Search

Your search keyword '"C. Belair"' showing total 25 results
Start Over Author "C. Belair"
25 results on '"C. Belair"'

1. Neuraxial analgesia is not associated with an increased risk of post-partum relapses in MS

Author

Caroline Lavie, Fabien Rollot, Françoise Durand-Dubief, Romain Marignier, Iuliana Ionescu, Romain Casey, Thibault Moreau, Patricia Tourniaire, Michael Hutchinson, Marie Béatrice D’Hooghe, David-Axel Laplaud, Pierre Clavelou, Jérôme De Sèze, Marc Debouverie, David Brassat, Jean Pelletier, Christine Lebrun-Frenay, Emmanuelle Le Page, Giovanni Castelnovo, Eric Berger, Patrick Hautecoeur, Olivier Heinzlef, Luca Durelli, Marinella Clerico, Maria Trojano, Francesco Patti, Sandra Vukusic, A. Alpérovitch, H. Carton, M.B. d’Hooghe, O. Hommes, M. Hutchinson, P. Adeleine, A. Biron, P. Cortinovis-Tourniaire, J. Grimaud, M. Hours, T. Moreau, S. Vukusic, C. Confavreux, G. Chauplannaz, D. Latombe, M. Clanet, G. Lau, L. Rumbach, J.Y. Goas, F. Rouhart, A. Mazingue, E. Roullet, M. Madigand, P. Hautecoeur, P. Brunet, G. Edan, C. Allaire, G. Riffault, J. Leche, T. Benoit, C. Simonin, F. Ziegler, J.C. Baron, Y. Rivrain, R. Dumas, D. Loche, J.C. Bourrin, B. Huttin, B. Delisse, I. Gibert, C. Boulay, M. Verceletto, G. Durand, G. Bonneviot, R. Gil, M.A. Hedreville, C. Belair, R.J. Poitevin, J.L. Devoize, P. Wyremblewski, F. Delestre, A. Setiey, G. Comi, M. Filippi, A. Ghezzi, V. Martinelli, P. Rossi, M. Zaffaroni, M.R. Tola, M.P. Amato, C. Fioretti, G. Meucci, M. Inglese, G.L. Mancardi, D. Gambi, A. Thomas, M. Cavazzuti, A. Citterio, A. Heltberg, H.J. Hansen, O. Fernandez, F. Romero, T. Arbizu, J.J. Hernandez, C. De Andres de Frutos, D. Geffner Sclarky, Y. Aladro Benito, P. Reyes Yanes, M Aguilar, J.A. Burguera, R. Yaya, W. Bonakim Dib, D. Arzua-Mouronte, C.J.M. Sindic, R. Medaer, H. Roose, K.M.J. Geens, D. Guillaume, M. Van Zandycke, J. Janssens, M. Cornette, L. Mol, F. Weilbach, P. Flachenecker, H.P. Hartung, J. Haas, I. Tendolkar, E. Sindrn, H.W. Kölmel, D. Reichel, M. Rauch, S. Preuss, S. Poser, E. Mauch, S. Strausser-Fuchs, H. Kolleger, S. Hawkins, S.J.L. Howell, J.E. Rees, A. Thompson, M. Johnson, M. Boggild, R.P. Gregory, D. Bates, I. Bone, C. Polman, S. Frequin, P. Jongen, J. Correia de Sa, M.E. Rio, S. Huber, J. Lechner-Scott, L. Kappos, I. Ionescu, C. Cornu, M. El-Etr, E.E. Baulieu, M Schumacher, D.H. Miller, M. Pugeat, C. d’Archangues, J. Conard, J. Ménard, R. Sitruk-Ware, C. Pelissier, S. Dat, J. Belaïsch-Allard, N. Athéa, D. Büschsenschutz, O. Lyon-Caen, R. Gonsette, J.P. Boissel, P. Ffrench, F. Durand-Dubief, F. Cotton, C. Pachai, L. Bracoud, G. Androdias, R. Marignier, D.A. Laplaud, S. Wiertlewski, C. Lanctin-Garcia, G. Couvreur, G. Madinier, P. Clavelou, F. Taithe, D. Aufauvre, N. Guy, A. Ferrier, J. De Sèze, N. Collongues, M. Debouverie, F. Viala, D. Brassat, A. Gerdelat-Mas, P. Henry, J. Pelletier, A. Rico-Lamy, C. Lebrun-Frenay, E. Lepage, V. Deburghraeve, G. Castelnovo, E. Berger, M. Blondiau, O. Heinzlef, M. Coustans, C. Clerc, L. Rieu, M. Lauxerois, G. Hinzelin, J.C. Ouallet, D. Minier, P. Vion, N. Gromaire-Fayolle, N. Derache, E. Thouvenot, M. Sallansonnet-Froment, P. Tourniaire, L. Toureille, F. Borgel, B. Stankoff, C. Moroianu, A.M. Guennoc, C.L. Tournier-Gervason, S. Peysson, M. Trojano, F. Patti, E. D’Amico, L. Motti, L. Durelli, A. Tavella, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Observatoire Français de la Sclérose En Plaques [Lyon] (OFSEP), Service de neurologie fonctionnelle et d'épileptologie [Hôpital Pierre Wertheimer-HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Henri Duffaut (Avignon), National MS Center Melsbroek, Vrije Universiteit Brussel [Bruxelles] (VUB), Vrije Universiteit Brussel (VUB), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service de Neurologie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Laboratoire de Neuroimagerie in Vivo (LNV), CHU Strasbourg-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), Service de neurologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université de Lorraine (UL), Neurologie vasculaire, pathologie neuro-dégénérative et explorations fonctionnelles du système nerveux [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Universitaire de Nice (CHU Nice), Université Côte d'Azur (UCA), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service de Neurologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Groupe Hospitalier de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL), centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], Università degli studi di Torino = University of Turin (UNITO), University of Catania [Italy], Hospices Civils de Lyon, Departement de Neurologie (HCL), Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], Protéines membranaires transductrices d'énergie (PMTE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut des Géosciences de l’Environnement (IGE), Institut de Recherche pour le Développement (IRD)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre de Recherches sur les Macromolécules Végétales (CERMAV ), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Environnement Ville Société (EVS), École normale supérieure - Lyon (ENS Lyon)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet [Saint-Étienne] (UJM)-École Nationale des Travaux Publics de l'État (ENTPE)-École nationale supérieure d'architecture de Lyon (ENSAL)-Centre National de la Recherche Scientifique (CNRS), Solvay (France), Laboratoire des Mécanismes et Transfert en Géologie (LMTG), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Institute of Evolutionary Biology, University of Edinburgh, Université de Lille, Sciences et Technologies, Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Différenciation, interaction, activation et migration des sous-populations lymphocitaires humaines, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Motricité, interactions, performance EA 4334 / Movement - Interactions - Performance (MIP), Le Mans Université (UM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR des Sciences et Techniques des Activités Physiques et Sportives (UFR STAPS), Laboratoire Ecologie Fonctionnelle et Environnement (ECOLAB), Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Laboratoire de Chimie Physique D'Orsay (LCPO), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), RMN et optique : De la mesure au biomarqueur, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Department of Neurology, CHU Lyon, Institut de Recherche de Chimie Paris (IRCP), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ministère de la Culture (MC), Hôpital de Hautepierre [Strasbourg], Laboratoire de Réactivité des Surfaces et des Interfaces (LRSI), Département de Physico-Chimie (DPC), CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Empenn, Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes 1 (UR1), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Service de Neurologie [Rennes] = Neurology [Rennes], CHU Pontchaillou [Rennes], Biologie des Interactions Neurones / Glie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation pour l'Aide à la Recherche sur la Sclérose en Plaques, European Leukodystrophies Association, PHRC National, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pierre Wertheimer, Département de Neurologie, Laboratoire de Mathématiques (LAMA), Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Nottingham Scientific Limited, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Turin, Università degli studi di Torino (UNITO), University of Bari Aldo Moro (UNIBA), Department of Neurosciences, Università degli studi di Catania [Catania], Centre de recherche en neurosciences de Lyon (CRNL), Neuroépidémiologie, Institut de Physique du Globe de Paris (IPGP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Centre National de la Recherche Scientifique (CNRS), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut de Recherche pour le Développement (IRD)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-École nationale supérieure d'architecture de Lyon (ENSAL)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École Nationale des Travaux Publics de l'État (ENTPE)-Université Jean Monnet [Saint-Étienne] (UJM)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université Lumière - Lyon 2 (UL2)-École normale supérieure - Lyon (ENS Lyon), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ministère de la Culture (MC), Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lavie, Caroline, Rollot, Fabien, Durand-Dubief, Françoise, Marignier, Romain, Ionescu, Iuliana, Casey, Romain, Moreau, Thibault, Tourniaire, Patricia, Hutchinson, Michael, D’Hooghe, Marie Béatrice, Laplaud, David-Axel, Clavelou, Pierre, De Sèze, Jérôme, Debouverie, Marc, Brassat, David, Pelletier, Jean, Lebrun-Frenay, Christine, Le Page, Emmanuelle, Castelnovo, Giovanni, Berger, Eric, Hautecoeur, Patrick, Heinzlef, Olivier, Durelli, Luca, Clerico, Marinella, Trojano, Maria, Patti, Francesco, Vukusic, Sandra, on behalf of PRIMS and POPARTMUS, Investigator, Filippi, Massimo, Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], Environnement, Ville, Société (EVS), École normale supérieure de Lyon (ENS de Lyon)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-École Nationale des Travaux Publics de l'État (ENTPE)-École nationale supérieure d'architecture de Lyon (ENSAL)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Neuroimagerie: méthodes et applications (Empenn), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut National de la Recherche Agronomique (INRA)-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), Laboratoire de glaciologie et géophysique de l'environnement (LGGE), Observatoire des Sciences de l'Univers de Grenoble (OSUG), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur les Macromolécules Végétales (CERMAV), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Laboratoire Motricité, Interactions, Performance, Université de Nantes (UN), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Ministère de la Culture (MC), Centre Hospitalier Universitaire de Strasbourg (CHU de Strasbourg ), CEA-Direction de l'Energie Nucléaire (CEA-DEN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-CEA-Direction de l'Energie Nucléaire (CEA-DEN), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Service de neurologie [Besançon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Service de Neurologie [CHU Besançon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Service de Neurologie [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Clinical sciences, Neuroprotection & Neuromodulation, and Neurology

