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1. Early movement restriction leads to maladaptive plasticity in the sensorimotor cortex and to movement disorders

Author: Delcour, Maxime, Russier, Michaël, Castets, Francis, Turle-Lorenzo, Nathalie, Canu, Marie-Hélène, Cayetanot, Florence, Barbe, Mary, Coq, Jacques-Olivier, Neurosciences sensorielles et cognitives (NSC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), 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), Aix Marseille Université (AMU), Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369 - ULR 4488 (URePSSS), Université d'Artois (UA)-Université de Lille-Université du Littoral Côte d'Opale (ULCO), Temple University [Philadelphia], Pennsylvania Commonwealth System of Higher Education (PCSHE), Gestionnaire, Hal Sorbonne Université, Université de Montréal (UdeM), Unité de Neurobiologie des canaux Ioniques et de la Synapse (UNIS - Inserm U1072), Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Université d'Artois (UA)-Université du Littoral Côte d'Opale (ULCO)-Université de Lille, Institut de Neurosciences de la Timone (INT), Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Neurophysiologie Respiratoire Expérimentale et Clinique, Université de Montréal [Montréal], Activité Physique, Muscle, Santé (EA4488), Université de Lille, Droit et Santé, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurobiologie intégrative et adaptative (NIA), Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique (CNRS), Univ. Littoral Côte d’Opale, Univ. Artois, Université de Lille, Laboratoire de Neurosciences intégratives et adaptatives [LNIA], Neurobiologie des Canaux Ioniques, Centre de recherche en neurobiologie - neurophysiologie de Marseille [CRN2M], Aix Marseille Université [AMU], Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369 - ULR 4488 [URePSSS], Institut de Neurosciences de la Timone [INT], and Dpt of Anatomy and Cell Biology [Oklahoma]
Subjects: Male, Neurons, Principal Component Analysis, Movement Disorders, Neuronal Plasticity, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Developmental disorders, Neurodevelopmental disorders, lcsh:R, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, lcsh:Medicine, Adaptation, Physiological, Article, Rats, [SDV] Life Sciences [q-bio], Hindlimb Suspension, Animals, Female, lcsh:Q, Sensorimotor Cortex, lcsh:Science, ComputingMilieux_MISCELLANEOUS
Abstract: International audience; Motor control and body representations in the central nervous system are built, i.e., patterned, during development by sensorimotor experience and somatosensory feedback/reafference. Yet, early emergence of locomotor disorders remains a matter of debate, especially in the absence of brain damage. For instance, children with developmental coordination disorders (DCD) display deficits in planning, executing and controlling movements, concomitant with deficits in executive functions. Thus, are early sensorimotor atypicalities at the origin of long-lasting abnormal development of brain anatomy and functions? We hypothesize that degraded locomotor outcomes in adulthood originate as a consequence of early atypical sensorimotor experiences that induce developmental disorganization of sensorimotor circuitry. We showed recently that postnatal sensorimotor restriction (SMR), through hind limb immobilization from birth to one month, led to enduring digitigrade locomotion with ankle-knee overextension, degraded musculoskeletal tissues (e.g., gastrocnemius atrophy), and clear signs of spinal hyperreflexia in adult rats, suggestive of spasticity; each individual disorder likely interplaying in self-perpetuating cycles. In the present study, we investigated the impact of postnatal SMR on the anatomical and functional organization of hind limb representations in the sensorimotor cortex and processes representative of maladaptive neuroplasticity. We found that 28 days of daily SMR degraded the topographical organization of somatosensory hind limb maps, reduced both somatosensory and motor map areas devoted to the hind limb representation and altered neuronal response properties in the sensorimotor cortex several weeks after the cessation of SMR. We found no neuroanatomical histopathology in hind limb sensorimotor cortex, yet increased glutamatergic neurotransmission that matched clear signs of spasticity and hyperexcitability in the adult lumbar spinal network. Thus, even in the absence of a brain insult, movement disorders and brain dysfunction can emerge as a consequence of reduced and atypical patterns of motor outputs and somatosensory feedback that induce maladaptive neuroplasticity. Our results may contribute to understanding the inception and mechanisms underlying neurodevelopmental disorders, such as DCD.
Published: 2018

2. Sleep quality and emotional reactivity cluster in bipolar disorders and impact on functioning

Author: Etain, B., Godin, O., Boudebesse, C., Aubin, V., Azorin, M., Bellivier, F., Bougerol, T., Courtet, P., Gard, S., Kahn, J.P., Passerieux, C., Collaborators, Face-Bd, Leboyer, M., Henry, C., Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Fondation FondaMental [Créteil], 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), Biomécanique cellulaire et respiratoire (BCR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Pôle de Psychiatrie [Hôpital Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital H. Mondor - A. Chenevier, Hôpital Princesse Grace [Monaco], Département Universitaire de Psychiatrie - [Hôpital Sainte Marguerite - APHM] (Hôpitaux Sud), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), 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), CHU Grenoble, Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre hospitalier Charles Perrens [Bordeaux], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Université de Lorraine (UL), Centre Hospitalier de Versailles André Mignot (CHV), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Variabilité de réponse aux psychotropes ( VariaPsy - U1144 ), Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ), Institut Pierre Louis d'Epidémiologie et de Santé Publique ( iPLESP ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Biomécanique cellulaire et respiratoire ( BCR ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital H. Mondor - A. Chenevier, Département Universitaire de Psychiatrie - [Hôpital Sainte Marguerite - APHM] ( Hôpitaux Sud ), Hôpital Sainte-Marguerite [CHU - APHM] ( Hôpitaux Sud ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Aix Marseille Université ( AMU ), 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 ), Neuropsychiatrie : recherche épidémiologique et clinique, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Hôpital Charles Perrens, Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Université de Lorraine ( UL ), Centre Hospitalier de Versailles (CHV), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud )-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Optimisation Thérapeutique en Neuropsychopharmacologie (VariaPsy - U1144), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital H. Mondor - A. Chenevier
Subjects: Adult, Male, Sleep Wake Disorders, medicine.medical_specialty, Bipolar disorder, [ SDV.MHEP.PSM ] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, 03 medical and health sciences, 0302 clinical medicine, Cluster analysis, Internal medicine, Sleep Initiation and Maintenance Disorders, medicine, Humans, Functioning, Reactivity (psychology), Sleep quality, Middle Aged, medicine.disease, Emotional dysregulation, Sleep in non-human animals, 030227 psychiatry, Poor sleep, Psychiatry and Mental health, Affect, Mood, Emotional reactivity, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Impulsive Behavior, Female, France, Psychology, Arousal, Sleep, 030217 neurology & neurosurgery, Stress, Psychological, Clinical psychology
Abstract: Objective:Bipolar disorders (BD) are characterized by sleep disturbances and emotional dysregulation both during acute episodes and remission periods. We hypothesized that sleep quality (SQ) and emotional reactivity (ER) defined clusters of patients with no or abnormal SQ and ER and we studied the association with functioning.Method:We performed a bi-dimensional cluster analysis using SQ and ER measures in a sample of 533 outpatients patients with BD (in remission or with subsyndromal mood symptoms). Clusters were compared for mood symptoms, sleep profile and functioning.Results:We identified three clusters of patients: C1 (normal ER and SQ, 54%), C2 (hypo-ER and low SQ, 22%) and C3 (hyper-ER and low SQ, 24%). C1 was characterized by minimal mood symptoms, better sleep profile and higher functioning than other clusters. Although highly different for ER, C2 and C3 had similar levels of subsyndromal mood symptoms as assessed using classical mood scales. When exploring sleep domains, C2 showed poor sleep efficiency and a trend for longer sleep latency as compared to C3. Interestingly, alterations in functioning were similar in C2 and C3, with no difference in any of the sub-domains.Conclusion:Abnormalities in ER and SQ delineated three clusters of patients with BD and significantly impacted on functioning.
Published: 2017

3. Affinity biosensors using recombinant native membrane proteins displayed on exosomes: application to botulinum neurotoxin B receptor

Author: Desplantes, Richard, Lévêque, Christian, Muller, Benjamin, Lotierzo, Manuela, Ferracci, Géraldine, Popoff, Michel, Seagar, Michael, Mamoun, Robert, El Far, Oussama, Unité de Neurobiologie des canaux Ioniques et de la Synapse (UNIS - Inserm U1072), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ciloa [Montpellier] (Cc90), Université Montpellier 2 - Sciences et Techniques (UM2), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Bactéries anaérobies et Toxines, Institut Pasteur [Paris], Institut Pasteur [Paris] (IP), Unité de Neurobiologie des canaux Ioniques et de la Synapse ( UNIS - Inserm U1072 ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Ciloa [Montpellier] ( Cc90 ), Université Montpellier 2 - Sciences et Techniques ( UM2 ), Centre de recherche en neurobiologie - neurophysiologie de Marseille ( CRN2M ), and El Far, Oussama
Subjects: Receptors, CXCR4, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Protein Conformation, Science, [ SDV.BIO ] Life Sciences [q-bio]/Biotechnology, Membrane Proteins, Biosensing Techniques, Exosomes, Protein Engineering, Article, Recombinant Proteins, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Synaptotagmin II, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Kv1.2 Potassium Channel, Medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Botulinum Toxins, Type A, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology
Abstract: Supplementary information accompanies this paper at doi : 10.1038/s41598-017-01198-1.; International audience; The development of simple molecular assays with membrane protein receptors in a native conformation still represents a challenging task. Exosomes are extracellular vesicles which, due to their stability and small size, are suited for analysis in various assay formats. Here, we describe a novel approach to sort recombinant fully native and functional membrane proteins to exosomes using a targeting peptide. Specific binding of high affinity ligands to the potassium channel Kv1.2, the G-protein coupled receptor CXCR4, and the botulinum neurotoxin type B (BoNT/B) receptor, indicated their correct assembly and outside out orientation in exosomes. We then developed, using a label-free optical biosensor, a new method to determine the kinetic constants of BoNT/B holotoxin binding to its receptor synaptotagmin2/GT1b ganglioside (k on = 2.3 ×10 5 M −1 .s −1 , k off = 1.3 10 −4 s −1), yielding an affinity constant (K D = 0.6 nM) similar to values determined from native tissue. In addition, the recombinant binding domain of BoNT/B, a potential vector for neuronal delivery, bound quasi-irreversibly to synaptotagmin 2/GT1b exosomes. Engineered exosomes provide thus a novel means to study membrane proteins for biotechnology and clinical applications. Determination of the binding kinetics of analytes is potentially extremely useful for drug development and assay validation. In principle, purified endogenous or recombinant membrane proteins can be integrated into a lipid environment, such as proteoliposomes, supported lipid bilayers or nanodiscs. However, this approach is not ideal, due to the fact that membrane proteins are difficult to produce, prone to denaturation and do not always retain their functional integrity in artificial lipid bilayers 1, 2. Exosomes are extracellular vesicles, produced by many cell types and can be detected or purified using anti-bodies 3, 4. Furthermore, the ability of exosomes to carry molecules from native or engineered parental cells and fuse with recipient cells to deliver their cargo, confers considerable biomedical potential 5, 6. Unlike intra-cellular vesicles, exosomes display homogeneous topology in which plasma membrane proteins have the same outside-out orientation as at the surface of intact cells. Moreover, exosomes can potentially provide the means of expressing recombinant proteins in small membrane vesicles that can be used as vaccine strategies 7, 8. Our principal aim was to develop a general approach to address recombinant membrane proteins to exosomes, using a specific targeting sequence to direct exosomal sorting of a set of membrane drug targets, with a particular focus on the botulinum neurotoxin/B (BoNT/B) receptor. BoNT serotypes A, B and E (BoNT/A, BoNT/B, BoNT/E), produced by the bacteria Clostridium botulinum are the main cause of human botulism and are produced as a complex of holotoxin (MW 150 000 Da) and several nontoxic proteins. Although BoNTs are among the most neurotoxic substances known, their ability to reversibly block cholinergic nerves has provided the basis 1 INSERM
Published: 2017

4. Use of LDL receptor-targeting peptide vectors for in vitro and in vivo cargo transport across the blood-brain barrier

Author: Molino, Yves, David, Marion, Varini, Karine, Jabès, Françoise, Gaudin, Nicolas, Fortoul, Aude, Bakloul, Karima, Masse, Maxime, Bernard, Anne, Drobecq, Lucile, Lécorché, Pascaline, Temsamani, Jamal, Jacquot, Guillaume, Khrestchatisky, Michel, Vect-Horus, Département génie civil et batiment ( DGCB ), ENTP, centre Lyonnais d'Acoustique ( CeLyA ), Université de Lyon, 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 ), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN ( NICN ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -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 ) -Université de la Méditerranée - Aix-Marseille 2, Département génie civil et batiment (DGCB), centre Lyonnais d'Acoustique (CeLyA), 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), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UMR_S567 / UMR 8104), 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)-Université de la Méditerranée - Aix-Marseille 2, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS)
Subjects: CNS drug delivery, [ SDV ] Life Sciences [q-bio], intracellular trafficking, [SDV]Life Sciences [q-bio], lysosome, receptor-mediated transcytosis, lipids (amino acids, peptides, and proteins), endosome
Abstract: International audience; The blood-brain barrier (BBB) prevents the entry of many drugs into the brain and, thus, is a major obstacle in the treatment of CNS diseases. There is some evidence that the LDL receptor (LDLR) is expressed at the BBB and may participate in the transport of endogenous ligands from blood to brain, a process referred to as receptor-mediated transcytosis. We previously described a family of peptide vectors that were developed to target the LDLR. In the present study, in vitro BBB models that were derived from either wild-type and LDLR knockout animals (ldlr(-/-)) were used to validate the specific LDLR-dependent transcytosis of LDL via a nondegradative route. We next showed that LDLR-targeting peptide vectors, whether in fusion or chemically conjugated to an Ab Fc fragment, promote binding to apical LDLR and transendothelial transfer of the Fc fragment across BBB monolayers via the same route as LDL. Finally, we demonstrated in vivo that LDLR significantly contributes to the brain uptake of vectorized Fc. We thus provide further evidence that LDLR is a relevant receptor for CNS drug delivery via receptor-mediated transcytosis and that the peptide vectors we developed have the potential to transport drugs, including proteins or Ab based, across the BBB.-Molino, Y., David, M., Varini, K., Jabès, F., Gaudin, N., Fortoul, A., Bakloul, K., Masse, M., Bernard, A., Drobecq, L., Lécorché, P., Temsamani, J., Jacquot, G., Khrestchatisky, M. Use of LDL receptor-targeting peptide vectors for in vitro and in vivo cargo transport across the blood-brain barrier.
Published: 2017

5. Genome-wide association studies with proteomics data reveal genes important for synthesis, transport and packaging of globulins in legume seeds

Author: Christine Le Signor, Julia Buitink, Valérie Labas, Jean Marie Prosperi, Delphine Aime, Jérôme Gouzy, Judith Burstin, Olivier Leprince, Karine Gallardo, Richard D. Thompson, Nevin D. Young, Amandine Bordat, Maya Belghazi, Agroécologie [Dijon], Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université Bourgogne Franche-Comté [COMUE] (UBFC), Biologie du fruit et pathologie (BFP), Université Sciences et Technologies - Bordeaux 1-Institut National de la Recherche Agronomique (INRA)-Université Bordeaux Segalen - Bordeaux 2, 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), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), Laboratoire des interactions plantes micro-organismes (LIPM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Department of Plant Pathology, Cornell University, Amélioration génétique et adaptation des plantes méditerranéennes et tropicales (UMR AGAP), Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro), Institut de Recherche en Horticulture et Semences (IRHS), Université d'Angers (UA)-Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, French National Research Agency : ANR-06-GPLA-0008, ANR-09-GENM-026, Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université Bourgogne Franche-Comté ( UBFC ), Biologie du fruit et pathologie ( BFP ), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique ( INRA ) -Université Sciences et Technologies - Bordeaux 1, 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 ), Physiologie de la reproduction et des comportements [Nouzilly] ( PRC ), Institut National de la Recherche Agronomique ( INRA ) -Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique ( CNRS ), Interactions plantes-microorganismes et santé végétale, Institut National de la Recherche Agronomique ( INRA ) -Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Amélioration génétique et adaptation des plantes méditerranéennes et tropicales ( UMR AGAP ), Institut national de la recherche agronomique [Montpellier] ( INRA Montpellier ) -Centre international d'études supérieures en sciences agronomiques ( Montpellier SupAgro ) -Centre de Coopération Internationale en Recherche Agronomique pour le Développement ( CIRAD ) -Institut national d’études supérieures agronomiques de Montpellier ( Montpellier SupAgro ), Institut de Recherche en Horticulture et Semences ( IRHS ), Université d'Angers ( UA ) -Institut National de la Recherche Agronomique ( INRA ) -AGROCAMPUS OUEST, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1 (UB), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Cornell University [New York], Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1, Université de Bourgogne (UB)-Institut National de la Recherche Agronomique (INRA)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de la Recherche Agronomique (INRA)-Université d'Angers (UA), Université Sciences et Technologies - Bordeaux 1-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA), and Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Proteomics, [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Candidate gene, [ SDV.BV ] Life Sciences [q-bio]/Vegetal Biology, protein quantity loci (PQL), Globulin, Physiology, legumes, Plant Science, Chromatin remodeling, 03 medical and health sciences, Gene Expression Regulation, Plant, Botany, Medicago truncatula, genome-wide association studies (GWAS), vegetable, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Electrophoresis, Gel, Two-Dimensional, Gene Regulatory Networks, Gene, Transcription factor, [ SDV.SA ] Life Sciences [q-bio]/Agricultural sciences, Plant Proteins, 2. Zero hunger, Genetics, seed proteome, amélioration génétique, biology, Pisum sativum (pea), Seed Storage Proteins, Peas, food and beverages, légume, biology.organism_classification, Protein Transport, 030104 developmental biology, Vicilin, Mutation, Seeds, biology.protein, qualité des semences, semence, globulins, Genome-Wide Association Study, Transcription Factors
Abstract: AGAP : équipe GE2pop; Improving nutritional seed quality is an important challenge in grain legume breeding. However, the genes controlling the differential accumulation of globulins, which are major contributors to seed nutritional value in legumes, remain largely unknown. We combined a search for protein quantity loci with genome-wide association studies on the abundance of 7S and 11S globulins in seeds of the model legume species Medicago truncatula. Identified genomic regions and genes carrying polymorphisms linked to globulin variations were then cross-compared with pea (Pisum sativum), leading to the identification of candidate genes for the regulation of globulin abundance in this crop. Key candidates identified include genes involved in transcription, chromatin remodeling, post-translational modifications, transport and targeting of proteins to storage vacuoles. Inference of a gene coexpression network of 12 candidate transcription factors and globulin genes revealed the transcription factor ABA-insensitive 5 (ABI5) as a highly connected hub. Characterization of loss-of-function abi5 mutants in pea uncovered a role for ABI5 in controlling the relative abundance of vicilin, a sulfur-poor 7S globulin, in pea seeds. This demonstrates the feasibility of using genome-wide association studies in M. truncatula to reveal genes that can be modulated to improve seed nutritional value.
Published: 2017

