Author: "FWF" / Topic: medicine - Searchworks@Jio Institute Digital Library Search Results

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51 results on '"FWF"'

1. Diabetic proximal motor neuropathy: Hypothetical new approaches

Author: FWF Hanna, JR Peters, MF Scanlon, and A Rees
Subjects: medicine.medical_specialty, Endocrinology, business.industry, Endocrinology, Diabetes and Metabolism, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Testosterone (patch), medicine.disease, Growth hormone, business, Motor neuropathy
Published: 1999
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2. Digesting the crisis: autophagy and coronaviruses

Author: Katharina Kainz, Maria A. Bauer, Didac Carmona-Gutierrez, Guido Kroemer, Sebastian J. Hofer, Frank Madeo, Andreas Zimmermann, Karl-Franzens-Universität [Graz, Autriche], BioHealth Graz [Graz, Autriche], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Cell Biology Platform [Villejuif], Institut Gustave Roussy (IGR), Pôle de biologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Chinese Academy of Medical Sciences [Suzhou, Chine] (CAMS), Karolinska University Hospital [Stockholm], BioTechMed Graz [Graz, Autriche], The authors are grateful to the Austrian Science Fund FWF (SFBLIPOTOX F3007&F3012, W1226, P29203, P29262, P27893) and the Austrian Federal Ministry of Education, Science and Research and the University of Graz for grants 'Unkonventionelle Forschung' and 'flysleep' (BMWFW-80.109/0001-WF/V/3b/2015). The authors also acknowledge the funding of DK Metabolic and Cardiovas-cular Disease (FWF) and the Doctoral College 'Metabolic and Cardiovascular Disease' (FWFW1226) as well as support from NAWI Graz and the BioTechMed-Graz flagship project 'EPIAge'. GK is supported by the Ligue contre le Cancer (équipe labellisée), Agence National de la Recherche (ANR) – Projets blancs, ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases, AMMICa US23/CNRS UMS3655, Association pour la recherche sur le cancer (ARC), Association 'Le Cancer du Sein, Parlons-en!', Cancéropôle Ile-de-France, Chancelerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale (FRM), a donation by Elior, European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR), Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome, Fondation Carrefour, High-end Foreign Expert Program in China (GDW20171100085), Institut National du Cancer (INCa), Inserm (HTE), Institut Universitaire de France, LeDucq Foundation, the LabEx Immuno-Oncology (ANR-18-IDEX-0001), the RHU Torino Lumière, the Seerave Foundation, the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), and the SIRIC Cancer Research and Personalized Medicine (CARPEM)., Bodescot, Myriam, Karl-Franzens-Universität Graz, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)
Subjects: 0209 industrial biotechnology, Coronavirus disease 2019 (COVID-19), viruses, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus, Cellular homeostasis, Inflammation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 02 engineering and technology, Biology, medicine.disease_cause, Biochemistry, Genetics and Molecular Biology (miscellaneous), Microbiology, Applied Microbiology and Biotechnology, Viewpoint, 020901 industrial engineering & automation, Immune system, Immunity, Virology, 0202 electrical engineering, electronic engineering, information engineering, Genetics, medicine, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, lcsh:QH301-705.5, Molecular Biology, sars, Coronavirus, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, 020208 electrical & electronic engineering, Autophagy, mers, virophagy, Cell Biology, immunity, 3. Good health, Cell biology, sars-cov-2, covid-19, lcsh:Biology (General), inflammation, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Parasitology, medicine.symptom
Abstract: International audience; Autophagy is a catabolic pathway with multifaceted roles in cellular homeostasis. This process is also involved in the antiviral response at multiple levels, including the direct elimination of intruding viruses (virophagy), the presentation of viral antigens, the fitness of immune cells, and the inhibition of excessive inflammatory reactions. In line with its central role in immunity, viruses have evolved mechanisms to interfere with or to evade the autophagic process, and in some cases, even to harness autophagy or constituents of the autophagic machinery for their replication. Given the devastating consequences of the current COVID-19 pandemic, the question arises whether manipulating autophagy might be an expedient approach to fight the novel coronavirus SARS-CoV-2. In this piece, we provide a short overview of the evidence linking autophagy to coronaviruses and discuss whether such links may provide actionable targets for therapeutic interventions.
Published: 2020
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3. Dogs fail to reciprocate the receipt of food from a human in a food-giving task

Author: Johannes Schullern-Schrattenhofen, Mayte Martínez, Lisa Poncet, Jim McGetrick, Marietta Amann, Friederike Range, Leona Fux, University of Veterinary Medicine [Vienna] (Vetmeduni), Ethologie animale et humaine (EthoS), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Austrian Science Fund (FWF) Austrian Science Fund (FWF) [W1262B29, P30704], DOC fellowship of the Austrian Academy of Sciences (OAW) at the Konrad Lorenz Institute of Ethology, University of Veterinary Medicine, Vienna, and Normandie Université (NU)-Normandie Université (NU)-Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0106 biological sciences, Social Cognition, Male, medicine.medical_treatment, Social Sciences, 01 natural sciences, Task (project management), [SCCO]Cognitive science, Learning and Memory, Sociology, Medicine and Health Sciences, Psychology, Cooperative Behavior, Reciprocity (cultural anthropology), Receipt, Mammals, Multidisciplinary, Animal Behavior, Pets and Companion Animals, Statistical Models, 05 social sciences, Statistics, Eukaryota, Social Discrimination, Prosocial behavior, Vertebrates, Physical Sciences, Medicine, Female, Social psychology, Research Article, Social Psychology, Science, Animal-assisted therapy, 010603 evolutionary biology, Human Learning, Dogs, Human-Animal Interaction, Animal welfare, medicine, Animals, Learning, Humans, 0501 psychology and cognitive sciences, 050102 behavioral science & comparative psychology, Nutrition, Behavior, Organisms, Cognitive Psychology, Biology and Life Sciences, Helping Behavior, Diet, Prosocial Behavior, Food, Amniotes, HUBzero, Cognitive Science, Test phase, Zoology, Mathematics, Neuroscience
Abstract: International audience; Domestic dogs have been shown to reciprocate help received from conspecifics in food-giving tasks. However, it is not yet known whether dogs also reciprocate help received from humans. Here, we investigated whether dogs reciprocate the receipt of food from humans. In an experience phase, subjects encountered a helpful human who provided them with food by activating a food dispenser, and an unhelpful human who did not provide them with food. Subjects later had the opportunity to return food to each human type, in a test phase, via the same mechanism. In addition, a free interaction session was conducted in which the subject was free to interact with its owner and with whichever human partner it had encountered on that day. Two studies were carried out, which differed in the complexity of the experience phase and the time lag between the experience phase and test phase. Subjects did not reciprocate the receipt of food in either study. Furthermore, no difference was observed in the duration subjects spent in proximity to, or the latency to approach, the two human partners. Although our results suggest that dogs do not reciprocate help received from humans, they also suggest that the dogs did not recognize the cooperative or uncooperative act of the humans during the experience phase. It is plausible that aspects of the experimental design hindered the emergence of any potential reciprocity. However, it is also possible that dogs are simply not prosocial towards humans in food-giving contexts.
Published: 2021
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4. Serum resistance and phase variation of a nasopharyngeal non-typeable Haemophilus influenzae isolate

Author: Sabine Lichtenegger, Philippe Glaser, Isabelle Bina, Sanel Durakovic, Stefan Schild, Joachim Reidl, Sarah Tutz, Institute of Hygiene, Microbiology and Environmental Medicine, Medical University of Graz, Graz, Austria, Institute of Molecular Biosciences, Karl-Franzens-Universität [Graz, Autriche], Ecologie et Evolution de la Résistance aux Antibiotiques / Ecology and Evolution of Antibiotics Resistance (EERA), Institut Pasteur [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), BioTechMed Graz [Graz, Autriche], Work was supported by the Austrian Science Fund (FWF) ERA-NET FWF I 662-B09 to SL, and JR. Clinical NTHi isolates were donatedby AGES-Graz (Agentur Gesundheit und ErnaehrungssicherheitGmbH/Zentrum fuer lebensmittelbedingte Infektionskrankheiten,Dr. Georg Steindl, AGES Graz) and the Institute for Hygieneand Microbiology (Dr. Thien-Tri Lam, University of Wuerzburg,Germany), University of Graz, Karl-Franzens-Universität Graz, and Institut Pasteur [Paris] (IP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Mutant, Clone (cell biology), medicine.disease_cause, Haemophilus influenzae, MESH: Genotype, chemistry.chemical_compound, MESH: Child, Nasopharynx, MESH: Immune Evasion, Child, education.field_of_study, MESH: Blood Bactericidal Activity, General Medicine, Antigenic Variation, Phenotype, Endocytosis, 3. Good health, MESH: Multilocus Sequence Typing, Infectious Diseases, MESH: Endocytosis, MESH: Glycosyltransferases, MESH: Antigenic Variation, lpsA, Adult, Microbiology (medical), Blood Bactericidal Activity, Genotype, 030106 microbiology, Population, Biology, MESH: Alveolar Epithelial Cells, Microbiology, Cell Line, 03 medical and health sciences, medicine, Humans, education, Immune Evasion, Phase variation, Serum resistance, MESH: Humans, Glycosyltransferases, MESH: Adult, MESH: Haemophilus influenzae, MESH: Nasopharynx, MESH: Cell Line, Sialic acid, 030104 developmental biology, chemistry, Alveolar Epithelial Cells, Multilocus sequence typing, Multilocus Sequence Typing
Abstract: International audience; Haemophilus influenzae harbours a complex array of factors to resist human complement attack. As non-typeable H. influenzae (NTHi) strains do not possess a capsule, their serum resistance mainly depends on other mechanisms including LOS decoration. In this report, we describe the identification of a highly serum resistant, nasopharyngeal isolate (NTHi23) by screening a collection of 77 clinical isolates. For NTHi23, we defined the MLST sequence type 1133, which matches the profile of a previously published invasive NTHi isolate. A detailed genetic analysis revealed that NTHi23 shares several complement evading mechanisms with invasive disease isolates. These mechanisms include the functional expression of a retrograde phospholipid trafficking system and the presumable decoration of the LOS structure with sialic acid. By screening the NTHi23 population for spontaneous decreased serum resistance, we identified a clone, which was about 103-fold more sensitive to complement-mediated killing. Genome-wide analysis of this isolate revealed a phase variation in the N'-terminal region of lpsA, leading to a truncated version of the glycosyltransferase (LpsA). We further showed that a NTHi23 lpsA mutant exhibits a decreased invasion rate into human alveolar basal epithelial cells. Since only a small proportion of the NTHi23 population expressed the serum sensitive phenotype, resulting from lpsA phase-off, we conclude that the nasopharyngeal environment selected for a population expressing the intact and functional glycosyltransferase.
Published: 2017
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5. Acyl-CoA-Binding Protein Is a Lipogenic Factor that Triggers Food Intake and Obesity

Author: Nektarios Tavernarakis, Mireia Niso-Santano, Lorenzo Galluzzi, Violeta Raverdy, Friedemann Loos, Guido Kroemer, François Pattou, Céline Cruciani-Guglielmacci, Patricia Boya, Justine Lallement, Frank Madeo, Jessica Denom, Ignacio Ramírez-Pardo, Karine Clément, Christophe Magnan, Isabelle Martins, Sylvère Durand, Raphaël G. P. Denis, Noélie Bossut, Maria Chiara Maiuri, Véronique Pelloux, Robert Caiazzo, Valentina Sica, Erwan Boedec, Alili Rohia, Stéphanie Migrenne-Li, José Manuel Bravo-San Pedro, Jonathan Pol, Nicolas Ramoz, Fernando Aranda, Philip Gorwood, Gerasimos Anagnostopoulos, Fanny Aprahamian, Carlos López-Otín, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Gustave Roussy (IGR), Université Paris-Saclay, Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigaciones Biológicas (CSIC), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Clinique des maladies mentales et de l'encéphale (CMME - Service de psychiatrie), Hôpital Sainte-Anne-Université Paris Descartes - Paris 5 (UPD5), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition et obésités: approches systémiques (nutriomics) (UMR-S 1269 INSERM - Sorbonne Université), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Apoptose, cancer et immunité (U848), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Weill Medical College of Cornell University [New York], Sandra and Edward Meyer Cancer Center [New-York], Yale University School of Medicine, BioTechMed-Graz, Graz University of Technology [Graz] (TU Graz)-Medical University Graz-Karl-Franzens-Universität [Graz, Autriche], Institute of Molecular Biosciences, Karl-Franzens-Universität [Graz, Autriche], University of Crete [Heraklion] (UOC), Institute of Molecular Biology and Biotechnology (IMBB-FORTH), Foundation for Research and Technology - Hellas (FORTH), Universidad de Oviedo [Oviedo], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), University of Science & Technology of China [Suzhou], Karolinska Institutet [Stockholm], The authors thank CRC Core Facilities (CGB, CHIC, and CEF). G.K. is supported by the Ligue Contre le Cancer (équipe labelisée), Agence National de la Recherche (ANR) – projets blancs, Cancéropôle Île-de-France, Chancelerie Des universités de Paris (Legs Poix), the European Research Council (ERC), Inserm Transfert, Fondation Carrefour, Institut National du Cancer (INCa), Inserm (HTE), Institut Universitaire de France, Leducq Foundation, the Labex immuno-Oncology, the RHU Torino Lumière, the Seattle Foundation, and the SIRICs SOCRATE and CARPEM. C.M. and C.C.-G. are supported by Agence National de la Recherche (ANR-16-CE14-0026, fat4brain proposal), C.L.-O. is supported by 'Juan de Madariaga fellowship', S.B. is supported by the Swedish Research Council Vetenskapsrådet (2015-05468) and the Austrian Science Fund FWF (P27183-B24), and F.M. is supported by the Austrian Science Fund FWF (grants P23490-B20, P29262, P24381, P29203, and P27893), DKplus Metabolic and Cardiovascular Diseases (W1226), Austrian Science Ministry, Karl Franzens University ('Unkonventionelle Forschung' and 'flysleep'), NAWI Graz, and BioTechMed-Graz flagship project 'EPIAge.' K.C. is supported by ANR MICRO-Obes and AP/HP (PHRC Microbaria). L.G. is supported by an intramural startup from the Department of Radiation Oncology of Weill Cornell Medical College (New York, US) and by Sotio a.c. (Prague, Czech Republic)., The authors thank PreclinICAN (Institute of Cardiometabolism and Nutrition, IHU-ICAN, Paris, France) and 'Plateforme Imageries du Vivant' INSERM UMR 970 (PARCC-HEGP) for analyses of mouse whole-body composition and Functional & Physiological Exploration Platform (FPE) of the Unit 'Biologie Fonctionnelle et Adaptative' (University Paris Diderot, Sorbonne Paris Cité, BFA, UMR 8251 CNRS, Paris, France) for metabolic analyses., Ligue Nationale contre le Cancer (France), Agence Nationale de la Recherche (France), Chancellerie des Universités de Paris, European Research Council, Institut National du Cancer (France), Fondation Leducq, Swedish Research Council, Austrian Science Fund, Federal Ministry of Science, Research and Economy (Austria), Bravo-San-Pedro, José Manuel [0000-0002-5781-1133], Sica, Valentina [0000-0003-2770-5847], Martins, Isabelle [0000-0003-0885-613X], Pol, Jonathan G. [0000-0002-8355-7562], Loos, Friedemann [0000-0002-5976-5978], Maiuri, Maria Chiara [0000-0001-9760-7674], Niso-Santano, Mireia [0000-0002-6506-422X], Aranda, Fernando [0000-0002-9364-474X], Gorwood, Philip [0000-0003-1845-3676], Ramoz, Nicolas [0000-0002-8070-9938], Cleḿent, Karine [0000-0002-2489-3355], Pelloux, Véronique [0000-0003-3630-4746], Raverdy, Violeta [0000-0001-5754-2028], Denis, Raphaël G.P. [0000-0002-7677-7460], Boya, Patricia [0000-0003-3045-951X], Galluzzi, Lorenzo [0000-0003-2257-8500 ], Madeo, Frank [0000-0002-5070-1329], Cruciani-Guglielmacci, Céline [0000-0002-2562-5360], Tavernarakis, Nektarios [0000-0002-5253-1466 ], López-Otín, Carlos [0000-0001-6964-1904], Magnan, Christophe [0000-0002-7044-2571], Kroemer, Guido [0000-0002-9334-4405], CCSD, Accord Elsevier, Université Paris Descartes - Paris 5 (UPD5)-Hôpital Sainte-Anne, Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Yale School of Medicine [New Haven, Connecticut] (YSM), Graz University of Technology [Graz] (TU Graz)-Karl-Franzens-Universität Graz-Medical University Graz, Karl-Franzens-Universität Graz, École Pratique des Hautes Études (EPHE), Centre de Psychiatrie et Neurosciences (U894), ANR-16-CE14-0026,Fat4Brain,Le métabolisme des lipides dans le cerveau est un regulateur essentiel de l'homéostasie énergétique(2016), Bravo-San Pedro, J. M., Sica, V., Martins, I., Pol, J., Loos, F., Maiuri, M. C., Durand, S., Bossut, N., Aprahamian, F., Anagnostopoulos, G., Niso-Santano, M., Aranda, F., Ramirez-Pardo, I., Lallement, J., Denom, J., Boedec, E., Gorwood, P., Ramoz, N., Clement, K., Pelloux, V., Rohia, A., Pattou, F., Raverdy, V., Caiazzo, R., Denis, R. G. P., Boya, P., Galluzzi, L., Madeo, F., Migrenne-Li, S., Cruciani-Guglielmacci, C., Tavernarakis, N., Lopez-Otin, C., Magnan, C., Kroemer, G., Bravo-San-Pedro, José Manuel, Sica, Valentina, Martins, Isabelle, Pol, Jonathan G., Loos, Friedemann, Maiuri, Maria Chiara, Niso-Santano, Mireia, Aranda, Fernando, Gorwood, Philip, Ramoz, Nicolas, Cleḿent, Karine, Pelloux, Véronique, Raverdy, Violeta, Denis, Raphaël G.P., Boya, Patricia, Galluzzi, Lorenzo, Madeo, Frank, Cruciani-Guglielmacci, Céline, Tavernarakis, Nektarios, López-Otín, Carlos, Magnan, Christophe, and Kroemer, Guido
Subjects: Male, 0301 basic medicine, obesity, Anorexia Nervosa, Physiology, Mice, Obese, Weight Gain, Eating, Mice, 0302 clinical medicine, lipid metabolism, Acyl-CoA-binding protein, Beta oxidation, media_common, Diazepam Binding Inhibitor, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 2. Zero hunger, 0303 health sciences, Leptin Deficiency, Chemistry, Fatty Acids, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Anorexia, 3. Good health, anorexia, Lipogenesis, Female, medicine.symptom, Human, autophagy, medicine.medical_specialty, media_common.quotation_subject, Context (language use), Cell Line, 03 medical and health sciences, Internal medicine, Macroautophagy, Weight Loss, Autophagy, medicine, Animals, Humans, Obesity, Molecular Biology, 030304 developmental biology, Animal, Lipogenesi, Appetite, Cell Biology, Weight Lo, Mice, Inbred C57BL, Lipid metabolism, 030104 developmental biology, Endocrinology, Fatty Acid, 030217 neurology & neurosurgery
Abstract: 24 p.-6 fig.-1 tab.-1 graph. abst., Autophagy facilitates the adaptation to nutritional stress. Here, we show that short-term starvation of cultured cells or mice caused the autophagy-dependent cellular release of acyl-CoA-binding protein (ACBP, also known as diazepam-binding inhibitor, DBI) and consequent ACBP-mediated feedback inhibition of autophagy. Importantly, ACBP levels were elevated in obese patients and reduced in anorexia nervosa. In mice, systemic injection of ACBP protein inhibited autophagy, induced lipogenesis, reduced glycemia, and stimulated appetite as well as weight gain. We designed three approaches to neutralize ACBP, namely, inducible whole-body knockout, systemic administration of neutralizing antibodies, and induction of antiACBP autoantibodies in mice. ACBP neutralization enhanced autophagy, stimulated fatty acid oxidation, inhibited appetite, reduced weight gain in the context of a high-fat diet or leptin deficiency, and accelerated weight loss in response to dietary changes. In conclusion, neutralization of ACBP might constitute a strategy for treating obesity and its co-morbidities., G.K. is supported by the Ligue Contre le Cancer (équipe labelisée); Agence National de la Recherche (ANR) – projets blancs; Cancéropôle Île-de-France; Chancelerie Des universités de Paris (Legs Poix); the European Research Council (ERC); Inserm Transfert, Fondation Carrefour; Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; Leducq Foundation; the Labex immuno-Oncology; the RHU Torino Lumière; the Seattle Foundation; and the SIRICs SOCRATE and CARPEM. C.M. and C.C.-G. are supported by Agence National de la Recherche (ANR-16-CE14-0026, fat4brain proposal); C.L.-O. is supported by “Juan de Madariaga fellowship”; S.B. is supported by the Swedish Research Council Vetenskapsrådet (2015-05468) and the Austrian Science Fund FWF (P27183-B24); and F.M. is supported by the Austrian Science Fund FWF (grants P23490-B20, P29262, P24381, P29203, and P27893), DKplus Metabolic and Cardiovascular Diseases (W1226), Austrian Science Ministry, Karl Franzens University (“Unkonventionelle Forschung” and “flysleep”), NAWI Graz, and BioTechMed-Graz flagship project “EPIAge.” K.C. is supported by ANR MICRO-Obes and AP/HP (PHRC Microbaria). L.G. is supported by an intramural startup from the Department of Radiation Oncology of Weill Cornell Medical College (New York, US) and by Sotio a.c. (Prague, Czech Republic).
Published: 2019
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6. Of mice, flies--and men? Comparing fungal infection models for large-scale screening efforts

Author: Martin E. A. Richter, Ekkehard Hiller, Bernhard Hube, Lydia Kasper, Sascha Brunke, Dominique Ferrandon, Christophe d'Enfert, Jessica Quintin, Steffen Rupp, Karl Kuchler, Ilse D. Jacobsen, Tobias Schwarzmüller, Department of Microbial Pathogenicity Mechanisms [Jena], Hans Knoell Institute, Center for Sepsis Control & Care, Jena University Hospital, Réponse immunitaire et developpement chez les insectes (RIDI - UPR 9002), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-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), Escuela de Ciencas Biologicas, Pontificia Universidad Catolica del Ecuador, Research Group Microbial Immunology, Hans Knöll Institute, Jena University Hospital [Jena], Fraunhofer Institute for Interfacial Engineering and Biotechnology (Fraunhofer IGB), Fraunhofer (Fraunhofer-Gesellschaft), Medizinische Universität Wien = Medical University of Vienna, Biologie et Pathogénicité fongiques, Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA), This work was supported via institutional support from CNRS, by the DeutscheForschungsgemeinschaft (DFG) and the Austrian Science Foundation (FWF) via a joint DACH project of the B.H. and K.K. laboratories (DFG HU 528/17-1 and FWF-I-746-B11), and by the German Federal Ministry of Education and Health (BMBF)and the FWF via the ERA-Net Pathogenomics project FunPath (BMBF-FKZ:0313931B and FWF-API-0125). The work of S.B., M.E.R. and B.H. was further supported by the German Federal Ministry of Education and Health (BMBF) Germany via the Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC, FKZ: 01EO1002). Work in the K.K. laboratory was supported by the Austrian Science Foundation FWF by a grant from the Christian Doppler Society., Université de Strasbourg (UNISTRA)-Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fraunhofer Institute for Interfacial Engineering and Biotechnology (IGB), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris], Brunke, Sascha, Quintin, Jessica, Pontificia Universidad Católica del Ecuador, Biologie et Pathogénicité fongiques (BPF), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP), RIBIERRE, Helene, and Publica
Subjects: MESH: Gene Ontology, Male, [SDV]Life Sciences [q-bio], Mutant, Medicine (miscellaneous), lcsh:Medicine, MESH: Logistic Models, Candida glabrata, MESH: Virulence, medicine.disease_cause, Polymerase Chain Reaction, Mice, Immunology and Microbiology (miscellaneous), [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Animals, Mutant library, Drosophila melanogaster, Alternative infection models, Signature-tagged mutagenesis, Fungal virulence factors, MESH: Candida glabrata, Pathogen, MESH: Organ Specificity, 0303 health sciences, Mutation, Virulence, 3. Good health, [SDV] Life Sciences [q-bio], Organ Specificity, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, lcsh:RB1-214, Research Article, MESH: Mutation, Neuroscience (miscellaneous), Biology, General Biochemistry, Genetics and Molecular Biology, Microbiology, MESH: Drosophila melanogaster, 03 medical and health sciences, MESH: Mycoses, medicine, lcsh:Pathology, Animals, Humans, Drosophila, MESH: Mice, 030304 developmental biology, MESH: Humans, 030306 microbiology, lcsh:R, fungi, MESH: Polymerase Chain Reaction, biology.organism_classification, MESH: Male, Disease Models, Animal, Gene Ontology, Logistic Models, Mycoses, MESH: Disease Models, Animal
Abstract: Studying infectious diseases requires suitable hosts for experimental in vivo infections. Recent years have seen the advent of many alternatives to murine infection models. However, the use of non-mammalian models is still controversial because it is often unclear how well findings from these systems predict virulence potential in humans or other mammals. Here, we compare the commonly used models, fruit fly and mouse (representing invertebrate and mammalian hosts), for their similarities and degree of correlation upon infection with a library of mutants of an important fungal pathogen, the yeast Candida glabrata. Using two indices, for fly survival time and for mouse fungal burden in specific organs, we show a good agreement between the models. We provide a suitable predictive model for estimating the virulence potential of C. glabrata mutants in the mouse from fly survival data. As examples, we found cell wall integrity mutants attenuated in flies, and mutants of a MAP kinase pathway had defective virulence in flies and reduced relative pathogen fitness in mice. In addition, mutants with strongly reduced in vitro growth generally, but not always, had reduced virulence in flies. Overall, we demonstrate that surveying Drosophila survival after infection is a suitable model to predict the outcome of murine infections, especially for severely attenuated C. glabrata mutants. Pre-screening of mutants in an invertebrate Drosophila model can, thus, provide a good estimate of the probability of finding a strain with reduced microbial burden in the mouse host., Summary: Can the fitness of deletion mutants in a murine model be predicted by their virulence in Drosophila melanogaster? For a fungal pathogen, the answer is, mostly, yes.
Published: 2015
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7. Native Wolbachia from Aedes albopictus Blocks Chikungunya Virus Infection In Cellulo