Subjects
relapses, Neurology, [SDV]Life Sciences [q-bio], MESH: Pregnancy Complications / physiopathology, 0302 clinical medicine, MESH: Pregnancy, Anesthesia, Conduction, Recurrence, MESH: Anesthesia, Conduction / adverse effects, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, reproductive and urinary physiology, relapse, Postpartum Period, post-partum, MESH: Follow-Up Studies, MESH: Multiple Sclerosis / physiopathology, Obstetrical Analgesia, MESH: Multiple Sclerosis / chemically induced, Anesthesia, Female, pregnancy, Adult, medicine.medical_specialty, Clinical Neurology, Multiple sclerosis, MESH: Postpartum Period, 03 medical and health sciences, medicine, Humans, Multiple sclerosi, Post partum, Retrospective Studies, Pregnancy, MESH: Humans, MESH: Pregnancy Complications / chemically induced, business.industry, Neurotoxicity, MESH: Adult, MESH: Retrospective Studies, neuraxial analgesia, medicine.disease, MESH: Recurrence, Multiple sclerosis, neuraxial analgesia, post-partum, pregnancy, Pregnancy Complications, Increased risk, Neurology (clinical), [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Female, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract

Background: Obstetrical analgesia remains a matter of controversy because of the fear of neurotoxicity of local anesthetics on demyelinated fibers or their potential relationship with subsequent relapses. Objective: To assess the impact of neuraxial analgesia on the risk of relapse during the first 3 months post-partum, with a focus on women who experienced relapses during pregnancy. Methods: We analyzed data of women followed-up prospectively during their pregnancies and at least 3 months post-partum, collected in the Pregnancy in Multiple Sclerosis (PRIMS) and Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPARTMUS) studies between 1992–1995 and 2005–2012, respectively. The association of neuraxial analgesia with the occurrence of a post-partum relapse was estimated by logistic regression analysis. Results: A total of 389 women were included, 215 from PRIMS and 174 from POPARTMUS. In total, 156 women (40%) had neuraxial analgesia. Overall, 24% experienced a relapse during pregnancy and 25% in the 3 months post-partum. Women with a pregnancy relapse were more likely to have a post-partum relapse (odds ratio (OR) = 1.83, p = 0.02), independently of the use of neuraxial analgesia. There was no association between neuraxial analgesia and post-partum relapse (OR = 1.08, p = 0.78). Conclusion: Neuraxial analgesia was not associated with an increased risk of post-partum relapses, whatever multiple sclerosis (MS) activity during pregnancy.

