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1. Zika virus enhances monocyte adhesion and transmigration favoring viral dissemination to neural cells

Author: Emma Partiot, Nilda Vanesa Ayala-Nunez, Jacky G. Goetz, Gautier Follain, Judith R.E. Roels, Anita Eckly, Béatrice Uring-Lambert, Maxime Chazal, Raphael Gaudin, Gillian Hale, Frank M. J. Jacobs, Sandrine Bourdoulous, Orestis Faklaris, Sherif R. Zaki, Aurélie Hirschler, Nolwenn Jouvenet, Margot Carocci, Florian Bakoa, Sarah Cianférani, Christine Carapito, Frédéric Doussau, Brigid C. Bollweg, François Delalande, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA), Institut National de la Santé et de la Recherche Médicale (INSERM), Immuno-Rhumatologie Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Centers for Disease Control and Prevention [Atlanta] (CDC), Centers for Disease Control and Prevention, Swammerdam Institute for Life Sciences, University of Amsterdam [Amsterdam] (UvA)-Center for Neurosciences, Génomique virale et vaccination, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Université Paris Descartes - Paris 5 (UPD5), 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 de Paris (UP), 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), Biologie et pharmacologie des plaquettes sanguines: hémostase, thrombose, transfusion, Université de Strasbourg (UNISTRA)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), Institut des Neurosciences Cellulaires et Intégratives (INCI), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), This work has received funding from the French State via the French National Research Agency (ANR) as part of the program Investissements d’avenir (IdEx Université de Strasbourg) to RG. This work was supported by an ATIP-AVENIR starting grant to RG. The research leading to these results has received funding from the People Program (Marie Curie Actions) of the European Union’s Seventh Framework Program (FP7/2007–2013) under REA grant agreement no. PCOFUND-GA-2013-609102, through the PRESTIGE program coordinated by Campus France, and from the French Agency for Research on AIDS and Viral Hepatitis (ANRS), both attributed to NVAN. Experiments conducted by G.F. and J.G.G. were funded by Plan Cancer (OptoMetaTrap), Ligue contre le Cancer, Idex Attractivités (University of Strasbourg), and by institutional funds from INSERM and University of Strasbourg. G.F. was supported by a doctoral fellowship from Ligue Contre le Cancer. Mass spectrometry experiments were supported by the French Proteomic Infrastructure (ProFI, ANR-10-INBS-08-03). F.B. is a recipient of a PhD grant provided by ANRT (Association Nationale de la Recherche et de la Technologie). N.J. is funded by Agence Nationale pour la Recherche (ANR-16-CE15-0025-01), Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur. CDC contributions to this paper written and edited by G.L.H. and B.C.B. in their private capacity. No official support or endorsement by the Centers for Disease Control and Prevention, Department of Health and Human Services is intended, nor should be inferred. All authors read, provided feedback, and approved the paper. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. The following reagent was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: HIV-1 NL4-3 AD8 Infectious Molecular Clone (pNL(AD8)) from Dr. Eric O. Freed (cat# 11346)., ANR-16-CE15-0025,Viro-Storm,Mécanismes de production incontrôlée de cytokines au cours de l'infection virale(2016), European Project: 609102,EC:FP7:PEOPLE,FP7-PEOPLE-2013-COFUND,PRESTIGE(2014), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), EFS-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), jouvenet, nolwenn, Mécanismes de production incontrôlée de cytokines au cours de l'infection virale - - Viro-Storm2016 - ANR-16-CE15-0025 - AAPG2016 - VALID, PRES Towards International Gain of Excellence - PRESTIGE - - EC:FP7:PEOPLE2014-09-01 - 2019-08-31 - 609102 - VALID, Equipe Direction scientifique, Sciences et Technologies de la Musique et du Son (STMS), Université Pierre et Marie Curie - Paris 6 (UPMC)-IRCAM-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-IRCAM-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), Neuro-Immunologie Virale, Virologie UMR1161 (VIRO), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Laboratoire de Photonique Quantique et Moléculaire (LPQM), Centre National de la Recherche Scientifique (CNRS)-CentraleSupélec-École normale supérieure - Cachan (ENS Cachan), Biologie et pharmacologie des plaquettes sanguines: hémostase, thrombose, transfusion (http://www.u949.inserm.fr/), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS, Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Spectrométrie de Masse BioOrganique, Département des Sciences Analytiques, Institut Pluridisciplinaire Hubert Curien, Strasbourg, France (LSMBO-DSA-IPHC), Centre National de la Recherche Scientifique (CNRS), Immunorhumathologie moléculaire, Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Molecular Neuroscience (SILS, FNWI)
Subjects: Central Nervous System, 0301 basic medicine, MESH: Neurons, General Physics and Astronomy, MESH: Organoids, MESH: Monocytes, Monocytes, Zika virus, 0302 clinical medicine, MESH: Transendothelial and Transepithelial Migration, Cerebellum, MESH: Animals, lcsh:Science, MESH: Embryonic Stem Cells, ComputingMilieux_MISCELLANEOUS, Zebrafish, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Neurons, Multidisciplinary, Zika Virus Infection, Cell adhesion molecule, food and beverages, Sciences du Vivant [q-bio]/Microbiologie et Parasitologie, Phenotype, 3. Good health, Cell biology, Organoids, Mechanisms of disease, medicine.anatomical_structure, MESH: Cell Survival, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, Endothelium, Cell Survival, Science, MESH: Zika Virus, Biology, MESH: Endothelium, Article, General Biochemistry, Genetics and Molecular Biology, Virus, MESH: Cell Adhesion, 03 medical and health sciences, Virology, medicine, Animals, Humans, MESH: Central Nervous System, Cellular microbiology, Cell adhesion, MESH: Zebrafish, Embryonic Stem Cells, MESH: Humans, Monocyte, fungi, Transendothelial and Transepithelial Migration, Zika Virus, General Chemistry, biology.organism_classification, Embryonic stem cell, MESH: Cerebellum, Disease Models, Animal, 030104 developmental biology, lcsh:Q, MESH: Disease Models, Animal, Cell Adhesion Molecules, MESH: Female, 030217 neurology & neurosurgery
Abstract: Zika virus (ZIKV) invades and persists in the central nervous system (CNS), causing severe neurological diseases. However the virus journey, from the bloodstream to tissues through a mature endothelium, remains unclear. Here, we show that ZIKV-infected monocytes represent suitable carriers for viral dissemination to the CNS using human primary monocytes, cerebral organoids derived from embryonic stem cells, organotypic mouse cerebellar slices, a xenotypic human-zebrafish model, and human fetus brain samples. We find that ZIKV-exposed monocytes exhibit higher expression of adhesion molecules, and higher abilities to attach onto the vessel wall and transmigrate across endothelia. This phenotype is associated to enhanced monocyte-mediated ZIKV dissemination to neural cells. Together, our data show that ZIKV manipulates the monocyte adhesive properties and enhances monocyte transmigration and viral dissemination to neural cells. Monocyte transmigration may represent an important mechanism required for viral tissue invasion and persistence that could be specifically targeted for therapeutic intervention., Zika virus (ZIKV) can infect the central nervous system, but it is not clear how it reaches the brain. Here, Ayala-Nunez et al. show in ex vivo and in vivo models that ZIKV can hitch a ride in monocytes in a Trojan Horse manner to cross the endothelium and disseminate the virus.
Published: 2019

2. The Flemmingsome reveals an ESCRT-to-membrane coupling via ALIX/syntenin/syndecan-4 required for completion of cytokinesis

Author: Quentin Giai Gianetto, Neetu Gupta-Rossi, Mariette Matondo, Stéphane Frémont, Frédérique Cuvelier, Audrey Salles, Julia Chamot-Rooke, Hervé Ménager, Florine Milin, Sandrine Schmutz, Cyril Addi, Murielle Rocancourt, Magalie Duchateau, Arnaud Echard, Thibaut Douché, Adrien Presle, Pascale Zimmermann, Trafic membranaire et Division cellulaire - Membrane Traffic and Cell Division, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Collège doctoral [Sorbonne universités], Sorbonne Université (SU), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Institut Pasteur [Paris], Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology (UTechS MSBio), Institut Pasteur [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Plateforme de Protéomique / Proteomics platform, Institut Pasteur [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, BioImagerie Photonique – Photonic BioImaging (UTechS PBI), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), This work has been supported by Institut Pasteur, CNRS, and ANR (AbCyStem, Cytosign) to A.E. C.A. received a fellowship from the Doctoral School Complexité du Vivant ED515, contrat n° 2412/2016 and AMX. A.P. received a fellowship from the Doctoral School Complexité du Vivant ED515, contrat n°2611 bis/2016 and Fondation ARC pour la recherche sur le cancer (DOC20190508876)., We thank R. Basto, G. Hickson, J. Mathieu, J.-R. Huyhn, R. Shaughnessy, M. Serres, and T. Wai for critical reading of the paper, the Echard Lab members for helpful discussions, the Recombinant antibodies platform (TAb-IP, Institut Curie, Paris) and the DSHB (University of Iowa) for antibodies. GFP-MKLP2 cells were from the Hyman Lab MPI-MCBG Dresden45., UTechS PBI is part of the France–BioImaging infrastructure network (FBI) supported by the French National Research Agency (ANR-10-INSB-04, Investments for the Future), and acknowledges support from ANR/FBI and the Région Ile-de-France (program 'Domaine d’Intérêt Majeur-Malinf') for the use of the Zeiss LSM 780 Elyra PS1 microscope. We thank P.H. Commere from the Utechs CB, Institut Pasteur for FACS sorting., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Collège Doctoral, Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), 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), and Salles, Audrey
Subjects: 0301 basic medicine, Syntenins, SYNDECAN, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Cell Cycle Proteins, Plasma protein binding, ABSCISSION, 0302 clinical medicine, ALIX, SYNTENIN, lcsh:Science, Multidisciplinary, Chemistry, MOLECULAR-MECHANISMS, Transmembrane protein, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], Multidisciplinary Sciences, Midbody, Science & Technology - Other Topics, MACHINERY, LATE STEPS, Protein Binding, Cell division, Science, BIOGENESIS, SCISSION, HIV Budding, Endosomes, macromolecular substances, General Biochemistry, Genetics and Molecular Biology, ESCRT, Article, 03 medical and health sciences, Abscission, Humans, Cytokinesis, Organelles, MIDBODY, Science & Technology, Endosomal Sorting Complexes Required for Transport, Calcium-Binding Proteins, Cell Membrane, General Chemistry, 030104 developmental biology, Membrane protein, Syndecan-4, lcsh:Q, 030217 neurology & neurosurgery, HeLa Cells
Abstract: Cytokinesis requires the constriction of ESCRT-III filaments on the side of the midbody, where abscission occurs. After ESCRT recruitment at the midbody, it is not known how the ESCRT-III machinery localizes to the abscission site. To reveal actors involved in abscission, we obtained the proteome of intact, post-abscission midbodies (Flemmingsome) and identified 489 proteins enriched in this organelle. Among these proteins, we further characterized a plasma membrane-to-ESCRT module composed of the transmembrane proteoglycan syndecan-4, ALIX and syntenin, a protein that bridges ESCRT-III/ALIX to syndecans. The three proteins are highly recruited first at the midbody then at the abscission site, and their depletion delays abscission. Mechanistically, direct interactions between ALIX, syntenin and syndecan-4 are essential for proper enrichment of the ESCRT-III machinery at the abscission site, but not at the midbody. We propose that the ESCRT-III machinery must be physically coupled to a membrane protein at the cytokinetic abscission site for efficient scission, uncovering common requirements in cytokinesis, exosome formation and HIV budding., ESCRT filaments drive the final abscission between two daughter cells but how they physically interact with the membrane is unclear. Using proteomics, the authors show that syndecan-4/syntenin/ALIX couples the ESCRT machinery to the abscission site and thus promotes efficient abscission.
Published: 2020

3. Metadata standards and practical guidelines for specimen and DNA curation when building barcode reference libraries for aquatic life

Author: Magali Schweizer, Frederik Leliaert, Jan Pawlowski, Rodolphe Rougerie, Frédéric Rimet, Torbjørn Ekrem, Alexis Canino, Teofana Chonova, David G. Mann, Agnès Bouchez, Régis Lionel Vivien, Christian Chauvin, Chloé Goulon, Valentin Vasselon, Romain Gastineau, Rosa Trobajo, Christophe Laplace-Treyture, Jonas Zimmermann, Eva Aylagas, Wolf-Henning Kusber, Andrzej Witkowski, Vona Méléder, Frédéric Marchand, Sinziana F. Rivera, Maria Kahlert, Muriel Gugger, Filipe O. Costa, Maria Holzmann, Benoît J.D. Ferrari, Serena Rasconi, Alexander M. Weigand, Regine Jahn, Fedor Čiampor, Florian Leese, Ángel Borja, Centre Alpin de Recherche sur les Réseaux Trophiques et Ecosystèmes Limniques (CARRTEL), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), King Abdullah University of Science and Technology (KAUST), Basque Research and Technology Alliance (BRTA), King Abdulaziz University, Ecosystèmes aquatiques et changements globaux (UR EABX), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Slovak Academy of Science [Bratislava] (SAS), Universidade do Minho, Swiss Centre for Applied Ecotoxicology (Ecotox Center), Ecole Polytechnique Fédérale de Lausanne (EPFL), Technical university of Szczecin, Collection des Cyanobactéries, Institut Pasteur [Paris], University of Geneva [Switzerland], Freie Universität Berlin, Swedish University of Agricultural Sciences (SLU), Universitat Duisberg-Essen, Botanic Garden Meise, Institute of Agrifood Research and Technology [Sant Carles de la Ràpita] (IRTA), Institute of Agrifood Research and Technology (IRTA), Royal Botanic Garden Edinburgh, Unité Expérimentale d'Ecologie et d'Ecotoxicologie Aquatique - U3E (Rennes, France) (U3E ), Université de Nantes (UN), Polish Academy of Sciences (PAN), ID-Gene ecodiagnostics [Geneva], Institut de Systématique, Evolution, Biodiversité (ISYEB ), Muséum national d'Histoire naturelle (MNHN)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles (UA), Laboratoire de Planétologie et Géodynamique [UMR 6112] (LPG), Université d'Angers (UA)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), SCIMABIO Interface SAS, Musée National d'Histoire Naturelle de Luxembourg (MNHN), Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU), This paper was written under COST Action DNAqua-Net. The European COST Action DNAqua-Net (CA 15219 collaborative network which gathers several hundreds of scientists and water managers, with the objective of developing new genetic tools for bioassessment and monitoring of aquatic ecosystems (Leese et al. 2016)., European Project, West Pomeranian University of Technology in Szczecin (ZUT), Universidade do Minho = University of Minho [Braga], Université de Genève = University of Geneva (UNIGE), Institut Pasteur [Paris] (IP), Meise Botanic Garden [Belgium] (Plantentuin), Institut de Recerca i Tecnologia Agroalimentàries = Institute of Agrifood Research and Technology (IRTA), Royal Botanic Garden [Edinburgh], Muséum national d'Histoire naturelle (MNHN)-École Pratique des Hautes Études (EPHE), Producció Animal, and Aigües Marines i Continentals
Subjects: 0106 biological sciences, 0301 basic medicine, Computer science, [SDV]Life Sciences [q-bio], Ciências Biológicas [Ciências Naturais], computer.software_genre, Barcode, 01 natural sciences, DNA barcoding, law.invention, law, QH540-549.5, aquatic organisms, media_common, Database, Ecology, Quality, Voucher, Identification (information), Aquatic organisms, quality, Biologie, Traceability, media_common.quotation_subject, reference library, Engenharia e Tecnologia::Engenharia do Ambiente, 010603 evolutionary biology, 03 medical and health sciences, Genetics (medical genetics to be 30107 and agricultural genetics to be 40402), Genetics, Quality (business), Relevance (information retrieval), 14. Life underwater, Molecular Biology, Nature and Landscape Conservation, Engenharia do Ambiente [Engenharia e Tecnologia], Metadata, Ciências Naturais::Ciências Biológicas, metadata, barcode, Reference library, DNA, 030104 developmental biology, traceability, Animal Science and Zoology, computer
Abstract: DNA barcoding and metabarcoding is increasingly used to effectively and precisely assess and monitor biodiversity in aquatic ecosystems. As these methods rely on data availability and quality of barcode reference libraries, it is important to develop and follow best practices to ensure optimal quality and traceability of the metadata associated with the reference barcodes used for identification. Sufficient metadata, as well as vouchers, corresponding to each reference barcode must be available to ensure reliable barcode library curation and, thereby, provide trustworthy baselines for downstream molecular species identification. This document (1) specifies the data and metadata required to ensure the relevance, the accessibility and traceability of DNA barcodes and (2) specifies the recommendations for DNA harvesting and for the storage of both voucher specimens/samples and barcode data, (undefined)
Published: 2021

4. MDR M. tuberculosis outbreak clone in Eswatini missed by Xpert has elevated bedaquiline resistance dated to the pre-treatment era

Author: Elisabeth Sanchez-Padilla, Nazir Ahmed Ismail, Thomas Kohl, Christian Utpatel, Patrick Beckert, Stefan Niemann, Claudio U. Köser, Harald Hoffmann, Sönke Andres, Robin M. Warren, Bouke C. de Jong, Marisa Klopper, Matthias Merker, Florian P. Maurer, Shaheed V. Omar, Katharina Kranzer, Maryline Bonnet, Bernhard Kerschberger, Viola Dreyer, Ivan Barilar, Elisa Ardizzoni, Birgit Schramm, Gugu Maphalala, Forschungszentrum Borstel - Research Center Borstel, German Center for Infection Research (DZIF), Heidelberg University, Epicentre [Paris] [Médecins Sans Frontières], University of Cambridge [UK] (CAM), National Institute for Communicable Diseases [Johannesburg] (NICD), University of Pretoria [South Africa], University of the Witwatersrand [Johannesburg] (WITS), Stellenbosch University, Institute of Tropical Medicine [Antwerp] (ITM), London School of Hygiene and Tropical Medicine (LSHTM), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Université Montpellier 1 (UM1)-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), 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), University of Namibia (UNAM), Parts of this work have been supported by the European Union TB-PAN-NET (FP7-223681) project, by Médecins Sans Frontières-Switzerland, and by German Center for Infection Research, Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germanys Excellence Strategy – EXC 2167, and Leibniz Science Campus Evolutionary Medicine of the LUNG (EvoLUNG). The funders had no role in the study design, in the collection, analysis, and interpretation of the data, in the writing of the report, and in the decision to submit the paper for publication., European Project: 223681,EC:FP7:HEALTH,FP7-HEALTH-2007-B,TB PAN-NET(2009), Niemann, Stefan [0000-0002-6604-0684], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, MESH: Mycobacterium tuberculosis, Antitubercular Agents, Drug resistance, Multidrug resistance, Disease Outbreaks, Clofazimine, chemistry.chemical_compound, Tuberculosis, Multidrug-Resistant, MESH: Disease Outbreaks, Diarylquinolines, MESH: Bacterial Proteins, Genetics (clinical), MESH: Microbial Sensitivity Tests, Resistance mutation, MESH: Diarylquinolines, Mycobacterium tuberculosis complex, Molecular Medicine, medicine.drug, MESH: Mutation, Tuberculosis, 030106 microbiology, Microbial Sensitivity Tests, Biology, 03 medical and health sciences, Bacterial Proteins, MESH: Eswatini, Genetics, medicine, Humans, Molecular Biology, MESH: Tuberculosis, Multidrug-Resistant, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Diagnostice escape, Research, MESH: Clone Cells, Resistance evolution, Treatment escape, Mycobacterium tuberculosis, rpoB, medicine.disease, biology.organism_classification, MESH: Antitubercular Agents, Virology, Clone Cells, Multiple drug resistance, MDR outbreak strains, 030104 developmental biology, chemistry, Treatment failure, Mutation, Bedaquiline, Eswatini
Abstract: Background Multidrug-resistant (MDR) Mycobacterium tuberculosis complex strains not detected by commercial molecular drug susceptibility testing (mDST) assays due to the RpoB I491F resistance mutation are threatening the control of MDR tuberculosis (MDR-TB) in Eswatini. Methods We investigate the evolution and spread of MDR strains in Eswatini with a focus on bedaquiline (BDQ) and clofazimine (CFZ) resistance using whole-genome sequencing in two collections ((1) national drug resistance survey, 2009–2010; (2) MDR strains from the Nhlangano region, 2014–2017). Results MDR strains in collection 1 had a high cluster rate (95%, 117/123 MDR strains) with 55% grouped into the two largest clusters (gCL3, n = 28; gCL10, n = 40). All gCL10 isolates, which likely emerged around 1993 (95% highest posterior density 1987–1998), carried the mutation RpoB I491F that is missed by commercial mDST assays. In addition, 21 (53%) gCL10 isolates shared a Rv0678 M146T mutation that correlated with elevated minimum inhibitory concentrations (MICs) to BDQ and CFZ compared to wild type isolates. gCL10 isolates with the Rv0678 M146T mutation were also detected in collection 2. Conclusion The high clustering rate suggests that transmission has been driving the MDR-TB epidemic in Eswatini for three decades. The presence of MDR strains in Eswatini that are not detected by commercial mDST assays and have elevated MICs to BDQ and CFZ potentially jeopardizes the successful implementation of new MDR-TB treatment guidelines. Measures to limit the spread of these outbreak isolates need to be implemented urgently.
Published: 2020

