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1. Membrane-bound human orphan cytochrome P450 2U1: Sequence singularities, construction of a full 3D model, and substrate docking

Author: Nicolas Pietrancosta, Jean-Luc Boucher, Daniel Mansuy, Gabriella Jonasson, Lionel Ducassou, François André, Laura Dhers, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie Physique D'Orsay (LCPO), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Systèmes glutamatergiques normaux et pathologiques = Normal and Pathologic Glutamatergic Neurons (NPS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Analyse, Interactions Moléculaires et Cellulaires (LBM-E2), Laboratoire des biomolécules (LBM UMR 7203), Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Chimie Moléculaire de Paris Centre (FR 2769), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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), French 'Ministere de l'Education et de la Recherche', University Paris Descartes, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques ( LCBPT - UMR 8601 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Chimie Physique D'Orsay ( LCPO ), Université Paris-Sud - Paris 11 ( UP11 ) -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 National de la Recherche Scientifique ( CNRS ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Institut des Sciences du Vivant Frédéric JOLIOT ( JOLIOT ), 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, Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS), and Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Saccharomyces cerevisiae Proteins, Stereochemistry, [SDV]Life Sciences [q-bio], Saccharomyces cerevisiae, Biochemistry, Conserved sequence, Hydroxylation, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Cytochrome P-450 Enzyme System, Humans, Cytochrome P450 Family 2, Heme, POPC, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, Arachidonic Acid, [ SDV ] Life Sciences [q-bio], biology, Cytochrome P450, Membranes, Artificial, General Medicine, Amino acid, Molecular Docking Simulation, 030104 developmental biology, chemistry, Structural Homology, Protein, Docking (molecular), Helix, Phosphatidylcholines, biology.protein, 030217 neurology & neurosurgery
Abstract: Background Human cytochrome P450 2U1 (CYP2U1) is an orphan CYP that exhibits several distinctive characteristics among the 57 human CYPs with a highly conserved sequence in almost all living organisms. Methods We compared its protein sequence with those of the 57 human CYPs and constructed a 3D structure of a full-length CYP2U1 model bound to a POPC membrane. We also performed docking experiments of arachidonic acid (AA) and N-arachidonoylserotonin (AS) in this model. Results The protein sequence of CYP2U1 displayed two unique characteristics when compared to those of the human CYPs, the presence of a longer N-terminal region upstream of the putative trans-membrane helix (TMH) containing 8 proline residues, and of an insert of about 20 amino acids containing 5 arginine residues between helices A′ and A. Its N-terminal part upstream of TMH involved an additional short terminal helix, in a manner similar to what was reported in the crystal structure of Saccharomyces cerevisiae CYP51. Our model also showed a specific interaction between the charged residues of insert AA′ and phosphate groups of lipid polar heads, suggesting a possible role of this insert in substrate recruitment. Docking of AA and AS in this model showed these substrates in channel 2ac, with the terminal alkyl chain of AA or the indole ring of AS close to the heme, in agreement with the reported CYP2U1-catalyzed AA and AS hydroxylation regioselectivities. Major conclusion and general significance This model should be useful to find new endogenous or exogenous CYP2U1 substrates and to interpret the regioselectivity of their hydroxylation.
Published: 2017

2. Neutron and beta imaging with Micromegas detectors with optical readout

Author: A. Cools, S. Aune, F. Beau, M. Benali, F.M. Brunbauer, T. Benoit, D. Desforge, E. Ferrer-Ribas, C. Malgorn, E. Oliveri, T. Papaevangelou, E.C. Pollacco, L. Ropelewski, A. Sari, Institut de Recherches sur les lois Fondamentales de l'Univers (IRFU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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), Laboratoire Capteurs et Architectures Electroniques (LCAE), Département Métrologie Instrumentation & Information (DM2I), Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, CERN [Genève], ANR-10-LABX-0038,P2IO,Physics of the 2 infinities and the origins(2010), and ANR-11-IDEX-0003,IPS,Idex Paris-Saclay(2011)
Subjects: instrumentation, Nuclear and High Energy Physics, Neutron-gamma discrimination, Beta imager, detector, Gamma imaging, neutrons, gamma-rays, Glass Micromegas, X-rays, beta-rays, Neutron radiography, Gaseous detector, [PHYS.PHYS.PHYS-INS-DET]Physics [physics]/Physics [physics]/Instrumentation and Detectors [physics.ins-det], Micromegas, nuclear instrumentation, Optical readout, MPGD
Abstract: International audience; Recent developments have shown that coupling a Micromegas gaseous detector on a glass substrate with a transparent anode and a CMOS camera enables the optical readout of Micromegas detectors with a good spatial resolution, demonstrating that the glass Micromegas detector is well-suited for imaging. This feasibility test has been effectuated with low-energy X-ray photons also permitting energy resolved imaging. This test opens the way to different applications. Here we will focus on two applications. Namely, neutron imaging for non-destructive examination of highly gamma-ray emitting objects, such as irradiated nuclear fuel or radioactive waste. And secondly, we are developing a beta imager for the cell tagging in the field of anticancerous drug studies.Both applications require to design the detectors in view of the specific constraints of reactor dismantling and medical applications: spatial resolution and strong gamma suppression for neutron imaging and precise rate and energy spectrum measurements for the beta.A dedicated system consisting of a glass Micromegas detector and an ultrasensitive camera has been designed and assembled. Here we present the first results from the characterization of the detectors, as well as the first acquired images.
Published: 2023

3. Gut-specific telomerase expression counteracts systemic aging in telomerase-deficient zebrafish

Author: Mounir El Maï, Malia Bird, Asma Allouche, Seniye Targen, Naz Şerifoğlu, Bruno Lopes-Bastos, Jean-Marie Guigonis, Da Kang, Thierry Pourcher, Jia-Xing Yue, Miguel Godinho Ferreira, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Sun Yat-Sen University [Guangzhou] (SYSU), Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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), Instituto Gulbenkian de Ciência [Oeiras] (IGC), and Fundação Calouste Gulbenkian
Subjects: Aging, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Neuroscience (miscellaneous), Geriatrics and Gerontology
Abstract: Telomere shortening is a hallmark of aging and is counteracted by telomerase. As in humans, the zebrafish gut is one of the organs with the fastest rate of telomere decline, triggering early tissue dysfunction during normal zebrafish aging and in prematurely aged telomerase mutants. However, whether telomere-dependent aging of an individual organ, the gut, causes systemic aging is unknown. Here we show that tissue-specific telomerase expression in the gut can prevent telomere shortening and rescues premature aging of tert−/−. Induction of telomerase rescues gut senescence and low cell proliferation, while restoring tissue integrity, inflammation and age-dependent microbiota dysbiosis. Averting gut aging causes systemic beneficial impacts, rescuing aging of distant organs such as reproductive and hematopoietic systems. Conclusively, we show that gut-specific telomerase expression extends the lifespan of tert−/− by 40%, while ameliorating natural aging. Our work demonstrates that gut-specific rescue of telomerase expression leading to telomere elongation is sufficient to systemically counteract aging in zebrafish.
Published: 2023

4. State of the art on microbubble cavitation monitoring and feedback control for blood-brain-barrier opening using focused ultrasound

Author: Mondou, Paul, Mériaux, Sébastien, Nageotte, Florent, Vappou, Jonathan, Novell, Anthony, Larrat, Benoit, Service NEUROSPIN (NEUROSPIN), 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), CEA- Saclay (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay, Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), and Direction de Recherche Fondamentale (CEA) (DRF (CEA))
Subjects: cavitation, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, brain, drug delivery, [PHYS.PHYS.PHYS-MED-PH]Physics [physics]/Physics [physics]/Medical Physics [physics.med-ph], focused ultrasound, blood-brain barrier, Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire, control, microbubbles, [PHYS.MECA.ACOU]Physics [physics]/Mechanics [physics]/Acoustics [physics.class-ph]
Abstract: International audience; Focused ultrasound is a non-invasive and highly promising method for targeted and reversible blood-brain barrier permeabilization. Numerous preclinical studies aim to optimize this localized drug delivery method in rodents and non-human primates. A few clinical trials have been initiated to treat various brain diseases in humans using simultaneous BBB permeabilization and drug injection. This review presents the state of the art of in vitro and in vivo cavitation control algorithms for BBB permeabilization using microbubbles and focused ultrasound. First, we described the different cavitation states, their physical significance in terms of microbubble behavior and their translation into the spectral composition of the backscattered signal. Then, we reported the different indexes calculated and used during the ultrasonic monitoring of cavitation. Finally, the different in vitro and in vivo cavitation control strategies described in the literature are presented and compared.
Published: 2023

5. X-ray imaging with Micromegas detectors with optical readout

Author: Cools, A., Aune, S., Beau, F., Brunbauer, F.M., Benoit, T., Desforge, D., Ferrer-Ribas, E., Kallitsopoulou, A., Malgorn, C., Oliveri, E., Papaevangelou, T., Pollacco, E.C., Ropelewski, L., Sari, A., Iguaz, F.J., Institut de Recherches sur les lois Fondamentales de l'Univers (IRFU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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), CERN [Genève], Laboratoire Capteurs et Architectures Electroniques (LCAE), Département Métrologie Instrumentation & Information (DM2I), Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), Cross-Disciplinary Program on Instrumentation and Detection (PTC-ID) of the French Alternative Energies and Atomic Energy Commission (CEA)., SOLEIL for provision of synchrotron radiation facilities (proposal number 99220033), RD51 at CERN, Weizmann Institute of Science, ANR-10-LABX-0038,P2IO,Physics of the 2 infinities and the origins(2010), and ANR-11-IDEX-0003,IPS,Idex Paris-Saclay(2011)
Subjects: Physics - Instrumentation and Detectors, neutron imaging, CMOS camera, FOS: Physical sciences, [PHYS.NEXP]Physics [physics]/Nuclear Experiment [nucl-ex], X-rays, synchrotron, beta-rays, cancer, [PHYS.PHYS.PHYS-INS-DET]Physics [physics]/Physics [physics]/Instrumentation and Detectors [physics.ins-det], Detectors and Experimental Techniques, physics.ins-det, nuclear instrumentation, instrumentation, detector, neutrons, Instrumentation and Detectors (physics.ins-det), gamma-rays, non-destructive examination, beta imaging, metrology, radioactivity, SOLEIL, ionizing radiation, radiography, Micromegas
Abstract: In the last years, optical readout of Micromegas gaseous detectors has been achieved by implementing a Micromegas detector on a glass anode coupled to a CMOS camera. Effective X-ray radiography was demonstrated using integrated imaging approach. High granularity values have been reached for low-energy X-rays from radioactive sources and X-ray generators. Detector characterization with X-ray radiography has led to two applications: neutron imaging for non-destructive examination of highly gamma-ray emitting objects and beta imaging for the single cell activity tagging in the field of oncology drug studies. First measurements investigating the achievable spatial resolution of the glass Micromegas detector at the SOLEIL synchrotron facility with a high-intensity and flat irradiation field will be shown in this article., Comment: 6 pages, 4 figures, 7th International Conference on Micro Pattern Gaseous Detectors, 11-16 December 20223, Weizmann Institute of Science, Rehovot, Israel
Published: 2022

6. QSM4SENIOR: Quantitative susceptibility mapping in the aging of the healthy brain

Author: Guevara, Miguel, Cam, Davy, Badagbon, Jacques, Bottlaender, Michel, Cointepas, Yann, Mangin, Jean-François, Rochefort, Ludovic De, Vignaud, Alexandre, Building large instruments for neuroimaging: from population imaging to ultra-high magnetic fields (BAOBAB), Service NEUROSPIN (NEUROSPIN), 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)-Centre National de la Recherche Scientifique (CNRS), Ventio, Institut d'Imagerie BioMédicale (I2BM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut d'imagerie neurofonctionnelle (IIN), Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École des hautes études en sciences sociales (EHESS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Ecole Nationale Supérieure des Télécommunications (ENST)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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), European Project: 824087 ,EOSC-Life, Service Hospitalier Frédéric Joliot (SHFJ), IFR de Neuroimagerie Fonctionnelle (IFR 49), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Neuroimagerie cognitive (LCogn), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Épilepsie de l'enfant et plasticité cérébrale (Inserm U663), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: SENIOR, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV]Life Sciences [q-bio], R2, QSM, cloud computing, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], iron load, Cloud, MRI
Abstract: This work presents preliminary results for the QSM4SENIOR project, a partnership between NeuroSpin (CEA) and Ventio. A poster was presented at QMR Lucca, Italy 2022, a joint workshop on MR phase, magnetic susceptibility and electrical properties mapping. It introduces a pipeline for computing the Quantitative Susceptibility Mapping (QSM) from the data of healthy senior participants (SENIOR database). The pipeline allows the computation of clean and exploitable QSM, thanks to a phase pre-processing to reduce the presence of artifacts in the 7T MRI data. These maps will be then used for studying the iron accumulation in the normal aging process. This computation was performed in a secured cloud environment, provided by de.NBI Cloud.
Published: 2022
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7. Atomic-level evolutionary information improves protein–protein interface scoring

