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1. Snf7 spirals sense and alter membrane curvature

Author

Nebojsa Jukic, Alma P. Perrino, Frédéric Humbert, Aurélien Roux, and Simon Scheuring

Subjects
Science
Abstract

Snf7 is the major component of the ESCRTIII membrane deformation system. Here, the authors used high-speed AFM to study Snf7 on nano-patterned and soft supports and show that loaded Snf7 spiral springs are curvature sensitive and deform membranes.

Published
2022
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2. Structural inhibition of dynamin-mediated membrane fission by endophilin

Author

Annika Hohendahl, Nathaniel Talledge, Valentina Galli, Peter S Shen, Frédéric Humbert, Pietro De Camilli, Adam Frost, and Aurélien Roux

Subjects
endocytosis, dynamin, BAR domain, endophilin, membrane fission, Medicine, Science, Biology (General), QH301-705.5
Abstract

Dynamin, which mediates membrane fission during endocytosis, binds endophilin and other members of the Bin-Amphiphysin-Rvs (BAR) protein family. How endophilin influences endocytic membrane fission is still unclear. Here, we show that dynamin-mediated membrane fission is potently inhibited in vitro when an excess of endophilin co-assembles with dynamin around membrane tubules. We further show by electron microscopy that endophilin intercalates between turns of the dynamin helix and impairs fission by preventing trans interactions between dynamin rungs that are thought to play critical roles in membrane constriction. In living cells, overexpression of endophilin delayed both fission and transferrin uptake. Together, our observations suggest that while endophilin helps shape endocytic tubules and recruit dynamin to endocytic sites, it can also block membrane fission when present in excess by inhibiting inter-dynamin interactions. The sequence of recruitment and the relative stoichiometry of the two proteins may be critical to regulated endocytic fission.

Published
2017
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4. Contribution of corticospinal tract and functional connectivity in hand motor impairment after stroke.

Author

Charlotte Rosso, Romain Valabregue, Yohan Attal, Patricia Vargas, Marie Gaudron, Flore Baronnet, Eric Bertasi, Frédéric Humbert, Anne Peskine, Vincent Perlbarg, Habib Benali, Stéphane Lehéricy, and Yves Samson

Subjects
Medicine, Science
Abstract

BackgroundMotor outcome after stroke is associated with reorganisation of cortical networks and corticospinal tract (CST) integrity. However, the relationships between motor severity, CST damage, and functional brain connectivity are not well understood. Here, the main objective was to study the effect of CST damage on the relationship between functional motor network connectivity and hand motor function in two groups of stroke patients: the severely (n=8) and the mildly impaired (n=14).MethodsTwenty-two carotid stroke patients with motor deficits were studied with magnetic resonance imaging (MRI) at 3 weeks, at 3 and 6 months. Healthy subjects (n=28) were scanned once. The CST injury was assessed by fractional anisotropy values. Functional connectivity was studied from a whole-hand grip task fMRI in a cortical and cerebellar motor network. Functional connectivity indexes were computed between these regions at each time point. The relationship between hand motor strength, ipsilesional CST damage and functional connectivity from the primary motor cortex (M1) was investigated using global and partial correlations.FindingsIn mildly impaired patients, cortico-cortical connectivity was disturbed at three weeks but returned to a normal pattern after 3 months. Cortico-cerebellar connectivity was still decreased at 6 months. In severely impaired patients, the cortico-cortical connectivity tended to return to a normal pattern, but the cortico-cerebellar connectivity was totally abolished during the follow-up. In the entire group of patients, the hand motor strength was correlated to the ipsilesional functional connectivity from M1. Partial correlations revealed that these associations were not anymore significant when the impact of CST damage was removed, except for the ipsilesional M1-contralateral cerebellum connectivity.ConclusionFunctional brain connectivity changes can be observed, even in severely impaired patients with no recovery. Upper limb function is mainly explained by the CST damage and by the ipsilesional cortico-cerebellar connectivity.