5. Interdisciplinary Research in Artificial Intelligence: Challenges and Opportunities

Author: Remy Kusters, Dusan Misevic, Hugues Berry, Antoine Cully, Yann Le Cunff, Loic Dandoy, Natalia Díaz-Rodríguez, Marion Ficher, Jonathan Grizou, Alice Othmani, Themis Palpanas, Matthieu Komorowski, Patrick Loiseau, Clément Moulin Frier, Santino Nanini, Daniele Quercia, Michele Sebag, Françoise Soulié Fogelman, Sofiane Taleb, Liubov Tupikina, Vaibhav Sahu, Jill-Jênn Vie, Fatima Wehbi, Centre de Recherche Interdisciplinaire / Center for Research and Interdisciplinarity [Paris, France] (CRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Artificial Evolution and Computational Biology (BEAGLE), Laboratoire d'InfoRmatique en Image et Systèmes d'information (LIRIS), Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-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), Imperial College London, Institut de Génétique et Développement de Rennes (IGDR), 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 ), Flowing Epigenetic Robots and Systems (Flowers), Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), École Nationale Supérieure de Techniques Avancées (ENSTA Paris), Laboratoire Images, Signaux et Systèmes Intelligents (LISSI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Performance analysis and optimization of LARge Infrastructures and Systems (POLARIS), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire d'Informatique de Grenoble (LIG), 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)-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), Nokia Bell Labs [Cambridge], TAckling the Underspecified (TAU), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de Recherche en Informatique (LRI), CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Hub France IA, Nokia Bell Labs [Paris-Saclay], Scool (Scool), Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Informatique, Signal et Automatique de Lille - UMR 9189 (CRIStAL), Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Thanks to the Bettencourt Schueller Foundation long term partnership, the workshop that gave rise to this paper was partially supported by the funding from CRI Research Collaboratory, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), 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)-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)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire d'InfoRmatique en Image et Systèmes d'information (LIRIS), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École Centrale de Lyon (ECL), Université de Lyon-Université Lumière - Lyon 2 (UL2)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Université Lumière - Lyon 2 (UL2), 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), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Unité d'Informatique et d'Ingénierie des Systèmes (U2IS), École Nationale Supérieure de Techniques Avancées (ENSTA Paris)-École Nationale Supérieure de Techniques Avancées (ENSTA Paris), Université de Rennes 1 (UR1), and 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 )
Subjects: Big Data, 0301 basic medicine, [SCCO.COMP]Cognitive science/Computer science, [INFO.INFO-NE]Computer Science [cs]/Neural and Evolutionary Computing [cs.NE], [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], 03 medical and health sciences, 0302 clinical medicine, Political science, Health care, Computer Science (miscellaneous), auditability, education, lcsh:T58.5-58.64, Ai education, business.industry, lcsh:Information technology, interdisciplinary science, Precision medicine, artificial intelligence, Transparency (behavior), ethics, Variety (cybernetics), 030104 developmental biology, [INFO.INFO-MA]Computer Science [cs]/Multiagent Systems [cs.MA], Perspective, Artificial intelligence, business, interpretability, 030217 neurology & neurosurgery, Information Systems
Abstract: The use of artificial intelligence (AI) in a variety of research fields is speeding up multiple digital revolutions, from shifting paradigms in healthcare, precision medicine and wearable sensing, to public services and education offered to the masses around the world, to future cities made optimally efficient by autonomous driving. When a revolution happens, the consequences are not obvious straight away, and to date, there is no uniformly adapted framework to guide AI research to ensure a sustainable societal transition. To answer this need, here we analyze three key challenges to interdisciplinary AI research, and deliver three broad conclusions: 1) future development of AI should not only impact other scientific domains but should also take inspiration and benefit from other fields of science, 2) AI research must be accompanied by decision explainability, dataset bias transparency as well as development of evaluation methodologies and creation of regulatory agencies to ensure responsibility, and 3) AI education should receive more attention, efforts and innovation from the educational and scientific communities. Our analysis is of interest not only to AI practitioners but also to other researchers and the general public as it offers ways to guide the emerging collaborations and interactions toward the most fruitful outcomes.
Published: 2020

6. Programming Strategies for Irregular Algorithms on the Emu Chick

Author: Jiajia Li, Ümit V. Çatalyürek, Rich Vuduc, Jeffrey Young, Bora Uçar, Eric R. Hein, Abdurrahman Yasar, Srinivas Eswar, Jason Riedy, Thomas M. Conte, Emu Technology, Georgia Institute of Technology [Atlanta], Pacific Northwest National Laboratory (PNNL), Optimisation des ressources : modèles, algorithmes et ordonnancement (ROMA), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de l'Informatique du Parallélisme (LIP), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-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-Centre National de la Recherche Scientifique (CNRS), Laboratoire de l'Informatique du Parallélisme (LIP), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), This work partially was supported by NSF Grant ACI-1339745 (XScala), an IARPA contract, and the Defense Advanced Research Projects Agency (DARPA) under agreement #HR0011-13-2-0001. Any opinions, findings, conclusions, or recommendations in this paper are solely those of the authors and do not necessarily reflect the position or the policy of the sponsors. Thanks also to the Emu Technology team for support and debugging assistance with the Emu Chick prototype, and to the reviewers for their thoughtful comments., École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL)
Subjects: FOS: Computer and information sciences, 0301 basic medicine, Computer science, [INFO.INFO-DS]Computer Science [cs]/Data Structures and Algorithms [cs.DS], Memory bandwidth, 02 engineering and technology, Thread (computing), 020202 computer hardware & architecture, Computer Science Applications, 03 medical and health sciences, 030104 developmental biology, Computational Theory and Mathematics, Application-specific integrated circuit, Computer Science - Distributed, Parallel, and Cluster Computing, Hardware and Architecture, Modeling and Simulation, 0202 electrical engineering, electronic engineering, information engineering, Graph alignment, Bandwidth (computing), Distributed, Parallel, and Cluster Computing (cs.DC), [INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], Field-programmable gate array, Algorithm, Software, Analysis of algorithms
Abstract: The Emu Chick prototype implements migratory memory-side processing in a novel hardware system. Rather than transferring large amounts of data across the system interconnect, the Emu Chick moves lightweight thread contexts to near-memory cores before the beginning of each remote memory read. Previous work has characterized the performance of the Chick prototype in terms of memory bandwidth and programming differences from more typical, non-migratory platforms, but there has not yet been an analysis of algorithms on this system. This work evaluates irregular algorithms that could benefit from the lightweight, memory-side processing of the Chick and demonstrates techniques and optimization strategies for achieving performance in sparse matrix-vector multiply operation (SpMV), breadth-first search (BFS), and graph alignment across up to eight distributed nodes encompassing 64 nodelets in the Chick system. We also define and justify relative metrics to compare prototype FPGA-based hardware with established ASIC architectures. The Chick currently supports up to 68x scaling for graph alignment, 80 MTEPS for BFS on balanced graphs, and 50% of measured STREAM bandwidth for SpMV.
Published: 2020

7. The interplay between innate lymphoid cells and T cells

Author: Gayetri Ramachandran, Rachel Golub, Marie Cherrier, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), M.C. is supported by INSERM and Association François Aupetit dedicated to patients suffering from IBD. R.G. work is supported by Institut Pasteur, Institut National de la Santé et de la Recherche Médicale, Université de Paris, and ANR project NASHILCCD8 (#18-CE15-0024-01)., We thank Serge van de Pavert for critical discussions and for review of the paper., ANR-18-CE15-0024,NASHILCCD8,Contribution des ILC et des cellules T CD8 à la stéatose hépatique non alcoolique et à sa progression vers l'hépatocarcinome.(2018), Vougny, Marie-Christine, APPEL À PROJETS GÉNÉRIQUE 2018 - Contribution des ILC et des cellules T CD8 à la stéatose hépatique non alcoolique et à sa progression vers l'hépatocarcinome. - - NASHILCCD82018 - ANR-18-CE15-0024 - AAPG2018 - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: 0301 basic medicine, Cell type, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Context (language use), Cell Communication, Biology, Gut flora, Adaptive Immunity, Lymphocyte Activation, Substrate Specificity, Immunomodulation, 03 medical and health sciences, 0302 clinical medicine, Immune system, T-Lymphocyte Subsets, Immunology and Allergy, Animals, Humans, skin and connective tissue diseases, Immunity, Cellular, Innate lymphoid cell, Cell Differentiation, Acquired immune system, biology.organism_classification, Immunity, Innate, body regions, 030104 developmental biology, Gene Expression Regulation, Host-Pathogen Interactions, [SDV.IMM]Life Sciences [q-bio]/Immunology, Neuroscience, Immunologic Memory, Function (biology), Homeostasis, Biomarkers, 030215 immunology, Signal Transduction
Abstract: International audience; ILCs and T cells are closely related functionally but they significantly differ in their ability to circulate, expand, and renew. Cooperation and reciprocal functional regulation suggest that these cell types are more complementary than simply redundant during immune responses. How ILCs shape T-cell responses is strongly dependent on the tissue and inflammatory context. Likewise, indirect regulation of ILCs by adaptive immunity is induced by environmental cues such as the gut microbiota. Here, we review shared requirements for the development and function of both cell types and divergences in the orchestration of prototypic immune functions. We discuss the diversity of functional interactions between T cells and ILCs during homeostasis and immune responses. Identifying the location and the nature of the tissue microenvironment in which these interactions are taking place may uncover the remaining mysteries of their close encounters.
Published: 2020

8. Clinical and epidemiological characteristics of 1420 European patients with mild‐to‐moderate coronavirus disease 2019

Author: Lechien, Jerome R., Chiesa‐Estomba, Carlos M., Place, Sammy, Van Laethem, Yves, Cabaraux, Pierre, Mat, Quentin, Huet, Kathy, Plzak, Jan, Horoi, Mihaela, Hans, Stéphane, Rosaria Barillari, Maria, Cammaroto, Giovanni, Fakhry, Nicolas, Martiny, Delphine, Ayad, Tareck, Jouffe, Lionel, Hopkins, Claire, Saussez, Sven, Blecic, Serge, De Siati, Daniele R., Leich, Pierre, Souchay, Christel, Rossi, Camelia, Journe, Fabrice, Hsieh, Julien, Ris, Laurence, El Afia, Fahd, Harmegnies, Bernard, Distinguin, Lea, Chekkoury‐Idrissi, Younes, Circiu, Marta, Lavigne, Philippe, Lopez Delgado, Irene, Calvo‐Henriquez, Christian, Falanga, Chiara, Coppee, Frederique, Le Bon, Serge Daniel, Rodriguez, Alexandra, Dequanter, Didier, Cornelis, Jean‐Philippe, Vergez, Sebastien, Koenen, Lukas, Giuditta, Mannelli, Molteni, Gabriele, Tucciarone, Manuel, Radulesco, Thomas, Khalife, Mohamad, Fourneau, Anne‐Francoise, Cherifi, Soraya, Manto, Mario, Michel, Justin, Mannelli, Giuditta, Cantarella, Giovanna, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Assistance Publique - Hôpitaux de Marseille (APHM), Laboratoire Parole et Langage (LPL), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), We would like to thank Bayesia (BayesiaLab?, Chang?, France) for the Network Analysis, Jean-Louis Vincent and Michel Van Haeverbeek for the review of the paper or their useful comments, the heads of the Hospitals, which have been involved in the study, for their help in the rapid conduction of the study and the agreement of ethics committees, the European Press/Media (i.e. Le Monde, La Libre, Le Soir, MediQuality, MedScape, and Le Specialiste) for their help in the spread of the information about the study, and FRMH & UMONS for the grant and the support., Lechien, J. R., Chiesa-Estomba, C. M., Place, S., Van Laethem, Y., Cabaraux, P., Mat, Q., Huet, K., Plzak, J., Horoi, M., Hans, S., Barillari, M. R., Cammaroto, G., Fakhry, N., Martiny, D., Ayad, T., Jouffe, L., Hopkins, C., Saussez, S., Blecic, S., De Siati, D. R., Leich, P., Souchay, C., Rossi, C., Journe, F., Hsieh, J., Ris, L., El Afia, F., Harmegnies, B., Distinguin, L., Chekkoury-Idrissi, Y., Circiu, M., Lavigne, P., Lopez Delgado, I., Calvo-Henriquez, C., Falanga, C., Coppee, F., Le Bon, S. D., Rodriguez, A., Dequanter, D., Cornelis, J. -P., Vergez, S., Koenen, L., Giuditta, M., Molteni, G., Tucciarone, M., Radulesco, T., Khalife, M., Fourneau, A. -F., Cherifi, S., Manto, M., Michel, J., Mannelli, G., and Cantarella, G.
Subjects: 0301 basic medicine, myalgia, Male, medicine, Original, [SDV]Life Sciences [q-bio], coronavirus, symptoms, Disease, epidemiological, 030204 cardiovascular system & hematology, patients, clinical, Olfaction Disorders, Taste Disorders, 0302 clinical medicine, Epidemiology, Sore throat, Prevalence, Nose, Age Factors, Headache, Middle Aged, 3. Good health, Europe, medicine.anatomical_structure, COVID-19, Female, patient, medicine.symptom, Symptom Assessment, Coronavirus Infections, Sex characteristics, Adult, medicine.medical_specialty, Pneumonia, Viral, 03 medical and health sciences, Betacoronavirus, Sex Factors, Throat, Internal medicine, Internal Medicine, Humans, Pandemics, covid‐19, rhinorrhea, business.industry, SARS-CoV-2, Bayes Theorem, Myalgia, coronaviru, 030104 developmental biology, business
Abstract: International audience; Background: The clinical presentation of European patients with mild-to-moderate COVID-19 infection is still unknown. Objective: To study the clinical presentation of COVID-19 in Europe. Methods: Patients with positive diagnosis of COVID-19 were recruited from 18 European hospitals. Epidemiological and clinical data were obtained through a standardized questionnaire. Bayesian analysis was used for analysing the relationship between outcomes. Results: A total of 1,420 patients completed the study (962 females, 30.7% of healthcare workers). The mean age of patients was 39.17 ± 12.09 years. The most common symptoms were headache (70.3%), loss of smell (70.2%), nasal obstruction (67.8%), cough (63.2%), asthenia (63.3%), myalgia (62.5%), rhinorrhea (60.1%), gustatory dysfunction (54.2%) and sore throat (52.9%). Fever was reported by 45.4%. The mean duration of COVID-19 symptoms of mild-to-moderate cured patients was 11.5 ± 5.7 days. The prevalence of symptoms significantly varied according to age and sex. Young patients more frequently had ear, nose and throat complaints, whereas elderly individuals often presented fever, fatigue and loss of appetite. Loss of smell, headache, nasal obstruction and fatigue were more prevalent in female patients. The loss of smell was a key symptom of mild-to-moderate COVID-19 patients and was not associated with nasal obstruction and rhinorrhea. Loss of smell persisted at least 7 days after the disease in 37.5% of cured patients. Conclusion: The clinical presentation of mild-to-moderate COVID-19 substantially varies according to the age and the sex characteristics of patients. Olfactory dysfunction seems to be an important underestimated symptom of mild-to-moderate COVID-19 that needs to be recognized as such by the WHO.
Published: 2020
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9. The nicotinic receptor alpha5 coding polymorphism rs16969968 as a major target in disease: Functional dissection and remaining challenges

Author: Uwe Maskos, Neurobiologie intégrative des Systèmes cholinergiques / Integrative Neurobiology of Cholinergic Systems (NISC), Sorbonne Université (SU)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), he author has received funding to carry out the work of his laboratory described in the Review article, as indicated in the published papers. No funding has been received that is directly relevant to this Review article. The author has no conflict of interest to declare., and Institut Pasteur [Paris] (IP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, human genetics, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Disease, Receptors, Nicotinic, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Biochemistry, nicotine addiction, drug discovery, 03 medical and health sciences, Cellular and Molecular Neuroscience, [SCCO]Cognitive science, 0302 clinical medicine, single nucleotide polymorphism, Animals, Humans, nicotinic acetylcholine receptor, Genetic association, [SCCO.NEUR]Cognitive science/Neuroscience, Human genetics, 3. Good health, schizophrenia, Nicotinic acetylcholine receptor, 030104 developmental biology, Nicotinic agonist, positive allosteric modulator, Genome-wide Association Studies, 030217 neurology & neurosurgery
Abstract: International audience; Nicotinic acetylcholine receptors (nAChRs) are major signalling molecules in the central and peripheral nervous system. Over the last decade, they have been linked to a number of major human psychiatric and neurological conditions, like smoking, schizophrenia, Alzheimer's disease and many others. Human Genome-Wide Association Studies (GWAS) have robustly identified genetic alterations at a locus of chromosome 15q to several of these diseases. In this review, we discuss a major coding polymorphism in the alpha5 subunit, referred to as α5SNP, and its functional dissection in vitro and in vivo. Its presence at high frequency in many human populations lends itself to pharmaceutical intervention in the context of 'positive allosteric modulators' (PAMs). We will present the prospects of this novel treatment, and the remaining challenges to identify suitable molecules.
Published: 2020

10. Potential of Aedes albopictus and Aedes aegypti (Diptera: Culicidae) to transmit yellow fever virus in urban areas in Central Africa

