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12 results on '"Région Ile-de-France"'

1. Considerable escape of SARS-CoV-2 Omicron to antibody neutralization

Author

Delphine Planas, Nell Saunders, Piet Maes, Florence Guivel-Benhassine, Cyril Planchais, Julian Buchrieser, William-Henry Bolland, Françoise Porrot, Isabelle Staropoli, Frederic Lemoine, Hélène Péré, David Veyer, Julien Puech, Julien Rodary, Guy Baele, Simon Dellicour, Joren Raymenants, Sarah Gorissen, Caspar Geenen, Bert Vanmechelen, Tony Wawina-Bokalanga, Joan Martí-Carreras, Lize Cuypers, Aymeric Sève, Laurent Hocqueloux, Thierry Prazuck, Félix A. Rey, Etienne Simon-Loriere, Timothée Bruel, Hugo Mouquet, Emmanuel André, Olivier Schwartz, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Vaccine Research Institute [Créteil, France] (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), École Doctorale Bio Sorbonne Paris Cité [Paris] (ED562 - BioSPC), Université Sorbonne Paris Cité (USPC)-Université Paris Cité (UPCité), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), 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), Génomique fonctionnelle des tumeurs solides = Functional Genomics of Solid Tumors [CRC] (FunGeST), 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)-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), Université libre de Bruxelles (ULB), University Hospitals Leuven [Leuven], Centre Hospitalier Régional d'Orléans (CHRO), Virologie Structurale - Structural Virology, Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, The Opera system was co-funded by Institut Pasteur and the Région ile de France (DIM1Health). Work in the O.S. laboratory is funded by Institut Pasteur, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, Fondation pour la Recherche Médicale (FRM), ANRS, the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), ANR/FRM Flash Covid PROTEO-SARS-CoV-2 and IDISCOVR. Work in the UPBI is funded by grant ANR-10-INSB-04-01 and Région Ile-de-France program DIM1-Health. D.P. is supported by the Vaccine Research Institute. The H.M. laboratory is funded by the Institut Pasteur, the Milieu Intérieur Program (ANR-10-LABX-69-01), the INSERM, REACTing, EU (RECOVER) and Fondation de France (00106077) grants. The E.S.-L. laboratory is funded by Institut Pasteur, the INCEPTION program (Investissements d’Avenir grant ANR-16-CONV-0005) and the French Government’s Investissement d’Avenir programme, Laboratoire d’Excellence ‘Integrative Biology of Emerging Infectious Diseases’ (grant no. ANR-10-LABX-62-IBEID). G.B. acknowledges support from the Internal Funds KU Leuven under grant agreement C14/18/094, and the Research Foundation–Flanders (Fonds voor Wetenschappelijk Onderzoek–Vlaanderen, G0E1420N, G098321N). P.M. acknowledges support from a COVID-19 research grant of ‘Fonds Wetenschappelijk Onderzoek’/Research Foundation–Flanders (grant no. G0H4420N). S.D. is supported by the Fonds National de la Recherche Scientifique (FNRS, Belgium) and also acknowledges support from the Research Foundation–Flanders (Fonds voor Wetenschappelijk Onderzoek–Vlaanderen, G098321N) and from the European Union Horizon 2020 project MOOD (grant no. 874850)., ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-COVI-0059,PROTEO-SARS-CoV-2,Protéomique du SARS-CoV-2(2020), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), European Project: 874850,H2020-SC1-2019-Single-Stage-RTD,MOOD(2020), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Vaccine Research Institute (VRI), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Pasteur [Paris]-Université Paris Cité (UPCité), 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)-École pratique des hautes études (EPHE), and European Project: 874850,MOOD

Subjects
MESH: Humans, MESH: Mutation, Multidisciplinary, MESH: ChAdOx1 nCoV-19, MESH: Neutralization Tests, MESH: Adult, MESH: Convalescence, MESH: Male, MESH: Antibodies, Monoclonal, MESH: Antibodies, Neutralizing, MESH: Belgium, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: COVID-19, MESH: Immunization, Secondary, MESH: SARS-CoV-2, MESH: Immune Evasion, MESH: BNT162 Vaccine, MESH: Phylogeny, MESH: Travel, MESH: Female, MESH: Antibodies, Viral
Abstract

The SARS-CoV-2 Omicron variant was first identified in November 2021 in Botswana and South Africa1-3. It has since spread to many countries and is expected to rapidly become dominant worldwide. The lineage is characterized by the presence of around 32 mutations in spike-located mostly in the N-terminal domain and the receptor-binding domain-that may enhance viral fitness and enable antibody evasion. Here we isolated an infectious Omicron virus in Belgium from a traveller returning from Egypt. We examined its sensitivity to nine monoclonal antibodies that have been clinically approved or are in development4, and to antibodies present in 115 serum samples from COVID-19 vaccine recipients or individuals who have recovered from COVID-19. Omicron was completely or partially resistant to neutralization by all monoclonal antibodies tested. Sera from recipients of the Pfizer or AstraZeneca vaccine, sampled five months after complete vaccination, barely inhibited Omicron. Sera from COVID-19-convalescent patients collected 6 or 12 months after symptoms displayed low or no neutralizing activity against Omicron. Administration of a booster Pfizer dose as well as vaccination of previously infected individuals generated an anti-Omicron neutralizing response, with titres 6-fold to 23-fold lower against Omicron compared with those against Delta. Thus, Omicron escapes most therapeutic monoclonal antibodies and, to a large extent, vaccine-elicited antibodies. However, Omicron is neutralized by antibodies generated by a booster vaccine dose. ispartof: NATURE vol:602 issue:7898 pages:671-+ ispartof: location:England status: published

