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1. Risk prediction tools in cardiovascular disease prevention: A report from the ESC Prevention of CVD Programme led by the European Association of Preventive Cardiology (EAPC) in collaboration with the Acute Cardiovascular Care Association (ACCA) and the Association of Cardiovascular Nursing and Allied Professions (ACNAP)

Author

Xavier Rossello, Jannick AN Dorresteijn, Arne Janssen, Ekaterini Lambrinou, Martijn Scherrenberg, Eric Bonnefoy-Cudraz, Mark Cobain, Massimo F Piepoli, Frank LJ Visseren, Paul Dendale, null This paper is a co-publication betw, Centro Nacional de Investigaciones Cardiovasculares Carlos III [Madrid, Spain] (CNIC), Instituto de Salud Carlos III [Madrid] (ISC), Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), University Medical Center [Utrecht], Jessa Ziekenhuis [Hasselt], Cyprus University of Technology, Hasselt University (UHasselt), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Service de Cardiologie Lyon (Hôpital Louis Pradel [CHU - HCL]), Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Imperial College London, University of Southern California (USC), Rossello, Xavier/0000-0001-6783-8463, Rossello, Xavier, Dorresteijn, Jannick A. N., JANSSEN, Arne, Lambrinou, Ekaterini, SCHERRENBERG, Martijn, Bonnefoy-Cudraz, Eric, Cobain, Mark, Piepoli, Massimo F., Visseren, Frank L. J., DENDALE, Paul, CarMeN, laboratoire, Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Male, Time Factors, Epidemiology, [SDV]Life Sciences [q-bio], Allied Health Personnel, Disease, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, Medical and Health Sciences, 0302 clinical medicine, prevention, Risk Factors, cardiovascular disease, Preventive Health Services, Advanced and Specialised Nursing, 030212 general & internal medicine, Cardiovascular nursing, Societies, Medical, Aged, 80 and over, biology, risk assessment, General Medicine, Middle Aged, Prognosis, Risk prediction, 3. Good health, [SDV] Life Sciences [q-bio], Preventive cardiology, Europe, Primary Prevention, Medical–Surgical Nursing, Cardiovascular Diseases, Practice Guidelines as Topic, Female, patient, Cardiology and Cardiovascular Medicine, Risk assessment, Algorithms, Adult, Cardiovascular Nursing, medicine.medical_specialty, Critical Care, Clinical Decision-Making, Cardiology, Decision Support Techniques, 03 medical and health sciences, Predictive Value of Tests, Health Sciences, Medical–Surgical, medicine, Humans, Medical history, Intensive care medicine, Association (psychology), Aged, Advanced and Specialized Nursing, patient Keywords Risk prediction, Acca, Models, Statistical, business.industry, biology.organism_classification, Lifetime risk, business, Forecasting
Abstract

Risk assessment and risk prediction have become essential in the prevention of cardiovascular disease. Even though risk prediction tools are recommended in the European guidelines, they are not adequately implemented in clinical practice. Risk prediction tools are meant to estimate prognosis in an unbiased and reliable way and to provide objective information on outcome probabilities. They support informed treatment decisions about the initiation or adjustment of preventive medication. Risk prediction tools facilitate risk communication to the patient and their family, and this may increase commitment and motivation to improve their health. Over the years many risk algorithms have been developed to predict 10-year cardiovascular mortality or lifetime risk in different populations, such as in healthy individuals, patients with established cardiovascular disease and patients with diabetes mellitus. Each risk algorithm has its own limitations, so different algorithms should be used in different patient populations. Risk algorithms are made available for use in clinical practice by means of - usually interactive and online available - tools. To help the clinician to choose the right tool for the right patient, a summary of available tools is provided. When choosing a tool, physicians should consider medical history, geographical region, clinical guidelines and additional risk measures among other things. Currently, the website is the only risk prediction tool providing prediction algorithms for all patient categories, and its implementation in clinical practice is suggested/advised by the European Association of Preventive Cardiology. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: this paper was produced within the framework of the ESC Prevention of Cardiovascular Disease Programme which is led by the European Association of Preventive Cardiology (EAPC) in collaboration with the Acute Cardiovascular Care Association (ACCA) and the Association of Cardiovascular Nursing and Allied Professions (ACNAP). The ESC Prevention of Cardiovascular Disease Programme is supported by unrestricted educational grants. The authors received no financial support for the research, authorship, and/or publication of this article. Rossello, X (corresponding author), Ctr Nacl Invest Cardiovasc CNIC Carlos III, Melchor Fernandez Almagro 3, Madrid 28029, Spain. fjrossello@cnic.es

Published
2020

2. Inhibition of angiogenesis and murine tumour growth by laminarin sulphate

Author

J. Donaldson, D.H. Paper, R. Hoffman, and H. Vogl

Subjects
Cancer Research, Angiogenesis, Basic fibroblast growth factor, Molecular Sequence Data, Neovascularization, Physiologic, Antineoplastic Agents, Chick Embryo, Biology, Models, Biological, Neovascularization, chemistry.chemical_compound, Laminarin, Mice, In vivo, Laminin, Polysaccharides, medicine, Animals, Fibrosarcoma, Cells, Cultured, Matrigel, Mice, Inbred C3H, Neovascularization, Pathologic, medicine.disease, bacterial infections and mycoses, Molecular biology, Drug Combinations, Oncology, chemistry, Carbohydrate Sequence, Immunology, biology.protein, Cattle, Proteoglycans, Collagen, Endothelium, Vascular, medicine.symptom, Research Article
Abstract

LAM S5 is a polysulphated derivative of the glucan laminarian that inhibits basic fibroblast growth factor (bFGF) binding and the bFGF-stimulated proliferation of fetal bovine heart endothelial (FBHE) cells. This report demonstrates that LAM S5 has anti-angiogenic activity, as shown by inhibition of tubule formation by endothelial cells cultured on Matrigel and inhibition of vascularisation of the chick chorioallantoic membrane. In addition, LAM S5 caused a tumour growth delay of the murine RIF-1 tumour of 2.6 days (P = 0.01). Images Figure 2

Published
1996

3. Elevated amounts of myocilin in the aqueous humor of transgenic mice cause significant changes in ocular gene expression

Author

Paul Russell, Walter Paper, Ernst R. Tamm, Dietrich A. Stephan, Sebastian Heersink, Rudolf Fuchshofer, and Markus Kroeber

Subjects
Genetically modified mouse, DNA, Complementary, genetic structures, Transgene, Blotting, Western, Mice, Transgenic, Biology, Article, Gene product, Aqueous Humor, Cellular and Molecular Neuroscience, Mice, Trabecular Meshwork, Gene expression, medicine, Animals, Humans, Eye Proteins, Gene, Myocilin, Cells, Cultured, Glycoproteins, Oligonucleotide Array Sequence Analysis, Regulation of gene expression, Reverse Transcriptase Polymerase Chain Reaction, Molecular biology, Sensory Systems, eye diseases, Ophthalmology, Cytoskeletal Proteins, medicine.anatomical_structure, Gene Expression Regulation, Trabecular meshwork, sense organs
Abstract

Myocilin is a 55-57kDa secreted glycoprotein and member of the olfactomedin family, which is mutated in some forms of primary open-angle glaucoma. To assess the effects of elevated amounts of myocilin on aqueous humor outflow dynamics in an in vivo system, transgenic betaB1-crystallin-MYOC mice have been developed that strongly overexpress myocilin in their eyes. The transgenic overexpression of myocilin results in an almost five-fold increase of secreted normal myocilin in the aqueous humor of betaB1-crystallin-MYOC mice. In the present study, we wanted to use betaB1-crystallin-MYOC as a tool to identify the response of ocular tissues to the presence of higher than normal amounts of myocilin, and to identify changes in gene expression that could help to shed light on the functional in vivo properties of myocilin. RNA was isolated from ocular tissues of betaB1-crystallin-MYOC mice and wild-type littermates. Changes in gene expression were determined by hybridization of gene microarrays and confirmed by real time RT-PCR and Western blotting. The expression of genes that had been found to be differentially regulated in betaB1-crystallin-MYOC mice was further analyzed in cultured human trabecular meshwork (HTM) cells treated with recombinant myocilin. Although betaB1-crystallin-MYOC mice do not have an obvious phenotype, a statistically significant up- and downregulation of several distinct genes was found when compared to gene expression in wild-type littermates. Among the genes that were found to be differentially regulated were Wasl, Ceacam1, and Spon2, which are involved in cell adhesion and cell-matrix interactions. Differences in expression were also found for Six1 which encodes for a transcription factor, and for Pftk1 whose gene product is a cdc2-related protein kinase. The expression of these genes was also found to be regulated in vitro in HTM cells treated with recombinant myocilin. Substantially higher amounts in ocular tissues of betaB1-crystallin-MYOC mice were found for connexin 46 and alphaB-crystallin. In addition, several genes that encode for olfactomedin proteins showed distinct changes in expression. Olfml3 was significantly downregulated, while Lphn1, Lphn2, and Lphn3 were significantly upregulated. Our findings support a role for myocilin in modulating cellular adhesion, and suggest functional processes that involve other proteins of the olfactomedin family.

Published
2008

4. 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

5. Tracking Animal Reservoirs of Pathogenic Leptospira: The Right Test for the Right Claim

Author

Koussay Dellagi, Patrick Mavingui, Pablo Tortosa, Yann Gomard, Steve Michael Goodman, Processus Infectieux en Milieu Insulaire Tropical (PIMIT), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IRD-Centre National de la Recherche Scientifique (CNRS), Direction Internationale de l'Institut Pasteur, Institut Pasteur [Paris] (IP), Association Vahatra [Antananarivo, Madagascar], Field Museum of Natural History [Chicago, USA], The sampling of Mormopterus acetabulosus on Mauritius was supported by a grant from European Research Development Fund (ERDF) 'Pathogènes associés à la Faune Sauvage Océan Indien' #31189. Original serological data presented in this paper were obtained under a grant from ERDF known as InterregV ECOSPIR 'Eco-épidemiologie des leptospires endémiques de l’Océan Indien: des bactéries à risque pour les populations humaines?' (number RE6875)., Tortosa, Pablo, Centre National de la Recherche Scientifique (CNRS)-IRD-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), and Institut Pasteur [Paris]

Subjects
Leptospira, 030231 tropical medicine, Zoology, Context (language use), Biology, Article, Microbiology, Serology, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Direct agglutination test, medicine, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, One Health, 030304 developmental biology, 0303 health sciences, animal reservoir, MAT, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, General Immunology and Microbiology, 030306 microbiology, Zoonosis, Public Health, Environmental and Occupational Health, [SDV.BA.MVSA] Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Gold standard (test), medicine.disease, biology.organism_classification, Leptospirosis, 3. Good health, Chronic infection, Infectious Diseases, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Medicine, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology
Abstract

Leptospirosis, caused by a pathogenic Leptospira bacteria, is the most prevalent zoonosis worldwide and in this context has been extensively investigated through a One Health framework. Diagnosis of human leptospirosis includes molecular and serological tools, with serological Microscopic Agglutination Test (MAT) still being considered as a gold standard. Mammals considered as biological reservoirs include species or populations that are able to maintain chronic infection and shed the bacteria via their urine in the environment. Leptospira bacteria are often investigated using the same diagnosis tool, serological MAT. However, MAT testing of putative animal reservoirs can lead to mis-interpretations as it can signal previous infection and not necessarily bring in robust information regarding the capacity of such sero-positive animals to maintain chronic infection. We use previously published data and present new results on introduced and endemic small mammals to show that MAT should not be used for the identification of reservoirs. By contrast, serological data are informative on the level of exposure of animals occupying a specific environment. Finally, we present a sequential methodology to investigate human leptospirosis in a One Health framework that associates molecular detection in humans and animals, together with MAT of human samples using Leptospira isolates obtained from reservoir animals occurring in the same environment.

