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1. The cellular coding of temperature in the mammalian cortex

Author: M. Vestergaard, M. Carta, G. Güney, J. F. A. Poulet, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Interdisciplinary Institute for Neuroscience [Bordeaux] (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut des sciences biologiques (INSB-CNRS), This work was supported by the European Research Council (ERC-2015-CoG-682422, J.F.A.P.), the European Union (3x3Dimaging 323945, J.F.A.P.), the Deutsche Forschungsgemeinschaft (DFG, FOR 2143, J.F.A.P., SFB 1315, J.F.A.P.), the Helmholtz Society (J.F.A.P.), the Centre National de la Recherche Scientifique (CNRS) (M.C.) and the Independent Research Fund Denmark (M.V.)., and European Project: 323945,EC:FP7:ICT,FP7-ICT-2013-C,3X3D IMAGING(2013)
Subjects: Multidisciplinary, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Function and Dysfunction of the Nervous System
Abstract: SummaryTemperature is a fundamental sensory modality separate from touch, with dedicated receptor channels and primary afferent neurons for cool and warm (Blix, 1882; Filingeri, 2016; Vriens et al., 2014). Unlike other modalities, however, the cortical encoding of temperature remains mysterious, with very few cortical neurons reported that respond to non-painful temperature and the presence of a ‘thermal cortex’ is debated (Bokiniec et al., 2018; Craig et al., 2000; Hellon et al., 1973; Milenkovic et al., 2014; Tsuboi et al., 1993). Using widefield and two-photon calcium imaging in the mouse forepaw system, here we identify cortical neurons that respond to cooling and/or warming with distinct spatial and temporal response properties. Surprisingly, we observed a representation of cool, but not warm, in the primary somatosensory cortex, but cool and warm in the posterior insular cortex (pIC). The representation of thermal information in pIC is robust, somatotopicallyarranged and reversible manipulations show a profound impact on thermal perception. Intriguingly, despite being positioned along the same one-dimensional sensory axis, the encoding of cool and warm is distinct, both in highly- and broadly- tuned neurons. Together, our results show that pIC contains the primary cortical representation of skin temperature and may help explain how the thermal system generates sensations of cool and warm.
Published: 2023

2. Rapport d'activités Guix-HPC 2021–2022

Author: Acary-Robert, Céline, Courtès, Ludovic, Dupont, Yann, Felšöci, Marek, Hinsen, Konrad, Lünsdorf, Ontje, Prins, Pjotr, Swartvagher, Philippe, Tournier, Simon, Wurmus, Ricardo, Grenoble Alpes Recherche-Infrastructure de CAlcul intensif et de Données (GRICAD), Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Service Expérimentation et Développement [Bordeaux] (SED), Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Nantes Université (Nantes Univ), COmposabilité Numerique and parallèle pour le CAlcul haute performanCE (CONCACE), Centre Européen de Recherche et de Formation Avancée en Calcul Scientifique (CERFACS)-Airbus [France]-Inria Bordeaux - Sud-Ouest, Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, The University of Tennessee Health Science Center [Memphis] (UTHSC), Topology-Aware System-Scale Data Management for High-Performance Computing (TADAAM), Laboratoire Bordelais de Recherche en Informatique (LaBRI), Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS)-Inria Bordeaux - Sud-Ouest, Université Paris Cité (UPCité), Inria, Max Delbrück Center for Molecular Medicine, and Utrecht Bioinformatics Center
Subjects: Open Science, HPC, [INFO]Computer Science [cs], Software Deployment, [INFO.INFO-OS]Computer Science [cs]/Operating Systems [cs.OS], [INFO.INFO-SE]Computer Science [cs]/Software Engineering [cs.SE], [INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], Reproducibility
Abstract: Guix-HPC is a collaborative effort to bring reproducible software deployment to scientific workflows and high-performance computing (HPC). Guix-HPC builds upon the GNU Guix software deployment tool and aims to make it a better tool for HPC practitioners and scientists concerned with reproducible research.This report highlights key achievements of Guix-HPC between our previous report a year ago and today, February 2023, including: developments in Guix and related tools such as the Guix Workflow Language, use cases of Guix in support of reproducible research and open science, and the celebration of ten years of Guix with a three-day conference.; Guix-HPC est un travail collaboratif pour donner les moyens du déploiement logiciel reproductible aux travaux scientifiques et au calcul intensif (HPC). Guix-HPC repose sur l'outil de déploiement logiciel GNU Guix et a pour ambition d’en faire un meilleur outil pour le calcul intensif et pour les scientifiques souhaitant faire des travaux de recherche reproductibles.Ce rapport souligne les réalisations clef de Guix-HPC depuis le précédent rapport, un an auparavant, et aujourd’hui, février 2023, avec notamment : les développements dans Guix et les outils qui lui sont liés, comme le Guix Workflow Language (GWL), les cas d’usage de Guix comme support à la recherche reproductible et à la science ouverte, et enfin la célébration de dix ans de Guix avec un colloque de trois jours.
Published: 2023

3. Long COVID and the cardiovascular system—elucidating causes and cellular mechanisms in order to develop targeted diagnostic and therapeutic strategies : A joint Scientific Statement of the ESC Working Groups on Cellular Biology of the Heart and Myocardial and Pericardial Diseases

Author: Mariann Gyöngyösi, Pilar Alcaide, Folkert W Asselbergs, Bianca J J M Brundel, Giovanni G Camici, Paula da Costa Martins, Péter Ferdinandy, Marianna Fontana, Henrique Girao, Massimiliano Gnecchi, Can Gollmann-Tepeköylü, Petra Kleinbongard, Thomas Krieg, Rosalinda Madonna, Melanie Paillard, Antonis Pantazis, Cinzia Perrino, Maurizio Pesce, Gabriele G Schiattarella, Joost P G Sluijter, Sabine Steffens, Carsten Tschöpe, Sophie Van Linthout, Sean M Davidson, Martins, Paula da Costa [0000-0002-0695-1187], Fontana, Marianna [0000-0002-9233-9831], Girao, Henrique [0000-0002-5786-8447], Gnecchi, Massimiliano [0000-0001-7435-4328], Kleinbongard, Petra [0000-0003-3576-3772], Krieg, Thomas [0000-0002-5192-580X], Perrino, Cinzia [0000-0002-2274-0048], Pesce, Maurizio [0000-0002-3097-8961], Sluijter, Joost PG [0000-0003-2088-9102], Steffens, Sabine [0000-0002-6892-9751], Van Linthout, Sophie [0000-0002-7581-7870], Apollo - University of Cambridge Repository, Medizinische Universität Wien = Medical University of Vienna, Tufts University School of Medicine [Boston], University Medical Center [Utrecht], Utrecht University [Utrecht], University College of London [London] (UCL), Amsterdam UMC - Amsterdam University Medical Center, Vrije Universiteit Amsterdam [Amsterdam] (VU), Universität Zürich [Zürich] = University of Zurich (UZH), University hospital of Zurich [Zurich], Maastricht University [Maastricht], Semmelweis University [Budapest], Pharmahungary Group [Szeged, Hungary] (PG), University of Coimbra [Portugal] (UC), Coimbra Institute for Clinical and Biomedical Research [Coimbra, Portugal] (iCBR - Faculty of Medicine), Università degli Studi di Pavia = University of Pavia (UNIPV), Fondazione IRCCS Policlinico San Matteo [Pavia], Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Addenbrooke's Hospital, Cambridge University NHS Trust, University of Pisa - Università di Pisa, Jefferson (Philadelphia University + Thomas Jefferson University), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Imperial College London, Royal Brompton and Harefield NHS Foundation Trust, University of Naples Federico II = Università degli studi di Napoli Federico II, Centro Cardiologico Monzino [Milano], Dpt di Scienze Cliniche e di Comunità [Milano] (DISCCO), Università degli Studi di Milano = University of Milan (UNIMI)-Università degli Studi di Milano = University of Milan (UNIMI)-Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Utrecht Brain Center [UMC], Ludwig-Maximilians-Universität München (LMU), Charité Campus Virchow-Klinikum (CVK), The Hatter Cardiovascular Institute (THCI), CarMeN, laboratoire, Gyöngyösi, Mariann, Alcaide, Pilar, Asselbergs, Folkert W, Brundel, Bianca J J M, Camici, Giovanni G, da Costa Martins, Paula, Ferdinandy, Péter, Fontana, Marianna, Girao, Henrique, Gnecchi, Massimiliano, Gollmann-Tepeköylü, Can, Kleinbongard, Petra, Krieg, Thoma, Madonna, Rosalinda, Paillard, Melanie, Pantazis, Antoni, Perrino, Cinzia, Pesce, Maurizio, Schiattarella, Gabriele G, Sluijter, Joost P G, Steffens, Sabine, Tschöpe, Carsten, Van Linthout, Sophie, and Davidson, Sean M
Subjects: Long COVID, Heart Diseases, Physiology, SARS-CoV-2, [SDV]Life Sciences [q-bio], Myocardium, Medizin, COVID-19, Heart, virus, Post COVID, Cardiovascular, [SDV] Life Sciences [q-bio], Post-Acute COVID-19 Syndrome, COVID-19 Testing, Cardiovascular and Metabolic Diseases, Physiology (medical), Humans, Cardiology and Cardiovascular Medicine, Cardiac
Abstract: Long COVID has become a world-wide, non-communicable epidemic, caused by long-lasting multiorgan symptoms that endure for weeks or months after SARS-CoV-2 infection has already subsided. This scientific document aims to provide insight into the possible causes and therapeutic options available for the cardiovascular manifestations of long COVID. In addition to chronic fatigue, which is a common symptom of long COVID, patients may present with chest pain, ECG abnormalities, postural orthostatic tachycardia, or newly developed supraventricular or ventricular arrhythmias. Imaging of the heart and vessels has provided evidence of chronic, post-infectious perimyocarditis with consequent left or right ventricular failure, arterial wall inflammation, or microthrombosis in certain patient populations. Better understanding of the underlying cellular and molecular mechanisms of long COVID will aid in the development of effective treatment strategies for its cardiovascular manifestations. A number of mechanisms have been proposed, including those involving direct effects on the myocardium, microthrombotic damage to vessels or endothelium, or persistent inflammation. Unfortunately, existing circulating biomarkers, coagulation, and inflammatory markers, are not highly predictive for either the presence or outcome of long COVID when measured 3 months after SARS-CoV-2 infection. Further studies are needed to understand underlying mechanisms, identify specific biomarkers, and guide future preventive strategies or treatments to address long COVID and its cardiovascular sequelae.
Published: 2023

4. Immortalized pathological human myoblasts: towards a universal tool for the study of neuromuscular disorders

Author: Vincent Mouly, J. Kim, Francesco Muntoni, Woodring E. Wright, Susanne Philippi, Sergiu C. Blumen, Ahmed Aamiri, Simone Spuler, Gillian Butler-Browne, Soraya Chaouch, James P. Di Santo, Nicolas Lévy, Kamel Mamchaoui, Annie Wolff, Prashanth Kumar Kandalla, Solenne Marie, Anne Bigot, Thomas Voit, Capucine Trollet, Elisa Negroni, Jean Lacau St Guily, 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), Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), The Dubowitz Neuromuscular Centre, University College of London [London] (UCL)-Institute of Child Health, Muscle Research Unit, Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association-Helmholtz-Gemeinschaft = Helmholtz Association-Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Neurology, Hillel Yaffe Medical Center, Department of Cell Biology, University of Texas Southwestern Medical Center [Dallas], Departement de Biologie, Faculté des sciences d'Agadir, This work was supported by the MYORES Network of Excellence (contract 511978) and TREAT-NMD (contract LSHM-CT-2006-036825) from the European Commission 6th FP, MYOAGE (contract HEALTH-F2-2009-223576) from the Seventh FP, the ANR Genopath-INAFIB, the ANR MICRORNAS, MyoGrad (GK1631, German Research Foundation), the Duchenne Parent Project Netherlands, CNRS, INSERM, University Pierre and Marie Curie, AFM (Association Française contre les Myopathies) (including network grant #15123), the Jain Foundation, Parents Project of Monaco, and the European Parent Project., European Project: 223576,EC:FP7:HEALTH,FP7-HEALTH-2007-B,MYOAGE(2009), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]-Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association-Helmholtz-Gemeinschaft = Helmholtz Association, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Laboratoire LBCM, BMC, Ed., and Understanding and combating human age-related muscle weakness - MYOAGE - - EC:FP7:HEALTH2009-01-01 - 2013-06-30 - 223576 - VALID
Subjects: lcsh:Diseases of the musculoskeletal system, Duchenne muscular dystrophy, Biology, Bioinformatics, Oculopharyngeal muscular dystrophy, 03 medical and health sciences, 0302 clinical medicine, medicine, Myocyte, Facioscapulohumeral muscular dystrophy, Orthopedics and Sports Medicine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Muscular dystrophy, Molecular Biology, 030304 developmental biology, 0303 health sciences, Research, Cell Biology, medicine.disease, Transplantation, Congenital muscular dystrophy, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], lcsh:RC925-935, Function and Dysfunction of the Nervous System, Immortalised cell line, 030217 neurology & neurosurgery
Abstract: Background Investigations into both the pathophysiology and therapeutic targets in muscle dystrophies have been hampered by the limited proliferative capacity of human myoblasts. Isolation of reliable and stable immortalized cell lines from patient biopsies is a powerful tool for investigating pathological mechanisms, including those associated with muscle aging, and for developing innovative gene-based, cell-based or pharmacological biotherapies. Methods Using transduction with both telomerase-expressing and cyclin-dependent kinase 4-expressing vectors, we were able to generate a battery of immortalized human muscle stem-cell lines from patients with various neuromuscular disorders. Results The immortalized human cell lines from patients with Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, congenital muscular dystrophy, and limb-girdle muscular dystrophy type 2B had greatly increased proliferative capacity, and maintained their potential to differentiate both in vitro and in vivo after transplantation into regenerating muscle of immunodeficient mice. Conclusions Dystrophic cellular models are required as a supplement to animal models to assess cellular mechanisms, such as signaling defects, or to perform high-throughput screening for therapeutic molecules. These investigations have been conducted for many years on cells derived from animals, and would greatly benefit from having human cell models with prolonged proliferative capacity. Furthermore, the possibility to assess in vivo the regenerative capacity of these cells extends their potential use. The innovative cellular tools derived from several different neuromuscular diseases as described in this report will allow investigation of the pathophysiology of these disorders and assessment of new therapeutic strategies.
Published: 2011

5. Mafa-dependent GABAergic activity promotes mouse neonatal apneas

Author: Laure Lecoin, Bowen Dempsey, Alexandra Garancher, Steeve Bourane, Pierre-Louis Ruffault, Marie-Pierre Morin-Surun, Nathalie Rocques, Martyn Goulding, Alain Eychène, Celio Pouponnot, Gilles Fortin, Jean Champagnat, Fortin, Gilles, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Signalisation, radiobiologie et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de Neurobiologie Alfred Fessard (INAF), Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), The Salk Institute for Biological Studies, Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), and Helmholtz-Gemeinschaft = Helmholtz Association
Subjects: Motor Neurons, Maf Transcription Factors, Large, Multidisciplinary, Apnea, [SDV]Life Sciences [q-bio], General Physics and Astronomy, General Chemistry, General Biochemistry, Genetics and Molecular Biology, [SDV] Life Sciences [q-bio], Mice, Animals, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Phosphorylation, Promoter Regions, Genetic, Function and Dysfunction of the Nervous System
Abstract: While apneas are associated with multiple pathological and fatal conditions, the underlying molecular mechanisms remain elusive. We report that a mutated form of the transcription factor Mafa (Mafa4A) that prevents phosphorylation of the Mafa protein leads to an abnormally high incidence of breath holding apneas and death in newborn Mafa4A/4A mutant mice. This apneic breathing is phenocopied by restricting the mutation to central GABAergic inhibitory neurons and by activation of inhibitory Mafa neurons while reversed by inhibiting GABAergic transmission centrally. We find that Mafa activates the Gad2 promoter in vitro and that this activation is enhanced by the mutation that likely results in increased inhibitory drives onto target neurons. We also find that Mafa inhibitory neurons are absent from respiratory, sensory (primary and secondary) and pontine structures but are present in the vicinity of the hypoglossal motor nucleus including premotor neurons that innervate the geniohyoid muscle, to control upper airway patency. Altogether, our data reveal a role for Mafa phosphorylation in regulation of GABAergic drives and suggest a mechanism whereby reduced premotor drives to upper airway muscles may cause apneic breathing at birth.
Published: 2022

6. Guix-HPC Activity Report 2020-2021: Reproducible software deployment for high-performance computing

Author: Bouttier, Pierre-Antoine, Courtès, Ludovic, Dupont, Yann, Felšöci, Marek, Gruber, Felix, Hinsen, Konrad, Isaac, Arun, Prins, Pjotr, Swartvagher, Philippe, Tournier, Simon, Wurmus, Ricardo, Grenoble Alpes Recherche-Infrastructure de CAlcul intensif et de Données (GRICAD), Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Service Expérimentation et Développement [Bordeaux] (SED), Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), École Centrale de Nantes (Nantes Univ - ECN), Nantes Université (Nantes Univ), Université de Bordeaux (UB), High-End Parallel Algorithms for Challenging Numerical Simulations (HiePACS), Laboratoire Bordelais de Recherche en Informatique (LaBRI), Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS)-Inria Bordeaux - Sud-Ouest, Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), The University of Tennessee Health Science Center [Memphis] (UTHSC), Topology-Aware System-Scale Data Management for High-Performance Computing (TADAAM), Université Paris Cité (UPCité), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Université Grenoble - Alpes, and Université Paris
Subjects: HPC, Software Deployment, [INFO.INFO-OS]Computer Science [cs]/Operating Systems [cs.OS], [INFO.INFO-SE]Computer Science [cs]/Software Engineering [cs.SE], [INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], Reproducibility
Abstract: Guix-HPC is a collaborative effort to bring reproducible software deployment to scientific workflows and high-performance computing (HPC). Guix-HPC builds upon the GNU Guix software deployment tool and aims to make it a better tool for HPC practitioners and scientists concerned with reproducible research. This report highlights key achievements of Guix-HPC between our previous report a year ago and today, February 2022. This report highlights developments on GNU Guix proper, but also downstream on Guix-Jupyter, the Guix Workflow Language, upstream with Software Heritage integration, as well as experience reports on end-to-end reproducible research article authoring pipelines.
Published: 2022

7. Guix-HPC Activity Report 2020-2021

Author: Bouttier, Pierre-Antoine, Courtès, Ludovic, Dupont, Yann, Felšöci, Marek, Gruber, Felix, Hinsen, Konrad, Isaac, Arun, Prins, Pjotr, Swartvagher, Philippe, Tournier, Simon, Wurmus, Ricardo, Grenoble Alpes Recherche-Infrastructure de CAlcul intensif et de Données (GRICAD), Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Service Expérimentation et Développement [Bordeaux] (SED), Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Nantes Université - École Centrale de Nantes (Nantes Univ - ECN), Nantes Université (Nantes Univ), Université de Bordeaux (UB), High-End Parallel Algorithms for Challenging Numerical Simulations (HiePACS), Laboratoire Bordelais de Recherche en Informatique (LaBRI), Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS)-Inria Bordeaux - Sud-Ouest, Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), The University of Tennessee Health Science Center [Memphis] (UTHSC), Topology-Aware System-Scale Data Management for High-Performance Computing (TADAAM), Université Paris Cité (UPCité), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Université Grenoble - Alpes, Université Paris, and Courtès, Ludovic
Subjects: [INFO.INFO-OS] Computer Science [cs]/Operating Systems [cs.OS], HPC, [INFO.INFO-SE] Computer Science [cs]/Software Engineering [cs.SE], [INFO.INFO-DC] Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], Software Deployment, [INFO.INFO-OS]Computer Science [cs]/Operating Systems [cs.OS], [INFO.INFO-SE]Computer Science [cs]/Software Engineering [cs.SE], [INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], Reproducibility
Abstract: Guix-HPC is a collaborative effort to bring reproducible software deployment to scientific workflows and high-performance computing (HPC). Guix-HPC builds upon the GNU Guix software deployment tool and aims to make it a better tool for HPC practitioners and scientists concerned with reproducible research. This report highlights key achievements of Guix-HPC between our previous report a year ago and today, February 2022. This report highlights developments on GNU Guix proper, but also downstream on Guix-Jupyter, the Guix Workflow Language, upstream with Software Heritage integration, as well as experience reports on end-to-end reproducible research article authoring pipelines.
Published: 2022

8. Pre-diagnostic C-reactive protein concentrations, CRP genetic variation and mortality among individuals with colorectal cancer in Western European populations

