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201. Topoisomerase 1 prevents replication stress at R-loop-enriched transcription termination sites

Author: Anna Biernacka, Philippe Pasero, Chun-Long Chen, Maga Rowicka, Krzysztof Ginalski, Ismael Padioleau, Lionel A. Sanz, Frédéric Chédin, Yaqun Liu, Magdalena Skrzypczak, Clément Mettling, Amélie Sarrazin, Anne Lyne Schmitz, Alexy Promonet, Yea-Lih Lin, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Sorbonne Université (SU), Université Paris sciences et lettres (PSL), Sorbonne Université (SU), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Laboratory of Bioinformatics and Systems Biology, Centre of New Technologies, University of Warsaw, 02-089 Warsaw, Poland, Plateforme RIO Imaging (PHIV MRI), Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, Galveston, TX 77555 USA., Unité de recherche Génétique Microbienne (UGM), and Institut National de la Recherche Agronomique (INRA)
Subjects: 0301 basic medicine, Transcription, Genetic, [SDV]Life Sciences [q-bio], Type I, General Physics and Astronomy, Ataxia Telangiectasia Mutated Proteins, Double-Stranded, chemistry.chemical_compound, 0302 clinical medicine, Transcription (biology), DNA Breaks, Double-Stranded, Phosphorylation, RNA, Small Interfering, lcsh:Science, Promoter Regions, Genetic, ComputingMilieux_MISCELLANEOUS, Terminator Regions, Genetic, Multidisciplinary, biology, Terminator Regions, Chromatin, Cell biology, DNA Topoisomerases, Type I, Gene Knockdown Techniques, DNA supercoil, Transcription, DNA Replication, Science, 1.1 Normal biological development and functioning, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Small Interfering, Article, Chromosomes, Genomic Instability, General Biochemistry, Genetics and Molecular Biology, Promoter Regions, 03 medical and health sciences, Genetic, Underpinning research, Genetics, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene, Topoisomerase, DNA Breaks, Human Genome, DNA replication, Promoter, General Chemistry, HEK293 Cells, 030104 developmental biology, chemistry, Hela Cells, biology.protein, RNA, lcsh:Q, Generic health relevance, R-Loop Structures, DNA Topoisomerases, 030217 neurology & neurosurgery, DNA, HeLa Cells
Abstract: R-loops have both positive and negative impacts on chromosome functions. To identify toxic R-loops in the human genome, here, we map RNA:DNA hybrids, replication stress markers and DNA double-strand breaks (DSBs) in cells depleted for Topoisomerase I (Top1), an enzyme that relaxes DNA supercoiling and prevents R-loop formation. RNA:DNA hybrids are found at both promoters (TSS) and terminators (TTS) of highly expressed genes. In contrast, the phosphorylation of RPA by ATR is only detected at TTS, which are preferentially replicated in a head-on orientation relative to the direction of transcription. In Top1-depleted cells, DSBs also accumulate at TTS, leading to persistent checkpoint activation, spreading of γ-H2AX on chromatin and global replication fork slowdown. These data indicate that fork pausing at the TTS of highly expressed genes containing R-loops prevents head-on conflicts between replication and transcription and maintains genome integrity in a Top1-dependent manner., While R-loops can alter cell homeostasis, it is unclear what determines their toxicity. Here, the authors, by using Top1 knockdown as a tool to enhance the formation of R-loops at certain genomic sites, reveal and characterize a proportion of R-loops that are more toxic to the cell by causing DNA damage.
Published: 2020

202. SETX (senataxin), the helicase mutated in AOA2 and ALS4, functions in autophagy regulation

Author: Michio Hirano, Saba Tadesse, Hervé Seitz, Bin Tian, Stella R. Hartono, Wencheng Li, James L. Manley, Francesco Lotti, Mainul Hoque, Katharine Stolz, Ubayed Muhith, Lionel A. Sanz, Paola Rinchetti, Patricia Richard, Frédéric Chédin, Juan Irizarry-Cole, Yueh Lin Tsai, Shuang Feng, Department of Biological Sciences, Columbia University , New York, NY, Stellate Therapeutics, JLABS @ NYC , New York, NY, Institut de génétique humaine (IGH), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, autophagy, R loop, DNA damage, R-loop, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, DRIP, senataxin, 03 medical and health sciences, Transcriptional regulation, LC3, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Motor Neurons, 030102 biochemistry & molecular biology, Amyotrophic Lateral Sclerosis, Autophagy, DNA Helicases, SETX, RNA, Helicase, Cell Biology, Multifunctional Enzymes, 3. Good health, Cell biology, 030104 developmental biology, lysosomal degradation, Gene Expression Regulation, biology.protein, AOA2, transcription regulation, RNA Helicases, Research Paper
Abstract: SETX (senataxin) is an RNA/DNA helicase that has been implicated in transcriptional regulation and the DNA damage response through resolution of R-loop structures. Mutations in SETX result in either of two distinct neurodegenerative disorders. SETX dominant mutations result in a juvenile form of amyotrophic lateral sclerosis (ALS) called ALS4, whereas recessive mutations are responsible for ataxia called ataxia with oculomotor apraxia type 2 (AOA2). How mutations in the same protein can lead to different phenotypes is still unclear. To elucidate AOA2 disease mechanisms, we first examined gene expression changes following SETX depletion. We observed the effects on both transcription and RNA processing, but surprisingly observed decreased R-loop accumulation in SETX-depleted cells. Importantly, we discovered a strong connection between SETX and the macroautophagy/autophagy pathway, reflecting a direct effect on transcription of autophagy genes. We show that SETX depletion inhibits the progression of autophagy, leading to an accumulation of ubiquitinated proteins, decreased ability to clear protein aggregates, as well as mitochondrial defects. Analysis of AOA2 patient fibroblasts also revealed a perturbation of the autophagy pathway. Our work has thus identified a novel function for SETX in the regulation of autophagy, whose modulation may have a therapeutic impact for AOA2. Abbreviations: 3ʹREADS: 3ʹ region extraction and deep sequencing; ACTB: actin beta; ALS4: amyotrophic lateral sclerosis type 4; AOA2: ataxia with oculomotor apraxia type 2; APA: alternative polyadenylation; AS: alternative splicing; ATG7: autophagy-related 7; ATP6V0D2: ATPase H+ transporting V0 subunit D2; BAF: bafilomycin A(1); BECN1: beclin 1; ChIP: chromatin IP; Chloro: chloroquine; CPT: camptothecin; DDR: DNA damage response; DNMT1: DNA methyltransferase 1; DRIP: DNA/RNA IP; DSBs: double strand breaks; EBs: embryoid bodies; FTD: frontotemporal dementia; GABARAP: GABA type A receptor-associated protein; GO: gene ontology; HR: homologous recombination; HTT: huntingtin; IF: immunofluorescence; IP: immunoprecipitation; iPSCs: induced pluripotent stem cells; KD: knockdown; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MN: motor neuron; MTORC1: mechanistic target of rapamycin kinase complex 1; PASS: PolyA Site Supporting; PFA: paraformaldehyde; RNAPII: RNA polymerase II; SCA: spinocerebellar ataxia; SETX: senataxin; SMA: spinal muscular atrophy; SMN1: survival of motor neuron 1, telomeric; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TSS: transcription start site; TTS: transcription termination site; ULK1: unc-51 like autophagy activating kinase 1; WB: western blot; WIPI2: WD repeat domain, phosphoinositide interacting 2; XRN2: 5ʹ-3ʹ exoribonuclease 2.
Published: 2020

203. TALC: Transcript-level Aware Long-read Correction

Author: Dany Severac, Andrew J. Oldfield, Aubin Thomas, William Ritchie, Lucile Broseus, Emeric Dubois, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-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), Oldfield, Andrew, and Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Statistics and Probability, Gene isoform, [INFO.INFO-AI] Computer Science [cs]/Artificial Intelligence [cs.AI], Computer science, Transcript level, computer.software_genre, Biochemistry, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], Transcriptome, 03 medical and health sciences, 0302 clinical medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Molecular Biology, 030304 developmental biology, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 0303 health sciences, RNA, High-Throughput Nucleotide Sequencing, Genomics, Sequence Analysis, DNA, Computer Science Applications, Transcriptome Sequencing, Computational Mathematics, Rna expression, Computational Theory and Mathematics, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Data mining, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], computer, 030217 neurology & neurosurgery, Algorithms, Software
Abstract: Motivation Long-read sequencing technologies are invaluable for determining complex RNA transcript architectures but are error-prone. Numerous ‘hybrid correction’ algorithms have been developed for genomic data that correct long reads by exploiting the accuracy and depth of short reads sequenced from the same sample. These algorithms are not suited for correcting more complex transcriptome sequencing data. Results We have created a novel reference-free algorithm called Transcript-level Aware Long-Read Correction (TALC) which models changes in RNA expression and isoform representation in a weighted De Bruijn graph to correct long reads from transcriptome studies. We show that transcript-level aware correction by TALC improves the accuracy of the whole spectrum of downstream RNA-seq applications and is thus necessary for transcriptome analyses that use long read technology. Availability and implementation TALC is implemented in C++ and available at https://github.com/lbroseus/TALC. Supplementary information Supplementary data are available at Bioinformatics online.
Published: 2020

204. Telomeric Chromatin and TERRA

Author: Jérôme Déjardin, Amandine Barral, Institut de génétique humaine (IGH), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0303 health sciences, Heterochromatin, [SDV]Life Sciences [q-bio], RNA, Biology, Telomere, Chromatin, 03 medical and health sciences, 0302 clinical medicine, Telomeric chromatin, Gene Expression Regulation, Structural Biology, Evolutionary biology, Telomeric dna, RNA, Long Noncoding, TERRA transcription, Molecular Biology, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Chromatin function in telomeres is poorly understood, but it is generally viewed as repressive. Yet, telomeric DNA sequences are transcribed into long non-coding RNAs named TElomere Repeat-containing RNA (TERRA). As TERRA molecules mostly localize at telomeres, major research efforts have been made to understand their functions, and how TERRA transcription is regulated and affects telomere structure. This review describes the current state of knowledge about the nature of chromatin at telomeres, its functions, and the relation between chromatin structure and TERRA.
Published: 2020

205. Mechanisms behind the Immunoregulatory Dialogue between Mesenchymal Stem Cells and Th17 Cells

Author: Christian Jorgensen, Rafael Contreras-Lopez, Claudia Terraza-Aguirre, Mauricio Campos-Mora, Farida Djouad, Roberto Elizondo-Vega, Patricia Luz-Crawford, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Universidad de Concepción - University of Concepcion [Chile], Universidad de los Andes [Santiago] (UANDES), This work was supported by Inserm, the University of Montpellier, and Fondation Arthritis, and Retiveau, Nolwenn
Subjects: MESH: Cell Differentiation, Encephalomyelitis, Autoimmune, Experimental, immunoregulation, MESH: Th17 Cells, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Review, Biology, Mesenchymal Stem Cell Transplantation, Immune system, In vivo, medicine, Animals, Humans, MESH: Animals, MESH: Mesenchymal Stem Cell Transplantation, Secretion, Th17 cells, MESH: Encephalomyelitis, Autoimmune, Experimental, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, lcsh:QH301-705.5, mesenchymal stem cells, MESH: Humans, Innate immune system, Multiple sclerosis, Mesenchymal stem cell, Cell Differentiation, General Medicine, medicine.disease, Phenotype, In vitro, Cell biology, MESH: Mesenchymal Stem Cells, lcsh:Biology (General)
Abstract: International audience; Mesenchymal stem cells (MSCs) exhibit potent immunoregulatory abilities by interacting with cells of the adaptive and innate immune system. In vitro, MSCs inhibit the differentiation of T cells into T helper 17 (Th17) cells and repress their proliferation. In vivo, the administration of MSCs to treat various experimental inflammatory and autoimmune diseases, such as rheumatoid arthritis, type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, and bowel disease showed promising therapeutic results. These therapeutic properties mediated by MSCs are associated with an attenuated immune response characterized by a reduced frequency of Th17 cells and the generation of regulatory T cells. In this manuscript, we review how MSC and Th17 cells interact, communicate, and exchange information through different ways such as cell-to-cell contact, secretion of soluble factors, and organelle transfer. Moreover, we discuss the consequences of this dynamic dialogue between MSC and Th17 well described by their phenotypic and functional plasticity.
Published: 2020

206. Sir2 takes affirmative action to ensure equal opportunity in replication origin licensing

Author: Armelle Lengronne, Philippe Pasero, Institut de génétique humaine (IGH), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: DNA Replication, Saccharomyces cerevisiae Proteins, Chromosomal Proteins, Non-Histone, Cell Cycle Proteins, Replication Origin, Saccharomyces cerevisiae, Origin of replication, Chromosomes, Euchromatin, 03 medical and health sciences, 0302 clinical medicine, Sirtuin 2, Minichromosome maintenance, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Commentaries, Heterochromatin, ComputingMilieux_MISCELLANEOUS, Silent Information Regulator Proteins, Saccharomyces cerevisiae, 030304 developmental biology, 0303 health sciences, Replication timing, Multidisciplinary, biology, DNA replication, DNA Helicases, Cell cycle, Chromatin, Cell biology, Histone, biology.protein, Origin recognition complex, 030217 neurology & neurosurgery
Abstract: In all eukaryotes, chromosomal DNA replication initiates at multiple sites distributed along chromosomes called origins of replication. The initiation of DNA synthesis is a two-step process involving the loading of the minichromosome maintenance (MCM) double hexamer on origins during the G1 phase of the cell cycle and the activation of licensed origins during the S phase (1). This strict temporal separation of origin licensing from firing ensures that a given origin is activated once and only once per cell cycle, thereby preventing overreplication of the genome (Fig. 1 A ). To avoid underreplication, cells must also ensure that initiation events are evenly distributed along chromosomes. This is achieved by licensing many more origins than actually needed (2, 3). Consequently, only a fraction of potential initiation sites are activated during the S phase, the remaining ones serving as backup origins when fork progression is impeded (4, 5). Origin activation follows a defined replication timing program, in which open chromatin domains replicate early in S phase and heterochromatin replicates late (1). This sequential activation of replication origins allows a tight coordination between DNA synthesis and the production of histones and dNTPs. Moreover, the replication program can be interrupted when forks encounter DNA lesions and restarted once replication stress is relieved (6). The correct execution of the replication timing program is therefore essential to maintain the integrity of eukaryotic genomes. Fig. 1. The histone deacetylase Sir2 dampens the activity of early origins to favor an equal distribution of initiation events throughout the budding yeast genome. ( A ) The activation of replication origins in budding yeast depends on the binding of the origin recognition complex (ORC) to autonomous replicating sequences (ARS) and the loading of Mcm2-7 double hexamers in a Cdc6- and Cdt1-dependent manner to form the prereplication complex (pre-RC). Although ORC is bound to origins … [↵][1]1To whom correspondence may be addressed. Email: ppasero{at}igh.cnrs.fr. [1]: #xref-corresp-1-1
Published: 2020

207. Animal Models for the Study of Nucleic Acid Immunity: Novel Tools and New Perspectives

Author: Dimitrios Vlachakis, Maxence Frétaud, Isabelle K. Vila, Christelle Langevin, Nadine Laguette, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Virologie et Immunologie Moléculaires (VIM (UR 0892)), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), School of Applied Biology and Biotechnology, Biomedical Research Foundation of the Academy of Athens (BRFAA), University Research Institute of Maternal and Child Health and Precision Medicine, National and Kapodistrian University of Athens (NKUA), ANRS ECTZ117448LA LIGUE pour la recherche contre le cancer AdjustEBOVGP-Dx, a European & Developing Countries Clinical Trials Partnership (EDCTP2) under the Horizon 2020 'Research and Innovation Actions' DESCA RIA2018EF-2081, European Project: 893772,DIM-CrIC, European Project: 637763,H2020,ERC-2014-STG,CrIC(2015), and European Project: 731014,VetBioNet(2017)
Subjects: [SDV]Life Sciences [q-bio], Drug Evaluation, Preclinical, Inflammation, Computational biology, Antiviral Agents, Article, Evolution, Molecular, 03 medical and health sciences, Mice, 0302 clinical medicine, Cytosol, Structural Biology, Immunity, Nucleic Acids, medicine, Animals, Heterogeneous information, Molecular Biology, Zebrafish, Organism, 030304 developmental biology, 0303 health sciences, biology, Signal transducing adaptor protein, Membrane Proteins, biology.organism_classification, Nucleotidyltransferases, Immunity, Innate, 3. Good health, High-Throughput Screening Assays, DNA, Viral, Interferon Type I, Models, Animal, Mutation, Nucleic acid, medicine.symptom, 030217 neurology & neurosurgery, Signal Transduction
Abstract: Unresolved inflammation fosters and supports a wide range of human pathologies. There is growing evidence for a role played by cytosolicnucleic acidsin initiating and supporting pathological chronic inflammation. In particular, the cGAS-STING pathway has emerged as central to the mounting of nucleic acid-dependenttype I interferonresponses, leading to the identification of small-molecule modulators of STING that have raised clinical interest. However, several new challenges have emerged, representing potential obstacles to efficient clinical translation. Indeed, the current literature underscores that nucleic acid-induced inflammatory responses are subjected to several layers of regulation, further suggesting complex coordination at the cell-type, tissue or organism level. Untangling the underlying processes is paramount to the identification of specific therapeutic strategies targeting deleterious inflammation. Herein, we present an overview of human pathologies presenting with deregulated interferon levels and with accumulation of cytosolicnucleic acids. We focus on the central role of the STING adaptor protein in these pathologies and discuss howin vivomodels have forged our current understanding of nucleic acid immunity. We present our opinion on the advantages and limitations of zebrafish and mice models to highlight their complementarity for the study of inflammatory human pathologies and the development of therapeutics. Finally, we discuss high-throughput screening strategies that generate multi-parametric datasets that allow integrative analysis of heterogeneous information (imaging and omics approaches). These approaches are likely to structure the future of screening strategies for the treatment of human pathologies.
Published: 2020

208. [Transcriptomes for serial analysis of gene expression]

Author: Jacques, Marti, David, Piquemal, Laurent, Manchon, Thérèse, Commes, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Skuldtech. Cap Delta - ZAC Euromedecine II. 1682, rue de la Valsière, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and MANCHON, Laurent
Subjects: DNA, Complementary, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Transcription, Genetic, Gene Expression Profiling, [SDV]Life Sciences [q-bio], fungi, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV] Life Sciences [q-bio], Gene Expression Regulation, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Databases, Nucleic Acid, Oligonucleotide Array Sequence Analysis
Abstract: International audience; The availability of the sequences for whole genomes is changing our understanding of cell biology. Functional genomics refers to the comprehensive analysis, at the protein level (proteome) and at the mRNA level (transcriptome) of all events associated with the expression of whole sets of genes. New methods have been developed for transcriptome analysis. Serial Analysis of Gene Expression (SAGE) is based on the massive sequential analysis of short cDNA sequence tags. Each tag is derived from a defined position within a transcript. Its size (14 bp) is sufficient to identify the corresponding gene and the number of times each tag is observed provides an accurate measurement of its expression level. Since tag populations can be widely amplified without altering their relative proportions, SAGE may be performed with minute amounts of biological extract. Dealing with the mass of data generated by SAGE necessitates computer analysis. A software is required to automatically detect and count tags from sequence files. Criterias allowing to assess the quality of experimental data can be included at this stage. To identify the corresponding genes, a database is created registering all virtual tags susceptible to be observed, based on the present status of the genome knowledge. By using currently available database functions, it is easy to match experimental and virtual tags, thus generating a new database registering identified tags, together with their expression levels. As an open system, SAGE is able to reveal new, yet unknown, transcripts. Their identification will become increasingly easier with the progress of genome annotation. However, their direct characterization can be attempted, since tag information may be sufficient to design primers allowing to extend unknown sequences. A major advantage of SAGE is that, by measuring expression levels without reference to an arbitrary standard, data are definitively acquired and cumulative. All publicly available data can thus be stored in a unique database, facilitating whole-genome analysis of differential expression between cell types, normal and diseased samples, or samples with and without drug treatment. SAGE data are readily amenable to statistical comparisons, allowing to determine the level of confidence of the observed variations. A major limitation of SAGE is that, because each analysis is obligatory performed on the whole set of expressed genes, it can hardly be performed on multiple samples, for example in kinetics studies or to compare the effects of large numbers of drugs. To overcome this limitation, high-throughput detection of a subset of mRNAs is more rapidly performed by parallel hybridization of mRNAs on arrays of nucleic acids immobilized on solid supports. From this point of view, a SAGE platform is a powerful instrument for selecting the most informative subset of genes, assembling them to design microarrays dedicated to a specific problem and calibrating measurement by comparison with a standard cell model for which SAGE data are available. This approach is an attractive alternative to strategies based exclusively on pangenomic arrays. A very large amount of SAGE data are already available and the problem is now to extract their biological meaning. Knowledge on metabolic pathways is already organized so that its successful integration in a SAGE platform can be undertaken. For other cell components and pathways, the problem lies on the lack of controlled vocabulary to describe gene activities, starting form a clear definition of the concept of biological function itself. Progress in gene and cell ontology is expected to facilitate computer-based extraction of biological knowledge from existing and forthcoming SAGE data.
Published: 2020

209. The Mi-2 nucleosome remodeler and the Rpd3 histone deacetylase are involved in piRNA-guided heterochromatin formation