Author: Raphael Guerois, Chloé Quignot, Pierre Granger, Pablo Chacón, Jessica Andreani, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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), Instituto de Química Física Rocasolano (IQFR), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), ANR-15-CE11-0008,CHIPSeT,Caracterisation Structurale des Couplages entre Chromatine et Homeostasie Protéique par Combinaison d'Analyses de Coevolution et de Perturbation des Interfaces de Complexes a Haut-Debit(2015), and ANR-18-CE45-0005,ESPRINet,Intégration de données hétérogènes évolutives, structurales et omiques pour la prédiction des réseaux d'interaction protéine-ARN(2018)
Subjects: Statistics and Probability, Computer science, Interface (computing), protein-protein interactions, Machine learning, computer.software_genre, Biochemistry, Protein–protein interaction, 03 medical and health sciences, 0302 clinical medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Evolutionary information, protein structure, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], protein evolution, Molecular Biology, protein scoring, 030304 developmental biology, 0303 health sciences, business.industry, Protein protein, 030302 biochemistry & molecular biology, Percentage point, structural bioinformatics, Benchmarking, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], protein docking, Computer Science Applications, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Computational Mathematics, Computational Theory and Mathematics, Docking (molecular), Complementarity (molecular biology), Container (abstract data type), Benchmark (computing), Artificial intelligence, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, Statistical potential, computer, 030217 neurology & neurosurgery
Abstract: Motivation The crucial role of protein interactions and the difficulty in characterizing them experimentally strongly motivates the development of computational approaches for structural prediction. Even when protein–protein docking samples correct models, current scoring functions struggle to discriminate them from incorrect decoys. The previous incorporation of conservation and coevolution information has shown promise for improving protein–protein scoring. Here, we present a novel strategy to integrate atomic-level evolutionary information into different types of scoring functions to improve their docking discrimination. Results We applied this general strategy to our residue-level statistical potential from InterEvScore and to two atomic-level scores, SOAP-PP and Rosetta interface score (ISC). Including evolutionary information from as few as 10 homologous sequences improves the top 10 success rates of individual atomic-level scores SOAP-PP and Rosetta ISC by 6 and 13.5 percentage points, respectively, on a large benchmark of 752 docking cases. The best individual homology-enriched score reaches a top 10 success rate of 34.4%. A consensus approach based on the complementarity between different homology-enriched scores further increases the top 10 success rate to 40%. Availability and implementation All data used for benchmarking and scoring results, as well as a Singularity container of the pipeline, are available at http://biodev.cea.fr/interevol/interevdata/. Supplementary information Supplementary data are available at Bioinformatics online.
Published: 2021

8. The cell polarity protein Vangl2 in the muscle shapes the neuromuscular synapse by binding to and regulating the tyrosine kinase MuSK

Author: Myriam Boëx, Steve Cottin, Marius Halliez, Stéphanie Bauché, Céline Buon, Nathalie Sans, Mireille Montcouquiol, Jordi Molgó, Muriel Amar, Arnaud Ferry, Mégane Lemaitre, Andrée Rouche, Dominique Langui, Asha Baskaran, Bertrand Fontaine, Julien Messéant, Laure Strochlic, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale (U1215 Inserm - UB), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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), Phénotypage du petit animal (UMS28), Sorbonne Université (SU), 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Strochlic, Laure
Subjects: [SDV]Life Sciences [q-bio], Muscle Fibers, Skeletal, Cell Polarity, Nerve Tissue Proteins, Cell Biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Protein-Tyrosine Kinases, Biochemistry, [SDV] Life Sciences [q-bio], Fatty Acids, Monounsaturated, Mice, Synapses, Animals, Receptors, Cholinergic, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology
Abstract: The development of the neuromuscular junction (NMJ) requires dynamic trans-synaptic coordination orchestrated by secreted factors, including Wnt family morphogens. To investigate how these synaptic cues in NMJ development are transduced, particularly in the regulation of acetylcholine receptor (AChR) accumulation in the postsynaptic membrane, we explored the function of Van Gogh–like protein 2 (Vangl2), a core component of Wnt planar cell polarity signaling. We found that conditional, muscle-specific ablation of Vangl2 in mice reproduced the NMJ differentiation defects seen in mice with global Vangl2 deletion. These alterations persisted into adulthood and led to NMJ disassembly, impaired neurotransmission, and deficits in motor function. Vangl2 and the muscle-specific receptor tyrosine kinase MuSK were functionally associated in Wnt signaling in the muscle. Vangl2 bound to and promoted the signaling activity of MuSK in response to Wnt11. The loss of Vangl2 impaired RhoA activation in cultured mouse myotubes and caused dispersed, rather than clustered, organization of AChRs at the postsynaptic or muscle cell side of NMJs in vivo. Our results identify Vangl2 as a key player of the core complex of molecules shaping neuromuscular synapses and thus shed light on the molecular mechanisms underlying NMJ assembly.
Published: 2022

9. Interaction of micro and nanoplastics with proteins

Author: Schvartz, M., Saudrais, F., Perrault, T., Aude, J.-C, Boulard, Y., Brotons, G., Chédin, S., Pin, Serge, Renault, J.-P, Laboratoire Interdisciplinaire sur l'Organisation Nanométrique et Supramoléculaire (LIONS), Nanosciences et Innovation pour les Matériaux, la Biomédecine et l'Energie (ex SIS2M) (NIMBE UMR 3685), Institut Rayonnement Matière de Saclay (IRAMIS), 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-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Rayonnement Matière de Saclay (IRAMIS), 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-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut des Molécules et Matériaux du Mans (IMMM), Le Mans Université (UM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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), CNRS, 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-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Institut Rayonnement Matière de Saclay (IRAMIS), and 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-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)
Subjects: [CHIM.MATE]Chemical Sciences/Material chemistry
Abstract: International audience; De grandes quantités de plastiques sont produites et rejetées dans la nature chaque année, certains étant ou devenant des Microplastiques ou des NanoPlastiques (regroupés dans MNP < 20 μm). Ces particules peuvent être introduites dans la chaîne alimentaire, et vont rapidement être entourées d’une couche de protéines appelée la corona. L’objectif de ce projet est d’étudier les interactions entre MNP et protéines pour comprendre le devenir et l’impact de ces matériaux polluants en milieux biologiques.Le premier axe d’étude porte sur des protéines isolées et bien connues. Actuellement nous avons mis des microparticules de polyéthylène et de polypropylène en contact avec de l’Albumine de sérum Bovin, ainsi qu’avec de l’hémoglobine porcine. L’utilisation de ces protéines modèles permet la compréhension des phénomènes qui régissent leur adsorption sur des MNP ainsi que l’observation éventuelle de l’altération de leur structure et de leur fonction.Le deuxième axe d’étude porte sur un système protéique plus complexe : un extrait protéique de levure (environ 5800 protéines). L’objectif est de comprendre, via des expériences de protéomique et des études statistiques, quels sont les déterminants physico-chimiques qui vont influer sur les interactions MNP/protéines.Ces deux axes nous permettront d’avoir une vision globale des interactions MNP/protéines : de la compréhension des mécanismes d’adsorption aux effets éventuels de ces particules sur les structures et fonctions biologiques des protéines.
Published: 2021

10. The Adipose Microenvironment Dysregulates the Mammary Myoepithelial Cells and Could Participate to the Progression of Breast Cancer

Author: François Fenaille, Caroline Decombat, Marion Vermerie, Florence Castelli, Charles Dumontet, Adrien Rossary, Laetitia Delort, Juliette Cholet, Céline Auxenfans, Florence Caldefie-Chezet, Unité de Nutrition Humaine (UNH), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), 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-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Etude du Métabolisme des Médicaments (LEMM), Service de Pharmacologie et Immunoanalyse (SPI), 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)-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)-Médicaments et Technologies pour la Santé (MTS), 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 des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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), Banque de tissus et de cellules, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), and Rossary, Adrien
Subjects: 0301 basic medicine, obesity, Cell type, mature adipocytes, Adipose tissue, [SDV.CAN]Life Sciences [q-bio]/Cancer, Inflammation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, myoepithelial cells, human adipose stem cells, Cell and Developmental Biology, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BDD] Life Sciences [q-bio]/Development Biology, medicine, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, lcsh:QH301-705.5, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Original Research, miRNA, Myoepithelial cell, Cancer, Cell Biology, medicine.disease, metabolomics, 3. Good health, breast cancer progression, 030104 developmental biology, lcsh:Biology (General), 030220 oncology & carcinogenesis, Cancer cell, Cancer research, medicine.symptom, Stem cell, Developmental Biology
Abstract: Breast cancer is the most common cancer among women worldwide. Overweight and obesity are now recognized as established risk factors for this pathology in postmenopausal women. These conditions are also believed to be responsible for higher recurrence and mortality rates. Reciprocal interactions have been described between adipose and cancer cells. An adipose microenvironment favors a greater proliferation of cancer cells, their invasion and even resistance to anti-cancer treatments. In addition, the chronic low-grade inflammation observed in obese individuals is believed to amplify these processes. Among the cell types present in the breast, myoepithelial cells (MECs), located at the interface of the epithelial cells and the stroma, are considered “tumor suppressor” cells. During the transition from ductal carcinomain situto invasive cancer, disorganization or even the disappearance of MECs is observed, thereby enhancing the ability of the cancer cells to migrate. As the adipose microenvironment is now considered as a central actor in the progression of breast cancer, our objective was to evaluate if it could be involved in MEC functional modifications, leading to the transition ofin situto invasive carcinoma, particularly in obese patients. Through a co-culture model, we investigated the impact of human adipose stem cells from women of normal weight and obese women, differentiated or not into mature adipocytes, on the functionality of the MECs by measuring changes in viability, apoptosis, gene, and miRNA expressions. We found that adipose cells (precursors and differentiated adipocytes) could decrease the viability of the MECs, regardless of the original BMI. The adipose cells could also disrupt the expression of the genes involved in the maintenance of the extracellular matrix and to amplify the expression of leptin and inflammatory markers. miR-122-5p and miR-132-3p could also be considered as targets for adipose cells. The metabolite analyses revealed specific profiles that may be involved in the growth of neoplastic cells. All of these perturbations could thus be responsible for the loss of tumor suppressor status of MECs and promote the transition fromin situto invasive carcinoma.
Published: 2021
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11. Gambierol Blocks a K+ Current Fraction without Affecting Catecholamine Release in Rat Fetal Adrenomedullary Cultured Chromaffin Cells