Author: Basile Kamgang, Aurelie P. Yougang, Theodel A. Wilson-Bahun, Armel N. Tedjou, Charles S. Wondji, Laurence Mousson, Anna-Bella Failloux, Marie Vazeille, Centre for Research in Infectious Diseases [Yaoundé] (CRID), Arbovirus et Insectes Vecteurs - Arboviruses and Insect Vectors, Institut Pasteur [Paris] (IP), Université de Yaoundé I, University Marien Ngouabi of Brazzaville (umng), Liverpool School of Tropical Medicine (LSTM), This study was supported by a Wellcome Trust Training Fellowship in Public Health and Tropical Medicine [grant number 204862/Z/16/Z] awarded to BK., We would like to thank the populations of different collection sites for their collaboration during the field works. BK, CSW and ABF designed the experiments. BK performed the research. MV and LM provided a technical help. ANT, APY, TAWB helped in mosquito collections, BK, CSW and ABF wrote the paper with contribution from all other authors., and Institut Pasteur [Paris]
Subjects: 0301 basic medicine, medicine.medical_specialty, Aedes albopictus, Epidemiology, 030106 microbiology, Immunology, wa_395, Mosquito Vectors, Aedes aegypti, Microbiology, Article, law.invention, 03 medical and health sciences, Aedes, law, Virology, Yellow Fever, Drug Discovery, parasitic diseases, medicine, Animals, Humans, qx_525, Africa, Central, Socioeconomics, yellow fever virus, vector competence, Central Africa, biology, Public health, Yellow fever, Outbreak, General Medicine, biology.organism_classification, medicine.disease, wc_530, 3. Good health, 030104 developmental biology, Infectious Diseases, Geography, Transmission (mechanics), Vector (epidemiology), [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, Parasitology
Abstract: International audience; Yellow Fever (YF) remains a major public health issue in Sub-Saharan Africa and South America, despite the availability of an effective vaccine. In Africa, most YF outbreaks are reported in West Africa. However, urban outbreaks occurred in 2016 in both Angola and the Democratic Republic of Congo (DRC), and imported cases were reported in Chinese workers coming back from Africa. In Central Africa, Cameroon and the Republic of Congo host a high proportion of non-vaccinated populations increasing the risk of urban outbreaks. The main vector is Aedes aegypti and possibly, Aedes albopictus, both being anthropophilic and domestic mosquitoes. Here, we provide evidence that both Ae. aegypti and Ae. albopictus in Cameroon and the Republic of Congo are able to transmit Yellow fever virus (YFV) with higher rates of infection, dissemination, and transmission for Ae. aegypti. We conclude that the potential of both Aedes species to transmit YFV could increase the risk of urban YF transmission and urge public health authorities to intensify their efforts to control domestic vectors, and extend vaccine coverage to prevent major YFV outbreak.
Published: 2019

11. Quantifying model evidence for yellow fever transmission routes in Africa

Author: Katy A. M. Gaythorpe, Laurence Cibrelus, Tini Garske, Kévin Jean, Imperial College London, Laboratoire Modélisation, épidémiologie et surveillance des risques sanitaires (MESuRS), Conservatoire National des Arts et Métiers [CNAM] (CNAM), Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), World Health Organisation (WHO), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Funding:This work was carried out as part of the Vaccine Impact Modelling Consortium (www.vaccineimpact.org),but the views expressed are those of the authors and not necessarily those of the Consortium or its funders.The funders were given the opportunity to review this paper prior to publication,but the final decision on the content of the publication was taken by the authors.We acknowledge joint Centre funding from the UK Medical Research Council and Department for International Development. The research leading to these results has received funding from the Bill & Melinda Gates foundation (OPP1117543,OPP1157270 http://www.gatesfoundation.org/)and from the Medical Research Council (MR/R015600/1https://mrc.ukri.org/)., HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), and Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)
Subjects: 0301 basic medicine, Viral Diseases, Epidemiology, Force of infection, Statics, Pathology and Laboratory Medicine, law.invention, Geographical Locations, Bayes' theorem, 0302 clinical medicine, law, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Aedes, Statistics, Medicine and Health Sciences, Public and Occupational Health, Biology (General), Ecology, Physics, Yellow fever, Linear model, Classical Mechanics, Vaccination and Immunization, Geography, Transmission (mechanics), Infectious Diseases, Serology, Computational Theory and Mathematics, INFECTIONS, Modeling and Simulation, Physical Sciences, Yellow fever virus, Life Sciences & Biomedicine, Research Article, Generalized linear model, Biochemistry & Molecular Biology, Bioinformatics, QH301-705.5, Immunology, Bayesian inference, Models, Biological, Biochemical Research Methods, BAYESIAN MODEL, Infectious Disease Epidemiology, 03 medical and health sciences, Cellular and Molecular Neuroscience, Yellow Fever, Genetics, medicine, Animals, Humans, Molecular Biology, 01 Mathematical Sciences, Ecology, Evolution, Behavior and Systematics, Estimation, Science & Technology, Models, Statistical, Biology and Life Sciences, Computational Biology, Bayes Theorem, 06 Biological Sciences, medicine.disease, 030104 developmental biology, People and Places, Africa, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Mathematical & Computational Biology, 08 Information and Computing Sciences, Preventive Medicine, 030217 neurology & neurosurgery
Abstract: Yellow fever is a vector-borne disease endemic in tropical regions of Africa, where 90% of the global burden occurs, and Latin America. It is notoriously under-reported with uncertainty arising from a complex transmission cycle including a sylvatic reservoir and non-specific symptom set. Resulting estimates of burden, particularly in Africa, are highly uncertain. We examine two established models of yellow fever transmission within a Bayesian model averaging framework in order to assess the relative evidence for each model’s assumptions and to highlight possible data gaps. Our models assume contrasting scenarios of the yellow fever transmission cycle in Africa. The first takes the force of infection in each province to be static across the observation period; this is synonymous with a constant infection pressure from the sylvatic reservoir. The second model assumes the majority of transmission results from the urban cycle; in this case, the force of infection is dynamic and defined through a fixed value of R0 in each province. Both models are coupled to a generalised linear model of yellow fever occurrence which uses environmental covariates to allow us to estimate transmission intensity in areas where data is sparse. We compare these contrasting descriptions of transmission through a Bayesian framework and trans-dimensional Markov chain Monte Carlo sampling in order to assess each model’s evidence given the range of uncertainty in parameter values. The resulting estimates allow us to produce Bayesian model averaged predictions of yellow fever burden across the African endemic region. We find strong support for the static force of infection model which suggests a higher proportion of yellow fever transmission occurs as a result of infection from an external source such as the sylvatic reservoir. However, the model comparison highlights key data gaps in serological surveys across the African endemic region. As such, conclusions concerning the most prevalent transmission routes for yellow fever will be limited by the sparsity of data which is particularly evident in the areas with highest predicted transmission intensity. Our model and estimation approach provides a robust framework for model comparison and predicting yellow fever burden in Africa. However, key data gaps increase uncertainty surrounding estimates of model parameters and evidence. As more mathematical models are developed to address new research questions, it is increasingly important to compare them with established modelling approaches to highlight uncertainty in structures and data., Author summary Yellow fever (YF) is notoriously under reported due to non-specific symptom spectrum and the true burden is highly uncertain as a result of a complex transmission cycle. As such, estimates surrounding YF burden are highly uncertain and the mechanisms behind transmission are often unclear. We assess these mechanisms and the resulting uncertainty by estimating two existing models of YF transmission within a product space framework. This allows us to produce updated estimates of transmission intensity and to compare the relative support for each model given the data. We find strong support for a model assuming a static force of infection, approximating the constant infection pressure from the sylvatic reservoir of YF. We also highlight areas where data is sparse, often the same areas estimated to have especially high transmission intensity. This is the first robust multi-model approach to applied YF modelling and provides a framework that could be extended to other disease models.
Published: 2019

12. Aberrant up-regulation of iNOS/NO system is correlated with an increased abundance of Foxp3+ cells and reduced effector/memory cell markers expression during colorectal cancer: immunomodulatory effects of cetuximab combined with chemotherapy

Author: Sonia Ait-Younes, Mourad Belkhelfa, Chafia Touil-Boukoffa, Yvan de Launoit, Hassen Mahfouf, Hayet Rafa, Nadira Delhem, Hayat Ait-Kaci, Olivier Moralès, Sabah Hetit, Oussama Medjeber, Sarra Benkhelifa, Said Belhadef, Mécanismes de tumorigenèse et thérapies ciblées, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), FGMGP/USTHB, Université d'Algérie, Hôpital Rouïba [Algerie], Le centre hospitalier universitaire (CHU) Mustapha Pacha [Alger], Centre Hospitalo-Universitaire de Béni-Messous, CHU Nafissa Hamoud [Hussein Dey], University of Sciences and Technology Houari Boumediene [Alger] (USTHB), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Droit et Santé, They also thank the national agency of research development in health (ATRSS) which supported their project (code project: 03/06/01/10/011). They have also received support from the SIRIC ONCO Lille., The authors would like to gratefully thank all the participants involved in this study as well as the technical staff of the department of oncology (Rouiba Hospital) and Anatomic Pathology Service (Mustapha Pacha Hospital). They greatly thank Meroua BOUCHEMAL, Arezki CHEKAOUI and Dr. Kahina TOURI (USTHB, Algiers, Algeria) for all help and support of this work. Special thanks are extended to Dr. Mohamed Boudjelal and Science Edit for the Developing World for editing the English Language of the paper., Université des Sciences et de la Technologie Houari Boumediene = University of Sciences and Technology Houari Boumediene [Alger] (USTHB), Institut de biologie de Lille - UMS 3702 (IBL), Université de Lille-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Colorectal cancer, [SDV]Life Sciences [q-bio], medicine.medical_treatment, MESH: Up-Regulation/physiology, MESH: Down-Regulation/drug effects, MESH: Aged, 80 and over, 0302 clinical medicine, Host immune responses, MESH: Nitric Oxide/metabolism, MESH: Colorectal Neoplasms/metabolism, Pharmacology (medical), ComputingMilieux_MISCELLANEOUS, MESH: Aged, MESH: Middle Aged, Cetuximab, MESH: Nitric Oxide Synthase Type II/metabolism, FOXP3, 3. Good health, medicine.anatomical_structure, MESH: Cetuximab/therapeutic use, iNOS/NO system, MESH: Up-Regulation/drug effects, medicine.symptom, medicine.drug, Immunology, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Immunologic Factors/metabolism, Peripheral blood mononuclear cell, Immunomodulation, 03 medical and health sciences, Immune system, MESH: Down-Regulation/physiology, medicine, MESH: Biomarkers, Tumor/metabolism, Cetuximab and chemotherapy, Colorectal Cancer, Pharmacology, Chemotherapy, MESH: Humans, business.industry, MESH: Adult, medicine.disease, MESH: Male, 030104 developmental biology, Cancer research, MESH: Colorectal Neoplasms/drug therapy, business, MESH: Female, Memory T cell, MESH: T-Lymphocytes, Regulatory/drug effects, 030217 neurology & neurosurgery, MESH: Forkhead Transcription Factors/metabolism
Abstract: International audience; Colorectal cancer (CRC) remains the most cancer type related to chronic inflammation; however, the mechanisms that link inflammation to CRC development and progression are still poorly understood. Our study aimed to investigate one of the prominent inflammatory response in cancers, iNOS/NO system. In this regard, we evaluated the link between the iNOS/NO system and CRC progression, its relation with the host immune responses and its response to cetuximab combined with chemotherapy. We found that the nitrite levels were nearly twice as high in metastatic CRC plasma and culture supernatants from PBMCs and tumor explants compared with those without metastases and healthy controls. Interestingly, we showed that the highest iNOS expression and NO levels are present in the damaged CRC tissues that have highest leukocyte infiltration. Our findings highlight the implication of iNOS/NO system in tissue alteration and leukocyte invasion. Thus, we observed imbalance between effector/memory T cell markers and Treg transcription factor (Foxp3). Accordingly, we detected higher IFNγ and T-bet expression levels in colorectal tumor tissues at early stage. In contrast, consistent with iNOS and Foxp3 expression, TGFβ, CTLA-4 and IL-10 were significantly related to the tumor stage progression. Furthermore, our study revealed that Cetuximab combined with chemotherapy treatment markedly down-regulates iNOS/NO system as well as IL-10 and TGFβ levels. Altogether, we conclude that cetuximab can potentiate the efficacy of chemotherapy, particularly by iNOS/NO system and immunosuppressive cytokines modulation. Thus, we suggest that iNOS/NO system may represent an attractive candidate biomarker for monitoring CRC progression, malignity and response to therapy.
Published: 2019

13. Transcription Profiling of Monocyte-Derived Macrophages Infected In Vitro With Two Strains of Streptococcus agalactiae Reveals Candidate Pathways Affecting Subclinical Mastitis in Cattle

Author: Lewandowska-Sabat, Anna Monika, Solberg, Trygve Roger, Lewandowska-Sabat, Anna, Kirsanova, Elena, Klopp, Christophe, Solberg, Trygve, Heringstad, Bjørg, Østerås, Olav, Boysen, Preben, Olsaker, Ingrid, Norwegian University of Life Sciences (NMBU), Geno Breeding & AI Assoc, Hamar, Norway, Unité de Mathématiques et Informatique Appliquées de Toulouse (MIAT INRA), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Norwegian Cattle Hlth Serv, As, Norway, TINE Extens Serv, As, Norway, and This paper is a part of the 'Multimast' project (no. 233778) funded by the Research Council of Norway, Tine and Geno.
Subjects: 0301 basic medicine, lcsh:QH426-470, [SDV]Life Sciences [q-bio], Biology, medicine.disease_cause, Microbiology, Streptococcus agalactiae, 03 medical and health sciences, 0302 clinical medicine, Immune system, Transcription (biology), medicine, Genetics, subclinical mastitis, Gene, Genetics (clinical), Subclinical infection, Original Research, Innate immune system, RNA sequencing, In vitro, Complement system, macrophages, pathway analysis, lcsh:Genetics, 030104 developmental biology, cattle, 030220 oncology & carcinogenesis, Molecular Medicine
Abstract: International audience; Macrophages are key cells of innate immune response and serve as the first line of defense against bacteria. Transcription profiling of bacteria-infected macrophages could provide important insights on the pathogenicity and host defense mechanisms during infection. We have examined transcription profiles of bovine monocyte-derived macrophages (bMDMs) isolated from the blood of 12 animals and infected in vitro with two strains of Streptococcus agalactiae. Illumina sequencing of RNA from 36 bMDMs cultures exposed in vitro to either one of two sequence types of S. agalactiae (ST103 or ST12) for 6 h and unchallenged controls was performed. Analyses of over 1,656 million high-quality paired-end sequence reads revealed 5,936 and 6,443 differentially expressed genes (p < 0.05) in bMDMs infected with ST103 and ST12, respectively, versus unchallenged controls. Moreover, 588 genes differentially expressed between bMDMs infected with ST103 versus ST12 were identified. Ingenuity pathway analysis of the differentially up-regulated genes in the bMDMs infected with ST103 revealed significant enrichment for granulocyte adhesion and diapedesis, while significant enrichment for the phagosome formation pathway was found among down-regulated genes. Moreover, Ingenuity pathway analysis of the differentially up-regulated genes in the bMDMs infected with ST12 showed significant enrichment for type 1/type 2 T helper cell activation, while the complement activation pathway was overrepresented in the down-regulated genes. Our study identified pathogen-induced regulation of key genes and pathways involved in the immune response of macrophages against infection but also likely involved in bacterial evasion of the host immune system. These results may contribute to better understanding of the mechanisms underlying subclinical infection such as bovine streptococcal mastitis.
Published: 2019
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14. Real-time analysis of the behaviour of groups of mice via a depth-sensing camera and machine learning

Author: Philippe Faure, Jean-Christophe Olivo-Marin, Fabrice de Chaumont, Nicolas Torquet, Albane Imbert, Stephane Dallongeville, Anne-Marie Le Sourd, Thomas Bourgeron, Elodie Ey, Thierry Legou, Thibault Lagache, Analyse d'images biologiques - Biological Image Analysis (BIA), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche et Innovation Technologique (CITECH), Institut Pasteur [Paris], Laboratoire Parole et Langage (LPL), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), This work was partially funded by the Institut Pasteur, the Bettencourt-Schueller Foundation, the Cognacq–Jay Foundation, the Conny–Maeva Foundation, the ERANET–NEURON SYNPATHY program, the Agence Nationale de la Recherche through grant number ANR-10-LABX-62-IBEID, France-BioImaging infrastructure through grant number ANR-10-INBS-04 and the INCEPTION program through grant number ANR-16-CONV-0005, the Centre National de la Recherche Scientifique, the University Paris Diderot, the BioPsy Labex, the Institut National du Cancer through grant number TABAC-16–022, the Foundation for Medical Research (Equipe DEQ20130326488), the Innovative Medicines Initiative Joint Undertaking through grant agreement number 115300, resources of which are composed of financial contributions from the European Union’s Seventh Framework Program (FP7/2007–2013) and EFPIA companies in kind contribution., The authors thank Y. Archambeau and P. Ollivon at the workshop of the Institut Pasteur for building the first 12 setups and advising on hardware, W. Meiniel for the mathematical proof for decisions of head/tail probability, Microsoft France for their technical support, P. Spinicelli for optical engineering and reading of the paper, R. Marée for machine learning support, B. König for advice and reading of biological experiments, J. N. Crawley for reading and providing comments on the manuscript, A. Barmpoutis for providing us with the early Kinect 2 driver and support, N. Chenouard for driving the use of the machine learning solution, P. Dugast for drawing the mice in the different behavioural events, A. Engelberg for checking the English, S. Wagner and R. Accardi for RFID advice, M. Marim for website development, and X. Montagutelli and M. Bérard for animal facility support., Analyse d'images biologiques - BioImage Analysis (AIQ), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris], Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Biomedical Engineering, Video Recording, Medicine (miscellaneous), Bioengineering, Nerve Tissue Proteins, Mouse tracking, Biology, Machine learning, computer.software_genre, Machine Learning, 03 medical and health sciences, Mice, 0302 clinical medicine, [INFO.INFO-TS]Computer Science [cs]/Signal and Image Processing, Animals, Autistic Disorder, Real time analysis, Social Behavior, Mice, Knockout, Behavior, Animal, business.industry, Microfilament Proteins, Computer Science Applications, Disease Models, Animal, 030104 developmental biology, Phenotype, Mutation, Identification (biology), Female, Artificial intelligence, business, computer, 030217 neurology & neurosurgery, Biotechnology, Behavioral Research
Abstract: Preclinical studies of psychiatric disorders use animal models to investigate the impact of environmental factors or genetic mutations on complex traits such as decision-making and social interactions. Here, we introduce a method for the real-time analysis of the behaviour of mice housed in groups of up to four over several days and in enriched environments. The method combines computer vision through a depth-sensing infrared camera, machine learning for animal and posture identification, and radio-frequency identification to monitor the quality of mouse tracking. It tracks multiple mice accurately, extracts a list of behavioural traits of both individuals and the groups of mice, and provides a phenotypic profile for each animal. We used the method to study the impact of Shank2 and Shank3 gene mutations—mutations that are associated with autism—on mouse behaviour. Characterization and integration of data from the behavioural profiles of Shank2 and Shank3 mutant female mice revealed their distinctive activity levels and involvement in complex social interactions. A method that combines a depth-sensing camera and machine learning can track the movements of up to four mice in real time and for several days, extracting both individual and group behavioural traits.
Published: 2019

15. Advantages and disadvantages of the use of the CSF Amyloid β (Aβ) 42/40 ratio in the diagnosis of Alzheimer’s Disease