Author: Séverine Chambeyron, Bruno Mugat, Simon Nicot, Kaoru Sato, Mikiko C. Siomi, Carolina Varela-Chavez, Christophe Jourdan, François Juge, Eugenia Basyuk, Alain Pélisson, Institut de génétique humaine (IGH), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Histone Deacetylase 1, Autoantigens, Non-coding RNAs, Epigenesis, Genetic, Histones, 0302 clinical medicine, Heterochromatin, Transposition, Drosophila Proteins, RNA, Small Interfering, lcsh:Science, ComputingMilieux_MISCELLANEOUS, Adenosine Triphosphatases, Regulation of gene expression, Multidisciplinary, Protein Inhibitors of Activated STAT, Nucleosomes, Cell biology, Drosophila melanogaster, Argonaute Proteins, Epigenetics, Female, endocrine system, Science, Piwi-interacting RNA, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Histone H3, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals, Nucleosome, Gene Silencing, [SDV.GEN]Life Sciences [q-bio]/Genetics, urogenital system, Ovary, fungi, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, 030104 developmental biology, Gene Expression Regulation, Histone deacetylase complex, lcsh:Q, Histone deacetylase, 030217 neurology & neurosurgery
Abstract: In eukaryotes, trimethylation of lysine 9 on histone H3 (H3K9) is associated with transcriptional silencing of transposable elements (TEs). In drosophila ovaries, this heterochromatic repressive mark is thought to be deposited by SetDB1 on TE genomic loci after the initial recognition of nascent transcripts by PIWI-interacting RNAs (piRNAs) loaded on the Piwi protein. Here, we show that the nucleosome remodeler Mi-2, in complex with its partner MEP-1, forms a subunit that is transiently associated, in a MEP-1 C-terminus-dependent manner, with known Piwi interactors, including a recently reported SUMO ligase, Su(var)2-10. Together with the histone deacetylase Rpd3, this module is involved in the piRNA-dependent TE silencing, correlated with H3K9 deacetylation and trimethylation. Therefore, drosophila piRNA-mediated transcriptional silencing involves three epigenetic effectors, a remodeler, Mi-2, an eraser, Rpd3 and a writer, SetDB1, in addition to the Su(var)2-10 SUMO ligase., In S. pombe, small non-coding RNA mediates heterochromatin formation by recruiting the nucleosome remodeling and histone deacetylase complex. Here, the authors show that fly nucleosome remodeler Mi-2 and histone deacetylase Rpd3 are involved in piRNA-dependent transcriptional silencing of transposable elements.
Published: 2020

210. Chromatin-associated MRN complex protects highly transcribing genes from genomic instability

Author: Celine Franckhauser, Poornima Basavarajaiah, Olivier Cuvier, Rosemary Kiernan, Victor Mac, Emmanuelle Beyne, Marion Helsmoortel, David Depierre, Jérôme Déjardin, Callum Burnard, Giuseppa Grasso, Sylvie Rouquier, Xavier Contreras, Kader Salifou, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), and Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)
Subjects: Genome instability, DNA damage, Cell Cycle Proteins, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, Genome, Genomic Instability, 03 medical and health sciences, 0302 clinical medicine, Gene expression, Humans, Molecular Biology, Gene, Research Articles, Cancer, 030304 developmental biology, MRE11 Homologue Protein, 0303 health sciences, Multidisciplinary, SciAdv r-articles, Nuclear Proteins, Chromatin, 3. Good health, Cell biology, MDC1, DNA-Binding Proteins, MRN complex, 030217 neurology & neurosurgery, Research Article, DNA Damage
Abstract: Chromatin-associated MRN protects highly transcribing genes from genomic instability., MRN-MDC1 plays a central role in the DNA damage response (DDR) and repair. Using proteomics of isolated chromatin fragments, we identified DDR factors, such as MDC1, among those highly associating with a genomic locus upon transcriptional activation. Purification of MDC1 in the absence of exogenous DNA damage revealed interactions with factors involved in gene expression and RNA processing, in addition to DDR factors. ChIP-seq showed that MRN subunits, MRE11 and NBS1, colocalized throughout the genome, notably at TSSs and bodies of actively transcribing genes, which was dependent on the RNAPII transcriptional complex rather than transcription per se. Depletion of MRN increased RNAPII abundance at MRE11/NBS1-bound genes. Prolonged MRE11 or NBS1 depletion induced single-nucleotide polymorphisms across actively transcribing MRN target genes. These data suggest that association of MRN with the transcriptional machinery constitutively scans active genes for transcription-induced DNA damage to preserve the integrity of the coding genome.
Published: 2020

211. Integration of high-throughput reporter assays identify a critical enhancer of the Ikzf1 gene

Author: Alomairi, Jaafar, Molitor, Anne, Sadouni, Nori, Hussain, Saadat, Torres, Magali, Saadi, Wiam, Dao, Lan, Charbonnier, Guillaume, Santiago-Algarra, David, Andrau, Jean Christophe, Puthier, Denis, Sexton, Tom, Spicuglia, Salvatore, Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine (IGH), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), ANR-17-CE12-0035,Silencer,Identification et analyse des éléments répresseurs génomiques(2017), ANR-18-CE12-0019,Epromoters,Contrôle de la réponse au stress par une nouvelle classe de promoteurs à activité enhancer(2018), ANR-11-IDEX-0001,Amidex,INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE(2011), ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), European Project: 678624,CHROMTOPOLOGY), Spinelli, Lionel, Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID, Identification et analyse des éléments répresseurs génomiques - - Silencer2017 - ANR-17-CE12-0035 - AAPG2017 - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Contrôle de la réponse au stress par une nouvelle classe de promoteurs à activité enhancer - - Epromoters2018 - ANR-18-CE12-0019 - AAPG2018 - VALID, INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE - - Amidex2011 - ANR-11-IDEX-0001 - IDEX - VALID, Initiative d'excellence - Par-delà les frontières, l'Université de Strasbourg - - UNISTRA2010 - ANR-10-IDEX-0002 - IDEX - VALID, Understanding and manipulating the dynamics of chromosome topologies in transcriptional control - CHROMTOPOLOGY) - 678624 - INCOMING, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Subjects: Epigenomics, Science, Enhancer elements, Genetic loci, [SDV]Life Sciences [q-bio], Cell Line, Ikaros Transcription Factor, Mice, Genes, Reporter, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Transcription factors, Animals, RNA, Messenger, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Thymocytes, Correction, Genomic signal processing, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Chromatin, Polymerase chain reaction, Gene regulation, [SDV] Life Sciences [q-bio], Enhancer Elements, Genetic, Gene Expression Regulation, Medicine, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]
Abstract: International audience; The Ikzf1 locus encodes the lymphoid specific transcription factor Ikaros, which plays an essential role in both T and B cell differentiation, while deregulation or mutation of IKZF1/ Ikzf1 is involved in leukemia. Tissue-specific and cell identity genes are usually associated with clusters of enhancers, also called super-enhancers, which are believed to ensure proper regulation of gene expression throughout cell development and differentiation. Several potential regulatory regions have been identified in close proximity of Ikzf1, however, the full extent of the regulatory landscape of the Ikzf1 locus is not yet established. In this study, we combined epigenomics and transcription factor binding along with high-through-put enhancer assay and 4C-seq to prioritize an enhancer element located 120 kb upstream of the Ikzf1 gene. We found that deletion of the E120 enhancer resulted in a significant reduction of Ikzf1 mRNA. However, the epigenetic landscape and 3D topology of the locus were only slightly affected, highlighting the complexity of the regulatory landscape regulating the Ikzf1 locus.
Published: 2020

212. Petits ARN régulateurs (microARN, siARN, piARN)

Author: Seitz, Hervé, Mockly, Sophie, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), AGROCAMPUS OUEST, and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics, piARN, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], microARN, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], siARN, [SDV.BDD]Life Sciences [q-bio]/Development Biology, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM]
Abstract: International audience; Introductory lectures given during the CNRS summer school "InteRNAt", organized in Sète from October 6 to October 10, 2019.; Contenu des cours introductifs donnés dans le cadre de l'école thématique du CNRS « InteRNAt » organisée à Sète du 6 au 10 octobre 2019.
Published: 2020

213. Petits ARN régulateurs (microARN, siARN, piARN): Cours introductif donné dans le cadre de l'école thématique du CNRS « InteRNAt » du 6 au 10 octobre 2019 (https://internat.sciencesconf.org/)

Author: Seitz, Hervé, Mockly, Sophie, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), AGROCAMPUS OUEST, and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics, piARN, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], microARN, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], siARN, [SDV.BDD]Life Sciences [q-bio]/Development Biology, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM]
Abstract: International audience; Introductory lectures given during the CNRS summer school "InteRNAt", organized in Sète from October 6 to October 10, 2019.; Contenu des cours introductifs donnés dans le cadre de l'école thématique du CNRS « InteRNAt » organisée à Sète du 6 au 10 octobre 2019.
Published: 2020

214. Homologous recombination and Mus81 promote replication completion in response to replication fork blockage

Author: Thibaud Vicat, Philippe Pasero, María Moriel-Carretero, Benjamin Pardo, Andrés Aguilera, Universidad de Sevilla. Departamento de Genética, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Universidad de Sevilla, Agence Nationale de la Recherche (France), Ligue Nationale contre le Cancer (France), Institut National du Cancer (France), Ministerio de Economía y Competitividad (España), Junta de Andalucía, Fondation pour la Recherche Médicale, and European Commission
Subjects: DNA Replication, RAD52, RAD51, Replication, Origin of replication, Biochemistry, Genomic Instability, S Phase, 03 medical and health sciences, Endonuclease, 0302 clinical medicine, Genetics, Humans, Mus81, Homologous Recombination, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, DNA synthesis, biology, BIR, DNA replication, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Articles, Endonucleases, MUS81, Recombination, 3. Good health, Cell biology, DNA-Binding Proteins, Fork restart, biology.protein, Rad51 Recombinase, Homologous recombination, 030217 neurology & neurosurgery
Abstract: Impediments to DNA replication threaten genome stability. The homologous recombination (HR) pathway has been involved in the restart of blocked replication forks. Here, we used a method to increase yeast cell permeability in order to study at the molecular level the fate of replication forks blocked by DNA topoisomerase I poisoning by camptothecin (CPT). Our results indicate that Rad52 and Rad51 HR factors are required to complete DNA replication in response to CPT. Recombination events occurring during S phase do not generally lead to the restart of DNA synthesis but rather protect blocked forks until they merge with convergent forks. This fusion generates structures requiring their resolution by the Mus81 endonuclease in G2/M. At the global genome level, the multiplicity of replication origins in eukaryotic genomes and the fork protection mechanism provided by HR appear therefore to be essential to complete DNA replication in response to fork blockage., This work was funded by grants from the “Agence Nationale pour la Recherche” (ANR, France), the “Institut National du Cancer” (INCa, France), the “Ligue contre le Cancer” (équipe labellisée, France), and the MSDAvenir Fund, France, to PP and from the Spanish Ministry of Economy and Competitiveness (BFU2013-42918P, and Consolider Ingenio 2010 CSD2007-015), the “Junta de Andalucia” (BIO-1238 and CVI-4567, Spain), and the European Union (FEDER) to AA. BP was supported by fellowships from the “Fondation Recherche Médicale” (SPF20121226243, France) and from the Spanish Ministry of Economy and Competitiveness (JCI 2009-04101). MMC was recipient of a predoctoral FPU training grant from the Spanish Ministry of Economy and Competitiveness and a postdoctoral grant from the Labex EpiGenMed, an “Investissements d’Avenir” program (ANR-10-LABX-12-01), France.
Published: 2020

215. The Set1 N-terminal domain and Swd2 interact with RNA polymerase II CTD to recruit COMPASS

Author: Marion Dubarry, Jongcheol Jeon, Vincent Géli, Luis M. Soares, Hyun Jin Bae, Stephen Buratowski, Catherine Dargemont, Jae-Hoon Kim, Harvard Medical School [Boston] (HMS), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Korea Advanced Institute of Science and Technology (KAIST), Foghorn Therapeutics [Cambridge, MA, États-Unis], Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), H.B. was supported by a postdoctoral fellowship from the Basic Science Research Program of the National Research Foundation of Korea (NRF), funded by the Ministry of Education (2015R1A6A3A03017730). This work was supported by grants from the National Research Foundation of Korea (NRF-2019R1A2C2090830) to J.K., from 'Ligue Nationale Contre le Cancer' (LNCC) (Equipe labellisée) to M.D. and V.G., and grants GM046498 and GM056663 from the U.S. National Institutes of Health to S.B., Bodescot, Myriam, Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)
Subjects: 0301 basic medicine, Molecular biology, [SDV]Life Sciences [q-bio], General Physics and Astronomy, RNA polymerase II, Biochemistry, environment and public health, Histones, 0302 clinical medicine, Histone methylation, Histone post-translational modifications, lcsh:Science, Regulation of gene expression, Multidisciplinary, biology, Chemistry, RNA-Binding Proteins, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Chromatin, Cell biology, Chromatin Immunoprecipitation Sequencing, RNA Polymerase II, Transcription, Protein Binding, Histone H3 Lysine 4, Saccharomyces cerevisiae Proteins, animal structures, Science, Saccharomyces cerevisiae, Methylation, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Histone H3, Protein Domains, Histone H2B, Point Mutation, Lysine, Ubiquitination, Histone-Lysine N-Methyltransferase, General Chemistry, 030104 developmental biology, [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], biology.protein, lcsh:Q, CTD, Protein Processing, Post-Translational, 030217 neurology & neurosurgery
Abstract: Methylation of histone H3 lysine 4 (H3K4) by Set1/COMPASS occurs co-transcriptionally, and is important for gene regulation. Set1/COMPASS associates with the RNA polymerase II C-terminal domain (CTD) to establish proper levels and distribution of H3K4 methylations. However, details of CTD association remain unclear. Here we report that the Set1 N-terminal region and the COMPASS subunit Swd2, which interact with each other, are both needed for efficient CTD binding in Saccharomyces cerevisiae. Moreover, a single point mutation in Swd2 that affects its interaction with Set1 also impairs COMPASS recruitment to chromatin and H3K4 methylation. A CTD interaction domain (CID) from the protein Nrd1 can partially substitute for the Set1 N-terminal region to restore CTD interactions and histone methylation. However, even when Set1/COMPASS is recruited via the Nrd1 CID, histone H2B ubiquitylation is still required for efficient H3K4 methylation, indicating that H2Bub acts after the initial recruitment of COMPASS to chromatin., Methylation of histone H3 lysine 4 (H3K4) by Set1/COMPASS occurs co-transcriptionally, and is important for gene regulation. Here the authors provide evidence that the Set1 N-terminal region and the COMPASS subunit Swd2 interact with RNA polymerase II CTD to recruit COMPASS in budding yeast.
Published: 2020

216. Characterization of immortalized human islet stromal cells reveals a MSC-like profile with pancreatic features

Author: Danièle Noël, Claire Bony, Guilhem Couderc, Orianne Villard, Jérôme Moreaux, Anne Wojtusciszyn, Bernard Klein, Jean-Luc Veyrune, Mathieu Armanet, John DeVos, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Département d'hématologie biologique[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), and Herrada, Anthony
Subjects: Stromal cell, Pancreatic islets, Mesenchymal stromal cells, Medicine (miscellaneous), Biology, Biochemistry, Genetics and Molecular Biology (miscellaneous), Cell therapy, lcsh:Biochemistry, Extracellular matrix, 03 medical and health sciences, 0302 clinical medicine, medicine, lcsh:QD415-436, CD90, Conditioned medium, 030304 developmental biology, lcsh:R5-920, 0303 health sciences, Mesenchymal stem cell, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell Biology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell biology, Transplantation, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Molecular Medicine, Pancreatic islet transplantation, Stem cell, lcsh:Medicine (General)
Abstract: BackgroundMesenchymal stromal cells (MSCs) represent an interesting tool to improve pancreatic islet transplantation. They have immunomodulatory properties and secrete supportive proteins. However, the functional properties of MSCs vary according to many factors such as donor characteristics, tissue origin, or isolation methods. To counteract this heterogeneity, we aimed to immortalize and characterize adherent cells derived from human pancreatic islets (hISCs), using phenotypic, transcriptomic, and functional analysis.MethodsAdherent cells derived from human islets in culture were infected with a hTERT retrovirus vector and then characterized by microarray hybridization, flow cytometry analysis, and immunofluorescence assays. Osteogenic, adipogenic, and chondrogenic differentiation as well as PBMC proliferation suppression assays were used to compare the functional abilities of hISCs and MSCs. Extracellular matrix (ECM) gene expression profile analysis was performed using the SAM (Significance Analysis of Microarrays) software, and protein expression was confirmed by western blotting.ResultshISCs kept an unlimited proliferative potential. They exhibited several properties of MSCs such as CD73, CD90, and CD105 expression and differentiation capacity. From a functional point of view, hISCs inhibited the proliferation of activated peripheral blood mononuclear cells. The transcriptomic profile of hISCs highly clusterized with bone marrow (BM)-MSCs and revealed a differential enrichment of genes involved in the organization of the ECM. Indeed, the expression and secretion profiles of ECM proteins including collagens I, IV, and VI, fibronectin, and laminins, known to be expressed in abundance around and within the islets, were different between hISCs and BM-MSCs.ConclusionWe generated a new human cell line from pancreatic islets, with MSCs properties and retaining some pancreatic specificities related to the production of ECM proteins. hISCs appear as a very promising tool in islet transplantation by their availability (as a source of inexhaustible source of cells) and ability to secrete a supportive “pancreatic” microenvironment.
Published: 2020

217. Factors of microinflammation in non-diabetic chronic kidney disease: a pilot study

Author: Stéphane Burtey, Jean-Paul Cristol, Jean-Philippe Lavigne, Thibault Sutra, Catherine Dunyach-Remy, Valerie Olivier, Pierre Corbeau, Olivier Moranne, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Nutrition et Alimentation des Populations aux Suds (NutriPass), Université Montpellier 1 (UM1)-Institut de Recherche pour le Développement (IRD)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Centre de néphrologie et transplantation rénale [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Aix Marseille Université (AMU), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Montpellier (UM), MORNET, Dominique, Institut de Recherche pour le Développement (IRD)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Montpellier (UM), and Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Assistance Publique - Hôpitaux de Marseille (APHM)
Subjects: 0301 basic medicine, Nephrology, Male, [SDV]Life Sciences [q-bio], medicine.medical_treatment, 030232 urology & nephrology, Pilot Projects, lcsh:RC870-923, medicine.disease_cause, Kidney Function Tests, Gastroenterology, chemistry.chemical_compound, 0302 clinical medicine, Medicine, education.field_of_study, 3. Good health, [SDV] Life Sciences [q-bio], C-Reactive Protein, Female, Hemodialysis, medicine.symptom, Research Article, medicine.medical_specialty, Population, Uremic toxins, Renal function, Inflammation, Microinflammation, Sulfuric Acid Esters, 03 medical and health sciences, Renal Dialysis, Internal medicine, CKD, Humans, Renal Insufficiency, Chronic, education, Uremia, Indoleacetic Acids, business.industry, Patient Acuity, lcsh:Diseases of the genitourinary system. Urology, medicine.disease, Gastrointestinal Microbiome, Oxidative Stress, 030104 developmental biology, chemistry, Bacterial translocation, Urea, business, Indican, Oxidative stress, Biomarkers, Kidney disease
Abstract: Background The relationships between digestive bacterial translocation, uremic toxins, oxidative stress and microinflammation in a population of chronic kidney disease (CKD) patients without metabolic nor inflammatory disease are unknown. Methods Bacterial translocation, uremic toxins, oxidative stress, and inflammation were assessed by measuring plasma levels of 16S ribosomal DNA (16S rDNA), p-cresyl sulfate (PCS), indoxyl sulfate (IS), indole acetic acid (IAA), F2-isoprostanes, hsCRP and receptor I of TNFα (RITNFα) in patients without metabolic nor inflammatory disease. 44 patients with CKD from stage IIIB to V and 14 controls with normal kidney function were included from the nephrology outpatients. 11 patients under hemodialysis (HD) were also included. Correlations between each factor and microinflammation markers were studied. Results 16S rDNA levels were not increased in CKD patients compared to controls but were decreased in HD compared to non-HD stage V patients (4.7 (3.9–5.3) vs 8.6 (5.9–9.7) copies/μl, p = 0.002). IS, PCS and IAA levels increased in HD compared to controls (106.3 (73.3–130.4) vs 3.17 (2.4–5.1) μmol/l, p p = 0.006 for PCS; and 3.7 (2.6–4.6) vs 1.3 (1.0–1.9) μmol/l, p = 0.0002 for IAA). Urea increased in non-HD stage V patients compared to controls (27.6 (22.7–30.9) vs 5.4 (4.8–6.4) mmol/l, p p = 0.7). RITNFα levels increased in HD patients compared to controls (12.6 (9.6–13.3) vs 1.1 (1.0–1.4) ng/ml, p p = 0.01) and remained stable in HD patients (2.9 (1.4–8.5) vs 5.1 (0.9–11.5) mg/l, p = 1). F2-isoprostanes did not differ in CKD patients compared to controls. Among uremic toxins, IS and urea were correlated to RITNFα (r = 0.8, p p = 0.01, 0.04 and 0.001 respectively). 16S rDNA, F2-isoprostanes were not correlated to microinflammation markers in our study. Conclusions In CKD patients without any associated metabolic nor inflammatory disease, only PCS, IS, and urea were correlated with microinflammation. Bacterial translocation was decreased in patients under HD and was not correlated to microinflammation.
Published: 2020