Author: Katharina Nimptsch, Krasimira Aleksandrova, Veronika Fedirko, Mazda Jenab, Marc J. Gunter, Peter D. Siersema, Kana Wu, Verena Katzke, Rudolf Kaaks, Salvatore Panico, Domenico Palli, Anne M May, Sabina Sieri, Bas Bueno-de-Mesquita, Karina Standahl, Maria-Jose Sánchez, Aurora Perez-Cornago, Anja Olsen, Anne Tjønneland, Catalina Bonet Bonet, Christina C. Dahm, María-Dolores Chirlaque, Valentina Fiano, Rosario Tumino, Aurelio Barricarte Gurrea, Marie-Christine Boutron-Ruault, Florence Menegaux, Gianluca Severi, Bethany van Guelpen, Young-Ae Lee, Tobias Pischon, HAL UVSQ, Équipe, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Harvard T.H. Chan School of Public Health, Leibniz Institute for Prevention Research and Epidemiology - BIPS, Leibniz Association, University of Bremen, The University of Texas M.D. Anderson Cancer Center [Houston], Emory University [Atlanta, GA], Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Radboud University Medical Center [Nijmegen], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), 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, World Health Organization, WHO, Cancer Prevention and Research Institute of Texas, CPRIT: RR200056, Kræftens Bekæmpelse, DCS, Deutsches Krebsforschungszentrum, DKFZ, Centre International de Recherche sur le Cancer, CIRC, National Research Council, NRC, University of Maryland School of Public Health, SPH, Medical Research Council, MRC: MR/M012190/1, Cancer Research UK, CRUK: C8221/A29017, World Cancer Research Fund, WCRF, Imperial College London, Institut National de la Santé et de la Recherche Médicale, Inserm, Bundesministerium für Bildung und Forschung, BMBF, Cancerfonden, Ministerie van Volksgezondheid, Welzijn en Sport, VWS, Ligue Contre le Cancer, Vetenskapsrådet, VR, Instituto de Salud Carlos III, ISCIII, Associazione Italiana per la Ricerca sul Cancro, AIRC, Deutsche Krebshilfe, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, MGEN, Consejería de Salud y Familias, Junta de Andalucía, NIHR Imperial Biomedical Research Centre, BRC, We acknowledge the use of data and biological samples from the EPIC-Asturias cohort, PI Jose-Ramon Quiros-Garcia and EPI-San Sebastian, PI Amiano Pilar. Veronika Fedirko is supported by the Cancer Prevention and Research Institute of Texas (CPRIT) Rising Stars Award (Grant ID RR200056). Where authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organization., The national cohorts are supported by: Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France), German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology - ICO (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (C8221/A29017 to EPIC-Oxford), Medical Research Council (MR/M012190/1 to EPIC-Oxford) (United Kingdom). The EPIC-Norfolk study (DOI https://doi.org/10.22025/2019.10.105.00004 ) has received funding from the Medical Research Council (MR/N003284/1 and MC-UU_12015/1) and Cancer Research UK (C864/A14136). We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research., The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC)., and We acknowledge the use of data and biological samples from the EPIC-Asturias cohort, PI Jose-Ramon Quiros-Garcia and EPI-San Sebastian, PI Amiano Pilar. Veronika Fedirko is supported by the Cancer Prevention and Research Institute of Texas (CPRIT) Rising Stars Award (Grant ID RR200056).
Subjects: Cancer Research, Cancer och onkologi, Public Health, Global Health, Social Medicine and Epidemiology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Polymorphism, Single Nucleotide, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Tumours of the digestive tract Radboud Institute for Health Sciences [Radboudumc 14], C-Reactive Protein, Oncology, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Cardiovascular and Metabolic Diseases, Risk Factors, Cancer and Oncology, Genetics, Humans, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Genetic Predisposition to Disease, Prospective Studies, Colorectal Neoplasms
Abstract: Background The role of elevated pre-diagnostic C-reactive protein (CRP) concentrations on mortality in individuals with colorectal cancer (CRC) remains unclear. Methods We investigated the association between pre-diagnostic high-sensitivity CRP concentrations and CRP genetic variation associated with circulating CRP and CRC-specific and all-cause mortality based on data from 1,235 individuals with CRC within the European Prospective Investigation into Cancer and Nutrition cohort using multivariable-adjusted Cox proportional hazards regression. Results During a median follow-up of 9.3 years, 455 CRC-specific deaths were recorded, out of 590 deaths from all causes. Pre-diagnostic CRP concentrations were not associated with CRC-specific (hazard ratio, HR highest versus lowest quintile 0.92, 95% confidence interval, CI 0.66, 1.28) or all-cause mortality (HR 0.91, 95% CI 0.68, 1.21). Genetic predisposition to higher CRP (weighted score based on alleles of four CRP SNPs associated with higher circulating CRP) was not significantly associated with CRC-specific mortality (HR per CRP-score unit 0.95, 95% CI 0.86, 1.05) or all-cause mortality (HR 0.98, 95% CI 0.90, 1.07). Among four investigated CRP genetic variants, only SNP rs1205 was significantly associated with CRC-specific (comparing the CT and CC genotypes with TT genotype, HR 0.54, 95% CI 0.35, 0.83 and HR 0.58, 95% CI 0.38, 0.88, respectively) and all-cause mortality (HR 0.58, 95% CI 0.40, 0.85 and 0.64, 95% CI 0.44, 0.92, respectively). Conclusions The results of this prospective cohort study do not support a role of pre-diagnostic CRP concentrations on mortality in individuals with CRC. The observed associations with rs1205 deserve further scientific attention.
Published: 2022

9. Combinatorial, additive and dose-dependent drug-microbiome associations

Author: Forslund, SK, Chakaroun, R, Zimmermann-Kogadeeva, M, Markó, L, Aron-Wisnewsky, J, Nielsen, T, Moitinho-Silva, L, Schmidt, TSB, Falony, G, Vieira-Silva, S, Adriouch, S, Alves, RJ, Assmann, K, Bastard, J-P, Birkner, T, Caesar, R, Chilloux, J, Coelho, LP, Fezeu, L, Galleron, N, Helft, G, Isnard, R, Ji, B, Kuhn, M, Le Chatelier, E, Myridakis, A, Olsson, L, Pons, N, Prifti, E, Quinquis, B, Roume, H, Salem, J-E, Sokolovska, N, Tremaroli, V, Valles-Colomer, M, Lewinter, C, Søndertoft, NB, Pedersen, HK, Hansen, TH, Amouyal, C, Andersson Galijatovic, EA, Andreelli, F, Barthelemy, O, Batisse, J-P, Belda, E, Berland, M, Bittar, R, Blottière, H, Bosquet, F, Boubrit, R, Bourron, O, Camus, M, Cassuto, D, Ciangura, C, Collet, J-P, Dao, M-C, Djebbar, M, Doré, A, Engelbrechtsen, L, Fellahi, S, Fromentin, S, Galan, P, Gauguier, D, Giral, P, Hartemann, A, Hartmann, B, Holst, JJ, Hornbak, M, Hoyles, L, Hulot, J-S, Jaqueminet, S, Jørgensen, NR, Julienne, H, Justesen, J, Kammer, J, Krarup, N, Kerneis, M, Khemis, J, Kozlowski, R, Lejard, V, Levenez, F, Lucas-Martini, L, Massey, R, Martinez-Gili, L, Maziers, N, Medina-Stamminger, J, Montalescot, G, Moute, S, Neves, AL, Olanipekun, M, Le Pavin, LP, Poitou, C, Pousset, F, Pouzoulet, L, Rodriguez-Martinez, A, Rouault, C, Silvain, J, Svendstrup, M, Swartz, T, Vanduyvenboden, T, Vatier, C, Walther, S, Gøtze, JP, Køber, L, Vestergaard, H, Hansen, T, Zucker, J-D, Hercberg, S, Oppert, J-M, Letunic, I, Nielsen, J, Bäckhed, F, Ehrlich, SD, Dumas, M-E, Raes, J, Pedersen, O, Clément, K, Stumvoll, M, Bork, P, The MetaCardis Consortium (Hoyles, L.), European Molecular Biology Laboratory [Heidelberg] (EMBL), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Berlin Institute of Health (BIH), German Center for Cardiovascular Research (DZHK), Universität Leipzig, Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Copenhagen = Københavns Universitet (UCPH), University of New South Wales [Sydney] (UNSW), Paul Scherrer Institute (PSI), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Heidelberg University, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Sorbonne Paris Nord-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Henri Mondor [Créteil], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], University of Gothenburg (GU), Imperial College London, MetaGenoPolis (MGP (US 1367)), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Paris-Saclay, Institut de cardiologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Chalmers University of Technology [Gothenburg, Sweden], Unité de modélisation mathématique et informatique des systèmes complexes [Bondy] (UMMISCO), Université de Yaoundé I-Institut de la francophonie pour l'informatique-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Gaston Bergé (Saint-Louis, Sénégal)-Université Cadi Ayyad [Marrakech] (UCA)-Sorbonne Université (SU)-Institut de Recherche pour le Développement (IRD [France-Nord]), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), 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 de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Biobyte Solutions [Heidelberg, Germany] (BS), IT University of Copenhagen (ITU), Sahlgrenska University Hospital [Gothenburg], 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), National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, McGill University and Genome Quebec Innovation Centre, Helmholtz Institute Ulm (HIU), Helmholtz Zentrum München = German Research Center for Environmental Health, University of Würzburg = Universität Würzburg, Yonsei University, MetaCardis Consortium*: Chloe Amouyal, Ehm Astrid Andersson Galijatovic, Fabrizio Andreelli, Olivier Barthelemy, Jean-Paul Batisse, Eugeni Belda, Magalie Berland, Randa Bittar, Hervé Blottière, Frederic Bosquet, Rachid Boubrit, Olivier Bourron, Mickael Camus, Dominique Cassuto, Cecile Ciangura, Jean-Philippe Collet, Maria-Carlota Dao, Morad Djebbar, Angélique Doré, Line Engelbrechtsen, Soraya Fellahi, Sebastien Fromentin, Pilar Galan, Dominique Gauguier, Philippe Giral, Agnes Hartemann, Bolette Hartmann, Jens Juul Holst, Malene Hornbak, Lesley Hoyles, Jean-Sebastien Hulot, Sophie Jaqueminet, Niklas Rye Jørgensen, Hanna Julienne, Johanne Justesen, Judith Kammer, Nikolaj Krarup, Mathieu Kerneis, Jean Khemis, Ruby Kozlowski, Véronique Lejard, Florence Levenez, Lea Lucas-Martini, Robin Massey, Laura Martinez-Gili, Nicolas Maziers, Jonathan Medina-Stamminger, Gilles Montalescot, Sandrine Moute, Ana Luisa Neves, Michael Olanipekun, Laetitia Pasero Le Pavin, Christine Poitou, Francoise Pousset, Laurence Pouzoulet, Andrea Rodriguez-Martinez, Christine Rouault, Johanne Silvain, Mathilde Svendstrup, Timothy Swartz, Thierry Vanduyvenboden, Camille Vatier, Stefanie Walther., ANR-16-IDEX-0004,ULNE,ULNE(2016), ANR-18-IBHU-0001,PreciDIAB,PreciDIAB Institute, the holistic approach of personal diabets care(2018), Dumas, Marc-Emmanuel, Universität Leipzig [Leipzig], Service de Nutrition [CHU Pitié-Salpétrière], Institut E3M [CHU Pitié-Salpêtrière], CHU Henri Mondor, Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-1901(ex CIC-1421)), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Imperial College London - National Heart and Lung Institute, and Division of Computational and Systems Medicine, Imperial College London, London, SW7 2AZ, UK
Subjects: Clostridiales, Science & Technology, Multidisciplinary, ANTIBIOTIC USE, IMPACT, Microbiota, [SDV]Life Sciences [q-bio], HUMAN GUT MICROBIOME, Atherosclerosis, Gastrointestinal Microbiome, [SDV] Life Sciences [q-bio], Multidisciplinary Sciences, PROTON PUMP INHIBITORS, Cardiovascular and Metabolic Diseases, GUIDELINE, Metabolome, MANAGEMENT, Humans, Science & Technology - Other Topics, ALTERS
Abstract: During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1-5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug-host-microbiome interactions in cardiometabolic disease. ispartof: NATURE vol:600 issue:7889 pages:500-+ ispartof: location:England status: published
Published: 2021

10. Age-related and disease locus-specific mechanisms contribute to early remodelling of chromatin structure in Huntington’s disease mice

Author: Alcalá-Vida, R., Seguin, J., Lotz, C., Molitor, A.M., Irastorza-Azcarate, I., Awada, A., Karasu, N., Bombardier, A., Cosquer, B., Skarmeta, J.L.G., Cassel, J.C., Boutillier, A.L., Sexton, T., Merienne, K., Laboratoire de neurosciences cognitives et adaptatives (LNCA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Universidad Pablo de Olavide [Sevilla] (UPO), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), ANR-17-CE12-0027,EpiHD,Rôle des mécanismes épigénétiques dans la maladie de Huntington(2017), ANR-10-LABX-0030,INRT,Integrative Biology : Nuclear dynamics- Regenerative medicine - Translational medicine(2010), ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), European Project: 678624,CHROMTOPOLOGY), CHDI Foundation, Agence Nationale de la Recherche (France), Centre National de la Recherche Scientifique (France), Université de Strasbourg, European Research Council, European Commission, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Anne Laurence, Boutillier, Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID, Rôle des mécanismes épigénétiques dans la maladie de Huntington - - EpiHD2017 - ANR-17-CE12-0027 - AAPG2017 - VALID, Integrative Biology : Nuclear dynamics- Regenerative medicine - Translational medicine - - INRT2010 - ANR-10-LABX-0030 - LABX - VALID, Initiative d'excellence - Par-delà les frontières, l'Université de Strasbourg - - UNISTRA2010 - ANR-10-IDEX-0002 - IDEX - VALID, and Understanding and manipulating the dynamics of chromosome topologies in transcriptional control - CHROMTOPOLOGY) - 678624 - INCOMING
Subjects: Epigenomics, Aging, congenital, hereditary, and neonatal diseases and abnormalities, [SDV]Life Sciences [q-bio], Science, Chromatin remodelling, Article, Animal disease models, mental disorders, Histone post-translational modifications, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], skin and connective tissue diseases, Neurons, Huntingtin Protein, Behavior, Animal, Gene Expression Profiling, Neurodegenerative Diseases, Huntington's disease, Chromatin Assembly and Disassembly, Chromatin, Corpus Striatum, nervous system diseases, Mice, Inbred C57BL, Disease Models, Animal, Huntington Disease, Gene Expression Regulation, Cardiovascular and Metabolic Diseases, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], sense organs, Trinucleotide Repeat Expansion
Abstract: © The Author(s) 2021., Temporal dynamics and mechanisms underlying epigenetic changes in Huntington’s disease (HD), a neurodegenerative disease primarily affecting the striatum, remain unclear. Using a slowly progressing knockin mouse model, we profile the HD striatal chromatin landscape at two early disease stages. Data integration with cell type-specific striatal enhancer and transcriptomic databases demonstrates acceleration of age-related epigenetic remodelling and transcriptional changes at neuronal- and glial-specific genes from prodromal stage, before the onset of motor deficits. We also find that 3D chromatin architecture, while generally preserved at neuronal enhancers, is altered at the disease locus. Specifically, we find that the HD mutation, a CAG expansion in the Htt gene, locally impairs the spatial chromatin organization and proximal gene regulation. Thus, our data provide evidence for two early and distinct mechanisms underlying chromatin structure changes in the HD striatum, correlating with transcriptional changes: the HD mutation globally accelerates age-dependent epigenetic and transcriptional reprogramming of brain cell identities, and locally affects 3D chromatin organization., This study was supported by CHDI foundation, Inc, the Agence Nationale de la Recherche (ANR-2017-CE12-0027), the Centre National de la Recherche Scientifique (CNRS) and the University of Strasbourg. R.A.V. was supported by post-doctoral fellowship from CHDI. J.S. and A.B. were bioinformatician and technician supported by CHDI. C.L. and A.A. were recipients of doctoral fellowships from the French government and the Association Huntington France (AHF), respectively. Work in the T.S. group is supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (Starting Grant 678624 - CHROMTOPOLOGY), the ATIP-Avenir program, and the grant ANR-10-LABX-0030-INRT, a French State fund managed by the Agence Nationale de la Recherche under the frame program Investissements d’Avenir ANR-10-IDEX-0002-02. A.M.M. was supported by funds from INCA. J.-L.G.-S. was supported by the Spanish government (grant no. BFU2016- 74961-P) and the institutional grant Unidad de Excelencia María de Maeztu (no. MDM-2016-0687). I.I.-A. was supported with a FEBS long-term fellowship.
Published: 2021

11. Cardiovascular magnetic resonance detects microvascular dysfunction in a mouse model of hypertrophic cardiomyopathy

Author: Andreas Pohlmann, Lucie Carrier, Fatimunnisa Qadri, Yi-Ching Lai, Min-Chi Ku, Frank Kober, Thoralf Niendorf, Michael Bader, Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin, DZHK (German Center of Cardiovascular Research), Partner Site Berlin, Centre de résonance magnétique biologique et médicale (CRMBM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, DZHK (German Center of Cardiovascular Research), Partner Site Hamburg, Department of Experimental Pharmacology and Toxicology, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Experimental and Clinical Research Center (ECRC), A Joint Cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Berlin, and Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Cardiac function curve, medicine.medical_specialty, Magnetic Resonance Spectroscopy, Arterial spin labelling (ASL), [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Myocardial blood flow (MBF), Hypertrophic cardiomyopathy (HCM), Magnetic Resonance Imaging, Cine, 030204 cardiovascular system & hematology, 030218 nuclear medicine & medical imaging, Vascular remodelling in the embryo, Mice, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Coronary Circulation, Internal medicine, medicine, Animals, Diseases of the circulatory (Cardiovascular) system, Radiology, Nuclear Medicine and imaging, Angiology, Radiological and Ultrasound Technology, business.industry, Research, Cardiac MRI (CMR), Hypertrophic cardiomyopathy, Blood flow, Cardiomyopathy, Hypertrophic, medicine.disease, Myocardial remodelling, Mice, Inbred C57BL, Perfusion, medicine.anatomical_structure, Microvascular dysfunction, Mice, Inbred DBA, Ventricle, Cardiovascular and Metabolic Diseases, RC666-701, Cardiology, cardiovascular system, Female, MYH7, Technology Platforms, Cardiology and Cardiovascular Medicine, business
Abstract: Background Hypertrophic cardiomyopathy (HCM) related myocardial vascular remodelling may lead to the reduction of myocardial blood supply and a subsequent progressive loss of cardiac function. This process has been difficult to observe and thus their connection remains unclear. Here we used non-invasive myocardial blood flow sensitive CMR to show an impairment of resting myocardial perfusion in a mouse model of naturally occurring HCM. Methods We used a mouse model (DBA/2 J; D2 mouse strain) that spontaneously carries variants in the two most susceptible HCM genes—Mybpc3 and Myh7 and bears the key features of human HCM. The C57BL/6 J (B6) was used as a reference strain. Mice with either B6 or D2 backgrounds (male: n = 4, female: n = 4) underwent cine-CMR for functional assessment at 9.4 T. Left ventricular (LV) wall thickness was measured in end diastolic phase by cine-CMR. Quantitative myocardial perfusion maps (male: n = 5, female: n = 5 in each group) were acquired from arterial spin labelling (cine ASL-CMR) at rest. Myocardial perfusion values were measured by delineating different regions of interest based on the LV segmentation model in the mid ventricle of the LV myocardium. Directly after the CMR, the mouse hearts were removed for histological assessments to confirm the incidence of myocardial interstitial fibrosis (n = 8 in each group) and small vessel remodelling such as vessel density (n = 6 in each group) and perivascular fibrosis (n = 8 in each group). Results LV hypertrophy was more pronounced in D2 than in B6 mice (male: D2 LV wall thickness = 1.3 ± 0.1 mm vs B6 LV wall thickness = 1.0 ± 0.0 mm, p p global = 7.5 ± 0.6 vs B6 MBFglobal = 9.3 ± 1.6 ml/g/min, p global = 6.6 ± 0.8 vs B6 MBFglobal = 8.2 ± 2.6 ml/g/min, p p p p Conclusions Our work describes an imaging marker using cine ASL-CMR with a potential to monitor vascular and myocardial remodelling in HCM.
Published: 2021

12. Dorsal raphe serotonin neurotransmission is required for the expression of nursing behavior and for pup survival

Author: Muzerelle, Aude, Soiza-Reilly, Mariano, Hainer, Cornelia, Ruet, Pierre-Louis, Lesch, Klaus-Peter, Bader, Michael, Alenina, Natalia, Scotto-Lomassese, Sophie, Gaspar, Patricia, Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Instituto de Fisiología, Biología Molecular y Neurociencias [Buenos Aires] (IFIBYNE), Facultad de Ciencias Exactas y Naturales [Buenos Aires] (FCEyN), Universidad de Buenos Aires [Buenos Aires] (UBA)-Universidad de Buenos Aires [Buenos Aires] (UBA), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, University of Würzburg, Sechenov First Moscow State Medical University, Maastricht University [Maastricht], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Universität zu Lübeck [Lübeck], Saint Petersburg State University (SPBU), United Institute of Geology, Geophysics and Mineralogy of the Russian Academy of Sciences, Siberian Branch of the Russian Academy of Sciences (SB RAS), 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)-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), RS: MHeNs - R3 - Neuroscience, Psychiatrie & Neuropsychologie, Gestionnaire, Hal Sorbonne Université, Universität zu Lübeck = University of Lübeck [Lübeck], 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], 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: Dorsal Raphe Nucleus, Male, Serotonin, DETERMINES MATERNAL-BEHAVIOR, Science, [SDV]Life Sciences [q-bio], 5-HT, DEVELOPMENTAL ROLE, Tryptophan Hydroxylase, Neural circuits, Synaptic Transmission, Article, Animals, ANXIETY, Maternal Behavior, NEURONS, Mice, Knockout, [SDV] Life Sciences [q-bio], OXYTOCIN, DEFICIENCY, MICE, Animals, Newborn, Cardiovascular and Metabolic Diseases, PROJECTIONS, Medicine, Female, Social neuroscience, DEPLETION
Abstract: International audience; Proper maternal care is an essential factor of reproductive success in mammals, involving a repertoire of behaviors oriented toward the feeding and care of the offspring. Among the neurotransmitters involved in the initiation of these behaviors, serotonin (5-HT) seems to play an important role. Here we compared pup-oriented maternal behaviors in mice with constitutive 5-HT depletion, the tryptophan hydroxylase 2-knock-out (Tph2-KO) and the Pet1-KO mice. We report that the only common pup-oriented defect in these 2 hyposerotoninergic models is a defective nursing in parturient mice and altered nursing-like (crouching) behavior in virgin mice, while pup retrieval defects are only present in Tph2-KO. Despite a normal mammary gland development and milk production, the defect in appropriate nursing is responsible for severe growth retardation and early lethality of pups born to hyposerotonergic dams. This nursing defect is due to acute rather constitutive 5-HT depletion, as it is reproduced by adult knockdown of Tph2 in the dorsal raphe nucleus in mothers with a prior normal maternal experience. We conclude that 5-HT innervation from the dorsal raphe is required for both the initiation and maintenance of a normal nursing behavior. Our findings may be related to observations of reduced maternal/infant interactions in human depression.
Published: 2021