Author: Evelyne Benoit, Sébastien Schlumberger, Jordi Molgó, Makoto Sasaki, Haruhiko Fuwa, Roland Bournaud, 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)-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 des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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), Laboratoire de neurobiologie cellulaire et moléculaire (NBCM), Centre National de la Recherche Scientifique (CNRS), Tohoku University [Sendai], and Chuo University (Chuo University)
Subjects: fetal adrenomedullary chromaffin cell, gambierol, potassium currents, calcium-activated K+ channels, ATP-sensitive K+ channels, catecholamine release, ATP-sensitive K$^+$ channels, [SDV.TOX]Life Sciences [q-bio]/Toxicology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Health, Toxicology and Mutagenesis, Toxicology
Abstract: International audience; Gambierol inhibits voltage-gated K+ (KV) channels in various excitable and non-excitable cells. The purpose of this work was to study the effects of gambierol on single rat fetal (F19–F20) adrenomedullary cultured chromaffin cells. These excitable cells have different types of KV channels and release catecholamines. Perforated whole-cell voltage-clamp recordings revealed that gambierol (100 nM) blocked only a fraction of the total outward K$^+$ current and slowed the kinetics of K$^+$ current activation. The use of selective channel blockers disclosed that gambierol did not affect calcium-activated K$^+$ (KCa) and ATP-sensitive K$^+$ (KATP) channels. The gambierol concentration necessary to inhibit 50% of the K$^+$ current-component sensitive to the polyether (IC50) was 5.8 nM. Simultaneous whole-cell current-clamp and single-cell amperometry recordings revealed that gambierol did not modify the membrane potential following 11s depolarizing current-steps, in both quiescent and active cells displaying repetitive firing of action potentials, and it did not increase the number of exocytotic catecholamine release events, with respect to controls. The subsequent addition of apamin and iberiotoxin, which selectively block the KCa channels, both depolarized the membrane and enhanced by 2.7 and 3.5-fold the exocytotic event frequency in quiescent and active cells, respectively. These results highlight the important modulatory role played by KCa channels in the control of exocytosis from fetal (F19–F20) adrenomedullary chromaffin cells.
Published: 2022

12. Optimal Anchoring of a Urea-based Foldamer Inhibitor of ASF1 Histone Chaperone Through Backbone Plasticity

Author: May Bakail, Seydou Traoré, Céline Douat, Gilles Guichard, Johanne Mbianda, Raphael Guerois, Marie E. Perrin, François Becher, Christophe André, Françoise Ochsenbein, Pierre Legrand, Gwenaëlle Moal, Chimie et Biologie des Membranes et des Nanoobjets (CBMN), Université Sciences et Technologies - Bordeaux 1-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-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), Service Hospitalier Frédéric Joliot (SHFJ), 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, Laboratoire d'immuno-allergie alimentaire (LI2A), Institut National de la Recherche Agronomique (INRA)-Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), 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)-Université Paris-Saclay-Médicaments et Technologies pour la Santé (MTS), 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, Université Panthéon-Sorbonne (UP1), Centre Régional AGRHYMET (CRA), Immunologie et chimie thérapeutiques (ICT), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS), École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Assemblage moléculaire et intégrité du génome (AMIG), Département Biochimie, Biophysique et Biologie Structurale (B3S), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Université Paris 1 Panthéon-Sorbonne (UP1), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), and Université de Bordeaux (UB)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: chemistry.chemical_classification, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], biology, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Peptidomimetic, Chemistry, Foldamer, Peptide, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Chromatin, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Folding (chemistry), [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Histone, Chaperone (protein), [CHIM.CRIS]Chemical Sciences/Cristallography, biology.protein, Biophysics, Side chain
Abstract: Sequence-specific oligomers with predictable folding patterns, i.e. foldamers provide new opportunities to mimic α-helical peptides and design inhibitors of protein-protein interactions. One major hurdle of this strategy is to retain the correct orientation of key side chains involved in protein surface recognition. Here, we show that the structural plasticity of a foldamer backbone may significantly contribute to the required spatial adjustment for optimal interaction with the protein surface. By using oligoureas as α-helix mimics, we designed a foldamer/peptide hybrid inhibitor of histone chaperone ASF1, a key regulator of chromatin dynamics. The crystal structure of its complex with ASF1 reveals a striking plasticity of the urea backbone, which adapts to the ASF1 surface to maintain the same binding interface. One additional benefit of generating ASF1 ligands with non-peptide oligourea segments is the resistance to proteolysis in human plasma which was highly improved compared to the cognate α-helical peptide.
Published: 2020

13. Impact du SARS-CoV2 sur la structuration de la prise en charge du cancer : exemple de la tenue des RCP de cancérologie en Occitanie

Author: Jean-Pierre Delord, Marie-José Renaudie, Rosine Guimbaud, Pierre-Adrien Dalbies, Eric Bauvin, David Azria, Pascale Grosclaude, Guillaume Cartron, Séverine Thibault, Laetitia Daubisse-Marliac, A&O (Apprentissage et Optimisation) (A&O), Laboratoire Interdisciplinaire des Sciences du Numérique (LISN), Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Science des Données (SDD), Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Algorithmes, Apprentissage et Calcul (AAC), Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Cancer de Montpellier (ICM), Réseau régional de cancérologie Onco-Occitanie, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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), CCSD, Accord Elsevier, CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Science des Données (SDD), CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Algorithmes, Apprentissage et Calcul (AAC), CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, medicine.medical_specialty, Cancer Research, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), [SDV]Life Sciences [q-bio], Multidisciplinary team, Hospital records, 03 medical and health sciences, 0302 clinical medicine, Medicine, Tumor board, Radiology, Nuclear Medicine and imaging, Interdisciplinary communication, In patient, business.industry, Attendance, Hematology, General Medicine, [SDV] Life Sciences [q-bio], 030104 developmental biology, Oncology, Radiology Nuclear Medicine and imaging, 030220 oncology & carcinogenesis, Family medicine, business, Coronavirus Infections
Abstract: This work examines the impact of the SARS-CoV2 epidemic and the organizational recommendations that have been issued since March 16 on tumor boards (TB) activity. The tumor board activity was measured from tumor board sheets extracted from the oncologic electronic file between January 7, 2019 and April 24, 2020. The pre-containment activity was compared to the activity of the containment periods but also to the equivalent periods in 2019. The number of meetings held, the average number of files reviewed per meeting including first presentations and the average number of physicians' attendance were the evaluation criteria. The study covered 191 TB that held 3943 multidisciplinary team meetings (MTM) and reviewed 72,070 files (including 30,127 first submissions). There was a moderate decrease of 8 % in the number of meetings after March 16, 2020. The number of files examined decreased by 23 % in the following month and even more by 33 % in the third period. The physicians' number who attended MTM also decreased by 25 %. The negative impact was higher in the Mediterranean part of the region. This first study of tumor board activity, covering a large region but little affected by the pandemic, shows that its impact on the participation to the MTM has been moderate. In addition, tumor boards have followed the recommendations for optimizing quorum. However, the decrease in average MTM activity, particularly for first submissions, suggests a potential delay in patient management. Complementary qualitative and quantitative works are warranted to estimate the real impact on carcinologic outcomes.
Published: 2020
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14. Impact of literacy on the functional connectivity of vision and language related networks

Author: Régine Kolinsky, Lucia Willadino Braga, Diana López-Barroso, Alexandre Guerreiro-Tauil, Stanislas Dehaene, Laurent D. Cohen, Michel Thiebaut de Schotten, Jose Morais, [López-Barroso,D, Thiebaut de Schotten,M, Cohen,L] Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université, Paris, France. [López-Barroso,D] Cognitive Neurology and Aphasia Unit, Centro de Investigaciones Médico-Sanitarias, Instituto de Investigación Biomédica de Malaga (IBIMA), Málaga, Spain. [López-Barroso,D] Area of Psychobiology, Faculty of Psychology and Speech Therapy, University of Malaga, Málaga, Spain. [Thiebaut de Schotten,M] Brain Connectivity and Behaviour Laboratory, Sorbonne Universities, Paris, France. [Thiebaut de Schotten,M] Groupe d’Imagerie Neurofonctionnelle, Institut des Maladies Neurodégénératives-UMR 5293, CNRS, CEA University of Bordeaux, Bordeaux, France. [Morais,J, Kolinsky,R] Unité de Recherche en Neurosciences Cognitives (UNESCOG), Center for Research in Cognition and Neurosciences (CRCN), Université Libre de Bruxelles (ULB), Brussels, Belgium. [Kolinsky,R] Fonds de la Recherche Scientifique-FNRS, Brussels, Belgium. [Braga,LW, Guerreiro-Tauil,A] SARAH Network, International Center for Neurosciences and Rehabilitation, Brasilia, Brazil. [Dehaene,S] Collège de France, Paris, France . [Dehaene,S] INSERM, Cognitive Neuroimaging Unit, NeuroSpin Center, France. [Dehaene,S] Commissariat a l ’Energie Atomique, Direction des Sciences du Vivant, Institut Frédéric Joliot, Neurospin Center, France . [Dehaene,S] Université Paris-Sud 11, Orsay, France. [Cohen,L] Assistance Publique Hôpitaux de Paris (AP-HP), Hôpital de la Pitié Salêtrière, Department of Neurology, Paris, France., This work was supported by the Cr edit Agricole Ile-de-France, the French Agence Nationale de la Recherche (project PHENOTYPES, no. ANR-13-JSV4-0001-01), the SARAH Network of Rehabilitation Hospitals, and the program 'Investissement d’avenir' (ANR-10-IAIHU-06). R. Kolinsky is Research Director of the Fonds de la Recherche Scientifique–FNRS(FRS–FNRS), Belgium., Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [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)-Centre National de la Recherche Scientifique (CNRS), Universidad de Málaga [Málaga] = University of Málaga [Málaga], Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Université libre de Bruxelles (ULB), Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Chaire Psychologie cognitive expérimentale, Collège de France (CdF (institution)), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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), Collège de France - Chaire Psychologie cognitive expérimentale, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-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), Gestionnaire, Hal Sorbonne Université, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, genetic structures, Psychiatry and Psychology::Behavior and Behavior Mechanisms::Behavior::Communication::Language [Medical Subject Headings], Literacy, Alfabetización, Visual Word Form Area, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], [SCCO]Cognitive science, Functional connectivity, 0302 clinical medicine, Reading (process), Neural Pathways, Image Processing, Computer-Assisted, Percepción visual, Psychiatry and Psychology::Psychological Phenomena and Processes::Mental Processes::Perception::Visual Perception [Medical Subject Headings], Visual word form area, Phenomena and Processes::Musculoskeletal and Neural Physiological Phenomena::Nervous System Physiological Phenomena::Nervous System Physiological Processes::Neuronal Plasticity [Medical Subject Headings], ComputingMilieux_MISCELLANEOUS, media_common, Lectura, Language, Brain Mapping, Neuronal Plasticity, 05 social sciences, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Diagnostic Imaging::Neuroimaging::Functional Neuroimaging::Brain Mapping [Medical Subject Headings], [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Middle Aged, Magnetic Resonance Imaging, Independent Component Analysis, Temporal Lobe, Left fronto-parietal network, Identification (information), Neurology, Female, Psychology, Cognitive psychology, VWFA, Adult, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Diagnostic Imaging::Tomography::Magnetic Resonance Imaging [Medical Subject Headings], Cognitive Neuroscience, media_common.quotation_subject, Check Tags::Male [Medical Subject Headings], 050105 experimental psychology, lcsh:RC321-571, 03 medical and health sciences, Region of interest, Lenguaje, Neurologie, Neuroplasticity, Learning to read, Humans, 0501 psychology and cognitive sciences, Information Science::Information Science::Communication::Language::Language Arts::Reading [Medical Subject Headings], Persons::Persons::Age Groups::Adult [Medical Subject Headings], lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Information Science::Information Science::Computing Methodologies::Image Processing, Computer-Assisted [Medical Subject Headings], Neurosciences cognitives, Persons::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], Age of Acquisition, Check Tags::Female [Medical Subject Headings], Anatomy::Nervous System::Central Nervous System::Brain::Prosencephalon::Telencephalon::Cerebrum::Cerebral Cortex::Temporal Lobe [Medical Subject Headings], Anatomy::Nervous System::Neural Pathways [Medical Subject Headings], [SDV.NEU.SC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, 030217 neurology & neurosurgery
Abstract: Learning to read leads to functional and structural changes in cortical brain areas related to vision and language. Previous evidence suggests that the Visual Word Form Area (VWFA), a region devoted to the recognition of letter strings in literate persons, acts as an interface between both systems. While different studies have performed univariate analyses to study the effects of literacy on brain function, little is known about its impact on whole functional networks, especially when literacy is acquired during adulthood. We investigated functional connectivity in three groups of adults with different literacy status: illiterates, ex-illiterates (i.e. who learned to read during adulthood), and literates (i.e. who learned to read in childhood). We used a data-driven, multivariate whole brain approach (Independent Component Analysis [ICA]) combined with a region of interest (ROI) analysis in order to explore the functional connectivity of the VWFA with four ICA networks related to vision and language functions. ICA allowed for the identification of four networks of interest: left fronto-parietal, auditory, medial visual and lateral visual functional networks, plus a control right fronto-parietal network. We explored the effects literacy on the connectivity between the VWFA and these networks, trying furthermore to disentangle the roles of reading proficiency and age of acquisition (i.e. literacy status) in these changes. Results showed that functional connectivity between the VWFA and the left fronto-parietal and lateral visual networks increased and decreased, respectively, with literacy. Moreover, the functional coupling of the VWFA and the auditory network decreased with literacy. This study provides novel insights in the mechanisms of reading acquisition and brain plasticity, putting to light the emergence of the VWFA as a bridge between language and vision. Further studies are required to characterize the interplay of proficiency and age of reading acquisition, and its relevance to models of brain plasticity across lifespan., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2020