Published
2019
Full Text
View/download PDF

2. Rate of pregnancy-related relapse in multiple sclerosis

Author

Confavreux C, Hutchinson M, Hours, Mm, Cortinovis Tourniaire, P, Alpérovitch, Moreau T. A., Carton, H., D’Hooghe, M. B., Hommes, O., Biron, A., Grimaud, J., Chauplannaz, G., Latombe, D., Clanet, M., Glau, G. Lau, Rumbach, L., Goas, J. Y., Rouhart, F., Ingue, A. Maz, Roullet, E., Madigand, M., Hautecoeur, P., Brunet, P., Edan, G., Allaire, C., Riffault, G., Leche, J., Benoit, T., Simonin, C., Ziegler, F., Baron, J. C., Rivrain, Y., Dumas, R., Loche, D., Bourrin, J. C., Huttin, B., Delisse, B., Gibert, I., Boulay, C., Verceletto, M., Durand, G., Bonneviot, G., Gil, R., Hedreville, M. A., Cbelair, C. Belair, Poitevin, R. J., Devoize, J. L., Pwyremblewski, P. Wyremblewski, Delestre, F., Setiey, A., Comi, G., Fillippi, M., Ghezzi, A., Martinelli, V., Rossi, P., Zaffaroni, M., Tola, M. R., Amato, M. P., Fioretti, C., Gmeucci, G. Meucci, Inglese, MARIA MATILDE, Mancardi, GIOVANNI LUIGI, Gambi, D., Thomas, A., Cavazzuti, M., Citterio, A., Aheltberg, A. Heltberg, Hansen, H. J., Fernandez, O., Romero, F., Arbizu, T., Hernandez, J. J., Frutos, C. De Andres de, Sclarky, D. Geffner, Benito, Y. Aladro, Yanez, P. Reyes, Aguilar, M., Burguera, J. A., Yaya, R., Dib, W. Bowakim, Sindic, C. J. M., Medaer, R., Roose, H., Geens, K. M. J., Guillaume, D., Zandycke, M. Van, Janssens, J., Cornette, M., Mol, L., Weilbach, F., Flachenecke, P., Hartung, H. P., Haas, J., Tendolkar, I., Sindern, E., Kölmel, H. W., Reichel, D., Rauch, M., Preuss, S., Poser, S., Mauch, E., Strasser Fuchs, S., Kollegger, H., Hawkins, S., Howell, S. J. L., Rees, J. E., Thompson, A., Johnson, M., Boggild, M., Gregory, R. P., Bates, D., Bone, I., Polman, C., Frequin, S., Jongen, P., J. Correia de, Sa, Rio, M. E., Huber, S., Lechner Scott, J., Confavreux, C, Hutchinson, M, Hours, Mm, Cortinovis Tourniaire, P, Moreau, T, the Pregnancy in Multiple Sclerosis, Group, Filippi, Massimo, and Comi, Giancarlo

Subjects
Adult, medicine.medical_specialty, Multiple Sclerosis, Obstetrical, Disease, Relapse rate, Kurtzke Expanded Disability Status Scale, Central nervous system disease, Pregnancy, Recurrence, medicine, Humans, Prospective Studies, Severe disability, Prospective cohort study, Post partum, Analgesia, Epidural, Analgesia, Obstetrical, Breast Feeding, Disease Progression, Female, Postpartum Period, Pregnancy Complications, Medicine (all), business.industry, Obstetrics, Multiple sclerosis, General Medicine, medicine.disease, Surgery, First trimester, Epidural, Gestation, Analgesia, business, Complication, Breast feeding, Postpartum period
Abstract

Background and Methods Multiple sclerosis often occurs in young women, and the effect of pregnancy on the disease is poorly understood. We studied 254 women with multiple sclerosis during 269 pregnancies in 12 European countries. The women were followed during their pregnancies and for up to 12 months after delivery to determine the rate of relapse per trimester and the score on the Kurtzke Expanded Disability Status Scale (range, 0 to 10, with higher scores indicating more severe disability). The relapse rate in each trimester was compared with the rate during the year before the pregnancy. The effects of epidural analgesia and breast-feeding on the frequency of relapse during the first three months post partum and the disability score at 12 months post partum were also determined. Results The mean (±SD) rate of relapse was 0.7±0.9 per woman per year in the year before pregnancy; it was 0.5±1.3 during the first trimester (P=0.03 for the comparison with the rate before pregnancy), 0.6±1.6 during the secon...

Published
1998

3. Increased p16 levels correlate with pRb alterations in human urothelial cells

Author

T, Yeager, W, Stadler, C, Belair, J, Puthenveettil, O, Olopade, and C, Reznikoff

Subjects
Carcinoma, Transitional Cell, Polymorphism, Genetic, Base Sequence, Molecular Sequence Data, Urinary Bladder, Chromosome Mapping, Gene Expression, Epithelial Cells, Polymerase Chain Reaction, Epithelium, Urinary Bladder Neoplasms, Tumor Cells, Cultured, Humans, Genes, Tumor Suppressor, RNA, Messenger, Chromosome Deletion, Genes, Retinoblastoma, Carrier Proteins, Chromosomes, Human, Pair 9, Cells, Cultured, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, DNA Primers, Repetitive Sequences, Nucleic Acid
Abstract

The CDKN2 (MTS1) gene is located at 9p21; its product, p16, inhibits the cyclin D/CDK4 complex that phosphorylates pRb, thus negatively regulating cell cycle progression [M. Serrano et al., Nature (Lond.), 366: 704, 1994; A. Kamb et al., Science (Washington DC), 264: 436, 1994; T. Nobori et al., Nature (Lond.), 368: 753, 1994]. CDKN2 mutations are more common in cultured human uroepithelial cells (HUC) than in uncultured bladder cancers. We examined the status of CDKN2/p16 in early and late passage (P) cultures of HUC. HUC immortalization was not accompanied by p16 loss, even in cells with a hemizygous 9p21-pter deletion, but late passage cultures with a p16 loss showed decreased generation time. Thus, the data do not indicate that CDKN2 is a candidate for a chromosome 9 senescence gene but suggest that p16 loss may confer a growth advantage in vitro. Significant differences in p16 levels were observed among HUC cell lines, but no CDKN2 mutations were detected. However, an inverse correlation between elevated p16 and loss of pRb function was observed (P10(-4)). Ten samples with normal pRb showed low or undetectable p16 levels, while seven samples with known pRb alterations showed abundant p16 but nevertheless grew vigorously in culture. These results support the hypothesis that p16 mediated cell cycle inhibition, as well as p16 regulation, occurs via pRb dependent pathway(s).

Published
1995

4. [Computed tomography in schizophrenic patients. Results from 15 patients. Review of the literature (author's transl)]

Author

M, Reynaud, C, Belair, A, Majdalani, and J, Metzger

Subjects
Adult, Male, Schizophrenia, Brain, Humans, Female, Atrophy, Middle Aged, Tomography, X-Ray Computed
Abstract

The authors analyzed the scans of 15 chronic schizophrenic patients, apparently deteriorated, all of whom were long standing in-patients. They found 11 pathological cases (6 cortical atrophies and ventricular enlargement, 3 ventricular enlargement, 1 cortical atrophy, 1 cerebellar atrophy). With one exception all these atrophies were slight. The authors findings are comparable with those already reported in other studies. The article also summarizes the results of earlier studies of schizophrenics, by pneumoencephalography which are similar. Although no firm conclusions can be drawn, for such a limited sample, in particular due to the lack of any visible correlation between the pictures obtained and clinical diagnosis or prognosis, the consistent appearance of tomographic anomalies justifies continued research on these lines.