13. Lymphocyte access to lymphoma is impaired by high endothelial venule regression

Author: Menzel L, Zschummel M, Crowley T, Franke V, Michael Grau, Ulbricht C, Hauser A, Siffrin V, Bajénoff M, Acton S, Akalin A, Lenz G, Willimsky G, Höpken U, Rehm A, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University College of London [London] (UCL), Bajenoff, Marc, and DUMENIL, Anita
Subjects: Cancer Research, Lymphoma, B-Cell, [SDV]Life Sciences [q-bio], Mice, Transgenic, chemokines, immunosurveillance, high endothelial venules, Article, Jurkat Cells, Mice, angiogenesis, Venules, Cell Movement, Animals, Humans, lymphotoxin beta-receptor, Lymphocytes, dendritic cells, tumor stroma, Endothelial Cells, virus diseases, blood endothelial cells, B cell lymphoma, [SDV] Life Sciences [q-bio], Technology Platforms, Function and Dysfunction of the Nervous System, immune cell trafficking
Abstract: Summary Blood endothelial cells display remarkable plasticity depending on the demands of a malignant microenvironment. While studies in solid tumors focus on their role in metabolic adaptations, formation of high endothelial venules (HEVs) in lymph nodes extends their role to the organization of immune cell interactions. As a response to lymphoma growth, blood vessel density increases; however, the fate of HEVs remains elusive. Here, we report that lymphoma causes severe HEV regression in mouse models that phenocopies aggressive human B cell lymphomas. HEV dedifferentiation occurrs as a consequence of a disrupted lymph-carrying conduit system. Mechanosensitive fibroblastic reticular cells then deregulate CCL21 migration paths, followed by deterioration of dendritic cell proximity to HEVs. Loss of this crosstalk deprives HEVs of lymphotoxin-β-receptor (LTβR) signaling, which is indispensable for their differentiation and lymphocyte transmigration. Collectively, this study reveals a remodeling cascade of the lymph node microenvironment that is detrimental for immune cell trafficking in lymphoma., Graphical abstract, Highlights • Aggressive B-cell-lymphoma-induced immunosuppressive niche in lymph nodes • Lymphoma causes a vascular remodeling cascade within the lymph node stroma • Loss of DC-HEV crosstalk deprives blood endothelial cells of LTβR signaling • Lymphoma-induced HEV dedifferentiation is detrimental for immune cell trafficking, Menzel et al. report high endothelial venules (HEVs) regression that is detrimental for immune cell trafficking in lymph nodes with lymphoma. HEV dedifferentiation occurs as a consequence of a disrupted conduit system and impairment of chemokine-guided lymphocyte migration. Loss of dendritic cell-HEV interaction abrogates lymphotoxin β-receptor signaling, required for HEV maintenance.
Published: 2021

14. Interferon signature in patients with STAT1 gain‐of‐function mutation is epigenetically determined

Author: Sofie E. Jørgensen, Pärt Peterson, Lili Milani, E. Graham Davies, Vincent Bondet, Mario Saare, Darragh Duffy, Epp Kaleviste, Sascha Sauer, Timothy Ronan Leahy, Helke Nurm, Trine H. Mogensen, Ann-Christine Syvänen, Kai Kisand, Winnie Ip, University of Tartu, Our Lady's Children's Hospital Crumlin (OLCHC), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Aarhus University [Aarhus], Aarhus University Hospital, Tallinn Children's Hospital [Tallinn, Estonia], Great Ormond Street Hospital for Children [London] (GOSH), Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Uppsala University, The research was funded by the European Union through the European Regional Development Fund (Project No 2014–2020.4.01.15‐0012), by Estonian Research Council (grants PUT1367 for KK, IUT 2‐2 for PP), and by [FP7/2007‐2013] under grant agreement number n° 262055 (ESGI). D. Duffy acknowledges support from the ANR (CE17001002) and Immunoqure for provision of mAbs for Simoa., European Project: 262055,EC:FP7:INFRA,FP7-INFRASTRUCTURES-2010-1,ESGI(2011), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), and ANR-16-CE17-0010,IFNX,Investigation des interferonopathies type I humaine(2016)
Subjects: STAT3 Transcription Factor, 0301 basic medicine, Immunology, chronic mucocutaneous candidiasis, Biology, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, Interferon, STAT1 gain-of-function mutation, medicine, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Epigenetics, Phosphorylation, epigenetics, Janus kinase 1, Chromatin binding, autoimmunity, Candidiasis, Chronic Mucocutaneous, 3. Good health, Chromatin, Intracellular signal transduction, STAT1 Transcription Factor, 030104 developmental biology, Gene Expression Regulation, Case-Control Studies, Gain of Function Mutation, Cancer research, type I interferon, [SDV.IMM]Life Sciences [q-bio]/Immunology, Chromatin Immunoprecipitation Sequencing, H3K4me3, Interferons, Chromatin immunoprecipitation, Protein Binding, Signal Transduction, 030215 immunology, medicine.drug
Abstract: International audience; STAT1 gain-of-function (GOF) variants lead to defective Th17 cell development and chronic mucocutaneous candidiasis (CMC), but frequently also to autoimmunity. Stimulation of cells with STAT1 inducing cytokines like interferons (IFN) result in hyperphosphorylation and delayed dephosphorylation of GOF STAT1. However, the mechanism how the delayed dephosphorylation exactly causes the increased expression of STAT1-dependent genes, and how the intracellular signal transduction from cytokine receptors is affected, remains unknown. In this study we show that the circulating levels of IFN-α were not persistently elevated in STAT1 GOF patients. Nevertheless, the expression of interferon signature genes was evident even in the patient with low or undetectable serum IFN-α levels. Chromatin immunoprecipitation (ChIP) experiments revealed that the active chromatin mark trimethylation of lysine 4 of histone 3 (H3K4me3), was significantly enriched in areas associated with interferon-stimulated genes in STAT1 GOF cells in comparison to cells from healthy donors. This suggests that the chromatin binding of GOF STAT1 variant promotes epigenetic changes compatible with higher gene expression and elevated reactivity to type I interferons, and possibly predisposes for interferon-related autoimmunity. The results also suggest that epigenetic rewiring may be responsible for treatment failure of Janus kinase 1/2 (JAK1/2) inhibitors in certain patients.
Published: 2019

15. The role of intraspinal sensory neurons in the control of quadrupedal locomotion

Author: Katrin Gerstmann, Nina Jurčić, Edith Blasco, Severine Kunz, Felipe de Almeida Sassi, Nicolas Wanaverbecq, Niccolò Zampieri, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), and ANR-16-CE92-0043,MotAct-CSF,Caractérisation du rôle physiologique des neurones bulbospinaux au contact du LCR dans le cerveau de mammifères.(2016)
Subjects: Mammals, Sensory Receptor Cells, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, General Biochemistry, Genetics and Molecular Biology, Mice, Spinal Cord, Animals, Technology Platforms, Function and Dysfunction of the Nervous System, General Agricultural and Biological Sciences, ComputingMilieux_MISCELLANEOUS, Locomotion, Swimming, Zebrafish
Abstract: From swimming to walking and flying, animals have evolved specific locomotor strategies to thrive in different habitats. All types of locomotion depend on the integration of motor commands and sensory information to generate precisely coordinated movements. Cerebrospinal-fluid-contacting neurons (CSF-cN) constitute a vertebrate sensory system that monitors CSF composition and flow. In fish, CSF-cN modulate swimming activity in response to changes in pH and bending of the spinal cord; however, their role in mammals remains unknown. We used mouse genetics to study their function in quadrupedal locomotion. We found that CSF-cN are directly integrated into spinal motor circuits. The perturbation of CSF-cN function does not affect general motor activity nor the generation of locomotor rhythm and pattern but results in specific defects in skilled movements. These results identify a role for mouse CSF-cN in adaptive motor control and indicate that this sensory system evolved a novel function to accommodate the biomechanical requirements of limb-based locomotion.
Published: 2022

16. Oscillations of Delta-like1 regulate the balance between differentiation and maintenance of muscle stem cells

Author: Zhang, Yao, Lahmann, Ines, Baum, Katharina, Shimojo, Hiromi, Mourikis, Philippos, Wolf, Jana, Kageyama, Ryoichiro, Birchmeier, Carmen, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, University of Potsdam, Kyoto University [Kyoto], Osaka University [Osaka], 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), Free University of Berlin (FU), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University of Potsdam = Universität Potsdam, Kyoto University, and Mourikis, Philippos
Subjects: [SDV] Life Sciences [q-bio], Cancer Research, Cell biology, Science, [SDV]Life Sciences [q-bio], Developmental biology, Genetics, Stem cells, Function and Dysfunction of the Nervous System, Systems biology, Article
Abstract: Cell-cell interactions mediated by Notch are critical for the maintenance of skeletal muscle stem cells. However, dynamics, cellular source and identity of functional Notch ligands during expansion of the stem cell pool in muscle growth and regeneration remain poorly characterized. Here we demonstrate that oscillating Delta-like 1 (Dll1) produced by myogenic cells is an indispensable Notch ligand for self-renewal of muscle stem cells in mice. Dll1 expression is controlled by the Notch target Hes1 and the muscle regulatory factor MyoD. Consistent with our mathematical model, our experimental analyses show that Hes1 acts as the oscillatory pacemaker, whereas MyoD regulates robust Dll1 expression. Interfering with Dll1 oscillations without changing its overall expression level impairs self-renewal, resulting in premature differentiation of muscle stem cells during muscle growth and regeneration. We conclude that the oscillatory Dll1 input into Notch signaling ensures the equilibrium between self-renewal and differentiation in myogenic cell communities., The cell source and dynamics of Notch ligands during the regulation of muscle stem cells is unclear. Here, the authors show that the Notch ligand Dll1 has to oscillate in order to control the balance between self-renewal and differentiation of muscle stem cells, with Hes1 acting as transcriptional pacemaker for the oscillatory network.
Published: 2021

17. Contribution of preclinical MRI to responsible animal research: living up to the 3R principle

Author: Armand Mensen, Pasquina Marzola, Henning M Reimann, Marlène Wiart, Cristina Barca, Catarina Tristão-Pereira, Angèle Viola, Cornelius Faber, Sonia Waiczies, Alice Busato, Lydia Wachsmuth, Bruno Pradier, Ileana O. Jelescu, Uwe Himmelreich, Jason M. Millward, University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), University of Bern, European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Ecole Polytechnique Fédérale de Lausanne (EPFL), Center for Biomedical Imaging [Lausanne] (CIBM), Università degli studi di Verona = University of Verona (UNIVR), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Westfälische Wilhelms-Universität Münster (WWU), and University of Verona (UNIVR)
Subjects: Animal Experimentation, 3R principle, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Biophysics, MEDLINE, Health informatics, animal welfare, 03 medical and health sciences, 0302 clinical medicine, pet, Medicine, Animals, Radiology, Nuclear Medicine and imaging, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Science & Technology, model, Radiological and Ultrasound Technology, Animal Welfare (journal), business.industry, Radiology, Nuclear Medicine & Medical Imaging, Magnetic Resonance Imaging, 3. Good health, MODEL, Disease Models, Animal, PET, preclinical MRI, Cardiovascular and Metabolic Diseases, Solid State Physics, Biomedical Engineering and Bioengineering, Imaging / Radiology, Health Informatics, Computer Appl. in Life Sciences, Commentary, Engineering ethics, Technology Platforms, business, Life Sciences & Biomedicine, 030217 neurology & neurosurgery
Abstract: ispartof: MAGNETIC RESONANCE MATERIALS IN PHYSICS BIOLOGY AND MEDICINE vol:34 issue:4 pages:469-474 ispartof: location:Germany status: published
Published: 2021

18. Reactive astrocyte nomenclature, definitions, and future directions

Author: Arthur M. Butt, Elena Galea, Richard M. Ransohoff, Raymond A. Swanson, Eduardo R. Zimmer, Christopher M. Norris, Gilles Bonvento, Andras Lakatos, Philip G. Haydon, Wei Ting Chen, Christine R. Rose, Alexey Semyanov, Nicola J. Allen, Anna V. Molofsky, Javier Vitorica, Seiji Okada, Alfonso Araque, Antonia Gutierrez, Masamitsu Iino, Alberto Serrano-Pozo, Vittorio Gallo, C. Justin Lee, Magdalena Götz, Baljit S. Khakh, Christian Steinhäuser, Bart De Strooper, Stéphane H. R. Oliet, Andrea Volterra, Swetlana Sirko, Kira E. Poskanzer, Michael V. Sofroniew, Giorgio Carmignoto, Elly M. Hol, Frank W. Pfrieger, Beatriz G. Pérez-Nievas, Ksenia V. Kastanenka, Keith K. Murai, James P. O'Callaghan, Ina B. Wanner, David H. Rowitch, Pierre J. Magistretti, Cinthia Farina, Marcela Pekna, Albee Messing, Jia Qian Wu, Shane A. Liddelow, Dieter Henrik Heiland, Anusha Mishra, Robert Zorec, Levi B. Wood, Marc R. Freeman, Matthew Holt, Luis Barbeito, Gabor C. Petzold, Luc Pellerin, Jeffrey D. Rothstein, Nathalie Rouach, Carole Escartin, Schuichi Koizumi, Gertrudis Perea, Dwight E. Bergles, Miriam Riquelme-Perez, Martine Cohen-Salmon, Stefanie Robel, James E. Goldman, Binhai Zheng, João Filipe Oliveira, Ari Barzilai, Steven A. Goldman, Brian A. MacVicar, Aude Panatier, Helmut Kettenmann, Alexei Verkhratsky, Amit Agarwal, Colm Cunningham, Blanca Diaz-Castro, Francisco J. Quintana, Milos Pekny, Harald Sontheimer, Benjamin Deneen, Vladimir Parpura, Service MIRCEN (MIRCEN), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Universitat Autònoma de Barcelona (UAB), ICREA Infection Biology Laboratory (Department of Experimental and Health Sciences), Universitat Pompeu Fabra [Barcelona] (UPF), University of Cambridge [UK] (CAM), National Institute for Occupational Safety and Health [Morgantown, WV, USA] (NIOSH), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), University Hospital Bonn, Massachusetts General Hospital [Charlestown, MA, États-Unis], University of Bonn, University of Lausanne (UNIL), Italian National Research Council [Padova, Italy], University of Padua [Italy], Heidelberg University, The Salk Institute for Biological Studies, University of Minnesota [MN, USA], Institut Pasteur de Montevideo, Réseau International des Instituts Pasteur (RIIP), Tel Aviv University [Tel Aviv], Johns Hopkins University School of Medicine [Baltimore], University of Portsmouth, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Trinity College Dublin, Baylor College of Medicine (BCM), Baylor University, University College of London [London] (UCL), University of Edinburgh, San Raffaele Scientific Institute, Vita-Salute San Raffaele University and Center for Translational Genomics and Bioinformatics, Vollum Institute, Vollum Institute OHSU, National Children's Hospital, Columbia University [New York], University of Rochester Medical Center (URMC), University of Copenhagen = Københavns Universitet (KU), Ludwig Maximilians Universitaet, SYNERGY, Excellence Cluster of Systems Neurology, Ludwig-Maximilians-Universität München (LMU), Universidad de Málaga [Málaga] = University of Málaga [Málaga], Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), Tufts University School of Medicine [Boston], University of Freiburg [Freiburg], Utrecht University [Utrecht], VIB-KU Leuven Center for Brain & Disease Research [Leuven, Belgium], Nihon University School of Medicine [Tokyo, Japan], Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, Yamanashi University, Institute for Basic Science [Daejeon] (IBS), New York University School of Medicine (NYU), New York University School of Medicine, NYU System (NYU)-NYU System (NYU), University of British Columbia (UBC), King Abdullah University of Science and Technology, University of Wisconsin-Madison, Oregon Health and Science University [Portland] (OHSU), University of California [San Francisco] (UCSF), University of California, McGill University Health Center [Montreal] (MUHC), University of Kentucky, Kyushu University [Fukuoka], Physiopathologie de la Plasticité Neuronale (Neurocentre Magendie - U1215 Inserm), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Minho [Braga], ICVS/3B's—PT Government Associate Laboratory [Braga, Portugal], Polytechnic Institute of Cávado and Ave, University of Alabama at Birmingham [ Birmingham] (UAB), University of Gothenburg (GU), Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Cajal Institute, King‘s College London, Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Third Rock Ventures, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry (IBCh RAS), Russian Academy of Sciences [Moscow] (RAS), Sechenov First Moscow State Medical University, Ludwig Maximilian University [Munich] (LMU), Institute for Stem Cell Research [Neuherberg], Helmholtz-Zentrum München (HZM), Universidad de Sevilla, Georgia Institute of Technology [Atlanta], The University of Texas Health Science Center at Houston (UTHealth), UC San Diego School of Medicine, Universidade Federal do Rio Grande do Sul [Porto Alegre] (UFRGS), University of Ljubljana, University of Manchester [Manchester], Ikerbasque - Basque Foundation for Science, Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), European Project: 722053,EU-GliaPhD - H2020-EU.1.3. H2020-EU.1.3.1., Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Universität Bonn = University of Bonn, Université de Lausanne = University of Lausanne (UNIL), Escartin, Carole [0000-0003-3613-4118], Galea, Elena [0000-0003-4537-9897], Lakatos, András [0000-0002-1301-2292], Petzold, Gabor C [0000-0002-0145-8641], Serrano-Pozo, Alberto [0000-0003-0899-7530], Volterra, Andrea [0000-0003-1069-1602], Araque, Alfonso [0000-0003-3840-1144], Barbeito, Luis [0000-0002-3047-232X], Bonvento, Gilles [0000-0002-2886-4228], Butt, Arthur M [0000-0001-7579-0746], Deneen, Benjamin [0000-0002-6335-1081], Farina, Cinthia [0000-0002-4466-9676], Gallo, Vittorio [0000-0002-2429-0845], Goldman, Steven A [0000-0002-5498-4303], Götz, Magdalena [0000-0003-1551-9203], Gutiérrez, Antonia [0000-0002-6264-6152], Haydon, Philip G [0000-0001-5698-6698], Heiland, Dieter H [0000-0002-9258-3033], Hol, Elly M [0000-0001-5604-2603], Holt, Matthew G [0000-0002-8958-4027], Koizumi, Schuichi [0000-0001-6184-3106], MacVicar, Brian A [0000-0003-4596-4623], Mishra, Anusha [0000-0002-3642-5049], Molofsky, Anna V [0000-0002-4709-2411], Okada, Seiji [0000-0002-5107-8209], Oliveira, João F [0000-0002-1005-2328], Panatier, Aude [0000-0002-6107-4463], Pekna, Marcela [0000-0003-2734-8237], Perea, Gertrudis [0000-0001-5924-9175], Pfrieger, Frank W [0000-0001-7085-1431], Poskanzer, Kira E [0000-0003-4830-8891], Rose, Christine R [0000-0002-9684-3592], Rothstein, Jeffrey D [0000-0003-2001-8470], Rouach, Nathalie [0000-0002-5574-888X], Rowitch, David H [0000-0002-0079-0060], Semyanov, Alexey [0000-0002-6800-0942], Sirko, Swetlana [0000-0001-5950-616X], Sontheimer, Harald [0000-0002-5843-9871], Swanson, Raymond A [0000-0002-3664-5359], Zorec, Robert [0000-0002-7478-3875], Sofroniew, Michael V [0000-0001-6075-0178], Verkhratsky, Alexei [0000-0003-2592-9898], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Aging, [SDV]Life Sciences [q-bio], Disease, pathology [Spinal Cord], Article, 03 medical and health sciences, 0302 clinical medicine, pathology [Aging], Response to injury, pathology [Brain], medicine, Psychology, Animals, Humans, ddc:610, Reactive Astrocyte, ComputingMilieux_MISCELLANEOUS, Spinal Cord Injuries, pathology [Astrocytes], Brain Diseases, Neurology & Neurosurgery, Extramural, business.industry, General Neuroscience, pathology [Brain Injuries], Neurosciences, pathology [Brain Diseases], Brain, 3. Good health, Brain Disorders, 030104 developmental biology, medicine.anatomical_structure, Spinal Cord, Astrocytes, Brain Injuries, Neurological, Cognitive Sciences, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], pathology [Spinal Cord Injuries], business, Neuroscience, 030217 neurology & neurosurgery, Astrocyte, Spinal cord pathology
Abstract: Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters—preferably in vivo—plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions., Funding: CNRS, CEA, ANR, and France Alzheimer to CE.; MCINN (PID2019-107633RB-I00) and Generalitat de Catalunya (2017-SGR547, Grup de demències Sant Pau) to E.G. US Centers for Disease Control and Prevention to J. P.O. Alzheimer’s Association (AACF-17-524184) and NIH-NIA (K08AG064039) to A.S.-P. DFG (SPP1757, STE 552/5, STE 552/4), EU (H2020-MSCA-ITN project 722053 EU-GliaPhD) and BMBF (16GW0182 CONNEXIN) to C.S. Swiss National Science Foundation grant 31003A 173124/1; SNSF NCCR ‘Transcure’ (51NF40-160620); Synapsis Foundation Heidi Seiler-Stiftung 2018-PI01 to A.Volterra. NIH-NINDS (NS084030), Dr. Miriam and Sheldon G. Adelson Medical Foundation and Wings for Life to M.V.S. The authors thank T. Yohannan of Alpha Language Services, Barcelona, for expert copy editing.
Published: 2021

