q-bio], Salivary alpha-Amylases, Metabonomics, OBESITY, MENDELIAN RANDOMIZATION, Female, Life Sciences & Biomedicine, Research Article, DESIR
Abstract: Background Salivary (AMY1) and pancreatic (AMY2) amylases hydrolyze starch. Copy number of AMY1A (encoding AMY1) was reported to be higher in populations with a high-starch diet and reduced in obese people. These results based on quantitative PCR have been challenged recently. We aimed to re-assess the relationship between amylase and adiposity using a systems biology approach. Methods We assessed the association between plasma enzymatic activity of AMY1 or AMY2, and several metabolic traits in almost 4000 French individuals from D.E.S.I.R. longitudinal study. The effect of the number of copies of AMY1A (encoding AMY1) or AMY2A (encoding AMY2) measured through droplet digital PCR was then analyzed on the same parameters in the same study. A Mendelian randomization analysis was also performed. We subsequently assessed the association between AMY1A copy number and obesity risk in two case-control studies (5000 samples in total). Finally, we assessed the association between body mass index (BMI)-related plasma metabolites and AMY1 or AMY2 activity. Results We evidenced strong associations between AMY1 or AMY2 activity and lower BMI. However, we found a modest contribution of AMY1A copy number to lower BMI. Mendelian randomization identified a causal negative effect of BMI on AMY1 and AMY2 activities. Yet, we also found a significant negative contribution of AMY1 activity at baseline to the change in BMI during the 9-year follow-up, and a significant contribution of AMY1A copy number to lower obesity risk in children, suggesting a bidirectional relationship between AMY1 activity and adiposity. Metabonomics identified a BMI-independent association between AMY1 activity and lactate, a product of complex carbohydrate fermentation. Conclusions These findings provide new insights into the involvement of amylase in adiposity and starch metabolism. Electronic supplementary material The online version of this article (doi:10.1186/s12916-017-0784-x) contains supplementary material, which is available to authorized users.
Published: 2017
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28. Discovery and mode of action of a novel analgesic β-toxin from the African spider Ceratogyrus darlingi

Author: Joshua S. Wingerd, Jennifer R. Deuis, Paul F. Alewood, Lotten Ragnarsson, Irina Vetter, Sébastien Dutertre, Richard J. Lewis, Gerald W. Zamponi, Chris Bladen, Volker Herzig, Silmara R. Sousa, Glenn F. King, Andreas Brust, Institute for Molecular Bioscience, University of Queensland [Brisbane], Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), and University of Calgary
Subjects: 0301 basic medicine, Physiology, Spider Venoms, lcsh:Medicine, Peptide, Gating, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Pharmacology, Toxicology, Pathology and Laboratory Medicine, Biochemistry, Ion Channels, Mice, Calcium Channels, N-Type, Medicine and Health Sciences, Toxins, Fluorometry, lcsh:Science, Membrane potential, chemistry.chemical_classification, Analgesics, Multidisciplinary, Voltage-dependent calcium channel, Animal Behavior, integumentary system, Physics, NAV1.7 Voltage-Gated Sodium Channel, Drugs, Spiders, 3. Good health, Electrophysiology, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Physical Sciences, Ion Channel Gating, Research Article, Arthropoda, Toxic Agents, Biophysics, Neurophysiology, Biology, Membrane Potential, 03 medical and health sciences, Arachnida, Animals, Humans, Pain Management, Mode of action, Ion channel, Behavior, Binding Sites, Venoms, lcsh:R, Organisms, Biology and Life Sciences, Proteins, Invertebrates, Rats, NAV1.1 Voltage-Gated Sodium Channel, 030104 developmental biology, chemistry, lcsh:Q, Peptides, Zoology, Neuroscience
Abstract: International audience; Spider venoms are rich sources of peptidic ion channel modulators with important therapeutical potential. We screened a panel of 60 spider venoms to find modulators of ion channels involved in pain transmission. We isolated, synthesized and pharmacologically characterized Cd1a, a novel peptide from the venom of the spider Ceratogyrus darlingi. Cd1a reversibly paralysed sheep blowflies (PD50 of 1318 pmol/g) and inhibited human Cav2.2 (IC50 2.6 μM) but not Cav1.3 or Cav3.1 (IC50 > 30 μM) in fluorimetric assays. In patch-clamp electrophysiological assays Cd1a inhibited rat Cav2.2 with similar potency (IC50 3 μM) without influencing the voltage dependence of Cav2.2 activation gating, suggesting that Cd1a doesn't act on Cav2.2 as a classical gating modifier toxin. The Cd1a binding site on Cav2.2 did not overlap with that of the pore blocker ω-conotoxin GVIA, but its activity at Cav2.2-mutant indicated that Cd1a shares some molecular determinants with GVIA and MVIIA, localized near the pore region. Cd1a also inhibited human Nav1.1-1.2 and Nav1.7-1.8 (IC50 0.1-6.9 μM) but not Nav1.3-1.6 (IC50 > 30 μM) in fluorimetric assays. In patch-clamp assays, Cd1a strongly inhibited human Nav1.7 (IC50 16 nM) and produced a 29 mV depolarising shift in Nav1.7 voltage dependence of activation. Cd1a (400 pmol) fully reversed Nav1.7-evoked pain behaviours in mice without producing side effects. In conclusion, Cd1a inhibited two anti-nociceptive targets, appearing to interfere with Cav2.2 inactivation gating, associated with the Cav2.2 α-subunit pore, while altering the activation gating of Nav1.7. Cd1a was inactive at some of the Nav and Cav channels expressed in skeletal and cardiac muscles and nodes of Ranvier, apparently contributing to the lack of side effects at efficacious doses, and suggesting potential as a lead for development of peripheral pain treatments.
Published: 2017
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29. Conotoxin Φ-MiXXVIIA from the Superfamily G2 Employs a Novel Cysteine Framework that Mimics Granulin and Displays Anti-Apoptotic Activity

Author: Alex Loukas, David Wilson, Michael J. Smout, Richard J. Lewis, Sébastien Dutertre, Paul F. Alewood, Irina Vetter, Ai-Hua Jin, Zoltan Dekan, Norelle L. Daly, Institute for Molecular Bioscience, University of Queensland [Brisbane], James Cook University (JCU), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), and Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)
Subjects: Models, Molecular, 0301 basic medicine, Signal peptide, Magnetic Resonance Spectroscopy, Protein Conformation, granulin, Granulin, snail venom, anti-apoptosis, Apoptosis, Catalysis, conotoxins, 03 medical and health sciences, 0302 clinical medicine, [CHIM]Chemical Sciences, Amino Acid Sequence, Disulfides, Conotoxin, Receptor, cysteine, Ion channel, Cell Proliferation, Granulins, Sequence Homology, Amino Acid, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Chemistry, Molecular Mimicry, Biological activity, General Chemistry, biology.organism_classification, 030104 developmental biology, Biochemistry, 030220 oncology & carcinogenesis, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Conus miles, Cysteine
Abstract: International audience; Conotoxins are a large family of disulfide-rich peptides that contain unique cysteine frameworks that target a broad range of ion channels and receptors. We recently discovered the 33-residue conotoxin Φ-MiXXVIIA from Conus miles with a novel cysteine framework comprising three consecutive cysteine residues and four disulfide bonds. Regioselective chemical synthesis helped decipher the disulfide bond connectivity and the structure of Φ-MiXXVIIA was determined by NMR spectroscopy. The 3D structure displays a unique topology containing two β-hairpins that resemble the N-terminal domain of granulin. Similar to granulin, Φ-MiXXVIIA promotes cell proliferation (EC50 17.85 μm) while inhibiting apoptosis (EC50 2.2 μm). Additional framework XXVII sequences were discovered with homologous signal peptides that define the new conotoxin superfamily G2. The novel structure and biological activity of Φ-MiXXVIIA expands the repertoire of disulfide-rich conotoxins that recognize mammalian receptors.
Published: 2017
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30. Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth

Author: Ming Jang Chua, Weijun Xu, Megan Sarah Jean Arnold, Raymond J. Pierce, Eric Prina, Suzanne Lamotte, Katherine T. Andrews, Gerald F. Späth, David P. Fairlie, Julien Lancelot, Tina S. Skinner-Adams, Griffith University [Brisbane], Institute for Molecular Bioscience, University of Queensland [Brisbane], Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Parasitologie moléculaire et Signalisation / Molecular Parasitology and Signaling, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), The authors' work was supported by Australian National Health and Medical Research Council (APP1093378 and APP1074016 to KTA and DPF), the A-PARADDISE program funded under the European Union's Seventh Framework Programme (grant agreement no. 602080 to KTA, DPF, JL, RJP, EP, GFS and SL) and Griffith University (GUIPRS and GUPRS scholarships to MJC). DF acknowledges an NHMRC Senior Principal Research Fellowship (1027369) and ARC grant (CE140100011)., European Project: 602080,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,A-PARADDISE(2014), 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)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ricard Andraos, Christel, and Anti-Parasitic Drug Discovery in Epigenetics - A-PARADDISE - - EC:FP7:HEALTH2014-02-01 - 2017-01-31 - 602080 - VALID
Subjects: 0301 basic medicine, Plasmodium, Indoles, Plasmodium berghei, Administration, Oral, Parasitemia, Hydroxamic Acids, Romidepsin, Histones, chemistry.chemical_compound, Mice, Depsipeptides, Panobinostat, Pharmacology (medical), Leishmania, Sulfonamides, Vorinostat, biology, Acetylation, Schistosoma mansoni, 3. Good health, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Plasmodium knowlesi, Schistosoma, medicine.drug, Histone Deacetylases, Article, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, Inhibitory Concentration 50, parasitic diseases, medicine, Animals, Humans, lcsh:RC109-216, Histone deacetylase, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Pharmacology, Life Cycle Stages, biology.organism_classification, medicine.disease, Virology, Malaria, Histone Deacetylase Inhibitors, 030104 developmental biology, HEK293 Cells, chemistry, Parasitology, Belinostat
Abstract: Malaria, schistosomiasis and leishmaniases are among the most prevalent tropical parasitic diseases and each requires new innovative treatments. Targeting essential parasite pathways, such as those that regulate gene expression and cell cycle progression, is a key strategy for discovering new drug leads. In this study, four clinically approved anti-cancer drugs (Vorinostat, Belinostat, Panobinostat and Romidepsin) that target histone/lysine deacetylase enzymes were examined for in vitro activity against Plasmodium knowlesi, Schistosoma mansoni, Leishmania amazonensis and L. donovani parasites and two for in vivo activity in a mouse malaria model. All four compounds were potent inhibitors of P. knowlesi malaria parasites (IC50 9–370 nM), with belinostat, panobinostat and vorinostat having 8–45 fold selectivity for the parasite over human neonatal foreskin fibroblast (NFF) or human embryonic kidney (HEK 293) cells, while romidepsin was not selective. Each of the HDAC inhibitor drugs caused hyperacetylation of P. knowlesi histone H4. None of the drugs was active against Leishmania amastigote or promastigote parasites (IC50 > 20 μM) or S. mansoni schistosomula (IC50 > 10 μM), however romidepsin inhibited S. mansoni adult worm parings and egg production (IC50 ∼10 μM). Modest in vivo activity was observed in P. berghei infected mice dosed orally with vorinostat or panobinostat (25 mg/kg twice daily for four days), with a significant reduction in parasitemia observed on days 4–7 and 4–10 after infection (P, Graphical abstract Image 1, Highlights • HDAC inhibitor cancer drugs have in vitro activity against P. knowlesi. • HDAC inhibitor drugs cause hyperacetylation of P. knowlesi histone H4. • HDAC inhibitor drugs are not active against Leishmania amastigotes or promastigotes. • Romidepsin inhibited S. mansoni adult worm parings and egg production. • Oral Panobinostat has better activity in P. berghei infected mice than Vorinostat.
Published: 2016
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31. ColoNav: patient navigation for colorectal cancer screening in deprived areas – Study protocol

Author: Franck Chauvin, Sophie Rousseau, Fabien Tinquaut, Valérie Buthion, J. Kalecinski, M. Pommier, V. Dutertre, Y. Benoist, Véronique Régnier, Aurélie Bourmaud, Mathieu Oriol, N. Lechopier, Camille Allary, Lechopier, Nicolas, Institut de Cancérologie Lucien Neuwirth, CHU Saint-Etienne, Département de Santé Publique, Institut de Cancérologie de la Loire Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)-Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Universitat Politècnica de Catalunya [Barcelona] (UPC), Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques Saint Etienne, Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Molecular Bioscience, University of Queensland [Brisbane], Sciences et Société, Historicité, Éducation et Pratiques (EA S2HEP), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, École normale supérieure - Lyon (ENS Lyon), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Institut français de l'Education (IFÉ), Unité de recherche en sciences humaines et sociales (URSHS), Institut Gustave Roussy (IGR), Département Anesthésie, Assistance Publique - Hôpitaux de Marseille (APHM), COACTIS (COACTIS), Université Lumière - Lyon 2 (UL2)-Université Jean Monnet [Saint-Étienne] (UJM), INCa, Ligue contre le cancer, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre d'Investigation Clinique - Epidémiologie Clinique Saint-Etienne (CIC-EC), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), École normale supérieure de Lyon (ENS de Lyon), COnception de l'ACTIon en Situation (COACTIS), and Université Lumière - Lyon 2 (UL2)-Université Jean Monnet - Saint-Étienne (UJM)
Subjects: Randomized control study, Male, Cancer Research, Colorectal cancer, Cost-Benefit Analysis, Health Services Accessibility, law.invention, Colorectal cancer screening, [SHS.HISPHILSO]Humanities and Social Sciences/History, Philosophy and Sociology of Sciences, Underserved Population, Study Protocol, 0302 clinical medicine, Randomized controlled trial, prevention, law, Cancer screening, Health care, Patient navigation, Medicine, Mass Screening, 030212 general & internal medicine, Health inequalities, Early Detection of Cancer, education.field_of_study, Public health, Middle Aged, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Female, France, Colorectal Neoplasms, medicine.medical_specialty, Implementation research, Population, Realistic evaluation, Vulnerable Populations, 03 medical and health sciences, [SHS.HISPHILSO] Humanities and Social Sciences/History, Philosophy and Sociology of Sciences, Genetics, Humans, education, Aged, Colorectal Cancer, Ethics, business.industry, Fecal occult blood, medicine.disease, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Family medicine, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract: Background The mass colorectal cancer screening program was implemented in 2008 in France, targeting 16 million French people aged between 50 and 74. The current adhesion is insufficient and the participation rate is even lower among the underserved population, increasing health inequalities within our health care system. Patient Navigation programs have proved their efficiency to promote the access to cancer screening and diagnosis. Methods/Design The purpose of the study is to assess the implementation of a patient navigation intervention that has been described in another cultural environment and another health care system. The main objective of the program is to increase the colorectal cancer screening participation rate among the deprived population through the intervention of a navigator to promote the Fecal Occult Blood Test (FOBT) and complementary exams. We performed a multisite cluster randomized controlled trial, with three groups (one experimental group and two control groups) for 18 months. Discussion The study attempts to give a better understanding of the adhesion barriers to colorectal cancer screening among underserved populations. If this project is cost-effective, it could create a dynamic based on peer approaches that could be developed for other cancer screening programs and other chronic diseases. Trial registration NCT02369757
Published: 2016
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32. Remodeling the zonula adherens in response to tension and the role of afadin in this response