Published
2021

2. ShareLoc — an open platform for sharing localization microscopy data

Author

Wei Ouyang, Jiachuan Bai, Manish Kumar Singh, Christophe Leterrier, Paul Barthelemy, Samuel F. H. Barnett, Teresa Klein, Markus Sauer, Pakorn Kanchanawong, Nicolas Bourg, Mickael M. Cohen, Benoît Lelandais, Christophe Zimmer, Imagerie et Modélisation - Imaging and Modeling, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Royal Institute of Technology [Stockholm] (KTH ), Sorbonne Université (SU), Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes (LBMCE), Institut de biologie physico-chimique (IBPC (FR_550)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Abbelight, Department of Biomedical Engineering [Singapore], National University of Singapore (NUS), Mechanobiology Institute [Singapore] (MBI), Max Planck Institute for Medical Research [Heidelberg], Max-Planck-Gesellschaft, University of Würzburg = Universität Würzburg, Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), C.L. acknowledges funding from CNRS ATIP AO2016. S.F.H.B. and P.K. acknowledge funding support from Mechanobiology Institute seed funding, Singapore Ministry of Education (MOE2019-T2-2-014) and National Research Foundation (QEP-P7). M.K.S., M.M.C. and C.Z. acknowledge funding by Agence Nationale de la Recherche (grant ANR 17 CE13 0026 02) and M.M.C. by Labex DYNAMO (ANR-11-LABX-0011-DYNAMO) and MITOFUSION (ANR-19-CE11-0018). J.B., B.L. and C.Z. acknowledge funding by Institut Pasteur, by the Région Ile-de-France in the framework of DIM ELICIT, and by the Inception program (Investissement d’Avenir grant ANR-16-CONV-0005)., We thank H. Harmse (EMBL-EBI) for help in linking ShareLoc to the EBI ontology lookup service, M. Schuetz and F. Woitzel for development and sharing of the potree and Fairy Dust viewers, respectively, M. Lelek for advice on metadata, J. Swedlow, J. Moore and S. Besson for stimulating several improvements of the platform, ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), ANR-17-CE13-0026,MOMIT,Dissection structurale de l'ancrage mitochondrial par imagerie super-résolutive(2017), ANR-11-LABX-0011,DYNAMO,Dynamique des membranes transductrices d'énergie : biogénèse et organisation supramoléculaire.(2011), and ANR-19-CE11-0018,MITOFUSION,Structure, assemblage et propriétés biophysiques des mitofusines(2019)

Subjects
Microscopy, Information Dissemination, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cell Biology, Molecular Biology, Biochemistry, Biotechnology
Abstract

International audience; Single-molecule localization microscopy (SMLM) has matured into one of the most widely used super-resolution imaging methods and has been used to address a broad spectrum of biological research questions1. This success has inspired the community to develop numerous computational techniques to extract localizations from raw images or turn them into biologically meaningful quantities [...]

Published
2022

3. An ancient divide in outer membrane tethering systems in bacteria suggests a mechanism for the diderm-to-monoderm transition

Author

Jerzy Witwinowski, Anna Sartori-Rupp, Najwa Taib, Nika Pende, To Nam Tham, Daniel Poppleton, Jean-Marc Ghigo, Christophe Beloin, Simonetta Gribaldo, Biologie Évolutive de la Cellule Microbienne - Evolutionary Biology of the Microbial Cell, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateforme BioImagerie Ultrastructurale – Ultrastructural BioImaging Platform (UTechS UBI), Institut Pasteur [Paris] (IP), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Génétique des Biofilms - Genetics of Biofilms, This work was supported by funding from the French National Research Agency (ANR) (no. Fir-OM ANR-16-CE12-0010), the Institut Pasteur’s Programmes Transversaux de Recherche (no. PTR 39-16), the French government’s Investissement d’Avenir Program, Laboratoire d’Excellence’s Integrative Biology of Emerging Infectious Diseases (grant no. ANR-10-LABX-62-IBEID) and the Fondation pour la Recherche Médicale (grant no. DEQ20180339185). N.P. is funded by a Pasteur-Roux Postdoctoral Fellowship from the Institut Pasteur. We thank A. Jiménez-Fernández for help with Veillonella genetics techniques. We thank the UTechS Photonic BioImaging (Imagopole), C2RT, Institut Pasteur (Paris, France) and the France BioImaging infrastructure network supported by the ANR (no. ANR-10–INSB–04, Investments for the Future), and the Région Ile-de-France (program Domaine d’Intérêt Majeur-Malinf) for the use of the Zeiss LSM 780 Elyra PS1 microscope. We thank S. Tachon from the NanoImaging Core facility of the Center for Technological Resources and Research of Institut Pasteur for assistance with the tomography acquisitions at the Titan Krios microscope. We thank the French Government Programme Investissements d’Avenir France BioImaging (FBI, no. ANR-10-INSB-04-01) for equipment support. We thank M. Nilges and the Equipex CACSICE (Centre d’analyse de systèmes complexes dans les environnements complexes) for providing the Falcon II direct detector. We thank the IT department at Institut Pasteur, Paris, for providing computational and storage services (TARS cluster)., ANR-16-CE12-0010,Fir-OM,Firmicutes avec une membrane externe: vers des nouveaux modeles d'étude de la transition monodermes/didermes(2016), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010)

Subjects
Microbiology (medical), Bacteria, MESH: Peptidoglycan, Lipoproteins, Immunology, MESH: Periplasm, Peptidoglycan, Cell Biology, MESH: Lipoproteins, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, Gram-Positive Bacteria, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Applied Microbiology and Biotechnology, Microbiology, MESH: Gram-Positive Bacteria, MESH: Bacteria, Periplasm, Genetics, MESH: Phylogeny, Phylogeny
Abstract