Published
1981

5. Full-length direct RNA sequencing uncovers stress granule-dependent RNA decay upon cellular stress.

Author

Dar SA, Malla S, Martinek V, Payea MJ, Lee CT, Martin J, Khandeshi AJ, Martindale JL, Belair C, and Maragkakis M

Subjects
Humans, RNA Helicases metabolism, RNA Helicases genetics, Stress Granules metabolism, Stress Granules genetics, Transcriptome, DNA Helicases metabolism, DNA Helicases genetics, Adaptor Proteins, Signal Transducing metabolism, Adaptor Proteins, Signal Transducing genetics, Ribosomes metabolism, Microtubule-Associated Proteins, RNA-Binding Proteins, RNA Stability genetics, Stress, Physiological genetics, Exoribonucleases metabolism, Exoribonucleases genetics, RNA Recognition Motif Proteins metabolism, RNA Recognition Motif Proteins genetics, Sequence Analysis, RNA, Poly-ADP-Ribose Binding Proteins metabolism, Poly-ADP-Ribose Binding Proteins genetics
Abstract

Cells react to stress by triggering response pathways, leading to extensive alterations in the transcriptome to restore cellular homeostasis. The role of RNA metabolism in shaping the cellular response to stress is vital, yet the global changes in RNA stability under these conditions remain unclear. In this work, we employ direct RNA sequencing with nanopores, enhanced by 5' end adapter ligation, to comprehensively interrogate the human transcriptome at single-molecule and -nucleotide resolution. By developing a statistical framework to identify robust RNA length variations in nanopore data, we find that cellular stress induces prevalent 5' end RNA decay that is coupled to translation and ribosome occupancy. Unlike typical RNA decay models in normal conditions, we show that stress-induced RNA decay is dependent on XRN1 but does not depend on deadenylation or decapping. We observed that RNAs undergoing decay are predominantly enriched in the stress granule transcriptome while inhibition of stress granule formation via genetic ablation of G3BP1 and G3BP2 rescues RNA length. Our findings reveal RNA decay as a key component of RNA metabolism upon cellular stress that is dependent on stress granule formation., Competing Interests: SD, SM, VM, MP, CL, JM, AK, JM, CB, MM No competing interests declared

Published
2024
Full Text
View/download PDF

6. Senescence suppresses the integrated stress response and activates a stress-remodeled secretory phenotype.

Author

Payea MJ, Dar SA, Anerillas C, Martindale JL, Belair C, Munk R, Malla S, Fan J, Piao Y, Yang X, Rehman A, Banskota N, Abdelmohsen K, Gorospe M, and Maragkakis M

Subjects
Humans, Phosphorylation, Protein Biosynthesis, Open Reading Frames, Senescence-Associated Secretory Phenotype genetics, Signal Transduction, Phenotype, Fibroblasts metabolism, RNA, Messenger metabolism, RNA, Messenger genetics, Inflammation Mediators metabolism, Activating Transcription Factor 4 metabolism, Activating Transcription Factor 4 genetics, Cellular Senescence, Eukaryotic Initiation Factor-2 metabolism, Eukaryotic Initiation Factor-2 genetics, Stress, Physiological
Abstract

Senescence is a state of indefinite cell-cycle arrest associated with aging, cancer, and age-related diseases. Here, we find that translational deregulation, together with a corresponding maladaptive integrated stress response (ISR), is a hallmark of senescence that desensitizes senescent cells to stress. We present evidence that senescent cells maintain high levels of eIF2α phosphorylation, typical of ISR activation, but translationally repress production of the stress response activating transcription factor 4 (ATF4) by ineffective bypass of the inhibitory upstream open reading frames (uORFs). Surprisingly, ATF4 translation remains inhibited even after acute proteotoxic and amino acid starvation stressors, resulting in a highly diminished stress response. We also find that stress augments the senescence-associated secretory phenotype with sustained remodeling of inflammatory factors expression that is suppressed by non-uORF carrying ATF4 mRNA expression. Our results thus show that senescent cells possess a unique response to stress, which entails an increase in their inflammatory profile., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Published
2024
Full Text
View/download PDF

7. Deep learning and direct sequencing of labeled RNA captures transcriptome dynamics.

Author

Martinek V, Martin J, Belair C, Payea MJ, Malla S, Alexiou P, and Maragkakis M

Abstract

In eukaryotes, genes produce a variety of distinct RNA isoforms, each with potentially unique protein products, coding potential or regulatory signals such as poly(A) tail and nucleotide modifications. Assessing the kinetics of RNA isoform metabolism, such as transcription and decay rates, is essential for unraveling gene regulation. However, it is currently impeded by lack of methods that can differentiate between individual isoforms. Here, we introduce RNAkinet, a deep convolutional and recurrent neural network, to detect nascent RNA molecules following metabolic labeling with the nucleoside analog 5-ethynyl uridine and long-read, direct RNA sequencing with nanopores. RNAkinet processes electrical signals from nanopore sequencing directly and distinguishes nascent from pre-existing RNA molecules. Our results show that RNAkinet prediction performance generalizes in various cell types and organisms and can be used to quantify RNA isoform half-lives. RNAkinet is expected to enable the identification of the kinetic parameters of RNA isoforms and to facilitate studies of RNA metabolism and the regulatory elements that influence it., (Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics 2024.)

Published
2024
Full Text
View/download PDF

8. Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging.

Author

Occean JR, Yang N, Sun Y, Dawkins MS, Munk R, Belair C, Dar S, Anerillas C, Wang L, Shi C, Dunn C, Bernier M, Price NL, Kim JS, Cui CY, Fan J, Bhattacharyya M, De S, Maragkakis M, de Cabo R, Sidoli S, and Sen P

Subjects
Animals, Mice, Humans, Mice, Inbred C57BL, Longevity genetics, Male, Alternative Splicing, Transcription, Genetic, Female, Gene Expression Regulation, DNA Methylation, Aging genetics, Aging metabolism, 5-Methylcytosine metabolism, 5-Methylcytosine analogs & derivatives, Liver metabolism, Cerebellum metabolism
Abstract

DNA hydroxymethylation (5hmC), the most abundant oxidative derivative of DNA methylation, is typically enriched at enhancers and gene bodies of transcriptionally active and tissue-specific genes. Although aberrant genomic 5hmC has been implicated in age-related diseases, its functional role in aging remains unknown. Here, using mouse liver and cerebellum as model organs, we show that 5hmC accumulates in gene bodies associated with tissue-specific function and restricts the magnitude of gene expression changes with age. Mechanistically, 5hmC decreases the binding of splicing associated factors and correlates with age-related alternative splicing events. We found that various age-related contexts, such as prolonged quiescence and senescence, drive the accumulation of 5hmC with age. We provide evidence that this age-related transcriptionally restrictive function is conserved in mouse and human tissues. Our findings reveal that 5hmC regulates tissue-specific function and may play a role in longevity., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Published
2024
Full Text
View/download PDF

9. Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.

Author

Seddighi S, Qi YA, Brown AL, Wilkins OG, Bereda C, Belair C, Zhang YJ, Prudencio M, Keuss MJ, Khandeshi A, Pickles S, Kargbo-Hill SE, Hawrot J, Ramos DM, Yuan H, Roberts J, Sacramento EK, Shah SI, Nalls MA, Colón-Mercado JM, Reyes JF, Ryan VH, Nelson MP, Cook CN, Li Z, Screven L, Kwan JY, Mehta PR, Zanovello M, Hallegger M, Shantaraman A, Ping L, Koike Y, Oskarsson B, Staff NP, Duong DM, Ahmed A, Secrier M, Ule J, Jacobson S, Reich DS, Rohrer JD, Malaspina A, Dickson DW, Glass JD, Ori A, Seyfried NT, Maragkakis M, Petrucelli L, Fratta P, and Ward ME

Subjects
Humans, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Peptides, Proteomics, Amyotrophic Lateral Sclerosis genetics, Frontotemporal Dementia genetics
Abstract

Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43-depleted human iPSC-derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43-depleted human iPSC-derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43-depleted human iPSC-derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.