Author: Markus Otto, Henrik Zetterberg, Piotr Lewczuk, Oskar Hansson, Sylvain Lehmann, Clinical Memory Research Unit [Malmö, Suède], Department of Clinical Sciences [Malmö, Suède], Lund University [Malmö, Suède]-Lund University [Malmö, Suède], Memory Clinic [Malmö, Suède], Skåne University Hospital [Malmö, Suède], 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), Department of Neurology [Ulm, Allemagne], Universität Ulm - Ulm University [Ulm, Allemagne], Clinical Neurochemistry Laboratory [Göteborg, Suède], Department of Psychiatry and Neurochemistry [Goteborg], Institute of Neuroscience and Physiology [Göteborg]-Sahlgrenska Academy at University of Gothenburg [Göteborg]-Institute of Neuroscience and Physiology [Göteborg]-Sahlgrenska Academy at University of Gothenburg [Göteborg], Department of Neurodegenerative Disease [Londres, Royaume-Uni], Institute of Neurology [London], University College of London [London] (UCL)-University College of London [London] (UCL), UK Dementia Research Institute (UK DRI), University College of London [London] (UCL), Department of Psychiatry and Psychotherapy [Erlangen, Allemagne], Universitätsklinikum Erlangen [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU)-Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Department of Neurodegeneration Diagnostics [Bialystok, Pologne], Medical University of Bialystok [Bialystok, Pologne], Lab for Clinical Neurochemistry and Neurochemical Dementia Diagnostics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU)-Friedrich-Alexander Universität Erlangen-Nürnberg (FAU)-Universitätsklinikum Erlangen [Erlangen, Allemagne], Fujirebio Europe sponsored this paper, however, it had no influence on its factual content. PL was supported by the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n° 115372, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. OH has acquired research support (for the institution) from Roche, GE Healthcare, Biogen, AVID Radiopharmaceuticals, Fujirebio and Euroimmun. HZ’s research is supported by the Swedish Research Council, the European Research Council, the Knut and Alice Wallenberg Foundation, the Olav Thon Foundation, the UK Dementia Research Institute at UCL and Swedish State Support for Clinical Research (ALFGBG)., Lund University [Lund]-Lund University [Lund], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Medical University of Białystok (MUB), and Bodescot, Myriam
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Neurology, Amyloid β, Cognitive Neuroscience, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Diagnostic accuracy, Disease, Review, Aβ 42/40 ratio, Alzheimer's Disease, lcsh:RC346-429, lcsh:RC321-571, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, Medizinische Fakultät, Alzheimer Disease, Internal medicine, medicine, Dementia, Humans, ddc:610, Alzheimer’s Disease, Cognitive impairment, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biochemical markers, lcsh:Neurology. Diseases of the nervous system, Cerebrospinal Fluid, Amyloid beta-Peptides, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, business.industry, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, Peptide Fragments, 030104 developmental biology, Aβ42/40 ratio, Neurology (clinical), business, 030217 neurology & neurosurgery, Amyloidβ Peptides, Biomarkers
Abstract: International audience; The cerebrospinal fluid (CSF) biochemical markers (biomarkers) Amyloidβ 42 (Aβ42), total Tau (T-tau) and Tau phosphorylated at threonine 181 (P-tau181) have proven diagnostic accuracy for mild cognitive impairment and dementia due to Alzheimer's Disease (AD). In an effort to improve the accuracy of an AD diagnosis, it is important to be able to distinguish between AD and other types of dementia (non-AD). The concentration ratio of Aβ42 to Aβ40 (Aβ42/40 Ratio) has been suggested to be superior to the concentration of Aβ42 alone when identifying patients with AD. This article reviews the available evidence on the use of the CSF Aβ42/40 ratio in the diagnosis of AD. Based on the body of evidence presented herein, it is the conclusion of the current working group that the CSF Aβ42/40 ratio, rather than the absolute value of CSF Aβ42, should be used when analysing CSF AD biomarkers to improve the percentage of appropriately diagnosed patients.
Published: 2019

16. Stochastic modeling reveals how motor protein and filament properties affect intermediate filament transport

Author: Sandrine Etienne-Manneville, Stéphanie Portet, Cécile Leduc, J. C. Dallon, Brigham Young University (BYU), Polarité cellulaire, Migration et Cancer - Cell Polarity, Migration and Cancer, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University of Manitoba [Winnipeg], This work was supported by: EPSRC grant numbers EP/K032208/1 and EP/R014604/1 and by La Ligue contre le cancer and the Institut Pasteur., The authors would like to thank the Isaac Newton Institute for Mathematical Sciences for support and hospitality during the programme 'Coupling Geometric PDE’s with Physics for Cell Morphology, Motility and Pattern Formation' when the work on this paper was undertaken., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and ANR-16-CE13-0019,SiFi2Net,Filaments intermédiaires: du filament unique au réseau(2016)
Subjects: 0301 basic medicine, Statistics and Probability, Materials science, [SDV]Life Sciences [q-bio], Dynein, Biological Transport, Active, Kinesins, Catch bond, macromolecular substances, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Microtubules, Models, Biological, General Biochemistry, Genetics and Molecular Biology, Quantitative Biology::Cell Behavior, Protein filament, Motor protein, Quantitative Biology::Subcellular Processes, 03 medical and health sciences, 0302 clinical medicine, Molecular motor, Vimentin, Intermediate filaments, Intermediate filament, Cytoskeleton, Stochastic Processes, General Immunology and Microbiology, Applied Mathematics, Dyneins, Molecular motors, General Medicine, Kinesin, Stochastic, 030104 developmental biology, Modeling and Simulation, Biophysics, General Agricultural and Biological Sciences, 030217 neurology & neurosurgery
Abstract: International audience; Intermediate filaments are a key component of the cytoskeleton. Their transport along microtubules plays an essential role in the control of the shape and structural organization of cells. To identify the key parameters responsible for the control of intermediate filament transport, we generated a model of elastic filament transport by microtubule-associated dynein and kinesin. The model is also applicable to the transport of any elastically-coupled cargoes. We investigate the effect of filament properties such as number of motor binding sites, length, and elasticity on motion of filaments. Additionally, we consider the effect of motor properties, i.e. off rates, on filament transport. When one motor has a catch bond off rate it dictates the motion, whereas when motors have the same type of off rate filaments can alternate between retrograde and anterograde motions. The elasticity of filaments optimizes the filament transport and the coordination of motors along the length of the filament.
Published: 2019

17. Quantitative genetic parameters for growth and wood properties in Eucalyptus 'urograndis' hybrid using near-infrared phenotyping and genome-wide SNP-based relationships

Author: Orzenil B. Silva-Junior, Bruno Marco de Lima, Shawn D. Mansfield, Carla Garcia, Dario Grattapaglia, Eduardo P. Cappa, BRUNO MARCO DE LIMA, USP, EDUARDO P. CAPPA, INSTITUTO NACIONAL DE TECNOLOGI´A AGROPECUARIA (INTA), ARGENTINA, ORZENIL BONFIM DA SILVA JUNIOR, Cenargen, CARLA GARCIA, INTERNATIONAL PAPER DO BRASIL ROD, SHAWN D. MANSFIELD, UNIVERSITY OF BRITISH COLUMBIA, CANADA, and DARIO GRATTAPAGLIA, Cenargen.
Subjects: 0106 biological sciences, 0301 basic medicine, Heredity, Plant Science, 01 natural sciences, Lignin, Trees, Spectrum Analysis Techniques, NEAR-INFRARED PEHNOTYPING, Data Management, education.field_of_study, Eucalyptus, Multidisciplinary, Spectroscopy, Near-Infrared, Organic Compounds, Plant Anatomy, Eukaryota, near-Infrared Spectroscopy, Phylogenetic Analysis, Genomics, Plants, Wood, Phylogenetics, Polimorfismo de un Solo Nucleótido, Chemistry, Phenotypes, Phenotype, Genetic gain, Physical Sciences, Medicine, Brazil, Genome, Plant, Research Article, Genetic Research, Computer and Information Sciences, Genética Cuantitativa, Genotype, Science, Population, Infrared Spectroscopy, Quantitative trait locus, Biology, Research and Analysis Methods, Polymorphism, Single Nucleotide, Quantitative Genetics, 03 medical and health sciences, Quantitative Trait, Heritable, MOLECULAR RELATIONSHIP, Species Specificity, Genetic variation, Genetics, Evolutionary Systematics, PEDIGREE RELATIONSHIP, education, Cellulose, Fenotipos, Hybrid, Taxonomy, Evolutionary Biology, Models, Genetic, Directional selection, Organic Chemistry, Organisms, Chemical Compounds, Biology and Life Sciences, Heritability, purl.org/becyt/ford/4.5 [https], Plant Breeding, 030104 developmental biology, Evolutionary biology, Single Nucleotide Polymorphism, Tree breeding, Hybridization, Genetic, purl.org/becyt/ford/4 [https], 010606 plant biology & botany
Abstract: A thorough understanding of the heritability, genetic correlations and additive and non-additive variance components of tree growth and wood properties is a requisite for effective tree breeding. This knowledge is essential to maximize genetic gain, that is, the amount of increase in trait performance achieved annually through directional selection. Understanding the genetic attributes of traits targeted by breeding is also important to sustain decade-long genetic progress, that is, the progress made by increasing the average genetic value of the offspring as compared to that of the parental generation. In this study, we report quantitative genetic parameters for fifteen growth, wood chemical and physical traits for the world-famous Eucalyptus urograndis hybrid (E. grandis × E. urophylla). These traits directly impact the optimal use of wood for cellulose pulp, paper, and energy production. A population of 1,000 trees sampled in a progeny trial was phenotyped directly or following the development and use of near-infrared spectroscopy calibration models. Trees were genotyped with 33,398 SNPs and 24,001 DArT-seq genome-wide markers and genomic realized relationship matrices (GRM) were used for parameter estimation with an individual-tree additive-dominant mixed model. Wood chemical properties and wood density showed stronger genetic control than growth, cellulose and fiber traits. Additive effects are the main drivers of genetic variation for all traits, but dominance plays an equally or more important role for growth, singularly in this hybrid. GRM´s with >10,000 markers provided stable relationships estimates and more accurate parameters than pedigrees by capturing the full genetic relationships among individuals and disentangling the non-additive from the additive genetic component. Low correlations between growth and wood properties indicate that simultaneous selection for wood traits can be applied with minor effects on genetic gain for growth. Conversely, moderate to strong correlations between wood density and chemical traits exist, likely due to their interdependency on cell wall structure such that responses to selection will be connected for these traits. Our results illustrate the advantage of using genomewide marker data to inform tree breeding in general and have important consequences for operational breeding of eucalypt urograndis hybrids. Fil: de Lima, Bruno Marco. Universidade de Sao Paulo; Brasil. Ministerio da Agricultura Pecuaria e Abastecimento de Brasil. Empresa Brasileira de Pesquisa Agropecuaria; Brasil Fil: Cappa, Eduardo Pablo. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación de Recursos Naturales. Instituto de Recursos Biológicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Silva Junior, Orzenil B.. Ministerio da Agricultura Pecuaria e Abastecimento de Brasil. Empresa Brasileira de Pesquisa Agropecuaria; Brasil. Universidade Católica de Brasília; Brasil Fil: Garcia, Carla. No especifíca; Fil: Mansfield, Shawn D.. University of British Columbia; Canadá Fil: Grattapaglia, Dario. Ministerio da Agricultura Pecuaria e Abastecimento de Brasil. Empresa Brasileira de Pesquisa Agropecuaria; Brasil. Universidade Católica de Brasília; Brasil
Published: 2019

18. Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants

Author: Jelena Melesina, Wolfgang Sippl, Tino Heimburg, Christophe Romier, Martin Marek, Karin Schmidtkunz, E. Ramos-Morales, Julien Lancelot, C. Da Veiga, Manfred Jung, Takayoshi Suzuki, Dina Robaa, Eric Ennifar, Dmitrii V. Kalinin, T.B. Shaik, Raymond J. Pierce, Alokta Chakrabarti, Ralph Holl, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Martin-Luther-Universität Halle Wittenberg (MLU), Albert-Ludwigs-Universität Freiburg, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), University of Münster, Kyoto Prefectural University of Medicine [Kyoto, Japon], Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), University of Hamburg, This work and the authors of this paper have been supported by funding from the European Union’s Seventh Framework Programme for research, technological development, and demonstration under grant agreements nos. 241865 (SEtTReND) and 602080 (A-ParaDDisE) as well as the German Research Foundation (DFG) to W.S. (Si868/13-1) and M.J. (Ju295/13-1). This study was supported by the grant ANR-10-LABX-0030-INRT, a French State fund managed by the Agence Nationale de la Recherche under the frame program Investissements d’Avenir ANR-10-IDEX-0002-02. C.R., M.M., T.B.S., E.R.M., and R.J.P. are supported by institutional funds from the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the Université de Strasbourg, the Institut Pasteur de Lille and the Université de Lille. W.S. was supported by the European Regional Development Fund of the European Commission. We acknowledge the support and the use of resources of the French Infrastructure for Integrated Structural Biology FRISBI ANR-10-INBS-05 and of Instruct-ERIC, We thank members of the ESRF-EMBL joint structural biology groups, the SOLEIL, and the Swiss Light Source (SLS) synchrotrons for the use of their beamline facilities and for help during data collection. We are grateful to Alastair McEwen (IGBMC) for his kind assistance during X-ray data collections., ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), European Project: 241865,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,SETTREND(2010), European Project: 602080,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,A-PARADDISE(2014), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), and Westfälische Wilhelms-Universität Münster = University of Münster (WWU)
Subjects: 0301 basic medicine, Indoles, [SDV]Life Sciences [q-bio], Molecular Dynamics Simulation, Hydroxamic Acids, Isozyme, Histone Deacetylases, Substrate Specificity, 03 medical and health sciences, Structure-Activity Relationship, 0302 clinical medicine, Catalytic Domain, Drug Discovery, Hydrolase, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Epigenetics, Amino Acid Sequence, Tyrosine, biology, Chemistry, Active site, HDAC8, Protein engineering, Triazoles, 3. Good health, Cell biology, Histone Deacetylase Inhibitors, Repressor Proteins, 030104 developmental biology, Histone, 030220 oncology & carcinogenesis, biology.protein, Molecular Medicine
Abstract: International audience; Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet the currently FDA-approved HDAC inhibitors nonspecifically target at least several of the 11 structurally similar but functionally different HDAC isozymes, which hampers their broad usage in clinical settings. Selective inhibitors targeting single HDAC isozymes are being developed, but precise understanding in molecular terms of their selectivity remains sparse. Here, we show that HDAC8-selective inhibitors adopt a L-shaped conformation required for their binding to a HDAC8-specific pocket formed by HDAC8 catalytic tyrosine and HDAC8 L1 and L6 loops. In other HDAC isozymes, a L1–L6 lock sterically prevents L-shaped inhibitor binding. Shielding of the HDAC8-specific pocket by protein engineering decreases potency of HDAC8-selective inhibitors and affects catalytic activity. Collectively, our results unravel key HDAC8 active site structural and functional determinants important for the design of next-generation chemical probes and epigenetic drugs.
Published: 2018

19. Optimization of a magnetic bead-based assay (MAGPIX®-Luminex) for immune surveillance of exposure to malaria using multiple Plasmodium antigens and sera from different endemic settings

Author: Aissata Basse, Inès Vigan-Womas, Alioune Dieye, Cheikh Loucoubar, Babacar Mbengue, Marie Louise Varela, Ronald Perraut, Aissatou Touré, Institut Pasteur de Dakar, Réseau International des Instituts Pasteur (RIIP), Institut Pasteur de Madagascar, Département Parasites et Insectes vecteurs - Department of Parasites and Insect Vectors, Institut Pasteur [Paris], This study was supported by grants from Institut Pasteur Fondation, from Rotary International, ACIP (Institut Pasteur, N°25_2012) and EDCTP—European & Developing Countries Clinical Trials Partnership., We thank Dr Odile Mercereau-Puijalon and Dr Shirley Longacre for constant support and providing antigens, we are grateful to Dr Shirley Longacre for revising this paper. We thank Drs Marc Jouan and Jérôme Salomon from Division International (Institut Pasteur, Paris) for their help to initiate this work in the very early steps. We are grateful to the villagers of Dielmo and Ndiop for their active participation and continuing collaboration in the project and Pr Bacary Diatta for help providing hospital samples., and Institut Pasteur [Paris] (IP)
Subjects: 0301 basic medicine, lcsh:Arctic medicine. Tropical medicine, lcsh:RC955-962, 030231 tropical medicine, Plasmodium falciparum, Protozoan Proteins, Antigens, Protozoan, Plasmodium malariae, Biology, lcsh:Infectious and parasitic diseases, Serology, 03 medical and health sciences, 0302 clinical medicine, Antigen, parasitic diseases, medicine, lcsh:RC109-216, Multiplex, Malaria, Falciparum, IgG response, Immunoassay, medicine.diagnostic_test, Immunomagnetic Separation, Magnetic beads assay, Methodology, medicine.disease, biology.organism_classification, 3. Good health, Malaria, 030104 developmental biology, Infectious Diseases, Immunology, biology.protein, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Parasitology, Antibody, Biomarkers
Abstract: International audience; Background: Serological markers are potentially useful tools for monitoring the progress of malaria control programs , but a better understanding of antibody response dynamics is necessary. The use of a magnetic bead-based immunoassay (MBA) is advantageous compared to ELISA, due to its multiplexing capacity, but limited information is available on the standardization and validation of this assay. Methods: Several parameters for multiplex testing of antibodies to Plasmodium antigens were analysed using a set of 4 antigens and 98 sera from Senegalese rural asymptomatic and urban symptomatic individuals. The 4 antigens included Plasmodium falciparum CSP and PfAMA1 peptides, recombinant P. falciparum MSP4p20 and a Plasmodium malariae CSP (PmCSP) peptide. Comparisons with ELISA were done using MSP4p20 and whole schizont extract (SE) antigens.Results: The use of fewer beads (1000 beads per well instead of 2000) and 5 µg of antigen per 10 6 bead were validated as lower amounts. The use of a carrier protein (BSA) was shown to be critical when using peptides and the effect of a 24 h delayed measures was evaluated (5-25% signal decrease). Analysis of Ab responses showed almost equally high levels and prevalence in all transmission settings. Clear distinctions between rural and urban malaria were noted using PmCSP and SE antigens.Conclusions: This study underlines the importance of further optimization of the MBA technique and highlights the interest of using multistage/multispecies antigens for surveillance of malaria in endemic settings.
Published: 2018

20. Crystal structures of a pentameric ion channel gated by alkaline pH show a widely open pore and identify a cavity for modulation

Author: Marc Delarue, Catherine Van Renterghem, Zaineb Fourati, Pierre-Jean Corringer, Ludovic Sauguet, Haidai Hu, Ákos Nemecz, Dynamique structurale des Macromolécules / Structural Dynamics of Macromolecules, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), Récepteurs Canaux - Channel Receptors, Á.N. and Z.F. were supported by Agence Nationale de Recherches Grant 13-BSV8-0020 'Pentagate.' H.H. was sponsored by the China Scholarship Council and Institut Pasteur., We thank Anaïs Menny for sharing expertise on plasmid constructions, the staff of the Crystallography Platform (PF6) in the Institut Pasteur for initial crystal screens, Reinis Reinholds Ruza for help in data collection, Jérôme Loc’h for help during structural refinement and picture preparation, Stacy Gellenoncourt for help in purification and crystallization of the sTeLIC R86A mutant, the staff of synchrotron beamlines in Soleil (Orsay) and European Synchrotron Radiation Facility (Grenoble) for data collection, Pierre Legrand (Soleil synchrotron) for suggestions on refinement in Buster, and Marc Gielen for suggestions during the paper preparation, ANR-13-BSV8-0020,Pentagate,Mécanismes d'activation et de désensibilisation d'un récepteur-canal pentamérique(2013), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Gating, Crystallography, X-Ray, Divalent, 03 medical and health sciences, chemistry.chemical_compound, Allosteric Regulation, Bacterial Proteins, [CHIM.CRIS]Chemical Sciences/Cristallography, structural biology, Binding site, crystallography, Ion channel, Tetramethylammonium, chemistry.chemical_classification, Multidisciplinary, ligand-gated ion channel, druggable cavity, Hydrogen-Ion Concentration, Ligand-Gated Ion Channels, electrophysiology, Transmembrane protein, Quaternary Ammonium Compounds, 030104 developmental biology, chemistry, Structural biology, PNAS Plus, Biophysics, Ligand-gated ion channel, Gammaproteobacteria
Abstract: International audience; Pentameric ligand-gated ion channels (pLGICs) constitute a widespread class of ion channels, present in archaea, bacteria, and eukaryotes. Upon binding of their agonists in the extracellular domain, the transmembrane pore opens, allowing ions to go through, via a gating mechanism that can be modulated by a number of drugs. Even though high-resolution structural information on pLGICs has increased in a spectacular way in recent years, both in bacterial and in eukaryotic systems, the structure of the open channel conformation of some intensively studied receptors whose structures are known in a nonactive (closed) form, such as Erwinia chrysanthemi pLGIC (ELIC), is still lacking. Here we describe a gammaproteobacterial pLGIC from an endo-symbiont of Tevnia jerichonana (sTeLIC), whose sequence is closely related to the pLGIC from ELIC with 28% identity. We provide an X-ray crystallographic structure at 2.3 Å in an active conformation, where the pore is found to be more open than any current conformation found for pLGICs. In addition, two charged restriction rings are present in the vestibule. Functional characterization shows sTeLIC to be a cationic channel activated at alkaline pH. It is inhibited by divalent cations, but not by quaternary ammonium ions, such as tetramethylammonium. Additionally, we found that sTeLIC is allosterically potentiated by aromatic amino acids Phe and Trp, as well as their derivatives, such as 4-bromo-cinnamate, whose cocrystal structure reveals a vestibular binding site equivalent to, but more deeply buried than, the one already described for benzodiazepines in ELIC.
Published: 2018