Author: Patrick Potier, Florence-Hélène Tran, Vincent Raquin, Yoann Saucereau, Patrick Mavingui, Claire Valiente Moro, Laboratoire d'Ecologie Microbienne - UMR 5557 (LEM), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Ecole Nationale Vétérinaire de Lyon (ENVL), Processus Infectieux en Milieu Insulaire Tropical (PIMIT), Centre National de la Recherche Scientifique (CNRS)-IRD-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Cyclotron Réunion Océan Indien (CYROI), Université de La Réunion (UR)-Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Agence Nationale de la Recherche (ANR) [ANR-2010-BLAN-170101], Fondation pour la Recherche et la Biodiversite (FRB) [FRBCD-AOOI-07-12], Action Concertee InterPasteurienne (ACIP) [A-10-2009], ERA-Net BiodivERsA network, ANR France [ANR-13-EBID-0007-01], FWF Austria [FWF I-1437], DFG Germany [DFG KL 2087/6-1], Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Lyon (ENVL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IRD-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), and Univ, Réunion
Subjects: Aedes albopictus, viruses, Host cells, lcsh:Medicine, Dengue virus, Biology, Virus Replication, medicine.disease_cause, Mosquitoes, Virus, Microbiology, Aedes, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, parasitic diseases, medicine, Viral replication, Animals, Humans, Chikungunya, Symbiosis, lcsh:Science, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Pathogen, Multidisciplinary, lcsh:R, fungi, Correction, virus diseases, biochemical phenomena, metabolism, and nutrition, Arboviral infection, biology.organism_classification, Virology, Phenotype, 3. Good health, [SDV.BA.ZI]Life Sciences [q-bio]/Animal biology/Invertebrate Zoology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.BA.ZI] Life Sciences [q-bio]/Animal biology/Invertebrate Zoology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Chikungunya Fever, Wolbachia, lcsh:Q, Chikungunya infection, Chikungunya virus, Arboviruses, Research Article
Abstract: International audience; Wolbachia, a widespread endosymbiont of terrestrial arthropods, can protect its host against viral and parasitic infections, a phenotype called "pathogen blocking". However, in some cases Wolbachia may have no effect or even enhance pathogen infection, depending on the host-Wolbachia-pathogen combination. The tiger mosquito Aedes albopictus is naturally infected by two strains of Wolbachia, wAlbA and wAlbB, and is a competent vector for different arboviruses such as dengue virus (DENV) and Chikungunya virus (CHIKV). Interestingly, it was shown in some cases that Ae. albopictus native Wolbachia strains are able to inhibit DENV transmission by limiting viral replication in salivary glands, but no such impact was measured on CHIKV replication in vivo. To better understand the Wolbachia/CHIKV/Ae. albopictus interaction, we generated a cellular model using Ae. albopictus derived C6/36 cells that we infected with the wAlbB strain. Our results indicate that CHIKV infection is negatively impacted at both RNA replication and virus assembly/secretion steps in presence of wAlbB. Using FISH, we observed CHIKV and wAlbB in the same mosquito cells, indicating that the virus is still able to enter the cell in the presence of the bacterium. Further work is needed to decipher molecular pathways involved in Wolbachia-CHIKV interaction at the cellular level, but this cellular model can be a useful tool to study the mechanism behind virus blocking phenotype induced by Wolbachia. More broadly, this underlines that despite Wolbachia antiviral potential other complex interactions occur in vivo to determine mosquito vector competence in Ae. albopictus.
Published: 2015
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8. Endothelial sprouting, proliferation, or senescence: tipping the balance from physiology to pathology

Author: Mühleder, Severin, Fernández-Chacón, Macarena, Garcia-Gonzalez, Irene, Benedito, Rui, FWF Austrian Science Fund, Fundación La Caixa, European Research Council, Centro Nacional de Investigaciones Cardiovasculares Carlos III (España), Ministerio de Economía, Industria y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), and Fundación ProCNIC
Subjects: Senescence, Aging, Cell cycle checkpoint, Vascular differentiation, Angiogenesis, Endothelial cells, medicine.medical_treatment, Neovascularization, Physiologic, Review, Disease, Biology, Cell-cycle arrest, Regenerative medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Cell Movement, Neoplasms, medicine, Humans, Molecular Biology, Cell Proliferation, 030304 developmental biology, Feedback, Physiological, Pharmacology, 0303 health sciences, Neovascularization, Pathologic, Cell growth, Growth factor, Endothelial Cells, Cell Biology, Cell biology, Cardiovascular Diseases, 030220 oncology & carcinogenesis, Malformations, Molecular Medicine, Signal transduction, Sprouting, Signal Transduction
Abstract: Therapeutic modulation of vascular cell proliferation and migration is essential for the effective inhibition of angiogenesis in cancer or its induction in cardiovascular disease. The general view is that an increase in vascular growth factor levels or mitogenic stimulation is beneficial for angiogenesis, since it leads to an increase in both endothelial proliferation and sprouting. However, several recent studies showed that an increase in mitogenic stimuli can also lead to the arrest of angiogenesis. This is due to the existence of intrinsic signaling feedback loops and cell cycle checkpoints that work in synchrony to maintain a balance between endothelial proliferation and sprouting. This balance is tightly and effectively regulated during tissue growth and is often deregulated or impaired in disease. Most therapeutic strategies used so far to promote vascular growth simply increase mitogenic stimuli, without taking into account its deleterious effects on this balance and on vascular cells. Here, we review the main findings on the mechanisms controlling physiological vascular sprouting, proliferation, and senescence and how those mechanisms are often deregulated in acquired or congenital cardiovascular disease leading to a diverse range of pathologies. We also discuss alternative approaches to increase the effectiveness of pro-angiogenic therapies in cardiovascular regenerative medicine. Severin Mühleder was funded by the Austrian Science Fund (FWF) project J4358. Macarena Fernández-Chacón and Irene Garcia-Gonzalez were supported by PhD fellowships from Fundación La Caixa (CX_E-2015-01 and CX-SO-16-1, respectively). Rui Benedito was funded by the European Research Council (ERC-2014-StG—638028), the Centro Nacional de Investigaciones Cardiovasculares (CNIC), and by the Ministerio de Economia, Industria y Competitividad (MEIC: SAF2013-44329-P, SAF2017-89299-P, and RYC-2013-13209). The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades (MCNU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Sí
Published: 2020
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9. The metabolomic signature of extreme longevity: naked mole rats versus mice

Author: Frank Madeo, Sylvère Durand, Deborah Lefevre, Mélanie Viltard, Christine Leroy, Maria Perez-Lanzon, Guido Kroemer, Gérard Friedlander, Fanny Aprahamian, Gestionnaire, Hal Sorbonne Université, Fondation pour la Recherche en Physiologie [Brussels, Belgium], Institut Gustave Roussy (IGR), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris Cité (UPCité), Université Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Karl-Franzens-Universität Graz, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), University of Science & Technology of China [Suzhou], Karolinska Institutet [Stockholm], Karolinska University Hospital [Stockholm], Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), GK is supported by the Ligue contre le Cancer (équipe labellisée), Agence National de la Recherche (ANR) – Projets blancs, ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases, Association pour la Recherche sur le Cancer (ARC), Cancéropôle Ile-de-France, Chancelerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale (FRM), a donation by Elior, European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR), Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome, Fondation Carrefour, High-end Foreign Expert Program in China (GDW20171100085 and GDW20181100051), Institut National du Cancer (INCa), Inserm (HTE), Institut Universitaire de France, LeDucq Foundation, the LabEx Immuno-Oncology (ANR-18-IDEX-0001), the RHU Torino Lumière, the Seerave Foundation, the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), and the SIRIC Cancer Research and Personalized Medicine (CARPEM). F.M. is grateful to the Austrian Science Fund FWF (SFB LIPOTOX F3007 & F3012, W1226, P29203, P29262, P27893, P 31727 and the Austrian Federal Ministry of Education, Science and Research and the University of Graz for grants 'Unkonventionelle Forschung-InterFast' and 'flysleep' (BMWFW 80.109/0001-WF/V/3b/2015) as well as the field of excellence program BioHealth. We acknowledge support from NAWI Graz and the BioTechMed-Graz flagship project 'EPIAge'. M.V. is grateful to the Ecole Nationale Vétérinaire d’Alfort (EnvA) and the Association De Prévoyance Santé (ADPS) partners of Allianz, for their invaluable help in establishing and funding the animal facility. M.P.L. is supported by Fondation pour la Recherche Médicale (FRM FDT201904008383)., Université de Paris (UP), and Karl-Franzens-Universität [Graz, Autriche]
Subjects: autophagy, Aging, Rodent, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine.medical_treatment, media_common.quotation_subject, Longevity, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Metabolomics, Species Specificity, biology.animal, spermidine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine, Metabolome, microbiota, Animals, 030304 developmental biology, media_common, meta-organism, 0303 health sciences, biology, Vitamin E, Mole Rats, catabolism, Laboratory mouse, Cell Biology, Rats, Spermidine, Metabolic pathway, antioxidants, Biochemistry, chemistry, 030220 oncology & carcinogenesis, Priority Research Paper
Abstract: International audience; The naked mole-rat (Heterocephalus glaber) is characterized by a more than tenfold higher life expectancy compared to another rodent species of the same size, namely, the laboratory mouse (Mus musculus). We used mass spectrometric metabolomics to analyze circulating plasma metabolites in both species at different ages. Interspecies differences were much more pronounced than age-associated alterations in the metabolome. Such interspecies divergences affected multiple metabolic pathways involving amino, bile and fatty acids as well as monosaccharides and nucleotides. The most intriguing metabolites were those that had previously been linked to pro-health and antiaging effects in mice and that were significantly increased in the long-lived rodent compared to its short-lived counterpart. This pattern applies to α-tocopherol (also known as vitamin E) and polyamines (in particular cadaverine, N8-acetylspermidine and N1,N8-diacetylspermidine), all of which were more abundant in naked mole-rats than in mice. Moreover, the age-associated decline in spermidine and N1-acetylspermidine levels observed in mice did not occur, or is even reversed (in the case of N1-acetylspermidine) in naked mole-rats. In short, the present metabolomics analysis provides a series of testable hypotheses to explain the exceptional longevity of naked mole-rats.
Published: 2019
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10. Separation of the Ca V 1.2‐Ca V 1.3 calcium channel duo prevents type 2 allergic airway inflammation

Author: Joerg Striessnig, Marion Mars, Brice Ronsin, Magali Savignac, Marc Moreau, Jean-Charles Guéry, Lucette Pelletier, Marine Michelet, Nicolas Giang, Antoine Magnan, Geoffrey G. Murphy, José E. Mejía, Grégory Bouchaud, Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), 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), Centre de Physiopathologie Toulouse Purpan (CPTP), Centre de biologie du développement (CBD), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche sur les Biopolymères, Interactions Assemblages (BIA), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse, Hôpital des Enfants, Unité de Gastroentérologie, Hépatologie et Nutrition, Département de Pédiatrie, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Eastern Michigan University, Universität Innsbruck [Innsbruck], Leopold Franzens Universität Innsbruck - University of Innsbruck, Austrian Science Fund (FWF) : P27809, Foundation for Medical Research : DEQ20180339187, and French Society of Allergology : A11013BS.
Subjects: Calcium metabolism, Th2 lymphocytes, Voltage-dependent calcium channel, Calcium channel, T cell, Immunology, chemistry.chemical_element, Tyrosine phosphorylation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Calcium, asthma, Ca(v)1, cytokines, Cell biology, chemistry.chemical_compound, Calcium imaging, medicine.anatomical_structure, chemistry, Transcription (biology), calcium channels, cardiovascular system, medicine, Immunology and Allergy, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, signaling
Abstract: International audience; Background Voltage-gated calcium (Ca(v)1) channels contribute to T-lymphocyte activation. Ca(v)1.2 and Ca(v)1.3 channels are expressed in Th2 cells but their respective roles are unknown, which is investigated herein. Methods We generated mice deleted for Ca(v)1.2 in T cells or Ca(v)1.3 and analyzed TCR-driven signaling. In this line, we developed original fast calcium imaging to measure early elementary calcium events (ECE). We also tested the impact of Ca(v)1.2 or Ca(v)1.3 deletion in models of type 2 airway inflammation. Finally, we checked whether the expression of both Ca(v)1.2 and Ca(v)1.3 in T cells from asthmatic children correlates with Th2-cytokine expression. Results We demonstrated non-redundant and synergistic functions of Ca(v)1.2 and Ca(v)1.3 in Th2 cells. Indeed, the deficiency of only one channel in Th2 cells triggers TCR-driven hyporesponsiveness with weakened tyrosine phosphorylation profile, a strong decrease in initial ECE and subsequent reduction in the global calcium response. Moreover, Ca(v)1.3 has a particular role in calcium homeostasis. In accordance with the singular roles of Ca(v)1.2 and Ca(v)1.3 in Th2 cells, deficiency in either one of these channels was sufficient to inhibit cardinal features of type 2 airway inflammation. Furthermore, Ca(v)1.2 and Ca(v)1.3 must be co-expressed within the same CD4(+) T cell to trigger allergic airway inflammation. Accordingly with the concerted roles of Ca(v)1.2 and Ca(v)1.3, the expression of both channels by activated CD4(+) T cells from asthmatic children was associated with increased Th2-cytokine transcription. Conclusions Thus, Ca(v)1.2 and Ca(v)1.3 act as a duo, and targeting only one of these channels would be efficient in allergy treatment.
Published: 2021
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11. Associations between specific IgE sensitization to 26 respiratory allergen molecules and HLA class II alleles in the EGEA cohort

Author: Raphaël Vernet, Valérie Siroux, Florence Demenais, Jean Bousquet, Christian Lupinek, Hubert Gheerbrant, Christophe Pison, Winfried F. Pickl, Alicia Guillien, Rachel Nadif, Emmanuelle Bouzigon, Rudolf Valenta, Isabelle Pin, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Service de pneumologie [Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Medizinische Universität Wien = Medical University of Vienna, Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of Vienna [Vienna], NRC Institute of immunology FMBA, Moscow Russian federation, Sechenov First Moscow State Medical University, The study was supported in part by ANR-19-CE36-0005-01 NIRVANA, Inserm Aviesan Itmo santé publique, the Scientific committee 'AGIR for chronic diseases,' grant F4605 of the Austrian Science Fund (FWF), by a grant from the Country of Lower Austria and by the Megagrant of the Government of the Russian Federation, grant number 14.W03.31.0024 to RV, and by the European Commission's Seventh Framework Program MeDALL under grant agreement no. 261357. Genotyping was supported grant from the European Commission (No. LSHB-CT-2006-018996-GABRIEL)., ANR-19-CE36-0005,NIRVANA,Facteurs génomiques impliqués dans l'effet des allergènes et virus respiratoires sur l'asthme(2019), European Project: 261357, BARBAGALLO, Maïlys, Facteurs génomiques impliqués dans l'effet des allergènes et virus respiratoires sur l'asthme - - NIRVANA2019 - ANR-19-CE36-0005 - AAPG2019 - VALID, the European Commission's Seventh Framework Program MeDALL under grant agreement no. - 261357 - INCOMING, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon (MACVIA-LR), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), and Commission Européenne-Commission Européenne-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO)
Subjects: Allergy, genetic epidemiology, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Population, [SDV.GEN] Life Sciences [q-bio]/Genetics, Human leukocyte antigen, Biology, medicine.disease_cause, Immunoglobulin E, specific IgE, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 03 medical and health sciences, 0302 clinical medicine, Allergen, Hypersensitivity, medicine, Humans, Immunology and Allergy, education, Alleles, Sensitization, 030304 developmental biology, 0303 health sciences, education.field_of_study, Timothy-grass, [SDV.GEN]Life Sciences [q-bio]/Genetics, HLA class-II genes, Allergens, medicine.disease, biology.organism_classification, 3. Good health, medicine.anatomical_structure, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Phleum, MeDALL allergen-chip, respiratory allergen, biology.protein, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Population study, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 030215 immunology
Abstract: International audience; Background: Allergy, the most frequent immune disorder affecting 30% of the world's population, is the consequence of immunoglobin E (IgE) sensitization to allergens. Among the genetic factors suspected to be involved in allergy, the HLA class-II genomic region is a strong candidate.Objective: To assess the association between HLA class-II alleles and specific IgE (sIgE) sensitization to a large number of respiratory allergen molecules.Methods: The analysis relied on 927 participants of the EGEA cohort, including 497 asthmatics. The study focuses on 26 aeroallergens recognized by sIgE in at least 5% of the study population (determined with the MEDALL chip with sIgE ≥ 0.3 ISU) and 23 imputed HLA class-II alleles. For each sIgE sensitization and HLA class-II allele, we fitted a logistic regression model accounting for familial dependence and adjusted for gender, age, and genetic principal components. p-values were corrected for multiple comparisons (False Discovery Rate).Results: Most of the 19 statistically significant associations observed regard pollen allergens (mugwort Art v 1, olive tree Ole e 1, timothy grass Phl p 2, Phl p 5 and plantain Pla l 1), three were mold allergen (Alternaria Alt a 1), and a single one regards house dust mite allergen (Der p 7). No association was observed with pet allergens. The strongest associations were found with mugwort Art v 1 (OR = 5.42 (95%CI, 3.30; 8.88), 4.14 (2.65; 6.47), 3.16 (1.88; 5.31) with DQB1*05:01, DQA1*01:01 and DRB1*01:01, respectively).Conclusion: Our results support the important role of HLA class-II alleles as immune response genes predisposing their carriers for sensitization to various major pollen allergens.
Published: 2021
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12. Air pollution and IgE sensitization in 4 European birth cohorts—the MeDALL project

Author: Magnus Wickman, Alet H. Wijga, Andrea von Berg, Gerard H. Koppelman, Inger Kull, Erik Melén, Anna Bergström, Tamara Schikowski, Judith M. Vonk, Dietrich Berdel, Joachim Heinrich, Marianne van Hage, Josep M. Antó, Christian Lupinek, Jean Bousquet, Olena Gruzieva, Rudolf Valenta, Iana Markevych, E. Thiering, Ulrike Gehring, Hicran Altug, Marie Standl, Vieillissement et Maladies chroniques : approches épidémiologique et de santé publique (VIMA), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), 211250, 261357 POIR.04.04.00-1763/18-00 Mead Johnson Nutrition Scottish Environment Protection Agency, SEPA European Commission, EC European Research Council, ERC: 757919 Svenska Forskningsrådet Formas Fundacja na rzecz Nauki Polskiej, FNP Austrian Science Fund, FWF: F4605 Hjärt-Lungfonden Karolinska Institutet, KI Vetenskapsrådet, VR Institut Universitaire de France, IUF: FKZ 20462296 Seventh Framework Programme, FP7 Ludwig-Maximilians-Universität München, LMU Forskningsrådet om Hälsa, Arbetsliv och Välfärd, FORTE: 2017-01146 European Regional Development Fund, FEDER Government Council on Grants, Russian Federation Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie, BMBWF Helmholtz Zentrum München, The research leading to these results has received funding from the European Community's Seventh Framework Program under grant agreement numbers: 211250 (European Study of Cohorts for Air Pollution Effects [ESCAPE]), and 261357 (Mechanisms of the Development of ALLergy [MeDALL]). Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) was supported by The Swedish Research Council, The Swedish Heart-Lung Foundation, Region Stockholm (ALF project, and database maintenance), the Strategic Research Programme in Epidemiology at Karolinska Institutet, the Swedish Research Council Formas and the Swedish Environment Protection Agency, the Swedish Asthma and Allergy Research Foundation, the Cancer and Allergy Foundation. E.M. is supported by a grant from the European Research Council (grant agreement 757919, TRIBAL). O.G. is supported by the Swedish Research Council for Health, Working Life and Welfare (FORTE 2017-01146). R.V. is supported the by Austrian Science Fund (grant F4605) and is a recipient of a Megagrant of the Government of the Russian Federation (grant 14.W03.31.0024). The Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study was supported by project grants from The Netherlands Organization for Health Research and Development, The Netherlands Organization for Scientific Research, The Netherlands Asthma Fund, The Netherlands Ministry of Spatial Planning, Housing, and the Environment, and The Netherlands Ministry of Health, Welfare, and Sport. U.G. was supported by a Grant of The Netherlands Organization for Scientific Research. The German Infant Study on the Influence of Nutrition Intervention PLUS Environmental and Genetic Influences on Allergy Development (GINIplus) study was mainly supported for the first 3 years of the Federal Ministry for Education, Science, Research and Technology (interventional arm) and Helmholtz Zentrum Munich (formerly GSF) (observational arm). The 4-year, 6-year, 10-year, and 15-year follow-up examinations of the GINIplus study were covered from the respective budgets of the 5 study centers (Helmholtz Zentrum Munich [formerly GSF], Research Institute at Marien-Hospital Wesel, LMU Munich, TU Munich), and from year 6 onward it was also supported with funding from from IUF-Leibniz Research Institute for Environmental Medicine at the University of D?sseldorf and by a grant from the Federal Ministry for Environment (IUF D?sseldorf [grant FKZ 20462296]). Furthermore, the 15-year follow-up examination of the GINIplus study was supported by the Commission of the European Communities, the Seventh Framework Program MeDALL project, and by the companies Mead Johnson and Nestl?. The Influences of Lifestyle-Related Factors on the Human Immune System and Development of Allergies in Childhood (LISA) study was mainly supported by grants from the Federal Ministry for Education, Science, Research and Technology and also from Helmholtz Zentrum Munich (formerly GSF), the Helmholtz Centre for Environmental Research-UFZ, Leipzig, the Research Institute at Marien-Hospital Wesel, Pediatric Practice, and Bad Honnef for the first 2 years. The 4-year, 6-year, 10-year, and 15-year follow-up examinations of the LISA study were covered from the respective budgets of the involved partners (Helmholtz Zentrum Munich [formerly GSF], the Helmholtz Centre for Environmental Research-UFZ, Leipzig, the Research Institute at Marien-Hospital Wesel, Pediatric Practice, Bad Honnef, and IUF?Leibniz-Research Institute for Environmental Medicine at the University of D?sseldorf) and also by a grant from the Federal Ministry for Environment (IUF D?sseldorf [grant FKZ 20462296]). Furthermore, the 15-year follow-up examination of the LISA study was supported by the Commission of the European Communities, the Seventh Framework Program: MeDALL project. I.M. is supported by a grant from the NeuroSmog: Determining the Impact of Air Pollution on the Developing Brain (grant POIR.04.04.00-1763/18-00) which is implemented as part of the TEAM-NET programme of the Foundation for Polish Science and cofinanced with funding from European Union resources obtained from the European Regional Development Fund under the Smart Growth Operational Programme., The research leading to these results has received funding from the European Community’s Seventh Framework Program under grant agreement numbers: 211250 (European Study of Cohorts for Air Pollution Effects [ESCAPE]), and 261357 (Mechanisms of the Development of ALLergy [MeDALL]). Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) was supported by The Swedish Research Council, The Swedish Heart-Lung Foundation, Region Stockholm (ALF project, and database maintenance), the Strategic Research Programme in Epidemiology at Karolinska Institutet, the Swedish Research Council Formas and the Swedish Environment Protection Agency, the Swedish Asthma and Allergy Research Foundation, the Cancer and Allergy Foundation . E.M. is supported by a grant from the European Research Council (grant agreement 757919 , TRIBAL). O.G. is supported by the Swedish Research Council for Health, Working Life and Welfare (FORTE 2017-01146 ). R.V. is supported the by Austrian Science Fund (grant F4605) and is a recipient of a Megagrant of the Government of the Russian Federation (grant 14.W03.31.0024). The Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study was supported by project grants from The Netherlands Organization for Health Research and Development, and The Netherlands Ministry of Health, Welfare, and Sport. U.G. was supported by a Grant of The Netherlands Organization for Scientific Research. The German Infant Study on the Influence of Nutrition Intervention PLUS Environmental and Genetic Influences on Allergy Development (GINIplus) study was mainly supported for the first 3 years of the Federal Ministry for Education, Science, Research and Technology (interventional arm) and Helmholtz Zentrum Munich (formerly GSF) (observational arm). The 4-year, 6-year, 10-year, and 15-year follow-up examinations of the GINIplus study were covered from the respective budgets of the 5 study centers (Helmholtz Zentrum Munich [formerly GSF], Research Institute at Marien-Hospital Wesel, LMU Munich, TU Munich), and from year 6 onward it was also supported with funding from from IUF-Leibniz Research Institute for Environmental Medicine at the University of Düsseldorf and by a grant from the Federal Ministry for Environment (IUF Düsseldorf [grant FKZ 20462296]). Furthermore, the 15-year follow-up examination of the GINIplus study was supported by the Commission of the European Communities, the Seventh Framework Program MeDALL project , and by the companies Mead Johnson and Nestlé. The Influences of Lifestyle-Related Factors on the Human Immune System and Development of Allergies in Childhood (LISA) study was mainly supported by grants from the Federal Ministry for Education, Science, Research and Technology and also from Helmholtz Zentrum Munich (formerly GSF), the Helmholtz Centre for Environmental Research-UFZ, Leipzig, the Research Institute at Marien-Hospital Wesel, Pediatric Practice, and Bad Honnef for the first 2 years. The 4-year, 6-year, 10-year, and 15-year follow-up examinations of the LISA study were covered from the respective budgets of the involved partners (Helmholtz Zentrum Munich [formerly GSF], the Helmholtz Centre for Environmental Research-UFZ, Leipzig, the Research Institute at Marien-Hospital Wesel, Pediatric Practice, Bad Honnef, and IUF–Leibniz-Research Institute for Environmental Medicine at the University of Düsseldorf) and also by a grant from the Federal Ministry for Environment (IUF Düsseldorf [grant FKZ 20462296]). Furthermore, the 15-year follow-up examination of the LISA study was supported by the Commission of the European Communities, the Seventh Framework Program: MeDALL project . I.M. is supported by a grant from the NeuroSmog: Determining the Impact of Air Pollution on the Developing Brain (grant POIR.04.04.00-1763/18-00 ) which is implemented as part of the TEAM-NET programme of the Foundation for Polish Science and cofinanced with funding from European Union resources obtained from the European Regional Development Fund under the Smart Growth Operational Programme., and Groningen Research Institute for Asthma and COPD (GRIAC)
Subjects: Male, Allergy, Respiratory Medicine and Allergy, [SDV]Life Sciences [q-bio], air pollution, 010501 environmental sciences, Immunoglobulin E, medicine.disease_cause, 01 natural sciences, sensitization, Cohort Studies, Allergic sensitization, 0302 clinical medicine, Allergen, Fel d 1, Immunology and Allergy, Medicine, Child, Sensitization, Lungmedicin och allergi, Timothy-grass, biology, cohort, Allergen extract, 3. Good health, Europe, medicine.anatomical_structure, Child, Preschool, Female, IgE, allergen, Adolescent, Immunology, Arbetsmedicin och miljömedicin, 03 medical and health sciences, children, Hypersensitivity, Humans, 0105 earth and related environmental sciences, business.industry, Infant, Newborn, Infant, Occupational Health and Environmental Health, medicine.disease, biology.organism_classification, meta-analysis, 030228 respiratory system, 13. Climate action, biology.protein, Air Pollution, Children, Cohort, Ige, Meta-analysis, business
Abstract: Background: Whether long-term exposure air to pollution has effects on allergic sensitization is controversial. Objective: Our aim was to investigate associations of air pollution exposure at birth and at the time of later biosampling with IgE sensitization against common food and inhalant allergens, or specific allergen molecules, in children aged up to 16 years. Methods: A total of 6163 children from 4 European birth cohorts participating in the Mechanisms of the Development of ALLergy [MeDALL] consortium were included in this meta-analysis of the following studies: Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) (Sweden), Influences of Lifestyle-Related Factors on the Human Immune System and Development of Allergies in Childhood (LISA)/German Infant Study on the Influence of Nutrition Intervention PLUS Environmental and Genetic Influences on Allergy Development (GINIplus) (Germany), and Prevention and Incidence of Asthma and Mite Allergy (PIAMA) (The Netherlands). The following indicators were modeled by land use regression: individual residential outdoor levels of particulate matter with aerodynamic diameters less than 2.5 μm, less than 10 μm, and between 2.5 and 10 μm; PM2.5 absorbance (a measurement of the blackness of PM2.5 filters); and nitrogen oxides levels. Blood samples drawn at ages 4 to 6 (n = 5989), 8 to 10 (n = 6603), and 15 to 16 (n = 5825) years were analyzed for IgE sensitization to allergen extracts by ImmunoCAP. Additionally, IgE against 132 allergen molecules was measured by using the MedALL microarray chip (n = 1021). Results: Air pollution was not consistently associated with IgE sensitization to any common allergen extract up to age 16 years. However, allergen-specific analyses suggested increased risks of sensitization to birch (odds ratio [OR] = 1.12 [95% CI = 1.01-1.25] per 10-μg/m3 increase in NO2 exposure). In a subpopulation with microarray data, IgE to the major timothy grass allergen Phleum pratense 1 (Phl p 1) and the cat allergen Felis domesticus 1 (Fel d 1) greater than 3.5 Immuno Solid-phase Allergen Chip standardized units for detection of IgE antibodies were related to PM2.5 exposure at birth (OR = 3.33 [95% CI = 1.40-7.94] and OR = 4.98 [95% CI = 1.59-15.60], respectively, per 5-μg/m3 increase in exposure). Conclusion: Air pollution exposure does not seem to increase the overall risk of allergic sensitization; however, sensitization to birch as well as grass pollen Phl p 1 and cat Fel d 1 allergen molecules may be related to specific pollutants. The research leading to these results has received funding from the European Community’s Seventh Framework Program under grant agreement numbers: 211250 (European Study of Cohorts for Air Pollution Effects [ESCAPE]), and 261357 (Mechanisms of the Development of ALLergy [MeDALL]). Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) was supported by The Swedish Research Council, The Swedish Heart-Lung Foundation, Region Stockholm (ALF project, and database maintenance), the Strategic Research Programme in Epidemiology at Karolinska Institutet, the Swedish Research Council Formas and the Swedish Environment Protection Agency, the Swedish Asthma and Allergy Research Foundation, the Cancer and Allergy Foundation. E.M. is supported by a grant from the European Research Council (grant agreement 757919, TRIBAL). O.G. is supported by the Swedish Research Council for Health, Working Life and Welfare (FORTE 2017-01146).
Published: 2021
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13. Aspergillus-Pseudomonas interaction, relevant to competition in airways