International audience; Recent data support the hypothesis that Gram-positive bacteria (monoderms) arose from Gram-negative ones (diderms) through loss of the outer membrane (OM), but how this happened remains unknown. As tethering of the OM is essential for cell envelope stability in diderm bacteria, its destabilization may have been involved in this transition. In the present study, we present an in-depth analysis of the four known main OM-tethering systems across the Tree of Bacteria (ToB). We show that the presence of such systems follows the ToB with a bimodal distribution matching the deepest phylogenetic divergence between Terrabacteria and Gracilicutes. Whereas the lipoprotein peptidoglycan-associated lipoprotein (Pal) is restricted to the Gracilicutes, along with a more sporadic occurrence of OmpA, and Braun's lipoprotein is present only in a subclade of Gammaproteobacteria, diderm Terrabacteria display, as the main system, the OmpM protein. We propose an evolutionary scenario whereby OmpM represents a simple, ancestral OM-tethering system that was later replaced by one based on Pal after the emergence of the Lol machinery to deliver lipoproteins to the OM, with OmpA as a possible transition state. We speculate that the existence of only one main OM-tethering system in the Terrabacteria would have allowed the multiple OM losses specifically inferred in this clade through OmpM perturbation, and we provide experimental support for this hypothesis by inactivating all four ompM gene copies in the genetically tractable diderm Firmicute Veillonella parvula. High-resolution imaging and tomogram reconstructions reveal a non-lethal phenotype in which vast portions of the OM detach from the cells, forming huge vesicles with an inflated periplasm shared by multiple dividing cells. Together, our results highlight an ancient shift of OM-tethering systems in bacterial evolution and suggest a mechanism for OM loss and the multiple emergences of the monoderm phenotype from diderm ancestors.

Published
2022

4. Comparison of landscape graph modelling methods for analysing pond network connectivity

Author

Claire Godet, Céline Clauzel, Laboratoire Dynamiques Sociales et Recomposition des Espaces (LADYSS), Université Paris 1 Panthéon-Sorbonne (UP1)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris Nanterre (UPN)-Université de Paris (UP), Région Ile-de-France, ARP-Astrance, TRAMARE, Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris Nanterre (UPN)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris Nanterre (UPN)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)

Subjects
0106 biological sciences, TRAMARE, Ecology, biology, Computer science, [SDV]Life Sciences [q-bio], 010604 marine biology & hydrobiology, Geography, Planning and Development, Epidalea calamita, Fragmentation (computing), Land cover, 15. Life on land, Network connectivity, biology.organism_classification, 010603 evolutionary biology, 01 natural sciences, Graph, [SHS]Humanities and Social Sciences, Natrix, [SDE]Environmental Sciences, Landscape ecology, Cartography, ComputingMilieux_MISCELLANEOUS, Nature and Landscape Conservation, Landscape connectivity
Abstract

Landscape fragmentation negatively impacts species populations by isolating them. Assessing landscape connectivity could help to improve biodiversity conservation. Among various methods available to model and analyse connectivity, graph-theoretic approaches are recognized as powerful tools, even if their ecological significance may be questionable in some cases. Indeed, there are many ways to construct a landscape graph and their impacts on the assessment of connectivity are rarely explored. Our aim was to compare three methods of constructing landscape graphs to identify differences and similarities in the resulting network connectivity. The methods can be distinguished according to the type of data used: expert opinions, field data or a combination of the two. The methodological framework was applied to seven pond-dwelling species (Alytes obstetricans, Bufo bufo, Epidalea calamita, Hyla arborea, Natrix natrix, Rana temporaria, Triturus cristatus) in the Ile-de-France region (France). Three common methods were applied to construct landscape graphs: (1) using a land cover map (LM) and expert opinions to define nodes and links; (2) using a habitat suitability model (HSM) and species occurrence data to define nodes and links; and (3) using a HSM to define nodes and a land cover map to define links (HSM_LM). To carry out our study, we produced a land cover map, collected and prepared input data for HSMs, generated HSMs to map the probability of species occurrence and constructed landscape graphs from the three methods. For each of them, several connectivity metrics were calculated and compared. The results revealed large differences in the statistical distribution of connectivity values, even though the spatial location of the main areas of low and high connectivity was roughly the same. In general, the LM method provided lower values of connectivity and smaller areas of high values than the other two, regardless of species. Conversely, the HSM method had the highest connectivity values, while the combined HSM_LM method appeared to be intermediate. Our study was not intended to conclude whether one method is better than another; only to point out that results vary greatly depending on the graph construction method. To evaluate the predictive performance of each model, a validation process should be conducted with another independent biological dataset, which was not available in our study. The high variability of results argues for taking care to ensure that the construction of models is carefully consistent with ecological assumptions and the objective pursued.