Published
2024
Full Text
View/download PDF

10. Differential Poly(A) Tail Length Analysis Using Nanopore Sequencing.

Author

Dar SA, Malla S, Belair C, and Maragkakis M

Subjects
Nucleotidyltransferases, RNA, Messenger genetics, RNA, Messenger metabolism, Nucleotides, Poly A genetics, Poly A metabolism, Nanopore Sequencing
Abstract

The poly(A) tail is a sequence of several adenosine nucleotides added to the 3' end of RNA molecules transcribed by polymerase II. The dynamics of poly(A) tail length play a significant role in regulating post-transcriptional gene expression by regulating the stability, translation, and decay of messenger RNAs. As a result, an accurate measurement of poly(A) tail length changes is important for understanding its regulatory function in different cellular contexts. Here, we outline a method for using nanopore sequencing and linear mixed models to analyze differences in poly(A) tail length across conditions., (© 2024. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Published
2024
Full Text
View/download PDF

11. Senescence suppresses the integrated stress response and activates a stress-enhanced secretory phenotype.

Author

Payea MJ, Dar SA, Anerillas C, Martindale JL, Belair C, Munk R, Malla S, Fan J, Piao Y, Yang X, Rehman A, Banskota N, Abdelmohsen K, Gorospe M, and Maragkakis M

Abstract

Senescence is a state of indefinite cell cycle arrest associated with aging, cancer, and age-related diseases. Here, using label-based mass spectrometry, ribosome profiling and nanopore direct RNA sequencing, we explore the coordinated interaction of translational and transcriptional programs of human cellular senescence. We find that translational deregulation and a corresponding maladaptive integrated stress response (ISR) is a hallmark of senescence that desensitizes senescent cells to stress. We present evidence that senescent cells maintain high levels of eIF2α phosphorylation, typical of ISR activation, but translationally repress production of the stress response transcription factor 4 (ATF4) by ineffective bypass of the inhibitory upstream open reading frames. Surprisingly, ATF4 translation remains inhibited even after acute proteotoxic and amino acid starvation stressors, resulting in a highly diminished stress response. Furthermore, absent a response, stress augments the senescence secretory phenotype, thus intensifying a proinflammatory state that exacerbates disease. Our results reveal a novel mechanism that senescent cells exploit to evade an adaptive stress response and remain viable., Competing Interests: Declaration of interests The authors declare no competing interests.

Published
2023
Full Text
View/download PDF

12. Deep learning and direct sequencing of labeled RNA captures transcriptome dynamics.

Author

Martinek V, Martin J, Belair C, Payea MJ, Malla S, Alexiou P, and Maragkakis M

Abstract

Quantification of the dynamics of RNA metabolism is essential for understanding gene regulation in health and disease. Existing methods rely on metabolic labeling of nascent RNAs and physical separation or inference of labeling through PCR-generated mutations, followed by short-read sequencing. However, these methods are limited in their ability to identify transient decay intermediates or co-analyze RNA decay with cis-regulatory elements of RNA stability such as poly(A) tail length and modification status, at single molecule resolution. Here we use 5-ethynyl uridine (5EU) to label nascent RNA followed by direct RNA sequencing with nanopores. We developed RNAkinet, a deep convolutional and recurrent neural network that processes the electrical signal produced by nanopore sequencing to identify 5EU-labeled nascent RNA molecules. RNAkinet demonstrates generalizability to distinct cell types and organisms and reproducibly quantifies RNA kinetic parameters allowing the combined interrogation of RNA metabolism and cis-acting RNA regulatory elements.

Published
2023
Full Text
View/download PDF

13. Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.

Author

Seddighi S, Qi YA, Brown AL, Wilkins OG, Bereda C, Belair C, Zhang Y, Prudencio M, Keuss MJ, Khandeshi A, Pickles S, Hill SE, Hawrot J, Ramos DM, Yuan H, Roberts J, Kelmer Sacramento E, Shah SI, Nalls MA, Colon-Mercado J, Reyes JF, Ryan VH, Nelson MP, Cook C, Li Z, Screven L, Kwan JY, Shantaraman A, Ping L, Koike Y, Oskarsson B, Staff N, Duong DM, Ahmed A, Secrier M, Ule J, Jacobson S, Rohrer J, Malaspina A, Glass JD, Ori A, Seyfried NT, Maragkakis M, Petrucelli L, Fratta P, and Ward ME

Abstract

Functional loss of TDP-43, an RNA-binding protein genetically and pathologically linked to ALS and FTD, leads to inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. However, the possibility of de novo protein synthesis from cryptic exon transcripts has not been explored. Here, we show that mRNA transcripts harboring cryptic exons generate de novo proteins both in TDP-43 deficient cellular models and in disease. Using coordinated transcriptomic and proteomic studies of TDP-43 depleted iPSC-derived neurons, we identified numerous peptides that mapped to cryptic exons. Cryptic exons identified in iPSC models were highly predictive of cryptic exons expressed in brains of patients with TDP-43 proteinopathy, including cryptic transcripts that generated de novo proteins. We discovered that inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Finally, we showed that these de novo peptides were present in CSF from patients with ALS. The demonstration of cryptic exon translation suggests new mechanisms for ALS pathophysiology downstream of TDP-43 dysfunction and may provide a strategy for novel biomarker development., Competing Interests: Competing interests: MAN, ZL, and SIS’s participation in this project was part of a competitive contract awarded to Data Tecnica International LLC by the National Institutes of Health to support open science research. MAN also currently serves as an advisor for Character Biosciences and Neuron23 Inc.

Published
2023
Full Text
View/download PDF

14. Effect of UV-absorbing Contact Lenses on Conjunctival Ultraviolet Autofluorescence.

Author

Haworth K and Belair C

Subjects
Adult, Cross-Sectional Studies, Female, Humans, Male, Optical Imaging, Sunlight, Young Adult, Absorption, Radiation physiology, Conjunctiva radiation effects, Contact Lenses, Hydrophilic, Corneal Diseases prevention & control, Radiation Injuries prevention & control, Ultraviolet Rays adverse effects
Abstract