Author: Alan S. Fanning, Marc-Antoine Fardin, Mark Peifer, Wangsun Choi, René-Marc Mège, Grégoire Peyret, Benoit Ladoux, Alpha S. Yap, Bipul R. Acharya, Department of Biology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Division of Cell Biology and Molecular Medicine, University of Queensland [Brisbane]- Institute for Molecular Bioscience, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Mechanobiology Institute [Singapore] (MBI), National University of Singapore (NUS), Lineberger Comprehensive Cancer Center (UNC Lineberger), Department of Cell Biology and Physiology, National Institutes of Health grant R01GM47957 - grant R01DK061397, Human Frontier Science Program, National Health and Medical Research Council of Australia (1037320 and 1044041), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), European Project: 617233,EC:FP7:ERC,ERC-2013-CoG,DURACELL(2014), ANR-11-IDEX-0005-02/11-LABX-0071,WHO AM I,Determinants de l’Identité : de la molécule à l’individu(2011), and Lineberger Comprehensive Cancer Center
Subjects: 0301 basic medicine, Scaffold protein, Tight junction, Cadherin, Adherens Junctions, Cell Biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Article, Cell biology, Contractility, Adherens junction, 03 medical and health sciences, 030104 developmental biology, Cytoskeleton, Cell adhesion, Research Articles, Actin
Abstract: During development, epithelial cells must generate and respond to tension without disrupting epithelial barrier function. The authors use superresolution microscopy in MDCK cells to examine how the zonula adherens (ZA) is remodeled in response to elevated contractility while maintain tissue integrity. They define key roles for zonula occludens family proteins in regulating contractility and for the scaffolding protein afadin in maintaining ZA architecture at tricellular junctions., Morphogenesis requires dynamic coordination between cell–cell adhesion and the cytoskeleton to allow cells to change shape and move without losing tissue integrity. We used genetic tools and superresolution microscopy in a simple model epithelial cell line to define how the molecular architecture of cell–cell zonula adherens (ZA) is modified in response to elevated contractility, and how these cells maintain tissue integrity. We previously found that depleting zonula occludens 1 (ZO-1) family proteins in MDCK cells induces a highly organized contractile actomyosin array at the ZA. We find that ZO knockdown elevates contractility via a Shroom3/Rho-associated, coiled-coil containing protein kinase (ROCK) pathway. Our data suggest that each bicellular border is an independent contractile unit, with actin cables anchored end-on to cadherin complexes at tricellular junctions. Cells respond to elevated contractility by increasing junctional afadin. Although ZO/afadin knockdown did not prevent contractile array assembly, it dramatically altered cell shape and barrier function in response to elevated contractility. We propose that afadin acts as a robust protein scaffold that maintains ZA architecture at tricellular junctions.
Published: 2016
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33. Transcriptome and proteome of Conus planorbis identify the nicotinic receptors as primary target for the defensive venom

Author: Sébastien Dutertre, S.W.A. Himaya, Irina Vetter, Ai-Hua Jin, Paul F. Alewood, Richard J. Lewis, Institut for Molecular Bioscience, University of Southern Queensland (USQ), Institute of Molecular Bioscience, University of Queensland [Brisbane], Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), and Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)
Subjects: Conotoxin, Proteome, Venom, Receptors, Nicotinic, Biology, Biochemistry, complex mixtures, Planorbis, Transcriptome, 03 medical and health sciences, Tandem Mass Spectrometry, Venomics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Conus, Conus planorbis, Animals, Molecular Biology, 030304 developmental biology, 0303 health sciences, Mass spectrometry, Venoms, 030302 biochemistry & molecular biology, Conus Snail, Animal proteomics, biology.organism_classification, Molecular biology, Nicotinic agonist, Evolutionary biology, Nicotinic receptors
Abstract: International audience; Most venomous predators have evolved complex venom primarily to immobilize their prey and secondarily to defend against predators. In a new paradigm, carnivorous marine gastropods of the genus Conus were shown to rapidly and reversibly switch between two types of venoms in response to predatory or defensive stimulus, suggesting that the defensive use of venom may have a more important role in venom evolution and specialization than previously thought. To further investigate this phenomenon, the defensive repertoire of a vermivorous species, Conus planorbis, was deciphered using second-generation sequencing coupled to high-throughput proteomics. The venom gland transcriptome of C. planorbis revealed 182 unique conotoxin precursors from 25 gene superfamilies, with superfamily T dominating in terms of read and paralog numbers. Analysis of the defense-evoked venom revealed that this vermivorous species uses a similarly complex arsenal to deter aggressors as more recently evolved fish- and mollusk-hunting species, with MS/MS validating 23 conotoxin sequences from six superfamilies. Pharmacological characterization of the defensive venom on human receptors identified the nicotinic acetylcholine receptors as a primary target. This work provides the first insights into the composition and biological activity of specifically evolved defensive venoms in vermivorous cone snails.
Published: 2015
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34. Intraspecific variations in Conus geographus defence-evoked venom and estimation of the human lethal dose

Author: Sébastien Dutertre, Paul F. Alewood, Ai-Hua Jin, Richard J. Lewis, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Institute of Molecular Bioscience, University of Queensland [Brisbane], NHMRC Program grant (R.J.L, P.F.A.), UQ postdoctoral fellowship (S.D), and Queensland Museum
Subjects: Proteomics, Spectrometry, Mass, Electrospray Ionization, Conotoxin, Molecular composition, Zoology, Venom, Toxicology, complex mixtures, Intraspecific competition, Cone snail, Species Specificity, omega-Conotoxin GVIA, Lethal dose, Animals, Humans, Envenomation, Conus geographus, biology, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Conus Snail, Anatomy, biology.organism_classification, Cone snails, Milking, Chromatography, Liquid
Abstract: International audience; Conus geographus is the most dangerous cone snail species known, with reported human fatality rates as high as 65%. Crude venom gland extracts have been used to determine animal LD50 and to aid the isolation of several potent paralytic toxins. However, not only is the composition of injected venoms known to differ significantly from that in dissected venom glands, but also to vary according to predatory or defensive stimuli. Therefore, to study the venom that is directly relevant to human envenomation, the defense-evoked venom of several specimens of C. geographus was collected and analyzed by standard LC–MS methods. The molecular composition of individual defense-evoked venom showed significant intraspecific variations, but a core of paralytic conotoxins including α-GI, α-GII, μ-GIIIA, ω-GVIA and ω-GVIIA was always present in large amounts, consistent with the symptomology and high fatality rate in humans. Differences between injected and dissected venoms obtained from the same specimen were also evident. Interestingly, an apparent linear correlation between the dry weight/volume of injected venom and the size of the shell allowed extrapolation to a human lethal dose (0.038–0.029 mg/kg) from an historic fatal case of C. geographus envenomation, which may help in the management of future victims.
Published: 2014
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35. Diversity and variability of NOD-like receptors in fungi

Author: Marina Lamacchia, Bostjan Kobe, Sven J. Saupe, Matthieu Paoletti, David James Sherman, Pascal Durrens, Asen Daskalov, Witold Dyrka, Models and Algorithms for the Genome ( MAGNOME), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Laboratoire Bordelais de Recherche en Informatique (LaBRI), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB), Institute for Molecular Bioscience and Centre for Infectious Disease Research, University of Queensland, plafrim, ANR-11-BSV3-0019,Mykimun,Reconnaissance hétérospécifique chez les champignons filamenteux : Des récepteurs à la réponse cellulaire(2011), Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), and Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS)
Subjects: NACHT, Reassortment, Molecular Sequence Data, Receptors, Cell Surface, Biology, Genome, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, NLR, Evolution, Molecular, Fungal Proteins, Genetics, Gene family, Amino Acid Sequence, Receptor, Gene, Ecology, Evolution, Behavior and Systematics, Research Articles, Conserved Sequence, Phylogeny, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Innate immune system, Concerted evolution, Polymorphism, Genetic, Effector, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], fungi, Fungi, immunity, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Protein Structure, Tertiary, Genome, Fungal, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are intracellular receptors that control innate immunity and other biotic interactions in animals and plants. NLRs have been characterized in plant and animal lineages, but in fungi, this gene family has not been systematically described. There is however previous indications of the involvement of NLR-like genes in nonself recognition and programmed cell death in fungi. We have analyzed 198 fungal genomes for the presence of NLRs and have annotated a total of 5,616 NLR candidates. We describe their phylogenetic distribution, domain organization, and evolution. Fungal NLRs are characterized by a great diversity of domain organizations, suggesting frequently occurring combinatorial assortments of different effector, NOD and repeat domains. The repeat domains are of the WD, ANK, and TPR type; no LRR motifs were found. As previously documented for WD-repeat domains of fungal NLRs, TPR, and ANK repeats evolve under positive selection and show highly conserved repeats and repeat length polymorphism, suggesting the possibility of concerted evolution of these repeats. We identify novel effector domains not previously found associated with NLRs, whereas others are related to effector domains of plant or animals NLRs. In particular, we show that the HET domain found in fungal NLRs may be related to Toll/interleukin-1 receptor domains found in animal and plant immune receptors. This description of fungal NLR repertoires reveals both similarities and differences with plant and animals NLR collections, highlights the importance of domain reassortment and repeat evolution and provides a novel entry point to explore the evolution of NLRs in eukaryotes.
Published: 2014
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36. Attenuated sensing of SHH by Ptch1 underlies evolution of bovine limbs