Published
2020

5. Small-RNA-mediated transgenerational silencing of histone genes impairs fertility in piRNA mutants

Author

Blaise Li, Martino Ugolini, Damarys Loew, Germano Cecere, Aleksei Samolygo, Céline Didier, Eric Cornes, Meetali Singh, Giorgia Barucci, Piergiuseppe Quarato, Florent Dingli, Mécanismes de l'Hérédité épigénétique / Mechanisms of epigenetic inheritance, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Scuola Normale Superiore di Pisa (SNS), Moscow Institute of Physics and Technology [Moscow] (MIPT), Laboratoire de Spectrométrie de Masse Protéomique, Institut Curie [Paris], This project has received funding from the Institut Pasteur, the CNRS and the European Research Council (ERC) under the EU Horizon 2020 research and innovation programme under grant agreement no. ERC-StG- 679243. G.B. is part of the Pasteur–Paris University (PPU) International PhD Program and has received funding from the EU Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement no. 665807. E.C. was supported by a Pasteur-Cantarini Fellowship program. F.D. and D.L. have received funding from Région Ile-de-France and Fondation pour la Recherche Médicale grants to support this study, We thank the members of the Cecere laboratory, D. Canzio, N. Iovino, R. Sawarkar and P. Andersen for discussions of the manuscript, the Miska, the Mello, the Kennedy, the Seydoux, the Claycomb, the Strome and the Dumont laboratories for sharing strains and/or antibodies. Some strains were provided by the CGC, funded by NIH Office of Research Infrastructure Programs (P40 OD010440)., and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Gene Editing, MESH: CRISPR-Cas Systems, Small RNA, MESH: Argonaute Proteins / deficiency, MESH: Caenorhabditis elegans Proteins / metabolism, Inheritance Patterns, MESH: RNA, Small Interfering / genetics, MESH: Argonaute Proteins / metabolism, medicine.disease_cause, MESH: RNA, Antisense / genetics, MESH: Argonaute Proteins / genetics, Animals, Genetically Modified, Histones, 0302 clinical medicine, MESH: Histones / metabolism, MESH: Animals, RNA, Small Interfering, MESH: Caenorhabditis elegans / genetics, Caenorhabditis elegans, Gene Editing, 0303 health sciences, Mutation, MESH: RNA, Messenger / metabolism, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Biological Evolution, Cell biology, Histone, MESH: Fertility / genetics, 030220 oncology & carcinogenesis, Argonaute Proteins, Piwi RNAs, MESH: RNA, Messenger / genetics, MESH: Gene Silencing, Epigenetic memory, endocrine system, MESH: Mutation, MESH: Caenorhabditis elegans / metabolism, Piwi-interacting RNA, MESH: Biological Evolution, Biology, Article, MESH: Animals, Genetically Modified, 03 medical and health sciences, medicine, Animals, Gene silencing, RNA, Antisense, Gene Silencing, RNA, Messenger, MESH: RNA, Antisense / metabolism, Caenorhabditis elegans Proteins, Gene, Repetitive Sequences, Nucleic Acid, 030304 developmental biology, MESH: RNA, Small Interfering / metabolism, MESH: Repetitive Sequences, Nucleic Acid, MESH: Histones / genetics, urogenital system, RNA, Cell Biology, biology.organism_classification, Fertility, RNAi, biology.protein, MESH: Caenorhabditis elegans Proteins / genetics, MESH: Inheritance Patterns, CRISPR-Cas Systems
Abstract

International audience; PIWI-interacting RNAs (piRNAs) promote fertility in many animals. However, whether this is due to their conserved role in repressing repetitive elements (REs) remains unclear. Here, we show that the progressive loss of fertility in Caenorhabditis elegans lacking piRNAs is not caused by derepression of REs or other piRNA targets but, rather, is mediated by epigenetic silencing of all of the replicative histone genes. In the absence of piRNAs, downstream components of the piRNA pathway relocalize from germ granules and piRNA targets to histone mRNAs to synthesize antisense small RNAs (sRNAs) and induce transgenerational silencing. Removal of the downstream components of the piRNA pathway restores histone mRNA expression and fertility in piRNA mutants, and the inheritance of histone sRNAs in wild-type worms adversely affects their fertility for multiple generations. We conclude that sRNA-mediated silencing of histone genes impairs the fertility of piRNA mutants and may serve to maintain piRNAs across evolution.

Published
2020

6. Single-molecule localization microscopy

Author

Markus Sauer, Florian Schueder, Melike Lakadamyali, Gerti Beliu, Melina Theoni Gyparaki, Suliana Manley, Ralf Jungmann, Juliette Griffié, Mickaël Lelek, Christophe Zimmer, Imagerie et Modélisation - Imaging and Modeling, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania, University of Würzburg = Universität Würzburg, Ludwig Maximilian University [Munich] (LMU), Max-Planck-Institut für Biochemie = Max Planck Institute of Biochemistry (MPIB), Max-Planck-Gesellschaft, Ecole Polytechnique Fédérale de Lausanne (EPFL), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), C.Z. acknowledges funding by Institut Pasteur, Fondation pour la Recherche Médicale (grant DEQ 20150331762), Région Ile de France, Agence Nationale de la Recherche and Investissement d’Avenir grant ANR-16-CONV-0005. M.La. acknowledges funding from the National Institutes of Health/National Institutes of General Medical Sciences (NIH/NIGMS) under grant RO1 GM133842-01. G.B. and M.S. acknowledge funding by the German Research Foundation (DFG) (SA829/19-1) and the European Regional Development Fund (EFRE project ‘Center for Personalized Molecular Immunotherapy’). F.S. and R.J. acknowledge support by the DFG through SFB1032 (project A11) and the Max Planck Society. J.G. and S.M. acknowledge funding by the European Union’s H2020 programme under the Marie Skłodowska-Curie grant BALTIC (to J.G.) and ERC Piko (to S.M.)., The authors apologize to the authors of numerous papers that could not be cited owing to limited space. M.Le. and C.Z. thank B. Lelandais for excellent comments on the manuscript and M. Singh for acquiring the image shown in Fig. 3b., ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania [Philadelphia], Max Planck Institute of Biochemistry (MPIB), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC)

Subjects
Single molecule localization, light-microscopy, Computer science, business.industry, General Medicine, Article, General Biochemistry, Genetics and Molecular Biology, optical reconstruction microscopy, diffraction-limit, Fluorescent labelling, 3-dimensional superresolution, live-cell, correlative superresolution fluorescence, Microscopy, Time course, Image acquisition, colocalization analysis, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Computer vision, Artificial intelligence, business, living cells, intramolecular spirocyclization, Image resolution, electron-microscopy
Abstract