15. Growth hormone aggregates activation of human dendritic cells is controlled by Rac1 and PI3 kinase signaling pathways

Author: Marc Pallardy, Isabelle Turbica, Yann Gallais, Myriam Nabhan, Inflammation, Chimiokines et Immunopathologie [Châtenay-Malabry], Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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), CEA- Saclay (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and CCSD, Accord Elsevier
Subjects: rac1 GTP-Binding Protein, Drug Compounding, p38 mitogen-activated protein kinases, [SDV]Life Sciences [q-bio], Pharmaceutical Science, RAC1, 02 engineering and technology, CDC42, Protein aggregation, 030226 pharmacology & pharmacy, Protein Aggregates, 03 medical and health sciences, 0302 clinical medicine, Phosphorylation, Protein kinase A, Cells, Cultured, PI3K/AKT/mTOR pathway, Human Growth Hormone, Chemistry, Kinase, Dendritic Cells, 021001 nanoscience & nanotechnology, Up-Regulation, 3. Good health, Cell biology, Chemokine CXCL10, [SDV] Life Sciences [q-bio], Mitogen-Activated Protein Kinases, Phosphatidylinositol 3-Kinase, 0210 nano-technology, Signal Transduction
Abstract: International audience; The presence of protein aggregates in biological products is suggested to promote immunogenicity, leading to the production of anti-drug antibodies with neutralizing capacities. This suggests a CD4$^+$ T-cell dependent adaptive immune response, thus a pivotal role for antigen-presenting cells, such as dendritic cells (DCs). We previously showed that human growth hormone aggregates induced DC maturation, with notably an increase in CXCL10 production. DC phenotypic modifications were sufficient to promote allogeneic CD4$^+$ T-cell proliferation with Th1 polarization. In this work, we identified the main intracellular signaling pathways involved in DC activation by human growth hormone aggregates, showing that aggregates induced p38 mitogen-activated protein kinase, extracellular signaleregulated kinase, and c-Jun N-terminal kinase phosphorylation, as well as nuclear factor kB subunit p65 nuclear translocation. Next, investigating the implication of Rho GTPases and phosphoinositide 3-kinase (PI3K) in activated DC showed that Rac1 and Cdc42 regulated the phosphorylation of MAP kinases, whereas PI3K was only implicated in c-Jun N-terminal kinase phosphorylation. Furthermore, we showed that Rac1 and PI3K pathways, but not Cdc42, regulated the production of CXCL10 via the MAP kinases and nuclear factor kB.Taken together, our results bring new insight on how protein aggregates could induce DC activation, leading to a better understanding of aggregates role in therapeutic proteins immunogenicity.
Published: 2020

16. Spectral and 3D model studies of the interaction of orphan human cytochrome P450 2U1 with substrates and ligands

Author: Lionel Ducassou, François André, Maryse Jaouen, Nicolas Pietrancosta, Julien Dairou, Jean-Luc Boucher, Laura Dhers, Booma Ramassamy, Daniel Mansuy, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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), Département Biochimie, Biophysique et Biologie Structurale (B3S), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Stress Oxydants et Détoxication (LSOD), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Systèmes glutamatergiques normaux et pathologiques = Normal and Pathologic Glutamatergic Neurons (NPS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Analyse, Interactions Moléculaires et Cellulaires (LBM-E2), Laboratoire des biomolécules (LBM UMR 7203), Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Chimie Moléculaire de Paris Centre (FR 2769), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Models, Molecular, 0301 basic medicine, Serotonin, Pyridines, Stereochemistry, [SDV]Life Sciences [q-bio], Biophysics, Debrisoquin, Arachidonic Acids, Ligands, Biochemistry, Molecular Docking Simulation, Substrate Specificity, LSOD, 03 medical and health sciences, chemistry.chemical_compound, Escherichia coli, Humans, Imidazole, Homology modeling, Cytochrome P450 Family 2, Molecular Biology, Arachidonic Acid, 030102 biochemistry & molecular biology, biology, Electron Spin Resonance Spectroscopy, Imidazoles, Hexacoordinate, Lauric Acids, Active site, Cytochrome P450, Recombinant Proteins, 030104 developmental biology, chemistry, Docking (molecular), Biocatalysis, biology.protein, Spectrophotometry, Ultraviolet, Oxidation-Reduction, B3S, Protein Binding
Abstract: Background Cytochrome P450 2U1 (CYP2U1) has been identified from the human genome and is highly conserved in the living kingdom. It is considered as an “orphan” protein as few data are available on its physiological function(s) and spectral characteristics. Its only known substrates reported so far are unsaturated fatty acids such as arachidonic acid (AA), and, more recently, N -arachidonoylserotonin (AS) and some xenobiotics related to debrisoquine (Deb) and terfenadine. Methods We have expressed CYP2U1 in E. coli and performed UV–vis and EPR spectroscopy experiments with purified CYP2U1 alone and in the presence of substrates and imidazole and pyridine derivatives. Docking experiments using a 3D homology model of CYP2U1 were done to explain the observed spectroscopic data and the different regioselectivities of the oxidations of AA and AS. Results The UV–vis and EPR spectra of native recombinant human CYP2U1 revealed a predominant low-spin hexacoordinate Fe III state. Imidazole (Im) derivatives, such as miconazole, acted as Fe III ligands, contrary to ketoconazole, whereas the previously described substrates AS and Deb led to “reverse type I” difference UV–vis spectra. These data, as well as the different regioselectivities of AA and AS oxidations, were supported by docking experiments performed on our previously reported CYP2U1 3D model. Major conclusion and general significance Our study describes for the first time the mode of interaction of several Fe III -heme ligands and substrates with the active site of CYP2U1 on the basis of spectroscopic and molecular docking data. The good agreement between these data validates the used CYP2U1 3D model which should help the design of new substrates or inhibitors of this orphan CYP.
Published: 2017

17. Enhancing surface coil sensitive volume with hybridized electric dipoles at 17.2 T

Author: Julien de Rosny, Tania S. Vergara Gomez, Frank Kober, Redha Abdeddaim, Stefan Enoch, Abdelwaheb Ourir, Camille Jouvaud, Marc Dubois, Luisa Ciobanu, Institut FRESNEL (FRESNEL), Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU), 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), CLARTE (CLARTE), Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (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 Langevin - Ondes et Images (UMR7587) (IL), 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Service NEUROSPIN (NEUROSPIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Electronique et des Technologies de l'Information (CEA-LETI), Université Grenoble Alpes (UGA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Université Grenoble Alpes (UGA), Institut Langevin - Ondes et Images, Université Paris Diderot - Paris 7 (UPD7)-ESPCI ParisTech-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA))
Subjects: Larmor precession, [PHYS]Physics [physics], Nuclear and High Energy Physics, Materials science, Field (physics), business.industry, Plane (geometry), Biophysics, Metamaterial, 010402 general chemistry, Condensed Matter Physics, 01 natural sciences, Biochemistry, Imaging phantom, 030218 nuclear medicine & medical imaging, 0104 chemical sciences, 03 medical and health sciences, Resonator, Electric dipole moment, 0302 clinical medicine, Optics, Signal-to-noise ratio (imaging), business
Abstract: International audience; Preclinical MR applications at 17.2 T can require field of views on the order of a few square centimeters. This is a challenging task as the proton Larmor frequency reaches 730 MHz. Most of the protocols at such frequencies are performed with surface transceiver coils for which the sensitive volume and the signal to noise ratio (SNR) is given by their size. Here we propose an approach based on metamaterials in order to enhance the sensitive volume of a commercial surface coil for small animal imaging at 17.2 T. We designed a passive resonator composed of four hybridized electric dipoles placed onto the floor of the MRI bed. Combining numerical and experimental results on a phantom and in vivo, we demonstrate a 20% increase of the sensitive volume in depth and 25% along the rostro-caudal axis while maintaining more than 85% of the local SNR right beneath the surface coil plane. Moreover, our solution gives the ability to double the average SNR in the region between 1.2 and 2 cm away from the loop using a single layer of 1 mm thick metallic wires easy to design and manufacture.
Published: 2019

18. Evaluation of the Spider (Phlogiellus genus) Phlotoxin 1 and Synthetic Variants as Antinociceptive Drug Candidates

Author: Tânia C. Gonçalves, Pierre Lesport, Sarah Kuylle, Enrico Stura, Justyna Ciolek, Gilles Mourier, Denis Servent, Emmanuel Bourinet, Evelyne Benoit, Nicolas Gilles, 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)-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), Sanofi-Aventis R&D, SANOFI Recherche, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Paris-Saclay (Neuro-PSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Sanofi R & D, Integrated Drug Discovery, In Vitro Biology & Pharmacology, 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)-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), Centre de recherche du CEA/DSV/iBiTec-S/SIMOPRO, Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), Département d'Ingénierie et d'Etudes des Protéines, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire de neurobiologie cellulaire et moléculaire (NBCM), Centre National de la Recherche Scientifique (CNRS), CEN/Saclay, bourinet, emmanuel, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV] Life Sciences [q-bio], mouse model of NaV1.7-mediated pain, Phlogiellus spider, NaV1.7 channel subtype, [SDV]Life Sciences [q-bio], lcsh:R, human voltage-gated ion channel subtypes, lcsh:Medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], phlotoxin 1
Abstract: Over the two last decades, venom toxins have been explored as alternatives to opioids to treat chronic debilitating pain. At present, approximately 20 potential analgesic toxins, mainly from spider venoms, are known to inhibit with high affinity the NaV1.7 subtype of voltage-gated sodium (NaV) channels, the most promising genetically validated antinociceptive target identified so far. The present study aimed to consolidate the development of phlotoxin 1 (PhlTx1), a 34-amino acid and 3-disulfide bridge peptide of a Phlogiellus genus spider, as an antinociceptive agent by improving its affinity and selectivity for the human (h) NaV1.7 subtype. The synthetic homologue of PhlTx1 was generated and equilibrated between two conformers on reverse-phase liquid chromatography and exhibited potent analgesic effects in a mouse model of NaV1.7-mediated pain. The effects of PhlTx1 and 8 successfully synthetized alanine-substituted variants were studied (by automated whole-cell patch-clamp electrophysiology) on cell lines stably overexpressing hNaV subtypes, as well as two cardiac targets, the hCaV1.2 and hKV11.1 subtypes of voltage-gated calcium (CaV) and potassium (KV) channels, respectively. PhlTx1 and D7A-PhlTx1 were shown to inhibit hNaV1.1−1.3 and 1.5−1.7 subtypes at hundred nanomolar concentrations, while their affinities for hNaV1.4 and 1.8, hCaV1.2 and hKV11.1 subtypes were over micromolar concentrations. Despite similar analgesic effects in the mouse model of NaV1.7-mediated pain and selectivity profiles, the affinity of D7A-PhlTx1 for the NaV1.7 subtype was at least five times higher than that of the wild-type peptide. Computational modelling was performed to deduce the 3D-structure of PhlTx1 and to suggest the amino acids involved in the efficiency of the molecule. In conclusion, the present structure−activity relationship study of PhlTx1 results in a low improved affinity of the molecule for the NaV1.7 subtype, but without any marked change in the molecule selectivity against the other studied ion channel subtypes. Further experiments are therefore necessary before considering the development of PhlTx1 or synthetic variants as antinociceptive drug candidates.
Published: 2019