Author: Dario Speziale, Sabrina Rodriguez, Andrew D. Courtney, Benoît Robert, Sandrine Floriot, Christophe Klopp, Jing Liu, Dagmar Iber, Philipp Germann, Javier Lopez-Rios, Christian Beisel, Yves Gallard, Amandine Duchesne, Sarah Barbey, Magdalena Müller-Gerbl, Denis Duboule, Carol Wicking, Robert Ivanek, Guillaume Andrey, Rolf Zeller, Kevin A. Peterson, Erkan Ünal, Andrew P. McMahon, Developmental Genetics, Department Biomedicine, University of Basel (Unibas), Génétique Animale et Biologie Intégrative (GABI), AgroParisTech-Institut National de la Recherche Agronomique (INRA), School of Life Sciences, Federal Institute of Technology Lausann, Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California (USC), Department of Biosystems Science and Engineering [ETH Zürich] (D-BSSE), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), Domaine expérimental animal du Pin (SEA), Institut National de la Recherche Agronomique (INRA), Institute of Anatomy, Department Biomedicine, Institute for Molecular Bioscience, University of Queensland [Brisbane], Unité de Biométrie et Intelligence Artificielle (UBIA), Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), Swiss Institute of Bioinformatics, Génétique Moléculaire de la Morphogénèse, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Department of Genetics and Evolution, Université de Genève (UNIGE), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Domaine Expérimental du Pin (DEP), Unité de Biométrie et Intelligence Artificielle (ancêtre de MIAT) (UBIA), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université de Genève = University of Geneva (UNIGE), Université de Lausanne (UNIL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]
Subjects: Male, Patched Receptors, Extremities/anatomy & histology/embryology, Mesenchyme, [SDV]Life Sciences [q-bio], Cell Surface/genetics/metabolism, Transgenic, Limb Buds/anatomy & histology/embryology, Mice, 03 medical and health sciences, Limb bud, 0302 clinical medicine, ddc:590, Nucleic Acid/genetics, Receptors, Gene expression, medicine, Animals, Hedgehog Proteins/metabolism, Limb development, Sonic hedgehog, Body Patterning, 030304 developmental biology, Regulation of gene expression, Mesoderm/metabolism, 0303 health sciences, Multidisciplinary, biology, Anatomy, Biological Evolution, Cell biology, Patched-1 Receptor, body regions, Developmental/genetics, medicine.anatomical_structure, Gene Expression Regulation, PTCH1, biology.protein, Evolutionary developmental biology, Cattle, Female, Regulatory Sequences, 030217 neurology & neurosurgery
Abstract: Chantier qualité spécifique "Auteurs Externes" département de Génétique animale : uniquement liaison auteur au référentiel HR-Access; The large spectrum of limb morphologies reflects the wide evolutionary diversification of the basic pentadactyl pattern in tetrapods. In even-toed ungulates (artiodactyls, including cattle), limbs are adapted for running as a consequence of progressive reduction of their distal skeleton to symmetrical and elongated middle digits with hoofed phalanges. Here we analyse bovine embryos to establish that polarized gene expression is progressively lost during limb development in comparison to the mouse. Notably, the transcriptional upregulation of the Ptch1 gene, which encodes a Sonic hedgehog (SHH) receptor, is disrupted specifically in the bovine limb bud mesenchyme. This is due to evolutionary alteration of a Ptch1 cis-regulatory module, which no longer responds to graded SHH signalling during bovine handplate development. Our study provides a molecular explanation for the loss of digit asymmetry in bovine limb buds and suggests that modifications affecting the Ptch1 cis-regulatory landscape have contributed to evolutionary diversification of artiodactyl limbs.
Published: 2014
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37. Transcriptome-wide identification of A > I RNA editing sites by inosine specific cleavage

Author: Ryan J. Taft, Eric Westhof, John S. Mattick, Pierre B. Cattenoz, Institute for Molecular Bioscience, and ARC Centre of Excellence in Bioinformatics, The University of Queensland, Brisbane, QLD 4072, Institut de biologie moléculaire et cellulaire (IBMC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, MESH: Sequence Analysis, DNA, Adenosine, RNA, Untranslated, MESH: Base Sequence, MESH: Guanosine, Transcriptome, MESH: RNA, Untranslated, MESH: Inosine, Mice, 0302 clinical medicine, Methods, MESH: Sequence Analysis, RNA, MESH: Animals, Ribonuclease T1, MESH: High-Throughput Nucleotide Sequencing, Genetics, 0303 health sciences, Genome, Guanosine, MESH: Genomics, Brain, High-Throughput Nucleotide Sequencing, Genomics, Glyoxal, Non-coding RNA, RNA editing, medicine.drug, MESH: Ribonuclease T1, RNase P, Molecular Sequence Data, Biology, MESH: Glyoxal, Deep sequencing, 03 medical and health sciences, MESH: Brain, MESH: Mice, Inbred C57BL, MESH: RNA, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Animals, MESH: RNA Editing, MESH: Genome, Inosine, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: Molecular Sequence Data, Base Sequence, Sequence Analysis, RNA, MESH: Transcriptome, RNA, Sequence Analysis, DNA, MESH: Adenosine, MESH: Male, Mice, Inbred C57BL, ADAR, RNA Editing, 030217 neurology & neurosurgery
Abstract: Adenosine to inosine (A > I) RNA editing, which is catalyzed by the ADAR family of proteins, is one of the fundamental mechanisms by which transcriptomic diversity is generated. Indeed, a number of genome-wide analyses have shown that A > I editing is not limited to a few mRNAs, as originally thought, but occurs widely across the transcriptome, especially in the brain. Importantly, there is increasing evidence that A > I editing is essential for animal development and nervous system function. To more efficiently characterize the complete catalog of ADAR events in the mammalian transcriptome we developed a high-throughput protocol to identify A > I editing sites, which exploits the capacity of glyoxal to protect guanosine, but not inosine, from RNAse T1 treatment, thus facilitating extraction of RNA fragments with inosine bases at their termini for high-throughput sequencing. Using this method we identified 665 editing sites in mouse brain RNA, including most known sites and suite of novel sites that include nonsynonymous changes to protein-coding genes, hyperediting of genes known to regulate p53, and alterations to non-protein-coding RNAs. This method is applicable to any biological system for the de novo discovery of A > I editing sites, and avoids the complicated informatic and practical issues associated with editing site identification using traditional RNA sequencing data. This approach has the potential to substantially increase our understanding of the extent and function of RNA editing, and thereby to shed light on the role of transcriptional plasticity in evolution, development, and cognition.
Published: 2013
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38. Systematic interrogation of the Conus marmoreus venom duct transcriptome with ConoSorter reveals 158 novel conotoxins and 13 new gene superfamilies