Single-molecule localization microscopy (SMLM) describes a family of powerful imaging techniques that dramatically improve spatial resolution over standard, diffraction-limited microscopy techniques and can image biological structures at the molecular scale. In SMLM, individual fluorescent molecules are computationally localized from diffraction-limited image sequences and the localizations are used to generate a super-resolution image or a time course of super-resolution images, or to define molecular trajectories. In this Primer, we introduce the basic principles of SMLM techniques before describing the main experimental considerations when performing SMLM, including fluorescent labelling, sample preparation, hardware requirements and image acquisition in fixed and live cells. We then explain how low-resolution image sequences are computationally processed to reconstruct super-resolution images and/or extract quantitative information, and highlight a selection of biological discoveries enabled by SMLM and closely related methods. We discuss some of the main limitations and potential artefacts of SMLM, as well as ways to alleviate them. Finally, we present an outlook on advanced techniques and promising new developments in the fast-evolving field of SMLM. We hope that this Primer will be a useful reference for both newcomers and practitioners of SMLM. This Primer explains the central concepts of single-molecule localization microscopy (SMLM) before discussing experimental considerations regarding fluorophores, optics and data acquisition, processing and analysis. The Primer further describes recent high-impact discoveries made by SMLM techniques and concludes by discussing emerging methodologies.

Published
2021

7. Genuage: visualize and analyze multidimensional single-molecule point cloud data in virtual reality

Author

Mohamed El Beheiry, Bassam Hajj, Clément Caporal, Jean-Baptiste Masson, Thomas Blanc, 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), Décision et processus Bayesiens - Decision and Bayesian Computation, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Département de Neuroscience - Department of Neuroscience, We acknowledge funding from the Fondation pour la recherche médicale (FRM, DEI20151234398) (B.H.), the Agence National de la recherche (ANR-19-CE42-0003-01) (B.H.), the LabEx CelTisPhyBio (ANR-10-LBX-0038, ANR-10-IDEX-0001-02) (B.H.) and the Institut Curie (B.H.). We recognize the support of France-BioImaging infrastructure grant ANR-10-INBS-04 (Investments for the future) (B.H.). We acknowledge the financial support of the Agence pour la Recherche sur le Cancer (ARC Foundation), ARC (B.H.) and DIM ELICIT (B.H.). We acknowledge funding from the Pasteur Institute (J.-B.M.), the sponsorships of CRPCEN, Gilead Science and foundation EDF (J.-B.M.), the ANR-17-CE23-0016 TRamWAy (J.-B.M.), the INCEPTION project (PIA/ANR- 16-CONV-0005, OG) (J.-B.M.), the programme d’investissement d’avenir supported by L’Agence Nationale de la Recherche ANR-19-P3IA-0001 Institut 3IA Prairie (J.-B.M.) and the support of the AVIRON grant from the Région Ile-de-France (DIM-ELICIT)., ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-17-CE23-0016,TRamWAy,L'Analyseur Automatique de Marches Aléatoires Biomoléculaires: La Science des molécules uniques à l'époque des données massives(2017), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), ANR-11-LABX-0038,CelTisPhyBio,Des cellules aux tissus: au croisement de la Physique et de la Biologie(2011), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Computer science, Point cloud, Image processing, Virtual reality, Biochemistry, 03 medical and health sciences, Software, Artificial Intelligence, Tubulin, Computer graphics (images), Image Processing, Computer-Assisted, Humans, [INFO.INFO-HC]Computer Science [cs]/Human-Computer Interaction [cs.HC], Dimension (data warehouse), Molecular Biology, 030304 developmental biology, 0303 health sciences, business.industry, [PHYS.PHYS.PHYS-ATM-PH]Physics [physics]/Physics [physics]/Atomic and Molecular Clusters [physics.atm-clus], Virtual Reality, Multidimensional data, Cell Biology, Single Molecule Imaging, Mitochondria, business, Algorithms, HeLa Cells, Biotechnology
Abstract

International audience; The quantity of experimentally recorded point cloud data, such generated in single-molecule experiments, is increasing continuously in both size and dimension. Gaining an intuitive understanding of the data and facilitating multi-dimensional data analysis remains a challenge. It is especially challenging when static distribution properties are not predictive of dynamical properties. Here, we report a new open-source software platform, Genuage, that enables the easy perception, interaction and analysis of complex multidimensional point cloud datasets by leveraging virtual reality. We illustrate the benefit of the Genuage with examples of three-dimensional static and dynamic localization microscopy datasets, as well as some synthetic datasets. Genuage has a large breadth of usage modes, due to its compatibility with arbitrary multidimensional data types extending beyond the single-molecule research community.

Published
2020

8. Early-life stress impairs postnatal oligodendrogenesis and adult emotional behaviour through activity-dependent mechanisms

Author

Belmira Lara da Silveira Andrade-da-Costa, Corentin Le Magueresse, Alberto Bacci, Anne Teissier, Angela Michela De Stasi, Vidita A. Vaidya, Jimmy Olusakin, Patricia Gaspar, Yuka Imamura Kawasawa, Gaspar, Patricia, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm - Paris Descartes), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiology and Pharmacology Department brazil [Recife, Brazil], Federal University of Pernambuco [Recife], 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), Departments of Pharmacology and Biochemistry and Molecular Biology [Hershey, PA, USA], Pennsylvania State University (Penn State), Penn State System-Penn State System-Institute for Personalized Medicine [Hershey, PA, USA], Department of Biological Sciences [TIFR] (DBS), Tata Institute for Fundamental Research (TIFR), The work was funded by the Labex BioPsy, the French Agence Nationale pour la Recherche (ANR-11-0004-02, ANR-16-0162), the DIM Région Ile de France, and the Behaviour and Brain Foundation Young Investigator-NARSAD Grant. BAdC received a scholarship from Coordination for the Improvement of Higher Education Personnel (CAPES), Brazil. JO is the recipient of the Ecole des Neurosciences de Paris (ENP) scholarship. AT is a CNRS (Centre National de la Recherche Scientifique) investigator., and ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011)