Purpose: The intended purpose of UV-absorbing contact lenses is to protect the cornea and posterior ocular structures from UV-induced damage. Few studies report conjunctival effects of UV-absorbing contact lens materials. The purpose of this study was to evaluate conjunctival ultraviolet autofluorescence (UVAF) for contact lens wearers of UV-absorbing and minimally UV-absorbing materials., Methods: Forty-four volunteers enrolled in the cross-sectional study. Three groups were recruited; non-contact lens wearers (n = 15), minimally UV-absorbing contact lens wearers (n = 15), and UV-absorbing contact lens wearers (n = 14). Ocular sun exposure was calculated using self-reported measures. Conjunctival UVAF images of temporal and nasal conjunctiva, acquired using a Nikon D7000 camera system adapted with appropriate flash and filter system, were analyzed using ImageJ. A sub-group of participants including only subjects with measurable UVAF was analyzed., Results: No significant differences were present between groups found similar for age, gender, and ocular sun exposure. The area of UVAF significantly increased following lens removal for UV-absorbing contact lens wearers compared with non-contact lens wearers. Furthermore, for contact lens wearers compared with non-lens wearers, area of UVAF was significantly greater between right and left eyes (p = .04 minimally UV-absorbing, p = .01 UV-absorbing), and between nasal (p = .046 minimally UV-absorbing, p = .01 UV-absorbing), and temporal (p = .01 UV-absorbing) areas. However, no significant difference was found between contact lens wearers of the two groups. No difference was found between nasal and temporal UVAF regions during contact lens wear (p = .28) or after lens removal (p = .16) (Mann-Whitney U)., Conclusions: Contact lens materials have conjunctival effects, with increased UVAF in both UV-absorbing and minimally UV-absorbing contact lens wearers compared with non-lens wearers. UV-absorbing and minimally UV-absorbing contact lens materials appear to influence nasal and temporal areas of the ocular surface equally.

Published
2020
Full Text
View/download PDF

15. The RNA exosome nuclease complex regulates human embryonic stem cell differentiation.

Author

Belair C, Sim S, Kim KY, Tanaka Y, Park IH, and Wolin SL

Subjects
Cross-Linking Reagents chemistry, Endoderm embryology, Endoderm metabolism, Forkhead Transcription Factors genetics, Forkhead Transcription Factors metabolism, Gene Expression Regulation, HeLa Cells, Humans, Long Interspersed Nucleotide Elements genetics, Mesoderm embryology, Mesoderm metabolism, MicroRNAs genetics, Phenotype, RNA isolation & purification, RNA, Long Noncoding genetics, RNA, Messenger genetics, RNA, Messenger metabolism, RNA, Small Interfering metabolism, Transcription, Genetic, Transgenes, Cell Differentiation, Exosome Multienzyme Ribonuclease Complex metabolism, Human Embryonic Stem Cells cytology, Human Embryonic Stem Cells metabolism
Abstract

A defining feature of embryonic stem cells (ESCs) is the ability to differentiate into all three germ layers. Pluripotency is maintained in part by a unique transcription network that maintains expression of pluripotency-specific transcription factors and represses developmental genes. While the mechanisms that establish this transcription network are well studied, little is known of the posttranscriptional surveillance pathways that degrade differentiation-related RNAs. We report that the surveillance pathway mediated by the RNA exosome nuclease complex represses ESC differentiation. Depletion of the exosome expedites differentiation of human ESCs into all three germ layers. LINE-1 retrotransposons and specific miRNAs, lncRNAs, and mRNAs that encode developmental regulators or affect their expression are all bound by the exosome and increase in level upon exosome depletion. The exosome restrains differentiation in part by degrading transcripts encoding FOXH1, a transcription factor crucial for mesendoderm formation. Our studies establish the exosome as a regulator of human ESC differentiation and reveal the importance of RNA decay in maintaining pluripotency., (© 2019 Belair et al.)

Published
2019
Full Text
View/download PDF

16. Noncoding RNA Surveillance: The Ends Justify the Means.

Author

Belair C, Sim S, and Wolin SL

Subjects
Animals, Exosomes metabolism, Humans, DNA, Fungal genetics, RNA, Untranslated genetics, Saccharomyces cerevisiae genetics
Abstract

Numerous surveillance pathways sculpt eukaryotic transcriptomes by degrading unneeded, defective, and potentially harmful noncoding RNAs (ncRNAs). Because aberrant and excess ncRNAs are largely degraded by exoribonucleases, a key characteristic of these RNAs is an accessible, protein-free 5' or 3' end. Most exoribonucleases function with cofactors that recognize ncRNAs with accessible 5' or 3' ends and/or increase the availability of these ends. Noncoding RNA surveillance pathways were first described in budding yeast, and there are now high-resolution structures of many components of the yeast pathways and significant mechanistic understanding as to how they function. Studies in human cells are revealing the ways in which these pathways both resemble and differ from their yeast counterparts, and are also uncovering numerous pathways that lack equivalents in budding yeast. In this review, we describe both the well-studied pathways uncovered in yeast and the new concepts that are emerging from studies in mammalian cells. We also discuss the ways in which surveillance pathways compete with chaperone proteins that transiently protect nascent ncRNA ends from exoribonucleases, with partner proteins that sequester these ends within RNPs, and with end modification pathways that protect the ends of some ncRNAs from nucleases.

Published
2018
Full Text
View/download PDF

17. Non-coding Y RNAs as tethers and gates: Insights from bacteria.

Author

Wolin SL, Belair C, Boccitto M, Chen X, Sim S, Taylor DW, and Wang HW

Subjects
Amino Acid Sequence, Animals, Molecular Sequence Data, Nucleic Acid Conformation, RNA, Untranslated chemistry, RNA-Binding Proteins metabolism, Ribonucleoproteins metabolism, RNA, Untranslated metabolism
Abstract

Non-coding RNAs (ncRNAs) called Y RNAs are abundant components of both animal cells and a variety of bacteria. In all species examined, these ~100 nt RNAs are bound to the Ro 60 kDa (Ro60) autoantigen, a ring-shaped protein that also binds misfolded ncRNAs in some vertebrate nuclei. Although the function of Ro60 RNPs has been mysterious, we recently reported that a bacterial Y RNA tethers Ro60 to the 3' to 5' exoribonuclease polynucleotide phosphorylase (PNPase) to form RYPER (Ro60/Y RNA/PNPase Exoribonuclease RNP), a new RNA degradation machine. PNPase is a homotrimeric ring that degrades single-stranded RNA, and Y RNA-mediated tethering of Ro60 increases the effectiveness of PNPase in degrading structured RNAs. Single particle electron microscopy of RYPER suggests that RNA threads through the Ro60 ring into the PNPase cavity. Further studies indicate that Y RNAs may also act as gates to regulate entry of RNA substrates into the Ro60 channel. These findings reveal novel functions for Y RNAs and raise questions about how the bacterial findings relate to the roles of these ncRNAs in animal cells. Here we review the literature on Y RNAs, highlighting their close relationship with Ro60 proteins and the hypothesis that these ncRNAs function generally to tether Ro60 rings to diverse RNA-binding proteins.