Author: Paul F. Alewood, Ryan J. Taft, Richard J. Lewis, Ai-Hua Jin, Sébastien Dutertre, Vincent Lavergne, Institute for Molecular Bioscience, University of Queensland [Brisbane], Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), and Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)
Subjects: Proteome, Molecular Sequence Data, Sequence alignment, Computational biology, Proteomics, Mass Spectrometry, Cone snail, 03 medical and health sciences, Venomics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Databases, Genetic, Genetics, Animals, Conopeptides, Conotoxin, Amino Acid Sequence, Peptide sequence, Conus marmoreus, 030304 developmental biology, 0303 health sciences, biology, Venoms, Methodology Article, 030302 biochemistry & molecular biology, Conus Snail, Computational Biology, ConoSorter, biology.organism_classification, Molecular biology, 3. Good health, UniProt, DNA microarray, Transcriptome, Conotoxins, Sequence Alignment, Algorithms, Biotechnology
Abstract: Background Conopeptides, often generically referred to as conotoxins, are small neurotoxins found in the venom of predatory marine cone snails. These molecules are highly stable and are able to efficiently and selectively interact with a wide variety of heterologous receptors and channels, making them valuable pharmacological probes and potential drug leads. Recent advances in next-generation RNA sequencing and high-throughput proteomics have led to the generation of large data sets that require purpose-built and dedicated bioinformatics tools for efficient data mining. Results Here we describe ConoSorter, an algorithm that categorizes cDNA or protein sequences into conopeptide superfamilies and classes based on their signal, pro- and mature region sequence composition. ConoSorter also catalogues key sequence characteristics (including relative sequence frequency, length, number of cysteines, N-terminal hydrophobicity, sequence similarity score) and automatically searches the ConoServer database for known precursor sequences, facilitating identification of known and novel conopeptides. When applied to ConoServer and UniProtKB/Swiss-Prot databases, ConoSorter is able to recognize 100% of known conotoxin superfamilies and classes with a minimum species specificity of 99%. As a proof of concept, we performed a reanalysis of Conus marmoreus venom duct transcriptome and (i) correctly classified all sequences previously annotated, (ii) identified 158 novel precursor conopeptide transcripts, 106 of which were confirmed by protein mass spectrometry, and (iii) identified another 13 novel conotoxin gene superfamilies. Conclusions Taken together, these findings indicate that ConoSorter is not only capable of robust classification of known conopeptides from large RNA data sets, but can also facilitate de novo identification of conopeptides which may have pharmaceutical importance.
Published: 2013
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39. Pinstripe: a suite of programs for integrating transcriptomic and proteomic datasets identifies novel proteins and improves differentiation of protein-coding and non-coding genes

Author: Ryan J. Taft, Michael B. Clark, Pierre B. Cattenoz, Marcel E. Dinger, Paulo P. Amaral, Seth W. Cheetham, John S. Mattick, Dennis K. Gascoigne, Dagmar Wilhelm, Institute for Molecular Bioscience, and ARC Centre of Excellence in Bioinformatics, The University of Queensland, Brisbane, QLD 4072, Institut de biologie moléculaire et cellulaire (IBMC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Proteomics, computer.software_genre, Biochemistry, Genome, 0302 clinical medicine, MESH: Sequence Analysis, RNA, MESH: Proteins, Databases, Protein, 0303 health sciences, MESH: Proteomics, MESH: Genomics, Genome project, Exons, Genomics, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Computer Science Applications, Computational Mathematics, Molecular Sequence Annotation, MESH: RNA, Long Noncoding, Computational Theory and Mathematics, 030220 oncology & carcinogenesis, RNA, Long Noncoding, Data mining, MESH: Computational Biology, Statistics and Probability, MESH: Databases, Protein, Sequence analysis, Computational biology, MESH: Molecular Sequence Annotation, Biology, 03 medical and health sciences, Open Reading Frames, MESH: Software, MESH: Gene Expression Profiling, MESH: Gene Library, Humans, MESH: Genome, RNA, Messenger, Molecular Biology, 030304 developmental biology, Gene Library, MESH: RNA, Messenger, MESH: Humans, Sequence Analysis, RNA, Gene Expression Profiling, Computational Biology, Proteins, MESH: Open Reading Frames, Gene expression profiling, ComputingMethodologies_PATTERNRECOGNITION, Genome Biology, MESH: Exons, computer, Software
Abstract: MOTIVATION: Comparing transcriptomic data with proteomic data to identify protein-coding sequences is a long-standing challenge in molecular biology, one that is exacerbated by the increasing size of high-throughput datasets. To address this challenge, and thereby to improve the quality of genome annotation and understanding of genome biology, we have developed an integrated suite of programs, called Pinstripe. We demonstrate its application, utility and discovery power using transcriptomic and proteomic data from publicly available datasets. RESULTS: To demonstrate the efficacy of Pinstripe for large-scale analysis, we applied Pinstripe's reverse peptide mapping pipeline to a transcript library including de novo assembled transcriptomes from the human Illumina Body Atlas (IBA2) and GENCODE v10 gene annotations, and the EBI Proteomics Identifications Database (PRIDE) peptide database. This analysis identified 736 canonical open reading frames (ORFs) supported by three or more PRIDE peptide fragments that are positioned outside any known coding DNA sequence (CDS). Because of the unfiltered nature of the PRIDE database and high probability of false discovery, we further refined this list using independent evidence for translation, including the presence of a Kozak sequence or functional domains, synonymous/non-synonymous substitution ratios and ORF length. Using this integrative approach, we observed evidence of translation from a previously unknown let7e primary transcript, the archetypical lncRNA H19, and a homolog of RD3. Reciprocally, by exclusion of transcripts with mapped peptides or significant ORFs (>80 codon), we identify 32 187 loci with RNAs longer than 2000 nt that are unlikely to encode proteins. AVAILABILITY AND IMPLEMENTATION: Pinstripe (pinstripe.matticklab.com) is freely available as source code or a Mono binary. Pinstripe is written in C# and runs under the Mono framework on Linux or Mac OS X, and both under Mono and .Net under Windows. CONTACT: m.dinger@garvan.org.au or j.mattick@garvan.org.au SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Published: 2012
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40. A novel approach for biomarker selection and the integration of repeated measures experiments from two assays

Author: Rodolphe Thiébaut, Kim-Anh Lê Cao, Benoit Liquet, Hakim Hocini, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Queensland Facility for Advanced Bioinformatics, University of Queensland [Brisbane]-Institute for Molecular Bioscience, INSERM U955, équipe 16, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), This work was supported, in part, by the Wound Management Innovation CRC (established and supported under the Australian Government's Cooperative Research Centres Program) for K-A.LC. Financial support of the VAC18 trial was provided by the French Natioanl Agency for Research on AIDS and Hepatitis (ANRS), Sanofi Pasteur provided HIV-LIPO-5 vaccine., Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Université Bordeaux Segalen - Bordeaux 2, and BMC, Ed.
Subjects: Gene Expression, Computational biology, Biology, Biochemistry, Biomarker selection, 03 medical and health sciences, 0302 clinical medicine, Structural Biology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Cluster Analysis, Humans, Computer Simulation, Molecular Biology, Throughput (business), 030304 developmental biology, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], AIDS Vaccines, 0303 health sciences, Clinical Trials as Topic, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Applied Mathematics, Gene Expression Profiling, Methodology Article, Repeated measures design, Discriminant Analysis, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Computer Science Applications, 030220 oncology & carcinogenesis, Multivariate Analysis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Cytokines, DNA microarray, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Transcriptome, Biomarkers
Abstract: International audience; BACKGROUND: High throughput 'omics' experiments are usually designed to compare changes observed between different conditions (or interventions) and to identify biomarkers capable of characterizing each condition. We consider the complex structure of repeated measurements from different assays where different conditions are applied on the same subjects. RESULTS: We propose a two-step analysis combining a multilevel approach and a multivariate approach to reveal separately the effects of conditions within subjects from the biological variation between subjects. The approach is extended to two-factor designs and to the integration of two matched data sets. It allows internal variable selection to highlight genes able to discriminate the net condition effect within subjects. A simulation study was performed to demonstrate the good performance of the multilevel multivariate approach compared to a classical multivariate method. The multilevel multivariate approach outperformed the classical multivariate approach with respect to the classification error rate and the selection of relevant genes. The approach was applied to an HIV-vaccine trial evaluating the response with gene expression and cytokine secretion. The discriminant multilevel analysis selected a relevant subset of genes while the integrative multilevel analysis highlighted clusters of genes and cytokines that were highly correlated across the samples. CONCLUSIONS: Our combined multilevel multivariate approach may help in finding signatures of vaccine effect and allows for a better understanding of immunological mechanisms activated by the intervention. The integrative analysis revealed clusters of genes, that were associated with cytokine secretion. These clusters can be seen as gene signatures to predict future cytokine response. The approach is implemented in the R package mixOmics (http://cran.r-project.org/) with associated tutorials to perform the analysisa.
Published: 2012
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41. Visualising associations between paired 'omics' data sets

