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105 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. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. Long-range spatial integration across contrast signs: a probabilistic mechanism?

Author: Osmund Keith Langley, Birgitta Dresp, Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), 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 des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM, U1114, Strasbourg, and Dresp, Birgitta
Subjects: Adult, genetic structures, MESH: Probability, media_common.quotation_subject, MESH: Space Perception, Models, Psychological, Luminance, 050105 experimental psychology, MESH: Psychophysics, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], Contrast Sensitivity, 03 medical and health sciences, 0302 clinical medicine, Optics, Psychophysics, Humans, Contrast (vision), 0501 psychology and cognitive sciences, Inducer, MESH: Models, Psychological, MESH: Contrast Sensitivity, Probability, media_common, Physics, MESH: Humans, business.industry, Angular distance, Orientation (computer vision), [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, 05 social sciences, Probabilistic logic, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, MESH: Adult, Sensory Systems, Ophthalmology, Space Perception, Line (geometry), business, Biological system, [SDV.NEU.SC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, 030217 neurology & neurosurgery, Sign (mathematics)
Abstract: International audience; It is widely assumed that the integration of orientation contrast across spatial gaps within the long-range regime is not selective to the contrast sign of the individual stimuli. Probabilistic models of perceptual integration, however, suggest that long-range spatial integration should be, if not selective, at least sensitive to local contrast signs. To clarify this issue, we tested predictions of a model based on conditional probabilistic weights of identical and opposite contrast signs in a simple spatial configuration of two co-linear lines. Contrast detection thresholds of the target line presented either by itself (control condition) or simultaneously with the co-linear inducer (test condition) were measured. The contrast sign of targets and inducers was varied so that all four possible combinations of signs were produced in the test conditions: (1) dark target with dark inducer, (2) dark target with bright inducer, (3) bright target with bright inducer and (4) bright target with dark inducer. The contrast intensity (Weber ratio) of dark and bright inducers was identical. The coaxial distance between target and inducer was constant in each of two experiments, testing for two distances that corresponded to an angular separation within the long-range domain of spatial integration as defined previously. It is found that targets and inducers with identical contrast signs produce significantly stronger facilitating effects on detection than stimuli with opposite signs. The data closely match predictions consistent with those of a probabilistic model of line contrast integration across spatial gaps and contrast signs within the long-range regime.
Published: 2005
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34. tPA promotes ADAMTS-4-induced CSPG degradation, thereby enhancing neuroplasticity following spinal cord injury

Author: Denis Vivien, Maxime Gauberti, Marcel Mersel, Jari Koistinaho, Véronique Agin, Carine Ali, Hubert Vaudry, Jean-Claude do Rego, Sighild Lemarchant, Mathilde Pruvost, Eric Maubert, Aurélien Briens, François Féron, Didier Petite, Evelyne Emery, Yannick Hommet, Yatma Gueye, Marie Hébert, Department of Neurobiology, University of Eastern Finland-A. I. Virtanen Institute for Molecular Sciences-Biocenter Kuopio, Sérine protéases et physiopathologie de l'unité neurovasculaire, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), 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), 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 Commun d'Analyse Comportementale (SCAC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-High-tech Research Infrastructures for Life Sciences (HeRacLeS), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuroendocrinologie cellulaire et moléculaire, Laboratoire de Chimie de la Matière Condensée de Paris (site ENSCP) (LCMCP (site ENSCP)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF (institution))-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2, Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Serine Proteinase Inhibitors, [SDV]Life Sciences [q-bio], Spinal cord injury, Tissue plasminogen activator, lcsh:RC321-571, Neurocan, Plasminogen Activator Inhibitor 1, medicine, Neurites, Animals, Rats, Wistar, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Cells, Cultured, Serpins, Spinal Cord Injuries, ComputingMilieux_MISCELLANEOUS, Metalloproteinase, Thrombospondin, Neuronal Plasticity, Chemistry, Regeneration (biology), ADAMTS, Neuropeptides, Recovery of Function, Spinal cord, medicine.disease, Axons, Cell biology, Rats, ADAM Proteins, medicine.anatomical_structure, Neuroprotective Agents, Chondroitin sulfate proteoglycans, Neurology, Spinal Cord, ADAMTS4 Protein, Female, Type 4 disintegrin and metalloproteinase with thrombospondin motifs, Neuroplasticity, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Procollagen N-Endopeptidase, Neuroscience, Spinal Cord Compression, medicine.drug
Abstract: Although tissue plasminogen activator (tPA) is known to promote neuronal remodeling in the CNS, no mechanism of how this plastic function takes place has been reported so far. We provide here in vitro and in vivo demonstrations that this serine protease neutralizes inhibitory chondroitin sulfate proteoglycans (CSPGs) by promoting their degradation via the direct activation of endogenous type 4 disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-4). Accordingly, in a model of compression-induced spinal cord injury (SCI) in rats, we found that administration of either tPA or its downstream effector ADAMTS-4 restores the tPA-dependent activity lost after the SCI and thereby, reduces content of CSPGs in the spinal cord, a cascade of events leading to an improved axonal regeneration/sprouting and eventually long term functional recovery. This is the first study to reveal a tPA-ADAMTS-4 axis and its function in the CNS. It also raises the prospect of exploiting such cooperation as a therapeutic tool for enhancing recovery after acute CNS injuries.
Published: 2014

35. Cav3.2 calcium channels: the key protagonist of the supraspinal effect of paracetamol

Author: Abdelkrim Alloui, Nicolas Kerckhove, Emmanuel Bourinet, Alain Eschalier, Jean Chemin, Mathieu Boudes, Amaury François, Christophe Mallet, Thomas Voets, Pharmacologie fondamentale et clinique de la douleur, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-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), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), CHU Clermont-Ferrand, Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherches sur les Herbivores - UMR 1213 (UMRH), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA), 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 d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and 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)
Subjects: Male, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Pharmacology, Membrane Potentials, chemistry.chemical_compound, Transient receptor potential channel, Calcium Channels, T-Type, Mice, 0302 clinical medicine, Ganglia, Spinal, Drug Interactions, 4-Aminopyridine, Cells, Cultured, Pain Measurement, Mice, Knockout, Neurons, 0303 health sciences, Voltage-dependent calcium channel, Morphine, Drug Administration Routes, Tetraethylammonium, Analgesics, Non-Narcotic, Analgesics, Opioid, Paracetamol, Neurology, Spinal Cord, AM404, medicine.drug, Analgesic, TRPV1, TRPV Cation Channels, 03 medical and health sciences, medicine, Potassium Channel Blockers, Animals, Humans, Cav3.2 channel, 030304 developmental biology, Acetaminophen, Arthritis, Potassium channel blocker, Anesthesiology and Pain Medicine, chemistry, Capsaicin, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Neurology (clinical), Analgesia, 030217 neurology & neurosurgery
Abstract: International audience; To exert its analgesic action, paracetamol requires complex metabolism to produce a brain-specific lipoamino acid compound, AM404, which targets central transient receptor potential vanilloid receptors (TRPV1). Lipoamino acids are also known to induce analgesia through T-type calcium-channel inhibition (Cav3.2). In this study we show that the antinociceptive effect of paracetamol in mice is lost when supraspinal Cav3.2 channels are inhibited. Therefore, we hypothesized a relationship between supraspinal Cav3.2 and TRPV1, via AM404, which mediates the analgesic effect of paracetamol. AM404 is able to activate TRPV1 and weakly inhibits Cav3.2. Interestingly, activation of TRPV1 induces a strong inhibition of Cav3.2 current. Supporting this, intracerebroventricular administration of AM404 or capsaicin produces antinociception that is lost in Cav3.2−/− mice. Our study, for the first time, 1) provides a molecular mechanism for the supraspinal antinociceptive effect of paracetamol; 2) identifies the relationship between TRPV1 and the v3.2 channel">Cav3.2 channel; and 3) suggests supraspinal Cav3.2 inhibition as a potential pharmacological strategy to alleviate pain.
Published: 2014