218. PRDM9 activity depends on HELLS and promotes local 5-hydroxymethylcytosine enrichment

Author: Mariko Teragaki, Julie A. J. Clément, Serge Urbach, Corinne Grey, Yukiko Imai, Mathilde Biot, Thomas Robert, Frédéric Baudat, Bernard de Massy, Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), 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 National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and de Massy, Bernard
Subjects: 0301 basic medicine, Male, Proteomics, Mouse, [SDV]Life Sciences [q-bio], genetic processes, HELLS, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, chemistry.chemical_compound, Mice, 0302 clinical medicine, Spermatocytes, Testis, meiosis, DNA Breaks, Double-Stranded, Biology (General), Homologous Recombination, ComputingMilieux_MISCELLANEOUS, PRDM9, Mice, Knockout, [SDV.BDLR.RS] Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, biology, Chemistry, General Neuroscience, General Medicine, Chromosomes and Gene Expression, Chromatin, Cell biology, Histone, 5-Methylcytosine, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Medicine, biological phenomena, cell phenomena, and immunity, lsh, Research Article, Spo11, QH301-705.5, Science, General Biochemistry, Genetics and Molecular Biology, [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals, Humans, Epigenetics, 5-Hydroxymethylcytosine, Binding Sites, Endodeoxyribonucleases, General Immunology and Microbiology, fungi, DNA Helicases, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Genetics and Genomics, Histone-Lysine N-Methyltransferase, recombination, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, enzymes and coenzymes (carbohydrates), 030104 developmental biology, biology.protein, 5hmC, Homologous recombination, 030217 neurology & neurosurgery, HeLa Cells
Abstract: International audience; Meiotic recombination starts with the formation of DNA double-strand breaks (DSBs) at specific genomic locations that correspond to PRDM9-binding sites. The molecular steps occurring from PRDM9 binding to DSB formation are unknown. Using proteomic approaches to find PRDM9 partners, we identified HELLS, a member of the SNF2-like family of chromatin remodelers. Upon functional analyses during mouse male meiosis, we demonstrated that HELLS is required for PRDM9 binding and DSB activity at PRDM9 sites. However, HELLS is not required for DSB activity at PRDM9-independent sites. HELLS is also essential for 5-hydroxymethylcytosine (5hmC) enrichment at PRDM9 sites. Analyses of 5hmC in mice deficient for SPO11, which catalyzes DSB formation, and in PRDM9 methyltransferase deficient mice reveal that 5hmC is triggered at DSB-prone sites upon PRDM9 binding and histone modification, but independent of DSB activity. These findings highlight the complex regulation of the chromatin and epigenetic environments at PRDM9-specified hotspots.
Published: 2020

219. FGF14 ‐related episodic ataxia: delineating the phenotype of Episodic Ataxia type 9

Author: Jessica Hadjadj, Florence Riant, Franck Rejou, Ganaelle Remerand, Véronique Humbertclaude, Pierre Meyer, Julie Piarroux, Lucile Pinson, Christine Coubes, Agathe Roubertie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Lariboisière, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 2Service de Génétique Moléculaire Neurovasculaire, Groupe hospitalier Saint-Louis - Lariboisière - Fernand Widal AP-HP, Paris, France, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service de Néonatologie [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service de Génétique Clinique, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier (INM), MORNET, Dominique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Service de néonatologie, CHU Estaing, Clermont-Ferrand, France, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: 0301 basic medicine, Adult, Male, Pediatrics, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, [SDV]Life Sciences [q-bio], Neurosciences. Biological psychiatry. Neuropsychiatry, Nystagmus, Brief Communication, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, RC346-429, Child, Episodic ataxia, business.industry, General Neuroscience, Postural tremor, Middle Aged, medicine.disease, Phenotype, Pedigree, Fibroblast Growth Factors, [SDV] Life Sciences [q-bio], 030104 developmental biology, Child, Preschool, Ataxia, Female, Neurology. Diseases of the nervous system, Neurology (clinical), medicine.symptom, business, Brief Communications, 030217 neurology & neurosurgery, RC321-571
Abstract: International audience; We report four patients from two families who presented attacks of childhood-onset episodic ataxia associated with pathogenic mutations in the FGF14 gene. Attacks were triggered by fever, lasted several days, and had variable frequencies. Nystagmus and/or postural tremor and/or learning disabilities were noticed in individuals harboring FGF14 mutation with or without episodic ataxia. These cases and literature data delineate the FGF14-mutation-related episodic ataxia phenotype: wide range of age at onset (from childhood to adulthood), variable durations and frequencies, triggering factors including fever, and association to chronic symptoms. We propose to add FGF14-related episodic ataxia to the list of primary episodic ataxia as Episodic Ataxia type 9.
Published: 2020

220. Kinome expression profiling to target new therapeutic avenues in multiple myeloma

Author: Jérôme Moreaux, Claire Gourzones, Nicolas Robert, Anke Maes, Michel Jourdan, Philippe Pasero, Elke De Bruyne, Guillaume Cartron, Angelique Bruyer, Anja Seckinger, Alboukadel Kassambara, Laure Vincent, Dirk Hose, Hugues de Boussac, Génétique, Reproduction et Développement (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Cellules souches normales et cancéreuses, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Vrije Universiteit Brussel (VUB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Interactions moléculaires et cancer (IMC (UMR 8126)), Signalisation, noyaux et innovations en cancérologie (UMR8126), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Heidelberg University Hospital [Heidelberg], Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), ANR-17-CE15-0024,TIE-Skip,Impact des immunoglobulines tronquées produites par saut d'exon dans les plasmocytes : vers des approches thérapeutiques utilisant des oligonucléotides antisens(2017), Vrije Universiteit Brussel, Clinical sciences, Faculty of Medicine and Pharmacy, Basic (bio-) Medical Sciences, and Hematology
Subjects: Melphalan, CHK1, SRPK1, Cell Cycle Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Protein Serine-Threonine Kinases, Article, Plasma Cell Disorders, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, MELK, medicine, Humans, Immunologic Factors, Kinome, CHEK1, Multiple myeloma (MM), Lenalidomide, Multiple myeloma, 030304 developmental biology, 0303 health sciences, Kinase, business.industry, MPS1/TTK), [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, medicine.disease, 3. Good health, Gene expression profiling, 030220 oncology & carcinogenesis, Cancer research, CDC7-DBF4, PLK4, Neoplasm Recurrence, Local, Multiple Myeloma, business, medicine.drug, Protein kinas-es (PBK
Abstract: International audience; Multiple myeloma (MM) account for approximately 10% of hematological malignancies and is the second most common hematological disorder. Kinases inhibitors are widely used and their efficiency for the treatment of cancers has been demonstrated. Here, in order to identify kinases of potential therapeutic interest for the treatment of MM, we investigated the prognostic impact of the kinome expression profile in large cohorts of patients. We identified 36 kinome-related genes significantly linked with a prognostic value to MM, and built a kinome index based on their expression. The Kinome Index (KI) is linked to prognosis, proliferation, differentiation, and relapse in MM. We then tested inhibitors targeting seven of the identified protein kinas-es (PBK, SRPK1, CDC7-DBF4, MELK, CHK1, PLK4, MPS1/TTK) in human myeloma cell lines. All tested inhibitors significantly reduced the viability of myeloma cell lines, and we confirmed the potential clinical interest of three of them on primary myeloma cells from patients. In addition, we demonstrated their ability to potentialize the toxicity of conventional treatments, including Melphalan and Lenalidomide. This highlights their potential beneficial effect in myeloma therapy. Three kinases inhibitors (CHK1i, MELKi and PBKi) overcome resistance to Lenalidomide, while CHK1, PBK and DBF4 inhibitors re-sensitize Melphalan resistant cell line to this conventional therapeutic agent. Altogether, we demonstrate that kinase inhibitors could be of therapeutic interest especially in high-risk myeloma patients defined by the KI. CHEK1, MELK, PLK4, SRPK1, CDC7-DBF4, MPS1/TTK and PBK inhibitors could represent new treatment options either alone or in combination with Melphalan or IMiD for refractory/relapsing myeloma patients.
Published: 2020

221. Cerebrospinal Fluid and Plasma Biomarkers do not Differ in the Presenile and Late-Onset Behavioral Variants of Frontotemporal Dementia

Author: Menjot De Champfleur, Nicolas, Maleska, Aleksandra, Marelli, Cecilia, Hourregue, Claire, Gutierrez, Laure-Anne, Paquet, Claire, Menjot de Champfleur, Nicolas, de Verbizier, Delphine, Jacob, Melissa, Dubois, Jonathan, Maleska, Aleksandra Maceski, Hirtz, Christophe, Navucet, Sophie, Bennys, Karim, Dumurgier, Julien, Cognat, Emmanuel, Berr, Claudine, Magnin, Eloi, Lehmann, Sylvain, Gabelle, Audrey, Département de Neuroradiologie[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Neurologie Cognitive [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpitaux Universitaires Saint-Louis, Lariboisière, Fernand-Widal, Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Histologie et de Biologie du Vieillissement, Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de médecine nucléaire [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institute of Research in Biotherapy, Laboratory of Biochemistry and Clinical Proteomics, Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Département de neurologie [Montpellier], Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Genetique des Maladies Vasculaires, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologies du système nerveux : recherche épidémiologique et clinique, Université Montpellier 1 (UM1)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Mémoire de Ressources et de Recherche [CHRU de Besançon] (CMRR), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques [CHRU de Besançon], Institut de génétique humaine (IGH), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Adult, Male, Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Glial Fibrillary Acid Protein, Late onset, tau Proteins, Neuropsychological Tests, Plasma biomarkers, Hippocampus, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, Glial Fibrillary Acidic Protein, Medicine, Humans, Age of Onset, Aged, Retrospective Studies, Aged, 80 and over, Amyloid beta-Peptides, business.industry, General Neuroscience, Neurodegeneration, Brain, Retrospective cohort study, General Medicine, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Peptide Fragments, Psychiatry and Mental health, Clinical Psychology, 030104 developmental biology, Frontotemporal Dementia, Positron-Emission Tomography, Biomarker (medicine), Female, Geriatrics and Gerontology, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery, Biomarkers, Frontotemporal dementia
Abstract: International audience; : Background:Memory troubles and hippocampal atrophy are considered more frequent and focal atrophy less severe in late-onset (>65 years) than in presenile behavioral variant frontotemporal dementia (bvFTD). Objective:To compare cerebrospinal fluid (CSF) and plasma biomarkers in late-onset and presenile bvFTD. Methods:Multicentric retrospective study (2007-2017) on patients with clinical diagnosis of bvFTD. Results:This study included 44 patients (67%) with presenile and 22 (33%) with late-onset bvFTD (comparable mean disease duration; n = 11 with causal mutations). Hippocampal atrophy was more frequent (80% versus 25.8%) and severe in late-onset bvFTD (median Scheltens score: 3 [0–4] versus 1 [0–3]), without difference after adjustment for age. Lobar atrophy and focal hypometabolism/hypoperfusion were not different between groups. The median CSF Aβ1-42 and phosphorylated tau (P-tau) concentrations were in the normal range and comparable between groups. Axonal neurodegeneration biomarkers were within the normal range (CSF T-tau; plasma T-tau in late-onset bvFTD) or higher (plasma neurofilament light chain (NFL); plasma T-tau in presenile bvFTD) than the normal values, but globally not different between bvFTD groups. Plasma glial fibrillary acid protein (GFAP) was strongly increased in both bvFTD groups compared with the values in controls of the same age. Conclusion:The CSF and plasma biomarker profiles did not suggest a more aggressive neurodegeneration in the presenile group (comparable T-tau, NFL, and GFAP levels) or the co-existence of Alzheimer’s disease in the late-onset group (comparable and within normal range CSF Aβ1-42 and P-tau). The severity of the neurodegenerative process seems comparable in presenile and late-onset bvFTD.
Published: 2020

222. Immunoglobulin Abnormalities in Gaucher Disease: an Analysis of 278 Patients Included in the French Gaucher Disease Registry

Author: Yann Nguyen, Dries Dobbelaere, Jérôme Stirnemann, Monia Bengherbia, Fabrice Camou, Samia Pichard, Karima Yousfi, Christine Serratrice, Agathe Masseau, Vanessa Leguy-Seguin, Marc G. Berger, Nadia Belmatoug, Dalil Hamroun, Bruno Fantin, Florent Lautredoux, Francis Gaches, Leonardo Astudillo, Anaïs Brassier, Bérengère Cador, Florence Dalbies, Yves-Marie Pers, Thierry Billette de Villemeur, Université de Lille, Hôpital Jeanne de Flandres, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), CHU Pontchaillou [Rennes], Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Trousseau [APHP], Centre Référence des Maladies Héréditaires du Métabolisme de l'Enfant et de l'Adulte [CHU Necker] (MaMEA 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), Service de réanimation médicale, CHU Bordeaux [Bordeaux]-Hôpital Saint-André, Hôpital Morvan - CHRU de Brest (CHU - BREST ), Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Jeanne de Flandres-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Joseph Ducuing - Varsovie [Toulouse] (HJD), Service de médecine interne et immunologie clinique (SOC 1) [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de médecine interne [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Département de Rhumatologie[Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie, Hôpital Robert Debré, Médecine Interne [Hôpital Saint-Joseph - Marseille], Aix Marseille Université (AMU)-Hôpital Saint-Joseph [Marseille], Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Dpt médecine interne [CHU Beaujon], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Universitaire de Genève, CHU Toulouse [Toulouse], Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Hôpital Joseph Ducuing
Subjects: Male, Gaucher disease, monoclonal gammopathy of unknown significance, multiple myeloma, monoclonal gammopathy, polyclonal gammopathy, genetic structures, Paraproteinemias, Gastroenterology, Cohort Studies, lcsh:Chemistry, 0302 clinical medicine, Risk Factors, Multiple myeloma, Medicine, lcsh:QH301-705.5, Spectroscopy, ddc:616, Lymphoma, Non-Hodgkin, Monoclonal gammopathy, Gamma globulin, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, General Medicine, Middle Aged, 3. Good health, Computer Science Applications, 030220 oncology & carcinogenesis, Female, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Monoclonal gammopathy of unknown significance, Immunoglobulins, Article, Catalysis, Inorganic Chemistry, 03 medical and health sciences, Disease registry, Internal medicine, Humans, Clinical significance, Physical and Theoretical Chemistry, Risk factor, Molecular Biology, Proportional Hazards Models, Retrospective Studies, business.industry, Proportional hazards model, Organic Chemistry, nutritional and metabolic diseases, medicine.disease, eye diseases, Lymphoma, nervous system diseases, lcsh:Biology (General), lcsh:QD1-999, ddc:618.97, Polyclonal gammopathy, gamma-Globulins, business, Glucocerebrosidase, 030215 immunology
Abstract: Gaucher disease (GD) is a rare lysosomal autosomal-recessive disorder due to deficiency of glucocerebrosidase, polyclonal gammopathy (PG) and/or monoclonal gammopathy (MG) can occur in this disease. We aimed to describe these immunoglobulin abnormalities in a large cohort of GD patients and to study the risk factors, clinical significance, and evolution. Data for patients enrolled in the French GD Registry were studied retrospectively. The risk factors of PG and/or MG developing and their association with clinical bone events and severe thrombocytopenia, two markers of GD severity, were assessed with multivariable Cox models and the effect of GD treatment on gammaglobulin levels with linear/logarithmic mixed models. Regression of MG and the occurrence of hematological malignancies were described. The 278 patients included (132 males, 47.5%) were followed up during a mean (SD) of 19 (14) years after GD diagnosis. PG occurred in 112/235 (47.7%) patients at GD diagnosis or during follow-up and MG in 59/187 (31.6%). Multivariable analysis retained age at GD diagnosis as the only independent risk factor for MG (&gt, 30 vs. &le, 30 years, HR 4.71, 95%CI [2.40&ndash, 9.27], p &lt, 0.001). Risk of bone events or severe thrombocytopenia was not significantly associated with PG or MG. During follow-up, non-Hodgkin lymphoma developed in five patients and multiple myeloma in one. MG was observed in almost one third of patients with GD. Immunoglobulin abnormalities were not associated with the disease severity. However, prolonged surveillance of patients with GD is needed because hematologic malignancies may occur.
Published: 2020
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223. Cohorte française de 41 patients porteurs d’une délétion 2q37

Author: Colson, Cindy, Ranguin, Kara, Richard, Nicolas, Audebert-Bellanger, Séverine, Bonnet-Dupeyron, Marie-Noëlle, Bonnet, Céline, Callier, Patrick, Fradin, Mélanie, Isidor, Bertrand, Marquet, Valentine, Nizon, Mathilde, Puechberty, Jacques, Schaefer, Elise, Tabet, Anne Claude, Toutain, Annick, Uguen, Kévin, Marie, Vincent, van Gils, Julien, Gérard, Marion, Gruchy, Nicolas, Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Nouvel Hôpital Civil de Strasbourg, Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics
Abstract: National audience; Le locus 2q37 est l’une des régions subtélomériques les plus fréquemment délétées, pouvant être à l’origine du syndrome microdélétionnel 2q37, aussi appelé syndrome d’Ostéodystrophie Héréditaire d’Albright-like (AHO-like) ou syndrome retard mental-brachydactylie (BDMR) (MIM 60043), d’expression clinique variable. Suite à un appel à collaboration nationale, 41 patients porteurs d’une délétion 2q37 isolée ont été recensés. Tous les diagnostics ont été posés par l’analyse chromosomique sur puces à ADN, et confirmés par FISH avec une sonde locus-spécifique 2q37. Les délétions sont de taille variable, de 14kb intragénique DIS3L2 à 9.6 Mb. La majorité des cas est non héritée, de probable survenue de novo. Cette cohorte, pédiatrique et adulte, permet de confirmer la variabilité phénotypique et d’affiner le phénotype post-natal (1 seul cas prénatal). Les deux signes principaux mais inconstants sont les difficultés légères à modérées des apprentissages associées à des troubles comportementaux notamment des difficultés attentionnelles, et la brachydactylie. La morphologie faciale typique précédemment rapportée est fréquente également dans notre cohorte. L’obésité (6/26), le surpoids (3/26), la petite taille (2/29) sont absents dans plus de 70% des cas. L’épilepsie est décrite dans 15% des cas. Les malformations sont le plus souvent cardiaques et rénales, de bon pronostic. D’autres particularités cliniques ont été soulignées (notamment malformations cérébrales non spécifiques, troubles du transit, trouble du sommeil, troubles squelettiques et hyperlaxité). Il s’agit de la plus grosse cohorte de patients non publiés (28/41) décrite à ce jour.
Published: 2020