Published
2013
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5. Vps60 initiates formation of alternative membrane-bound ESCRT-III filaments

Author

Anna-Katharina Pfitzner, Henry Zivkovic, Frédéric Humbert, and Aurélien Roux

Subjects
macromolecular substances
Abstract

Endosomal sorting complex required for transport-III (ESCRT-III)-driven membrane remodeling participates in many crucial cellular functions, from cell division to endosome maturation, and occurs on essentially all cellular organelles. In eukaryotes, ESCRT-III displays a remarkable molecular diversity in its subunits which may have been acquired through evolution to perform novel cellular functions. Here, we describe and characterize a novel ESCRT-III polymer initiated by the subunit Vps60. Membrane-bound Vps60 polymers recruit ESCRT-III subunits Vps2, Vps24, Did2 and Ist1, and undergo polymer turnover powered by the ATPase Vps4. Snf7- and Vps60 filaments can coexist on membranes without interacting. Their nucleation, polymerization and recruitment of downstream subunits remains unaffected by the presence of the respective other polymer. Taken together, our results suggest Vps60 and Snf7 form distinct ESCRT-III polymers, which overall, supports the notion of evolutionary diversification of ESCRT-III assemblies to perform specific cellular functions.

Published
2022
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6. Snf7 spirals sense and alter membrane curvature

Author

Nebojsa Jukic, Alma P. Perrino, Frédéric Humbert, Aurélien Roux, and Simon Scheuring

Subjects
Multidisciplinary, Membranes, Endosomal Sorting Complexes Required for Transport, Lipid Bilayers, General Physics and Astronomy, General Chemistry, Microscopy, Atomic Force, General Biochemistry, Genetics and Molecular Biology
Abstract

Endosomal Sorting Complex Required for Transport III (ESCRT-III) is a conserved protein system involved in many cellular processes resulting in membrane deformation and scission, topologically away from the cytoplasm. However, little is known about the transition of the planar membrane-associated protein assembly into a 3D structure. High-speed atomic force microscopy (HS-AFM) provided insights into assembly, structural dynamics and turnover of Snf7, the major ESCRT-III component, on planar supported lipid bilayers. Here, we develop HS-AFM experiments that remove the constraints of membrane planarity, crowdedness, and support rigidity. On non-planar membranes, Snf7 monomers are curvature insensitive, but Snf7-spirals selectively adapt their conformation to membrane geometry. In a non-crowded system, Snf7-spirals reach a critical radius, and remodel to minimize internal stress. On non-rigid supports, Snf7-spirals compact and buckle, deforming the underlying bilayer. These experiments provide direct evidence that Snf7 is sufficient to mediate topological transitions, in agreement with the loaded spiral spring model.

Published
2021

7. Amphiphysin (BIN1) negatively regulates dynamin 2 for normal muscle maturation

Author

Aurélien Roux, Ivana Prokic, Belinda S. Cowling, Frédéric Humbert, Anne-Sophie Nicot, Hichem Tasfaout, Christine Kretz, Bruno Rinaldi, Aymen Rabai, Jocelyn Laporte, Sylvie Friant, IGBMC-Médecine translationnelle et neurogénétique, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique moléculaire, génomique, microbiologie (GMGM), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Biochemistry Department - University of Geneva, and University of Geneva [Switzerland]

Subjects
0301 basic medicine, Gene isoform, Muscle Fibers, Skeletal, Nerve Tissue Proteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Dynamin II, Mice, 03 medical and health sciences, 0302 clinical medicine, In vivo, medicine, Animals, Protein Isoforms, Adaptor Proteins, Signal Transducing, Dynamin, Mice, Knockout, [SDV.GEN]Life Sciences [q-bio]/Genetics, Tumor Suppressor Proteins, Skeletal muscle, General Medicine, medicine.disease, In vitro, Cell biology, 030104 developmental biology, medicine.anatomical_structure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Amphiphysin, Alzheimer's disease, 030217 neurology & neurosurgery, Intracellular, Research Article, Myopathies, Structural, Congenital
Abstract