36. Early Functional Deficit and Microglial Disturbances in a Mouse Model of Amyotrophic Lateral Sclerosis

Author: Maria dM Vivanco, Jean-Charles Sabourin, Yannick Nicolas Gerber, Miriam Rábano, Florence E. Perrin, 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), 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: Nervous system, Central Nervous System, Anatomy and Physiology, Time Factors, nervous-system, Mouse, BIOCHEMISTRY AND MOLECULAR BIOLOGY, lcsh:Medicine, motor-neuron disease, Disease, animal-models, Pathogenesis, Behavioral Neuroscience, Mice, 0302 clinical medicine, Molecular Cell Biology, Neurobiology of Disease and Regeneration, Amyotrophic lateral sclerosis, Muscle Components, lcsh:Science, Musculoskeletal System, Parkinsons-disease, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Multidisciplinary, Microglia, Animal Models, Flow Cytometry, 3. Good health, medicine.anatomical_structure, Spinal Cord, AGRICULTURAL AND BIOLOGICAL SCIENCES, Muscle, Research Article, Nervous System Physiology, Genetically modified mouse, medicine.medical_specialty, spinal-cord, Neuromuscular Junction, Neurophysiology, Mice, Transgenic, Motor Activity, transgenic mice, Neuromuscular junction, Neurological System, 03 medical and health sciences, Model Organisms, medicine, Animals, Humans, Pathological, Biology, 030304 developmental biology, Motor Systems, business.industry, Superoxide Dismutase, MEDICINE, [SCCO.NEUR]Cognitive science/Neuroscience, Amyotrophic Lateral Sclerosis, lcsh:R, astrocytes, treadmill gait analysis, medicine.disease, Surgery, Disease Models, Animal, superoxide-dismutase, Mutation, Nervous System Components, lcsh:Q, business, Neuroscience, familial ALS, 030217 neurology & neurosurgery, Cytometry
Abstract: 11 p. Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by selective motoneurons degeneration. There is today no clear-cut pathogenesis sequence nor any treatment. However growing evidences are in favor of the involvement, besides neurons, of several partners such as glia and muscles. To better characterize the time course of pathological events in an animal model that recapitulates human ALS symptoms, we investigated functional and cellular characteristics of hSOD1(G93A) mice.-- Methods and Findings: We have evaluated locomotor function of hSOD1(G93A) mice through dynamic walking patterns and spontaneous motor activity analysis. We detected early functional deficits that redefine symptoms onset at 60 days of age, i.e. 20 days earlier than previously described. Moreover, sequential combination of these approaches allows monitoring of motor activity up to disease end stage. To tentatively correlate early functional deficit with cellular alterations we have used flow cytometry and immunohistochemistry approaches to characterize neuromuscular junctions, astrocytes and microglia. We show that (1) decrease in neuromuscular junction's number correlates with motor impairment, (2) astrocytes number is not altered at pre- and early-symptomatic ages but intraspinal repartition is modified at symptoms onset, and (3) microglia modifications precede disease onset. At pre-symptomatic age, we show a decrease in microglia number whereas at onset of the disease two distinct microglia sub-populations emerge. -- Conclusions: In conclusion, precise motor analysis updates the onset of the disease in hSOD1(G93A) mice and allows locomotor monitoring until the end stage of the disease. Early functional deficits coincide with alterations of neuromuscular junctions. Importantly, we identify different sets of changes in microglia before disease onset as well as at early-symptomatic stage. This finding not only brings a new sequence of cellular events in the natural history of the disease, but it may also provide clues in the search for biomarkers of the disease, and potential therapeutic targets. This work was supported by the Spanish Government, Plan Nacional de I+D+I 2008-2011 and the Institudo de Salud Carlos III- Subdirección General de Evaluación y Fomento de la investigación [PI10/00709 to FEP], the “Fondation pour la Recherche Médicale" to FEP and the patient organizations “Demain Debout Aquitaine" (to YNG)and “Verticale" (to FEP). No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Published: 2012

37. Unlike Physical Exercise, Modified Environment Increases the Lifespan of SOD1G93A Mice However Both Conditions Induce Cellular Changes

Author: Jean Charles Sabourin, Florence E. Perrin, Yannick Nicolas Gerber, Jean-Philippe Hugnot, 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), 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, BIOCHEMISTRY AND MOLECULAR BIOLOGY, regular exercise, Mouse, medicine.medical_treatment, amyotrophic-lateral-sclerosis, microglia, lcsh:Medicine, Bioinformatics, Motor Neuron Diseases, Mice, 0302 clinical medicine, Neurotrophic factors, Neurobiology of Disease and Regeneration, enriched-environment, Medicine, Amyotrophic lateral sclerosis, neurotrophic factor, lcsh:Science, Motor Neurons, 0303 health sciences, Multidisciplinary, Animal Models, Neurology, Spinal Cord, AGRICULTURAL AND BIOLOGICAL SCIENCES, Immunohistochemical Analysis, Neuroglia, Research Article, spinal-cord, mouse model, Immunology, Physical Exertion, Neuromuscular Junction, Physical exercise, growth-factor, Environment, 03 medical and health sciences, disease progression, Model Organisms, Life Expectancy, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Sports and Exercise Medicine, Biology, 030304 developmental biology, Environmental enrichment, MEDICINE, Superoxide Dismutase, business.industry, Growth factor, [SCCO.NEUR]Cognitive science/Neuroscience, Amyotrophic Lateral Sclerosis, Multifactorial disease, lcsh:R, medicine.disease, Muscular paralysis, Immunologic Techniques, Etiology, Clinical Immunology, lcsh:Q, ALS, business, 030217 neurology & neurosurgery, Neuroscience
Abstract: 8 p. Background: Amyotrophic lateral sclerosis (ALS) is characterized by a gradual muscular paralysis resulting from progressive motoneurons death. ALS etiology remains unknown although it has been demonstrated to be a multifactorial disease involving several cellular partners. There is currently no effective treatment. Even if the effect of exercise is under investigation for many years, whether physical exercise is beneficial or harmful is still under debate.-- Methods and Findings: We investigated the effect of three different intensities of running exercises on the survival of SOD1(G93A) mice. At the early-symptomatic stage (P60), males were isolated and randomly assigned to 5 conditions: 2 sedentary groups ("sedentary" and "sedentary treadmill" placed on the inert treadmill), and 3 different training intensity groups (5 cm/s, 10 cm/s and 21 cm/s; 15 min/day, 5days/week). We first demonstrated that an appropriate "control" of the environment is of the utmost importance since comparison of the two sedentary groups evidenced an 11.6% increase in survival in the "sedentary treadmill" group. Moreover, we showed by immunohistochemistry that this increased lifespan is accompanied with motoneurons survival and increased glial reactivity in the spinal cord. In a second step, we showed that when compared with the proper control, all three running-based training did not modify lifespan of the animals, but result in motoneurons preservation and changes in glial cells activation. -- Conclusions/Significance: We demonstrate that increase in survival induced by a slight daily modification of the environment is associated with motoneurons preservation and strong glial modifications in the lumbar spinal cord of SOD1(G93A). Using the appropriate control, we then demonstrate that all running intensities have no effect on the survival of ALS mice but induce cellular modifications. Our results highlight the critical importance of the control of the environment in ALS studies and may explain discrepancy in the literature regarding the effect of exercise in ALS. This study was supported by the Fondation de l’Avenir [ET7–456 to FEP], the Spanish Government, Plan Nacional de I+D+I 2008–2011 and ISCIII - Subdirección General de Evaluación y Fomento de la Investigación [PI10/00709 to FEP], the Basque Government, Fondo Común de Cooperación Aquitania-Euskadi and Proyectos de Investigacion Sanitaria [to FEP], the Association Demain Debout Aquitaine [to YNG] and the Swiss National Science Foundation [to ACK]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Published: 2012