Published
2021

6. 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

7. RNA Extraction from Ears and Draining Lymph Nodes of Mice Infected with Leishmania amazonensis

Author

Emilie Giraud, Evie Melanitou, Interactions Virus-Insectes - Insect-Virus Interactions (IVI), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Département Parasites et Insectes vecteurs - Department of Parasites and Insect Vectors, Institut Pasteur [Paris], This work was supported by institutional funding from the Institut Pasteur., We are grateful to the members of the Immunophysiology and Parasitism Unit for their recommendations for these experimental procedures and their participation to the original work described in the published paper from where this protocol is derived (Giraud et al. al., 2019b, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)

Subjects
Mouse, Strategy and Management, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Industrial and Manufacturing Engineering, Microbiology, Dermis, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, medicine, Methods Article, Parasite hosting, Vector (molecular biology), Ear pinna dermis, Lymph nodes, biology, Mechanical Engineering, Metals and Alloys, RNA, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, biology.organism_classification, medicine.disease, 3. Good health, Sandfly, RNA isolation, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, medicine.anatomical_structure, Visceral leishmaniasis, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, RNA extraction, Lymph, Leishmania amazonensis
Abstract

International audience; Parasites of the genus Leishmania infect the mammalian hosts, including mice and humans and cause cutaneous or visceral leishm aniasis depending upon the parasite species transmitted by the vector sandfly. Leishmania amazonensis is one of the Leishmania species responsible for th e cutaneous form of the disease. We have inoculated with these parasites the ear dermis of mice. RNA preparations were performed from fragmented tissues using a buffer containing guanidin isothiocynate (RLT buffer, RNeasy Mini Kit, Qiagen, SAS, France) and β mercaptoethanol. Both reagents facilitate the isolation of intact RNA from tissues and the use of the RNeasy Kits present with several advantages that facilitate the isolation of pure non degraded total RNA: i) T his method allows to avoid the presence o f phenol in the RNA extraction buffer, commonly used in alternative protocols; ii) Moreover Diethylpyrocarbonate (DEPC) treatment of glassware, to avoid RNAses contamination of the samples, is not required with this protocol; iii) F inally, it is a fast pro cedure and the isolated total RNA may be concentrated in a small volume thus facilitating its use for downstream experimental procedures.

Published
2020

8. 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

9. 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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10. 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

11. 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

12. 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

13. Single low-dose primaquine for blocking transmission of plasmodium falciparum malaria - a proposed model-derived age-based regimen for sub-Saharan Africa

Author

Muhindo Mavoko, Htee Khu Naw, Estrella Lasry, Nicholas J. White, Sodiomon B. Sirima, Melissa C. Kapulu, Mores Loolpapit, Marie Claire Henry, Thomas N. Williams, Alfred Ngwa Amambua, Claude Rwagacondo, Rick M. Fairhurst, Nicholas P. J. Day, Joseph Okebe, Umberto D'Alessandro, Mahamadou Diakite, Rindra Randremanana, Mavuto Mukaka, James A. Berkley, Jean-Pierre Van Geertruyden, Charles O Obonyo, Malcolm E. Molyneux, Muna Affara, Philipe Brasseur, Peter G. Kremsner, Pascal Lutumba, Endalamaw Gadisa, Abraham Aseffa, Grace Malenga, Caterina I. Fanello, Grant Dorsey, Karen I. Barnes, Zolia Yah, Jane Achan, Patrice Piola, Kathryn Maitland, Chandy C. John, Davis Nwakanma, Joel J. Jones, W. Robert Taylor, Birgit Schramm, Marie A. Onyamboko, Junior Matangila, Philip Bejon, Geneva University Hospital (HUG), Mahidol Oxford Tropical Medicine Research Unit (MORU), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], KEMRI-Wellcome Trust Research Programme (KWTRP), Imperial College London, University of Oxford [Oxford], Medical Research Council Unit The Gambia (MRC), University of Antwerp (UA), University of Kinshasa (UNIKIN), Unité de Recherche sur les Maladies Infectieuses Tropicales Emergentes (URMITE), Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP), Epicentre [Paris] [Médecins Sans Frontières], Kinshasa Mahidol Oxford Research Unit (KIMORU), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], Ecole de Santé Publique de Kinshasa (KSPH ou ESP), National Malaria Control Programme, Ministry of Health and Social Welfare, National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Malaria Research and Training Center [Bamako, Mali], Université de Bamako, Queen Elizabeth Hospital, University of Liverpool, Kenya Medical Research Institute (KEMRI), Armauer Hansen Research Institute (AHRI), Amref Health Africa [Kenya], African Medical and Research Foundation (AMREF), Centre de Recherche Entomologique de Cotonou (CREC), Ministère de la Santé, University of California [San Francisco] (UCSF), University of California, Indiana University - Purdue University Indianapolis (IUPUI), Indiana University System, Centre National de Recherche et de Formation sur le Paludisme [Ouagadougou, Burkina Faso] (CNRFP), Groupe de recherche action en santé (GRAS), University of Cape Town, University of Tübingen, TNW is supported by a Fellowship from the Wellcome Trust (202800). The KEMRI–Wellcome Trust Research Programme in Kenya is funded through a Strategic Award from the KEMRI–Wellcome Trust Research Programme (203077). RMF was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, US National Institutes of Health. NJW is a Wellcome Trust Principal Fellow., We acknowledge with gratitude the Demographic Health Survey of USAID for permission to download data from their website. This paper is published with permission from the Director of KEMRI., University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, University of Oxford, Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, University of California [San Francisco] (UC San Francisco), University of California (UC), RANDRIAMANANTSOA, Volatiana Manohisoa, and Wellcome Trust

Subjects
Male, Primaquine, Antimalarials / therapeutic use, lcsh:Medicine, MESH: Dose-Response Relationship, Drug, MESH: Clinical Protocols, MESH: Aged, 80 and over, 0302 clinical medicine, Clinical Protocols, MESH: Child, Epidemiology, 030212 general & internal medicine, Malaria, Falciparum, Child, MESH: Plasmodium falciparum, Aged, 80 and over, MESH: Aged, MESH: Middle Aged, biology, MESH: Malaria, Falciparum, Age Factors, 11 Medical And Health Sciences, General Medicine, Middle Aged, MESH: Primaquine, MESH: Infant, 3. Good health, MESH: Glucosephosphate Dehydrogenase Deficiency, Tolerability, MESH: Young Adult, Child, Preschool, Primaquine / administration & dosage, Female, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Research Article, medicine.drug, Adult, medicine.medical_specialty, Adolescent, Plasmodium falciparum, 030231 tropical medicine, Antimalarials / adverse effects, Antimalarials, Malaria, Falciparum / prevention & control, Young Adult, 03 medical and health sciences, Pharmacokinetics, Age-based dosing, General & Internal Medicine, Internal medicine, parasitic diseases, medicine, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, MESH: Africa South of the Sahara, Dosing, Africa South of the Sahara, ddc:613, Aged, MESH: Adolescent, MESH: Age Factors, MESH: Humans, Dose-Response Relationship, Drug, business.industry, lcsh:R, Malaria, Falciparum / transmission, MESH: Child, Preschool, Infant, MESH: Adult, medicine.disease, biology.organism_classification, MESH: Antimalarials, MESH: Male, Malaria, Regimen, Glucosephosphate Dehydrogenase Deficiency, Primaquine / adverse effects, Primaquine / therapeutic use, Antimalarials / administration & dosage, Malaria, Falciparum / drug therapy, Transmission blocking, Human medicine, business, MESH: Female
Abstract

Background In 2012, the World Health Organization recommended blocking the transmission of Plasmodium falciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), without testing for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients with uncomplicated falciparum malaria. We sought to develop an age-based SLDPQ regimen that would be suitable for sub-Saharan Africa. Methods Using data on the anti-infectivity efficacy and tolerability of primaquine (PQ), the epidemiology of anaemia, and the risks of PQ-induced acute haemolytic anaemia (AHA) and clinically significant anaemia (CSA), we prospectively defined therapeutic-dose ranges of 0.15–0.4 mg PQ base/kg for children aged 1–5 years and 0.15–0.5 mg PQ base/kg for individuals aged ≥6 years (therapeutic indices 2.7 and 3.3, respectively). We chose 1.25 mg PQ base for infants aged 6–11 months because they have the highest rate of baseline anaemia and the highest risks of AHA and CSA. We modelled an anthropometric database of 661,979 African individuals aged ≥6 months (549,127 healthy individuals, 28,466 malaria patients and 84,386 individuals with other infections/illnesses) by the Box–Cox transformation power exponential and tested PQ doses of 1–15 mg base, selecting dosing groups based on calculated mg/kg PQ doses. Results From the Box–Cox transformation power exponential model, five age categories were selected: (i) 6–11 months (n = 39,886, 6.03%), (ii) 1–5 years (n = 261,036, 45.46%), (iii) 6–9 years (n = 20,770, 3.14%), (iv) 10–14 years (n = 12,155, 1.84%) and (v) ≥15 years (n = 328,132, 49.57%) to receive 1.25, 2.5, 5, 7.5 and 15 mg PQ base for corresponding median (1st and 99th centiles) mg/kg PQ base of: (i) 0.16 (0.12–0.25), (ii) 0.21 (0.13–0.37), (iii) 0.25 (0.16–0.38), (iv) 0.26 (0.15–0.38) and (v) 0.27 (0.17–0.40). The proportions of individuals predicted to receive optimal therapeutic PQ doses were: 73.2 (29,180/39,886), 93.7 (244,537/261,036), 99.6 (20,690/20,770), 99.4 (12,086/12,155) and 99.8% (327,620/328,132), respectively. Conclusions We plan to test the safety of this age-based dosing regimen in a large randomised placebo-controlled trial (ISRCTN11594437) of uncomplicated falciparum malaria in G6PDd African children aged 0.5 − 11 years. If the regimen is safe and demonstrates adequate pharmacokinetics, it should be used to support malaria elimination. Electronic supplementary material The online version of this article (doi:10.1186/s12916-017-0990-6) contains supplementary material, which is available to authorized users.