19. Miyoshi myopathy and limb girdle muscular dystrophy R2 are the same disease

Author: Moore, Ursula, Gordish, Heather, Diaz-Manera, Jordi, James, Meredith K, Mayhew, Anna G, Guglieri, Michela, Fernandez-Torron, Roberto, Rufibach, Laura E, Feng, Jia, Blamire, Andrew M, Carlier, Pierre G, Spuler, Simone, Day, John W, Jones, Kristi J, Bharucha-Goebel, Diana X, Salort-Campana, Emmanuelle, Pestronk, Alan, Walter, Maggie C, Paradas, Carmen, Stojkovic, Tanya, Mori-Yoshimura, Madoka, Bravver, Elena, Pegoraro, Elena, Lowes, Linda Pax, Mendell, Jerry R, Bushby, Kate, Straub, Volker, Jain COS Consortium, Newcastle University [Newcastle], Georgetown University [Washington] (GU), CIBER de Enfermedades Raras (CIBERER), Hospital de la Santa Creu i Sant Pau, 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), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, The University of Sydney, National Institutes of Health [Bethesda] (NIH), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Ludwig-Maximilians-Universität München (LMU), Hospital Universitario Virgen del Rocío [Sevilla], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Padova = University of Padua (Unipd), Abigail Wexner Research Institute, Nationwide Children's Hospital, Centre de référence des maladies rares neuromusculaires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Universita degli Studi di Padova, Jain Foundation, and International Centre for Genomic Medicine in Neuromuscular Diseases
Subjects: 0301 basic medicine, Male, [SDV]Life Sciences [q-bio], Disease, Clinical trials methodology, 0302 clinical medicine, [185] Muscle disease, Child, Genetics (clinical), Muscle disease, Muscle Weakness, medicine.diagnostic_test, [21] Clinical trials methodology, Anatomy, Middle Aged, Magnetic Resonance Imaging, 3. Good health, Limb girdle weakness, Muscular Atrophy, Phenotype, Neurology, Child, Preschool, Disease Progression, Female, Function and Dysfunction of the Nervous System, Cohort study, Adult, Dysferlinopathy, Miyoshi myopathy, Adolescent, [54] Cohort study, Lower limb weakness, [16] Clinical neurology examination, 03 medical and health sciences, Young Adult, medicine, Humans, Clinical neurology examination, [176] All neuromuscular disease, business.industry, Infant, Newborn, Infant, Magnetic resonance imaging, medicine.disease, Clinical trial, Distal Myopathies, 030104 developmental biology, Muscular Dystrophies, Limb-Girdle, Pediatrics, Perinatology and Child Health, Neurology (clinical), business, 030217 neurology & neurosurgery, Limb-girdle muscular dystrophy, All neuromuscular disease
Abstract: The Jain COS Consortium., This study aims to determine clinically relevant phenotypic differences between the two most common phenotypic classifications in dysferlinopathy, limb girdle muscular dystrophy R2 (LGMDR2) and Miyoshi myopathy (MMD1). LGMDR2 and MMD1 are reported to involve different muscles, with LGMDR2 showing predominant limb girdle weakness and MMD1 showing predominant distal lower limb weakness. We used heatmaps, regression analysis and principle component analysis of functional and Magnetic Resonance Imaging data to perform a cross-sectional review of the pattern of muscle involvement in 168 patients from the Jain Foundation's international Clinical Outcomes Study for Dysferlinopathy. We demonstrated that there is no clinically relevant difference in proximal vs distal involvement between diagnosis. There is a continuum of distal involvement at any given degree of proximal involvement and patients do not fall into discrete distally or proximally affected groups. There appeared to be geographical preference for a particular diagnosis, with MMD1 being more common in Japan and LGMDR2 in Europe and the USA. We conclude that the dysferlinopathies do not form two distinct phenotypic groups and therefore should not be split into separate cohorts of LGMDR2 and MM for the purposes of clinical management, enrolment in clinical trials or access to subsequent treatments., The estimated $4 million USD needed to fund this study was provided by the Jain Foundation. Volker Straub was supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1.
Published: 2021

20. Endothelial Cell Orientation and Polarity Are Controlled by Shear Stress and VEGF Through Distinct Signaling Pathways

Author: Vion, Anne-Clémence, Perovic, Tijana, Petit, Charlie, Hollfinger, Irene, Bartels-Klein, Eireen, Frampton, Emmanuelle, Gordon, Emma, Claesson-Welsh, Lena, Gerhardt, Holger, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, University of Queensland [Brisbane], Uppsala University, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Vion, Anne-clemence, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and 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)
Subjects: Fysiologi, Physiology, Cellbiologi, Cell Biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, VEGF, signaling pathways, shear stress, signaling/signaling pathways, Cardiovascular and Metabolic Diseases, endothelial cell, blood flow, signaling, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Original Research
Abstract: International audience; Vascular networks form, remodel and mature under the influence of multiple signals of mechanical or chemical nature. How endothelial cells read and interpret these signals, and how they integrate information when they are exposed to both simultaneously is poorly understood. Here, we show using flow-induced shear stress and VEGF-A treatment on endothelial cells in vitro , that the response to the magnitude of a mechanical stimulus is influenced by the concentration of a chemical stimulus, and vice versa. By combining different flow levels and different VEGF-A concentrations, front-rear polarity of endothelial cells against the flow direction was established in a flow and VEGF-A dose-response while their alignment with the flow displayed a biphasic response depending on the VEGF-A dose (perpendicular at physiological dose, aligned at no or pathological dose of VEGF-A). The effect of pharmaceutical inhibitors demonstrated that while VEGFR2 is essential for both polarity and orientation establishment in response to flow with and without VEGF-A, different downstream effectors were engaged depending on the presence of VEGF-A. Thus, Src family inhibition (c-Src, Yes, Fyn together) impaired alignment and polarity without VEGF-A while FAK inhibition modified polarity and alignment only when endothelial cells were exposed to VEGF-A. Studying endothelial cells in the aortas of VEGFR2 Y949F mutant mice and SRC iEC – KO mice confirmed the role of VEGFR2 and specified the role of c-SRC in vivo . Endothelial cells of VEGFR2 Y949F mutant mice lost their polarity and alignment while endothelial cells from SRC iEC – KO mice only showed reduced polarity. We propose here that VEGFR2 is a sensor able to integrate chemical and mechanical information simultaneously and that the underlying pathways and mechanisms activated will depend on the co-stimulation. Flow alone shifts VEGFR2 signaling toward a Src family pathway activation and a junctional effect (both in vitro and in vivo ) while flow and VEGF-A together shift VEGFR2 signaling toward focal adhesion activation ( in vitro ) both modifying cell responses that govern orientation and polarity.
Published: 2021

21. A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans

Author: Henry Houlden, Thomas Haaf, Pratishtha Varshney, Christian Beetz, Hamid Galehdari, Lucy A Dunbar, Alireza Sedaghat, Richard J.H. Smith, Michael R. Bowl, Aziz El-Amraoui, Kevin T. Booth, David Murphy, Neda Mazaheri, Sandrine Vitry, Kumar N. Alagramam, Ben Fowler, Shruthi VijayKumar, Aboulfazl Rad, Hela Azaiez, Cassidy Petree, Barbara Vona, Sheng-Jia Lin, Gholamreza Shariati, Reza Maroofian, Franz Rüschendorf, Gaurav K. Varshney, EL-AMRAOUI, Aziz, ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER - - LIGHT4DEAF2015 - ANR-15-RHUS-0001 - RHUS - VALID, Surdité d'apparition tardive et progressive: de la physiopathologie à la thérapie - - HearInNoise2017 - ANR-17-CE16-0017 - AAPG2017 - VALID, Julius-Maximilians-Universität Würzburg (JMU), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Shahid Chamran University of Ahvaz (SCU), Oklahoma Medical Research Foundation (OMRF), MRC Harwell Institute [UK], University College of London [London] (UCL), University of Iowa [Iowa City], Harvard Medical School [Boston] (HMS), Déficits Sensoriels Progressifs, Pathophysiologie et Thérapie / Progressive Sensory Disorders, Pathophysiology and Therapy (DSP), Sorbonne Université (SU)-Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, CENTOGENE AG, Case Western Reserve University [Cleveland], Ahvaz Jundishapur University of Medical Sciences (AJUMS), Narges Medical Genetics and Prenatal Diagnostics, Open Access funding enabled and organized by Projekt DEAL. This work was supported by Intramural Funding (fortüne) at the University of Tübingen (2545-1-0 to BV), the Ministry of Science, Research and Art Baden-Württemberg (to BV), the Medical Research Council (MC_UP_1503/2 to MRB), ANR light4deaf (ANR-15-RHUS-0001), HearInNoise (ANR-17-CE16-0017), LHW-stiftung to AE), and a grant from NIH/COBRE GM103636 (Project 3), the Presbyterian Health Foundation (PHF) Grant to GKV. This study was funded in part by NIDCDs R01s DC002842 and DC012049 to RJS and T32 GM007748 to KTB. LAD is a Medical Research Council DPhil student (1774724)., We would like to extend our gratitude to the family for their participation. We thank Dr. Caroline Lekszas, Dr. Daniel Liedtke, and Dr. Indrajit Nanda from the Institute of Human Genetics at the University of Würzburg for their technical expertise., ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015), ANR-17-CE16-0017,HearInNoise,Surdité d'apparition tardive et progressive: de la physiopathologie à la thérapie(2017), Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Carver College of Medicine, University of Iowa, Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Institute of Neurology - UCL/Queen Square [London, UK] (IN-UCL-QS), Institut Pasteur [Paris], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University Hospitals of Cleveland, This work was supported by Intramural Funding (fortüne) at the University of Tübingen (2545-1-0 to B.V.), the Ministry of Science, Research and Art Baden-Württemberg (to B.V.), the Medical Research Council (MC_UP_1503/2 to M.R.B), ANR light4deaf (ANR-15-RHUS-0001), HearInNoise (ANR-17-CE16-0017), LHW-stiftung (to A.E.), and a grant from NIH/COBRE GM103636 (Project 3), the Presbyterian Health Foundation (PHF) Grant to G.K.V. This study was funded in part by NIDCDs R01s DC002842 and DC012049 to R.J.S and T32 GM007748 to K.T.B. L.A.D is a Medical Research Council DPhil student (1774724)., Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Déficits Sensoriels Progressifs, Pathophysiologie et Thérapie / Progressive Sensory Disorders, PathoPhysiology and Therapy (DSP)
Subjects: Male, Tetraspanins, [SDV]Life Sciences [q-bio], Gene Expression, MESH: Base Sequence, Consanguinity, Mice, 0302 clinical medicine, Missense mutation, MESH: Animals, Zebrafish, Genetics (clinical), Exome sequencing, Original Investigation, Genetics, 0303 health sciences, Chromosome Mapping, Disease gene identification, MESH: Amino Acid Substitution, Stop codon, Pedigree, [SDV] Life Sciences [q-bio], Female, Sensorineural hearing loss, MESH: Membrane Proteins, Chromosomes, Human, Pair 4, medicine.symptom, Adult, MESH: Chromosomes, Human, Pair 4, MESH: Gene Expression, Hearing loss, MESH: Pedigree, Hearing Loss, Sensorineural, Genes, Recessive, Locus (genetics), Biology, MESH: Hair Cells, Auditory, Inner, 03 medical and health sciences, MESH: Whole Exome Sequencing, Exome Sequencing, medicine, otorhinolaryngologic diseases, Animals, Humans, Point Mutation, ddc:610, MESH: Zebrafish, MESH: Mice, Alleles, MESH: Genes, Recessive, 030304 developmental biology, MESH: Point Mutation, MESH: Consanguinity, Hair Cells, Auditory, Inner, MESH: Humans, Base Sequence, MESH: Alleles, Intron, Membrane Proteins, MESH: Adult, medicine.disease, MESH: Male, Amino Acid Substitution, MESH: Hearing Loss, Sensorineural, Cardiovascular and Metabolic Diseases, MESH: Chromosome Mapping, MESH: Tetraspanins, MESH: Female, 030217 neurology & neurosurgery
Abstract: Deafness, the most frequent sensory deficit in humans, is extremely heterogeneous with hundreds of genes involved. Clinical and genetic analyses of an extended consanguineous family with pre-lingual, moderate-to-profound autosomal recessive sensorineural hearing loss, allowed us to identify CLRN2, encoding a tetraspan protein, as a new deafness gene. Homozygosity mapping followed by exome sequencing identified a 14.96 Mb locus on chromosome 4p15.32p15.1 containing a likely pathogenic missense variant in CLRN2 (c.494C > A, NM_001079827.2) segregating with the disease. Using in vitro RNA splicing analysis, we show that the CLRN2 c.494C > A variant leads to two events: (1) the substitution of a highly conserved threonine (uncharged amino acid) to lysine (charged amino acid) at position 165, p.(Thr165Lys), and (2) aberrant splicing, with the retention of intron 2 resulting in a stop codon after 26 additional amino acids, p.(Gly146Lysfs*26). Expression studies and phenotyping of newly produced zebrafish and mouse models deficient for clarin 2 further confirm that clarin 2, expressed in the inner ear hair cells, is essential for normal organization and maintenance of the auditory hair bundles, and for hearing function. Together, our findings identify CLRN2 as a new deafness gene, which will impact future diagnosis and treatment for deaf patients.
Published: 2021

22. Metagenomic assessment of the global distribution of bacteria and fungi

Author: BAHRAM, Mohammad, NETHERWAY, Tarquin, FRIOUX, Clémence, FERRETTI, Pamela, COELHO, Luis Pedro, GEISEN, Stefan, BORK, Peer, HILDEBRAND, Falk, Swedish University of Agricultural Sciences (SLU), from patterns to models in computational biodiversity and biotechnology (PLEIADE), 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)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Biodiversité, Gènes & Communautés (BioGeCo), Université de Bordeaux (UB)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Earlham Institute [Norwich], Quadram Institute, European Molecular Biology Laboratory [Heidelberg] (EMBL), Netherlands Institute of Ecology - NIOO-KNAW (NETHERLANDS), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Funding was provided by Swedish Research Council (Vetenskapsrådet grant no: 2017‐05019 and Biotechnology and Biological Sciences research Council (Institute Strategic Programme Gut Microbes and Health BB/r012490/1 and its constituent project BBS/E/F/000Pr10355)., Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS)-Inria Bordeaux - Sud-Ouest, and Biotechnology and Biological Sciences Research Council (BBSRC)
Subjects: Microbiology (Microbiology in the medical area to be 30109), Ecology, fungi, Biochemistry and Molecular Biology, Life Science, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], [SDE.BE]Environmental Sciences/Biodiversity and Ecology, Laboratory of Nematology, PE&RC, Laboratorium voor Nematologie
Abstract: International audience; Bacteria and fungi are of uttermost importance in determining environmental and host functioning. Despite close interactions between animals, plants, their associated microbiomes,and the environment they inhabit, the distribution and role of bacteria and especially fungi across host and environments as well as the cross-habitat determinants of their community compositions remain little investigated. Using a uniquely broad global dataset of 13,483 metagenomes, we analyzed the microbiome structure and function of 25 host-associated and environmental habitats, focusing on potential interactions between bacteria and fungi. We found that themetagenomic relative abundance ratio of bacteria-to-fungi is a distinctive microbial feature of habitats. Compared to fungi, the cross-habitat distribution pattern of bacteria was more strongly driven by habitat type. Fungal diversity was depleted in host-associated communities compared with those in the environment, particularly terrestrial habitats, whereas this diversity pattern was less pronounced for bacteria. The relative gene functional potential of bacteria or fungi reflectedtheir diversity patterns and appeared to depend on a balance between substrate availability and biotic interactions. Alongside helping to identify hotspots and sources of microbial diversity, our study provides support for differences in assembly patterns and processes between bacterial and fungal communities across different habitats.
Published: 2021

23. Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology

Author: Bel Lassen, Pierre, Nielsen, Trine, Bergh, Per-Olof, Rouault, Christine, André, Sébastien, Marquet, Florian, Andreelli, Fabrizio, Salem, Joe-Elie, Assmann, Karen, Bastard, Jean-Philippe, Forslund, Sofia, Le Chatelier, Emmanuelle, Falony, Gwen, Pons, Nicolas, Prifti, Edi, Quinquis, Benoit, Roume, Hugo, Vieira-Silva, Sara, Hansen, Tue, Pedersen, Helle Krogh, Lewinter, Christian, Sønderskov, Nadja, Vestergaard, Henrik, Raes, Jeroen, Nielsen, Jens, Bork, Peer, Ehrlich, S. Dusko, Pedersen, Oluf, Aron-Wisneswky, Judith, Clément, Karine, Bäckhed, Fredrik, Molinaro, Antonio, Lassen, Pierre, Henricsson, Marcus, Wu, Hao, Adriouch, Solia, Belda, Eugeni, Chakaroun, Rima, Nielse, Trine, Bergh, Christine, Rouault, Sébastien, Andr, Florian, Marquet, Fabrizio, Andreelli, Joe-Elie, Salem, Karen, Assmann, Jean-Philippe, Bastard, Sofia, Forslund, Emmanuelle, Le Chatelier, Gwen, Falon, Nicolas, Pons, Edi, Prift, Benoit, Quinquis, Hugo, Roume, Sara, Vieira-Silv, Tue, Hansen, Krogh, Pedersen, Christian, Lewinter, Nadja, The, Metacardis, Køber, Lars, Vestergaar, Henrik, Hansen, Torben, Zucker, Jean-Daniel, Galan, Pilar, Dumas, Marc-Emmanuel, Rae, Jeroen, Oppert, Jean-Michel, Letunic, Ivica, Nielse, Jens, Ehrlic, S, Stumvoll, Michael, Pederse, Oluf, Aron-Wisnewsky, Judith, Bäckhe, Fredrik, Sahlgrenska Center for Cardiovascular and Metabolic Research, Partenaires INRAE, Sahlgrenska University Hospital, Nutrition et obésités: approches systémiques (nutriomics) (UMR-S 1269 INSERM - Sorbonne Université), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche en Nutrition Humaine d'Ile-de-France (CRNH-IDF), Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Sorbonne Paris Nord, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), 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], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université (SU), Medical Department III – Endocrinology, Nephrology, Rheumatology, Universität Leipzig [Leipzig], Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Centre d'Investigation Clinique de Paris Est, Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital Tenon [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Experimental and Clinical Research Center [Berlin, Germany], Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association-Helmholtz-Gemeinschaft = Helmholtz Association-Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Bacteriology, Université Catholique de Louvain (UCL), VIB-KU Leuven Center for Microbiology [Belgium], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Unité de modélisation mathématique et informatique des systèmes complexes [Bondy] (UMMISCO), Sorbonne Université (SU)-Universtié Yaoundé 1 [Cameroun]-Université Cadi Ayyad [Marrakech] (UCA)-Université Gaston Bergé (Saint-Louis, Sénégal)-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de la francophonie pour l'informatique-Institut de Recherche pour le Développement (IRD [France-Nord]), Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Metabolism, Digestion and Reproduction, Imperial College London, National Heart and Lung Institute [London] (NHLI), Royal Brompton and Harefield NHS Foundation Trust-Imperial College London, Centre de Recherche en Nutrition Humaine - Ile de France (CRNH - IDF), Biobyte Solutions GMBH, Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Sorbonne Paris Nord, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Sahlgrenska Academy at University of Gothenburg [Göteborg], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Helmholtz-Gemeinschaft = Helmholtz Association-Helmholtz-Gemeinschaft = Helmholtz Association-Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Helmholtz-Gemeinschaft = Helmholtz Association, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Rega Institute for Medical Research [Leuven, België], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), 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)-CHU Pitié-Salpêtrière [AP-HP], Université de Yaoundé I-Institut de la francophonie pour l'informatique-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Gaston Bergé (Saint-Louis, Sénégal)-Université Cadi Ayyad [Marrakech] (UCA)-Sorbonne Université (SU)-Institut de Recherche pour le Développement (IRD [France-Nord]), Chalmers University of Technology [Göteborg], European Molecular Biology Laboratory [Heidelberg] (EMBL), Université Sorbonne Paris Nord-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, HAL-SU, Gestionnaire, Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Nord-Institut National Agronomique Paris-Grignon (INA P-G)-Sorbonne Université (SU)-CETAF-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut de Recherche pour le Développement (IRD [France-Nord])-Institut de la francophonie pour l'informatique-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Gaston Bergé (Saint-Louis, Sénégal)-Université Cadi Ayyad [Marrakech] (UCA)-Université de Yaoundé I-Sorbonne Université (SU), Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Auteur indépendant, Commission of the European Communities, and Universität Leipzig
Subjects: 0301 basic medicine, Male, ACCURATE METHOD, endocrine system diseases, Metabolite, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Type 2 diabetes, GUT MICROBIOME, GLUCOSE, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, [CHIM] Chemical Sciences, Prediabetes, lcsh:Science, 2. Zero hunger, RISK, Multidisciplinary, biology, INSULIN SENSITIVITY, Imidazoles, HOMEOSTASIS MODEL ASSESSMENT, Middle Aged, 3. Good health, Multidisciplinary Sciences, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Science & Technology - Other Topics, Enterotype, Female, Adult, medicine.medical_specialty, Science, Carbohydrate metabolism, Microbiology, digestive system, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, INTESTINAL MICROBIOTA, Internal medicine, medicine, Humans, [CHIM]Chemical Sciences, Histidine, Author Correction, PHYSIOLOGY, Aged, Science & Technology, Bacteria, General Chemistry, Metabolism, medicine.disease, biology.organism_classification, Gastrointestinal Microbiome, MetaCardis Consortium, METAGENOME, INDIVIDUALS, 030104 developmental biology, chemistry, Diabetes Mellitus, Type 2, Cardiovascular and Metabolic Diseases, lcsh:Q, Bacteroides
Abstract: Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism., Gut microbial metabolism of nutrients contributes to metabolic diseases, and the histidine metabolite imidazole propionate (ImP) is produced by type 2 diabetes (T2D) associated microbiome. Here the authors report that circulating ImP levels are increased in subjects with prediabetes or T2D in three European populations, and this increase associates with altered gut microbiota rather than dietary histidine.
Published: 2020