38. Modélisation mathématique de l'activité électrophysiologique des neurones auditifs primaires

Author: Michel, Christophe, STAR, ABES, 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 (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier II - Sciences et Techniques du Languedoc, and Jérôme Bourien
Subjects: Stimulation électrique, Referred therapeutically, Visée thérapeutique, Electric stimulation, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Mathematical modeling, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Auditory neuron, Modélisation mathématique, Neurone auditif, Cochlea, Cochlée
Abstract: In response to sound stimulation, inner hair cell triggers glutamate release onto the dendrite-like processes of primary auditory neurons and drives action potentials, which are convey to the central nervous system. Whereas knowledge of the transfer function at the ribbon synapse has considerably progress, little is known about the voltage-gated ionic channels which shape the action potential. Here, we provide a comprehensive computational model bridging the gap between the voltage-dependent currents measured in vitro on fresh isolated primary auditory neurons and spikes (extracellular action potentials) recorded in vivo from guinea pig auditory nerve fibers.Voltage-dependent currents (Na+ and K+) of SGNs somata patch-clamp recordings were fitted by a Hodgkin-Huxley model with a full trace identification algorithm. Node of Ranvier model was designed from the hypothesis that channel expressed on soma were identical, but differ in density. Simulated spikes were adjusted in order to match in vivo single-unit recordings with gradient-descent algorithm. Computation of the data allows to the identification of: i) one fast inward Na current (GNa activation: V1/2=-33 mV, τact< 0.5 ms; inactivation: V1/2=-61 mV, τinact < 2 ms); and ii) two K conductances, a high voltage-activated delayed-rectifier component (GKH, activation: V1/2=-41 mV; τact < 2.5 ms) and a low voltage-activated component (GKL, activation: V1/2=-56 mV; τact < 5 ms). Node of Ranvier model generate spikes that fit with in vivo recordings. Interestingly, the different spike durations along the tonotopic axis measured in vivo (i.e. 450 µs peak-to-peak duration versus 250 µs for 1 to 20 kHz, respectively) was explain by a gradual change in Na and K channel densities along the cochlea (GNa ~78 nS, GKL ~9 nS, GKH ~3 nS at 1 kHz versus GNa ~90 nS, GKL ~12 nS, GKH ~6 nS at 20 kHz).This study identifies the ionic conductances and densities, which shape the action potential waveform of auditory nerve fibers and suggests that the interplay of fast inward Na+ current and the two K+ enables the auditory nerve fibers to sustain high firing rates. In addition, this node of Ranvier model provides a valuable tool to design new electrical stimulation strategies for cochlear implants., En réponse à une stimulation sonore, la cellule ciliée interne libère du glutamate qui va activer des récepteurs distribués sur le bouton post-synaptique. Les courants post-synaptiques vont ensuite dépolariser la terminaison périphérique des neurones auditifs primaires, et initier le déclenchement d'un potentiel d'action. Tandis que la connaissance des mécanismes pré-synaptiques a considérablement progressé ces 10 dernières années, les mécanismes responsables de l'initiation des potentiels d'action sont encore méconnus. Dans cette étude, nous avons déterminé les conductances ioniques nécessaires au déclenchement des potentiels d'action. Les paramètres biophysiques des conductances (Na+ et K+) ont été identifiés (algorithme d'identification trace entière) à partir d'enregistrements de patch clamp acquis sur les corps cellulaires. Un modèle mathématique de nœud de Ranvier a ensuite été développé en faisant l'hypothèse que les canaux présents sur le corps cellulaire et sur un nœud de Ranvier étaient de même nature mais en densité différente. Les paramètres de ce modèle ont été identifiés pour reproduire les potentiels d'action extracellulaire au moyen d'un algorithme de descente du gradient. Nous avons identifié : i) un courant Na+ entrant rapide (GNa activation: V1/2=-33 mV, tau_act< 0.5 ms; inactivation: V1/2=-61 mV, tau_inact < 2 ms) et deux courants K+ sortants, un rectifiant retardé activé à haut seuil (GKH, activation: V1/2=-41 mV; tau_act < 2.5 ms) et un activé à bas seuil (GKL, activation: V1/2=-56 mV; tau_act < 5 ms). Le modèle de nœud de Ranvier génère des potentiels d'action extracellulaire similaires à ceux enregistrés in vivo. La différence de durée du potentiel d'action observée le long de l'axe tonotopique (i.e. 450 µs de durée pic à pic à 1 kHz contre 250 µs à 20 kHz) s'explique parfaitement par un gradient de densité en canaux ioniques le long de la cochlée (GNa ~78 nS, GKL ~9 nS, GKH ~3 nS à 1 kHz contre GNa ~90 nS, GKL ~12 nS, GKH ~6 nS à 20 kHz).Cette étude a permis d'identifier les conductances ioniques et les densités de canaux responsables de l'initiation des potentiels d'action dans les neurones auditifs primaires. Elle suggère que la coopération entre le courant Na+ et des 2 courants K+ est probablement à l'origine de la haute fréquence de décharge de ces neurones. Le modèle de nœud de Ranvier permet en outre de tester de nouvelles stratégies de stimulation électrique dans le contexte de l'implant cochléaire.
Published: 2012

39. RP1 and autosomal dominant rod-cone dystrophy: novel mutations, a review of published variants, and genotype-phenotype correlation.: RP1mutations in French adRP patients