224. Kaposi sarcoma among people living with HIV in the French DAT'AIDS cohort between 2010 and 2015

Author: Obry-Roguet, Véronique, Duvivier, Claudine, Lions, Caroline, Huleux, Thomas, Jacomet, Christine, Ferry, Tristan, Cheret, Antoine, Allavena, Clotilde, Bani-Sadr, Firouzé, Palich, Romain, Cabié, André, Pugliese, Pascal, Delobel, Pierre, Lamaury, Isabelle, Hustache-Mathieu, Laurent, Bregigeon, Sylvie, Makinson, Alain, Rey, David, Poizot-Martin, Isabelle, Hustache‐Mathieu, Laurent, Drobacheff‐Thiébaut, C., Foltzer, A., Bouiller, K., Hustache‐ Mathieu, L., Chirouze, C., LEPILLER, Q., Bozon, F., Babre, O, Brunel, A.S., Muret, P., Laurichesse, H., Lesens, O., Vidal, M., Mrozek, N., Aumeran, C., Baud, O., Corbin, V., Letertre‐Gibert, P., Casanova, S., Prouteau, J., Fabre, I., Curlier, E., Ouissa, R., Herrmann‐Storck, C., Tressieres, B., Bonijoly, T., Receveur, M.C., Boulard, F., Daniel, C., Clavel, C., Merrien, D., Perré, P., Guimard, T., Bollangier, O., Leautez, S., Morrier, M., Laine, L., Ader, F., Becker, A., Biron, F., Boibieux, A., Cotte, L., Miailhes, P., Perpoint, T., Roux, S., Triffault‐Fillit, C., Degroodt, S., Brochier, C., Valour, F., Chidiac, C., Ménard, A., Belkhir, A.Y., Colson, P., Dhiver, C., Madrid, A., Martin‐Degioanni, M., Meddeb, L., Mokhtari, M., Motte, A., Raoux, A., Ravaux, I., Tamalet, C., Tomei, C., Tissot Dupont, H., Zaegel‐Faucher, O., Obry‐Roguet, Véronique, Laroche, H, Orticoni, M., Soavi, M.J., Geneau de Lamarlière, P, Ressiot, E, Ducassou, M.J., Jaquet, I., Galie, S., Galinier, A., Martinet, P., Landon, M., Ritleng, A.S., Ivanova, A., Debreux, C., Poizot‐Martin, I., Abel, S., Cabras, O., Cuzin, L., Guitteaud, K., Illiaquer, M., Pierre‐François, S., Osei, L., Pasquier, J., Rome, K., Sidani, E., Turmel, JM, Varache, C., Atoui, N., Bistoquet, M., Delaporte, E., Le Moing, V., Meftah, N., Merle de Boever, C., Montes, B., Montoya Ferrer, A., Tuaillon, E., Reynes, J., André, M., Boyer, L., Bouillon, MP., Delestan, M., Rabaud, C., May, T., Hoen, B., Bernaud, C., Billaud, E., Biron, C., Bonnet, B., Bouchez, S., Boutoille, D., Brunet‐Cartier, C., Deschanvres, C., Hall, N., Morineau, P., Reliquet, V., Sécher, S., Cavellec, M., Soria, A., Paredes, E., Ferre, V., André‐Garnier, E., Rodallec, A., Lefebvre, M., Grossi, O., Aubry, O., Raffi, F., Breaud, S., Ceppi, C., Chirio, D., Cua, E., Dellamonica, P., Demonchy, E., De Monte, A., Durant, J., Etienne, C., Ferrando, S., Garraffo, R., Michelangeli, C., Mondain, V., Naqvi, A., Oran, N., Perbost, I., Pillet, S., Pradier, C., Prouvost‐Keller, B., Risso, K., Rio, V., Roger, PM., Rosenthal, E., Sausse, S., Touitou, I., Wehrlen‐Pugliese, S., Zouzou, G., Hocqueloux, L., Prazuck, T., Gubavu, C., Sève, A., Maka, A., Boulard, C., Thomas, G., Lerolle, N., Landman, R., Joly, V., Ghosn, J., Rioux, C., Lariven, S., Gervais, A., Lescure, F.X., Matheron, S., Louni, F., Julia, Z., Mackoumbou‐Nkouka, C., Le Gac, S., Charpentier, C., Descamps, D., Peytavin, G., Yazdanpanah, Y., Amazzough, K., Benabdelmoumen, G., Bossi, P., Cessot, G., Charlier, C., Consigny, P.H., Danion, F., Dureault, A., Goesch, J., Guery, R., Henry, B., Jidar, K., Lanternier, F., Loubet, P., Lortholary, O., Louisin, C., Lourenco, J., Parize, P., Pilmis, B., Touam, F, Valantin, M.A., Tubiana, R., Agher, R, Seang, S., Schneider, L., Blanc, C., Katlama, C., Berger, J.L., N'guyen, Y., Lambert, D., Kmiec, I., Hentzien, M., Brunet, A., Brodard, V., Bani‐Sadr, Firouze, Tattevin, P., Revest, M., Souala, F., Baldeyrou, M., Patrat‐Delon, S., Chapplain, J.M., Bénézit, F., Dupont, M., Poinot, M., Maillard, A., Pronier, C., Lemaitre, F., Guennoun, C., Poisson‐Vanier, M., Jovelin, T., Sinteff, J.P., Arvieux, C., Botelho‐Nevers, E., Gagneux‐Brunon, A., Frésard, Anne, Ronat, V., Lucht, F., Fischer, P., Partisani, M., Cheneau, C., Priester, M, Batard, ML, Bernard‐Henry, C, de Mautort, E, Fafi‐Kremer, S., Alvarez, M., Biezunski, N., Debard, A., Delpierre, C., Lansalot, P., Lelievre, L., Martin‐Blondel, G., Piffaut, M., Porte, L., Saune, K., Ajana, F., Aïssi, E., Alcaraz, I., Baclet, V., Bocket, L., Boucher, A., Choisy, P., Lafon‐Desmurs, B., Meybeck, A., Pradier, M., Robineau, O., Viget, N., Valette, M., Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Centre d'infectiologie Necker-Pasteur [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Tourcoing, Département des Maladies Infectieuses et Tropicales [CHU Gabriel-Montpied, Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], Pathogénie des Staphylocoques – Staphylococcal Pathogenesis, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Services des maladies infectieuses [CH Turcoing], Centre Hospitalier de Tourcoing, Service de maladies infectieuses et tropicales [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Reims (CHU Reims), Alliance for International medical Action (ALIMA), Service de Maladies Infectieuses et Tropicales [Fort-de-France, Martinique], CHU de la Martinique [Fort de France]-Hôpital Pierre Zobda-Quitman [CHU de la Martinique], CHU de la Martinique [Fort de France]-Centre Hospitalier Universitaire de Martinique [Fort-de-France, Martinique], Service de Maladies Infectieuses [Nice], Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pointe-à-Pitre/Abymes [Guadeloupe], service de maladies infectieuses CHU J Minjoz Besancon, Hôpital Jean Minjoz, Service d'Immuno-hématologie clinique [Hôpital Sainte Marguerite - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Universtié Yaoundé 1 [Cameroun]-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Laboratoire d'Ingénierie Circulation Transport (LICIT), Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-École Nationale des Travaux Publics de l'État (ENTPE)-Université de Lyon, Laboratoire Chrono-environnement - CNRS - UFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Universitaire de Besançon (CHU Besançon), Université libre de Bruxelles (ULB), Hôpital Gabriel Montpied, Service des Maladies Infectieuses et Tropicales, Centre Hospitalier Universitaire de Clermont-Ferrand, Laboratoire Microorganismes : Génome et Environnement - Clermont Auvergne (LMGE), Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), CHU Gabriel Montpied (CHU), CHU Clermont-Ferrand, CCLIN Sud-Est – Centre de Coordination de la Lutte contre les Infections Nosocomiales Sud-Est, Montpellier Research in Management (MRM), Université Montpellier 1 (UM1)-Université Paul-Valéry - Montpellier 3 (UPVM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Perpignan Via Domitia (UPVD)-Groupe Sup de Co Montpellier (GSCM) - Montpellier Business School-Université de Montpellier (UM), Laboratoire Traitement et Communication de l'Information (LTCI), Télécom ParisTech-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS), Pathologies Pulmonaires et Plasticité Cellulaire - UMR-S 1250 (P3CELL), Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hosp Civils Lyon, Serv Malad Infect, Lyon, France, Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Equipe 15, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon], Service de Maladies Infectieuses et Tropicales [Hôpital de la Croix-Rousse - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Institut Hospitalier Universitaire Méditerranée Infection (IHU AMU), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie, plasticité tissulaire et métabolisme énergétique (NPTME), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), CECIL, Space Research Institute of the Russian Academy of Sciences (IKI), Russian Academy of Sciences [Moscow] (RAS), Système membranaires, photobiologie, stress et détoxication (SMPSD), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre IRD de Montpellier (IRD), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre d'études et de recherche sur les services de santé et la qualité de vie (CEReSS), Aix Marseille Université (AMU), Service des Maladies Infectieuses et Tropicales [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Bell Labs (BELL), Lucent Technologies, Service des maladies infectieuses et tropicales, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Saint-Jacques, Centre hospitalier universitaire de Nantes (CHU Nantes), Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Service des maladies infectieuses et tropicales [CHU Nantes], Plant Biomechanics Group, Botanischer Garten, Albert-Ludwigs-Universität Freiburg, Service de virologie [CHU Nantes], Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service des maladies infectieuses, Centre Hospitalier Universitaire de Nice (CHU Nice)-University Hospital, CHU Nice [Cimiez], Hôpital Cimiez [Nice] (CHU), Centre Hospitalier Universitaire de Nice (CHU Nice), Hopital l'Archet, Centre d'Information et de Soins de I'Immunodéficience Humaine (CISIH). Hôpital l'Archet 1, Hôpital l'Archet, Public Health Department, Hôpital de l'Archet, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse, Infectious Diseases Department, Université Montpellier 1 (UM1), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre Régional de recherche et de Formation à la prise en charge Clinique de Fann (CRCF), CHNU Fann, Registre EPIMAD, CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Amiens-Picardie-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre d'Etudes Lasers Intenses et Applications (CELIA), Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Bordeaux (UB), Pharmacie de l'Hôpital Bichat, UMR CNRS 8179, Université de Lille, Sciences et Technologies-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Service de rhumatologie [Strasbourg], CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Pathogénie des infections systémiques (UMR_S 570), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service des maladies infectieuses [CHU Pitié-Salêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Service des maladies infectieuses et tropicales [CHU Pitié-Salpêtrière], Laboratoire d'aérologie (LA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Centre National d'Études Spatiales [Toulouse] (CNES)-Météo France-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Météo France-Centre National de la Recherche Scientifique (CNRS), McGill University = Université McGill [Montréal, Canada], Service des maladies infectieuses et réanimation médicale, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), Service de pneumologie, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], CHU Pontchaillou [Rennes], SEV, Groupe d'Etudes et de Contrôle des Variétés et des Semences (GEVES), Service de virologie [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), University Hospital and University Jean Monnet, 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), 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), Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), 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-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Virologie et pathogenèse virale (VPV), Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP), Centre Hospitalier Gustave Dron [Tourcoing], Infection à VIH, réservoirs, diversité génétique et résistance aux antirétroviraux (ARV) (EA 7327), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Département d'Hématologie Clinique [CHU Nantes] (Hôtel-Dieu), Hôtel-Dieu de Nantes-Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Martinique [Fort-de-France, Martinique], Maladies infectieuses et tropicales dans la Caraïbe (MAITC EA 4537), CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de la Martinique [Fort de France]-Université des Antilles (UA), Centre d'Investigation Clinique Antilles-Guyane (CIC - Antilles Guyane), Université des Antilles et de la Guyane (UAG)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre de Physiopathologie Toulouse Purpan (CPTP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Maladies infectieuses et tropicales [CHU Toulouse], Pôle Inflammation, infection, immunologie et loco-moteur [CHU Toulouse] (Pôle I3LM Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Dermatologie et Maladies infectieuses [Pointe-à-Pitre], CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Centre de Gestion du Risque Infectieux Nosocomial [Pointe-à-Pitre] (CGRIN), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Infectious and Tropical Diseases Department [Montpellier], Institut de Recherche pour le Développement (IRD)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dat'AIDS study group: C Drobacheff-Thiébaut, A Foltzer, K Bouiller, C Chirouze, Q Lepiller, F Bozon, O Babre, A S Brunel, P Muret, H Laurichesse, O Lesens, M Vidal, N Mrozek, C Aumeran, O Baud, V Corbin, P Letertre-Gibert, S Casanova, J Prouteau, I Fabre, E Curlier, R Ouissa, C Herrmann-Storck, B Tressieres, T Bonijoly, M C Receveur, F Boulard, C Daniel, C Clavel, D Merrien, P Perré, T Guimard, O Bollangier, S Leautez, M Morrier, L Laine, F Ader, A Becker, F Biron, A Boibieux, L Cotte, P Miailhes, T Perpoint, S Roux, C Triffault-Fillit, S Degroodt, C Brochier, F Valour, C Chidiac, A Ménard, A Y Belkhir, P Colson, C Dhiver, A Madrid, M Martin-Degioanni, L Meddeb, M Mokhtari, A Motte, A Raoux, I Ravaux, C Tamalet, C Toméi, H Tissot Dupont, O Zaegel-Faucher, H Laroche, M Orticoni, M J Soavi, P Geneau de Lamarlière, E Ressiot, M J Ducassou, I Jaquet, S Galie, A Galinier, P Martinet, M Landon, A S Ritleng, A Ivanova, C Debreux, S Abel, O Cabras, L Cuzin, K Guitteaud, M Illiaquer, S Pierre-François, L Osei, J Pasquier, K Rome, E Sidani, J M Turmel, C Varache, N Atoui, M Bistoquet, E Delaporte, V Le Moing, N Meftah, C Merle de Boever, B Montes, A Montoya Ferrer, E Tuaillon, J Reynes, M André, L Boyer, M P Bouillon, M Delestan, C Rabaud, T May, B Hoen, C Bernaud, E Billaud, C Biron, B Bonnet, S Bouchez, D Boutoille, C Brunet-Cartier, C Deschanvres, N Hall, T Jovelin, P Morineau, V Reliquet, S Sécher, M Cavellec, A Soria, E Paredes, V Ferré, E André-Garnier, A Rodallec, M Lefebvre, O Grossi, O Aubry, F Raffi, S Breaud, C Ceppi, D Chirio, E Cua, P Dellamonica, E Demonchy, A De Monte, J Durant, C Etienne, S Ferrando, R Garraffo, C Michelangeli, V Mondain, A Naqvi, N Oran, I Perbost, S Pillet, C Pradier, B Prouvost-Keller, K Risso, V Rio, P M Roger, E Rosenthal, S Sausse, I Touitou, S Wehrlen-Pugliese, G Zouzou, L Hocqueloux, T Prazuck, C Gubavu, A Sève, A Maka, C Boulard, G Thomas, C Goujard, Y Quertainmont, E Teicher, N Lerolle, O Deradji, A Barrail-Tran, R Landman, V Joly, J Ghosn, C Rioux, S Lariven, A Gervais, F X Lescure, S Matheron, F Louni, Z Julia, C Mackoumbou-Nkouka, S Le Gac, C Charpentier, D Descamps, G Peytavin, Y Yazdanpanah, K Amazzough, G Benabdelmoumen, P Bossi, G Cessot, C Charlier, P H Consigny, F Danion, A Dureault, J Goesch, R Guery, B Henry, K Jidar, F Lanternier, P Loubet, O Lortholary, C Louisin, J Lourenco, P Parize, B Pilmis, F Touam, M A Valantin, R Tubiana, R Agher, S Seang, L Schneider, C Blanc, C Katlama, J L Berger, Y N'Guyen, D Lambert, I Kmiec, M Hentzien, A Brunet, V Brodard, P Tattevin, M Revest, F Souala, M Baldeyrou, S Patrat-Delon, J M Chapplain, F Benezit, M Dupont, M Poinot, A Maillard, C Pronier, F Lemaitre, C Guennoun, M Poisson-Vanier, T Jovelin, J P Sinteff, C Arvieux, E Botelho-Nevers, A Gagneux-Brunon, A Frésard, V Ronat, F Lucht, P Fischer, M Partisani, C Cheneau, M Priester, M L Batard, C Bernard-Henry, E de Mautort, S Fafi-Kremer, M Alvarez, N Biezunski, A Debard, C Delpierre, P Lansalot, L Lelièvre, G Martin-Blondel, M Piffaut, L Porte, K Saune, F Ajana, E Aïssi, I Alcaraz, V Baclet, L Bocket, A Boucher, P Choisy, B Lafon-Desmurs, A Meybeck, M Pradier, O Robineau, N Viget, M Valette., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Pasteur [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Pasteur [Paris], Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), 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)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Amiens-Picardie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC), 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 d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Recherches Translationnelles sur le VIH et les maladies infectieuses (TransVIHMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche pour le Développement (IRD)-Université Montpellier 1 (UM1)-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Universtié Yaoundé 1 [Cameroun]-Université de Montpellier (UM), Université Paul-Valéry - Montpellier 3 (UPVM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Perpignan Via Domitia (UPVD)-Université Montpellier 1 (UM1)-Groupe Sup de Co Montpellier (GSCM) - Montpellier Business School-Université de Montpellier (UM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Centre National d'Études Spatiales [Toulouse] (CNES)-Météo France-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Centre National d'Études Spatiales [Toulouse] (CNES)-Météo France-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, and Dupuis, Christine
Subjects: 0301 basic medicine, Pediatrics, medicine.medical_specialty, MESH: Sarcoma, Kaposi* / epidemiology, [SDV]Life Sciences [q-bio], 030106 microbiology, HIV Infections, Dermatology, Skin Infectiology, Venereology and Sexual Health, 03 medical and health sciences, 0302 clinical medicine, Acquired immunodeficiency syndrome (AIDS), medicine, Humans, MESH: HIV Infections* / complications, 030212 general & internal medicine, Sarcoma, Kaposi, Retrospective Studies, Response rate (survey), MESH: Acquired Immunodeficiency Syndrome, MESH: Herpesvirus 8, Human, Acquired Immunodeficiency Syndrome, MESH: Humans, business.industry, Kaposi sarcoma, HIV, Retrospective cohort study, MESH: Retrospective Studies, MESH: HIV Infections* / drug therapy, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], medical dermatology, Regimen, Infectious Diseases, Clinical research, clinical research, Herpesvirus 8, Human, Cohort, oncology, Original Article, Sarcoma, business, Viral load, MESH: HIV Infections* / epidemiology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Background - Although antiretroviral therapy (ART) has reduced the risk of Kaposi sarcoma (KS), KS cases still occur in HIV-infected people. Objective - To describe all KS cases observed between 2010 and 2015 in a country with high ART coverage. Methods - Retrospective study using longitudinal data from 44 642 patients in the French Dat'AIDS multicenter cohort. Patients' characteristics were described at KS diagnosis according to ART exposure and to HIV-plasma viral load (HIV-pVL) (≤50 or >50) copies/mL. Results - Among the 209 KS cases diagnosed during the study period, 33.2% occurred in ART naïve patients, 17.3% in ART-experienced patients and 49.5% in patients on ART, of whom 23% for more than 6 months. Among these patients, 24 (11.5%) had HIV-pVL ≤50 cp/mL, and 16 (66%) were treated with a boosted-PI-based regimen. The distribution of KS localization did not differ by ART status nor by year of diagnosis. Limitations - Data on human herpesvirus 8, treatment modalities for KS and response rate were not collected. Conclusion - Half of KS cases observed in the study period occurred in patients not on ART, reflecting the persistence of late HIV diagnosis. Factors associated with KS in patients on ART with HIV-pVL ≤50 cp/mL remain to be explored.
Published: 2020

225. The HSP90/R2TP assembly chaperone promotes cell proliferation in the intestinal epithelium

Author: Marina Ferrand, Edouard Bertrand, Bénédicte Lemmers, Claire Abeza, Francina Langa, Conception Paul, Céline Verheggen, Valérie Pinet, Dominique Helmlinger, Bérengère Pradet-Balade, Rossano Lattanzio, Ciro Longobardi, Michael Hahne, Philippe Jay, François Gerbe, Monica Gabola, Julie Bremond, Chloé Maurizy, Nicola Tinari, Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Ingénierie génétique murine - Mouse Genetics Engineering Center (CIGM), Institut Pasteur [Paris] (IP), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine (IGH), Università degli studi 'G. d'Annunzio' Chieti-Pescara [Chieti-Pescara] (Ud'A), Centre de recherche en Biologie cellulaire de Montpellier (CRBM), The work was supported by La Ligue Nationale Contre le Cancer (équipes labelisées to E.B., P.J.) and the INCa grants PLBIO 2016-161 to D.H., E.B., M.H., B.P.B., and PLBIO 2018-158 to P.J. C.M. and C.A. had fellowships from la Ligue Nationale Contre le Cancer., Guerineau, Nathalie C., Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut Pasteur [Paris], 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), Centre de recherche en Biologie Cellulaire (CRBM), and Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)
Subjects: Cellular differentiation, General Physics and Astronomy, MESH: Mice, Knockout, 0302 clinical medicine, Chaperones, MESH: Microscopy, Confocal, MESH: Animals, Intestinal Mucosa, Tissue homeostasis, Cells, Cultured, Mice, Knockout, 0303 health sciences, Multidisciplinary, Microscopy, Confocal, biology, Chemistry, Stem Cells, Intestinal stem cells, Intestinal epithelium, 3. Good health, Cell biology, MESH: Epithelial Cells, 030220 oncology & carcinogenesis, MESH: Intestinal Mucosa, Stem cell, MESH: Molecular Chaperones, MESH: Cells, Cultured, Protein Binding, MESH: Mice, Transgenic, Science, Mice, Transgenic, MESH: Stem Cells, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MESH: Cell Proliferation, MESH: HSP90 Heat-Shock Proteins, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Protein Binding, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, HSP90 Heat-Shock Proteins, Progenitor cell, PI3K/AKT/mTOR pathway, 030304 developmental biology, Cell Proliferation, MESH: Humans, Cell growth, Epithelial Cells, General Chemistry, Mice, Inbred C57BL, Chaperone (protein), biology.protein, Molecular Chaperones
Abstract: The R2TP chaperone cooperates with HSP90 to integrate newly synthesized proteins into multi-subunit complexes, yet its role in tissue homeostasis is unknown. Here, we generated conditional, inducible knock-out mice for Rpap3 to inactivate this core component of R2TP in the intestinal epithelium. In adult mice, Rpap3 invalidation caused destruction of the small intestinal epithelium and death within 10 days. Levels of R2TP substrates decreased, with strong effects on mTOR, ATM and ATR. Proliferative stem cells and progenitors deficient for Rpap3 failed to import RNA polymerase II into the nucleus and they induced p53, cell cycle arrest and apoptosis. Post-mitotic, differentiated cells did not display these alterations, suggesting that R2TP clients are preferentially built in actively proliferating cells. In addition, high RPAP3 levels in colorectal tumors from patients correlate with bad prognosis. Here, we show that, in the intestine, the R2TP chaperone plays essential roles in normal and tumoral proliferation., RPAP3 is a subunit of the R2TP complex, a co-chaperone of HSP90, with substrate proteins involved in transcription, ribosome biogenesis, DNA repair and cell growth. Here the authors report that deletion of Rpap3 abrogates cell proliferation and homeostasis in mouse intestine, partly through destabilization of PI3K-like kinases, while elevated RPAP3 levels in colorectal tumors are associated with poor prognosis.
Published: 2020

226. Widespread activation of developmental gene expression characterized by PRC1-dependent chromatin looping

Author: Quentin Szabo, Anne-Marie Martinez, G. L. Papadopoulos, Giacomo Cavalli, Vincent Loubiere, Institut de génétique humaine (IGH), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV]Life Sciences [q-bio], Repressor, macromolecular substances, Biology, Response Elements, 03 medical and health sciences, Mice, 0302 clinical medicine, Neural Stem Cells, Gene expression, Genetics, Animals, Genes, Developmental, Enhancer, Promoter Regions, Genetic, Gene, Psychological repression, Research Articles, 030304 developmental biology, Regulation of gene expression, Polycomb Repressive Complex 1, 0303 health sciences, Multidisciplinary, SciAdv r-articles, Gene Expression Regulation, Developmental, Cell Differentiation, Chromatin, Cell biology, Drosophila melanogaster, Enhancer Elements, Genetic, Imaginal Discs, Genetic Loci, PRC1, 030217 neurology & neurosurgery, Research Article, Protein Binding
Abstract: Polycomb repressive complex 1 shapes 3D loops associated with transcription of key developmental genes., Polycomb repressive complexes 1 and 2 have been historically described as transcriptional repressors, but recent reports suggest that PRC1 might also support activation, although the underlying mechanisms remain elusive. Here, we show that stage-specific PRC1 binding at a subset of active promoters and enhancers during Drosophila development coincides with the formation of three-dimensional (3D) loops, an increase in expression during development and repression in PRC1 mutants. Dissection of the dachshund locus indicates that PRC1-anchored loops are versatile architectural platforms that persist when surrounding genes are transcriptionally active and fine-tune their expression. The analysis of RING1B binding profiles and 3D contacts during neural differentiation in mice suggests that this role is conserved in mammals.
Published: 2020

227. In cases of familial primary ovarian insufficiency and disorders of gonadal development, consider NR5A1/SF-1 sequence variants

Author: Sylvie Manouvrier-Hanu, Maryse Cartigny, Pascal Philibert, Juliette Bertrand-Delepine, Yves Morel, Didier Dewailly, Delphine Mallet, Sophie Catteau-Jonard, Françoise Paris, Christine Lefevre, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Jeanne de Flandre [Lille], and Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC))
Subjects: Adult, Male, 0301 basic medicine, NR5A1/SF-1 sequence variant, endocrine system, Genetic counseling, Disorders of Sex Development, Primary ovarian insufficiency, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Steroidogenic Factor 1, Bioinformatics, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Adrenal insufficiency, medicine, Humans, Genetic Predisposition to Disease, Gene, Sequence (medicine), Hypospadias, 030219 obstetrics & reproductive medicine, business.industry, Obstetrics and Gynecology, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, medicine.disease, Phenotype, Pedigree, 3. Good health, 030104 developmental biology, Reproductive Medicine, Disorders of gonadal development, Mutation, Female, Development of the gonads, business, Developmental Biology, Hormone
Abstract: International audience; Research question: Primary ovarian insufficiency (POI) is defined as the early exhaustion of ovarian function, before the age of 40 years. Its origin is genetic in 20-25% of cases. In rare cases, sequence variants of the NR5A1/SF-1 gene may result in POI, or in various disorders of gonadal development (DGD) or adrenal insufficiency.Design: This study describes the cases of two families in which the association of DGD and POI enabled a diagnosis of NR5A1 deleterious variations. Their clinical, hormonal, ultrasound and genetic characteristics are reported.Results: The mothers of the affected children were 21 and 29 years when POI was diagnosed. Each nonetheless had two spontaneous pregnancies. The children have different phenotypes and different forms of DGD. None of the affected family members had adrenal insufficiency. A new sequence variant of the NR5A1 gene was identified in one family: p.Cys283Phe (c.848G>T), and the NR5A1 sequence variant c.86G>C was found in the other family.Conclusion: Sequence variation of the NR5A1 gene is a possibility that must be considered when a woman with POI or a diminished ovarian reserve has a family member or child with DGD. If a variant is identified, genetic counselling is essential for the patient and his/her family.
Published: 2020