6. Optimization and in Vivo Validation of Peptide Vectors Targeting the LDL Receptor

Author: Nicolas Gaudin, Géraldine Ferracci, Jean-Daniel Malcor, Pascaline Lécorché, Mathieu Laurencin, Cedric Malicet, Guillaume Jacquot, Salvatore Cisternino, Vincent Dive, Marion David, Karine Varini, Fanny Gassiot, Maxime Masse, Michel Khrestchatisky, Aude Faucon, Maria Smirnova, Karima Abouzid, Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Université Pierre et Marie Curie - Paris 6 (UPMC), Optimisation Thérapeutique en Neuropsychopharmacologie (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Stress Cellulaire, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Département génie civil et batiment (DGCB), ENTP, centre Lyonnais d'Acoustique (CeLyA), Université de Lyon, Observatoire astronomique de Strasbourg, Observatoire astronomique de Strasbourg (ObAS), Université de Strasbourg (UNISTRA)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO) (SIMoS), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Agence Nationale de la Recherche, Fonds Unique Interministériel, Association Nationale de la Recherche et de la Technologie, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Cochin ( UMR_S567 / UMR 8104 ), 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 Pierre et Marie Curie - Paris 6 ( UPMC ), Institut des Sciences Chimiques de Rennes ( ISCR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Ecole Nationale Supérieure de Chimie de Rennes-Institut National des Sciences Appliquées ( INSA ) -Centre National de la Recherche Scientifique ( CNRS ), Variabilité de réponse aux psychotropes ( VariaPsy - U1144 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ), 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 ), Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de génétique et de physiologie moléculaire et cellulaire ( CGPhiMC ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Département génie civil et batiment ( DGCB ), centre Lyonnais d'Acoustique ( CeLyA ), Observatoire astronomique de Strasbourg ( ObAS ), Université de Strasbourg ( UNISTRA ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'Ingénierie Moléculaire des Protéines ( SIMOPRO ), Département Médicaments et Technologies pour la Santé ( DMTS ), Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN ( NICN ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)
Subjects: 0301 basic medicine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Genetic Vectors, tissue distribution, Pharmaceutical Science, Peptide, CHO Cells, Biology, peptide vector, 03 medical and health sciences, Mice, Structure-Activity Relationship, 0302 clinical medicine, Cricetulus, Drug Delivery Systems, In vivo, Drug Discovery, Animals, LDLR knockout, Receptor, Peptide ligand, LDLR targeting, chemistry.chemical_classification, Mice, Knockout, medicinal chemistry based optimization, In vitro, Endocytosis, Peptide Fragments, Amino acid, High uptake, Mice, Inbred C57BL, 030104 developmental biology, chemistry, Biochemistry, Receptors, LDL, 030220 oncology & carcinogenesis, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, LDL receptor, Molecular Medicine
Abstract: International audience; Active targeting and delivery to pathophysiological organs of interest is of paramount importance to increase specific accumulation of therapeutic drugs or imaging agents while avoiding systemic side effects. We recently developed a family of new peptide ligands of the human and rodent LDL receptor (LDLR), an attractive cell-surface receptor with high uptake activity and local enrichment in several normal or pathological tissues (Malcor et al., J. Med. Chem. 2012, 55 (5), 2227). Initial chemical optimization of the 15-mer, all natural amino acid compound 1/VH411 (DSGL[CMPRLRGC]cDPR) and structure-activity relationship (SAR) investigation led to the cyclic 8 amino acid analogue compound 22/VH445 ([cMPRLRGC]c) which specifically binds hLDLR with a KD of 76 nM and has an in vitro blood half-life of ∼3 h. Further introduction of non-natural amino acids led to the identification of compound 60/VH4106 ([(d)-"Pen"M"Thz"RLRGC]c), which showed the highest KD value of 9 nM. However, this latter analogue displayed the lowest in vitro blood half-life (∼1.9 h). In the present study, we designed a new set of peptide analogues, namely, VH4127 to VH4131, with further improved biological properties. Detailed analysis of the hLDLR-binding kinetics of previous and new analogues showed that the latter all displayed very high on-rates, in the 10(6) s(-1.)M(-1) range, and off-rates varying from the low 10(-2) s(-1) to the 10(-1) s(-1) range. Furthermore, all these new analogues showed increased blood half-lives in vitro, reaching ∼7 and 10 h for VH4129 and VH4131, respectively. Interestingly, we demonstrate in cell-based assays using both VH445 and the most balanced optimized analogue VH4127 ([cM"Thz"RLRG"Pen"]c), showing a KD of 18 nM and a blood half-life of ∼4.3 h, that its higher on-rate correlated with a significant increase in both the extent of cell-surface binding to hLDLR and the endocytosis potential. Finally, intravenous injection of tritium-radiolabeled (3)H-VH4127 in wild-type or ldlr -/- mice confirmed their active LDLR targeting in vivo. Overall, this study extends our previous work toward a diversified portfolio of LDLR-targeted peptide vectors with validated LDLR-targeting potential in vivo.
Published: 2016

7. Legume adaptation to sulfur deficiency revealed by comparing nutrient allocation and seed traits inMedicago truncatula

Author: Charlène Tadla, Jean-Christophe Avice, Eric Vieren, Valérie Labas, Hélène Zuber, Daniel Wipf, Karine Gallardo, Raphaël Lugan, Christophe Salon, Delphine Aime, Christine Le Signor, Germain Poignavent, Julia Buitink, Maya Belghazi, Anne-Lise Santoni, Agroécologie [Dijon], Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut de biologie moléculaire des plantes ( IBMP ), Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ), 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 ), Physiologie de la reproduction et des comportements [Nouzilly] ( PRC ), Institut National de la Recherche Agronomique ( INRA ) -Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique ( CNRS ), Plate-forme d'Analyse Intégrative des Biomarqueurs, Institut National de la Recherche Agronomique ( INRA ), Institut de Recherche en Horticulture et Semences ( IRHS ), Université d'Angers ( UA ) -Institut National de la Recherche Agronomique ( INRA ) -AGROCAMPUS OUEST, Ecophysiologie Végétale, Agronomie et Nutritions ( EVA ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Recherche Agronomique ( INRA ), Regional Council of Burgundy 2009-9201AAO040S00680, SERAPIS project (Fonds Unique Interministeriel) F1209006E, Genoplante QualityLegSeed project GPLA06036G, Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut de biologie moléculaire des plantes (IBMP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), 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), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA), Institut de Recherche en Horticulture et Semences (IRHS), Université d'Angers (UA)-Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Ecophysiologie Végétale, Agronomie et Nutritions (EVA), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Recherche Agronomique (INRA), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Chlorophyll, 0106 biological sciences, [ SDV.BV ] Life Sciences [q-bio]/Vegetal Biology, nutrient allocation, Oligosaccharides, Plant Science, 01 natural sciences, chemistry.chemical_compound, Nutrient, Biomass, Legume, 2. Zero hunger, 0303 health sciences, biology, Sulfates, food and beverages, legume, Adaptation, Physiological, Medicago truncatula, Sulfate transport, medicado truncatula, sulfate transport, Phenotype, Organ Specificity, Germination, Seeds, Carbohydrate Metabolism, Oxidation-Reduction, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], Nitrogen, chemistry.chemical_element, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Models, Biological, sulfur deficiency, 03 medical and health sciences, Raffinose, seed composition, Genetics, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, RNA, Messenger, [ SDV.OT ] Life Sciences [q-bio]/Other [q-bio.OT], Sulfur dioxide, 030304 developmental biology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biological Transport, Cell Biology, 15. Life on land, biology.organism_classification, Sulfur, Carbon, Plant Leaves, germination, chemistry, Agronomy, Imbibition, 010606 plant biology & botany
Abstract: Reductions in sulfur dioxide emissions and the use of sulfur-free mineral fertilizers are decreasing soil sulfur levels and threaten the adequate fertilization of most crops. To provide knowledge regarding legume adaptation to sulfur restriction, we subjected Medicago truncatula, a model legume species, to sulfur deficiency at various developmental stages, and compared the yield, nutrient allocation and seed traits. This comparative analysis revealed that sulfur deficiency at the mid-vegetative stage decreased yield and altered the allocation of nitrogen and carbon to seeds, leading to reduced levels of major oligosaccharides in mature seeds, whose germination was dramatically affected. In contrast, during the reproductive period, sulfur deficiency had little influence on yield and nutrient allocation, but the seeds germinated slowly and were characterized by low levels of a biotinylated protein, a putative indicator of germination vigor that has not been previously related to sulfur nutrition. Significantly, plants deprived of sulfur at an intermediary stage (flowering) adapted well by remobilizing nutrients from source organs to seeds, ensuring adequate quantities of carbon and nitrogen in seeds. This efficient remobilization of photosynthates may be explained by vacuolar sulfate efflux to maintain leaf metabolism throughout reproductive growth, as suggested by transcript and metabolite profiling. The seeds from these plants, deprived of sulfur at the floral transition, contained normal levels of major oligosaccharides but their germination was delayed, consistent with low levels of sucrose and the glycolytic enzymes required to restart seed metabolism during imbibition. Overall, our findings provide an integrative view of the legume response to sulfur deficiency.
Published: 2013

8. Mechanosensory hair cells express two molecularly distinct mechanotransduction channels

Author: Nicolas Grillet, Bertrand Coste, Christopher L. Cunningham, Sarah Harkins-Perry, Ardem Patapoutian, Bo Zhao, Ulrich Müller, Robert Fettiplace, Zizhen Wu, Navid Zebarjadi, Maryline Beurg, Sanjeev S. Ranade, The Scripps Research institute (TSRI), The Scripps Research Institute, Chinese Academy of Agricultural Mechanization Sciences (CCCME), 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), Centre Interlangues - Texte, Image, Langage (TIL), Université de Bourgogne (UB), Neurophysiologie de la Synapse Auditive, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU de Bordeaux Pellegrin [Bordeaux]-Neuroscience Institute, Department of Neuroscience, Johns Hopkins University (JHU), The Scripps Research institute ( TSRI ), Chinese Academy of Agricultural Mechanization Sciences [Beijing], 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 ), Centre Interlangues - Texte, Image, Langage ( TIL ), Université de Bourgogne ( UB ), Université de Bordeaux ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU de Bordeaux Pellegrin [Bordeaux]-Neuroscience Institute, Institute of Geosciences, Goethe-University Frankfurt am Main, and The Scripps Research Institute [La Jolla, San Diego]
Subjects: 0301 basic medicine, Auditory perception, genetic structures, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Biology, Mechanotransduction, Cellular, Article, Stereocilia, 03 medical and health sciences, Hair Cells, Auditory, otorhinolaryngologic diseases, medicine, Animals, Mechanotransduction, Biological sciences, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, integumentary system, General Neuroscience, Membrane Proteins, Cell biology, 030104 developmental biology, medicine.anatomical_structure, Touch Perception, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Mutation, Calcium, sense organs, Hair cell, Neuroscience, Hair
Abstract: Auditory hair cells contain mechanotransduction channels that rapidly open in response to sound-induced vibrations. Surprisingly, we report here that auditory hair cells contain two molecularly distinct mechanotransduction channels. One ion channel is activated by sound and is responsible for sensory transduction. This sensory transduction channel is expressed in hair-cell stereocilia and previous studies show that its activity is affected by mutations in the genes encoding the transmembrane proteins TMHS/LHFPL5, TMIE and TMC1/2. We show here that the second ion channel is expressed at the apical surface of hair cells and contains the Piezo2 protein. The activity of the Piezo2-dependent channel is controlled by the intracellular Ca2+ concentration and can be recorded following disruption of the sensory transduction machinery or more generally by disruption of the sensory epithelium. We thus conclude that hair cells express two molecularly and functionally distinct mechanotransduction channels with different subcellular distribution.
Published: 2016

9. Contactin-Associated Protein 1 (CNTNAP1) Mutations Induce Characteristic Lesions of the Paranodal Region

Author: Alex Magee, Stéphane Mathis, Robert A. Ouvrier, Jean Michel Vallat, Laurent Magy, Yann Péréon, Bertrand Isidor, B. Cogne, Stephan Züchner, Laurence Richard, Mathilde Nizon, Jérôme Devaux, 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), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Limoges, Atlantic Gene Therapies, Centres de Référence des Canalopathies Musculaires et des Maladies Neuro-musculaires Paris-Est, Service de Neurologie [CHU Limoges], Service de Génétique, 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), John P. Hussman Institute for Human Genomics, University of Miami Leonard M. Miller School of Medicine (UMMSM), Astrophysique Interprétation Modélisation (AIM (UMR_7158 / UMR_E_9005 / UM_112)), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7), Laboratoire d'études spatiales et d'instrumentation en astrophysique (LESIA), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Observatoire de Paris, PSL Research University (PSL)-PSL Research University (PSL)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), 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 ), University of Miami Miller School of Medicine, Laboratoire AIM, Université Paris Diderot - Paris 7 ( UPD7 ) -Centre d'Etudes de Saclay, Laboratoire d'études spatiales et d'instrumentation en astrophysique ( LESIA ), and Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Observatoire de Paris-Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: 0301 basic medicine, Nervous system, Male, Pathology, medicine.medical_specialty, Cell Adhesion Molecules, Neuronal, CNTNAP1, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Schwann cell, Biology, Nerve biopsy, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Myelin, 0302 clinical medicine, Sural Nerve, medicine, Humans, Contactin, Axon, Node of Ranvier, medicine.diagnostic_test, Infant, Newborn, General Medicine, Axolemma, 3. Good health, Pedigree, 030104 developmental biology, medicine.anatomical_structure, Neurology, nervous system, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Mutation, Original Article, Neurology (clinical), Sciatic nerve, 030217 neurology & neurosurgery
Abstract: International audience; Congenital hypomyelinating neuropathy is a rare neonatal syndrome responsible for hypotonia and weakness. Nerve microscopic examination shows amyelination or hypomyelination. Recently, mutations in CNTNAP1 have been described in a few patients. CNTNAP1 encodes contactin-associated protein 1 (caspr-1), which is an essential component of the paranodal junctions of the peripheral and central nervous systems, and is necessary for the establishment of transverse bands that stabilize paranodal axo-glial junctions. We present the results of nerve biopsy studies of three patients from two unrelated, non-consanguineous families with compound heterozygous CNTNAP1 mutations. The lesions were identical, characterized by a hypomyelinating process; on electron microscopy, we detected, in all nodes of Ranvier, subtle lesions that have never been previously described in human nerves. Transverse bands of the myelin loops were absent, with a loss of attachment between myelin and the axolemma; elongated Schwann cell processes sometimes dissociated the Schwann cell and axon membranes that bound the space between them. These lesions were observed in the area where caspr-1 is located and are reminiscent of the lesions reported in sciatic nerves of caspr-1 null mice. CNTNAP1 mutations appear to induce characteristic ultrastructural lesions of the paranodal region.
Published: 2016

10. Mutations in GLDN, Encoding Gliomedin, a Critical Component of the Nodes of Ranvier, Are Responsible for Lethal Arthrogryposis

Author: Loic Quevarec, Constance Manso, Annie Laquerrière, Jérôme Devaux, Fabien Guimiot, Florence Petit, Marta Gut, Florent Marguet, Marie Gonzales, Ivo Gut, Romulus Grigorescu, Sandra Whalen, Jérome Maluenda, Annick Toutain, Anne Dieux Coeslier, Alexandre J. Vivanti, Judith Melki, Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Biologie du Développement, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Institut méditerranéen de biodiversité et d'écologie marine et continentale (IMBE), Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UMR237-Aix Marseille Université (AMU)-Avignon Université (AU), Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre for Genomic Regulation [Barcelona] (CRG), Universitat Pompeu Fabra [Barcelona] (UPF)-Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Centre Nacional D'Anàlisi Genómica, Parc Cientific de Barcelona, Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement (Néovasc), 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)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), 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), Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Avignon Université (AU)-Aix Marseille Université (AMU)-Institut de recherche pour le développement [IRD] : UMR237-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, 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), CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Institut méditerranéen de biodiversité et d'écologie marine et continentale ( IMBE ), Université d'Avignon et des Pays de Vaucluse ( UAPV ) -Aix Marseille Université ( AMU ) -Institut de recherche pour le développement [IRD] : UMR237-Centre National de la Recherche Scientifique ( CNRS ), Anthropologie bio-culturelle, Droit, Ethique et Santé ( ADES ), Aix Marseille Université ( AMU ) -EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique ( CNRS ), Hôpital Bretonneau-CHRU Tours, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Génétique et Embryologie, Centre for Genomic Regulation [Barcelona] ( CRG ), Universitat Pompeu Fabra [Barcelona]-Centro Nacional de Analisis Genomico [Barcelona] ( CNAG ), Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement ( Néovasc ), Institute for Research and Innovation in Biomedicine ( IRIB ), Université de Rouen Normandie ( UNIROUEN ), 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 ), Service d'Anatomie et Cytologie Pathologique [Rouen], CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), 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 ), and Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre
Subjects: Male, 0301 basic medicine, Cell Adhesion Molecules, Neuronal, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Nerve Tissue Proteins, Biology, 03 medical and health sciences, 0302 clinical medicine, Genetic linkage, Report, Ranvier's Nodes, Genetics, medicine, Humans, Exome, Nerve Growth Factors, Fetal Death, Alleles, Genetics (clinical), Exome sequencing, ComputingMilieux_MISCELLANEOUS, Arthrogryposis, Arthrogryposis multiplex congenita, Cell adhesion molecule, Infant, Newborn, Membrane Proteins, Disease gene identification, Axons, Pedigree, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Peripheral nervous system, Mutation, Female, Sciatic nerve, medicine.symptom, Cell Adhesion Molecules, 030217 neurology & neurosurgery, Protein Binding
Abstract: Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through linkage analysis, homozygosity mapping, and exome sequencing in four unrelated families affected by lethal AMC, we identified biallelic mutations in GLDN in the affected individuals. GLDN encodes gliomedin, a secreted cell adhesion molecule involved in the formation of the nodes of Ranvier. Transmission electron microscopy of the sciatic nerve from one of the affected individuals showed a marked lengthening defect of the nodes. The GLDN mutations found in the affected individuals abolish the cell surface localization of gliomedin and its interaction with its axonal partner, neurofascin-186 (NF186), in a cell-based assay. The axoglial contact between gliomedin and NF186 is essential for the initial clustering of Na+ channels at developing nodes. These results indicate a major role of gliomedin in node formation and the development of the peripheral nervous system in humans. These data indicate that mutations of GLDN or CNTNAP1 (MIM: 616286), encoding essential components of the nodes of Ranvier and paranodes, respectively, lead to inherited nodopathies, a distinct disease entity among peripheral neuropathies.
Published: 2016

11. Cord blood collection and banking from a population with highly diverse geographic origins increase HLA diversity in the registry and do not lower the proportion of validated cord blood units: experience of the Marseille cord blood bank

