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175 results on '"Physiopathologie et thérapie des déficits sensoriels et moteurs"'

1. Exacerbated age-related hearing loss in mice lacking the p43 mitochondrial T3 receptor

Author: Affortit, Corentin, Casas, François, Ladrech, Sabine, Ceccato, Jean-Charles, Bourien, Jérôme, Coyat, Carolanne, Puel, Jean-Luc, Lenoir, Marc, Wang, Jing, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Dynamique Musculaire et Métabolisme (DMEM), Université de Montpellier (UM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Neurobiologie de l'audition-plasticité synaptique, Institut National de la Santé et de la Recherche Médicale (INSERM), China Agriculture University [Beijing], Fondation de l'Avenir Et2-675, Fondation Gueules Cassees 77-2017, ANR-10-LABX-0012,EpiGenMed,From Genome and Epigenome to Molecular Medicine: turning new paradigms in biology into the therapeutic strategies of tomorrow(2010), Institut des Neurosciences de Montpellier (INM), Raynaud, Christelle, and Laboratoires d'excellence - From Genome and Epigenome to Molecular Medicine: turning new paradigms in biology into the therapeutic strategies of tomorrow - - EpiGenMed2010 - ANR-10-LABX-0012 - LABX - VALID
Subjects: Male, Aging, Receptors, Thyroid Hormone, Age-related hearing loss, Thyroid hormones, [SDV]Life Sciences [q-bio], Presbycusis, T3 receptor, [SDV] Life Sciences [q-bio], p43 mitochondrial, Mice, lcsh:Biology (General), otorhinolaryngologic diseases, p43 mitochondrial T3 receptor, Animals, Mitochondrial dysfunction, lcsh:QH301-705.5, Research Article
Abstract: Background Age-related hearing loss (ARHL), also known as presbycusis, is the most common sensory impairment seen in elderly people. However, the cochlear aging process does not affect people uniformly, suggesting that both genetic and environmental (e.g., noise, ototoxic drugs) factors and their interaction may influence the onset and severity of ARHL. Considering the potential links between thyroid hormone, mitochondrial activity, and hearing, here, we probed the role of p43, a N-terminally truncated and ligand-binding form of the nuclear receptor TRα1, in hearing function and in the maintenance of hearing during aging in p43−/− mice through complementary approaches, including in vivo electrophysiological recording, ultrastructural assessments, biochemistry, and molecular biology. Results We found that the p43−/− mice exhibit no obvious hearing loss in juvenile stages, but that these mice developed a premature, and more severe, ARHL resulting from the loss of cochlear sensory outer and inner hair cells and degeneration of spiral ganglion neurons. Exacerbated ARHL in p43−/− mice was associated with the early occurrence of a drastic fall of SIRT1 expression, together with an imbalance between pro-apoptotic Bax, p53 expression, and anti-apoptotic Bcl2 expression, as well as an increase in mitochondrial dysfunction, oxidative stress, and inflammatory process. Finally, p43−/− mice were also more vulnerable to noise-induced hearing loss. Conclusions These results demonstrate for the first time a requirement for p43 in the maintenance of hearing during aging and highlight the need to probe the potential link between human THRA gene polymorphisms and/or mutations and accelerated age-related deafness or some adult-onset syndromic deafness. Supplementary Information The online version contains supplementary material available at 10.1186/s12915-021-00953-1.
Published: 2021

2. Maladaptive activation of Nav1.9 channels by nitric oxide causes triptan-induced medication overuse headache

Author: Bonnet, Caroline, Hao, Jizhe, Osorio, Nancy, Donnet, Anne, Penalba, Virginie, Ruel, Jérôme, Delmas, Patrick, Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), and CNRS and the Fondation pour la Recherche Médicale (FRM 2013 DEQ20130326482 to P.D.)
Subjects: nervous system, [SDV]Life Sciences [q-bio], Science, Headache, Diseases, lcsh:Q, lcsh:Science, Article, Neurological disorders, Migraine
Abstract: Medication-overuse headaches (MOH) occur with both over-the-counter and pain-relief medicines, including paracetamol, opioids and combination analgesics. The mechanisms that lead to MOH are still uncertain. Here, we show that abnormal activation of Nav1.9 channels by Nitric Oxide (NO) is responsible for MOH induced by triptan migraine medicine. Deletion of the Scn11a gene in MOH mice abrogates NO-mediated symptoms, including cephalic and extracephalic allodynia, photophobia and phonophobia. NO strongly activates Nav1.9 in dural afferent neurons from MOH but not normal mice. Abnormal activation of Nav1.9 triggers CGRP secretion, causing artery dilatation and degranulation of mast cells. In turn, released mast cell mediators potentiates Nav1.9 in meningeal nociceptors, exacerbating inflammation and pain signal. Analysis of signaling networks indicates that PKA is downregulated in trigeminal neurons from MOH mice, relieving its inhibitory action on NO-Nav1.9 coupling. Thus, anomalous activation of Nav1.9 channels by NO, as a result of chronic medication, promotes MOH., The precise mechanisms that lead to medication-overuse headaches (MOH), which can occur with both over-the-counter and prescription pain-relief medicines, are still uncertain. In this study, authors show that the abnormal activation of dural nociceptor Nav1.9 channels by Nitric Oxide is responsible for triptan-induced MOH, causing hyperexcitability of dural nociceptors and headache.
Published: 2019

3. Warburg-like effect is a hallmark of complex I assembly defects

Author: Naïg Gueguen, Anaïs Lebert, Guy Lenaers, Patrizia Amati-Bonneau, Magalie Barth, Mariame Selma Kane, Cédric Gadras, Pascal Reynier, David Goudenège, Dominique Bonneau, Valérie Desquiret-Dumas, Stéphanie Leruez, Stéphanie Chupin, Daniel Henrion, Morgane Le Mao, Céline Wetterwald, Vincent Procaccio, Salim Khiati, Géraldine Leman, Guillaume Geffroy, Lydie Tessier, Arnaud Chevrollier, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), ARN : régulations naturelle et artificielle, Université Bordeaux Segalen - Bordeaux 2-Institut Européen de Chimie et de Biologie-Institut National de la Santé et de la Recherche Médicale (INSERM), Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biochimie et Génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Réseau Maladies Métaboliques, Hôpitaux Universitaires du Grand Ouest, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Physiopathologie et thérapie des déficits sensoriels et moteurs, and Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Mitochondrial Diseases, [SDV]Life Sciences [q-bio], Citric Acid Cycle, Regulator, 03 medical and health sciences, 0302 clinical medicine, Humans, Glycolysis, RNA, Small Interfering, Overproduction, Molecular Biology, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, Principal Component Analysis, Reactive oxygen species, Electron Transport Complex I, ATP synthase, biology, Catabolism, NADH Dehydrogenase, Fibroblasts, Pyruvate dehydrogenase complex, Warburg effect, Mitochondria, Cell biology, 030104 developmental biology, Metabolic Engineering, chemistry, 030220 oncology & carcinogenesis, biology.protein, Molecular Medicine, RNA Interference, Reactive Oxygen Species
Abstract: Due to its pivotal role in NADH oxidation and ATP synthesis, mitochondrial complex I (CI) emerged as a crucial regulator of cellular metabolism. A functional CI relies on the sequential assembly of nuclear- and mtDNA-encoded subunits; however, whether CI assembly status is involved in the metabolic adaptations in CI deficiency still remains largely unknown. Here, we investigated the relationship between CI functions, its structure and the cellular metabolism in 29 patient fibroblasts representative of most CI mitochondrial diseases. Our results show that, contrary to the generally accepted view, a complex I deficiency does not necessarily lead to a glycolytic switch, i.e. the so-called Warburg effect, but that this particular metabolic adaptation is a feature of CI assembly defect. By contrast, a CI functional defect without disassembly induces a higher catabolism to sustain the oxidative metabolism. Mechanistically, we demonstrate that reactive oxygen species overproduction by CI assembly intermediates and subsequent AMPK-dependent Pyruvate Dehydrogenase inactivation are key players of this metabolic reprogramming. Thus, this study provides a two-way-model of metabolic responses to CI deficiencies that are central not only in defining therapeutic strategies for mitochondrial diseases, but also in all pathophysiological conditions involving a CI deficiency.
Published: 2019

4. Lipidomics Reveals Triacylglycerol Accumulation Due to Impaired Fatty Acid Flux in Opa1-Disrupted Fibroblasts

Author: Dominique Bonneau, Charlotte Veyrat-Durebex, Arnaud Chevrollier, Stéphanie Chupin, Gilles Simard, Guy Lenaers, Judith Kouassi Nzoughet, Cinzia Bocca, Mariame Selma Kane, Pascal Reynier, Juan Manuel Chao de la Barca, Vincent Procaccio, Jennifer Alban, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: 0301 basic medicine, endocrine system, [SDV]Life Sciences [q-bio], Apoptosis, Mitochondrion, Biochemistry, GTP Phosphohydrolases, Mice, 03 medical and health sciences, chemistry.chemical_compound, Lipid droplet, Lipidomics, Animals, Beta oxidation, Cells, Cultured, Triglycerides, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, chemistry.chemical_classification, Phosphatidylethanolamine, 030102 biochemistry & molecular biology, Chemistry, Cell Membrane, Fatty Acids, Fatty acid, Mitochondrial membrane fusion, General Chemistry, Fibroblasts, eye diseases, Mitochondria, Cell biology, 030104 developmental biology, Sphingomyelin
Abstract: OPA1 is a dynamin GTPase implicated in mitochondrial membrane fusion. Despite its involvement in lipid remodeling, the function of OPA1 has never been analyzed by whole-cell lipidomics. We used a nontargeted, reversed-phase lipidomics approach, validated for cell cultures, to investigate OPA1-inactivated mouse embryonic fibroblasts ( Opa1 -/- MEFs). This led to the identification of a wide range of 14 different lipid subclasses comprising 212 accurately detected lipids. Multivariate and univariate statistical analyses were then carried out to assess the differences between the Opa1 -/- and Opa1 +/+ genotypes. Of the 212 lipids identified, 69 were found to discriminate between Opa1 -/- MEFs and Opa1 +/+ MEFs. Among these lipids, 34 were triglycerides, all of which were at higher levels in Opa1 -/- MEFs with fold changes ranging from 3.60 to 17.93. Cell imaging with labeled fatty acids revealed a sharp alteration of the fatty acid flux with a reduced mitochondrial uptake. The other 35 discriminating lipids included phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamine, and sphingomyelins, mainly involved in membrane remodeling, and ceramides, gangliosides, and phosphatidylinositols, mainly involved in apoptotic cell signaling. Our results show that the inactivation of OPA1 severely affects the mitochondrial uptake of fatty acids and lipids through membrane remodeling and apoptotic cell signaling.
Published: 2019

5. Next generation sequencing in family with MNGIE syndrome associated to optic atrophy: Novel homozygous POLG mutation in the C-terminal sub-domain leading to mtDNA depletion

Author: David Goudenège, Pascal Reynier, Majida Charif, Rahma Felhi, Dominique Bonneau, Mongia Hachicha, Lamia Sfaihi, Céline Bris, Leila Ammar-Keskes, Guy Lenaers, Patrizia Amati-Bonneau, Valérie Desquiret-Dumas, Vincent Procaccio, Faiza Fakhfakh, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Hedi Chaker Hospital [Sfax], Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Pediatrics, Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, This work was supported by the Ministry of Higher Education and Scientific Research in Tunisia, University of Sfax. We acknowledge the support from the Institut National de la Santé et de la Recherche Médicale (INSERM), France, Centre National de la Recherche Scientifique (CNRS), France, the Université d'Angers, the University Hospital of Angers, the Région Pays de Loire and Angers Loire Métropole, France., and We would like to thank all the member of the family for their cooperation in the present study.
Subjects: Male, 0301 basic medicine, Mitochondrial DNA, Nuclear gene, Adolescent, [SDV]Life Sciences [q-bio], Clinical Biochemistry, MtDNA depletion, Oxidative phosphorylation, Biology, OPA1, DNA, Mitochondrial, Biochemistry, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Muscular Dystrophy, Oculopharyngeal, Mitochondrial Encephalomyopathies, medicine, Humans, Thymidine phosphorylase, Child, ComputingMilieux_MISCELLANEOUS, Genetics, Ophthalmoplegia, mtDNA depletion, Intestinal Pseudo-Obstruction, Biochemistry (medical), Pathogenic variants, General Medicine, medicine.disease, DNA Polymerase gamma, 3. Good health, Optic Atrophy, Cytosol, 030104 developmental biology, POLG, 030220 oncology & carcinogenesis, MNGIE, Mutation
Abstract: Introduction Mitochondrial diseases are a group of disorders caused mainly by the impairment of the mitochondrial oxidative phosphorylation process, due to mutations either in the mitochondrial or nuclear genome. Among them, the mitochondrial neuro-gastrointestinal encephalo-myopathy (MNGIE) syndrome affects adolescents or young adults, and is mostly caused by TYMP mutations encoding a cytosolic thymidine phosphorylase (TP). Patients and methods The present study reports the molecular investigation by next-generation re-sequencing of 281 nuclear genes, encoding mitochondrial proteins, of consanguineous family including two individuals with MNGIE syndrome associated to optic atrophy. Bioinformatic analysis was also performed in addition to mtDNA deletion screening and mtDNA copy number quantification in blood of the two patients which were carried out by solf clipping program and qPCR respectively. Results Next-generation re-sequencing revealed a novel homozygous c.2391G > T POLG mutation (p.M797I) co-occurring with the hypomorphic c.1311A > G OPA1 variant (p.I437M). Analysis of the mitochondrial genome in the two patients disclosed mtDNA depletion in blood, but no deletion. Bio-informatics investigations supported the pathogenicity of the novel POLG mutation that is located in the C-terminal subdomain and might change POLG 3D structure, stability and function. Conclusion The novel homozygous p.M797I POLG mutation is responsible for MNGIE combined to optic atrophy and mtDNA depletion in the two patients.
Published: 2019

6. The effect of PTC124 on choroideremia fibroblasts and iPSC-derived RPE raises considerations for therapy

Author: Valerie De Luca, David Baux, Vasiliki Kalatzis, Nicolas Cereso, Simona Torriano, Anne-Françoise Roux, Christian P. Hamel, Isabelle Meunier, Nejla Erkilic, Mariya Moosajee, Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Montpellier (UM), Service d'Ophtalmologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Guy de Chauliac, Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Department of Ophthalmology [London, UK], Great Ormond Street Hospital for Children [London] (GOSH), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), roussel, pascale, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), IFR3, and Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Induced Pluripotent Stem Cells, lcsh:Medicine, Retinal Pigment Epithelium, Biology, Article, Choroideremia, 03 medical and health sciences, chemistry.chemical_compound, medicine, Humans, Induced pluripotent stem cell, lcsh:Science, Zebrafish, Cells, Cultured, Oxadiazoles, Multidisciplinary, Retinal pigment epithelium, lcsh:R, Retinal, Fibroblasts, medicine.disease, biology.organism_classification, Stop codon, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, chemistry, Proteasome inhibitor, Cancer research, lcsh:Q, Retinal Dystrophies, medicine.drug
Abstract: Inherited retinal dystrophies (IRDs) are caused by mutations in over 200 genes, resulting in a range of therapeutic options. Translational read-through inducing drugs (TRIDs) offer the possibility of treating multiple IRDs regardless of the causative gene. TRIDs promote ribosomal misreading of premature stop codons, which results in the incorporation of a near-cognate amino acid to produce a full-length protein. The IRD choroideremia (CHM) is a pertinent candidate for TRID therapy, as nonsense variants cause 30% of cases. Recently, treatment of the UAA nonsense-carrying CHM zebrafish model with the TRID PTC124 corrected the underlying biochemical defect and improved retinal phenotype. To be clinically relevant, we studied PTC124 efficiency in UAA nonsense-carrying human fibroblasts and induced pluripotent stem cell-derived retinal pigment epithelium, as well as in a UAA-mutated CHM overexpression system. We showed that PTC124 treatment induces a non-significant trend for functional rescue, which could not be improved by nonsense-mediated decay inhibition. Furthermore, it does not produce a detectable CHM-encoded protein even when coupled with a proteasome inhibitor. We suggest that drug efficiency may depend upon on the target amino acid and its evolutionary conservation, and argue that patient cells should be screened in vitro prior to inclusion in a clinical trial.
Published: 2018

7. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial

Author: Sonia S Anand, Jackie Bosch, John W Eikelboom, Stuart J Connolly, Rafael Diaz, Peter Widimsky, Victor Aboyans, Marco Alings, Ajay K Kakkar, Katalin Keltai, Aldo P Maggioni, Basil S Lewis, Stefan Störk, Jun Zhu, Patricio Lopez-Jaramillo, Martin O'Donnell, Patrick J Commerford, Dragos Vinereanu, Nana Pogosova, Lars Ryden, Keith A A Fox, Deepak L Bhatt, Frank Misselwitz, John D Varigos, Thomas Vanassche, Alvaro A Avezum, Edmond Chen, Kelley Branch, Darryl P Leong, Shrikant I Bangdiwala, Robert G Hart, Salim Yusuf, JORGELINA SALA, LUIS CARTASEGNA, MARISA VICO, MIGUEL ANGEL HOMINAL, EDUARDO HASBANI, ALBERTO CACCAVO, CESAR ZAIDMAN, DANIEL VOGEL, ADRIAN HRABAR, PABLO OMAR SCHYGIEL, CARLOS CUNEO, HUGO LUQUEZ, IGNACIO J. MACKINNON, RODOLFO ANDRES AHUAD GUERRERO, JUAN PABLO COSTABEL, INES PALMIRA BARTOLACCI, OSCAR MONTANA, MARIA BARBIERI, OSCAR GOMEZ VILAMAJO, RUBEN OMAR GARCIA DURAN, LILIA BEATRIZ SCHIAVI, MARCELO GARRIDO, ADRIAN INGARAMO, ANSELMO PAULINO BORDONAVA, MARIA JOSE PELAGAGGE, LEONARDO NOVARETTO, JUAN PABLO ALBISU DI GENNERO, LUZ MARIA IBANEZ SAGGIA, MOIRA ALVAREZ, NESTOR ALEJANDRO VITA, STELLA MARIS MACIN, RICARDO DARIO DRAN, MARCELO CARDONA, LUIS GUZMAN, RODOLFO JUAN SARJANOVICH, JESUS CUADRADO, SEBASTIAN NANI, MARCOS RAUL LITVAK BRUNO, CAROLINA CHACON, LAURA ELENA MAFFEI, DIEGO GRINFELD, NATALIA VENSENTINI, CLAUDIO RODOLFO MAJUL, HECTOR LUCAS LUCIARDI, PATRICIA DEL CARMEN GONZALEZ COLASO, FREDY ANTONI FERRE PACORA, PAUL VAN DEN HEUVEL, PETER VERHAMME, BAVO ECTOR, PHILIPPE DEBONNAIRE, PHILIPPE VAN DE BORNE, JEAN LEROY, HERMAN SCHROE, PASCAL VRANCKX, IVAN ELEGEERT, ETIENNE HOFFER, KARL DUJARDIN, CLARISSE INDIO DO BRASIL, DALTON PRECOMA, JOSE ANTONIO ABRANTES, EULER MANENTI, GILMAR REIS, JOSE SARAIVA, LILIA MAIA, MAURO HERNANDES, PAULO ROSSI, FABIO ROSSI DOS SANTOS, SERGIO LUIZ ZIMMERMANN, RAFAEL RECH, EDUARDO ABIB JR, PAULO LEAES, ROBERTO BOTELHO, OSCAR DUTRA, WEIMAR SOUZA, MARIA BRAILE, NILO IZUKAWA, JOSE CARLOS NICOLAU, LUIZ FERNANDO TANAJURA, CARLOS VICENTE SERRANO JUNIOR, CESAR MINELLI, LUIZ ANTONIO NASI, LIVIA OLIVEIRA, MARCELO JOSE DE CARVALHO CANTARELLI, RICHARD TYTUS, SHEKHAR PANDEY, EVA LONN, JAMES CHA, SAUL VIZEL, MOHAN BABAPULLE, ANDRE LAMY, KEVIN SAUNDERS, JOSEPH BERLINGIERI, BOB KIAII, RAKESH BHARGAVA, PRAVINSAGAR MEHTA, LAURIE HILL, DAVID FELL, ANDY LAM, FAISAL AL-QOOFI, CRAIG BROWN, ROBERT PETRELLA, JOSEPH A RICCI, ANTHONY GLANZ, NICOLAS NOISEUX, KEVIN BAINEY, FATIMA MERALI, MICHAEL HEFFERNAN, ANTHONY DELLA SIEGA, GILLES R DAGENAIS, FRANCOIS DAGENAIS, STEEVE BRULOTTE, MICHEL NGUYEN, MICHAEL HARTLEIB, RANDOLPH GUZMAN, RONALD BOURGEOIS, DENNIS RUPKA, YAARIV KHAYKIN, GILBERT GOSSELIN, THAO HUYNH, CLAUDE PILON, JEAN CAMPEAU, FRANCIS PICHETTE, ARIEL DIAZ, JAMES JOHNSTON, PRAVIN SHUKLE, GREGORY HIRSCH, PAUL RHEAULT, WLODZIMIERZ CZARNECKI, ANNIE ROY, SHAH NAWAZ, STEPHEN FREMES, DINKAR SHUKLA, GABRIEL JANO, JORGE LEONARDO COBOS, RAMON CORBALAN, MARCELO MEDINA, LEONARDO NAHUELPAN, CARLOS RAFFO, LUIS PEREZ, SERGIO POTTHOFF, BENJAMIN STOCKINS, PABLO SEPULVEDA, CHRISTIAN PINCETTI, MARGARITA VEJAR, HONGYAN TIAN, XUESI WU, YUANNAN KE, KAIYING JIA, PENGFEI YIN, ZHAOHUI WANG, LITIAN YU, SHULIN WU, ZONGQUI WU, SHAO WEN LIU, XIAO JUAN BAI, YANG ZHENG, PING YANG, YUN MEI YANG, JIWEI ZHANG, JUNBO GE, XIAO PING CHEN, JUNXIA LI, TAO HONG HU, RUIYAN ZHANG, ZHE ZHENG, XIN CHEN, LIANG TAO, JIANPING LI, WEIJIAN HUANG, GUOSHENG FU, CHUNJIAN LI, YUGANG DONG, CHUNSHENG WANG, XINMIN ZHOU, YE KONG, ARISTIDES SOTOMAYOR, JOSE LUIS ACCINI MENDOZA, HENRY CASTILLO, MIGUEL URINA, GUSTAVO AROCA, MARITZA PEREZ, DORA INES MOLINA DE SALAZAR, GREGORIO SANCHEZ VALLEJO, MANZUR J FERNANDO, HENRY GARCIA, LUIS HERNANDO GARCIA, EDGAR ARCOS, JUAN GOMEZ, FRANCISCO CUERVO MILLAN, FREDY ALBERTO TRUJILLO DADA, BORIS VESGA, GUSTAVO ADOLFO MORENO SILGADO, EVA ZIDKOVA, JEAN-CLAUDE LUBANDA, MARKETA KALETOVA, RADIM KRYZA, GABRIEL MARCINEK, MAREK RICHTER, JINDRICH SPINAR, JIRI MATUSKA, MARTIN TESAK, ZUZANA MOTOVSKA, MARIAN BRANNY, JIRI MALY, MARTIN MALY, MARTIN WIENDL, LENKA FOLTYNOVA CAISOVA, JOSEF SLABY, PETR VOJTISEK, JAN PIRK, LENKA SPINAROVA, MIROSLAVA BENESOVA, JULIA CANADYOVA, MIROSLAV HOMZA, JINDRICH FLORIAN, ROSTISLAV POLASEK, ZDENEK COUFAL, VLADIMIRA SKALNIKOVA, RADIM BRAT, MIROSLAV BRTKO, PETR JANSKY, JAROSLAV LINDNER, PAVEL MARCIAN, ZBYNEK STRAKA, MARTIN TRETINA, YAN CARLOS DUARTE, FREDDY POW CHON LONG, MAYRA SANCHEZ, JOSE LOPEZ, CARMITA PERUGACHI, RICARDO MARMOL, FREDDY TRUJILLO, PABLO TERAN, JAAKKO TUOMILEHTO, HENRI TUOMILEHTO, MARJA-LEENA TUOMINEN, ILKKA KANTOLA, GABRIEL STEG, VICTOR ABOYANS, FLORENCE LECLERCQ, EMILE FERRARI, FRANCK BOCCARA, EMMANUEL MESSAS, PATRICK MISMETTI, MARIE ANTOINETTE SEVESTRE, GUILLAUME CAYLA, PASCAL MOTREFF, STEFAN STOERK, HANS-DIRK DUENGEN, CHRISTOPH STELLBRINK, OSMAN GUEROCAK, CHRISTOPH KADEL, RUEDIGER BRAUN-DULLAEUS, MICHAEL JESERICH, CHRISTIAN OPITZ, HANS-FRIEDRICH VOEHRINGER, KARL-FRIEDRICH APPEL, BERNHARD WINKELMANN, THOMAS DORSEL, SIGRID NIKOL, HARALD DARIUS, JURGEN RANFT, SEBASTIAN SCHELLONG, WOLFGANG JUNGMAIR, PIROZE DAVIERWALA, MARC VORPAHL, LASZLO BAJNOK, ZOLTAN LASZLO, EBRAHIM NOORI, GABOR VERESS, ANDRAS VERTES, ANDRAS ZSARY, ERNO KIS, LASZLO KORANYI, JUDIT BAKAI, ZOLTAN BODA, FERENC POOR, ZOLTAN JARAI, VENDEL KEMENY, JOHN BARTON, BRENDAN MCADAM, ANDREW MURPHY, PETER CREAN, NIALL MAHON, RONAN CURTIN, BRIAIN MACNEILL, SEAN DINNEEN, MAJDI HALABI, REUVEN ZIMLICHMAN, DAVID ZELTSER, YOAV TURGEMAN, ELIEZER KLAINMAN, BASIL LEWIS, AMOS KATZ, SHAUL ATAR, EUGENIA NIKOLSKY, STEFANO BOSI, MONICA NALDI, POMPILIO FAGGIANO, DEBORA ROBBA, LUCIO MOS, GIANFRANCO SINAGRA, FRANCO COSMI, LUIGI OLTRONA VISCONTI, DE MATTEIS CARMINE, GIUSEPPE DI PASQUALE, MATTEO DI BIASE, SARA MANDORLA, MARINO BERNARDINANGELI, GIOVANNI CARLO PICCINNI, MICHELE MASSIMO GULIZIA, MARCELLO GALVANI, FLAVIO VENTURI, GIORGIO MOROCUTTI, MARIA GRAZIA BALDIN, CARLO OLIVIERI, GIAN PIERO PERNA, VINCENZO CIRRINCIONE, TAKAYASU KANNO, HIROYUKI DAIDA, YUKIO OZAKI, NAOMASA MIYAMOTO, SHINICHI HIGASHIUE, HIROSHI DOMAE, SHINOBU HOSOKAWA, HIROO KOBAYASHI, TAKEHIKO KURAMOCHI, KENSHI FUJII, KAZUAKI MIZUTOMI, KEIJIRO SAKU, KAZUO KIMURA, YOSHIHARU HIGUCHI, MITSUNORI ABE, HARUHITO OKUDA, TOSHIYUKI NODA, TERUAKI MITA, ATSUSHI HIRAYAMA, HARUHIKO ONAKA, MORIAKI INOKO, MITSUGU HIROKAMI, MUNENORI OKUBO, YUTAKA AKATSUKA, MIZUHO IMAMAKI, HARUO KAMIYA, MAMORU MANITA, TOSHIHARU HIMI, HIDEKI UENO, YUJI HISAMATSU, JUNYA AKO, YASUHIRO NISHINO, HIDEO KAWAKAMI, YUTAKA YAMADA, YUKIHIRO KORETSUNE, TAKAHISA YAMADA, TETSURO YOSHIDA, HIDEKI SHIMOMURA, NORIYUKI KINOSHITA, AKIHIKO TAKAHASHI, KHALID YUSOFF, WAN AZMAN WAN AHMAD, MUHAMMAD RADZI ABU HASSAN, SAZZLI KASIM, AIZAI AZAN ABDUL RAHIM, DIMON MOHD ZAMRIN, MASAHARU MACHIDA, YORIHIKO HIGASHINO, NORIAKI UTSU, AKIHIKO NAKANO, SHIGERU NAKAMURA, TETSUO HASHIMOTO, KENJI ANDO, TOMOHIRO SAKAMOTO, F.J. PRINS, DIRK LOK, JOHANNES GERT-JAN MILHOUS, ERIC VIERGEVER, FRANK WILLEMS, HENK SWART, MARCO ALINGS, ROB BREEDVELD, KEES-JAN DE VRIES, ROGER VAN DER BORGH, FANNY OEI, STIENEKE ZOET-NUGTEREN, HANS KRAGTEN, JEAN PAUL HERRMAN, PAUL VAN BERGEN, MARCEL GOSSELINK, EDUARD HOEKSTRA, ERWIN ZEGERS, EELKO RONNER, FRANK DEN HARTOG, GERARD BARTELS, PETER NIEROP, COEN VAN DER ZWAAN, JACOB VAN ECK, EDWIN VAN GORSELEN, BJORN GROENEMEIJER, PIETER HOOGSLAG, MARC ROBERT DE GROOT, ALDRIN LOYOLA, DENNIS JOSE SULIT, NANNETTE REY, MARIA TERESA ABOLA, DANTE MORALES, ELLEN PALOMARES, MARC EVANS ABAT, GREGORIO ROGELIO, PHILIP CHUA, JOSE CARLO DEL PILAR, JOHN DENNIS ALCARAZ, GERALDINE EBO, LOUIE TIRADOR, JOSEFINA CRUZ, JOHN ANONUEVO, ARTHUR PITARGUE, MARIANNA JANION, TOMASZ GUZIK, GRZEGORZ GAJOS, MACIEJ ZABOWKA, ANDRZEJ RYNKIEWICZ, MARLENA BRONCEL, ANDRZEJ SZUBA, DANUTA CZARNECKA, PAWEL MAGA, IRINA STRAZHESKO, YURY VASYUK, ZHANNA SIZOVA, YURY POZDNYAKOV, OLGA BARBARASH, MIKHAIL VOEVODA, TATIANA POPONINA, ALEXEY REPIN, IRINA OSIPOVA, ANNA EFREMUSHKINA, NINA NOVIKOVA, OLEG AVERKOV, DMITRY ZATEYSHCHIKOV, ARKADIY VERTKIN, AZA AUSHEVA, PATRICK COMMERFORD, SAADIYA SEEDAT, LOUIS VAN ZYL, JAN ENGELBRECHT, ELLEN MAKONLI MAKOTOKO, CATHARINA ELIZABETH PRETORIUS, ZAID MOHAMED, ADRIAN HORAK, THOMAS MABIN, ERIC KLUG, JANG-HO BAE, CHEOLHO KIM, CHONG-JIN KIM, DONG-SOO KIM, YONG JIN KIM, SEUNGJAE JOO, JONG-WON HA, CHUL SOO PARK, JANG YOUNG KIM, YOUNG-KWON KIM, CHRISTINA JARNERT, THOMAS MOOE, MIKAEL DELLBORG, INGEMAR TORSTENSSON, PER ALBERTSSON, LARS JOHANSSON, FARIS AL-KHALILI, HENRIK ALMROTH, TOMMY ANDERSSON, EMIL PANTEV, BENGT-OLOV TENGMARK, BO LIU, GUNDARS RASMANIS, CARL-MAGNUS WAHLGREN, TIZIANO MOCCETTI, ALEXANDER PARKHOMENKO, VIRA TSELUYKO, VOLODYMYR VOLKOV, OLENA KOVAL, LYUDMYLA KONONENKO, OLEKSANDR PROKHOROV, VALERIY VDOVYCHENKO, ANDRIY BAZYLEVYCH, LEONID RUDENKO, VADYM VIZIR, OLEKSANDR KARPENKO, YAROSLAV MALYNOVSKY, VALENTYNA KOVAL, BORYS STOROZHUK, JAMES COTTON, ASOK VENKATARAMAN, ANDREW MORIARTY, DEREK CONNOLLY, PATRICK DAVEY, ROXY SENIOR, INDERPAUL BIRDI, JOHN CALVERT, PATRICK DONNELLY, JASPER TREVELYAN, JUSTIN CARTER, AARON PEACE, DAVID AUSTIN, NEVILLE KUKREJA, THOMAS HILTON, SUNNY SRIVASTAVA, RONALD WALSH, RONALD FIELDS, JOSEPH HAKAS, EDWARD PORTNAY, HARINDER GOGIA, ABRAHAM SALACATA, JOHN J. HUNTER, J MICHAEL BACHARACH, NICOLAS SHAMMAS, DAMODHAR SURESH, RICKY SCHNEIDER, PAUL GURBEL, SUBHASH BANERJEE, PAUL GRENA, NOEL BEDWELL, STEPHEN SLOAN, STEVEN LUPOVITCH, ANAND SONI, KATHLEEN GIBSON, RENEE SANGRIGOLI, RAJENDRA MEHTA, PETER I-HSUAN TSAI, EVE GILLESPIE, STEPHEN DEMPSEY, GLENN HAMROFF, ROBERT BLACK, ELLIS LADER, JOHN B. KOSTIS, VERA BITTNER, WILLIAM MCGUINN, KELLEY BRANCH, VINAY MALHOTRA, STEPHEN MICHAELSON, MICHAEL VACANTE, MATTHEW MCCORMICK, RALUCA ARIMIE, ALAN CAMP, GEORGE DAGHER, N. MATHEW KOSHY, STEPHEN THEW, FREDERICK COSTELLO, MARK HEIMAN, ROBERT CHILTON, MICHAEL MORAN, FREDRIC ADLER, ANTHONY COMEROTA, ANDREW SEIWERT, WILLIAM FRENCH, HARVEY SEROTA, ROBERT HARRISON, FAISAL BAKAEEN, SHUAB OMER, LOKESH CHANDRA, ALAN WHELAN, ANDREW BOYLE, PHILIP ROBERTS-THOMSON, JAMES ROGERS, PATRICK CARROLL, DAVID COLQUHOUN, JAMES SHAW, PETER BLOMBERY, JOHN AMERENA, CHRIS HII, ALISTAIR ROYSE, BHUWAN SINGH, JOSEPH SELVANAYAGAM, SHIRLEY JANSEN, WINGCHI LO, CHRISTOPHER HAMMETT, ROHAN POULTER, SESHASAYEE NARASIMHAN, HENRIK WIGGERS, HENRIK NIELSEN, GUNNAR GISLASON, LARS KOBER, KIM HOULIND, VIBEKE BOENELYKKE SOERENSEN, ULRIK DIXEN, JENS REFSGAARD, ELISABETH ZEUTHEN, PETER SOEGAARD, MARIAN HRANAI, LUDOVIT GASPAR, DANIEL PELLA, KATARINA HATALOVA, ERIKA DROZDAKOVA, IOAN COMAN, DOINA DIMULESCU, DRAGOS VINEREANU, MIRCEA CINTEZA, CRINA SINESCU, CATALINA ARSENESCU, IMRE BENEDEK, ELENA BOBESCU, DAN DOBREANU, DAN GAITA, ADRIAN IANCU, ADRIANA ILIESIU, DANIEL LIGHEZAN, LUCIAN PETRESCU, OCTAVIAN PIRVU, IULIA TEODORESCU, DAN TESLOIANU, MARIUS MARCIAN VINTILA, OVIDIU CHIONCEL, Divisions of Cardiology and Thromboembolism McMaster University Hamiton, Population Health Research Institute, McMaster University [Hamilton, Ontario], Service de Chirurgie Thoracique et Vasculaire - Médecine vasculaire [CHU Limoges], CHU Limoges, Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Research Center [Associazione Nazionale Medici Cardiologi Ospedalieri] (ANMCO Research Center), Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO), Department of Statistics, University of Haifa [Haifa], Cardiology, University and Emergency Hospital, University of Edinburgh, VA Boston Healthcare System, Hamilton General Hospital, Universidad Autonoma de Madrid (UAM), Cardiology Department, Dipartimento di Bioscienze, University of Parma, University of Barcelona, Hospital Clinic Barcelona, Laval University and Hospital Heart and Lung Institute, UVSQ - UFR des sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), University Hospital Brno, Masaryk University, Department of Public Health, Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Galilée, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Pasteur [Nice] (CHU), Service de Cardiologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe de recherche sur la thrombose (GRT (EA 3065)), Université Jean Monnet [Saint-Étienne] (UJM), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), CHU Gabriel Montpied (CHU), CHU Clermont-Ferrand, Department of Medicine (DEBRECEN - Dpt Medicine), University of Debrecen, University of Trieste, Lab Dev Cell Biol,Bunkyo Ku, The University of Tokyo, The Netherlands Organisation for Applied Scientific Research (TNO), Regional Specialist Hospital in Wroclaw, Research and Development Centre, Kamienskiego, Division of Angiology, Wroclaw Medical University, Sahlgrenska University Hospital/Östra, Cardiocentro Ticino [Lugano], University of Zürich [Zürich] (UZH), Danylo Halytskyi Lviv National Medical University, Department of Cardiology, Sandwell General Hospital, Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Rigshospitalet [Copenhagen], Université de Médecine Carol Davila, Cardiology Department [Târgu Mureș], University of Medicine and Pharmacy of Târgu Mureș, Institute for Cardiovascular Diseases C.C. Iliescu, Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM), Associazione Nazionale Medici Cardiologi Ospedalieri [Firenze] (ANMCO), University of Parma = Università degli studi di Parma [Parme, Italie], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), CHU Saint-Antoine [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), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), CHU Gabriel Montpied [Clermont-Ferrand], The University of Tokyo (UTokyo), Universität Zürich [Zürich] = University of Zurich (UZH), and Copenhagen University Hospital
Subjects: Carotid Artery Diseases, Male, Myocardial Infarction, MESH: Lower Extremity, 030204 cardiovascular system & hematology, THERAPY, Stroke/epidemiology, MESH: Dose-Response Relationship, Drug, 0302 clinical medicine, Rivaroxaban, prevention, Hemorrhage/chemically induced, MESH: Peripheral Arterial Disease, MESH: Double-Blind Method, guidelines, MESH: Incidence, 030212 general & internal medicine, Cardiovascular Diseases/mortality, risk, RISK, MESH: Aged, MESH: Middle Aged, Incidence, General Medicine, Middle Aged, 3. Good health, Stroke, MESH: Myocardial Infarction, Lower Extremity, Cardiovascular Diseases, MESH: Platelet Aggregation Inhibitors, Factor Xa Inhibitors/administration & dosage, Drug Therapy, Combination, Female, MESH: Factor Xa Inhibitors, OUTPATIENTS, MESH: Rivaroxaban, management, MESH: Hemorrhage, metaanalysis, Lower Extremity/blood supply, Rivaroxaban/administration & dosage, Hemorrhage, MESH: Drug Administration Schedule, Amputation, Surgical, Drug Administration Schedule, MESH: Stroke, Peripheral Arterial Disease, 03 medical and health sciences, Double-Blind Method, atherothrombosis, Myocardial Infarction/epidemiology, MANAGEMENT, Humans, MESH: Amputation, MESH: Aspirin, Aspirin/administration & dosage, Platelet Aggregation Inhibitors/administration & dosage, METAANALYSIS, Aged, MESH: Humans, Aspirin, Dose-Response Relationship, Drug, MESH: Carotid Artery Diseases, MORTALITY, MESH: Cardiovascular Diseases, cardiovascular event rates, PREVENTION, CARDIOVASCULAR EVENT RATES, MESH: Male, outpatients, atrial-fibrillation, MESH: Drug Therapy, Combination, MESH: Morbidity, Carotid Artery Diseases/complications, lower-extremity amputation, Peripheral Arterial Disease/complications, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Morbidity, MESH: Female, Platelet Aggregation Inhibitors, Amputation/statistics & numerical data, Factor Xa Inhibitors
Abstract: BACKGROUND: Patients with peripheral artery disease have an increased risk of cardiovascular morbidity and mortality. Antiplatelet agents are widely used to reduce these complications.METHODS: This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of peripheral artery disease), of the carotid arteries (previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle-brachial index of less than 0·90. After a 30-day run-in period, patients were randomly assigned (1:1:1) to receive oral rivaroxaban (2·5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban twice a day (5 mg with aspirin placebo once a day), or to aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomisation was computer generated. Each treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation. The primary outcome was cardiovascular death, myocardial infarction or stroke; the primary peripheral artery disease outcome was major adverse limb events including major amputation. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.FINDINGS: Between March 12, 2013, and May 10, 2016, we enrolled 7470 patients with peripheral artery disease from 558 centres. The combination of rivaroxaban plus aspirin compared with aspirin alone reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke (126 [5%] of 2492 vs 174 [7%] of 2504; hazard ratio [HR] 0·72, 95% CI 0·57-0·90, p=0·0047), and major adverse limb events including major amputation (32 [1%] vs 60 [2%]; HR 0·54 95% CI 0·35-0·82, p=0·0037). Rivaroxaban 5 mg twice a day compared with aspirin alone did not significantly reduce the composite endpoint (149 [6%] of 2474 vs 174 [7%] of 2504; HR 0·86, 95% CI 0·69-1·08, p=0·19), but reduced major adverse limb events including major amputation (40 [2%] vs 60 [2%]; HR 0·67, 95% CI 0·45-1·00, p=0·05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 vs 48 [2%] of 2504; HR 1·61, 95% CI 1·12-2·31, p=0·0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2504 in the aspirin alone group (HR 1·68, 95% CI 1·17-2·40; p=0·0043).INTERPRETATION: Low-dose rivaroxaban taken twice a day plus aspirin once a day reduced major adverse cardiovascular and limb events when compared with aspirin alone. Although major bleeding was increased, fatal or critical organ bleeding was not. This combination therapy represents an important advance in the management of patients with peripheral artery disease. Rivaroxaban alone did not significantly reduce major adverse cardiovascular events compared with asprin alone, but reduced major adverse limb events and increased major bleeding.FUNDING: Bayer AG.
Published: 2018

8. Hereditary spastic paraplegia and prominent sensorial involvement: think MAG mutations!

Author: Gaël Manes, Isabelle Meunier, Agathe Roubertie, Guy Lenaers, Nicolas Leboucq, Cécile Delettre, Agnès Guichet, Emmanuelle Sarzi, François Rivier, Pierre Meyer, Raul Junta Morales, Majida Charif, Guillaume Taieb, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département de neurologie [Montpellier], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), MORNET, Dominique, and Institut des Neurosciences de Montpellier (INM)
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Hereditary spastic paraplegia, [SDV]Life Sciences [q-bio], Neurosciences. Biological psychiatry. Neuropsychiatry, Brief Communication, medicine.disease_cause, Compound heterozygosity, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Intellectual disability, medicine, Spastic, Humans, Child, RC346-429, ComputingMilieux_MISCELLANEOUS, Paraplegia, Mutation, Spastic Paraplegia, Hereditary, business.industry, General Neuroscience, Brain, medicine.disease, Magnetic Resonance Imaging, Pedigree, nervous system diseases, [SDV] Life Sciences [q-bio], Myelin-Associated Glycoprotein, Phenotype, 030104 developmental biology, nervous system, Female, Cerebellar atrophy, Neurology (clinical), Neurology. Diseases of the nervous system, Brief Communications, business, 030217 neurology & neurosurgery, RC321-571
Abstract: Homozygous mutations in MAG, encoding the myelin‐associated glycoprotein, a transmembrane component of the myelin sheath, have been associated with SPG 75 recessive spastic paraplegia. Here, we report the first patient with two compound heterozygous novel MAG mutations (p.A151V and p.S373R) and early developmental delay with a progressive complex phenotype characterized by spastic paraplegia, peripheral sensorimotor neuropathy, intellectual disability, and sensorial dysfunctions with severe optic atrophy and hearing involvement. Brain imaging showed progressive global cerebellar atrophy. We propose that complex hereditary spastic paraplegia, with axonal and demyelinating polyneuropathy, sensorial impairment and intellectual disability might suggest MAG mutations.
Published: 2019

9. Nicotinamide Deficiency in Primary Open-Angle Glaucoma

Author: Kouassi Nzoughet, Judith, Chao de La Barca, Juan Manuel, Guehlouz, Khadidja, Coulbault, Laurent, Allouche, Stéphane, Bocca, Cinzia, Muller, Jeanne, Gohier, Philippe, Simard, Gilles, Milea, Dan, Desquiret-Dumas, Valérie, Leman, Géraldine, Wetterwald, Celine, Chupin, Stéphanie, Lebert, Anaïs, Khiati, Salim, Le Mao, Morgane, Geffroy, Guillaume, Kane, Mariame Selma, Chevrollier, Arnaud, Goudenège, David, Gadras, Cédric, Tessier, Lydie, Barth, Magalie, Leruez, Stéphanie, Amati-Bonneau, Patrizia, Henrion, Daniel, Bonneau, Dominique, Procaccio, Vincent, Reynier, Pascal, Lenaers, Guy, Gueguen, Naïg, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de biochimie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Singapore Eye Research Institute, Singapore National Eye Centre, ARN : régulations naturelle et artificielle, Université Bordeaux Segalen - Bordeaux 2-Institut Européen de Chimie et de Biologie-Institut National de la Santé et de la Recherche Médicale (INSERM), Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biochimie et Génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Réseau Maladies Métaboliques, Hôpitaux Universitaires du Grand Ouest, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA)
Subjects: 0301 basic medicine, Adult, Male, Niacinamide, Intraocular pressure, Spectrometry, Mass, Electrospray Ionization, medicine.medical_specialty, Open angle glaucoma, [SDV]Life Sciences [q-bio], Urology, Glaucoma, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Humans, Intraocular Pressure, ComputingMilieux_MISCELLANEOUS, Aged, 030304 developmental biology, Therapeutic strategy, Aged, 80 and over, 0303 health sciences, Nicotinamide, Case-control study, Nicotinamide deficiency, Middle Aged, medicine.disease, 3. Good health, 030104 developmental biology, Endocrinology, chemistry, Case-Control Studies, Plasma concentration, Cohort, 030221 ophthalmology & optometry, Female, 030217 neurology & neurosurgery, Glaucoma, Open-Angle, Cohort study, Chromatography, Liquid
Abstract: PurposeTo investigate the plasma concentration of nicotinamide in primary open-angle glaucoma (POAG).MethodsPlasma of 34 POAG individuals were compared to that of 30 age-and sex-matched controls using a semi-quantitative method based on liquid chromatography coupled to high-resolution mass spectrometry. Subsequently, an independent quantitative method, based on liquid chromatography coupled to mass spectrometry, was used to assess nicotinamide concentration in the plasma from the same initial cohort and from a replicative cohort of 20 POAG individuals and 15 controls.ResultsUsing the semi-quantitative method, the plasma nicotinamide concentration was significantly lower in the initial cohort of POAG individuals compared to and further confirmed in the same cohort, using the targeted quantitative method, with mean concentrations of 0.14 µM (median: 0.12 µM; range: 0.06-0.28 µM) in the POAG group (−30 %;p= 0.022), and 0.19 µM (median: 0.18 µM; range: 0.08-0.47 µM) in the control group. The quantitative dosage also disclosed a significantly lower plasma nicotinamide concentration (−33 %;p= 0.011) in the replicative cohort with mean concentrations of 0.14 µM (median: 0.14 µM; range: 0.09-0.25 µM) in the POAG group, and 0.19 µM (median: 0.21 µM; range: 0.09-0.26 µM) in the control group.ConclusionsGlaucoma is associated with lower plasmatic nicotinamide levels, compared to controls, suggesting that nicotinamide supplementation might become a future therapeutic strategy. Further studies are needed, in larger cohorts, to confirm these preliminary findings.
Published: 2019