228. Identification and characterization of base-substitution mutations in the macronuclear genome of the ciliate Tetrahymena thermophila

Author: Kazufumi Mochizuki, Lu Fu, Guangying Wang, Wei Miao, Jie Xiong, Yunxin Fu, Institute of Hydrobiology [Wuhan], Chinese Academy of Sciences [Beijing] (CAS), University of Chinese Academy of Sciences [Beijing] (UCAS), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and The University of Texas Health Science Center at Houston (UTHealth)
Subjects: AcademicSubjects/SCI01140, Genome evolution, MassARRAY, genome evolution, medicine.disease_cause, Genome, [SDV.MP.PRO]Life Sciences [q-bio]/Microbiology and Parasitology/Protistology, Tetrahymena thermophila, Evolution, Molecular, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Polyploid, Macronucleus, Genetics, medicine, somatic mutation, Ciliophora, Ecology, Evolution, Behavior and Systematics, polyploidy, 030304 developmental biology, 0303 health sciences, Mutation, ciliated protozoa, biology, Tetrahymena, AcademicSubjects/SCI01130, biology.organism_classification, Adaptation, Genome, Protozoan, 030217 neurology & neurosurgery, Research Article
Abstract: Polyploidy can provide adaptive advantages and drive evolution. Amitotic division of the polyploid macronucleus (MAC) in ciliates acts as a nonsexual genetic mechanism to enhance adaptation to stress conditions and thus provides a unique model to investigate the evolutionary role of polyploidy. Mutation is the primary source of the variation responsible for evolution and adaptation; however, to date, de novo mutations that occur in ciliate MAC genomes during these processes have not been characterized and their biological impacts are undefined. Here, we carried out long-term evolution experiments to directly explore de novo MAC mutations and their molecular features in the model ciliate, Tetrahymena thermophila. A simple but effective method was established to detect base-substitution mutations in evolving populations whereas filtering out most of the false positive base-substitutions caused by repetitive sequences and the programmed genome rearrangements. The detected mutations were rigorously validated using the MassARRAY system. Validated mutations showed a strong G/C→A/T bias, consistent with observations in other species. Moreover, a progressive increase in growth rate of the evolving populations suggested that some of these mutations might be responsible for cell fitness. The established mutation identification and validation methods will be an invaluable resource to make ciliates an important model system to study the role of polyploidy in evolution.
Published: 2020

229. Genomic databases

Author: Hutchins, James R. A., Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Diego Forero, George Patrinos
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, 03 medical and health sciences, ComputingMethodologies_PATTERNRECOGNITION, 0302 clinical medicine, [SDV]Life Sciences [q-bio], [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: International audience; Genomic sequence data are revolutionizing biology, enabling genome-wide investigations into gene function and expression, and genomic organization. Use of human genomic data is expected to have huge impacts on pathology and the development of personalized therapies. Genome reference sequences for thousands of organisms are freely available from Internet-based genomic databases. Sequence data can be directly downloaded or searched via genome browsers, user-friendly software generating interactive graphical outputs of relevant chromosomal regions with rich annotations, including genes, epigenetic data, and sequence variants. This chapter provides an overview of the major genomic databases and genome browsers, describing various approaches for searching them, including using identifiers for genes and molecules, karyotype bands, chromosomal coordinates, sequences, and motifs. Software approaches for performing more complex genomic searches are described. Emphasis is placed on the human genome, including how information relating to genome plasticity, such as sequence and structural variants, can be visualized and retrieved.
Published: 2020

230. SAMHD1 acts at stalled replication forks to prevent interferon induction

Author: Yea-Lih Lin, Vincenzo Costanzo, Karina Zadorozhny, Anne-Lyne Schmitz, Flavie Coquel, Alexandra Cribier, Maria Joao Silva, Philippe Pasero, Bernard S. Lopez, Hervé Técher, Clément Mettling, Amélie Sarrazin, Antoine Barthe, Andrei Chabes, Elodie Dardillac, Jadwiga Nieminuszczy, Monsef Benkirane, Alexy Promonet, L. Krejci, Wojciech Niedzwiedz, Sushma Sharma, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Intégrité du génome et cancers (IGC), Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), BioCampus Montpellier (BCM), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Institut de théorie des phénomènes physiques (EPFL), and Ecole Polytechnique Fédérale de Lausanne (EPFL)
Subjects: 0106 biological sciences, 0301 basic medicine, [SDV]Life Sciences [q-bio], Cell- och molekylärbiologi, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 01 natural sciences, Molecular biology, 3. Good health, 03 medical and health sciences, 030104 developmental biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Cell and Molecular Biology, 010606 plant biology & botany
Abstract: International audience; DNA replication is an extremely complex process, involving thousands of replication forks progressing along chromosomes. These forks are requently slowed down or stopped by various obstacles, such as secondary DNA structures, chromatin-acting proteins or a lack of nucleotides. Thisslowing down, known as replicative stress, plays a central role in tumour development. Complex processes, which are not yet fully understood, are set up to respond to this stress. Certain nucleases, such as MRE11 and DNA2, degrade the neo-replicated DNA at the level of blocked forks, allowing the replication to restart. The interferon pathway is a defense mechanism against pathogens that detects the presence of foreign nucleic acids in the cytoplasm and activates the innate immune response. DNA fragments resulting from genomic DNA metabolism (repair, retrotransposition) can diffuse into the cytoplasm and activate this pathway. A pathological manifestation of this process is the Aicardi-Goutières syndrome, a rare disease characterized by chronic inflammation leading to neurodegenerative and developmental problems. In this encephalopathy, it has been suggested that DNA replication may generate cytosolic DNA fragments, but the mechanisms involved have not beencharacterized. SAMHD1 is frequently mutated in the Aicardi-Goutières syndrome as well as in some cancers, but its role in the etiology of these diseases was largely unknown. We show that cytosolic DNA accumulates in SAMHD1-deficient cells, particularly in the presence of replicative stress, activating the interferon response. SAMHD1 is important for DNA replication under normal conditions and for the processing of stopped forks, independent of its dNTPase activity. In addition, SAMHD1 stimulates the exonuclease activity of MRE11 in vitro. When SAMHD1 is absent, degradation of neosynthesized DNA is inhibited, which prevents activation of the replication checkpoint and leads to failure to restart the replication forks. Resection of the replication forks is performed by an alternative mechanism which releases DNA fragments into the cytosol, activating the interferon response. The results obtained show, for the first time, a direct link between the response to replication stress and the production of interferons. These results have important implications for our understanding of the Aicardi-Goutières syndrome and cancers related to SAMHD1. For example, we have shown that MRE11 and RECQ1 are responsible for the production of DNA fragments that trigger the inflammatory response in cells deficient for SAMHD1. We can therefore imagine that blocking the activity of these enzymes could decrease the production of DNA fragments and, ultimately, the activation of innate immunity in these cells. In addition, the interferon pathway plays an essential role in the therapeutic efficacy of irradiation and certain chemotherapeutic agents such as oxaliplatin. Modulating this response could therefore be of much wider interest in anti-tumour therapy; La réplication de l’ADN est un processus extrêmement complexe, impliquant des milliers de fourches de réplication progressant le long des chromosomes. Ces fourches sont fréquemment ralenties ou arrêtées par différents obstacles, tels que des structures secondaires de l’ADN, des protéines agissant sur la chromatine ou encore un manque de nucléotides. Ce ralentissement, qualifié de stress réplicatif, joue un rôle central dans le développement tumoral. Des processus complexes, qui ne sont pas encore totalement connus, sont mis en place pour répondre à ce stress. Certaines nucléases, comme MRE11 et DNA2, dégradent l’ADN néorépliqué au niveau des fourches bloquées, ce qui permet le redémarrage des réplisomes. La voie interféron est un mécanisme de défense contre les agents pathogènes qui détecte la présence d’acides nucléiques étrangers dans le cytoplasme et active la réponse immunitaire innée. Des fragments d’ADN issus du métabolisme de l’ADN génomique (réparation, rétrotransposition) peuvent diffuser dans le cytoplasme et activer cette voie. Une manifestation pathologique de ce processus est le syndrome d’Aicardi-Goutières, une maladie rare caractérisée par une inflammation chronique générant des problèmes neurodégénératifs et développementaux. Dans le cadre de cette encéphalopathie, il a été suggéré que la réplication de l’ADN pouvait générer des fragments d’ADN cytosoliques, mais les mécanismes impliqués n’avaient pas été caractérisés. SAMHD1 est fréquemment muté dans le syndrome d’Aicardi-Goutières ainsi que dans certains cancers, mais son rôle dans l’étiologie de ces maladies était jusqu’à présent largement inconnu. Nous montrons que de l’ADN cytosolique s’accumule dans les cellules déficientes pour SAMHD1, particulièrement en présence de stress réplicatif, activant la réponse interféron. Par ailleurs, SAMHD1 est important pour la réplication de l’ADN en conditions normales et pour le processing des fourches arrêtées, indépendamment de son activité dNTPase. De plus, SAMHD1 stimule l’activité exonucléase de MRE11 in vitro. Lorsque SAMHD1 est absent, la dégradation de l’ADN néosynthétisé est inhibée, ce qui empêche l’activation du checkpoint de réplication et entraine un défaut de redémarrage des fourches de réplication. De plus, la résection des fourches de réplication est réalisée par un mécanisme alternatif qui libère des fragments d’ADN dans le cytosol, activant la réponse interféron. Les résultats obtenus montrent, pour la première fois, un lien direct entre la réponse au stress réplicatif et la production d’interférons. Ces résultats ont des conséquences importantes dans notre compréhension du syndrome d’Aicardi Goutières et des cancers liés à SAMHD1. Par exemple, nous avons démontré que MRE11 et RECQ1 sont responsables de la production des fragments d’ADN qui déclenchent la réponse inflammatoire dans les cellules déficientes pour SAMHD1. Nous pouvons donc imaginer que bloquer l’activité de ces enzymes pourrait diminuer la production des fragments d’ADN et, in fine, l’activation de l’immunité innée dans ces cellules. Par ailleurs, la voie interférons joue un rôle essentiel dans l’efficacité thérapeutique de l’irradiation et de certains agents chimiothérapiques comme l’oxaliplatine. Moduler cette réponse pourrait donc avoir un intérêt beaucoup plus large en thérapie anti-tumorale
Published: 2020

231. Non-invasive immunological exploration of the premature newborn infant

Author: Sereme, Y., Michel, M., Mezouar, S., Pinchemel, S., Chartier, C., Blanchard, P., Tran, T. A., Corbeau, P., Filleron, A., Vitte, J., Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Laboratoire d'Ingénierie des Matériaux de Bretagne (LIMATB), Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université de Brest (UBO), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: [SDV]Life Sciences [q-bio], education, social sciences, health care economics and organizations
Abstract: European-Academy-of-Allergology-and-Clinical-Immunology Digital Congress (EAACI), London, ENGLAND, JUN 06-08, 2020
Published: 2020

232. Lysyl-tRNA synthetase produces diadenosine tetraphosphate to curb STING-dependent inflammation

Author: Barbara Nawrot, Renata Kaczmarek, Andrew S. Marriott, Armel Houel, Sophia Kossida, A. L. Valadao, Nadine Laguette, K. Polak, Christelle Langevin, Dimitrios Vlachakis, Nigel J. Jones, Baptiste Auzemery, Isabelle K. Vila, Pierre Boudinot, Clara Taffoni, Thaneas Prabakaran, Stéphanie Déjardin, Jessica Guerra, Søren R. Paludan, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Genetics, Agricultural University of Athens, Laboratory of Genetics, Department of Biomedicine, Aarhus University [Aarhus], Edge Hill University, Department of Bioorganic Chemistry Centre of Molecular and Macromolecular Studies Polish Academy of Sciences, Polish Academy of Sciences (PAN), Virologie et Immunologie Moléculaires (VIM (UR 0892)), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Biochemistry, University of Liverpool, ANRS French National Research Agency (ANR) 109560, Fondation ARC pour la Recherche sur le Cancer PJA20141201605, Merck Sharp and Dohme Avenir (M.S.D.-GnoSTic), M.S.D., Prix Roger PROPICE pour la recherche sur le cancer du pancreas of the Fondation pour la Recherche Medicale (FRM), SIRIC Montpellier Cancer Grant INCa_Inserm_DGOS_12553, Research Development Fund grant from North West Cancer Research (UK), Novo Nordisk Foundation NNF18OC0030274, Lundbeckfonden R198-2015-171 R268-2016-3927, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, CR863 CR968, European Project: 637763,H2020,ERC-2014-STG,CrIC(2015), European Project: 786602,ENVISION, Genetics Laboratory [Agricultural University of Athens], and Agricultural University of Athens
Subjects: [SDV]Life Sciences [q-bio], Inflammation, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, In vivo, medicine, Health and Medicine, Research Articles, Cancer, 030304 developmental biology, 0303 health sciences, Multidisciplinary, SciAdv r-articles, RNA, biochemical phenomena, metabolism, and nutrition, In vitro, eye diseases, 3. Good health, Cell biology, Sting, chemistry, 030220 oncology & carcinogenesis, Stimulator of interferon genes, bacteria, medicine.symptom, Ap4A, DNA, Research Article
Abstract: The LysRS-Ap4A axis impairs cGAS-STING pathway activation, delaying nucleic acid-driven innate immune responses., Inflammation is an essential part of immunity against pathogens and tumors but can promote disease if not tightly regulated. Self and non-self-nucleic acids can trigger inflammation, through recognition by the cyclic GMP-AMP (cGAMP) synthetase (cGAS) and subsequent activation of the stimulator of interferon genes (STING) protein. Here, we show that RNA:DNA hybrids can be detected by cGAS and that the Lysyl-tRNA synthetase (LysRS) inhibits STING activation through two complementary mechanisms. First, LysRS interacts with RNA:DNA hybrids, delaying recognition by cGAS and impeding cGAMP production. Second, RNA:DNA hybrids stimulate LysRS-dependent production of diadenosine tetraphosphate (Ap4A) that in turn attenuates STING-dependent signaling. We propose a model whereby these mechanisms cooperate to buffer STING activation. Consequently, modulation of the LysRS-Ap4A axis in vitro or in vivo interferes with inflammatory responses. Thus, altogether, we establish LysRS and Ap4A as pharmacological targets to control STING signaling and treat inflammatory diseases.
Published: 2020

233. Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites

Author: Zellweger, Ralph, Chauvin, Maëva, Bec, Nicole, Larroque, Christian, Lopes, Massimo, Basbous, Jihane, Aze, Antoine, CHALOIN, Laurent, Lebdy, Rana, Hodroj, Dana, Ribeyre, Cyril, Larroque, Marion, Shepard, Caitlin, Kim, Baek, Pruvost, Alain, Moreaux, Jérôme, Maiorano, Domenico, Méchali, Marcel, Constantinou, Angelos, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Cancer de Montpellier (ICM), Emory University School of Medicine, Emory University [Atlanta, GA], 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), Ribeyre, Cyril, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Infections rétrovirales et signalisation cellulaire (IRSC), Université Montpellier 1 (UM1)-Centre National de la Recherche Scientifique (CNRS), Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 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), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: DNA Replication, endocrine system, Transcription, Genetic, Xenopus, Antineoplastic Agents, DNA polymerase eta, Genome Integrity, Repair and Replication, law.invention, Amidohydrolases, Xenopus laevis, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Plasmid, Downregulation and upregulation, law, Transcription (biology), Neoplasms, Genetics, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, Dihydrothymine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cytotoxicity, Uracil, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, biology, DNA replication, biology.organism_classification, 3. Good health, Cell Transformation, Neoplastic, chemistry, Biochemistry, 030220 oncology & carcinogenesis, Dihydropyrimidinase, Cancer cell, Recombinant DNA, DNA
Abstract: Metabolic alterations support cellular transformation. Noticeably, cellular transformation and cancer progression is associated with accumulation of dihydrouracil and dihydrothymine. However, it remains elusive how dihydropyrimidine metabolites affect cellular phenotypes. Dihydropyrimidines are degraded by dihydropyrimidinase (DHP). This zinc metalloenzyme is upregulated in solid tumors but not in the corresponding normal tissues. Here we show that DHP silencing in transformed cell lines is cytotoxic. Increasing the level of dihydropyrimidines inhibited DNA replication and transcription. It induced replication stress signaling by ATR and p53 stabilization. Remarkably, cells lacking DHP accumulated DNA-protein crosslinks (DPCs). Among DPCs, covalently trapped translesion DNA polymerase eta contributed to the cytotoxicity of dihydropyrimidines. Furthermore, we show that the plant flavonoid dihydromyricetin inhibits the activity of recombinant human DHP. Cellular treatment with dihydromyricetin triggered DPCs-dependent DNA replication stress. This study defines dihydropyrimidines as potentially cytotoxic metabolites that may offer an opportunity for therapeutic-targeting of DHP activity in solid tumors.
Published: 2020

234. Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial

Author: Raul Juntas-Morales, Marius Mickunas, Massimo Locati, Timothy Tree, Nicolas Pageot, John De Vos, Jean-Luc Veyrune, P. Nigel Leigh, William Camu, Ulf Andreasson, Christine Payan, Janine Kirby, Pamela J. Shaw, Ammar Al-Chalabi, Christophe Masseguin, Safa Saker, Carey M. Suehs, Cecilia Garlanda, Henrik Zetterberg, Andrea Malaspina, Gilbert Bensimon, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Immunobiology, King‘s College London, Département d'hématologie biologique[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, BESPIM, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service de pharmacologie médicale [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), Humanitas University [Milan] (Hunimed), University of Milan, Barts & The London School of Medicine and Dentistry, University of Gothenburg (GU), Department of Neuroscience, Academic Neurology Unit, University of Sheffield, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Généthon, Dementia Research Centre [London] (DRC), University College of London [London] (UCL), Institute of Psychiatry, Psychology & Neuroscience, King's College London, Brighton and Sussex Medical School (BSMS), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service de Pharmacologie médicale [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), Università degli Studi di Milano = University of Milan (UNIMI), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Gestionnaire, HAL Sorbonne Université 5
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Placebo-controlled study, Antineoplastic Agents, Placebo, T-Lymphocytes, Regulatory, General Biochemistry, Genetics and Molecular Biology, Randomised clinical trial, Immunophenotyping, Double blind, 03 medical and health sciences, 0302 clinical medicine, Aldesleukin, T-Lymphocyte Subsets, Internal medicine, Medicine, Humans, Amyotrophic lateral sclerosis, Adverse effect, Aged, Aged, 80 and over, business.industry, Low dose, Amyotrophic Lateral Sclerosis, Low dose interleukin-2, General Medicine, Regulatory T cells, Middle Aged, medicine.disease, Recombinant Proteins, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Treatment Outcome, Neuro-inflammation, 030220 oncology & carcinogenesis, Pharmacodynamics, Cytokines, Interleukin-2, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Chemokines, business, Biomarkers, Research Paper
Abstract: Background\ud \ud Low-dose interleukin-2 (ld-IL-2) enhances regulatory T-cell (Treg) function in auto-inflammatory conditions. Neuroinflammation being a pathogenic feature of amyotrophic lateral sclerosis (ALS), we evaluated the pharmacodynamics and safety of ld-IL-2 in ALS subjects.\ud \ud \ud Methods\ud \ud We performed a single centre, parallel three-arm, randomised, double-blind, placebo-controlled study. Eligibility criteria included age < 75 years, disease duration < 5 years, riluzole treatment > 3 months, and a slow vital capacity ≥ 70% of normal. Patients were randomised (1:1:1) to aldesleukin 2 MIU, 1 MIU, or placebo once daily for 5 days every 4 weeks for 3 cycles. Primary outcome was change from baseline in Treg percentage of CD4+ T cells (%Tregs) following a first cycle. Secondary laboratory outcomes included: %Treg and Treg number following repeated cycles, and plasma CCL2 and neurofilament light chain protein (NFL) concentrations as surrogate markers of efficacy. Safety outcomes included motor-function (ALSFRS-R), slow vital capacity (SVC), and adverse event reports. This trial is registered with ClinicalTrials.gov, NCT02059759.\ud \ud \ud Findings\ud \ud All randomised patients (12 per group), recruited from October 2015 to December 2015, were alive at the end of follow-up and included in the intent-to-treat (ITT) analysis. No drug-related serious adverse event was observed. Non-serious adverse events occurred more frequently with the 1 and 2 MIU IL-2 doses compared to placebo, including injection site reactions and flu-like symptoms. Primary outcome analysis showed a significant increase (p < 0·0001) in %Tregs in the 2 MIU and 1 MIU arms (mean [SD]: 2 MIU: +6·2% [2·2]; 1 MIU: +3·9% [1·2]) as compared to placebo (mean [SD]: -0·49% [1·3]). Effect sizes (ES) were large in treated groups: 2 MIU ES=3·7 (IC95%: 2·3–4·9) and 1 MIU ES=3·5 (IC95%: 2·1–4·6). Secondary outcomes showed a significant increase in %Tregs following repeated cycles (p < 0·0001) as compared to placebo, and a dose-dependent decrease in plasma CCL2 (p = 0·0049). There were no significant differences amongst the three groups on plasma NFL levels.\ud \ud \ud Interpretation\ud \ud Ld-IL-2 is well tolerated and immunologically effective in subjects with ALS. These results warrant further investigation into their eventual therapeutic impact on slowing ALS disease progression.\ud \ud \ud Funding\ud \ud : The French Health Ministry (PHRC-I-14-056), EU H2020 (grant #633413), and the Association pour la Recherche sur la SLA (ARSLA).
Published: 2020
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235. FHL1 is a key player of chikungunya virus tropism and pathogenesis