Author: Audo, Isabelle, Mohand-Saïd, Saddek, Dhaenens, Claire-Marie, Germain, Aurore, Orhan, Elise, Antonio, Aline, Hamel, Christian, Sahel, José-Alain, Bhattacharya, Shomi, Zeitz, Christina, Institut de la Vision, 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), UCL-Institute of Ophthalmology, UF Génopathies - Laboratoire de Biochimie et Biologie Moléculaire [Lille] (LBBM), Université de Lille, Sciences et Technologies-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, 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), Fondation Ophtalmologique Adolphe de Rothschild, Department of Celular Therapy and Regenerative Medicine (CABIMER), Andalusian Molecular Biology and Regenerative Medicine Centre, The project was financially supported by the Department of Paris, Foundation Fighting Blindness (I.A. FFB Grant N°: CD-CL-0808-0466-CHNO and the CIC503 recognized as an FFB center, FFB Grant No: C-CMM-0907-0428-INSERM04), ANR (S.S.B). NIHR Biomedical Research Centre for Ophthalmology and The Special Trustees of Moorfields Eye Hospital London, Foundation Voir et Entendre (C.Z) and French Ministry of Health (C.H. PHRC # 2008-A01238-47)., and Marazova, Katia
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics, sense organs, [SDV.GEN] Life Sciences [q-bio]/Genetics, eye diseases
Abstract: International audience; Rod-cone dystrophies (RP) are a clinically and genetically heterogeneous group of inherited retinal disorders characterized by photoreceptor degeneration. RP1 is a major gene underlying autosomal dominant (ad) RP though prevalence figures vary depending on the origin of the cases from 0%-10% of all adRP. Some mutations in RP1 also lead to autosomal recessive RP. Herein we review all previously reported and several novel RP1 mutations in relation to the associated phenotype in patients from a French adRP cohort. Prevalence studies from this cohort show that 5.3% of the cases have RP1 mutations. This is in accordance with other studies reported from UK and USA. The majority of mutations represent truncating mutations which are located in a hot spot region of the gene. Similarly, we identified in total four novel deletions and nonsense mutations, of which two may represent recurrent mutations in this population. In addition a novel missense mutation of uncertain pathogenicity was identified. Including our findings, to date 43 RP1 mutations are known to cause adRP. Variable penetrance of the disease was observed in our and other cohorts. Most patients with RP1 mutations show classical signs of RP with relatively preserved central vision and visual field. ©2011 Wiley Periodicals, Inc.
Published: 2012

40. Critical Roles of Transitional Cells and Na/K-ATPase in the Formation of Vestibular Endolymph

Author: Mélanie Cavalier, Christian Chabbert, Cécile Travo, Sophie Gaboyard, Julie Quentin, Jacques Barhanin, Sylvain Bartolami, Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université Montpellier 2 - Sciences et Techniques (UM2)-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), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), 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), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Bartolami, Sylvain, 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), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), and Université Nice Sophia Antipolis (... - 2019) (UNS)
Subjects: Male, Time Factors, Endolymph, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Gadolinium, Pyridinium Compounds, Ouabain, Membrane Potentials, Mice, 0302 clinical medicine, Mechanotransduction, Enzyme Inhibitors, Saccule and Utricle, Bumetanide, Mice, Knockout, 0303 health sciences, General Neuroscience, Gene Expression Regulation, Developmental, Articles, Endocytosis, Cell biology, medicine.anatomical_structure, Potassium Channels, Voltage-Gated, Female, Sodium-Potassium-Exchanging ATPase, medicine.drug, medicine.medical_specialty, Sodium-Potassium-Chloride Symporters, Biology, 03 medical and health sciences, Organ Culture Techniques, Internal medicine, medicine, Animals, Na+/K+-ATPase, Rats, Wistar, 030304 developmental biology, Transepithelial potential difference, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Epithelial Cells, Rats, Mice, Inbred C57BL, Quaternary Ammonium Compounds, Endocrinology, Aminoglycosides, Animals, Newborn, Potassium, Cotransporter, 030217 neurology & neurosurgery, Homeostasis
Abstract: The mechanotransduction of vestibular sensory cells depends on the high endolymphatic potassium concentration ([K+]) maintained by a fine balance between K+secretion and absorption by epithelial cells. Despite the crucial role of endolymph as an electrochemical motor for mechanotransduction, little is known about the processes that govern endolymph formation. To address these, we took advantage of an organotypic rodent model, which regenerates a genuine neonatal vestibular endolymphatic compartment, facilitating the determination of endolymphatic [K+] and transepithelial potential (Vt) during endolymph formation. While mature Vt levels are almost immediately achieved, K+accumulates to reach a steady [K+] by day 5 in culture. Inhibition of sensory cell K+efflux enhances [K+] regardless of the blocker used (FM1.43, amikacin, gentamicin, or gadolinium). Targeting K+secretion with bumetanide partially and transiently reduces [K+], while ouabain application andKcne1deletion almost abolishes it. Immunofluorescence studies demonstrate that dark cells do not express Na-K-2Cl cotransporter 1 (the target of bumetanide) in cultured and young mouse utricles, while Na/K-ATPase (the target of ouabain) is found in dark cells and transitional cells. This global analysis of the involvement of endolymphatic homeostasis actors in the immature organ (1) confirms that KCNE1 channels are necessary for K+secretion, (2) highlights Na/K-ATPase as the key endolymphatic K+provider and shows that Na-K-2Cl cotransporter 1 has a limited impact on K+influx, and (3) demonstrates that transitional cells are involved in K+secretion in the early endolymphatic compartment.
Published: 2011

41. Anatomical study of serotonergic innervation and 5-HT1A receptor in the human spinal cord

Author: G Boniface, Florence E. Perrin, Luc Bauchet, Marisa Teigell, Nicolas Lonjon, Alain Privat, Jean-Philippe Hugnot, J J Rodriguez, Yannick Nicolas Gerber, Histoire et Sources des Mondes antiques (HiSoMA), Centre National de la Recherche Scientifique (CNRS)-Université Jean Monnet [Saint-Étienne] (UJM)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Université Lumière - Lyon 2 (UL2)-École normale supérieure - Lyon (ENS Lyon), 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 Neurochirurgie [Montpellier], CHU Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), EAU (EAU), Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Gui de Chauliac [Montpellier], Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institute of Experimental Medicine, and Czech Academy of Sciences [Prague] (CAS)
Subjects: Adult, Male, Cancer Research, Adolescent, Immunology, Biology, Serotonergic, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, medicine, Animals, Humans, Receptor, Spinal cord injury, 5-HT receptor, ComputingMilieux_MISCELLANEOUS, Aged, 030304 developmental biology, Rexed laminae, 0303 health sciences, nociceptive pathway, [SCCO.NEUR]Cognitive science/Neuroscience, Cell Biology, Anatomy, Middle Aged, medicine.disease, Spinal cord, Rats, serotonin, locomotion, Transplantation, medicine.anatomical_structure, Spinal Cord, Receptor, Serotonin, 5-HT1A, Female, Original Article, Serotonin, genito-urinary tract, Neuroscience, 030217 neurology & neurosurgery, Serotonergic Neurons
Abstract: International audience; Serotonergic innervation of the spinal cord in mammals has multiple roles in the control of motor, sensory and visceral functions. In rats, functional consequences of spinal cord injury at thoracic level can be improved by a substitutive transplantation of serotonin (5-HT) neurons or regeneration under the trophic influence of grafted stem cells. Translation to either pharmacological and/or cellular therapies in humans requires the mapping of the spinal cord 5-HT innervation and its receptors to determine their involvement in specific functions. Here, we have performed a preliminary mapping of serotonergic processes and serotonin-lA (5-HT1A) receptors in thoracic and lumbar segments of the human spinal cord. As in rodents and non-human primates, 5-HT profiles in human spinal cord are present in the ventral horn, surrounding motoneurons, and also contact their presumptive dendrites at lumbar level. 5-HT1A receptors are present in the same area, but are more densely expressed at lumbar level. 5-HT profiles are also present in the intermediolateral region, where 5-HT1A receptors are absent. Finally, we observed numerous serotonergic profiles in the superficial part (equivalent of Rexed lamina II) of the dorsal horn, which also displayed high levels of 5-HT1A receptors. These findings pave the way for local specific therapies involving cellular and/or pharmacological tools targeting the serotonergic system.
Published: 2011