Author: Ignacio González, Sébastien Déjean, Melissa J. Davis, Kim-Anh Lê Cao, Institut de Mathématiques de Toulouse UMR5219 (IMT), Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Bioscience, University of Queensland [Brisbane], Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0303 health sciences, Computer science, Systems biology, Methodology, Genomics, Proteomics, Omics, Biochemistry, Data science, Computer Science Applications, Visualization, Omics data, 03 medical and health sciences, Computational Mathematics, 0302 clinical medicine, Computational Theory and Mathematics, Genetics, Molecular Biology, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: Background Each omics platform is now able to generate a large amount of data. Genomics, proteomics, metabolomics, interactomics are compiled at an ever increasing pace and now form a core part of the fundamental systems biology framework. Recently, several integrative approaches have been proposed to extract meaningful information. However, these approaches lack of visualisation outputs to fully unravel the complex associations between different biological entities. Results The multivariate statistical approaches ‘regularized Canonical Correlation Analysis’ and ‘sparse Partial Least Squares regression’ were recently developed to integrate two types of highly dimensional ‘omics’ data and to select relevant information. Using the results of these methods, we propose to revisit few graphical outputs to better understand the relationships between two ‘omics’ data and to better visualise the correlation structure between the different biological entities. These graphical outputs include Correlation Circle plots, Relevance Networks and Clustered Image Maps. We demonstrate the usefulness of such graphical outputs on several biological data sets and further assess their biological relevance using gene ontology analysis. Conclusions Such graphical outputs are undoubtedly useful to aid the interpretation of these promising integrative analysis tools and will certainly help in addressing fundamental biological questions and understanding systems as a whole. Availability The graphical tools described in this paper are implemented in the freely available R package mixOmics and in its associated web application.
Published: 2012
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42. The Reality of Pervasive Transcription

Author: Felix Schlesinger, Joel Rozowsky, Claes Wahlestedt, Peter F. Stadler, Marcel E. Dinger, Paulo P. Amaral, John L. Rinn, Michael B. Clark, Ryan J. Taft, Mark Gerstein, Chris P. Ponting, John S. Mattick, Kevin V. Morris, Yoshihide Hayashizaki, Piero Carninci, Thomas R. Gingeras, Antonin Morillon, Department of Computer Science, Southern Connecticut State University, Universitat Pompeu Fabra [Barcelona] (UPF), Institute for Molecular Bioscience, University of Queensland [Brisbane], MRC Functional Genomics Unit, University of Oxford [Oxford], Carl-Maria-von-Weber-Gesamtausgabe, Universität Paderborn (UPB), Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Sorbonne Université (SU), Boise State University, Cold Spring Harbor Laboratory, RIKEN Center for Life Science Technologies (RIKEN CLST), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), and Publica
Subjects: Epigenomics, DNA, Complementary, Transcription, Genetic, QH301-705.5, [SDV]Life Sciences [q-bio], Biology, ENCODE, Genome, General Biochemistry, Genetics and Molecular Biology, Deep sequencing, 03 medical and health sciences, 0302 clinical medicine, Transcription (biology), Databases, Genetic, Animals, Humans, Genetics and Genomics/Genomics, Biology (General), Gene, ComputingMilieux_MISCELLANEOUS, Oligonucleotide Array Sequence Analysis, 030304 developmental biology, Expressed Sequence Tags, Mammals, Genetics, 0303 health sciences, Tiling array, General Immunology and Microbiology, Sequence Analysis, RNA, General Neuroscience, Intron, Genetics and Genomics/Bioinformatics, Evolutionary biology, Perspective, Genetics and Genomics/Gene Discovery, Artifacts, General Agricultural and Biological Sciences, 030217 neurology & neurosurgery
Abstract: Current estimates indicate that only about 1.2% of the mammalian genome codes for amino acids in proteins. However, mounting evidence over the past decade has suggested that the vast majority of the genome is transcribed, well beyond the boundaries of known genes, a phenomenon known as pervasive transcription [1]. Challenging this view, an article published in PLoS Biology by van Bakel et al. concluded that “the genome is not as pervasively transcribed as previously reported” [2] and that the majority of the detected low-level transcription is due to technical artefacts and/or background biological noise. These conclusions attracted considerable publicity [3]–[6]. Here, we present an evaluation of the analysis and conclusions of van Bakel et al. compared to those of others and show that (1) the existence of pervasive transcription is supported by multiple independent techniques; (2) re-analysis of the van Bakel et al. tiling arrays shows that their results are atypical compared to those of ENCODE and lack independent validation; and (3) the RNA sequencing dataset used by van Bakel et al. suffered from insufficient sequencing depth and poor transcript assembly, compromising their ability to detect the less abundant transcripts outside of protein-coding genes. We conclude that the totality of the evidence strongly supports pervasive transcription of mammalian genomes, although the biological significance of many novel coding and noncoding transcripts remains to be explored.
Published: 2011
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43. Processing of nanocomposite foams in supercritical carbon dioxide. Part I: Effect of surfactant

Author: Andrew K. Whittaker, Jean-François Gérard, Jannick Duchet-Rumeau, Thi Thanh Van Ngo, Ingénierie des Matériaux Polymères - Laboratoire des Matériaux Macromoléculaires (IMP-LMM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Bioscience, University of Queensland [Brisbane], and Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Materials science, Polymers and Plastics, Nucleation, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, chemistry.chemical_compound, Materials Chemistry, Composite material, In situ polymerization, Polystyrene, Nanocomposite, Organic Chemistry, [CHIM.MATE]Chemical Sciences/Material chemistry, 021001 nanoscience & nanotechnology, Exfoliation joint, Foam, Supercritical fluid, 0104 chemical sciences, Montmorillonite, [CHIM.POLY]Chemical Sciences/Polymers, chemistry, Chemical engineering, Polymerization, Clay, 0210 nano-technology
Abstract: International audience; Polystyrene-clay nanocomposites were prepared by in situ polymerization to achieve the better dispersion of lamellar silicates i.e. montmorillonite and fluorohectorite and were used to process foams with supercritical CO2. Clay Polymer interactions were modulated by varying the surface treatment of clays: a physical interface was formed with the compatible surfactant showing aromatic groups (MMT-benz) and a chemical interface was created after reaction of methacrylate group (MMT-MHAB) with the styrene monomer. The dispersion of nanocomposites and the microstructure of resulting foams are very dependent on the quality of the clay/matrix interface. With the compatible clay, exfoliation of aromatic clay in polystyrene matrix is obtained at all scales. On the other hand, with the reactive clay, intercalated primary particles are obtained but the size of foam cells is the smallest and cell density is the highest. Our results suggest that the nucleation occurs primarily on physico-chemical nucleation sites that are the carbonyl group of the tethered copolymers synthesized on reactive clay and that present a strong affinity for CO2. The relaxation times determined by using solid-state NMR spectroscopy are consistent with the formation of the in situ copolymers. (C) 2010 Elsevier Ltd. All rights reserved.
Published: 2010
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44. Use of Venom Peptides to Probe Ion Channel Structure and Function