Author: Paolo Visca, Gabriele Sass, Karl V. Clemons, Shajia R Ansari, John C. Penner, Eric Déziel, David A. Stevens, Hasan Nazik, Hemi Shah, Hubertus Haas, Anna-Maria Dietl, Marie-Christine Groleau, California Institute for Medical Research (CIMR), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Istanbul University, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Innsbruck Medical University [Austria] (IMU), Roma Tre University, These studies were partially supported by a gift from John Flatley, CIMR no. 3770 and by a grant from the Child Health Research Institute, Stanford Transdisciplinary Initiatives Program, CIMR no. 3777. This work was partially supported by the Austrian Science Fund/Infect-ERA program (FWF grant I1616/Infect-ERA project AspMetNet to HH). A-M.D. is an associate student of the HOROS doctoral program (W1253), The authors thank Marife Martinez for excellent technical support, Sass, Gabriele, Nazik, Hasan, Penner, John, Shah, Hemi, Ansari, Shajia R, Clemons, Karl V, Groleau, Marie-Christine, Dietl, Anna-Maria, Visca, Paolo, Haas, Hubertu, Déziel, Eric, and Stevens, David A
Subjects: MESH: Aspergillus fumigatus/growth & development, Siderophore, MESH: Respiratory Tract Infections/pathology, medicine.disease_cause, Aspergillus fumigatus, cystic fibrosis, chemistry.chemical_compound, skin and connective tissue diseases, Respiratory Tract Infections, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, MESH: Oligopeptides/metabolism, 0303 health sciences, Pyoverdine, biology, pyoverdine, MESH: Pseudomonas aeruginosa/growth & development, Pseudomonas, MESH: Pseudomonas aeruginosa/genetics, General Medicine, 3. Good health, Infectious Diseases, Pseudomonas aeruginosa, Oligopeptides, MESH: Mutation, Virulence Factors, Virulence, MESH: Aspergillosis/microbiology, Microbiology, microbial interaction, 03 medical and health sciences, MESH: Respiratory Tract Infections/microbiology, MESH: Virulence Factors/genetics, medicine, Aspergillosis, Humans, Pseudomonas Infections, MESH: Pseudomonas Infections/microbiology, cystic fibrosi, 030304 developmental biology, MESH: Aspergillosis/pathology, MESH: Humans, MESH: Oligopeptides/genetics, 030306 microbiology, MESH: Pseudomonas Infections/pathology, Biofilm, MESH: Virulence Factors/metabolism, biochemical phenomena, metabolism, and nutrition, bacterial infections and mycoses, biology.organism_classification, MESH: Microbial Interactions, Quorum sensing, chemistry, Mutation, Aspergillus fumigatu, Microbial Interactions
Abstract: International audience; In airways of immunocompromised patients and individuals with cystic fibrosis, Pseudomonas aeruginosa and Aspergillus fumigatus are the most common opportunistic bacterial and fungal pathogens. Both pathogens form biofilms and cause acute and chronic illnesses. Previous studies revealed that P. aeruginosa is able to inhibit A. fumigatus biofilms in vitro. While numerous P. aeruginosa molecules have been shown to affect A. fumigatus, there never has been a systematic approach to define the principal causative agent. We studied 24 P. aeruginosa mutants, with deletions in genes important for virulence, iron acquisition, or quorum sensing, for their ability to interfere with A. fumigatus biofilms. Cells, planktonic or biofilm culture filtrates of four P. aeruginosa mutants, pvdD-pchE-, pvdD-, lasR-rhlR-, and lasR-, inhibited A. fumigatus biofilm metabolism or planktonic A. fumigatus growth significantly less than P. aeruginosa wild type. The common defect of these four mutants was a lack in the production of the P. aeruginosa siderophore pyoverdine. Pure pyoverdine affected A. fumigatus biofilm metabolism, and restored inhibition by the above mutants. In lungs from cystic fibrosis patients, pyoverdine production and antifungal activity correlated. The key inhibitory mechanism for pyoverdine was iron-chelation and denial of iron to A. fumigatus. Further experiments revealed a counteracting, self-protective mechanism by A. fumigatus, based on A. fumigatus siderophore production.
Published: 2019
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14. A fully human anti-BMP6 antibody reduces the need for erythropoietin in rodent models of the anemia of chronic disease

Author: Chiara Volani, Dominik Wolf, Verena Petzer, Stephanie Arndt, Sieghart Sopper, Markus Seifert, Sylvia Berger, Richard Hilbe, Christa Pfeifhofer-Obermair, Natascha Brigo, Alexander Hoffmann, Felix Böhm, Anja K. Bosserhoff, Jonathan Papworth, Lara Valente de Souza, Léon Kautz, Laura von Raffay, Volker Germaschewski, Matthew Wake, Igor Theurl, Luke Bayliss, Cecilia Deantonio, Malte Asshoff, Manfred Nairz, Egon Demetz, Piotr Tymoszuk, Prunelle Perrier, Philipp Grubwieser, Joana Carvalho, Stefanie Dichtl, Guenter Weiss, Department of Internal Medicine, Innsbruck Medical University, Innsbruck, Austria., Med Univ Innsbruck, Dept Internal Med 5, Hematol & Oncol, Innsbruck, Austria, Kymab Ltd, Cambridge, England, Med Univ Innsbruck, Christian Doppler Lab Iron Metab & Anemia Res, Innsbruck, Austria, Univ Med Ctr Regensburg, Dept Dermatol, Regensburg, Germany, Friedrich Alexander Univ Erlangen Nurnberg, Inst Biochem, Emil Fischer Ctr, Erlangen, Germany, Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Univ Clin Bonn, Internal Med 3, Oncol Oncol Immunooncol & Rheumatol, Bonn, Germany, doctoral college project (W1253 HOROS), Austrian Research Funds (FWF) Project (P 28302), Verein zur Forderung von Forschung und Weiterbildung in Infektiologie und Immunologie, Innsbruck, Christian Doppler Society, Austria, Krebshilfe Tirol project (15024), and Austrian Society of Hematology and Medical Oncology (OeGHO)
Subjects: Darbepoetin alfa, Bone Morphogenetic Protein 6, Ferroportin, Muscle Proteins, Pharmacology, Biochemistry, Mice, Random Allocation, 0302 clinical medicine, Bone Marrow, hemic and lymphatic diseases, Cation Transport Proteins, Erythroid Precursor Cells, 0303 health sciences, biology, Polysaccharides, Bacterial, Antibodies, Monoclonal, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Anemia, Drug Synergism, Hematology, Hep G2 Cells, Recombinant Proteins, 3. Good health, 030220 oncology & carcinogenesis, Erythropoiesis, Cytokines, medicine.drug, Anemia of chronic disease, Iron, Immunology, 03 medical and health sciences, Red Cells, Iron, and Erythropoiesis, Hepcidin, medicine, Animals, Humans, Renal Insufficiency, Chronic, Erythropoietin, 030304 developmental biology, Dose-Response Relationship, Drug, business.industry, Arthritis, Cell Biology, medicine.disease, biology.protein, business
Abstract: Recombinant erythropoietin (EPO) and iron substitution are a standard of care for treatment of anemias associated with chronic inflammation, including anemia of chronic kidney disease. A black box warning for EPO therapy and concerns about negative side effects related to high-dose iron supplementation as well as the significant proportion of patients becoming EPO resistant over time explains the medical need to define novel strategies to ameliorate anemia of chronic disease (ACD). As hepcidin is central to the iron-restrictive phenotype in ACD, therapeutic approaches targeting hepcidin were recently developed. We herein report the therapeutic effects of a fully human anti-BMP6 antibody (KY1070) either as monotherapy or in combination with Darbepoetin alfa on iron metabolism and anemia resolution in 2 different, well-established, and clinically relevant rodent models of ACD. In addition to counteracting hepcidin-driven iron limitation for erythropoiesis, we found that the combination of KY1070 and recombinant human EPO improved the erythroid response compared with either monotherapy in a qualitative and quantitative manner. Consequently, the combination of KY1070 and Darbepoetin alfa resulted in an EPO-sparing effect. Moreover, we found that suppression of hepcidin via KY1070 modulates ferroportin expression on erythroid precursor cells, thereby lowering potentially toxic-free intracellular iron levels and by accelerating erythroid output as reflected by increased maturation of erythrocyte progenitors. In summary, we conclude that treatment of ACD, as a highly complex disease, becomes more effective by a multifactorial therapeutic approach upon mobilization of endogenous iron deposits and stimulation of erythropoiesis.
Published: 2019
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15. Hot topics in the mechanisms of pulmonary arterial hypertension disease: cancer-like pathobiology, the role of the adventitia, systemic involvement, and right ventricular failure

Author: Marlene Rabinovitch, Wolfgang M. Kuebler, Brian B. Graham, Norbert F. Voelkel, Grazyna Kwapiszewska, Elena A. Goncharova, Soni Savai Pullamsetti, Christophe Guignabert, Kurt R. Stenmark, Edda Spiekerkoetter, Harm Jan Bogaard, Division of Pulmonary and Critical Care Medicine [Stanford, CA, USA] (Cardiovascular Institute), Stanford University-Stanford Cardiovascular Institute-Wall Center for Pulmonary Vascular Disease [Stanford, CA, USA], Division of Pulmonary, Allergy and Critical Care Medicine [Pittsburgh, PA, États-Unis], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Department of Bioengineering [Pittsburgh, PA, USA], University of Pittsburgh (PITT), Université Paris-Saclay, Université Paris-Sud [Le Kremlin-Bicêtre] (Faculté de Médecine), Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre chirurgical Marie Lannelongue, Department of Pediatrics [Denver, CO, USA] (School of Medicine), University of Colorado [Denver], Cardio Vascular Pulmonary Research Lab [Denver, CO, USA], Ludwig Boltzmann Institute for Lung Vascular Research [Graz], Stanford Cardiovascular Institute, Vrije Universiteit Medical Centre (VUMC), Vrije Universiteit Amsterdam [Amsterdam] (VU), VU University Medical Center [Amsterdam], Pulmonary Sciences and Critical Care [Denver, CO, USA] (School of Medicine), Max Planck Institute for Heart and Lung Research (MPI-HLR), Max-Planck-Gesellschaft, University of Giessen and Marburg Lung Center (UGMLC), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Keenan Research Centre for Biomedical Science [Toronto, ON, Canada], Li Ka Shing Knowledge Institute [Toronto, ON, Canada]-St. Michael’s Hopsital [Toronto, ON, Canada], Department of Surgery [Toronto, ON, Canada], University of Toronto, Department of Physiology [Toronto, ON, Canada], Université de Toronto [Canada]-Mount Sinai Hospital [Toronto, Canada] (MSH)-Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], ES: NHLBI R01 HL128734, Department of Defense PR161256, Wall Center for Pulmonary Vascular Disease Stanford, Pulmonary Hypertension Association Career Development Grant. EAG: NIH/NHLBI R01HL130261, 2R01HL113178. CG: ANR-16-CE17-0014 (TAMIRAH), National Agency for Research (ANR), DEQ20150331712 (Equipe FRM 2015), Fondation de la Recherche Me´dicale (FRM), De´partement HospitaloUniversitaire Thorax Innovation (TORINO), Fonds de Dotation Recherche en Sante´ Respiratoire–(FRSR)–Fondation du Souffle (FdS), French Pulmonary Hypertension Association (HTAP France). KS: NIH/NHLBI: PPG P01 HL014985, 1R01HL125827, and DoD PR140977. GK: FWF P27848. MR: R01 HL074186, R01 HL087118, R01 HL122887, R01 HL138473, P01 HL108797, R24 HL123767, K12 HL120001. NV: none. HJB: Dutch Cardiovascular Alliance, PHAEDRA-IMPACT Consortium. BG: NHLBI P01HL014985, R03HL133306, and R01HL135872. SSP: The Max Planck Society, DFG, SFB 1213 (Project A01, A05), and the Excellence Cluster 147 CardioPulmonary System (ECCPS, EXC 147). WMK: HSFC G-16-00013171, DFG KU1218/9-1, DZHK, DZL, and ORF SCORR (RE07-086)., ANR-16-CE17-0014,TAMIRAH,Cibler l'activation anormale du récepteur des minéralocorticoïdes dans l'Hypertension Artérielle Pulmonaire : Une étude translationnelle vers un traitement(2016), Guignabert, Christophe, Cibler l'activation anormale du récepteur des minéralocorticoïdes dans l'Hypertension Artérielle Pulmonaire : Une étude translationnelle vers un traitement - - TAMIRAH2016 - ANR-16-CE17-0014 - AAPG2016 - VALID, Centre Chirurgical Marie Lannelongue (CCML)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Toronto-Mount Sinai Hospital [Toronto, Canada] (MSH)-Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], Pulmonary medicine, and ACS - Pulmonary hypertension & thrombosis
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, Neointima, medicine.medical_specialty, Systemic disease, lcsh:Diseases of the circulatory (Cardiovascular) system, vascular remodeling, [SDV]Life Sciences [q-bio], Disease, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 030204 cardiovascular system & hematology, Cardiorespiratory Medicine and Haematology, Cardiovascular, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 03 medical and health sciences, 0302 clinical medicine, Rare Diseases, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Adventitia, right ventricle function and dysfunction, Medicine, 2.1 Biological and endogenous factors, Aetiology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Lung, lcsh:RC705-779, business.industry, Cancer, lcsh:Diseases of the respiratory system, Leading Edge Science, medicine.disease, experimental pulmonary hypertension, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Hot topics, Ventricle, lcsh:RC666-701, Cardiology, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Right ventricular failure, Pro-Con debate, business
Abstract: International audience; In order to intervene appropriately and develop disease-modifying therapeutics for pulmonary arterial hypertension, it is crucial to understand the mechanisms of disease pathogenesis and progression. We herein discuss four topics of disease mechanisms that are currently highly debated, yet still unsolved, in the field of pulmonary arterial hypertension. Is pulmonary arterial hypertension a cancer-like disease? Does the adventitia play an important role in the initiation of pulmonary vascular remodeling? Is pulmonary arterial hypertension a systemic disease? Does capillary loss drive right ventricular failure? While pulmonary arterial hypertension does not replicate all features of cancer, anti-proliferative cancer therapeutics might still be beneficial in pulmonary arterial hypertension if monitored for safety and tolerability. It was recognized that the adventitia as a cell-rich compartment is important in the disease pathogenesis of pulmonary arterial hypertension and should be a therapeutic target, albeit the data are inconclusive as to whether the adventitia is involved in the initiation of neointima formation. There was agreement that systemic diseases can lead to pulmonary arterial hypertension and that pulmonary arterial hypertension can have systemic effects related to the advanced lung pathology, yet there was less agreement on whether idiopathic pulmonary arterial hypertension is a systemic disease per se. Despite acknowledging the limitations of exactly assessing vascular density in the right ventricle, it was recognized that the failing right ventricle may show inadequate vascular adaptation resulting in inadequate delivery of oxygen and other metabolites. Although the debate was not meant to result in a definite resolution of the specific arguments, it sparked ideas about how we might resolve the discrepancies by improving our disease modeling (rodent models, large-animal studies, studies of human cells, tissues, and organs) as well as standardization of the models. Novel experimental approaches, such as lineage tracing and better three-dimensional imaging of experimental as well as human lung and heart tissues, might unravel how different cells contribute to the disease pathology.
Published: 2019
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16. Intermicrobial interaction: Aspergillus fumigatus siderophores protect against competition by Pseudomonas aeruginosa

Author: Shajia R Ansari, Eric Déziel, David A. Stevens, Hubertus Haas, Anna-Maria Dietl, Gabriele Sass, California Institute for Medical Research (CIMR), Innsbruck Medical University [Austria] (IMU), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, This research was funded by John Flatley (CIMR no. 3770) to D.A.S., Child Health Research Institute, Stanford Transdisciplinary Initiatives Program (CIMR no. 3777) to D.A.S., Austrian Science Fund/Infect-ERA program (FWF grant I1616/Infect-ERA project AspMetNet) to H.H., and HOROS program (W1253) to A.-M.D., and The authors thank Marife Martinez for excellent technical support. The A. fumigatus mutant strain AfΔsidA was kindly provided by M. M. Moore, Department of Biological Sciences, Simon Fraser University, Burnaby, Canada.
Subjects: 0301 basic medicine, Siderophore, Siderophores, Pathology and Laboratory Medicine, medicine.disease_cause, Aspergillus fumigatus, chemistry.chemical_compound, Drug Metabolism, Microbial Physiology, Medicine and Health Sciences, skin and connective tissue diseases, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Fungal Pathogens, Multidisciplinary, Pyoverdine, biology, Chemistry, Microbial Growth and Development, Eukaryota, Pseudomonas Aeruginosa, Bacterial Pathogens, Aspergillus, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Fungal Molds, Medical Microbiology, Celastrol, Engineering and Technology, Medicine, Pathogens, Oligopeptides, Research Article, Heat Treatment, Science, 030106 microbiology, Mycology, Fungus, Microbiology, 03 medical and health sciences, Pseudomonas, Antibiosis, medicine, Pharmacokinetics, Microbial Pathogens, Pharmacology, Bacteria, Pseudomonas aeruginosa, Bacterial Growth, Organisms, Fungi, Wild type, Biofilm, Biology and Life Sciences, Bacteriology, biology.organism_classification, bacterial infections and mycoses, 030104 developmental biology, Manufacturing Processes, Biofilms, Bacterial Biofilms, Developmental Biology
Abstract: International audience; Pseudomonas aeruginosa and Aspergillus fumigatus are pathogens frequently co-inhabiting immunocompromised patient airways, particularly in people with cystic fibrosis. Both microbes depend on the availability of iron, and compete for iron in their microenvironment. We showed previously that the P. aeruginosa siderophore pyoverdine is the main instrument in battling A. fumigatus biofilms, by iron chelation and denial of iron to the fungus. Here we show that A. fumigatus siderophores defend against anti-fungal P. aeruginosa effects. P. aeruginosa supernatants produced in the presence of wildtype A. fumigatus planktonic supernatants (Afsup) showed less activity against A. fumigatus biofilms than P. aeruginosa supernatants without Afsup, despite higher production of pyoverdine by P. aeruginosa. Supernatants of A. fumigatus cultures lacking the sidA gene (AfΔsidA), unable to produce hydroxamate siderophores, were less capable of protecting A. fumigatus biofilms from P. aeruginosa supernatants and pyoverdine. AfΔsidA biofilm was more sensitive towards inhibitory effects of pyoverdine, the iron chelator deferiprone (DFP), or amphothericin B than wildtype A. fumigatus biofilm. Supplementation of sidA-deficient A. fumigatus biofilm with A. fumigatus siderophores restored resistance to pyoverdine. The A. fumigatus siderophore production inhibitor celastrol sensitized wildtype A. fumigatus biofilms towards the anti-fungal activity of DFP. In conclusion, A. fumigatus hydroxamate siderophores play a pivotal role in A. fumigatus competition for iron against P. aeruginosa.
Published: 2019
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17. International external quality assurance of JAK2 V617F quantification

Author: Julia Asp, Marta Vorland, Anni Aggerholm, Lasse Kjær, Karl Haslam, Elisabeth Oppliger Leibundgut, Rajko Kusec, Karolina Matiakowska, Robert Kralovics, Frank Dicker, Alessandro Pancrazzi, Morten Andersen, Lars Palmqvist, Sylvie Hermouet, Margarida Coucelo, Bruno Cassinat, Filippo Navaglia, Andrey Sudarikov, Aleksandar Eftimov, Vibe Skov, Thomas Kielsgaard Kristensen, François Girodon, Laurence Lodé, Niels Pallisgaard, Eric Lippert, Jiri Schwarz, Marzena Wojtaszewska, Hajnalka Andrikovics, Guy Wayne Novotny, Dorota Link-Lenczowska, Susanna Akiki, Melanie J. Percy, Dina Naguib, Beatriz Bellosillo, Department of Clinical Chemistry and Transfusion Medicine [Gothenburg, Sweden] (Institute of Biomedicine), University of Gothenburg (GU)-Sahlgrenska Academy at University of Gothenburg [Göteborg], Department of Hematology [Roskilde, Denmark], Zealand University Hospital [Roskilde, Denmark], Department of Pathology [Barcelona, Spain], Hospital del Mar [Barcelona, Spain], Department of Pathology [Odense, Denmark], Odense University Hospital [Odense, Denmark], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Munich Leukemia Laboratory [Munich, Germany], Institute of Hematology and Blood Transfusion [Prague, Czech Republic], Department of Hematology and Bone Marrow Transplantation [Poznan, Poland], Poznan University of Medical Sciences [Poznan, Poland], Department of Laboratory Medicine and Pathology [Doha, Qatar], Qatar Rehabilitation Institute (QRI)-Hamad Bin Khalifa Medical City (HBKM), Aarhus University Hospital, Rigshospitalet [Copenhagen], Copenhagen University Hospital, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), University of Bern [Bern, Switzerland] (University Hospital Bern ), Centro di Ricerca e Innovazione per le Malattie Mieloproliferative - CRIMM [ Florence, Italy], Haukeland University Hospital, University of Bergen (UiB), Central Hospital of Southern Pest [Budapest, Hungary], CeMM Research Center for Molecular Medicine [Vienna, Austria], Austrian Academy of Sciences (OeAW), Department of Internal Medicine I [Vienna, Austria], Medizinische Universität Wien = Medical University of Vienna, Service de Biologie Cellulaire [AP-HP, Hôpital Saint-Louis], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Clinical Hematology Unit, Hospital Pediátrico [Coimbra, Portugal], Centro Hospitalar e Universitário [Coimbra], Center for Biomolecular Pharmaceutical Analyses [Skopje, Republic of Macedonia] (Faculty of Pharmacy), University of Ss. Cyril and Methodius in Skopje, Macedonia (UKIM), St James’s Hospital [Dublin, Ireland], Zagreb School of Medicine [Zagreb, Croatia] (Dubrava University Hospital), University of Zagreb, Molecular Diagnostics Laboratory [Krakow, Poland] (Hematology Diagnostics Department), Jagiellonian University Hospital [Krakow, Poland], Hématologie Biologique [CHU de Montpellier], Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Faculty of Medicine [Bydgoszcz, Poland], Nicolaus Copernicus University [Toruń], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Department of Laboratory Medicine [Padova, Italy], University - Hospital of Padova [Italy], Department of Hematology & Department of Pathology [Herlev, Denmark] (Molecular Unit), Herlev and Gentofte Hospital-University of Copenhagen = Københavns Universitet (KU), Belfast City Hospital [Belfast, UK], National Research Center for Hematology [Moscow, Russia], Molecular Mechanisms of Chronic Inflammation in Hematological Diseases (CRCINA-ÉQUIPE 16), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Laboratoire d'Hematologie [CHU Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), RK acknowledges the support received by the Austrian Science Fund (FWF): F4702-B20 and P29018-B30., Bernardo, Elizabeth, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Service de Biologie Cellulaire [Saint-Louis], Ss. Cyril and Methodius University in Skopje (UKIM), Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Azienda Ospedale Università di Padova = Hospital-University of Padua (AOUP), Herlev and Gentofte Hospital-University of Copenhagen = Københavns Universitet (UCPH), and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: Male, medicine.medical_specialty, Standardization, Quality Assurance, Health Care, Computer science, media_common.quotation_subject, Mutation, Missense, [SDV.CAN]Life Sciences [q-bio]/Cancer, 610 Medicine & health, Real-Time Polymerase Chain Reaction, Real-Time Polymerase Chain Reaction/standards, Myeloproliferative neoplasms, 03 medical and health sciences, External quality assurance, JAK2 V617F, Quantitative PCR, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, hemic and lymphatic diseases, medicine, Humans, Medical physics, Quality (business), Instrumentation (computer programming), Pathology, Molecular, media_common, Janus Kinase 2/genetics, business.industry, Amino acid substitution, Hematology, General Medicine, Janus Kinase 2, Amino Acid Substitution, Pathology, Molecular/standards, 030220 oncology & carcinogenesis, Female, business, Quality assurance, 030215 immunology
Abstract: IF 2.845; International audience; External quality assurance (EQA) programs are vital to ensure high quality and standardized results in molecular diagnostics. It is important that EQA for quantitative analysis takes into account the variation in methodology. Results cannot be expected to be more accurate than limits of the technology used, and it is essential to recognize factors causing substantial outlier results. The present study aimed to identify parameters of specific importance for JAK2 V617F quantification by quantitative PCR, using different starting materials, assays, and technical platforms. Sixteen samples were issued to participating laboratories in two EQA rounds. In the first round, 19 laboratories from 11 European countries analyzing JAK2 V617F as part of their routine diagnostics returned results from in-house assays. In the second round, 25 laboratories from 17 countries participated. Despite variations in starting material, assay setup and instrumentation the laboratories were generally well aligned in the EQA program. However, EQA based on a single technology appears to be a valuable tool to achieve standardization of the quantification of JAK2 V617F allelic burden.
Published: 2019
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18. Fluorescence-Based Nanoparticle Tracking Analysis and Flow Cytometry for Characterization of Endothelial Extracellular Vesicle Release

Author: Jaana Schneider, Wolfgang Holnthoner, Johannes Zipperle, Marianne Pultar, Johannes Grillari, Severin Mühleder, Johannes Oesterreicher, Austrian Research Promotion Agency, FWF Austrian Science Fund, Particle Metrix, Austrian Research Promotion Agency FFG, and Austrian Science Fund
Subjects: 0301 basic medicine, Nanoparticle tracking analysis, Cell Fractionation, Article, nano particle tracking, Fluorescence, Catalysis, Umbilical vein, Flow cytometry, lcsh:Chemistry, Inorganic Chemistry, Extracellular Vesicles, 03 medical and health sciences, 0302 clinical medicine, Cell-Derived Microparticles, Human Umbilical Vein Endothelial Cells, medicine, Humans, Secretion, Particle Size, Physical and Theoretical Chemistry, lcsh:QH301-705.5, Molecular Biology, Cells, Cultured, Spectroscopy, medicine.diagnostic_test, Chemistry, Cell Cycle, Organic Chemistry, Endothelial Cells, General Medicine, Extracellular vesicle, Flow Cytometry, Microvesicles, Computer Science Applications, Characterization (materials science), fluorescence triggering flow cytometry, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, Cell Tracking, 030220 oncology & carcinogenesis, Biophysics, Nanoparticles, Biomarkers
Abstract: As extracellular vesicles (EVs) have become a prominent topic in life sciences, a growing number of studies are published on a regular basis addressing their biological relevance and possible applications. Nevertheless, the fundamental question of the true vesicular nature as well as possible influences on the EV secretion behavior have often been not adequately addressed. Furthermore, research regarding endothelial cell-derived EVs (EndoEVs) often focused on the large vesicular fractions comprising of microvesicles (MV) and apoptotic bodies. In this study we aimed to further extend the current knowledge of the influence of pre-isolation conditions, such as cell density and conditioning time, on EndoEV release from human umbilical vein endothelial cells (HUVECs). We combined fluorescence nanoparticle tracking analysis (NTA) and the established fluorescence-triggered flow cytometry (FT-FC) protocol to allow vesicle-specific detection and characterization of size and surface markers. We found significant effects of cell density and conditioning time on both abundance and size distribution of EndoEVs. Additionally, we present detailed information regarding the surface marker display on EVs from different fractions and size ranges. Our data provide crucial relevance for future projects aiming to elucidate EV secretion behavior of endothelial cells. Moreover, we show that the influence of different conditioning parameters on the nature of EndoEVs has to be considered. This research was funded by the Austrian Research promotion agency and Particle Metrix. Severin Mühleder was funded by the Austrian Science Fund (FWF) project J4358. Sí
Published: 2020
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19. MicroRNAs facilitate skeletal muscle maintenance and metabolic suppression in hibernating brown bears