Published
2018

14. Characterization of antibody response in neuroinvasive infection caused by Toscana virus

Author

Giada Rossini, Rémi N. Charrel, Vittorio Sambri, Silvia Morini, P. Cenni, Caterina Vocale, Nazli Ayhan, M. P. Landini, Anna Pierro, Paolo Gaibani, Stefania Varani, Michele Bartoletti, Antonio Mastroianni, F. Prati, Luigi Raumer, S. Schivazappa, Russell E. Lewis, S. Ficarelli, CRREM Laboratory [Bologna, Italy] (Unit of Microbiology), University hospital - Policlinico S.Orsola-Malpighi [Bologna, Italy], Unit of Microbiology [Pievesestina, Italy] (The Romagna Hub Laboratory), The Romagna Hub Laboratory [Pievesestina, Italy], Emergence des Pathologies Virales (EPV), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medical and Surgical Science [Bologna, Italy] (Infectious Disease Unit), University of Bologna/Università di Bologna, Infectious Disease Unit [Forlì, Italy], G.B. Morgagni-Pierantoni Hospital [Forlì, Italy], Infectious Disease Division [Reggio Emilia, Italy], Reggio Emilia Hospital [Italy], Emergency Department [Imola, Italy], Imola Hospital S. Maria della Scaletta [Imola, Italy], Department of Experimental, Diagnostic and Specialty Medicine [Bologna, Italy] (DIMES), Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), This work was supported by the University of Bologna (RFO2013e2015 to SV, MPL) and by the Emilia-Romagna Region (Lab P3 funds). This work was also supported in part by the European Virus Archive goes Global (EVAg) project that has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 653316 (to RNC), the EDENext FP7- n261504 EU project (to RNC) and this paper is catalogued by the EDENext Steering Committee (http://www.edenext.eu) as EDENext467. The work of RNC was done under the frame of EurNegVec COST Action TD1303., European Project: 653316,H2020,H2020-INFRAIA-2014-2015,EVAg(2015), European Project: 261504,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,EDENEXT(2011), University of Bologna, 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, Pierro, A., Ficarelli, S., Ayhan, N., Morini, S., Raumer, L., Bartoletti, M., Mastroianni, A., Prati, F., Schivazappa, S., Cenni, P., Vocale, C., Rossini, G., Gaibani, P., Sambri, V., Landini, M.P., Lewis, R.E., Charrel, R.N., and Varani, S.

Subjects
Adult, Male, 0301 basic medicine, Microbiology (medical), Patients' follow-up, IgG avidity test, 030231 tropical medicine, 030106 microbiology, Antibodies, Viral, Bunyaviridae Infections, Antibody production, Neutralizing antibodies, Immunoglobulin G, Neutralization, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Neutralizing antibodie, medicine, Humans, Avidity, Toscana virus infection, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology, Toscana virus, Meningoencephalitis, Sandfly fever Naples virus, General Medicine, Middle Aged, medicine.disease, biology.organism_classification, Antibodies, Neutralizing, Meningitis, Viral, Virology, 3. Good health, Infectious Diseases, Immunoglobulin M, Immunology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein, Female, Antibody, Meningitis
Abstract

Among sandfly-borne pathogens, Toscana virus (TOSV) is a prominent cause of summer meningitis in Mediterranean Europe. Here, we assessed the kinetics of anti-TOSV antibodies over time in 41 patients diagnosed with TOSV-meningitis or meningoencephalitis in North-eastern Italy. Objectives: Among sandfly-borne pathogens, Toscana virus (TOSV) is a prominent cause of summer meningitis in Mediterranean Europe. Here, we assessed the kinetics of anti-TOSV antibodies over time in 41 patients diagnosed with TOSV meningitis or meningoencephalitis in northeastern Italy. Methods: Acute and follow-up serum samples were collected up to 20 months after diagnosis of TOSV infection and tested for the presence of specific antibody using immunoenzymatic and indirect immunofluorescence assays. In addition, maturation of anti-TOSV IgG over time was evaluated as well as production of neutralizing antibodies. Results: Specific IgM and IgG response was present at diagnosis in 100% of patients; TOSV-specific IgM and IgG were detected in patients' sera up to 6 and 20 months after diagnosis, respectively. The avidity index (AI) increased over the first month after infection in 100% of patients and most cases exceeded 60% by Day 30 post infection. The AI subsequently plateaued then declined at 20 months after diagnosis. Finally, neutralization assay to TOSV was performed in 217 sera collected from 41 patients; 69.6% of tested samples resulted in reactive and moderate levels of neutralizing antibodies observed during all phases of infection despite high titres of total anti-TOSV IgG. Conclusions: Specific antibody response develops rapidly and is long-lasting for neuroinvasive TOSV infection. Serodiagnosis of neuroinvasive TOSV requires simultaneous detection of specific IgM and IgG. Moderate levels of neutralizing antibodies were maintained over the study period, while the protective role of antibodies lacking neutralizing activity is unclear and requires further evaluation.

Published
2017

15. 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

16. 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

17. 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

18. 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

19. Description of compensatory gyrA mutations restoring fluoroquinolone susceptibility in Mycobacterium tuberculosis

Author

Stéphanie Petrella, Alexandra Aubry, Nicolas Veziris, Hélène Ferrand, Claudine Mayer, Aurélie Bouige, Alix Pantel, Stéphanie Matrat, Wladimir Sougakoff, Université Pierre et Marie Curie - Paris 6 (UPMC), Microbiologie structurale - Structural Microbiology (Microb. Struc. (UMR_3528 / U-Pasteur_5)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Parts of this paper were presented at the ‘International Conference on Antimicrobial Agents and Chemotherapy’, USA, 2011 (C1-626), and at the EMBO Conference ‘Tuberculosis 2012’, France, 2012 (TUBERCULOSIS2012/000269)., Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence des Mycobactéries et de la Résistance aux Antituberculeux [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux, Bactériologie-Hygiène [CHU Pitié-Salpêtrière] ], and CHU Pitié-Salpêtrière [APHP]

Subjects
0301 basic medicine, MESH: Mycobacterium tuberculosis, DNA Mutational Analysis, Mutant, Antitubercular Agents, medicine.disease_cause, DNA gyrase, MESH: Recombinant Proteins, Suppression, Genetic, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Pharmacology (medical), MESH: DNA Mutational Analysis, MESH: Suppression, Genetic, MESH: Inhibitory Concentration 50, Mutation, MESH: Microbial Sensitivity Tests, biology, Chemistry, MESH: Escherichia coli, Recombinant Proteins, 3. Good health, MESH: Mutagenesis, Site-Directed, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, DNA Gyrase, DNA supercoil, Fluoroquinolones, medicine.drug, MESH: DNA Gyrase, Microbiology (medical), 030106 microbiology, Mutation, Missense, Microbial Sensitivity Tests, Microbiology, Mycobacterium tuberculosis, Inhibitory Concentration 50, 03 medical and health sciences, Drug Resistance, Bacterial, MESH: Drug Resistance, Bacterial, Escherichia coli, medicine, Humans, Pharmacology, MESH: Mutation, Missense, MESH: Humans, Mutagenesis, MESH: Fluoroquinolones, biology.organism_classification, MESH: Antitubercular Agents, Mutagenesis, Site-Directed, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Ofloxacin
Abstract

International audience; OBJECTIVES:Resistance to fluoroquinolones (FQs) in Mycobacterium tuberculosis (Mtb) is mainly due to mutations in DNA gyrase (GyrA2B2), with the most common substitutions located at positions 90 and 94 in GyrA. Two clinical MDR Mtb (MDR-TB) strains harbouring an A90E or D94N substitution in GyrA were found to be surprisingly susceptible to FQs (ofloxacin MIC ≤2 mg/L). We studied the impact of the additional GyrA substitutions found in these strains (T80A and T80A + A90G, respectively) on FQ susceptibility.METHODS:Mutants of interest were generated by site-specific mutagenesis of GyrA alleles. WT and mutant TB DNA gyrase subunits were overexpressed in Escherichia coli and purified, and the in vitro susceptibility to FQs of their DNA supercoiling reaction was studied.RESULTS:IC50s of mutant gyrase complexes bearing GyrA D94N and A90E were 3- to 36-fold higher than WT IC50s, whereas IC50s of gyrase bearing T80A + A90G + D94N and T80A + A90E were close to the WT IC50s.CONCLUSIONS:We demonstrated that substitutions T80A and A90G restore FQ susceptibility when associated with a substitution implicated in high-level FQ resistance. Line probe assay misclassification of MDR-TB strains as pre-XDR or XDR can be corrected by sequence analysis of gyrA.

Published
2016

20. 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

21. Environment, epigenetics and neurodegeneration: Focus on nutrition in Alzheimer's disease

Author

Marco Lucarelli, Andrea Fuso, Vincenzina Nicolia, Department of Surgery, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Department of Cellular Biotechnologies and Haematology, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]-Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), European Center for Brain Research (CERC)/Santa Lucia Foundation I.R.C.C.S., This paper was supported by funding from the EC 7th Framework Program (FP7/2007–2013) grant no. 278486 'DEVELAGE' and from the Sapienza Università di Roma, Scientific Research Programs 2012 and 2013., European Project: 278486,EC:FP7:HEALTH,FP7-HEALTH-2011-two-stage,DEVELAGE(2012), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA)

Subjects
Adult, Aging, Nutritional Status, Disease, Biology, Alzheimer's Disease, Biochemistry, Epigenesis, Genetic, Endocrinology, Alzheimer Disease, Mental stress, Genetics, medicine, Humans, Genetic Predisposition to Disease, Epigenetics, Neurodegeneration, Molecular Biology, Organism, DNA methylation, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Age Factors, food and beverages, Neurodegenerative Diseases, Cell Biology, Epigenome, medicine.disease, 3. Good health, B vitamins, Vitamin B Complex, Gene-Environment Interaction, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience, epigenetics, neurodegeneration, Alzheimer's disease
Abstract

International audience; Many different environmental factors (nutrients, pollutants, chemicals, physical activity, lifestyle, physical and mental stress) can modulate epigenetic markers in the developing and adult organism. Epigenetics, in turn, can cause and is associated with several neurodegenerative and aging-dependent human diseases. Alzheimer's disease certainly represents one of the most relevant neurodegenerative disorders due to its incidence and its huge socio-economic impact. Therefore, it is easy to understand why recent literature focuses on the epigenetic modifications associated with Alzheimer's disease and other neurodegenerative disorders. One of the most intriguing and, at the same time, worrying evidence is that even "mild" environmental factors (such as behavioral or physical stress) as well as the under-threshold exposure to pollutants and chemicals, can be effective. Finally, even mild nutrients disequilibria can result in long-lasting and functional alterations of many epigenetic markers, although they don't have an immediate acute effect. Therefore, we will probably have to re-define the current risk threshold for many factors, molecules and stresses. Among the many different environmental factors affecting the epigenome, nutrition represents one of the most investigated fields; the reasons are probably that each person interacts with nutrients and that, in turn, nutrients can modulate at molecular level the epigenetic biochemical pathways. The role that nutrition can exert in modulating epigenetic modifications in Alzheimer's disease will be discussed with particular emphasis on the role of B vitamins and DNA methylation.