Author: Christophe Picard, Jeremy Magalon, J. Di Cristofaro, P. Le Coz, C Bordoni, Christian Chabannon, C Gilbertas, M Berthomieu, Marc Gamerre, Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), 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), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, Anthropologie bio-culturelle, Droit, Ethique et Santé ( ADES ), Aix Marseille Université ( AMU ) -EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique ( CNRS ), 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 ), Centre de Recherche en Cancérologie de Marseille ( CRCM ), Aix Marseille Université ( AMU ) -Institut Paoli-Calmettes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Etablissement Français du Sang - Alpes-Méditerranée ( EFS - Alpes-Méditerranée ), Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Laboratoire Chrono-environnement - UFC (UMR 6249) (LCE), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), and Dubois Frid, Caroline
Subjects: Male, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Population, Human leukocyte antigen, European descent, HLA Antigens, Humans, Bone Marrow Donors Worldwide, Medicine, Registries, 10. No inequality, education, ComputingMilieux_MISCELLANEOUS, Transplantation, education.field_of_study, business.industry, Haplotype, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Fetal Blood, [SDV.ETH]Life Sciences [q-bio]/Ethics, 3. Good health, [SDV] Life Sciences [q-bio], Haplotypes, Blood Preservation, Cord blood, Immunology, Blood Banks, [ SDV.ETH ] Life Sciences [q-bio]/Ethics, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, France, business, Demography, Diversity (business)
Abstract: Several Cord Blood (CB) Bank studies suggested that ethnicity impaired CB unit (CBU) qualification. The Bone Marrow Donors Worldwide registries present an over-representation of unrelated donors (UD) from Northwestern European descent. This raises the question of equality of access to hematopoietic stem cells transplant, especially in the Mediterranean zone, which has taken in many waves of immigration. The aim of our study is to address whether, in the Marseille CB Bank, CBU qualification rate is impaired by geographic origin. The study compared biological characteristics of 106 CBU disqualified for total nucleated cell (TNC) count (dCBU) and 136 qualified CBU in relation to registry enrichment and haplotype origin. A high proportion (>80%) of both dCBU and CBU had at least one non-European haplotype and enrich CB and UD registries to a higher extent than those with two European haplotypes (P
Published: 2015

12. Combination of romidepsin with cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated patients with peripheral T-cell lymphoma: a non-randomised, phase 1b/2 study

Author: Dupuis , Jehan, Morschhauser , Franck, Ghesquières , Hervé, Tilly , Hervé, Casasnovas , Olivier, Thieblemont , Catherine, Ribrag , Vincent, Bossard , Céline, Bras , Fabien Le, Bachy , Emmanuel, Hivert , Bénédicte, Nicolas-Virelizier , Emmanuelle, Jardin , Fabrice, Bastie , Jean-Noel, Amorim , Sandy, Lazarovici , Julien, Martin , Antoine, Coiffier , Bertrand, Le Bras , Fabien, Institut de Mathématiques de Toulouse UMR5219 ( IMT ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National des Sciences Appliquées - Toulouse ( INSA Toulouse ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -PRES Université de Toulouse-Université Paul Sabatier - Toulouse 3 ( UPS ) -Université Toulouse - Jean Jaurès ( UT2J ) -Université Toulouse 1 Capitole ( UT1 ), Service d'hématologie, Hôpital Claude Huriez-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Groupe d'étude des proliférations lymphoïdes ( GPL ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Département d'hématologie [Gustave Roussy], Institut Gustave Roussy ( IGR ), Centre Européen de Réalité Virtuelle ( CERV ), École Nationale d'Ingénieurs de Brest ( ENIB ), Centre International de Recherche en Infectiologie ( CIRI ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), 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 ), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer ( LabEx LipSTIC ), Institut National de la Recherche Agronomique ( INRA ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École pratique des hautes études ( EPHE ) -Institut Gustave Roussy ( IGR ) -Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ) -Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), Laboratoire de Parasitologie-Mycologie [Paris], Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université Paris Diderot - Paris 7 ( UPD7 ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), CHU Henri Mondor, Institut de Mathématiques de Toulouse UMR5219 (IMT), Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UPS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-PRES Université de Toulouse-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Hôpital Claude Huriez-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut Gustave Roussy (IGR), Centre Européen de Réalité Virtuelle (CERV), École Nationale d'Ingénieurs de Brest (ENIB), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), 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), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université Paris Diderot - Paris 7 (UPD7), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), and Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)
Subjects: [SDV.CAN]Life Sciences [q-bio]/Cancer, [ SDV.CAN ] Life Sciences [q-bio]/Cancer
Abstract: International audience; Romidepsin is a histone deacetylase inhibitor approved in the USA for patients with recurrent or refractory peripheral T-cell lymphoma and has shown activity in this setting with mainly haematological and gastrointestinal toxicity. Although it has limited efficacy, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy is widely used for treatment of de-novo peripheral T-cell lymphoma. We aimed to assess the safety, tolerability, and activity of romidepsin combined with CHOP in patients with previously untreated disease.; We enrolled patients aged 18-80 years with histologically proven, previously untreated, peripheral T-cell lymphoma (Eastern Cooperative Oncology Group performance status ≤2) into a dose-escalation (phase 1b) and expansion (phase 2) study at nine Lymphoma Study Association centres in France. In the dose-escalation phase, we allocated consecutive blocks of three participants to receive eight 3 week cycles of CHOP (intravenous cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1.4 mg/m(2) [maximum 2 mg] on day 1 and oral prednisone 40 mg/m(2) on days 1-5) in association with varying doses of romidepsin. The starting dose was 10 mg/m(2) intravenously on days 1 and 8 of each cycle, and we used a 3 + 3 design. We assessed dose-limiting toxicities only during the first two cycles. The primary endpoint was to determine the recommended dose for the combination. For the phase 2 study, we aimed to increase the cohort of patients receiving the recommended dose to a total of 25 patients. Patients were assessed for safety outcomes at least twice per cycle according to the Common Terminology Criteria for Adverse Events, version 4.0. Safety analyses included all patients who received at least one dose of romidepsin and CHOP. This trial is registered at the European Clinical Trials Database (EudraCT), number 2010-020962-91 and ClinicalTrials.gov, number NCT01280526.; Between Jan 13, 2011, and May 21, 2013, we enrolled 37 patients (18 treated in phase 1b and 19 patients in phase 2). Three of six patients initially treated at 10 mg/m(2) had a dose-limiting toxicity. The dose-escalation committee decided to modify the study protocol to redefine dose-limiting toxicities with regard to haematological toxicity. Three patients were treated with 8 mg/m(2) of romidepsin, an additional three at 10 mg/m(2) (one dose-limiting toxicity), and six patients at 12 mg/m(2) (three dose-limiting toxicities). We chose romidepsin 12 mg/m(2) as the recommended dose for phase 2. Of the 37 patients treated, three had early cardiac events (two myocardial infarctions and one acute cardiac failure). No deaths were attributable to toxicity. 25 (68%) of 37 patients had at least one serious adverse event. Overall, the most frequent serious adverse events were febrile neutropenia (five [14%] of 37 patients), physical health deterioration (five [14%]), lung infection (four [11%]), and vomiting (three [8%]). 33 (89%) of patients had grade 3-4 neutropenia, and 29 (78%) had grade 3-4 thrombocytopenia.; Romidepsin can be combined with CHOP but this combination should now be tested in comparison to CHOP alone in a randomised trial.; Celgene.
Published: 2015

13. Identity of the NMDA receptor coagonist is synapse specific and developmentally regulated in the hippocampus

Author: Le Bail, Matildé, Martineau, Magalie, Sacchi, Silvia, Yatsenko, Natalia, Radzishevsky, Inna, Conrod, Sandrine, Ouares, Karima Ait, Wolosker, Herman, Pollegioni, Loredano, Billard, Jean Marie, Mothet, Jean Pierre, Snyder, Solomon H., 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), Westfälische Wilhelms-Universität Münster (WWU), Universitá degli Studi dell’Insubria, Rappaport faculty of Medicine, Technion - Israel Institute of Technology [Haifa], Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellular Biophysics, Laboratoire Interdisciplinaire de Physique [Saint Martin d’Hères] (LIPhy), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Department of Biotechnology and Molecular Sciences, 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 ), Laboratoire Interdisciplinaire de Physique [Saint Martin d’Hères] ( LIPhy ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Universitá degli Studi dell’Insubria = University of Insubria [Varese] (Uninsubria), Centre de Psychiatrie et Neurosciences (U894), and Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)
Subjects: Male, [SDV]Life Sciences [q-bio], Long-Term Potentiation, Glycine, Hippocampus, Hippocampal formation, Biology, Receptors, N-Methyl-D-Aspartate, NMDA receptors, Synapse, Glutamatergic, mental disorders, Receptors, Serine, Animals, Hippocampal, CA1 Region, Hippocampal, ComputingMilieux_MISCELLANEOUS, Neurons, Multidisciplinary, [ SDV ] Life Sciences [q-bio], Coagonist, Developmental switch, Animals, Newborn, Astrocytes, Dentate Gyrus, Rats, Synapses, Dentate gyrus, musculoskeletal, neural, and ocular physiology, CA1 Region, Long-term potentiation, Newborn, nervous system, PNAS Plus, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], NMDA receptor, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience, N-Methyl-D-Aspartate
Abstract: International audience; NMDA receptors (NMDARs) require the coagonists D-serine or glycine for their activation, but whether the identity of the coagonist could be synapse specific and developmentally regulated remains elusive. We therefore investigated the contribution of D-serine and glycine by recording NMDAR-mediated responses at hippocampal Schaffer collaterals (SC)-CA1 and medial perforant path-dentate gyrus (mPP-DG) synapses in juvenile and adult rats. Selective depletion of endogenous coagonists with enzymatic scavengers as well as pharmacological inhibition of endogenous D-amino acid oxidase activity revealed that D-serine is the preferred coagonist at SC-CA1 mature synapses, whereas, unexpectedly, glycine is mainly involved at mPP-DG synapses. Nevertheless, both coagonist functions are driven by the levels of synaptic activity as inferred by recording long-term potentiation generated at both connections. This regional compartmentalization in the coagonist identity is associated to different GluN1/GluN2A to GluN1/GluN2B subunit composition of synaptic NMDARs. During postnatal development, the replacement of GluN2B- by GluN2A-containing NMDARs at SC-CA1 synapses parallels a change in the identity of the coagonist from glycine to D-serine. In contrast, NMDARs subunit composition at mPP-DG synapses is not altered and glycine remains the main coagonist throughout postnatal development. Altogether, our observations disclose an unprecedented relationship in the identity of the coagonist not only with the GluN2 subunit composition at synaptic NMDARs but also with astrocyte activity in the developing and mature hippocampus that reconciles the complementary functions of D-serine And Glycine In Modulating Nmdars During The Maturation Of Tripartite Glutamatergic Synapses.
Published: 2015

14. A special issue on physiological aspects of mechanosensing

Author: Bertrand Coste, Patrick Delmas, Eric Honoré, 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), Institut de recherche en astrophysique et planétologie (IRAP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neurosciences Cognitives & Computationnelles (LNC2), Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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)-Université Côte d'Azur (UCA), 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 ), Institut de recherche en astrophysique et planétologie ( IRAP ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Observatoire Midi-Pyrénées ( OMP ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Interlangues - Texte, Image, Langage ( TIL ), Université de Bourgogne ( UB ), Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Institut national des sciences de l'Univers (INSU - CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Centre National de la Recherche Scientifique (CNRS)-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)-Université Côte d'Azur (UCA)
Subjects: Autonomic function, Sensory Receptor Cells, Physiology, media_common.quotation_subject, 030303 biophysics, Clinical Biochemistry, Cellular homeostasis, Biology, Mechanotransduction, Cellular, 03 medical and health sciences, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Physiology (medical), Chaotic environment, Perception, Animals, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, media_common, 0303 health sciences, Communication, Mechanosensation, business.industry, Evolutionary pressure, Touch, Mechanosensitive channels, Stress, Mechanical, business
Abstract: Perception of mechanical stimuli is critically important for sensing the surrounding environment. As Aristotle pointed out in 350 BC (De Anima 3.12, 434b—1ff), all living organisms,frombacteriatomammals,relyonmechanosensationfor their survival. A unicellular paramecium, navigating its way through a chaotic environment, relies on mechanosensitive proteins to avoid obstacles. The cricket escapes the spider by possessingincredibly sensitivehairs,whichare abletopickup the faintest change in air flows. Crocodiles are dotted of thousands of highly sensitive mechanosensory receptors that enable them to sense the movement of their preys through vibrations in the water. Examples are endless in the animal kingdom. In humans, mechanosensation constitutes the physiological foundation for the senses of touch, pain, and hearing for regulation of multiple autonomic functions and for social exchange [4, 8–11]. Mechanosensation is ubiquitous in biological systems. Primary mechanosensitive processes have probably evolved as backup mechanisms for cell protection during osmotic swelling. Through evolutionary pressure, a number of mechanosensory structures have then emerged to accomplish a wide array of specialized tasks, ranging from cellular homeostasis to our ability of hearing and discriminative touch. Thus, mechanosensory structures exhibit some sort of homoplasy, all being specialized in the detection of force-related stimuli but arising from different evolutionary origins. The importanceof mechanosensoryinputsfor the existence of life justifies the effort made to understand its molecular origin(s). The basis for cell mechanosensation is a coupling of externalmechanicalforcestothechemicalreactionsthatoccur
Published: 2014

15. Piezo channels: from structure to function

Author: Yasmine Mechioukhi, Bertrand Coste, Linda Volkers, 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), Laboratoire de Neurosciences Cognitives & Computationnelles (LNC2), Département d'Etudes Cognitives - ENS Paris (DEC), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), Centre Interlangues - Texte, Image, Langage ( TIL ), Université de Bourgogne ( UB ), Dumonceaud, Corinne, École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL)
Subjects: Cell physiology, Physiology, Clinical Biochemistry, Sensation, Sensory system, Biology, Mechanotransduction, Cellular, Models, Biological, Ion Channels, Cell membrane, Structure-Activity Relationship, 03 medical and health sciences, 0302 clinical medicine, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Physiology (medical), medicine, Animals, Humans, Mechanotransduction, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Ion channel, 030304 developmental biology, 0303 health sciences, Communication, business.industry, PIEZO1, medicine.anatomical_structure, Stress, Mechanical, business, Ion Channel Gating, Neuroscience, 030217 neurology & neurosurgery, Function (biology), Communication channel
Abstract: International audience; Mechanotransduction is the conversion of mechanical stimuli into biological signals. It is involved in the modulation of diverse cellular functions such as migration, proliferation, differentiation, and apoptosis as well as in the detection of sensory stimuli such as air vibration and mechanical contact. Therefore, mechanotransduction is crucial for organ development and homeostasis and plays a direct role in hearing, touch, proprioception, and pain. Multiple molecular players involved in mechanotransduction have been identified in the past, among them ion channels directly activated by cell membrane deformation. Most of these channels have well-established roles in lower organisms but are not conserved in mammals or fail to encode mechanically activated channels in mammals due to non-conservation of mechanotransduction property. A family of mechanically activated channels that counts only two members in human, piezo1 and 2, has emerged recently. Given the lack of valid mechanically activated channel candidates in mammals in the past decades, particular attention is given to piezo channels and their potential roles in various biological functions. This review summarizes our current knowledge on these ion channels.
Published: 2014

16. A MEN1 syndrome with a paraganglioma

Author: Yvan Jamilloux, F. Archambeaud, Judith Favier, Manuela Delage-Corre, Stéphanie Lopez, Anne Barlier, M.-P. Teissier, Muriel Mathonnet, S. Galinat, Morgane Pertuit, Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Biologie Moléculaire ( MARSEILLE - Biolo Moléculaire ), Assistance Publique - Hôpitaux de Marseille ( APHM ), Interactions cellulaires neuroendocriniennes ( ICN ), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique ( CNRS ), Service de Médecine interne B, Endocrinologie, Diabète, Maladies métaboliques [CHU Limoges], CHU Limoges, Homéostasie Cellulaire et Pathologies ( HCP ), Université de Limoges ( UNILIM ) -Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ) -CHU Limoges, Service de Chirurgie digestive, endocrinienne et générale [CHU Limoges], 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 ), 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), Laboratoire de Biologie Moléculaire (MARSEILLE - Biolo Moléculaire), Assistance Publique - Hôpitaux de Marseille (APHM), Interactions cellulaires neuroendocriniennes (ICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-CHU Limoges, 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), 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), and Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)
Subjects: endocrine system, congenital, hereditary, and neonatal diseases and abnormalities, endocrine system diseases, SDHB, DNA Mutational Analysis, Mutation, Missense, Short Report, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Adrenocortical adenoma, Paraganglioma, Germline mutation, Proto-Oncogene Proteins, Genetics, medicine, Humans, Missense mutation, Abnormalities, Multiple, MEN1, Multiple endocrine neoplasia, Genetics (clinical), [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Syndrome, medicine.disease, Adrenal Cortex Neoplasms, Pedigree, 3. Good health, Pancreatic Neoplasms, Radiography, Cancer research, Female, Primary hyperparathyroidism
Abstract: International audience; Germline mutations of the MEN1 gene cause multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder characterized by tumors of the parathyroids, the pancreas, and the anterior pituitary. Paraganglioma (PGL) is a rare endocrine tumor, which can be sporadic or genetically determined. To date, PGL has never been reported as a feature of MEN1.We report here a patient presenting three features of MEN1 syndrome (hyperparathyroidism, pancreatic neuroendocrine tumor, and adrenocortical adenoma) associated with PGL. Genetic analysis of MEN1 gene revealed a new missense mutation in exon 5 (AGGAAG), causing the substitution of arginine by lysine at codon 275. Screening for other genetic disorders (SDHx, TMEM127, MAX, CDKN1B) causing PGL was negative. Immunohistochemical analyses showed normal levels of succinate dehydrogenase (SDH)A and SDHB in the PGL. The proband's sister, bearing the mutation, had primary hyperparathyroidism. It was the first typical MEN1 syndrome reported with an extra-adrenal PGL.
Published: 2014

17. Hepatocyte pathway alterations in response to in vitro Crimean Congo hemorrhagic fever virus infection

Author: Christophe Fraisier, Gláucia Paranhos-Baccalà, Vinh Vu Hai, Christophe N. Peyrefitte, Raquel Rodrigues, Lionel Almeras, Maya Belghazi, Stéphanie Bourdon, Luc Camoin, Unité de Recherche en Biologie et Epidémiologie Parasitaires, Institut de Médecine Tropicale du Service de Santé des Armées-Centre National de la Recherche Scientifique (CNRS), 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), Emerging Pathogens Department, BIOMERIEUX, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Médecine Tropicale du Service de Santé des Armées-Centre National de la Recherche Scientifique ( CNRS ), 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 ), Institut Cochin ( 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 ), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Proteomics, Cancer Research, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Biology, Virus, Immune system, Multiplicity of infection, Viral entry, Interferon, Virology, medicine, Animals, Humans, [ SDV ] Life Sciences [q-bio], Liver cell, Proteins, 3. Good health, Infectious Diseases, Apoptosis, Hemorrhagic Fever Virus, Crimean-Congo, Hepatocytes, Hemorrhagic Fever, Crimean, Crimean Congo hemorrhagic fever virus, medicine.drug
Abstract: International audience; Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus responsible for hemorrhagic manifestations and multiple organ failure, with a high mortality rate. In infected humans, damage to endothelial cells and vascular leakage may be a direct result of virus infection or an immune response-mediated indirect effect. The main target cells are mononuclear phagocytes, endothelial cells and hepatocytes; the liver being a key target for the virus, which was described as susceptible to interferon host response and to induce apoptosis. To better understand the early liver cell alterations due to virus infection, the protein profile of in vitro CCHFV-infected HepG2 cells was analyzed using two quantitative proteomic approaches, 2D-DIGE and iTRAQ. A set of 243 differentially expressed proteins was identified. Bioinformatics analysis (Ingenuity Pathways Analysis) revealed multiple host cell pathways and functions altered after CCHFV infection, with notably 106 proteins related to cell death, including 79 associated with apoptosis. Different protein networks emerged with associated pathways involved in inflammation, oxidative stress and apoptosis, ubiquitination/sumoylation, regulation of the nucleo-cytoplasmic transport, and virus entry. Collectively, this study revealed host liver protein abundances that were modified at the early stages of CCHFV infection, offering an unparalleled opportunity of the description of the potential pathogenesis processes and of possible targets for antiviral research.
Published: 2014