Author: Kenneth B. Storey, Blandine Chazarin, Sylvain Giroud, Guillemette Gauquelin-Koch, Bryan E. Luu, Jon M. Arnemo, Fabrice Bertile, Etienne Lefai, Jon E. Swenson, Alina L. Evans, Biology, SAMS, MCGill University, Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Department of Integrative Biology and Evolution, Research Institute of Wildlife Ecology, University of Veterinary Medicine Vienna, Norwegian University of Life Sciences, Faculty of Environmental Sciences and Natural Resource Management (NMBU), Norvegian Institute for Nature Research, Centre National d’Études Spatiales [Paris] (CNES), Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Forestry & Wildlife Management, Inland Norway University of Applied Sciences - Høgskolen i Innlandet, Wildlife Fish and Environment Studies, Swedish University of Agricultural Sciences (SLU), McGill University = Université McGill [Montréal, Canada], Unité de Nutrition Humaine (UNH), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), 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), Department of Wildlife, Fish and Environmental Studies, Centre National D'etudes Spatiales874Natural Sciences and Engineering Research Council of Canada6793Universite de Strasbourg Center National de la Recherche Scientifique Miljodirektoratet Naturvardsverket Svenska Jagareforbundet Austrian Science Fund (FWF) Centre National D'etudes Spatiales, and 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)
Subjects: 0301 basic medicine, Hibernation, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], Physiology, Glucose uptake, Clinical Biochemistry, Inflammation, ubiquitin ligase, noncoding RNA, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Downregulation and upregulation, atrophy, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, RNA, Messenger, Muscle, Skeletal, biology, Skeletal muscle, myomiR, Cell Biology, medicine.disease, Muscle atrophy, Mef2a, Cell biology, Ubiquitin ligase, Ursus arctos, MicroRNAs, Muscular Atrophy, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, biology.protein, medicine.symptom, Ursidae, Signal Transduction
Abstract: Early ViewOnline Version of Record before inclusion in an issue; Hibernating brown bears, Ursus arctos, undergo extended periods of inactivity and yet these large hibernators are resilient to muscle disuse atrophy. Physiological characteristics associated with atrophy resistance in bear muscle have been examined (e.g., muscle mechanics, neural activity) but roles for molecular signaling/regulatory mechanisms in the resistance to muscle wasting in bears still require investigation. Using quantitative reverse transcription PCR (RT-qPCR), the present study characterized the responses of 36 microRNAs linked with development, metabolism, and regeneration of skeletal muscle, in the vastus lateralis of brown bears comparing winter hibernating and summer active animals. Relative levels of mRNA of selected genes (mef2a, pax7, id2, prkaa1, and mstn) implicated upstream and downstream of the microRNAs were examined. Results indicated that hibernation elicited a myogenic microRNA, or "myomiR", response via MEF2A-mediated signaling. Upregulation of MEF2A-controlled miR-1 and miR-206 and respective downregulation of pax7 and id2 mRNA are suggestive of responses that promote skeletal muscle maintenance. Increased levels of metabolic microRNAs, such as miR-27, miR-29, and miR-33, may facilitate metabolic suppression during hibernation via mechanisms that decrease glucose uptake and fatty acid oxidation. This study identified myomiR-mediated mechanisms for the promotion of muscle regeneration, suppression of ubiquitin ligases, and resistance to muscle atrophy during hibernation mediated by observed increases in miR-206, miR-221, miR-31, miR-23a, and miR-29b. This was further supported by the downregulation of myomiRs associated with a muscle injury and inflammation (miR-199a and miR-223) during hibernation. The present study provides evidence of myomiR-mediated signaling pathways that are activated during hibernation to maintain skeletal muscle functionality in brown bears.
Published: 2019
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20. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

Author: Dustin G. Brown, Tove Hultman, Judith Weisz, H. Kim Lyerly, Paola A. Marignani, Ann-Karin Olsen, Rabindra Roy, Kim Moorwood, Masoud H. Manjili, Monica Vaccari, Jesse Roman, Hasiah Ab Hamid, Kalan R. Prudhomme, Periyadan K. Krishnakumar, Chenfang Dong, Tiziana Guarnieri, Leandro S. D'Abronzo, Gloria M. Calaf, Amelia K Charles, Emanuela Corsini, Yunus A. Luqmani, Graeme Williams, Louis Vermeulen, Pankaj Vadgama, Sarah N Bay, Véronique Maguer-Satta, Sabine A. S. Langie, Christian C. Naus, Le Jian, Gladys N. Nangami, Lorenzo Memeo, Stephanie C. Casey, Thomas Sanderson, Takemi Otsuki, Nichola Cruickshanks, William H. Bisson, Sudjit Luanpitpong, Jonathan Whitfield, Ahmed Lasfar, Yon Rojanasakul, A. Ivana Scovassi, Shelley A. Harris, Ferdinando Chiaradonna, Richard Ponce-Cusi, Gregory T. Wolf, Valérian Dormoy, Roslida Abd Hamid, Hyun Ho Park, Matilde E. Lleonart, William K. Decker, Maria Romano, Leroy Lowe, Fabio Marongiu, Jan Vondráček, Chiara Mondello, Luc Leyns, Josiah Ochieng, Pratima Nangia-Makker, Edward A. Ratovitski, Zhiwei Hu, Jayadev Raju, Hemad Yasaei, Rafaela Andrade-Vieira, Jordan Woodrick, Hideko Sone, Harini Krishnan, W. Kimryn Rathmell, Andrew Collins, Luoping Zhang, Barry J. Barclay, Amaya Azqueta, Laura Soucek, Marc A. Williams, David O. Carpenter, Roberta Palorini, Rita Nahta, Juan Fernando Martinez-Leal, Firouz Darroudi, Rita Dornetshuber-Fleiss, James E. Klaunig, Elizabeth P. Ryan, Qiang Shawn Cheng, Arthur Berg, Andrew Ward, Gudrun Koppen, Tao Chen, Petr Heneberg, Michael Gilbertson, Amedeo Amedei, Sakina E. Eltom, Ezio Laconi, Joseph Christopher, Hiroshi Kondoh, Neetu Singh, Danielle J Carlin, Marion Chapellier, Michalis V. Karamouzis, Rekha Mehta, Tae-Jin Lee, Annamaria Colacci, Venkata S. Sabbisetti, Mark Wade, Micheline Kirsch-Volders, Patricia Ostrosky-Wegman, Isabelle R. Miousse, Patricia A. Thompson, Philippa D. Darbre, Frederik J. van Schooten, Sofia Pavanello, Igor Koturbash, Binhua P. Zhou, Ranjeet Kumar Sinha, Anna C. Salzberg, Mahara Valverde, Fahd Al-Mulla, Julia Kravchenko, Nicole Kleinstreuer, Carolyn J. Baglole, Menghang Xia, Samira A. Brooks, Amancio Carnero, Gunnar Brunborg, Sandra S. Wise, Daniel C. Koch, John Pierce Wise, Rabeah Al-Temaimi, Laetitia Gonzalez, Lisa J. McCawley, R. Brooks Robey, Gary S. Goldberg, Thierry Massfelder, Linda S M Gulliver, Olugbemiga Ogunkua, Emilio Rojas, Eun-Yi Moon, Lin Li, Silvana Papagerakis, Nik van Larebeke, Adela Lopez de Cerain Salsamendi, Staffan Eriksson, Simona Romano, Dean W. Felsher, Paramita M. Ghosh, Karine A. Cohen-Solal, Paul Dent, Jun Sun, Carmen Blanco-Aparicio, Riccardo Di Fiore, Chia-Wen Hsu, Mahin Khatami, Kannan Badri Narayanan, Francis Martin, Colleen S. Curran, Dale W. Laird, William H. Goodson, Abdul Manaf Ali, Valerie Odero-Marah, Michael J. Gonzalez, Renza Vento, Liang Tzung Lin, Clement G. Yedjou, Hosni Salem, Hsue-Yin Hsu, Zhenbang Chen, Nuzhat Ahmed, Gerard Wagemaker, Sandra Ryeom, Stefano Forte, Debasish Roy, Nancy B. Kuemmerle, Robert C. Castellino, Po Sing Leung, Wilhelm Engström, National Institute of Environmental Health Sciences (US), Research Council of Norway, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Red Temática de Investigación Cooperativa en Cáncer (España), European Commission, Junta de Andalucía, Ministerio de Educación y Ciencia (España), Ministero dell'Istruzione, dell'Università e della Ricerca, University of Oslo, Regione Emilia Romagna, National Institutes of Health (US), Consejo Nacional de Ciencia y Tecnología (México), Associazione Italiana per la Ricerca sul Cancro, National Research Foundation of Korea, Ministry of Education, Science and Technology (South Korea), Fondo Nacional de Desarrollo Científico y Tecnológico (Chile), Ministry of Education, Culture, Sports, Science and Technology (Japan), Japan Science and Technology Agency, Ministry of Science and Technology (Taiwan), Arkansas Biosciences Institute, Czech Science Foundation, Fundación Fero, Swim Across America, American Cancer Society, Research Foundation - Flanders, Austrian Science Fund, Institut National de la Santé et de la Recherche Médicale (France), Natural Sciences and Engineering Research Council of Canada, Farmacologie en Toxicologie, RS: NUTRIM - R4 - Gene-environment interaction, Goodson, William H, Lowe, Leroy, Carpenter, David O, Gilbertson, Michael, Manaf Ali, Abdul, Lopez de Cerain Salsamendi, Adela, Lasfar, Ahmed, Carnero, Amancio, Azqueta, Amaya, Amedei, Amedeo, Charles, Amelia K, Collins, Andrew R, Ward, Andrew, Salzberg, Anna C, Colacci, Annamaria, Olsen, Ann Karin, Berg, Arthur, Barclay, Barry J, Zhou, Binhua P, Blanco Aparicio, Carmen, Baglole, Carolyn J, Dong, Chenfang, Mondello, Chiara, Hsu, Chia Wen, Naus, Christian C, Yedjou, Clement, Curran, Colleen S, Laird, Dale W, Koch, Daniel C, Carlin, Danielle J, Felsher, Dean W, Roy, Debasish, Brown, Dustin G, Ratovitski, Edward, Ryan, Elizabeth P, Corsini, Emanuela, Rojas, Emilio, Moon, Eun Yi, Laconi, Ezio, Marongiu, Fabio, Al Mulla, Fahd, Chiaradonna, Ferdinando, Darroudi, Firouz, Martin, Francis L, Van Schooten, Frederik J, Goldberg, Gary S, Wagemaker, Gerard, Nangami, Gladys N, Calaf, Gloria M, Williams, Graeme, Wolf, Gregory T, Koppen, Gudrun, Brunborg, Gunnar, Lyerly, H. Kim, Krishnan, Harini, Ab Hamid, Hasiah, Yasaei, Hemad, Sone, Hideko, Kondoh, Hiroshi, Salem, Hosni K, Hsu, Hsue Yin, Park, Hyun Ho, Koturbash, Igor, Miousse, Isabelle R, Scovassi, A. Ivana, Klaunig, James E, Vondráček, Jan, Raju, Jayadev, Roman, Jesse, Wise, John Pierce, Whitfield, Jonathan R, Woodrick, Jordan, Christopher, Joseph A, Ochieng, Josiah, Martinez Leal, Juan Fernando, Weisz, Judith, Kravchenko, Julia, Sun, Jun, Prudhomme, Kalan R, Narayanan, Kannan Badri, Cohen Solal, Karine A, Moorwood, Kim, Gonzalez, Laetitia, Soucek, Laura, Jian, Le, D'Abronzo, Leandro S, Lin, Liang Tzung, Li, Lin, Gulliver, Linda, Mccawley, Lisa J, Memeo, Lorenzo, Vermeulen, Loui, Leyns, Luc, Zhang, Luoping, Valverde, Mahara, Khatami, Mahin, Romano, MARIA FIAMMETTA, Chapellier, Marion, Williams, Marc A, Wade, Mark, Manjili, Masoud H, Lleonart, Matilde E, Xia, Menghang, Gonzalez, Michael J, Karamouzis, Michalis V, Kirsch Volders, Micheline, Vaccari, Monica, Kuemmerle, Nancy B, Singh, Neetu, Cruickshanks, Nichola, Kleinstreuer, Nicole, van Larebeke, Nik, Ahmed, Nuzhat, Ogunkua, Olugbemiga, Krishnakumar, P. K, Vadgama, Pankaj, Marignani, Paola A, Ghosh, Paramita M, Ostrosky Wegman, Patricia, Thompson, Patricia A, Dent, Paul, Heneberg, Petr, Darbre, Philippa, Sing Leung, Po, Nangia Makker, Pratima, Cheng, Qiang Shawn, Robey, R. Brook, Al Temaimi, Rabeah, Roy, Rabindra, Andrade Vieira, Rafaela, Sinha, Ranjeet K, Mehta, Rekha, Vento, Renza, Di Fiore, Riccardo, Ponce Cusi, Richard, Dornetshuber Fleiss, Rita, Nahta, Rita, Castellino, Robert C, Palorini, Roberta, Abd Hamid, Roslida, Langie, Sabine A. S, Eltom, Sakina E, Brooks, Samira A, Ryeom, Sandra, Wise, Sandra S, Bay, Sarah N, Harris, Shelley A, Papagerakis, Silvana, Romano, Simona, Pavanello, Sofia, Eriksson, Staffan, Forte, Stefano, Casey, Stephanie C, Luanpitpong, Sudjit, Lee, Tae Jin, Otsuki, Takemi, Chen, Tao, Massfelder, Thierry, Sanderson, Thoma, Guarnieri, Tiziana, Hultman, Tove, Dormoy, Valérian, Odero Marah, Valerie, Sabbisetti, Venkata, Maguer Satta, Veronique, Rathmell, W. Kimryn, Engström, Wilhelm, Decker, William K, Bisson, William H, Rojanasakul, Yon, Luqmani, Yunu, Chen, Zhenbang, Hu, Zhiwei, Goodson, W., Lowe, L., Carpenter, D., Gilbertson, M., Ali, A., de Cerain Salsamendi, A., Lasfar, A., Carnero, A., Azqueta, A., Amedei, A., Charles, A., Collins, A., Ward, A., Salzberg, A., Colacci, A., Olsen, A., Berg, A., Barclay, B., Zhou, B., Blanco-Aparicio, C., Baglole, C., Dong, C., Mondello, C., Hsu, C., Naus, C., Yedjou, C., Curran, C., Laird, D., Koch, D., Carlin, D., Felsher, D., Roy, D., Brown, D., Ratovitski, E., Ryan, E., Corsini, E., Rojas, E., Moon, E., Laconi, E., Marongiu, F., Al-Mulla, F., Chiaradonna, F., Darroudi, F., Martin, F., Van Schooten, F., Goldberg, G., Wagemaker, G., Nangami, G., Calaf, G., Williams, G., Wolf, G., Koppen, G., Brunborg, G., Kim Lyerly, H., Krishnan, H., Hamid, H., Yasaei, H., Sone, H., Kondoh, H., Salem, H., Hsu, H., Park, H., Koturbash, I., Miousse, I., Ivana Scovassi, A., Klaunig, J., Vondráček, J., Raju, J., Roman, J., Wise, J., Whitfield, J., Woodrick, J., Christopher, J., Ochieng, J., Martinez-Leal, J., Weisz, J., Kravchenko, J., Sun, J., Prudhomme, K., Narayanan, K., Cohen-Solal, K., Moorwood, K., Gonzalez, L., Soucek, L., Jian, L., D'Abronzo, L., Lin, L., Li, L., Gulliver, L., Mccawley, L., Memeo, L., Vermeulen, L., Leyns, L., Zhang, L., Valverde, M., Khatami, M., Romano, M., Chapellier, M., Williams, M., Wade, M., Manjili, M., Lleonart, M., Xia, M., Gonzalez, M., Karamouzis, M., Kirsch-Volders, M., Vaccari, M., Kuemmerle, N., Singh, N., Cruickshanks, N., Kleinstreuer, N., Van Larebeke, N., Ahmed, N., Ogunkua, O., Krishnakumar, P., Vadgama, P., Marignani, P., Ghosh, P., Ostrosky-Wegman, P., Thompson, P., Dent, P., Heneberg, P., Darbre, P., Leung, P., Nangia-Makker, P., Cheng, Q., Brooks Robey, R., Al-Temaimi, R., Roy, R., Andrade-Vieira, R., Sinha, R., Mehta, R., Vento, R., Di Fiore, R., Ponce-Cusi, R., Dornetshuber-Fleiss, R., Nahta, R., Castellino, R., Palorini, R., Hamid, R., Langie, S., Eltom, S., Brooks, S., Ryeom, S., Wise, S., Bay, S., Harris, S., Papagerakis, S., Romano, S., Pavanello, S., Eriksson, S., Forte, S., Casey, S., Luanpitpong, S., Lee, T., Otsuki, T., Chen, T., Massfelder, T., Sanderson, T., Guarnieri, T., Hultman, T., Dormoy, V., Odero-Marah, V., Sabbisetti, V., Maguer-Satta, V., Kimryn Rathmell, W., Engström, W., Decker, W., Bisson, W., Rojanasakul, Y., Luqmani, Y., Chen, Z., Hu, Z., Goodson, W.H., Carpenter, D.O., Ali, A.M., de Cerain Salsamendi, A.L., Charles, A.K., Collins, A.R., Salzberg, A.C., Olsen, A.-K., Barclay, B.J., Zhou, B.P., Baglole, C.J., Hsu, C.-W., Naus, C.C., Curran, C.S., Laird, D.W., Koch, D.C., Carlin, D.J., Felsher, D.W., Brown, D.G., Ryan, E.P., Moon, E.-Y., Martin, F.L., Van Schooten, F.J., Goldberg, G.S., Calaf, G.M., Wolf, G.T., Hamid, H.A., Salem, H.K., Hsu, H.-Y., Park, H.H., Miousse, I.R., Klaunig, J.E., Vondracek, J., Wise, J.P., Whitfield, J.R., Christopher, J.A., Martinez-Leal, J.F., Prudhomme, K.R., Narayanan, K.B., Cohen-Solal, K.A., D'Abronzo, L.S., Lin, L.-T., Mccawley, L.J., Romano, M.F., Williams, M.A., Manjili, M.H., Gonzalez, M.J., Karamouzis, M.V., Kuemmerle, N.B., Krishnakumar, P.K., Marignani, P.A., Ghosh, P.M., Leung, P.S., Cheng, Q.S., Sinha, R.K., Castellino, R.C., Hamid, R.A., Langie, S.A.S., Brooks, S.A., Wise, S.S., Bay, S.N., Harris, S.A., Casey, S.C., Lee, T.-J., Engstrom, W., Decker, W.K., Bisson, W.H., sans affiliation, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), We gratefully acknowledge the support of the National Institute of Health-National Institute of Environmental Health Sciences (NIEHS) conference grant travel support (R13ES023276), Glenn Rice, Office of Research and Development, United States Environmental Protection Agency, Cincinnati, OH, USA also deserves thanks for his thoughtful feedback and inputs on the manuscript, William H.Goodson III was supported by the California Breast Cancer Research Program, Clarence Heller Foundation and California Pacific Medical Center Foundation, Abdul M.Ali would like to acknowledge the financial support of the University of Sultan Zainal Abidin, Malaysia, Ahmed Lasfar was supported by an award from the Rutgers Cancer Institute of New Jersey, Ann-Karin Olsen and Gunnar Brunborg were supported by the Research Council of Norway (RCN) through its Centres of Excellence funding scheme (223268/F50), Amancio Carnero’s lab was supported by grants from the Spanish Ministry of Economy and Competitivity, ISCIII (Fis: PI12/00137, RTICC: RD12/0036/0028) co-funded by FEDER from Regional Development European Funds (European Union), Consejeria de Ciencia e Innovacion (CTS-1848) and Consejeria de Salud of the Junta de Andalucia (PI-0306-2012), Matilde E. Lleonart was supported by a trienal project grant PI12/01104 and by project CP03/00101 for personal support. Amaya Azqueta would like to thank the Ministerio de Educacion y Ciencia (‘Juande la Cierva’ programme, 2009) of the Spanish Government for personal support, Amedeo Amedei was supported by the Italian Ministry of University and Research (2009FZZ4XM_002), and the University of Florence (ex60%2012), Andrew R.Collins was supported by the University of Oslo, Annamaria Colacci was supported by the Emilia-Romagna Region - Project ‘Supersite’ in Italy, Carolyn Baglole was supported by a salary award from the Fonds de recherche du Quebec-Sante (FRQ-S), Chiara Mondello’s laboratory is supported by Fondazione Cariplo in Milan, Italy (grant n. 2011-0370), Christian C.Naus holds a Canada Research Chair, Clement Yedjou was supported by a grant from the National Institutes of Health (NIH-NIMHD grant no. G12MD007581), Daniel C.Koch is supported by the Burroughs Wellcome Fund Postdoctoral Enrichment Award and the Tumor Biology Training grant: NIH T32CA09151, Dean W. Felsher would like to acknowledge the support of United States Department of Health and Human Services, NIH grants (R01 CA170378 PQ22, R01 CA184384, U54 CA149145, U54 CA151459, P50 CA114747 and R21 CA169964), Emilio Rojas would like to thank CONACyT support 152473, Ezio Laconi was supported by AIRC (Italian Association for Cancer Research, grant no. IG 14640) and by the Sardinian Regional Government (RAS), Eun-Yi Moon was supported by grants from the Public Problem-Solving Program (NRF-015M3C8A6A06014500) and Nuclear R&D Program (#2013M2B2A9A03051296 and 2010-0018545) through the National Research Foundation of Korea (NRF) and funded by the Ministry of Education, Science and Technology (MEST) in Korea, Fahd Al-Mulla was supported by the Kuwait Foundation for the Advancement of Sciences (2011-1302-06), Ferdinando Chiaradonna is supported by SysBioNet, a grant for the Italian Roadmap of European Strategy Forum on Research Infrastructures (ESFRI) and by AIRC (Associazione Italiana Ricerca sul Cancro, IG 15364), Francis L.Martin acknowledges funding from Rosemere Cancer Foundation, he also thanks Lancashire Teaching Hospitals NHS trust and the patients who have facilitated the studies he has undertaken over the course of the last 10 years, Gary S.Goldberg would like to acknowledge the support of the New Jersey Health Foundation, Gloria M.Calaf was supported by Fondo Nacional de Ciencia y Tecnología (FONDECYT), Ministerio de Educación de Chile (MINEDUC), Universidad de Tarapacá (UTA), Gudrun Koppen was supported by the Flemish Institute for Technological Research (VITO), Belgium, Hemad Yasaei was supported from a triennial project grant (Strategic Award) from the National Centre for the Replacement, Refinement and Reduction (NC3Rs) of animals in research (NC.K500045.1 and G0800697), Hiroshi Kondoh was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan Science and Technology Agency and by JST, CREST, Hsue-Yin Hsu was supported by the Ministry of Science and Technology of Taiwan (NSC93-2314-B-320-006 and NSC94-2314-B-320-002), Hyun Ho Park was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) of the Ministry of Education, Science and Technology (2012R1A2A2A01010870) and a grant from the Korea Healthcare Technology R&D project, Ministry of Health and Welfare, Republic of Korea (HI13C1449), Igor Koturbash is supported by the UAMS/NIH Clinical and Translational Science Award (UL1TR000039 and KL2TR000063) and the Arkansas Biosciences Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000, Jan Vondráček acknowledges funding from the Czech Science Foundation (13-07711S), Jesse Roman thanks the NIH for their support (CA116812), John Pierce Wise Sr. and Sandra S.Wise were supported by National Institute of Environmental Health Sciences (ES016893 to J.P.W.) and the Maine Center for Toxicology and Environmental Health, Jonathan Whitfield acknowledges support from the FERO Foundation in Barcelona, Spain, Joseph Christopher is funded by Cancer Research UK and the International Journal of Experimental Pathology, Julia Kravchenko is supported by a philanthropic donation by Fred and Alice Stanback, Jun Sun is supported by a Swim Across America Cancer Research Award, Karine A.Cohen-Solal is supported by a research scholar grant from the American Cancer Society (116683-RSG-09-087-01-TBE), Laetitia Gonzalez received a postdoctoral fellowship from the Fund for Scientific Research–Flanders (FWO-Vlaanderen) and support by an InterUniversity Attraction Pole grant (IAP-P7-07), Laura Soucek is supported by grant #CP10/00656 from the Miguel Servet Research Contract Program and acknowledges support from the FERO Foundation in Barcelona, Spain, Liang-Tzung Lin was supported by funding from the Taipei Medical University (TMU101-AE3-Y19), Linda Gulliver is supported by a Genesis Oncology Trust (NZ) Professional Development Grant, and the Faculty of Medicine, University of Otago, Dunedin, New Zealand, Louis Vermeulen is supported by a Fellowship of the Dutch Cancer Society (KWF, UVA2011-4969) and a grant from the AICR (14–1164), Mahara Valverde would like to thank CONACyT support 153781, Masoud H. Manjili was supported by the office of the Assistant Secretary of Defense for Health Affairs (USA) through the Breast Cancer Research Program under Award No. W81XWH-14-1-0087 Neetu Singh was supported by grant #SR/FT/LS-063/2008 from the Department of Science and Technology, Government of India, Nicole Kleinstreuer is supported by NIEHS contracts (N01-ES 35504 and HHSN27320140003C), P.K. Krishnakumar is supported by the Funding (No. T.K. 11-0629) of King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia, Paola A.Marignani is supported by the Dalhousie Medical Research Foundation, The Beatrice Hunter Cancer Institute and CIHR and the Nova Scotia Lung Association, Paul Dent is the holder of the Universal Inc.Chair in Signal Transduction Research and is supported with funds from PHS grants from the NIH (R01-CA141704, R01-CA150214, R01-DK52825 and R01-CA61774), Petr Heneberg was supported by the Charles University in Prague projects UNCE 204015 and PRVOUK P31/2012, and by the Czech Science Foundation projects P301/12/1686 and 15-03834Y, Po Sing Leung was supported by the Health and Medical Research Fund of Food and Health Bureau, Hong Kong Special Administrative Region, Ref. No: 10110021, Qiang Cheng was supported in part by grant NSF IIS-1218712, R. Brooks Robey is supported by the United States Department of Veterans Affairs, Rabindra Roy was supported by United States Public Health Service Grants (RO1 CA92306, RO1 CA92306-S1 and RO1 CA113447), Rafaela Andrade-Vieira is supported by the Beatrice Hunter Cancer Research Institute and the Nova Scotia Health Research Foundation, Renza Vento was partially funded by European Regional Development Fund, European Territorial Cooperation 2007–13 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–13) and grants from the Italian Ministry of Education, University and Research (MIUR) ex-60%, 2007, Riccardo Di Fiore was a recipient of fellowship granted by European Regional Development Fund, European Territorial Cooperation 2007–2013 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–2013), Rita Dornetshuber-Fleiss was supported by the Austrian Science Fund (FWF, project number T 451-B18) and the Johanna Mahlke, geb.-Obermann-Stiftung, Roberta Palorini is supported by a SysBioNet fellowship, Roslida Abd Hamid is supported by the Ministry of Education, Malaysia-Exploratory Research Grant Scheme-Project no: ERGS/1-2013/5527165, Sabine A.S.Langie is the beneficiary of a postdoctoral grant from the AXA Research Fund and the Cefic-LRI Innovative Science Award 2013, Sakina Eltom is supported by NIH grant SC1CA153326, Samira A.Brooks was supported by National Research Service Award (T32 ES007126) from the National Institute of Environmental Health Sciences and the HHMI Translational Medicine Fellowship, Sandra Ryeom was supported by The Garrett B. Smith Foundation and the TedDriven Foundation, Thierry Massfelder was supported by the Institut National de la Santé et de la Recherche Médicale INSERM and Université de Strasbourg, Thomas Sanderson is supported by the Canadian Institutes of Health Research (CIHR, MOP-115019), the Natural Sciences and Engineering Council of Canada (NSERC, 313313) and the California Breast Cancer Research Program (CBCRP, 17UB-8703), Tiziana Guarnieri is supported by a grant from Fundamental Oriented Research (RFO) to the Alma Mater Studiorum University of Bologna, Bologna, Italy and thanks the Fondazione Cassa di Risparmio di Bologna and the Fondazione Banca del Monte di Bologna e Ravenna for supporting the Center for Applied Biomedical Research, S.Orsola-Malpighi University Hospital, Bologna, Italy, W.Kimryn Rathmell is supported by the V Foundation for Cancer Research and the American Cancer Society, William K.Decker was supported in part by grant RP110545 from the Cancer Prevention Research Institute of Texas, William H.Bisson was supported with funding from the NIH P30 ES000210, Yon Rojanasakul was supported with NIH grant R01-ES022968, Zhenbang Chen is supported by NIH grants (MD004038, CA163069 and MD007593), Zhiwei Hu is grateful for the grant support from an institutional start-up fund from The Ohio State University College of Medicine and The OSU James Comprehensive Cancer Center (OSUCCC) and a Seed Award from the OSUCCC Translational Therapeutics Program., Sans affiliation, Courcelles, Michel, Goodson, W, Lowe, L, Carpenter, D, Gilbertson, M, Ali, A, de Cerain Salsamendi, A, Lasfar, A, Carnero, A, Azqueta, A, Amedei, A, Charles, A, Collins, A, Ward, A, Salzberg, A, Colacci, A, Olsen, A, Berg, A, Barclay, B, Zhou, B, Blanco Aparicio, C, Baglole, C, Dong, C, Mondello, C, Hsu, C, Naus, C, Yedjou, C, Curran, C, Laird, D, Koch, D, Carlin, D, Felsher, D, Roy, D, Brown, D, Ratovitski, E, Ryan, E, Corsini, E, Rojas, E, Moon, E, Laconi, E, Marongiu, F, Al Mulla, F, Chiaradonna, F, Darroudi, F, Martin, F, Van Schooten, F, Goldberg, G, Wagemaker, G, Nangami, G, Calaf, G, Williams, G, Wolf, G, Koppen, G, Brunborg, G, Kim Lyerly, H, Krishnan, H, Hamid, H, Yasaei, H, Sone, H, Kondoh, H, Salem, H, Hsu, H, Park, H, Koturbash, I, Miousse, I, Ivana Scovassi, A, Klaunig, J, Vondráček, J, Raju, J, Roman, J, Wise, J, Whitfield, J, Woodrick, J, Christopher, J, Ochieng, J, Martinez Leal, J, Weisz, J, Kravchenko, J, Sun, J, Prudhomme, K, Narayanan, K, Cohen Solal, K, Moorwood, K, Gonzalez, L, Soucek, L, Jian, L, D'Abronzo, L, Lin, L, Li, L, Gulliver, L, Mccawley, L, Memeo, L, Vermeulen, L, Leyns, L, Zhang, L, Valverde, M, Khatami, M, Romano, M, Chapellier, M, Williams, M, Wade, M, Manjili, M, Lleonart, M, Xia, M, Gonzalez, M, Karamouzis, M, Kirsch Volders, M, Vaccari, M, Kuemmerle, N, Singh, N, Cruickshanks, N, Kleinstreuer, N, Van Larebeke, N, Ahmed, N, Ogunkua, O, Krishnakumar, P, Vadgama, P, Marignani, P, Ghosh, P, Ostrosky Wegman, P, Thompson, P, Dent, P, Heneberg, P, Darbre, P, Leung, P, Nangia Makker, P, Cheng, Q, Brooks Robey, R, Al Temaimi, R, Roy, R, Andrade Vieira, R, Sinha, R, Mehta, R, Vento, R, Di Fiore, R, Ponce Cusi, R, Dornetshuber Fleiss, R, Nahta, R, Castellino, R, Palorini, R, Hamid, R, Langie, S, Eltom, S, Brooks, S, Ryeom, S, Wise, S, Bay, S, Harris, S, Papagerakis, S, Romano, S, Pavanello, S, Eriksson, S, Forte, S, Casey, S, Luanpitpong, S, Lee, T, Otsuki, T, Chen, T, Massfelder, T, Sanderson, T, Guarnieri, T, Hultman, T, Dormoy, V, Odero Marah, V, Sabbisetti, V, Maguer Satta, V, Kimryn Rathmell, W, Engström, W, Decker, W, Bisson, W, Rojanasakul, Y, Luqmani, Y, Chen, Z, and Hu, Z
Subjects: Cancer Research, Carcinogenesis, [SDV]Life Sciences [q-bio], METHOXYCHLOR-INDUCED ALTERATIONS, Review, Pharmacology, MESH: Carcinogens, Environmental, Carcinogenic synergies, Chemical mixtures, Neoplasms, MESH: Animals, MESH: Neoplasms, Carcinogenesi, Risk assessment, Cancer, ACTIVATED PROTEIN-KINASES, Medicine (all), Low dose, 1. No poverty, Cumulative effects, BREAST-CANCER CELLS, General Medicine, Environmental exposure, MESH: Carcinogenesis, BIO/10 - BIOCHIMICA, EPITHELIAL-MESENCHYMAL TRANSITION, 3. Good health, [SDV] Life Sciences [q-bio], Environmental Carcinogenesis, ESTROGEN-RECEPTOR-ALPHA, Human, MESH: Environmental Exposure, ENDOCRINE-DISRUPTING CHEMICALS, TARGETING TISSUE FACTOR, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Prototypical chemical disruptors, Exposure, [SDV.CAN] Life Sciences [q-bio]/Cancer, Environmental health, medicine, [SDV.EE.SANT] Life Sciences [q-bio]/Ecology, environment/Health, Carcinogen, Environmental carcinogenesis, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, MESH: Humans, Animal, POLYBROMINATED DIPHENYL ETHERS, Environmental Exposure, medicine.disease, MESH: Hazardous Substances, Carcinogens, Environmental, MIGRATION INHIBITORY FACTOR, VASCULAR ENDOTHELIAL-CELLS, Hazardous Substance, Neoplasm
Abstract: Goodson, William H. et al., © The Author 2015. Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology., We gratefully acknowledge the support of the National Institute of Health-National Institute of Environmental Health Sciences (NIEHS) conference grant travel support (R13ES023276); Glenn Rice, Office of Research and Development, United States Environmental Protection Agency, Cincinnati, OH, USA also deserves thanks for his thoughtful feedback and inputs on the manuscript; William H.Goodson III was supported by the California Breast Cancer Research Program, Clarence Heller Foundation and California Pacific Medical Center Foundation; Abdul M.Ali would like to acknowledge the financial support of the University of Sultan Zainal Abidin, Malaysia; Ahmed Lasfar was supported by an award from the Rutgers Cancer Institute of New Jersey; Ann-Karin Olsen and Gunnar Brunborg were supported by the Research Council of Norway (RCN) through its Centres of Excellence funding scheme (223268/F50), Amancio Carnero’s lab was supported by grants from the Spanish Ministry of Economy and Competitivity, ISCIII (Fis: PI12/00137, RTICC: RD12/0036/0028) co-funded by FEDER from Regional Development European Funds (European Union), Consejeria de Ciencia e Innovacion (CTS-1848) and Consejeria de Salud of the Junta de Andalucia (PI-0306-2012); Matilde E. Lleonart was supported by a trienal project grant PI12/01104 and by project CP03/00101 for personal support. Amaya Azqueta would like to thank the Ministerio de Educacion y Ciencia (‘Juande la Cierva’ programme, 2009) of the Spanish Government for personal support; Amedeo Amedei was supported by the Italian Ministry of University and Research (2009FZZ4XM_002), and the University of Florence (ex60%2012); Andrew R.Collins was supported by the University of Oslo; Annamaria Colacci was supported by the Emilia-Romagna Region - Project ‘Supersite’ in Italy; Carolyn Baglole was supported by a salary award from the Fonds de recherche du Quebec-Sante (FRQ-S); Chiara Mondello’s laboratory is supported by Fondazione Cariplo in Milan, Italy (grant n. 2011-0370); Christian C.Naus holds a Canada Research Chair; Clement Yedjou was supported by a grant from the National Institutes of Health (NIH-NIMHD grant no. G12MD007581); Daniel C.Koch is supported by the Burroughs Wellcome Fund Postdoctoral Enrichment Award and the Tumor Biology Training grant: NIH T32CA09151; Dean W. Felsher would like to acknowledge the support of United States Department of Health and Human Services, NIH grants (R01 CA170378 PQ22, R01 CA184384, U54 CA149145, U54 CA151459, P50 CA114747 and R21 CA169964); Emilio Rojas would like to thank CONACyT support 152473, Ezio Laconi was supported by AIRC (Italian Association for Cancer Research, grant no. IG 14640) and by the Sardinian Regional Government (RAS); Eun-Yi Moon was supported by grants from the Public Problem-Solving Program (NRF-015M3C8A6A06014500) and Nuclear R&D Program (#2013M2B2A9A03051296 and 2010-0018545) through the National Research Foundation of Korea (NRF) and funded by the Ministry of Education, Science and Technology (MEST) in Korea; Fahd Al-Mulla was supported by the Kuwait Foundation for the Advancement of Sciences (2011-1302-06); Ferdinando Chiaradonna is supported by SysBioNet, a grant for the Italian Roadmap of European Strategy Forum on Research Infrastructures (ESFRI) and by AIRC (Associazione Italiana Ricerca sul Cancro; IG 15364); Francis L.Martin acknowledges funding from Rosemere Cancer Foundation; he also thanks Lancashire Teaching Hospitals NHS trust and the patients who have facilitated the studies he has undertaken over the course of the last 10 years; Gary S.Goldberg would like to acknowledge the support of the New Jersey Health Foundation; Gloria M.Calaf was supported by Fondo Nacional de Ciencia y Tecnología (FONDECYT), Ministerio de Educación de Chile (MINEDUC), Universidad de Tarapacá (UTA); Gudrun Koppen was supported by the Flemish Institute for Technological Research (VITO), Belgium; Hemad Yasaei was supported from a triennial project grant (Strategic Award) from the National Centre for the Replacement, Refinement and Reduction (NC3Rs) of animals in research (NC.K500045.1 and G0800697); Hiroshi Kondoh was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan Science and Technology Agency and by JST, CREST; Hsue-Yin Hsu was supported by the Ministry of Science and Technology of Taiwan (NSC93-2314-B-320-006 and NSC94-2314-B-320-002); Hyun Ho Park was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) of the Ministry of Education, Science and Technology (2012R1A2A2A01010870) and a grant from the Korea Healthcare Technology R&D project, Ministry of Health and Welfare, Republic of Korea (HI13C1449); Igor Koturbash is supported by the UAMS/NIH Clinical and Translational Science Award (UL1TR000039 and KL2TR000063) and the Arkansas Biosciences Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000; Jan Vondráček acknowledges funding from the Czech Science Foundation (13-07711S); Jesse Roman thanks the NIH for their support (CA116812), John Pierce Wise Sr. and Sandra S.Wise were supported by National Institute of Environmental Health Sciences (ES016893 to J.P.W.) and the Maine Center for Toxicology and Environmental Health; Jonathan Whitfield acknowledges support from the FERO Foundation in Barcelona, Spain; Joseph Christopher is funded by Cancer Research UK and the International Journal of Experimental Pathology; Julia Kravchenko is supported by a philanthropic donation by Fred and Alice Stanback; Jun Sun is supported by a Swim Across America Cancer Research Award; Karine A.Cohen-Solal is supported by a research scholar grant from the American Cancer Society (116683-RSG-09-087-01-TBE); Laetitia Gonzalez received a postdoctoral fellowship from the Fund for Scientific Research–Flanders (FWO-Vlaanderen) and support by an InterUniversity Attraction Pole grant (IAP-P7-07); Laura Soucek is supported by grant #CP10/00656 from the Miguel Servet Research Contract Program and acknowledges support from the FERO Foundation in Barcelona, Spain; Liang-Tzung Lin was supported by funding from the Taipei Medical University (TMU101-AE3-Y19); Linda Gulliver is supported by a Genesis Oncology Trust (NZ) Professional Development Grant, and the Faculty of Medicine, University of Otago, Dunedin, New Zealand; Louis Vermeulen is supported by a Fellowship of the Dutch Cancer Society (KWF, UVA2011-4969) and a grant from the AICR (14–1164); Mahara Valverde would like to thank CONACyT support 153781; Masoud H. Manjili was supported by the office of the Assistant Secretary of Defense for Health Affairs (USA) through the Breast Cancer Research Program under Award No. W81XWH-14-1-0087 Neetu Singh was supported by grant #SR/FT/LS-063/2008 from the Department of Science and Technology, Government of India; Nicole Kleinstreuer is supported by NIEHS contracts (N01-ES 35504 and HHSN27320140003C); P.K. Krishnakumar is supported by the Funding (No. T.K. 11-0629) of King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia; Paola A.Marignani is supported by the Dalhousie Medical Research Foundation, The Beatrice Hunter Cancer Institute and CIHR and the Nova Scotia Lung Association; Paul Dent is the holder of the Universal Inc.Chair in Signal Transduction Research and is supported with funds from PHS grants from the NIH (R01-CA141704, R01-CA150214, R01-DK52825 and R01-CA61774); Petr Heneberg was supported by the Charles University in Prague projects UNCE 204015 and PRVOUK P31/2012, and by the Czech Science Foundation projects P301/12/1686 and 15-03834Y; Po Sing Leung was supported by the Health and Medical Research Fund of Food and Health Bureau, Hong Kong Special Administrative Region, Ref. No: 10110021; Qiang Cheng was supported in part by grant NSF IIS-1218712; R. Brooks Robey is supported by the United States Department of Veterans Affairs; Rabindra Roy was supported by United States Public Health Service Grants (RO1 CA92306, RO1 CA92306-S1 and RO1 CA113447); Rafaela Andrade-Vieira is supported by the Beatrice Hunter Cancer Research Institute and the Nova Scotia Health Research Foundation, Renza Vento was partially funded by European Regional Development Fund, European Territorial Cooperation 2007–13 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–13) and grants from the Italian Ministry of Education, University and Research (MIUR) ex-60%, 2007; Riccardo Di Fiore was a recipient of fellowship granted by European Regional Development Fund, European Territorial Cooperation 2007–2013 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–2013); Rita Dornetshuber-Fleiss was supported by the Austrian Science Fund (FWF, project number T 451-B18) and the Johanna Mahlke, geb.-Obermann-Stiftung; Roberta Palorini is supported by a SysBioNet fellowship; Roslida Abd Hamid is supported by the Ministry of Education, Malaysia-Exploratory Research Grant Scheme-Project no: ERGS/1-2013/5527165; Sabine A.S.Langie is the beneficiary of a postdoctoral grant from the AXA Research Fund and the Cefic-LRI Innovative Science Award 2013; Sakina Eltom is supported by NIH grant SC1CA153326; Samira A.Brooks was supported by National Research Service Award (T32 ES007126) from the National Institute of Environmental Health Sciences and the HHMI Translational Medicine Fellowship; Sandra Ryeom was supported by The Garrett B. Smith Foundation and the TedDriven Foundation; Thierry Massfelder was supported by the Institut National de la Santé et de la Recherche Médicale INSERM and Université de Strasbourg; Thomas Sanderson is supported by the Canadian Institutes of Health Research (CIHR; MOP-115019), the Natural Sciences and Engineering Council of Canada (NSERC; 313313) and the California Breast Cancer Research Program (CBCRP; 17UB-8703); Tiziana Guarnieri is supported by a grant from Fundamental Oriented Research (RFO) to the Alma Mater Studiorum University of Bologna, Bologna, Italy and thanks the Fondazione Cassa di Risparmio di Bologna and the Fondazione Banca del Monte di Bologna e Ravenna for supporting the Center for Applied Biomedical Research, S.Orsola-Malpighi University Hospital, Bologna, Italy; W.Kimryn Rathmell is supported by the V Foundation for Cancer Research and the American Cancer Society; William K.Decker was supported in part by grant RP110545 from the Cancer Prevention Research Institute of Texas; William H.Bisson was supported with funding from the NIH P30 ES000210; Yon Rojanasakul was supported with NIH grant R01-ES022968; Zhenbang Chen is supported by NIH grants (MD004038, CA163069 and MD007593); Zhiwei Hu is grateful for the grant support from an institutional start-up fund from The Ohio State University College of Medicine and The OSU James Comprehensive Cancer Center (OSUCCC) and a Seed Award from the OSUCCC Translational Therapeutics Program.
Published: 2015
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21. Seasonal changes in eicosanoid metabolism in the brown bear