10. eKLIPse: a sensitive tool for the detection and quantification of mitochondrial DNA deletions from next-generation sequencing data

Author: Pascal Reynier, Dominique Bonneau, Vincent Procaccio, Céline Bris, Estelle Colin, Virginie Hoffmann, Véronique Paquis-Flucklinger, Patrizia Amati-Bonneau, Claude Jardel, Benoit Rucheton, Guy Lenaers, Valérie Desquiret-Dumas, David Goudenège, Sylvie Bannwarth, Anne-Sophie Lebre, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB), Service de génétique médicale, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
Subjects: 0301 basic medicine, Mitochondrial DNA, Mitochondrial Diseases, Nuclear gene, Mitochondrial disease, [SDV]Life Sciences [q-bio], Computational biology, 030105 genetics & heredity, Biology, DNA, Mitochondrial, DNA sequencing, 03 medical and health sciences, Genotype, medicine, Humans, Gene, Genetic Association Studies, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Sequence Deletion, Base Sequence, Breakpoint, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, medicine.disease, Phenotype, Mitochondria, 030104 developmental biology, Software
Abstract: Accurate detection of mitochondrial DNA (mtDNA) alterations is essential for the diagnosis of mitochondrial diseases. The development of high-throughput sequencing technologies has enhanced the detection sensitivity of mtDNA pathogenic variants, but the detection of mtDNA rearrangements, especially multiple deletions, is still poorly processed. Here, we present eKLIPse, a sensitive and specific tool allowing the detection and quantification of large mtDNA rearrangements from single and paired-end sequencing data. The methodology was first validated using a set of simulated data to assess the detection sensitivity and specificity, and second with a series of sequencing data from mitochondrial disease patients carrying either single or multiple deletions, related to pathogenic variants in nuclear genes involved in mtDNA maintenance. eKLIPse provides the precise breakpoint positions and the cumulated percentage of mtDNA rearrangements at a given gene location with a detection sensitivity lower than 0.5% mutant. eKLIPse software is available either as a script to be integrated in a bioinformatics pipeline, or as user-friendly graphical interface to visualize the results through a Circos representation ( https://github.com/dooguypapua/eKLIPse ). Thus, eKLIPse represents a useful resource to study the causes and consequences of mtDNA rearrangements, for further genotype/phenotype correlations in mitochondrial disorders.
Published: 2019

11. Dominant mutations in mtDNA maintenance gene SSBP1 cause optic atrophy and foveopathy

Author: Cécile Delettre, Gaël Manes, Mélanie Quiles, Guy Lenaers, Marie O. Pequignot, Ulrich Kellner, Béatrice Bocquet, Helmut Wilhelm, Chantal Cazevieille, Audrey Sénéchal, Maria Solà, Fenna Hensen, Bernd Wissinger, Emmanuelle Sarzi, Camille Piro-Mégy, Xavier Zanlonghi, Aleix Tarrés-Solé, David Goudenège, Agathe Roubertie, Nicole Weisschuh, Christian P. Hamel, Majida Charif, Johannes N. Spelbrink, Arka Chakraborty, Agnès Muller, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroimmunologie des annélides (NA), Université de Lille, Sciences et Technologies-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Institute for Ophthalmic Research [Tübingen, Germany] (Centre for Ophthalmology), University of Tübingen, Service Exploration Fonctionnelle de la Vision, Clinique Sourdille, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía y Competitividad (España), Generalitat de Catalunya, European Commission, Ministerio de Educación y Formación Profesional (España), LENAERS, Guy, and Institut des Neurosciences de Montpellier (INM)
Subjects: 0301 basic medicine, Male, genetic structures, [SDV]Life Sciences [q-bio], Mitochondrion, GTP Phosphohydrolases, 0302 clinical medicine, Missense mutation, Child, ComputingMilieux_MISCELLANEOUS, Genetics, Aged, 80 and over, Neurodegeneration, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], General Medicine, Middle Aged, 3. Good health, Mitochondria, [SDV] Life Sciences [q-bio], DNA-Binding Proteins, 030220 oncology & carcinogenesis, Female, Research Article, Adult, DNA Replication, Mitochondrial DNA, Adolescent, Mutation, Missense, Biology, DNA-binding protein, DNA, Mitochondrial, Mitochondrial Proteins, 03 medical and health sciences, Atrophy, All institutes and research themes of the Radboud University Medical Center, Optic Atrophy, Autosomal Dominant, Exome Sequencing, medicine, Humans, Gene, Aged, Binding protein, medicine.disease, eye diseases, Ophthalmology, 030104 developmental biology, Commentary, sense organs
Abstract: © 2020, Piro-Mégy et al., Mutations in genes encoding components of the mitochondrial DNA (mtDNA) replication machinery cause mtDNA depletion syndromes (MDSs), which associate ocular features with severe neurological syndromes. Here, we identified heterozygous missense mutations in single-strand binding protein 1 (SSBP1) in 5 unrelated families, leading to the R38Q and R107Q amino acid changes in the mitochondrial single-stranded DNA-binding protein, a crucial protein involved in mtDNA replication. All affected individuals presented optic atrophy, associated with foveopathy in half of the cases. To uncover the structural features underlying SSBP1 mutations, we determined a revised SSBP1 crystal structure. Structural analysis suggested that both mutations affect dimer interactions and presumably distort the DNA-binding region. Using patient fibroblasts, we validated that the R38Q variant destabilizes SSBP1 dimer/tetramer formation, affects mtDNA replication, and induces mtDNA depletion. Our study showing that mutations in SSBP1 cause a form of dominant optic atrophy frequently accompanied with foveopathy brings insights into mtDNA maintenance disorders., This study was supported by the Spanish Ministry of Science, Innovation and Universities, MINECO (BFU2015-70645-R, RTI2018-101015-B-100 to MS), the Generalitat de Catalunya (2014-SGR-997 and 2017-SGR-1192 to MS), and the European Union (FP7-HEALTH-2012-306029-2 to MS). ATS was awarded with an FPU fellowship from the Ministry of Education, Professional Formation (MEFP). The Structural Biology Unit at IBMB-CSIC is a “Maria de Maeztu” Unit of Excellence awarded by MINECO (MDM-2014-0435). This work was supported by the “Prinses Beatrix Spierfonds” and the “Stichting Spieren voor Spieren” (W.OR15-05 to JNS).
Published: 2019

12. Metabolomic Profiling of Aqueous Humor in Glaucoma Points to Taurine and Spermine Deficiency: Findings from the Eye-D Study

Author: Jeanne Muller, Gilles Simard, Philippe Gohier, Dan Milea, Juan Manuel Chao de la Barca, Cédric Annweiler, Vincent Procaccio, Patrizia Amati-Bonneau, Dominique Bonneau, Pascal Reynier, Adrien Buisset, Guy Lenaers, Stéphanie Leruez, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Robarts Research Institute [Canada], University of Western Ontario (UWO), Laboratoire de Psychologie des Pays de la Loire (LPPL), Université d'Angers (UA)-Université de Nantes - UFR Lettres et Langages (UFRLL), Université de Nantes (UN)-Université de Nantes (UN), Singapore Eye Research Institute, Singapore National Eye Centre, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Taurine, primary open-angle glaucoma, genetic structures, [SDV]Life Sciences [q-bio], Spermine, Cataract Extraction, Biochemistry, Aqueous Humor, 03 medical and health sciences, chemistry.chemical_compound, Internal medicine, Carnitine, Lipidomics, medicine, Humans, Metabolomics, Amino Acids, ComputingMilieux_MISCELLANEOUS, Aged, chemistry.chemical_classification, Aged, 80 and over, 030102 biochemistry & molecular biology, General Chemistry, Middle Aged, eye diseases, Amino acid, Glutamine, Hydroxyproline, 030104 developmental biology, Endocrinology, glaucoma, chemistry, lipidomics, Female, Leucine, Isoleucine, Glaucoma, Open-Angle, medicine.drug
Abstract: International audience; We compared the metabolomic profile of aqueous humor from patients with primary open-angle glaucoma (POAG; n = 26) with that of a group of age- and sex-matched non-POAG controls (n = 26), all participants undergoing cataract surgery. Supervised paired partial least-squares discriminant analysis showed good predictive performance for test sets with a median area under the receiver operating characteristic of 0.89 and a p-value of 0.0087. Twenty-three metabolites allowed discrimination between the two groups. Univariate analysis after the Benjamini–Hochberg correction showed significant differences for 13 of these metabolites. The POAG metabolomic signature indicated reduced concentrations of taurine and spermine and increased concentrations of creatinine, carnitine, three short-chain acylcarnitines, 7 amino acids (glutamine, glycine, alanine, leucine, isoleucine, hydroxyl-proline, and acetyl-ornithine), 7 phosphatidylcholines, one lysophosphatidylcholine, and one sphingomyelin. This suggests an alteration of metabolites involved in osmoprotection (taurine and creatinine), neuroprotection (spermine, taurine, and carnitine), amino acid metabolism (7 amino acids and three acylcarnitines), and the remodeling of cell membranes drained by the aqueous humor (hydroxyproline and phospholipids). Five of these metabolic alterations, already reported in POAG plasma, concern spermine, C3 and C4 acylcarnitines, PC aa 34:2, and PC aa 36:4, thus highlighting their importance in the pathogenesis of glaucoma.
Published: 2019

13. Pathogenicity of novel atypical variants leading to choroideremia as determined by functional analyses

Author: Gema García-García, Simona Torriano, Nejla Erkilic, Christel Vaché, David Baux, Michel Koenig, Isabelle Meunier, Valérie Faugère, Anne-Françoise Roux, Christian P. Hamel, Xavier Zanlonghi, Vasiliki Kalatzis, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinique Sourdille, Institut de Génétique Moléculaire de Montpellier (IGMM), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Subjects: [SDV]Life Sciences [q-bio], Alu element, Retrotransposon, Biology, MESH: Alu insertion, CHM, REP1, prenylation, promoter substitution, Choroideremia, 03 medical and health sciences, Western blot, Alu Elements, Transcription (biology), Genetics, Transcriptional regulation, medicine, Humans, Genetic Predisposition to Disease, Nucleotide, Promoter Regions, Genetic, Gene, Genetics (clinical), 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Base Sequence, medicine.diagnostic_test, 030305 genetics & heredity, Exons, medicine.disease, 3. Good health, chemistry, Mutation
Abstract: International audience; Choroideremia is a monogenic X-linked recessive chorioretinal disease linked to pathogenic variants in the CHM gene. These variants are commonly base-pair changes, frameshifts, or large deletions. However, a few rare or unusual events comprising large duplications, a retrotransposon insertion, a pseudo-exon activation, and two c-98 promoter substitutions have also been described. Following an exhaustive molecular diagnosis, we identified and characterized three novel atypical disease-causing variants in three unrelated male patients. One is a first-ever reported Alu insertion within CHM and the other two are nucleotide substitutions, c.-90C>G and c.-108A>G, affecting highly conserved promoter positions. RNA analysis combined with western blot and functional assays of patient cells established the pathogenicity of the Alu insertion and the c.-90C>G alteration. Furthermore, luciferase reporter assays suggested a CHM transcription defect associated with the c.-90C>G and c.-108A>G variants. These findings broaden our knowledge of the mutational spectrum and the transcriptional regulation of the CHM gene.
Published: 2019

14. Enriched Differentiation of Human Otic Sensory Progenitor Cells Derived From Induced Pluripotent Stem Cells

Author: Alejandra Lopez-Juarez, Hanae Lahlou, Azel Zine, Arnaud Fontbonne, Said Assou, Emmanuel Nivet, Neurosciences sensorielles et cognitives (NSC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de neurophysiopathologie (INP), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), This research was funded by the European Community’s Seventh Framework Programme under grant agreement No. 603029 (Project OTOSTEM). ‘‘La Fondation Pour l’Audition’’ (Paris,France) provided Ph.D. fellowship to HL., European Project: 603029,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,OTOSTEM(2013), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: 0301 basic medicine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Population, embryonic hair cells, Biology, Fibroblast growth factor, lcsh:RC321-571, Transcriptome, otic development, 03 medical and health sciences, Cellular and Molecular Neuroscience, Progenitor cell, Induced pluripotent stem cell, education, Molecular Biology, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Original Research, human induced pluripotent cells, education.field_of_study, FGF10, transcriptome (RNA-seq), Wnt signaling pathway, human otic progenitor cells, Cell biology, 030104 developmental biology, in vitro differentiation, sense organs, Stem cell, Neuroscience
Abstract: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306956/pdf/fnmol-11-00452.pdf; International audience; Age-related neurosensory deficit of the inner ear is mostly due to a loss of hair cells (HCs). Development of stem cell-based therapy requires a better understanding of factors and signals that drive stem cells into otic sensory progenitor cells (OSPCs) to replace lost HCs. Human induced pluripotent stem cells (hiPSCs) theoretically represent an unlimited supply for the generation of human OSPCs in vitro. In this study, we developed a monolayer-based differentiation system to generate an enriched population of OSPCs via a stepwise differentiation of hiPSCs. Gene and protein expression analyses revealed the efficient induction of a comprehensive panel of otic/placodal and late otic markers over the course of the differentiation. Furthermore, whole transcriptome analysis confirmed a developmental path of OSPC differentiation from hiPSCs. We found that modulation of WNT and transforming growth factor-β (TGF-β) signaling combined with fibroblast growth factor 3 (FGF3) and FGF10 treatment over a 6-day period drives the expression of early otic/placodal markers followed by late otic sensory markers within 13 days, indicative of a differentiation into embryonic-like HCs. In summary, we report a rapid and efficient strategy to generate an enriched population of OSPCs from hiPSCs, thereby establishing the value of this approach for disease modeling and cell-based therapies of the inner ear.
Published: 2018

15. Reply to Micarelli et al. Commentary on The Balance of Sleep: Role of the Vestibular Sensory System

Author: Martin Hitier, Marie-Laure Machado, Christian Chabbert, Stephane Besnard, Paul F. Smith, Joseph Toulouse, Brahim Tighilet, Anne Legall, Neurophysiologie Clinique, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Mobilités : Vieillissement, Pathologie, Santé (COMETE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurosciences sensorielles et cognitives (NSC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Otago [Dunedin, Nouvelle-Zélande], Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service des Explorations Fonctionnelles [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Caen Normandie (UNICAEN), and Normandie Université (NU)-Normandie Université (NU)
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, [SDV]Life Sciences [q-bio], [SHS.PSY]Humanities and Social Sciences/Psychology, Sensory system, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Physiology (medical), medicine, Humans, ComputingMilieux_MISCELLANEOUS, Balance (ability), Vestibular system, Sleep Apnea, Obstructive, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, Sleep apnea, medicine.disease, Sleep in non-human animals, 030228 respiratory system, Neurology, Neurology (clinical), business, Sleep, 030217 neurology & neurosurgery
Abstract: International audience
Published: 2018

16. Alteration of Extracellular Nucleotide Metabolism in Pseudoxanthoma Elasticum

Author: Viola Pomozi, Ludovic Martin, Salim Khiati, Olivier Le Saux, Guy Lenaers, Daniel Henrion, Gennady G. Yegutkin, Gilles Kauffenstein, Georges Leftheriotis, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), ARN : régulations naturelle et artificielle, Université Bordeaux Segalen - Bordeaux 2-Institut Européen de Chimie et de Biologie-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Hawai'i [Honolulu] (UH), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Dermatology, and Université d'Angers (UA)
Subjects: Male, 0301 basic medicine, Adenosine, [SDV]Life Sciences [q-bio], Biochemistry, Mice, chemistry.chemical_compound, Adenosine Triphosphate, Loss of Function Mutation, Pseudoxanthoma Elasticum, 5'-Nucleotidase, Aorta, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, biology, Middle Aged, Purinergic signalling, Pseudoxanthoma elasticum, 3. Good health, Adenosine Diphosphate, Liver, Female, Multidrug Resistance-Associated Proteins, medicine.drug, Adult, Adenosine monophosphate, medicine.medical_specialty, ABCC6, Dermatology, GPI-Linked Proteins, Article, 03 medical and health sciences, Nucleotidase, Internal medicine, medicine, Animals, Humans, Molecular Biology, ACDC, ta1182, Cell Biology, ta3121, medicine.disease, 030104 developmental biology, Endocrinology, chemistry, biology.protein, ATP-Binding Cassette Transporters, Adenosine triphosphate
Abstract: Pseudoxanthoma elasticum (PXE) is a rare genetic condition primarily caused by hepatic ABCC6 transporter dysfunction. Most clinical manifestations of PXE are due to premature calcification of elastic fibers. However, the vascular impact of PXE is pleiotropic and remains ill defined. ABCC6 expression has recently been associated with cellular nucleotide export. We studied the impact of ABCC6 deficiency on blood levels of aden-osine triphosphate and related metabolites and on soluble nucleotidase activities in PXE patients and Abcc6(−/−) mice. In addition, we investigated the expression of genes encoding ectocellular purinergic signaling proteins in mouse liver and aorta. Plasma adenosine triphosphate and pyrophosphate levels were significantly reduced in PXE patients and in Abcc6(−/−) mice, whereas adenosine concentration was not modified. Moreover, 5′-nucleotidase/CD73 activity was increased in the serum of PXE patients and Abcc6(−/−) mice. Consistent with alterations of purinergic signaling, the expression of genes involved in purine and phosphate transport/metabolism was dramatically modified in Abcc6(−/−) mouse aorta, with much less impact on the liver. ABCC6 deficiency causes impaired vascular homeostasis and tissue perfusion. Our findings suggest that these alterations are linked to changes in extracellular nucleotide metabolism that are remote from the liver. This opens new perspectives for the understanding of PXE pathophysiology.
Published: 2018

17. Study of mitochondrial function in placental insufficiency

Author: Valérie Seegers, Geraldine Gascoin, Vincent Procaccio, Naïg Gueguen, Guillaume Legendre, Majida Cherif, Valérie Desquiret-Dumas, Salim Khiati, Tiphaine Lefebvre, Guillaume Geffroy, Ombeline Roche, Guy Lenaers, Odile Blanchet, Pascal Reynier, Laboratoire d'Ecologie Alpine (LECA ), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), ARN : régulations naturelle et artificielle, Université Bordeaux Segalen - Bordeaux 2-Institut Européen de Chimie et de Biologie-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CEntre de REcherches en MAthématiques de la DEcision (CEREMADE), Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), PRES Université Nantes Angers Le Mans (UNAM), and Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC)
Subjects: 0301 basic medicine, Adult, medicine.medical_specialty, Mitochondrial DNA, Placenta, [SDV]Life Sciences [q-bio], Respiratory chain, Placental insufficiency, Mitochondrion, DNA, Mitochondrial, Polymerase Chain Reaction, Preeclampsia, Electron Transport, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Pregnancy, Internal medicine, medicine, Humans, reproductive and urinary physiology, ComputingMilieux_MISCELLANEOUS, 030219 obstetrics & reproductive medicine, Fetal Growth Retardation, business.industry, Obstetrics and Gynecology, medicine.disease, Placental Insufficiency, Mitochondria, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Reproductive Medicine, Haplotypes, Case-Control Studies, embryonic structures, Female, business, Maternal Serum Screening Tests, Developmental Biology, Human mitochondrial DNA haplogroup
Abstract: Introduction It has been suggested that mitochondria play a crucial role in sustaining pregnancy and foetal growth. The aim of the study was to assess the influence of mitochondrial functions and genetics on placental insufficiency diseases. Methods A total of 115 patients were recruited, subdivided into 74 placenta samples and 41 maternal blood samples: placental insufficiency diseases including intra uterine growth restriction (IUGR) (n = 35), preeclampsia (PE) (n = 13), IUGR associated to PE (PER) (n = 25); and controls (n = 42). Haplogroups were determined for all patients. Eighty-six placenta samples were studied for quantitative and qualitative analyses of mtDNA: IUGR (n = 25), PE (n = 1), PER (n = 18) and controls (n = 42). Sixteen placenta samples were selected for functional analysis: IUGR (n = 6), PER (n = 2) and controls (n = 8). Results Mitochondrial DNA copy numbers and rearrangements and haplogroup distribution were not significantly altered in the patient group. Enzyme activity and expression of respiratory chain complexes were also comparable between both groups. Discussion Our results do not argue in favour of a mitochondrial involvement in placental insufficiency, suggesting that the glycolytic pathway may represent a key energetic source in placental insufficiency diseases.
Published: 2018

18. The accumulation of assembly intermediates of the mitochondrial complex I matrix arm is reduced by limiting glucose uptake in a neuronal-like model of MELAS syndrome