Subjects
Male, 0301 basic medicine, Physiology, Emotions, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Prefrontal Cortex, Biology, Article, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Pregnancy, [SDV.BDD] Life Sciences [q-bio]/Development Biology, medicine, Animals, Premovement neuronal activity, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Receptor, Prefrontal cortex, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Molecular Biology, Cell Proliferation, 030304 developmental biology, Diminution, 0303 health sciences, Maternal deprivation, Behavior, Animal, Depression, Maternal Deprivation, Lineage markers, Oligodendrocyte differentiation, Cognition, Phenotype, Oligodendrocyte, Oligodendroglia, Psychiatry and Mental health, 030104 developmental biology, medicine.anatomical_structure, nervous system, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuron, Neuroscience, Stress, Psychological, 030217 neurology & neurosurgery
Abstract

Exposure to stress during early life (infancy/childhood) has long-term effects on the structure and function of the prefrontal cortex (PFC) and increases the risk for adult depression and anxiety disorders. However, little is known about the molecular and cellular mechanisms of these effects. Here we focused on changes induced by chronic maternal separation during the first two weeks of postnatal life. Unbiased mRNA expression profiling in the medial PFC (mPFC) of maternally separated (MS) pups identified an increased expression of myelin-related genes and a decreased expression of immediate early genes. Oligodendrocyte lineage markers and birthdating experiments indicated a precocious oligodendrocyte differentiation in the mPFC at P15, leading to a depletion of the oligodendrocyte progenitor pool in MS adults. We tested the role of neuronal activity in oligodendrogenesis, using designed receptors exclusively activated by designed drugs (DREADDs) techniques. hM4Di or hM3Dq constructs were transfected into mPFC neurons using fast-acting AAV8 viruses. Reduction of mPFC neuron excitability during the first two postnatal weeks caused a premature differentiation of oligodendrocytes similar to the MS pups, while chemogenetic activation normalized it in the MS animals. Bidirectional manipulation of neuron excitability in the mPFC during the P2-P14 period had long lasting effects on adult emotional behaviours and on temporal object recognition: hM4Di mimicked MS effects, while hM3Dq prevented the pro-depressive effects and short term memory impairment of MS. Thus, our results identify neuronal activity as a critical target of early life stress and demonstrate its function in controlling both postnatal oligodendrogenesis and adult mPFC-related behaviors.

Published
2019

9. Inertial Alternating Generalized Forward–Backward Splitting for Image Colorization

Author

Fabien Pierre, Mila Nikolova, Pauline Tan, Centre de Mathématiques et de Leurs Applications (CMLA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria), Augmentation visuelle d'environnements complexes (MAGRIT-POST), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Algorithms, Computation, Image and Geometry (LORIA - ALGO), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Projet soutenu par l'attribution d'une allocation de recherche Région Ile-de-France (DIM Math Innov), MAGRIT, ANR-14-CE27-0019,MIRIAM,Restauration Multi-Images: des Mathématiques Appliqueés à l'Industrie de l'Imagerie.(2014), Centre de Mathématiques et de Leurs Applications ( CMLA ), École normale supérieure - Cachan ( ENS Cachan ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire Lorrain de Recherche en Informatique et ses Applications ( LORIA ), Institut National de Recherche en Informatique et en Automatique ( Inria ) -Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ), Visual Augmentation of Complex Environments ( MAGRIT ), INRIA Lorraine, Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Laboratoire Lorrain de Recherche en Informatique et ses Applications ( LORIA ), Institut National de Recherche en Informatique et en Automatique ( Inria ) -Université Henri Poincaré - Nancy 1 ( UHP ) -Université Nancy 2-Institut National Polytechnique de Lorraine ( INPL ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Henri Poincaré - Nancy 1 ( UHP ) -Université Nancy 2-Institut National Polytechnique de Lorraine ( INPL ) -Centre National de la Recherche Scientifique ( CNRS ), ANR-14-CE27-0019,MIRIAM,Restauration Multi-Images: des Mathématiques Appliqueés à l'Industrie de l'Imagerie. ( 2014 ), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), and Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[ MATH.MATH-OC ] Mathematics [math]/Optimization and Control [math.OC], Statistics and Probability, Inertial frame of reference, Accelerated methods, Computer science, Generalization, 02 engineering and technology, Bregman divergence, Separable space, Acceleration, [ INFO.INFO-TI ] Computer Science [cs]/Image Processing, Convergence (routing), Biconvex nonsmooth optimization, 0202 electrical engineering, electronic engineering, information engineering, Block (data storage), Coupling, Alternating minimizations, Image colorization, Applied Mathematics, Condensed Matter Physics, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], Modeling and Simulation, 020201 artificial intelligence & image processing, [MATH.MATH-OC]Mathematics [math]/Optimization and Control [math.OC], Geometry and Topology, Computer Vision and Pattern Recognition, Algorithm
Abstract

International audience; In this paper, we propose a novel accelerated alternating optimization scheme to solve block-biconvex nonsmooth problems whose objectives can be split into smooth (separable) regularizers and simple coupling terms. The proposed method performs a Bregman distance based generalization of the well-known forward-backward splitting for each block, along with an inertial strategy which aims at getting empirical acceleration. We discuss the theoretical convergence of the proposed scheme and provide numerical experiments on image colorization.