21. A test for gene-environment interaction in the presence of measurement error in the environmental variable

Author: Hugues Aschard, Donna Spiegelman, Molin Wang, Vincent Laville, Pete Kraft, Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Harvard T.H. Chan School of Public Health, The authors thank the reviewers for their helpful comments that have improved the paper. This research is supported by grant R01CA050597 from the National Cancer Institute (NCI) and R21HG007687 from the National Human Genome Research Institute (NHGRI). The authors have no conflict of interest to declare., and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Epidemiology, Genome-wide association study, Breast Neoplasms, MESH: Logistic Models, Interaction, Logistic regression, 01 natural sciences, Article, Correlation, 010104 statistics & probability, 03 medical and health sciences, Bias, Statistics, Linear regression, MESH: Bias, Humans, normal discriminant analysis, MESH: Genetic Variation, MESH: Models, Genetic, 0101 mathematics, Gene–environment interaction, gene-environment interaction test, Genetics (clinical), Mathematics, [STAT.AP]Statistics [stat]/Applications [stat.AP], Observational error, MESH: Humans, Models, Genetic, Genetic Variation, Reproducibility of Results, MESH: Gene-Environment Interaction, Linear discriminant analysis, 3. Good health, MESH: Reproducibility of Results, 030104 developmental biology, Logistic Models, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, genome-wide association studies, MESH: Genome-Wide Association Study, Gene-Environment Interaction, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], [STAT.ME]Statistics [stat]/Methodology [stat.ME], measurement error, MESH: Breast Neoplasms, Genome-Wide Association Study
Abstract: International audience; The identification of gene-environment interactions in relation to risk of human diseases has been challenging. One difficulty has been that measurement error in the exposure can lead to massive reductions in the power of the test, as well as in bias toward the null in the interaction effect estimates. Leveraging previous work on linear discriminant analysis, we develop a new test of interaction between genetic variants and a continuous exposure that mitigates these detrimental impacts of exposure measurement error in ExG testing by reversing the role of exposure and the diseases status in the fitted model, thus transforming the analysis to standard linear regression. Through simulation studies, we show that the proposed approach is valid in the presence of classical exposure measurement error as well as when there is correlation between the exposure and the genetic variant. Simulations also demonstrated that the reverse test has greater power compared to logistic regression. Finally, we confirmed that our approach eliminates bias from exposure measurement error in estimation. Computing times are reduced by as much as fivefold in this new approach. For illustrative purposes, we applied the new approach to an ExGWAS study of interactions with alcohol and body mass index among 1,145 cases with invasive breast cancer and 1,142 controls from the Cancer Genetic Markers of Susceptibility study.
Published: 2018

22. Survival of the Fattest: Evolutionary Trade-offs in Cellular Resource Storage

Author: Vincent Danos, Andrea Y. Weiße, Guillaume Terradot, Andreea Beica, University of Edinburgh, Analyse Statique par Interprétation Abstraite (ANTIQUE), Département d'informatique - ENS Paris (DI-ENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria), Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), The research reported in this paper was partly funded by the ERC Project RULE/320823, Département d'informatique de l'École normale supérieure (DI-ENS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL)
Subjects: 0301 basic medicine, Resource (biology), General Computer Science, Computer science, Survival of the fittest, [SDV]Life Sciences [q-bio], 030106 microbiology, Trade offs, Biomass, Storage, Evolutionary strategies, Theoretical Computer Science, Gene regulation, Mechanistic cell models, 03 medical and health sciences, Variable (computer science), 030104 developmental biology, Cell physiology, Metabolites, Production (economics), [INFO]Computer Science [cs], Biochemical engineering
Abstract: International audience; Cells derive resources from their environments and use them to fuel the biosynthetic processes that determine cell growth. Depending on how responsive the biosynthetic processes are to the availability of intracellular resources, cells can build up different levels of resource storage. Here we use a recent mathematical model of the coarse-grained mechanisms that drive cellular growth to investigate the effects of cellular resource storage on growth. We show that, on the one hand, there is a cost associated with high levels of storage resulting from the loss of stored resources due to dilution. We further show that, on the other hand, high levels of storage can benefit cells in variable environments by increasing biomass production during transitions from one medium to another. Our results thus suggest that cells may face trade-offs in their maintenance of resource storage based on the frequency of environmental change.
Published: 2018

23. Taxonomy of prokaryotic viruses: 2017 update from the ICTV Bacterial and Archaeal Viruses Subcommittee

Author: Adriaenssens, Evelien M, Wittmann, Johannes, Kuhn, Jens H, Turner, Dann, Sullivan, Matthew B., Dutilh, Bas E, Jang, Ho Bin, van Zyl, Leonardo J, Klumpp, Jochen, Lobocka, Malgorzata, Moreno Switt, Andrea I, Rumnieks, Janis, Edwards, Robert A, Uchiyama, Jumpei, Alfenas-Zerbini, Poliane, Petty, Nicola K, Kropinski, Andrew M, Barylski, Jakub, Gillis, Annika, Clokie, Martha R C, Prangishvili, David, Lavigne, Rob, Aziz, Ramy Karam, Duffy, Siobain, Krupovic, Mart, Poranen, Minna M., Knezevic, Petar, Enault, Francois, Tong, Yigang, Oksanen, Hanna M., Rodney Brister, J, Sub Bioinformatics, Theoretical Biology and Bioinformatics, University of Liverpool, Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH / Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures (DSMZ), National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), University of the West of England [Bristol] (UWE Bristol), Ohio State University [Columbus] (OSU), Utrecht University [Utrecht], Radboud University Medical Center [Nijmegen], University of the Western Cape, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Polish Academy of Sciences (PAN), Universidad Andrés Bello - UNAB (CHILE), Latvian Biomedical Research and Study Centre [Rīga], San Diego State University (SDSU), Azabu University, Universidade Federal de Vicosa (UFV), iThree Institute, University of Technology Sydney (UTS), University of Guelph, Adam Mickiewicz University in Poznań (UAM), Université Catholique de Louvain = Catholic University of Louvain (UCL), University of Leicester, Biologie Moléculaire du Gène chez les Extrêmophiles (BMGE), Institut Pasteur [Paris], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Cairo University, University of Warwick [Coventry], University of Helsinki, University of Novi Sad, Laboratoire Microorganismes : Génome et Environnement (LMGE), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Beijing Institute of Microbiology and Epidemiology, This work was funded in part through Battelle Memorial Institute’s prime contract with the US National Institute of Allergy and Infectious Diseases (NIAID) under Contract No. HHSN272200700016I (J.H.K.). B.E.D. was supported by the Netherlands Organization for Scientific Research (NWO), Vidi Grant 864.14.004. R.A.E was supported by grant MCB-1330800 from the National Science Foundation. J.R.B. was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. R.L. is a member of the phagebiotics research community, supported by FWO Vlaanderen. M.M.P. was supported by the Academy of Finland (272507). A.G. was supported by the National Fund for Scientific Research (FNRS). H.M.O. was supported by University of Helsinki funding for Instruct-F1 research infrastructure., The committee would like to thank Dr. Graham Hatfull (University of Pittsburgh) for permitting us to use Actinobacteriophage Database electron micrographs in 2017’s taxonomy proposals. The authors thank Laura Bollinger (National Institutes of Health/National Institute of Allergy and Infectious Diseases, Integrated Research Facility at Fort Detrick, Frederick, MD, USA) for editing this paper., University of the Western Cape (UWC), Universidad Andrés Bello [Santiago] (UNAB), Universidade Federal de Viçosa = Federal University of Viçosa (UFV), Institut Pasteur [Paris] (IP), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), UCL - SST/ELI/ELIM - Applied Microbiology, Sub Bioinformatics, and Theoretical Biology and Bioinformatics
Subjects: 0301 basic medicine, Archaeal Viruses, viruses, [SDV]Life Sciences [q-bio], 030106 microbiology, education, Coronacrisis-Taverne, Zoology, Computational biology, Biology, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, 03 medical and health sciences, Phylogenetics, Virology, MESH: Archaeal Viruses, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Bacteriophages, MESH: Bacteriophages, Virus classification, Taxonomy, General Medicine, 030104 developmental biology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, ICTV bacterial, Classification methods, Taxonomy (biology), Bacterial virus
Abstract: International audience; The prokaryotic virus community is represented at the International Committee on Taxonomy of Viruses (ICTV) by the Bacterial and Archaeal Viruses Subcommittee. Since our last report [5], the committee composition has changed, and a large number of taxonomic proposals (TaxoProps) were submitted to the ICTV Executive Committee (EC) for approval.
Published: 2018

24. Long cold exposure induces transcriptional and biochemical remodelling of xylem secondary cell wall in Eucalyptus

Author: Victor Carocha, Raphael Ployet, Jacqueline Grima-Pettenati, Marçal Soler, Nathalie Ladouce, Ana Alves, Luc Harvengt, José-Carlos Rodrigues, Christiane Marque, Chantal Teulières, Fabien Mounet, Laboratoire de Recherche en Sciences Végétales (LRSV), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), RAIZ – Forestry & Paper Research Institut, Régulation et Dynamique de la Formation du Bois, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Centro de Estudos Florestais, Technical University of Lisbon-Instituto Superior de Agronomia, Laboratoire de Biotechnologie, Institut Technologique Forêt Cellulose Bois-construction Ameublement (FCBA), Biologie du fruit et pathologie (BFP), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1, Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and FCBA
Subjects: 0106 biological sciences, 0301 basic medicine, Physiology, Plant Science, Biology, 01 natural sciences, Cell wall, Transcriptome, 03 medical and health sciences, chemistry.chemical_compound, Cell Wall, Gene Expression Regulation, Plant, Xylem, Botany, Lignin, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, ComputingMilieux_MISCELLANEOUS, Hybrid, Regulation of gene expression, Eucalyptus, Abiotic stress, Gene Expression Profiling, food and beverages, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], 15. Life on land, Cold Temperature, 030104 developmental biology, chemistry, Secondary cell wall, 010606 plant biology & botany
Abstract: Although eucalypts are the most planted hardwood trees worldwide, the majority of them are frost sensitive. The recent creation of frost-tolerant hybrids such as Eucalyptus gundal plants (E. gunnii × E. dalrympleana hybrids), now enables the development of industrial plantations in northern countries. Our objective was to evaluate the impact of cold on the wood structure and composition of these hybrids, and on the biosynthetic and regulatory processes controlling their secondary cell-wall (SCW) formation. We used an integrated approach combining histology, biochemical characterization and transcriptomic profiling as well as gene co-expression analyses to investigate xylem tissues from Eucalyptus hybrids exposed to cold conditions. Chilling temperatures triggered the deposition of thicker and more lignified xylem cell walls as well as regulation at the transcriptional level of SCW genes. Most genes involved in lignin biosynthesis, except those specifically dedicated to syringyl unit biosynthesis, were up-regulated. The construction of a co-expression network enabled the identification of both known and potential new SCW transcription factors, induced by cold stress. These regulators at the crossroads between cold signalling and SCW formation are promising candidates for functional studies since they may contribute to the tolerance of E. gunnii × E. dalrympleana hybrids to cold.
Published: 2018

25. Secretory lipase from the human pathogen Leishmania major: Heterologous expression in the yeast Pichia pastoris and biochemical characterization

Author: Madiha Bou Ali, Youssef Gargouri, Saoussen Ben Ayed, Aymen Bali, Yassine Ben Ali, Dhafer Laouini, École Nationale d'Ingénieurs de Sfax | National School of Engineers of Sfax (ENIS), Université de Sfax - University of Sfax, Laboratoire de Transmission, Contrôle et Immunobiologie des Infections - Laboratory of Transmission, Control and Immunobiology of Infection (LR11IPT02), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), and The authors would like to thank Mr. Anouar Fendri, Professor of English, who kindly proofread this paper.
Subjects: 0301 basic medicine, Models, Molecular, MESH: Leishmania major/genetics, MESH: Enzyme Stability, MESH: Hydrogen-Ion Concentration, Protein Conformation, Gene Expression, MESH: Amino Acid Sequence, MESH: Base Sequence, 01 natural sciences, Biochemistry, Pichia, MESH: Protein Conformation, Enzyme Stability, MESH: Pichia/genetics, Leishmania major, MESH: Lipase/antagonists & inhibitors, Cloning, Molecular, Enzyme Inhibitors, Leishmania, MESH: Lipase/metabolism, biology, Chemistry, Temperature, General Medicine, Hydrogen-Ion Concentration, MESH: Temperature, Parasite, MESH: Biocatalysis, MESH: Models, Molecular, MESH: Gene Expression, Leishmania donovani, Triacylglycerol lipase, MESH: Sequence Alignment, MESH: Leishmania major/enzymology, Pichia pastoris, 03 medical and health sciences, Humans, MESH: Cloning, Molecular, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Lipase, MESH: Humans, Base Sequence, MESH: Enzyme Inhibitors/pharmacology, 010401 analytical chemistry, MESH: Lipase/chemistry, biology.organism_classification, Yeast, 0104 chemical sciences, 030104 developmental biology, MESH: Lipase/genetics, biology.protein, Biocatalysis, Heterologous expression, Sequence Alignment
Abstract: International audience; Leishmaniasis is a parasitic reticuloendotheliosis whose pathogen is a zooflagellate belonging to the genus Leishmania transmitted by the bite of an infected phlebotome. Recently, a unique secretory lipase from the human pathogen Leishmania donovani Ldlip3 has been identified and characterized. This lipase has a high identity with a putative triacylglycerol lipase of Leishmania major (Lmlip2). In the present study, Lmlip2 was expressed in the eukaryotic heterologous expression system Pichia pastoris as tagged enzyme of 308 amino acids. Maximal protein production was reached after 2 days of fermentation. Optimal Lmlip2 lipase activity was measured using the pH stat technique at pH 8 at 26 °C using vinyl esters and triacylglycerols (true lipids) as substrates. Moreover, biochemical characterization of Lmlip2 contained in culture supernatant, illustrates that L. major secreted lipase is active and stable at low temperatures especially 26°and prefer neutral pH; concerning substrate specificityLmlip2 presents a preference for short chains lipid substrates vinyl esters such as VC2, VC3 and VC4 likewise, it is capable to hydrolyze long chain triacylglycerols like olive oil. Metal ions and surfactants tested in this study decrease Lmlip2 activity. Further studies are needed to clarify the relation between the lipase activity and the virulence. Thus, it could lead to the identification of novel targets to block cutaneous Leishmaniasis in human hosts.
Published: 2018

26. Evolutionary history of carbon monoxide dehydrogenase/acetyl-CoA synthase, one of the oldest enzymatic complexes

Author: Panagiotis S. Adam, Simonetta Gribaldo, Guillaume Borrel, Biologie Evolutive de la Cellule Microbienne - Evolutionary Biology of the Microbial Cell, Institut Pasteur [Paris] (IP), Université Paris Diderot - Paris 7 (UPD7), P.S.A. is supported by a PhD fellowship from Paris Diderot University and by funds from the PhD Programme 'Frontières du Vivant (FdV)–Programme Bettencourt.' G.B. is a recipient of a Roux-Cantarini fellowship from the Institut Pasteur. S.G. acknowledges funding from the French National Agency for Research Grant ArchEvol (ANR-16-CE02-0005-01)., We thank Alexander Probst for feedback on an earlier version of the paper, and two anonymous reviewers whose comments helped improve clarity and correctness of the manuscript., ANR-16-CE02-0005,Arch-Evol,Approches phylogenomiques pour étudier l'origine et évolution des Archées(2016), and Institut Pasteur [Paris]
Subjects: 0301 basic medicine, Enzyme complex, MESH: Genome, Archaeal, LUCA, [SDV]Life Sciences [q-bio], MESH: Genome, Bacterial, Genome, Corrections, chemistry.chemical_compound, Genome, Archaeal, MESH: Multienzyme Complexes/genetics, methanogens, Phylogeny, MESH: Phylogeny, Genetics, Carbon Monoxide, Multidisciplinary, Last universal ancestor, Carbon fixation, Acetyl-CoA, MESH: Carbon Cycle, Aldehyde Oxidoreductases, Biological Evolution, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, PNAS Plus, MESH: Bacteria/enzymology, Wood–Ljungdahl pathway, Wood-Ljungdahl pathway, MESH: Aldehyde Oxidoreductases/metabolism, Carbon monoxide dehydrogenase, 030106 microbiology, MESH: Bacteria/genetics, Acetate-CoA Ligase, Bacterial genome size, Biology, MESH: Biological Evolution, MESH: Aldehyde Oxidoreductases/genetics, Carbon Cycle, 03 medical and health sciences, MESH: Carbon Monoxide/metabolism, Multienzyme Complexes, MESH: Archaea/genetics, evolution, MESH: Acetate-CoA Ligase/metabolism, MESH: Multienzyme Complexes/metabolism, MESH: Archaea/enzymology, Bacteria, MESH: Acetate-CoA Ligase/genetics, Archaea, acetogens, 030104 developmental biology, chemistry, biology.protein, Genome, Bacterial
Abstract: Erratum in : Correction for Adam et al., Evolutionary history of carbon monoxide dehydrogenase/acetyl-CoA synthase, one of the oldest enzymatic complexes. [Proc Natl Acad Sci U S A. 2018]; International audience; Carbon monoxide dehydrogenase/acetyl-CoA synthase (CODH/ ACS) is a five-subunit enzyme complex responsible for the carbonyl branch of the Wood-Ljungdahl (WL) pathway, considered one of the most ancient metabolisms for anaerobic carbon fixation, but its origin and evolutionary history have been unclear. While traditionally associated with methanogens and acetogens, the presence of CODH/ACS homologs has been reported in a large number of un-cultured anaerobic lineages. Here, we have carried out an exhaustive phylogenomic study of CODH/ACS in over 6,400 archaeal and bacterial genomes. The identification of complete and likely functional CODH/ACS complexes in these genomes significantly expands its distribution in microbial lineages. The CODH/ACS complex displays astounding conservation and vertical inheritance over geological times. Rare intradomain and interdomain transfer events might tie into important functional transitions, including the acquisition of CODH/ACS in some archaeal methanogens not known to fix carbon, the tinkering of the complex in a clade of model bacterial acetogens, or emergence of archaeal-bacterial hybrid complexes. Once these transfers were clearly identified, our results allowed us to infer the presence of a CODH/ACS complex with at least four subunits in the last universal common ancestor (LUCA). Different scenarios on the possible role of ancestral CODH/ACS are discussed. Despite common assumptions, all are equally compatible with an autotrophic, mixotrophic, or heterotrophic LUCA. Functional characterization of CODH/ACS from a larger spectrum of bacterial and archaeal lineages and detailed evolutionary analysis of the WL methyl branch will help resolve this issue.
Published: 2018