Author: Valérie Desquiret-Dumas, Daniel Henrion, Aurelie Renaud, Céline Bris, Guillaume Geffroy, Vincent Procaccio, Pascal Reynier, Rayane Benyahia, Dominique Bonneau, Sophie Belal, Naïg Gueguen, Samuel Frey, Aurore Inisan, Arnaud Chevrollier, Franck Letournel, Guy Lenaers, Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Centre D'Etude et de Recherche Interdisciplinaire de l'UFR LAC (CERILAC (EA_4410)), Université Paris Diderot - Paris 7 (UPD7), Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Micro et Nanomédecines Translationnelles (MINT), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA)
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Mitochondrial DNA, Glucose uptake, Mitochondrial disease, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Oxidative phosphorylation, Mitochondrion, MELAS syndrome, Oxidative Phosphorylation, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Cell Line, Tumor, medicine, MELAS Syndrome, Humans, Point Mutation, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Neurons, Electron Transport Complex I, Chemistry, medicine.disease, Mitochondria, 030104 developmental biology, Endocrinology, Glucose, Mitochondrial biogenesis, Molecular Medicine, Female, 030217 neurology & neurosurgery, Ketogenic diet
Abstract: Ketogenic diet (KD) which combined carbohydrate restriction and the addition of ketone bodies has emerged as an alternative metabolic intervention used as an anticonvulsant therapy or to treat different types of neurological or mitochondrial disorders including MELAS syndrome. MELAS syndrome is a severe mitochondrial disease mainly due to the m.3243A > G mitochondrial DNA mutation. The broad success of KD is due to multiple beneficial mechanisms with distinct effects of very low carbohydrates and ketones. To evaluate the metabolic part of carbohydrate restriction, transmitochondrial neuronal-like cybrid cells carrying the m.3243A > G mutation, shown to be associated with a severe complex I deficiency was exposed during 3 weeks to glucose restriction. Mitochondrial enzyme defects were combined with an accumulation of complex I (CI) matrix intermediates in the untreated mutant cells, leading to a drastic reduction in CI driven respiration. The severe reduction of CI was also paralleled in post-mortem brain tissue of a MELAS patient carrying high mutant load. Importantly, lowering significantly glucose concentration in cell culture improved CI assembly with a significant reduction of matrix assembly intermediates and respiration capacities were restored in a sequential manner. In addition, OXPHOS protein expression and mitochondrial DNA copy number were significantly increased in mutant cells exposed to glucose restriction. The accumulation of CI matrix intermediates appeared as a hallmark of MELAS pathophysiology highlighting a critical pathophysiological mechanism involving CI disassembly, which can be alleviated by lowering glucose fuelling and the induction of mitochondrial biogenesis, emphasizing the usefulness of metabolic interventions in MELAS syndrome.
Published: 2018

19. Reply: The expanding neurological phenotype of DNM1L-related disorders

Author: Isabelle Meunier, Tanguy Chaumette, Dominique Bonneau, Benoît Funalot, Aurelien Paris, Didier Bouccara, Marlène Rio, Patrizia Amati-Bonneau, Jean-Michel Rozet, Guy Lenaers, Pascal Reynier, Cécile Delettre, Arnaud Chevrollier, Vincent Procaccio, Majida Charif, Christian P. Hamel, Sylvie Gerber, Selma Kane, Raphael Calmon, Josseline Kaplan, Claire Angebault, Jennifer Alban, Mélanie Quiles, Hiromi Sesaki, Nathalie Boddaert, Stéphanie Leruez, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropathies du système nerveux entérique et pathologies digestives, implication des cellules gliales entériques, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Chirurgie otologique mini-invasive robotisée, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Department of Cell Biology, Baltimore, Johns Hopkins University School of Medicine, Handicaps génétiques de l'enfant (Inserm U393), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), LENAERS, Guy, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Institut des Neurosciences de Montpellier (INM)
Subjects: 0301 basic medicine, Dynamins, [SDV]Life Sciences [q-bio], education, Bioinformatics, Mitochondrial Dynamics, GTP Phosphohydrolases, Mitochondrial Proteins, 03 medical and health sciences, 0302 clinical medicine, Text mining, Optic Atrophy, Autosomal Dominant, Medicine, Humans, ComputingMilieux_MISCELLANEOUS, business.industry, Phenotype, eye diseases, [SDV] Life Sciences [q-bio], 030104 developmental biology, Mutation, Neurology (clinical), business, Microtubule-Associated Proteins, 030217 neurology & neurosurgery
Abstract: Comment on :Mutations in DNM1L, as in OPA1, result in dominant optic atrophy despite opposite effects on mitochondrial fusion and fission. [Brain. 2017]The expanding neurological phenotype of DNM1L-related disorders. [Brain. 2018]; International audience; Letter to the editor
Published: 2018

20. Modeling human early otic sensory cell development with induced pluripotent stem cells

Author: Arnaud Fontbonne, Azel Zine, Alejandra Lopez-Juarez, Emmanuel Nivet, Hanae Lahlou, Neurosciences sensorielles et cognitives (NSC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de neurophysiopathologie (INP), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), European Project: 603029,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,OTOSTEM(2013), Nivet, Emmanuel, and Human stem cell applications for the treatment of hearing loss - OTOSTEM - - EC:FP7:HEALTH2013-11-01 - 2017-10-31 - 603029 - VALID
Subjects: 0301 basic medicine, Physiology, Cellular differentiation, medicine.medical_treatment, Fibroblast growth factor, lcsh:Medicine, Stem cells, Biochemistry, Endocrinology, Cell Signaling, Animal Cells, Inner ear, Medicine and Health Sciences, Cell differentiation, Induced pluripotent stem cell, lcsh:Science, Notch signaling, Multidisciplinary, Receptors, Notch, Paired box, Stem-cell therapy, Cell biology, Anatomy, Cellular Types, Stem cell, Research Article, Signal Transduction, Pluripotency, animal structures, Cell Potency, Induced Pluripotent Stem Cells, Notch signaling pathway, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Cell fate determination, Biology, 03 medical and health sciences, Protein Domains, Growth Factors, Genetics, medicine, Humans, Cell Lineage, Progenitor cell, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Endocrine Physiology, lcsh:R, Biology and Life Sciences, Proteins, Cell Biology, 030104 developmental biology, Ears, Ear, Inner, lcsh:Q, Gene expression, sense organs, Head, Developmental Biology
Abstract: International audience; The inner ear represents a promising system to develop cell-based therapies from human induced pluripotent stem cells (hiPSCs). In the developing ear, Notch signaling plays multiple roles in otic region specification and for cell fate determination. Optimizing hiPSC induction for the generation of appropriate numbers of otic progenitors and derivatives, such as hair cells, may provide an unlimited supply of cells for research and cell-based therapy. In this study, we used monolayer cultures, otic-inducing agents, Notch modulation, and marker expression to track early and otic sensory lineages during hiPSC differentiation. Otic/placo-dal progenitors were derived from hiPSC cultures in medium supplemented with FGF3/ FGF10 for 13 days. These progenitor cells were then treated for 7 days with retinoic acid (RA) and epidermal growth factor (EGF) or a Notch inhibitor. The differentiated cultures were analyzed in parallel by qPCR and immunocytochemistry. After the 13 day induction, hiPSC-derived cells displayed an upregulated expression of a panel of otic/placodal markers. Strikingly, a subset of these induced progenitor cells displayed key-otic sensory markers , the percentage of which was increased in cultures under Notch inhibition as compared to RA/EGF-treated cultures. Our results show that modulating Notch pathway during in vitro differentiation of hiPSC-derived otic/placodal progenitors is a valuable strategy to promote the expression of human otic sensory lineage genes.
Published: 2018

21. Identification and modelling of fast and slow I h current components in vestibular ganglion neurons

Author: Jean-Luc Puel, Gilles Desmadryl, Jérôme Bourien, Christine Azevedo Coste, Christophe B Michel, Bruce P. Graham, Physiologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Artificial movement and gait restoration (DEMAR), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Physiologie des Adaptations Nutritionnelles [UMR_A1280] (PhAN), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Inria Sophia Antipolis - Méditerranée (CRISAM), Institut des Neurosciences de Montpellier (INM), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Subjects: Male, Voltage clamp, computational modelling, Models, Neurological, Scarpa's ganglion, Action Potentials, hyperpolarization-activated cation current, Biology, Vestibular Nerve, Cyclic nucleotide, chemistry.chemical_compound, [SPI]Engineering Sciences [physics], Mice, Ganglia, Sensory, medicine, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Animals, Inner ear, Computer Simulation, voltage clamp, Vestibular system, Computational Neuroscience, Neurons, vestibular, General Neuroscience, Electrophysiology, medicine.anatomical_structure, chemistry, Excitatory postsynaptic potential, Female, Neuron, hyperpolarization‐activated cation current, Neuroscience, Algorithms
Abstract: International audience; Previous experimental data indicates the hyperpolarization-activated cation (Ih ) current, in the inner ear, consists of two components [different hyperpolarization-activated cyclic nucleotide-gated (HCN) subunits] which are impossible to pharmacologically isolate. To confirm the presence of these two components in vestibular ganglion neurons we have applied a parameter identification algorithm which is able to discriminate the parameters of the two components from experimental data. Using simulated data we have shown that this algorithm is able to identify the parameters of two populations of non-inactivated ionic channels more accurately than a classical method. Moreover, the algorithm was demonstrated to be insensitive to the key parameter variations. We then applied this algorithm to Ih current recordings from mouse vestibular ganglion neurons. The algorithm revealed the presence of a high-voltage-activated slow component and a low-voltage-activated fast component. Finally, the electrophysiological significance of these two Ih components was tested individually in computational vestibular ganglion neuron models (sustained and transient), in the control case and in the presence of cAMP, an intracellular cyclic nucleotide that modulates HCN channel activity. The results suggest that, first, the fast and slow components modulate differently the action potential excitability and the excitatory postsynaptic potentials in both sustained and transient vestibular neurons and, second, the fast and slow components, in the control case, provide different information about characteristics of the stimulation and this information is significantly modified after modulation by cAMP.
Published: 2015

22. Successful immunosuppressant-free heterotopic transplantation of tracheal allografts in the pig

Author: Christophe Mariette, Julien De Wolf, Eric Kipnis, Thomas Hubert, Ramadan Jashari, Pierre Fayoux, Alexandre Ung, Christophe Zawadzki, Mathias Brieu, Marie-Christine Copin, Alain Wurtz, Laboratoire de Mécanique de Lille - FRE 3723 (LML), Université de Lille, Sciences et Technologies-Centrale Lille-Centre National de la Recherche Scientifique (CNRS), Centrale Lille, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Lille 2 - Faculté de Médecine, European Homograft Bank [Bruxelles] (EHB), Clinique Saint-Jean [Bruxelles], Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Jeanne de Flandre [Lille], Chirurgie générale et Digestive, Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille, Département de Pathologie, Interface sang vaisseaux et réparation cardiovasculaire, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Sciences et Technologies-Ecole Centrale de Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS), and Ecole Centrale de Lille
Subjects: Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Transplantation, Heterotopic, Swine, Lymphocyte, medicine.medical_treatment, 030204 cardiovascular system & hematology, Revascularization, Cryopreservation, 03 medical and health sciences, 0302 clinical medicine, Immune Tolerance, medicine, Animals, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, ComputingMilieux_MISCELLANEOUS, Tissue Survival, business.industry, Cartilage, General Medicine, Allografts, medicine.disease, Epithelium, Surgery, Trachea, Transplantation, surgical procedures, operative, medicine.anatomical_structure, 030228 respiratory system, Tissue bank, Female, Cardiology and Cardiovascular Medicine, business, Omentum, Calcification
Abstract: OBJECTIVES It has been demonstrated that both heterotopic and orthotopic transplants of epithelium-denuded cryopreserved tracheal allografts are feasible in immunosuppressant-free rabbits. Validation of these results in large animals is required before considering clinical applications. We evaluated the viability, immune tolerance and strain properties of such tracheal allografts heterotopically transplanted in a pig model. METHODS Ten tracheal segments, 5 short (5 rings) and 5 long (10 rings), were obtained from male Landrace pigs. The tracheal segments were surgically denuded of their epithelium, then cryopreserved and stored in a tissue bank for 33 to 232 days. After thawing, tracheal segments stented with a silicone tube were wrapped in the omentum in 2 groups of 5 female recipients. The animals did not receive any immunosuppressive drugs. The animals were euthanized from Day 6 to Day 90 in both groups. RESULTS An effective revascularization of allografts regardless of length was observed. Lymphocyte infiltrate was shown in the early postoperative period and became non-significant after 30 days. Allografts displayed high levels of neoangiogenesis and viable cartilage rings with islets of calcification. Biomechanical measurements demonstrated strain properties similar to those of a fresh tracheal segment from Day 58. CONCLUSIONS Our results demonstrate the acceptability and satisfactory stiffness of epithelium-denuded cryopreserved tracheal allografts implanted in the omentum, despite the absence of immunosuppressive drugs. Since the omentum has the capability to reach the tracheal region, this approach should be investigated in the setting of orthotopic transplants in a pig model before considering clinical applications.
Published: 2017

23. Wolfram syndrome: MAMs' connection?

Author: Benjamin Delprat, Tangui Maurice, Cécile Delettre, Mécanismes moléculaires dans les démences neurodégénératives (MMDN), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), This work was supported by external ressources from 'Institut National de la Santé et de la Recherche Médicale' (INSERM), Université de Montpellier, and Association Syndrome de Wolfram (Grand-Champ, France) and grants from the Agence Nationale pour la Recherche (ANR-12-JSV1-0008-01), Fondation pour la Recherche Médicale, and Fondation de France., ANR-12-JSV1-0001,LIPIDOPAIN,Implication des métabolites des acide gars polyinsaturés et des récepteurs canaux 'TRP' dans l'hypersensibilité viscérale(2012), Delprat, Benjamin, Jeunes Chercheuses et Jeunes Chercheurs - Implication des métabolites des acide gars polyinsaturés et des récepteurs canaux 'TRP' dans l'hypersensibilité viscérale - - LIPIDOPAIN2012 - ANR-12-JSV1-0001 - JC - VALID, Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Montpellier 2 - Sciences et Techniques (UM2)-École pratique des hautes études (EPHE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: 0301 basic medicine, Cancer Research, Wolfram syndrome, [SDV]Life Sciences [q-bio], Immunology, Disease, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Review Article, Mitochondrion, Bioinformatics, Endoplasmic Reticulum, Models, Biological, 03 medical and health sciences, Cellular and Molecular Neuroscience, [SCCO]Cognitive science, Atrophy, Diabetes mellitus, medicine, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Humans, Amyotrophic lateral sclerosis, lcsh:QH573-671, Pathological, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS, business.industry, lcsh:Cytology, Endoplasmic reticulum, [SCCO.NEUR]Cognitive science/Neuroscience, Wolfram Syndrome, Cell Biology, Intracellular Membranes, medicine.disease, Endoplasmic Reticulum Stress, 3. Good health, Mitochondria, [SDV] Life Sciences [q-bio], 030104 developmental biology, business
Abstract: Wolfram syndrome (WS) is a rare neurodegenerative disease, the main pathological hallmarks of which associate with diabetes, optic atrophy, and deafness. Other symptoms may be identified in some but not all patients. Prognosis is poor, with death occurring around 35 years of age. To date, no treatment is available. WS was first described as a mitochondriopathy. However, the localization of the protein on the endoplasmic reticulum (ER) membrane challenged this hypothesis. ER contacts mitochondria to ensure effective Ca2+ transfer, lipids transfer, and apoptosis within stabilized and functionalized microdomains, termed “mitochondria-associated ER membranes” (MAMs). Two types of WS are characterized so far and Wolfram syndrome type 2 is due to mutation in CISD2, a protein mostly expressed in MAMs. The aim of the present review is to collect evidences showing that WS is indeed a mitochondriopathy, with established MAM dysfunction, and thus share commonalities with several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, as well as metabolic diseases, such as diabetes.
Published: 2017

24. LRIT3 Differentially Affects Connectivity and Synaptic Transmission of Cones to ON- and OFF-Bipolar Cells

Author: Serge Picaud, Yan Cao, Kirill A. Martemyanov, Marion Neuillé, Connon I. Thomas, Romain Caplette, Christina Zeitz, Debbie Guerrero-Given, José-Alain Sahel, Isabelle Audo, Christian P. Hamel, Naomi Kamasawa, Institut de la Vision, 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), Department of Neuroscience, Scripps Research Institute, Max Planck Florida Institute for Neuroscience (MPFI), Max-Planck-Gesellschaft, Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), University College of London [London] (UCL), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Académie des Sciences, Institut de France, University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), 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), The Scripps Research Institute [La Jolla, San Diego], Académie des Sciences [Paris], Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), and HAL UPMC, Gestionnaire
Subjects: Male, 0301 basic medicine, Retinal Bipolar Cells, retina, multielectrode array, DNA Mutational Analysis, Neurotransmission, Biology, Synaptic Transmission, Retinal ganglion, Synapse, Mice, Young Adult, 03 medical and health sciences, Night Blindness, Postsynaptic potential, Electroretinography, Myopia, medicine, Animals, Humans, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, TRPM1, Retrospective Studies, Mice, Knockout, congenital stationary night blindness, Retina, electron microscopy, Metabotropic glutamate receptor 6, Membrane Proteins, Eye Diseases, Hereditary, Genetic Diseases, X-Linked, DNA, Dendrites, Anatomy, Immunohistochemistry, Microscopy, Electron, 030104 developmental biology, medicine.anatomical_structure, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Mutation, Synapses, Retinal Cone Photoreceptor Cells, Female, sense organs, LRIT3, Visual Neuroscience, Neuroscience, Immunostaining
Abstract: International audience; Purpose: Mutations in LRIT3 lead to complete congenital stationary night blindness (cCSNB). Using a cCSNB mouse model lacking Lrit3 (nob6), we recently have shown that LRIT3 has a role in the correct localization of TRPM1 (transient receptor potential melastatin 1) to the dendritic tips of ON-bipolar cells (BCs), contacting both rod and cone photoreceptors. Furthermore, postsynaptic clustering of other mGluR6 cascade components is selectively eliminated at the dendritic tips of cone ON-BCs. The purpose of this study was to further define the role of LRIT3 in structural and functional organization of cone synapses.Methods: Exhaustive electroretinogram analysis was performed in a patient with LRIT3 mutations. Multielectrode array recordings were performed at the level of retinal ganglion cells in nob6 mice. Targeting of GluR1 and GluR5 at the dendritic tips of OFF-BCs in nob6 retinas was assessed by immunostaining and confocal microscopy. The ultrastructure of photoreceptor synapses was evaluated by electron microscopy in nob6 mice.Results: The patient with LRIT3 mutations had a selective ON-BC dysfunction with relatively preserved OFF-BC responses. In nob6 mice, complete lack of ON-pathway function with robust, yet altered signaling processing in OFF-pathways was detected. Consistent with these observations, molecules essential for the OFF-BC signaling were normally targeted to the synapse. Finally, synaptic contacts made by ON-BC but not OFF-BC neurons with the cone pedicles were disorganized without ultrastructural alterations in cone terminals, horizontal cell processes, or synaptic ribbons.Conclusions: These results suggest that LRIT3 is likely involved in coordination of the transsynaptic communication between cones and ON-BCs during synapse formation and function.
Published: 2017

25. Onset of Spinal Cord Astrocyte Precursor Emigration from the Ventricular Zone Involves the Zeb1 Transcription Factor

Author: Douglas S. Darling, David Ohayon, C. Claus Stolt, Tsuyoshi Takagi, Alexandre Pattyn, Alain Garces, William D. Richardson, Yujiro Higashi, Chadi Soukkarieh, Willy Joly, Eric Agius, Jean-Charles Sabourin, Patrick Carroll, Jean-Philippe Hugnot, Pascal de Santa Barbara, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Toulouse [Toulouse], Faculté des Sciences [Damascus], Damascus University, Centre du service humain Aichi, Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de biologie du développement (CBD), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University of Louisville, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Erlangen-Nürnberg, Université College London, Saarland University [Saarbrücken], Développement et évolution du système nerveux (DESN), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), MORNET, Dominique, Institut des Neurosciences de Montpellier (INM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Damas = Damascus University, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), and École normale supérieure - Paris (ENS-PSL)
Subjects: 0301 basic medicine, Aging, cell migration, [SDV]Life Sciences [q-bio], Regulator, Biology, General Biochemistry, Genetics and Molecular Biology, White matter, Mice, 03 medical and health sciences, astrocyte, Cell Movement, medicine, Animals, Zeb2, Progenitor cell, lcsh:QH301-705.5, development, ComputingMilieux_MISCELLANEOUS, Body Patterning, Zeb1, GFAP, Stem Cells, Gene Expression Regulation, Developmental, Zinc Finger E-box-Binding Homeobox 1, spinal cord, Cell Differentiation, Embryo, Mammalian, Spinal cord, Cell biology, Neuroepithelial cell, [SDV] Life Sciences [q-bio], Cadherin-1, 030104 developmental biology, medicine.anatomical_structure, lcsh:Biology (General), Astrocytes, Mutation, Immunology, Ventricular zone, oligodendrocyte, Astrocyte, Sox9
Abstract: SummaryDuring spinal cord development, astrocyte precursors arise from neuroepithelial progenitors, delaminate from the ventricular zone, and migrate toward their final locations where they differentiate. Although the mechanisms underlying their early specification and late differentiation are being deciphered, less is known about the temporal control of their migration. Here, we show that the epithelial-mesenchymal transition regulator Zeb1 is expressed in glial precursors and report that loss of Zeb1 function specifically delays the onset of astrocyte precursor delamination from the ventricular zone, correlating with transient deregulation of the adhesion protein Cadherin-1. Consequently, astrocyte precursor invasion into the Zeb1−/− mutant white matter is delayed, and induction of their differentiation is postponed. These findings illustrate how fine regulation of adhesive properties influences the onset of neural precursor migration and further support the notion that duration of exposure of migrating astrocyte precursors to environmental cues and/or their correct positioning influence the timing of their differentiation.
Published: 2016

26. Culture conditions have an impact on the maturation of traceable, transplantable mouse embryonic stem cell-derived otic progenitor cells

Author: Abboud, Nesrine, Fontbonne, Arnaud, Watabe, Isabelle, Tonetto, Alain, Brezun, Jean Michel, Feron, François, Zine, Azel, Aix-Marseille Université - Faculté des Sciences (AMU SCI), Aix Marseille Université (AMU), Laboratoire de Neurosciences intégratives et adaptatives (LNIA), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Equipe avenir HUMAN EMBRYONIC STEM CELLS AS A MODEL TO DELINEATE THE EARLY CARDIAC TRANSCRIPTIONAL NETWORKS: TOWARD A BETTER UNDERSTANDING OF CARDIAC CONGENITAL AND GENETIC DISEASES., Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et thérapie des déficits sensoriels et moteurs, and Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV]Life Sciences [q-bio], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], sense organs, ComputingMilieux_MISCELLANEOUS
Abstract: International audience; The generation of replacement inner ear hair cells (HCs) remains a challenge and stem cell therapy holds the potential for developing therapeutic solutions to hearing and balance disorders. Recent developments have made significant strides in producing mouse otic progenitors using cell culture techniques to initiate HC differentiation. However, no consensus has been reached as to efficiency and therefore current methods remain unsatisfactory. In order to address these issues, we compare the generation of otic and HC progenitors from embryonic stem (ES) cells in two cell culture systems: suspension vs. adherent conditions. In the present study, an ES cell line derived from an Atoh1-green fluorescent protein (GFP) transgenic mouse was used to track the generation of otic progenitors, initial HCs and to compare these two differentiation systems. We used a two-step short-term differentiation method involving an induction period of 5 days during which ES cells were cultured in the presence of Wnt/transforming growth factor TGF-β inhibitors and insulin-like growth factor IGF-1 to suppress mesoderm and reinforce presumptive ectoderm and otic lineages. The generated embryoid bodies were then differentiated in medium containing basic fibroblast growth factor (bFGF) for an additional 5 days using either suspension or adherent culture methods. Upon completion of differentiation, quantitative polymerase chain reaction analysis and immunostaining monitored the expression of otic/HC progenitor lineage markers. The results indicate that cells differentiated in suspension cultures produced cells expressing otic progenitor/HC markers at a higher efficiency compared with the production of these cell types within adherent cultures. Furthermore, we demonstrated that a fraction of these cells can incorporate into ototoxin-injured mouse postnatal cochlea explants and express MYO7A after transplantation.
Published: 2016