Published
2019

10. Low-density lipoprotein receptor-deficient hepatocytes differentiated from induced pluripotent stem cells allow familial hypercholesterolemia modeling, CRISPR/Cas-mediated genetic correction, and productive hepatitis C virus infection

Author

Eric Bruckert, Jean-Marie Heslan, E. Luce, Laia Tolosa, Samir Saheb, Arielle R. Rosenberg, Anne Dubart-Kupperschmitt, María José Gómez-Lechón, Angélique Fourrier, Jérôme Caron, Tuan Huy Nguyen, Maxime Villaret, Anne Weber, Véronique Pène, Physiopathogenèse et Traitement des Maladies du Foie [Villejuif], Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virologie de l'hépatite C (EA 4474), Université Paris Descartes - Paris 5 (UPD5), Unidad de Hepatología Experimental [Valencia, Spain], Hospital Universitari La Fe, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service d’Endocrinologie, Métabolisme et Prévention des Risques Cardio-Vasculaires [CHU Pitié-Salpêtrière], 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), Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Liver Unit, Clínica Universitaria, CIBER-EHD, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), MESR (French Ministry for Education and Research),Fondation pour la Recherche Médicale (FDT20160435349),DHU Hepatinov,French Society for Hematology (SFH), Fondation pour la Recherche Médicale (FDT20160435349),Région Ile de France/DIM Biothérapies,Nantes Métropole and the Pays de la Loire Region., ANR-10-RFCS-0004,Liv-iPS,Modélisation et approches thérapeutiques de maladies génétiques hépatiques à l'aide de cellules iPS spécifiques de patients(2010), European Project: 278152,EC:FP7:HEALTH,FP7-HEALTH-2011-two-stage,INNOVALIV(2011), Le Bihan, Sylvie, Recherche finalisée sur les cellules souches - Modélisation et approches thérapeutiques de maladies génétiques hépatiques à l'aide de cellules iPS spécifiques de patients - - Liv-iPS2010 - ANR-10-RFCS-0004 - RFCS - VALID, Innovative strategies to generate human hepatocytes for treatment ofmetabolic Liver diseases: Tools for personalized cell therapy - INNOVALIV - - EC:FP7:HEALTH2011-12-01 - 2014-11-30 - 278152 - VALID, Physiopathogénèse et Traitement des Maladies du Foie, Hôpital Paul Brousse-Université Paris-Saclay, Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Service d'Endocrinologie, Métabolisme et Prévention des Maladies Cardio-vasculaires [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Genetic enhancement, Medicine (miscellaneous), Hepacivirus, Familial hypercholesterolemia, medicine.disease_cause, Cell therapy, 0302 clinical medicine, lcsh:QD415-436, Promoter Regions, Genetic, Induced pluripotent stem cell, Gene Editing, lcsh:R5-920, Cell models, Cell Differentiation, Cardiovascular disease, Hepatitis C, 3. Good health, [SDV] Life Sciences [q-bio], Cholesterol, Phenotype, 030220 oncology & carcinogenesis, Molecular Medicine, lipids (amino acids, peptides, and proteins), Proprotein Convertase 9, Stem cell, lcsh:Medicine (General), Apolipoprotein A-II, Plasmids, Sterol Regulatory Element Binding Protein 2, Genome editing, Hepatitis C virus, Induced Pluripotent Stem Cells, Biology, Antiviral Agents, Biochemistry, Genetics and Molecular Biology (miscellaneous), Virus, lcsh:Biochemistry, Hyperlipoproteinemia Type II, 03 medical and health sciences, Gene therapy, medicine, Humans, Research, Cell Biology, medicine.disease, Personalized medicine, Molecular biology, 030104 developmental biology, Receptors, LDL, LDL receptor, Hepatocytes, CRISPR-Cas Systems, Sofosbuvir, Lipoprotein
Abstract

Background Familial hypercholesterolemia type IIA (FH) is due to mutations in the low-density lipoprotein receptor (LDLR) resulting in elevated levels of low-density lipoprotein cholesterol (LDL-c) in plasma and in premature cardiovascular diseases. As hepatocytes are the only cells capable of metabolizing cholesterol, they are therefore the target cells for cell/gene therapy approaches in the treatment of lipid metabolism disorders. Furthermore, the LDLR has been reported to be involved in hepatitis C virus (HCV) entry into hepatocytes; however, its role in the virus infection cycle is still disputed. Methods We generated induced pluripotent stem cells (iPSCs) from a homozygous LDLR-null FH-patient (FH-iPSCs). We constructed a correction cassette bearing LDLR cDNA under the control of human hepatic apolipoprotein A2 promoter that targets the adeno-associated virus integration site AAVS1. We differentiated both FH-iPSCs and corrected FH-iPSCs (corr-FH-iPSCs) into hepatocytes to study statin-mediated regulation of genes involved in cholesterol metabolism. Upon HCV particle inoculation, viral replication and production were quantified in these cells. Results We showed that FH-iPSCs displayed the disease phenotype. Using homologous recombination mediated by the CRISPR/Cas9 system, FH-iPSCs were genetically corrected by the targeted integration of a correction cassette at the AAVS1 locus. Both FH-iPSCs and corr-FH-iPSCs were then differentiated into functional polarized hepatocytes using a stepwise differentiation approach (FH-iHeps and corr-FH-iHeps). The correct insertion and expression of the correction cassette resulted in restoration of LDLR expression and function (LDL-c uptake) in corr-FH-iHeps. We next demonstrated that pravastatin treatment increased the expression of genes involved in cholesterol metabolism in both cell models. Moreover, LDLR expression and function were also enhanced in corr-FH-iHeps after pravastatin treatment. Finally, we demonstrated that both FH-iHeps and corr-FH-iHeps were as permissive to viral infection as primary human hepatocytes but that virus production in FH-iHeps was significantly decreased compared to corr-FH-iHeps, suggesting a role of the LDLR in HCV morphogenesis. Conclusions Our work provides the first LDLR-null FH cell model and its corrected counterpart to study the regulation of cholesterol metabolism and host determinants of HCV life cycle, and a platform to screen drugs for treating dyslipidemia and HCV infection. Electronic supplementary material The online version of this article (10.1186/s13287-019-1342-6) contains supplementary material, which is available to authorized users.