24. Author Correction: Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology

Author: Ivica Letunic, Pilar Galan, Karen E. Assmann, Gwen Falony, Nicolas Pons, Fredrik Bäckhed, Trine Nielsen, Per-Olof Bergh, Lars Køber, Jens Nielsen, S. Dusko Ehrlich, Eugeni Belda, Henrik Vestergaard, Edi Prifti, Florian Marquet, Marc-Emmanuel Dumas, Jean-Michel Oppert, Michael Stumvoll, Sara Vieira-Silva, Pierre Bel Lassen, Jeroen Raes, Helle Krogh Pedersen, Judith Aron-Wisnewsky, Torben Hansen, Antonio Molinaro, Peer Bork, Oluf Pedersen, Christine Rouault, Benoit Quinquis, Christian Lewinter, Joe-Elie Salem, Rima Chakaroun, Tue H. Hansen, Fabrizio Andreelli, Hao Wu, Nadja B Sønderskov, Solia Adriouch, Sébastien André, Karine Clément, Jean-Daniel Zucker, Marcus Henricsson, Hugo Roume, Sofia K. Forslund, Jean-Philippe Bastard, University of Gothenburg (GU), Sahlgrenska University Hospital [Gothenburg], Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche en Nutrition Humaine d'Ile-de-France (CRNH-IDF), Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Sorbonne Paris Nord, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Universität Leipzig, University of Copenhagen = Københavns Universitet (UCPH), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), 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], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), VIB-KU Leuven Center for Microbiology [Leuven, Belgium], Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), 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), Unité de modélisation mathématique et informatique des systèmes complexes [Bondy] (UMMISCO), Université de Yaoundé I-Institut de la francophonie pour l'informatique-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Gaston Bergé (Saint-Louis, Sénégal)-Université Cadi Ayyad [Marrakech] (UCA)-Sorbonne Université (SU)-Institut de Recherche pour le Développement (IRD [France-Nord]), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Sorbonne Paris Nord-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Imperial College London, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Biobyte Solutions GMBH, Chalmers University of Technology [Gothenburg, Sweden], European Molecular Biology Laboratory [Heidelberg] (EMBL), Universität Heidelberg [Heidelberg] = Heidelberg University, MetaCardis Consortium: Renato Alves, Chloe Amouyal, Ehm Astrid Andersson Galijatovic, Olivier Barthelemy, Jean-Paul Batisse, Magalie Berland, Randa Bittar, Hervé Blottière, Frederic Bosquet, Rachid Boubrit, Olivier Bourron, Mickael Camus, Dominique Cassuto, Julien Chilloux, Cecile Ciangura, Luis Pedro Coelho, Jean-Philippe Collet, Maria-Carlota Dao, Morad Djebbar, Angélique Doré, Line Engelbrechtsen, Soraya Fellahi, Leopold Fezeu, Sebastien Fromentin, Philippe Giral, Jens Peter Gøtze, Agnes Hartemann, Jens Juul Holst, Serge Hercberg, Gerard Helft, Malene Hornbak, Jean-Sebastien Hulot, Richard Isnard, Sophie Jaqueminet, Niklas Rye Jørgensen, Hanna Julienne, Johanne Justesen, Judith Kammer, Nikolaj Krarup, Mathieu Kerneis, Jean Khemis, Nadja Buus Kristensen, Michael Kuhn, Véronique Lejard, Florence Levenez, Lea Lucas-Martini, Robin Massey, Nicolas Maziers, Jonathan Medina-Stamminger, Gilles Montalescot, Sandrine Moutel, Laetitia Pasero Le Pavin, Christine Poitou, Francoise Pousset, Laurence Pouzoulet, Sebastien Schmidt, Lucas Moitinho-Silva, Johanne Silvain, Nataliya Sokolovska, Sothea Touch, Mathilde Svendstrup, Timothy Swartz, Thierry Vanduyvenboden, Camille Vatier, Stefanie Walther., Lesnik, Philippe, Universität Leipzig [Leipzig], Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Universität Heidelberg [Heidelberg]
Subjects: Multidisciplinary, Imidazole propionate, Science, [SDV]Life Sciences [q-bio], General Physics and Astronomy, General Chemistry, Pharmacology, Biology, medicine.disease, General Biochemistry, Genetics and Molecular Biology, [SDV] Life Sciences [q-bio], Microbial ecology, Diabetes mellitus, medicine
Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-20412-9.
Published: 2020

25. SUMOylation of Enzymes and Ion Channels in Sensory Neurons Protects against Metabolic Dysfunction, Neuropathy, and Sensory Loss in Diabetes

Author: Christian Njoo, Stefan G. Lechner, Mirko Moroni, Francisco J. Taberner, Faramarz Faghihi, Daniel Rangel Rojas, Thomas Fleming, Alexandra Andrieux, Nitin Agarwal, Gary R. Lewin, Pooja Gupta, Kiran Kumar Bali, Anne Dejean, Esther Herpel, Rohini Kuner, Peter P. Nawroth, Damir Omberbasic, Heidelberg University, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Organisation Nucléaire et Oncogenèse / Nuclear Organization and Oncogenesis, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Heidelberg University Hospital [Heidelberg], This work was supported by Deutsche Forschungsgemeinschaft grants SFB1118 (project B06) (to N.A. and R.K.), SFB1118 (projects A04, S02, and S01) (to P.P.N., E.H., and T.F.), SFB1158 (project A01) (to S.G.L.), and SFB1158 (project A03) (to P.P.N.). R.K. is a member of the Molecular Medicine Partnership Unit, Heidelberg and a principal investigator in the Excellence Cluster 'CellNetworks' of Heidelberg University., The authors are grateful to D. Baumgartl-Ahlert for technical assistance. We acknowledge support from the Interdisciplinary Neurobehavioral Core (INBC), the Proteomics facility, and the Metabolomics facility at Heidelberg University. We acknowledge support from the tissue bank of the National Centre for Tumour Diseases (NCT, Heidelberg, Germany) in accordance with the regulations of the tissue bank and approval from the ethics committee of Heidelberg University (Ethic Votes 206/2005 and 207/2005)., and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Male, Nociception, Diabetic neuropathy, MESH: Nociception, [SDV]Life Sciences [q-bio], SUMO protein, Mice, 0302 clinical medicine, Diabetic Neuropathies, MESH: Sensory Receptor Cells, Ganglia, Spinal, MESH: Animals, Cells, Cultured, General Neuroscience, MESH: Sumoylation, 3. Good health, MESH: HEK293 Cells, MESH: Glycolysis, Female, MESH: Ganglia, Spinal, Glycolysis, MESH: Cells, Cultured, Sensory Receptor Cells, Citric Acid Cycle, TRPV1, TRPV Cation Channels, Sensory system, Neuropathology, 03 medical and health sciences, MESH: Citric Acid Cycle, MESH: Mice, Inbred C57BL, Diabetes mellitus, medicine, Animals, Humans, MESH: Mice, MESH: Humans, business.industry, MESH: Diabetic Neuropathies, Sumoylation, medicine.disease, MESH: Male, Mice, Inbred C57BL, Metabolic pathway, 030104 developmental biology, Peripheral neuropathy, HEK293 Cells, MESH: TRPV Cation Channels, MESH: Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating), Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating), business, Neuroscience, MESH: Female, 030217 neurology & neurosurgery
Abstract: International audience; Diabetic peripheral neuropathy (DPN) is a highly frequent and debilitating clinical complication of diabetes that lacks therapies. Cellular oxidative stress regulates post-translational modifications, including SUMOylation. Here, using unbiased screens, we identified key enzymes in metabolic pathways and ion channels as novel molecular targets of SUMOylation that critically regulated their activity. Sensory neurons of diabetic patients and diabetic mice demonstrated changes in the SUMOylation status of metabolic enzymes and ion channels. In support of this, profound metabolic dysfunction, accelerated neuropathology, and sensory loss were observed in diabetic gene-targeted mice selectively lacking the ability to SUMOylate proteins in peripheral sensory neurons. TRPV1 function was impaired by diabetes-induced de-SUMOylation as well as by metabolic imbalance elicited by de-SUMOylation of metabolic enzymes, facilitating diabetic sensory loss. Our results unexpectedly uncover an endogenous post-translational mechanism regulating diabetic neuropathy in patients and mouse models that protects against metabolic dysfunction, nerve damage, and altered sensory perception.
Published: 2020

26. SIX1 and SIX4 homeoproteins regulate PAX7+ progenitor cell properties during fetal epaxial myogenesis

Author: Fabien Le Grand, Josiane Demignon, Stephen J. Tapscott, Athanassia Sotiropoulos, Pascal Maire, Elisa Negroni, Rouba Madani, Benjamin Saintpierre, Vincent Mouly, Carmen Birchmeier, Helge Amthor, Nathalie Chaverot, Maud Wurmser, Hiroshi Sakai, Shahragim Tajbakhsh, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Cellules Souches et Développement / Stem Cells and Development, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Ehime University [Matsuyama], Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), M.W was supported by successive fellowships from the University de Paris, the Association Française contre les Myopathies (AFM), and the Agence Nationale pour la Recherche (ANR-16-CE14-0032-01). Financial support was provided by the AFM (n°16427 and 17406), the ANR-16-CE14-0002-01, the Institut National de la Santé et de la Recherche Médicale (INSERM) and the Centre National de la Recherche Scientifique (CNRS). S.T. acknowledges funding support from Institut Pasteur, Agence Nationale de la Recherche (Laboratoire d’Excellence Revive, Investissement d’Avenir, ANR-10-LABX-73)., ANR-16-CE14-0032,MYOLINC,Contrôles génétique et épigénétique des types de fibres musculaires squelettiques(2016), ANR-16-CE14-0002,BMP-MYOSTEM,Régulation des cellules souches du muscle squelettique adulte par la signalisation des ' Bone morphogenetic proteins '(2016), ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Ehime University [Matsuyama, Japon], and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Six1, Six4, Homing, Stem cells, Biology, Muscle Development, Transcriptome, 03 medical and health sciences, Mice, 0302 clinical medicine, Myocyte, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Progenitor cell, Muscle, Skeletal, Molecular Biology, 030304 developmental biology, Homeodomain Proteins, Mice, Knockout, 0303 health sciences, Myogenesis, PAX7 Transcription Factor, Pax7, Cell biology, Transplantation, Trans-Activators, Homeobox, PAX7, Stem cell, Function and Dysfunction of the Nervous System, 030217 neurology & neurosurgery, Developmental Biology
Abstract: International audience; Pax7 expression marks stem cells in developing skeletal muscles and adult satellite cells during homeostasis and muscle regeneration. The genetic determinants that control the entrance into the myogenic program and the appearance of PAX7+ cells during embryogenesis are poorly understood. SIX homeoproteins are encoded by the Sine oculis homeobox related Six1-Six6 genes in vertebrates. Six1, Six2, Six4 and Six5 are expressed in the muscle lineage. Here we tested the hypothesis that Six1 and Six4 could participate in the genesis of myogenic stem cells. We show that fewer PAX7+ cells occupy a satellite cell position between the myofiber and its associated basal lamina in Six1 and Six4 (s1s4KO) at E18. However, PAX7+ cells are detected in remaining muscle masses present in the epaxial region of the double mutant embryos and are able to divide and contribute to muscle growth. To further characterize the properties of s1s4KO PAX7+ cells, we analyzed their transcriptome and tested their properties after transplantation in adult regenerating tibialis anterior (TA) muscle. Mutant stem cells form hypotrophic myofibers that are not innervated but retain the ability to self-renew.
Published: 2020

27. Afadin Signaling at the Spinal Neuroepithelium Regulates Central Canal Formation and Gait Selection

Author: Skarlatou, S., Hérent, C., Toscano, E., Mendes, C.S., Bouvier, J., Zampieri, N., Neuroscience Research Center and Cluster of Excellence NeuroCure, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Faculdade de Ciências Médicas (CEDOC), Centro de Estudos de Doenças Crónicas (CEDOC), and NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
Subjects: Male, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Nectins, gait, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Animals, Afadin, central canal development, 030304 developmental biology, premotor connectivity, Motor Neurons, 0303 health sciences, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Biochemistry, Genetics and Molecular Biology(all), Microfilament Proteins, spinal cord, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, spinal interneurons, nervous system, Mutation, Female, locomotor circuits, Function and Dysfunction of the Nervous System, Spinal Canal, 030217 neurology & neurosurgery, Signal Transduction
Abstract: International audience; Afadin, a scaffold protein controlling the activity of the nectin family of cell adhesion molecules, regulates important morphogenetic processes during development. In the central nervous system, afadin has critical roles in neuronal migration, axonal elongation, and synapse formation. Here we examine the role of afadin in development of spinal motor circuits. Afadin elimination in motor neuron progenitors results in striking locomotor behavior: left-right limb alternation is substituted by synchronous activation, characteristic of bound gait. We find that afadin function at the neuroepithelium is required for structural organization of the spinal midline and central canal morphogenesis. Perturbation of afadin results in formation of two central canals, aberrant contralateral wiring of different classes of spinal premotor interneurons, and loss of left-right limb alternation, highlighting important developmental principles controlling the assembly of spinal motor circuits.
Published: 2020

28. Statin therapy is associated with lower prevalence of gut microbiota dysbiosis

Author: Hugo Roume, Gwen Falony, Jean-Daniel Zucker, Sothea Touch, Lars Køber, Sofia K. Forslund, Fabrizio Andreelli, Stanislav Dusko Ehrlich, Luis Pedro Coelho, Peer Bork, Jens Nielsen, Karen E. Assmann, Marc-Emmanuel Dumas, Thi Thuy Duyen Nguyen, Christine Rouault, Sara Vieira-Silva, Helle Krogh Pedersen, Torben Hansen, Eugeni Belda, Sebastian Proost, Nathalie Galleron, Mireia Valles-Colomer, Christian Lewinter, Trine Nielsen, Jens Peter Gøtze, Michael Stumvoll, Pilar Galan, Jean-Michel Oppert, Judith Aron-Wisnewsky, Jean-Sébastien Hulot, Ivica Letunic, Nadja B Søndertoft, Benoit Quinquis, Joe-Elie Salem, Karine Clément, Tue H. Hansen, Rima Chakaroun, Fredrik Bäckhed, Nicolas Pons, Jens J. Holst, Henrik Vestergaard, Edi Prifti, Jean-Phillippe Bastard, Jeroen Raes, Oluf Pedersen, Valentina Tremaroli, Rega Institute for Medical Research [Leuven, België], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Dept Biol Struct, Flanders Institute for Biotechnology, Integromics [Paris], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), 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], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université (SU)-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], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université (SU), Service de nutrition [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Medical Department III – Endocrinology, Nephrology, Rheumatology, Universität Leipzig [Leipzig], Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Nutrition et obésités: approches systémiques (nutriomics) (UMR-S 1269 INSERM - Sorbonne Université), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Bacteriology, Université Catholique de Louvain (UCL), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Catholique de Louvain = Catholic University of Louvain (UCL), Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universität Leipzig, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], European Molecular Biology Laboratory [Heidelberg] (EMBL), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), VIB-KU Leuven Center for Microbiology [Leuven, Belgium], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Unité de modélisation mathématique et informatique des systèmes complexes [Bondy] (UMMISCO), Université de Yaoundé I-Institut de la francophonie pour l'informatique-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Gaston Bergé (Saint-Louis, Sénégal)-Université Cadi Ayyad [Marrakech] (UCA)-Sorbonne Université (SU)-Institut de Recherche pour le Développement (IRD [France-Nord]), University of Gothenburg (GU), MetaGenoPolis (MGP (US 1367)), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Tenon [AP-HP], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Fudan University [Shanghai], CIC - HEGP (CIC 1418), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Department of Metabolism, Digestion and Reproduction, Imperial College London, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Sorbonne Paris Nord-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biobyte Solution, Department of Biology and Biological Engineering, Chalmers University of Technology, Chalmers University of Technology [Gothenburg, Sweden], European Molecular Biology Laboratory (EMBL), University of Heidelberg, Medical Faculty, University of Würzburg, Wallenberg Laboratory, Göteborgs Universitet (GU), The promotor of the clinical study was the Assistance Publique Hôpitaux de Paris (APHP). S.V.-S. was supported by a post-doctoral fellowship from the Research Foundation Flanders (FWO Vlaanderen). The Raes laboratory is supported by the VIB Grand Challenges programme, KU Leuven, the Rega Institute for Medical Research, and the FWO EOS program (30770923). The Novo Nordisk Foundation Center for Basic Metabolic Research., ANR-11-DPBS-0001,MGP,MetaGenoPolis(2011), ANR-10-IAHU-0005,ICAN,Institut de Cardiologie-Métabolisme-Nutrition(2010), European Project: 305312,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,METACARDIS(2012), Service de Diabétologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de biochimie et hormonologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Service de Nutrition [CHU Pitié-Salpétrière], Institut E3M [CHU Pitié-Salpêtrière], LE CHATELIER, Emmanuelle, Démonstrateurs - MetaGenoPolis - - MGP2011 - ANR-11-DPBS-0001 - DPBS - VALID, Instituts Hospitalo-Universitaires - Institut de Cardiologie-Métabolisme-Nutrition - - ICAN2010 - ANR-10-IAHU-0005 - IAHU - VALID, Metagenomics in Cardiometabolic Diseases - METACARDIS - - EC:FP7:HEALTH2012-11-01 - 2017-10-31 - 305312 - VALID, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), VIB-KU Leuven Center for Microbiology [Belgium], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Recherche pour le Développement (IRD [France-Nord])-Institut de la francophonie pour l'informatique-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Gaston Bergé (Saint-Louis, Sénégal)-Université Cadi Ayyad [Marrakech] (UCA)-Université de Yaoundé I-Sorbonne Université (SU), Service de diabétologie [CHU Pitié-Salpétrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-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), CIC Paris Est, Royal Brompton and Harefield NHS Foundation Trust-Imperial College London, Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), and 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)
Subjects: 0301 basic medicine, Male, Feces/microbiology, [SDV]Life Sciences [q-bio], Overweight, Gut flora, Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage, Cohort Studies, Feces, 0302 clinical medicine, Prevalence, Medicine, Bacteroides, Gastrointestinal Microbiome/drug effects, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, education.field_of_study, Multidisciplinary, biology, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Cohort, Enterotype, Female, medicine.symptom, Inflammatory Bowel Diseases/microbiology, Obesity/microbiology, medicine.medical_specialty, Bacteroides/isolation & purification, Population, 03 medical and health sciences, Internal medicine, Humans, Microbiome, Obesity, education, Faecalibacterium, business.industry, medicine.disease, biology.organism_classification, Inflammatory Bowel Diseases, Gastrointestinal Microbiome, MetaCardis Consortium, Dysbiosis/epidemiology, 030104 developmental biology, Cross-Sectional Studies, Dysbiosis, Faecalibacterium/isolation & purification, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business, Body mass index
Abstract: Microbiome community typing analyses have recently identified the Bacteroides2 (Bact2) enterotype, an intestinal microbiota configuration that is associated with systemic inflammation and has a high prevalence in loose stools in humans1,2. Bact2 is characterized by a high proportion of Bacteroides, a low proportion of Faecalibacterium and low microbial cell densities1,2, and its prevalence varies from 13% in a general population cohort to as high as 78% in patients with inflammatory bowel disease2. Reported changes in stool consistency3 and inflammation status4 during the progression towards obesity and metabolic comorbidities led us to propose that these developments might similarly correlate with an increased prevalence of the potentially dysbiotic Bact2 enterotype. Here, by exploring obesity-associated microbiota alterations in the quantitative faecal metagenomes of the cross-sectional MetaCardis Body Mass Index Spectrum cohort (n = 888), we identify statin therapy as a key covariate of microbiome diversification. By focusing on a subcohort of participants that are not medicated with statins, we find that the prevalence of Bact2 correlates with body mass index, increasing from 3.90% in lean or overweight participants to 17.73% in obese participants. Systemic inflammation levels in Bact2-enterotyped individuals are higher than predicted on the basis of their obesity status, indicative of Bact2 as a dysbiotic microbiome constellation. We also observe that obesity-associated microbiota dysbiosis is negatively associated with statin treatment, resulting in a lower Bact2 prevalence of 5.88% in statin-medicated obese participants. This finding is validated in both the accompanying MetaCardis cardiovascular disease dataset (n = 282) and the independent Flemish Gut Flora Project population cohort (n = 2,345). The potential benefits of statins in this context will require further evaluation in a prospective clinical trial to ascertain whether the effect is reproducible in a randomized population and before considering their application as microbiota-modulating therapeutics. A cross-sectional analysis of participants in the MetaCardis Body Mass Index Spectrum cohort finds that the higher prevalence of gut microbiota dysbiosis in individuals with obesity is not observed in those who take statin drugs.
Published: 2020

29. Lymphoma Angiogenesis Is Orchestrated by Noncanonical Signaling Pathways

Author: Kerstin Gerlach, Thomas Kammertöns, Thomas Hehlgans, Anne-Clémence Vion, Myroslav Zapukhlyak, Uta E. Höpken, Armin Rehm, Holger Gerhardt, Georg Lenz, Marleen Gloger, Ioannis Anagnostopoulos, Maria Zschummel, Lutz Menzel, Michael Grau, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), and Helmholtz-Gemeinschaft = Helmholtz Association
Subjects: 0301 basic medicine, Cancer Research, Indoles, Lymphoma, Angiogenic Switch, Angiogenesis, Biopsy, Vascular Endothelial Growth Factor C, Notch signaling pathway, Mice, Transgenic, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Naphthalenes, Biology, Neovascularization, Mice, 03 medical and health sciences, 0302 clinical medicine, Lymphotoxin beta Receptor, Cell Line, Tumor, Human Umbilical Vein Endothelial Cells, Tumor Microenvironment, medicine, Animals, Humans, Naphthyridines, Lymphotoxin-alpha, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, Neovascularization, Pathologic, Gene Expression Profiling, Vascular Endothelial Growth Factor Receptor-3, medicine.disease, Xenograft Model Antitumor Assays, Endothelial stem cell, Disease Models, Animal, 030104 developmental biology, Oncology, Vascular endothelial growth factor C, 030220 oncology & carcinogenesis, Cancer research, Lymph Nodes, medicine.symptom, Signal transduction, Signal Transduction
Abstract: Tumor-induced remodeling of the microenvironment relies on the formation of blood vessels, which go beyond the regulation of metabolism, shaping a maladapted survival niche for tumor cells. In high-grade B-cell lymphoma, angiogenesis correlates with poor prognosis, but attempts to target established proangiogenic pathways within the vascular niche have been inefficient. Here, we analyzed Myc-driven B-cell lymphoma–induced angiogenesis in mice. A few lymphoma cells were sufficient to activate the angiogenic switch in lymph nodes. A unique morphology of dense microvessels emerged without obvious tip cell guidance and reliance on blood endothelial cell (BEC) proliferation. The transcriptional response of BECs was inflammation independent. Conventional HIF1α or Notch signaling routes prevalent in solid tumors were not activated. Instead, a nonconventional hypersprouting morphology was orchestrated by lymphoma-provided VEGFC and lymphotoxin (LT). Interference with VEGF receptor-3 and LTβ receptor signaling pathways abrogated lymphoma angiogenesis, thus revealing targets to block lymphomagenesis. Significance: In lymphoma, transcriptomes and morphogenic patterns of the vasculature are distinct from processes in inflammation and solid tumors. Instead, LTβR and VEGFR3 signaling gain leading roles and are targets for lymphomagenesis blockade.
Published: 2020