Author: Beate M. Kümmerer, Laura Pezzi, Mohamed Lamine Hafirassou, Lucie Gueneau, Constance Delaugerre, Gisèle Bonne, Thibaud Goupil, Vasiliya Kril, Monsef Benkirane, Julien Burlaud-Gaillard, Lucie Bonnet-Madin, R. Juntas-Morales, Anne Bertrand Legout, Thérèse Couderc, Laurent Meertens, Etienne Simon-Loriere, Philippe Roingeard, Ali Amara, Marc Lecuit, Rabah Ben Yaou, Sophia Rafasse, Alexis Brugier, Xavier de Lamballerie, Pierre-Olivier Vidalain, Cécile Doyen, Athena Labeau, Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Biologie des Infections - Biology of Infection, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Bonn = University of Bonn, Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Institut Pasteur [Paris] (IP), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Modélisation et Immunologie pour la Thérapie (CBMIT), Université Paris Descartes - Paris 5 (UPD5), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Service des Maladies infectieuses et tropicales [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (UMR_S_944)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Bonn, Institut Pasteur [Paris], Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), DIAKITE, andrée, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), and Centre de Recherche en Myologie
Subjects: 0106 biological sciences, 0301 basic medicine, viruses, [SDV]Life Sciences [q-bio], Muscle Proteins, Pathogenesis, MESH: Chikungunya Fever, Viral Nonstructural Proteins, Virus Replication, medicine.disease_cause, 01 natural sciences, Mice, Four and a Half LIM domains 1 Tropism, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Animals, Chikungunya, Host factor, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Intracellular Signaling Peptides and Proteins, virus diseases, General Medicine, MESH: Tropism, LIM Domain Proteins, 3. Good health, [SDV] Life Sciences [q-bio], [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Chikungunya virus, MESH: LIM Domain Proteins, Viral protein, Virus infection, Alphavirus, Tropism, Virus, 03 medical and health sciences, MESH: Muscle Proteins, MESH: Intracellular Signaling Peptides and Proteins, medicine, Animals, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Mice, Aedes, MESH: Virus Replication, MESH: Chikungunya virus, biology.organism_classification, Virology, 030104 developmental biology, Infectious disease (medical specialty), Chikungunya Fever, MESH: Viral Nonstructural Proteins, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 010606 plant biology & botany
Abstract: Chikungunya is an infectious disease caused by the chikungunya virus (CHIKV), an alphavirus transmitted to humans by Aedes mosquitoes, and for which there is no licensed vaccine nor antiviral treatments. By using a loss-of-function genetic screen, we have recently identified the FHL1 protein as an essential host factor for CHIKV tropism and pathogenesis. FHL1 is highly expressed in muscles cells and fibroblasts, the main CHIKV-target cells. FHL1 interacts with the viral protein nsP3 and plays a critical role in CHIKV genome amplification. Experiments in vivo performed in FHL1-deficient mice have shown that these animals are resistant to infection and do not develop muscular lesions. Altogether these observations, published in the journal Nature [1], show that FHL1 is a key host factor for CHIKV pathogenesis and identify the interaction between FHL1 and nsP3 as a promising target for the development of new antiviral strategies., Le chikungunya est une maladie infectieuse causée par le virus chikungunya (CHIKV), un alphavirus transmis à l’Homme par les moustiques Aedes et contre lequel il n’existe ni vaccin, ni traitements antiviraux. En utilisant une approche de crible génétique par perte de fonction, nous avons récemment identifié la protéine FHL1 comme un facteur cellulaire essentiel pour le tropisme et la pathogénèse du CHIKV. FHL1 est une molécule présente majoritairement dans les cellules musculaires et les fibroblastes, les cibles privilégiées de CHIKV. FHL1 interagit avec la protéine virale nsP3 et joue un rôle décisif dans le mécanisme d’amplification du génome de CHIKV. Des expériences in vivo chez des souris déficientes pour FHL1 ont montré que ces animaux sont résistants à l’infection et ne développent pas de lésions musculaires. L’ensemble de ces observations publiées dans la revue Nature [1] montrent que FHL1 est un facteur cellulaire clé pour la pathogénèse de CHIKV et identifient l’interaction entre FHL1 et nsp3 comme une cible prometteuse pour le développement de nouvelles stratégies antivirales
Published: 2020

236. 4D Genome Rewiring during Oncogene-Induced and Replicative Senescence

Author: Franck Pellestor, Jean-Marc Lemaitre, Quentin Szabo, Giorgio L. Papadopoulos, Juan Carlos Rivera-Mulia, Satish Sati, Pauline Bouret, Giacomo Cavalli, Daniel Jost, Modesto Orozco, Frédéric Bantignies, François Serra, Boyan B. Bonev, Lauriane Fritsch, David Castillo, David M. Gilbert, Paul Bensadoun, Josep Ll. Gelpi, Vincent Loubiere, Cédric Vaillant, Marc A. Marti-Renom, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Helmholtz Zentrum München = German Research Center for Environmental Health, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Barcelona Institute of Science and Technology (BIST), University of Minnesota Medical School, University of Minnesota System, CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Barcelona Supercomputing Center - Centro Nacional de Supercomputacion (BSC - CNS), University of Barcelona, Laboratoire de Physique de l'ENS Lyon (Phys-ENS), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Florida State University [Tallahassee] (FSU), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: Senescence, DNA (Cytosine-5-)-Methyltransferase 1, senescence, Heterochromatin, Carcinogenesis, [SDV]Life Sciences [q-bio], Bisulfite sequencing, Biology, Genome, Cromatina, 03 medical and health sciences, replicative senescence, 0302 clinical medicine, Oncogènesi, Envelliment, Hi-C, Humans, Molecular Biology, Gene, Cells, Cultured, Cellular Senescence, In Situ Hybridization, Fluorescence, 030304 developmental biology, Regulation of gene expression, 0303 health sciences, Genome, Human, DNMT1, oncogene-induced senescence, Cell Biology, Epigenome, Oncogenes, chromatin compartments, DNA Methylation, Fibroblasts, Chromatin Assembly and Disassembly, Epigenètica, Chromatin, Cell biology, Genòmica, Epigenetics, gene regulation, 030217 neurology & neurosurgery, Genètica, 3D genome architecture
Abstract: To understand the role of the extensive senescence-associated 3D genome reorganization, we generated genome-wide chromatin interaction maps, epigenome, replication-timing, whole-genome bisulfite sequencing, and gene expression profiles from cells entering replicative senescence (RS) or upon oncogene-induced senescence (OIS). We identify senescence-associated heterochromatin domains (SAHDs). Differential intra- versus inter-SAHD interactions lead to the formation of senescence-associated heterochromatin foci (SAHFs) in OIS but not in RS. This OIS-specific configuration brings active genes located in genomic regions adjacent to SAHDs in close spatial proximity and favors their expression. We also identify DNMT1 as a factor that induces SAHFs by promoting HMGA2 expression. Upon DNMT1 depletion, OIS cells transition to a 3D genome conformation akin to that of cells in replicative senescence. These data show how multi-omics and imaging can identify critical features of RS and OIS and discover determinants of acute senescence and SAHF formation. Work at the M.A.M.-R. lab was supported by the European Research Council under the 7th Framework Program FP7/2007-2013 (ERC grant agreement 609989), the European Union’s Horizon 2020 research and innovation programme (grant agreement 676556), the Ministry of Economy and Competitiveness (BFU2017-85926-P), and the Agència de Gestió d’Ajuts Universitaris i de Recerca, AGAUR (SGR468). Work at CRG, BIST, and UPF was in part funded by the Spanish Ministry of Economy and Competitiveness, ‘‘Centro de Excelencia Severo Ochoa 2013-2017’’ (SEV-2012-0208), and ‘‘Centro de Excelencia María de Maeztu 2016-2019.’’ This article/publication is based upon work from COST Action CA18127, supported by COST (European Cooperation in Science and Technology)
Published: 2020
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237. A transposon story : from TE content to TE dynamic invasion of Drosophila genomes using the single-molecule sequencing technology from Oxford Nanopore

Author: Séverine Chambeyron, Nelly Burlet, Judit Salces-Ortiz, Bruno Mugat, Philippe Veber, François Sabot, Nguyet Thi-Minh Dang, Alain Pélisson, Marie Fablet, Cristina Vieira, Yuki Ogyama, Vincent Mérel, Matthieu Boulesteix, Mourdas Mohamed, Dany Severac, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Diversité, adaptation, développement des plantes (UMR DIADE), Institut de Recherche pour le Développement (IRD [France-Sud])-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Eléments transposables, évolution, populations, Département génétique, interactions et évolution des génomes [LBBE] (GINSENG), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Universitat Pompeu Fabra [Barcelona] (UPF), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), 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)-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), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-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), Fondation pour la Recherche Médicale, Agence Nationale de la Recherche (France), and Centre National de la Recherche Scientifique (France)
Subjects: 0301 basic medicine, Transposable element, Drosophila simulans, Piwi-interacting RNA, ONT, Computational biology, piRNA, Genome, Article, Transposition (music), 03 medical and health sciences, Nanopores, 0302 clinical medicine, Chromosome (genetic algorithm), [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Melanogaster, Animals, lcsh:QH301-705.5, Drosophila melanogaster, ComputingMilieux_MISCELLANEOUS, [SDV.GEN]Life Sciences [q-bio]/Genetics, biology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Medicine, biology.organism_classification, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 030104 developmental biology, lcsh:Biology (General), DNA Transposable Elements, Drosophila, Nanopore sequencing, transposable elements, Transposable elements, 030217 neurology & neurosurgery
Abstract: Transposable elements (TEs) are the main components of genomes. However, due to their repetitive nature, they are very difficult to study using data obtained with short-read sequencing technologies. Here, we describe an efficient pipeline to accurately recover TE insertion (TEI) sites and sequences from long reads obtained by Oxford Nanopore Technology (ONT) sequencing. With this pipeline, we could precisely describe the landscapes of the most recent TEIs in wild-type strains of Drosophila melanogaster and Drosophila simulans. Their comparison suggests that this subset of TE sequences is more similar than previously thought in these two species. The chromosome assemblies obtained using this pipeline also allowed recovering piRNA cluster sequences, which was impossible using short-read sequencing. Finally, we used our pipeline to analyze ONT sequencing data from a D. melanogaster unstable line in which LTR transposition was derepressed for 73 successive generations. We could rely on single reads to identify new insertions with intact target site duplications. Moreover, the detailed analysis of TEIs in the wild-type strains and the unstable line did not support the trap model claiming that piRNA clusters are hotspots of TE insertions., This research was funded by the Fondation pour la Recherche Médicale, grant number “DEQ20180339167” to S.C, by the ANR Exhyb to C.V., by the CNRS.
Published: 2020

238. Crosstalk between Hepatitis B Virus and the 3D Genome Structure

Author: João Diogo Dias, Nazim Sarica, Axel Cournac, Romain Koszul, Christine Neuveut, Institut de génétique humaine (IGH), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Régulation spatiale des Génomes - Spatial Regulation of Genomes, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and This research was funded by Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS), grant number EZT88522. J.D.D. was supported by ANRS.
Subjects: Hepatitis B virus, Carcinoma, Hepatocellular, MESH: Hepatitis B, Chronic, [SDV]Life Sciences [q-bio], viruses, spatial nuclear organization, [SDV.CAN]Life Sciences [q-bio]/Cancer, Genome, Viral, Virus Replication, Hepatitis B, Chronic, Virology, HBV, Animals, Humans, MESH: Animals, MESH: Carcinoma, Hepatocellular, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Hepatitis B, HBV cccDNA, MESH: Virus Replication, Hepatitis B, MESH: DNA, Viral, MESH: Hepatitis B virus, Infectious Diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, DNA, Viral, MESH: DNA, Circular, MESH: Genome, Viral, DNA, Circular, DNA viruses, gene regulation
Abstract: International audience; Viruses that transcribe their DNA within the nucleus have to adapt to the existing cellular mechanisms that govern transcriptional regulation. Recent technological breakthroughs have highlighted the highly hierarchical organization of the cellular genome and its role in the regulation of gene expression. This review provides an updated overview on the current knowledge on how the hepatitis B virus interacts with the cellular 3D genome and its consequences on viral and cellular gene expression. We also briefly discuss the strategies developed by other DNA viruses to co-opt and sometimes subvert cellular genome spatial organization.
Published: 2022

239. STING orchestrates the crosstalk between polyunsaturated fatty acid metabolism and inflammatory responses

Author: Isabelle K. Vila, Hanane Chamma, Alizée Steer, Mathilde Saccas, Clara Taffoni, Evgenia Turtoi, Line S. Reinert, Saqib Hussain, Johanna Marines, Lei Jin, Xavier Bonnefont, Mathieu Hubert, Olivier Schwartz, Soren R. Paludan, Gaetan Van Simaeys, Gilles Doumont, Bijan Sobhian, Dimitrios Vlachakis, Andrei Turtoi, Nadine Laguette, Institut de génétique humaine (IGH), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Aarhus University [Aarhus], Albany Medical College, Institut de Génomique Fonctionnelle (IGF), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Aarhus University Hospital, Center for Microscopy and Molecular Imaging (IBMM - CMMI), Université libre de Bruxelles (ULB), Agricultural University of Athens, Biomedical Research Foundation of the Academy of Athens (BRFAA), National and Kapodistrian University of Athens (NKUA), We acknowledge the SIRIC Montpellier Cancer grant (INCa_Inserm_DGOS_12553), Metamus-RAM and iExplore-RAM animal facilities, the Laboratoire de Mesures Physiques of the University of Montpellier for access to the MS instruments, the MRI imaging facility, member of the national infrastructure France-BioImaging infrastructure supported by the French National Research Agency (ANR-10-INBS-04, 'Investments for the future'), and Ross Tomaino from the Taplin Mass Spectrometry Facility of Harvard Medical School for MS analysis. We thank T. Emilien, A. Sedda, C. de Maeseneire, N. Passon, and C. Van Heymbeek for their contribution. We thank the Cyclotron team from the Erasme Hospital, Brussels, Belgium, for the FDG provision. Work in N.L.’s laboratory is supported by the European Research Council (ERC-Stg CrIC: 637763, ERC-PoC DIM-CrIC: 893772), la Ligue pour la Recherche contre le Cancer, and the Agence Nationale de Recherche sur le Sida et les Hépatites Virales (ANRS: ECTZ117448). H.C. is supported by a PhD fellowship from la Ligue pour la Recherche contre le Cancer. C.T. is supported by the Merck Sharp and Dohme Avenir (MSD-Avenir – GnoSTic) program and an ANRS fellowship (ECTZ119088). J.M. is supported by a Conventions Industrielles de Formation par la Recherche (CIFRE) fellowship from the Agence Nationale de Recherche Technologie (ANRT). A.S. is supported by the ERC-PoC DIM-CrIC (893772). I.K.V. is supported by the ERC-Stg CrIC (637763) and the Fondation pour la Recherche Médicale (ARF20170938586). Work in S.R.P.’s laboratory is supported by the European Research Council (ERC-AdG ENVISION, 786602), the Novo Nordisk Foundation (NNF18OC0030274), and the Lundbeck Foundation (R198-2015-171 and R268-2016-3927). Work in A.T.’s laboratory is supported by a SIRIC Montpellier Cancer grant (INCa_Inserm_DGOS_12553), the Fondation de France (grant no. 00078461), and a LabEx MabImprove Starting Grant. X.B. is supported by ANR GH-gen (ANR-18-CE14-0017). The Center for Microscopy and Molecular Imaging (CMMI) is supported by the European Regional Development Fund (ERDF), the Walloon Region, the Fondation ULB, the Fonds Erasme, and Association Vinçotte Nuclear (AVN). G.D. is supported by the European Regional Development Fund (ERDF) and the Walloon Region. Work in O.S.’s lab is funded by Institut Pasteur, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, 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, Fondation pour la Recherche Médicale. Schematic representations were created with https://biorender.com, We thank M. Benkirane, G. Cavalli, J. Déjardin, and B. de Massy for discussions and comments. We thank C. Goujon and B. Bonaventure for CRISPR/Cas9 gRNA sequences., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-LABX-0053,MAbImprove,Optimization of therapeutic monoclonal antibodies development Better antibodies, better developed AND better used(2010), ANR-18-CE14-0017,GH-Gen,Origine et fonction du generateur hypophysaire de pulses d'hormone de croissance(2018), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-20-COVI-0062,proteoCOVID,Protéomique clinique de la protéine SARS-CoV-2 Spike pour optimiser sa détection et le développement de tests sérologiques(2020), European Project: 637763,H2020,ERC-2014-STG,CrIC(2015), European Project: 893772,DIM-CrIC, European Project: 786602,ENVISION, Virus et Immunité - Virus and immunity, Guerineau, Nathalie C., Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, Laboratoires d'excellence - Optimization of therapeutic monoclonal antibodies development Better antibodies, better developed AND better used - - MAbImprove2010 - ANR-10-LABX-0053 - LABX - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Origine et fonction du generateur hypophysaire de pulses d'hormone de croissance - - GH-Gen2018 - ANR-18-CE14-0017 - AAPG2018 - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Laboratoires d'excellence - Initiative for the creation of a Vaccine Research Institute - - VRI2010 - ANR-10-LABX-0077 - LABX - VALID, Protéomique clinique de la protéine SARS-CoV-2 Spike pour optimiser sa détection et le développement de tests sérologiques - - proteoCOVID2020 - ANR-20-COVI-0062 - COVID-19 - VALID, Molecular basis of the cross-talk between chronic inflammation and cancer - CrIC - - H20202015-04-01 - 2020-03-31 - 637763 - VALID, Decreasing Pancreatic Adenocarcinoma-related Inflammation using small molecule inhibitors of STING - DIM-CrIC - 893772 - INCOMING, Novel mechanisms of early defense against virus infections - ENVISION - 786602 - INCOMING, Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), BioCampus Montpellier (BCM), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), AZELEAD, 377 Rue du Professeur Blayac, 34080 Montpellier, France, 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), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: Fatty Acid Desaturases, Physiology, [SDV]Life Sciences [q-bio], nucleic acid immunity, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, cytosolic DNA, Article, 03 medical and health sciences, 0302 clinical medicine, delta-6 Desaturase, Humans, FADS2, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, 030304 developmental biology, Inflammation, Metabolic Syndrome, interferon responses, 0303 health sciences, Cell Biology, Lipid Metabolism, eye diseases, 3. Good health, [SDV] Life Sciences [q-bio], Fatty Acids, Unsaturated/metabolism, inflammation, 030220 oncology & carcinogenesis, Fatty Acids, Unsaturated, metabolism, Fatty Acid Desaturases/genetics, STING, cGAS, polyunsaturated fatty acids
Abstract: Summary Concerted alteration of immune and metabolic homeostasis underlies several inflammation-related pathologies, ranging from metabolic syndrome to infectious diseases. Here, we explored the coordination of nucleic acid-dependent inflammatory responses and metabolic homeostasis. We reveal that the STING (stimulator of interferon genes) protein regulates metabolic homeostasis through inhibition of the fatty acid desaturase 2 (FADS2) rate-limiting enzyme in polyunsaturated fatty acid (PUFA) desaturation. STING ablation and agonist-mediated degradation increased FADS2-associated desaturase activity and led to accumulation of PUFA derivatives that drive thermogenesis. STING agonists directly activated FADS2-dependent desaturation, promoting metabolic alterations. PUFAs in turn inhibited STING, thereby regulating antiviral responses and contributing to resolving STING-associated inflammation. Thus, we have unveiled a negative regulatory feedback loop between STING and FADS2 that fine-tunes inflammatory responses. Our results highlight the role of metabolic alterations in human pathologies associated with aberrant STING activation and STING-targeting therapies., Graphical abstract, Highlights • STING inhibits FADS2-dependent desaturation of PUFAs and LC-PUFAs • STING activation leads to upregulation of FADS2-associated desaturase activity • STING agonists activate FADS2-dependent PUFA and LC-PUFA desaturation • PUFAs inhibit STING-dependent inflammatory responses, The stimulator of interferon genes (STING) is a central regulator of nucleic acid-associated inflammatory responses. Here, Vila et al. discover that STING regulates polyunsaturated fatty acid (PUFA) metabolism, and in turn, PUFAs inhibit STING-dependent inflammation. This cross-regulation is central to the maintenance of metabolic homeostasis.
Published: 2022

240. DDR Inc., one business, two associates

Author: María Moriel-Carretero, Philippe Pasero, Benjamin Pardo, Institut de génétique humaine (IGH), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: DNA Replication, Saccharomyces cerevisiae Proteins, Cell cycle checkpoint, DNA replication initiation, DNA damage, [SDV]Life Sciences [q-bio], Saccharomyces cerevisiae, Adaptation, Biological, Mrc1, Biology, 03 medical and health sciences, chemistry.chemical_compound, Rad9, Gene Expression Regulation, Fungal, Genetics, Mediators, 030304 developmental biology, S-phase checkpoint, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, Effector, fungi, 030302 biochemistry & molecular biology, DNA replication, Replication stress, General Medicine, Cell cycle, biology.organism_classification, Cell biology, chemistry, S Phase Cell Cycle Checkpoints, biological phenomena, cell phenomena, and immunity, Biomarkers, DNA, DNA Damage, Signal Transduction
Abstract: International audience; Eukaryotic cells activate cell cycle checkpoints in response to DNA damage. In Saccharomyces cerevisiae, the DNA damage response is achieved by the activation of the sensor kinases Mec1 and Tel1 and transmitted to the effector kinase Rad53. Rad9 and Mrc1 are thought to differentially mediate the activation of Rad53 depending on the cell cycle phase. Rad9 can respond to DNA lesions throughout the cell cycle, whereas Mrc1 responds to replication impediments in S phase. It was not clear if Rad9 and Mrc1 were triggering the same response to DNA damage occurring in S phase. By carefully studying the kinetics of activation of Rad53 by different types of replication stresses, we recently showed that Rad9 and Mrc1 cooperate in time and space to trigger a unique response to DNA damage in S phase. This primarily includes the control of both DNA replication initiation and elongation. After showing that Rad9 plays a preponderant role during S phase, the data presented here provocatively suggest that Mrc1 could also mediate the activation of Rad53 outside of S phase.
Published: 2018