Published
2015

22. Neutrophil Extracellular Traps are Involved in the Innate Immune Response to Infection with Leptospira

Author

Emilia Scharrig, María Florencia Ferrer, Agostina Carestia, Mathieu Picardeau, Maia Cédola, Ricardo Martín Gómez, Mirta Schattner, Gabriela Pretre, Ricardo Drut, CCT La Plata-CONICET-Facultad de Ciencias Veterinarias [La Plata, PBA, Argentine], Universidad Nacional de la Plata [Argentine] (UNLP), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), Children Hospital 'Superiora Sor María Ludovica' LA PLATA, Biologie des Spirochètes / Biology of Spirochetes, Institut Pasteur [Paris], This work was supported by PICTs grant 12-0434 (RMG) and 11-733 (MS) from ANPCyT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., Conceived and designed the experiments: MP MS RMG. Performed the experiments: ES AC MFF GP. Analyzed the data: MC RD. Contributed reagents/materials/analysis tools: MP. Wrote the paper: MS RMG., and Institut Pasteur [Paris] (IP)

Subjects
Male, lcsh:Arctic medicine. Tropical medicine, Neutrophils, lcsh:RC955-962, [SDV]Life Sciences [q-bio], Inflammation, Extracellular Traps, Microbiology, purl.org/becyt/ford/1 [https], Ciencias Biológicas, Mice, 03 medical and health sciences, neutrophils, Immunity, In vivo, Leptospira, medicine, Animals, Humans, leptospirosis, Leptospirosis, purl.org/becyt/ford/1.6 [https], Ciencias Exactas, 030304 developmental biology, 0303 health sciences, Innate immune system, biology, 030306 microbiology, lcsh:Public aspects of medicine, Public Health, Environmental and Occupational Health, lcsh:RA1-1270, Nets, Neutrophil extracellular traps, biology.organism_classification, Immunity, Innate, 3. Good health, Mice, Inbred C57BL, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, medicine.symptom, Leptospira interrogans, Virología, Ex vivo, CIENCIAS NATURALES Y EXACTAS, Research Article
Abstract

NETosis is a process by which neutrophils extrude their DNA together with bactericidal proteins that trap and/or kill pathogens. In the present study, we evaluated the ability of Leptospira spp. to induce NETosis using human ex vivo and murine in vivo models. Microscopy and fluorometric studies showed that incubation of human neutrophils with Leptospira interrogans serovar Copenhageni strain Fiocruz L1-130 (LIC) resulted in the release of DNA extracellular traps (NETs). The bacteria number, pathogenicity and viability were relevant factors for induction of NETs, but bacteria motility was not. Entrapment of LIC in the NETs resulted in LIC death; however, pathogenic but not saprophytic Leptospira sp. exerted nuclease activity and degraded DNA. Mice infected with LIC showed circulating NETs after 2 days post-infection (dpi). Depletion of neutrophils with mAb1A8 significantly reduced the amount of intravascular NETs in LIC-infected mice, increasing bacteremia at 3 dpi. Although there was a low bacterial burden, scarce neutrophils and an absence of inflammation in the early stages of infection in the kidney and liver, at the beginning of the leptospiruric phase, the bacterial burden was significantly higher in kidneys of neutrophil-depleted-mice compared to non-depleted and infected mice. Surprisingly, interstitial nephritis was of similar intensity in both groups of infected mice. Taken together, these data suggest that LIC triggers NETs, and that the intravascular formation of these DNA traps appears to be critical not only to prevent early leptospiral dissemination but also to preclude further bacterial burden., Instituto de Biotecnologia y Biologia Molecular, Facultad de Ciencias Exactas, Facultad de Ciencias Médicas

Published
2015

23. Use of a New High Resolution Melting Method for Genotyping Pathogenic Leptospira spp

Author

Amélie Desvars, Alain Michault, Florence Naze, Pascale Bourhy, Mathieu Picardeau, Laboratoire de Bactériologie-Parasitologie-Virologie-Hygiène, Groupe Hospitalier Sud Réunion (GHSR), Centre Collaborateur FAO/OMS pour l'épidémiologie de la leptospirose, Institut Pasteur [Paris] (IP), Centre National de Référence de la Leptospirose - National Reference Center Leptospirosis (CNR), Biologie des Spirochètes / Biology of Spirochetes, The authors have no support or funding to report., Conceived and designed the experiments: AM MP PB. Performed the experiments: FN AD. Analyzed the data: AD MP AM PB. Contributed reagents/materials/analysis tools: FN PB. Wrote the paper: FN AD MP PB AM., and Institut Pasteur [Paris]

Subjects
Serotype, DNA, Bacterial, Genotype, Genotyping Techniques, [SDV]Life Sciences [q-bio], lcsh:Medicine, Minisatellite Repeats, Nucleic Acid Denaturation, Real-Time Polymerase Chain Reaction, Melting curve analysis, High Resolution Melt, Species Specificity, Leptospira, medicine, Cluster Analysis, Humans, lcsh:Science, Genotyping, Genetics, Multidisciplinary, biology, lcsh:R, biology.organism_classification, medicine.disease, Leptospirosis, Virology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, lcsh:Q, Leptospira interrogans, Software, Research Article
Abstract

Background Leptospirosis is a worldwide zoonosis that is endemic in tropical areas, such as Reunion Island. The species Leptospira interrogans is the primary agent in human infections, but other pathogenic species, such as L. kirschner and L. borgpetersenii, are also associated with human leptospirosis. Methods and Findings In this study, a melting curve analysis of the products that were amplified with the primer pairs lfb1 F/R and G1/G2 facilitated an accurate species classification of Leptospira reference strains. Next, we combined an unsupervised high resolution melting (HRM) method with a new statistical approach using primers to amplify a two variable-number tandem-repeat (VNTR) for typing at the subspecies level. The HRM analysis, which was performed with ScreenClust Software, enabled the identification of genotypes at the serovar level with high resolution power (Hunter-Gaston index 0.984). This method was also applied to Leptospira DNA from blood samples that were obtained from Reunion Island after 1998. We were able to identify a unique genotype that is identical to that of the L. interrogans serovars Copenhageni and Icterohaemorrhagiae, suggesting that this genotype is the major cause of leptospirosis on Reunion Island. Conclusions Our simple, rapid, and robust genotyping method enables the identification of Leptospira strains at the species and subspecies levels and supports the direct genotyping of Leptospira in biological samples without requiring cultures.

Published
2015

24. Concerns about the widespread use of rodent models for human risk assessments of endocrine disruptors

Author

Gabriel Livera, René Frydman, Delphine Moison, Vincent Muczynski, Alexandra Benachi, René Habert, R. Lambrot, Abdelali Lehraiki, Virginie Rouiller-Fabre, Geraldine Delbes, Tiphany Grisin, Christine Levacher, Marie-Justine Guerquin, Sébastien Messiaen, Thierry N’Tumba-Byn, Stabilité génétique, Cellules Souches et Radiations (SCSR (U_967)), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de gynécologie-obstétrique, médecine de la reproduction [Béclère], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), The work of our group presented in this paper was supported byUniversité Paris Diderot-Paris 7, CEA, INSERM, the FrenchAgence pour la Santé et la Sécurité dans l’Environnement et le Travail (AFSSET), the French Agence Nationale de SécuritéSanitaire de l’Alimentation, de l’Environnement et du Travail(ANSES Contrat EST62010/2/046), the Agence Nationale de laRecherche (ANR, contrat Phtalatestis and contrat MECABPA)and the Ministère de l’Ecologie, du Développement Durable,des Transports et du Logement (Programme ANTIOPES –Storm). None of the authors received any personal financialremuneration or funding for research studies from anychemical industrial company., ANR-07-SEST-0019,PHTALATESTIS,Effets et mécanismes d'action des phtalates sur le développement et les fonctions du testicule chez la souris et l'homme(2007), ANR-11-CESA-0001,MECABPA,Effets et mécanismes d'action du bisphénol A (BPA) sur le développement et les fonctions des gonades foetales chez la souris, la brebis et l'homme(2011), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), Courcelles, Michel, Santé-environnement et Santé-travail - Effets et mécanismes d'action des phtalates sur le développement et les fonctions du testicule chez la souris et l'homme - - PHTALATESTIS2007 - ANR-07-SEST-0019 - SEST - VALID, Contaminants et Environnements : Métrologie, santé, Adaptabilité, Comportements et Usages - Effets et mécanismes d'action du bisphénol A (BPA) sur le développement et les fonctions des gonades foetales chez la souris, la brebis et l'homme - - MECABPA2011 - ANR-11-CESA-0001 - CESA - VALID, Cellules Souches et Radiations (SCSR - U 967), Université Paris-Sud - Paris 11 (UP11) - Commissariat à l'énergie atomique et aux énergies alternatives (CEA) - Université Paris Diderot - Paris 7 (UPD7) - Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11) - Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Antoine Béclère, and Institut National de la Recherche Scientifique [Québec] (INRS) - Réseau International des Instituts Pasteur (RIIP) - Institut Armand Frappier

Subjects
Animal Experimentation, Male, Embryology, medicine.medical_specialty, Cell type, Rodent, [SDV]Life Sciences [q-bio], Retinoic acid, Rodentia, Review, Endocrine Disruptors, Risk Assessment, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Internal medicine, biology.animal, Testis, Toxicity Tests, medicine, Animals, Humans, Endocrine system, Animal testing, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology, Gametogenesis, 030304 developmental biology, 0303 health sciences, Fetus, 030219 obstetrics & reproductive medicine, biology, Phthalate, Obstetrics and Gynecology, Cell Biology, Rats, 3. Good health, [SDV.TOX] Life Sciences [q-bio]/Toxicology, [SDV] Life Sciences [q-bio], Reproductive Medicine, chemistry, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Models, Animal, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract

International audience; Fetal testis is a major target of endocrine disruptors (EDs). During the last 20 years, we have developed an organotypic culture system that maintains the function of the different fetal testis cell types and have used this approach as a toxicological test to evaluate the effects of various compounds on gametogenesis and steroidogenesis in rat, mouse and human testes. We named this test rat, mouse and human fetal testis assay. With this approach, we compared the effects of six potential EDs ((mono-(2-ethylhexyl) phthalate (MEHP), cadmium, depleted uranium, diethylstilboestrol (DES), bisphenol A (BPA) and metformin) and one signalling molecule (retinoic acid (RA)) on the function of rat, mouse and human fetal testis at a comparable developmental stage. We found that the response is similar in humans and rodents for only one third of our analyses. For instance, RA and MEHP have similar negative effects on gametogenesis in the three species. For another third of our analyses, the threshold efficient concentrations that disturb gametogenesis and/or steroidogenesis differ as a function of the species. For instance, BPA and metformin have similar negative effects on steroidogenesis in human and rodents, but at different threshold doses. For the last third of our analyses, the qualitative response is species specific. For instance, MEHP and DES affect steroidogenesis in rodents, but not in human fetal testis. These species differences raise concerns about the extrapolation of data obtained in rodents to human health risk assessment and highlight the need of rigorous comparisons of the effects in human and rodent models, when assessing ED risk.