18. COSTaM : tool design for a controlled tactile stimulation

Author: Bueno, Marie-Ange, Crest, Marcel, Monteil, Guy, Berthier, Yves, LEMAIRE-SEMAIL, Betty, Massi, Francesco, Vinter, Annie, Aimonetti, Jean-Marc, Carpentier, Luc, Cornuault, Pierre-Henri, Giraud, Frédéric, Camillieri, Brigitte, Ribot-Ciscar, Edith, Witt, Arnaud, Gentaz, Edouard, Mith, Setha, Laboratoire de Physique et Mécanique Textiles (LPMT), Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-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), 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), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire de Mécanique des Contacts et des Structures [Villeurbanne] (LaMCoS), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche sur les Composants logiciels et matériels pour l'Information et la Communication Avancé - USR 3380 (IRCICA), Université de Lille-Centre National de la Recherche Scientifique (CNRS), ENSITM-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)-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), Université Aix-Marseille, Faculté de Médecine secteur Nord (Centre de Recherche en Neurobiologie-Neurophysiologie de Marseille (CRN2M)), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: body regions, tactile perception, [PHYS.MECA]Physics [physics]/Mechanics [physics]
Abstract: International audience; Tactile stimulation is used in the rehabilitation of damage to the central or peripheral nervous system and in brain injury recovery. Tactile deficits of the hand are currently diagnosed through the evaluation of pain thresholds, spatial discrimination, vibration sensitivity and by using filaments or tuning forks, without truly established protocols. The global goal of the COSTaM project is to develop a tactile stimulator to identify tactile disorders and allow specific rehabilitation. The first step is to study the response of healthy individuals to complex textures in different ways : perceptive discrimination, study of friction and vibration between textures and the finger and the response of each kind of cutaneous mechanoreceptor. Three kinds of real textures have been chosen: relief, braking and fibrous. The use of a tactile stimulator, based on the modulation of the coefficient of friction with the finger, has been validated for the simulation of the braking descriptor.
Published: 2014

19. Elicitin Genes Expressed In Vitro by Certain Tobacco Isolates of Phytophthora parasitica Are Down Regulated During Compatible Interactions

Author: Colas , F, Conrod , Sandrine, VENARD , Paul, Keller , Harald, Ricci , Pierre, Panabières , Franck, Colas , Virginie, Interactions plantes-microorganismes et santé végétale (IPMSV), Institut National de la Recherche Agronomique (INRA)-Université Nice Sophia Antipolis (... - 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), 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 ), Institut Sophia Agrobiotech [Sophia Antipolis] ( ISA ), Centre National de la Recherche Scientifique ( CNRS ) -Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Institut National de la Recherche Agronomique ( INRA ), Interactions Plantes Microorganismes et Santé Végétale, Institut National de la Recherche Agronomique ( INRA ), UR 0254 Unité de recherche Génétique et Amélioration des Plantes, 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), Institut Sophia Agrobiotech (ISA), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA), Institut Sophia Agrobiotech [Sophia Antipolis] (ISA), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Recherche Agronomique (INRA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS)
Subjects: Phytophthora, 0106 biological sciences, Hypersensitive response, [ SDV.BV ] Life Sciences [q-bio]/Vegetal Biology, Physiology, [SDV]Life Sciences [q-bio], Nicotiana tabacum, Molecular Sequence Data, Down-Regulation, Virulence, Enzyme-Linked Immunosorbent Assay, Biology, 01 natural sciences, Microbiology, 03 medical and health sciences, Solanum lycopersicum, Sequence Homology, Nucleic Acid, Tobacco, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, DNA, Fungal, Pathogen, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Base Sequence, [ SDV ] Life Sciences [q-bio], Reverse Transcriptase Polymerase Chain Reaction, 030306 microbiology, Algal Proteins, fungi, Proteins, food and beverages, Elicitin, General Medicine, Phytophthora nicotianae, Blotting, Northern, biology.organism_classification, 3. Good health, Plants, Toxic, POUVOIR PATHOGENE, Agronomy and Crop Science, Systemic acquired resistance, 010606 plant biology & botany
Abstract: International audience; Phytophthora spp. secrete proteins called elicitins in vitro that can specifically induce hypersensitive response and systemic acquired resistance in tobacco. In Phytophthora parasitica, the causal agent of black shank, most isolates virulent on tobacco are unable to produce elicitins in vitro. Recently, however, a few elicitin-producing P. parasitica strains virulent on tobacco have been isolated. We investigated the potential diversity of elicitin genes in P. parasitica isolates belonging to different genotypes and with various virulence levels toward tobacco as well as elicitin expression pattern in vitro and in planta. Although elicitins are encoded by a multigene family, parAl is the main elicitin gene expressed. This gene is highly conserved among isolates, regardless of the elicitin production and virulence levels toward tobacco. Moreover, we show that elicitin-producing P. parasitica isolates virulent on tobacco down regulate parAl expression during compatible interactions, whichever host plant is tested. Conversely, one elicitin-producing P. parasitica isolate that is pathogenic on tomato and avirulent on tobacco still expresses parAl in the compatible interaction. Therefore, some P. parasitica isolates may evade tobacco recognition by down regulating parA1 in planta. The in planta down regulation of parA1 may constitute a suitable mechanism for P. parasitica to infect tobacco without deleterious consequences for the pathogen.
Published: 2001

20. Excitatory drive of cortical fast-spiking GABAergic interneurons is set by D-serine acting on NMDA receptors

Author: Pierre Lecouflet, Steeve Maldera, Brigitte Potier, Loredano Pollegioni, Jean-Pierre Mothet, Laboratoire Lumière, Matière et Interfaces (LuMIn), CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), Universitá degli Studi dell’Insubria = University of Insubria [Varese] (Uninsubria), Mothet, Jean-Pierre, Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: nervous system, musculoskeletal, neural, and ocular physiology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, mental disorders, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
Abstract: N-methyl-D-aspartate receptors (NMDARs) populate GABAergic interneurons, where they play a critical role in shaping circuit motifs and memory. However, we are largely ignoring whether and how NMDARs at GABAergic interneurons are gated by signals released in their surrounding microenvironment. Here we explore the dynamics of the co-agonist site occupancy by D-serine and glycine at glutamatergic synapses onto parvalbumin positive GABAergic interneurons in the adolescent prefrontal cortex, an area central to complex cognitive operation. We discovered that D-serine but not glycine is required for maintaining the activity of NMDAR at the GABAergic interneurons and that the identity of the co-agonist is not determined by the synaptic regime. Our study extends the physiological implications of D-serine in brain physiopathology by uncovering its control of inhibitory synaptic networks through NMDARs.
Published: 2022

21. Apnées obstructives et mixtes chez le souriceau DMSXL, modèle de la forme congénitale de la maladie de Steinert

Author: Sizun, Eléonore, Huguet-Lachon, Aline, Ramanantsoa, N., Cayetanot, Florence, Bodineau, Laurence, Gallego, Jorge, Gourdon, Geneviève, Matrot, Boris, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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), Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Université Paris Diderot - Paris 7 (UPD7), and Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Myotonic dystrophy type 1, Respiratory Function, [SCCO.NEUR]Cognitive science/Neuroscience, Newborn, Transgenic mouse model, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience
Published: 2022

22. Simultaneous hyper- and hypomethylation at imprinted loci in a subset of patients with GNAS epimutations underlies a complex and different mechanism of multilocus methylation defect in pseudohypoparathyroidism type 1b

Author: Virginie Steunou, Salah Azzi, Christelle Reynes, Nathalie Sakakini, Anne Barlier, Guiomar Perez de Nanclares, Boris Keren, Caroline Silve, Sandra Chantot, Stéphanie Maupetit-Méhouas, Agnès Linglart, Irene Netchine, Immunologie et génétique du diabète de type 1, génétique multifactorielle en endocrinologie pédiatrique (U986), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de biochimie hormonale, métabolique et génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Aide à la Décision pour une Médecine Personnalisé - Laboratoire de Biostatistique, Epidémiologie et Recherche Clinique - EA 2415 (AIDMP), Université Montpellier 1 (UM1)-Université de Montpellier (UM), Laboratorio de Genética Molecular, Unidad de Investigación, Hospital de Txagorritxu, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), 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), Immunologie et génétique du diabète de type 1, génétique multifactorielle en endocrinologie pédiatrique ( U986 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Technologies avancées pour le génôme et la clinique ( TAGC ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Aide à la Décision pour une Médecine Personnalisé - Laboratoire de Biostatistique, Epidémiologie et Recherche Clinique - EA 2415 ( AIDMP ), Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière ( CRICM ), 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 ), and Centre de recherche en neurobiologie - neurophysiologie de Marseille ( CRN2M )
Subjects: musculoskeletal diseases, MESH : GTP-Binding Protein alpha Subunits, Gs, MESH : Cohort Studies, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Cohort Studies, 03 medical and health sciences, Genomic Imprinting, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], MESH: DNA Methylation, Genetics, medicine, GNAS complex locus, Chromogranins, GTP-Binding Protein alpha Subunits, Gs, Humans, MESH : Pseudohypoparathyroidism, Imprinting (psychology), [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Cohort Studies, Genetics (clinical), 030304 developmental biology, 0303 health sciences, MESH: Humans, MESH: Polymorphism, Single Nucleotide, MESH : Humans, MESH : Polymorphism, Single Nucleotide, 030305 genetics & heredity, MESH: Pseudohypoparathyroidism, MESH : Genomic Imprinting, Methylation, DNA Methylation, MESH: GTP-Binding Protein alpha Subunits, Gs, medicine.disease, Molecular biology, Phenotype, Uniparental disomy, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], MESH: Genomic Imprinting, Pseudohypoparathyroidism, DNA methylation, biology.protein, Genomic imprinting, MESH : DNA Methylation
Abstract: International audience; Most patients with pseudohypoparathyroidism type 1b (PHP-1b) display a loss of imprinting (LOI) encompassing the GNAS locus resulting in PTH resistance. In other imprinting disorders, such as Russell-Silver or Beckwith-Wiedemann syndrome, we and others have shown that the LOI is not restricted to one imprinted locus but may affect other imprinted loci for some patients. Therefore, we hypothesized that patients with PHP-1b might present multilocus imprinting defects. We investigated, in 63 patients with PHP-1b, the methylation pattern of eight imprinted loci: GNAS, ZAC1, PEG1/MEST, ICR1, and ICR2 on chromosome 11p15, SNRPN, DLK1/GTL2 IG-DMR, and L3MBTL1. We found multilocus imprinting defects in four PHP-1b patients carrying broad LOI at the GNAS locus (1) simultaneous hypermethylation at L3MBTL1 differentially methylated region 3 (DMR3), and hypomethylation at PEG1/MEST DMR (n = 1), (2) hypermethylation at the L3MBTL1 (DMR3) (n = 1) and at the DLK1/GTL2 IG-DMR (n = 1), and (3) hypomethylation at the L3MBTL1 DMR3 (n = 1). We suggest that mechanisms underlying multilocus imprinting defects in PHP-1b differ from those of other imprinting disorders having only multilocus loss of methylation. Furthermore, our results favor the hypothesis of "epidominance", that is, the phenotype is controlled by the most severely affected imprinted locus.
Published: 2013

23. Higher risk of death among MEN1 patients with mutations in the JunD interacting domain: a Groupe d'etude des Tumeurs Endocrines (GTE) cohort study

Author: Bruno Vergès, Albert Beckers, Brigitte Delemer, Vincent Rohmer, Arnaud Murat, Jean-Marc Kuhn, Philippe Ruszniewski, Christine Binquet, Julien Thevenon, Philippe Caron, Georges Weryha, Michel Rodier, Sophie Giraud, F. Archambeaud, I. Guilhem, Morgane Le Bras, Philippe Chanson, Béatrice Parfait, Jean-Louis Sadoul, Lionel Groussin, Patricia Niccoli, Catherine Cardot-Bauters, Philippe Bouchard, Eric Baudin, Françoise Duron, Michel Renard, Hélène Bihan, Véronique Kerlan, P. Lecomte, Catherine Lombard-Bohas, Abderrahmane Bourredjem, Anne Barlier, Emilie Castermans, Françoise Borson-Chazot, Bernard Goichot, Olivier Chabre, Antoine Tabarin, Alain Calender, Laurence Faivre, Hélène Du Boullay, Pierre Goudet, Eric Clauser, Alfred Penfornis, Marie-Françoise Odou, Université Joseph Fourier - Grenoble 1 ( UJF ), Immunovirologie et polymorphisme génétique, Université de Nantes ( UN ), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon ( HCL ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de médecine nucléaire, Fédération d'endocrinologie-Groupement hospitalier Lyon-Est, 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 ), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon ( HCL ), Service d'Endocrinologie ( BORDEAUX - Endocrino ), CHU Bordeaux [Bordeaux], Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux ( Inserm U745 ), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Biologie du Cancer et de l'Infection ( BCI - UMR S1036 ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Grenoble Alpes ( UGA ), Service d'Endocrinologie ( LIEGE - Endocrino ), Université de Liège, Department of Gastroenterology, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Beaujon, Pathologie et virologie moléculaire ( PVM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'Endocrinologie - Diabète - Nutrition [Reims], Université de Reims Champagne-Ardenne ( URCA ) -Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims ( CHU Reims ), Laboratoire Microorganismes : Génome et Environnement ( LMGE ), Université Blaise Pascal - Clermont-Ferrand 2 ( UBP ) -Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Universitaire [Rennes], Service d'Endocrinologie ( ANGERS - Endocrino ), CHU Angers, Département de Médecine Interne et Nutrition, CHU Strasbourg, Service d'Endocrinologie ( TOULOUSE - Endocrino ), CHU Toulouse [Toulouse], Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Université Paris-Sud - Paris 11 ( UP11 ) -IFR93-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ), Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Service d'Endocrinologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Service d'Endocrinologie ( TOURS - Endocrino ), CHRU Tours, Service de diabétologie - endocrinologie, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( PCVP / CARDIO ), Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Conservatoire National des Arts et Métiers - Paris ( CNAM Paris ), Conservatoire National des Arts et Métiers [CNAM] ( CNAM ), Unité de Recherche en Epidémiologie Nutritionnelle ( UREN ), Institut National de la Recherche Agronomique ( INRA ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Université Paris 13 ( UP13 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Médecine interne B, Endocrinologie, Diabète, Maladies métaboliques [CHU Limoges], CHU Limoges, Groupe d'Etude de la Thrombose de Bretagne Occidentale ( GETBO ), Université de Brest ( UBO ), Service d'Endocrinologie ( CHRU - Endocrino ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Service de Diabétologie, Service des maladies métaboliques et endocriniennes, Hôpital Universitaire Carémeau [Nîmes], Service d'Endocrinologie ( NICE - Endocrino ), CHU Nice, Université Blaise Pascal - Clermont-Ferrand 2 ( UBP ) -Centre National de la Recherche Scientifique ( CNRS ) -Université d'Auvergne - Clermont-Ferrand I ( UdA ), Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( EA 3920) ( PCVP / CARDIO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ) -Université Bourgogne Franche-Comté [COMUE] ( UBFC ), Université Joseph Fourier - Grenoble 1 (UJF), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-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), 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), Hospices Civils de Lyon (HCL), Service d'Endocrinologie (BORDEAUX - Endocrino), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Endocrinologie (LIEGE - Endocrino), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pathologie et virologie moléculaire (PVM (UMR_7151)), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Université de Reims Champagne-Ardenne (URCA)-Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Université d'Auvergne - Clermont-Ferrand I (UdA), Service d'Endocrinologie (ANGERS - Endocrino), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service d'Endocrinologie (TOULOUSE - Endocrino), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR93-Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'Endocrinologie (TOURS - Endocrino), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de Diabétologie - Endocrinologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( EA 3920) (PCVP / CARDIO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Service d'Endocrinologie (CHRU - Endocrino), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service d'Endocrinologie, Diabétologie et Maladies Métaboliques (CHU de Dijon), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service d'Endocrinologie (NICE - Endocrino), Centre Hospitalier Universitaire de Nice (CHU Nice), Université de Nantes (UN), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-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)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Beaujon, Pathologie et virologie moléculaire (PVM), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université de Brest (UBO), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Fédération d'endocrinologie, Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Centre National de la Recherche Scientifique (CNRS), Service Endocrinologie, maladies métaboliques et nutrition [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( UR 3920) (PCVP / CARDIO), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Institut Brestois Santé Agro Matière (IBSAM), and Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO)
Subjects: Oncology, Male, endocrine system diseases, Proto-Oncogene Proteins c-jun, [SDV]Life Sciences [q-bio], Disease, medicine.disease_cause, MESH: Protein Structure, Tertiary, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, MESH : Female, Genetics (clinical), Mutation, General Medicine, MESH: Follow-Up Studies, MESH : Risk Factors, 3. Good health, 030220 oncology & carcinogenesis, Cohort, MESH : Proto-Oncogene Proteins, Female, MESH : Mutation, MESH : Protein Structure, Tertiary, MESH : Proto-Oncogene Proteins c-jun, MESH : Multiple Endocrine Neoplasia Type 1, Cohort study, medicine.medical_specialty, endocrine system, MESH: Mutation, Genetic counseling, MESH : Male, MESH: Multiple Endocrine Neoplasia Type 1, 030209 endocrinology & metabolism, Biology, 03 medical and health sciences, Internal medicine, Proto-Oncogene Proteins, Genetics, medicine, Multiple Endocrine Neoplasia Type 1, Humans, MEN1, Family, Molecular Biology, MESH: Family, MESH: Humans, MESH: Proto-Oncogene Proteins c-jun, [ SDV ] Life Sciences [q-bio], Proportional hazards model, MESH : Humans, Cancer, MESH : Follow-Up Studies, medicine.disease, MESH: Male, Protein Structure, Tertiary, MESH: Proto-Oncogene Proteins, Cancer research, MESH : Family, MESH: Female, Follow-Up Studies
Abstract: International audience; Multiple endocrine neoplasia syndrome type 1 (MEN1), which is secondary to mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Although genotype-phenotype studies have so far failed to identify any statistical correlations, some families harbor recurrent tumor patterns. The function of MENIN is unclear, but has been described through the discovery of its interacting partners. Mutations in the interacting domains of MENIN functional partners have been shown to directly alter its regulation abilities. We report on a cohort of MEN1 patients from the Groupe d'étude des Tumeurs Endocrines. Patients with a molecular diagnosis and a clinical follow-up, totaling 262 families and 806 patients, were included. Associations between mutation type, location or interacting factors of the MENIN protein and death as well as the occurrence of MEN1-related tumors were tested using a frailty Cox model to adjust for potential heterogeneity across families. Accounting for the heterogeneity across families, the overall risk of death was significantly higher when mutations affected the JunD interacting domain (adjusted HR = 1.88: 95%-CI = 1.15-3.07). Patients had a higher risk of death from cancers of the MEN1 spectrum (HR = 2.34; 95%-CI = 1.23-4.43). This genotype-phenotype correlation study confirmed the lack of direct genotype-phenotype correlations. However, patients with mutations affecting the JunD interacting domain had a higher risk of death secondary to a MEN1 tumor and should thus be considered for surgical indications, genetic counseling and follow-up.
Published: 2013