27. Characteristics of laser stimulation by near infrared pulses of retinal and vestibular primary neurons

Author: Gilles Desmadryl, Agnès Muller, Michel Dumas, Fabrice Bardin, Jean-Michel Bec, Christian Chabbert, Cécile Travo, Emmanuelle S. Albert, Isabelle Marc, Institut d’Electronique et des Systèmes (IES), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Radiations et composants (RADIAC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), IMT - MINES ALES (IMT - MINES ALES), Institut Mines-Télécom [Paris] (IMT), Laboratoire de Génie Informatique et Ingénierie de Production (LGI2P), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Mathématiques, Informatique, Physique, et Applications / Université de Nîmes (MIPA), and Université de Nîmes (UNIMES)
Subjects: Retinal Ganglion Cells, Patch-Clamp Techniques, Light, Action Potentials, Scarpa's ganglion, Dermatology, Vestibular Nerve, 01 natural sciences, Retinal ganglion, law.invention, 010309 optics, Mice, 03 medical and health sciences, 0302 clinical medicine, Optics, law, 0103 physical sciences, medicine, Animals, Fiber Optic Technology, Laser power scaling, Rats, Wistar, Cells, Cultured, retinal ganglion neuron, vestibular, Chemistry, Pulse (signal processing), business.industry, Far-infrared laser, Temperature, Pulse duration, Laser, vestibular ganglion neuron, Rats, laser, Mice, Inbred C57BL, medicine.anatomical_structure, [SPI.OPTI]Engineering Sciences [physics]/Optics / Photonic, [SDV.IB]Life Sciences [q-bio]/Bioengineering, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Surgery, Neuron, Lasers, Semiconductor, business, Photic Stimulation, 030217 neurology & neurosurgery
Abstract: Background and Objective The optical stimulation of neurons from pulsed infrared lasers has appeared over the last years as an alternative to classical electric stimulations based on conventional electrodes. Laser stimulation could provide a better spatial selectivity allowing single-cell stimulation without prerequisite contact. In this work we present relevant physical characteristics of a non-lethal stimulation of cultured mouse vestibular and retinal ganglion neurons by single infrared laser pulses. Study Design/Materials and Methods Vestibular and retinal ganglion neurons were stimulated by a 100–400 mW pulsed laser diode beam (wavelengths at 1,470, 1,535, 1,875 nm) launched into a multimode optical fiber positioned at a few hundred micrometers away from the neurons. Ionic exchange measurements at the neuron membrane were achieved by whole-cell patch-clamp recordings. Stimulation and damage thresholds, duration and repetition rate of stimulation and temperature were investigated. Results All three lasers induced safe and reproducible action potentials (APs) on both types of neurons. The radiant exposure thresholds required to elicit APs range from 15 ± 5 to 100 ± 5 J cm−2 depending on the laser power and on the pulse duration. The damage thresholds, observed by a vital dye, were significantly greater than the stimulation thresholds. In the pulse duration range of our study (2–30 milliseconds), similar effects were observed for the three lasers. Measurements of the local temperature of the neuron area show that radiant exposures required for reliable stimulations at various pulse durations or laser powers correspond to a temperature increase from 22°C (room temperature) to 55–60°C. Stimulations by laser pulses at repetition rate of 1, 2, and 10 Hz during 10 minutes confirmed that the neurons were not damaged and were able to survive such temperatures. Conclusion These results show that infrared laser radiations provide a possible way to safely stimulate retinal and vestibular ganglion neurons. A similar temperature threshold is required to trigger neurons independently of variable energy thresholds, suggesting that an absolute temperature is required. Lasers Surg. Med. 44: 736–745, 2012. © 2012 Wiley Periodicals, Inc.
Published: 2012

28. Synthesis of Quinoline Dicarboxylic Esters as Biocompatible Fluorescent Tags

Author: Favre-Besse, Franck-Cyril, Poirel, Odile, Bersot, Tiphaine, Kim-Grellier, Elodie, Daumas, Stéphanie, El Mestikawy, Salah, Laras, Younes, Hugues, Vincent, Chandrasekaran, Yogesh, Blanchard-Desce, Mireille, Acher, Francine, Pietrancosta, Nicolas, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie des Maladies du Système Nerveux Central, 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), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Moléculaires (ISM), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Centre National de la Recherche Scientifique (CNRS), Chimie et Photonique Moléculaires (CPM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des biomolécules (LBM UMR 7203), Chimie Moléculaire de Paris Centre (FR 2769), Université Pierre et Marie Curie - Paris 6 (UPMC)-ESPCI ParisTech-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-ESPCI ParisTech-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1 (UB)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-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)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), 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)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - 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), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), and Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Electrons, 010402 general chemistry, Photochemistry, 01 natural sciences, Absorption, chemistry.chemical_compound, [CHIM]Chemical Sciences, Organic chemistry, Dicarboxylic Acids, ComputingMilieux_MISCELLANEOUS, Fluorescent Dyes, Molecular Structure, 010405 organic chemistry, Organic Chemistry, Quinoline, Regioselectivity, Esters, Chromophore, Biocompatible material, Fluorescence, 0104 chemical sciences, Spectrometry, Fluorescence, chemistry, Electrophile, Quinolines, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Absorption (chemistry), Excitation
Abstract: A series of dicarboxylic quinoline derivatives bearing electron-releasing or -withdrawing substituents have been synthesized using mono- or/and biphasic methodologies. By controlling the regioselectivity of addition into our electrophilic intermediate, we also characterized by which mechanism the Doebner-Miller cyclization step occurred. As anticipated, electron-releasing substituents induce a red shift of the low-energy absorption allowing excitation in the visible region. In addition, by playing on the strength and position of the electron-releasing substituents, chromophore having interesting fluorescent properties such as large Stoke shifts, good fluorescent quantum yields, emission in the visible green-yellow region and reasonable two-photon absorption in the NIR region have been obtained. These small-size fluorophores, which can be made water-soluble and have been shown to be non-toxic, can be hetero- and/or polyfunctionalized and thus represent promising key units for fluorescence-based physiological experiments with low background interactions.
Published: 2012

29. Le site de référence du Partenariat européen d’innovation pour un vieillissement actif et en bonne santé MACVIA-LR (contre les maladies chroniques pour un vieillissement en bonne santé en Languedoc-Roussillon)

Author: Bousquet, Jean, Bourret, Rodolphe, Camuzat, Thierry, Augé, Philippe, Domy, Philippe, Bringer, Jacques, Nicolas, Nicolas, Jonquet, Olivier, de la Coussaye, Jean-Emmanuel, Noguès, Michel, Robine, JM, Avignon, Antoine, Blain, Hubert, Bernard, Bernard, Dray, Gérard, Dufour, Vincent, Fouletier, Mireille, Hève, Didier, Jeandel, Jean, Laffont, Isabel, Larrey, Dominique, Laune, Daniel, Laurent, Laurent, Marès, Pierre, Marion, Marion, Pastor, Eric, Pélissier, Jacques-Yvon, Radier-Pontal, François, Reynes, Jacques, Royère, Emilie, Ychou, Marc, Bedbrook, Anna, Granier, Sophie, Abécassis, Frédéric, Albert, Sylvie, Adnet, Paule, Amouyal, Michel, Arnavieilhe, Sylvie, Asteriou, Trias, Attalin, Vincent, Aubas, Pierre, Azevedo Coste, Christine, Badin, Mélanie, Bakhti, Karima, Baptista, Gregory, Bardy, Benoit, Battesti, Pierre, Bénézet, Olivier, Bernard, Pierre-Louis, Berr, Claudine, Berthe, Jacquie, Bobia, Xavier, Bockaert, Joël, Boegner, Catherine, Boichot, Sylvie, Bonnin, Huei-Yune, Boulet, Philippe, Bouly, Stéphane, Boubakri, Chokri, Bourdin, Arnaud, Bourrain, Jean-Luc, Bourrel, Gérard, Bouix, Vincent, Breuker, Cyril, Bruguière, Valérie, Burille, Jacques, Cade, Stéphane, David, David, Calmels, Marie-Virginie, Camu, William, Canovas, Gérard, Carre, Véronique, Cavalli, Giacomo, Cayla, Guillaume, Chiron, Raphaël, Claret, Pierre-Geraud, Coignard, Pauline, Coroian, Flavia-Oana, Costa, Pierre, Cottalorda, Jérôme, Coulet, Bertrand, Coupet, Anne, Courrouy-Michel, Christine, Courtet, Philippe, Cristol, Jean-Paul, Cros, Valérie, Cuisinier, Frédéric, Daien, Claire, Danko, Marianna, Dauenhauer, Philippe, Dauzat, Michel, Davy, Jean, Delignières, Didier, Demoly, Pascal, Desplan, Matthieu, Dhivert-Donnadieu, Henriette, Dujol, Pierre, Dupeyron, Arnaud, Dupeyron, Gérard, Engberink, Oude, Enjalbert, Michel, Fattal, Charles, Fernandes, Jérôme, Fesler, Pierre, Fraisse, Philippe, Froger, Jérôme, Gabrion, Philippe, Galano, Emilie, Gellerat-Rogier, Marion, Gellis, Anthony, Goucham, Arnaud-Yves, Gouzi, Fares, Gressard, Florence, Gris, Jean-Christophe, Guillot, Bernard, Guiraud, David, Handweiler, Valérie, Hantkié, Olivier, Hayot, Maurice, Herisson, Christian, Heroum, Cherif, Hoa, Didier, Jacquemin, Sylvain, Jaber, Samir, Jakovenko, Dominique, Jorgensen, Christophe, Journot, Laurent, Kaczorek, Michel, Kouyoumdjian, Pascal, Labauge, Pierre, Landreau, Liliane, Lapierre, Martine, Leblond, Catherine, Léglise, Marie-Suzanne, Lemaitre, Jean, Le Moing, Vincent, Le Quellec, Alain, Leclercq, François, Lehmann, Sylvain, Lognos, Béatrice, Lussert, Jean, Makinson, Alain, Mandrick, Kevin, Marmelat, Vincent, Martin-Gousset, Pierre, Matheron, Amélie, Mathieu, Gwen, Meissonnier, Marc, Mercier, Grégoire, Messner, Patrick, Meunier, Cyril, Mondain, Michel, Punta-Morales, Raul, Morel, Jacques, Morquin, David, Mottet, Denis, Nerin, Philippe, Nicolas, Pierre, Ninot, Gregory, Nouvel, Fabrice, Ortiz, Jean, Paccard, Delphine, Pandraud, Guillaume, Pasdelou, Pierre, Pasquié, Jean-Luc, Patte, Karine, Perrey, Stéphane, Pers, Yves-Marie, Picot, Christine, Pin, Philippe, Pinto, Nathalie, Porte, Emilie, Portejoie, Fabienne, Pujol, Jean, Quantin, Xavier, Quéré, Isabelle, Raffort, Nathalie, Ramdani, Sofiane, Ribstein, Jean, Rédini-Martinez, Martine, Richard, Sylvain, Ritchie, Karen, Riso, Pierre, Rivier, Francois, Rolland, Christine, Roubille, François, Sablot, Denis, Savy, Jean-Luc, Schifano, Laurent, Senesse, Pierre, Sicard, Roland, Soua, Baya, Stephan, Yannick, Strubel, Denise, Sultan, Ariane, Taddei-Ologeanu, Roxana, Tallon, Guillaume, Tanfin, Michel, Tassery, Hervé, Tavares, Isabel, Torre, Kjerstin, Touchon, Jacques, Tribout, Vincent, Uziel, Alain, Van De Perre, Philippe, Vasquez, Xavier, Verdier, Jean-Michel, Vergne-Richard, Céline, Vergotte, Grégoire, Vian, Laurence, Viarouge-Reunier, Christine, Vialla, François, Viart, Frédéric, Villain, Max, Villiet, Maxime, Viollet, Emilie, Wojtusciszyn, Anne, Aoustin, Martine, Bourquin, Christian, Mercier, Jacques, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon (MACVIA-LR), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Commission Européenne-Commission Européenne-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Université de Montpellier (UM), Département d'anesthésie-réanimation[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Caractéristiques féminines des dysfonctions des interfaces cardio-vasculaires (EA 2992), Université Montpellier 1 (UM1)-Université de Montpellier (UM), CERMES3 - Centre de recherche Médecine, sciences, santé, santé mentale, société (CERMES3 - UMR 8211 / U988 / UM 7), École des hautes études en sciences sociales (EHESS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Euromov (EuroMov), Hadassah Hebrew University Medical Center [Jerusalem], Laboratoire de Génie Informatique et Ingénierie de Production (LGI2P), IMT - MINES ALES (IMT - MINES ALES), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Institut Mines-Télécom [Paris] (IMT), Agence Régionale de la Santé (ARS), Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Roche Pharma Research and Early Development [Basel] (pRED), F. Hoffmann-La Roche [Basel], Laboratoire de Géochimie Isotopique Environnementale (GIS) / Université de Nîmes (GIS), Université de Nîmes (UNIMES)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Genre (LARHRA GENRE), LAboratoire de Recherche Historique Rhône-Alpes - UMR5190 (LARHRA), Université Pierre Mendès France - Grenoble 2 (UPMF)-École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Control of Artificial Movement and Intuitive Neuroprosthesis (CAMIN), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Centre Européen de Réalité Virtuelle (CERV), École Nationale d'Ingénieurs de Brest (ENIB), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Génomique Fonctionnelle (IGF), Centre Mutualiste de Rééducation et de Réadaptation Fonctionnelles de KERPAPE [Ploemeur] (CMRRF), Centre Mutualiste de Rééducation et de Réadaptation Fonctionnelles de Kerpape, Laboratoire de Bioingénierie et NanoSciences (LBN), Institut de Génétique Moléculaire de Montpellier (IGMM), Dynamique des capacités humaines et des conduites de santé (EPSYLON), Université Montpellier 1 (UM1)-Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Montpellier (UM), Laboratory of Cardio-Vascular Physiology (LCVP), Université Montpellier 1 (UM1), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Rééducation et Réadaptation Neuro Orthopédique [Nîmes] (Pôle NACRRE), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre Mutualiste de Réeducation Neurologique Propara (PROPARA), Languedoc Mutualité, Oc Santé [Montpellier], Interactive Digital Humans (IDH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Unité de Rééducation Neurologique, Centre Hélio-Marin CHU Nîmes, Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Centre Bouffard-Vercelli, Laboratoire de Mécanique et Technologie (LMT), École normale supérieure - Cachan (ENS Cachan)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département Conception et conduite des véhicules Aéronautiques et Spatiaux (DCAS), Institut Supérieur de l'Aéronautique et de l'Espace (ISAE-SUPAERO), Lab-STICC_TB_CID_TOMS, Laboratoire des sciences et techniques de l'information, de la communication et de la connaissance (Lab-STICC), Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS), Service de Rhumatologie [CHRU Montpellier], Aix-Marseille Université - Faculté des Sciences du Sport (AMU FSS), Aix Marseille Université (AMU), HORIBA Medical (HORIBA ABX SAS), HORIBA Scientific [France], Unité Mathématique, Informatique et Génome (MIG), Institut National de la Recherche Agronomique (INRA), Interactions, Corpus, Apprentissages, Représentations (ICAR), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-INRP-Ecole Normale Supérieure Lettres et Sciences Humaines (ENS LSH)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut du Cancer de Montpellier (ICM), Biocommunication en Cardio-Métabolique (BC2M), Cognition, Action, et Plasticité Sensorimotrice [Dijon - U1093] (CAPS), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche et de Diagnostic sur le Sida [Abidjan, Côte d'Ivoire] (CeDreS), Centre Hospitalier Universitaire de Treichville [Abidjan, Côte d'Ivoire] (CHU de Treichville), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Dynamiques du droit (DD), Centre de pharmacologie et innovation dans le diabète (CPID), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Université Pierre Mendès France - Grenoble 2 (UPMF)-École normale supérieure de Lyon (ENS de Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-École normale supérieure de Lyon (ENS de Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), 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), 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), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Unité Mathématique Informatique et Génome (MIG), École normale supérieure de Lyon (ENS de Lyon)-Université Lumière - Lyon 2 (UL2)-INRP-Ecole Normale Supérieure Lettres et Sciences Humaines (ENS LSH)-Centre National de la Recherche Scientifique (CNRS), École Pratique des Hautes Études (EPHE), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-École des hautes études en sciences sociales (EHESS), Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Université Lumière - Lyon 2 (UL2)-École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Université Lumière - Lyon 2 (UL2)-École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Inria Sophia Antipolis - Méditerranée (CRISAM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS), Complexité, Innovation, Activités Motrices et Sportives (CIAMS), Université Paris-Sud - Paris 11 (UP11)-Université d'Orléans (UO), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Commission Européenne-Commission Européenne-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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), 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), Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 1 (UM1), and Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)
Subjects: Aged, 80 and over, Male, Aging, Biomedical Research, Frail Elderly, [SDV]Life Sciences [q-bio], Malnutrition, Health Promotion, Social Environment, MESH: Accidental Falls, Public-Private Sector Partnerships, Medication Adherence, Europe, Health Planning, Chronic Disease, Humans, Female, Accidental Falls, MESH: Aging, France, Independent Living, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Aged
Abstract: International audience; Le site de référence du Partenariat européen d'innovation pour un vieillissement actif et en bonne santé MACVIA-LR (contre les maladies chroniques pour un vieillissement en bonne santé en Languedoc-Roussillon)
Published: 2015

30. Le site de référence du Partenariat européen d’innovation pour un vieillissement actif et en bonne santé MACVIA-LR (contre les maladies chroniques pour un vieillissement en bonne santé en Languedoc-Roussillon)