27. Current and future distribution of Aedes aegypti and Aedes albopictus (Diptera : Culicidae) in WHO Eastern Mediterranean Region

Author: Johannes Charlier, Ward Bryssinckx, Valérie De Waele, Frédéric Simard, Evans Buliva, Abdulhafid Hussain, Nhu Nguyen Tran Minh, Muhammad Mukhtar, David Roiz, Nabil Haddad, Ali Bouattour, Guy Hendrickx, Els Ducheyne, Osama Mahmoud, Mamunur Rahman Malik, Avia-GIS [Zoersel], WHO - Regional Office for the Eastern Mediterranean [Cairo, Egypt] (EMRO), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Université Libanaise, Diversity, ecology, evolution & Adaptation of arthropod vectors (MIVEGEC-DEEVA), Evolution des Systèmes Vectoriels (ESV), 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]), Ministry of Health Oman, Directorate of Malaria Control [Islamabad] (DoMC), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP), Ministry of Health and Human Services [Somalia], Vector Control Group (MIVEGEC-VCG), This work was supported by the WHO Regional Office for the Eastern Mediterranean. The work was supported partially by the project InvaCosts (ANR-14-CE02-0021-01). Field work in Lebanon was supported by the WHO National Bureau (LEB1409860)., We thank the numerous entomologists and health officers of the EMR who shared data with the WHO Regional Office for the Eastern Mediterranean. Ms. Barwa and Dr. Zayed are gratefully acknowledged for their technical assistance. We gratefully acknowledge the valuable input of the anonymous reviewers on the first version of this paper., ANR-14-CE02-0021,InvaCosts,Insectes envahissants et leurs couts pour la biodiversité, l'économie et la santé humaine(2014), and Regional Office for the Eastern Mediterranean [Cairo] (EMRO)
Subjects: 0301 basic medicine, Species distribution, Distribution (economics), Geographic Mapping, Distribution, medicine.disease_cause, Population density, MESH: Mosquito Vectors, MESH: Yellow Fever/diagnosis, Dengue fever, Dengue, MESH: Aedes, 0302 clinical medicine, Aedes aegypti, Aedes, MESH: Animals, Chikungunya, MESH: Dengue/diagnosis, Surveillance, biology, Mediterranean Region, Aedes albopictus, Geography, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Yellow Fever/epidemiology, lcsh:R858-859.7, Yellow fever, Cartography, MESH: Forecasting, General Computer Science, 030231 tropical medicine, MESH: Dengue/epidemiology, Mosquito Vectors, lcsh:Computer applications to medicine. Medical informatics, World Health Organization, MESH: Mediterranean Region/epidemiology, 03 medical and health sciences, Zika, MESH: World Health Organization, Species Specificity, MESH: Geographic Mapping, Yellow Fever, medicine, MESH: Species Specificity, Animals, Humans, MESH: Humans, business.industry, Research, Public Health, Environmental and Occupational Health, 15. Life on land, medicine.disease, biology.organism_classification, General Business, Management and Accounting, Spatial model, 030104 developmental biology, Culicidae, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Culicidae, Forecasting
Abstract: Background Aedes-borne diseases as dengue, zika, chikungunya and yellow fever are an emerging problem worldwide, being transmitted by Aedes aegypti and Aedes albopictus. Lack of up to date information about the distribution of Aedes species hampers surveillance and control. Global databases have been compiled but these did not capture data in the WHO Eastern Mediterranean Region (EMR), and any models built using these datasets fail to identify highly suitable areas where one or both species may occur. The first objective of this study was therefore to update the existing Ae. aegypti (Linnaeus, 1762) and Ae. albopictus (Skuse, 1895) compendia and the second objective was to generate species distribution models targeted to the EMR. A final objective was to engage the WHO points of contacts within the region to provide feedback and hence validate all model outputs. Methods The Ae. aegypti and Ae. albopictus compendia provided by Kraemer et al. (Sci Data 2:150035, 2015; Dryad Digit Repos, 2015) were used as starting points. These datasets were extended with more recent species and disease data. In the next step, these sets were filtered using the Köppen–Geiger classification and the Mahalanobis distance. The occurrence data were supplemented with pseudo-absence data as input to Random Forests. The resulting suitability and maximum risk of establishment maps were combined into hard-classified maps per country for expert validation. Results The EMR datasets consisted of 1995 presence locations for Ae. aegypti and 2868 presence locations for Ae. albopictus. The resulting suitability maps indicated that there exist areas with high suitability and/or maximum risk of establishment for these disease vectors in contrast with previous model output. Precipitation and host availability, expressed as population density and night-time lights, were the most important variables for Ae. aegypti. Host availability was the most important predictor in case of Ae. albopictus. Internal validation was assessed geographically. External validation showed high agreement between the predicted maps and the experts’ extensive knowledge of the terrain. Conclusion Maps of distribution and maximum risk of establishment were created for Ae. aegypti and Ae. albopictus for the WHO EMR. These region-specific maps highlighted data gaps and these gaps will be filled using targeted monitoring and surveillance. This will increase the awareness and preparedness of the different countries for Aedes borne diseases. Electronic supplementary material The online version of this article (10.1186/s12942-018-0125-0) contains supplementary material, which is available to authorized users.
Published: 2018

28. Structure and function of theLeptospira interrogansperoxide stress regulator (PerR), an atypical PerR devoid of a structural metal-binding site

Author: Patrick Weber, Nadia Benaroudj, Frederick Saul, Sarah Dubrac, Annie Landier, Bénédicte Beaudeau, Raléb Taher, Mounira Kebouchi, Ahmed Haouz, Mathieu Picardeau, Biologie des Spirochètes / Biology of Spirochetes, Institut Pasteur [Paris], Cristallographie (Plateforme) - Crystallography (Platform), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Biologie des Bactéries pathogènes à Gram-positif, This work was supported by the Institut Pasteur and Agence National de la Recherche Grant ANR-08-MIE-018., M. K., R. T., A. L., B. B., and P. W. performed experiments. F. S., A. H., S. D., M. P., and N. B. conceived, performed, and analyzed experiments. N. B. conceived and coordinated the study and wrote the paper. All authors approved the final version of the manuscript.We acknowledge SOLEIL for provision of synchrotron radiation facilities, and we thank the staff of beamline PROXIMA 1 for assistance. We are grateful to Gerald Murray and Ben Adler for providing the perR mutant. We thank Gouzel Karimova, Isabelle Michaud-Soret, and Victor Duarte for critically reading the manuscript and for helpful discussions., ANR-08-MIEN-0018,LEPTOVIR,Les leptospires : de la génétique à la pathogénèse(2008), Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Signal Transduction, 0301 basic medicine, MESH: Leptospira interrogans, [SDV]Life Sciences [q-bio], Mutant, Regulatory site, Metal Binding Site, Cell Cycle Proteins, spirochaetes, Biochemistry, Peroxide, chemistry.chemical_compound, Metalloprotein, oxidative stress, structural biology, spirochetes, MESH: Bacterial Proteins, Leptospira, chemistry.chemical_classification, biology, Chemistry, régulation transcriptionnelle, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, transcription regulation, Leptospira interrogans, Protein Binding, Signal Transduction, Repressor, Mitosis, PerR, reactive oxygen species (ROS), Microbiology, 03 medical and health sciences, MESH: Cell Cycle Proteins, Bacterial Proteins, métalloprotéine, MESH: Protein Binding, microbiologie, Molecular Biology, Binding Sites, metalloprotein, stress oxydatif, Cell Biology, MESH: Mitosis, biology.organism_classification, 030104 developmental biology, MESH: Binding Sites, Structural biology
Abstract: International audience; Peroxide sensing is essential for bacterial survival during aerobic metabolism and host infection. Peroxide stress regulators (PerRs) are homodimeric transcriptional repressors with each monomer typically containing both structural and regulatory metal-binding sites. PerR binding to gene promoters is controlled by the presence of iron in the regulatory site, and iron-catalyzed oxidation of PerR by H2O2 leads to the dissociation of PerR from DNA. In addition to a regulatory metal, most PerRs require a structural metal for proper dimeric assembly. We present here a structural and functional characterization of the PerR from the pathogenic spirochete Leptospira interrogans, a rare example of PerR lacking a structural metal-binding site. In vivo studies showed that the leptospiral PerR belongs to the peroxide stimulon in pathogenic species and is involved in controlling resistance to peroxide. Moreover, a perR mutant had decreased fitness in other host-related stress conditions, including at 37 °C or in the presence of superoxide anion. In vitro, leptospiral PerR could bind to the perR promoter region in a metal-dependent manner. The crystal structure of the leptospiral PerR revealed an asymmetric homodimer, with one monomer displaying complete regulatory metal coordination in the characteristic caliper-like DNA-binding conformation and the second monomer exhibiting disrupted regulatory metal coordination in an open non-DNA-binding conformation. This structure showed that leptospiral PerR assembles into a dimer in which a metal-induced conformational switch can occur independently in the two monomers. Our study demonstrates that structural metal binding is not compulsory for PerR dimeric assembly and for regulating peroxide stress.
Published: 2018

29. Developing a MEMS device with built-in microfluidics for biophysical single cell characterization

Author: Chann Lagadec, Dominique Collard, Hiroyuki Fujita, Manabu Ataka, Gregoire Perret, Momoko Kumemura, Yuki Takayama, Samuel Meignan, Mehmet C. Tarhan, Stanislav L. Karsten, Institut d’Électronique, de Microélectronique et de Nanotechnologie - UMR 8520 (IEMN), Centrale Lille-Institut supérieur de l'électronique et du numérique (ISEN)-Université de Valenciennes et du Hainaut-Cambrésis (UVHC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF), Physique-IEMN (PHYSIQUE-IEMN), Centrale Lille-Institut supérieur de l'électronique et du numérique (ISEN)-Université de Valenciennes et du Hainaut-Cambrésis (UVHC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF)-Centrale Lille-Institut supérieur de l'électronique et du numérique (ISEN)-Université de Valenciennes et du Hainaut-Cambrésis (UVHC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF), Laboratory for Integrated Micro Mechatronics Systems (LIMMS), The University of Tokyo (UTokyo)-Centre National de la Recherche Scientifique (CNRS), Kyushu Institute of Technology (Kyutech), The University of Tokyo (UTokyo), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Plasticité Cellulaire et Cancer - U908 (CPAC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Physique - IEMN (PHYSIQUE - IEMN), IEMN, Collection, and Acknowledgments:Authors would like to thank the VLSI Design and Education Center (VDEC, The Universityof Tokyo, Japan) for the mask production, IRCL (Institut pour la Recherche sur le Cancer de Lille, France) forhosting SMMiL-E facilities and V. Menon for critical reading of the paper. Y.T. thanks the University of Lille andthe SIRIC ONCO-Lille, and M.C.T. thanks Région Hauts-de-France for financial support.
Subjects: 0301 basic medicine, Materials science, lcsh:Mechanical engineering and machinery, [SPI.NANO] Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics, Microfluidics, microfluidics, single cell analysis, 02 engineering and technology, Capacitive displacement sensor, Article, Displacement (vector), 03 medical and health sciences, [SPI]Engineering Sciences [physics], [SPI.MECA.BIOM] Engineering Sciences [physics]/Mechanics [physics.med-ph]/Biomechanics [physics.med-ph], lcsh:TJ1-1570, Electrical measurements, Electrical and Electronic Engineering, [SPI.NANO]Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics, ComputingMilieux_MISCELLANEOUS, Microelectromechanical systems, [SDV.IB] Life Sciences [q-bio]/Bioengineering, Microchannel, biophysical cell characterization, business.industry, MEMS design, Mechanical Engineering, [SPI.MECA.BIOM]Engineering Sciences [physics]/Mechanics [physics.med-ph]/Biomechanics [physics.med-ph], 021001 nanoscience & nanotechnology, Characterization (materials science), 030104 developmental biology, Control and Systems Engineering, Optoelectronics, [SDV.IB]Life Sciences [q-bio]/Bioengineering, 0210 nano-technology, business, Actuator, bioMEMS
Abstract: This study combines the high-throughput capabilities of microfluidics with the sensitive measurements of microelectromechanical systems (MEMS) technology to perform biophysical characterization of circulating cells for diagnostic purposes. The proposed device includes a built-in microchannel that is probed by two opposing tips performing compression and sensing separately. Mechanical displacement of the compressing tip (up to a maximum of 14 &micro, m) and the sensing tip (with a quality factor of 8.9) are provided by two separate comb-drive actuators, and sensing is performed with a capacitive displacement sensor. The device is designed and developed for simultaneous electrical and mechanical measurements. As the device is capable of exchanging the liquid inside the channel, different solutions were tested consecutively. The performance of the device was evaluated by introducing varying concentrations of glucose (from 0.55 mM (0.1%) to 55.5 mM (10%)) and NaCl (from 0.1 mM to 10 mM) solutions in the microchannel and by monitoring changes in the mechanical and electrical properties. Moreover, we demonstrated biological sample handling by capturing single cancer cells. These results show three important capabilities of the proposed device: mechanical measurements, electrical measurements, and biological sample handling. Combined in one device, these features allow for high-throughput multi-parameter characterization of single cells.
Published: 2018

30. Purinergic Signaling: A Common Path in the Macrophage Response against Mycobacterium tuberculosis and Toxoplasma gondii

Author: Laetitia Petit-Jentreau, Ludovic Tailleux, Janine L. Coombes, University of Liverpool, Pathogénomique mycobactérienne intégrée, Institut Pasteur [Paris] (IP), Génétique mycobactérienne - Mycobacterial genetics, The present work was supported by the University of Liverpool. JLC is a lecturer at the University of Liverpool, UK, LT is a researcher at Institut Pasteur, France, and LP-J is a postdoctoral researcher on the JLC's Biotechnology and Biological Sciences Research Council (BBSRC) grant (BB/M023540/1) at the University of Liverpool, UK., LP-J wrote the paper with input from LT and JLC. All authors revised the manuscript, and approved it for publication., and Institut Pasteur [Paris]
Subjects: 0301 basic medicine, Microbiology (medical), Immunology, lcsh:QR1-502, Toxoplasma gondii, Microbiology, lcsh:Microbiology, 03 medical and health sciences, Immune system, Purinergic Agents, Macrophage, innate immunity, Innate immune system, biology, Intracellular parasite, Purinergic receptor, Mycobacterium tuberculosis, biology.organism_classification, purinergic agents, nucleotides, 3. Good health, macrophages, ATP, 030104 developmental biology, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Intracellular
Abstract: International audience; Immune responses are essential for the protection of the host against external dangers or infections and are normally efficient in the clearance of invading microbes. However, some intracellular pathogens have developed strategies to replicate and survive within host cells resulting in latent infection associated with strong inflammation. This excessive response can cause cell and tissue damage and lead to the release of the intracellular content, in particular the nucleotide pool, into the extracellular space. Over the last decade, new studies have implicated metabolites from the purinergic pathway in shaping the host immune response against intracellular pathogens and proved their importance in the outcome of the infection. This review aims to summarize how the immune system employs the purinergic system either to fight the pathogen, or to control collateral tissue damage. This will be achieved by focusing on the macrophage response against two intracellular pathogens, the human etiologic agent of tuberculosis, Mycobacterium tuberculosis and the protozoan parasite, Toxoplasma gondii.
Published: 2017
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31. High Rates of Neutralizing Antibodies to Toscana and Sandfly Fever Sicilian Viruses in Livestock, Kosovo

Author: Kurtesh Sherifi, Rémi N. Charrel, Kristaq Berxholi, Arber Taraku, Nazli Ayhan, Emergence des Pathologies Virales (EPV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM), University of Prishtina, Agricultural University of Tirana, This work was supported in part by the European Virus Archive Goes Global project, which has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 653316, the EDENext FP7-no. 261504 European Union project and this paper is catalogued by the EDENext Steering Committee as EDENext469 (http://www.edenext.eu). The work of N.A. and R.N.C. was conducted under the frame of EurNegVec COST Action TD1303. N.A. is supported by the Fondation Mediterranee Infection., European Project: 653316,H2020,H2020-INFRAIA-2014-2015,EVAg(2015), European Project: 261504,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,EDENEXT(2011), BUISINE, Soline, European Virus Archive goes global - EVAg - - H20202015-04-01 - 2019-03-31 - 653316 - VALID, and Biology and control of vector-borne infections in Europe - EDENEXT - - EC:FP7:HEALTH2011-01-01 - 2015-06-30 - 261504 - VALID
Subjects: 0301 basic medicine, Phlebovirus, Epidemiology, Kosovo, vector-borne infections, lcsh:Medicine, Mediterranean, Antibodies, Viral, 0302 clinical medicine, Phlebotomus Fever, Sandfly Fever Sicilian Virus, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Toscana virus, biology, Incidence, Dispatch, 3. Good health, Infectious Diseases, Epidemiological Monitoring, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Bunyaviridae, Microbiology (medical), Livestock, 030231 tropical medicine, Arbovirus, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, Balkan, medicine, Animals, Humans, lcsh:RC109-216, viruses, sandfly fever Sicilian virus, Sheep, lcsh:R, Sandfly fever Naples virus, biology.organism_classification, medicine.disease, Antibodies, Neutralizing, Virology, Insect Vectors, Sandfly, 030104 developmental biology, arbovirus, High Rates of Neutralizing Antibodies to Toscana and Sandfly Fever Sicilian Viruses in Livestock, Kosovo, Cattle, Psychodidae, sand flies
Abstract: Kurtesh Sherifi and Rémi N. Charrel contributed equally to this article; International audience; Toscana and sandfly fever Sicilian viruses (TOSV and SFSV, respectively), both transmitted by sand flies, are prominent human pathogens in the Old World. Of 1,086 serum samples collected from cattle and sheep during 2013 in various regions of Kosovo (Balkan Peninsula), 4.7% and 53.4% had neutralizing antibodies against TOSV and SFSV, respectively.
Published: 2017

32. Inovação na gestão de lições aprendidas em um Projeto de ti com a adoção de mídia social

Author: Roberto Winter, Marcirio Silveira Chaves, and This paper was funded by the CNPq project entitled 'Web 2.0 Technologies in Management of Lessons Learned in Projects,' under Grant Number 408117/2013-3.
Subjects: 0301 basic medicine, Knowledge management, Computer science, Reuse, lcsh:Business, lessons learned, web 2.0, Information Technology Projects, Social Media, Field (computer science), lcsh:Social Sciences, 03 medical and health sciences, Gestão do Conhecimento, Lições Aprendidas, Projetos de Tecnologia da Informação, Mídias Sociais, DSR, TAR, Social media, Action research, Productivity, Dissemination, lcsh:Commerce, business.industry, Information technology, Management, lcsh:H, 030104 developmental biology, lcsh:HF1-6182, Design science research, business, lcsh:HF5001-6182
Abstract: This research explores the gap in the management of lessons learned (MLL) in an Information Technology project (IT), validating a model (named Target) with the support of a wiki platform in a medium-sized company in the IT industry. This model supports the following MLL processes: awareness, collection, verification, storage, dissemination and reuse. This study adopts the paradigm of the Design Science Research and the Technical Action Research method to instantiate the Target model in the implementation phase of an IT project. The theoretical contribution lies in the practical utility of an LL model, which was validated in the field promoting innovation in the MLL. The practical implications can be seen in the company's learning to introduce the MLL, improve design productivity, increase employee collaboration and better disseminate knowledge., Esta pesquisa explora a lacuna na gestão de lições aprendidas (GLA) em um projeto de Tecnologia da Informação (TI), validando um modelo (denominado Target) com o apoio de uma plataforma wiki em uma empresa de médio porte no setor de TI. Este modelo suporta os seguintes processos do GLA: conscientização, coleta, verificação, armazenamento, disseminação e reuso. Este estudo adota o paradigma Design Science Research e o Método de Pesquisa-ação Técnica para instanciar o modelo Target na fase de implementação de um projeto de TI. A contribuição teórica reside na utilidade prática de um modelo de GLA, que foi validado no campo promovendo inovação na GLA. As implicações práticas podem ser vistas no aprendizado da empresa para introduzir o GLA, melhorar a produtividade do projeto, aumentar a colaboração dos funcionários e disseminar melhor o conhecimento.
Published: 2017

33. Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence

Author: Verena Königer, D. Scott Merrell, Roman Andriiovych Moskalenko, Rainer Haas, Thomas Borén, Sara Henriksson, Jafar Mahdavi, Abhijit Chowdhury, Johan Ögren, Anders Hofer, Jay V. Solnick, Dan Danielsson, Sara K. Lindén, Dag Ilver, Konstantinos S. Papadakos, Susanne Vikström, Jörgen Ådén, Jan Holgersson, Gerhard Gröbner, Alexej Schmidt, Jeanna Bugaytsova, Oscar Björnham, Göran O. Bylund, Rolf Sjöström, Stefan Oscarson, Dionyssios N. Sgouras, Lori M. Hansen, Yevgen A Chernov, Anders Esberg, Kristof Moonens, Christopher Aisenbrey, Charles Kelly, Ludmilla A. Morozova-Roche, Jeannette M. Whitmire, Beatriz Martinez-Gonzalez, Asish K. Mukhopadhyay, Angela Eldridge, Nicklas Strömberg, Robert H. Gilman, Andre Dubois, Lars Engstrand, Staffan Schedin, Brett A. Chromy, Justine Younson, Matthew Goldman, Anna Shevtsova, Macarena P. Quintana-Hayashi, Hui Liu, Magnus Unemo, Lena Rakhimova, Anna Åberg, Sebastian Suerbaum, Anna Arnqvist, Pär Gideonsson, Maréne Landström, Douglas E. Berg, Kristoffer Brännström, Anders Olofsson, Melissa Mendez, G. Balakrish Nair, Han Remaut, Umeå University, School of Life Sciences, University of Nottingham, UK (UON), Sahlgrenska Academy at University of Gothenburg [Göteborg], Université libre de Bruxelles (ULB), VIB-VUB Center for Structural Biology [Bruxelles], VIB [Belgium], Sumy State University, Max Von Pettenkofer Institute (MVP), Ludwig-Maximilians-Universität München (LMU), Uniformed Services University of the Health Sciences (USUHS), King‘s College London, Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU), School of Digestive and Liver Diseases [Kolkata] (SDLD), National Institute of Cholera and Enteric Diseases, Translational Health Science and Technology Institute [Faridabad] (THSTI), Institut Pasteur Hellénique, Réseau International des Instituts Pasteur (RIIP), Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Karolinska Institutet [Stockholm], Örebro University Hospital [Örebro, Sweden], Hannover Medical School [Hannover] (MHH), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), School of Chemistry and Chemical Biology (UCD), University College Dublin [Dublin] (UCD), University of California [Davis] (UC Davis), University of California, German Center for Infection Research, Partnersite Munich (DZIF), Département d'Informatique [Bruxelles] (ULB), Faculté des Sciences [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), University of California [San Diego] (UC San Diego), This work was supported by grants from Vetenskapsrådet (VR/M) to T.B. and S.K.L., Cancerfonden to T.B. and A.A., VR/NT to A.A. and S. Schedin, Formas to S.K.L., the J.C. Kempe and Seth M. Kempe Memorial Foundation, the Knut and Alice Wallenberg Foundation (2012.0090) to T.B. and M.L., European Union Seventh Framework Program GastricGlycoExplorer ITN grant number 316929 to T.B. and Y.A.C., Magn. Bergvall’s Foundation to S. Schedin, DFG (SFB 900/A1) to S. Suerbaum, DFG (HA2697/16-1) to R.H., FP6 ANR-06-PATHO-00701 ERA-NET and Actions Concertées Inter-Pasteuriennes (ACIP) (2006) to D.N.S., NIH R01DK063041 to D.E.B., NIH CA082312 to D.S.M., NIH AI070803 and AI081037 to J.V.S., CSIR project, India (No. 37(1640)/14/EMR –II) to A.K.M., and VIB and FWO (grants: G033717N and 12H8416N) to K.M. and H.R., This paper is dedicated to the memory of our friend, collaborator, and co-author Dr. Andre Dubois, a great scientist who contributed importantly both intellectually and materially to this project. We thank S. Michopoulos and G. Mantzaris for H. pylori clinical isolates and Ö. Furberg (NoPolo.se), N. Ulander (softplanbangkok.com), S. Lindström, and M. Borén for the digital movie, tech, art, and figure work, respectively., Vrije Universiteit Brussel, Basic (bio-) Medical Sciences, Structural Biology Brussels, and Department of Bio-engineering Sciences
Subjects: 0301 basic medicine, MESH: Hydrogen-Ion Concentration, Gastric acidity, MESH: Helicobacter Infections/pathology, MESH: Helicobacter pylori/physiology, Disease, adaptation, Bacterial Adhesion, polymorphism, acid responsiveness, MESH: Bacterial Adhesion, Bacterial, Hydrogen-Ion Concentration, gastric acidity, Adhesins, 3. Good health, Cell and molecular biology, medicine.anatomical_structure, Infectious Diseases, MESH: Gastric Mucosa/microbiology, Medical Microbiology, 030106 microbiology, Immunology, Digestive Diseases - (Peptic Ulcer), Biology, blood group antigen-binding adhesion, Microbiology, Helicobacter Infections, diversity, Vaccine Related, 03 medical and health sciences, Virology, ABO blood group system, Biodefense, Gastric mucosa, medicine, MESH: Helicobacter Infections/microbiology, multimerization, Adhesins, Bacterial, subpopulations, Helicobacter pylori, Prevention, gastric cancer, MESH: Adhesins, Bacterial/metabolism, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Gastric Mucosa/pathology, Bacterial adhesin, Chronic infection, 030104 developmental biology, Emerging Infectious Diseases, Gastric Mucosa, Parasitology, Digestive Diseases
Abstract: The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen andthat bio-selection and changes in BabA bindingproperties through mutation and recombination with babA-related genes are selected by differencesamong individuals and by changes in gastric acidity over time. These processes generate diverse H.pylori subpopulations, in which BabA's adaptive evolution contributes to H.pylori persistence and overt gastric disease.
Published: 2017

34. Analysis of gap junctional intercellular communications using a dielectrophoresis-based microchip

Author: Dominique Heymann, Bénédicte Brounais-Le Royer, Franck Verrecchia, Marta Tellez-Gabriel, Hannah K. Brown, Céline Charrier, Mathilde Mullard, Heymann, Dominique, European Training Network on Cancer-Induced Bone Diseases - BONE-NET - - EC:FP7:PEOPLE2011-02-01 - 2015-01-31 - 264817 - VALID, Equipe LIGUE Nationale Contre le Cancer 2012, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratotio Hematologia Oncologica y de Transplantes [Barcelona, Spain], Institut Investigacions Biomèdiques (IBB) Sant Pau [Barcelona, Spain]-Hospital de la Santa Creu i Sant Pau, Department of Oncology and Metabolism [Sheffield, UK], The University of Sheffield [Sheffield, U.K.], European Associated Laboratory [Sheffield, UK] (Sarcoma Research Unit), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), This paper was written as a part of a research project which received funding from the Seventh Framework Programme ([FP7/2007-2013]) under grant agreement n◦264817–BONE-NET. This work was also supported by the Bone Cancer Research Trust (UK, research project number 144681)., European Project: 264817,EC:FP7:PEOPLE,FP7-PEOPLE-2010-ITN,BONE-NET(2011), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: 0301 basic medicine, Histology, Bone microenvironment, Computer science, Bone Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Communication, Time-Lapse Imaging, Pathology and Forensic Medicine, Electrophoresis, Microchip, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.CAN] Life Sciences [q-bio]/Cancer, Bone tumours, Cell Line, Tumor, Humans, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Osteosarcoma, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Osteoblasts, Gap junction, Multiple applications, Gap Junctions, Cell Differentiation, Mesenchymal Stem Cells, Gap junctional intercellular communication, Cell Biology, General Medicine, Dielectrophoresis, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Molecular analysis, Cell biology, 030104 developmental biology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 030220 oncology & carcinogenesis, Dielectrophoresis device, Intracellular
Abstract: International audience; Please cite this article in press as: Tellez-Gabriel, M., et al., Analysis of gap junctional intercellular communications using a dielectrophoresis-based microchip. Gap junctions are transmembrane structures that directly connect the cytoplasm of adjacent cells, making intercellular communications possible. It has been shown that the behaviour of several tumours – such as bone tumours – is related to gap junction intercellular communications (GJIC). Several methodologies are available for studying GJIC, based on measuring different parameters that are useful for multiple applications, such as the study of carcinogenesis for example. These methods nevertheless have several limitations. The present manuscript describes the setting up of a dielectrophoresis (DEP)-based lab-on-a-chip platform for the real-time study of Gap Junctional Intercellular Communication between osteosarcoma cells and the main cells accessible to their microenvironment. We conclude that using the DEParray technology for the GJIC assessment has several advantages comparing to current techniques. This methodology is less harmful for cells integrity; cells can be recovered after interaction to make further molecular analysis; it is possible to study GJIC in real time; we can promote cell interactions using up to five different populations. The setting up of this new methodology overcomes several difficulties to perform experiments for solving questions about GJIC process that we are not able to do with current technics.
Published: 2017

35. Tumour heterogeneity: the key advantages of single-cell analysis

Author: Francois Lamoureux, Marta Tellez-Gabriel, Benjamin Ory, Dominique Heymann, Marie-Françoise Heymann, Laboratorio Hematologia Oncologica y de Transplantes [Barcelona, Spain], Institut Investigacions Biomèdiques (IBB) Sant Pau [Barcelona, Spain]-Hospital de la Santa Creu i Sant Pau, Equipe LIGUE Nationale Contre le Cancer 2012, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Oncology and Metabolism [Sheffield, UK], The University of Sheffield [Sheffield, U.K.], European Associated Laboratory [Sheffield, UK] (Sarcoma Research Unit), This paper was written as a part of a research project which received funding from the Seventh Framework Programme ([FP7/2007-2013]) under grant agreement n 264817—BONE-NET. This work was supported by the Bone Cancer Research Trust (UK, research project number 144681)., European Project: 264817,EC:FP7:PEOPLE,FP7-PEOPLE-2010-ITN,BONE-NET(2011), Heymann, Dominique, and European Training Network on Cancer-Induced Bone Diseases - BONE-NET - - EC:FP7:PEOPLE2011-02-01 - 2015-01-31 - 264817 - VALID
Subjects: 0301 basic medicine, Tumour heterogeneity, circulating tumour cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease, Review, Biology, Bioinformatics, Catalysis, lcsh:Chemistry, Inorganic Chemistry, 03 medical and health sciences, Genetic Heterogeneity, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Single-cell analysis, [SDV.CAN] Life Sciences [q-bio]/Cancer, single cells, Neoplasms, Gene expression, Biopsy, medicine, Humans, Epigenetics, Physical and Theoretical Chemistry, Neoplasm Metastasis, lcsh:QH301-705.5, Molecular Biology, Spectroscopy, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, medicine.diagnostic_test, Organic Chemistry, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Neoplastic Cells, Circulating, Phenotype, 3. Good health, Computer Science Applications, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Cancer cell, Cancer research, Single-Cell Analysis, heterogeneity
Abstract: International audience; Tumour heterogeneity refers to the fact that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation, and metastatic potential. This phenomenon occurs both between tumours (inter-tumour heterogeneity) and within tumours (intra-tumour heterogeneity), and it is caused by genetic and non-genetic factors. The heterogeneity of cancer cells introduces significant challenges in using molecular prognostic markers as well as for classifying patients that might benefit from specific therapies. Thus, research efforts for characterizing heterogeneity would be useful for a better understanding of the causes and progression of disease. It has been suggested that the study of heterogeneity within Circulating Tumour Cells (CTCs) could also reflect the full spectrum of mutations of the disease more accurately than a single biopsy of a primary or metastatic tumour. In the last years many high throughput methodologies have raised for the study of heterogeneity at different levels (i.e.: RNA, DNA, protein, epigenetic events). The aim of the current review is to stress clinical implications of tumour heterogeneity, as well as current available methodologies for their study with a specific attention to those able to assess heterogeneity at the single cell level.
Published: 2016

36. Actin activates Pseudomonas aeruginosa ExoY nucleotidyl cyclase toxin and ExoY-like effector domains from MARTX toxins

Author: Undine Mechold, Abdelkader Namane, Cosmin Saveanu, Vasily Ogryzko, Alexander Belyy, Daniel Ladant, Lina Worpenberg, Souad Fellous, Dorothée Raoux-Barbot, Christien Merrifield, Elodie Assayag, Violaine David, Louis Renault, Véronique Henriot, Biochimie des Interactions Macromoléculaires / Biochemistry of Macromolecular Interactions, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Gamaleya Research Center, Génétique des Interactions Macromoléculaires, Signalisation, noyaux et innovations en cancérologie (UMR8126), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), This project was funded by the Institut Pasteur under #PTR425 to U.M. and C.S. and by CNRS. A.B. was supported by a stipend from the Pasteur—Paris University (PPU) International PhD Program. We acknowledge the core facilities of Imagerie-Gif,(http://www.i2bc.paris-saclay.fr), supported by ‘France-BioImaging’ (ANR-10-INBS-04-01). This paper is dedicated to the memory of Vasily Ogryzko (1960–2016)., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Biochimie des Interactions Macromoléculaires, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Signalisation, noyaux et innovations en cancérologie ( UMR8126 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), and ANR-10-INBS-04-01/10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée ( 2010 )
Subjects: 0301 basic medicine, Science, Bacterial Toxins, General Physics and Astronomy, macromolecular substances, Saccharomyces cerevisiae, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [ SDV.MP.BAC ] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Filamentous actin, Cyclase, Article, General Biochemistry, Genetics and Molecular Biology, Type three secretion system, Adenylyl cyclase, 03 medical and health sciences, Cyclic nucleotide, chemistry.chemical_compound, Bacterial Proteins, ExoY, Type III Secretion Systems, Adenylate cyclase, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Actin, Multidisciplinary, Virulence, Mass spectrometry, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Chemistry, Effector, General Chemistry, Transfection, Guanylate cyclase, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Actins, 3. Good health, Cell biology, 030104 developmental biology, Glucosyltransferases, Mutation, Pseudomonas aeruginosa, Protein Binding
Abstract: The nucleotidyl cyclase toxin ExoY is one of the virulence factors injected by the Pseudomonas aeruginosa type III secretion system into host cells. Inside cells, it is activated by an unknown eukaryotic cofactor to synthesize various cyclic nucleotide monophosphates. ExoY-like adenylate cyclases are also found in Multifunctional-Autoprocessing Repeats-in-ToXin (MARTX) toxins produced by various Gram-negative pathogens. Here we demonstrate that filamentous actin (F-actin) is the hitherto unknown cofactor of ExoY. Association with F-actin stimulates ExoY activity more than 10,000 fold in vitro and results in stabilization of actin filaments. ExoY is recruited to actin filaments in transfected cells and alters F-actin turnover. Actin also activates an ExoY-like adenylate cyclase MARTX effector domain from Vibrio nigripulchritudo. Finally, using a yeast genetic screen, we identify actin mutants that no longer activate ExoY. Our results thus reveal a new sub-group within the class II adenylyl cyclase family, namely actin-activated nucleotidyl cyclase (AA-NC) toxins., The ExoY toxin is injected by Pseudomonas aeruginosa into host cells, where it is activated by an unknown host factor. Here the authors identify such factor as filamentous actin.
Published: 2016

37. Larval nutritional stress affects vector life history traits and human malaria transmission

Author: Thierry Lefèvre, Amélie Vantaux, Anna Cohuet, Olivier Roux, Benjamin Roche, Kounbobr Roch Dabiré, 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]), Institut de Recherche en Sciences de la Santé (IRSS), CNRST, Transmission-Interactions-Adaptations hôtes/vecteurs/pathogènes (MIVEGEC-TRIAD), Evolution des Systèmes Vectoriels (ESV), 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]), Institut de Recherche en Sciences de la Santé (IRSS) / Centre Muraz, Unité de modélisation mathématique et informatique des systèmes complexes [Bondy] (UMMISCO), Université Cadi Ayyad [Marrakech] (UCA)-Université de Yaoundé I-Université Gaston Bergé (Saint-Louis, Sénégal)-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de la francophonie pour l'informatique-Université Pierre et Marie Curie - Paris 6 (UPMC), Diversity, ecology, evolution & Adaptation of arthropod vectors (MIVEGEC-DEEVA), This study was funded by the ANR grant 11-PDOC-006-01 to TL., We would like to thank all of the children and their parents who participated in this study, as well as the local authorities for their support, and Andrea Yockey-Dejean for proofreading the paper. We are very grateful to the IRSS staff in Burkina Faso for technical assistance., and Institut de Recherche pour le Développement (IRD)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université de Yaoundé I-Institut de la francophonie pour l'informatique-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Gaston Bergé (Saint-Louis, Sénégal)-Université Cadi Ayyad [Marrakech] (UCA)
Subjects: 0301 basic medicine, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Plasmodium falciparum, Zoology, Insect, MESH: Insect Vectors, Biology, Article, law.invention, Life history theory, 03 medical and health sciences, MESH: Plasmodium falciparum/growth & development, law, Stress, Physiological, Anopheles, parasitic diseases, medicine, Gametocyte, Animals, Humans, MESH: Animals, MESH: Stress, Physiological, Life History Traits, media_common, Larva, Multidisciplinary, MESH: Humans, MESH: Life History Traits, MESH: Anopheles/parasitology, Ecology, fungi, MESH: Anopheles/growth & development, medicine.disease, Fecundity, 3. Good health, Insect Vectors, Malaria, MESH: Larva/parasitology, MESH: Malaria/transmission, 030104 developmental biology, Transmission (mechanics), MESH: Larva/growth & development, Vector (epidemiology), Female, MESH: Female
Abstract: Exposure to stress during an insect’s larval development can have carry-over effects on adult life history traits and susceptibility to pathogens. We investigated the effects of larval nutritional stress for the first time using field mosquito vectors and malaria parasites. In contrast to previous studies, we show that larval nutritional stress may affect human to mosquito transmission antagonistically: nutritionally deprived larvae showed lower parasite prevalence for only one gametocyte carrier; they also had lower fecundity. However, they had greater survival rates that were even higher when infected. When combining these opposing effects into epidemiological models, we show that larval nutritional stress induced a decrease in malaria transmission at low mosquito densities and an increase in transmission at high mosquito densities, whereas transmission by mosquitoes from well-fed larvae was stable. Our work underscores the importance of including environmental stressors towards understanding host–parasite dynamics to improve disease transmission models and control.
Published: 2016

38. Integrated Analysis of Environment, Cattle and Human Serological Data: Risks and Mechanisms of Transmission of Rift Valley Fever in Madagascar