19. On the genetic bases of incomplete hippocampal inversion: a genome-wide association study

Author: Cury, Claire, Scelzi, Marzia A, Toro, Roberto, Frouin, Vincent, Artiges, Eric, Heinz, Andreas, Walter, Henrik, Lemaître, Hervé, Martinot, Jean-Luc, Poline, Jean-Baptiste, Smolka, Michael N., Schumann, Gunter, Altmann, Andre, Colliot, Olivier, Empenn, Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes 1 (UR1), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Centre for Medical Image Computing (CMIC), University College of London [London] (UCL), Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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), Adolescent psychopathology and Medicine, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Université de Cergy Pontoise (UCP), Université Paris-Seine, Ecole des Neurosciences de Paris Île de France (ENP), Ecole des Neurosciences de Paris, Lawrence Berkeley National Laboratory [Berkeley] (LBNL), Technische Universität Dresden = Dresden University of Technology (TU Dresden), Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-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), Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), 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)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuroimagerie: méthodes et applications (Empenn), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-Centre National de la Recherche Scientifique (CNRS), and Cury, Claire
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.GEN] Life Sciences [q-bio]/Genetics, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2019

20. Extensive exploration of a novel rat model of Parkinson's disease using partial 6-hydroxydopamine lesion of dopaminergic neurons suggests new therapeutic approaches

Author: Jean-Bernard Deloye, Gabrielle Chicheri, Lydie Nadal-Desbarats, Jackie Vergote, Sylvie Chalon, Sylvie Bodard, Patrick Emond, Claire Tronel, Steven Vetel, Frédéric Dollé, Johnny Vercouillie, Sophie Serrière, Antoine Lefèvre, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d’Investigation Clinique [Tours] CIC 1415 (CIC ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Zionexa [Paris, France], Service Hospitalier Frédéric Joliot (SHFJ), 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, Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service de Médecine Nucléaire [Tours], 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), Chalon, Sylvie, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)
Subjects: Male, Tyrosine 3-Monooxygenase, [SDV]Life Sciences [q-bio], PET imaging, Nigrostriatal pathway, Striatum, Lesion, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Neuroinflammation, medicine, Translocator protein, Animals, Rats, Wistar, Oxidopamine, dopamine transporter, 030304 developmental biology, Dopamine transporter, Dopamine Plasma Membrane Transport Proteins, 0303 health sciences, Tyrosine hydroxylase, biology, Chemistry, Dopaminergic Neurons, Dopaminergic, Parkinson Disease, Receptors, GABA-A, metabolomics, Corpus Striatum, Rats, [SDV] Life Sciences [q-bio], Disease Models, Animal, medicine.anatomical_structure, nervous system, Positron-Emission Tomography, Metabolome, biology.protein, Microglia, medicine.symptom, Carrier Proteins, Neuroscience, 030217 neurology & neurosurgery, TSPO
Abstract: Parkinson's disease (PD) is characterized by the degeneration of dopaminergic (DA) neurons constituting the nigrostriatal pathway. Neuroinflammation, related to microglial activation, plays an important role in this process. Exploration of animal models of PD using neuroimaging modalities allows to better understand the pathophysiology of the disease. Here, we fully explored a moderate lesion model in the rat in which 6-hydroxydopamine was unilaterally delivered in three sites along the striatum. The degenerative process was assessed through in vivo Positron Emission Tomography (PET) imaging and in vitro autoradiographic quantitation of the striatal dopamine transporter (DAT) and immunostaining of tyrosine hydroxylase (TH). The microglial activation was studied through in vitro autoradiographic quantitation of the 18 kDa translocator protein (TSPO) in the striatum and CD11b staining in the SN. In addition, a targeted metabolomics exploration was performed in both these structures using mass spectrometry coupled to HPLC. Our results showed a reproducible decrease in the striatal DAT density associated with a reduction in the number of TH-positive cells in the SN and striatum, reflecting a robust moderate degeneration of nigrostriatal DA neurons. In addition, we observed strong microglia activation in both the striatum and SN ipsilateral to the lesion, highlighting that this moderate degeneration of DA neurons was associated with a marked neuroinflammation. Our metabolomics studies revealed alterations of specific metabolites and metabolic pathways such as carnitine, arginine/proline, and histidine metabolisms. These results bring new insights in the PD mechanism knowledge and new potential targets for future therapeutic strategies.
Published: 2019

21. Aptamer Efficacies for In Vitro and In Vivo Modulation of $\alpha$C-Conotoxin PrXA Pharmacology

Author: Taiwe, Germain Sotoing, Montnach, Jérôme, Nicolas, Sébastien, Waard, Stéphan De, Fiore, Emmanuelle, Peyrin, Eric, El-Aziz, Tarek Mohamed Abd, Amar, Muriel, Molgó, Jordi, Ronjat, Michel, Servent, Denis, Ravelet, Corinne, Waard, Michel De, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Buéa, Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Département de pharmacochimie moléculaire (DPM ), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Zoology Department, Minia University, Service d’Ingénierie Moléculaire des Protéines, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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 des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Smartox Biotechnologies, ANR-11-LABX-0015,ICST,Canaux ioniques d'intérêt thérapeutique(2011), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Université Grenoble Alpes (UGA), SERVENT, Denis, and Laboratoires d'excellence - Canaux ioniques d'intérêt thérapeutique - - ICST2011 - ANR-11-LABX-0015 - LABX - VALID
Subjects: Male, Myoclonus, oligonucleotide, SELEX Aptamer Technique, venom, Aptamers, Nucleotide, Receptors, Nicotinic, cone peptide, DNA aptamer, Article, Cell Line, lcsh:QD241-441, Disease Models, Animal, Mice, αC-conotoxin PrXA, toxin neutralization, lcsh:Organic chemistry, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, $\alpha$C-conotoxin PrXA, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Animals, Female, Conotoxins
Abstract: The medical staff is often powerless to treat patients affected by drug abuse or misuse and poisoning. In the case of envenomation, the treatment of choice remains horse sera administration that poses a wealth of other medical conditions and threats. Previously, we have demonstrated that DNA-based aptamers represent powerful neutralizing tools for lethal animal toxins of venomous origin. Herein, we further pursued our investigations in order to understand whether all toxin-interacting aptamers possessed equivalent potencies to neutralize &alpha, C-conotoxin PrXA in vitro and in vivo. We confirmed the high lethality in mice produced by &alpha, C-conotoxin PrXA regardless of the mode of injection and further characterized myoclonus produced by the toxin. We used high-throughput patch-clamp technology to assess the effect of &alpha, C-conotoxin PrXA on ACh-mediated responses in TE671 cells, responses that are carried by muscle-type nicotinic receptors. We show that 2 out of 4 aptamers reduce the affinity of the toxin for its receptor, most likely by interfering with the pharmacophore. In vivo, more complex responses on myoclonus and mice lethality are observed depending on the type of aptamer and mode of administration (concomitant or differed). Concomitant administration always works better than differed administration indicating the stability of the complex in vivo. The most remarkable conclusion is that an aptamer that has no or a limited efficacy in vitro may nevertheless be functional in vivo probably owing to an impact on the biodistribution or pharmacokinetics of the toxin in vivo. Overall, the results highlight that a blind selection of aptamers against toxins leads to efficient neutralizing compounds in vivo regardless of the mode of action. This opens the door to the use of aptamer mixtures as substitutes to horse sera for the neutralization of life-threatening animal venoms, an important WHO concern in tropical areas.
Published: 2019

22. High Therapeutic Efficacy of a New Survivin LSP-Cancer Vaccine Containing CD4+ and CD8+ T-Cell Epitopes

Author: Fanny Onodi, Chahrazed Maherzi-Mechalikh, Alice Mougel, Nadine Ben Hamouda, Charlotte Taboas, Fabien Gueugnon, Thi Tran, Herve Nozach, Elodie Marcon, Alain Gey, Magali Terme, Ahmed Bouzidi, Bernard Maillere, Jérôme Kerzerho, Eric Tartour, Corinne Tanchot, Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)
Subjects: Cancer Research, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, long synthetic peptide, lcsh:RC254-282, Epitope, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigen, tumor associated survivin antigen, medicine, Cytotoxic T cell, business.industry, Immunogenicity, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Immunotherapy, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Tumor antigen, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Cancer research, T-cell responses, Cancer vaccine, immunotherapy, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, business, cancer vaccine, 030215 immunology
Abstract: International audience; The efficacy of an antitumoral vaccine relies both on the choice of the antigen targeted and on its design. The tumor antigen survivin is an attractive target to develop therapeutic cancer vaccines because of its restricted over-expression and vital functions in most human tumors. Accordingly, several clinical trials targeting survivin in various cancer indications have been conducted. Most of them relied on short peptide-based vaccines and showed promising, but limited clinical results. In this study, we investigated the immunogenicity and therapeutic efficacy of a new long synthetic peptide (LSP)-based cancer vaccine targeting the tumor antigen survivin (SVX). This SVX vaccine is composed of three long synthetic peptides containing several CD4+ and CD8+ T-cell epitopes, which bind to various HLA class II and class I molecules. Studies in healthy individuals showed CD4+ and CD8+ T-cell immunogenicity of SVX peptides in human, irrespective of the individual's HLA types. Importantly, high frequencies of spontaneous T-cell precursors specific to SVX peptides were also detected in the blood of various cancer patients, demonstrating the absence of tolerance against these peptides. We then demonstrated SVX vaccine's high therapeutic efficacy against four different established murine tumor models, associated with its capacity to generate both specific cytotoxic CD8+ and multifunctional Th1 CD4+ T-cell responses. When tumors were eradicated, generated memory T-cell responses protected against rechallenge allowing long-term protection against relapses. Treatment with SVX vaccine was also found to reshape the tumor microenvironment by increasing the tumor infiltration of both CD4+ and CD8+ T cells but not Treg cells therefore tipping the balance toward a highly efficient immune response. These results highlight that this LSP-based SVX vaccine appears as a promising cancer vaccine and warrants its further clinical development.
Published: 2018

23. Inhibition of central de novo ceramide synthesis restores insulin signaling in hypothalamus and enhances β-cell function of obese Zucker rats

Author: Campana, Mélanie, Bellini, Lara, Rouch, Claude, Rachdi, Latif, Coant, Nicolas, Butin, Noémie, Bandet, Cécile, Philippe, Erwann, Meneyrol, Kelly, Kassis, Nadim, Dairou, Julien, Hajduch, Eric, Colsch, Benoit, Magnan, Christophe, Le Stunff, Hervé, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche Croissance et signalisation (UMR_S 845), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Etude du Métabolisme des Médicaments (LEMM), Service de Pharmacologie et Immunoanalyse (SPI), 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)-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)-Médicaments et Technologies pour la Santé (MTS), 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), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), 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), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-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)-Université Paris Cité (UPCité), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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 des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), École pratique des hautes études (EPHE), and Hajduch, Eric
Subjects: OZR, Obese Zucker rat, Blood Glucose, lcsh:Internal medicine, Hypothalamus, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Ceramides, d4-palmitate, Deuterium-labeled palmitate, Cell Line, ER, endoplasmic reticulum, Ceramide, Mice, IR, insulin resistance, HFD, high fat diet, Thr-308, Threonine 308, Insulin-Secreting Cells, M, myriocin, Animals, Insulin, Obesity, Hypotalamus, lcsh:RC31-1245, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, ICV, intracerebroventricular, Ser-473, Serine 473, C2-Cer, C2-Ceramide, LZR, Lean Zucker rat, Insulin secretion, PKCs, proteins kinase C, T2D, Type 2 diabetes mellitus, DH-C2-cer, dihydroceramide, Insulin resistance, SPT2, Serine-palmitoyl transferase 2, Rats, Rats, Zucker, CerS, ceramide Synthase, Original Article, Lipotoxicity, Signal Transduction
Abstract: Objectives Hypothalamic lipotoxicity has been shown to induce central insulin resistance and dysregulation of glucose homeostasis; nevertheless, elucidation of the regulatory mechanisms remains incomplete. Here, we aimed to determine the role of de novo ceramide synthesis in hypothalamus on the onset of central insulin resistance and the dysregulation of glucose homeostasis induced by obesity. Methods Hypothalamic GT1-7 neuronal cells were treated with palmitate. De novo ceramide synthesis was inhibited either by pharmacological (myriocin) or molecular (si-Serine Palmitoyl Transferase 2, siSPT2) approaches. Obese Zucker rats (OZR) were intracerebroventricularly infused with myriocin to inhibit de novo ceramide synthesis. Insulin resistance was determined by quantification of Akt phosphorylation. Ceramide levels were quantified either by a radioactive kinase assay or by mass spectrometry analysis. Glucose homeostasis were evaluated in myriocin-treated OZR. Basal and glucose-stimulated parasympathetic tonus was recorded in OZR. Insulin secretion from islets and β-cell mass was also determined. Results We show that palmitate impaired insulin signaling and increased ceramide levels in hypothalamic neuronal GT1-7 cells. In addition, the use of deuterated palmitic acid demonstrated that palmitate activated several enzymes of the de novo ceramide synthesis pathway in hypothalamic cells. Importantly, myriocin and siSPT2 treatment restored insulin signaling in palmitate-treated GT1-7 cells. Protein kinase C (PKC) inhibitor or a dominant-negative PKCζ also counteracted palmitate-induced insulin resistance. Interestingly, attenuating the increase in levels of hypothalamic ceramides with intracerebroventricular infusion of myriocin in OZR improved their hypothalamic insulin-sensitivity. Importantly, central myriocin treatment partially restored glucose tolerance in OZR. This latter effect is related to the restoration of glucose-stimulated insulin secretion and an increase in β-cell mass of OZR. Electrophysiological recordings also showed an improvement of glucose-stimulated parasympathetic nerve activity in OZR centrally treated with myriocin. Conclusion Our results highlight a key role of hypothalamic de novo ceramide synthesis in central insulin resistance installation and glucose homeostasis dysregulation associated with obesity., Highlights • de novo ceramide synthesis induces hypothalamic insulin resistance through PKCζ. • Hypothalamic ceramides induce glucose homeostasis dysregulation seen with obesity. • Hypothalamic ceramides mediate inhibition of insulin secretion induced by obesity. • Hypothalamic ceramides decreases β cell mass in obese rats. • Hypothalamic ceramides decreases parasympathetic tonus.
Published: 2018