Author: Stéphane Blanc, Georg Tascher, Isabelle Chery, Sylvain Giroud, Guillemette Gauquelin-Koch, Jon E. Swenson, Jon M. Arnemo, Etienne Lefai, Chantal Simon, Justine Bertrand-Michel, Fabrice Bertile, Alina L. Evans, Department of Integrative Biology and Evolution, Research Institute of Wildlife Ecology, University of Veterinary Medicine Vienna, Department of Forestry and Wildlife Management, Hedmark University College, Département Ecologie, Physiologie et Ethologie (DEPE-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Plateau de lipidomique, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Claude de Preval, Centre National d'Études Spatiales [Toulouse] (CNES), Norwegian Institute for Nature Research (NINA), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-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), 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), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Plateau MetaToul-LIPIDOMIQUE = MetaToul-Lipidomics, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), 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)-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)-MetaToul-MetaboHUB, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Norwegian Environmental Agency, Swedish Environmental Protection Agency, Polish-Norwegian Research Program POL-NOR/198352/85/2013, Austrian Science Fund (FWF) P27267-B25, 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 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), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT)
Subjects: 0301 basic medicine, Hibernation, medicine.medical_specialty, Thromboxane, Zoology and botany: 480 [VDP], VDP::Zoologiske og botaniske fag: 480, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Animals, Ursus, Fatty acids, Muscle, Skeletal, Zoologiske og botaniske fag: 480 [VDP], Ecology, Evolution, Behavior and Systematics, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, Leukotriene, Original Paper, biology, Eicosanoid metabolism, Chemistry, Skeletal muscle, General Medicine, biology.organism_classification, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Metabolism, Eicosanoid, [SDE]Environmental Sciences, cardiovascular system, Prostaglandins, Eicosanoids, VDP::Zoology and botany: 480, lipids (amino acids, peptides, and proteins), Seasons, 030217 neurology & neurosurgery, Ursidae, Polyunsaturated fatty acid
Abstract: International audience; Polyunsaturated fatty acids (PUFAs) exert several important functions across organ systems. During winter, hibernators divert PUFAs from oxidation, retaining them in their tissues and membranes, to ensure proper body functions at low body temperature. PUFAs are also precursors of eicosanoids with pro- and anti-inflammatory properties. This study investigated seasonal changes in eicosanoid metabolism of free-ranging brown bears (Ursus arctos). By using a lipidomic approach, we assessed (1) levels of specific omega-3 and omega-6 fatty acids involved in the eicosanoid cascade and (2) concentrations of eicosanoids in skeletal muscle and blood plasma of winter hibernating and summer active bears. We observed significant seasonal changes in the specific omega-3 and omega-6 precursors. We also found significant seasonal alterations of eicosanoid levels in both tissues. Concentrations of pro-inflammatory eicosanoids, such as thromboxane B2, 5-hydroxyeicosatetraenoic acid (HETE), and 15-HETE and 18-HETE, were significantly lower in muscle and/or plasma of hibernating bears compared to summer-active animals. Further, plasma and muscle levels of 5,6-epoxyeicosatrienoic acid (EET), as well as muscle concentration of 8,9-EET, tended to be lower in bears during winter hibernation vs. summer. We also found lower plasma levels of anti-inflammatory eicosanoids, such as 15dPGJ(2) and PGE(3), in bears during winter hibernation. Despite of the limited changes in omega-3 and omega-6 precursors, plasma and muscle concentrations of the products of all pathways decreased significantly, or remained unchanged, independent of their pro- or anti-inflammatory properties. These findings suggest that hibernation in bears is associated with a depressed state of the eicosanoid cascade.
Published: 2018
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22. Studies of Pseudomonas aeruginosa Mutants Indicate Pyoverdine as the Central Factor in Inhibition of Aspergillus fumigatus Biofilm

Author: Hemi Shah, Gabriele Sass, Ansari, Eric Déziel, David A. Stevens, Hubertus Haas, Hasan Nazik, Paolo Visca, Anna-Maria Dietl, John C. Penner, Marie-Christine Groleau, Karl V. Clemons, California Institute for Medical Research (CIMR), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Istanbul University, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Innsbruck Medical University [Austria] (IMU), Roma Tre University, These studies were partially supported by a gift from John Flatley (CIMR no. 3770) and by a grant from the Child Health Research Institute, Stanford Transdisciplinary Initiatives Program (CIMR no. 3777). This work was partially supported by the Austrian Science Fund/Infect-ERA program (FWF grant I1616/Infect-ERA project AspMetNet to H.H.). A.-M.D. is an associate student of the HOROS doctoral program (W1253)., Sass, G, Nazik, H, Penner, J, Shah, H, Ansari, Sr, Clemons, Kv, Groleau, Mc, Dietl, Am, Visca, P, Haas, H, Déziel, E, and Stevens, Da
Subjects: 0301 basic medicine, Siderophore, Cystic Fibrosis, [SDV]Life Sciences [q-bio], MESH: Virulence, medicine.disease_cause, biofilm, Aspergillus fumigatus, chemistry.chemical_compound, iron, Peptide Synthases, Pathogen, MESH: Bacterial Proteins, mutants, MESH: Iron, Pyoverdine, Virulence, biology, pyoverdine, MESH: Peptide Synthases, 3. Good health, Pseudomonas aeruginosa, MESH: Pseudomonas aeruginosa, MESH: Oligopeptides, MESH: Aspergillus fumigatus, Oligopeptides, Research Article, MESH: Mutation, MESH: Cystic Fibrosis, MESH: Trans-Activators, 030106 microbiology, MESH: Biofilms, Microbiology, 03 medical and health sciences, Bacterial Proteins, Antibiosis, medicine, intermicrobial interaction, Humans, mutant, Molecular Biology, MESH: Antibiosis, MESH: Humans, Biofilm, biology.organism_classification, 030104 developmental biology, chemistry, Mutation, Trans-Activators, Aspergillus fumigatu, biofilms, Bacteria
Abstract: Pseudomonas aeruginosa and Aspergillus fumigatus are common opportunistic bacterial and fungal pathogens, respectively. They often coexist in airways of immunocompromised patients and individuals with cystic fibrosis, where they form biofilms and cause acute and chronic illnesses. Hence, the interactions between them have long been of interest and it is known that P. aeruginosa can inhibit A. fumigatus in vitro . We have approached the definition of the inhibitory P. aeruginosa molecules by studying 24 P. aeruginosa mutants with various virulence genes deleted for the ability to inhibit A. fumigatus biofilms. The ability of P. aeruginosa cells or their extracellular products produced during planktonic or biofilm growth to affect A. fumigatus biofilm metabolism or planktonic A. fumigatus growth was studied in agar and liquid assays using conidia or hyphae. Four mutants, the pvdD pchE , pvdD , lasR rhlR , and lasR mutants, were shown to be defective in various assays. This suggested the P. aeruginosa siderophore pyoverdine as the key inhibitory molecule, although additional quorum sensing-regulated factors likely contribute to the deficiency of the latter two mutants. Studies of pure pyoverdine substantiated these conclusions and included the restoration of inhibition by the pyoverdine deletion mutants. A correlation between the concentration of pyoverdine produced and antifungal activity was also observed in clinical P. aeruginosa isolates derived from lungs of cystic fibrosis patients. The key inhibitory mechanism of pyoverdine was chelation of iron and denial of iron to A. fumigatus . IMPORTANCE Interactions between human pathogens found in the same body locale are of vast interest. These interactions could result in exacerbation or amelioration of diseases. The bacterium Pseudomonas aeruginosa affects the growth of the fungus Aspergillus fumigatus . Both pathogens form biofilms that are resistant to therapeutic drugs and host immunity. P. aeruginosa and A. fumigatus biofilms are found in vivo , e.g., in the lungs of cystic fibrosis patients. Studying 24 P. aeruginosa mutants, we identified pyoverdine as the major anti- A. fumigatus compound produced by P. aeruginosa . Pyoverdine captures iron from the environment, thus depriving A. fumigatus of a nutrient essential for its growth and metabolism. We show how microbes of different kingdoms compete for essential resources. Iron deprivation could be a therapeutic approach to the control of pathogen growth.
Published: 2018
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23. The microbiota: an underestimated actor in radiation-induced lesions?