International audience; Regulation of skeletal muscle development and organization is a complex process that is not fully understood. Here, we focused on amphiphysin 2 (BIN1, also known as bridging integrator-1) and dynamin 2 (DNM2), two ubiquitous proteins implicated in membrane remodeling and mutated in centronuclear myopathies (CNMs). We generated Bin1-/- Dnm2+/- mice to decipher the physiological interplay between BIN1 and DNM2. While Bin1-/- mice die perinatally from a skeletal muscle defect, Bin1-/- Dnm2+/- mice survived at least 18 months, and had normal muscle force and intracellular organization of muscle fibers, supporting BIN1 as a negative regulator of DNM2. We next characterized muscle-specific isoforms of BIN1 and DNM2. While BIN1 colocalized with and partially inhibited DNM2 activity during muscle maturation, BIN1 had no effect on the isoform of DNM2 found in adult muscle. Together, these results indicate that BIN1 and DNM2 regulate muscle development and organization, function through a common pathway, and define BIN1 as a negative regulator of DNM2 in vitro and in vivo during muscle maturation. Our data suggest that DNM2 modulation has potential as a therapeutic approach for patients with CNM and BIN1 defects. As BIN1 is implicated in cancers, arrhythmia, and late-onset Alzheimer disease, these findings may trigger research directions and therapeutic development for these common diseases.

Published
2017
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9. Relaxation of Loaded ESCRT-III Spiral Springs Drives Membrane Deformation

Author

Nicolas Chiaruttini, Simon Scheuring, Aurélien Roux, Lorena Redondo-Morata, Martin Lenz, Frédéric Humbert, Adai Colom, Biochemistry Department - University of Geneva, University of Geneva [Switzerland], BIO-AFM-LAB Bio Atomic Force Microscopy Laboratory (Bio-AFM-Lab), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Swiss National Centre for Competence in Research Programme Chemical Biology (NCCR-Chemical Biology), Laboratoire de Physique Théorique et Modèles Statistiques (LPTMS), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11), AR acknowledges funding support from: Human Frontier Science Program (HFSP), Young Investigator Grant #RGY0076-2008: the European Research Council (ERC), starting (consolidator) grant #311536-MEMFIS: the Swiss National Fund for Research, grants #131003A_130520 and #131003A_149975. NC acknowledges the European Commission for the Marie-Curie post-doctoral fellowship CYTOCUT #300532-2011. SS acknowledges funding support from: Agence Nationale de la Recherche, France (ANR), ANR-Nano (ANR-12-BS10-009-01) and ANR-BBMS (ANR-12-BSV8-0006-01) grants, and a European Research Council (ERC) Starting Grant (#310080). ML's group belongs to the CNRS consortium CellTiss and is supported by grants from Université Paris-Sud and CNRS, Marie Curie Integration Grant PCIG12-GA-2012-334053 and 'Investissements d'Avenir' LabEx PALM (ANR-10-LABX-0039-PALM)., ANR-12-BS10-0009,Opt-Spect-HS-AFM,Intégration de la microscopie optique avec la microscopie à forces atomiques à haute vitesse et développement de la spectroscopie moléculaire de forces à haute vitesse(2012), ANR-12-BSV8-0006,AFM-2-BioMed,Assemblage des proteines dans des membranes de tissus sains et pathologiques par Microscopie à Force Atomique(2012), ANR-11-IDEX-0003,IPS,Idex Paris-Saclay(2011), European Project: 311536,EC:FP7:ERC,ERC-2012-StG_20111109,MEMFIS(2013), European Project: 300532,EC:FP7:PEOPLE,FP7-PEOPLE-2011-IEF,CYTOCUT(2012), European Project: 310080,EC:FP7:ERC,ERC-2012-StG_20111109,MEM-STRUCT-AFM(2013), Université de Genève = University of Geneva (UNIGE), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM) - Aix Marseille Université (AMU), Centre National de la Recherche Scientifique (CNRS) - Université Paris-Sud - Paris 11 (UP11), ANR-11-IDEX-0003-02/10-LABX-0039, PALM, Physics: Atoms, Light, Matter(2011), European Project : 300532, EC:FP7:PEOPLE, FP7-PEOPLE-2011-IEF, CYTOCUT(2012), Le Vaou, Claudine, BLANC - Intégration de la microscopie optique avec la microscopie à forces atomiques à haute vitesse et développement de la spectroscopie moléculaire de forces à haute vitesse - - Opt-Spect-HS-AFM2012 - ANR-12-BS10-0009 - BLANC - VALID, BLANC - Assemblage des proteines dans des membranes de tissus sains et pathologiques par Microscopie à Force Atomique - - AFM-2-BioMed2012 - ANR-12-BSV8-0006 - BLANC - VALID, Idex Paris-Saclay - - IPS2011 - ANR-11-IDEX-0003 - IDEX - VALID, Mechanical Understanding of Membrane Fission in Endocytosis and Cytokinesis - MEMFIS - - EC:FP7:ERC2013-01-01 - 2017-12-31 - 311536 - VALID, Cytokinesis’ final cut: mechanics of abscission and ESCRT-III mediated membrane fission. - CYTOCUT - - EC:FP7:PEOPLE2012-07-01 - 2014-06-30 - 300532 - VALID, and The Structure and Assembly of Membrane Proteins in Native Membranes studied by AFM - MEM-STRUCT-AFM - - EC:FP7:ERC2013-01-01 - 2017-12-31 - 310080 - VALID