42. Infrared laser stimulation of retinal and vestibular neurons

Author: Michel Dumas, Emmanuelle S. Albert, Christian P. Hamel, Jean-Michel Bec, Isabelle Marc, Christian Chabbert, Fabrice Bardin, Gerard Dupeyron, Institut d’Electronique et des Systèmes (IES), 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), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU 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), 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), Centre d'Electronique et de Micro-optoélectronique de Montpellier (CEM2), and Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Laser-tissue interaction, Materials science, [SDV]Life Sciences [q-bio], Stimulation, 010402 general chemistry, 01 natural sciences, Semiconductor laser theory, law.invention, 03 medical and health sciences, law, medicine, retinal ganglion cell, 030304 developmental biology, 0303 health sciences, business.industry, Far-infrared laser, Photothermal therapy, Laser, vestibular ganglion cell, neuron, 0104 chemical sciences, Electrophysiology, medicine.anatomical_structure, Retinal ganglion cell, Biophysics, [SPI.OPTI]Engineering Sciences [physics]/Optics / Photonic, Optoelectronics, Neuron, business
Abstract: International audience; The study of laser-neuron interaction has gained interest over the last few years not only for understanding of fundamental mechanisms but also for medical applications such as prosthesis because of the non-invasive characteristic of the laser stimulation. Several authors have shown that near infrared lasers are able to stimulate neurons. It is suggested that a thermal gradient induced by the absorption of the laser radiation on cells is the primary effect but the exact mechanism remains unclear. We show in this work that infrared laser radiations provide a possible way for stimulating retinal and vestibular ganglion cells. We describe relevant physical characteristics allowing safe and reproducible neuron stimulations by single infrared pulses. Calcium fluorescence imaging and electrophysiological recordings have been used to measure ionic exchanges at the neuron membrane. The stimulation system is based on a pulsed laser diode beam of a few mW. Effects of three different wavelengths (from 1470 to 1875 nm) and stimulation durations have been investigated. Variations of the stimulation energy thresholds suggest that the main physical parameter is the water optical absorption. Measurements of the temperature at the cell membrane show that a constant temperature rise is required to stimulate neurons, suggesting a photothermal process.
Published: 2011

43. Exploring Molecular Mechanisms That Underlie Cellular Response to Laser Stimulation in Retinal Ganglion Cells

Author: Albert, E.S., Bec, J.M., Bardin, Fabrice, Marc, Isabelle, Payet, O., Lenaers, Guy, Hamel, Christian P, Dumas, M., Muller, A., Chabbert, C., 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 Génie Informatique et Ingénierie de Production (LGI2P), IMT - MINES ALES (IMT - MINES ALES), and Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)
Subjects: [SPI]Engineering Sciences [physics], genetic structures, sense organs, ganglion cells, signal transduction, laser
Abstract: International audience; Purpose: Blindness in patients with retinitis pigmentosa (RP) is associated to a primary degeneration of photoreceptors and a secondary loss of cells from the inner retinal layers. Yet in these patients most of the bipolar and retinal ganglion cells (RGC) remain intact for many years, with their ability to transduce some visual information and consequently, providing with excitable cells that can be stimulated by electrical prosthetic stimulations. Such an approach is presently impeded both by the use of conventional electrodes which cannot transmit with high fidelity the wide range of visual stimulations encountered under normal condition and by the gliosis ensuing from the presence and function of the electrodes within the sensory organ . These drawbacks could be bypassed by mid-infra red laser stimulation which allows increased spatial resolution without direct cellular contact.Methods: We used an experimental set up to stimulate purified RGC or retina slices with a 1870-nm wavelength beam guided by an optical fibre of 105µm diameter. We evaluated the biological response by calcium imaging and electrophysiological recordings (whole cell patch clamp method).Results: We demonstrated that with a stimulation threshold energy of 1J/cm2>E>3J/cm2, we can generate in RGCs reproducible calcium transients and variations of membrane potential with or without further evoked action potentials without being harmful for the neurons. The application of calcium and sodium voltage dependant channels blockers confirmed the biological effects of laser stimulation without elucidating yet the biological mechanisms triggered by this method of stimulation of this type of neuron.Conclusions: Based on present data, mid-infrared laser stimulation represents a realistic alternative process to stimulate RGCs and restore visual stimuli in patients suffering severe RP. Work is in progress to increase the efficiency of the laser stimulus and RGCs sensitivity. We are presently working on the identification of the cellular elements and intracellular cascades involved in the cell response.
Published: 2010

44. Src kinase activation is mandatory for MDA-9/syntenin-mediated activation of nuclear factor-kappaB

Author: Zhao-zhong Su, Swadesh K. Das, C. Prévost, Paul B. Fisher, H. Aissaoui, H. Boukerche, H. Hirbec, Devanand Sarkar, Virginia Commonwealth University (VCU), Hémostase, Inflammation et sepsis (EA 4609), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), 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 Hirbec, Hélène
Subjects: MAPK/ERK pathway, Transcriptional Activation, Cancer Research, mda-9/syntenin, Transcription, Genetic, Syntenins, PDZ domain, PDZ Domains, Biology, Article, Focal adhesion, 03 medical and health sciences, Gene Knockout Techniques, 0302 clinical medicine, Genetics, Humans, Point Mutation, NF-kB, Gene Silencing, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], RNA, Small Interfering, Protein kinase A, Molecular Biology, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Melanoma, src, 030304 developmental biology, Sequence Deletion, 0303 health sciences, NF-kappa B, NFKB1, Phosphoproteins, 3. Good health, Cell biology, Genes, src, 030220 oncology & carcinogenesis, Cancer cell, Immunology, Signal transduction, Proto-oncogene tyrosine-protein kinase Src
Abstract: International audience; The scaffolding postsynaptic density-95/disks large/zonula occludens-1 (PDZ) domain-containing protein melanoma differentiation associated gene-9 (MDA-9)/syntenin is a tandem PDZ protein overexpressed in human melanoma, and breast and gastric cancer cells. MDA-9/syntenin affects cancer cell motility and invasion through distinct biochemical and signaling pathways, including focal adhesion kinase and p38 mitogen-activated protein kinase (MAPK), resulting in activation of the nuclear factor (NF)-kappaB pathway. MDA-9/syntenin also promotes melanoma metastasis by activating c-Src, but how c-Src regulates NF-kappaB activation is unclear. Using a human melanoma model, we document that MDA-9/syntenin-c-Src interactions are positive regulators of NF-kappaB activation. Inhibition of c-Src by PP2 treatment, by blocking c-Src or mda-9/syntenin expression with small interfering RNA, or in c-Src (-/-) knockout cell lines, reduces NF-kappaB activation following overexpression of mda-9/syntenin or c-Src. Deletion or point mutations of the PDZ binding motif preventing MDA-9/syntenin association with c-Src reveals that both PDZ domains, with PDZ2 being the dominant module, are required for activating downstream signaling pathways, including p38 MAPK and NF-kappaB. We also document that MDA-9/syntenin-c-Src complexes functionally cooperate with NF-kappaB to promote anchorage-independent growth, motility and invasion of melanoma cells. These findings underscore PDZ domains of MDA-9/syntenin as promising potential therapeutic targets for intervening in a decisive component of cancer progression, namely, metastatic tumor spread.
Published: 2010