Author: Harry Sokol, Timon E. Adolph, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Paris Saclay (COmUE), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), Innsbruck Medical University, Partenaires INRAE, Equipe ATIP-Avenir, Austrian Science Fund (FWF) [P 29379-B28], and Tyrolian Science Fund (TWF) [0404/1812]
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Context (language use), Inflammation, Disease, Biology, Enteritis, Microbiology, 03 medical and health sciences, medicine, Radiation Enteritis, Humans, ComputingMilieux_MISCELLANEOUS, Microbiota, Gastroenterology, medicine.disease, 3. Good health, Intestines, Colonisation, 030104 developmental biology, Immunology, medicine.symptom, Intestinal Disorder, Dysbiosis
Abstract: The co-evolution of humans and microbes that colonise the GI tract is shaped by environmental factors and evolved to promote health.1 Microbial derangements (termed dysbiosis) have been observed for a variety of intestinal and extraintestinal diseases.1 Metabolic, autoimmune, liver and intestinal disorders have been linked to microbial dysbiosis which promotes susceptibility to inflammatory disease in some cases as largely assessed in animal models.2 Intestinal dysbiosis has also been implicated in colorectal cancer3 and microbes may determine treatment response for non-intestinal malignancies.4 For more than 10 years, intestinal microbial alterations have been associated with localised radiation in humans and mouse models.5–8 Importantly, mice that lack colonisation of microbes (ie, raised germ free) were resistant to lethal radiation enteritis, indicating that the microbiota controls intestinal disease processes consequent to radiation-induced damage.9 In this context, however, the …
Published: 2018
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24. The bright and the dark side of human antibody responses to flaviviruses: lessons for vaccine design

Author: Franz X. Heinz, Karin Stiasny, Marie-Christine Vaney, Félix A. Rey, Mariano Dellarole, Virologie Structurale - Structural Virology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institute of Virology (Vienna), Medizinische Universität Wien = Medical University of Vienna, FAR, MCV, and MD acknowledge support from the French ANR (grant ANR‐13‐ISV8‐0002‐01), Institut Pasteur, CNRS, and the LABEX IBEID. FXH and KS acknowledge support from the Austrian Science Fund FWF., ANR-13-ISV8-0002,flavistem,La protéine E des flavivirus : interactions et fusion membranaire(2013), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, flavivirus structure, viruses, Review, Biology, Antibodies, Viral, Biochemistry, Dengue fever, Flavivirus Infections, 03 medical and health sciences, Epitopes, Structural Biology, antibody neutralization, Genetics, medicine, Animals, Humans, Antibody-dependent enhancement, antibody-dependent enhancement, Original antigenic sin, Molecular Biology, Antigens, Viral, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Viral Vaccine, Flavivirus, Viral Vaccines, fla- vivirus structure, medicine.disease, biology.organism_classification, Virology, Antibodies, Neutralizing, Microbiology, Virology & Host Pathogen Interaction, 3. Good health, Vaccination, particle heterogeneity, 030104 developmental biology, Immunization, Antibody Formation, antibody‐dependent enhancement, vaccine design, Synthetic Biology & Biotechnology
Abstract: International audience; Zika and dengue viruses belong to the Flavivirus genus, a close group of antigenically related viruses that cause significant arthro-pod-transmitted diseases throughout the globe. Although infection by a given flavivirus is thought to confer lifelong protection, some of the patient's antibodies cross-react with other flaviviruses without cross-neutralizing. The original antigenic sin phenomenon may amplify such antibodies upon subsequent heterologous flavivirus infection, potentially aggravating disease by antibody-dependent enhancement (ADE). The most striking example is provided by the four different dengue viruses, where infection by one serotype appears to predispose to more severe disease upon infection by a second one. A similar effect was postulated for sequential infections with Zika and dengue viruses. In this review, we analyze the molecular determinants of the dual antibody response to flavivirus infection or vaccination in humans. We highlight the role of conserved partially cryptic epitopes giving rise to cross-reacting and poorly neutralizing, ADE-prone antibodies. We end by proposing a strategy for developing an epitope-focused vaccine approach to avoid eliciting undesirable antibodies while focusing the immune system on producing protective antibodies only.
Published: 2017
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25. Ibuprofen and ketoprofen potentiate UVA-induced cell death by a photosensitization process

Author: Bignon, Emmanuelle, Marazzi, Marco, Besancenot, Vanessa, Gattuso, Hugo, Drouot, Guillaume, Morell, Christophe, Eriksson, Leif A., Grandemange, Stephanie, Dumont, Elise, Monari, Antonio, 0000-0001-7158-7994, 0000-0001-5654-3109, 0000-0001-9464-1463, Laboratoire de Chimie - UMR5182 (LC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Institut de Chimie du CNRS (INC), Chemometrics and Theoretical Chemistry - Chimiométrie et chimie théorique, Institut des Sciences Analytiques (ISA), Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Centre de Recherche en Automatique de Nancy (CRAN), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Dept Chem & Mol Biol, University of Gothenburg (GU), This research was supported by the COST action 'MOLIM: Molecules in Motion'. M.M. is thankful to the French and Austrian National Research Agencies (ANR and FWF, respectively) for a grant under the 'DeNeTheor' project. Support from the COST 'Action Biomimetic Radical Chemistry' in the form of a STSM is also acknowledged. L.A.E. gratefully acknowledges financial support from the Faculty of Science at University of Gothenburg, and the Swedish Research Council (VR). We acknowledge grants of computing time at the C3SE supercomputing center, via the Swedish National Infrastructure for Computing (SNIC)., ANR-15-CE29-0027,DeNeTheor,Etats Excités et Dynamique de Complexes de Re(I) Fonctionnalisés en Interaction avec des Métalloprotéines: Nouvelles Méthodes Théoriques pour la Simulation et le Contrôle des Propriétés à l'Etat Excité dans un Environnement Biologique(2015), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Chemometrics and theoretical chemistry. - Chimiométrie et chimie théorique, Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL)
Subjects: Models, Molecular, Photosensitizing Agents, Cell Death, Molecular Structure, Cell Survival, Ultraviolet Rays, Science, Apoptosis, Drug Synergism, Ibuprofen, Article, Structure-Activity Relationship, Ketoprofen, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Cell Line, Tumor, Humans, Medicine
Abstract: International audience; Nonsteroidal 2-arylproprionic acids are widely used, over-the-counter, anti-inflammatory drugs. Photosensitivity is a commonly overlooked adverse effect of these drugs. Based on the combined use of cell viability assays and molecular modeling, we prove and rationalize the photochemical pathways triggering photosensitization for two drugs, ibuprofen and ketoprofen. As its parent compound benzophenone, ketoprofen produces singlet oxygen, upon triplet manifold population. However, ibuprofen and ketoprofen photodissociate and hence may generate two highly reactive radicals. The formation of metastable aggregates between the two drugs and B-DNA is also directly probed by molecular dynamics. Our approach characterizes the coupled influence of the drug's intrinsic photochemistry and the interaction pattern with DNA. The photosensitization activity of nonsteroidal 2-arylproprionic acids, being added to gels and creams for topical use, should be crucially analyzed and rationalized to enact the proper preventive measures.
Published: 2017
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26. Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts

Author: Heinrich Kovar, Jozef Ban, Norbert Kraut, Jan-Michael Peters, Mark Pearson, Francisco X. Real, Petra van der Lelij, Simone Lieb, Thomas Hoffmann, Julian Jude, Johannes Zuber, Todd Waldman, Mark Petronczki, Gordana Wutz, Katrina J. Falkenberg, Andreas Schlattl, Raphaela Schwentner, Catarina P. Santos, FWF Austrian Science Fund, Austrian Research Promotion Agency, European Research Council, Asociación Española Contra el Cáncer, and National Institutes of Health (Estados Unidos)
Subjects: 0301 basic medicine, Synthetic lethality, Cell division, 0302 clinical medicine, Biology (General), Mitotic catastrophe, health care economics and organizations, Cohesin, 0303 health sciences, Genetic interaction, General Neuroscience, Nuclear Proteins, Antigens, Nuclear, General Medicine, Cell biology, 3. Good health, Establishment of sister chromatid cohesion, 030220 oncology & carcinogenesis, Medicine, Human, Cohesin complex, QH301-705.5, Cell Survival, Science, Cancer biology, Mitosis, Biology, Chromosomes, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Cell Line, Tumor, medicine, Humans, 030304 developmental biology, General Immunology and Microbiology, Cancer, Suicide gene, medicine.disease, 030104 developmental biology, Cancer cell, Cancer research, Synthetic Lethal Mutations
Abstract: Recent genome analyses have identified recurrent mutations in the cohesin complex in a wide range of human cancers. Here we demonstrate that the most frequently mutated subunit of the cohesin complex, STAG2, displays a strong synthetic lethal interaction with its paralog STAG1. Mechanistically, STAG1 loss abrogates sister chromatid cohesion in STAG2 mutated but not in wild-type cells leading to mitotic catastrophe, defective cell division and apoptosis. STAG1 inactivation inhibits the proliferation of STAG2 mutated but not wild-type bladder cancer and Ewing sarcoma cell lines. Restoration of STAG2 expression in a mutated bladder cancer model alleviates the dependency on STAG1. Thus, STAG1 and STAG2 support sister chromatid cohesion to redundantly ensure cell survival. STAG1 represents a vulnerability of cancer cells carrying mutations in the major emerging tumor suppressor STAG2 across different cancer contexts. Exploiting synthetic lethal interactions to target recurrent cohesin mutations in cancer, e.g. by inhibiting STAG1, holds the promise for the development of selective therapeutics. We would like to thank Monika Kriz and Renate Schnitzer for clonal analysis. The IMP is supported by Boehringer Ingelheim. Research in the laboratory of J-MP is funded by the Austrian Science Fund (SFB-F34 and Wittgenstein award Z196-B20) and the Austrian Research Promotion Agency (Head- quarter grants FFG-834223 and FFG-852936, Laura Bassi Centre for Optimized Structural Studies grant FFG-840283). Research in the laboratory of JZ was funded by a Starting Grant of the European Research Council (ERC no. 336860) and SFB grant F4710 of the Austrian Science Fund (FWF). Research on Ewing sarcoma in the laboratory of HK was funded by the Austrian Science Fund ERA- Net grant I 1225-B19. Work in the lab of FXR was funded by a grant from Fundacio´ n Cientı´fica de la Asociacio´ n Espan˜ ola Contra el Ca´ ncer, Madrid, Spain. Research in the laboratory of TW is supported by National Institute of Health grant R01CA169345 and an Innovation Grant from Alex’s Lemonade Stand Sí
Published: 2017
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27. Pathways of immediate hypothermia and leukocyte infiltration in an adjuvant-free mouse model of anaphylaxis

Author: Philipp Starkl, Riccardo Sibilano, Laurent L. Reber, Hajime Karasuyama, Bianca Balbino, Stephen J. Galli, Pierre Bruhns, Thomas Marichal, Mindy Tsai, Nicolas Gaudenzio, Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Stanford University School of Medicine [Stanford], Stanford University [Stanford], Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine [CA, USA], Department of Immune Regulation [Tokyo, Japan], Graduate School of Medical and Dental Sciences [Tokyo, Japan]-Tokyo Medical and Dental University [Japan] (TMDU), B.B. was supported by a stipend from the Pasteur–Paris University (PPU) International PhD Program. R.S. was supported by the Lucile Packard Foundation for Children's Health and the Stanford National Institutes of Health (NIH)/NCRR CTSA award number UL1 RR025744. P.S. was supported by a Max Kade Fellowship of the Max Kade Foundation and the Austrian Academy of Sciences and a Schroedinger Fellowship of the Austrian Science Fund (FWF, J3399-B21) and is supported by a European Commission Marie Skłodowska-Curie Individual Fellowship (H2020-MSCA-IF-2014 655153). T.M. was supported by the Marie Curie International Outgoing Fellowship for Career Development (299954) and supported by a 'Charge de recherches' fellowship of the Belgian National Fund for Scientific Research (F.R.S-FNRS). N.G. was the recipient of a fellowship from the French 'Fondation pour la Recherche Médicale FRM.' P.B. acknowledges support from the European Research Council (ERC)–Seventh Framework Program (ERC-2013-CoG 616050), the Institut National de la Santé et de la Recherche Médicale (INSERM), and the Institut Pasteur. L.L.R. acknowledges support from the French 'Fondation pour la Recherche Médicale FRM,' the Stanford Pediatric Research Fund of the Lucile Packard Foundation for Children's Health and the Stanford CTSA (National Institutes of Health grant UL1 RR025744), NIH grant K99AI110645, the European Commission Marie Skłodowska-Curie Individual Fellowship (H2020-MSCA-IF-2014 656086), and the French 'Institut National de la Santé et de la Recherche Médicale' (INSERM). S.J.G. acknowledges support from NIH grants AI023990, CA072074, AI070813, AR067145, U19 AI104209, and NS 080062, the Tobacco-Related Disease Research Program at the University of California, and the Department of Pathology, Stanford University School of Medicine., European Project: 655153,H2020,H2020-MSCA-IF-2014,IgEPath(2015), European Project: 616050,EC:FP7:ERC,ERC-2013-CoG,MYELOSHOCK(2014), European Project: 656086,H2020,H2020-MSCA-IF-2014,AllergyBLOCK(2015), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Sean N. Parker Center for Allergy and Asthma Research [Stanford], Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), 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), Tokyo Medical and Dental University [Japan] (TMDU), and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Complement Pathway, Alternative, MESH: Anaphylaxis / immunology, MESH: Receptors, IgG / metabolism, MESH: Adjuvants, Immunologic, Hypothermia, Immunoglobulin E, MESH: Mast Cells / immunology, mast cells/basophils, MESH: Mice, Knockout, MESH: Receptors, IgE / metabolism, Mice, chemistry.chemical_compound, neutrophils, MESH: Hypothermia, Cell Movement, Leukocytes, Immunology and Allergy, antibodies, MESH: Animals, Mast Cells, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, MESH: Cell Movement, Cells, Cultured, Mice, Knockout, biology, Fc receptors, MESH: Mast Cells, Mast cell, MESH: Mast Cells / transplantation, medicine.anatomical_structure, MESH: Receptors, IgE / genetics, monocytes/macrophages, MESH: Immunization, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, Histamine, MESH: Cells, Cultured, CPA3, MESH: Leukocytes / immunology, mouse model, Immunology, Inflammation, MESH: Receptors, IgE, MESH: Receptors, IgG, MESH: Macrophages / immunology, Rodents, Article, MESH: Leukocytes, 03 medical and health sciences, Adjuvants, Immunologic, MESH: Hypothermia / immunology, MESH: Mice, Inbred C57BL, medicine, anaphylaxis, Animals, Humans, MESH: Receptors, IgG / genetics, Complement Pathway, Classical, MESH: Mice, MESH: Humans, Platelet-activating factor, Receptors, IgE, business.industry, Macrophages, Receptors, IgG, MESH: Macrophages, MESH: Complement Pathway, Classical, allergy, Mice, Inbred C57BL, MESH: Anaphylaxis, Disease Models, Animal, Ovalbumin, 030104 developmental biology, chemistry, inflammation, biology.protein, Immunization, MESH: Disease Models, Animal, business, MESH: Complement Pathway, Alternative
Abstract: Background Conflicting results have been obtained regarding the roles of Fc receptors and effector cells in models of active systemic anaphylaxis (ASA). In part, this might reflect the choice of adjuvant used during sensitization because various adjuvants might differentially influence the production of particular antibody isotypes. Objective We developed an "adjuvant-free" mouse model of ASA and assessed the contributions of components of the "classical" and "alternative" pathways in this model. Methods Mice were sensitized intraperitoneally with ovalbumin at weekly intervals for 6 weeks and challenged intraperitoneally with ovalbumin 2 weeks later. Results Wild-type animals had immediate hypothermia and late-phase intraperitoneal inflammation in this model. These features were reduced in mice lacking the IgE receptor FceRI, the IgG receptor FcγRIII or the common γ-chain FcRγ. FcγRIV blockade resulted in a partial reduction of inflammation without any effect on hypothermia. Depletion of monocytes/macrophages with clodronate liposomes significantly reduced the hypothermia response. By contrast, depletion of neutrophils or basophils had no significant effects in this ASA model. Both the hypothermia and inflammation were dependent on platelet-activating factor and histamine and were reduced in 2 types of mast cell (MC)–deficient mice. Finally, engraftment of MC-deficient mice with bone marrow–derived cultured MCs significantly exacerbated the hypothermia response and restored inflammation to levels similar to those observed in wild-type mice. Conclusion Components of the classical and alternative pathways contribute to anaphylaxis in this adjuvant-free model, with key roles for MCs and monocytes/macrophages.
Published: 2017
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28. Specific IgE and IgG measured by the MeDALL allergen-chip depend on allergen and route of exposure: The EGEA study

Author: Isabelle Pin, M. Wickman, Mirela Curin, Christian Lupinek, Karin C. Lødrup Carlsen, Jean Bousquet, Rudolf Valenta, Yvonne Resch, Renata Kiss, I. Skrindo, Valérie Siroux, Jocelyne Just, Rachel Nadif, Susanne Vrtala, Thomas Keil, Josep M. Antó, Erik Melén, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) ( IAB ), Centre Hospitalier Universitaire [Grenoble] ( CHU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Etablissement français du sang - Auvergne-Rhône-Alpes ( EFS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Service d'allergologie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie ( UPMC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Vieillissement et Maladies chroniques : approches épidémiologique et de santé publique ( VIMA ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Department of Pathophysiology and Allergy Research [Vienna, Austria] (Division of Immunopathology), Medizinische Universität Wien = Medical University of Vienna, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Epidemiology and Health Economics [Berlin, Germany] (Institute of Social Medicine), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Institute for Clinical Epidemiology and Biometry [Würzburg, Germany], Julius-Maximilians-Universität Würzburg (JMU), Department of Paediatrics [Oslo, Norway], Oslo University Hospital [Oslo], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Institute of Environmental Medicine [Stockholm, Sweden], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm]-Astrid Lindgren Children's Hospital, Sachs’ Children and Youth Hospital [Stockholm, Sweden], Vieillissement et Maladies chroniques : approches épidémiologique et de santé publique (VIMA), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Otorhinolaryngology [Lørenskog, Norway], Akershus University Hospital [Lørenskog], Christian Doppler Laboratory for the Development of Allergen chips [Vienna, Austria] (Department of Pathophysiology & Allergy Research), Medizinische Universität Wien = Medical University of Vienna-Center for Pathophysiology, Infectiology and Immunology [Vienna, Austria], Center for Research in Environmental Epidemiology (CREAL), Universitat Pompeu Fabra [Barcelona] (UPF)-Catalunya ministerio de salud, Hospital del Mar Medical Research Institute [Barcelona, Spain] (IMIM), Universitat Pompeu Fabra [Barcelona] (UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Mechanisms of the Development of Allergy (MeDALL-FP7), University of Groningen [Groningen]-Uppsala Universitet [Uppsala]-Universiteit Gent = Ghent University (UGENT)-Georg-August-University = Georg-August-Universität Göttingen, CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), The study was supported in part by Inserm Aviesan Itmo santé publique, the Scientific committee 'AGIR for chronic diseases', grant F4605 of the Austrian Science Fund (FWF) to RV and by the European Commission’s Seventh Framework 29 Program MeDALL under grant agreement no. 261357., European Project: 261357,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,MEDALL(2010), Centre de l'Asthme et des Allergies [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Oslo University Hospital [Oslo, Norway], Georg-August-University [Göttingen]-University of Groningen [Groningen]-Uppsala Universitet [Uppsala]-Universiteit Gent = Ghent University [Belgium] (UGENT), Faraldo, Beatrice, Mechanisms of the Development of ALLergy - MEDALL - - EC:FP7:HEALTH2010-12-01 - 2015-05-31 - 261357 - VALID, Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université
Subjects: 0301 basic medicine, Male, Epidemiology, [SDV]Life Sciences [q-bio], Microarray, medicine.disease_cause, Immunoglobulin E, Airborne allergen, Atopy, Cohort Studies, food allergens, 0302 clinical medicine, Allergen, immune system diseases, MeDALL, Immunology and Allergy, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, education.field_of_study, biology, Cohort, Environmental exposure, cohort, Middle Aged, respiratory system, Allergen components, 3. Good health, [SDV] Life Sciences [q-bio], EGEA, Female, epidemiology, France, IgE, Respiratory allergens, microarray, Ragweed, Adult, Allergen immunotherapy, IgG, Immunology, Population, Cross Reactions, 03 medical and health sciences, [ SDV.IMM.ALL ] Life Sciences [q-bio]/Immunology/Allergology, medicine, otorhinolaryngologic diseases, Humans, allergen components, education, Skin Tests, Environmental Exposure, Allergens, medicine.disease, biology.organism_classification, Asthma, respiratory tract diseases, 030104 developmental biology, Cross-Sectional Studies, 030228 respiratory system, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Immunoglobulin G, biology.protein, Food allergens, Immunization, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Follow-Up Studies, respiratory allergens
Abstract: Background: The nature of allergens and route and dose of exposure may affect the natural development of IgE and IgG responses. Objective: We sought to investigate the natural IgE and IgG responses toward a large panel of respiratory and food allergens in subjects exposed to different respiratory allergen loads. Methods: A cross-sectional analysis was conducted in 340 adults of the EGEA (Epidemiological study of the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy) (170 with and 170 without asthma) cohort. IgE and IgG responses to 47 inhalant and food allergen components were analyzed in sera using allergen microarray and compared between 5 French regions according to the route of allergen exposure (inhaled vs food allergens). Results: Overall 48.8% of the population had allergen-specific IgE levels of 0.3 ISAC standardized units (ISU) or more to at least 1 of the 47 allergens with no significant differences across the regions. For ubiquitous respiratory allergens (ie, grass, olive/ash pollen, house dust mites), specific IgE did not show marked differences between regions and specific IgG (≥0.5 ISU) was present in most subjects everywhere. For regionally occurring pollen allergens (ragweed, birch, cypress), IgE sensitization was significantly associated with regional pollen exposure. For airborne allergens cross-reacting with food allergens, frequent IgG recognition was observed even in regions with low allergen prevalence (Bet v 1) or for allergens less frequently recognized by IgE (profilins). Conclusions: The variability in allergen-specific IgE and IgG frequencies depends on exposure, route of exposure, and overall immunogenicity of the allergen. Allergen contact by the oral route might preferentially induce IgG responses. The study was supported in part by Inserm Aviesan Itmo santé publique, the Scientific committee “AGIR for chronic diseases,” grant F4605 of the Austrian Science Fund (FWF [Fonds zur Förderung der wissenschaftlichen Forschung]) to R.V. and by the European Commission's Seventh Framework 29 Program MeDALL under grant agreement no. 261357.
Published: 2017
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29. Large scale phosphoprotein profiling to explore Drosophila cold acclimation regulatory mechanisms

Author: Colinet, Hervé, Pineau, Charles, Com, Emmanuel, Ecosystèmes, biodiversité, évolution [Rennes] (ECOBIO), Centre National de la Recherche Scientifique (CNRS)-Observatoire des Sciences de l'Univers de Rennes (OSUR)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Proteomics Core Facility (Protim), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Plateforme Génomique Santé Biogenouest®, actions incitatives 'defis scientifiques emergents' from University of Rennes1 and SUZUKILL project [ANR-15-CE21-0017-01, FWF I 2604-B25], Biogenouest, Conseil Regional de Bretagne, IBiSA, ANR-15-CE21-0017,Suzukill,Gestion de la tolérance au froid et de la qualité des mouches, Drosophila suzukii, produites en masse pour faciliter la mise en place d'un contrôle biologique par les méthodes de lâchers d'insectes stériles et incompatibles(2015), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Observatoire des Sciences de l'Univers de Rennes (OSUR), Université de Rennes (UR)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Rennes 2 (UR2)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Rennes 2 (UR2)-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), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Plateforme Génomique Santé Biogenouest®, Unité d'Ecologie et de Biogéographie (UEB), Université Catholique de Louvain = Catholic University of Louvain (UCL), Groupe d'Etude de la Reproduction Chez l'Homme et les Mammiferes (GERHM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Jonchère, Laurent, Gestion de la tolérance au froid et de la qualité des mouches, Drosophila suzukii, produites en masse pour faciliter la mise en place d'un contrôle biologique par les méthodes de lâchers d'insectes stériles et incompatibles - - Suzukill2015 - ANR-15-CE21-0017 - AAPG2015 - VALID, Briand, Valerie, and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Phosphopeptides, Proteomics, Science, Acclimatization, Molecular Sequence Annotation, Phosphoproteins, Article, [SDE.BE] Environmental Sciences/Biodiversity and Ecology, Cold Temperature, [SDV.BA.ZI]Life Sciences [q-bio]/Animal biology/Invertebrate Zoology, Drosophila melanogaster, Gene Ontology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BA.ZI] Life Sciences [q-bio]/Animal biology/Invertebrate Zoology, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Medicine, Animals, Drosophila Proteins, Protein Interaction Maps, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, Phosphorylation, ComputingMilieux_MISCELLANEOUS
Abstract: The regulatory mechanisms involved in the acquisition of thermal tolerance are unknown in insects. Reversible phosphorylation is a widespread post-translational modification that can rapidly alter proteins function(s). Here, we conducted a large-scale comparative screening of phosphorylation networks in adult Drosophila flies that were cold-acclimated versus control. Using a modified SIMAC method followed by a multiple MS analysis strategy, we identified a large collection of phosphopeptides (about 1600) and phosphoproteins (about 500) in both groups, with good enrichment efficacy (80%). The saturation curves from the four biological replicates revealed that the phosphoproteome was rather well covered under our experimental conditions. Acclimation evoked a strong phosphoproteomic signal characterized by large sets of unique and differential phosphoproteins. These were involved in several major GO superclusters of which cytoskeleton organization, positive regulation of transport, cell cycle, and RNA processing were particularly enriched. Data suggest that phosphoproteomic changes in response to acclimation were mainly localized within cytoskeletal network, and particularly within microtubule associated complexes. This study opens up novel research avenues for exploring the complex regulatory networks that lead to acquired thermal tolerance.
Published: 2017
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30. The tyrosine kinase inhibitor imatinib mesylate suppresses uric acid crystal-induced acute gouty arthritis in mice

Author: Dongmin Kang, Stephan Rogalla, Bianca Balbino, Riccardo Sibilano, Harini Raghu, Philipp Starkl, Christopher H. Contag, Stephen J. Galli, Steven Sensarn, William H. Robinson, Laurent L. Reber, Jeremy Sokolove, Mindy Tsai, Nicolas Gaudenzio, Department of Pathology [Stanford], Stanford Medicine, Stanford University-Stanford University, Sean N. Parker Center for Allergy and Asthma Research [Stanford], Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Stanford School of Medicine [Stanford], Molecular Imaging Program at Stanford (MIPS), EWHA Womans University (EWHA), Veterans Affairs Palo Alto Healthcare System [Palo Alto, CA, États-Unis], Department of Microbiology and Immunology [Stanford], L.L.R. acknowledges support from the Arthritis National Research Foundation (ANRF), National Institutes of Health grant K99 AI110645, the European Commission (Marie Skłodowska-Curie Individual Fellowship H2020-MSCA-IF-2014 656086) and the Institut National de la Santé et de la Recherche Médicale (INSERM), P.S. was supported by a Max Kade Fellowship of the Max Kade Foundation and the Austrian Academy of Sciences and a Schroedinger Fellowship of the Austrian Science Fund (FWF): J3399-B21, B.B. was supported by a stipend from the Pasteur - Paris University (PPU) International Ph.D. Program, R.S. was supported by the Lucile Packard Foundation for Children’s Health and the Stanford NIH/NCRR CTSA award number UL1 RR025744, N.G. was the recipient of a fellowship from the French 'Fondation pour la Recherche Médicale FRM', S.R. was supported in part by the George Will Foundation, C.H.C. acknowledges the Chambers Family Foundation Fund for Excellence in Pediatric Research, and the Child Health Research Institute at Stanford for their generous support, S.J.G. acknowledges support from National Institutes of Health grants U19 AI104209, NS 080062, and R01 AR067145 and the Department of Pathology, Stanford University School of Medicine., We thank Dr. Rajadas and the Stanford Biomaterials and Advanced Drug Delivery (BioADD) Laboratory core for the production of the imatinib-loaded PLGA nanoparticles., HAL UPMC, Gestionnaire, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Veterans Affairs Palo Alto Healthcare System
Subjects: 0301 basic medicine, Gout, MESH: Protein Kinase Inhibitors / administration & dosage, lcsh:Medicine, Arthritis, MESH: Uric Acid / chemistry, Pharmacology, Pathology and Laboratory Medicine, Mouse models, Tyrosine-kinase inhibitor, Mice, chemistry.chemical_compound, 0302 clinical medicine, Medicine and Health Sciences, Nanotechnology, MESH: Animals, lcsh:Science, Musculoskeletal System, Immune Response, Routes of Administration, MESH: Crystallization, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Multidisciplinary, Arthritis, Gouty, Animal Models, Protein-Tyrosine Kinases, 3. Good health, Experimental Organism Systems, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Rheumatoid arthritis, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Physical Sciences, Imatinib Mesylate, Legs, Engineering and Technology, Anatomy, Crystallization, Tyrosine kinase, Injections, Intraperitoneal, MESH: Injections, Intraperitoneal, Research Article, medicine.drug, medicine.medical_specialty, Materials by Structure, medicine.drug_class, Inflammatory Diseases, Materials Science, Immunology, Intraperitoneal injections, MESH: Imatinib Mesylate / administration & dosage, Research and Analysis Methods, Crystals, 03 medical and health sciences, MESH: Protein-Tyrosine Kinases / antagonists & inhibitors, Model Organisms, Signs and Symptoms, Rheumatology, MESH: Imatinib Mesylate / pharmacology, Diagnostic Medicine, MESH: Mice, Inbred C57BL, Internal medicine, medicine, Animals, Protein Kinase Inhibitors, MESH: Mice, 030203 arthritis & rheumatology, Inflammation, MESH: Arthritis, Gouty / prevention & control, business.industry, lcsh:R, Limbs (Anatomy), Ankles, Biology and Life Sciences, Imatinib, medicine.disease, MESH: Uric Acid / adverse effects, MESH: Protein Kinase Inhibitors / pharmacology, Uric Acid, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Imatinib mesylate, chemistry, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Uric acid, Nanoparticles, lcsh:Q, business
Abstract: International audience; Gouty arthritis is caused by the deposition of monosodium urate (MSU) crystals in joints. Despite many treatment options for gout, there is a substantial need for alternative treatments for patients unresponsive to current therapies. Tyrosine kinase inhibitors have demonstrated therapeutic benefit in experimental models of antibody-dependent arthritis and in rheumatoid arthritis in humans, but to date, the potential effects of such inhibitors on gouty arthritis has not been evaluated. Here we demonstrate that treatment with the tyrosine kinase inhibitor imatinib mesylate (imatinib) can suppress inflammation induced by injection of MSU crystals into subcutaneous air pouches or into the ankle joint of wild type mice. Moreover, imatinib treatment also largely abolished the lower levels of inflammation which developed in IL-1R1-/- or KitW-sh/W-sh mice, indicating that this drug can inhibit IL-1-independent pathways, as well as mast cell-independent pathways, contributing to pathology in this model. Imatinib treatment not only prevented ankle swelling and synovial inflammation when administered before MSU crystals but also diminished these features when administrated after the injection of MSU crystals, a therapeutic protocol more closely mimicking the clinical situation in which treatment occurs after the development of an acute gout flare. Finally, we also assessed the efficiency of local intra-articular injections of imatinib-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles in this model of acute gout. Treatment with low doses of this long-acting imatinib:PLGA formulation was able to reduce ankle swelling in a therapeutic protocol. Altogether, these results raise the possibility that tyrosine kinase inhibitors might have utility in the treatment of acute gout in humans.
Published: 2017
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31. A TNFRSF14-FcɛRI-mast cell pathway contributes to development of multiple features of asthma pathology in mice