Subjects
Models, Molecular, [PHYS]Physics [physics], Endosomal Sorting Complexes Required for Transport, Biochemistry, Genetics and Molecular Biology(all), Viral budding, Lipid Bilayers, Intracellular Membranes, macromolecular substances, Biology, Curvature, General Biochemistry, Genetics and Molecular Biology, ESCRT, [PHYS] Physics [physics], Membrane, Rigidity (electromagnetism), Biochemistry, Polymerization, Membrane curvature, Yeasts, ddc:540, Biophysics, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Lipid bilayer, Virus Release
Abstract

International audience; 13 ESCRT-III is required for lipid membrane remodeling in many cellular processes, from abscission 14 to viral budding and multi-vesicular body biogenesis. However, how ESCRT-III polymerization 15 generates membrane curvature remains debated. Here we show that Snf7, the main component 16 of ESCRT-III, polymerizes into spirals at the surface of lipid bilayers. When covering the entire 17 membrane surface, these spirals stopped growing when densely packed: they had a polygonal 18 shape, suggesting that lateral compression could deform them. We reasoned that Snf7 spirals 19 could function as spiral springs. By measuring the polymerization energy and the rigidity of Snf7 20 filaments, we showed that they were deformed while growing in a confined area. Furthermore, 21 we observed that the elastic expansion of compressed Snf7 spirals generated an area difference 22 between the two sides of the membrane and thus curvature. This spring-like activity underlies the 23 driving force by which ESCRT-III could mediate membrane deformation and fission. 24 2

Published
2015
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10. Connectivity between Right Inferior Frontal Gyrus and Supplementary Motor Area Predicts After-Effects of Right Frontal Cathodal tDCS on Picture Naming Speed