Published
2014

25. Immunotherapy reduces allergen-mediated CD66b expression and myeloperoxidase levels on human neutrophils from allergic patients

Author

Antonio Vega, Miguel Blanca, Cristina Chamorro, Javier Monteseirín, Inmaculada Ventura, Elisa Gomez, Rocío Aroca, Ramón Pérez-Cano, [Aroca,R, Chamorro,C, Vega,A, Ventura,A, Gómez,E, Monteseirín,J] Servicio Regional de Inmunología y Alergia, Hospital Universitario Virgen Macarena, Sevilla, Spain. [Pérez-Cano,R, Monteseirín,J] Departamento de Medicina, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain. [Blanca,M] Research Laboratory, Carlos Haya Hospital-Fundacion IMABIS, Málaga, Spain., and Conceived and designed the experiments: JM. Performed the experiments: RA CC AV IV EG. Analyzed the data: JM. Wrote the paper: JM MB AV RPC.

Subjects
Hipersensibilidad, Lipopolysaccharides, Male, Allergy, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Glycoproteins::Membrane Glycoproteins::GPI-Linked Proteins [Medical Subject Headings], Pulmonology, Neutrophils, Physiology, medicine.medical_treatment, lcsh:Medicine, medicine.disease_cause, Immunoglobulin E, Biochemistry, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Allergen, Animal Cells, Immune Physiology, Molecular Cell Biology, Allergies, Medicine and Health Sciences, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Glycoproteins::Membrane Glycoproteins::Cell Adhesion Molecules [Medical Subject Headings], lcsh:Science, Immune Response, CEACAM8 protein, human, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies::Immunoglobulin Isotypes::Immunoglobulin E [Medical Subject Headings], Cells, Cultured, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Therapeutic Irrigation::Nasal Lavage::Nasal Lavage Fluid [Medical Subject Headings], Multidisciplinary, Immune System Proteins, biology, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Oxidoreductases::Peroxidases::Peroxidase [Medical Subject Headings], Flow Cytometry, Up-Regulation, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Biological Therapy::Immunomodulation::Immunotherapy::Immunosuppression::Desensitization, Immunologic [Medical Subject Headings], Inmunoglobulina E, Myeloperoxidase, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Cytological Techniques::Cell Separation::Flow Cytometry [Medical Subject Headings], Female, Nasal Lavage Fluid, Immunotherapy, medicine.symptom, Cellular Types, Research Article, Adult, Neutrófilos, Immune Cells, Immunology, Diseases::Immune System Diseases::Hypersensitivity [Medical Subject Headings], Check Tags::Male [Medical Subject Headings], Inflammation, GPI-Linked Proteins, Antibodies, Chemicals and Drugs::Carbohydrates::Glycoconjugates::Lipopolysaccharides [Medical Subject Headings], Antígenos CD, Antigens, CD, medicine, Named Groups::Persons::Age Groups::Adult [Medical Subject Headings], Hypersensitivity, Cell Adhesion, Humans, Asthma, Peroxidase, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Up-Regulation [Medical Subject Headings], lcsh:R, Immunity, Biology and Life Sciences, Proteins, Cell Biology, medicine.disease, Check Tags::Female [Medical Subject Headings], Desensitization, Immunologic, Anatomy::Cells::Cells, Cultured [Medical Subject Headings], Immunoglobulin G, biology.protein, Moléculas de Adhesión Celular, Chemicals and Drugs::Biological Factors::Antigens::Antigens, Surface::Antigens, Differentiation::Antigens, CD [Medical Subject Headings], Clinical Immunology, lcsh:Q, Anatomy::Cells::Blood Cells::Leukocytes::Granulocytes::Neutrophils [Medical Subject Headings], Cell Adhesion Molecules, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies::Immunoglobulin Isotypes::Immunoglobulin G [Medical Subject Headings]
Abstract

Journal Article; Research Support, Non-U.S. Gov't; CD66b is a member of the carcinoembryonic antigen family, which mediates the adhesion between neutrophils and to endothelial cells. Allergen-specific immunotherapy is widely used to treat allergic diseases, and the molecular mechanisms underlying this therapy are poorly understood. The present work was undertaken to analyze A) the in vitro effect of allergens and immunotherapy on cell-surface CD66b expression of neutrophils from patients with allergic asthma and rhinitis and B) the in vivo effect of immunotherapy on cell-surface CD66b expression of neutrophils from nasal lavage fluid during the spring season. Myeloperoxidase expression and activity was also analyzed in nasal lavage fluid as a general marker of neutrophil activation. RESULTS CD66b cell-surface expression is upregulated in vitro in response to allergens, and significantly reduced by immunotherapy (p

Published
2014

26. Microarray-based Identification of Individual HERV Loci Expression: Application to Biomarker Discovery in Prostate Cancer

Author

Claire Rodriguez-Lafrasse, Myriam Decaussin-Petrucci, Philippe Pérot, Valérie Cheynet, Alain Ruffion, François Mallet, Guy Oriol, Nathalie Mugnier, BIOMERIEUX, Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, This work was supported by bioMérieux SA, the Hospices Civils de Lyon and the French public agency OSEO (Advanced Diagnostics for New Therapeutic Approaches, a French government-funded program dedicated to personalized medicine). PP, VC, GO, NM, and FM are employees of bioMérieux SA. PP, NM and FM have submitted patent applications covering the findings of this paper, and We thank Cecile Montgiraud, Juliette Gimenez, Magali Jaillard and Bertrand Bonnaud for their contribution to the initial development and optimization of the HERV-V2 protocol. We also wish to thank Hader Haidous for his guidance on ethical considerations.

Subjects
Male, General Chemical Engineering, Endogenous retrovirus, Gene Expression, Genome, Transcriptome, 0302 clinical medicine, Affymetrix, Diagnosis, RNA, Neoplasm, Tumor Markers, Cancer Biology, Oligonucleotide Array Sequence Analysis, MESH: Aged, Genetics, 0303 health sciences, MESH: Middle Aged, General Neuroscience, Prostate, Middle Aged, prostate cancer, 3. Good health, MESH: DNA, Single-Stranded, 030220 oncology & carcinogenesis, Medicine, MESH: Biomarkers, Tumor, microarray, MESH: Endogenous Retroviruses, PCA3, DNA, Complementary, Human Endogenous Retroviruses, NcRNA transcription, DNA, Single-Stranded, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, ENCODE, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Biomarkers, Tumor, Humans, Molecular Biology, 030304 developmental biology, Aged, Prostatectomy, MESH: Humans, General Immunology and Microbiology, Microarray analysis techniques, Pharmacological, Endogenous Retroviruses, Prostatic Neoplasms, MESH: DNA, Complementary, MESH: RNA, Neoplasm, Biological, Microarray Analysis, MESH: Male, Retroviridae, MESH: Prostatic Neoplasms, MESH: Oligonucleotide Array Sequence Analysis, Human genome, Issue 81, HERV, Biomarkers
Abstract

International audience; The prostate-specific antigen (PSA) is the main diagnostic biomarker for prostate cancer in clinical use, but it lacks specificity and sensitivity, particularly in low dosage values 1. 'How to use PSA' remains a current issue, either for diagnosis as a gray zone corresponding to a concentration in serum of 2.5-10 ng/ml which does not allow a clear differentiation to be made between cancer and noncancer 2 or for patient follow-up as analysis of post-operative PSA kinetic parameters can pose considerable challenges for their practical application 3,4. Alternatively, noncoding RNAs (ncRNAs) are emerging as key molecules in human cancer, with the potential to serve as novel markers of disease, e.g. PCA3 in prostate cancer 5,6 and to reveal uncharacterized aspects of tumor biology. Moreover, data from the ENCODE project published in 2012 showed that different RNA types cover about 62% of the genome. It also appears that the amount of transcriptional regulatory motifs is at least 4.5x higher than the one corresponding to protein-coding exons. Thus, long terminal repeats (LTRs) of human endogenous retroviruses (HERVs) constitute a wide range of putative/candidate transcriptional regulatory sequences, as it is their primary function in infectious retroviruses. HERVs, which are spread throughout the human genome, originate from ancestral and independent infections within the germ line, followed by copy-paste propagation processes and leading to multicopy families occupying 8% of the human genome (note that exons span 2% of our genome). Some HERV loci still express proteins that have been associated with several pathologies including cancer 7-10. We have designed a high-density microarray, in Affymetrix format, aiming to optimally characterize individual HERV loci expression, in order to better understand whether they can be active, if they drive ncRNA transcription or modulate coding gene expression. This tool has been applied in the prostate cancer field (Figure 1).

Published
2013

27. β-lactam antibiotics promote bacterial mutagenesis via an RpoS-mediated reduction in replication fidelity

Author

Jörg Vogel, Ivan Matic, S. Crussard, Jesús Blázquez, Luisa Laureti, Zeynep Baharoglu, Didier Mazel, F. Darfeuille, Alexandro Rodríguez-Rojas, Arnaud Gutierrez, Heni Abida, Robustesse et évolvabilité de la vie (U1001), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Departamento de Biotecnología Microbiana, Centro Nacional de Biotecnología [Madrid] (CNB-CSIC), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Plasticité du Génome Bactérien - Bacterial Genome Plasticity (PGB), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Régulations Naturelles et Artificielles (ARNA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux Ségalen [Bordeaux 2], Julius-Maximilians-Universität Würzburg (JMU), This work was supported by the FP7-HEALTH-F3-2010-241476 and ANR-09-BLAN-0251 grants. A.G. was supported by a fellowship from the French Ministry of Science and Education. D.M. was supported by the Institut Pasteur, Centre National de la Recherche Scientifique (CNRS-UMR 3525), the French National Research Agency (ANR-08-MIE-016), LABEX IBEID and the European Union Seventh Framework Programme EvoTAR. Z.B. was supported by a postdoctoral fellowship from the DIM Malinf. J.B. was supported by grants PI10/00105 (FIS) and REIPI (RD06/0008), both from Ministerio de Ciencia e Innovacion, Instituto de Salud Carlos III., We thank Dan Andersson’s lab (Uppsala University, Sweden) for providing the anti-DinB antibody, Marie Francoise Norel (Pasteur Institute, Paris) for providing the anti-RpoS antibody and Paul Modrich’s lab for providing the anti-MutS antibody., I.M., A.G., D.M., J.B., F.D. and J.V. designed the research and wrote the paper. A.G., L.L., H.A. and S.C. performed experiments with E. coli. Z.B. performed experiments and analysed data with V. cholerae. A.R.R. performed experiments and analysed data with P. aeruginosa. F.D. and J.V. performed in vitro experiments with SdsR and analysed data., ANR-09-BLAN-0251,bactadapt(2009), ANR-08-MIEN-0016,IIRE,Integrase d'integron recombinaison et expression(2008), European Project: 241476,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,PAR(2010), European Project: 282004,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,EVOTAR(2011), HOFFMANN, Isabelle, Blanc - - bactadapt2009 - ANR-09-BLAN-0251 - Blanc - VALID, Maladies Infectieuses et environnement - Integrase d'integron recombinaison et expression - - IIRE2008 - ANR-08-MIEN-0016 - MIE - VALID, Predicting antibiotic resistance - PAR - - EC:FP7:HEALTH2010-04-01 - 2013-03-31 - 241476 - VALID, Evolution and Transfer of Antibiotic Resistance - EVOTAR - - EC:FP7:HEALTH2011-10-01 - 2015-09-30 - 282004 - VALID, Centro Nacional de Biotecnologia, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU)