Author: Miren David, Ariane Sultan, Guillaume Pandraud, Benoît G. Bardy, Jacques Morel, Giacomo Cavalli, Sylvain Jacquemin, Christine Rolland, Cyril Breuker, Philippe Boulet, Gregoire Mercier, Stéphane Bouly, Valérie Bruguière, Gwen Mathieu, Marc Meissonnier, Hervé Tassery, Vincent Marmelat, Michel Dauzat, Hubert Blain, Gérard Dray, Cyril Laurent, Christine Viarouge-Reunier, Marie Virginie Calmels, François Rivier, Gérard Dupeyron, Gérard Bourrel, Jacquie Berthe, Philippe Domy, Béatrice Lognos, Martine Aoustin, Davide Caimmi, Michel Kaczorek, Mélanie Badin, Pierre Nicolas, Alain Le Quellec, Sylvie Boichot, Vincent Le Moing, C. Boegner, Jérôme Fernandes, Michel Amouyal, Matthieu Desplan, Jean Paul Cristol, T. Camuzat, Karima Bakhti, Jean Michel Verdier, Paule Adnet, Christophe Jorgensen, Denis Sablot, Jean Ribstein, Henriette Dhivert-Donnadieu, Céline Vergne-Richard, Emilie Porte, Christine Azevedo, Isabelle Quéré, Dominique Jakovenko, Marion Gellerat-Rogier, Michel Tanfin, Karen Ritchie, Flavia Oana Coroian, Bernard Guillot, Fabrice Nouvel, J. Pelissier, Anna Bedbrook, Daniel Laune, Jean-Luc Bourrain, Yves Marie Pers, Jean Luc Savy, Chantal Marion, Cherif Heroum, Marianna Danko, Grégoire Vergotte, Françoise Radier-Pontal, Jean Luc Pasquié, Olivier Bénézet, Bernard Combe, Sylvain Richard, Liliane Landreau, Valérie Cros, Isabelle Rédini-Martinez, Emilie Viollet, David Guiraud, François Roubille, Jérôme Froger, Bertrand Coulet, Laurent Journot, Marie Suzanne Léglise, Sylvie Arnavieilhe, Isabel Tavares, Samir Jaber, Olivier Jonquet, David Morquin, Philippe Van de Perre, Roland Sicard, Raphaël Chiron, Vincent Tribout, Pierre Senesse, Xavier Quantin, Jacques Touchon, Kevin Mandrick, Alain Uziel, Vincent Bouix, Marie Christine Picot, Philippe Augé, Martine Lapierre, Antoine Avignon, Eric Pastor, Pascal Demoly, Kjerstin Torre, Jacques Mercier, Jean-Marie Robine, Dominique Larrey, D. J. Costa, Grégory Ninot, Laurent Schifano, Baya Soua, Anne Wojtusciszyn, Jean-Christophe Gris, Didier Delignières, Florence Gressard, Marie Pierre Pasdelou, Fabienne Portejoie, Michel Mondain, Philippe Nérin, Olivier Hantkié, Xavier Bobia, Delphine Paccard, Pierre Géraud Claret, Maxime Villiet, Jacques Burille, Christian Hérisson, Guillaume Tallon, V. Attalin, Jean Emmanuel de la Coussaye, William Camu, Didier Hoa, Chokri Boubakri, Jacques Reynes, Michel Enjalbert, Pascal Kouyoumdjian, Anthony Gellis, Jean Marc Lussert, Jean Philippe Pin, Christian Bourquin, Jean-Marc Lemaitre, Rodolphe Bourret, Isabelle Laffont, Claudine Berr, Marie Christine Courrouy-Michel, Nicolas Giraudeau, Trias Asteriou, Catherine Leblond, Cyril Meunier, Sylvain Lehmann, M. Nogues, Denise Strubel, Raul Punta-Morales, Alain Makinson, Jacques Bringer, Stéphane Perrey, Nathalie Pinto, Yannick Stephan, Charles Fattal, Jean Marc Davy, Arnaud Bourdin, Emilie Royère, Arnaud Dupeyron, Claire Daien, François Vialla, Frédéric Viart, Joël Bockaert, Arnaud Yves Goucham, Pierre Aubas, Huei Yune Bonnin, Fares Gouzi, Véronique Carre, Nicolas Best, Jean Pierre Riso, Jérome Cottalorda, Max Villain, Philippe Dauenhauer, Patrick Messner, Amélie Matheron, Claude Jeandel, Roxana Taddei-Ologeanu, Bernard Alomène, Sylvie Albert, Stéphane Cade, Gérard Canovas, Pauline Coignard, Karine Patte, Sofiane Ramdani, Frédéric Abecassis, Maurice Hayot, Marc Ychou, Anne Laure Coupet, Nathalie Raffort, D. Heve, Philippe Gabrion, Pierre Mares, Pierre Labauge, Marie Pierre Battesti, Denis Mottet, Philippe Fraisse, Jean Bousquet, Jean Louis Pujol, Emilie Galano, Pierre Fesler, Vincent Dufour, Gregory Baptista, Pierre Louis Bernard, Mireille Fouletier, Pierre Dujol, Xavier Vasquez, Jean Paul Ortiz, Pierre Martin-Gousset, Philippe Courtet, Oude Engberink, Valérie Handweiler, S. Granier, Laurence Vian, Françoise Leclercq, Frédéric Cuisinier, Pierre Costa, Guillaume Cayla, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon (MACVIA-LR), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Commission Européenne-Commission Européenne-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Département d'anesthésie-réanimation[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier], Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Caractéristiques féminines des dysfonctions des interfaces cardio-vasculaires (EA 2992), Université Montpellier 1 (UM1)-Université de Montpellier (UM), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Department of Geriatrics - Efficiency and Deficiency Laboratory, Hadassah Hebrew University Medical Center [Jerusalem], IMT - MINES ALES (IMT - MINES ALES), Institut Mines-Télécom [Paris] (IMT), Département de Biostatistiques, Agence Régionale de Santé Languedoc Roussillon (ARS), Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Roche Pharma Research and Early Development [Basel] (pRED), F. Hoffmann-La Roche [Basel], Service de gynécologie-obstétrique, Mécanismes adaptatifs : des organismes aux communautés (MAOAC), Centre National de la Recherche Scientifique (CNRS)-Collège de France (CdF)-Muséum national d'Histoire naturelle (MNHN), Laboratoire de Géochimie Isotopique Environnementale (GIS) / Université de Nîmes (GIS), Université de Nîmes (UNIMES)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Genre (LARHRA GENRE), LAboratoire de Recherche Historique Rhône-Alpes - UMR5190 (LARHRA), Centre National de la Recherche Scientifique (CNRS)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Université Lumière - Lyon 2 (UL2)-École normale supérieure - Lyon (ENS Lyon)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Université Lumière - Lyon 2 (UL2)-École normale supérieure - Lyon (ENS Lyon)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Grenoble Alpes (UGA), Département de Médecine générale, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Control of Artificial Movement and Intuitive Neuroprosthesis (CAMIN), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Département de médecine générale, Université de Montpellier (UM), Euromov (EuroMov), Centre Européen de Réalité Virtuelle (CERV), École Nationale d'Ingénieurs de Brest (ENIB), Laboratoire de Mathématiques Blaise Pascal (LMBP), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS), Pathologies du système nerveux : recherche épidémiologique et clinique, Université Montpellier 1 (UM1)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), CERFRANCE Nord Est - Ile de France, Réseau de Vigilance en Dermato-Allergologie - Groupe d'Etudes et de Recherches en DERmato-Allergologie (Revidal-Gerda), Réseau de Vigilance en Dermato-Allergologie (Revidal), Centre Mutualiste de Rééducation et de Réadaptation Fonctionnelles de KERPAPE [Ploemeur] (CMRRF), Centre Mutualiste de Rééducation et de Réadaptation Fonctionnelles de Kerpape, Laboratoire de Bioingénierie et NanoSciences (LBN), Institut de Génétique Moléculaire de Montpellier (IGMM), Dynamique des capacités humaines et des conduites de santé (EPSYLON), Université Montpellier 1 (UM1)-Université Paul-Valéry - Montpellier 3 (UM3)-Université de Montpellier (UM), Laboratory of Cardio-Vascular Physiology (LCVP), Université Montpellier 1 (UM1), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Rééducation et Réadaptation Neuro Orthopédique [Nîmes] (Pôle NACRRE), Hôpital Universitaire Carémeau [Nîmes], Centre Mutualiste de Réeducation Neurologique Propara (PROPARA), Languedoc Mutualité, Oc Santé Montpellier, Artificial movement and gait restoration (DEMAR), Unité de Rééducation Neurologique, Centre Hélio-Marin CHU Nîmes, Department de Dermatologie, Médecine physique et de réadaptation, Hôpital Lapeyronie [Montpellier] (CHU), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), 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), Service de Chirurgie Orthopédique, Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Centre Bouffard-Vercelli, Laboratoire de Mécanique et Technologie (LMT), École normale supérieure - Cachan (ENS Cachan)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Plateforme de Protéomique Clinique, CHU Saint-Eloi, Recherches Translationnelles sur le VIH et les maladies infectieuses (TransVIHMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche pour le Développement (IRD)-Université Montpellier 1 (UM1)-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Universtié Yaoundé 1 [Cameroun]-Université de Montpellier (UM), Département Conception et conduite des véhicules Aéronautiques et Spatiaux (DCAS), Institut Supérieur de l'Aéronautique et de l'Espace (ISAE-SUPAERO), Lab-STICC_TB_CID_TOMS, Laboratoire des sciences et techniques de l'information, de la communication et de la connaissance (Lab-STICC), École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de recherche souterrain de Meuse/Haute-Marne, Agence Nationale de gestion des Déchets Radioactifs, Aix-Marseille Université - Faculté des Sciences du Sport (AMU FSS), Aix Marseille Université (AMU), HORIBA Medical (HORIBA ABX SAS), HORIBA Scientific [France], Unité Mathématique, Informatique et Génome (MIG), Institut National de la Recherche Agronomique (INRA), Interactions, Corpus, Apprentissages, Représentations (ICAR), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-INRP-Ecole Normale Supérieure Lettres et Sciences Humaines-Centre National de la Recherche Scientifique (CNRS), Unité clinique d'Immuno-Rhumatologie & Thérapeutique des maladies ostéo-articulaires, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie, Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS), UNICANCER - Institut régional du Cancer [Montpellier] (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Biocommunication en Cardio-Métabolique (BC2M), Neuropsychiatrie : recherche épidémiologique et clinique, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département d'oncologie médicale et digestive, Centre de cancérologie Val d'Aurelle, Complexité, Innovation, Activités Motrices et Sportives (CIAMS), Université d'Orléans (UO)-Université Paris-Sud - Paris 11 (UP11), Cognition, Action, et Plasticité Sensorimotrice [Dijon - U1093] (CAPS), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche et de Diagnostic sur le Sida (CeDreS), CHU Treichville, Interaction entre Systèmes Protéiques et Différenciation dans la Cellule Tumorale (ISPDCT), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Dynamiques du droit (DD), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Centre National de la Recherche Scientifique (CNRS), Centre de pharmacologie et innovation dans le diabète (CPID), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre National de la Recherche Scientifique (CNRS), Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Gui de Chauliac, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] ( PhyMedExp ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), IMT - Mines Alès Ecole Mines - Télécom ( IMT - MINES ALES ), Agence Régionale de Santé Languedoc Roussillon ( ARS ), Institut de Recherche en Infectiologie de Montpellier ( IRIM ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ), Roche Pharma Research and Early Development [Basel] ( pRED ), Centre Hospitalier Régional Universitaire de Nîmes ( CHRU Nîmes ), Mécanismes adaptatifs : des organismes aux communautés ( MAOAC ), Muséum National d'Histoire Naturelle ( MNHN ) -Collège de France ( CdF ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Géochimie Isotopique Environnementale (GIS) / Université de Nîmes ( GIS ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Nîmes ( UNIMES ), Institut de recherche en cancérologie de Montpellier ( IRCM ), Université Montpellier 1 ( UM1 ) -CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon ( MACVIA-LR ), Université Montpellier 1 ( UM1 ) -World Health Organization ( WHO/OMS ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre Hospitalier Régional Universitaire de Nîmes ( CHRU Nîmes ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ) -European Innovation Partnership on Active and Healthy Ageing Reference Site, Agence Nationale de Sécurité Sanitaire, de l'Alimentation, de l'environnement et du Travail ( ANSES ), ANSES, Genre ( LARHRA GENRE ), LAboratoire de Recherche Historique Rhône-Alpes - UMR5190 ( LARHRA ), Centre National de la Recherche Scientifique ( CNRS ) -Université Jean Moulin - Lyon III-Université Lumière - Lyon 2 ( UL2 ) -École normale supérieure - Lyon ( ENS Lyon ) -Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Grenoble Alpes ( UGA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Jean Moulin - Lyon III-Université Lumière - Lyon 2 ( UL2 ) -École normale supérieure - Lyon ( ENS Lyon ) -Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Grenoble Alpes ( UGA ), Université Montpellier 1 ( UM1 ), Artificial movement and gait restoration ( DEMAR ), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier ( LIRMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ) -Inria Sophia Antipolis - Méditerranée ( CRISAM ), Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ), Université de Montpellier ( UM ), Euromov ( EuroMov ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Centre Européen de Réalité Virtuelle ( CERV ), École Nationale d'Ingénieurs de Brest ( ENIB ), Laboratoire de Mathématiques Blaise Pascal ( LMBP ), Université Blaise Pascal - Clermont-Ferrand 2 ( UBP ) -Centre National de la Recherche Scientifique ( CNRS ), Université Montpellier 1 ( UM1 ) -IFR76-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de Génomique Fonctionnelle ( IGF ), Centre National de la Recherche Scientifique ( CNRS ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Réseau de Vigilance en Dermato-Allergologie - Groupe d'Etudes et de Recherches en DERmato-Allergologie ( Revidal-Gerda ), Réseau de Vigilance en Dermato-Allergologie ( Revidal ), Centre Mutualiste de Rééducation et de Réadaptation Fonctionnelles de KERPAPE [Ploemeur] ( CMRRF ), Laboratoire de Bioingénierie et NanoScience-UM, Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Dynamique des capacités humaines et des conduites de santé ( EPSYLON ), Université Paul-Valéry - Montpellier 3 ( UM3 ) -Université Jean Monnet [Saint-Étienne] ( UJM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Laboratory of Cardio-Vascular Physiology ( LCVP ), Institut Pierre Louis d'Epidémiologie et de Santé Publique ( iPLESP ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Département de Rééducation et Réadaptation Neuro Orthopédique [Nîmes] ( Pôle NACRRE ), Centre Mutualiste de Réeducation Neurologique Propara ( PROPARA ), Hôpital Lapeyronie [Montpellier] ( CHU ), Institut de Génomique Fonctionnelle - Montpellier GenomiX ( IGF MGX ), Laboratoire de Mécanique et Technologie ( LMT ), École normale supérieure - Cachan ( ENS Cachan ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), CHU Saint-Eloi-Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Recherches Translationnelles sur le VIH et les maladies infectieuses ( TransVIHMI ), Université Montpellier 1 ( UM1 ) -Université Cheikh Anta Diop ( UCAD ) -Universtié Yaoundé 1 (Cameroun)-Université de Montpellier ( UM ), Département Conception et conduite des véhicules Aéronautiques et Spatiaux ( DCAS ), Institut Supérieur de l'Aéronautique et de l'Espace ( ISAE-SUPAERO ), Laboratoire des sciences et techniques de l'information, de la communication et de la connaissance ( Lab-STICC ), École Nationale d'Ingénieurs de Brest ( ENIB ) -Université de Bretagne Sud ( UBS ) -Université de Brest ( UBO ) -Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques ( IBNM ), Université de Brest ( UBO ) -Université européenne de Bretagne ( UEB ) -ENSTA Bretagne-Institut Mines-Télécom [Paris]-Centre National de la Recherche Scientifique ( CNRS ) -École Nationale d'Ingénieurs de Brest ( ENIB ) -Université de Bretagne Sud ( UBS ) -Université de Brest ( UBO ) -Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques ( IBNM ), Université de Brest ( UBO ) -Université européenne de Bretagne ( UEB ) -ENSTA Bretagne-Institut Mines-Télécom [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Aix-Marseille Université - Faculté des Sciences du Sport ( AMU FSS ), Aix Marseille Université ( AMU ), HORIBA Medical ( HORIBA ABX SAS ), Unité Mathématique, Informatique et Génome ( MIG ), Institut National de la Recherche Agronomique ( INRA ), Interactions, Corpus, Apprentissages, Représentations ( ICAR ), École normale supérieure - Lyon ( ENS Lyon ) -Université Lumière - Lyon 2 ( UL2 ) -INRP-Ecole Normale Supérieure Lettres et Sciences Humaines-Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Lapeyronie, Institut de Chimie des Substances Naturelles ( ICSN ), Centre National de la Recherche Scientifique ( CNRS ), UNICANCER - Institut régional du Cancer [Montpellier] ( ICM ), Efficience Déficience Motrice [Montpellier] ( EDM ), Centre de pharmacologie et innovation dans le diabète ( CPID ), Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Centre National de la Recherche Scientifique ( CNRS ), Complexité, Innovation, Activités Motrices et Sportives ( CIAMS ), Université Paris-Sud - Paris 11 ( UP11 ) -Université d'Orléans ( UO ), Cognition, Action, et Plasticité Sensorimotrice [Dijon - U1093] ( CAPS ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Montpellier 2 - Sciences et Techniques ( UM2 ) -IFR76-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de recherche et de Diagnostic sur le Sida ( CeDreS ), Interaction entre Systèmes Protéiques et Différenciation dans la Cellule Tumorale ( ISPDCT ), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique ( CNRS ), Dynamiques du droit ( DD ), Centre National de la Recherche Scientifique ( CNRS ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Commission Européenne-Commission Européenne-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), CERMES3 - Centre de recherche Médecine, sciences, santé, santé mentale, société (CERMES3 - UMR 8211 / U988 / UM 7), École des hautes études en sciences sociales (EHESS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Génie Informatique et Ingénierie de Production (LGI2P), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Agence Régionale de la Santé (ARS), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre Mendès France - Grenoble 2 (UPMF)-École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Inria Sophia Antipolis - Méditerranée (CRISAM), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Montpellier (UM), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Oc Santé [Montpellier], Interactive Digital Humans (IDH), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Service de Rhumatologie [CHRU Montpellier], École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-INRP-Ecole Normale Supérieure Lettres et Sciences Humaines (ENS LSH)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Institut du Cancer de Montpellier (ICM), Université Paris-Sud - Paris 11 (UP11)-Université d'Orléans (UO), Centre de recherche et de Diagnostic sur le Sida [Abidjan, Côte d'Ivoire] (CeDreS), Centre Hospitalier Universitaire de Treichville [Abidjan, Côte d'Ivoire] (CHU de Treichville), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 1 (UM1), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), Muséum national d'Histoire naturelle (MNHN)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS), and CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Aging, [ SDV ] Life Sciences [q-bio], business.industry, [SDV]Life Sciences [q-bio], General Medicine, MESH: Accidental Falls, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Medicine, 030211 gastroenterology & hepatology, Accidental Falls, MESH: Aging, 030212 general & internal medicine, business, Humanities, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Le site de référence du Partenariat européen d'innovation pour un vieillissement actif et en bonne santé MACVIA-LR (contre les maladies chroniques pour un vieillissement en bonne santé en Languedoc-Roussillon)
Published: 2015

31. Tmprss3, a Transmembrane Serine Protease Deficient in Human DFNB8/10 Deafness, Is Critical for Cochlear Hair Cell Survival at the Onset of Hearing

Author: Stylianos E. Antonarakis, Benjamin Delprat, Florence François, Lydie Fasquelle, Jean-Luc Puel, Michel Guipponi, Christian Chabbert, Elizabeth Neidhart, Sophie Gaboyard, Marc Lenoir, Guy Rebillard, Stéphanie Ventéo, Anne-Laure Mausset-Bonnefont, Hamish S. Scott, Jing Wang, Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Yale University [New Haven], Neurobiologie de l'audition-plasticité synaptique, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de Génie Electrique de Grenoble (G2ELab), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut Polytechnique de Grenoble - Grenoble Institute of Technology, Cellules souches mésenchymateuses, environnement articulaire et immunothérapies de la polyarthrite rhumatoide, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Genetic Medicine and Development [Geneva], and Université de Genève (UNIGE)
Subjects: Male, Pathology, medicine.medical_specialty, Serine Proteases/chemistry/genetics/metabolism, Cell Survival, Nonsense mutation, Biology, Biochemistry, Hearing/physiology, Mice, 03 medical and health sciences, 0302 clinical medicine, Hearing, Hair Cells, Auditory, otorhinolaryngologic diseases, medicine, Animals, Humans, ddc:576.5, Inner ear, Molecular Biology, Cochlea, 030304 developmental biology, Vestibular system, Mice, Inbred C3H, 0303 health sciences, Behavior, Animal, Hair Cells, Auditory/cytology, Cell Membrane/metabolism, Cell Membrane, Membrane Proteins, Molecular Bases of Disease, Cell Biology, Anatomy, medicine.anatomical_structure, Auditory brainstem response, Cochlea/metabolism, Organ of Corti, Vestibule, Mutation, Membrane Proteins/chemistry/genetics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, sense organs, Hair cell, Serine Proteases, 030217 neurology & neurosurgery, HeLa Cells
Abstract: International audience; Mutations in the type II transmembrane serine protease 3 (TMPRSS3) gene cause non-syndromic autosomal recessive deafness (DFNB8/10), characterized by congenital or childhood onset bilateral profound hearing loss. In order to explore the physiopathology of TMPRSS3 related deafness, we have generated an ethyl-nitrosourea-induced mutant mouse carrying a protein-truncating nonsense mutation in Tmprss3 (Y260X) and characterized the functional and histological consequences of Tmprss3 deficiency. Auditory brainstem response revealed that wild type and heterozygous mice have normal hearing thresholds up to 5 months of age, whereas Tmprss3 Y260X homozygous mutant mice exhibit severe deafness. Histological examination showed degeneration of the organ of Corti in adult mutant mice. Cochlear hair cell degeneration starts at the onset of hearing, postnatal day 12, in the basal turn and progresses very rapidly toward the apex, reaching completion within 2 days. Given that auditory and vestibular deficits often co-exist, we evaluated the balancing abilities of Tmprss3 Y260X mice by using rotating rod and vestibular behavioral tests. Tmprss3 Y260X mice effectively displayed mild vestibular syndrome that correlated histologi-cally with a slow degeneration of saccular hair cells. In situ hybridization in the developing inner ear showed that Tmprss3 mRNA is localized in sensory hair cells in the cochlea and the vestibule. Our results show that Tmprss3 acts as a permissive factor for cochlear hair cells survival and activation at the onset of hearing and is required for saccular hair cell survival. This mouse model will certainly help to decipher the molecular mechanisms underlying DFNB8/10 deafness and cochlear function.
Published: 2011

32. Label-free non-linear microscopy to measure myelin outcome in a rodent model of Charcot-Marie-Tooth diseases

Author: Claire Perrin-Tricaud, Amel Rizgui, Hervé Rigneault, Nicolas Tricaud, Hassan Boukhaddaoui, Jade Berthelot, Helene Hajjar, Chamroeun Sar, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut FRESNEL (FRESNEL), Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU), MOSAIC (MOSAIC), Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU), Institut des Neurosciences de Montpellier (INM), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), and Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, General Physics and Astronomy, Schwann cell, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, Myelin, 0302 clinical medicine, peripheral nervous system, Charcot-Marie-Tooth Disease, In vivo, Live cell imaging, demyelinating diseases, Animals, Medicine, Schwann cells, General Materials Science, Myelin Sheath, Microscopy, business.industry, General Engineering, nonlinear optical microscopy, General Chemistry, Sciatic Nerve, Rats, 3. Good health, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, nervous system, Peripheral nervous system, [SPI.OPTI]Engineering Sciences [physics]/Optics / Photonic, Sciatic nerve, business, 030217 neurology & neurosurgery, Preclinical imaging, Ex vivo
Abstract: Myelin sheath produced by Schwann cells covers and nurtures axons to speed up nerve conduction in peripheral nerves. Demyelinating peripheral neuropathies result from the loss of this myelin sheath and so far, no treatment exists to prevent Schwann cell demyelination. One major hurdle to design a therapy for demyelination is the lack of reliable measures to evaluate the outcome of the treatment on peripheral myelin in patients but also in living animal models. Non-linear microscopy techniques which include second harmonic generation (SHG), third harmonic generation (THG) and coherent anti-stokes Raman scattering (CARS) were used to image myelin ex vivo and in vivo in the sciatic nerve of healthy and demyelinating mice and rats. SHG did not label myelin and THG required too much light power to be compatible with live imaging. CARS is the most reliable of these techniques for in vivo imaging and it allows for the analysis and quantification of myelin defects in a rat model of CMT1A disease. This microscopic technique therefore constitutes a promising, reliable and robust readout tool in the development of new treatments for demyelinating peripheral neuropathies.
Published: 2018

33. A Mesenchymal-Like ZEB1+ Niche Harbors Dorsal Radial Glial Fibrillary Acidic Protein-Positive Stem Cells in the Spinal Cord

Author: Jean-Philippe Hugnot, Lionel Simonneau, Chantal Ripoll, Azel Zine, Alain Privat, Jean Valmier, Helmut Kettenmann, Jean-Charles Sabourin, Pierre-Olivier Guichet, Jeroen Charité, Alain Garces, David Ohayon, Karin B. Ackema, Alexandre Pattyn, Florence E. Perrin, Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Département Bioélectronique (BEL-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-CMP-GC, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de Développement, Plasticité et Vieillissement du Système Nerveux (U 336), Institut National de la Santé et de la Recherche Médicale (INSERM), Développement et évolution du système nerveux (DESN), École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Doublecortin Protein, Green Fluorescent Proteins, Kruppel-Like Transcription Factors, Mice, Transgenic, Mice, 03 medical and health sciences, 0302 clinical medicine, Neurosphere, Glial Fibrillary Acidic Protein, Animals, Stem Cell Niche, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, 030304 developmental biology, Homeodomain Proteins, Neurons, 0303 health sciences, Glial fibrillary acidic protein, biology, Stem Cells, [SCCO.NEUR]Cognitive science/Neuroscience, Gene Expression Regulation, Developmental, Zinc Finger E-box-Binding Homeobox 1, Cell Biology, Actins, Neural stem cell, Cell biology, Neuroepithelial cell, Lumbar Spinal Cord, Spinal Cord, GDF7, Immunology, biology.protein, Molecular Medicine, Stem cell, 030217 neurology & neurosurgery, Developmental Biology, Adult stem cell
Abstract: In humans and rodents the adult spinal cord harbors neural stem cells located around the central canal. Their identity, precise location, and specific signaling are still ill-defined and controversial. We report here on a detailed analysis of this niche. Using microdissection and glial fibrillary acidic protein (GFAP)-green fluorescent protein (GFP) transgenic mice, we demonstrate that neural stem cells are mostly dorsally located GFAP+ cells lying ependymally and subependymally that extend radial processes toward the pial surface. The niche also harbors doublecortin protein (Dcx)+ Nkx6.1+ neurons sending processes into the lumen. Cervical and lumbar spinal cord neural stem cells maintain expression of specific rostro-caudal Hox gene combinations and the niche shows high levels of signaling proteins (CD15, Jagged1, Hes1, differential screening-selected gene aberrative in neuroblastoma [DAN]). More surprisingly, the niche displays mesenchymal traits such as expression of epithelial-mesenchymal-transition zinc finger E-box-binding protein 1 (ZEB1) transcription factor and smooth muscle actin. We found ZEB1 to be essential for neural stem cell survival in vitro. Proliferation within the niche progressively ceases around 13 weeks when the spinal cord reaches its final size, suggesting an active role in postnatal development. In addition to hippocampus and subventricular zone niches, adult spinal cord constitutes a third central nervous system stem cell niche with specific signaling, cellular, and structural characteristics that could possibly be manipulated to alleviate spinal cord traumatic and degenerative diseases. Disclosure of potential conflicts of interest is found at the end of this article.
Published: 2009