Author: Annelise Tran, Vladimir Grosbois, Jean-Pierre Ravalohery, Fanjasoa Rakotomanana, Jean-Michel Heraud, Soa Fy Andriamandimby, Christophe Rogier, Seta Andriamamonjy, Véronique Chevalier, Benoit Durand, Marie-Marie Olive, Animal et gestion intégrée des risques (UPR AGIRs), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Unité de Virologie [Antananarivo, Madagascar] (IPM), Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Laboratoire de santé animale, sites de Maisons-Alfort et de Dozulé, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Réseau International des Instituts Pasteur (RIIP), This study was supported in part by funds raised by (i) CIRAD (ii) the Centre National d'Etudes Spatiales (CNES, grant # 131163/00) (iii) the Institut Pasteur de Madagascar. Human field work was funded by the Institut Pasteur of Madagascar (Internal Project through the ZORA (ZOonoses, Rodent and Arboviruses) project and the Centers for Disease Control and Prevention (CDC, and Cooperative Agreement #U51/IP000327). Moreover, this material is based upon work supported by the U. S. Department of Homeland Security under the Center of Excellence of Emerging and Zoonotic Animal Diseases Grant Award Number 2010-ST061-AG0001. Cattle study was supported in part by funds raised by World Health Organization (WHO) and the Food and Agriculture Organization of the United Nations (FAO) through the Central Emergency Response Fund of the United Nations. The views and conclusions contained in this paper are those of the authors and should not be interpreted as necessarily representing the official policies, either explicit or implicit, of the U. S. Department of Homeland Security. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Subjects: Veterinary medicine, Epidemiology, Pathology and Laboratory Medicine, law.invention, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Analyse du risque, MESH: Cattle Diseases, MESH: Animals, Neglected tropical diseases, Mammals, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, MESH: Middle Aged, 000 - Autres thèmes, Fièvre de la Vallée du Rift, Anopheles, Ruminants, 3. Good health, Transmission (mechanics), MESH: Young Adult, Densité de population, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Enzootic, Infectious diseases, L72 - Organismes nuisibles des animaux, Genre humain, Bétail, Livestock, lcsh:RC955-962, MESH: Culex, Microbiology, MESH: Anopheles, 03 medical and health sciences, MESH: Cross-Sectional Studies, Madagascar, MESH: Humans, MESH: Seroepidemiologic Studies, Tropical diseases, Public Health, Environmental and Occupational Health, Organisms, lcsh:RA1-1270, MESH: Adult, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 15. Life on land, medicine.disease, Invertebrates, Insect Vectors, 030104 developmental biology, Africa, Cattle, MESH: Female, MESH: Antibodies, Viral, 0301 basic medicine, RNA viruses, Cattle Diseases, Disease Vectors, L73 - Maladies des animaux, Mosquitoes, Serology, Geographical Locations, MESH: Madagascar, law, Zoonoses, Facteur de risque, Bunyaviruses, Medicine and Health Sciences, MESH: Rift Valley Fever, Comportement humain, Rift Valley fever, 2. Zero hunger, biology, lcsh:Public aspects of medicine, Agriculture, Facteur du milieu, Medical microbiology, Insects, MESH: Cattle, Vecteur de maladie, Vertebrates, Viruses, MESH: Rift Valley fever virus, Seasons, Pathogens, Research Article, lcsh:Arctic medicine. Tropical medicine, Zone humide, Arthropoda, Distribution géographique, Culex, 030231 tropical medicine, Viral diseases, MESH: Insect Vectors, Virus de la fièvre de la vallée du Rift, Sérologie, Bovines, medicine, Seroprevalence, Animals, MESH: Environment, Transmission des maladies, Biology and life sciences, Viral pathogens, Morbidité, biology.organism_classification, Rift Valley fever virus, MESH: Male, Microbial pathogens, Amniotes, People and Places, Earth Sciences, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract: Background Rift Valley fever (RVF) is a vector-borne disease affecting ruminants and humans. Madagascar was heavily affected by RVF in 2008–2009, with evidence of a large and heterogeneous spread of the disease. The identification of at-risk environments is essential to optimize the available resources by targeting RVF surveillance in Madagascar. Herein, the objectives of our study were: (i) to identify the environmental factors and areas favorable to RVF transmission to both cattle and human and (ii) to identify human behaviors favoring human infections in Malagasy contexts. Methodology/Principal Findings First, we characterized the environments of Malagasy communes using a Multiple Factor Analysis (MFA). Then, we analyzed cattle and human serological data collected at national level using Generalized Linear Mixed Models, with the individual serological status (cattle or human) as the response, and MFA factors, as well as other potential risk factors (cattle density, human behavior) as explanatory variables. Cattle and human seroprevalence rates were positively associated to humid environments (p, Author Summary Rift Valley fever virus (RVFV) is a pathogen that causes a vector-borne tropical disease. The disease affects ruminants and humans and severely impacts the health and economy of affected countries. Madagascar was heavily affected by Rift Valley fever (RVF) in 2008–2009, with evidence of a large and heterogeneous spread of the disease. Our study aims at identifying environmental and human-related risk factors for RVFV transmission. First, we characterized Malagasy environments according to their putative influence on RVFV mosquito density and population dynamics. Then we statistically analyzed cattle and human serological data collected at a national level with the individual serological status as response, and Malagasy environments previously characterized by climatic and landscape variables as well as other potential risk factors as explanatory variables. Our results identified humid environments of the western, north-western and eastern parts of the island as risky areas. The identification of at-risk environments is essential to focus veterinary surveillance and control of RVFV.
Published: 2016

39. Circulating Tumor Cells: A Review of Non-EpCAM-Based Approaches for Cell Enrichment and Isolation

Author: Antoine Chalopin, Benjamin Ory, Lidia Rodriguez Calleja, Marta Tellez Gabriel, Dominique Heymann, Equipe LIGUE Nationale Contre le Cancer 2012, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Oncology and Metabolism [Sheffield, UK], The University of Sheffield [Sheffield, U.K.], This paper was written as a part of research project which received funding from the Seventh Framework Program [(FP7/2007-2013) under grant agreement no. 264817—BONE-NET and this work was supported by the Fondation de France (Engt no. 16390)]., European Project: 264817,EC:FP7:PEOPLE,FP7-PEOPLE-2010-ITN,BONE-NET(2011), Heymann, Dominique, and European Training Network on Cancer-Induced Bone Diseases - BONE-NET - - EC:FP7:PEOPLE2011-02-01 - 2015-01-31 - 264817 - VALID
Subjects: 0301 basic medicine, Epithelial-Mesenchymal Transition, Clinical Biochemistry, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Separation, Biology, Cell enrichment, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Circulating tumor cell, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Antigen, Single-cell analysis, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigens, Neoplasm, Biomarkers, Tumor, Humans, Epithelial–mesenchymal transition, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, business.industry, Biochemistry (medical), Mesenchymal stem cell, Epithelial cell adhesion molecule, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Epithelial Cell Adhesion Molecule, Neoplastic Cells, Circulating, 3. Good health, 030104 developmental biology, chemistry, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 030220 oncology & carcinogenesis, Immunology, Cancer research, Personalized medicine, Single-Cell Analysis, business, Cell Adhesion Molecules
Abstract: BACKGROUND Circulating tumor cells (CTCs) are biomarkers for noninvasively measuring the evolution of tumor genotypes during treatment and disease progression. Recent technical progress has made it possible to detect and characterize CTCs at the single-cell level in blood. CONTENT Most current methods are based on epithelial cell adhesion molecule (EpCAM) detection, but numerous studies have demonstrated that EpCAM is not a universal marker for CTC detection because it fails to detect both carcinoma cells that undergo epithelial-mesenchymal transition (EMT) and CTCs of mesenchymal origin. Moreover, EpCAM expression has been found in patients with benign diseases. A large proportion of the current studies and reviews about CTCs describe EpCAM-based methods, but there is evidence that not all tumor cells can be detected using this marker. Here we describe the most recent EpCAM-independent methods for enriching, isolating, and characterizing CTCs on the basis of physical and biological characteristics and point out the main advantages and disadvantages of these methods. SUMMARY CTCs offer an opportunity to obtain key biological information required for the development of personalized medicine. However, there is no universal marker of these cells. To strengthen the clinical utility of CTCs, it is important to improve existing technologies and develop new, non–EpCAM-based systems to enrich and isolate CTCs.
Published: 2016

40. Coordinated recruitment of Spir actin nucleators and myosin V motors to Rab11 vesicle membranes

Author: Andreas T. Grasskamp, Martin Kollmar, Janine Tittel, Margaret A. Titus, Petra Schwille, Eugen Kerkhoff, Florian Chardon, Bruno Goud, Thomas Weidemann, Gilles Malherbe, Olena Pylypenko, Annette Samol-Wolf, Bruno Baron, Patrick England, Carina Ida Luise Michel, Sabine Weiss, Alistair N. Hume, Anne Houdusse, Tobias Welz, Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University Hospital Regensburg, Max-Planck-Institut für Biochemie = Max Planck Institute of Biochemistry (MPIB), Max-Planck-Gesellschaft, Max-Planck-Institut für Biophysikalische Chemie - Max Planck Institute for Biophysical Chemistry [Göttingen], Motilité structurale, Compartimentation et dynamique cellulaires (CDC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), University of Nottingham, UK (UON), Biophysique des macromolécules et leurs interactions, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Minnesota [Twin Cities] (UMN), University of Minnesota System, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), This paper was supported by the following grants:Centre National de la Recherche Scientifique to Anne Houdusse, Olena Pylypenko., Deutsche Forschungsgemeinschaft SPP 1464: KO 2251/13-1 to Martin Kollmar., Bayerische Forschungsstiftung WFKMS Nr. F2 - 5121.4.3.1 ‐10c (BayGene) to Eugen Kerkhoff., Fondation de la Recherche Medicale ING20140129255 to Anne Houdusse., Agence Nationale de la Recherche ANR-13-BSV8-0019-01 to Anne Houdusse., National Science Foundation MCB-1244235 to Margaret A Titus., University of Minnesota Medical School Award, E-0915-04 to Margaret A Titus., Deutsche Forschungsgemeinschaft SPP 1464: SCHW 716/11-1, -2 to Petra Schwille., Ligue Contre le Cancer RS16/75-67 to Anne Houdusse., Fondation ARC pour la Recherche sur le Cancer SFI20121205398 to Anne Houdusse., Deutsche Forschungsgemeinschaft SPP 1464: KE 447/10-1, -2 to Eugen Kerkhoff., We acknowledge SOLEIL for provision of synchrotron radiation facilities (proposal 20141015) and we would like to thank Pierre Legrand and Beatriz Guimares for assistance in using beamline PX1. We thank Sandra Lemke, Carsten Grashoff, Yilmaz Niyaz (Zeiss) and Volker Buschmann (Picoquant) for their generous support in FLIM. We thank Mitsuo Ikebe for providing a MyoVb cDNA. We acknowledge Wikayatou Attanda and Charles Gauquelin for support in recombinant protein production. We also acknowledge Damarys Loew and Vanessa Masson (Curie Institute Protein Mass Spectrometry Platform) for the peptide fingerprint analysis of Spir-2 constructs. BG, AHo, OP, GM, FC are part of the Labex CelTisPhyBio 11-LBX-0038, which is part of the IDEX PSL (ANR-10-IDEX-0001-02 PSL)., Max Planck Institute of Biochemistry (MPIB), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: 0301 basic medicine, Models, Molecular, Protein Conformation, none, [SDV]Life Sciences [q-bio], Arp2/3 complex, Microfilament, Crystallography, X-Ray, vesicle transport, Myosin head, Mice, 0302 clinical medicine, MESH: Protein Conformation, biophysics, Myosin, cell biology, structural biology, MESH: Animals, Biology (General), Actin nucleation, MESH: Protein Multimerization, General Neuroscience, Microfilament Proteins, General Medicine, Biophysics and Structural Biology, MESH: rab GTP-Binding Proteins/chemistry, Cell biology, MESH: rab GTP-Binding Proteins/metabolism, Medicine, MESH: Cytoplasmic Vesicles/metabolism, MESH: Membranes/metabolism, MESH: Models, Molecular, Research Article, Protein Binding, Myosin light-chain kinase, QH301-705.5, Science, Myosin Type V, MESH: Microfilament Proteins/chemistry, MESH: Microfilament Proteins/metabolism, macromolecular substances, Biology, General Biochemistry, Genetics and Molecular Biology, actin motor proteins, 03 medical and health sciences, MESH: Myosin Type V/metabolism, Animals, MESH: Protein Binding, Actin-binding protein, MESH: Mice, MESH: Myosin Type V/chemistry, Membranes, Spire, General Immunology and Microbiology, Cytoplasmic Vesicles, myosin V, Actin remodeling, MESH: Crystallography, X-Ray, 030104 developmental biology, rab GTP-Binding Proteins, Rab11, biology.protein, Protein Multimerization, actin nucleation, 030217 neurology & neurosurgery
Abstract: There is growing evidence for a coupling of actin assembly and myosin motor activity in cells. However, mechanisms for recruitment of actin nucleators and motors on specific membrane compartments remain unclear. Here we report how Spir actin nucleators and myosin V motors coordinate their specific membrane recruitment. The myosin V globular tail domain (MyoV-GTD) interacts directly with an evolutionarily conserved Spir sequence motif. We determined crystal structures of MyoVa-GTD bound either to the Spir-2 motif or to Rab11 and show that a Spir-2:MyoVa:Rab11 complex can form. The ternary complex architecture explains how Rab11 vesicles support coordinated F-actin nucleation and myosin force generation for vesicle transport and tethering. New insights are also provided into how myosin activation can be coupled with the generation of actin tracks. Since MyoV binds several Rab GTPases, synchronized nucleator and motor targeting could provide a common mechanism to control force generation and motility in different cellular processes. DOI: http://dx.doi.org/10.7554/eLife.17523.001

41. Isolation and sequencing of Dashli virus, a novel Sicilian-like virus in sandflies from Iran; genetic and phylogenetic evidence for the creation of one novel species within the Phlebovirus genus in the Phenuiviridae family

Author: Xavier de Lamballerie, E. Javadian, Cigdem Alkan, Nourina Rahbarian, Bulent Alten, Laurence Bichaud, Nazli Ayhan, Mehdi Badakhshan, Vahideh Moin Vaziri, Rémi N. Charrel, BUISINE, Soline, European Virus Archive goes global - EVAg - - H20202015-04-01 - 2019-03-31 - 653316 - VALID, Biology and control of vector-borne infections in Europe - EDENEXT - - EC:FP7:HEALTH2011-01-01 - 2015-06-30 - 261504 - VALID, 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), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Department of Parasitology and Mycology [Tehran, Iran] (School of Medicine), Shahid Beheshti University of Medical Sciences [Tehran, Iran], Department of Medical Entomology and Vector Control [Tehran, Iran] (School of Public Health), Tehran University of Medical Sciences-Institute of Public Health Research [Tehran, Iran], Cellular and Molecular Biology Research Center [Tehran, Iran] (SBU), Shahid Beheshti University of Medical Sciences [Tehran] (SBUMS), Hacettepe University = Hacettepe Üniversitesi, Hôpital de la Timone [CHU - APHM] (TIMONE), This work was supported through funds received from EU grant FP7-261504 EDENext and this paper is catalogued by the EDENext Steering Committee (http://www.edenext.eu), the European Virus Archive goes Global (EVAg) project in the European Union's Horizon 2020 research and innovation programme under grant agreement No 653316 (http://global.european- virus-archive.com/). The present article partly was supported by Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. (Grant No: 1573) The work of RNC was done under the frame of EurNegVec (TD1303) COST Action., European Project: 653316,H2020,H2020-INFRAIA-2014-2015,EVAg(2015), European Project: 261504,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,EDENEXT(2011), and Shahid Beheshti University-Shahid Beheshti University
Subjects: 0301 basic medicine, Male, Phlebovirus, RNA viruses, Fevers, Iran, Disease Vectors, Pathology and Laboratory Medicine, Database and Informatics Methods, Phlebotomus Fever, Bunyaviruses, Medicine and Health Sciences, Sandfly Fever Sicilian Virus, Phylogeny, Data Management, Genetics, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology, Phylogenetic tree, lcsh:Public aspects of medicine, Phylogenetic Analysis, Gene Pool, 3. Good health, Phylogenetics, Infectious Diseases, Medical Microbiology, Viral Pathogens, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Viruses, RNA, Viral, Female, Gene pool, Pathogens, Sequence Analysis, Research Article, Computer and Information Sciences, lcsh:Arctic medicine. Tropical medicine, lcsh:RC955-962, Bioinformatics, Genome, Viral, Research and Analysis Methods, Microbiology, Virus, 03 medical and health sciences, Signs and Symptoms, Amino Acid Sequence Analysis, Diagnostic Medicine, Animals, Humans, Evolutionary Systematics, Microbial Pathogens, Taxonomy, Evolutionary Biology, Base Sequence, Population Biology, Sequence Analysis, RNA, Public Health, Environmental and Occupational Health, Organisms, Biology and Life Sciences, lcsh:RA1-1270, biology.organism_classification, Rift Valley fever virus, Sandfly, Insect Vectors, Sand Flies, Species Interactions, 030104 developmental biology, Microbial genetics, Psychodidae, Population Genetics
Abstract: Phlebotomine sandflies are vectors of phleboviruses that cause sandfly fever or meningitis with significant implications for public health. Although several strains of these viruses had been isolated in Iran in the late 1970's, there was no recent data about the present situation at the outset of this study. Entomological investigations performed in 2009 and 2011 in Iran collected 4,770 sandflies from 10 different regions. Based on morphological identification, they were sorted into 315 pools according to species, sex, trapping station and date of capture. A phlebovirus, provisionally named Dashli virus (DASHV), was isolated from one pool of Sergentomyia spp, and subsequently DASHV RNA was detected in a second pool of Phlebotomus papatasi. Genetic and phylogenetic analyses based on complete coding genomic sequences indicated that (i) DASHV is most closely related to the Iranian isolates of Sandfly fever Sicilian virus [SFSV], (ii) there is a common ancestor to DASHV, Sandfly fever Sicilian- (SFS) and SFS-like viruses isolated in Italy, India, Turkey, and Cyprus (lineage I), (iii) DASHV is more distantly related with Corfou and Toros viruses (lineage II) although common ancestry is supported with 100% bootstrap, (iii) lineage I can be subdivided into sublineage Ia including all SFSV, SFCV and SFTV except those isolated in Iran which forms sublineage Ib (DASHV). Accordingly, we suggest to approve Sandfly fever Sicilian virus species consisting of the all aforementioned viruses. Owing that most of these viruses have been identified in human patients with febrile illness, DASHV should be considered as a potential human pathogen in Iran., Author summary Phlebotomine sandflies are vectors of phleboviruses that cause sandfly fever or meningitis with significant implications for public health. Although several strains of these viruses had been isolated in Iran in the late 1970's, there was no recent data about the present situation at the outset of this study. Entomological investigations performed in 2009 and 2011 in Iran collected 4,770 sandflies from 10 different regions. A phlebovirus, provisionally named Dashli virus (DASHV), was isolated / detected in two pools. DASHV strain was isolated in cell culture and complete genome sequence was determined. Sequence analysis indicated that (i) DASHV is most closely related to the Iranian isolates of Sandfly fever Sicilian virus [SFSV], a virus that is known to cause self-resolutive incapacitating febrile illness in humans, (ii) there is a common ancestor to DASHV and all other variants of SFSV isolated in Italy, India, Turkey, and Cyprus (lineage I), (iii) DASHV is more distantly related with Corfou and Toros viruses (lineage II) although common ancestry is supported with 100% bootstrap, (iii) lineage I can be subdivided into sublineage Ia including all SFSV strains, whereas Iranian viruses are most closely related and should be individualized as DASHV (sublineage Ib). Although discovered first in the 1940's, SFSV is still listed as "tentative species" by the International Committee for Taxonomy of Viruses. Based on the results described in this study, we propose to approve Sandfly fever Sicilian virus species. Owing that most of these viruses have been identified in human patients with febrile illness, DASHV should be considered as a potential human pathogen in Iran.
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