Subjects
DNA Replication, medicine.drug_class, [SDV]Life Sciences [q-bio], Antibiotics, General Physics and Astronomy, Sigma Factor, MESH: DNA Replication, Biology, beta-Lactams, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, Microbiology, 03 medical and health sciences, Antibiotic resistance, Bacterial Proteins, MESH: beta-Lactams, MESH: Anti-Bacterial Agents, Escherichia coli, medicine, Vibrio cholerae, MESH: Bacterial Proteins, 030304 developmental biology, MESH: Mutagenesis, 0303 health sciences, Multidisciplinary, Bacteria, 030306 microbiology, Pseudomonas aeruginosa, MESH: Escherichia coli, Mutagenesis, MESH: Reactive Oxygen Species, MESH: Sigma Factor, General Chemistry, biochemical phenomena, metabolism, and nutrition, Anti-Bacterial Agents, 3. Good health, [SDV] Life Sciences [q-bio], MESH: Bacteria, Regulon, MESH: Pseudomonas aeruginosa, bacteria, Reactive Oxygen Species, rpoS, MESH: Vibrio cholerae
Abstract

Antimicrobials: mismatch excels when ampicillin runs low. [Nat Rev Microbiol. 2013]; International audience; Regardless of their targets and modes of action, subinhibitory concentrations of antibiotics can have an impact on cell physiology and trigger a large variety of cellular responses in different bacterial species. Subinhibitory concentrations of β-lactam antibiotics cause reactive oxygen species production and induce PolIV-dependent mutagenesis in Escherichia coli. Here we show that subinhibitory concentrations of β-lactam antibiotics induce the RpoS regulon. RpoS regulon induction is required for PolIV-dependent mutagenesis because it diminishes the control of DNA-replication fidelity by depleting MutS in E. coli, Vibrio cholerae and Pseudomonas aeruginosa. We also show that in E. coli, the reduction in mismatch-repair activity is mediated by SdsR, the RpoS-controlled small RNA. In summary, we show that mutagenesis induced by subinhibitory concentrations of antibiotics is a genetically controlled process. Because this mutagenesis can generate mutations conferring antibiotic resistance, it should be taken into consideration for the development of more efficient antimicrobial therapeutic strategies.

Published
2013

28. Synchrotron FTIR microspectroscopy of Escherichia coli at single-cell scale under silver-induced stress conditions

Author

Claire Saulou, Muriel Mercier-Bonin, Isabelle Fourquaux, Paul Dumas, Claude Maranges, Frédéric Jamme, Muriel Cocaign-Bousquet, Laurence Girbal, Génie et Microbiologie des Procédés Alimentaires (GMPA), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT), Unité de recherche sur les Biopolymères, Interactions Assemblages (BIA), Institut National de la Recherche Agronomique (INRA), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT), Centre de Microscopie Électronique Appliquée à la Biologie (CMEAB), Toulouse Réseau Imagerie-Genotoul ( TRI-Genotoul), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), The authors gratefully acknowledge the 'BioPleasure' project of the Research National Agency (ANR-07-BLAN-0196-01) for funding., The research described in this paper was performed at the French national synchrotron facility SOLEIL (Gif-sur- Yvette, France), using the SMIS beamline (proposal no 20090556)., ANR-07-BLAN-0196,BIOPLEASURE,Plasma - surface engineering for biofilm prevention(2007), AgroParisTech-Institut National de la Recherche Agronomique (INRA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées, Institut National des Sciences Appliquées (INSA), Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Toulouse Réseau Imagerie-Genotoul ( TRI-Genotoul), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital de Rangueil, and CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]

Subjects
In situ, Analytical chemistry, medicine.disease_cause, Biochemistry, Analytical Chemistry, 03 medical and health sciences, Stress, Physiological, Spectroscopy, Fourier Transform Infrared, medicine, Escherichia coli, Fourier transform infrared spectroscopy, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Protein secondary structure, 030304 developmental biology, 0303 health sciences, biology, Ionic silver, 030306 microbiology, Chemistry, Synchrotron FTIR-ATR microspectroscopy, Single-cell scale, [CHIM.MATE]Chemical Sciences/Material chemistry, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Antibacterial effect, Transmission electron microscopy, Attenuated total reflection, Ultrastructure, Biophysics, Silver Nitrate, Single-Cell Analysis, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Synchrotrons, Bacteria
Abstract

International audience; The present work was focused on elucidating biochemical changes in the model bacterium Escherichia coli exposed to ionic silver mediated stress, at a single-cell scale. In order to achieve this, in situ synchrotron Fourier-transform infrared (sFTIR) microspectroscopy was performed, for the first time, on individual cells by attenuated total reflectance (ATR) combined with the use of zinc-selenide hemisphere for high spatial resolution. In a first part, the potential of the method was evaluated on bacteria subjected to a lethal 100 μM AgNO3 concentration for 2 h compared to untreated 100 % viable cells. Differences in cell composition were assessed for the C–H stretching and protein spectral regions, indicating that the inhibitory action was targeted against both fatty acids and proteins. Transmission electron microscopy (TEM) confirmed morphological damages of the cell ultrastructure. The relevance of ATR-sFTIR microspectroscopy for highlighting the heterogeneity in Ag+-mediated effects within a given bacterial population was also pointed out. In a second part, cells were exposed to sub-lethal Ag+ concentrations (

Published
2013

29. Genetically engineered T cells bearing chimeric nanoconstructed receptors harboring TAG-72-specific camelid single domain antibodies as targeting agents

Author

Zahra Sharifzadeh, S. Moein Moghimi, Fatemeh Rahbarizadeh, Davoud Ahmadvand, Mohammad Ali Shokrgozar, Fereidoun Mahboudi, Fatemeh Rahimi Jamnani, Institut Pasteur d'Iran, Réseau International des Instituts Pasteur (RIIP), Department of Medical Biotechnology, Tarbiat Modares University [Tehran]-Faculty of Medical Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Biotechnology Research Center, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Nano-Science Center [Copenhagen], Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU), Nanomedicine Laboratory, Centre of Pharmaceutical Nanotechnology and Nanotoxicology-University of Copenhagen = Københavns Universitet (KU), and This paper was supported by Pasteur Institute of Iran, Tehran, Iran, the Biotechnology Committee of Tarbiat Modares University (TMU-88-8-67), Tehran, Iran and from the Danish Agency for Science, Technology and Innovative (det Strategiske Forskningsråd) reference 09-065746/DSF to SMM.

Subjects
Cancer Research, Leukemia, T-Cell, medicine.medical_treatment, T cell, Recombinant Fusion Proteins, T-Lymphocytes, Biology, Lymphocyte Activation, Transfection, Immunotherapy, Adoptive, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigen, Antibody Specificity, Antigens, Neoplasm, Peptide Library, medicine, Animals, Humans, Chimeric antigen receptor, 030304 developmental biology, Glycoproteins, 0303 health sciences, Immunogenicity, CD28, Immunotherapy, Single-Domain Antibodies, Molecular biology, 3. Good health, Cell biology, Oligoclonal single domain antibodies, Receptors, Antigen, medicine.anatomical_structure, Oncology, TAG-72, 030220 oncology & carcinogenesis, Immunoglobulin G, Colonic Neoplasms, biology.protein, Carcinoma, Squamous Cell, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, Genetic Engineering, Camelids, New World, HT29 Cells, Signal Transduction
Abstract

International audience; Despite the preclinical success of adoptive therapy with T cells bearing chimeric nanoconstructed antigen receptors (CARs), certain limitations of this therapeutic approach such as the immunogenicity of the antigen binding domain, the emergence of tumor cell escape variants and the blocking capacity of soluble antigen still remain. Here, we address these issues using a novel CAR binding moiety based on the oligoclonal camelid single domain antibodies. A unique set of 13 single domain antibodies were selected from an immunized camel phage library based on their target specificity and binding affinity. A combination of these single domain antibodies was used to generate four tumor associated glycoprotein (TAG-72)-specific CARs harboring an identical antigen binding site, but with different signaling and spacer domains. Although all four CARs were functionally active against the TAG-72 expressing tumor cells, the combination of CD3ζ, OX40, CD28 as well as the CH3-CH2-hinge-hinge domains most efficiently triggered T cell activation. Importantly, CAR mediated functions were not blocked by the soluble TAG-72 antigen at a supraphysiological concentration. Our approach may have the potential to reverse multiple tumor immune evasion mechanisms, avoid CAR immunogenicity, and overcome problems in cancer gene therapy with engineered nanoconstructs.

Published
2012

30. p53 regulates epithelial–mesenchymal transition through microRNAs targeting ZEB1 and ZEB2