45. TRPM1 Is Mutated in Patients with Autosomal-Recessive Complete Congenital Stationary Night Blindness

Author: Xavier Guillonneau, Veselina Moskova-Doumanova, Marie-Elise Lancelot, Kinga M. Bujakowska, José-Alain Sahel, Samuel G. Jacobson, Elfride De Baere, Daniel F. Schorderet, Sabine Defoort-Dhellemmes, Christina Zeitz, Agnes B. Renner, Wolfgang Berger, Aline Antonio, Isabelle Audo, Susanne Kohl, Saddek Mohand-Said, Bart P. Leroy, Markus N. Preising, Antje Bernd, Charlotte M. Poloschek, Bernd Wissinger, Eberhart Zrenner, Christian P. Hamel, Ulrich Kellner, Emeline F. Nandrot, Birgit Lorenz, Francis L. Munier, Thierry Léveillard, Isabelle Drumare, Shomi S. Bhattacharya, Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), Institute of Ophthalmology [London], University College of London [London] (UCL), Institute for Ophthalmic Research [Tübingen, Germany] (Centre for Ophthalmology), University of Tübingen, Center for Medical Genetics [Ghent], Ghent University Hospital, Universiteit Gent = Ghent University [Belgium] (UGENT), Fondation Asile des aveugles - Hôpital Ophtalmique Jules-Gonin [Lausanne], Ecole Polytechnique Fédérale de Lausanne (EPFL), University of Lausanne (UNIL), Justus-Liebig-University [Gießen, Germany], AugenZentrum Siegburg-MVZ ADTC Siegburg GmbH [Germany], University Medical Center of Regensburg [Regensburg, Germany], University Clinics Tuebingen [Germany], University of Freiburg [Freiburg], Neurosciences fonctionnelles et pathologies (NFP), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Hôpital Roger Salengro [Lille], 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 Saint-Éloi [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Universität Zürich [Zürich] = University of Zurich (UZH), University of Pennsylvania [Philadelphia], University of Zurich, Zeitz, C, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Universiteit Gent = Ghent University (UGENT), Université de Lausanne = University of Lausanne (UNIL), Justus-Liebig-Universität Gießen = Justus Liebig University (JLU), University of Pennsylvania, and Nandrot, Emeline
Subjects: Male, Candidate gene, Heterozygote, 2716 Genetics (clinical), Nonsense mutation, TRPM Cation Channels, Genes, Recessive, 610 Medicine & health, Biology, medicine.disease_cause, Nuclear Family, 03 medical and health sciences, 11124 Institute of Medical Molecular Genetics, 0302 clinical medicine, 1311 Genetics, Night Blindness, Night vision, Report, medicine, Electroretinography, Genetics, Missense mutation, Humans, Genetics(clinical), [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Genetics (clinical), TRPM1, 030304 developmental biology, Congenital stationary night blindness, 0303 health sciences, Mutation, medicine.diagnostic_test, Models, Genetic, Homozygote, Pedigree, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, 030221 ophthalmology & optometry, 570 Life sciences, biology, Female, sense organs
Abstract: International audience; Night vision requires signaling from rod photoreceptors to adjacent bipolar cells in the retina. Mutations in the genes NYX and GRM6, expressed in ON bipolar cells, lead to a disruption of the ON bipolar cell response. This dysfunction is present in patients with complete X-linked and autosomal-recessive congenital stationary night blindness (CSNB) and can be assessed by standard full-field electroretinography (ERG), showing severely reduced rod b-wave amplitude and slightly altered cone responses. Although many cases of complete CSNB (cCSNB) are caused by mutations in NYX and GRM6, in~60% of the patients the gene defect remains unknown. Animal models of human diseases are a good source for candidate genes, and we noted that a cCSNB phenotype present in homozygous Appaloosa horses is associated with downregulation of TRPM1. TRPM1, belonging to the family of transient receptor potential channels, is expressed in ON bipolar cells and therefore qualifies as an excellent candidate. Indeed, mutation analysis of 38 patients with CSNB identified ten unrelated cCSNB patients with 14 different mutations in this gene. The mutation spectrum comprises missense, splice-site, deletion, and nonsense mutations. We propose that the cCSNB phenotype in these patients is due to the absence of functional TRPM1 in retinal ON bipolar cells.
Published: 2009
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46. Pituitary adenylate cyclase-activating polypeptide inhibits food intake in mice through activation of the hypothalamic melanocortin system

Author: Isabelle Boutelet, Philippe Brabet, Patrice Bizet, Hubert Vaudry, Sylvie Jégou, Alain Fournier, Jean-Claude do Rego, Jean Costentin, Guillaume Gourcerol, Lourdes Mounien, Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), International Associated laboratory Samuel de Champlain, Institut National de la Recherche Scientifique [Québec] (INRS)-Université de Rouen Normandie (UNIROUEN), Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Centre National de la Recherche Scientifique (CNRS), Neuropsycho-pharmacologie expérimentale, Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Peptide Pharmacology, Institut National de la Recherche Scientifique [Québec] (INRS)-Université du Québec à Montréal = University of Québec in Montréal (UQAM), 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), Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement (Néovasc), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hamel, Christian, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Normandie Université (NU)
Subjects: Blood Glucose, Male, medicine.medical_specialty, endocrine system, Pro-Opiomelanocortin, Vasoactive intestinal peptide, Hypothalamus, Neuropeptide, Biology, Eating, Mice, 03 medical and health sciences, 0302 clinical medicine, Proopiomelanocortin, Melanocortin receptor, Internal medicine, medicine, Animals, Glucose homeostasis, Neuropeptide Y, Melanocyte-Stimulating Hormones, RNA, Messenger, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030304 developmental biology, Mice, Knockout, Neurons, Pharmacology, 0303 health sciences, Dose-Response Relationship, Drug, digestive, oral, and skin physiology, Arcuate Nucleus of Hypothalamus, Peptide Fragments, Psychiatry and Mental health, Pituitary adenylate cyclase-activating peptide, Endocrinology, biology.protein, Pituitary Adenylate Cyclase-Activating Polypeptide, Receptor, Melanocortin, Type 4, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Melanocortin, Corticosterone, 030217 neurology & neurosurgery, hormones, hormone substitutes, and hormone antagonists, Receptor, Melanocortin, Type 3, Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I, Vasoactive Intestinal Peptide
Abstract: International audience; Pituitary adenylate cyclase-activating polypeptide (PACAP) and the proopiomelanocortin (POMC)-derived peptide, alpha-melanocyte-stimulating hormone (alpha-MSH), exert anorexigenic activities. While alpha-MSH is known to inhibit food intake and stimulate catabolism via activation of the central melanocortin-receptor MC4-R, little is known regarding the mechanism by which PACAP inhibits food consumption. We have recently found that, in the arcuate nucleus of the hypothalamus, a high proportion of POMC neurons express PACAP receptors. This observation led us to investigate whether PACAP may inhibit food intake through a POMC-dependent mechanism. In mice deprived of food for 18 h, intracerebroventricular administration of PACAP significantly reduced food intake after 30 min, and this effect was reversed by the PACAP antagonist PACAP6-38. In contrast, vasoactive intestinal polypeptide did not affect feeding behavior. Pretreatment with the MC3-R/MC4-R antagonist SHU9119 significantly reduced the effect of PACAP on food consumption. Central administration of PACAP induced c-Fos mRNA expression and increased the proportion of POMC neuron-expressing c-Fos mRNA in the arcuate nucleus. Furthermore, PACAP provoked an increase in POMC and MC4-R mRNA expression in the hypothalamus, while MC3-R mRNA level was not affected. POMC mRNA level in the arcuate nucleus of PACAP-specific receptor (PAC1-R) knock-out mice was reduced as compared with wild-type animals. Finally, i.c.v. injection of PACAP provoked a significant increase in plasma glucose level. Altogether, these results indicate that PACAP, acting through PAC1-R, may inhibit food intake via a melanocortin-dependent pathway. These data also suggest a central action of PACAP in the control of glucose metabolism.
Published: 2009