Author: Sébastien Dutertre, Richard J. Lewis, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Institute for Molecular Bioscience, and University of Queensland [Brisbane]
Subjects: Protein Conformation, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Quantitative Structure-Activity Relationship, Venom, Peptide, Biology, Biochemistry, Peptide Mapping, complex mixtures, Ion Channels, 03 medical and health sciences, Protein structure, Animals, Humans, Conotoxin, Molecular Biology, Ion channel, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Scorpion toxin, Venoms, 030302 biochemistry & molecular biology, Minireviews, Cell Biology, 3. Good health, Structure and function, chemistry, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Molecular probe, Peptides
Abstract: International audience; Venoms of snakes, scorpions, spiders, insects, sea anemones, and cone snails are complex mixtures of mostly peptides and small proteins that have evolved for prey capture and/or defense. These deadly animals have long fascinated scientists and the public. Early studies isolated lethal components in the search for cures and understanding of their mechanisms of action. Ion channels have emerged as targets for many venom peptides, providing researchers highly selective and potent molecular probes that have proved invaluable in unraveling ion channel structure and function. This minireview highlights molecular details of their toxin-receptor interactions and opportunities for development of peptide therapeutics.
Published: 2010
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45. Integrative mixture of experts to combine clinical factors and gene markers

Author: Geoffrey J. McLachlan, Emmanuelle Meugnier, Kim-Anh Lê Cao, meugnier, emmanuelle, Institute for Molecular Bioscience, University of Queensland [Brisbane], Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), and Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Statistics and Probability, Genetic Markers, Male, Gene Expression, Computational biology, Biology, Bioinformatics, Medical Oncology, 01 natural sciences, Biochemistry, Models, Biological, 010104 statistics & probability, 03 medical and health sciences, Bayes' theorem, medicine, Biomarkers, Tumor, Humans, Relevance (information retrieval), 0101 mathematics, Molecular Biology, Categorical variable, Selection (genetic algorithm), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Oligonucleotide Array Sequence Analysis, 0303 health sciences, Models, Statistical, Models, Genetic, Gene Expression Profiling, Cancer, Computational Biology, Prostatic Neoplasms, Reproducibility of Results, Bayes Theorem, medicine.disease, Original Papers, 3. Good health, Computer Science Applications, [STAT] Statistics [stat], Gene expression profiling, [STAT]Statistics [stat], Computational Mathematics, Computational Theory and Mathematics, Genetic marker, DNA microarray, Algorithms
Abstract: Motivation: Microarrays are being increasingly used in cancer research to better characterize and classify tumors by selecting marker genes. However, as very few of these genes have been validated as predictive biomarkers so far, it is mostly conventional clinical and pathological factors that are being used as prognostic indicators of clinical course. Combining clinical data with gene expression data may add valuable information, but it is a challenging task due to their categorical versus continuous characteristics. We have further developed the mixture of experts (ME) methodology, a promising approach to tackle complex non-linear problems. Several variants are proposed in integrative ME as well as the inclusion of various gene selection methods to select a hybrid signature. Results: We show on three cancer studies that prediction accuracy can be improved when combining both types of variables. Furthermore, the selected genes were found to be of high relevance and can be considered as potential biomarkers for the prognostic selection of cancer therapy. Availability: Integrative ME is implemented in the R package integrativeME (http://cran.r-project.org/). Contact: k.lecao@uq.edu.au Supplementary information: Supplementary data are available at Bioinformatics online.
Published: 2010

46. integrOmics: an R package to unravel relationships between two omics data sets

Author: Kim-Anh Lê Cao, Sébastien Déjean, Ignacio González, Institute for Molecular Bioscience, University of Queensland [Brisbane], Institut de Mathématiques de Toulouse UMR5219 (IMT), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Proteomics, Statistics and Probability, Databases, Factual, Feature selection, Genomics, Biology, computer.software_genre, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Partial least squares regression, Metabolomics, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Systems Biology, Computational Biology, Omics, Regression, Computer Science Applications, Applications Note, Computational Mathematics, R package, Computational Theory and Mathematics, 030220 oncology & carcinogenesis, Data mining, Canonical correlation, computer, Software, Curse of dimensionality
Abstract: Motivation: With the availability of many ‘omics’ data, such as transcriptomics, proteomics or metabolomics, the integrative or joint analysis of multiple datasets from different technology platforms is becoming crucial to unravel the relationships between different biological functional levels. However, the development of such an analysis is a major computational and technical challenge as most approaches suffer from high data dimensionality. New methodologies need to be developed and validated. Results: integrOmics efficiently performs integrative analyses of two types of ‘omics’ variables that are measured on the same samples. It includes a regularized version of canonical correlation analysis to enlighten correlations between two datasets, and a sparse version of partial least squares (PLS) regression that includes simultaneous variable selection in both datasets. The usefulness of both approaches has been demonstrated previously and successfully applied in various integrative studies. Availability: integrOmics is freely available from http://CRAN.R-project.org/ or from the web site companion (http://math.univ-toulouse.fr/biostat) that provides full documentation and tutorials. Contact: k.lecao@uq.edu.au Supplementary information: Supplementary data are available at Bioinformatics online.
Published: 2009
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47. Brn-2 represses microphthalmia-associated transcription factor expression and marks a distinct subpopulation of microphthalmia-associated transcription factor-negative melanoma cells

Author: Lionel Larue, Richard A. Sturm, Jane C. Goodall, Colin R. Goding, Laurence Denat, Dominique Kobi, Paolo Nuciforo, Irwin Davidson, Suzanne Carreira, Signaling and Development Laboratory, Marie Curie Research Institute, Régulations cellulaires et oncogenèse (RCO), Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), FIRC, Institute of Molecular Oncology, Melanogenix Group, University of Queensland [Brisbane]-Institute for Molecular Bioscience-Queensland Bioscience Precinct, Ludwig Institute for Cancer Research, University of Oxford [Oxford], Peney, Maité, and University of Oxford
Subjects: Cancer Research, MESH: Base Sequence, MESH: Down-Regulation, Metastasis, Mice, 0302 clinical medicine, Tumor Cells, Cultured, MESH: Animals, Melanoma, Regulation of gene expression, 0303 health sciences, Mice, Inbred BALB C, MESH: Gene Expression Regulation, Neoplastic, Microphthalmia-associated transcription factor, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, MESH: Microphthalmia-Associated Transcription Factor, Female, Protein Binding, Cell signaling, MESH: Melanoma, Molecular Sequence Data, Transplantation, Heterologous, MESH: Mice, Inbred BALB C, Down-Regulation, Mice, Nude, MESH: POU Domain Factors, Biology, Melanocyte, 03 medical and health sciences, MESH: Homeodomain Proteins, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Biomarkers, Tumor, MESH: Mice, Nude, Animals, Humans, MESH: Protein Binding, Neoplasm Invasiveness, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Tumor Cells, Cultured, Transcription factor, neoplasms, MESH: Transplantation, Heterologous, MESH: Mice, 030304 developmental biology, Homeodomain Proteins, Microphthalmia-Associated Transcription Factor, MESH: Molecular Sequence Data, MESH: Humans, Base Sequence, MESH: Neoplasm Invasiveness, medicine.disease, Transplantation, Immunology, POU Domain Factors, MESH: Tumor Markers, Biological, Cancer research, MESH: Female
Abstract: The origin of tumor heterogeneity is poorly understood, yet it represents a major barrier to effective therapy. In melanoma and in melanocyte development, the microphthalmia-associated transcription factor (Mitf) controls survival, differentiation, proliferation, and migration/metastasis. The Brn-2 (N-Oct-3, POU3F2) transcription factor also regulates melanoma proliferation and is up-regulated by BRAF and β-catenin, two key melanoma-associated signaling molecules. Here, we show that Brn-2 also regulates invasiveness and directly represses Mitf expression. Remarkably, in melanoma biopsies, Mitf and Brn-2 each mark a distinct subpopulation of melanoma cells, providing a striking illustration of melanoma tumor heterogeneity with implications for melanoma therapy. [Cancer Res 2008;68(19):7788–94]
Published: 2008
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48. Molecular Engineering of Conotoxins: The Importance of Loop Size to α-Conotoxin Structure and Function