Author

Young-Jun Jeon, Flavia Pichiorri, Angelo Veronese, Pascal Pineau, Anne Dejean, Tae Jin Lee, Hansjuerg Alder, Agnès Marchio, Stefano Volinia, Taewan Kim, Jeff Palatini, Chang Gong Liu, Sung Suk Suh, Carlo M. Croce, Comprehensive Cancer Center [Colombus], Ohio State University [Columbus] (OSU), Molecular, Cellular, and Developmental Biology Program [Columbus] (MCDB), Organisation Nucléaire et Oncogenèse, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was funded by National Cancer Institute grant RC2 CA148302., We thank Dr. B. Vogelstein for p53+/+ and p53−/− RKO cells, Dr. Gustavo Leone for p53+/+ and p53−/− MEFs, Dr. Gregory J. Goodall for pCIneo-hRL-ZEB1/2 constructs, and Dr. Anders H. Lund for pcDNA3-Zeb2-HA constructs. We also thank Dr. Kay Huebner (The Ohio State University), Dr. Thomas D. Schmittgen (The Ohio State University), and Susan Lutz for careful editing of this paper, and Sharon Palko and Dorothee Wernicke-Jameson for the administrative support., Pineau, Pascal, and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, MESH: Zinc Finger E-box-Binding Homeobox 1, genetics/metabolism, biosynthesis/genetics, Metastasis, genetics/metabolism/pathology, 0302 clinical medicine, MESH: Liver Neoplasms, Immunology and Allergy, genetics, RNA, Neoplasm, Neoplasm Metastasis, MESH: Carcinoma, Hepatocellular, MESH: Tumor Suppressor Protein p53, 0303 health sciences, digestive, oral, and skin physiology, Liver Neoplasms, Hep G2 Cells, MESH: Gene Expression Regulation, Neoplastic, MESH: Transcription Factors, Gene Expression Regulation, Neoplastic, MESH: Repressor Proteins, 030220 oncology & carcinogenesis, embryonic structures, Female, Transcriptional Activation, Carcinoma, Hepatocellular, Epithelial-Mesenchymal Transition, Immunology, Repressor, MESH: Hep G2 Cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, MESH: Gene Expression Profiling, [SDV.CAN] Life Sciences [q-bio]/Cancer, microRNA, MESH: Homeodomain Proteins, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Epithelial–mesenchymal transition, Transcription factor, Zinc Finger E-box Binding Homeobox 2, 030304 developmental biology, MESH: Zinc Finger E-box Binding Homeobox 2, Homeodomain Proteins, Neoplastic, MESH: Humans, Gene Expression Profiling, Carcinoma, Brief Definitive Report, Zinc Finger E-box-Binding Homeobox 1, Hepatocellular, Cell Biology, HCCS, medicine.disease, MESH: RNA, Neoplasm, MESH: Neoplasm Metastasis, MESH: Male, Repressor Proteins, Gene expression profiling, MicroRNAs, MESH: Epithelial-Mesenchymal Transition, Gene Expression Regulation, Tumor progression, Cancer research, RNA, Neoplasm, MESH: Transcriptional Activation, genetics/metabolism/pathology, Epithelial-Mesenchymal Transition, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Hep G2 Cells, Homeodomain Proteins, biosynthesis/genetics, Humans, Liver Neoplasms, genetics/metabolism/pathology, Male, MicroRNAs, genetics/metabolism, Neoplasm Metastasis, RNA, genetics/metabolism, Repressor Proteins, biosynthesis/genetics, Transcription Factors, biosynthesis/genetics, Transcriptional Activation, genetics, Tumor Suppressor Protein p53, Tumor Suppressor Protein p53, MESH: Female, MESH: MicroRNAs, 030215 immunology, Transcription Factors
Abstract

By transactivating expression of miRNAs that repress expression of the ZEB1 and ZEB2 transcription factors, p53 inhibits the epithelial–mesenchymal transition., p53 suppresses tumor progression and metastasis. Epithelial–mesenchymal transition (EMT) is a key process in tumor progression and metastasis. The transcription factors ZEB1 and ZEB2 promote EMT. Here, we show that p53 suppresses EMT by repressing expression of ZEB1 and ZEB2. By profiling 92 primary hepatocellular carcinomas (HCCs) and 9 HCC cell lines, we found that p53 up-regulates microRNAs (miRNAs), including miR-200 and miR-192 family members. The miR-200 family members transactivated by p53 then repress ZEB1/2 expression. p53-regulated miR-192 family members also repress ZEB2 expression. Inhibition or overexpression of the miRNAs affects p53-regulated EMT by altering ZEB1 and ZEB2 expression. Our findings indicate that p53 can regulate EMT, and that p53-regulated miRNAs are critical mediators of p53-regulated EMT.

Published
2011

31. DNA barcoding in the rust genus Chrysomyxa and its implications for the phylogeny of the genus

Author

Wolfgang Maier, Mathieu Allaire, Richard C. Hamelin, Agathe Vialle, Nicolas Feau, Biodiversité, Gènes & Communautés (BioGeCo), Institut National de la Recherche Agronomique (INRA)-Université de Bordeaux (UB), Natural Resources Canada (NRCan), Centre d’étude de la forêt, Université Laval [Québec] (ULaval), Ruhr University Bochum (RUB), University of British Columbia (UBC), and This paper is dedicated to Patricia Crane, our colleague deceased in 2010, who was a dedicated urediniologist and who contributed her knowledge and samples to this publication. We thank Dr Scott A. Redhead and Louise Lefebvre from the National Mycological Herbarium and Pierre DesRochers from Natural Resources Canada for kindly providing important herbarium strains, Marie-Josee Bergeron and Isabelle Lamarre from Natural Resources Canada for constructive comments on the manuscript This research was financially supported through the Canadian Barcode of Life Research Network from Genome Canada through the Ontario Genomics Institute, Natural Sciences and Engineering Research of Canada, and other sponsors at www.BOLNET.org.

Subjects
0106 biological sciences, 0301 basic medicine, Species complex, Physiology, Chrysomyxa pyrolae, phylogeny, 010603 evolutionary biology, 01 natural sciences, DNA barcoding, 03 medical and health sciences, Genus, Botany, DNA, Ribosomal Spacer, Genetics, medicine, DNA barcode, mitochondrial heteroplasmon, Internal transcribed spacer, fungal pathogen, DNA, Fungal, species complex, Molecular Biology, Ecology, Evolution, Behavior and Systematics, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Electronic Data Processing, Coleosporium, biology, Basidiomycota, cone rusts, Cell Biology, General Medicine, 030108 mycology & parasitology, 15. Life on land, biology.organism_classification, Chrysomyxa, chrysomyxa needle rusts, medicine.drug_formulation_ingredient, Chrysomyxa ledi, mycology
Abstract

International audience; Chrysomyxa rusts are fungal pathogens widely present in the boreal forest. Taxonomic delimitation and precise species identification are difficult within this genus because several species display similar morphological features. We applied a DNA barcode system based on the ribosomal internal transcribed spacer region (ITS), large subunit (28S) ribosomal RNA gene, mitochondrial cytochrome oxidase 1 (CO1) and mitochondrial NADH dehydrogenase subunit 6 (NAD6) in 86 strains from 16 different Chrysomyxa species, including members of the Chrysomyxa ledi species complex. The nuclear ITS and 28S loci revealed higher resolving power than the mitochondrial genes. Amplification of the full CO1 barcode region failed due to the presence of introns limiting the dataset obtained with this barcode. In most cases the ITS barcodes were in agreement with taxonomic species based on phenotypic characters. Nevertheless we observed genetically distinct (different DNA barcodes) lineages within Chrysomyxa pyrolae and Chrysomyxa rhododendri, providing some evidence for allopatric speciation within these morphologically defined species. This finding, together with the observed pattern of host specificities of the studied rust fungi, suggest that species diversification within the C. ledi species complex might be governed by a set of factors such as specialisation to certain Ericaceae species as telial hosts and to a lesser extent specialization to different spruce species as aecial hosts. Moreover allopatric speciation by geographic disruption of species also seems to take place. When our data were integrated into a broader phylogenetic framework the Chrysomyxa genus unexpectedly was not resolved as a monophyletic group. Indeed the spruce cone rusts C. pyrolae and C. monesis coalesced with the pine needle rusts belonging to the genus Coleosporium, whereas the microcyclic species Chrysomyxa weirii was embedded within a clade comprising the genus Melampsora.

Published
2011

32. Malaria risk in Corsica, former hot spot of malaria in France

Author

Gilbert Le Goff, Céline Toty, Hélène Barré, Daniel Couret, Nil Rahola, Didier Fontenille, Isabelle Larget-Thiery, Caractérisation et contrôle des populations de vecteurs, Institut de Recherche pour le Développement (IRD), Direction de la Solidarité et de la Santé de Corse et de Corse-du-Sud, Sciences pour l'environnement (SPE), Centre National de la Recherche Scientifique (CNRS)-Université Pascal Paoli (UPP), Centre de Production et Infection des Anophèles (plateforme) - Center for the Production and Infection of Anopheles (platform) (CEPIA), Institut Pasteur [Paris], The paper is catalogued by the EDEN Steering Committee as EDEN 232 http://www.eden-fp6project.net/., Université Pascal Paoli (UPP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), and Centre de Production et Infection des Anophèles (Plateforme) (CEPIA)

Subjects
Risk, Entomology, lcsh:Arctic medicine. Tropical medicine, lcsh:RC955-962, 030231 tropical medicine, Plasmodium vivax, Plasmodium falciparum, MESH: Malaria, Zoology, MESH: Insect Vectors, Biology, Plasmodium, Polymerase Chain Reaction, lcsh:Infectious and parasitic diseases, MESH: Anopheles, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Anopheles, parasitic diseases, medicine, Animals, Humans, MESH: Animals, lcsh:RC109-216, MESH: Plasmodium falciparum, 0303 health sciences, MESH: Humans, MESH: Risk, 030306 microbiology, Ecology, Research, Outbreak, MESH: Polymerase Chain Reaction, medicine.disease, biology.organism_classification, 3. Good health, Insect Vectors, Malaria, MESH: Plasmodium vivax, MESH: France, Infectious Diseases, Parasitology, France
Abstract

Background The prevalence of Plasmodium falciparum and Plasmodium vivax malaria was very high in Corsica just before the Second World War. The last outbreak was in 1972 and the most recent indigenous case was in 2006. Results Analysis of historical data shows that anopheline vectors were abundant. Recent surveys demonstrated that potential vectors are still present in Corsica, despite the likely disappearance of Anopheles sacharovi. Moreover, P. falciparum can develop experimentally into these mosquitoes, notably Anopheles labranchiae, which is locally abundant, and parasites are regularly introduced into the island. Discussion, Conclusions The presence of vectors, the introduction of parasites and the conducive climate raise questions about the possibility of malaria re-emerging and becoming re-established in Corsica. Analysis of historic and current parasitological and entomological data shows that the current theoretical risk of indigenous cases or malaria foci is negligible, particularly since there is very little contact between humans and Anopheles mosquitoes, Plasmodium carriers are reliably treated and there is a widespread vector control on the island.