30. Rapport d'activité Guix-HPC 2018–2019

Author: Courtès, Ludovic, Garlick, Paul, Hinsen, Konrad, Prins, Pjotr, Wurmus, Ricardo, Service Expérimentation et Développement [Bordeaux] (SED), Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Tourbillion Technology, Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), Health Science Center, The University of Tennessee [Knoxville], Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Inria Bordeaux Sud-Ouest, Synchrotron SOLEIL, and Max Delbrück Center for Molecular Medicine
Subjects: [INFO.INFO-OS]Computer Science [cs]/Operating Systems [cs.OS], [INFO.INFO-SE]Computer Science [cs]/Software Engineering [cs.SE], [INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC]
Abstract: Guix-HPC is a collaborative effort to bring reproducible software deployment to scientific workflows and high-performance computing (HPC). Guix-HPC builds upon the GNU Guix software deployment tool and aims to make it a better tool for HPC practitioners and scientists concerned with reproducible research.This report highlights key achievements of Guix-HPC between our previous report a year ago and today, February 2020. This year was marked by a major milestone: the release in May 2019 of GNU Guix 1.0, seven years and more than 40,000 commits after its inception.
Published: 2020

31. Guix-HPC Activity Report 2018–2019

Author: Courtès, Ludovic, Garlick, Paul, Hinsen, Konrad, Prins, Pjotr, Wurmus, Ricardo, Service Expérimentation et Développement [Bordeaux] (SED), Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Tourbillion Technology, Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), Health Science Center, The University of Tennessee [Knoxville], Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Inria Bordeaux Sud-Ouest, Synchrotron SOLEIL, and Max Delbrück Center for Molecular Medicine
Subjects: [INFO.INFO-OS]Computer Science [cs]/Operating Systems [cs.OS], [INFO.INFO-SE]Computer Science [cs]/Software Engineering [cs.SE], [INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC]
Abstract: Guix-HPC is a collaborative effort to bring reproducible software deployment to scientific workflows and high-performance computing (HPC). Guix-HPC builds upon the GNU Guix software deployment tool and aims to make it a better tool for HPC practitioners and scientists concerned with reproducible research.This report highlights key achievements of Guix-HPC between our previous report a year ago and today, February 2020. This year was marked by a major milestone: the release in May 2019 of GNU Guix 1.0, seven years and more than 40,000 commits after its inception.
Published: 2020

32. Rapport d’activité Guix-HPC 2019–2020

Author: Braun, Lars-Dominik, Courtès, Ludovic, Prins, Pjotr, Tournier, Simon, Wurmus, Ricardo, Leibniz Institute for Psychology (ZPID), Service Expérimentation et Développement [Bordeaux] (SED), Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), The University of Tennessee Health Science Center [Memphis] (UTHSC), Université de Paris (UP), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Inria Bordeaux Sud-Ouest, ZPID, Université Paris Cité (UPCité), and Leibniz
Subjects: HPC, Software deployment, [INFO.INFO-OS]Computer Science [cs]/Operating Systems [cs.OS], [INFO.INFO-SE]Computer Science [cs]/Software Engineering [cs.SE], [INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], Reproducibility
Abstract: Guix-HPC is a collaborative effort to bring reproducible software deployment to scientific workflows and high-performance computing (HPC). Guix-HPC builds upon the GNU Guix software deployment tool and aims to make it a better tool for HPC practitioners and scientists concerned with reproducible research. This report highlights key achievements of Guix-HPC between our previous report a year ago and today, February 2021.This report highlights developments on GNU Guix proper, but also downstream on Guix-Jupyter, the Guix Workflow Language, as well as tools for end-to-end reproducible research article authoring pipelines.
Published: 2020

33. Guix-HPC Activity Report 2019–2020

Author: Braun, Lars-Dominik, Courtès, Ludovic, Prins, Pjotr, Tournier, Simon, Wurmus, Ricardo, Leibniz Institute for Psychology (ZPID), Service Expérimentation et Développement [Bordeaux] (SED), Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), The University of Tennessee Health Science Center [Memphis] (UTHSC), Université de Paris (UP), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Inria Bordeaux Sud-Ouest, and ZPID
Subjects: HPC, Software deployment, [INFO.INFO-OS]Computer Science [cs]/Operating Systems [cs.OS], [INFO.INFO-SE]Computer Science [cs]/Software Engineering [cs.SE], [INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], Reproducibility
Abstract: Guix-HPC is a collaborative effort to bring reproducible software deployment to scientific workflows and high-performance computing (HPC). Guix-HPC builds upon the GNU Guix software deployment tool and aims to make it a better tool for HPC practitioners and scientists concerned with reproducible research. This report highlights key achievements of Guix-HPC between our previous report a year ago and today, February 2021.This report highlights developments on GNU Guix proper, but also downstream on Guix-Jupyter, the Guix Workflow Language, as well as tools for end-to-end reproducible research article authoring pipelines.
Published: 2020

34. Machine learning-based classification to improve Gas Chromatography-Mass spectrometry data processing

Author: Gloaguen, Yoann, Borgsmüller, Nico, Opialla, Tobias, Blanc, Eric, Sicard, Emilie, Royer, Anne Lise, Le Bizec, Bruno, Durand, Stéphanie, Migné, Carole, Pétéra, Mélanie, Pujos-Guillot, Estelle, Giacomoni, Franck, Guitton, Yann, Beule, Dieter, Kirwan, Jennifer, Core Unit Bioinformatics, Berlin Institute of Health (BIH), Berlin Institute of Health Metabolomics Platform, DEU, Max Delbrück Center for Molecular Medicine, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), MetaboHUB, Laboratoire d'étude des Résidus et Contaminants dans les Aliments (LABERCA), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Unité de Nutrition Humaine (UNH), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], [CHIM.OTHE]Chemical Sciences/Other
Abstract: Methodological & Technological developments Methodological & Technological developmentsMethodological & Technological developments; IntroductionLack of reliable peak detection impedes automated analysis of large-scale gas chromatography-mass spectrometry (GCMS) metabolomics datasets. Performance and outcome of individual peak-picking algorithms can differ widely depending on both algorithmic approach and parameters, as well as data acquisition method. Therefore, comparing and contrasting between algorithms is difficult.Technological and methodological innovationWe present part of the work published in [1] and implemented in our workflow for improved peak picking (WiPP),focusing on the use of machine learning-based classification to optimize and improve different steps of the common GC-MS metabolomics data processing workflow. Our approach evaluates the quality of detected peaks using a machine learning based classification scheme based on seven peak classes. The quality information returned by the classifier for each individual peak is merged with results from different peak detection algorithms to create one final high-quality peak set for immediate down-stream analysis.Results and impactWe benchmarked our workflow to standard compound mixes and a complex biological dataset, demonstrating that peak detection is improved. Furthermore, the approach can provide an impartial performance comparison of different peak picking algorithms. We also discuss the applicability of the approach to liquid chromatography-mass spectrometry data.References[1] Gloaguen, Y.; Borgsmüller, N. et al. WiPP: Workflow for Improved Peak Picking for Gas Chromatography-MassSpectrometry (GC-MS) Data. Metabolites 2019, 9, 171.
Published: 2020

35. Correction to: Biological determinants of physical activity across the life course: a 'Determinants of Diet and Physical Activity' (DEDIPAC) umbrella systematic literature review

Author: Giancarlo Condello, Laura Capranica, Greet Cardon, Alessandra Sannella, Camille Perchoux, Angela Polito, Marieke De Craemer, Tobias Pischon, Holger Schulz, Con Burns, Wolfgang Schlicht, Katina Aleksovska, Marco Colotto, Anna Puggina, Sylvia Hansen, Aileen Kennedy, Tara Coppinger, Angela Carlin, Astrid Steinbrecher, Lina Jaeschke, Ciaran MacDonncha, Donatella Ciarapica, Martina Kanning, Stefania Boccia, Giorgio Napolitano, Andrea Di Blasio, Luca Giraldi, Simon Chantal, Julie Anne Nazare, Rhoda Sohun, Sara D’Haese, Fiona Chun Man Ling, Johann Issartel, Walter Ricciardi, Licia Iacoviello, Agnes Luzak, Cristina Cortis, Christoph Buck, Pascal Izzicupo, CarMeN, laboratoire, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Leibniz Institute for Prevention Research and Epidemiology - BIPS, Leibniz Association, Cork Institute of Technology (CIT), Universiteit Gent = Ghent University (UGENT), University of Limerick (UL), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), 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)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Universitat de València (UV), National Institute for Research on Food and Nutrition [Rome, Italy] (INRAN), University of Rome 'Foro Italico', Università degli studi di Cassino e del Lazio Meridionale (UNICAS), University 'G. d'Annunzio' of Chieti-Pescara [Chieti and Pescara, Italy], University of Stuttgart, Istituto Neurologico Mediterraneo (NEUROMED I.R.C.C.S.), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA)-University of Naples Federico II = Università degli studi di Napoli Federico II, Dublin City University [Dublin] (DCU), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Victoria University [Melbourne], Helmholtz Zentrum München = German Research Center for Environmental Health, Italian National Institute of Health (ISS), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università cattolica del Sacro Cuore [Roma] (Unicatt), Universiteit Gent = Ghent University [Belgium] (UGENT), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), 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), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]-Università degli studi di Napoli Federico II, Helmholtz-Zentrum München (HZM), and Fondazione 'Policlinico Universitario A. Gemelli' [Rome]
Subjects: Gerontology, medicine.medical_specialty, Sports medicine, [SDV]Life Sciences [q-bio], Physical activity, Correction, Physical Therapy, Sports Therapy and Rehabilitation, 030229 sport sciences, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, Systematic review, medicine, Life course approach, Orthopedics and Sports Medicine, 030212 general & internal medicine, Psychology, ComputingMilieux_MISCELLANEOUS
Abstract: Despite the large number of studies and reviews available, the evidence regarding the biological determinants of physical activity (PA) is inconclusive. In this umbrella review, we summarized the current evidence on the biological determinants of PA across the life course, by pooling the results of the available systematic literature reviews (SLRs) and meta-analyses (MAs).We conducted an online search on MEDLINE, ISI Web of Science, Scopus, and SPORTDiscus databases up to January 2018. SLRs and MAs of observational studies that investigated the association between biological determinants of PA and having PA as outcome were considered eligible. The extracted data were assessed based on the importance of the determinants, the strength of evidence, and the methodological quality.We identified 19 reviews of which most were of moderate methodological quality. Determinants that were studied most frequently among all ages and demonstrated evidence suggesting a positive association to PA were younger age, being male, higher health status, and higher physical fitness levels. Among adults, normal birth weight was found to be positively associated to PA with convincing strength of evidence, while findings among adolescents were inconsistent and with limited strength of evidence.Different social or behavioral factors may contribute to the decrease of PA with age and among females versus males, and creating programmes targeted at diverse ages, female population, and adults with abnormal birth weight is recommended. Future studies should use prospective study designs, standardized definitions of PA, and objective measurement methods of PA assessment.
Published: 2020

36. NF-κB signaling in tanycytes mediates inflammation-induced anorexia

Author: Vanessa Neve, Anders Blomqvist, Markus Schwaninger, David Engblom, Jan Wenzel, Ruth Schmidt-Ullrich, Ronny Haenold, Sarah Gallet, Sivaraj Mohana Sundaram, Mareike Böttcher, Adriano Zager, Vincent Prevot, Kiseko Shionoya, Helge Müller-Fielitz, Xiaoyu Liu, Ning Quan, Prevot, Vincent, Lübeck University of Applied Sciences, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Linköping University (LIU), Florida Atlantic University [Boca Raton], Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Leibniz Association, Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), and ANR-16-CE37-0006,HypNeurogen,Physiopathologie de la niche neurogénique hypothalamique(2016)
Subjects: 0301 basic medicine, Cancer Research, Tanycytes, Gene Expression, Systemic inflammation, Mice, 0302 clinical medicine, NEMO, Prostaglandin E2, In Situ Hybridization, Sickness behavior, Intracellular Signaling Peptides and Proteins, NF-kappa B, Biochemistry and Molecular Biology, Immunohistochemistry, Anorexia, 3. Good health, Hypothalamus, IL-1β, Gene Knockdown Techniques, Inflammation-induced anorexia, Cytokines, Original Article, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Inflammation Mediators, medicine.symptom, Signal Transduction, medicine.drug, lcsh:Internal medicine, medicine.medical_specialty, In flammation-induced anorexia, IL-1 beta, Ependymoglial Cells, 030209 endocrinology & metabolism, Inflammation, 03 medical and health sciences, Internal medicine, medicine, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], lcsh:RC31-1245, Molecular Biology, Transcription factor, business.industry, Cancer, Cell Biology, medicine.disease, Rats, Disease Models, Animal, 030104 developmental biology, Endocrinology, business, Biomarkers, Biokemi och molekylärbiologi
Abstract: Objectives Infections, cancer, and systemic inflammation elicit anorexia. Despite the medical significance of this phenomenon, the question of how peripheral inflammatory mediators affect the central regulation of food intake is incompletely understood. Therefore, we have investigated the sickness behavior induced by the prototypical inflammatory mediator IL-1β. Methods IL-1β was injected intravenously. To interfere with IL-1β signaling, we deleted the essential modulator of NF-κB signaling (Nemo) in astrocytes and tanycytes. Results Systemic IL-1β increased the activity of the transcription factor NF-κB in tanycytes of the mediobasal hypothalamus (MBH). By activating NF-κB signaling, IL-1β induced the expression of cyclooxygenase-2 (Cox-2) and stimulated the release of the anorexigenic prostaglandin E2 (PGE2) from tanycytes. When we deleted Nemo in astrocytes and tanycytes, the IL-1β-induced anorexia was alleviated whereas the fever response and lethargy response were unchanged. Similar results were obtained after the selective deletion of Nemo exclusively in tanycytes. Conclusions Tanycytes form the brain barrier that mediates the anorexic effect of systemic inflammation in the hypothalamus., Graphical abstract Image 1, Highlights • Systemic IL-1β activates NF-κB in tanycytes. • IL-1β induces the expression of Ptgs2 (Cox-2) and the release of PGE2 from tanycytes. • NEMO-dependent NF-κB signaling in tanycytes is required for anorexia induced by IL-1β. • Tanycytes are not involved in fever and lethargy induced by IL-1β.
Published: 2020

37. Editorial: Monocyte Heterogeneity and Function

Author: Florent Ginhoux, Alexander Mildner, Emmanuel L. Gautier, Andreas Schlitzer, Claudia Jakubzick, Chen Varol, Calum Bain, Pierre Guermonprez, Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Agency for science, technology and research [Singapore] (A*STAR), Shanghai Jiao Tong University School of Medicine, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), 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], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Bonn, Geisel School of Medicine at Dartmouth, Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], University of Edinburgh, King‘s College London, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), 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)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Tel Aviv University (TAU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Gestionnaire, Hal Sorbonne Université, Gautier, Emmanuel, Duke-NUS Medical School [Singapore], German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), AP-HP - Hôpital Bichat - Claude Bernard [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: lcsh:Immunologic diseases. Allergy, MESH: Inflammation, Cancer Research, [SDV]Life Sciences [q-bio], Immunology, Inflammation, 010402 general chemistry, Chronic inflammatory disease, MESH: Monocytes, 01 natural sciences, 03 medical and health sciences, immunology [Monocytes], Inflammation resolution, immunology [Inflammation], Fibrosis, cardiovascular disease, medicine, Immunology and Allergy, Humans, cancer, ddc:610, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, MESH: Humans, business.industry, Monocyte, fibrosis, Cancer, MESH: Macrophages, chronic inflammatory disease, immunology [Macrophages], medicine.disease, 0104 chemical sciences, macrophages, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, inflammation, inflammation resolution, medicine.symptom, lcsh:RC581-607, business, monocytes, Function (biology)
Abstract: International audience; No abstract available
Published: 2020

38. C/EBPβ-Dependent Epigenetic Memory Induces Trained Immunity in Hematopoietic Stem Cells

Author: Orit Matcovitch-Natan, Bérengère de Laval, Sandrine Sarrazin, Caroline Huber, Julien Maurizio, Eyal David, Susanne Reinhardt, Gregory Gimenez, Bertrand Nadel, Christophe Bordi, Prashanth K. Kandalla, Achim Leutz, Gabriel Brisou, Louise Simonnet, Alexander Mildner, Ido Amit, Michael H. Sieweke, Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Inovarion, Institute of Anatomy and Center for Regenerative Therapies, TU Dresden (CRTD), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Weizmann Institute of Science [Rehovot, Israël], Biotechnology Center, and Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden = Dresden University of Technology (TU Dresden), Institut de Microbiologie de la Méditerranée (IMM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-17-CE15-0007,HSCmemory,Exploration de l'existence d'une fonction et d'une mémoire immunitaire au niveau de la Cellules Souche Hématopoïétique.(2017), and ANR-18-CE12-0019,Epromoters,Contrôle de la réponse au stress par une nouvelle classe de promoteurs à activité enhancer(2018)
Subjects: Epigenomics, Myeloid, [SDV]Life Sciences [q-bio], Secondary infection, Biology, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, Immune system, Immunity, Genetics, medicine, Humans, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Myelopoiesis, 0303 health sciences, Innate immune system, CCAAT-Enhancer-Binding Protein-beta, Cell Biology, biochemical phenomena, metabolism, and nutrition, Hematopoietic Stem Cells, Immunity, Innate, 3. Good health, Cell biology, Haematopoiesis, medicine.anatomical_structure, 030220 oncology & carcinogenesis, bacteria, Molecular Medicine, Stem cell, 030217 neurology & neurosurgery
Abstract: Summary Hematopoietic stem cells (HSCs) maintain life-long production of immune cells and can directly respond to infection, but sustained effects on the immune response remain unclear. We show that acute immune stimulation with lipopolysaccharide (LPS) induced only transient changes in HSC abundance, composition, progeny, and gene expression, but persistent alterations in accessibility of specific myeloid lineage enhancers occurred, which increased responsiveness of associated immune genes to secondary stimulation. Functionally, this was associated with increased myelopoiesis of pre-exposed HSCs and improved innate immunity against the gram-negative bacterium P. aeruginosa. The accessible myeloid enhancers were enriched for C/EBPβ targets, and C/EBPβ deletion erased the long-term inscription of LPS-induced epigenetic marks and gene expression. Thus, short-term immune signaling can induce C/EBPβ-dependent chromatin accessibility, resulting in HSC-trained immunity, during secondary infection. This establishes a mechanism for how infection history can be epigenetically inscribed in HSCs as an integral memory function of innate immunity.
Published: 2020
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39. Visualizing the functional 3D shape and topography of long noncoding RNAs by single-particle atomic force microscopy and in-solution hydrodynamic techniques

Author: Manikandan Karuppasamy, Paolo Annibale, Isabel Chillón, Tina Uroda, Jean-Marie Teulon, Marco Marcia, Jean-Luc Pellequer, Ombeline Pessey, European Molecular Biology Laboratory [Grenoble] (EMBL), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), ISBG: UMS 3518 CNRS-CEA-UJF-EMBL, BM29-BioSAXS beamline, AFM platform at the IBS, ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), ANR-15-CE11-0003,lincRNPs,Principes moleculaires de reconnaissance entre la proteine Polycomb SCML2A et longs ARN non-codants(2015), European Project: PJA-20191209284, European Project: ECTZ18552, and European Project: 18CN047-00
Subjects: MESH: Microscopy, Atomic Force, 0303 health sciences, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Atomic force microscopy, Chemistry, Resolution (electron density), DNA replication, RNA, Computational biology, Microscopy, Atomic Force, MESH: Image Processing, Computer-Assisted, General Biochemistry, Genetics and Molecular Biology, Characterization (materials science), MESH: Hydrodynamics, 03 medical and health sciences, 0302 clinical medicine, MESH: RNA, Long Noncoding, Microscopy, Hydrodynamics, Image Processing, Computer-Assisted, RNA, Long Noncoding, 030217 neurology & neurosurgery, Topology (chemistry), Function (biology), 030304 developmental biology
Abstract: International audience; Long noncoding RNAs (lncRNAs) are recently discovered transcripts that regulate vital cellular processes, such as cellular differentiation and DNA replication, and are crucially connected to diseases. Although the 3D structures of lncRNAs are key determinants of their function, the unprecedented molecular complexity of lncRNAs has so far precluded their 3D structural characterization at high resolution. It is thus paramount to develop novel approaches for biochemical and biophysical characterization of these challenging targets. Here, we present a protocol that integrates non-denaturing lncRNA purification with in-solution hydrodynamic analysis and single-particle atomic force microscopy (AFM) imaging to produce highly homogeneous lncRNA preparations and visualize their 3D topology at ~15-Å resolution. Our protocol is suitable for imaging lncRNAs in biologically active conformations and for measuring structural defects of functionally inactive mutants that have been identified by cell-based functional assays. Once optimized for the specific target lncRNA of choice, our protocol leads from cloning to AFM imaging within 3-4 weeks and can be implemented using state-of-the-art biochemical and biophysical instrumentation by trained researchers familiar with RNA handling and supported by AFM and small-angle X-ray scattering (SAXS) experts.
Published: 2019