Author

Chiara Zavanone, Yohan Attal, P. Vargas, Yves Samson, Christine Delmaire, Romain Valabregue, Sabine Meunier, Stéphane Lehéricy, Charlotte Rosso, Damian M. Herz, Laurent D. Cohen, Frédéric Humbert, Céline Arbizu, Axel Thielscher, Arnaud Messé, Hartwig R. Siebner, S. Ferrieux, Center for NeuroImaging Research-Human MRI Neuroimaging core facility for clinical research [ICM Paris] (CENIR), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universidad Nacional de San Antonio Abad del Cusco (UNSAAC), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Inria Paris-Rocquencourt, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-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)-CHU Pitié-Salpêtrière [AP-HP], Laboratoire d'Imagerie Fonctionnelle (LIF), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-IFR49-Institut National de la Santé et de la Recherche Médicale (INSERM), Services de neuroradiologie [Lille], Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Danish Research Centre for Magnetic Resonance (DRCMR), Hvidovre Hospital, Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière (NEMESIS-CRICM), 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)-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 Neuro-Imagerie de Recherche (CENIR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), 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)-CHU Pitié-Salpêtrière [AP-HP], Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-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)-CHU Pitié-Salpêtrière [AP-HP], Service de Neuroradiologie [CHU Pitié-Salpêtrière], Colliot, Olivier, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-CHU Pitié-Salpêtrière [AP-HP], and 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)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
Male, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, medicine.medical_treatment, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Functional magnetic resonance imaging, [INFO.INFO-IM] Computer Science [cs]/Medical Imaging, MESH: Frontal Lobe, Brain mapping, tDCS, [INFO.INFO-CV] Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Neural Pathways, Image Processing, Computer-Assisted, MESH: Brain Mapping, Language, MESH: Aged, Brain Mapping, MESH: Middle Aged, Cross-Over Studies, medicine.diagnostic_test, Transcranial direct-current stimulation, Supplementary motor area, General Neuroscience, Motor Cortex, MESH: Electric Stimulation, Middle Aged, SMA, MESH: Image Processing, Computer-Assisted, Frontal Lobe, medicine.anatomical_structure, Diffusion tensor imaging, [INFO.INFO-TI] Computer Science [cs]/Image Processing [eess.IV], Frontal lobe, MESH: Young Adult, MESH: Language, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], Female, Psychology, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, MESH: Diffusion Tensor Imaging, Motor cortex, Adult, Biophysics, MESH: Motor Cortex, MESH: Cross-Over Studies, lcsh:RC321-571, Young Adult, medicine, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Humans, Electrodes, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, [SPI.SIGNAL] Engineering Sciences [physics]/Signal and Image processing, Aged, MESH: Humans, MESH: Neural Pathways, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], MESH: Adult, MESH: Electrodes, MESH: Male, Electric Stimulation, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Neurology (clinical), Neuroscience, MESH: Female, Diffusion MRI
Abstract

Background: Cathodal transcranial direct current stimulation (tDCS) of the right frontal cortex improves language abilities in post-stroke aphasic patients. Yet little is known about the effects of right frontal cathodal tDCS on normal language function. Objective/hypothesis: To explore the cathodal tDCS effects of the right-hemispheric homologue of Broca's area on picture naming in healthy individuals. We hypothesized that cathodal tDCS improves picture naming and that this effect is determined by the anatomical and functional connectivity of the targeted region. Methods: Cathodal and sham tDCS were applied to the right inferior frontal gyrus in 24 healthy subjects before a picture-naming task. All participants were studied with magnetic resonance imaging at pre-interventional baseline. Probabilistic tractography and dynamic causal modeling of functional brain activity during a word repetition task were applied to characterize anatomical and functional connectivity. Results: Subjects named pictures faster after cathodal relative to sham tDCS. The accelerating effect of tDCS was explained by a reduced frequency of very slow responses. tDCS-induced acceleration of picture naming correlated with larger volumes of the tract connecting the right Broca's area and the supplementary motor area (SMA) and greater functional coupling from the right SMA to the right Broca's area. Conclusions: The results support the notion that the after-effects of tDCS on brain function are at least in part determined by the anatomical and functional connectivity of the targeted region.

Published
2014

11. Assessment of corticospinal tract (CST) damage in acute stroke patients: Comparison of tract-specific analysis versus segmentation of a CST template

Author

Frédéric Humbert, Charlotte Rosso, P. Vargas, Stéphane Lehéricy, Marie Gaudron, Yves Samson, Eric Bertasi, Romain Valabregue, 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), Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière (NEMESIS-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)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université 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), and 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)

Subjects
Adult, Carotid Artery Diseases, Male, Pathology, medicine.medical_specialty, Statistics as Topic, Pyramidal Tracts, Motor Activity, Sensitivity and Specificity, 030218 nuclear medicine & medical imaging, Diagnosis, Differential, Correlation, 03 medical and health sciences, Imaging, Three-Dimensional, 0302 clinical medicine, Reference Values, Image Interpretation, Computer-Assisted, Fractional anisotropy, medicine, Humans, Radiology, Nuclear Medicine and imaging, Segmentation, Dominance, Cerebral, Stroke, Aged, Acute stroke, Neurologic Examination, Brain Mapping, business.industry, Cerebral Infarction, Middle Aged, Image Enhancement, medicine.disease, Magnetic Resonance Imaging, Oxygen, Diffusion Tensor Imaging, Corticospinal tract, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Nuclear medicine, business, 030217 neurology & neurosurgery, Tractography, Diffusion MRI
Abstract