24. Association of transcallosal motor fibres with function of both hands after unilateral neonatal arterial ischemic stroke

Author: Groeschel, Samuel, Hertz‐Pannier, Lucie, Delion, Matthieu, Loustau, Sébastien, Husson, Béatrice, Kossorotoff, Manoelle, Renaud, Cyrille, Nguyen The Tich, Sylvie, Chabrier, Stéphane, Dinomais, Mickaël, Darteyre, Stéphane, Dégano, Céline, Deron, Johanna, Dray, Gérard, Drutel, Laure, Lazaro, Leila, Lefranc, Jérémie, Peyric, Emeline, Presles, Emilie, Ravel, Magaly, Thébault, Guillaume, Vuillerot, Carole, Department of Child Neurology, University Hospital Tübingen, Tübingen, Germany, Unité de recherche en NeuroImagerie Applicative Clinique et Translationnelle (UNIACT), Service NEUROSPIN (NEUROSPIN), 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)-Université Paris-Saclay, Département de neurochirurgie [Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Laboratoire d'Analyse, Topologie, Probabilités (LATP), Université Paul Cézanne - Aix-Marseille 3-Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique (CNRS), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Groupe de recherche sur la thrombose (GRT (EA 3065)), Université Jean Monnet [Saint-Étienne] (UJM), Service de neurologie pédiatrique, service de médecine physique et réadaptation pédiatrique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Bellevue-CHU de Saint-Etienne, Laboratoire Angevin de Recherche en Ingénierie des Systèmes (LARIS), Université d'Angers (UA), PRES Université Nantes Angers Le Mans (UNAM), Department of Pediatrics, French Polynesia Hospital, Laboratoire de Génie Informatique et Ingénierie de Production (LGI2P), IMT - MINES ALES (IMT - MINES ALES), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Service de pédiatrie, Le CHCB, Centre Hospitalier de la Côte Basque, CHRU de Brest - Département de Pédiatrie (CHU BREST Pédiatrie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Dynamique des capacités humaines et des conduites de santé (EPSYLON), Université Montpellier 1 (UM1)-Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Montpellier (UM), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, 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 des Sciences du Vivant Frédéric JOLIOT (JOLIOT), Laboratoire Angevin de Recherche en Mathématiques (LAREMA), Université d'Angers (UA)-Centre National de la Recherche Scientifique (CNRS), Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), CHU Lille, AVCnn study group: Stéphane Darteyre, Céline Dégano, Johanna Deron, Gérard Dray, Laure Drutel, Manoëlle Kossorotoff, Leila Lazaro, Jérémie Lefranc, Emeline Peyric, Emilie Presles, Magaly Ravel, Guillaume Thébault, Carole Vuillerot, Gerard, Marie-Françoise, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université Montpellier 1 (UM1)-Université Paul-Valéry - Montpellier 3 (UM3)-Université de Montpellier (UM), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), and ANR-11-LABX-0020,LEBESGUE,Centre de Mathématiques Henri Lebesgue : fondements, interactions, applications et Formation(2011)
Subjects: Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Pyramidal Tracts, Lesion volume, Motor Activity, Corpus callosum, Functional Laterality, Brain Ischemia, Corpus Callosum, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Developmental Neuroscience, 030225 pediatrics, medicine.artery, medicine, Humans, Association (psychology), Child, medicine.diagnostic_test, Motor Cortex, Magnetic resonance imaging, Anatomy, Organ Size, Hand, Arterial Ischemic Stroke, Magnetic Resonance Imaging, [SDV] Life Sciences [q-bio], Stroke, Diffusion Tensor Imaging, Pediatrics, Perinatology and Child Health, Corticospinal tract, Middle cerebral artery, Female, Neurology (clinical), Psychology, 030217 neurology & neurosurgery, Diffusion MRI
Abstract: International audience; AIM: The objective of this study was to investigate the involvement of the motor fibres of the corpus callosum after unilateral neonatal arterial ischemic stroke (NAIS) of the middle cerebral artery territory and the relationship to both ipsilesional and contralesional hand function.METHOD: Using high-resolution structural magnetic resonance imaging (MRI), functional MRI, and magnetic resonance diffusion-tractography, we compared the midsagittal area of the motor part of the corpus callosum (defined by the fibres connecting the precentral gyri) between 33 7-year-old children after unilateral NAIS and 31 typically developing 7-year-old children. Hand motor performance was assessed by the box and blocks test.RESULTS: Children after NAIS showed on average significantly smaller motor corpus callosum area compared to typically developing children (p|t|)=0.034) and ipsilesional hand motor performance (Pr(>|t|)=0.006) after controlling for lesion volume and sex. In a post-hoc analysis the additional contribution of corticospinal tract damage was evaluated.INTERPRETATION: Compared to typically developing children, children after NAIS exhibited a smaller motor part of their corpus callosum associated with reduced contralesional but also ipsilesional manual dexterity. These results indicate that the affection of transcallosal motor fibres in unilateral NAIS might be of functional relevance and an important part of the involved structural network that should be elucidated in further studies.TRIAL REGISTRATION: ClinicalTrials.gov NCT02511249.© 2017 Mac Keith Press.
Published: 2017

25. Green mamba peptide targets type-2 vasopressin receptor against polycystic kidney disease

Author: Sabrina Sigismeau, Loïc Quinton, Hélène Orcel, Jérôme Nevoux, Nicolas Gilles, Steve Peigneur, Ralph Witzgall, Justyna Ciolek, Laura Droctové, Enrico A. Stura, Gilles Mourier, Fabrice Beau, Edwin De Pauw, Marc Lombès, Laura Vera, Denis Servent, Helen Reinfrank, Jan Tytgat, Bernard Mouillac, Christiane Mendre, Say Viengchareun, Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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), University of Regensburg - Institute for Molecular and Cellular Anatomy, Université Paris Sud-Paris Saclay, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Toxicology, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Receptors, Vasopressin, Time Factors, [SDV]Life Sciences [q-bio], Kunitz peptide, Crystallography, X-Ray, Mice, 0302 clinical medicine, Aquaretic, Cricetinae, Polycystic kidney disease, Cyclic AMP, Aprotinin, Trypsin, Receptor, Vasopressin receptor, Kidney, Polycystic Kidney Diseases, Multidisciplinary, Biological Sciences, 3. Good health, medicine.anatomical_structure, Female, Antidiuretic Hormone Receptor Antagonists, medicine.drug, Signal Transduction, Snake Venoms, medicine.medical_specialty, CHO Cells, Tachyphylaxis, Biology, 03 medical and health sciences, Cricetulus, Internal medicine, medicine, Animals, Humans, Natriuretic Peptides, Dendroaspis, polycystic kidney disease, Benzazepines, medicine.disease, snake toxin, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, HEK293 Cells, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Tolvaptan, Peptides, 030217 neurology & neurosurgery
Abstract: International audience; Polycystic kidney diseases (PKDs) are genetic disorders that can cause renal failure and death in children and adults. Lowering cAMP in cystic tissues through the inhibition of the type-2 vasopressin receptor (V2R) constitutes a validated strategy to reduce disease progression. We identified a peptide from green mamba venom that exhibits nanomolar affinity for the V2R without any activity on 155 other G-protein-coupled receptors or on 15 ionic channels. Mambaquaretin-1 is a full antagonist of the V2R activation pathways studied: cAMP production, beta-arrestin interaction, and MAP kinase activity. This peptide adopts the Kunitz fold known to mostly act on potassium channels and serine proteases. Mambaquaretin-1 interacts selectively with the V2R through its first loop, in the same manner that aprotinin inhibits trypsin. Injected in mice, mambaquaretin-1 increases in a dose-dependent manner urine outflow with concomitant reduction of urine osmolality, indicating a purely aquaretic effect associated with the in vivo blockade of V2R. CD1-pcy/pcy mice, a juvenile model of PKD, daily treated with 13 [Formula: see text]g of mambaquaretin-1 for 99 d, developed less abundant (by 33%) and smaller (by 47%) cysts than control mice. Neither tachyphylaxis nor apparent toxicity has been noted. Mambaquaretin-1 represents a promising therapeutic agent against PKDs.
Published: 2017

26. Surface morphology in tungsten and RAFM steel exposed to helium plasma in PSI-2

Author: Ryuichi Sakamoto, Naoaki Yoshida, Christian Grisolia, Céline Martin, Grégory Pieters, Bernard Rousseau, B. Pégourié, Arkadi Kreter, E. Bernard, National Institute for Fusion Science (NIFS), Institut de Recherche sur la Fusion par confinement Magnétique (IRFM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Forschungszentrum Jülich GmbH | Centre de recherche de Juliers, Helmholtz-Gemeinschaft = Helmholtz Association, Physique des interactions ioniques et moléculaires (PIIM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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), Service de Chimie Bio-Organique et de Marquage (SCBM), 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)-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), The National Research Nuclear University MEPhI (Moscow Engineering Physics Institute) [Moscow, Russia], Research Institute for Applied Mechanics [Fukuoka] (RIAM), Kyushu University, and Kyushu University [Fukuoka]
Subjects: Morphology (linguistics), Materials science, tungsten, chemistry.chemical_element, helium, Tungsten, Condensed Matter Physics, erosion, 01 natural sciences, Helium plasma, Atomic and Molecular Physics, and Optics, 010305 fluids & plasmas, chemistry, RAFM steel, [PHYS.PHYS.PHYS-PLASM-PH]Physics [physics]/Physics [physics]/Plasma Physics [physics.plasm-ph], 0103 physical sciences, [PHYS.COND.CM-MS]Physics [physics]/Condensed Matter [cond-mat]/Materials Science [cond-mat.mtrl-sci], surface morphology, Composite material, 010306 general physics, Mathematical Physics
Abstract: International audience; Impact of the helium plasma exposure on the surface modification in tungsten and RAFM (Reduced Activation Ferritic/Martensitic) steel have been investigated on the linear plasma device PSI-2 assuming the condition of DEMO first wall. In tungsten, a nanoscale undulating surface structure, which has a periodic arrangement, is formed under low temperature conditions below fuzz nanostructure formation threshold ∼ 1000 K. Interval and direction of the undulation shows dependence on the crystal orientation. A large variation in surface level up to 200 nm has been observed among grains at a fluence of $_{3 ×10}$$^{26}$ He/m$^{-2}$ showing dependence of the surface erosion rate on the crystal orientation. The {100} plane in which the undulating surface structure is not formed shows the highest erosion rate. This significant erosion is due to the multistage sputtering through impurity. In RAFM steel, sponge-like nanostructure is developed and it grows with increasing helium fluence beyond 1 $\mu$m. In the sponge-like nanostructure, a composition change from the base material is observed in which the tungsten ratio increases while the iron ratio decreases showing differences in sputtering ratio depending on the atomic mass.
Published: 2017