241. Barriers and levers in screening and care for alcohol use disorders among French general practitioners: results from a computer-assisted telephone interview-based survey

Author: BARRE, TANGUI, Nordmann, Sandra, Casanova, Danielle, Levy-Bellaiche, Sabrina, Simon, Nicolas, Carrieri, Maria-Patrizia, Costa, Marie, Yaya, Issifou, Mora, Marion, Marcellin, Fabienne, Villotitch, Antoine, Berenger, Cyril, Tanti, Marc, Cutarella, Christophe, POLOMENI, Pierre, Maradan, Gwenaelle, Roux, Perrine, Rolland, Benjamin, Carrieri, Patrizia Maria, Coste, Marion, Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Nîmes (CHU de Nîmes), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Observatoire régional de la santé Provence-Alpes-Côte d'Azur [Marseille] (ORS PACA), Centre d'épidémiologie et de santé publique des armées (CESPA), Service de Santé des Armées, Clinique Saint-Barnabé, Service d'addictologie [Bondy], AP-HP Hôpital Jean-Verdier [Bondy], Pharmacologie de la mort neuronale et de la plasticité cérébrale, IFR114-Université de Lille, Droit et Santé, Centre d'épidémiologie et de santé publique des armées [Marseille] (CESPA), Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Costa, Marie
Subjects: medicine.medical_specialty, Psychological intervention, 030508 substance abuse, Medicine (miscellaneous), Alcohol use disorder, alcohol use disorder, 03 medical and health sciences, 0302 clinical medicine, mental disorders, medicine, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, screening survey, Public health, controlled drinking, medicine.disease, 3. Good health, Psychiatry and Mental health, Telephone interview, Controlled drinking, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Family medicine, General practice, alcohol use disorder management, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 0305 other medical science, Psychology
Abstract: International audience; Alcohol use disorders (AUD) is a major public health concern. General practitioners (GP) must play a key role in identifying this disorder and offering appropriate interventions. The authors conducted a survey among French GP in the Provence – Alpes – Côte-d’Azur (PACA) region to better understand their practices regarding AUD. Random sampling was used to enrol 101 GP in a 15-minute survey. A Computer-Assisted Telephone Interview exploring demographic and professional characteristics was conducted using a questionnaire. One third (31.7%) of the participants systematically addressed alcohol use with their patients whereas six (5.9%) never addressed it. Logistic regression analyses showed that after adjustment for the number of AUD patients followed up (odds ratio [OR] = 1.92; 95% confidence interval [CI] [1.19, 3.08]) and GP interest in addiction medicine (5.41 [2.17, 13.40]), GP who systematically screened patients for AUD were more likely to accept controlled drinking as a therapeutic goal (5.41 [2.17, 13.33]), and to perceive patient denial of AUD as a major barrier to care (1.39 [0.60, 3.22]). GP providing care for AUD were more likely to monitor tobacco cessation (9.08 [2.60, 31.64]) and to prescribe opioid maintenance treatment (7.35 [2.52, 21.41]). Alcohol screening is insufficient in general practice in France. Providing updated guidelines is essential to foster experience in this field among GP.
Published: 2018

242. HTT is a repressor of ABL activity required for APP induced axonal growth

Author: Lee G. Fradkin, Jean-Maurice Dura, Brittany S. Leger, Ana Boulanger, Germain U. Busto, Claire Marquilly, James A. Walker, Edward Giniger, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), St James University Hospital, Massachusetts General Hospital [Boston], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), and ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010)
Subjects: Huntingtin, Mutant, Axonal Transport, 0302 clinical medicine, Animal Cells, Fluorescence Resonance Energy Transfer, Amyloid precursor protein, Axon, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Neurons, Huntingtin Protein, 0303 health sciences, ABL, Effector, Drosophila Melanogaster, Eukaryota, Polyglutamine tract, 3. Good health, Cell biology, Phenotypes, Huntington Disease, Spectrophotometry, Hyperexpression Techniques, Cellular Types, HTT, Embryonic Development, Repressor, 03 medical and health sciences, Alzheimer Disease, Memory, Genetics, Humans, Molecular Biology Techniques, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Mushroom Bodies, Molecular Biology Assays and Analysis Techniques, fungi, Organisms, Biology and Life Sciences, Invertebrates, nervous system, Mutation, Nerve Degeneration, Animal Studies, FRET, Acyltransferases, 030217 neurology & neurosurgery, Appl signaling, Neuroscience, Cloning, Developmental Biology, Cancer Research, Life Cycles, [SDV]Life Sciences [q-bio], QH426-470, Fluorophotometry, axonal growth, Amyloid beta-Protein Precursor, Nerve Fibers, Spectrum Analysis Techniques, Larvae, hemic and lymphatic diseases, Drosophila Proteins, Genetics (clinical), biology, Chemistry, Animal Models, Insects, medicine.anatomical_structure, Experimental Organism Systems, Mushroom bodies, Drosophila, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Drosophila melanogaster, Signal transduction, Signal Transduction, Research Article, congenital, hereditary, and neonatal diseases and abnormalities, animal structures, Arthropoda, Research and Analysis Methods, Model Organisms, mental disorders, Gene Expression and Vector Techniques, medicine, Animals, Learning, Kinase activity, 030304 developmental biology, Cell Biology, biology.organism_classification, mushroom body, Axons, Cellular Neuroscience, biology.protein, Zoology, Entomology
Abstract: Huntington’s disease is a progressive autosomal dominant neurodegenerative disorder caused by the expansion of a polyglutamine tract at the N-terminus of a large cytoplasmic protein. The Drosophila huntingtin (htt) gene is widely expressed during all developmental stages from embryos to adults. However, Drosophila htt mutant individuals are viable with no obvious developmental defects. We asked if such defects could be detected in htt mutants in a background that had been genetically sensitized to reveal cryptic developmental functions. Amyloid precursor protein (APP) is linked to Alzheimer’s disease. Appl is the Drosophila APP ortholog and Appl signaling modulates axon outgrowth in the mushroom bodies (MBs), the learning and memory center in the fly, in part by recruiting Abl tyrosine kinase. Here, we find that htt mutations suppress axon outgrowth defects of αβ neurons in Appl mutant MB by derepressing the activity of Abl. We show that Abl is required in MB αβ neurons for their axon outgrowth. Importantly, both Abl overexpression and lack of expression produce similar phenotypes in the MBs, indicating the necessity of tightly regulating Abl activity. We find that Htt behaves genetically as a repressor of Abl activity, and consistent with this, in vivo FRET-based measurements reveal a significant increase in Abl kinase activity in the MBs when Htt levels are reduced. Thus, Appl and Htt have essential but opposing roles in MB development, promoting and suppressing Abl kinase activity, respectively, to maintain the appropriate intermediate level necessary for axon growth., Author summary Understanding the normal physiological roles of proteins involved in neurodegenerative diseases can provide significant insight into disease mechanisms. Drosophila offers a powerful system in which to ask these fundamental questions. Both Htt, related to Huntington’s disease, and Appl, related to Alzheimer’s disease, have well-conserved single orthologs in the fly genome. Appl has been shown to be a conserved modulator of a Wnt-PCP signaling pathway required for axon outgrowth in the mushroom body (MB) in the Drosophila brain. However, roles for Htt in fly brain development have not been reported. Unexpectedly, we found that htt mutations suppress the axon outgrowth defects of Appl mutants in the MB, indicating a link between these two neurodegenerative proteins and a cryptic role of Htt during development. Abl tyrosine kinase is a downstream effector of the Appl receptor, and we show here that Abl is also required for MB axon outgrowth. Importantly, Abl activity must be tightly regulated as evidenced by our observations that both under and overexpression of Abl result in similar axonal defects. We demonstrate that Htt is an inhibitor of Abl activity and provide evidence that the phenotypic rescue of αβ axons in Appl mutants by reducing htt is mediated by the restoration of proper levels of Abl signaling. These data, therefore, suggest that Appl and Htt act antagonistically to maintain an optimal balance of activation and inhibition of Abl, and thereby promote the growth of MB αβ axons.
Published: 2019

243. Multimorbidity in Elderly Persons According to the Year of Diagnosis of Human Immunodeficiency Virus Infection: A Cross-sectional Dat’AIDS Cohort Study

Author: Demontès, Marie, Eymard Duvernay, Sabrina, Allavena, Clotilde, Jovelin, Thomas, Reynes, Jacques, Hentzien, Maxime, Ravaux, Isabelle, Delobel, Pierre, Bregigeon, Sylvie, Rey, David, Ferry, Tristan, Gagneux-Brunon, Amandine, Robineau, Olivier, Pugliese, Pascal, Duvivier, Claudine, Cabié, André, Chirouze, Catherine, Jacomet, Christine, Lamaury, Isabelle, Merrien, Dominique, Hoen, Bruno, Hocqueloux, Laurent, Cheret, Antoine, Katlama, Christine, Arvieux, Cédric, Krolak-Salmon, Pierre, Makinson, Alain, Drobacheff-Thiébaut, C, Foltzer, A, Bouiller, K, Hustache- Mathieu, L, Chirouze, C, Lepiller, Q, Bozon, F, Babre, O, Brunel, S, Muret, P, Laurichesse, H, Lesens, O, Vidal, M, Mrozek, N, Aumeran, C, Baud, O, Corbin, V, Letertre-Gibert, P, Casanova, S, Prouteau, J, Jacomet, C, Lamaury, I, Fabre, I, Curlier, E, Ouissa, R, Herrmann-Storck, C, Tressieres, B, Bonijoly, T, Receveur, C, Boulard, F, Daniel, C, Clavel, C, Merrien, D, Perré, P, Guimard, T, Bollangier, O, Leautez, S, Morrier, M, Laine, L, Ader, F, Becker, A, Biron, F, Boibieux, A, Cotte, L, Ferry, T, Miailhes, P, Perpoint, T, Roux, S, Triffault-Fillit, C, Degroodt, S, Brochier, C, Valour, F, Chidiac, C, Ménard, A, Belkhir, Y, Colson, P, Dhiver, C, Madrid, A, Martin-Degiovani, M, Meddeb, L, Mokhtari, M, Motte, A, Raoux, A, Ravaux, I, Tamalet, C, Toméi, C, Tissot Dupont, H, Brégigeon, S, Zaegel-Faucher, O, Obry-Roguet, V, Laroche, H, Orticoni, M, Soavi, J, Geneau de Lamarlière, P, Ressiot, E, Ducassou, J, Jaquet, I, Galie, S, Galinier, A, Martinet, P, Landon, M, Ritleng, S, Ivanova, A, Debreux, C, Lions, C, Poizot-Martin, I, Abel, S, Cabras, O, Cuzin, L, Guitteaud, K, Illiaquer, M, Pierre-François, S, Osei, L, Pasquier, J, Rome, K, Sidani, E, Turmel, M, Varache, C, Cabié, A, Atoui, N, Bistoquet, M, Delaporte, E, Le Moing, V, Makinson, A, Meftah, N, Merle de Boever, C, Montes, B, Montoya Ferrer, A, Tuaillon, E, Reynes, J, André, M, Boyer, L, Bouillon, P, Delestan, M, Rabaud, C, May, T, Hoen, B, Allavena, C, Bernaud, C, Billaud, E, Biron, C, Bonnet, B, Bouchez, S, Boutoille, D, Brunet-Cartier, C, Deschanvres, C, Hall, N, Jovelin, T, Morineau, P, Reliquet, V, Sécher, S, Cavellec, M, Soria, A, Ferré, V, André-Garnier, E, Rodallec, A, Lefebvre, M, Grossi, O, Aubry, O, Raffi, F, Pugliese, P, Breaud, S, Ceppi, C, Chirio, D, Cua, E, Dellamonica, P, Demonchy, E, de Monte, A, Durant, J, Etienne, C, Ferrando, S, Garraffo, R, Michelangeli, C, Mondain, V, Naqvi, A, Oran, N, Perbost, I, Pillet, S, Pradier, C, Prouvost-Keller, B, Risso, K, Rio, V, Roger, P, Rosenthal, E, Sausse, S, Touitou, I, Wehrlen-Pugliese, S, Zouzou, G, Hocqueloux, L, Prazuck, T, Gubavu, C, Sève, A, Maka, A, Boulard, C, Thomas, G, Cheret, A, Goujard, C, Quertainmont, Y, Teicher, E, Lerolle, N, Deradji, O, Barrail-Tran, A, Landman, R, Joly, V, Ghosn, J, Rioux, C, Lariven, S, Gervais, A, Lescure, F, Matheron, S, Louni, F, Julia, Z, Mackoumbou-Nkouka, C, Le Gac, S, Charpentier, C, Descamps, D, Peytavin, G, Yazdanpanah, Y, Amazzough, K, Avettand-Fenoël, V, Benabdelmoumen, G, Bossi, P, Cessot, G, Charlier, C, Consigny, P, Danion, F, Dureault, A, Duvivier, C, Goesch, J, Guery, R, Henry, B, Jidar, K, Lanternier, F, Loubet, P, Lortholary, O, Louisin, C, Lourenco, J, Parize, P, Pilmis, B, Touam, F, Valantin, M, Tubiana, R, Agher, R, Seang, Sophie, Schneider, L, Palich, R, Blanc, C, Katlama, C, Berger, J, N’guyen, Y, Lambert, D, Kmiec, I, Hentzien, M, Brunet, A, Brodard, V, Bani-Sadr, F, Tattevin, P, Revest, M, Souala, F, Baldeyrou, M, Patrat-Delon, S, Chapplain, J, Benezit, F, Dupont, M, Poinot, M, Maillard, A, Pronier, C, Lemaitre, F, Guennoun, C, Poisson-Vanier, M, Sinteff, J, Arvieux, C, Botelho-Nevers, E, Gagneux-Brunon, A, Frésard, A, Ronat, V, Lucht, F, Fischer, P, Partisani, M, Cheneau, C, Priester, M, Batard, L, Bernard-Henry, C, de Mautort, E, Fafi-Kremer, S, Rey, D, Alvarez, M, Biezunski, N, Debard, A, Delpierre, C, Lansalot, P, Lelièvre, L, Martin-Blondel, G, Piffaut, M, Porte, L, Saune, K, Delobel, P, Ajana, F, Aïssi, E, Alcaraz, I, Baclet, V, Bocket, L, Boucher, A, Choisy, P, Huleux, T, Lafon-Desmurs, B, Meybeck, A, Pradier, M, Robineau, O, Viget, N, Valette, M, Hospices Civils de Lyon (HCL), Recherches Translationnelles sur le VIH et les maladies infectieuses (TransVIHMI), Université Montpellier 1 (UM1)-Institut de Recherche pour le Développement (IRD)-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Universtié Yaoundé 1 [Cameroun]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de maladies infectieuses et tropicales [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Nantes (UN), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire de Reims (CHU Reims), Institut Hospitalier Universitaire Méditerranée Infection (IHU AMU), Pathogénie des Staphylocoques – Staphylococcal Pathogenesis, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université de Saint-Etienne, Service Universitaire des Maladies Infectieuses et du Voyageur [Tourcoing], Centre Hospitalier Tourcoing, Service de Maladies Infectieuses [Nice], Centre d'infectiologie Necker-Pasteur [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Service de Maladies Infectieuses et Tropicales [Fort-de-France, Martinique], CHU de la Martinique [Fort de France]-Hôpital Pierre Zobda-Quitman [CHU de la Martinique], CHU de la Martinique [Fort de France]-Centre Hospitalier Universitaire de Martinique [Fort-de-France, Martinique], Laboratoire Chrono-environnement - UFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), service de maladies infectieuses CHU J Minjoz Besancon, Hôpital Jean Minjoz, Département des Maladies Infectieuses et Tropicales [CHU Gabriel-Montpied, Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Pointe-à-Pitre/Abymes [Guadeloupe], Centre Hospitalier Compiègne-Noyon, Centre d'Investigation Clinique Antilles-Guyane (CIC - Antilles Guyane), CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française]-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles et de la Guyane (UAG), Centre Hospitalier Régional d'Orléans (CHR), Services des maladies infectieuses [CH Turcoing], Centre Hospitalier de Tourcoing, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service des maladies infectieuses et réanimation médicale, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Besançon (CHU Besançon), Université libre de Bruxelles (ULB), Hôpital Gabriel Montpied, Service des Maladies Infectieuses et Tropicales, Centre Hospitalier Universitaire de Clermont-Ferrand, Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Microorganismes : Génome et Environnement - Clermont Auvergne (LMGE), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA), CCLIN Sud-Est – Centre de Coordination de la Lutte contre les Infections Nosocomiales Sud-Est, Service de Maladies Infectieuses et Tropicales (SMIT), CHU de Treichville, Laboratoire Traitement et Communication de l'Information (LTCI), Télécom ParisTech-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS), Hosp Civils Lyon, Serv Malad Infect, Lyon, France, Institut de biologie et chimie des protéines [Lyon] (IBCP), Hôpital de la Croix-Rousse [CHU - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Equipe 15, 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)-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), Service de Maladies Infectieuses et Tropicales [Hôpital de la Croix-Rousse - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Laboratoire de Mécanique et Technologie (LMT), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Centre interrégional de référence Rhône-Alpes - Auvergne des infections ostéo-articulaires complexes, Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service d'Immuno-hématologie clinique [Hôpital Sainte Marguerite - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Assistance Publique - Hôpitaux de Marseille (APHM), Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Space Research Institute of the Russian Academy of Sciences (IKI), Russian Academy of Sciences [Moscow] (RAS), DDSIS 76, Système membranaires, photobiologie, stress et détoxication (SMPSD), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-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), Centre IRD de Montpellier (IRD), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre d'études et de recherche sur les services de santé et la qualité de vie (CEReSS), Aix Marseille Université (AMU), Service des Maladies Infectieuses et Tropicales [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Bell Labs (BELL), Lucent Technologies, Centre hospitalier universitaire de Nantes (CHU Nantes), Unité de Nutrition Humaine - Clermont Auvergne (UNH), Université Clermont Auvergne (UCA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service des maladies infectieuses et tropicales [CHU Nantes], Océan du Large et Variabilité Climatique (OLVAC), Laboratoire d'études en Géophysique et océanographie spatiales (LEGOS), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National d'Études Spatiales [Toulouse] (CNES)-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Plant Biomechanics Group, Botanischer Garten, Albert-Ludwigs-Universität Freiburg, Hôtel-Dieu de Nantes, Service de virologie [CHU Nantes], Département Etude des Réacteurs (DER), CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service des maladies infectieuses, Centre Hospitalier Universitaire de Nice (CHU Nice)-University Hospital, CHU Nice [Cimiez], Hôpital Cimiez [Nice] (CHU), Centre Hospitalier Universitaire de Nice (CHU Nice), Hopital l'Archet, Centre d'Information et de Soins de I'Immunodéficience Humaine (CISIH). Hôpital l'Archet 1, Hôpital l'Archet, Public Health Department, Hôpital de l'Archet, Institut de génétique humaine (IGH), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Infectious Diseases Department, Université Montpellier 1 (UM1), Environnements et Paléoenvironnements OCéaniques (EPOC), Observatoire aquitain des sciences de l'univers (OASU), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre Régional de recherche et de Formation à la prise en charge Clinique de Fann (CRCF), CHNU Fann, Registre EPIMAD, CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Amiens-Picardie-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre d'Etudes Lasers Intenses et Applications (CELIA), Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Bordeaux (UB), Pharmacie de l'Hôpital Bichat, UMR CNRS 8179, Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Sciences et Technologies, Laboratoire de Virologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5), Service de rhumatologie [Strasbourg], CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Pathogénie des infections systémiques (UMR_S 570), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC), Service des maladies infectieuses [CHU Pitié-Salêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], McGill University, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), Service de pneumologie, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Centre de Physique des Particules de Marseille (CPPM), Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Aix Marseille Université (AMU), CHU Pontchaillou [Rennes], SEV, Groupe d'Etudes et de Contrôle des Variétés et des Semences (GEVES), Service de virologie [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes], CHU Saint-Etienne, University Hospital and University Jean Monnet, 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), 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), Laboratoire de Virologie [Strasbourg], Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Virologie et pathogenèse virale (VPV), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, CHU de Fort de France, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche pour le Développement (IRD)-Université Montpellier 1 (UM1)-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Universtié Yaoundé 1 [Cameroun]-Université de Montpellier (UM), Université de Montpellier (UM), Service des Maladies Infectieuses et Tropicales [Hôpital de la Conception] (SMIT), Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Centre de Physiopathologie Toulouse Purpan (CPTP - U1043 INSERM - UMR5282 CNRS - UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Groupe Immunité des Muqueuses et Agents Pathogènes (GIMAP), Université Jean Monnet [Saint-Étienne] (UJM), Centre d'investigation clinique Antilles-Guyane (CIC - Antilles Guyane), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU de la Martinique [Fort de France]-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], CHD Vendee (La Roche Sur Yon), Service des maladies infectieuses et tropicales, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Saint-Jacques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Institut de Recherche pour le Développement (IRD), Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Centre de Physiopathologie Toulouse Purpan (CPTP), Pathogénie des Staphylocoques – Staphylococcal Pathogenesis (StaPath), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Médical de l'Institut Pasteur (CMIP), Institut Pasteur [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de la Martinique [Fort de France]-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service des Maladies Infectieuses et Tropicales [CHU Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques, Centre Hospitalier Régional d'Orléans (CHRO), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service des maladies infectieuses et réanimation médicale [Rennes] = Infectious Disease and Intensive Care [Rennes], Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Jean Monnet - Saint-Étienne (UJM), Institut Pasteur [Paris] (IP), Laboratoire Chrono-environnement (UMR 6249) (LCE), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre Médical de l'Institut Pasteur, Service des maladies infectieuses et réanimation médicale [Rennes], Département Maladies Infectieuses et Tropicales, Hôpital Universitaire, Montpellier, France, Service Maladies infectieuses et tropicales [CHU Toulouse], Pôle Inflammation, infection, immunologie et loco-moteur [CHU Toulouse] (Pôle I3LM Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire Marseille, CHU Marseille, School of Civil and Environmental Engineering [Sydney], University of New South Wales [Sydney] (UNSW), Laboratoire d'Ingénierie Circulation Transport (LICIT UMR TE ), École Nationale des Travaux Publics de l'État (ENTPE)-Université de Lyon-Université Gustave Eiffel, Institut Cochin (IC UM3 (UMR 8104 / U1016)), CHU de la Martinique [Fort de France], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Clermont-Ferrand, Stratégies thérapeutiques contre l'infection VIH et les maladies virales associées [iPLesp] (THERAVIR), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: Male, 0301 basic medicine, Microbiology (medical), medicine.medical_specialty, multimorbidity, [SDV]Life Sciences [q-bio], HIV Infections, comorbidities, elderly, Cachexia, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Acquired immunodeficiency syndrome (AIDS), [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Internal medicine, Diabetes mellitus, medicine, Humans, 030212 general & internal medicine, Aged, 2. Zero hunger, Acquired Immunodeficiency Syndrome, business.industry, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, aging, virus diseases, HIV, medicine.disease, 030112 virology, Comorbidity, Obesity, CD4 Lymphocyte Count, 3. Good health, Cross-Sectional Studies, Infectious Diseases, Cohort, Coinfection, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Cohort study
Abstract: Background We assessed prevalence of multimorbidity (MM) according to year of human immunodeficiency virus (HIV) diagnosis in elderly people living with HIV (PLWH). Methods This was a cross-sectional study of MM in PLWH aged ≥70 years from the Dat’AIDS French multicenter cohort. MM was defined as at least 3 coexistent morbidities of high blood pressure, diabetes mellitus, osteoporosis, non-AIDS cancer, chronic renal failure, cardiovascular and cerebrovascular disease, obesity, undernutrition, or hypercholesterolemia. Logistic regression models evaluated the association between MM and calendar periods of HIV diagnosis (1983–1996, 1997–2006, and 2007–2018). The secondary analysis evaluated MM as a continuous outcome, and a sensitivity analysis excluded PLWH with nadir CD4 count Results Between January 2017 and September 2018, 2476 PLWH were included. Median age was 73 years, 75% were men, median CD4 count was 578 cells/μL, and 94% had controlled viremia. MM prevalence was 71%. HBP and hypercholesterolemia were the most prevalent comorbidities. After adjustment for age, gender, smoking status, hepatitis C and hepatitis B virus coinfection, group of exposure, nadir CD4 count, CD4:CD8 ratio, and last CD4 level, calendar period of diagnosis was not associated with MM (P = .169). MM was associated with older age, CD4/CD8 ratio Conclusions MM prevalence was high and increased with age, low CD4/CD8 ratio, and nadir CD4 count
Published: 2019