Published
2013
Full Text
View/download PDF

18. Helicobacter pylori interferes with an embryonic stem cell micro RNA cluster to block cell cycle progression.

Author

Belair C, Baud J, Chabas S, Sharma CM, Vogel J, Staedel C, and Darfeuille F

Abstract

Background: MicroRNAs, post-transcriptional regulators of eukaryotic gene expression, are implicated in host defense against pathogens. Viruses and bacteria have evolved strategies that suppress microRNA functions, resulting in a sustainable infection. In this work we report that Helicobacter pylori, a human stomach-colonizing bacterium responsible for severe gastric inflammatory diseases and gastric cancers, downregulates an embryonic stem cell microRNA cluster in proliferating gastric epithelial cells to achieve cell cycle arrest., Results: Using a deep sequencing approach in the AGS cell line, a widely used cell culture model to recapitulate early events of H. pylori infection of gastric mucosa, we reveal that hsa-miR-372 is the most abundant microRNA expressed in this cell line, where, together with hsa-miR-373, it promotes cell proliferation by silencing large tumor suppressor homolog 2 (LATS2) gene expression. Shortly after H. pylori infection, miR-372 and miR-373 synthesis is highly inhibited, leading to the post-transcriptional release of LATS2 expression and thus, to a cell cycle arrest at the G1/S transition. This downregulation of a specific cell-cycle-regulating microRNA is dependent on the translocation of the bacterial effector CagA into the host cells, a mechanism highly associated with the development of severe atrophic gastritis and intestinal-type gastric carcinoma., Conclusions: These data constitute a novel example of host-pathogen interplay involving microRNAs, and unveil the couple LATS2/miR-372 and miR-373 as an unexpected mechanism in infection-induced cell cycle arrest in proliferating gastric cells, which may be relevant in inhibition of gastric epithelium renewal, a major host defense mechanism against bacterial infections.

Published
2011
Full Text
View/download PDF

19. Helicobacter pylori and gastric cancer: possible role of microRNAs in this intimate relationship.

Author

Belair C, Darfeuille F, and Staedel C

Subjects
Gene Expression Regulation, Humans, MicroRNAs metabolism, Helicobacter Infections complications, Helicobacter pylori pathogenicity, MicroRNAs genetics, Stomach Neoplasms microbiology
Abstract

Chronic infection by Helicobacter pylori is a major risk factor for gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma. H. pylori possesses a set of virulence factors, including the CagA effector, which interferes with intracellular signalling pathways and mediates phenotypic alterations, strongly evoking neoplasic transformation. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression involved in development, cell proliferation and immune responses. miRNAs are frequently altered in cancers, revealing their functions as oncogenes or tumour suppressors. However, the role, if any, that miRNAs play in the host cell responses to H. pylori remains unknown. This review considers the possible involvement of some miRNAs, including miR-146, miR-155, miR-21, miR-27a, miR-106-93-25 and miR-221-222 clusters and the miR-200 family in H. pylori-induced infection and gastric cancers. Further exploration of miRNA-mediated gene silencing, taking into account the relationship between host targets and bacterial effectors, will most certainly bring new insights into the control of gene expression in human gastric cells chronically infected by H. pylori.

Published
2009
Full Text
View/download PDF

20. Construction and application of a zebrafish array comparative genomic hybridization platform.

Author

Freeman JL, Ceol C, Feng H, Langenau DM, Belair C, Stern HM, Song A, Paw BH, Look AT, Zhou Y, Zon LI, and Lee C

Subjects
Animals, Animals, Genetically Modified, Chromosomes, Artificial, Bacterial, Disease Models, Animal, Humans, In Situ Hybridization, Fluorescence, Melanoma genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Reproducibility of Results, Rhabdomyosarcoma genetics, Zebrafish metabolism, Comparative Genomic Hybridization methods, Genes, Tumor Suppressor, Oligonucleotide Array Sequence Analysis methods, Oncogenes, Zebrafish genetics
Abstract

The zebrafish is emerging as a prominent model system for studying the genetics of human development and disease. Genetic alterations that underlie each mutant model can exist in the form of single base changes, balanced chromosomal rearrangements, or genetic imbalances. To detect genetic imbalances in an unbiased genome-wide fashion, array comparative genomic hybridization (CGH) can be used. We have developed a 5-Mb resolution array CGH platform specifically for the zebrafish. This platform contains 286 bacterial artificial chromosome (BAC) clones, enriched for orthologous sequences of human oncogenes and tumor suppressor genes. Each BAC clone has been end-sequenced and cytogenetically assigned to a specific location within the zebrafish genome, allowing for ease of integration of array CGH data with the current version of the genome assembly. This platform has been applied to three zebrafish cancer models. Significant genomic imbalances were detected in each model, identifying different regions that may potentially play a role in tumorigenesis. Hence, this platform should be a useful resource for genetic dissection of additional zebrafish developmental and disease models as well as a benchmark for future array CGH platform development.

Published
2009
Full Text
View/download PDF

21. Regulating mRNA translation with a kiss.

Author

Dausse E, Belair C, Staedel C, and Toulmé JJ

Subjects
Cell Line, Tumor, Hepacivirus genetics, Humans, Nucleic Acid Conformation, RNA, Messenger chemistry, RNA, Viral chemistry, Aptamers, Nucleotide chemistry, Gene Expression Regulation, Protein Biosynthesis
Abstract

Loop-loop interactions mediate the recognition between RNA hairpins leading to the formation of so-called kissing complexes. Both the size and the sequence of the loop are critical for ensuring stable interaction. Using in vitro selection we have characterized a few loop sequences that lead to the formation of highly stable kissing complexes. These sequences constitute targets of interest for the rational design of RNA stem loop ligands. Such an appropriate target sequence was identified in a sub-domain of the Internal Ribosomal Entry Site (IRES) of the Hepatitis C Virus (HCV) mRNA. We synthesized chemically-modified RNA hairpins and demonstrated that they specifically reduced the expression of a HCV IRES driven reporter gene in cultured cells.

Published
2008
Full Text
View/download PDF

22. Homozygous nonsense mutation in the MCEE gene and siRNA suppression of methylmalonyl-CoA epimerase expression: a novel cause of mild methylmalonic aciduria.

Author

Dobson CM, Gradinger A, Longo N, Wu X, Leclerc D, Lerner-Ellis J, Lemieux M, Belair C, Watkins D, Rosenblatt DS, and Gravel RA

Subjects
Cell Culture Techniques, Cell Line, Child, Female, Fibroblasts, Genetic Complementation Test, HeLa Cells, Homozygote, Humans, Male, Membrane Transport Proteins genetics, Mitochondrial Membrane Transport Proteins, Mitochondrial Proteins genetics, Polymerase Chain Reaction, RNA Interference, RNA, Small Interfering, Transfection, Codon, Nonsense, Metabolism, Inborn Errors genetics, Methylmalonic Acid urine, Racemases and Epimerases genetics
Abstract