Author: Mindy Tsai, Joseph D. Hernandez, Mang Yu, Sonja Zahner, Stephen B. Montgomery, Axel Roers, Oliwia W Zurek, Nicolas Gaudenzio, Philipp Starkl, Stephen J. Galli, Mitchell Kronenberg, Laurent L. Reber, Marianne K. DeGorter, Riccardo Sibilano, Department of Pathology [Stanford], Stanford Medicine, Stanford University-Stanford University, Department of Genetics [Stanford], Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pediatrics [Stanford], Research Center for Molecular Medicine of the Austrian Academy of Sciences [Vienna, Austria] (CeMM ), Austrian Academy of Sciences (OeAW), La Jolla Institute for Immunology [La Jolla, CA, États-Unis], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Sean N. Parker Center for Allergy and Asthma Research [Stanford], This work was supported by US National Institutes of Health (NIH) grants to S.J.G. (U19AI104209 and R01AR067145), M.K. (R01AI61516) and L.L.R. (K99AI110645), fellowships from the Lucile Packard Foundation for Children’s Health to R.S. (UL1 RR025744) and J.D.H. (UL1 TR001085), the Fondation pour la Recherche Medicale (FRM) SPE20130326582 and Philippe foundation to N.G., a Schroedinger Fellowship of the Austrian Science Fund (FWF) J3399-B21 to P.M.S., an NIH postdoctoral fellowship (2T32AI007290-31) to O.W.Z., the Department of Pathology and the Sean N. Parker Center for Allergy and Asthma Research, Stanford University., and Pistre, Karine
Subjects: 0301 basic medicine, Pathology, General Physics and Astronomy, Immunoglobulin E, MESH: Mice, Knockout, MESH: Ovalbumin / immunology, Immunoglobulin G, MESH: Receptors, IgE / metabolism, MESH: Genotype, MESH: Ovalbumin / toxicity, Mice, 0302 clinical medicine, Antigen Sensitization, MESH: Asthma / pathology, MESH: Animals, MESH: Mast Cells / physiology, Mast Cells, Mice, Knockout, MESH: Immunoglobulin G, Multidisciplinary, biology, MESH: Gene Expression Regulation / drug effects, MESH: Bronchoalveolar Lavage Fluid / cytology, MESH: Immunoglobulin E, Chronic inflammation, Mast cell, MESH: Antigens, Dermatophagoides / toxicity, 3. Good health, medicine.anatomical_structure, MESH: Receptors, IgE / genetics, Airway Remodeling, Mucosal immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Tumor necrosis factor alpha, Antibody, medicine.symptom, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Bronchoalveolar Lavage Fluid, Receptors, Tumor Necrosis Factor, Member 14, MESH: Antigens, Dermatophagoides / immunology, medicine.medical_specialty, Genotype, [SDV.IMM] Life Sciences [q-bio]/Immunology, Ovalbumin, Science, MESH: Asthma / metabolism, Inflammation, Article, Antibodies, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Mediator, medicine, Animals, Antigens, Dermatophagoides, MESH: Mice, Receptors, IgE, business.industry, MESH: Asthma / chemically induced, MESH: Antibodies, General Chemistry, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, MESH: Receptors, Tumor Necrosis Factor, Member 14 / genetics, Asthma, respiratory tract diseases, MESH: Airway Remodeling, 030104 developmental biology, Gene Expression Regulation, Immunology, biology.protein, MESH: Receptors, Tumor Necrosis Factor, Member 14 / metabolism, business, MESH: Female, 030215 immunology
Abstract: Asthma has multiple features, including airway hyperreactivity, inflammation and remodelling. The TNF superfamily member TNFSF14 (LIGHT), via interactions with the receptor TNFRSF14 (HVEM), can support TH2 cell generation and longevity and promote airway remodelling in mouse models of asthma, but the mechanisms by which TNFSF14 functions in this setting are incompletely understood. Here we find that mouse and human mast cells (MCs) express TNFRSF14 and that TNFSF14:TNFRSF14 interactions can enhance IgE-mediated MC signalling and mediator production. In mouse models of asthma, TNFRSF14 blockade with a neutralizing antibody administered after antigen sensitization, or genetic deletion of Tnfrsf14, diminishes plasma levels of antigen-specific IgG1 and IgE antibodies, airway hyperreactivity, airway inflammation and airway remodelling. Finally, by analysing two types of genetically MC-deficient mice after engrafting MCs that either do or do not express TNFRSF14, we show that TNFRSF14 expression on MCs significantly contributes to the development of multiple features of asthma pathology., TNFSF14 (LIGHT) contributes to airway inflammation and remodelling. Here the authors show that TNFSF14 acting on its receptor TNFRSF14 on mast cells enhances their IgE-dependent activation and that interference with this pathway attenuates features of asthma pathology in mice.
Published: 2016
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32. Error-Robust Modes of the Retinal Population Code

Author: Mark L. Ioffe, Michael J. Berry, Olivier Marre, Jason S. Prentice, Gašper Tkačik, Adrianna Loback, Princeton Neuroscience Institute [Princeton, NJ, États-Unis] (PNI), Princeton University, Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Physics [Princeton, NJ, États-Unis], Institute of Science and Technology [Austria] (IST Austria), Department of Molecular Biology [Princeton, NJ, États-Unis], JSP was supported by a C.V. Starr Fellowship from the Starr Foundation (http://www.starrfoundation.org/). GT was supported by Austrian Research Foundation (https://www.fwf.ac.at/en/) grant FWF P25651. MJB received support from National Eye Institute (https://nei.nih.gov/) grant EY 14196 and from the National Science Foundation grant 1504977., Bodescot, Myriam, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Institute of Science and Technology [Klosterneuburg, Austria] (IST Austria)
Subjects: Retinal Ganglion Cells, 0301 basic medicine, Nervous system, Physiology, Entropy, Markov models, Action Potentials, Synaptic Transmission, chemistry.chemical_compound, 0302 clinical medicine, Animal Cells, Medicine and Health Sciences, Hidden Markov models, lcsh:QH301-705.5, Cells, Cultured, Neurons, education.field_of_study, Ecology, Physics, Anatomy, Ganglion, Physical sciences, Electrophysiology, medicine.anatomical_structure, Computational Theory and Mathematics, Modeling and Simulation, Thermodynamics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cellular Types, Research Article, Ganglion Cells, Ocular Anatomy, Models, Neurological, Population, Neurophysiology, Biology, Membrane Potential, Retinal ganglion, Retina, 03 medical and health sciences, Cellular and Molecular Neuroscience, Ocular System, Genetics, medicine, Humans, Computer Simulation, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], education, Molecular Biology, Vision, Ocular, Ecology, Evolution, Behavior and Systematics, Models, Statistical, Biology and Life Sciences, Afferent Neurons, Correction, Probability theory, Retinal, Statistical model, Cell Biology, Probability Distribution, Retinal waves, 030104 developmental biology, chemistry, lcsh:Biology (General), Cellular Neuroscience, Nerve Net, Neuroscience, Mathematics, 030217 neurology & neurosurgery
Abstract: Across the nervous system, certain population spiking patterns are observed far more frequently than others. A hypothesis about this structure is that these collective activity patterns function as population codewords–collective modes–carrying information distinct from that of any single cell. We investigate this phenomenon in recordings of ∼150 retinal ganglion cells, the retina’s output. We develop a novel statistical model that decomposes the population response into modes; it predicts the distribution of spiking activity in the ganglion cell population with high accuracy. We found that the modes represent localized features of the visual stimulus that are distinct from the features represented by single neurons. Modes form clusters of activity states that are readily discriminated from one another. When we repeated the same visual stimulus, we found that the same mode was robustly elicited. These results suggest that retinal ganglion cells’ collective signaling is endowed with a form of error-correcting code–a principle that may hold in brain areas beyond retina., Author Summary Neurons in most parts of the nervous system represent and process information in a collective fashion, yet the nature of this collective code is poorly understood. An important constraint placed on any such collective processing comes from the fact that individual neurons’ signaling is prone to corruption by noise. The information theory and engineering literatures have studied error-correcting codes that allow individual noise-prone coding units to “check” each other, forming an overall representation that is robust to errors. In this paper, we have analyzed the population code of one of the best-studied neural systems, the retina, and found that it is structured in a manner analogous to error-correcting schemes. Indeed, we found that the complex activity patterns over ~150 retinal ganglion cells, the output neurons of the retina, could be mapped onto collective code words, and that these code words represented precise visual information while suppressing noise. In order to analyze this coding scheme, we introduced a novel quantitative model of the retinal output that predicted neural activity patterns more accurately than existing state-of-the-art approaches.
Published: 2016
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33. Structural basis of potent Zika-dengue virus antibody cross-neutralization

Author: Franz X. Heinz, Juthathip Mongkolsapaya, Ahmed Haouz, Arvind Sharma, Patrick England, Van-Mai Cao-Lormeau, Wanwisa Dejnirattisai, Félix A. Rey, Anavaj Sakuntabhai, Iris Medits, Etienne Simon-Loriere, Gavin R. Screaton, Karin Stiasny, Alexander Rouvinski, Giovanna Barba-Spaeth, Marie Christine Vaney, Virologie Structurale - Structural Virology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Division of Immunology and Inflammation, Department of Medicine, Imperial College London-Hammersmith Hospital Campus, Medizinische Universität Wien = Medical University of Vienna, Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Emerging Infectious Diseases, Institut Louis Malardé [Papeete] (ILM), Institut de Recherche pour le Développement (IRD)-Institut de Recherche pour le Développement (IRD), Cristallographie (Plateforme) - Crystallography (Platform), Biophysique des Macromolécules et de leurs Interactions, Siriraj Hospital, Mahidol University, Mahidol University [Bangkok], We acknowledge support from the European Commission FP7 Programme for the DENFREE project under Grant Agreement number 282 378FP7 (F.A.R., J.M., G.R.S. and A.Sa.), the 'Integrative Biology of Emerging Infectious Diseases' Labex (Laboratoire d’Excellence) grant number ANR-10-LABX-62-IBEID (French Government’s 'Investissements d’Avenir' program ) (F.A.R.), the transnational ANR/FWF grant FlaviStem/I1378 (F.A.R. and K.S.), the Medical Research Council, UK (J.M.), the National Institute for Health Research Biomedical Research Centre, Funding Scheme, UK (G.R.S.), and the NEUTRAVIR grant from Région ile-de-France (DIM-Maladies Infectieuses) (P.E., A.H. and F.A.R., ANR-13-ISV8-0002,flavistem,La protéine E des flavivirus : interactions et fusion membranaire(2013), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 282378,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,DENFREE(2012), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Medical Research Council (MRC), Wellcome Trust, and Commission of the European Communities
Subjects: DYNAMICS, 0301 basic medicine, Models, Molecular, viruses, [SDV]Life Sciences [q-bio], Antigen-Antibody Complex, Dengue virus, medicine.disease_cause, Crystallography, X-Ray, Epitope, Zika virus, Dengue fever, Dengue, Epitopes, 0302 clinical medicine, Viral Envelope Proteins, INFECTION, Virus maturation, IN-VIVO, FLAVIVIRUSES, Phylogeny, Multidisciplinary, Zika Virus Infection, Antibodies, Monoclonal, REACTIVE ANTIBODIES, FUSION-LOOP, 3. Good health, Multidisciplinary Sciences, Flavivirus, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Science & Technology - Other Topics, Brazil, General Science & Technology, Dengue Vaccines, Biology, Cross Reactions, MATURATION, Microbiology, 03 medical and health sciences, ENHANCEMENT, medicine, Humans, Antibody-dependent enhancement, Dengue vaccine, Science & Technology, RECEPTOR, RECOGNITION, Viral Vaccines, Zika Virus, Dengue Virus, biology.organism_classification, medicine.disease, Virology, Antibodies, Neutralizing, 030104 developmental biology, 030217 neurology & neurosurgery
Abstract: International audience; Zika virus is a member of the Flavivirus genus that had not been associated with severe disease in humans until the recent outbreaks, when it was linked to microcephaly in newborns in Brazil and to Guillain-Barré syndrome in adults in French Polynesia. Zika virus is related to dengue virus, and here we report that a subset of antibodies targeting a conformational epitope isolated from patients with dengue virus also potently neutralize Zika virus. The crystal structure of two of these antibodies in complex with the envelope protein of Zika virus reveals the details of a conserved epitope, which is also the site of interaction of the envelope protein dimer with the precursor membrane (prM) protein during virus maturation. Comparison of the Zika and dengue virus immunocomplexes provides a lead for rational, epitope-focused design of a universal vaccine capable of eliciting potent cross-neutralizing antibodies to protect simultaneously against both Zika and dengue virus infections.
Published: 2016
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34. Cracking the elusive alignment hypothesis: the microtubule–cellulose synthase nexus unraveled

Author: Benoit Landrein, Martin Bringmann, Staffan Persson, Christian Schudoma, Marie-Theres Hauser, Olivier Hamant, Max Planck Institute of Molecular Plant Physiology (MPI-MP), Max-Planck-Gesellschaft, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Université de Lyon (COMUE), Reproduction et développement des plantes (RDP), École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Universität für Bodenkultur Wien = University of Natural Resources and Life [Vienne, Autriche] (BOKU), Max-Planck Gesellschaft, through the DFG [PE1642/5-1], Austrian Science Fund (FWF) [SFB F37/F03707, P14477-GEN, P11001-GEN], Agence Nationale de la Recherche [ANR-10-BLAN-1516], TROST from the BMELV (German Ministry for Food, Agriculture and Consumer Protection) [22011208], Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-École normale supérieure - Lyon (ENS Lyon), and Universität für Bodenkultur Wien [Vienne, Autriche] (BOKU)
Subjects: Models, Molecular, 0106 biological sciences, [SDV]Life Sciences [q-bio], Turgor pressure, FUNCTIONAL ASSOCIATION, Plant Development, PROTEIN, Context (language use), Review, ORGANIZATION, Plant Science, Microtubules, Plant Roots, 01 natural sciences, Cell membrane, Cell wall, 03 medical and health sciences, chemistry.chemical_compound, Cell Wall, Microtubule, Plant Cells, Extracellular, medicine, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, BIOSYNTHESIS, Cellulose, Cell Shape, Plant Physiological Phenomena, Plant Proteins, 030304 developmental biology, 0303 health sciences, CORTICAL MICROTUBULES, ATP synthase, biology, Cell Membrane, ARABIDOPSIS HYPOCOTYL, Plants, Cell biology, medicine.anatomical_structure, chemistry, Glucosyltransferases, PLASMA-MEMBRANE, biology.protein, GENETIC-EVIDENCE, COMPLEXES, PLANT-CELL WALLS, 010606 plant biology & botany
Abstract: International audience; Directed plant cell growth is governed by deposition and alterations of cell wall components under turgor pressure. A key regulatory element of anisotropic growth, and hence cell shape, is the directional deposition of cellulose microfibrils. The microfibrils are synthesized by plasma membrane-located cellulose synthase complexes that co-align with and move along cortical microtubules. That the parallel relation between cortical microtubules and extracellular microfibrils is causal has been named the alignment hypothesis. Three recent studies revealed that the previously identified pom2 mutant codes for a large cellulose synthases interacting (CSI1) protein which also binds cortical microtubules. This review summarizes these findings, provides structure function models and discusses the inferred mechanisms in the context of plant growth.
Published: 2012
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35. Measured and modelled sublimation on the tropical Glaciar Artesonraju, Perú

Author: Michael Winkler, J. Gomez, Irmgard Juen, Patrick Wagnon, George Kaser, Thomas Mölg, Tropical Glaciology Group, Faculty of Geo- and Atmospheric Sciences, University of Innsbruck, Laboratoire de glaciologie et géophysique de l'environnement (LGGE), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire des Sciences de l'Univers de Grenoble (OSUG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national des sciences de l'Univers (INSU - CNRS)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS), Unidad de Glaciología y Recursos Hídricos, Austrian Science Foundation (FWF) grants number P16113-N06 and P20089-N10., Observatoire des Sciences de l'Univers de Grenoble (OSUG), and Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 010504 meteorology & atmospheric sciences, 0207 environmental engineering, 02 engineering and technology, Atmospheric sciences, 01 natural sciences, Wind speed, Conservación de glaciares, Glacier mass balance, medicine, Surface roughness, Cambio climático, [SDU.STU.GL]Sciences of the Universe [physics]/Earth Sciences/Glaciology, 020701 environmental engineering, Monitoreo de lagunas y glaciares, lcsh:Environmental sciences, 0105 earth and related environmental sciences, Earth-Surface Processes, Water Science and Technology, lcsh:GE1-350, geography, geography.geographical_feature_category, lcsh:QE1-996.5, Humidity, Glacier, Seasonality, medicine.disease, lcsh:Geology, 13. Climate action, Environmental science, Sublimation (phase transition), Water vapor
Abstract: Original abstract: Sublimation plays a decisive role in the surface energy and mass balance of tropical glaciers. During the dry season (May–September) low specific humidity and high surface roughness favour the direct transition from ice to vapour and drastically reduce the energy available for melting. However, field measurements are scarce and little is known about the performance of sublimation parameterisations in glacier mass balance and runoff models. During 15 days in August 2005 sublimation was measured on the tongue of Glaciar Artesonraju (8°58' S, 77°38' W) in the Cordillera Blanca, Perú, using simple lysimeters. Indicating a strong dependence on surface roughness, daily totals of sublimation range from 1–3 kg m-2 for smooth to 2–5 kg m-2 for rough conditions. (The 15-day means at that time of wind speed and specific humidity were 4.3 m s-1 and 3.8 g kg-1, respectively.) Measured sublimation was related to characteristic surface roughness lengths for momentum (zm) and for the scalar quantities of temperature and water vapour (zs), using a process-based mass balance model. Input data were provided by automatic weather stations, situated on the glacier tongue at 4750 m a.s.l. and 4810 m a.s.l., respectively. Under smooth conditions the combination zm=2.0 mm and zs=1.0 mm appeared to be most appropriate, for rough conditions zm=20.0 mm and zs=10.0 mm fitted best. Extending the sublimation record from April 2004 to December 2005 with the process-based model confirms, that sublimation shows a clear seasonality. 60–90% of the energy available for ablation is consumed by sublimation in the dry season, but only 10–15% in the wet season (October–April). The findings are finally used to evaluate the parameterisation of sublimation in the lower-complexity mass balance model ITGG, which has the advantage of requiring precipitation and air temperature as only input data. It turns out that the implementation of mean wind speed is a possible improvement for the representation of sublimation in the ITGG model. Artículo en acceso abierto Menciona que la sublimación juega un papel decisivo en la energía de la superficie y el balance de masa de los glaciares tropicales. Señala además que durante la estación seca (de mayo a septiembre), la baja humedad específica y la gran rugosidad de la superficie favorecen la transición directa del hielo al vapor y reducen drásticamente la energía disponible para la fusión. Sin embargo, las mediciones de campo son escasas y se sabe poco acerca del rendimiento de las parametrizaciones de sublimación en los modelos de escorrentía y balance de masa de glaciares. Por ello, durante 15 días, en agosto de 2005, se midió la sublimación en la lengua de Glaciar Artesonraju en la Cordillera Blanca (Perú) utilizando lisímetros simples e indicando una fuerte dependencia de la rugosidad de la superficie, los totales diarios de sublimación varían de 1 a 3 kgm - 2 para suavizar a 2–5 kgm - 2 para condiciones ásperas.
Published: 2009
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36. Autochthonous chikungunya transmission and extreme climate events in Southern France

Author: Frédéric Simard, Philippe Boussès, Christophe Paupy, David Roiz, Didier Fontenille, 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 Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), This work was funded by the ERA-Net BiodivERsA, project CG-INVAMOFECT with the national funders ANR-13-EBID-0007-01 France, FWF I-1434 Austria, and DFG KL2087/6-1 Gremany as part of the 2012-2013 BiodivERsA call for research proposals., and ANR-13-EBID-0007,GC-INVAMOFECT,GLOBAL CHANGE AND INVASIVE MOSQUITOES AS INFECTIOUS DISEASE RISKS IN EUROPE(2013)
Subjects: lcsh:Arctic medicine. Tropical medicine, Aedes albopictus, lcsh:RC955-962, Climate, Rain, viruses, [SDV]Life Sciences [q-bio], Population Dynamics, 030231 tropical medicine, Climate change, medicine.disease_cause, law.invention, 03 medical and health sciences, 0302 clinical medicine, Aedes, law, parasitic diseases, medicine, Animals, Humans, Chikungunya, 030304 developmental biology, 0303 health sciences, biology, Ecology, lcsh:Public aspects of medicine, Flooding (psychology), Global warming, fungi, Public Health, Environmental and Occupational Health, virus diseases, lcsh:RA1-1270, biology.organism_classification, 3. Good health, Infectious Diseases, Transmission (mechanics), 13. Climate action, Vector (epidemiology), Chikungunya Fever, Female, France, Chikungunya virus, Research Article
Abstract: Background Extreme precipitation events are increasing as a result of ongoing global warming, but controversy surrounds the relationship between flooding and mosquito-borne diseases. A common view among the scientific community and public health officers is that heavy rainfalls have a flushing effect on breeding sites, which negatively affects vector populations, thereby diminishing disease transmission. During 2014 in Montpellier, France, there were at least 11 autochthonous cases of chikungunya caused by the invasive tiger mosquito Aedes albopictus in the vicinity of an imported case. We show that an extreme rainfall event increased and extended the abundance of the disease vector Ae. albopictus, hence the period of autochthonous transmission of chikungunya. Methodology/Principal Findings We report results from close monitoring of the adult and egg population of the chikungunya vector Ae. albopictus through weekly sampling over the entire mosquito breeding season, which revealed an unexpected pattern. Statistical analysis of the seasonal dynamics of female abundance in relation to climatic factors showed that these relationships changed after the heavy rainfall event. Before the inundations, accumulated temperatures are the most important variable predicting Ae. albopictus seasonal dynamics. However, after the inundations, accumulated rainfall over the 4 weeks prior to capture predicts the seasonal dynamics of this species and extension of the transmission period. Conclusions/Significance Our empirical data suggests that heavy rainfall events did increase the risk of arbovirus transmission in Southern France in 2014 by favouring a rapid rise in abundance of vector mosquitoes. Further studies should now confirm these results in different ecological contexts, so that the impact of global change and extreme climatic events on mosquito population dynamics and the risk of disease transmission can be adequately understood., Author Summary During last years, we have seen an astonishing expansion of Chikungunya virus and an increase in dengue cases worldwide, together with the worldwide expansion of the Asian tiger mosquito Aedes albopictus. In addition, extreme rainfall events are envisaged to become increasingly likely as a result of ongoing climate change, but controversy surrounds the relationship between extreme rainfall events and mosquito-borne diseases. The common view in most works on climate and mosquito-borne diseases is that heavy rainfalls produce a flushing effect of immature mosquitoes in breeding containers, diminishing the mosquito abundance and in turn diminishing disease transmission. We analysed the relationships between the autochthonous chikungunya transmission in Montpellier (Southern France) in 2014, an extreme rainfall event that flooded the city, and a close monitoring of the vector Ae. albopictus, revealing an unexpected pattern. This extreme rainfall event did not, in fact, decrease but instead had increased the global risk of chikungunya transmission by sustaining high abundance of the disease vector Ae. albopictus, hence extending the transmission period. We propose that an effort on source reduction campaigns must be implemented after heavy rainfall events. These results are relevant to those involved in the surveillance and control of chikungunya and dengue transmission in temperate as well as tropical areas.
Published: 2015
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37. Immediate T-Helper 17 Polarization Upon Triggering CD11b/c on HIV-Exposed Dendritic Cells

Author: Teunis B. H. Geijtenbeek, Gianfranco Pancino, Günter Weiss, Olivier Lambotte, Paul Kellam, Ralf Gallasch, Cornelia Lass-Flörl, Doris Wilflingseder, Zlatko Trajanoski, Hubert Hackl, Andrea Schroll, Wilfried Posch, Dan Frampton, Asier Sáez-Cirión, Laurence Weiss, Guibert, Marie-Genevieve, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), University College of London [London] (UCL), Wellcome Trust Genome Campus, Régulation des Infections Rétrovirales, Institut Pasteur [Paris] (IP), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), HIV, Inflammation et persistance - HIV, Inflammation and Persistence, Service de Médecine Interne - Immunologie Clinique [AP-HP Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Régulation de la réponse immune, infection VIH-1 et autoimmunité, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), This work was supported by the Austrian Science Fund (grants FWF P22165 and P24598 to D. W., SFB 021 to Z. T., and P25389 to W. P.), the Oesterreichische Nationalbank Anniversary Fund (project 14875 to W. P.), and the Agence Nationale de la Recherche Contre le SIDA et les Hépatites Virales (to A. S.-C.)., Amsterdam institute for Infection and Immunity, Infectious diseases, Experimental Immunology, Innsbruck Medical University [Austria] (IMU), Institut Pasteur [Paris], and HIV, Inflammation et persistance
Subjects: Adult, Male, opsonization, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, CD11c, chemical and pharmacologic phenomena, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigen, medicine, Immunology and Allergy, Humans, complement, Antigens, 030304 developmental biology, 0303 health sciences, CD11b Antigen, biology, Follicular dendritic cells, CD11b, Cell Differentiation, Complement System Proteins, Dendritic Cells, Middle Aged, MAPK, 3. Good health, CD11c Antigen, Antibody opsonization, Infectious Diseases, Cytokine, Integrin alpha M, Immunology, biology.protein, HIV-1, Th17 Cells, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Th17, Ex vivo, 030215 immunology
Abstract: International audience; Early on in human immunodeficiency virus (HIV) type 1 infection, gut T-helper (Th) 17 cells are massively depleted leading eventually to compromised intestinal barrier function and excessive immune activation. In contrast, the functional Th17 cell compartment of the gut is well-maintained in nonpathogenic simian immunodeficiency virus infection as well as HIV-1 long-term nonprogressors. Here, we show that dendritic cells (DCs) loaded with HIV-1 bearing high surface complement levels after incubation in plasma from HIV-infected individuals secreted significantly higher concentrations of Th17-polarizing cytokines than DCs exposed to nonopsonized HIV-1. The enhanced Th17-polarizing capacity of in vitro-generated and BDCA-1(+) DCs directly isolated from blood was linked to activation of ERK. In addition, C3a produced from DCs exposed to complement-opsonized HIV was associated with the higher Th17 polarization. Our in vitro and ex vivo data, therefore, indicate that complement opsonization of HIV-1 strengthens DC-mediated antiviral immune functions by simultaneously triggering Th17 expansion and intrinsic C3 formation via DC activation.
Published: 2015
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38. Pseudomonas aeruginosa manipulates redox and iron homeostasis of its microbiota partner Aspergillus fumigatus via phenazines