27. Mambalgin-1 Pain-relieving Peptide, Stepwise Solid-phase Synthesis, Crystal Structure, and Functional Domain for Acid-sensing Ion Channel 1a Inhibition

Author: Enrico A. Stura, Thomas Besson, Gilles Mourier, Pascal Kessler, Sylvie Diochot, Eric Lingueglia, Dominique Douguet, Anne Baron, Mathieu Leblanc, Livia Tepshi, Miguel Salinas, Denis Servent, 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)-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 de pharmacologie moléculaire et cellulaire (IPMC), 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), LTMB équipe 2 (LTMB2), 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)-Médicaments et Technologies pour la Santé (MTS), Université de Bordeaux (UB), Institut National de la Santé et de la Recherche Médicale (INSERM), 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)-Université Côte d'Azur (UCA), Institut de Biologie et de Technologies de Saclay (IBITECS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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), 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 du CEA/DSV/iBiTec-S/SIMOPRO, 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), and BARON, Anne
Subjects: 0301 basic medicine, Stereochemistry, Peptide, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Biochemistry, Protein Structure, Secondary, Xenopus laevis, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Solid-phase synthesis, Neurobiology, Peptide synthesis, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Nuclear Magnetic Resonance, Biomolecular, Molecular Biology, Acid-sensing ion channel, Ion channel, ComputingMilieux_MISCELLANEOUS, Elapid Venoms, chemistry.chemical_classification, Peptide chemical synthesis, Sodium channel, Cell Biology, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Protein Structure, Tertiary, Rats, Acid Sensing Ion Channels, 030104 developmental biology, chemistry, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Oocytes, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Pharmacophore, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Peptides, 030217 neurology & neurosurgery, [CHIM.CHEM]Chemical Sciences/Cheminformatics
Abstract: Mambalgins are peptides isolated from mamba venom that specifically inhibit a set of acid-sensing ion channels (ASICs) to relieve pain. We show here the first full stepwise solid phase peptide synthesis of mambalgin-1 and confirm the biological activity of the synthetic toxin both in vitro and in vivo. We also report the determination of its three-dimensional crystal structure showing differences with previously described NMR structures. Finally, the functional domain by which the toxin inhibits ASIC1a channels was identified in its loop II and more precisely in the face containing Phe-27, Leu-32, and Leu-34 residues. Moreover, proximity between Leu-32 in mambalgin-1 and Phe-350 in rASIC1a was proposed from double mutant cycle analysis. These data provide information on the structure and on the pharmacophore for ASIC channel inhibition by mambalgins that could have therapeutic value against pain and probably other neurological disorders.
Published: 2016

28. Unsupervised spectral clustering for segmentation of dynamic PET images

Author: Simon Stute, Irène Buvat, Sylvie Chalon, Laurent Galineau, Clovis Tauber, Jamal Charara, Hiba Zbib, Jean-Marc Girault, Sandrine Mouysset, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lebanese University [Beirut] (LU), Algorithmes Parallèles et Optimisation (IRIT-APO), Institut de recherche en informatique de Toulouse (IRIT), Université Toulouse Capitole (UT Capitole), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse Capitole (UT Capitole), Université Fédérale Toulouse Midi-Pyrénées, Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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), (OATAO), Open Archive Toulouse Archive Ouverte, Commissariat à l'Energie Atomique et aux énergies alternatives - CEA (FRANCE), Centre National de la Recherche Scientifique - CNRS (FRANCE), Institut National Polytechnique de Toulouse - INPT (FRANCE), Institut National de la Santé et de la Recherche Médicale - INSERM (FRANCE), Lebanese University - LU (LEBANON), Université Toulouse III - Paul Sabatier - UT3 (FRANCE), Université Toulouse - Jean Jaurès - UT2J (FRANCE), Université Toulouse 1 Capitole - UT1 (FRANCE), Université de Tours (FRANCE), Institut de Recherche en Informatique de Toulouse - IRIT (Toulouse, France), Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse 1 Capitole (UT1), Institut National Polytechnique de Toulouse - Toulouse INP (FRANCE), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT), Université Libanaise, Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Hospitalier Frédéric Joliot (SHFJ), and Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA))
Subjects: Nuclear and High Energy Physics, Computer science, Correlation clustering, ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION, 02 engineering and technology, Clustering, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Spectral clustering, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, 0202 electrical engineering, electronic engineering, information engineering, Segmentation, Electrical and Electronic Engineering, Cluster analysis, Global optimization, ComputingMilieux_MISCELLANEOUS, business.industry, Segmentation-based object categorization, Pattern recognition, Recherche d'information, Image segmentation, Weighting, Nuclear Energy and Engineering, [INFO.INFO-IR]Computer Science [cs]/Information Retrieval [cs.IR], 020201 artificial intelligence & image processing, Artificial intelligence, Segmentation of dynamic PET image, [INFO.INFO-IR] Computer Science [cs]/Information Retrieval [cs.IR], business
Abstract: International audience; Segmentation of dynamic PET images is needed to extract the time activity curves (TAC) of regions of interest (ROI). These TAC can be used in compartmental models for in vivo quantification of the radiotracer target. While unsupervised clustering methods have been proposed to segment PET sequences, they are often sensitive to initial conditions or favour convex shaped clusters. Kinetic spectral clustering (KSC) of dynamic PET images was recently proposed to handle arbitrary shaped clusters in the space in which they are identified. While improved results were obtained with KSC compared to three state of art methods, its use for clinical applications is still hindered by the manual setting of several parameters. In this paper, we develop an extension of KSC to automatically estimate the parameters involved in the method and to make it deterministic. First, a global search procedure is used to locate the optimal cluster centroids from the projected data. Then an unsupervised clustering criterion is tailored and used in a global optimization scheme to automatically estimate the scale parameter and the weighting factors involved in the proposed Automatic and Deterministic Kinetic Spectral Clustering (AD-KSC). We validate the method using GATE Monte Carlo simulations of dynamic numerical phantoms and present results on real dynamic images. The deterministic results obtained with AD-KSC agree well with those obtained with optimal manual parameterization of KSC, and improve the ROI identification compared to three other clustering methods. The proposed approach could have significant impact for quantification of dynamic PET images in molecular imaging studies.
Published: 2015

29. A Tandem of SH3-like Domains Participates in RNA Binding in KIN17, a Human Protein Activated in Response to Genotoxics

Author: Joël Couprie, Sophie Zinn-Justin, Enrico A. Stura, Ghislaine Pinon-Lataillade, M. Schiltz, Muriel Gondry, Albane le Maire, Jaime F. Angulo, Mireille Moutiez, Département d'Ingenierie et d'Etudes des Protéines (DIEP), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Ecole Polytechnique Fédérale de Lausanne (EPFL), Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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), 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)-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), and CEA, DSV, DRR, Service de Génomique Fonctionnelle
Subjects: RNA-binding protein, Biology, DNA-binding protein, src Homology Domains, Structural Biology, Humans, SH3-like fold, Binding site, Nuclear protein, Molecular Biology, Gene, Regulation of gene expression, Binding Sites, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], KIN17 protein, Lysine, Nuclear Proteins, RNA-Binding Proteins, RNA, Tungsten Compounds, RNA binding, Cell biology, DNA-Binding Proteins, Gene Expression Regulation, Biochemistry, tungstate, TAF4, X-ray structure, Mutagens
Abstract: International audience; The human KIN17 protein is an essential nuclear protein conserved from yeast to human and expressed ubiquitously in mammals. Suppression of Rts2, the yeast equivalent of gene KIN17, renders the cells unviable, and silencing the human KIN17 gene slows cell growth dramatically. Moreover, the human gene KIN17 is up-regulated following exposure to ionizing radiations and UV light, depending on the integrity of the human global genome repair machinery. Its ectopic over-expression blocks S-phase progression by inhibiting DNA synthesis. The C-terminal region of human KIN17 is crucial for this anti-proliferation effect. Its high-resolution structure, presented here, reveals a tandem of SH3-like subdomains. This domain binds to ribonucleotide homopolymers with the same preferences as the whole protein. Analysis of its structure complexed with tungstate shows structural variability within the domain. The interaction with tungstate is mediated by several lysine residues located within a positively charged groove at the interface between the two subdomains. This groovecould be the site of interaction with RNA, since mutagenesis of two of these highly conserved lysine residue weakens RNA binding
Published: 2006

30. Alteration of the in vivo nicotinic receptor density in ADNFLE patients: a PET study

Author: H. Valette, Denis Servent, Eylert Brodtkorb, B. Steinborn, D. Roumenov, Sameer M. Zuberi, W. Saba, Michel Bottlaender, A. Hufnagel, Antonio Gambardella, Fabienne Picard, Carole Fruchart-Gaillard, D. Bruel, M.-A. Schöllhorn-Peyronneau, Department of Neurology [Genève], Hôpitaux Universitaires de Genève (HUG), Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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), 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)-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), Department of Psychiatry [St. Olav's hospital, Trondheim], St. Olav's Hospital, Royal Hospital for Sick Children [Edinburgh], Università degli Studi 'Magna Graecia' di Catanzaro = University of Catanzaro (UMG), Poznan University of Medical Sciences [Poland] (PUMS), Department of Neurology [Duisburg-Essen], and Universität Duisburg-Essen = University of Duisburg-Essen [Essen]
Subjects: Adult, Male, Fluorine Radioisotopes, medicine.medical_specialty, Pyridines, [SDV]Life Sciences [q-bio], Epilepsy, Frontal Lobe, Autosomal dominant nocturnal frontal lobe epilepsy, Receptors, Nicotinic, Mesencephalon, Cerebellum, Internal medicine, Image Processing, Computer-Assisted, medicine, Humans, genetics, Prefrontal cortex, Cells, Cultured, Geographic difference, fluoro-A-85380, Brain, medicine.disease, PET, medicine.anatomical_structure, Endocrinology, Nicotinic agonist, nervous system, Frontal lobe, Cerebral cortex, Positron-Emission Tomography, Mutation, ADNFLE, Azetidines, Female, Orbitofrontal cortex, Neurology (clinical), Brainstem, nicotinic receptor, Psychology, Neuroscience
Abstract: International audience; Nicotinic acetylcholine receptors (nAChRs) are involved in a familial form of frontal lobe epilepsy, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). In several ADNFLE families, mutations were identified in the nAChR $\alpha$4 or $\beta$2 subunit, which together compose the main cerebral nAChR. Electrophysiological assessment using in vitro expression systems indicated a gain of function of the mutant receptors. However the precise mechanisms by which they contribute to the pathogenesis of a focal epilepsy remain obscure, especially since $\alpha$4$\beta$2 nAChRs are known to be widely distributed within the entire brain. PET study using [18F]-F-A-85380, a high affinity agonist at the $\alpha$4$\beta$2 nAChRs, allows the determination of the regional distribution and density of the nAChRs in healthy volunteers and in ADNFLE patients, thus offering a unique opportunity to investigate some in vivo consequences of the molecular defect. We have assessed nAChR distribution in eight non-smoking ADNFLE patients (from five families) bearing an identified mutation in nAChRs and in seven age-matched non-smoking healthy volunteers using PET and [$^{18}$F]-F-A-85380. Parametric images of volume of distribution (Vd) were generated as the ratio of tissue to plasma radioactivities. The images showed a clear difference in the pattern of the nAChR density in the brains of the patients compared to the healthy volunteers. Vd values revealed a significant increase (between 12 and 21%, P < 0.05) in the ADNFLE patients in the mesencephalon, the pons and the cerebellum when compared to control subjects. Statistical parametric mapping (SPM) was then used to better analyse subtle regional differences. This analysis confirmed clear regional differences between patients and controls: patients had increased nAChR density in the epithalamus, ventral mesencephalon and cerebellum, but decreased nAChR density in the right dorsolateral prefrontal region. In five patients who underwent an additional [18F]-fluorodeoxyglucose (FDG) PET experiment, hypometabolism was observed in the neighbouring area of the right orbitofrontal cortex. The demonstration of a regional nAChR density decrease in the prefrontal cortex, despite the known distribution of these receptors throughout the cerebral cortex, is consistent with a focal epilepsy involving the frontal lobe. We also propose that the nAChR density increase in mesencephalon is involved in the pathophysiology of ADNFLE through the role of brainstem ascending cholinergic systems in arousal.
Published: 2006