244. The ORC ubiquitin ligase OBI1 promotes DNA replication origin firing

Author: Isabelle Peiffer, Yvon Sterkers, Philippe Coulombe, Axel Delamarre, Slavica Stanojcic, Joelle Nassar, Marcel Méchali, Stéphane Bocquet, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Biologie, Génétique et Pathologie des Pathogènes Eucaryotes (MIVEGEC-BioGEPPE), Pathogènes, Environnement, Santé Humaine (EPATH), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: 0301 basic medicine, DNA Replication, Proteomics, DNA replication initiation, Science, Ubiquitin-Protein Ligases, [SDV]Life Sciences [q-bio], Origin Recognition Complex, General Physics and Astronomy, Replication Origin, 02 engineering and technology, Origin of replication, General Biochemistry, Genetics and Molecular Biology, Article, S Phase, DNA replication factor CDT1, 03 medical and health sciences, Ubiquitin, Humans, lcsh:Science, ComputingMilieux_MISCELLANEOUS, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, biology, Chemistry, G1 Phase, Ubiquitination, General Chemistry, Cell cycle, 021001 nanoscience & nanotechnology, Origin firing, GINS, DNA replication origin, Cell biology, Ubiquitin ligase, 030104 developmental biology, biology.protein, lcsh:Q, 0210 nano-technology, Origin selection
Abstract: DNA replication initiation is a two-step process. During the G1-phase of the cell cycle, the ORC complex, CDC6, CDT1, and MCM2–7 assemble at replication origins, forming pre-replicative complexes (pre-RCs). In S-phase, kinase activities allow fork establishment through (CDC45/MCM2–7/GINS) CMG-complex formation. However, only a subset of all potential origins becomes activated, through a poorly understood selection mechanism. Here we analyse the pre-RC proteomic interactome in human cells and find C13ORF7/RNF219 (hereafter called OBI1, for ORC-ubiquitin-ligase-1) associated with the ORC complex. OBI1 silencing result in defective origin firing, as shown by reduced CMG formation, without affecting pre-RC establishment. OBI1 catalyses the multi-mono-ubiquitylation of a subset of chromatin-bound ORC3 and ORC5 during S-phase. Importantly, expression of non-ubiquitylable ORC3/5 mutants impairs origin firing, demonstrating their relevance as OBI1 substrates for origin firing. Our results identify a ubiquitin signalling pathway involved in origin activation and provide a candidate protein for selecting the origins to be fired., DNA replication is initiated at defined genomic sites called origins of replication following ORC pre-replicative complex assembly. Here the authors identify a protein ubiquitylating ORC that is involved in origin activation and may act as a selector of origins to be fired.
Published: 2019

245. Maternal embryonic leucine zipper kinase is a novel target for diffuse large B cell lymphoma and mantle cell lymphoma

Author: Eline Menu, Ken Maes, Philip Vlummens, Julie Devin, Karin Vanderkerken, Anke Maes, Elke De Bruyne, Hendrik De Raeve, Vanessa Szablewski, Jérôme Moreaux, Kim De Veirman, Vrije Universiteit Brussel (VUB), Center for Medical Genetics [Ghent], Ghent University Hospital, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre National de la Recherche Scientifique (CNRS), Service de Biopathologie [CHRU Montpellier], Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Clinical sciences, Faculty of Medicine and Pharmacy, Basic (bio-) Medical Sciences, Hematology, Experimental Pathology, Pathology, and R&D centraal
Subjects: Gene Expression, Apoptosis, Lymphoma, Mantle-Cell, Maternal embryonic leucine zipper kinase, Mice, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, MELK, Medicine and Health Sciences, Molecular Targeted Therapy, cancer cell, Medicine(all), 0303 health sciences, B-cell lymphoma, non-Hodgkin lymphoma, Cell Cycle, PROLIFERATION, INHIBITOR, Hematology, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Treatment Outcome, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, GROWTH, Female, aggressive B cell non-Hodgkin lymphomas, Lymphoma, Large B-Cell, Diffuse, EXPRESSION, PROMISING THERAPEUTIC TARGET, mantle cell lymphoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, Diffuse large B cell lymphoma, Protein Serine-Threonine Kinases, Biology, lcsh:RC254-282, Article, mantle cell lymphoma (MCL), 03 medical and health sciences, Cell Line, Tumor, Biomarkers, Tumor, medicine, Animals, Humans, RITUXIMAB, Naphthyridines, Protein Kinase Inhibitors, B cell, 030304 developmental biology, Diffuse large B cell lymphoma (DLBCL), Dose-Response Relationship, Drug, Cell growth, Translational research, EFFICACY, medicine.disease, Xenograft Model Antitumor Assays, Lymphoma, Disease Models, Animal, DISCOVERY, Cancer cell, Cancer research, FOXM1, RADIATION, Mantle cell lymphoma, Diffuse large B-cell lymphoma, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are among the most aggressive B cell non-Hodgkin lymphomas. Maternal embryonic leucine zipper kinase (MELK) plays a role in cancer cell cycle progression and is associated with poor prognosis in several cancer cell types. In this study, the role of MELK in DLBCL and MCL and the therapeutic potential of MELK targeting is evaluated. MELK is highly expressed in DLBCL and MCL patient samples, correlating with a worse clinical outcome in DLBCL. Targeting MELK, using the small molecule OTSSP167, impaired cell growth and survival and induced caspase-mediated apoptosis in the lymphoma cells. Western blot analysis revealed that MELK targeting decreased the phosphorylation of FOXM1 and the protein levels of EZH2 and several mitotic regulators, such as Cdc25B, cyclin B1, Plk-1, and Aurora kinases. In addition, OTSSP167 also sensitized the lymphoma cells to the clinically relevant Bcl-2 inhibitor venetoclax by strongly reducing Mcl1 levels. Finally, OTSSP167 treatment of A20-inoculated mice resulted in a significant prolonged survival. In conclusion, targeting MELK with OTSSP167 induced strong anti-lymphoma activity both in vitro and in vivo. These findings suggest that MELK could be a potential new target in these aggressive B cell malignancies.
Published: 2019

246. Global chromatin conformation differences in the Drosophila dosage compensated chromosome X

Author: Giacomo Cavalli, Emilia Maria Cristina Mazza, Mattia Forcato, Tom Sexton, Daniel Jost, Koustav Pal, Cédric Vaillant, Elisa Salviato, Francesco Ferrari, Enrico Lugli, Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Biologie Computationnelle et Mathématique (TIMC-IMAG-BCM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Joliot Curie, École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS), Humanitas Clinical and Research Center [Rozzano, Milan, Italy], Jost, Daniel, Università degli Studi di Modena e Reggio Emilia (UNIMORE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and École normale supérieure de Lyon (ENS de Lyon)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Transcriptional Activation, 0301 basic medicine, X Chromosome, Science, [SDV]Life Sciences [q-bio], Molecular Conformation, General Physics and Astronomy, Biology, Chromatin structure, Article, Chromosomes, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Chromosome (genetic algorithm), Downregulation and upregulation, Genes, X-Linked, Dosage Compensation, Genetic, Animals, Drosophila Proteins, Dosage compensation, lcsh:Science, X chromosome, ComputingMilieux_MISCELLANEOUS, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], Multidisciplinary, Embryo, General Chemistry, biology.organism_classification, Dosage compensation complex, Chromatin, Chromosomes, Insect, Computational biology and bioinformatics, Gene regulation, Cell biology, [SDV] Life Sciences [q-bio], Drosophila melanogaster, 030104 developmental biology, lcsh:Q, Female, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], 030217 neurology & neurosurgery
Abstract: In Drosophila melanogaster the single male chromosome X undergoes an average twofold transcriptional upregulation for balancing the transcriptional output between sexes. Previous literature hypothesised that a global change in chromosome structure may accompany this process. However, recent studies based on Hi-C failed to detect these differences. Here we show that global conformational differences are specifically present in the male chromosome X and detectable using Hi-C data on sex-sorted embryos, as well as male and female cell lines, by leveraging custom data analysis solutions. We find the male chromosome X has more mid-/long-range interactions. We also identify differences at structural domain boundaries containing BEAF-32 in conjunction with CP190 or Chromator. Weakening of these domain boundaries in male chromosome X co-localizes with the binding of the dosage compensation complex and its co-factor CLAMP, reported to enhance chromatin accessibility. Together, our data strongly indicate that chromosome X dosage compensation affects global chromosome structure., In Drosophila, dosage compensation involves a twofold transcriptional upregulation of the single male chromosome X. Here the authors show that global conformational differences are specifically present in the male X chromosome and detectable using Hi-C data, indicating that dosage compensation affects global chromosome structure.
Published: 2019

247. Methanogenic Archaea: Emerging Partners in the Field of Allergic Diseases

Author: Soraya Mezouar, Youssouf Sereme, Michel Drancourt, Joana Vitte, Ghiles Grine, Pierre Corbeau, J.L. Mège, Microbes évolution phylogénie et infections (MEPHI), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: animal structures, Antimicrobial peptides, Biology, Microbiology, Proinflammatory cytokine, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Three-domain system, medicine, Hypersensitivity, Immunology and Allergy, Animals, Humans, Giant Virus, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, 030306 microbiology, Microbiota, Human microbiome, Inflammasome, General Medicine, Allergens, biology.organism_classification, Archaea, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, Host-Pathogen Interactions, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Disease Susceptibility, Bacteria, medicine.drug
Abstract: Archaea, which form one of four domains of life alongside Eukarya, Bacteria, and giant viruses, have long been neglected as components of the human microbiota and potential opportunistic infectious pathogens. In this review, we focus on methanogenic Archaea, which rely on hydrogen for their metabolism and growth. On one hand, methanogenic Archaea in the gut are functional associates of the fermentative digestion of dietary fibers, favoring the production of beneficial short-chain fatty acids and likely contributing to the weaning reaction during the neonatal window of opportunity. On the other hand, methanogenic Archaea trigger the activation of innate and adaptive responses and the generation of specific T and B cells in animals and humans. In mouse models, lung hypersensitivity reactions can be induced by inhaled methanogenic Archaea mimicking human professional exposure to organic dust. Changes in methanogenic Archaea of the microbiota are detected in an array of dysimmune conditions comprising inflammatory bowel disease, obesity, malnutrition, anorexia, colorectal cancer, and diverticulosis. At the subcellular level, methanogenic Archaea are activators of the TLR8-dependent NLRP3 inflammasome, modulate the release of antimicrobial peptides and drive the production of proinflammatory, Th-1, Th-2, and Th-17 cytokines. Our objective was to introduce the most recent and major pieces of evidence supporting the involvement of Archaea in the balance between health and dysimmune diseases, with a particular focus on atopic and allergic conditions.
Published: 2019

248. Anticorps anti-CD38 dans le myélome multiple

Author: Jérôme Moreaux, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Département Hématologie biologique [CHRU Montpellier], Pôle Biologie-Pathologie [CHRU Montpellier], and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: Programmed cell death, Phagocytosis, [SDV]Life Sciences [q-bio], CD38, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Medicine, Cytotoxicity, Multiple myeloma, Antibody-dependent cell-mediated cytotoxicity, biology, business.industry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, General Medicine, medicine.disease, 3. Good health, Cytolysis, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Antibody, business, 030215 immunology
Abstract: International audience; The high CD38 expression by plasma cells together with the biological functions of CD38 resulted in the development of CD38 antibodies for the treatment of multiple myeloma (MM) patients. The cytolytic activity of CD38 antibodies is mediated by complement-dependent cytoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), direct cell death effects and immunomodulatory effects. CD38 antibodies have demonstrated their clinical benefit as single agent or in combination for the treatment of multiple myeloma patients and will contribute to further improvement in the outcome of MM patients.; La forte expression de la molécule CD38 par les cellules plasmocytaires ainsi que son rôle biologique dans la régulation de l’adhérence et la migration cellulaire, avec des fonctions de signalisation, a conduit au développement d’anticorps spécifiques pour le traitement de patients atteints de myélome multiple (MM). Ces anticorps induisent en effet la mort des cellules de myélome multiple par des mécanismes de lyse cellulaire dépendante du complément (CDC), de cytotoxicité cellulaire dépendante des anticorps (ADCC), de phagocytose cellulaire dépendant des anticorps (ADCP), mais aussi par des mécanismes directs d’induction de mort cellulaire. Ils ont de plus des effets immunomodulateurs liés à l’élimination de cellules immunitaires immunosuppressives qui expriment également CD38. Bien qu’ayant des actions variables par rapport à ce registre d’activité si on les compare entre eux, les anticorps anti-CD38 ont démontré une activité clinique significative, seuls ou en combinaison avec diverses molécules, chez les patients atteints de MM. Ils contribueront sans aucun doute à des progrès majeurs pour la prise en charge thérapeutique des patients atteints de MM.
Published: 2019

249. Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner

Author: Theodoros I. Roumeliotis, Jérôme Moreaux, Julia Gilhodes, Julien Mazieres, Marie-Jeanne Pillaire, Hélène Tourrière, Valérie Bergoglio, Julien N Bianco, Jean-Sébastien Hoffmann, Yea-Lih Lin, Amélie Lusque, Anne-Lyne Schmitz, Jyoti S. Choudhary, Magali Lacroix-Triki, Philippe Pasero, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), 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), Institut Claudius Regaud, CHU Toulouse [Toulouse], Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), The institute of cancer research [London], Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Larose, Catherine, 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), and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: 0301 basic medicine, Timeless, Science, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Adenocarcinoma of Lung, Breast Neoplasms, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, 02 engineering and technology, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Genomic Instability, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Stress, Physiological, Cell Line, Tumor, medicine, Humans, Tumor growth, lcsh:Science, Adaptor Proteins, Signal Transducing, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, Replication stress, Intracellular Signaling Peptides and Proteins, Signal transducing adaptor protein, General Chemistry, HCT116 Cells, 021001 nanoscience & nanotechnology, medicine.disease, Primary tumor, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], 030104 developmental biology, Cell culture, Checkpoint Kinase 1, Cancer cell, MCF-7 Cells, lcsh:Q, Cancer development, biological phenomena, cell phenomena, and immunity, Colorectal Neoplasms, 0210 nano-technology, DNA Damage, HeLa Cells
Abstract: Oncogene-induced replication stress (RS) promotes cancer development but also impedes tumor growth by activating anti-cancer barriers. To determine how cancer cells adapt to RS, we have monitored the expression of different components of the ATR-CHK1 pathway in primary tumor samples. We show that unlike upstream components of the pathway, the checkpoint mediators Claspin and Timeless are overexpressed in a coordinated manner. Remarkably, reducing the levels of Claspin and Timeless in HCT116 cells to pretumoral levels impeded fork progression without affecting checkpoint signaling. These data indicate that high level of Claspin and Timeless increase RS tolerance by protecting replication forks in cancer cells. Moreover, we report that primary fibroblasts adapt to oncogene-induced RS by spontaneously overexpressing Claspin and Timeless, independently of ATR signaling. Altogether, these data indicate that enhanced levels of Claspin and Timeless represent a gain of function that protects cancer cells from of oncogene-induced RS in a checkpoint-independent manner., Oncogene-induced replication stress (RS) promotes cancer development. Here, the authors report that cancer cells adapt to oncogene-induced RS by overexpressing downstream components of ATR-CHK1 pathway, Claspin and Timeless, which have protective role at the replication forks independent of their checkpoint function.
Published: 2019

250. Mutant NR5A1/SF-1 in patients with disorders of sex development shows defective activation of theSOX9TESCO enhancer

Author: Anthony Daniel Bird, Andrew H. Sinclair, Vincent R. Harley, Brittany Croft, Faustine Declosmenil, Peter Koopman, Louisa Mabel Ludbrook, Francis Poulat, Ken McElreavey, Kevin Christopher Knower, Brett Daniel Fisher, Janelle Ryan, Anu Bashamboo, Rajini Sreenivasan, University of Melbourne, Monash University [Victoria, Australia], Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hudson Institute of Medical Research [Clayton], Génétique du Développement humain - Human developmental genetics, Institut Pasteur [Paris] (IP), Murdoch Children’s Research Institute [Melbourne, Australia], Institute for Molecular Bioscience, University of Queensland [Brisbane], and This work was supported by the National Health and Medical Research Council of Australia (NHMRC) Program Grants 334314 and 546517 to V.H., P.K., and A.S. and by the Victorian Government's Operational Infrastructure Support Program (OIS). R.S. was supported by an Australian Postgraduate Award. B.C. is supported by an Australian Government Research Training Program Scholarship, through Monash University. V.H., P.K.. and A.S. are supported by NHMRC Research Fellowships.
Subjects: Male, 0301 basic medicine, Steroidogenic factor 1, MESH: Sequence Analysis, DNA, testis-specific enhancer of SOX9, Mutant, sex determination, DSD, Ligands, Steroidogenic Factor 1, medicine.disease_cause, 0302 clinical medicine, MESH: Child, MESH: Ligands, Disorders of sex development, Child, Genetics (clinical), Regulation of gene expression, Genetics, Mutation, MESH: Infant, Newborn, MESH: Disorder of Sex Development, 46,XY, SOX9 Transcription Factor, MESH: Infant, MESH: Gene Expression Regulation, Enhancer Elements, Genetic, Testis determining factor, MESH: HEK293 Cells, Child, Preschool, SF-1, SOX9, Protein Binding, Adult, MESH: Mutation, Adolescent, 030209 endocrinology & metabolism, Biology, MESH: SOX9 Transcription Factor, 03 medical and health sciences, MESH: Computer Simulation, medicine, MESH: Protein Binding, Humans, Computer Simulation, Enhancer, MESH: Adolescent, MESH: Humans, Disorder of Sex Development, 46,XY, MESH: Child, Preschool, Infant, Newborn, Infant, MESH: Adult, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Sequence Analysis, DNA, MESH: Steroidogenic Factor 1, medicine.disease, MESH: Male, HEK293 Cells, 030104 developmental biology, Gene Expression Regulation, MESH: Enhancer Elements, Genetic
Abstract: International audience; Nuclear receptor subfamily 5 group A member 1/Steroidogenic factor 1 (NR5A1; SF-1; Ad4BP) mutations cause 46,XY disorders of sex development (DSD), with phenotypes ranging from developmentally mild (e.g., hypospadias) to severe (e.g., complete gonadal dysgenesis). The molecular mechanism underlying this spectrum is unclear. During sex determination, SF-1 regulates SOX9 (SRY [sex determining region Y]-box 9) expression. We hypothesized that SF-1 mutations in 46,XY DSD patients affect SOX9 expression via the Testis-specific Enhancer of Sox9 core element, TESCO. Our objective was to assess the ability of 20 SF-1 mutants found in 46,XY DSD patients to activate TESCO. Patient DNA was sequenced for SF-1 mutations and mutant SF-1 proteins were examined for transcriptional activity, protein expression, sub-cellular localization and in silico structural defects. Fifteen of the 20 mutants showed reduced SF-1 activation on TESCO, 11 with atypical sub-cellular localization. Fourteen SF-1 mutants were predicted in silico to alter DNA, ligand or cofactor interactions. Our study may implicate aberrant SF-1-mediated transcriptional regulation of SOX9 in 46,XY DSDs.
Published: 2018

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