Purpose: To compare two techniques to assess corticospinal tract (CST) damage in stroke patients: tract-specific analysis by probabilistic tractography and segmentation using a CST template. Materials and Methods: We extracted fractional anisotropy (FA) values, the FA ratio, and mean diffusivity (MD) in 18 stroke patients and 21 healthy volunteers matched for age and sex. We compared the two methods in order to determine their ability to detect 1) differences between diffusion tensor imaging (DTI) parameters of healthy volunteers and stroke patients, 2) the correlation between DTI parameters and clinical scores, and 3) the correlation between DTI parameters and blood oxygen level-dependent (BOLD) signals in a fist-closure task. Results: FA values were higher with the tractography approach than with the segmentation method, but differences between the ipsilesional CST and the homologous region in healthy subjects were detected using both methods. In patients, clinical scores were significantly correlated with FA values and FA ratios with both methods. The BOLD signal was positively correlated with FA values for CST with the segmentation but not with the tractography approach. Conclusion: CST damage in stroke patients can be assessed by either probabilistic tractography or segmentation of a CST template. Although each method has advantages and limitations, both are sensitive enough to detect differences among stroke patients and identify specific correlations with clinical scores. J. Magn. Reson. Imaging 2013;37:836–845. © 2012 Wiley Periodicals, Inc.

Published
2013
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12. Membrane shape at the edge of the dynamin helix sets location and duration of the fission reaction

Author

Valentina Galli, Luis Dinis, Aurélien Roux, Giovanni Cappello, John Manzi, Martin Lenz, Frédéric Humbert, Nicolas Chiaruttini, Sandrine Morlot, Marius Klein, Department of Biochemistry, Université de Genève = University of Geneva (UNIGE), Physico-Chimie-Curie (PCC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Nanobiophysique, Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique Théorique et Modèles Statistiques (LPTMS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Cappello, Giovanni, University of Geneva [Switzerland], Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC), and Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)

Subjects
Dynamins, endocrine system, Fission, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Endocytic cycle, macromolecular substances, Biology, Endocytosis, Models, Biological, Article, General Biochemistry, Genetics and Molecular Biology, Cercopithecus aethiops, 03 medical and health sciences, 0302 clinical medicine, Chlorocebus aethiops, Animals, 030304 developmental biology, Spontaneous fission, Dynamin, Dynamins/metabolism, 0303 health sciences, [PHYS.PHYS.PHYS-BIO-PH] Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Biochemistry, Genetics and Molecular Biology(all), Cell Membrane/metabolism, Cell Membrane, Elastic energy, Biochemistry, Membrane curvature, Nuclear fission, Guanosine Triphosphate/metabolism, ddc:540, COS Cells, Biophysics, SNARE Proteins/metabolism, Guanosine Triphosphate, biological phenomena, cell phenomena, and immunity, SNARE Proteins, 030217 neurology & neurosurgery
Abstract

International audience; The GTPase dynamin polymerizes into a helical coat that constricts membrane necks of endocytic pits to promote their fission. However, the dynamin mechanism is still debated because constriction is necessary but not sufficient for fission. Here, we show that fission occurs at the interface between the dynamin coat and the uncoated membrane. At this location, the considerable change in membrane curvature increases the local membrane elastic energy, reducing the energy barrier for fission. Fission kinetics depends on tension, bending rigidity, and the dynamin constriction torque. Indeed, we experimentally find that the fission rate depends on membrane tension in vitro and during endocytosis in vivo. By estimating the energy barrier from the increased elastic energy at the edge of dynamin and measuring the dynamin torque, we show that the mechanical energy spent on dynamin constriction can reduce the energy barrier for fission sufficiently to promote spontaneous fission.