Author: Sébastien Dutertre, Simon T. Nevin, Richard J. Lewis, Ching-I Anderson Wang, David J. Craik, David J. Adams, Norelle L. Daly, Paul F. Alewood, Ai-Hua Jin, Institute for Molecular Bioscience, University of Queensland [Brisbane], Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), and Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)
Subjects: alpha7 Nicotinic Acetylcholine Receptor, Molecular model, Stereochemistry, Xenopus, Molecular Sequence Data, Snails, Receptors, Nicotinic, Protein Engineering, complex mixtures, Structure-Activity Relationship, 03 medical and health sciences, 0302 clinical medicine, Drug Discovery, Animals, Amino Acid Sequence, Disulfides, Conotoxin, Nuclear Magnetic Resonance, Biomolecular, Protein secondary structure, Adrenergic alpha-Antagonists, 030304 developmental biology, Acetylcholine receptor, 0303 health sciences, Sequence Homology, Amino Acid, Chemistry, Circular Dichroism, Nicotinic acetylcholine receptor, Nicotinic agonist, nervous system, Docking (molecular), [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Molecular Medicine, Conotoxins, 030217 neurology & neurosurgery, Cysteine
Abstract: International audience; Alpha-conotoxins are competitive antagonists of nicotinic acetylcholine receptors (nAChRs). The majority of currently characterized alpha-conotoxins have a 4/7 loop size, and the major features of neuronal alpha-conotoxins include a globular disulfide connectivity and a helical structure centered around the third of their four cysteine residues. In this study, a novel "molecular pruning" approach was undertaken to define the relationship between loop size, structure, and function of alpha-conotoxins. This involved the systematic truncation of the second loop in the alpha-conotoxin [A10L]PnIA [4/7], a potent antagonist of the alpha7 nAChR. The penalty for truncation was found to be decreased conformational stability and increased susceptibility to disulfide bond scrambling. Truncation down to 4/4[A10L]PnIA maintained helicity and did not significantly reduce electrophysiological activity at alpha7 nAChRs, whereas 4/3[A10L]PnIA lost both alpha7 nAChR activity and helicity. In contrast, all truncated analogues lost approximately 100-fold affinity at the AChBP, a model protein for the extracellular domain of the nAChR. Docking simulations identified several hydrogen bonds lost upon truncation that provide an explanation for the reduced affinities observed at the alpha7 nAChR and AChBP.
Published: 2008
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49. Applications of free energy calculations to chemistry and biology

Author: Alan E. Mark, Thomas Simonson, Vijay S. Pande, Christophe Chipot, Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Institute for Molecular Bioscience, University of Queensland [Brisbane], Departments of Chemistry and of Structural Biology, Stanford University, Laboratoire de Biochimie de l'Ecole polytechnique (BIOC), Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X), and Christophe Chipot, Andrew Pohorille
Subjects: 0303 health sciences, Binding free energy, Chemistry, 010402 general chemistry, 01 natural sciences, 0104 chemical sciences, Gibbs free energy, 03 medical and health sciences, symbols.namesake, Computational chemistry, Chemical physics, symbols, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Energy (signal processing), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: International audience
Published: 2007
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50. Endosome-to-cytosol transport of viral nucleocapsids

Author: Rémy Sadoul, Pierre-Philippe Luyet, Neil Emans, Jean Gruenberg, Isabelle Le Blanc, Anne Petiot, Robert G. Parton, Nicolas Demaurex, Charles Ferguson, Nathalie Mayran, Julien Fauré, Véronique Pons, Fraboulet, Sandrine, Biochemistry Department, Université de Genève = University of Geneva (UNIGE), Department of Molecular & Cell Biology [Berkeley], University of California [Berkeley] (UC Berkeley), University of California (UC)-University of California (UC), Institute for Molecular Bioscience, University of Queensland [Brisbane], Institut Pasteur Korea - Institut Pasteur de Corée, Réseau International des Instituts Pasteur (RIIP), Glycobiologie et signalisation cellulaire, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Experimental Pathology, Department of Physiology, Centre médical universitaire, Neurodegenerescence et Plasticite, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the Swiss National Science Foundation (J.G.), the International Human Frontier Science Program (J.G and RGP), and the Australian National Health and Medical Research Council (RGP). ILB was supported by the award of the Bettencourt Foundation price (Prix des Jeunes Chercheurs), by the French Cancer Research Association (ARC) and by the Roche Foundation. VP was supported by the Roche Foundation and EMBO., University of Geneva [Switzerland], University of California [Berkeley], and University of California-University of California
Subjects: MESH: Signal Transduction, MESH: Vesicular Transport Proteins, Time Factors, viruses, Endocytic cycle, Vesicular Transport Proteins, MESH: Cricetinae, Epithelial Cells/virology, MESH: Microscopy, Fluorescence, Virus Replication, Membrane Fusion, Phosphoproteins/genetics/physiology, Lysophospholipids/physiology, Cytosol, Phosphatidylinositol Phosphates, MESH: Cytosol, MESH: Vesicular stomatitis Indiana virus, Cricetinae, Membrane Fusion/drug effects/physiology, MESH: Animals, Fibroblasts/virology, Sorting Nexins, Cytosol/metabolism/ultrastructure, 0303 health sciences, biology, Vesicle, 030302 biochemistry & molecular biology, MESH: Phosphatidylinositol Phosphates, 3. Good health, Cell biology, MESH: Cattle, Vesicular stomatitis virus, MESH: Epithelial Cells, MESH: RNA, Viral, ddc:540, Nucleocapsid/metabolism, RNA, Viral, Monoglycerides, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Virus Replication/genetics, MESH: Monoglycerides, Signal Transduction, Endosome, MESH: Biological Transport, MESH: Nucleocapsid, RNA, Viral/biosynthesis/metabolism, Endosomes, MESH: Microscopy, Electron, Transport Vesicles/metabolism/ultrastructure, MESH: Membrane Fusion, MESH: Phosphoproteins, Vesicular stomatitis Indiana virus, Article, MESH: Lysophospholipids, Cell Line, 03 medical and health sciences, Viral envelope, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Transport Vesicles, Animals, Humans, Vesicular stomatitis Indiana virus/physiology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Nucleocapsid, Transport Vesicles, ddc:612, Biological Transport/physiology, 030304 developmental biology, Vesicular Transport Proteins/genetics/physiology, MESH: Humans, Endosomal Sorting Complexes Required for Transport, Signal Transduction/physiology, MESH: Time Factors, MESH: Virus Replication, Lipid bilayer fusion, Biological Transport, Epithelial Cells, Cell Biology, Fibroblasts, biology.organism_classification, Phosphoproteins, MESH: Cell Line, MESH: Hela Cells, Microscopy, Electron, Microscopy, Fluorescence, Cytoplasm, MESH: Endosomes, MESH: Fibroblasts, Phosphatidylinositol Phosphates/physiology, Cattle, Endosomes/metabolism/ultrastructure, Lysophospholipids, HeLa Cells
Abstract: International audience; During viral infection, fusion of the viral envelope with endosomal membranes and nucleocapsid release were thought to be concomitant events. We show here that for the vesicular stomatitis virus they occur sequentially, at two successive steps of the endocytic pathway. Fusion already occurs in transport intermediates between early and late endosomes, presumably releasing the nucleocapsid within the lumen of intra-endosomal vesicles, where it remains hidden. Transport to late endosomes is then required for the nucleocapsid to be delivered to the cytoplasm. This last step, which initiates infection, depends on the late endosomal lipid lysobisphosphatidic acid (LBPA) and its putative effector Alix/AIP1, and is regulated by phosphatidylinositol-3-phosphate (PtdIns3P) signalling via the PtdIns3P-binding protein Snx16. We conclude that the nucleocapsid is exported into the cytoplasm after the back-fusion of internal vesicles with the limiting membrane of late endosomes, and that this process is controlled by the phospholipids LBPA and PtdIns3P and their effectors.
Published: 2005
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