34. Molecular screening of 980 cases of suspected hereditary optic neuropathy with a report on 77 novelOPA1mutations

Author: Dan Milea, Carmen Ayuso, Arnaud Chevrollier, Josseline Kaplan, Christophe Verny, Pascal Reynier, Hélène Dollfus, Sabine Defoort, Patrizia Amati-Bonneau, Xavier Zanlonghi, Christian P. Hamel, Catherine Vignal, Sylvie Odent, Vincent Procaccio, Dominique Bonneau, Jean‐Francois Charlin, Marc Ferré, De Villemeur, Hervé, Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biochimie et Génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Service de neurologie [Angers], Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Servicio de genetica, Fundacion Jimenez Diaz [Madrid] (FJD), Laboratoire de Neurosciences Fonctionnelles et Pathologies (LNFP), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Département d'Ophtalmologie, Fondation Rothschild, Clinique Sourdille, Service d'Ophtalmologie [Rennes] = Ophtalmology [Rennes], CHU Pontchaillou [Rennes], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Genetics of Sensory Diseases, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d'Ophtalmologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Guy de Chauliac, Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Neurovasculaire Intégrée (BNVI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique clinique, hôpital Sud, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université d'Angers ( UA ) -CHU Angers, Copenhague University Hospital, University of Copenhagen ( KU ), Laboratoire de Génétique Médicale, Université Louis Pasteur - Strasbourg I-Hôpital de Hautepierre [Strasbourg]-AVENIR-Inserm, fundacion Jimenez Diaz, Laboratoire de Neurosciences Fonctionnelles et Pathologies ( LNFP ), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique ( CNRS ), Service d'Ophtalmologie, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Sud, Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Guy de Chauliac, Université Montpellier 2 - Sciences et Techniques ( UM2 ) -IFR76-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Biologie Neurovasculaire Intégrée, Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Fondation Ophtalmologique Adolphe de Rothschild [Paris], and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier]
Subjects: Mitochondrial DNA, genetic structures, Optic Atrophy, Hereditary, Leber, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, medicine.disease_cause, DNA, Mitochondrial, GTP Phosphohydrolases, Optic neuropathy, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Optic Atrophies, Hereditary, Optic Atrophy, Autosomal Dominant, Genetics, medicine, Humans, Genetic Testing, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Family history, Genetics (clinical), Genetic testing, [SDV.GEN]Life Sciences [q-bio]/Genetics, Mutation, medicine.diagnostic_test, Proteins, medicine.disease, Hereditary Optic Atrophy, eye diseases, 3. Good health, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, [ SDV.MHEP.OS ] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, 030221 ophthalmology & optometry, Optic Atrophy 1, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, 030217 neurology & neurosurgery
Abstract: International audience; We report the results of molecular screening in 980 patients carried out as part of their work-up for suspected hereditary optic neuropathies. All the patients were investigated for Leber's hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA), by searching for the ten primary LHON-causing mtDNA mutations and examining the entire coding sequences of the OPA1 and OPA3 genes, the two genes currently identified in ADOA. Molecular defects were identified in 440 patients (45% of screened patients). Among these, 295 patients (67%) had an OPA1 mutation, 131 patients (30%) had an mtDNA mutation, and 14 patients (3%), belonging to three unrelated families, had an OPA3 mutation. Interestingly, OPA1 mutations were found in 157 (40%) of the 392 apparently sporadic cases of optic atrophy. The eOPA1 locus-specific database now contains a total of 204 OPA1 mutations, including 77 novel OPA1 mutations reported here. The statistical analysis of this large set of mutations has led us to propose a diagnostic strategy that should help with the molecular work-up of optic neuropathies. Our results highlight the importance of investigating LHON-causing mtDNA mutations as well as OPA1 and OPA3 mutations in cases of suspected hereditary optic neuropathy, even in absence of a family history of the disease.
Published: 2009

35. Minimum information about animal experiments: supplier is also important

Author: Luc Bauchet, Christian B. Brøchner, Monica Prieto, Manuel Gaviria, Henri Haton, Vincent Costalat, Nicolas Lonjon, Florence E. Perrin, Alain Privat, Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Hamel, Christian, Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurochirurgie [Hôpital Gui de Chauliac], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier], Service de neuroradiologie, Neuréva Inc.-INM, Hôpital Saint Eloi (CHRU Montpellier), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: Animal Experimentation, Biomedical Research, Computer science, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Sensory system, 03 medical and health sciences, Cellular and Molecular Neuroscience, Animal.strain, 0302 clinical medicine, Control theory, medicine, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Rats, Wistar, Set (psychology), Spinal cord injury, Spinal Cord Injuries, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Recovery of Function, Anatomy, Functional recovery, medicine.disease, Rats, Disease Models, Animal, Vertebral canal, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030217 neurology & neurosurgery
Abstract: International audience; It has now been established that functional recovery after spinal cord injury (SCI) depends on several parameters, including animal strain. Here we demonstrate that rats from the same strain (Wistar) but from two independent commercial suppliers present different motor, sensory, and autonomic outcomes after a standard model of SCI, the so-called compression model. Recovery is correlated with the extension of the lesion, and we show that the vertebral canal diameter varies between the two suppliers. To substantiate this point, we carried out another set of experiments, with the so-called contusion model, which requires bone ablation and thus whose extension is not related to vertebral canal diameter. We show that there is no difference between the two suppliers. The purpose of our communication is to alert researchers on how crucial it is to control experimental parameters as closely as possible and to establish a standard for animal experiment in order to avoid unexpected biases.
Published: 2009

36. A human spinal cord cell promotes motoneuron survival and maturation in vitro

Author: Keith Langley, Marcel Mersel, Jan de Weille, Christine Fabre, Alain Privat, Didier Petite, Clovis Rakotoarivelo, Caroline Rouleau, Hamel, Christian, Physiopathologie et thérapie des déficits sensoriels et moteurs, and Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Neurite, Cell Survival, Neurogenesis, Cell, Immunocytochemistry, Polycarbonate filter, Nerve Tissue Proteins, Biology, Rats, Sprague-Dawley, Cellular and Molecular Neuroscience, Atrophy, Microscopy, Electron, Transmission, Neurites, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Amyotrophic lateral sclerosis, Cells, Cultured, Motor Neurons, Stem Cells, musculoskeletal, neural, and ocular physiology, Infant, Newborn, Fibroblasts, Embryo, Mammalian, musculoskeletal system, medicine.disease, Spinal cord, Coculture Techniques, In vitro, Rats, Cell biology, medicine.anatomical_structure, Spinal Cord, nervous system, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience
Abstract: International audience; Primary cultures of motoneurons represent a good experimental model for studying mechanisms underlying certain spinal cord pathologies, such as amyotrophic lateral sclerosis and spinal bulbar muscular atrophy (Kennedy's disease). However, a major problem with such culture systems is the relatively short cell survival times, which limits the extent of motoneuronal maturation. In spite of supplementing culture media with various growth factors, it remains difficult to maintain motoneurons viable longer than 10 days in vitro. This study employs a new approach, in which rat motoneurons are plated on a layer of cultured cells derived from newborn human spinal cord. For all culture periods, more motoneurons remain viable in such cocultures compared with control monocultures. Moreover, although no motoneurons survive in control cultures after 22 days, viable motoneurons were observed in cocultures even after 7 weeks. Although no significant difference in neurite length was observed between 8-day mono- and cocultures, after 22 and 50 days in coculture motoneurons had a very mature morphology. They extended extremely robust, very long neurites, which formed impressive branched networks. Data obtained using a system in which the spinal cord cultures were separated from motoneurons by a porous polycarbonate filter suggest that soluble factors released from the supporting cells are in part responsible for the beneficial effects on motoneurons. Several approaches, including immunocytochemistry, immunoblotting, and electron microscopy, indicated that these supporting cells, capable of extending motoneuron survival and enhancing neurite growth, had an undifferentiated or poorly differentiated, possibly mesenchymal phenotype.
Published: 2009

37. Efficient and specific transduction of cochlear supporting cells by adeno-associated virus serotype 5

Author: Xavier Estivill, Frédéric Venail, Maria L. Arbonés, Ester Ballana, Jing Wang, Assumpció Bosch, Jean-Luc Puel, Genes and Disease Program, Centre de Regulacio´ Geno´mica-CRG-UPF, Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre for Biomedical Research on Epidemiology and Public Health, CIBER de Epidemiología y Salud Pública (CIBERESP), Centre for Biomedical Research on Rare Diseases, CIBER de Enfermedades Raras (CIBERER), Department of Biochemistry and Molecular Biology, Centre of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona (UAB), and Hamel, Christian
Subjects: Calbindins, Receptor, Platelet-Derived Growth Factor alpha, Phalloidine, MESH: Receptor, Platelet-Derived Growth Factor alpha, Genetic enhancement, MESH: Membrane Glycoproteins, Peripherins, Gene Expression, MESH: Intermediate Filament Proteins, MESH: Dependovirus, medicine.disease_cause, Connexins, MESH: Animals, Newborn, Mice, Transduction (genetics), 0302 clinical medicine, Intermediate Filament Proteins, Neurofilament Proteins, Transduction, Genetic, MESH: Genetic Vectors, MESH: Cochlea, MESH: Glial Fibrillary Acidic Protein, MESH: Animals, MESH: Nerve Tissue Proteins, MESH: Neurofilament Proteins, Adeno-associated virus, 0303 health sciences, Membrane Glycoproteins, General Neuroscience, Genetic transfer, Peripherin, Dependovirus, MESH: Transduction, Genetic, Cochlea, Connexin 26, medicine.anatomical_structure, Myosin VIIa, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Phalloidine, MESH: Gene Expression, Genetic Vectors, Green Fluorescent Proteins, Guinea Pigs, Nerve Tissue Proteins, Myosins, Biology, MESH: Hair Cells, Auditory, Inner, MESH: Guinea Pigs, 03 medical and health sciences, Organ Culture Techniques, S100 Calcium Binding Protein G, MESH: Green Fluorescent Proteins, Glial Fibrillary Acidic Protein, otorhinolaryngologic diseases, medicine, Animals, Inner ear, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Mice, Tropism, MESH: Myelin Basic Proteins, 030304 developmental biology, Hair Cells, Auditory, Inner, MESH: Calcium-Binding Protein, Vitamin D-Dependent, Myelin Basic Protein, MESH: Myosins, MESH: Organ Culture Techniques, MESH: Connexins, Animals, Newborn, Immunology, sense organs, Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; Congenital deafness, affecting 1 in 1000 neonates, can lead to major problems in speech, cognitive and psychosocial development. Congenital deafness is mainly caused by mutations in connexins, hemi-channel proteins forming gap-junctions between supporting cells in the sensory epithelia. We describe a high tropism of AAV5 serotype for the supporting cells of the cochlea, both in vitro in postnatal day 4 mouse explants, and in vivo in the adult guinea-pig inner ear, through scala media perfusion. AAV5 transduction correlates with PDGFRalpha expression, previously reported as AAV5 receptor. This vector could be of major interest in addressing gene therapy approaches to deafness as well as for studying basic aspects of inner-ear development and hearing mechanisms.
Published: 2008

38. Pure-Tone Threshold Description of an Elderly French Screened Population

Author: Dominique Hillaire, Michel Mondain, Jean-Luc Puel, Claudine Berr, Christelle Pommie, Catherine Blanchet, Service ORL, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier], Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologies du système nerveux : recherche épidémiologique et clinique, Université Montpellier 1 (UM1)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), and Hamel, Christian
Subjects: Male, Norm (group), Hearing Loss, Conductive, Audiology, MESH: Occupational Exposure, Cohort Studies, MESH: Aged, 80 and over, Risk Factors, MESH: Risk Factors, Medicine, Longitudinal Studies, MESH: Longitudinal Studies, MESH: Cohort Studies, Hearing Loss, Mixed Conductive-Sensorineural, Aged, 80 and over, MESH: Aged, education.field_of_study, medicine.diagnostic_test, Pure tone, MESH: Hearing Loss, Conductive, Age Factors, Ear, Sensory Systems, Audiometry, Pure-Tone, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], France, medicine.symptom, MESH: Auditory Threshold, Cohort study, Ototoxic medication use, medicine.medical_specialty, Hearing loss, Hearing Loss, Sensorineural, Population, MESH: Audiometry, Pure-Tone, MESH: Hearing Loss, Mixed Conductive-Sensorineural, MESH: Noise, Sex Factors, MESH: Sex Factors, Occupational Exposure, Humans, Medical history, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Hearing Loss, MESH: Hearing Loss, education, Aged, MESH: Age Factors, MESH: Humans, business.industry, MESH: Ear, MESH: Hearing Loss, Noise-Induced, Auditory Threshold, MESH: Male, MESH: France, Hearing Loss, Noise-Induced, MESH: Hearing Loss, Sensorineural, Otorhinolaryngology, Neurology (clinical), Audiometry, Noise, business, MESH: Female
Abstract: International audience; OBJECTIVES: To describe the distribution of pure-tone hearing thresholds of a Caucasian population living in the south of France aged 70 years and older. To establish age- and sex-adjusted normative hearing thresholds based on results of subjects free of noise and ototoxic drug exposure and to compare them with hearing thresholds of exposed (E) subjects. DESIGN: Cross-sectional analysis of a longitudinal epidemiologic cohort study. SETTING: Montpellier suburb, south of France. PARTICIPANTS: A total of 778 subjects 70 years old and older were examined. Noise exposure, ototoxic medication use, and medical history were collected. Hearing thresholds were obtained via pure-tone audiometry. After excluding patients with ear-related disease, 659 subjects were further analyzed (270 men and 389 women). Noise or ototoxic medication exposure was found in 364 subjects (E subjects), whereas 295 had no exposure (nonexposed [NE] subjects). METHODS: Median pure-tone thresholds, lower deviation, and upper deviation were calculated for the NE subjects with a statistical method similar to the ISO 7029 norm and were compared with thresholds of E subjects. RESULTS: Hearing thresholds, especially in high frequencies, increased with age more for women than for men. Median thresholds of E subjects were significantly higher than those for the NE sample in men. CONCLUSION: Age- and sex-adjusted hearing thresholds could well be useful in the study of the impact of environmental and genetic factors on hearing loss in the elderly. The next step would be to quantify the impact of noise, ototoxic drug exposure, and genetics using these age- and sex-adjusted thresholds.
Published: 2008

39. Motor activity induces release of serotonin in the dorsal horn of the rat lumbar spinal cord

Author: Alain Privat, Christine Gerin, Jean-Rene´ Teilhac, Kristin Smith, Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Anatomy and Cell Biology, UIC, Department of Biological Sciences [Chicago], Chicago State University, and Hamel, Christian
Subjects: Male, Serotonin, Time Factors, MESH: Rats, Microdialysis, Central nervous system, MESH: Rats, Sprague-Dawley, Motor Activity, Somatosensory system, Serotonergic, MESH: Hydroxyindoleacetic Acid, MESH: Lumbosacral Region, Article, Rats, Sprague-Dawley, MESH: Spinal Cord, chemistry.chemical_compound, MESH: Behavior, Animal, medicine, Animals, MESH: Animals, MESH: Microdialysis, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Chromatography, High Pressure Liquid, Neurotransmitter, Chromatography, High Pressure Liquid, Spinocerebellar tract, Behavior, Animal, business.industry, General Neuroscience, MESH: Time Factors, Lumbosacral Region, Hydroxyindoleacetic Acid, Spinal cord, MESH: Male, MESH: Motor Activity, Rats, Lumbar Spinal Cord, medicine.anatomical_structure, Spinal Cord, chemistry, MESH: Serotonin, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], business, Neuroscience
Abstract: Literature highlights that serotonergic descending pathways [14] are implicated in somatosensory functions in the spinal cord and that serotonin (5-HT) in the dorsal horn might play a role in motor function through proprioceptive feedback [3, 8, 9, 13]. We hypothesized that 5-HT release in dorsal horn might represent an important factor in the completion of locomotion by facilitation of the spinocerebellar tract [8] and/or by modulation of spinal reflex pathways [9]. The present study demonstrates that during locomotor activity, 5-HT is released in layers II, III, IV, V of Rexed laminae. Microdialysis in combination with HPLC was used to measure concentrations of neurotransmitters in the lumbar dorsal horn before, during, and after a treadmill running exercise. Our results show a significant 41% increase of 5-HT release within the dorsal horn during a running exercise. 5-HT release is temporally related to exercise. The present study demonstrates that dorsal horn 5-HT release might modulate locomotion.
Published: 2008

40. Comparison of Echo-Planar Diffusion-Weighted Imaging and Delayed Postcontrast T1-Weighted MR Imaging for the Detection of Residual Cholesteatoma

Author: Alain Bonafe, Alain Uziel, Michel Mondain, Frédéric Venail, V. Poirrier, Service de pédiatrie ENT, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Gui de Chauliac, Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neuroradiologie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier], and Hamel, Christian
Subjects: Male, MESH: Echo-Planar Imaging, medicine.medical_treatment, MESH: Observer Variation, Residual, MESH: Magnetic Resonance Imaging, 030218 nuclear medicine & medical imaging, MESH: Aged, 80 and over, Postoperative Complications, 0302 clinical medicine, MESH: Postoperative Complications, MESH: Child, T1 weighted, Medicine, Prospective Studies, Child, 030223 otorhinolaryngology, Prospective cohort study, MESH: Aged, Aged, 80 and over, Observer Variation, MESH: Middle Aged, Cholesteatoma, Middle Ear, Echo-Planar Imaging, Cholesteatoma, MESH: Follow-Up Studies, Middle Aged, Magnetic Resonance Imaging, Child, Preschool, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Radiology, Adult, medicine.medical_specialty, Adolescent, Ear, Middle, MESH: Diffusion Magnetic Resonance Imaging, MESH: Ear, Middle, Sensitivity and Specificity, MESH: Cholesteatoma, Middle Ear, 03 medical and health sciences, Humans, Middle Ear Cholesteatoma, Radiology, Nuclear Medicine and imaging, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Head & Neck, Aged, MESH: Adolescent, MESH: Humans, business.industry, MESH: Child, Preschool, MESH: Adult, Tympanoplasty, medicine.disease, Mr imaging, MESH: Male, MESH: Prospective Studies, MESH: Sensitivity and Specificity, Diffusion Magnetic Resonance Imaging, Neurology (clinical), business, Nuclear medicine, MESH: Female, Follow-Up Studies, Diffusion MRI
Abstract: International audience; BACKGROUND AND PURPOSE: Echo-planar diffusion-weighted imaging (DWI) and delayed postcontrast T1-weighted MR imaging (DPI) have been proposed in previous studies to detect residual middle ear cholesteatomas, with varying results. We assessed and compared these 2 techniques in patients with canal wall-up tympanoplasty. MATERIALS AND METHODS: This was a prospective cohort study. Patients who underwent surgery for middle ear cholesteatoma had CT scanning 9 months after the surgery. If opacity was observed (64%) on CT scans, DWI and DPI were performed before second-look surgery. CT, MR imaging, and surgical data were available for 31 patients. Charts were reviewed independently by 3 blinded examiners. Interobserver agreement for MR imaging was calculated (Cohen kappa). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for these techniques: 1) alone or in association, and 2) according to the residual cholesteatoma size measured during surgery. RESULTS: Interobserver agreement was better for DWI (kappa = 0.81) than for DPI (kappa = 0.51). Sensitivity, specificity, PPV, and NPV values were 60%, 72.73%, 80%, and 50%, respectively, with DWI; and 90%, 54.55%, 78.26%, and 75%, respectively, with DPI. With cholesteatomas >5 mm, the sensitivity and specificity of DWI reached 100% and 88%, respectively, with values for DPI reaching 100% and 80%, respectively. The association of both techniques only allowed improvements in the specificity for lesions >5 mm. CONCLUSIONS: Both techniques gave acceptable results for residual cholesteatoma detection. DWI is more specific but less sensitive than DPI. Their concurrent use may benefit patients by avoiding undue surgery.
Published: 2008

41. Granule Cell Survival is Deficient in PAC1−/− Mutant Cerebellum

Author: Liana I. Tascau, Philippe Brabet, Anthony Falluel-Morel, Katie Sokolowski, Emanuel DiCicco-Bloom, Hamel, Christian, Department of Neuroscience and Cell Biology, Rutgers Biomedical and Health Sciences, Rutgers University System (Rutgers)-Rutgers University System (Rutgers), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pediatrics, and Rutgers, The State University of New Jersey [New Brunswick] (RU)
Subjects: endocrine system, medicine.medical_specialty, Cerebellum, Cell Survival, Endogeny, Biology, Mice, Cellular and Molecular Neuroscience, Internal medicine, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Receptor, Mice, Knockout, Neurons, DNA synthesis, Caspase 3, Neurogenesis, Wild type, DNA, General Medicine, Granule cell, Mice, Inbred C57BL, Endocrinology, medicine.anatomical_structure, Apoptosis, Pituitary Adenylate Cyclase-Activating Polypeptide, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], hormones, hormone substitutes, and hormone antagonists, Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
Abstract: International audience; PACAP exerts neuroprotective effects during development, especially in the cerebellum where PAC1 receptor and ligand are both expressed. However, while previous studies using PACAP injections in postnatal animals defined trophic effects of exogenous peptide, the role of endogenous PACAP remains unexplored. Here, we used PAC1(-/-) mice to investigate the role of PACAP receptor signaling in postnatal day 7 cerebellum. There was no difference in DNA synthesis in the cerebellar EGL of PAC1(-/-) compared to wild type animals, assessed using thymidine incorporation and BrdU immunohistochemistry. In contrast, we found that a significant proportion of newly generated neurons were eliminated before they successfully differentiated in the granule cell layer. In aggregate, these results suggest that endogenous PACAP plays an important role in cell survival during cerebellar development, through the activation of the PAC1 receptor.
Published: 2008

42. Fibroblast growth factor homologous factor 1 (FHF1) is expressed in a subpopulation of calcitonin gene-related peptide-positive nociceptive neurons in the murine dorsal root ganglia