31. AFM Characterization of Tilt and Intrinsic Flexibility of Rhodobacter sphaeroides Light Harvesting Complex 2 (LH2)

Author: Jean-Louis Rigaud, Bruno Robert, Daniel Lévy, Sergio Marco, Cécile Breyton, Simon Scheuring, Jérôme Seguin, Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Recherche Correspondant du CEA (LRC-CEA), Université Sciences et Technologies - Bordeaux 1-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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), Système membranaires, photobiologie, stress et détoxication (SMPSD), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Physico-chimie moléculaire des membranes biologiques (PCMMB), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université Sciences et Technologies - Bordeaux 1 (UB)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Physico-Chimie-Curie (PCC), Institut Curie-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)
Subjects: Models, Molecular, Protein Conformation, Cryo-electron microscopy, Detergents, Molecular Sequence Data, Photosynthetic Reaction Center Complex Proteins, MESH: Pliability, MESH: Amino Acid Sequence, Rhodobacter sphaeroides, Microscopy, Atomic Force, 010402 general chemistry, 01 natural sciences, Light-harvesting complex, 03 medical and health sciences, MESH: Protein Conformation, Structural Biology, Amino Acid Sequence, Pliability, Lipid bilayer, Molecular Biology, Integral membrane protein, 030304 developmental biology, MESH: Microscopy, Atomic Force, 0303 health sciences, MESH: Molecular Sequence Data, Crystallography, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], biology, Chemistry, MESH: Crystallography, Cell Membrane, Cryoelectron Microscopy, Resolution (electron density), MESH: Rhodobacter sphaeroides, biology.organism_classification, 0104 chemical sciences, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], MESH: Photosynthetic Reaction Center Complex Proteins, Membrane, Membrane protein, MESH: Cryoelectron Microscopy, MESH: Dimethylamines, MESH: Models, Molecular, Dimethylamines, MESH: Cell Membrane, MESH: Detergents
Abstract: International audience; Atomic force microscopy (AFM) has developed into a powerful tool to investigate membrane protein surfaces in a close-to-native environment. Here we report on the surface topography of Rhodobacter sphaeroides light harvesting complex 2 (LH2) reconstituted into two-dimensional crystals. These photosynthetic trans-membrane proteins formed cylindrical oligomeric complexes, which inserted tilted into the lipid membrane. This peculiar packing of an integral membrane protein allowed us to determine oligomerization and tilt of the LH2 complexes, but also protrusion height and intrinsic flexibility of their individual subunits. Furthermore the surface contouring reliability and limits of the atomic force microscopy could be studied. The two-dimensional crystals examined had sizes of up to 5 microm and, as revealed by a 10 A cryo electron microscopy projection map, p22(1)2(1) crystal symmetry. The unit cell had dimensions of a = b = 150 A and gamma = 90 degrees, and housed four nonameric complexes, two pointing up and two pointing down. AFM topographs of these 2D crystals had a lateral resolution of 10 A. Further, the high vertical resolution of approximately 1 A, allowed the protrusion height of the cylindrical LH2 complexes over the membrane to be determined. This was maximally 13.1 A on one side and 3.8 A on the other. Interestingly, the protrusion height varied across the LH2 complexes, showing the complexes to be inserted with a 6.2 degree tilt with respect to the membrane plane. A detailed analysis of the individual subunits showed the intrinsic flexibility of the membrane protruding peptide stretches to be equal and independent of their protrusion height. Furthermore, our analysis of membrane proteins within this peculiar packing confirmed the high vertical resolution of the atomic force microscopy on biological samples, and led us to conclude that the image acquisition function was equally accurate for contouring protrusions with heights up to approximately 15 A.
Published: 2003

32. Cyclodipeptide synthases are a family of tRNA-dependent peptide bond-forming enzymes

Author: Steven Dubois, Rachel Amouroux, Jean-Luc Pernodet, Marie Courçon, Cédric Masson, Sylvie Lautru, Robert Thai, Karine Tuphile, Carine Tellier, Sandrine Braud, Muriel Gondry, Pascal Belin, Alain Lecoq, Ludovic Sauguet, Roger Genet, Shin-ichi Hashimoto, Mickaël Jacquet, Institut de génétique et microbiologie [Orsay] (IGM), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Enzymologie et Biosynthèse Peptidique Non Ribosomale (BIOSYN), Département Microbiologie (Dpt Microbio), Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), 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 du CEA/DSV/iBiTec-S/SIMOPRO, 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)), Institut de Biosciences et de Biotechnologies de Grenoble (ex-IRTSV) (BIG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes (UGA), Institut de Biologie et de Technologies de Saclay (IBITECS), Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), KYOWA HAKKO BIO Co Ltd, Département d'Ingénierie et d'Etudes des Protéines, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (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), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])
Subjects: [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Stereochemistry, Molecular Sequence Data, MESH: Streptomyces, 01 natural sciences, Substrate Specificity, Bacterial protein, 03 medical and health sciences, Albonoursin, RNA, Transfer, Nonribosomal peptide, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Biological property, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Peptide bond, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Peptide Synthases, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, MESH: Molecular Sequence Data, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], biology, 010405 organic chemistry, Cell Biology, biology.organism_classification, MESH: Peptide Synthases, MESH: RNA, Transfer, Streptomyces, 0104 chemical sciences, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Enzyme, Streptomyces noursei, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, chemistry, Biochemistry, Transfer RNA, Biocatalysis, MESH: Substrate Specificity, MESH: Biocatalysis
Abstract: International audience; Cyclodipeptides and their derivatives belong to the diketopiperazine (DKP) family, which is comprised of a broad array of natural products that exhibit useful biological properties. In the few known DKP biosynthetic pathways, nonribosomal peptide synthetases (NRPSs) are involved in the synthesis of cyclodipeptides that constitute the DKP scaffold, except in the albonoursin (1) pathway. Albonoursin, or cyclo(alpha,beta-dehydroPhe-alpha,beta-dehydroLeu), is an antibacterial DKP produced by Streptomyces noursei. In this pathway, the formation of the cyclo(Phe-Leu) (2) intermediate is catalyzed by AlbC, a small protein unrelated to NRPSs. We demonstrated that AlbC uses aminoacyl-tRNAs as substrates to catalyze the formation of the DKP peptide bonds. Moreover, several other bacterial proteins, presenting moderate similarity to AlbC, also use aminoacyl-tRNAs to synthesize various cyclodipeptides. Therefore, AlbC and these related proteins belong to a newly defined family of enzymes that we have named cyclodipeptide synthases (CDPSs).
Published: 2009

33. Methionine Residues in Exoproteins and Their Recycling by Methionine Sulfoxide Reductase AB Serve as an Antioxidant Strategy in Bacillus cereus .

Author: Madeira JP, Alpha-Bazin BM, Armengaud J, and Duport C
Abstract: During aerobic respiratory growth, Bacillus cereus is exposed to continuously reactive oxidant, produced by partially reduced forms of molecular oxygen, known as reactive oxygen species (ROS). The sulfur-containing amino acid, methionine (Met), is particularly susceptible to ROS. The major oxidation products, methionine sulfoxides, can be readily repaired by methionine sulfoxide reductases, which reduce methionine sulfoxides [Met(O)] back to methionine. Here, we show that methionine sulfoxide reductase AB (MsrAB) regulates the Met(O) content of both the cellular proteome and exoproteome of B. cereus in a growth phase-dependent manner. Disruption of msrAB leads to metabolism changes resulting in enhanced export of Met(O) proteins at the late exponential growth phase and enhanced degradation of exoproteins. This suggests that B. cereus can modulate its capacity and specificity for protein export/secretion through the growth phase-dependent expression of msrAB . Our results also show that cytoplasmic MsrAB recycles Met residues in enterotoxins, which are major virulence factors in B. cereus .
Published: 2017
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33 results on '"Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT)"'

1. Membrane-bound human orphan cytochrome P450 2U1: Sequence singularities, construction of a full 3D model, and substrate docking

2. Neutron and beta imaging with Micromegas detectors with optical readout

3. Gut-specific telomerase expression counteracts systemic aging in telomerase-deficient zebrafish

4. State of the art on microbubble cavitation monitoring and feedback control for blood-brain-barrier opening using focused ultrasound

5. X-ray imaging with Micromegas detectors with optical readout

6. QSM4SENIOR: Quantitative susceptibility mapping in the aging of the healthy brain

7. Atomic-level evolutionary information improves protein–protein interface scoring

8. The cell polarity protein Vangl2 in the muscle shapes the neuromuscular synapse by binding to and regulating the tyrosine kinase MuSK

9. Interaction of micro and nanoplastics with proteins

10. The Adipose Microenvironment Dysregulates the Mammary Myoepithelial Cells and Could Participate to the Progression of Breast Cancer

11. Gambierol Blocks a K+ Current Fraction without Affecting Catecholamine Release in Rat Fetal Adrenomedullary Cultured Chromaffin Cells

12. Optimal Anchoring of a Urea-based Foldamer Inhibitor of ASF1 Histone Chaperone Through Backbone Plasticity

13. Impact du SARS-CoV2 sur la structuration de la prise en charge du cancer : exemple de la tenue des RCP de cancérologie en Occitanie

14. Impact of literacy on the functional connectivity of vision and language related networks

15. Growth hormone aggregates activation of human dendritic cells is controlled by Rac1 and PI3 kinase signaling pathways

16. Spectral and 3D model studies of the interaction of orphan human cytochrome P450 2U1 with substrates and ligands

17. Enhancing surface coil sensitive volume with hybridized electric dipoles at 17.2 T

18. Evaluation of the Spider (Phlogiellus genus) Phlotoxin 1 and Synthetic Variants as Antinociceptive Drug Candidates

19. On the genetic bases of incomplete hippocampal inversion: a genome-wide association study

20. Extensive exploration of a novel rat model of Parkinson's disease using partial 6-hydroxydopamine lesion of dopaminergic neurons suggests new therapeutic approaches

21. Aptamer Efficacies for In Vitro and In Vivo Modulation of $\alpha$C-Conotoxin PrXA Pharmacology

22. High Therapeutic Efficacy of a New Survivin LSP-Cancer Vaccine Containing CD4+ and CD8+ T-Cell Epitopes

23. Inhibition of central de novo ceramide synthesis restores insulin signaling in hypothalamus and enhances β-cell function of obese Zucker rats

24. Association of transcallosal motor fibres with function of both hands after unilateral neonatal arterial ischemic stroke

25. Green mamba peptide targets type-2 vasopressin receptor against polycystic kidney disease

26. Surface morphology in tungsten and RAFM steel exposed to helium plasma in PSI-2

27. Mambalgin-1 Pain-relieving Peptide, Stepwise Solid-phase Synthesis, Crystal Structure, and Functional Domain for Acid-sensing Ion Channel 1a Inhibition

28. Unsupervised spectral clustering for segmentation of dynamic PET images

29. A Tandem of SH3-like Domains Participates in RNA Binding in KIN17, a Human Protein Activated in Response to Genotoxics

30. Alteration of the in vivo nicotinic receptor density in ADNFLE patients: a PET study

31. AFM Characterization of Tilt and Intrinsic Flexibility of Rhodobacter sphaeroides Light Harvesting Complex 2 (LH2)

32. Cyclodipeptide synthases are a family of tRNA-dependent peptide bond-forming enzymes

33. Methionine Residues in Exoproteins and Their Recycling by Methionine Sulfoxide Reductase AB Serve as an Antioxidant Strategy in Bacillus cereus .

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