40. Endothelial PKA activity regulates angiogenesis by limiting autophagy through phosphorylation of ATG16L1

Author: Oliver Popp, Fabio Stanchi, Holger Gerhardt, Pavel I. Nedvetsky, Gunnar Dittmar, Kerstin Zühlke, Xiaocheng Zhao, Anne-Clémence Vion, Enno Klussmann, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), and Helmholtz-Gemeinschaft = Helmholtz Association
Subjects: 0301 basic medicine, Life Sciences & Biomedicine - Other Topics, Mouse, Angiogenesis, PROTEIN-KINASES, Regulator, Autophagy-Related Proteins, MOUSE, Umbilical vein, DISEASE, Mice, angiogenesis, 0302 clinical medicine, Biology (General), Phosphorylation, ATG16L1, SPECIFICITY, Chemistry, General Neuroscience, General Medicine, VEGF, 3. Good health, Cell biology, chemical genetics, 030220 oncology & carcinogenesis, Medicine, Technology Platforms, Life Sciences & Biomedicine, Research Article, Human, autophagy, QH301-705.5, Science, Neovascularization, Physiologic, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, Biochemistry and Chemical Biology, Animals, Humans, Protein kinase A, Biology, Science & Technology, COMPLEX, General Immunology and Microbiology, HYPERTENSION, Autophagy, Endothelial Cells, Correction, Cell Biology, DEGRADATION, Cyclic AMP-Dependent Protein Kinases, 030104 developmental biology, IL-1-BETA, Cardiovascular and Metabolic Diseases, CELL BEHAVIOR, protein kinase A, Protein Processing, Post-Translational, Genetic screen
Abstract: The cAMP-dependent protein kinase A (PKA) regulates various cellular functions in health and disease. In endothelial cells PKA activity promotes vessel maturation and limits tip cell formation. Here, we used a chemical genetic screen to identify endothelial-specific direct substrates of PKA in human umbilical vein endothelial cells (HUVEC) that may mediate these effects. Amongst several candidates, we identified ATG16L1, a regulator of autophagy, as novel target of PKA. Biochemical validation, mass spectrometry and peptide spot arrays revealed that PKA phosphorylates ATG16L1α at Ser268 and ATG16L1β at Ser269, driving phosphorylation-dependent degradation of ATG16L1 protein. Reducing PKA activity increased ATG16L1 protein levels and endothelial autophagy. Mouse in vivo genetics and pharmacological experiments demonstrated that autophagy inhibition partially rescues vascular hypersprouting caused by PKA deficiency. Together these results indicate that endothelial PKA activity mediates a critical switch from active sprouting to quiescence in part through phosphorylation of ATG16L1, which in turn reduces endothelial autophagy. ispartof: ELIFE vol:8 ispartof: location:England status: published
Published: 2019

41. Inducer exclusion in Firmicutes: insights into the regulation of a carbohydrate ATP binding cassette transporter fromLactobacillus caseiBL23 by the signal transducing protein P‐Ser46‐HPr

Author: Erwin Schneider, Constanze Homburg, Carolin Hobe, Anke Licht, Josef Deutscher, Sebastian Beck, Holger Dobbek, Martin Bommer, Steven Wuttge, Humboldt-Universität zu Berlin, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Expression Génétique Microbienne (EGM (UMR_8261 / FRE_3630)), Institut de biologie physico-chimique (IBPC (FR_550)), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Helmholtz Zentrum Berlin fur Materialien und Energie (HZB), Freie Universitat Berlin, Humboldt-Universitat zu Berlin, Max-Delbruck-Centrum and the Leibniz-Institut fur Molekulare Pharmakologie, Deutsche Forschungsgemeinschaft [SCHN 274/15-1, SCHN 274/15-2], and SFB [1078]
Subjects: 0301 basic medicine, Lactobacillus casei, [SDV]Life Sciences [q-bio], Protein subunit, 030106 microbiology, Catabolite repression, Firmicutes, ATP-binding cassette transporter, macromolecular substances, Biology, Microbiology, Carbon utilization, 03 medical and health sciences, chemistry.chemical_compound, Bacterial Proteins, Serine, Phosphorylation, Maltose, Phosphoenolpyruvate Sugar Phosphotransferase System, Molecular Biology, Binding protein, Phosphotransferases, PEP group translocation, biology.organism_classification, DNA-Binding Proteins, Repressor Proteins, Lacticaseibacillus casei, Biochemistry, chemistry, Mutagenesis, Mutation, bacteria, ATP-Binding Cassette Transporters, Signal Transduction
Abstract: International audience; Catabolite repression is a mechanism that enables bacteria to control carbon utilization. As part of this global regulatory network, components of the phosphoenolpyruvate:carbohydrate phosphotransferase system inhibit the uptake of less favorable sugars when a preferred carbon source such as glucose is available. This process is termed inducer exclusion. In bacteria belonging to the phylum Firmicutes, HPr, phosphorylated at serine 46 (P-Ser46-HPr) is the key player but its mode of action is elusive. To address this question at the level of purified protein components, we have chosen a homolog of the Escherichia coli maltose/maltodextrin ATP-binding cassette transporter from Lactobacillus casei (MalE1-MalF1G1K1(2)) as a model system. We show that the solute binding protein, MalE1, binds linear and cyclic maltodextrins but not maltose. Crystal structures of MalE1 complexed with these sugars provide a clue why maltose is not a substrate. P-Ser46-HPr inhibited MalE1/maltotetraose-stimulated ATPase activity of the transporter incorporated in proteoliposomes. Furthermore, cross-linking experiments revealed that P-Ser46-HPr contacts the nucleotide-binding subunit, MalK1, in proximity to the Walker A motif. However, P-Ser46-HPr did not block binding of ATP to MalK1. Together, our findings provide first biochemical evidence that P-Ser-HPr arrests the transport cycle by preventing ATP hydrolysis at the MalK1 subunits of the transporter.
Published: 2017

42. Engineering of PEDF-Expressing Primary Pigment Epithelial Cells by the SB Transposon System Delivered by pFAR4 Plasmids

Author: Nina Harmening, Zsuzsanna Izsvák, Marie Pastor, Peter Walter, Gabriele Thumann, Csaba Miskey, Martina Kropp, Zoltán Ivics, Laurence D. Hurst, Daniel Scherman, Cécile Prat-Souteyrand, Attila Sebe, Sandra Johnen, Corinne Marie, Sabine Diarra, University of Geneva [Switzerland], Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Paul-Ehrlich-Institute - Federal Institute for Vaccines and Biomedicines (EPI), University of Bath [Bath], Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), RWTH Aachen University, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Université de Genève = University of Geneva (UNIGE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), and ORANGE, Colette
Subjects: 0301 basic medicine, primary pigment epithelial cells, pigment epithelium-derived factor, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, sleeping beauty transposon system, Transgene, Genetic enhancement, VECTOR, neovascular age-related macular degeneration, Biology, GENE-TRANSFER, TRANSGENE EXPRESSION, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, PEDF, Drug Discovery, medicine, SITE SELECTION, ddc:610, SLEEPING-BEAUTY TRANSPOSITION, Genetics, PIGGYBAC TRANSPOSON, TRANSPLANTATION, PURIFYING SELECTION, lcsh:RM1-950, DNA SIZE, pFAR4 miniplasmids, Transfection, Macular degeneration, medicine.disease, Sleeping Beauty transposon system, MACULAR DEGENERATION, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, 3. Good health, ddc:616.8, Vascular endothelial growth factor, Transplantation, non-viral ex vivo gene therapy, 030104 developmental biology, lcsh:Therapeutics. Pharmacology, chemistry, Cardiovascular and Metabolic Diseases, 030220 oncology & carcinogenesis, Cancer research, Molecular Medicine, Original Article, sense organs
Abstract: Neovascular age-related macular degeneration (nvAMD) is characterized by choroidal blood vessels growing into the subretinal space, leading to retinal pigment epithelial (RPE) cell degeneration and vision loss. Vessel growth results from an imbalance of pro-angiogenic (e.g., vascular endothelial growth factor [VEGF]) and anti-angiogenic factors (e.g., pigment epithelium-derived factor [PEDF]). Current treatment using intravitreal injections of anti-VEGF antibodies improves vision in about 30% of patients but may be accompanied by side effects and non-compliance. To avoid the difficulties posed by frequent intravitreal injections, we have proposed the transplantation of pigment epithelial cells modified to overexpress human PEDF. Stable transgene integration and expression is ensured by the hyperactive Sleeping Beauty transposon system delivered by pFAR4 miniplasmids, which have a backbone free of antibiotic resistance markers. We demonstrated efficient expression of the PEDF gene and an optimized PEDF cDNA sequence in as few as 5 × 103 primary cells. At 3 weeks post-transfection, PEDF secretion was significantly elevated and long-term follow-up indicated a more stable secretion by cells transfected with the optimized PEDF transgene. Analysis of transgene insertion sites in human RPE cells showed an almost random genomic distribution. The results represent an important contribution toward a clinical trial aiming at a non-viral gene therapy of nvAMD. Keywords: neovascular age-related macular degeneration, non-viral ex vivo gene therapy, sleeping beauty transposon system, pFAR4 miniplasmids, primary pigment epithelial cells, pigment epithelium-derived factor
Published: 2017

43. Lipidome determinants of maximal lifespan in mammals

Author: Gary R. Lewin, Lothar Willmitzer, Nigel C. Bennett, Julia Marchal, Florian Schroeder, Zhen Liu, Fanelie Wanert, Andrei Seluanov, Vera Gorbunova, Damir Omerbašić, Jane Reznick, Philipp Khaitovich, Jorge Azpurua, Svante Pääbo, Fabien Pifferi, Patrick Giavalisco, Pierrick Regnard, Katarzyna Bozek, Peng Shi, Ekaterina Khrameeva, Fabienne Aujard, Max Planck Institute for Evolutionary Anthropology [Leipzig], Max-Planck-Gesellschaft, Skolkovo Institute of Science and Technology [Moscow] (Skoltech), University of Pretoria [South Africa], Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, University of Rochester [USA], European Synchrotron Radiation Facility (ESRF), Mécanismes adaptatifs : des organismes aux communautés (MAOAC), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Mécanismes Adaptatifs et Evolution (MECADEV), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Institute of Zoology, Chinese Academy of Sciences [Beijing], Max-Planck-Institut für Molekulare Pflanzenphysiologie (MPI-MP), and Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Multidisciplinary, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Science, Longevity, Zoology, Body size, Biology, Lipidome, Article, 03 medical and health sciences, 030104 developmental biology, Basal metabolic rate, Medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Stabilizing selection, Clade, Function and Dysfunction of the Nervous System, media_common
Abstract: Maximal lifespan of mammalian species, even if closely related, may differ more than 10-fold, however the nature of the mechanisms that determine this variability is unresolved. Here, we assess the relationship between maximal lifespan duration and concentrations of more than 20,000 lipid compounds, measured in 669 tissue samples from 6 tissues of 35 species representing three mammalian clades: primates, rodents and bats. We identify lipids associated with species’ longevity across the three clades, uncoupled from other parameters, such as basal metabolic rate, body size, or body temperature. These lipids clustered in specific lipid classes and pathways, and enzymes linked to them display signatures of greater stabilizing selection in long-living species, and cluster in functional groups related to signaling and protein-modification processes. These findings point towards the existence of defined molecular mechanisms underlying variation in maximal lifespan among mammals.
Published: 2017

44. Maximizing binary interactome mapping with a minimal number of assays

Author: Sudharshan Rangarajan, Philipp Trepte, Luke Lambourne, Soon Gang Choi, Patricia Cassonnet, Irma Lemmens, Javier De Las Rivas, Tong Hao, Wenting Bian, Marc Vidal, Eloi P. Coutant, Pierre-Olivier Vidalain, David E. Hill, Caroline Demeret, Mélanie Dos Santos, Michael A. Calderwood, Louis Jones, Julien Olivet, Kerstin Spirohn, Sylvie van der Werf, Erich E. Wanker, Jan Tavernier, Yves Jacob, Yves L. Janin, Jean-Claude Twizere, Katja Luck, Dana-Farber Cancer Institute [Boston], Université de Liège, Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Harvard Medical School [Boston] (HMS), Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), Universiteit Gent = Ghent University [Belgium] (UGENT), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Chimie et Biocatalyse, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Universidad de Salamanca, This work was supported by a Claudia Adams Barr Award to S.G.C., a Fonds de la Recherche Scientifique (F.R.S.-FNRS)-Télévie Grant and a Wallonia-Brussels International (WBI)-World Excellence Fellowship to J.O., NHGRI grants U41HG001715 awarded to M.V., D.E.H. and M.A.C, and P50HG004233 awarded to M.V. We acknowledge the support of Labex IBEID (10-LABX-0062). M.V. is a Chercheur Qualifié Honoraire from the Fonds de la Recherche Scientifique (FRS-FNRS, Wallonia-Brussels Federation, Belgium)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Fonds de la Recherche Scientifique (Fédération Wallonie-Bruxelles), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Universiteit Gent = Ghent University (UGENT), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris], Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Ghent University [Belgium] (UGENT), Max Delbrück Center for Molecular Medicine [Berlin], and ANR-10-LABX-0062/10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)
Subjects: Proteomics, 0301 basic medicine, Proteome, Computer science, Science, High-throughput screening, Proteomic analysis, General Physics and Astronomy, Binary number, 02 engineering and technology, Computational biology, Genome, Interactome, Article, General Biochemistry, Genetics and Molecular Biology, Protein expression, 03 medical and health sciences, Two-Hybrid System Techniques, Protein Interaction Mapping, Humans, Protein Interaction Maps, lcsh:Science, Databases, Protein, Multidisciplinary, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Proteins, General Chemistry, 021001 nanoscience & nanotechnology, Protein-protein interaction networks, High-Throughput Screening Assays, HEK293 Cells, 030104 developmental biology, Protein–protein interaction networks, lcsh:Q, Biological Assay, Systematic mapping, Function and Dysfunction of the Nervous System, 0210 nano-technology, Completeness (statistics), HeLa Cells
Abstract: © The Author(s) 2019., Complementary assays are required to comprehensively map complex biological entities such as genomes, proteomes and interactome networks. However, how various assays can be optimally combined to approach completeness while maintaining high precision often remains unclear. Here, we propose a framework for binary protein-protein interaction (PPI) mapping based on optimally combining assays and/or assay versions to maximize detection of true positive interactions, while avoiding detection of random protein pairs. We have engineered a novel NanoLuc two-hybrid (N2H) system that integrates 12 different versions, differing by protein expression systems and tagging configurations. The resulting union of N2H versions recovers as many PPIs as 10 distinct assays combined. Thus, to further improve PPI mapping, developing alternative versions of existing assays might be as productive as designing completely new assays. Our findings should be applicable to systematic mapping of other biological landscapes., This work was supported by a Claudia Adams Barr Award to S.G.C., a Fonds de la Recherche Scientifique (F.R.S.- FNRS)-Télévie Grant and a Wallonia-Brussels International (WBI)-World Excellence Fellowship to J.O., NHGRI grants U41HG001715 awarded to M.V., D.E.H. and M.A.C, and P50HG004233 awarded to M.V. We acknowledge the support of Labex IBEID (10- LABX-0062). M.V. is a Chercheur Qualifié Honoraire from the Fonds de la Recherche Scientifique (FRS-FNRS, Wallonia-Brussels Federation, Belgium).
Published: 2019

45. Postnatal Tshz3 deletion drives altered corticostriatal function and autism spectrum disorder-like behavior

Author: Michèle Carlier, Pierre L. Roubertoux, Christina Frahm, Laurent Fasano, Mehdi Metwaly, Dany Severac, Paolo Gubellini, Alistair N. Garratt, Bernard Jacq, Ahmed Fatmi, Pascal Salin, Dorian Chabbert, Xavier Caubit, Bianca Habermann, Lydia Kerkerian-Le Goff, Emeric Dubois, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Laboratoire de psychologie cognitive (LPC), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de génétique et physiologie du développement (LGPD), Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), ANR-17-CE16-0030,TSHZ3inASD,Rôle de TSHZ3 dans le développement et la fonction de systèmes neuronaux impliqués dans les troubles du spectre autistique(2017), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), ANR-11-IDEX-0001,Amidex,INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE(2011), ANR-17-EURE-0029,nEURo*AMU,Marseille NeuroSchool, une formation d'excellence(2017), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-BioCampus (BCM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, MESH: Chromosomes, Human, Pair 19, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Haploinsufficiency, Striatum, MESH: Mice, Knockout, MESH: Synapses, Mice, 0302 clinical medicine, MESH: Behavior, Animal, MESH: Gene Expression Regulation, Developmental, MESH: Animals, Autism spectrum disorder, MESH: Heterozygote, Mice, Knockout, MESH: Autism Spectrum Disorder, Behavior, Animal, Gene Expression Regulation, Developmental, MESH: Transcription Factors, 3. Good health, TSHZ3, Synaptopathy, Knockout mouse, Cortex, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Glutamatergic synapse, MESH: Haploinsufficiency, Chromosome Deletion, Function and Dysfunction of the Nervous System, Heterozygote, MESH: Chromosome Deletion, Biology, behavioral disciplines and activities, 03 medical and health sciences, mental disorders, MESH: Homeodomain Proteins, medicine, Animals, Humans, MESH: Mice, Biological Psychiatry, Homeodomain Proteins, MESH: Humans, Sociability, medicine.disease, MESH: Male, Disease Models, Animal, 030104 developmental biology, Stereotypies, MESH: Gene Deletion, Synapses, Homeobox, MESH: Disease Models, Animal, Chromosomes, Human, Pair 19, Neuroscience, MESH: Female, Gene Deletion, 030217 neurology & neurosurgery, Transcription Factors
Abstract: International audience; BACKGROUND: Heterozygous deletion of the TSHZ3 gene, encoding for the teashirt zinc-finger homeobox family member 3 (TSHZ3) transcription factor that is highly expressed in cortical projection neurons (CPNs), has been linked to an autism spectrum disorder (ASD) syndrome. Similarly, mice with Tshz3 haploinsufficiency show ASD-like behavior, paralleled by molecular changes in CPNs and corticostriatal synaptic dysfunctions. Here, we aimed at gaining more insight into "when" and "where" TSHZ3 is required for the proper development of the brain, and its deficiency crucial for developing this ASD syndrome. METHODS: We generated and characterized a novel mouse model of conditional Tshz3 deletion, obtained by crossing Tshz3 flox/flox with CaMKIIalpha-Cre mice, in which Tshz3 is deleted in CPNs from postnatal day 2 to 3 onward. We characterized these mice by a multilevel approach combining genetics, cell biology, electrophysiology, behavioral testing, and bioinformatics. RESULTS: These conditional Tshz3 knockout mice exhibit altered cortical expression of more than 1000 genes, w50% of which have their human orthologue involved in ASD, in particular genes encoding for glutamatergic syn-apse components. Consistently, we detected electrophysiological and synaptic changes in CPNs and impaired corticostriatal transmission and plasticity. Furthermore, these mice showed strong ASD-like behavioral deficits. CONCLUSIONS: Our study reveals a crucial postnatal role of TSHZ3 in the development and functioning of the corticostriatal circuitry and provides evidence that dysfunction in these circuits might be determinant for ASD pathogenesis. Our conditional Tshz3 knockout mouse constitutes a novel ASD model, opening the possibility for an early postnatal therapeutic window for the syndrome linked to TSHZ3 haploinsufficiency.
Published: 2019

46. WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

Author: Cristina Beltrami, Owen J. L. Rackham, Costanza Emanueli, Nithya Devapragash, Wei-Ping Yu, Xi-Ming Sun, Stuart A. Cook, Norbert Hubner, Francesco Pesce, Ee Ling Heng, Elisabeth Tan, Aida Moreno-Moral, Enrique Lara-Pezzi, Gianni D Angelini, Enrico Petretto, Huimei Chen, Paul J.R. Barton, Nathan Harmston, Michal Pravenec, Sebastian Schafer, Maxime Rotival, Nicole Tee, Massimilano Mancini, Leanne E. Felkin, Leonardo Bottolo, Prashant K. Srivastava, Kirill Shkura, Cardiovascular and Metabolic Disorders [Singapor] (cvmd), Duke-NUS Medical School [Singapore], Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Ospedale San Giovanni di Dio, Firenze, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Faculty of Medicine [London, UK], Imperial College London, Agency for science, technology and research [Singapore] (A*STAR), Institute of Molecular and Cell Biology, National University of Singapore (NUS)-Agency for science, technology and research [Singapore] (A*STAR), MRC London Institute of Medical Sciences (LMC), National Heart Centre Singapore (NHCS), Royal Brompton and Harefield NHS Foundation Trust, Cardiovascular Research Centre [London], Centro Nacional de Investigaciones Cardiovasculares Carlos III [Madrid, Spain] (CNIC), Instituto de Salud Carlos III [Madrid] (ISC), University of Bristol [Bristol], Institute of Physiology [Prague], Czech Academy of Sciences [Prague] (CAS), University of Cambridge [UK] (CAM), The Alan Turing Institute, MRC Biostatistics Unit [Cambridge, UK], Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], The research was primarily supported by National Medical Research Council (NMRC) Singapore grant NMRC/CBRG/0106/2016 (to E.P.) and the British Heart Foundation (BHF) Ph.D. Studentship grant FS/11/25/28740 (to E.P). We acknowledge additional funding support from European Union FP7 CardioNeT-ITN-289600 (to E.L.-P., S.A.C., and P.J.R.B.), Heart Research UK (to P.J.R.B.), NIHR CV BRU of Royal Brompton and Harefield, NHS Foundation Trust (to S.A.C. and P.J.R.B.), BHF (to S.A.C.), Leducq Foundation (to S.A.C.), MRC UK (to S.A.C.), BHF Program Grant no. RG/15/5/31446 (to C.E. and E.P.). M.P. was supported by Praemium Academiae award of the Czech Academy of Sciences and grant 14-36804G from the Czech Science Foundation., We wish to thank Dr. Jacques Behmoaras for contributing critical and constructive comments to the manuscript., European Project: 289600,EC:FP7:PEOPLE,FP7-PEOPLE-2011-ITN,CARDIONET(2012), Moreno-Moral, Aida [0000-0002-8155-3146], Barton, Paul J. R. [0000-0002-1165-7767], Schafer, Sebastian [0000-0002-6909-8275], Bottolo, Leonardo [0000-0002-6381-2327], Cook, Stuart A. [0000-0001-6628-194X], Petretto, Enrico [0000-0003-2163-5921], Apollo - University of Cambridge Repository, National Medical Research Council (Singapur), British Heart Foundation, Unión Europea. Comisión Europea, National Institutes of Health (Estados Unidos), Czech Science Foundation, Fondation Leducq, NHS Foundation Trusth, University of Bari Aldo Moro (UNIBA), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Leducq Foundation for Cardiovascular Research, Commission of the European Communities, Heart Research UK, Medical Research Council (MRC), Barton, Paul JR [0000-0002-1165-7767], and Cook, Stuart A [0000-0001-6628-194X]
Subjects: Male, 45/43, BLOOD-PRESSURE, 02 engineering and technology, MESH: Protein Isoforms, MESH: Heart Diseases / genetics, Mice, Transforming Growth Factor beta, 42/44, Fibrosis, Protein Isoforms, Medicine, MESH: Animals, lcsh:Science, MESH: Ubiquitin-Protein Ligases / genetics, MESH: Fibrosis / metabolism, MESH: Genetic Predisposition to Disease* / genetics, GENE-EXPRESSION, Regulation of gene expression, Extracellular Matrix Proteins, MESH: Middle Aged, MESH: Fibrosis / genetics, TGF-BETA, MESH: Heart Diseases / metabolism, MESH: Ubiquitin-Protein Ligases / metabolism, 3. Good health, Cell biology, Ubiquitin ligase, FIBROBLAST, MESH: Young Adult, Science & Technology - Other Topics, 64/60, Cardiomyopathies, 0210 nano-technology, Cardiac function curve, Science, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, REVEALS, Humans, Aged, MESH: Adolescent, Science & Technology, MESH: Humans, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], IDENTIFICATION, MESH: Smad2 Protein / metabolism, MESH: Extracellular Matrix Proteins / metabolism, MESH: Adult, MESH: Cardiomyopathies / metabolism, medicine.disease, 030104 developmental biology, Cardiovascular and Metabolic Diseases, E3 UBIQUITIN LIGASE, RAT, DETERMINANT, lcsh:Q, Myocardial fibrosis, MESH: Female, 0301 basic medicine, Cardiac fibrosis, General Physics and Astronomy, Smad2 Protein, Gene Regulatory Networks, 13/89, MESH: Aged, MESH: Transforming Growth Factor beta / metabolism, Multidisciplinary, biology, MESH: Smad2 Protein / genetics, article, Middle Aged, MESH: Cardiomyopathies / genetics, 021001 nanoscience & nanotechnology, 692/4019/592/75/74, MESH: Gene Expression Regulation, Multidisciplinary Sciences, Centre for Surgical Research, HEART-FAILURE, Female, 38/39, Adult, Adolescent, Heart Diseases, MESH: Mice, Transgenic, Ubiquitin-Protein Ligases, Mice, Transgenic, 14/32, 82/80, Young Adult, Animals, Genetic Predisposition to Disease, 14/35, MESH: Mice, Pressure overload, business.industry, General Chemistry, MESH: Male, Gene Expression Regulation, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Ubiquitin ligases, Heart failure, 13/51, biology.protein, 631/45/474/2073, MESH: Gene Regulatory Networks, business
Abstract: Cardiac fibrosis is a final common pathology in inherited and acquired heart diseases that causes cardiac electrical and pump failure. Here, we use systems genetics to identify a pro-fibrotic gene network in the diseased heart and show that this network is regulated by the E3 ubiquitin ligase WWP2, specifically by the WWP2-N terminal isoform. Importantly, the WWP2-regulated pro-fibrotic gene network is conserved across different cardiac diseases characterized by fibrosis: human and murine dilated cardiomyopathy and repaired tetralogy of Fallot. Transgenic mice lacking the N-terminal region of the WWP2 protein show improved cardiac function and reduced myocardial fibrosis in response to pressure overload or myocardial infarction. In primary cardiac fibroblasts, WWP2 positively regulates the expression of pro-fibrotic markers and extracellular matrix genes. TGFβ1 stimulation promotes nuclear translocation of the WWP2 isoforms containing the N-terminal region and their interaction with SMAD2. WWP2 mediates the TGFβ1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2., Pathological cardiac fibrosis is a hallmark of diseases leading to heart failure. Here, the authors used systems genetics to identify a pro-fibrotic gene network regulated by WWP2, a E3 ubiquitin ligase, which orchestrates the nucleocytoplasmic shuttling and transcriptional activity of SMAD2 in the diseased heart.
Published: 2019

47. Teashirt 1 (Tshz1) is essential for the development, survival and function of hypoglossal and phrenic motor neurons in mouse

Author: Charlotte Chaimowicz, Gilles Fortin, Andrew Woehler, Carmen Birchmeier, Alistair N. Garratt, Cyril Cheret, Pierre-Louis Ruffault, Niccolò Zampieri, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Hypoglossal Nerve, Mouse, [SDV]Life Sciences [q-bio], Apoptosis, Phrenic motor column, Mice, 0302 clinical medicine, ComputingMilieux_MISCELLANEOUS, bcl-2-Associated X Protein, Motor neurons, 0303 health sciences, Respiration, musculoskeletal system, Diaphragm (structural system), Phrenic Nerve, Plethysmography, medicine.anatomical_structure, Tshz1, Breathing, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Technology Platforms, Function and Dysfunction of the Nervous System, Research Article, Aerophagia, Hypoglossal nucleus, Cell Survival, Diaphragm, Mice, Transgenic, Biology, 03 medical and health sciences, Tongue, medicine, Animals, Molecular Biology, Transcription factor, 030304 developmental biology, Progenitor, Homeodomain Proteins, Motor neuron, Repressor Proteins, Electrophysiology, Animals, Newborn, nervous system, Mutation, Neuroscience, 030217 neurology & neurosurgery, Developmental Biology
Abstract: Feeding and breathing are essential motor functions and rely on the activity of hypoglossal and phrenic motor neurons that innervate the tongue and diaphragm, respectively. Little is known about the genetic programs that control the development of these neuronal subtypes. The transcription factor Tshz1 is strongly and persistently expressed in developing hypoglossal and phrenic motor neurons. We used conditional mutation of Tshz1 in the progenitor zone of motor neurons (Tshz1MNΔ) to show that Tshz1 is essential for survival and function of hypoglossal and phrenic motor neurons. Hypoglossal and phrenic motor neurons are born in correct numbers, but many die between embryonic day 13.5 and 14.5 in Tshz1MNΔ mutant mice. In addition, innervation and electrophysiological properties of phrenic and hypoglossal motor neurons are altered. Severe feeding and breathing problems accompany this developmental deficit. Although motor neuron survival can be rescued by elimination of the pro-apoptotic factor Bax, innervation, feeding and breathing defects persist in Bax−/−; Tshz1MNΔ mutants. We conclude that Tshz1 is an essential transcription factor for the development and physiological function of phrenic and hypoglossal motor neurons., Summary: Mutation of Tshz1 in mice impairs the development of hypoglossal and phrenic motor neurons, leading to severe breathing and feeding problems that are ultimately lethal.
Published: 2019

48. Artery-vein specification in the zebrafish trunk is pre-patterned by heterogeneous Notch activity and balanced by flow-mediated fine-tuning

Author: Ilse Geudens, Véronique Gebala, Baptiste Coxam, Katja Meier, Anne-Clémence Vion, Andre Rosa, Silvanus Alt, Holger Gerhardt, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), and Helmholtz-Gemeinschaft = Helmholtz Association
Subjects: Vein, ANGIOGENESIS, 0302 clinical medicine, NETWORK, Zebrafish, [SDV.BDD]Life Sciences [q-bio]/Development Biology, GENE-EXPRESSION, 0303 health sciences, VENOUS DIFFERENTIATION, Receptors, Notch, Cell Polarity, Anatomy, Arteries, GRIDLOCK, Artery, Haemodynamic, Endothelial stem cell, medicine.anatomical_structure, Lymphatic system, cardiovascular system, Developmental patterning, Life Sciences & Biomedicine, Research Article, Signal Transduction, Notch, Notch signaling pathway, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, DLL4, Veins, 03 medical and health sciences, Genetic Heterogeneity, medicine, Posterior cardinal vein, Animals, Molecular Biology, 030304 developmental biology, Body Patterning, Lymphatic Vessels, Science & Technology, COMPLEX, Endothelial Cells, biology.organism_classification, Trunk, ENDOTHELIAL-CELLS, Cardiovascular and Metabolic Diseases, Regional Blood Flow, Angiogenesis, 030217 neurology & neurosurgery, Developmental Biology
Abstract: How developing vascular networks acquire the right balance of arteries, veins and lymphatic vessels to efficiently supply and drain tissues is poorly understood. In zebrafish embryos, the robust and regular 50:50 global balance of intersegmental veins and arteries that form along the trunk prompts the intriguing question of how does the organism keep ‘count’? Previous studies have suggested that the ultimate fate of an intersegmental vessel (ISV) is determined by the identity of the approaching secondary sprout emerging from the posterior cardinal vein. Here, we show that the formation of a balanced trunk vasculature involves an early heterogeneity in endothelial cell behaviour and Notch signalling activity in the seemingly identical primary ISVs that is independent of secondary sprouting and flow. We show that Notch signalling mediates the local patterning of ISVs, and an adaptive flow-mediated mechanism subsequently fine-tunes the global balance of arteries and veins along the trunk. We propose that this dual mechanism provides the adaptability required to establish a balanced network of arteries, veins and lymphatic vessels., Highlighted Article: A stepwise dual mechanism involving Notch signalling and flow provides the adaptability required to establish a balanced network of arteries and veins in the zebrafish trunk.
Published: 2019

49. Combined Analysis of Metabolomes, Proteomes, and Transcriptomes of Hepatitis C Virus–Infected Cells and Liver to Identify Pathways Associated With Disease Development

Author: Ralf Bartenschlager, Kazuaki Chayama, Joachim Lupberger, Nabeel Bardeesy, Eloi R. Verrier, Nicolaas Van Renne, Tom Croonenborghs, Philipp Mertins, Armando Andres Roca Suarez, Steven A. Carr, Frank Jühling, Yujin Hoshida, Evelyn Ramberger, Mirjam B. Zeisel, Olivier Gevaert, Nourdine Hamdane, Marine A. Oudot, Gergö Meszaros, Alessia Virzì, Mohsen Nabian, Thomas F. Baumert, Daniel Brumaru, Romeo Ricci, Rileen Sinha, Naoto Fujiwara, Hussein El Saghire, Simonetta Bandiera, Marko Jovanovic, Carole Jamey, Celine Everaert, Shaunt Fereshetian, Nathalie Pochet, Laura Heydmann, Sarah C. Durand, Nassim Dali-Youcef, Atish Mukherji, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Harvard-MIT Division of Health Sciences and Technology [Cambridge], Massachusetts Institute of Technology (MIT), Evergrande Center for Immunologic Diseases [Boston, MA, USA] (Ann Romney Center for Neurologic Diseases), Brigham & Women's Hospital, Harvard Medical School, Université de Strasbourg (UNISTRA), Laboratoire de Biochimie et de Biologie Moléculaire, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Department of Infectious Diseases [Heidelberg, Germany], Heidelberg University Hospital [Heidelberg], Division of Virus-Associated Carcinogenesis [Heidelberg, Germany], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), The Broad Institute [Cambridge, MA, USA], Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT), Proteomics Platform [Berlin, Germany], Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association-Helmholtz-Gemeinschaft = Helmholtz Association-Helmholtz Society [Berlin, Germany], Institute of Public Health [Berlin, Germany], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Hiroshima University, Liver Research Project Center [Hiroshima, Japan], Massachusetts General Hospital [Boston], Harold C. Simmons Comprehensive Cancer Center [Dallas, TX, États-Unis], University of Texas Southwestern Medical Center [Dallas], Cell Circuits Program [Cambridge, MA, USA], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Stanford Center for BioMedical Informatics Research (BMIR), Stanford University, Department of Neurology [Cambridge, MA, USA] (Ann Romney Center for Neurologic Diseases), Harvard Medical School [Boston] (HMS)-Brigham and Women's Hospital [Boston], Department of Neurology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Pôle hépato-digestif [Strasbourg], Nouvel Hôpital Civil, Hospices Civils de Strasbourg-Institut Hospitalo-Universitaire de strasbourg, This work was supported by the European Union (ERC-AdG-2014 HEPCIR to Thomas F. Baumert and Yujin Hoshida and EU H2020 HEPCAR 667273 to Thomas F. Baumert and Joachim Lupberger), the Agence nationale de recherche sur le sida et les hépatites virales (ECTZ4236 to Joachim Lupberger and ECTZ4446 to Armando Andres Roca Suarez), the French Cancer Agency (ARC IHU201301187 to Thomas F. Baumert), the US Department of Defense (W81XWH-16-1-0363 to Thomas F. Baumert and Yujin Hoshida), the National Institutes of Health (National Institute of Allergy and Infectious Diseases R03AI131066 to Nathalie Pochet and Thomas F. Baumert, National Cancer Institute 1R21CA209940 to Nathalie Pochet, Thomas F. Baumert, and Olivier Gevaert, National Institute of Allergy and Infectious Diseases 5U19AI123862-02 to Thomas F. Baumert, National Cancer Institute/Informatics Technology for Cancer Research (ITCR) U01 CA214846 to Nathalie Pochet and Olivier Gevaert), the Fondation de l’Université de Strasbourg (HEPKIN) (TBA-DON-0002) and the INSERM Plan Cancer 2019-2023 to Thomas F. Baumert. This work has benefitted from support by the Initiative of Excellence IDEX-Unistra (ANR-10-IDEX-0002-02 to Joachim Lupberger) and has been published under the framework of the LABEX ANR-10-LAB-28 (HEPSYS). INSERM Plan Cancer, IDEX, and LABEX are initiatives from the French program 'Investments for the Future.' The work of Ralf Bartenschlager was supported by the Deutsche Forschungsgemeinschaft (TRR179, TP9). Kazuaki Chayama was supported by the Research Program on Hepatitis from the Japanese Agency for Medical Research and Development (AMED) Japan (JP18fk0210020h0002). The work of Romeo Ricci and Gergö Meszaros was supported by a European Research Council (ERC) starting grant (ERC-2011-StG, 281271-STRESS METABOL), by the European Foundation for the Study of Diabetes (EFSD)/Lilly European Diabetes Research Program grant, and by the ANR-10-LABX-0030-INRT grant, a French State fund managed by the ANR under the frame program Investissements d’Avenir ANR-10-IDEX0002-02., daulny, anne, and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Proteomics, Cirrhosis, Peroxisome proliferator-activated receptor, Datasets as Topic, Hepacivirus, medicine.disease_cause, Sciences du Vivant [q-bio]/Cancer, Transcriptome, Liver disease, Mice, 0302 clinical medicine, Sciences du Vivant [q-bio]/Immunologie, HCC, chemistry.chemical_classification, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Fatty liver, Gastroenterology, Sciences du Vivant [q-bio]/Biotechnologies, metabolic disease, 3. Good health, Liver, Hepatocellular carcinoma, 030211 gastroenterology & hepatology, signal transduction, STAT3 Transcription Factor, Hepatitis C virus, Biology, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, 03 medical and health sciences, Cell Line, Tumor, medicine, Peroxisomes, Animals, Humans, Metabolomics, Transplantation Chimera, Hepatology, Gene Expression Profiling, immune regulation, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatitis C, Chronic, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, digestive system diseases, Disease Models, Animal, 030104 developmental biology, Glucose, chemistry, Cancer research, Hepatocytes, Steatohepatitis, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Comment inMulti-omic Analyses Reveal Complex Interactions Between HCV and Hepatocytes Demonstrating That the Red Queen Is Up and Running. [Gastroenterology. 2019]; International audience; BACKGROUND & AIMS:The mechanisms of hepatitis C virus (HCV) infection, liver disease progression, and hepatocarcinogenesis are only partially understood. We performed genomic, proteomic, and metabolomic analyses of HCV-infected cells and chimeric mice to learn more about these processes.METHODS:Huh7.5.1dif (hepatocyte-like cells) were infected with culture-derived HCV and used in RNA sequencing, proteomic, metabolomic, and integrative genomic analyses. uPA/SCID (urokinase-type plasminogen activator/severe combined immunodeficiency) mice were injected with serum from HCV-infected patients; 8 weeks later, liver tissues were collected and analyzed by RNA sequencing and proteomics. Using differential expression, gene set enrichment analyses, and protein interaction mapping, we identified pathways that changed in response to HCV infection. We validated our findings in studies of liver tissues from 216 patients with HCV infection and early-stage cirrhosis and paired biopsy specimens from 99 patients with hepatocellular carcinoma, including 17 patients with histologic features of steatohepatitis. Cirrhotic liver tissues from patients with HCV infection were classified into 2 groups based on relative peroxisome function; outcomes assessed included Child-Pugh class, development of hepatocellular carcinoma, survival, and steatohepatitis. Hepatocellular carcinomas were classified according to steatohepatitis; the outcome was relative peroxisomal function.RESULTS:We quantified 21,950 messenger RNAs (mRNAs) and 8297 proteins in HCV-infected cells. Upon HCV infection of hepatocyte-like cells and chimeric mice, we observed significant changes in levels of mRNAs and proteins involved in metabolism and hepatocarcinogenesis. HCV infection of hepatocyte-like cells significantly increased levels of the mRNAs, but not proteins, that regulate the innate immune response; we believe this was due to the inhibition of translation in these cells. HCV infection of hepatocyte-like cells increased glucose consumption and metabolism and the STAT3 signaling pathway and reduced peroxisome function. Peroxisomes mediate β-oxidation of very long-chain fatty acids; we found intracellular accumulation of very long-chain fatty acids in HCV-infected cells, which is also observed in patients with fatty liver disease. Cells in livers from HCV-infected mice had significant reductions in levels of the mRNAs and proteins associated with peroxisome function, indicating perturbation of peroxisomes. We found that defects in peroxisome function were associated with outcomes and features of HCV-associated cirrhosis, fatty liver disease, and hepatocellular carcinoma in patients.CONCLUSIONS:We performed combined transcriptome, proteome, and metabolome analyses of liver tissues from HCV-infected hepatocyte-like cells and HCV-infected mice. We found that HCV infection increases glucose metabolism and the STAT3 signaling pathway and thereby reduces peroxisome function; alterations in the expression levels of peroxisome genes were associated with outcomes of patients with liver diseases. These findings provide insights into liver disease pathogenesis and might be used to identify new therapeutic targets.
Published: 2019

50. WiPP: workflow for improved peak picking for gas chromatography-mass spectrometry (GC-MS) data

Author: Yann Guitton, Emilie Sicard, Jennifer A. Kirwan, Nico Borgsmüller, Bruno Le Bizec, Carole Migné, Franck Giacomoni, Mélanie Pétéra, Eric Blanc, Yoann Gloaguen, Anne-Lise Royer, Tobias Opialla, Dieter Beule, Stéphanie Durand, Estelle Pujos-Guillot, Core Unit Bioinformatics, Berlin Institute of Health (BIH), Berlin Institute of Health Metabolomics Platform, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Berlin Institute for Medical Systems Biology, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), MetaboHUB, Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Laboratoire d'étude des Résidus et Contaminants dans les Aliments (LABERCA), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Max Delbrück Center for Molecular Medicine, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, 1019, unité de Nutrition Humaine, Institut National de la Recherche Agronomique (INRA), Université Clermont Auvergne (UCA), Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), and Institut National de la Recherche Agronomique (INRA)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)
Subjects: [SPI.OTHER]Engineering Sciences [physics]/Other, Cancer Research, Computer science, peak detection, lcsh:QR1-502, computer.software_genre, 01 natural sciences, lcsh:Microbiology, Article, 03 medical and health sciences, Metabolomics, parameter optimisation, support vector machine, peak classification, 030304 developmental biology, 0303 health sciences, 010401 analytical chemistry, metabolomics, 0104 chemical sciences, pre-processing workflow, Workflow, machine learning, Cardiovascular and Metabolic Diseases, gas chromatography-mass spectrometry (GC-MS), Data mining, Gas chromatography–mass spectrometry, Technology Platforms, Classifier (UML), computer
Abstract: High false positive rates in GC-MS metabolomics peak detection is a common issue that impedes automated analysis of large-scale datasets. There is a growing need for improving the reliability and scalability of data analysis workflows. Many algorithms are available for peak detection [1], a crucial step for the data analysis, but performance and outcome can differ widely depending on both algorithmic approach and data acquisition method. This makes it difficult to compare and contrast between algorithms without extensive manual intervention.nnWe present a workflow for improved peak picking (WiPP), a parameter optimizing, multi-algorithm peak detection workflow for GC-MS metabolomics, which automatically evaluates the quality of detected peaks using machine learning-based classification. First, the classifier is trained to distinguish between real compound related peaks and false positive peaks. Then the algorithm parameters are scored based on the quality of detected peaks and optimized accordingly. This procedure is repeated for two peak detection algorithms and subsequently both algorithms are run in parallel on the entire data set with the optimized parameters. The qualitative information returned by the classifier for every peak is then used to merge individual algorithm results into one final high confidence peak set.nnUsing this approach, we show that automated detection and evaluation of peak quality is improved. The additional quantitative and qualitative information generated by the classifier allows:nnO_LIa novel way to classify peaks based on seven classes and thus objectively to assess their qualitynC_LIO_LIimpartial performance comparison of different peak picking algorithmsnC_LIO_LIautomated parameter optimization for each individual peak picking algorithmnC_LIO_LIa final, improved high quality peak list to be generated for statistical or further analyses.nC_LInnIt achieves this while minimising the operator-time required by packaging this within a fully automated workflow. The modular design allows extension, adjustment and improvement of the workflow using different or additional peak detection algorithms and classifiers. Importantly, due to the fully automated implementation, the workflow is suitable for large-scale studies.nnThe pipeline supports mzML, mzData and NetCDF formats and is implemented in python using snakemake, a reproducible and scalable workflow management system, it is available on GitHub (https://github.com/bihealth/WiPP).
Published: 2019

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