24. Piezo-electrically driven mechanical stimulation of sensory neurons

Author: Hao, Jizhe, Ruel, Jérôme, Coste, Bertrand, Roudaut, Yann, Crest, Marcel, 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 ), Université Montpellier 1 ( UM1 ), Laboratoire de neurophysiologie cellulaire ( LNPC ), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique ( CNRS ), 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), Université Montpellier 1 (UM1), Laboratoire de neurophysiologie cellulaire (LNPC), and Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Patch-Clamp Techniques, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Electricity, Sensory Receptor Cells, Ganglia, Spinal, Animals, Rats, Wistar, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Mechanotransduction, Cellular, Electrophysiological Phenomena, Mechanical Phenomena, Rats
Abstract: International audience; Mechanotransduction, the conversion of a mechanical stimulus into a biological response, constitutes the basis of a variety of physiological functions such as the senses of touch, balance, proprioception, blood pressure, and hearing. In vertebrates, mechanosensation is mediated by mechanosensory neurons, whose cell bodies are located in trigeminal and dorsal root ganglia. Here, we describe an in vitro model of mechanotransduction that provides an opportunity to explore the properties of mechanosensitive channels in mammalian sensory neurons. The mechano-clamp method allows applying local force on plasma membrane of whole-cell patch-clamped sensory neurons. This technique uses a mechanical probe driven by a computer-assisted piezoelectric microstage to repeatedly stimulate sensory neurons with accurate control of stimulus strength, duration, and speed.
Published: 2013

25. Inactivation of Socs3 in the Hypothalamus Enhances the Hindbrain Response to Endogenous Satiety Signals via Oxytocin Signaling

Author: Emmanuel Moyse, Alexandre Benani, Luc Pénicaud, Françoise Muscatelli, Emmanuelle Nédélec, Sylvian Bauer, Fabienne Schaller, Valéry Matarazzo, Institut de Biologie du Développement de Marseille ( IBDM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Pharmacologie Endocrinienne, Hôpital Lariboisière, 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), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U901), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique, Institut National de la Sante et de la Recherche Medicale, Institut National de la Recherche Agronomique, Universite Aix-Marseille, Societe Francaise de Nutrition, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en neurobiologie - neurophysiologie de Marseille ( CRN2M ), Institut de neurobiologie de la Méditerranée ( INMED ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Physiologie de la reproduction et des comportements [Nouzilly] ( PRC ), Institut National de la Recherche Agronomique ( INRA ) -Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique ( CNRS ), Aix Marseille Université (AMU)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), Centre National de la Recherche Scientifique (CNRS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ProdInra, Archive Ouverte, Institut National de la Santé et de la Recherche Médicale (INSERM), Aviesan, and Centre National de la Recherche Scientifique (CNRS)
Subjects: Leptin, medicine.medical_specialty, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], [SDV]Life Sciences [q-bio], [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, Hypothalamus, Hindbrain, Suppressor of Cytokine Signaling Proteins, Biology, Oxytocin, Devazepide, Satiety Response, Energy homeostasis, 03 medical and health sciences, Eating, Mice, 0302 clinical medicine, Hormone Antagonists, Internal medicine, medicine, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], SOCS3, [ SDV.OT ] Life Sciences [q-bio]/Other [q-bio.OT], ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, [SDV.OT] Life Sciences [q-bio]/Other [q-bio.OT], General Neuroscience, digestive, oral, and skin physiology, Articles, Rhombencephalon, Endocrinology, Suppressor of Cytokine Signaling 3 Protein, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Receptors, Cholecystokinin, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery, Homeostasis, Hormone, medicine.drug, Signal Transduction
Abstract: Leptin is an adipocyte-derived hormone that controls energy balance by acting primarily in the CNS, but its action is lost in common forms of obesity due to central leptin resistance. One potential mechanism for such leptin resistance is an increased hypothalamic expression of Suppressor of cytokine signaling 3 (Socs3), a feedback inhibitor of the Jak-Stat pathway that prevents Stat3 activation. Ample studies have confirmed the important role of Socs3 in leptin resistance and obesity. However, the degree to which Socs3 participates in the regulation of energy homeostasis in nonobese conditions remains largely undetermined. In this study, using adult mice maintained under standard diet, we demonstrate thatSocs3deficiency in the mediobasal hypothalamus (MBH) reduces food intake, protects against body weight gain, and limits adiposity, suggesting that Socs3 is necessary for normal body weight maintenance. Mechanistically, MBH Socs3-deficient mice display increased hindbrain sensitivity to endogenous, meal-related satiety signals, mediated by oxytocin signaling. Thus, oxytocin signaling likely mediates the effect of hypothalamic leptin on satiety circuits of the caudal brainstem. This provides an anatomical substrate for the effect of leptin on meal size, and more generally, a mechanism for how the brain controls short-term food intake as a function of the energetic stores available in the organism to maintain energy homeostasis. Any dysfunction in this pathway could potentially lead to overeating and obesity.
Published: 2012

26. Metabolic profile of inflammation in the hippocampus

Author: Combaz , X., Cayre , M., Le Fur , Y., Pecchi , E., Courtes , S., Confort-Gouny , S., Ratiney , H., Cozzone , P.J., Viola , A., Centre de résonance magnétique biologique et médicale ( CRMBM ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Biologie du Développement de Marseille ( IBDM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de recherche en neurobiologie - neurophysiologie de Marseille ( CRN2M ), 5 - RMN et optique : De la mesure aux biomarqueurs, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé ( CREATIS ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Hospices Civils de Lyon ( HCL ) -Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Hospices Civils de Lyon ( HCL ) -Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de résonance magnétique biologique et médicale (CRMBM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), 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), RMN et optique : De la mesure au biomarqueur, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [ SPI.SIGNAL ] Engineering Sciences [physics]/Signal and Image processing, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing
Abstract: International audience; Purpose/Introduction: Intracerebral injections are used in animal models of brain pathologies to evaluate the therapeutic impact of drugs, which cannot cross the blood brain barrier. These procedures not only cause lesions at the site of injection, but also may affect brain metabolism as a consequence of inflammation even in distant locations. In order to identify these perturbations we performed an in vivo 1H-MRS study of mice receiving an intracerebroventricular (icv) injection of saline and analyzed the metabolic profile of the dendate gyrus, a neurogenic niche in the adult brain.
Published: 2012

27. Structural Insights into Antibody Sequestering and Neutralizing of Na+ Channel α-Type Modulator from Old World Scorpion Venom

Author: Grégoire Mondielli, Yves Bourne, Sandrine Conrod, Marie-France Martin-Eauclaire, Igor P. Fabrichny, Pascale Marchot, 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), Université de Provence - Aix-Marseille 1, Architecture et fonction des macromolécules biologiques (AFMB), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), 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 ), Architecture et fonction des macromolécules biologiques ( AFMB ), Centre National de la Recherche Scientifique ( CNRS ) -Aix Marseille Université ( AMU ) -Institut National de la Recherche Agronomique ( INRA ), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), and Dumonceaud, Corinne
Subjects: animal structures, medicine.drug_class, Stereochemistry, Androctonus australis, Molecular Sequence Data, Static Electricity, Immunology, Molecular Modeling, Scorpion Venoms, Enzyme-Linked Immunosorbent Assay, Biology, Crystallography, X-Ray, Monoclonal antibody, complex mixtures, Biochemistry, Epitope, Antibodies, Sodium Channels, Scorpions, Epitopes, 03 medical and health sciences, Protein structure, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Antigen, medicine, Animals, Amino Acid Sequence, Antigens, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 030304 developmental biology, Antiserum, 0303 health sciences, Dose-Response Relationship, Drug, Sequence Homology, Amino Acid, 030302 biochemistry & molecular biology, Cell Biology, Analytical Biochemistry, biology.organism_classification, Protein Structure, Tertiary, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Kinetics, Docking (molecular), Protein Structure and Folding, Crystal Structure, Immunotherapy, Neurotoxin
Abstract: International audience; The Old World scorpion Androctonus australis hector (Aah) produces one of the most lethal venoms for humans. Peptidic α-toxins AahI to AahIV are responsible for its potency, with AahII accounting for half of it. All four toxins are high affinity blockers of the fast inactivation phase of mammalian voltage-activated Na(+) channels. However, the high antigenic polymorphism of α-toxins prevents production of a polyvalent neutralizing antiserum, whereas the determinants dictating their trapping by neutralizing antibodies remain elusive. From an anti-AahII mAb, we generated an antigen binding fragment (Fab) with high affinity and selectivity for AahII and solved a 2.3 Å-resolution crystal structure of the complex. Sequestering of the C-terminal region of the bound toxin within a groove formed by the Fab combining loops is associated with a toxin orientation and main and side chain conformations that dictate the AahII antigenic specificity and efficient neutralization. From an anti-AahI mAb, we also preformed and crystallized a high affinity AahI-Fab complex. The 1.6 Å-resolution structure solved revealed a Fab molecule devoid of a bound AahI and with combining loops involved in packing interactions, denoting expulsion of the bound antigen upon crystal formation. Comparative analysis of the groove-like combining site of the toxin-bound anti-AahII Fab and planar combining surface of the unbound anti-AahI Fab along with complementary data from a flexible docking approach suggests occurrence of distinctive trapping orientations for the two toxins relative to their respective Fab. This study provides complementary templates for designing new molecules aimed at capturing Aah α-toxins and suitable for immunotherapy.
Published: 2012

28. The nucleus accumbens 5-HTR₄-CART pathway ties anorexia to hyperactivity

Author: Jean, A., Laurent, L., Bockaert, J., Charnay, Y., Dusticier, N., Nieoullon, A., Barrot, M., Neve, R., Compan, V., 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), Laboratoire de Neurosciences Intégratives et Cliniques - UFC (EA 481) (NEURO), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Franche-Comté (UFC), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS), Hôpitaux Universitaires de Genève (HUG), Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology (MIT), Université de Nîmes (UNIMES), 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 ), Laboratoire de Neurosciences Intégratives et Cliniques - UFC ( NEURO ), Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Institut de Biologie du Développement de Marseille ( IBDM ), Hôpitaux Universitaires de Genève ( HUG ), Institut des Neurosciences Cellulaires et Intégratives ( INCI ), Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ), Massachusetts Institute of Technology ( MIT ), Université de Nîmes ( UNIMES ), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), and Laboratoire de Neurosciences Intégratives et Cliniques - UFC (UR 481) (NEURO)
Subjects: MESH : Cocaine, MESH : Amphetamine, MESH : Male, MESH : Piperidines, MESH : Nucleus Accumbens, MESH : Propane, MESH: Receptors, Serotonin, 5-HT4, MESH : Real-Time Polymerase Chain Reaction, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Mice, Knockout, MESH: Propane, MESH: Cocaine, MESH : Mice, mental disorders, MESH: Amphetamine, MESH : Hyperkinesis, MESH: Animals, MESH: Hyperkinesis, MESH : N-Methyl-3,4-methylenedioxyamphetamine, MESH: Mice, MESH : Anorexia, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, MESH: Real-Time Polymerase Chain Reaction, digestive, oral, and skin physiology, MESH : Receptors, Serotonin, 5-HT4, MESH: Male, MESH: Piperidines, MESH : Serotonin 5-HT4 Receptor Antagonists, MESH : Mice, Knockout, MESH: N-Methyl-3,4-methylenedioxyamphetamine, MESH: Serotonin 5-HT4 Receptor Antagonists, MESH: Anorexia, MESH : Animals, MESH: Nucleus Accumbens
Abstract: International audience; In mental diseases, the brain does not systematically adjust motor activity to feeding. Probably, the most outlined example is the association between hyperactivity and anorexia in Anorexia nervosa. The neural underpinnings of this 'paradox', however, are poorly elucidated. Although anorexia and hyperactivity prevail over self-preservation, both symptoms rarely exist independently, suggesting commonalities in neural pathways, most likely in the reward system. We previously discovered an addictive molecular facet of anorexia, involving production, in the nucleus accumbens (NAc), of the same transcripts stimulated in response to cocaine and amphetamine (CART) upon stimulation of the 5-HT(4) receptors (5-HTR(4)) or MDMA (ecstasy). Here, we tested whether this pathway predisposes not only to anorexia but also to hyperactivity. Following food restriction, mice are expected to overeat. However, selecting hyperactive and addiction-related animal models, we observed that mice lacking 5-HTR(1B) self-imposed food restriction after deprivation and still displayed anorexia and hyperactivity after ecstasy. Decryption of the mechanisms showed a gain-of-function of 5-HTR(4) in the absence of 5-HTR(1B), associated with CART surplus in the NAc and not in other brain areas. NAc-5-HTR(4) overexpression upregulated NAc-CART, provoked anorexia and hyperactivity. NAc-5-HTR(4) knockdown or blockade reduced ecstasy-induced hyperactivity. Finally, NAc-CART knockdown suppressed hyperactivity upon stimulation of the NAc-5-HTR(4). Additionally, inactivating NAc-5-HTR(4) suppressed ecstasy's preference, strengthening the rewarding facet of anorexia. In conclusion, the NAc-5-HTR(4)/CART pathway establishes a 'tight-junction' between anorexia and hyperactivity, suggesting the existence of a primary functional unit susceptible to limit overeating associated with resting following homeostasis rules.
Published: 2012

29. Cyclin-dependent kinase inhibitor 1B (CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds

Author: Misu Lee, Thierry Brue, Adrian Daly, M. Tichomirowa, F. Archambeaud, Vincent Rohmer, Emily Castermans, Patrice Rodien, Maria Yaneva, Marily Theodoropoulou, Françoise Borson-Chazot, Antoine Tabarin, Brigitte Delemer, Véronique Kerlan, Anne Barlier, Ilaria Marinoni, Christine Cortet Rudelli, Alain Enjalbert, Bruno Estour, J.-L. Sadoul, Carmen Fajardo Montañana, Marie Lise Jaffrain-Rea, Luciana Ansaneli Naves, Vincent Bours, Jean-Louis Wémeau, Sabina Zacharieva, Alfred Penfornis, Natalia S. Pellegata, Mirtha Guitelman, P. Lecomte, Philippe Caron, Catherine Verhaege, Albert Beckers, Fabio R. Faucz, Institute of Pathology [Neuherberg] ( PATH ), Helmholtz-Zentrum München ( HZM ), 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 ), Centre de recherches métalexicographiques et dictionnairiques francophones ( CRMDF ), Université de Cergy Pontoise ( UCP ), Université Paris-Seine-Université Paris-Seine-Centre National de la Recherche Scientifique ( CNRS ), Service endocrinologie, Université Jean Monnet [Saint-Étienne] ( UJM ) -Hôpital Bellevue, Geothalg, Université de Liège, Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( PCVP / CARDIO ), Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Service de diabétologie - endocrinologie, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Service d'Endocrinologie - Diabète - Nutrition [Reims], Université de Reims Champagne-Ardenne ( URCA ) -Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims ( CHU Reims ), Service d'Endocrinologie ( CHRU - Endocrino ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Groupe d'Etude de la Thrombose de Bretagne Occidentale ( GETBO ), Université de Brest ( UBO ), Institute of Pathology [Neuherberg] (PATH), Helmholtz Zentrum München = German Research Center for Environmental Health, 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), Centre de recherches métalexicographiques et dictionnairiques francophones (CRMDF), Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Centre National de la Recherche Scientifique (CNRS), Service Endocrinologie - Diabète et Maladies métaboliques [CHU Saint-Etienne], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM), Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( UR 3920) (PCVP / CARDIO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service de Diabétologie - Endocrinologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université de Reims Champagne-Ardenne (URCA)-Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Service d'Endocrinologie (CHRU - Endocrino), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Helmholtz-Zentrum München (HZM), Université Jean Monnet [Saint-Étienne] (UJM)-Hôpital Bellevue, Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( EA 3920) (PCVP / CARDIO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Institut Brestois Santé Agro Matière (IBSAM), and Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO)
Subjects: Adenoma, Male, Cancer Research, Genotype, Endocrinology, Diabetes and Metabolism, In silico, 030209 endocrinology & metabolism, Pituitary tumours, Biology, medicine.disease_cause, Germline, no keywords, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Pituitary adenoma, Cell Line, Tumor, Acromegaly, Genetics, medicine, Humans, Family, Pituitary Neoplasms, CDKN1B-p27, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Multiple endocrine neoplasia, Carney complex, Mutation, Intracellular Signaling Peptides and Proteins, Genetic Variation, medicine.disease, Oncology, 030220 oncology & carcinogenesis, Cancer research, Female, CDKN1B, Cyclin-Dependent Kinase Inhibitor p27, HeLa Cells
Abstract: Familial isolated pituitary adenoma (FIPA) occurs in families and is unrelated to multiple endocrine neoplasia type 1 and Carney complex. Mutations inAIPaccount only for 15–25% of FIPA families.CDKN1Bmutations cause MEN4 in which affected patients can suffer from pituitary adenomas. With this study, we wanted to assess whether mutations inCDKN1Boccur among a large cohort ofAIPmutation-negative FIPA kindreds. Eighty-eightAIPmutation-negative FIPA families were studied and 124 affected subjects underwent sequencing ofCDKN1B. Functional analysis of putativeCDKN1Bmutations was performed usingin silicoandin vitroapproaches. GermlineCDKN1Banalysis revealed two nucleotide changes: c.286A>C (p.K96Q) and c.356T>C (p.I119T).In vitro, the K96Q change decreased p27 affinity for Grb2 but did not segregate with pituitary adenoma in the FIPA kindred. The I119T substitution occurred in a female patient with acromegaly. p27I119Tshows an abnormal migration pattern by SDS–PAGE. Three variants (p.S56T, p.T142T, and c.605+36C>T) are likely nonpathogenic becauseIn vitroeffects were not seen. In conclusion, two patients had germline sequence changes inCDKN1B, which led to functional alterations in the encoded p27 proteinsin vitro. Such rareCDKN1Bvariants may contribute to the development of pituitary adenomas, but their low incidence and lack of clear segregation with affected patients makeCDKN1Bsequencing unlikely to be of use in routine genetic investigation of FIPA kindreds. However, further characterization of the role ofCDKN1Bin pituitary tumorigenesis in these and other cases could help clarify the clinicopathological profile of MEN4.
Published: 2012

30. Pituitary stalk interruption syndrome in 83 patients: novel HESX1 mutation and severe hormonal prognosis in malformative forms