47. Allylnitrile metabolism by CYP2E1 and other CYPs leads to distinct lethal and vestibulotoxic effects in the mouse

Author: Sandra Saldaña-Ruíz, Christian Chabbert, Pere Boadas-Vaello, Eric Jover, Jordi Llorens, Josep M. Bayona, Carla Soler-Martín, Hamel, Christian, Departament de Ciencies Fisiologiques II, Universitat de Barcelona (UB), Departament de Química Ambiental, Institut de Diagnòstic Ambiental i Estudis de l'Aigua ? CSIC, 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 Universitat de Barcelona
Subjects: MESH: Epoxy Compounds, Equilibrium (Physiology), MESH: Solvents, MESH: Aryl Hydrocarbon Hydroxylases, Pharmacology, Toxicology, MESH: Mice, Knockout, MESH: Dose-Response Relationship, Drug, Cytochrome P-450 CYP2A6, Hydroxylation, Mice, chemistry.chemical_compound, MESH: Acetone, 0302 clinical medicine, Cytochrome P-450 Enzyme System, Ear diseases, MESH: Allyl Compounds, MESH: Behavior, Animal, Cytochrome P-450 Enzyme Inhibitors, MESH: Animals, Enzyme Inhibitors, Mice, Knockout, 0303 health sciences, Behavior, Animal, MESH: Indicators and Reagents, Cytochrome P-450 CYP2E1, CYP2E1, MESH: Nitriles, 3. Good health, Allyl Compounds, Cytochrome P-450 CYP2E1 Inhibitors, Nitrils, Vestibular Diseases, Biochemistry, MESH: Enzyme Inhibitors, Toxicity, MESH: Cytochrome P-450 Enzyme System, Vertigo, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Aryl Hydrocarbon Hydroxylases, Vestibule, Labyrinth, MESH: Vestibular Diseases, Nitrile, medicine.drug, Equilibri (Fisiologia), CYP2A5, Cyanide, MESH: Vestibular Function Tests, Vestibular toxicity, Acetone, Productes químics, 03 medical and health sciences, Ototoxicity, MESH: Cyanides, Nitriles, medicine, Animals, Toxicologia, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cytochrome P450 Family 2, Chemical products, MESH: Mice, 030304 developmental biology, Cyanides, Dose-Response Relationship, Drug, Methoxsalen, Vertigen, Metabolism, Vestibular Function Tests, medicine.disease, Xenobiotic metabolism, chemistry, Malalties de l'orella, MESH: Cytochrome P-450 CYP2E1, Solvents, Epoxy Compounds, Indicators and Reagents, MESH: Vestibule, Labyrinth, 030217 neurology & neurosurgery, Drug metabolism
Abstract: 12 pages, 9 figures, 1 table.-- PMID: 18990727 [PubMed]., This study addressed the hypothesis that the vestibular or lethal toxicities of allylnitrile depend on CYP2E1-mediated bioactivation. Wild-type (129S1) and CYP2E1-null male mice were exposed to allylnitrile at doses of 0, 0.5, 0.75, or 1.0 mmol/kg (po), following exposure to drinking water with 0 or 1% acetone, which induces CYP2E1 expression. Induction of CYP2E1 activity by acetone in 129S1 mice and lack of activity in null mice was confirmed in liver microsomes. Vestibular toxicity was assessed using a behavioral test battery and illustrated by scanning electron microscopy observation of the sensory epithelia. In parallel groups, concentrations of allylnitrile and cyanide were assessed in blood after exposure to 0.75 mmol/kg of allylnitrile. Following allylnitrile exposure, mortality was lower in CYP2E1-null than in 129S1 mice, and increased after acetone pretreatment only in 129S1 mice. This increase was associated with higher blood concentrations of cyanide. In contrast, no consistent differences were recorded in vestibular toxicity between 129S1 and CYP2E1-null mice, and between animals pretreated with acetone or not. Additional experiments evaluated the effect on the toxicity of 1.0 mmol/kg allylnitrile of the nonselective P450 inhibitor, 1-aminobenzotriazole, the CYP2E1-inhibitor, diallylsulfide, and the CYP2A5 inhibitor, methoxsalen. In 129S1 mice, aminobenzotriazole decreased both mortality and vestibular toxicity, whereas diallylsulfide decreased mortality only. In CYP2E1-null mice, aminobenzotriazole and methoxsalen, but not diallylsulfide, blocked allylnitrile-induced vestibular toxicity. We conclude that CYP2E1-mediated metabolism of allylnitrile leads to cyanide release and acute mortality, probably through alpha-carbon hydroxylation, and hypothesize that epoxidation of the beta-gamma double bond by CYP2A5 mediates vestibular toxicity., Ministry of Science and Innovation (Spain)/Fondo Europeo de Desarrollo Regional (European Union) (grant numbers BFU2006-00343/BFI, CGL2005-02846/BOS); Generalitat of Catalonia (grant number 2005SGR00022); and Centre National d'Etudes Spatiales (France) (grant number DAR2006/2007).
Published: 2009

48. Reliability and complications of 500 consecutive cochlear implantations

Author: Françoise Artières, Alain Uziel, Ann Levi, Jean Pierre Piron, Michel Mondain, Frédéric Venail, Marielle Sicard, 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 ORL, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier], and Hamel, Christian
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, medicine.medical_treatment, Deafness, Young Adult, 03 medical and health sciences, Postoperative Complications, 0302 clinical medicine, Cochlear implant, Humans, Medicine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Child, 030223 otorhinolaryngology, Survival rate, Aged, Retrospective Studies, Aged, 80 and over, Palsy, business.industry, Incidence (epidemiology), Infant, Retrospective cohort study, General Medicine, Middle Aged, medicine.disease, Cochlear Implantation, Facial paralysis, 3. Good health, Surgery, Cochlear Implants, Otorhinolaryngology, Child, Preschool, Equipment Failure, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], business, Complication, Meningitis, 030217 neurology & neurosurgery
Abstract: International audience; OBJECTIVES: To assess device failures as well as early postoperative, late postoperative, and medical complications occurring after cochlear implantation and to discuss their causes and treatments. Study DESIGN: Retrospective study of 500 consecutive cochlear implantations. SETTING: Tertiary referral center. PATIENTS: All patients receiving cochlear implants at our institution between 1989 and 2006. MAIN OUTCOME MEASURES: All complications and treatments were systematically reviewed with a maximum follow-up of 18 years. The number of reimplantations was calculated according to follow-up duration to determine the cochlear implant survival rate. Specific risks of reimplantation were calculated for groups with differing durations of implantation. RESULTS: The overall rate of complications was 16.0% (79 of 500), with minor complications accounting for 5.6%; major complications, 3.2%; and reimplantations, 7.2%. Reasons for revision surgery were device failure, infection, trauma, and "soft device failure" (failure despite normal results from integrity testing). Revision surgery was performed in 51 of the 500 cases (10.2%), and other complications were managed medically (28 of 500; 5.6%). The rate of hard and soft device failures was 6% (30 of 500). Seventy-two percent of reimplantations occurred within 5 years. The risk of severe infection (eventually requiring explantation) was 1.4% (7 of 500). There was 1 case of transient facial palsy following surgery (0.2%), and the incidence of postsurgical meningitis was 0. CONCLUSIONS: Cochlear implantation is a safe technique with a relatively low complication rate; however, certain complications may require specific attention to prevent or correct them.
Published: 2008