Published
2012

13. Expression of recombinant proteins in a lipid A mutant of Escherichia coli BL21 with a strongly reduced capacity to induce dendritic cell activation and maturation

Author

Jean-François Gauchat, Amélie Benoit de Coignac, Gersende Caron, Alain Beck, Karine Maisnier-Patin, Martine Malissard, Frédéric Humbert, Thien Ngoc Nguyen, Sylvie Chevalier, Pascale Jeannin, Giovanni Magistrelli, Yves Delneste, Jean-Pierre Aubry, Dominique Velin, and Isabelle Cognet

Subjects
DNA, Bacterial, Immunology, Lymphocyte Antigen 96, Receptors, Cell Surface, Biology, In Vitro Techniques, medicine.disease_cause, law.invention, Lipid A, law, Antigens, CD, medicine, Escherichia coli, Immunology and Allergy, Drosophila Proteins, Humans, Receptor, CD86, Toll-like receptor, Innate immune system, Membrane Glycoproteins, Base Sequence, Tumor Necrosis Factor-alpha, Interleukin-8, Toll-Like Receptors, NF-kappa B, Cell Differentiation, Dendritic cell, Dendritic Cells, Molecular biology, Recombinant Proteins, Toll-Like Receptor 4, Mutagenesis, Insertional, Genes, Bacterial, Antigens, Surface, Mutation, Recombinant DNA, B7-2 Antigen
Abstract

Mutations in the Escherichia coli (E. coli) and Salmonella lpxM gene have been shown to result in strains which grow normally and which produce a non-myristoylated lipopolysaccharide (nmLPS) with strongly reduced endotoxicity. Using homologous recombination, we inactivated the lpxM gene in BL21 (DE3), a strain widely used for the production of recombinant proteins. This led to a derivative unaffected in its capacity to support the production of recombinant proteins. This new strain expresses non-myristoylated LPS that induces markedly less activation and maturation of monocyte-derived dendritic cells (DC), as assessed by nuclear translocation of nuclear factor kappa B (NF-κB), production of TNF-α and IL-8 or expression of CD86. Activation of the main signal transducing receptor for extracellular LPS, Toll like receptor (TLR) 4 in conjunction with the soluble accessory protein MD-2 was also markedly decreased. The modified BL21 strain represents a new application of lpxM inactivation for the expression of proteins to be tested on dendritic cells or other LPS sensitive cells/receptor complexes. It is likely to be useful for the identification of new proteins activating the innate immune response and to reducing the risk linked with low level of endotoxin contamination in therapeutic recombinant proteins.

Published
2002

14. Characterization of fibrosurfin, an interfibrillar component of sea urchin catch connective tissues

Author

Jean-Yves Exposito, Robert Garrone, Frédéric Humbert, Caroline Cluzel, and Claire Lethias

Subjects
Mineralized tissues, DNA, Complementary, Molecular Sequence Data, Biochemistry, Western blot, biology.animal, Consensus sequence, medicine, Animals, Amino Acid Sequence, Molecular Biology, Sea urchin, chemistry.chemical_classification, Expressed sequence tag, Extracellular Matrix Proteins, biology, medicine.diagnostic_test, Proteins, Cell Biology, Immunogold labelling, Amino acid, chemistry, Connective Tissue, Sea Urchins, Tube feet
Abstract

The Sea URchin Fibrillar (SURF) domain is a four-cysteine module present in the amino-propeptide of the sea urchin 2α fibrillar collagen chain. Despite numerous international genome and expressed sequence tag projects, computer searches have so far failed to identify similar domains in other species. Here, we have characterized a new sea urchin protein of 2656 amino acids made up of a series of epidermal growth factor-like and SURF modules. From its striking similarity to the modular organization of fibropellins, we called this new protein fibrosurfin. This protein is acidic with a calculated pI of 4.12. Eleven of the 17 epidermal growth factor-like domains correspond to the consensus sequence of calcium-binding type. By Western blot and immunofluorescence analyses, this protein is not detectable during embryogenesis. In adult tissues, fibrosurfin is co-localized with the amino-propeptide of the 2α fibrillar collagen chain in several collagenous ligaments, i.e., test sutures, spine ligaments, peristomial membrane, and to a lesser extent, tube feet. Finally, immunogold labeling indicates that fibrosurfin is an interfibrillar component of collagenous tissues. Taken together, the data suggest that proteins possessing SURF modules are localized in the vicinity of mineralized tissues and could be responsible for the unique properties of sea urchin mutable collagenous tissues.

Published
2001

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