Author: Raja Brauner, Jean Gaudart, Gilbert Simonin, Thierry Brue, Emilie Carmona, Frédérique Albarel, Anne Barlier, Nourredine Kaffel, Frederic Castinetti, Alain Enjalbert, P. Lecomte, Alexandru Saveanu, Rachel Reynaud, 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), Université Paris Descartes - Paris 5 (UPD5), Méthodes Algorithmes pour l'Ordonnancement et les Réseaux (MAORE), 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), Laboratoire d'Enseignement et de Recherche sur le Traitement de l'Information Médicale (LERTIM), Université de la Méditerranée - Aix-Marseille 2, 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 ), Université Paris Descartes - Paris 5 ( UPD5 ), Méthodes Algorithmes pour l'Ordonnancement et les Réseaux ( MAORE ), 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 ), Laboratoire d'Enseignement et de Recherche sur le Traitement de l'Information Médicale ( LERTIM ), Methods, Algorithms for Operations REsearch (MAORE), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, MESH : Transcription Factors, Endocrinology, Diabetes and Metabolism, Pedigree chart, Hypopituitarism, MESH : Child, Preschool, medicine.disease_cause, MESH : Pituitary Gland, MESH: Magnetic Resonance Imaging, 0302 clinical medicine, Endocrinology, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], MESH : Child, MESH: Otx Transcription Factors, MESH: Pituitary Gland, MESH: SOXB1 Transcription Factors, MESH: Child, MESH : Female, MESH : Homeodomain Proteins, Child, 0303 health sciences, education.field_of_study, Mutation, Otx Transcription Factors, MESH : Otx Transcription Factors, MESH : SOXB1 Transcription Factors, Incidence (epidemiology), MESH : Infant, General Medicine, MESH: Transcription Factors, Magnetic Resonance Imaging, MESH: Infant, Ectopic Posterior Pituitary, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], medicine.anatomical_structure, Child, Preschool, Pituitary Gland, Cohort, Female, MESH : Mutation, medicine.medical_specialty, MESH: Mutation, Adolescent, MESH : Male, LIM-Homeodomain Proteins, Population, 030209 endocrinology & metabolism, Biology, 03 medical and health sciences, Posterior pituitary, Internal medicine, MESH : Adolescent, MESH : Magnetic Resonance Imaging, MESH: Homeodomain Proteins, medicine, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], education, 030304 developmental biology, Homeodomain Proteins, MESH: Adolescent, MESH: Humans, SOXB1 Transcription Factors, MESH : Humans, MESH: Child, Preschool, Infant, medicine.disease, MESH: Male, MESH: Female, Transcription Factors
Abstract: BackgroundPituitary stalk interruption syndrome (PSIS) is a particular entity in the population of patients with hypopituitarism. Only rare cases have a known genetic cause.Objectivesi) To compare subgroups with or without extra-pituitary malformations (EPM) in a cohort of PSIS patients to identify predictive factors of evolution, ii) to determine the incidence of mutations of the known pituitary transcription factor genes in PSIS.Study designWe analyzed features of 83 PSIS patients from 80 pedigrees and screened HESX1, LHX4, OTX2, and SOX3 genes.ResultsPSIS had a male predominance and was rarely familial (5%). Pituitary hypoplasia was observed only in the group with EPM. Multiple hormone deficits were observed significantly more often with versus without EPM (87.5 vs 69.5% respectively). Posterior pituitary location along the stalk was a significant protective factor regarding severity of hormonal phenotype. A novel HESX1 causative mutation was found in a consanguineous family, and two LHX4 mutations were present in familial PSIS.ConclusionPSIS patients with EPM had a more severe hormonal disorder and pituitary imaging status, suggesting an antenatal origin. HESX1 or LHX4 mutations accounted for
Published: 2011

31. A label-free biosensor assay for botulinum neurotoxin B in food and human serum

Author: Christelle Mazuet, Christian Lévêque, Emmanuel Jover, Géraldine Ferracci, Michael Seagar, Marie-Pierre Blanchard, Séverine Marconi, Michel R. Popoff, 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 ), Carcinogenèse Hépatique et Virologie Moléculaire, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre National de Référence des Bactéries Anaérobies et du Botulisme - Bactéries Anaérobies et Toxines ( CNR ), Institut Pasteur [Paris], Institut des Neurosciences Cellulaires et Intégratives ( INCI ), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique ( CNRS ), Unité de Neurobiologie des canaux Ioniques et de la Synapse ( UNIS - Inserm U1072 ), 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), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Référence des Bactéries Anaérobies et Botulisme - National Reference Center Anaerobic Bacteria and Botulism (CNR), Institut Pasteur [Paris] (IP), Institut des Neurosciences Cellulaires et Intégratives (INCI), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Unité de Neurobiologie des canaux Ioniques et de la Synapse (UNIS - Inserm U1072), and Centre National de Référence des Bactéries Anaérobies et du Botulisme - Bactéries Anaérobies et Toxines (CNR)
Subjects: Serum, Botulinum Toxins, MESH: Annexin A5, Vesicle-Associated Membrane Protein 2, medicine.medical_treatment, MESH : Corpus Striatum, 01 natural sciences, Biochemistry, Substrate Specificity, MESH: Botulinum Toxins, MESH: Helium, Mice, MESH : Glutamic Acid, Clostridium botulinum, MESH : Serum, MESH: Animals, MESH: Receptors, GABA-A, MESH : Adaptation, Physiological, MESH: Vesicle-Associated Membrane Protein 2, 0303 health sciences, VAMP2, MESH : Substrate Specificity, Vesicle, In vitro toxicology, MESH: Reference Values, MESH: Serum, MESH: Glutamic Acid, MESH : Protein Array Analysis, MESH : Pulmonary Artery, 3. Good health, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], MESH: Surface Plasmon Resonance, MESH : Thrombosis, MESH: N-Methylaspartate, MESH : Inert Gas Narcosis, MESH : Botulism, MESH : Synaptic Vesicles, Biological Assay, MESH: Membrane Proteins, MESH : Food, MESH : Surface Plasmon Resonance, MESH : Dopamine, MESH: Pulmonary Artery, Biophysics, MESH: Anesthetics, MESH: Botulism, MESH: Biological Assay, MESH: Tetralogy of Fallot, MESH : Atmospheric Pressure, Synaptic vesicle, MESH : Neurons, MESH : Food Analysis, 03 medical and health sciences, In vivo, Humans, MESH: Thrombosis, Molecular Biology, MESH : Crystallography, MESH: Receptors, N-Methyl-D-Aspartate, Protease, MESH: Humans, MESH : Tetralogy of Fallot, 010401 analytical chemistry, MESH: Child, Preschool, MESH : Humans, MESH: Atmospheric Pressure, MESH : Receptors, GABA-A, MESH : Muscle, Smooth, Vascular, Surface Plasmon Resonance, MESH : Clostridium botulinum, medicine.disease, 0104 chemical sciences, MESH: Peritoneovenous Shunt, Food, MESH : Membrane Proteins, MESH : Lipid Bilayers, MESH : Biological Assay, MESH : Receptors, N-Methyl-D-Aspartate, MESH : Annexin A5, Food Analysis, MESH: Neurons, Biosensing Techniques, MESH : Child, Preschool, MESH : Nitrogen, MESH: Corpus Striatum, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Botulism, Botulinum Toxins, Type A, MESH: Nitrogen, Chemistry, MESH: Protein Array Analysis, MESH : Rats, MESH: Lipid Bilayers, MESH: Crystallography, MESH : Hydrogen, MESH: Hydrogen, MESH: Muscle, Smooth, Vascular, MESH : Anesthetics, MESH : Botulinum Toxins, MESH: Fibrosis, MESH : Fibrosis, MESH: Inert Gas Narcosis, MESH : Urate Oxidase, Synaptic Vesicles, MESH : Peritoneovenous Shunt, MESH: Urate Oxidase, MESH : Vesicle-Associated Membrane Protein 2, MESH: Biosensing Techniques, MESH: Food, Carrot juice, MESH: Clostridium botulinum, MESH: Rats, MESH: Food Analysis, Protein Array Analysis, MESH: Substantia Nigra, MESH: Dopamine, In Vitro Techniques, MESH : Reference Values, MESH : Helium, MESH : Mice, medicine, Animals, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Mice, 030304 developmental biology, MESH : Substantia Nigra, MESH : Biosensing Techniques, Cell Biology, MESH: Synaptic Vesicles, Molecular biology, MESH: Adaptation, Physiological, Rats, MESH: Substrate Specificity, MESH : Animals, MESH : N-Methylaspartate
Abstract: International audience; Botulinum neurotoxins (BoNTs) are among the most toxic substances known. Surveillance and diagnostics require methods for rapid detection of BoNTs in complex media such as foodstuffs and human serum. We have developed in vitro assays to specifically detect the protease activity of botulinum neurotoxin B (BoNT/B) on a time scale of minutes. Cleavage of the BoNT/B substrate VAMP2, a membrane SNARE protein associated with synaptic vesicles, was monitored using real-time surface plasmon resonance to measure vesicle capture by specific antibodies coupled to microchips. The assay is functional in low-ionic-strength buffers and stable over a wide range of pH values (5.5-9.0). Endoproteolytic cleavage of VAMP2 was detected in 10 min with 2 pM native BoNT/B holotoxin. Contamination of liquid food products such as carrot juice, apple juice, and milk with low picomolar amounts of BoNT/B was revealed within 3h. BoNT/B activity was detected in sera from patients with type B botulism but not in healthy controls or patients with other neurological diseases. This robust, sensitive, and rapid protein chip assay is appropriate for monitoring BoNT/B in food products and diagnostic tests for type B botulism and could replace the current in vivo mouse bioassay.
Published: 2011

32. La neurobiologie de la nutrition. Une grande fonction neuroendocrine

Author: Rachidi, Fatima, Moyse, Emmanuel, 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), Aix-Marseille Université - Faculté des Sciences (AMU SCI), Aix Marseille Université (AMU), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Institut de psychiatrie et neurosciences (U894 / UMS 1266), 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 Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), 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 ), Aix-Marseille Université - Faculté des Sciences ( AMU SCI ), Aix Marseille Université ( AMU ), Physiologie de la reproduction et des comportements [Nouzilly] ( PRC ), Institut National de la Recherche Agronomique ( INRA ) -Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique ( CNRS ), Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Centre de Psychiatrie et Neurosciences (U894), and Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], [ SDV.OT ] Life Sciences [q-bio]/Other [q-bio.OT]
Abstract: absent
Published: 2011

33. Hepatocyte growth factor-Met signaling is required for Runx1 extinction and peptidergic differentiation in primary nociceptive neurons

Author: Françoise Helmbacher, Yang Liu, Igor M. Samokhvalov, Lise Rodat-Despoix, Patrick Delmas, Eduardo Gascon, Pascale Malapert, Aziz Moqrich, Stéphane Gaillard, Flavio Maina, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), 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), ANR-06-NEUR-0039,OlfLocalTrans,Traduction locale axonale et dendritique dans le développement et le renouvellement du système olfactif(2006), Institut de Biologie du Développement de Marseille ( IBDM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de recherche en neurobiologie - neurophysiologie de Marseille ( CRN2M ), and ANR-06-NEURO-0039,OlfLocalTrans,Traduction locale axonale et dendritique dans le développement et le renouvellement du système olfactif ( 2006 )
Subjects: MESH: Hepatocyte Growth Factor, MESH: Signal Transduction, Cellular differentiation, MESH : Neuropeptides, MESH: Proto-Oncogene Proteins c-met, MESH: Neuropeptides, MESH : Nociceptors, MESH: Mice, Knockout, Mice, 0302 clinical medicine, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Ganglia, Spinal, hemic and lymphatic diseases, MESH: Animals, MESH: Nociceptors, Receptor, Cells, Cultured, Mice, Knockout, 0303 health sciences, education.field_of_study, Hepatocyte Growth Factor, General Neuroscience, Nociceptors, Cell Differentiation, Articles, Proto-Oncogene Proteins c-met, MESH : Mice, Transgenic, Core Binding Factor Alpha 2 Subunit, embryonic structures, Nociceptor, Hepatocyte growth factor, MESH: Ganglia, Spinal, Signal transduction, MESH : Cell Differentiation, Signal Transduction, medicine.drug, MESH: Cells, Cultured, MESH : Core Binding Factor Alpha 2 Subunit, MESH: Cell Differentiation, MESH : Proto-Oncogene Proteins c-met, MESH: Mice, Transgenic, Models, Neurological, Population, Neuropeptide, MESH : Cell Lineage, Mice, Transgenic, Calcitonin gene-related peptide, Biology, 03 medical and health sciences, MESH: Models, Neurological, MESH : Mice, MESH : Cells, Cultured, medicine, Animals, MESH : Models, Neurological, Cell Lineage, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], education, MESH: Mice, 030304 developmental biology, MESH : Signal Transduction, Neuropeptides, MESH: Cell Lineage, MESH: Core Binding Factor Alpha 2 Subunit, MESH : Ganglia, Spinal, MESH : Hepatocyte Growth Factor, nervous system, MESH : Mice, Knockout, MESH : Animals, Neuroscience, 030217 neurology & neurosurgery
Abstract: Nociceptors in peripheral ganglia display a remarkable functional heterogeneity. They can be divided into the following two major classes: peptidergic and nonpeptidergic neurons. Although RUNX1 has been shown to play a pivotal role in the specification of nonpeptidergic neurons, the mechanisms driving peptidergic differentiation remain elusive. Here, we show that hepatocyte growth factor (HGF)-Met signaling acts synergistically with nerve growth factor-tyrosine kinase receptor A to promote peptidergic identity in a subset of prospective nociceptors. We providein vivoevidence that a population of peptidergic neurons, derived from the RUNX1 lineage, require Met activity for the proper extinction ofRunx1and optimal activation ofCGRP(calcitonin gene-related peptide). Moreover, we show that RUNX1 in turn represses Met expression in nonpeptidergic neurons, revealing a bidirectional cross talk between Met and RUNX1. Together, our novel findings support a model in which peptidergic versus nonpeptidergic specification depends on a balance between HGF-Met signaling andRunx1extinction/maintenance.
Published: 2010

34. Structural insights into the exquisite selectivity of neurexin/neuroligin synaptic interactions

Author: Palmer Taylor, Pascale Marchot, Géraldine Ferracci, Sandrine Conrod, Philippe Leone, Yves Bourne, Davide Comoletti, Simon U Garcia, Architecture et fonction des macromolécules biologiques (AFMB), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Université de Provence - Aix-Marseille 1, Department of pharmacology, University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), 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), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), University of California-University of California, Architecture et fonction des macromolécules biologiques ( AFMB ), Centre National de la Recherche Scientifique ( CNRS ) -Aix Marseille Université ( AMU ) -Institut National de la Recherche Agronomique ( INRA ), University of California [San Diego] ( UC San Diego ), Centre de recherche en neurobiologie - neurophysiologie de Marseille ( CRN2M ), and Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: Models, Molecular, MESH : Molecular Sequence Data, Neurexin, MESH : Alternative Splicing, Neuroligin, Plasma protein binding, MESH: Amino Acid Sequence, Crystallography, X-Ray, MESH: Synapses, MESH: Protein Structure, Tertiary, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 0302 clinical medicine, MESH: Nerve Tissue Proteins, Surface plasmon resonance, MESH : Nerve Tissue Proteins, 0303 health sciences, MESH : Amino Acid Sequence, MESH : Sequence Alignment, General Neuroscience, MESH: Alternative Splicing, MESH : Protein Binding, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], MESH: Surface Plasmon Resonance, Dissociation constant, Biochemistry, MESH: Membrane Proteins, MESH : Surface Plasmon Resonance, MESH : Carrier Proteins, MESH : Protein Structure, Tertiary, MESH : Synapses, MESH: Models, Molecular, Protein Binding, MESH : Models, Molecular, Cell Adhesion Molecules, Neuronal, Molecular Sequence Data, MESH: Sequence Alignment, Sequence alignment, Nerve Tissue Proteins, MESH: Carrier Proteins, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Humans, MESH: Protein Binding, Amino Acid Sequence, Binding site, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, MESH : Protein Processing, Post-Translational, 030304 developmental biology, Binding Sites, MESH: Humans, MESH: Molecular Sequence Data, General Immunology and Microbiology, MESH : Humans, Alternative splicing, Membrane Proteins, Surface Plasmon Resonance, MESH: Crystallography, X-Ray, Protein Structure, Tertiary, Alternative Splicing, MESH: Binding Sites, MESH : Membrane Proteins, MESH: Protein Processing, Post-Translational, Synapses, Biophysics, MESH : Crystallography, X-Ray, Carrier Proteins, Protein Processing, Post-Translational, Sequence Alignment, MESH : Binding Sites, 030217 neurology & neurosurgery
Abstract: International audience; The extracellular domains of neuroligins and neurexins interact through Ca(2+) to form flexible trans-synaptic associations characterized by selectivity for neuroligin or neurexin subtypes. This heterophilic interaction, essential for synaptic maturation and differentiation, is regulated by gene selection, alternative mRNA splicing and post-translational modifications. A new, 2.6 A-resolution crystal structure of a soluble neurexin-1beta-neuroligin-4 (Nrx1beta-NL4) complex permits a detailed description of the Ca(2+)-coordinated interface and unveils concerted positional rearrangements of several residues of NL4, not observed in neuroligin-1, associated with Nrx1beta binding. Surface plasmon resonance analysis of the binding of structure-guided Nrx1beta mutants towards NL4 and neuroligin-1 shows that flexibility of the Nrx1beta-binding site in NL4 is reflected in a greater dissociation constant of the complex and higher sensitivity to ionic strength and pH variations. Analysis of neuroligin mutants points to critical functions for two respective residues in neuroligin-1 and neuroligin-2 in governing the affinity of the complexes. Although neuroligin-1 and neuroligin-2 have pre-determined conformations that respectively promote and prevent Nrx1beta association, unique conformational reshaping of the NL4 surface is required to permit Nrx1beta association.
Published: 2010

35. Structural determinants for interaction of partial agonists with acetylcholine binding protein and neuronal α7 nicotinic acetylcholine receptor

Author: Sandrine Conrod, William R. Kem, Ryan E. Hibbs, Gerlind Sulzenbacher, Palmer Taylor, Pascale Marchot, Yves Bourne, Todd T. Talley, Jianxin Shi, Architecture et fonction des macromolécules biologiques (AFMB), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), 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), Department of Pharmacology, Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California [San Diego] (UC San Diego), University of California-University of California, Ingénierie des protéines (IP), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Architecture et fonction des macromolécules biologiques ( AFMB ), Centre National de la Recherche Scientifique ( CNRS ) -Aix Marseille Université ( AMU ) -Institut National de la Recherche Agronomique ( INRA ), National Cancer Institute ( NIH ), 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 ), University of California [San Diego] ( UC San Diego ), Ingénierie des protéines ( IP ), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique ( CNRS ), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), and University of California (UC)-University of California (UC)
Subjects: Models, Molecular, Agonist, Indoles, Protein Conformation, Pyridines, medicine.drug_class, Stereochemistry, [SDV]Life Sciences [q-bio], Tropisetron, Biology, Crystallography, X-Ray, Benzylidene Compounds, Partial agonist, Article, Anabasine, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, chemistry.chemical_compound, Acetylcholine binding, 0302 clinical medicine, Anabaseine, Aplysia, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Nicotinic Agonists, Receptor, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, 030304 developmental biology, Acetylcholine receptor, 0303 health sciences, [ SDV ] Life Sciences [q-bio], General Immunology and Microbiology, General Neuroscience, Hydrogen-Ion Concentration, Acetylcholine, Nicotinic acetylcholine receptor, Nicotinic agonist, chemistry, Biochemistry, Carrier Proteins, 030217 neurology & neurosurgery, Protein Binding
Abstract: International audience; The pentameric acetylcholine-binding protein (AChBP) is a soluble surrogate of the ligand binding domain of nicotinic acetylcholine receptors. Agonists bind within a nest of aromatic side chains contributed by loops C and F on opposing faces of each subunit interface. Crystal structures of Aplysia AChBP bound with the agonist anabaseine, two partial agonists selectively activating the alpha7 receptor, 3-(2,4-dimethoxybenzylidene)-anabaseine and its 4-hydroxy metabolite, and an indole-containing partial agonist, tropisetron, were solved at 2.7-1.75 A resolution. All structures identify the Trp 147 carbonyl oxygen as the hydrogen bond acceptor for the agonist-protonated nitrogen. In the partial agonist complexes, the benzylidene and indole substituent positions, dictated by tight interactions with loop F, preclude loop C from adopting the closed conformation seen for full agonists. Fluctuation in loop C position and duality in ligand binding orientations suggest molecular bases for partial agonism at full-length receptors. This study, while pointing to loop F as a major determinant of receptor subtype selectivity, also identifies a new template region for designing alpha7-selective partial agonists to treat cognitive deficits in mental and neurodegenerative disorders.
Published: 2009