Published
2019

11. Correction to: Vector quantile regression and optimal transport, from theory to numerics

Author

Victor Chernozhukov, Guillaume Carlier, Gwendoline De Bie, Alfred Galichon, CEntre de REcherches en MAthématiques de la DEcision (CEREMADE), Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL), Méthodes numériques pour le problème de Monge-Kantorovich et Applications en sciences sociales (MOKAPLAN), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Massachusetts Institute of Technology (MIT), Département de Mathématiques et Applications - ENS Paris (DMA), École normale supérieure - Paris (ENS-PSL), New York University [New York] (NYU), NYU System (NYU), Département d'économie (Sciences Po) (ECON), Sciences Po (Sciences Po)-Centre National de la Recherche Scientifique (CNRS), and Funding from Région Ile-de-France grant is acknowledged. Funding from NSF Grant DMS-1716489 is acknowledged.

Subjects
Statistics and Probability, JEL: C - Mathematical and Quantitative Methods/C.C5 - Econometric Modeling/C.C5.C51 - Model Construction and Estimation, Economics and Econometrics, Entropic regularization, [SHS.ECO]Humanities and Social Sciences/Economics and Finance, Quantile regression, Mathematics (miscellaneous), Latent factors, Applied mathematics, Optimal transport with mean independence constraints, JEL: C - Mathematical and Quantitative Methods/C.C6 - Mathematical Methods • Programming Models • Mathematical and Simulation Modeling/C.C6.C60 - General, Vector quantile regression, Social Sciences (miscellaneous), Mathematics
Abstract

Original article was published online August 12th, 2020, with open access, at DOI 10.1007/s00181-020-01919-y.This is the corrected version, published online September 11th, 2020 and printed in January 2022 issue of Empirical Economics.; International audience; In this paper, we first revisit the Koenker and Bassett variational approach to (univariate) quantile regression, emphasizing its link with latent factor representations and correlation maximization problems. We then review the multivariate extension due to Carlier et al. (Ann Statist 44(3):1165–92, 2016,; J Multivariate Anal 161:96–102, 2017) which relates vector quantile regression to an optimal transport problem with mean independence constraints. We introduce an entropic regularization of this problem, implement a gradient descent numerical method and illustrate its feasibility on univariate and bivariate examples.

Published
2020

12. Balancing immunity and tolerance: genetic footprint of natural selection in the transcriptional regulatory region of HLA-G

Author

Philippe Moreau, Audrey Sabbagh, B Patillon, Erick C. Castelli, Pierre Luisi, D. Courtin, Hafid Laayouni, Jacqueline Milet, André Garcia, Laure Gineau, Eduardo Antônio Donadi, Natalia F. Cagnin, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Brasil), Instituto Nacional de Bioinformática (España), Région Ile-de-France, Instituto de Salud Carlos III, Université Paris-Sud, and Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brasil)

Subjects
genetic processes, Immunology, Population, information science, Human leukocyte antigen, Biology, POLIMORFISMO, environment and public health, Linkage Disequilibrium, Immune tolerance, Immunity, HLA-G, Genetic variation, Immune Tolerance, Genetics, Humans, Regulatory Elements, Transcriptional, Selection, Genetic, education, Genetics (clinical), Selection (genetic algorithm), HLA-G Antigens, education.field_of_study, Polymorphism, Genetic, Natural selection, biochemical phenomena, metabolism, and nutrition, Genetics, Population, Haplotypes, health occupations
Abstract

Gineau, L. et al., © 2015 Macmillan Publishers Limited. Human leukocyte antigen-G (HLA-G) has well-recognized immunosuppressive properties modulating the activity of many immune system cells, and polymorphisms observed at the HLA-G 5′ upstream regulatory region (5′URR) may influence gene transcriptional regulation. In this study, we characterized the sequence variation and haplotype structure of the HLA-G 5′URR in worldwide populations to investigate the evolutionary history of the HLA-G promoter and shed some light into the mechanisms that may underlie HLA-G expression control. A 1.4-kb region, encompassing the known HLA-G regulatory elements, was sequenced in three African populations from Senegal, Benin and Congo, and data were combined with those available in the literature, resulting in a total of 1411 individuals from 21 worldwide populations. High levels of nucleotide and haplotype diversities, excess of intermediate-frequency variants and reduced population differentiation were observed at this locus when compared with the background genomic variation. These features support a strong molecular signature of balancing selection at HLA-G 5′URR, probably as a result of the competing needs to maintain both a maternal-fetal immune tolerance and an efficient host immune response to invading pathogens during human evolution. An extended analysis of a 300-kb region surrounding HLA-G revealed that this region is not involved in a hitchhiking effect and may be the direct target of selection., This work was supported by the binational collaborative research program CAPES-COFECUB (grant #653/09) and by the Spanish National Institute for Bioinformatics (www.inab.org). LG was supported by grants from Région Ile-de-France. PL was supported by a PhD fellowship from ‘Acción Estratrégica de Salud, en el Marco del Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2008–2011’ from Instituto de Salud Carlos III. BP was supported by a PhD fellowship from the doctoral program in Public Health from Paris Sud University. ECC was supported by the Brazilian Council for Scientific and Technological Development—CNPq (grant # 304471/2013-5). EAD was supported by the Brazilian Council for Scientific and Technological Development—CNPq Project (grant # 476036/2013-5).

Published
2014

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