Published
2010

33. Characterization of Staphylococcus aureus strains associated with food poisoning outbreaks in France

Author

Jacques-Antoine Hennekinne, Annaëlle Kerouanton, L. Petit, C. Letertre, Anne Brisabois, O. Chesneau, M.L. De Buyser, Agence Française de Sécurité Sanitaire des Aliments (AFSSA), Agents antibactériens, Institut Pasteur [Paris], We acknowledge the technical assistance of Trinh Tam Dao, Marie-Odile Delbart, Muriel Marault, and Anne Morvan. We dedicate this paper to the memory of Névine El Solh who contributed to the phage-typing and who passed away in January 2005., and Institut Pasteur [Paris] (IP)

Subjects
Salmonella, Enterotoxin, MESH: Base Sequence, medicine.disease_cause, SmaI, Disease Outbreaks, MESH: Genotype, Enterotoxins, Genotype, MESH: Staphylococcus aureus, MESH: Enterotoxins, Cluster Analysis, MESH: Disease Outbreaks, MESH: Phylogeny, Phylogeny, 2. Zero hunger, 0303 health sciences, General Medicine, PFGE, 3. Good health, Electrophoresis, Gel, Pulsed-Field, Phenotype, MESH: Electrophoresis, Gel, Pulsed-Field, Staphylococcus aureus, MESH: Staphylococcal Food Poisoning, France, Staphylococcal Food Poisoning, Food Contamination, Biology, MESH: Phenotype, Microbiology, Food-poisoning, 03 medical and health sciences, medicine, Pulsed-field gel electrophoresis, Humans, MESH: Food Microbiology, 030304 developmental biology, MESH: Humans, Base Sequence, 030306 microbiology, Outbreak, MESH: Food Contamination, MESH: Cluster Analysis, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: France, Food Microbiology, Food Science
Abstract

International audience; Enterotoxins produced by Staphylococcus aureus are responsible for staphylococcal food-poisoning outbreaks (SFPO). In France, SFPO are the second cause of food-borne diseases after Salmonella. However, very little is known about the strains involved. The objective of this study was to characterize the staphylococcal strains related to these SFPO through phenotypic and genotypic analyses. A total of 178 coagulase-positive staphylococcal isolates recovered from 31 SFPO (1981-2002) were screened through biotyping. Thirty-three strains representative of the different biotypes in each SFPO were further examined for SmaI macrorestriction-type, phage-type, resistance to various antimicrobial drugs, presence of staphylococcal enterotoxin (se) genes sea to sei, and production of enterotoxins SEA to SED. All these 33 strains were identified as S. aureus species: 27 were of human biotypes and six ovine or non-host-specific biotypes. Most (74.1%) strains reacted with group III phages. Eleven strains were resistant to at least two classes of antibiotics and among them, two were resistant to methicillin. Twenty-nine strains carried one or several of the eight se genes tested; the gene sea was most common (n=23), and often linked to sed (n=12) or seh (n=5). The novel se genes seg-i were in all cases associated with se genes sea to sed except for one strain which carried only seg and sei. Pulsed-Field Gel Electrophoresis (PFGE) of SmaI macrorestriction digests of the 33 strains discriminated 32 PFGE patterns grouped into nine biotype-specific clusters. All five strains carrying sea and seh were grouped together into the same sub-cluster. Three of the four se-gene-negative strains were in one PFGE cluster: all four should be tested for se genes not included in this study and, if negative, be further investigated for the presence of unidentified SEs.

Published
2007

34. PGC-1β: A Regulator of Mitochondrial Function with Subtle Roles in Energy Metabolism

Author

Adrienn Kis, Mark Campbell, Mohammad Bohlooly-Y, Keira Curtis, Barbara Cannon, Matej Orešič, E. Dale Abel, Vlad G. Zaha, Gema Medina-Gomez, Sheldon E. Litwin, Mercedes Jimenez-Linan, Antonio Vidal-Puig, Sihem Boudina, Kimberly T Fountain, Leonard H Storlien, Miguel López, Margaret Blount, Ping Hu, Helena M. Feldmann, Christopher J. Lelliott, Mikael Bjursell, Natasa Petrovic, Dongfang Zhang, Nadeene Parker, Maria Strömstedt, Aline Meirhaeghe, Michael Snaith, Autard, Delphine, Department of Clinical Biochemistry, University of Cambridge [UK] (CAM), AstraZeneca, The Wenner-Gren Institute, Stockholm University, Division of Cardiology, University of Utah, Division of Endocrinology, Metabolism, and Diabetes, Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, 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, Droit et Santé, Technical Research Centre of Finland, VTT Technical Research Centre of Finland (VTT), The work presented in this paper was supported by grants from the British Heart Foundation, Wellcome Trust Integrative Physiology, and Diabetes Wellness Research Foundation (to AVP lab), and NIH grants RO1HL73167 and UO1HL70525 from the National Institutes of Health and the Ben and Iris Margolis Foundation (to EDA - Established Investigator of the American Heart Association). Support was from the European Union (DLARFID), the Swedish Research Council, and the Swedish Cancer Society (to BC lab).

Subjects
Male, MESH: Cold Temperature, Adipose tissue, White adipose tissue, Mitochondrion, MESH: Mice, Knockout, Mitochondria, Heart, chemistry.chemical_compound, Mice, Norepinephrine, 0302 clinical medicine, Adipose Tissue, Brown, Heart Rate, Brown adipose tissue, Body Fat Distribution, Diabetes/Endocrinology/Metabolism, MESH: Thermogenesis, MESH: Animals, Biology (General), MESH: Heart Rate, Mice, Knockout, Mammals, 0303 health sciences, MESH: Muscle, Skeletal, General Neuroscience, MESH: Energy Metabolism, Heart, Thermogenesis, Mus (Mouse), Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, MESH: Gene Expression Regulation, Mitochondria, Cold Temperature, medicine.anatomical_structure, Liver, MESH: Adipose Tissue, White, Synopsis, Female, MESH: Mitochondria, Heart, General Agricultural and Biological Sciences, Metabolic Networks and Pathways, Research Article, MESH: Electron Transport Chain Complex Proteins, medicine.medical_specialty, QH301-705.5, MESH: Mitochondria, MESH: Trans-Activators, Adipose Tissue, White, Biology, MESH: Diet, Atherogenic, MESH: Adipose Tissue, Brown, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Adrenergic Agents, Internal medicine, MESH: Norepinephrine, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, MESH: Body Fat Distribution, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Muscle, Skeletal, MESH: Mice, 030304 developmental biology, Soleus muscle, General Immunology and Microbiology, Triglyceride, Body Weight, medicine.disease, MESH: Adrenergic Agents, MESH: Male, MESH: Body Weight, MESH: Heart, Endocrinology, chemistry, Electron Transport Chain Complex Proteins, Gene Expression Regulation, MESH: Metabolic Networks and Pathways, Trans-Activators, Diet, Atherogenic, Steatosis, Energy Metabolism, MESH: Female, 030217 neurology & neurosurgery, Transcription Factors, MESH: Liver
Abstract

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1β (PGC-1β) has been implicated in important metabolic processes. A mouse lacking PGC-1β (PGC1βKO) was generated and phenotyped using physiological, molecular, and bioinformatic approaches. PGC1βKO mice are generally viable and metabolically healthy. Using systems biology, we identified a general defect in the expression of genes involved in mitochondrial function and, specifically, the electron transport chain. This defect correlated with reduced mitochondrial volume fraction in soleus muscle and heart, but not brown adipose tissue (BAT). Under ambient temperature conditions, PGC-1β ablation was partially compensated by up-regulation of PGC-1α in BAT and white adipose tissue (WAT) that lead to increased thermogenesis, reduced body weight, and reduced fat mass. Despite their decreased fat mass, PGC1βKO mice had hypertrophic adipocytes in WAT. The thermogenic role of PGC-1β was identified in thermoneutral and cold-adapted conditions by inadequate responses to norepinephrine injection. Furthermore, PGC1βKO hearts showed a blunted chronotropic response to dobutamine stimulation, and isolated soleus muscle fibres from PGC1βKO mice have impaired mitochondrial function. Lack of PGC-1β also impaired hepatic lipid metabolism in response to acute high fat dietary loads, resulting in hepatic steatosis and reduced lipoprotein-associated triglyceride and cholesterol content. Altogether, our data suggest that PGC-1β plays a general role in controlling basal mitochondrial function and also participates in tissue-specific adaptive responses during metabolic stress., The authors conduct an in-depth analysis of a PGC-1β knockout mouse; these animals posses specific defects in basal mitochondrial function and adaptation to metabolic stress.

Published
2006

35. Peroxisome proliferator-activated receptor-α activation as a mechanism of preventive neuroprotection induced by chronic fenofibrate treatment

Author

Olivier Pétrault, Bernard Dupuis, Isabelle Six, Régis Bordet, Patrick Gelé, Christophe Furman, Bart Staels, Dominique Deplanque, Roméo Cecchelli, Patrick Duriez, Muriel Bouly, Didier Leys, Jean-Charles Fruchart, Stéphane Nion, Université Lille 2 - Faculté de Médecine, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Récepteurs nucléaires, lipoprotéines et athérosclérose, 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, Droit et Santé, Réseau International des Instituts Pasteur (RIIP), Université d'Artois (UA), Laboratoire de Physiopathologie de la Barrière Hémato-Encéphalique (LBHE), P.G. was supported by a grant from 'Conseil Régional Nord Pas de Calais et Centre Hospitalier Régional et Universitaire de Lille. ' This work was supported by grants from ' Génopole Lille Nord-Pas de Calais '(#01360124) and Institut National de la Santé et de la Recherche Médicale (CReS4CR02F)., and We thank Alexandra Tavernier-Sommerville for her assistance with the English version of this paper.

Subjects
Middle Cerebral Artery, Mouse, Nitric Oxide Synthase Type II, Receptors, Cytoplasmic and Nuclear, Peroxisome proliferator-activated receptor, medicine.disease_cause, Rats, Inbred WKY, Mice, 0302 clinical medicine, Fenofibrate, Mice, Knockout, chemistry.chemical_classification, 0303 health sciences, biology, General Neuroscience, Infarction, Middle Cerebral Artery, Cerebral Infarction, Intercellular Adhesion Molecule-1, Neuroprotection, Vasodilation, Nitric oxide synthase, Stroke, Neuroprotective Agents, Cerebrovascular Circulation, Middle cerebral artery, medicine.symptom, medicine.drug, PPAR-α, medicine.medical_specialty, Adhesion proteins, Nitric Oxide Synthase Type III, Development/Plasticity/Repair, Ischemia, Vascular Cell Adhesion Molecule-1, Mice, Transgenic, Inflammation, Time, 03 medical and health sciences, Apolipoproteins E, medicine.artery, Internal medicine, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, business.industry, Prevention, medicine.disease, Rats, Mice, Inbred C57BL, Disease Models, Animal, Endocrinology, chemistry, Oxidative stress, biology.protein, Nitric Oxide Synthase, business, 030217 neurology & neurosurgery, Transcription Factors
Abstract

International audience; The treatment of ischemic strokes is limited to the prevention of cerebrovascular risk factors and to the modulation of the coagulation cascade during the acute phase. Anew therapeutic strategy could be to preventively protect the brain against noxious biological reactions induced by cerebral ischemia such as oxidative stress and inflammation to minimize their neurological consequences. Here, we show that a peroxisome proliferator-activated receptor (PPAR-α) activator, fenofibrate, protects against cerebral injury by anti-oxidant and antiinflammatory mechanisms. A 14 d preventive treatment with fenofibrate reduces susceptibility to stroke in apolipoprotein E-deficient mice as well as decreases cerebral infarct volume in C57BL/6 wild-type mice. The neuroprotective effect of fenofibrate is completely absent in PPAR-α-deficient mice, suggesting that PPAR-α activation is involved as a mechanism of the protection against cerebral injury. Furthermore, this neuroprotective effect appears independently of any improvement in plasma lipids or glycemia and is associated with (1) an improvement in middle cerebral artery sensitivity to endothelium-dependent relaxation unrelated to an increase in nitric oxide synthase (NOS) type III expression, (2) a decrease in cerebral oxidative stress depending on the increase in numerous antioxidant enzyme activities, and (3) the prevention of ischemia-induced expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in cerebral vessels without any change in NOS II expression. These data demonstrate that PPAR-α could be a new pharmacological target to preventively reduce the deleterious neurological consequences of stroke in mice and suggest that PPAR-α activators could preventively decrease the severity of stroke in humans.

Published
2003