Author: Jean Valmier, Stéphanie Ventéo, Patrick Carroll, Agnès Fichard-Carroll, Sylvie Puech, Ilana Mechaly, Thomas Hubert, Steeve Bourane, Hamel, Christian, Physiopathologie et thérapie des déficits sensoriels et moteurs, and Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: MESH: Neurons, Fluorescent Antibody Technique, MESH: Neuropeptides, Fibroblast growth factor, Sodium Channels, Mice, Neurotrophic factors, MESH: Reverse Transcriptase Polymerase Chain Reaction, Ganglia, Spinal, MESH: Animals, MESH: Nociceptors, MESH: Fluorescent Antibody Technique, In Situ Hybridization, Neurons, Sodium channel activity, Reverse Transcriptase Polymerase Chain Reaction, General Neuroscience, MESH: Receptor, trkA, Nociceptors, Axotomy, Peripherin, Immunohistochemistry, Cell biology, Nociception, MESH: Ganglia, Spinal, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Fibroblast Growth Factors, Neurofilament, Calcitonin Gene-Related Peptide, Blotting, Western, MESH: Axotomy, Calcitonin gene-related peptide, Biology, MESH: Sodium Channels, MESH: In Situ Hybridization, MESH: Mice, Inbred C57BL, MESH: Blotting, Western, MESH: Calcitonin Gene-Related Peptide, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], RNA, Messenger, Receptor, trkA, MESH: Mice, NAV1.9 Voltage-Gated Sodium Channel, MESH: RNA, Messenger, Sodium channel, Neuropeptides, MESH: Immunohistochemistry, Fibroblast Growth Factors, Mice, Inbred C57BL, nervous system, Neuroscience
Abstract: International audience; Dorsal root ganglia (DRG) neurons exhibit a wide molecular heterogeneity in relation to the various sensory modalities (mechanoception, thermoception, nociception) that they subserve. Finding markers of subpopulations is an important step in understanding how these neurons convey specific information. We identified fibroblast growth factor homologous factor 1 (FHF1) in a search for markers of subpopulations of DRG neurons. FHFs constitute a family of four factors that share some structural properties with fibroblast growth factors (FGFs) but are functionally distinct. They are expressed in specific subsets of neurons and are involved in the modulation of sodium channel activity. The pattern of expression of FHF1 in the DRG was determined during development, in the adult and after axotomy. We show that in the adult, FHF1 is expressed in two populations, one composed of nociceptors and another in which no neurotrophic factor receptors were detected (panTrk-/c-Ret-). Interestingly, in the nociceptors, FHF1 expression was restricted to a subset of TrkA+/calcitonin gene-related peptide (CGRP)-positive neurons. Neurofilament 200 (NF-200) and peripherin labeling indicates that 70% of the FHF1-expressing neurons contribute to A-fibers and 30% to C-fibers. FHF1 interacts with the Na(v)1.9 sodium channel isoform, which is strongly expressed in cRet+/isolectin-B4 binding neurons, but we show that FHF1 is not expressed in the cRet+/IB4+ subclass and that it does not colocalize with Na(v)1.9. Our results argue strongly against the possibility that FHF1 has a modulatory effect on this channel in cRet+/IB4+ neurons, but FHF1 could play a role in a distinct subset of TrkA+/CGRP+ nociceptors.
Published: 2008

43. Physiology, pharmacology and plasticity at the inner hair cell synaptic complex

Author: Jing Wang, Guy Rebillard, Jérôme Ruel, Jean-Luc Puel, Michel Eybalin, Ruth Lloyd, Rémy Pujol, Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Montpellier 1 (UM1), and Hamel, Christian
Subjects: MESH: Cell Differentiation, Time Factors, Amino Acid Transport System X-AG, Efferent, Glutamic Acid, AMPA receptor, Neurotransmission, Ribbon synapse, MESH: Synapses, chemistry.chemical_compound, MESH: Cell Proliferation, MESH: Ear Diseases, Excitatory Amino Acid Agonists, medicine, Animals, Humans, Regeneration, MESH: Animals, MESH: Neuronal Plasticity, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Receptors, AMPA, Ear Diseases, Neurotransmitter, Cochlear Nerve, Cell Proliferation, MESH: Humans, MESH: Cochlear Nerve, Hair Cells, Auditory, Inner, Neuronal Plasticity, Chemistry, MESH: Time Factors, MESH: Regeneration, Cochlear nerve, Cell Differentiation, MESH: Glutamic Acid, Sensory Systems, MESH: Hair Cells, Inner, MESH: Evoked Potentials, Auditory, medicine.anatomical_structure, MESH: Receptors, AMPA, Synapses, Evoked Potentials, Auditory, NMDA receptor, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Amino Acid Transport System X-AG, Hair cell, MESH: Excitatory Amino Acid Agonists, Neuroscience
Abstract: This report summarizes recent neuropharmacological data at the IHC afferent/efferent synaptic complex: the type of Glu receptors and transporter involved and the modulation of this fast synaptic transmission by the lateral efferents. Neuropharmacological data were obtained by coupling the recording of cochlear potentials and single unit of the auditory nerve with intra-cochlear applications of drugs (multi-barrel pipette). We also describe the IHC afferent/efferent functioning in pathological conditions. After acoustic trauma or ischemia, acute disruption of IHC-auditory dendrite synapses are seen. However, a re-growth of the nerve fibres and a re-afferentation of the IHC were completely done 5 days after injury. During this synaptic repair, multiple presynaptic bodies were commonly found, either linked to the membrane or "floating" in ectopic positions. In the meantime, the lateral efferents directly contact the IHCs. The demonstration that NMDA receptors blockade delayed the re-growth of neurites suggests a neurotrophic role of NMDA receptors in pathological conditions.
Published: 2007

44. Collagen XVI is a neural component of the developing and regenerating dorsal root ganglia extracellular matrix

Author: Thomas Hubert, Sabine Ratzinger, Susanne Grässel, Sophie Grimal, Ilana Méchaly, Agnès Fichard-Carroll, Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Orthopaedics, Universität Regensburg (UR), and Hamel, Christian
Subjects: Dorsum, MESH: Nerve Regeneration, medicine.medical_treatment, MESH: Neurons, MESH: Extracellular Matrix, MESH: Protein Isoforms, Extracellular matrix, Mice, MESH: In Situ Hybridization, Ganglia, Spinal, MESH: Collagen, Component (UML), medicine, Animals, Protein Isoforms, MESH: Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Mice, Molecular Biology, In Situ Hybridization, Neurons, Chemistry, Anatomy, Sciatic Nerve, Extracellular Matrix, Nerve Regeneration, Cell biology, MESH: Sciatic Nerve, Female, MESH: Ganglia, Spinal, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Collagen, Axotomy, MESH: Female
Abstract: International audience; Collagen XVI is a homotrimeric molecule harbouring similarities to the FACIT (fibril-associated collagens with interrupted triple helices) family of collagens (Grassel et al., 1996). Collagen XVI is expressed in skin and cartilage where it is integrated into tissue specific aggregates (Grassel et al., 1999; Kassner et al., 2003). In the nervous system, collagen XVI has been detected at lowlevel in the brain and a strong expression was also reported in spinal root fibers during development (Lai and Chu, 1996). In dorsal root ganglia (DRG), analysis of SAGE banks performed by our group during development and after nerve injury (Mechaly et al., 2006) shows a fluctuation of collagen XVI expression between the different conditions and prompted us to study it further. DRGs contain the cell bodies of neurons, the axons of which transmit sensory information from the periphery to the central nervous system. While it is well known that during development and regeneration, neurites require extracellular matrix molecules for growth and guidance (Hari et al., 2004), the composition and the role of the matrix surrounding neurons in the ganglia itself have solicited little interest. Here, we show that collagen XVI is a component of the developingDRG extracellular matrix, that following nerve injury, its expression is increased around neuronal cell bodies and that neurons express collagen XVI in the peripheral nervous system.
Published: 2007

45. Blocking c-Jun-N-terminal kinase signaling can prevent hearing loss induced by both electrode insertion trauma and neomycin ototoxicity

Author: Jing Wang, Jean-Luc Puel, Azel Zine, Eelam Adil, Thomas R. Van De Water, Jiao He, Christophe Bonny, Thomas J. Balkany, Adrien A. Eshraghi, Michael Bublik, Hamel, Christian, Cochlear Implant Research Program, Department of Otolaryngology, University of Miami Leonard M. Miller School of Medicine (UMMSM), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Lausanne = University of Lausanne (UNIL)
Subjects: MESH: Signal Transduction, medicine.medical_specialty, Free Radicals, MAP Kinase Signaling System, Hearing loss, Guinea Pigs, MESH: Neomycin, Apoptosis, Pharmacology, MESH: Guinea Pigs, MESH: Free Radicals, Ototoxicity, MESH: Anti-Bacterial Agents, otorhinolaryngologic diseases, Animals, Medicine, MESH: Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Hearing Loss, MESH: Hearing Loss, Electrodes, Cochlea, MESH: Caspases, biology, MESH: Peptides, MESH: MAP Kinase Signaling System, business.industry, MESH: Apoptosis, Aminoglycoside, c-jun, JNK Mitogen-Activated Protein Kinases, Neomycin, MESH: Electrodes, MESH: JNK Mitogen-Activated Protein Kinases, medicine.disease, Sensory Systems, Anti-Bacterial Agents, Surgery, Caspases, Mitogen-activated protein kinase, biology.protein, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Signal transduction, medicine.symptom, Peptides, business, Signal Transduction, medicine.drug
Abstract: International audience; Neomycin ototoxicity and electrode insertion trauma both involve activation of the mitogen activated protein kinase (MAPK)/c-Jun-N-terminal kinase (JNK) cell death signal cascade. This article discusses mechanisms of cell death on a cell biology level (e.g. necrosis and apoptosis) and proposes the blocking of JNK signaling as a therapeutic approach for preventing the development of a permanent hearing loss that can be initiated by either neomycin ototoxicity or electrode insertion trauma. Blocking of JNK molecules incorporates the use of a peptide inhibitor (i.e. D-JNKI-1), which is specific for all three isoforms of JNK and has been demonstrated to prevent loss of hearing following either electrode insertion trauma or loss of both hearing and hair cells following exposure to an ototoxic level of neomycin. We present previously unpublished results that control for the effect of perfusate washout of aminoglycoside antibiotic by perfusion of the scala tympani with an inactive form of D-JNKI-1 peptide, i.e. JNKI-1(mut) peptide, which was not presented in the original J. Neurosci. article that tested locally delivered D-JNKI-1 peptide against both noise- and neomycin-induced hearing loss (i.e. Wang, J., Van De Water, T.R., Bonny, C., de Ribaupierre, F., Puel, J.L., Zine, A. 2003a. A peptide inhibitor of c-Jun N-terminal kinase protects against both aminoglycoside and acoustic trauma-induced auditory hair cell death and hearing loss. J. Neurosci. 23, 8596-8607). D-JNKI-1 is a cell permeable peptide that blocks JNK signaling at the level of the three JNK molecular isoforms, which when blocked prevents the increases in hearing thresholds and the loss of auditory hair cells. This unique therapeutic approach may have clinical application for preventing: (1) hearing loss caused by neomycin ototoxicity; and (2) the progressive component of electrode insertion trauma-induced hearing loss.
Published: 2007

46. Dynamic expression of FXYD6 in the inner ear suggests a role of the protein in endolymph homeostasis and neuronal activity

Author: Jean-Luc Puel, Käthi Geering, Benjamin Delprat, Department of Pharmacology and Toxicology, Université de Lausanne (UNIL), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Montpellier 1 (UM1), Hamel, Christian, and Université de Lausanne = University of Lausanne (UNIL)
Subjects: medicine.medical_specialty, Time Factors, Endolymph, Endocochlear potential, Molecular Sequence Data, Xenopus, Biology, Ion Channels, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, otorhinolaryngologic diseases, medicine, Animals, Premovement neuronal activity, Inner ear, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Amino Acid Sequence, Na+/K+-ATPase, Cochlea, 030304 developmental biology, Neurons, 0303 health sciences, Base Sequence, Gene Expression Regulation, Developmental, biology.organism_classification, Immunohistochemistry, Rats, Cell biology, Alternative Splicing, medicine.anatomical_structure, Endocrinology, Ear, Inner, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], sense organs, Sodium-Potassium-Exchanging ATPase, 030217 neurology & neurosurgery, Homeostasis, Developmental Biology
Abstract: A key protein in the production and in the maintenance of the endocochlear potential is the Na,K-ATPase. Previously, we have shown that FXYD6 is a modulator of the Na,K-ATPase expressed in the inner ear (Delprat et al. [2007] J Biol Chem 282:7450-7456). To investigate the potential role of FXYD6 in inner ear function, we studied the developmental expression of FXYD6. Reverse transcriptase-polymerase chain reaction analysis demonstrates that FXYD6 is present as two splice variants. Both variants coimmunoprecipitate with Na,K-ATPase after expression in Xenopus oocytes. Immunohistochemistry of the cochlea (from birth to postnatal day 30) shows that FXYD6 is expressed in several epithelial cells important for endolymph homeostasis. Marked similarities were found in the developmental expression patterns of FXYD6 and Na,K-ATPase, suggesting functional cooperation between the two proteins in the generation and maintenance of the endocochlear potential and ion composition of the endolymph. Developmental Dynamics 236:2534-2540, 2007. (c) 2007 Wiley-Liss, Inc.
Published: 2007

47. Loss of the transcription factor Meis1 prevents sympathetic neurons target-field innervation and increases susceptibility to sudden cardiac death

Author: Sarah Karam, Jean Valmier, Fabrice Bouilloux, Neal G. Copeland, Jérôme Thireau, Frédéric Marmigère, Yves Dauvilliers, Stéphanie Ventéo, Nancy A. Jenkins, Charlotte Farah, Sylvain Richard, Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie des adaptations cardiovasculaires à l'Exercice, Avignon Université (AU), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Methodist Hospital Research Institute, Houston, MORNET, Dominique, Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: 0301 basic medicine, Mouse, [SDV]Life Sciences [q-bio], Apoptosis, Mice, 0302 clinical medicine, Gene expression, Biology (General), Myeloid Ecotropic Viral Integration Site 1 Protein, ComputingMilieux_MISCELLANEOUS, General Neuroscience, neurotrophin, General Medicine, 3. Good health, Cell biology, Neoplasm Proteins, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, cardiac conduction, Medicine, Stem cell, Neurotrophin, Research Article, QH301-705.5, Science, Nerve fiber, Endosomes, Biology, arrhythmia, General Biochemistry, Genetics and Molecular Biology, developmental biology, 03 medical and health sciences, stem cells, clathrin, Cardiac conduction, medicine, Gene silencing, Animals, endocytosis, Genetic Predisposition to Disease, Gene Silencing, Transcription factor, Homeodomain Proteins, General Immunology and Microbiology, Cell Biology, 030104 developmental biology, Death, Sudden, Cardiac, Developmental Biology and Stem Cells, Autonomic Nervous System Diseases, homeodomain, Immunology, biology.protein, Neuron, 030217 neurology & neurosurgery
Abstract: Although cardio-vascular incidents and sudden cardiac death (SCD) are among the leading causes of premature death in the general population, the origins remain unidentified in many cases. Genome-wide association studies have identified Meis1 as a risk factor for SCD. We report that Meis1 inactivation in the mouse neural crest leads to an altered sympatho-vagal regulation of cardiac rhythmicity in adults characterized by a chronotropic incompetence and cardiac conduction defects, thus increasing the susceptibility to SCD. We demonstrated that Meis1 is a major regulator of sympathetic target-field innervation and that Meis1 deficient sympathetic neurons die by apoptosis from early embryonic stages to perinatal stages. In addition, we showed that Meis1 regulates the transcription of key molecules necessary for the endosomal machinery. Accordingly, the traffic of Rab5+ endosomes is severely altered in Meis1-inactivated sympathetic neurons. These results suggest that Meis1 interacts with various trophic factors signaling pathways during postmitotic neurons differentiation. DOI: http://dx.doi.org/10.7554/eLife.11627.001, eLife digest Nerve cells called sympathetic neurons can control the activity of almost all of our organs without any conscious thought on our part. For example, these nerve cells are responsible for accelerating the heart rate during exercise. In a developing embryo, there are initially more of these neurons than are needed, and only those that develop correctly and form a connection with a target cell will survive. This is because the target cells provide the growing neurons with vital molecules called neurotrophins, which are trafficked back along the nerve fiber and into the main body of the nerve cell to ensure its survival. However, it is largely unknown which proteins or genes are also involved in this developmental process. Now, Bouilloux, Thireau et al. show that if a gene called Meis1 is inactivated in mice, the sympathetic neurons start to develop and grow nerve fibers, but then fail to establish connections with their target cells and finally die. The Meis1 gene encodes a transcription factor, which is a protein that regulates gene activity. Therefore, Bouilloux, Thireau et al. looked for the genes that are regulated by this transcription factor in sympathetic neurons. This search uncovered several genes that are involved in the packaging and trafficking of molecules within cells. Other experiments then revealed that the trafficking of molecules back along the nerve fiber was altered in mutant neurons in which the Meis1 gene had been inactivated. Furthermore, Meis1 mutant mice had problems with their heart rate, especially during exercise, and an increased risk of dying from a sudden cardiac arrest. These findings reveal a transcription factor that helps to establish a connection between a neuron and its target, and that activates a pattern of gene expression that works alongside the neurotrophin-based signals. Since all neurons undergo similar processes during development, future work could ask if comparable patterns of gene expression exist in other types of neurons, and if problems with such processes contribute to some neurodegenerative diseases. DOI: http://dx.doi.org/10.7554/eLife.11627.002
Published: 2015

48. Transmission Eigenchannels and the Densities of States of Random Media

Author: Xiaojun Cheng, Zhou Shi, Matthieu Davy, Azriel Z. Genack, Jing Wang, Institut d'Electronique et de Télécommunications de Rennes (IETR), Université de Nantes (UN)-Université de Rennes 1 (UR1), 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)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Department of Physics, Queens College, CUNY (QC), Queens College [CUNY] (QC), City University of New York [New York] (CUNY)-City University of New York [New York] (CUNY), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut d'Électronique et des Technologies du numéRique (IETR), Université de Nantes (UN)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), DMR-1207446, National Science Foundation, DGA, and Nantes Université (NU)-Université de Rennes 1 (UR1)
Subjects: Physics, [PHYS]Physics [physics], Anderson localization, Angular frequency, Condensed matter physics, Field (physics), Scattering, ComputerSystemsOrganization_COMPUTER-COMMUNICATIONNETWORKS, FOS: Physical sciences, General Physics and Astronomy, Disordered Systems and Neural Networks (cond-mat.dis-nn), Condensed Matter - Disordered Systems and Neural Networks, Exponential function, Transmission (telecommunications), Condensed Matter::Superconductivity, Density of states, Scaling, ComputingMilieux_MISCELLANEOUS, Optics (physics.optics), Physics - Optics
Abstract: We show in microwave measurements and computer simulations that the contribution of each eigenchannel of the transmission matrix to the density of states (DOS) is the derivative with angular frequency of a composite phase shift. The accuracy of the measurement of the DOS determined from transmission eigenchannels is confirmed by the agreement with the DOS found from the decomposition of the field into modes. The distribution of the DOS, which underlies the Thouless number, is substantially broadened in the Anderson localization transition. We find a crossover from constant to exponential scaling of fluctuations of the DOS normalized by its average value. These results illuminate the relationships between scattering, stored energy and dynamics in complex media., Supplementary Information included at the end of the document
Published: 2015

49. Inhibition of the c-Jun N-Terminal Kinase-Mediated Mitochondrial Cell Death Pathway Restores Auditory Function in Sound-Exposed Animals

Author: Christophe Bonny, Jing Wang, Sabine Ladrech, Thomas R. Van De Water, Jean-Luc Puel, Jérôme Ruel, Hamel, Christian, Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoires Auris SAS, Division de Génétique Médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Department of Otolaryngology, and University of Miami [Coral Gables]
Subjects: Proto-Oncogene Proteins c-jun, Apoptosis, Sound exposure, MESH: Animals, Phosphorylation, bcl-2-Associated X Protein, MESH: Peptides, Microfilament Proteins, c-jun, Cytochromes c, MESH: Cytochromes c, Anatomy, Mitochondria, Cell biology, Protein Transport, medicine.anatomical_structure, Caspases, Molecular Medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Hair cell, Signal transduction, Programmed cell death, MAP Kinase Signaling System, MESH: Mitochondria, MESH: Phosphorylat, Guinea Pigs, MESH: Carrier Proteins, Biology, MESH: Hair Cells, MESH: Guinea Pigs, Necrosis, MESH: Microfilament Proteins, Hair Cells, Auditory, otorhinolaryngologic diseases, medicine, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Protein kinase A, Cochlea, MESH: Necrosis, Pharmacology, MESH: Caspases, MESH: MAP Kinase Signaling System, MESH: Apoptosis, JNK Mitogen-Activated Protein Kinases, MESH: Hearing Loss, Noise-Induced, MESH: JNK Mitogen-Activated Protein Kinases, Hearing Loss, Noise-Induced, Round Window, Ear, Carrier Proteins, Peptides
Abstract: We tested and characterized the therapeutic value of round window membrane-delivered (RWM) d-JNKI-1 peptide (Bonny et al., 2001) against sound trauma-induced hearing loss. Morphological characteristics of sound-damaged hair cell nuclei labeled by Hoechst staining show that apoptosis is the predominant mode of cell death after sound trauma. Analysis of the events occurring after sound trauma demonstrates that c-Jun N-terminal kinase (JNK)/stress-activated protein kinase activates a mitochondrial cell death pathway (i.e., activation of Bax, release of cytochrome c, activation of procaspases, and cleavage of fodrin). Fluorescein isothiocyanate (FITC)-conjugated d-JNKI-1 peptide applied onto an intact cochlear RWM diffuses through this membrane and penetrates cochlear tissues with the exception of the stria vascularis. A time sequence of fluorescence measurements demonstrates that FITC-labeled d-JNKI-1 remains in cochlear tissues for as long as 3 weeks. In addition to blocking JNK-mediated activation of a mitochondrial cell death pathway, RWM-delivered d-JNKI-1 prevents hair cell death and development of a permanent shift in hearing threshold that is caused by sound trauma in a dose-dependent manner (EC50 = 2.05 microM). The therapeutic window for protection of the cochlea from sound trauma with RWM delivery of d-JNKI-1 extended out to 12 h after sound exposure. These results show that the mitogen-activated protein kinase/JNK signaling pathway plays a crucial role in sound trauma-initiated hair cell death. Blocking this signaling pathway with RWM delivery of d-JNKI-1 may have significant therapeutic value as a therapeutic intervention to protect the human cochlea from the effects of sound trauma.
Published: 2006

50. OPA1 alternate splicing uncouples an evolutionary conserved function in mitochondrial fusion from a vertebrate restricted function in apoptosis.: OPA1 isoforms in mitochondrial fusion or apoptosis

Author: Pascale Belenguer, Laurent Baricault, Cécile Delettre, Aurélien Olichon, Ghizlane Elachouri, Guy Lenaers, Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et thérapie des déficits sensoriels et moteurs, and Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: fusion, Mitochondrion, Biology, OPA1, GTP Phosphohydrolases, Evolution, Molecular, Mitochondrial Proteins, 03 medical and health sciences, Exon, 0302 clinical medicine, Sequence Analysis, Protein, Yeasts, Protein Interaction Mapping, Tumor Cells, Cultured, Animals, Humans, Protein Isoforms, Molecular Biology, 030304 developmental biology, Dynamin, Genetics, 0303 health sciences, Alternative splicing, apoptosis, alternate splicing, Cell Biology, Cell biology, mitochondria, Alternative Splicing, Microscopy, Fluorescence, mitochondrial fusion, Mitochondrial Membranes, RNA splicing, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Mitochondrial fission, 030217 neurology & neurosurgery, Function (biology), HeLa Cells
Abstract: In most eucaryote cells, release of apoptotic proteins from mitochondria involves fission of the mitochondrial network and drastic remodelling of the cristae structures. The intramitochondrial dynamin OPA1, as a potential central actor of these processes, exists as eight isoforms resulting from the alternate splicing combinations of exons (Ex) 4, 4b and 5b, which functions remain undetermined. Here, we show that Ex4 that is conserved throughout evolution confers functions to OPA1 involved in the maintenance of the DeltaPsi(m) and in the fusion of the mitochondrial network. Conversely, Ex4b and Ex5b, which are vertebrate specific, define a function involved in cytochrome c release, an apoptotic process also restricted to vertebrates. The drastic changes of OPA1 variant abundance in different organs suggest that nuclear splicing can control mitochondrial dynamic fate and susceptibility to apoptosis and pathologies.
Published: 2006

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