36. Exploration of intraclonal adaptation mechanisms of Pseudomonas brassicacearum facing cadmium toxicity

Author: Lisa Sanchez, Sandrine Conrod, Agnes Fekete, Delphine Pages, Xavier Gidrol, Wafa Achouak, Philippe Schmitt-Kopplin, Thierry Heulin, Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) ( BIAM ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), 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 ), Laboratoire Biopuces ( BIOPUCES ), Chair of Analytical Food Chemistry, Technische Universität München [München] ( TUM ), International Consortium for the Environmental Implications of Nanotechnology (iCEINT), Aix en Provence, France, Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) (BIAM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), 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), Laboratoire Biopuces (BIOPUCES), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [ SDV.BV ] Life Sciences [q-bio]/Vegetal Biology, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Adaptation, Biological, Biology, Microbiology, Transcriptome, Cell wall, 03 medical and health sciences, chemistry.chemical_compound, Downregulation and upregulation, Pseudomonas, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Amino Acids, Ecology, Evolution, Behavior and Systematics, Research Articles, 030304 developmental biology, Oligonucleotide Array Sequence Analysis, 0303 health sciences, [ SDV ] Life Sciences [q-bio], 030306 microbiology, Microarray analysis techniques, Gene Expression Profiling, biology.organism_classification, Molecular biology, In vitro, Gene expression profiling, Oxidative Stress, Phenotype, Biochemistry, chemistry, Putrescine, Pseudomonas brassicacearum, Cadmium
Abstract: International audience; Pseudomonas brassicacearum forms phenotypic variants in vitro as well as in planta during root colonization under natural conditions, leading to subpopulations (phase I and II cells) that differ in colony morphology and production of exoenzymes/secondary metabolites. The maximal concentration of cadmium allowing both variants growth was 25 muM; however, phase II cells accumulated fivefold higher Cd than phase I cells, even though both variants showed the same growth rate and kinetics, comprising a long stasis period (50 h). The whole transcriptome analysis of both variants in response to Cd was investigated using the home-made DNA microarrays. This analysis revealed completely different adaptation mechanisms developed by each variant to withstand and grow in the presence of the toxic. A re-organization of the cell wall to limit Cd entrance was noticed for phase I cells, as genes encoding levan exopolymers were downregulated at the expense of an upregulation of genes encoding alginate, and an upregulation of transporters such as cadA, and a downregulation of copper transporters. Phase II cells were unable to prevent Cd entrance and recruited genes under the control of oxyR and soxR regulation to face osmotic and oxidant stresses generated by Cd. Putrescine and spermidine metabolism appeared to play a central role in Cd tolerance. Microarray data were validated by biological analyses such as motility, oxidative stress assay, metabolite profiling with ICR-FT/MS and UPLC, capillary electrophoresis analysis of biogenic amines.
Published: 2007

37. Phenotypic Variation of Pseudomonas brassicacearum as a Plant Root-Colonization Strategy

Author: Valérie Cohen, Sandrine Conrod, Thierry Heulin, Wafa Achouak, International Consortium for the Environmental Implications of Nanotechnology (iCEINT), Aix en Provence, France, 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 ), Centre Lillois d’Études et de Recherches Sociologiques et Économiques - UMR 8019 ( CLERSE ), Université de Lille-Université du Littoral Côte d'Opale ( ULCO ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) ( BIAM ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), 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), Centre Lillois d’Études et de Recherches Sociologiques et Économiques - UMR 8019 (CLERSÉ), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) (BIAM), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: [ SDV.BV ] Life Sciences [q-bio]/Vegetal Biology, Physiology, [SDV]Life Sciences [q-bio], Population, Arabidopsis, Colony Count, Microbial, Biology, Plant Roots, Microbiology, Agar plate, 03 medical and health sciences, Pseudomonas, Arabidopsis thaliana, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, education, Soil Microbiology, 030304 developmental biology, Gel electrophoresis, 0303 health sciences, Rhizosphere, education.field_of_study, [ SDV ] Life Sciences [q-bio], 030306 microbiology, Genetic Variation, General Medicine, biology.organism_classification, Molecular biology, Culture Media, Phenotype, Pseudomonas brassicacearum, Agronomy and Crop Science, Flagellin, Plasmids, Pseudomonadaceae
Abstract: International audience; Pseudomonas brassicacearum was isolated as a major root-colonizing population from Arabidopsis thaliana. The strain NFM421 of P. brassicacearum undergoes phenotypic variation during A. thaliana and Brassica napus root colonization in vitro as well as in soil, resulting in different colony appearance on agar surfaces. Bacteria forming translucent colonies (phase II cells) essentially were localized at the surface of young roots and root tips, whereas wild-type cells (phase I cells) were localized at the basal part of roots. The ability of phase II cells to spread and colonize new sites on root surface correlates with over-production of flagellin as evidenced by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of surface proteins and microsequencing. Moreover, phase II cells showed a higher ability to swim and to swarm on semisolid agar medium. Phase I and phase II cells of P. brassicacearum NFM421 were tagged genetically with green fluorescent protein and red fluorescent protein. Confocal scanning laser microscopy was used to localize phase II cells on secondary roots and root tips of A. thaliana, whereas phase I cells essentially were localized at the basal part of roots. These experiments were conducted in vitro and in soil. Phenotypic variation on plant roots is likely to be a colonization strategy that may explain the high colonization power of P. brassicacearum.
Published: 2004

38. Variability of quantal NMDA to AMPA current ratio in nucleus tractus solitarii neurons

Author: Layal Saliba, Fabien Tell, Florian Gackière, Jean-Pierre Kessler, Caroline Strube, 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), and Strube, Caroline
Subjects: 0303 health sciences, [SHS.SOCIO]Humanities and Social Sciences/Sociology, Chemistry, musculoskeletal, neural, and ocular physiology, Kainate receptor, AMPA receptor, 03 medical and health sciences, Glutamatergic, 0302 clinical medicine, nervous system, Silent synapse, Excitatory postsynaptic potential, Biophysics, NMDA receptor, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Glutamatergic synapse, Long-term depression, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: The ratio between AMPA and NMDA receptors is a key factor governing integrative and plastic properties of excitatory glutamatergic synapses. To determine whether the respective proportions of AMPA and NMDA receptors are similar or vary across a neuron's synapse, we analyzed the variability of NMDA and AMPA currents in quantal responses recorded from neurons located in the nucleus tractus solitarii. We found that the average NMDA to AMPA current ratio strongly differed between recorded neurons and that most of the intra-neuronal current ratio variability was attributable to fluctuations in NMDA current. We next performed computer simulations with a Monte Carlo model of a glutamatergic synapse to estimate the part of AMPA and NMDA currents fluctuations induced by stochastic factors. We found that NMDA current variability mainly resulted from strong channel noise with few influence of release variations. On the contrary, partly because of the presence of subconductance states, AMPA receptor channel noise was low and AMPA current fluctuations tightly reflected changes in the amount of glutamate released. We next showed that these two factors, channel noise and fluctuations in glutamate release, were sufficient to explain the observed variability of the NMDA to AMPA current ratio in quantal events recorded from the same neuron. We therefore concluded that the proportion of AMPA and NMDA receptors was similar, or roughly similar, across synapses onto the same target cell.
Published: 2021

39. Astrocytic VMAT2 in the developing prefrontal cortex is required for normal grooming behavior in mice

Author: Bianca Maria Bondiolotti, P. Bezzi, Nicole Déglon, Alicia Molinero Perez, Luca Pucci, Corrado Calì, Francesco Petrelli, Jean-Pierre Mothet, Tamara Zehnder, Glenn Dallérac, Lorenzo Magrassi, Bruno Giros, Fulvio Magara, Linda D. Simmler, Université de Lausanne = University of Lausanne (UNIL), 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), McGill University = Université McGill [Montréal, Canada], Università degli Studi di Pavia = University of Pavia (UNIPV), Laboratoire Lumière, Matière et Interfaces (LuMIn), CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), Université de Genève = University of Geneva (UNIGE), University of Rome la Sapienza, Departement of internal medicine and laboratory of gene expression, Dallérac, Glenn, Lausanne University Hospital, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), University of Lausanne (UNIL), Università degli Studi di Pavia, and University of Geneva [Switzerland]
Subjects: 0303 health sciences, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Striatum, AMPA receptor, Biology, Vesicular monoamine transporter 2, Phenotype, behavioral disciplines and activities, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, nervous system, Dopamine, Obsessive compulsive, medicine, biology.protein, NMDA receptor, Prefrontal cortex, Neuroscience, 030217 neurology & neurosurgery, psychological phenomena and processes, 030304 developmental biology, medicine.drug
Abstract: Astrocytes control synaptic activity by modulating peri-synaptic concentrations of ion and neurotransmitters including dopamine and, as such, can be critically involved in the modulation of some aspect of mammalian behavior. Here we report that genetic mouse model with a reduced medial prefrontal cortex (mPFC) dopamine levels, arising from astrocyte-specific conditional deletion of vesicular monoamine transporter 2 (VMAT2; aVMTA2cKO mice) shows excessive grooming and anxiety-like behaviour. The VMAT2cKO mice also develop a synaptic pathology, expressed through increased relative AMPA vs. NMDA receptor currents in synapses of the dorsal striatum receiving inputs from the mPFC. Importantly, behavioural and synaptic phenotypes are prevented by reexpression of mPFC VMAT2, showing that the deficits are driven by mPFC astrocytes. By analysing human tissue samples, we found that VMAT2 is expressed in human mPFC astrocytes, corroborating the potential translational relevance of our observations in mice. Our study shows that impairments of the astrocytic-control of dopamine in the mPFC has a profound impact on circuit function and behaviours, which resemble symptoms of anxiety disorders and obsessive compulsive disorder (OCD).
Published: 2021

40. Advancing respiratory-cardiovascular physiology with the working heart-brainstem preparation over 25 years

Author: Julian F. R. Paton, Benedito H. Machado, Davi J. A. Moraes, Daniel B. Zoccal, Ana P. Abdala, Jeffrey C. Smith, Vagner R. Antunes, David Murphy, Mathias Dutschmann, Rishi R. Dhingra, Robin McAllen, Anthony E. Pickering, Richard J. A. Wilson, Trevor A. Day, Nicole O. Barioni, Andrew M. Allen, Clément Menuet, Joseph Donnelly, Igor Felippe, Walter M. St‐John, Department of Economics, University of Wisconsin, UCL, Institute of Neurology [London], 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), Université Mount Royal/Mount Royal University [Calgary, AB, Canada] (MRU), J. Craig Venter Institute [La Jolla, USA] (JCVI), University of California [San Diego] (UC San Diego), University of California (UC), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and A.P.A. -R01 AT008632 -CRCNS. A.M.A. -Australian Research Council (DP170104582) and Australian National Health and Medical Research Council (APP1156727). V.R.A. Sao Paulo Research Foundation (FAPESP 2019/19894-8) and National Council for Development of Science and Technology (CNPq -Research Fellow: no. 304970/2017-4). R.R.D. -National Institutes of Health (U01 EB021960). J.D. -Clinical Fellowship from the Neurological Foundation of New Zealand. I.S.A.F. -University of Auckland PhD scholarship. B.H.M. Sao Paulo Research Foundation (FAPESP-2018/15957-2) and the National Council for Development of Science and Technology (CNPq-309338/2020-4). C.M. -Agence Nationale de la Recherche (ANR-21-CE14-0009-01). D.J.A.M. -FAPESP (2019/11863-6 and 2021/06886-7) and CNPq (437375/2018-8 and 313719/2020-9). J.F.R.P. -Health Research Council of New Zealand (19/687) and the Sidney Taylor Trust. A.E.P. was funded by a Wellcome Trust Clinical research fellowship. J.C.S. -Intramural Research Program of the NIH, NINDS. T.A.D. -Natural Sciences and Engineering Research Council of Canada Discovery grants (NSERC RGPIN-2016-04915). R.J.A. W. -Canada Institute of Health Research (CIHR201603PJT/366421). N.O.B. -SIDS Calgary Society.
Subjects: gasp, hypertension, hypoxia, Physiology, [SDV]Life Sciences [q-bio], chemoreceptor, Respiration, respiratory rhythm generation, Kölliker–Fuse, Heart, cardiac ganglion, sympathetic, sympathetic-respiratory coupling, Rats, RATOS, Cardiovascular Physiological Phenomena, Mice, eupnoea, Animals, cardiac vagus, pre-Bötzingercomplex, Lung, Anaesthesia Pain and Critical Care, Brain Stem
Abstract: Twenty-five years ago, a new physiological preparation called the working heart–brainstem preparation (WHBP) was introduced with the claim it would provide a new platform allowing studies not possible before in cardiovascular, neuroendocrine, autonomic and respiratory research. Herein, we review some of the progress made with the WHBP, some advantages and disadvantages along with potential future applications, and provide photographs and technical drawings of all the customised equipment used for the preparation. Using mice or rats, the WHBP is an in situ experimental model that is perfused via an extracorporeal circuit benefitting from unprecedented surgical access, mechanical stability of the brain for whole cell recording and an uncompromised use of pharmacological agents akin to in vitro approaches. The preparation has revealed novel mechanistic insights into, for example, the generation of distinct respiratory rhythms, the neurogenesis of sympathetic activity, coupling between respiration and the heart and circulation, hypothalamic and spinal control mechanisms, and peripheral and central chemoreceptor mechanisms. Insights have been gleaned into diseases such as hypertension, heart failure and sleep apnoea. Findings from the in situ preparation have been ratified in conscious in vivo animals and when tested have translated to humans. We conclude by discussing potential future applications of the WHBP including two-photon imaging of peripheral and central nervous systems and adoption of pharmacogenetic tools that will improve our understanding of physiological mechanisms and reveal novel mechanisms that may guide new treatment strategies for cardiorespiratory diseases.
Published: 2021

41. Dopaminergic neuromodulation of prefrontal cortex activity requires the NMDA receptor coagonist d-serine

Author: Staffan Schmidt, Joseph T. Coyle, Micaela Galante, Glenn Dallérac, Kevin C. F. Fone, Silvia Sacchi, Grégoire Levasseur, Jan Kehr, David J. G. Watson, Brigitte Potier, Xia Li, Pierre Lecouflet, Alain M. Gardier, Loredano Pollegioni, Thu Ha Pham, Rachel Asselot, Angelo Contarino, Pascal Fossat, Jean-Pierre Mothet, Millan Mark, Andrey Besedin, Ginetta Collo, Thomas Freret, Jean-Michel Rivet, Nadege Morisot, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire Lumière, Matière et Interfaces (LuMIn), CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), Institut de Neurosciences cognitives et intégratives d'Aquitaine (INCIA), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS), Universitá degli Studi dell’Insubria = University of Insubria [Varese] (Uninsubria), 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), Université Paris Saclay (COmUE), University of Nottingham, UK (UON), Pronexus Analytical AB, 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), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherches SERVIER (IRS), Harvard Medical School [Boston] (HMS), McLean Hospital [Belmont, Ma.], Università degli Studi di Brescia = University of Brescia (UniBs), Faculté de Pharmacie [Châtenay-Malabry], Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11)-Université Paris-Sud - Paris 11 (UP11)-Université Paris-Saclay, The Protein Factory 2.0, Dipartimento di Biotecnologie e Scienze della Vita, Laboratoire de Neuropharmacologie, Centre de Recherche en Epidémiologie et Santé des Populations, School of Life Sciences, Queen's Medical Centre, Centre for Thérapeutique Innovation in Neuropsychiatry, Department of Psychiatry, Harvard Medical School, USA, Laboratory for Psychiatric and Molecular Neuroscience, Università degli Studi di Brescia [Brescia], The ProFactory 2.0, Dipartimento di Biotecnologie e Scienze della Vita, Universitá degli Studi dell’Insubria, and Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, serine racemase knockout mice, D1- and D2-type receptors, NMDA receptors, d-serine, schizophrenia, Dopamine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Racemases and Epimerases, Glutamic Acid, Prefrontal Cortex, Biology, Receptors, N-Methyl-D-Aspartate, Synaptic Transmission, Receptors, Dopamine, Mice, 03 medical and health sciences, Glutamatergic, 0302 clinical medicine, Neuromodulation, Serine, medicine, Animals, Prefrontal cortex, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Multidisciplinary, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Dopaminergic, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Long-term potentiation, D-serine, Schizophrenia, Serine racemase knockout mice, Biological Sciences, medicine.anatomical_structure, Synaptic plasticity, NMDA receptor, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience, 030217 neurology & neurosurgery, medicine.drug
Abstract: International audience; Prefrontal control of cognitive functions critically depends upon glutamatergic transmission and N-methyl D-aspartate (NMDA) receptors, the activity of which is regulated by dopamine. Yet whether the NMDA receptor coagonist d -serine is implicated in the dopamine–glutamate dialogue in the prefrontal cortex (PFC) and other brain areas remains unexplored. Here, using electrophysiological recordings, we show that d -serine is required for the fine-tuning of glutamatergic neurotransmission, neuronal excitability, and synaptic plasticity in the PFC through the actions of dopamine at D 1 and D 3 receptors. Using in vivo microdialysis, we show that D 1 and D 3 receptors exert a respective facilitatory and inhibitory influence on extracellular levels and activity of d -serine in the PFC, with actions expressed primarily via the cAMP/protein kinase A (PKA) signaling cascade. Further, using functional magnetic resonance imaging (fMRI) and behavioral assessment, we show that d -serine is required for the potentiation of cognition by D 3 R blockade as revealed in a test of novel object recognition memory. Collectively, these results unveil a key role for d -serine in the dopaminergic neuromodulation of glutamatergic transmission and PFC activity, findings with clear relevance to the pathogenesis and treatment of diverse brain disorders involving alterations in dopamine–glutamate cross-talk.
Published: 2021