Methylmalonyl-CoA epimerase (MCE) catalyzes the interconversion of D- and L-methylmalonyl-CoA in the pathway responsible for the degradation of branched chain amino acids, odd chain-length fatty acids, and other metabolites. Despite the occurrence of metabolic disorders in the enzymatic step occurring immediately upstream of MCE (propionyl-CoA carboxylase) and downstream of MCE (adenosylcobalamin-dependent methylmalonyl-CoA mutase), no disease-causing mutations have been described affecting MCE itself. A patient, formerly identified as belonging to the cblA complementation group of vitamin B12 disorders but lacking mutations in the affected gene, MMAA, was tested for mutations in the MCEE gene. The patient's fibroblasts had normal levels of adenosylcobalamin compared to controls, whereas other cblA cell lines typically had reduced levels of the cofactor. As well, this patient had a milder form of methylmalonic aciduria than usually observed in cblA patients. The patient was found to be homozygous for a c.139C>T (p.R47X) mutation in MCEE by sequence analysis that was confirmed by restriction digestion of PCR products. One sibling, also with mild methylmalonic aciduria, was homozygous for the mutation. Both parents and one other sibling were heterozygous. A nearby insertion polymorphism, c.41-160_161insT, heterozygous in both parents, showed the wild-type configuration on the mutant alleles. To assess the impact of isolated MCE deficiency in cultured cells, HeLa cells were transfected with a selectable vector containing MCEE-specific small interfering RNA (siRNA) to suppress gene expression. The reduced level of MCEE mRNA resulted in the reduction of [14C]-propionate incorporation into cellular macromolecules. However, siRNA only led to a small reduction in pathway activity, suggesting that previously postulated non-enzymatic conversion of D- to L-methylmalonyl-CoA may contribute to some flux through the pathway. We conclude that the patient's MCEE defect was responsible for the mild methylmalonic aciduria, confirming a partial requirement for the enzymatic activity in humans.

Published
2006
Full Text
View/download PDF

23. Increased p16 levels correlate with pRb alterations in human urothelial cells.

Author

Yeager T, Stadler W, Belair C, Puthenveettil J, Olopade O, and Reznikoff C

Subjects
Base Sequence, Carcinoma, Transitional Cell genetics, Cells, Cultured, Cellular Senescence, Chromosome Mapping, Cyclin-Dependent Kinase Inhibitor p16, DNA Primers, Epithelial Cells, Epithelium metabolism, Gene Expression, Genes, Tumor Suppressor, Humans, Molecular Sequence Data, Polymerase Chain Reaction, Polymorphism, Genetic, RNA, Messenger analysis, RNA, Messenger biosynthesis, Repetitive Sequences, Nucleic Acid, Tumor Cells, Cultured, Urinary Bladder cytology, Urinary Bladder Neoplasms genetics, Carrier Proteins genetics, Chromosome Deletion, Chromosomes, Human, Pair 9, Genes, Retinoblastoma, Urinary Bladder metabolism
Abstract

The CDKN2 (MTS1) gene is located at 9p21; its product, p16, inhibits the cyclin D/CDK4 complex that phosphorylates pRb, thus negatively regulating cell cycle progression [M. Serrano et al., Nature (Lond.), 366: 704, 1994; A. Kamb et al., Science (Washington DC), 264: 436, 1994; T. Nobori et al., Nature (Lond.), 368: 753, 1994]. CDKN2 mutations are more common in cultured human uroepithelial cells (HUC) than in uncultured bladder cancers. We examined the status of CDKN2/p16 in early and late passage (P) cultures of HUC. HUC immortalization was not accompanied by p16 loss, even in cells with a hemizygous 9p21-pter deletion, but late passage cultures with a p16 loss showed decreased generation time. Thus, the data do not indicate that CDKN2 is a candidate for a chromosome 9 senescence gene but suggest that p16 loss may confer a growth advantage in vitro. Significant differences in p16 levels were observed among HUC cell lines, but no CDKN2 mutations were detected. However, an inverse correlation between elevated p16 and loss of pRb function was observed (P < 10(-4)). Ten samples with normal pRb showed low or undetectable p16 levels, while seven samples with known pRb alterations showed abundant p16 but nevertheless grew vigorously in culture. These results support the hypothesis that p16 mediated cell cycle inhibition, as well as p16 regulation, occurs via pRb dependent pathway(s).

Published
1995

24. Long-term genome stability and minimal genotypic and phenotypic alterations in HPV16 E7-, but not E6-, immortalized human uroepithelial cells.

Author

Reznikoff CA, Belair C, Savelieva E, Zhai Y, Pfeifer K, Yeager T, Thompson KJ, DeVries S, Bindley C, and Newton MA

Subjects
Base Sequence, Cell Line, DNA Primers genetics, DNA, Viral genetics, Epithelium, Genotype, Humans, In Situ Hybridization, Fluorescence, Karyotyping, Models, Biological, Molecular Sequence Data, Papillomaviridae classification, Phenotype, Urinary Bladder, Cell Transformation, Viral genetics, Papillomaviridae genetics
Abstract

Parameters of genome instability and morphological alterations associated with cell transformation were studied in an isogeneic set of clonal human uroepithelial cell (HUC) lines immortalized by the human papilloma virus 16 (HPV16) E6 and/or E7 gene(s). HPV16 E6 binds p53, leading to rapid degradation of p53, whereas E7 binds and alters pRb and other proteins. We report that two independent E7-immortalized HUC lines showed minimal phenotypic or genotypic alterations, except that both lines contained amplification of 20q DNA sequences and a greater polyploidization at an early passage. The E7-immortalized HUC line resembled normal HUC lines, except that they failed to senesce. In contrast, the E6-immortalized HUC lines were morphologically altered, contained numerous random chromosome aberrations, and showed unstable evolving karyotypes with passage in culture. No amplified DNA sequences were detected in E6-immortalized HUC lines. Instead, clonal losses of chromosome regions (i.e., -3p, -6q, -9p), putatively containing tumor suppressor or senescence genes, accompanied the E6-HUC immortalization event. E6-immortalized HUC lines showed transformed phenotypes similar to E6/E7-HUC lines. The difference in genome stability between E6- and E7-immortalized HUC was highly significant statistically (p-value < 10(-6). Thus, the HPV16 E7 gene led to HUC immortalization by a pathway that blocked cellular senescence, but did not disrupt genome stability. These results implicate p53 loss, but not pRb alteration, in genome destabilization.

Published
1994
Full Text
View/download PDF

25. [Computed tomography in schizophrenic patients. Results from 15 patients. Review of the literature (author's transl)].

Author

Reynaud M, Belair C, Majdalani A, and Metzger J

Subjects
Adult, Atrophy diagnostic imaging, Brain pathology, Female, Humans, Male, Middle Aged, Brain diagnostic imaging, Schizophrenia pathology, Tomography, X-Ray Computed
Abstract

The authors analyzed the scans of 15 chronic schizophrenic patients, apparently deteriorated, all of whom were long standing in-patients. They found 11 pathological cases (6 cortical atrophies and ventricular enlargement, 3 ventricular enlargement, 1 cortical atrophy, 1 cerebellar atrophy). With one exception all these atrophies were slight. The authors findings are comparable with those already reported in other studies. The article also summarizes the results of earlier studies of schizophrenics, by pneumoencephalography which are similar. Although no firm conclusions can be drawn, for such a limited sample, in particular due to the lack of any visible correlation between the pictures obtained and clinical diagnosis or prognosis, the consistent appearance of tomographic anomalies justifies continued research on these lines.

Published
1981

Catalog

Books, media, physical & digital resources
See catalog results