49. A mono-allelic bivalent chromatin domain controls tissue-specific imprinting at Grb10

Author: Stormy J. Chamberlain, Jean-Philippe Hugnot, Terry Magnuson, Robert Feil, Lionel A. Sanz, Jean Charles Sabourin, Amandine Henckel, Philippe Arnaud, Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Department of Genetics, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-Carolina Center for the Genome Sciences, 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), Hamel, Christian, Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), The University of North Carolina at Chapel Hill-Carolina Center for the Genome Sciences, 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)-Université de Montpellier (UM)
Subjects: Male, Cellular differentiation, GRB10 Adaptor Protein, MESH: Neurons, MESH : Promoter Regions, Genetic, MESH: Mice, Knockout, Histones, Mice, 0302 clinical medicine, MESH : Embryo, Mammalian, MESH : Female, MESH: Animals, Imprinting (psychology), Promoter Regions, Genetic, MESH: CpG Islands, Cells, Cultured, Genetics, Mice, Knockout, Neurons, MESH: Histones, 0303 health sciences, biology, MESH : Chromatin, General Neuroscience, Stem Cells, Polycomb Repressive Complex 2, Brain, MESH : GRB10 Adaptor Protein, Cell Differentiation, MESH : CpG Islands, Chromatin, Histone, MESH: Repressor Proteins, MESH : Stem Cells, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH : Repressor Proteins, MESH : Cell Differentiation, Bivalent chromatin, MESH: Cells, Cultured, MESH: Cell Differentiation, MESH : Male, MESH : Mice, Inbred C57BL, MESH: Stem Cells, General Biochemistry, Genetics and Molecular Biology, Bivalent (genetics), Article, MESH : Neurons, MESH: Chromatin, 03 medical and health sciences, Genomic Imprinting, MESH: Brain, MESH: Mice, Inbred C57BL, MESH : Mice, MESH : Cells, Cultured, MESH: Promoter Regions, Genetic, Animals, MESH : Histones, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Molecular Biology, Gene, MESH: Mice, Alleles, 030304 developmental biology, General Immunology and Microbiology, MESH: Alleles, MESH: Embryo, Mammalian, MESH : Genomic Imprinting, Embryo, Mammalian, MESH: Male, MESH: Genomic Imprinting, Mice, Inbred C57BL, Repressor Proteins, MESH: GRB10 Adaptor Protein, MESH : Brain, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], biology.protein, MESH : Mice, Knockout, CpG Islands, MESH : Animals, Genomic imprinting, MESH : Alleles, MESH: Female, 030217 neurology & neurosurgery
Abstract: International audience; Genomic imprinting is a developmental mechanism that mediates parent-of-origin-specific expression in a subset of genes. How the tissue specificity of imprinted gene expression is controlled remains poorly understood. As a model to address this question, we studied Grb10, a gene that displays brain-specific expression from the paternal chromosome. Here, we show in the mouse that the paternal promoter region is marked by allelic bivalent chromatin enriched in both H3K4me2 and H3K27me3, from early embryonic stages onwards. This is maintained in all somatic tissues, but brain. The bivalent domain is resolved upon neural commitment, during the developmental window in which paternal expression is activated. Our data indicate that bivalent chromatin, in combination with neuronal factors, controls the paternal expression of Grb10 in brain. This finding highlights a novel mechanism to control tissue-specific imprinting.
Published: 2008

50. Cochlear stem/progenitor cells from a postnatal cochlea respond to Jagged1 and demonstrate that notch signaling promotes sphere formation and sensory potential

Author: Thomas R. Van De Water, Julien Santo, Jean Charles Sabourin, Alain Uziel, Jean-Philippe Hugnot, Azel Zine, Christian Chabbert, Etienne Savary, 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 de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), University of Miami Ear Institute, University of Miami Leonard M. Miller School of Medicine (UMMSM)-University of Miami [Coral Gables], Service ORL, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier], and Hamel, Christian
Subjects: MESH: Signal Transduction, Embryology, MESH: Calcium-Binding Proteins, MESH: Recombinant Proteins, Mice, 0302 clinical medicine, Myosin, MESH: Cochlea, Serrate-Jagged Proteins, MESH: Animals, Cells, Cultured, 0303 health sciences, education.field_of_study, Receptors, Notch, Stem Cells, Cell Differentiation, Recombinant Proteins, Cochlea, Cell biology, Endothelial stem cell, medicine.anatomical_structure, Intercellular Signaling Peptides and Proteins, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Hair cell, MESH: Membrane Proteins, Signal Transduction, Adult stem cell, MESH: Cells, Cultured, MESH: Cell Differentiation, Population, Notch signaling pathway, MESH: Stem Cells, Biology, 03 medical and health sciences, medicine, otorhinolaryngologic diseases, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Progenitor cell, education, MESH: Intercellular Signaling Peptides and Proteins, MESH: Mice, 030304 developmental biology, Calcium-Binding Proteins, Membrane Proteins, Immunology, sense organs, MESH: Receptors, Notch, Jagged-1 Protein, 030217 neurology & neurosurgery, Developmental Biology
Abstract: International audience; Hair cells and supporting cells of the mammalian cochlea terminally differentiate during development. Recent in vitro evidence suggests the presence of hair cell progenitors in the postnatal cochlea. Phenotypic properties of these cells and factors that promote their ability to generate spheres in aggregate cultures have not been reported. We define an in vitro system that allows stem/progenitor cells harvested from the early postnatal cochlea to develop into spheres. These spheres contain Abcg2, Jagged1 and Notch1 positive progenitor cells that can divide and generate new hair cell-like cells, i.e. immunopositive for specific hair cell markers, including Myosin VI, Myosin VIIa, Math1 and ability to uptake FM1-43. We demonstrate that reducing Notch signaling with a gamma secretase inhibitor decreases the number of spheres generated following treatment of the stem/progenitor cell cultures. Additionally, activation of Notch by an exogenous soluble form of a Notch ligand, i.e. Jagged1 protein, promotes sphere formation and the sensory potential of cochlear stem/progenitor cells. Our findings suggest that Notch1/Jagged1 signaling plays a role in maintaining a population of Abcg2 sensory stem/progenitor cells in the postnatal cochlea.
Published: 2008

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