42. 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

43. Cervical osteomyelitis: A new identity of dreaded complication following pharyngeal cancer treatment

Author: Patrick Dessi, Nicolas Fakhry, Stéphane Fuentes, Andreas Stein, Thomas Graillon, Matthieu Bardou, Piseth Seng, Emmanuel Zamparini, Aix-Marseille Université - Faculté de médecine (AMU MED), Aix Marseille Université (AMU), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Service des Maladies Infectieuses et Tropicales (SMIT Marseille), Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), ORL et Chirurgie cervico-faciale pédiatrique - [Hôpitaux Timone et Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)- Hôpital Nord [CHU - APHM], Laboratoire Parole et Langage (LPL), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), 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), Département de Neurochirurgie [CHU Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), LA CONCEPTION - Service ORL et chirurgie cervico-faciale [CHU- APHM], Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), CCSD, Accord Elsevier, Service des Maladies Infectieuses et Tropicales [Hôpital de la Conception] (SMIT), and Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU)- Hôpital Nord [CHU - APHM]-Assistance Publique - Hôpitaux de Marseille (APHM)
Subjects: Male, 0301 basic medicine, Microbiology (medical), [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine.medical_specialty, [SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, Cutaneous Fistula, Fistula, medicine.medical_treatment, 030106 microbiology, Laryngectomy, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cervical osteomyelitis, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, Postoperative Complications, 0302 clinical medicine, Anti-Infective Agents, [SDV.CAN] Life Sciences [q-bio]/Cancer, Pharyngeal cancer, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine, Humans, lcsh:RC109-216, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, Cervical cancer, business.industry, Mortality rate, Osteomyelitis, Pharyngeal Neoplasms, General Medicine, Middle Aged, medicine.disease, 3. Good health, Surgery, Treatment Outcome, Infectious Diseases, Debridement, Pharynx, Female, Complication, business, Chemoradiotherapy, Follow-Up Studies
Abstract: Background: Cervical osteomyelitis following the treatment of pharyngeal cancer with laryngectomy and chemoradiotherapy is poorly reported. Methods: Six cases of cervical osteomyelitis occurring over a 1-year period are described herein. These are reviewed alongside four cases reported previously in the literature. Results: Among the total 10 cases, the average age of the patients was 58.7 years. The period between laryngectomy and the diagnosis of cervical osteomyelitis was on average 3 years and 1 month and the male to female sex ratio was 9:1. Two patients had a history of cervical fistula with an esophageal prosthesis, one had a spontaneous cervical fistula, one had a pharyngeal cutaneous fistula, and one had an esophageal prosthesis without any fistula. At the time of diagnosis, seven had a history of cervical pain (70%) and nine had a neurological deficit (90%). Seven patients (70%) underwent surgery; one (10%) was contraindicated for a general anesthetic and two (20%) died before any intervention. The indication for surgery was a neurological deficit for six patients (60%) and the requirement for lavage and debridement for two patients (20%). The average length of antimicrobial treatment was 12.7 weeks. The outcome was favorable for six patients. Four patients died. Conclusions: Cervical osteomyelitis is a serious but rarely reported complication following the treatment of pharyngeal cancer with chemoradiotherapy and laryngectomy. Cervical pain was the first sign to appear, sometimes 1 year before any other sign. Physicians should be aware of this dreaded complication, which is probably underdiagnosed and is related to an increased mortality rate. Keywords: Cervical osteomyelitis, Laryngectomy, Larynx carcinoma, Cervical cancer, Infection
Published: 2019

44. Ion channels as key partners of cytoskeleton in cancer disease

Author: Mohamed Chamlali, Halima Ouadid-Ahidouch, Lise Rodat-Despoix, 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), Laboratoire de Physiologie Cellulaire et Moléculaire - UR UPJV 4667 (LPCM), and Université de Picardie Jules Verne (UPJV)
Subjects: Scaffold protein, Cancer Research, Chemistry, [SDV]Life Sciences [q-bio], Cancer, Disease, medicine.disease, Ion Channels, Cell biology, Oncology, Intracellular signaling pathways, Neoplasms, Genetics, medicine, Humans, Cellular Morphology, Signal transduction, Cytoskeleton, Ion channel
Abstract: International audience; Several processes occur during tumor development including changes in cell morphology, a reorganization of the expression and distribution of the cytoskeleton proteins as well as ion channels. If cytoskeleton proteins and ion channels have been widely investigated in understanding cancer mechanisms, the interaction between these two elements and the identification of the associated signaling pathways are only beginning to emerge. In this review, we summarize the work published over the past 15 years relating to the roles played by ion channels in these mechanisms of reorganization of the cellular morphology, essential to metastatic dissemination, both through the physical interactions with elements of the cytoskeleton and by intracellular signaling pathways involved.
Published: 2021

45. Colour-blind Diversity. How the Diversity Label Reshaped Anti-discrimination Policies in Three French Local Governments

Author: Laure Bereni, Manon Torres, Renaud Epstein, Epstein, Renaud, Karen Schönwälder, Centre Maurice Halbwachs (CMH), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS), Groupe d'Analyse des Politiques Publiques (GAPP), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Centre de recherches sociologiques sur le droit et les institutions pénales (CESDIP), CY Cergy Paris Université (CY)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Ministère de la Justice-Centre National de la Recherche Scientifique (CNRS), Institut national d'études démographiques (INED), École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Ministère de la Justice-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cultural Studies, Sociology and Political Science, [SHS.SOCIO] Humanities and Social Sciences/Sociology, media_common.quotation_subject, 0507 social and economic geography, colour-blindness, Public administration, Colour blind, Political science, 050602 political science & public administration, certificationlabel, ComputingMilieux_MISCELLANEOUS, media_common, Diversity, [SHS.SOCIO]Humanities and Social Sciences/Sociology, 05 social sciences, 16. Peace & justice, [SHS.SCIPO]Humanities and Social Sciences/Political science, 0506 political science, anti-discriminationpolicy, Anthropology, Local government, localgovernment, France, 050703 geography, Qualitative research, Diversity (politics)
Abstract: International audience; Drawing on the qualitative study of three French local governments (Paris, Nantes and the Seine-Saint-Denis department), this article examines the implementation of local anti-discrimination policy during the 2010s. To what extent have these local governments, particularly eager to assert "diversity" values, renegotiated the dominant, colour-blind perspective prevailing at the national level? To address this question, we examined how they used a policy instrument called the 'Diversity Label'. We found that in the three cases, the commitment to the label reinforced both the institutionalization and the managerialization of anti-discrimination policy. Yet, in Nantes and Paris, it also led to a deracialization of anti-discrimination policy-i.e. to the obliteration of its ethno-racial dimension. The Seine-Saint-Denis department, where the majority group tends to become a minority, appears as a contrasting case, as ethno-racial concerns have remained central.
Published: 2021

46. Quantitative assessment of sciatic nerve changes in CMT1A patients using magnetic resonance neurography

Author: Fortanier, Etienne, Ogier, Augustin C., Delmont, Emilien, Lefebvre, Marie‐Noëlle, Viout, Patrick, Guye, Maxime, Bendahan, David, Attarian, Shahram, Centre de référence des maladies neuromusculaires et de la SLA, Hôpital de la Timone [CHU - APHM] (TIMONE), Images et Modèles (I&M), Laboratoire d'Informatique et Systèmes (LIS), Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), 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), CIC-CPCET, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 7339, Centre National de la Recherche Scientifique, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)
Subjects: Charcot-Marie-Tooth type 1A, neurography, quantitative, muscle, [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS, MRI
Abstract: International audience
Published: 2020

47. Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection

Author: Nouara Yahi, Coralie Di Scala, Jacques Fantini, Henri Chahinian, Institut National des Sciences Appliquées - Centre Val de Loire (INSA CVL), Institut National des Sciences Appliquées (INSA), Aix Marseille Université (AMU), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Debanne, Dominique, Unité de Neurobiologie des canaux Ioniques et de la Synapse (UNIS - Inserm U1072), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)
Subjects: Models, Molecular, 0301 basic medicine, [SDV]Life Sciences [q-bio], Spike, medicine.disease_cause, 0302 clinical medicine, Sequence Analysis, Protein, Pharmacology (medical), Molecular Targeted Therapy, 030212 general & internal medicine, skin and connective tissue diseases, ComputingMilieux_MISCELLANEOUS, Coronavirus, Host cell surface, Chloroquine, General Medicine, 3. Good health, [SDV] Life Sciences [q-bio], Drug repositioning, Infectious Diseases, Spike Glycoprotein, Coronavirus, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, medicine.symptom, Coronavirus Infections, Hydroxychloroquine, Microbiology (medical), Viral protein, Pneumonia, Viral, 030106 microbiology, Biology, Virus, Betacoronavirus, 03 medical and health sciences, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Protein Structure, Quaternary, Pandemics, Ganglioside, SARS-CoV-2, COVID-19, Virology, Protein Structure, Tertiary, Mechanism of action, Viral replication, Pandemic SARS-CoV-2
Abstract: International audience; The recent emergence of the novel pathogenic SARS-coronavirus 2 (SARS-CoV-2) is responsible for a worldwide pandemic. Given the global health emergency, drug repositioning is the most reliable option to design an efficient therapy for infected patients without delay. The first step of the viral replication cycle [i.e. attachment to the surface of respiratory cells, mediated by the spike (S) viral protein] offers several potential therapeutic targets. The S protein uses the angiotension-converting enzyme-2 (ACE-2) receptor for entry, but also sialic acids linked to host cell surface gangliosides. Using a combination of structural and molecular modelling approaches, this study showed that chloroquine (CLQ), one of the drugs currently under investigation for SARS-CoV-2 treatment, binds sialic acids and gangliosides with high affinity. A new type of ganglioside-binding domain at the tip of the N-terminal domain of the SARS-CoV-2 S protein was identified. This domain (111-158), which is fully conserved among clinical isolates worldwide, may improve attachment of the virus to lipid rafts and facilitate contact with the ACE-2 receptor. This study showed that, in the presence of CLQ [or its more active derivative, hydroxychloroquine (CLQ-OH)], the viral S protein is no longer able to bind gangliosides. The identification of this new mechanism of action of CLQ and CLQ-OH supports the use of these repositioned drugs to cure patients infected with SARS-CoV-2. The in-silico approaches used in this study might also be used to assess the efficiency of a broad range of repositioned and/or innovative drug candidates before clinical evaluation.
Published: 2020

48. Dysfunction of homeostatic control of dopamine by astrocytes in the developing prefrontal cortex leads to cognitive impairments

Author: Corrado Calì, Tamara Zehnder, Graham Knott, Sébastien Sultan, Luca Pucci, Cedric S. Asensio, Robert H. Edwards, Paola Bezzi, Nicole Déglon, Francesco Petrelli, Andrei Ivanov, Glenn Dallérac, Vidar Gundersen, Andrea Chicca, Jürg Gertsch, Nicolas Toni, Jean-Pierre Mothet, Salvatore Lecca, Frank Kirchhoff, Bruno Giros, Fulvio Magara, Department of Fundamental Neurosciences, [University of Lausanne], Université de Lausanne (UNIL), 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), Laboratoire Lumière, Matière et Interfaces (LuMIn), CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), Université de Lausanne = University of Lausanne (UNIL), Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), University of Naples Federico II = Università degli studi di Napoli Federico II, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Fer à Moulin, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Universität Bern [Bern] (UNIBE), Laboratoire de Photonique Quantique et Moléculaire (LPQM), École normale supérieure - Cachan (ENS Cachan)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), University of California [San Francisco] (UC San Francisco), University of California (UC), Division of Anatomy [Oslo], Department of Molecular Medicine [Oslo], Institute of Basic Medical Sciences [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO)-Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO)-Institute of Basic Medical Sciences [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Ecole Polytechnique Fédérale de Lausanne (EPFL), Saarland University [Saarbrücken], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), éTICC, Laboratoire Aimé Cotton (LAC), École normale supérieure - Cachan (ENS Cachan)-Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Cachan (ENS Cachan)-Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Napoli Federico II, Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universität Bern [Bern], Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-École normale supérieure - Cachan (ENS Cachan)-Laboratoire de Photonique Quantique et Moléculaire (LPQM), École normale supérieure - Cachan (ENS Cachan)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), University of California [San Francisco] (UCSF), University of California, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-École normale supérieure - Cachan (ENS Cachan), Centre interdisciplinaire de recherche en biologie (CIRB), Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PSL Research University (PSL)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Paris-Saclay (Neuro-PSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Mathematics and Computing in Automatic Control and Optimization for the User (MIAOU), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-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), Laboratoire de neurobiologie cellulaire et moléculaire (NBCM), and Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, Physiology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], astrocytes, dopamine, VMAT2, neurons, monoamine transporter, Vesicular monoamine transporter 2, Synaptic Transmission, Rats, Sprague-Dawley, Mice, 0302 clinical medicine, synaptic-transmission, Homeostasis, 610 Medicine & health, Prefrontal cortex, Mice, Knockout, biology, Executive functions, Psychiatry and Mental health, Excitatory postsynaptic potential, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neural development, medicine.drug, MESH: Neuroscience, brain, Prefrontal Cortex, clearance, Neurotransmission, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Dopamine, expression, medicine, Animals, Cognitive Dysfunction, gene, Molecular Biology, MESH: Physiology, organic cation transporter-3, proteins, Rats, 030104 developmental biology, biology.protein, 570 Life sciences, central-nervous-system, Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; Astrocytes orchestrate neural development by powerfully coordinating synapse formation and function and, as such, may be critically involved in the pathogenesis of neurodevelopmental abnormalities and cognitive deficits commonly observed in psychiatric disorders. Here, we report the identification of a subset of cortical astrocytes that are competent for regulating dopamine (DA) homeostasis during postnatal development of the prefrontal cortex (PFC), allowing for optimal DA-mediated maturation of excitatory circuits. Such control of DA homeostasis occurs through the coordinated activity of astroglial vesicular monoamine transporter 2 (VMAT2) together with organic cation transporter 3 and monoamine oxidase type B, two key proteins for DA uptake and metabolism. Conditional deletion of VMAT2 in astrocytes postnatally produces loss of PFC DA homeostasis, leading to defective synaptic transmission and plasticity as well as impaired executive functions. Our findings show a novel role for PFC astrocytes in the DA modulation of cognitive performances with relevance to psychiatric disorders.
Published: 2020

49. Dysfunctional D-aspartate metabolism in BTBR mouse model of idiopathic autism

Author: Masae Sekine, Massimo Pasqualetti, Daniela Punzo, Alberto Galbusera, Masumi Katane, Francesco Errico, Hiroshi Homma, Tommaso Nuzzo, Mattia Miroballo, Alessandro Gozzi, Jean-Pierre Mothet, Alessandro Usiello, Yasuaki Saitoh, Nuzzo, T., Sekine, M., Punzo, D., Miroballo, M., Katane, M., Saitoh, Y., Galbusera, A., Pasqualetti, M., Errico, F., Gozzi, A., Mothet, J. -P., Homma, H., Usiello, A., 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), Laboratoire Lumière, Matière et Interfaces (LuMIn), CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), Nuzzo, T, Sekine, M, Punzo, D, Miroballo, M, Katane, M, Saitoh, Y, Galbusera, A, Pasqualetti, M, Errico, F, Gozzi, A, Mothet, Jp, and Homma, H
Subjects: 0301 basic medicine, D-aspartate oxidase, medicine.medical_specialty, Autism spectrum disorder, D-aspartate, D-serine, NMDA receptors, Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], Biophysics, Hippocampus, Gene Expression, Prefrontal Cortex, Mice, Transgenic, AMPA receptor, Biology, Biochemistry, Analytical Chemistry, Serine, 03 medical and health sciences, Glutamatergic, Mice, 0302 clinical medicine, Hippocampu, Internal medicine, mental disorders, medicine, Animals, d-serine, Molecular Biology, Chromatography, High Pressure Liquid, Metabotropic glutamate receptor 5, Animal, D-Aspartic Acid, Brain, Biomarker, NMDA receptor, Disease Models, Animal, 030104 developmental biology, Endocrinology, 030217 neurology & neurosurgery, Biomarkers, Ionotropic effect
Abstract: Background Autism spectrum disorders (ASD) comprise a heterogeneous group of neurodevelopmental conditions characterized by impairment in social interaction, deviance in communication, and repetitive behaviors. Dysfunctional ionotropic NMDA and AMPA receptors, and metabotropic glutamate receptor 5 activity at excitatory synapses has been recently linked to multiple forms of ASD. Despite emerging evidence showing that d -aspartate and d -serine are important neuromodulators of glutamatergic transmission, no systematic investigation on the occurrence of these D-amino acids in preclinical ASD models has been carried out. Methods Through HPLC and qPCR analyses we investigated d -aspartate and d -serine metabolism in the brain and serum of four ASD mouse models. These include BTBR mice, an idiopathic model of ASD, and Cntnap2−/−, Shank3−/−, and 16p11.2+/− mice, three established genetic mouse lines recapitulating high confidence ASD-associated mutations. Results Biochemical and gene expression mapping in Cntnap2−/−, Shank3−/−, and 16p11.2+/− failed to find gross cerebral and serum alterations in d -aspartate and d -serine metabolism. Conversely, we found a striking and stereoselective increased d -aspartate content in the prefrontal cortex, hippocampus and serum of inbred BTBR mice. Consistent with biochemical assessments, in the same brain areas we also found a robust reduction in mRNA levels of d -aspartate oxidase, encoding the enzyme responsible for d -aspartate catabolism. Conclusions Our results demonstrated the presence of disrupted d -aspartate metabolism in a widely used animal model of idiopathic ASD. General significance Overall, this work calls for a deeper investigation of D-amino acids in the etiopathology of ASD and related developmental disorders.
Published: 2020

50. Surgical indications for pituitary tumors during pregnancy: a literature review

Author: Thomas Cuny, Nicolas Bruder, Frederic Castinetti, Thierry Brue, Marie Cousin, Frédérique Albarel, Isabelle Morange, Henry Dufour, Blandine Courbiere, Thomas Graillon, TASSISTRO, Virginie, 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), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'endocrinologie, diabète, maladies métaboliques [Hôpital de la Conception - APHM], Aix Marseille Université (AMU), Institut méditerranéen de biodiversité et d'écologie marine et continentale (IMBE), Avignon Université (AU)-Aix Marseille Université (AMU)-Institut de recherche pour le développement [IRD] : UMR237-Centre National de la Recherche Scientifique (CNRS), Laboratoire Interdisciplinaire Récits, Cultures et Sociétés (LIRCES), 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)-Université Côte d'Azur (UCA), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Hôpital de la Timone [CHU - APHM] (TIMONE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), and Université Nice Sophia Antipolis (... - 2019) (UNS)
Subjects: Pediatrics, medicine.medical_specialty, Visual acuity, [SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, 030209 endocrinology & metabolism, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Meningioma, 03 medical and health sciences, Craniopharyngioma, 0302 clinical medicine, Endocrinology, Pituitary adenoma, Pregnancy, Pituitary cyst, medicine, Endocrine system, Humans, Pituitary Neoplasms, Pituitary ACTH Hypersecretion, Transsphenoidal surgery, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, business.industry, Pituitary tumors, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Female, Surgery, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: International audience; Purpose: Surgical indications for pituitary tumors during pregnancy are rare, and are derived from a balance between expected benefits, particularly for maternal benefits, and anesthetic/surgical risks.Methods: A literature review was performed to define the optimal surgical indications for pituitary adenomas (PA) and other pituitary tumors during pregnancy.Results: Main benefits are expected in case of critical visual impairment and/or life-threatening endocrine disturbances. Multidisciplinary patient management is systematically required although nonobstetric surgery presents a reasonable risk during pregnancy. The risks of congenital malformation during the first trimester and those of premature birth during the third trimester make the second trimester the optimal period for surgery. In prolactin-secreting, nonsecreting, GH- and TSH-secreting PAs, transsphenoidal surgery (TS) is recommended in cases involving severe visual impairment, characterized by severe visual field deficit, visual acuity impairment, and abnormal optical coherence tomography findings, and when no other medical alternatives are possible and/or sufficient. Uncontrolled and severe Cushing’s disease (CD) during pregnancy increases both maternal and fetal morbimortality, thus justifying TS or sometimes dopamine agonist therapy as a safer alternative. Finally, metyrapone, ketoconazole, or bilateral adrenalectomy could be recommended in certain cases after the failure of medical therapies and/or TS. Surgery is also required for suprasellar meningiomas, craniopharyngiomas, and pituitary cysts in the case of severe visual deficit.Conclusion: Surgical indications for pituitary tumors are rare during pregnancy; therefore, surgery should be avoided when possible. Further, the second trimester should be considered as the optimal surgical period. Severe visual disturbance and uncontrolled CD are the main surgical indications during pregnancy.
Published: 2020

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