Author: Anne Beauvais, Benoit Briard, Jean-Paul Latgé, Gaëtan L. A. Mislin, Virginie Lair, Beatrix E. Lechner, Marie-Christine Prévost, Hubertus Haas, Perrine Bomme, Aspergillus, Institut Pasteur [Paris], Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Microscopie ultrastructurale (plate-forme), Innsbruck Medical University [Austria] (IMU), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche de Chimie Paris (IRCP), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ministère de la Culture (MC), Research in the Aspergillus Unit of JP Latgé was supported by the Association Vaincre La Mucoviscidose (RF20140501052/1/1/141). B.E. Lechner and H. Haas were supported by the FWF project 1346-B21., Institut Pasteur [Paris] (IP), and Innsbruck Medical University = Medizinische Universität Innsbruck (IMU)
Subjects: Iron, medicine.disease_cause, Redox, Article, Aspergillus fumigatus, Microbiology, 03 medical and health sciences, chemistry.chemical_compound, Pyocyanin, Superoxides, medicine, Mode of action, skin and connective tissue diseases, Reactive nitrogen species, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Reactive oxygen species, Multidisciplinary, biology, 030306 microbiology, Pseudomonas aeruginosa, Microbiota, biology.organism_classification, Sciences du Vivant [q-bio]/Microbiologie et Parasitologie, Reactive Nitrogen Species, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Biochemistry, chemistry, Phenazines, Oxidation-Reduction, Function (biology)
Abstract: The opportunistic fungal pathogen Aspergillus fumigatus is increasingly found as a coinfecting agent along with Pseudomonas aeruginosa in cystic fibrosis patients. Amongst the numerous molecules secreted by P. aeruginosa during its growth, phenazines constitute a major class. P. aeruginosa usually secreted four phenazines, pyocyanin (PYO), phenazine-1-carboxamide (PCN), 1-hydroxyphenazine (1-HP) and phenazine-1-carboxylic acid (PCA). These phenazines inhibited the growth of A. fumigatus but the underlying mechanisms and the impact of these four phenazines on A. fumigatus biology were not known. In the present study, we analyzed the functions of the four phenazines and their mode of action on A. fumigatus. All four phenazines showed A. fumigatus growth inhibitory effects by inducing production of reactive oxygen species (ROS), specifically O2·− and reactive nitrogen species (RNS), ONOO−. A. fumigatus Sod2p was the major factor involved in resistance against the ROS and RNS induced by phenazines. Sub-inhibitory concentrations of PYO, PCA and PCN promote A. fumigatus growth by an independent iron-uptake acquisition. Of the four phenazines 1-HP had a redox-independent function; being able to chelate metal ions 1-HP induced A. fumigatus iron starvation. Our data show the fine-interactions existing between A. fumigatus and P. aeruginosa, which can lead to stimulatory or antagonistic effects.
Published: 2015
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39. A new human mast cell line expressing a functional IgE receptor converts to tumorigenic growth by KIT D816V transfection

Author: Harald Herrmann, Rosine Saleh, Emir Hadzijusufovic, Hélène Merle-Béral, Magali Legarff-Tavernier, Peter Valent, Frédéric Subra, Michel Arock, Florence Nguyen-Khac, Patrice Dubreuil, Katharina Blatt, Catherine Blanc, Sabine Cerny-Reiterer, Michael Willmann, Elise Chapiro, Vanessa Desplat, Siham Bibi, Thomas Rülicke, Ghaith Wedeh, Patrick Bonnemye, Sylvie Jeanningros, Irina Sadovnik, Angewandte Physik, Universität Paderborn (UPB), Medizinische Universität Wien = Medical University of Vienna, Service d'hématologie biologique [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Division of Hematology/Hemostaseology, Medical University Vienna, Ludwig Boltzmann Cluster Oncology, Fondation de France, Austrian Science Fund (FWF), SFB project [F4611, F4704-B20], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Paderborn ( UPB ), Service d'hématologie biologique, CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE)
Subjects: Immunology, Blotting, Western, Stem cell factor, Context (language use), Cell Separation, Mice, SCID, Immunoglobulin E, Transfection, Biochemistry, Proinflammatory cytokine, Cell Line, Mice, Mastocytosis, Systemic, Mice, Inbred NOD, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Animals, Humans, Mast Cells, Systemic mastocytosis, Mice, Knockout, biology, Cell Biology, Hematology, medicine.disease, Mast cell, Flow Cytometry, Molecular biology, 3. Good health, Proto-Oncogene Proteins c-kit, medicine.anatomical_structure, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], biology.protein, Mast cell sarcoma, Heterografts
Abstract: International audience; In systemic mastocytosis (SM), clinical problems arise from factor-independent proliferation of mast cells (MCs) and the increased release of mediators by MCs, but no human cell line model for studying MC activation in the context of SM is available. We have created a stable stem cell factor (SCF)-dependent human MC line, ROSA(KIT WT), expressing a fully functional immunoglobulin E (IgE) receptor. Transfection with KIT D816V converted ROSA(KIT WT) cells into an SCF-independent clone, ROSA(KIT D816V), which produced a mastocytosis-like disease in NSG mice. Although several signaling pathways were activated, ROSA(KIT D816V) did not exhibit an increased, but did exhibit a decreased responsiveness to IgE-dependent stimuli. Moreover, NSG mice bearing ROSA(KIT D816V)-derived tumors did not show mediator-related symptoms, and KIT D816V-positive MCs obtained from patients with SM did not show increased IgE-dependent histamine release or CD63 upregulation. Our data show that KIT D816V is a disease-propagating oncoprotein, but it does not activate MCs to release proinflammatory mediators, which may explain why mediator-related symptoms in SM occur preferentially in the context of a coexisting allergy. ROSA(KIT D816V) may provide a valuable tool for studying the pathogenesis of mastocytosis and should facilitate the development of novel drugs for treating SM patients.
Published: 2014
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40. Diverse intracellular pathogens activate type III interferon expression from peroxisomes

Author: Hélène Bierne, Jonathan C. Kagan, Charlotte Odendall, Evelyn Dixit, Lee Gehrke, Ann Fiegen Durbin, Fabrizia Stavru, Steeve Boulant, Pascale Cossart, Kate M Franz, Harvard Medical School [Boston] (HMS), Interactions Bactéries-Cellules (UIBC), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Department of Microbiology and Immunobiology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology (MIT), Department of Infectious Diseases - Virology Schaller research group at CellNetworks and Deutsches Krebsforschungszentrum (DKFZ), Universität Heidelberg [Heidelberg], US National Institutes of Health (AI093589 AI072955 P30 DK34854 CA159132 ), Burroughs Wellcome Fund, Crohn's and Colitis Foundation of America, Agence National de la Recherche (ANR project Mitopatho), Erwin Schrodinger Fellowship of the Austrian Science Fund (FWF), Herchel Smith Graduate Fellowship Program, Massachusetts Institute of Technology-Boston Children's Hospital Collaborative grant, European Research Council Advanced Grant (233348 ), Howard Hughes Medical Institute, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Universität Heidelberg [Heidelberg] = Heidelberg University
Subjects: Cellular differentiation, [SDV]Life Sciences [q-bio], p38 Mitogen-Activated Protein Kinases, DEAD-box RNA Helicases, Mice, Intestinal mucosa, RNA interference, Interferon, Immunology and Allergy, Enzyme Inhibitors, Intestinal Mucosa, RNA, Small Interfering, Receptors, Immunologic, genes, innate immunity, independent antiviral response, Cell Differentiation, cell line, Tyrphostins, 3. Good health, Cell biology, STAT1 Transcription Factor, DEAD Box Protein 58, RNA Interference, Signal transduction, Vidarabine, Signal Transduction, medicine.drug, Pyridones, Immunology, Antineoplastic Agents, Biology, Reoviridae, hepatitis-c virus, Article, Cyclohexanes, medicine, Peroxisomes, Intestinal epithelial cell differentiation, Animals, Humans, Innate immune system, dengue virus, pathway, Intracellular parasite, ifn-lambda-s, Janus Kinase 2, Immunity, Innate, infection, Reoviridae Infections, membrane-proteins, Benzimidazoles, Interferons
Abstract: Type I interferon responses are considered the primary means by which viral infections are controlled in mammals. Despite this view, several pathogens activate antiviral responses in the absence of type I interferons. The mechanisms controlling type I interferon-independent responses are undefined. We found that RIG-I like receptors (RLRs) induce type III interferon expression in a variety of human cell types, and identified factors that differentially regulate expression of type I and type III interferons. We identified peroxisomes as a primary site of initiation of type III interferon expression, and revealed that the process of intestinal epithelial cell differentiation upregulates peroxisome biogenesis and promotes robust type III interferon responses in human cells. These findings highlight the importance of different intracellular organelles in specific innate immune responses.
Published: 2014
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41. The pH-Responsive PacC Transcription Factor of Aspergillus fumigatus Governs Epithelial Entry and Tissue Invasion during Pulmonary Aspergillosis

Author: Darius Armstrong-James, Maryam Safari, Hong Liu, Elaine Bignell, Markus Schrettl, Angela M. Cheverton, Carol A. Munro, Dan Chen, Alberto Muñoz, Natalie D. Fedorova, Shinobu Saijo, Louise A. Walker, Timothy C. Cairns, Susanne Herbst, Scott G. Filler, Margherita Bertuzzi, William C. Nierman, Hubertus Haas, Eduardo A. Espeso, Laura Alcazar-Fuoli, Nick D. Read, Noverr, Mairi C, Medical Research Council (Reino Unido), Biotechnology and Biological Sciences Research Council (Reino Unido), Wellcome Trust, Imperial College London (Reino Unido), FWF Austrian Science Fund, and National Institutes of Health (Estados Unidos)
Subjects: Cell, Aspergillus fumigatus, Mice, Transcriptional regulation, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, Biology (General), Aetiology, Lung, Fungal Pathogens, 0303 health sciences, Fungal protein, Hydrogen-Ion Concentration, 3. Good health, medicine.anatomical_structure, Infectious Diseases, Aspergillus Fumigatus, Medical Microbiology, Respiratory, Infection, Research Article, Proteases, QH301-705.5, Immunology, Mycology, Biology, Microbiology, Fungal Proteins, 03 medical and health sciences, In vivo, Virology, Genetics, medicine, Animals, Microbial Pathogens, Molecular Biology, Transcription factor, Actin, 030304 developmental biology, 030306 microbiology, Biology and Life Sciences, Epithelial Cells, RC581-607, biology.organism_classification, Animal Models of Infection, Emerging Infectious Diseases, Parasitology, Pulmonary Aspergillosis, Immunologic diseases. Allergy, Transcription Factors
Abstract: 20 p.-8 fig. Margherita Bertuzzi et alt., Destruction of the pulmonary epithelium is a major feature of lung diseases caused by the mould pathogen Aspergillus fumigatus. Although it is widely postulated that tissue invasion is governed by fungal proteases, A. fumigatus mutants lacking individual or multiple enzymes remain fully invasive, suggesting a concomitant requirement for other pathogenic activities during host invasion. In this study we discovered, and exploited, a novel, tissue non-invasive, phenotype in A.fumigatus mutants lacking the pH-responsive transcription factor PacC. Our study revealed a novel mode of epithelial entry,occurring in a cell wall-dependent manner prior to protease production, and via the Dectin-1 b-glucan receptor. DpacC mutants are defective in both contact-mediated epithelial entry and protease expression, and significantly attenuated for pathogenicity in leukopenic mice. We combined murine infection modelling, in vivo transcriptomics, and in vitro infections of human alveolar epithelia, to delineate two major, and sequentially acting, PacC-dependent processes impacting epithelial integrity in vitro and tissue invasion in the whole animal. We demonstrate that A. fumigatus spores and germlings are internalised by epithelial cells in a contact-, actin-, cell wall- and Dectin-1 dependent manner and DpacC mutants, which aberrantly remodel the cell wall during germinative growth, are unable to gain entry into epithelial cells, both in vitro and in vivo. We further show that PacC acts as a global transcriptional regulator of secreted molecules during growth in the leukopenic mammalian lung, and profile the full cohort of secreted gene products expressed during invasive infection. Our study reveals a combinatorial mode of tissue entry dependent upon sequential, and mechanistically distinct, perturbations of the pulmonary epithelium and demonstrates, for the first time a protective role for Dectin-1 blockade in epithelial defences. Infecting DpacC mutants are hypersensitive to cell wall-active antifungal agents highlighting the value of PacC signalling as a target for antifungal therapy., This work was supported in part by grants to EMB from the MRC (G0501164) and BBSRC (BB/G009619/1), to EMB and NDR from the Wellcome Trust(WT093596MA), to MB from Imperial College London (Division of Investigative Sciences PhD Studentship), to HH from the ERA-NET PathoGenoMics project TRANSPAT, Austrian Science Foundation (FWF I282-B09), to SGF from the National Institutes of Health, USA (R01AI073829). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Published: 2014
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42. Systematic phenotyping of a large-scale Candida glabrata deletion collection reveals novel antifungal tolerance genes

Author: Biao Ma, Walter Glaser, Dominique Ferrandon, Marina Marcet-Houben, Ken Haynes, Jessica Quintin, Ute Zeidler, Fabian Istel, Brendan P. Cormack, Ingrid E. Frohner, Sascha Brunke, Katja Seider, Christophe d'Enfert, Brian Green, Sophie Bachellier-Bassi, Lauren Ames, Steffen Rupp, Karl Kuchler, Ilse D. Jacobsen, Ekkehard Hiller, Helmut Jungwirth, Vitor Cabral, Michael Tscherner, Arnaud Firon, Tobias Schwarzmüller, Murielle Chauvel, Bernhard Hube, Toni Gabaldón, Publica, Medizinische Universität Wien = Medical University of Vienna, Johns Hopkins University School of Medicine [Baltimore], Imperial College London, Fraunhofer Institute for Interfacial Engineering and Biotechnology (IGB), Center for sepsis control care, Friedrich Schiller University Jena [Jena, Germany], Leibniz Institute for Natural Product Research and Infection Biology (Hans Knoell Institute), Friedrich-Schiller-Universität Jena, University of Exeter, Biologie et Pathogénicité fongiques, Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris], Cellule Pasteur UPMC, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris], Centre for Genomic Regulation [Barcelona] (CRG), Universitat Pompeu Fabra [Barcelona]-Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut für Molekulare Biowissenschaften [Graz], Karl-Franzens-Universität Graz, This work was supported by the Austrian Science Foundation FWF through the ERA-Net Pathogenomics project FunPath to KK (FWF-API-0125), SR (BMBF: 0313931A), TG, CD, DF and BH, and in part by the Christian Doppler Society to KK. BC and BM were supported in part by NIH RO1AI46223. BH and SB were supported by the German Federal Ministry of Education and Research (BMBF) through FKZ: 01EO1002. TG was funded in part by grants from the Spanish ministry of science and innovation (GEN2006-27784E, BFU2009-09168). KH was funded by the BBSRC (BB/F005210/1). DF was also partly supported by CNRS and the Fondation pour la recherche Medicale (Programme Equipe FRM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., ANR-06-PATH-0005,FUNPATH,Genomic approaches to unravel the molecular mechanisms of pathogenicity in the human fungal pathogen candida glabrata(2006), Fraunhofer Institute for Interfacial Engineering and Biotechnology (Fraunhofer IGB), Fraunhofer (Fraunhofer-Gesellschaft), Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany], Biologie et Pathogénicité fongiques (BPF), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP), Universitat Pompeu Fabra [Barcelona] (UPF)-Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), lenormand, christelle, and Programme de recherche transnational Pathogenomics (ERA-NET) - Genomic approaches to unravel the molecular mechanisms of pathogenicity in the human fungal pathogen candida glabrata - - FUNPATH2006 - ANR-06-PATH-0005 - PATHO - VALID
Subjects: Azoles, Antifungal Agents, Antifungal drug, Candida glabrata, Biochemistry, biofilm, Echinocandins, Gene Knockout Techniques, chemistry.chemical_compound, MESH: Lipopeptides, Caspofungin, Cell Wall, MESH: Azoles, saccharomyces cerevisiae, délétion, Biology (General), Candida albicans, MESH: Candida glabrata, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, MESH: Gene Knockout Techniques, 0303 health sciences, Fungal protein, MESH: Microbial Sensitivity Tests, biology, Candidiasis, Fungal genetics, MESH: Candidiasis, phénotype, Phenotype, Medical Microbiology, antifongique, MESH: Fungal Proteins, paroi cellulaire, Functional genomics, Research Article, medicine.drug, Echinocandin, QH301-705.5, Immunology, Microbial Sensitivity Tests, MESH: Biofilms, MESH: Phenotype, Microbiology, MESH: Drug Resistance, Fungal, Fungal Proteins, Lipopeptides, pathogène fongique, 03 medical and health sciences, MESH: Cell Wall, Drug Resistance, Fungal, Osmotic Pressure, Virology, MESH: Gene Library, Genetics, medicine, azole, Microbial Pathogens, Molecular Biology, Gene Library, 030304 developmental biology, 030306 microbiology, MESH: Echinocandins, Biology and Life Sciences, RC581-607, MESH: Osmotic Pressure, biology.organism_classification, bacterial infections and mycoses, MESH: Antifungal Agents, [SDV.MP.MYC] Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, chemistry, MESH: Gene Deletion, Biofilms, Parasitology, Immunologic diseases. Allergy, Gene Deletion
Abstract: The opportunistic fungal pathogen Candida glabrata is a frequent cause of candidiasis, causing infections ranging from superficial to life-threatening disseminated disease. The inherent tolerance of C. glabrata to azole drugs makes this pathogen a serious clinical threat. To identify novel genes implicated in antifungal drug tolerance, we have constructed a large-scale C. glabrata deletion library consisting of 619 unique, individually bar-coded mutant strains, each lacking one specific gene, all together representing almost 12% of the genome. Functional analysis of this library in a series of phenotypic and fitness assays identified numerous genes required for growth of C. glabrata under normal or specific stress conditions, as well as a number of novel genes involved in tolerance to clinically important antifungal drugs such as azoles and echinocandins. We identified 38 deletion strains displaying strongly increased susceptibility to caspofungin, 28 of which encoding proteins that have not previously been linked to echinocandin tolerance. Our results demonstrate the potential of the C. glabrata mutant collection as a valuable resource in functional genomics studies of this important fungal pathogen of humans, and to facilitate the identification of putative novel antifungal drug target and virulence genes., Author Summary Clinical infections by the yeast-like pathogen Candida glabrata have been ever-increasing over the past years. Importantly, C. glabrata is one of the most prevalent causes of drug-refractory fungal infections in humans. We have generated a novel large-scale collection encompassing 619 bar-coded C. glabrata mutants, each lacking a single gene. Extensive profiling of phenotypes reveals a number of novel genes implicated in tolerance to antifungal drugs that interfere with proper cell wall function, as well as genes affecting fitness of C. glabrata both during normal growth and under environmental stress. This fungal deletion collection will be a valuable resource for the community to study mechanisms of virulence and antifungal drug tolerance in C. glabrata, which is particularly relevant in view of the increasing prevalence of infections caused by this important human fungal pathogen.
Published: 2014
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43. Uncovering Wolbachia diversity upon artificial host transfer

Author: Daniela I, Schneider, Markus, Riegler, Wolfgang, Arthofer, Hervé, Merçot, Christian, Stauffer, Wolfgang J, Miller, Evolution des Génomes Eucaryotes (EGE), Evolution Paris Seine, Université des Antilles et de la Guyane (UAG)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles et de la Guyane (UAG)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Austrian Science Fund [FWF P19206-B17, P22634-B17], EU-COST Action [FA0701], Université des Antilles et de la Guyane (UAG)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles et de la Guyane (UAG)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Nice Sophia Antipolis (1965 - 2019) (UNS)
Subjects: Science, Molecular Sequence Data, [SDV.BID]Life Sciences [q-bio]/Biodiversity, Polymorphism, Single Nucleotide, Synteny, Host Specificity, Gene Frequency, parasitic diseases, Animals, Amino Acids, Conserved Sequence, reproductive and urinary physiology, Base Sequence, Nucleotides, Ovary, Gene Transfer Techniques, Genetic Variation, Ceratitis capitata, biochemical phenomena, metabolism, and nutrition, Genes, Bacterial, Codon, Terminator, bacteria, Medicine, Drosophila, Female, Wolbachia, Research Article
Abstract: International audience; The common endosymbiotic Wolbachia bacteria influence arthropod hosts in multiple ways. They are mostly recognized for their manipulations of host reproduction, yet, more recent studies demonstrate that Wolbachia also impact host behavior, metabolic pathways and immunity. Besides their biological and evolutionary roles Wolbachia are new potential biological control agents for pest and vector management. Importantly, Wolbachia-based control strategies require controlled symbiont transfer between host species and predictable outcomes of novel Wolbachia-host associations. Theoretically, this artificial horizontal transfer could inflict genetic changes within transferred Wolbachia populations. This could be facilitated through de novo mutations in the novel recipient host or changes of haplotype frequencies of polymorphic Wolbachia populations when transferred from donor to recipient hosts. Here we show that Wolbachia resident in the European cherry fruit fly, Rhagoletis cerasi, exhibit ancestral and cryptic sequence polymorphism in three symbiont genes, which are exposed upon microinjection into the new hosts Drosophila simulans and Ceratitis capitata. Our analyses of Wolbachia in microinjected D. simulans over 150 generations after microinjection uncovered infections with multiple Wolbachia strains in trans-infected lines that had previously been typed as single infections. This confirms the persistence of low-titer Wolbachia strains in microinjection experiments that had previously escaped standard detection techniques. Our study demonstrates that infections by multiple Wolbachia strains can shift in prevalence after artificial host transfer driven by either stochastic or selective processes. Trans-infection of Wolbachia can claim fitness costs in new hosts and we speculate that these costs may have driven the shifts of Wolbachia strains that we saw in our model system.
Published: 2013
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44. Discovery of depsides and depsidones from lichen as potent inhibitors of microsomal prostaglandin E2 synthase-1 using pharmacophore models

Author: Judith M. Rollinger, Hermann Stuppner, Oliver Werz, Julia Bauer, Stefan M. Noha, Birgit Waltenberger, Chollet Marylene, Joël Boustie, Daniela Schuster, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, University of Innsbruck, Institut des Sciences Chimiques de Rennes (ISCR), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), AureliaSan GmbH (Tuebingen, Germany), the Standortagentur Tirol (TWF) the Austrian Science Fund (FWF) [NFN S10711, S10703, S10701], Leopold Franzens Universität Innsbruck - University of Innsbruck, Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), and Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Models, Molecular, 01 natural sciences, Biochemistry, Lactones, Drug Discovery, General Pharmacology, Toxicology and Pharmaceutics, Prostaglandin E2, Prostaglandin-E Synthases, 0303 health sciences, ATP synthase, Drug discovery, Anti-Inflammatory Agents, Non-Steroidal, MESH: Lichens, MESH: Anti-Inflammatory Agents, Non-Steroidal, 3. Good health, Intramolecular Oxidoreductases, MESH: Depsides, Molecular Medicine, Pharmacophore, MESH: Models, Molecular, MESH: Lactones, medicine.drug, musculoskeletal diseases, Lichens, Stereochemistry, In silico, Biology, Depsides, Article, Cell Line, MESH: Microsomes, 03 medical and health sciences, MESH: Computer Simulation, MESH: Drug Discovery, Microsomes, medicine, Humans, Computer Simulation, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 030304 developmental biology, Pharmacology, Virtual screening, MESH: Humans, 010405 organic chemistry, Organic Chemistry, MESH: Intramolecular Oxidoreductases, 0104 chemical sciences, MESH: Cell Line, Microsome, biology.protein
Abstract: International audience; Nature in silico: Virtual screening using validated pharmacophore models identified lichen depsides and depsidones as potential inhibitors of mPGES-1, an emerging target for NSAIDs. Evaluation of the virtual hits in a cell-free assay revealed physodic acid and perlatolic acid as potent inhibitors of mPGES-1 (IC(50) = 0.4 and 0.43 μM, respectively), indicating that these natural products have potential as novel anti-inflammatory agents.
Published: 2012
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45. The Light Chains of Microtubule-Associated Proteins MAP1A and MAP1B Interact with alpha 1-Syntrophin in the Central and Peripheral Nervous System

Author: Luise Descovich, Douglas E. Albrecht, Stanley C. Froehner, Fatiha Nothias, Rainer Noiges, Friedrich Propst, Irmgard Fischer, Heike Fuhrmann-Stroissnigg, Régénération et croissance de l'axone = Axonal Growth and Regeneration (NPS-12), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Austrian Science Fund (FWF) [F607], City of Vienna [J-15/05], National Institutes of Health [NS33145], Austrian Academy of Sciences, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Central Nervous System, Cytoplasm, GTPase-activating protein, EGF-like domain, Muscle Proteins, Protein domains, Microtubules, Biochemistry, Mice, 0302 clinical medicine, EVH1 domain, Sciatic nerves, Molecular Cell Biology, Schwann cells, Cytoskeleton, Recombinant proteins, 0303 health sciences, Multidisciplinary, Neuronal Morphology, Signal transducing adaptor protein, Cell Differentiation, Cellular Structures, Cell biology, Pleckstrin homology domain, Protein Transport, Medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Microtubule-Associated Proteins, Protein Binding, Research Article, Signal Transduction, Cell Adhesion Molecules, Neuronal, Science, Protein domain, PDZ domain, Biology, 03 medical and health sciences, Developmental Neuroscience, Neuroglial Development, Peripheral Nervous System, DNA-binding proteins, Animals, 030304 developmental biology, Calcium-Binding Proteins, Membrane Proteins, Proteins, Protein interactions, Cell membranes, Cytoskeletal Proteins, Cellular Neuroscience, DEP domain, Molecular Neuroscience, Ranvier's nodes, 030217 neurology & neurosurgery, Developmental Biology, Neuroscience
Abstract: International audience; Microtubule-associated proteins of the MAP1 family (MAP1A, MAP1B, and MAP1S) share, among other features, a highly conserved COOH-terminal domain approximately 125 amino acids in length. We conducted a yeast 2-hybrid screen to search for proteins interacting with this domain and identified alpha 1-syntrophin, a member of a multigene family of adapter proteins involved in signal transduction. We further demonstrate that the interaction between the conserved COOH-terminal 125-amino acid domain (which is located in the light chains of MAP1A, MAP1B, and MAP1S) and alpha 1-syntrophin is direct and occurs through the pleckstrin homology domain 2 (PH2) and the postsynaptic density protein 95/disk large/zonula occludens-1 protein homology domain (PDZ) of alpha 1-syntrophin. We confirmed the interaction of MAP1B and alpha 1-syntrophin by co-localization of the two proteins in transfected cells and by co-immunoprecipitation experiments from mouse brain. In addition, we show that MAP1B and alpha 1-syntrophin partially co-localize in Schwann cells of the murine sciatic nerve during postnatal development and in the adult. However, intracellular localization of alpha 1-syntrophin and other Schwann cell proteins such as ezrin and dystrophin-related protein 2 (DRP2) and the localization of the axonal node of Ranvier-associated protein Caspr1/paranodin were not affected in MAP1B null mice. Our findings add to a growing body of evidence that classical MAPs are likely to be involved in signal transduction not only by directly modulating microtubule function, but also through their interaction with signal transduction proteins.
Published: 2012
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46. PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans

Author: Anais Grall, Céline Derbois, Matthieu Le Gallo, Ingrid Hausser, Laetitia Lagoutte, Sébastien Küry, Judith Fischer, Catherine André, Emmanuelle Bourrat, Emmanuel Bensignor, Sandrine Planchais, Franz P.W. Radner, Éric Guaguère, Francis Galibert, Rudolf Zechner, Susanne Grond, Jacques Fontaine, Robert Zimmermann, Gwang-Jin Kim, Mark Lathrop, Frédérique Degorce-Rubiales, Anne Thomas, Didier Pin, Christophe Hitte, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Clinique Vétérinaire Saint Bernard, Institute of Molecular Biosciences, Karl-Franzens-Universität Graz, Service de dermatologie [Paris], Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of dermatology, University clinic Heidelberg, Electron Microscopy Core Facility, Universität Heidelberg [Heidelberg], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Génomique d'Evry (IG), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institute for Human Genetics, University Clinic Freiburg, Faculty for Biology, University of Freiburg [Freiburg], Laboratoire d'Anatomie Pathologique Vétérinaire du Sud-Ouest, Animal Genetics Laboratory, Antagene, Service d'ORL et de Chirurgie Cervicofaciale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Clinique Vétérinaire de la Boulais, Clinique vétérinaire, Clinique vétérinaire, Bruxelles, Interactions Cellules Environnement - UR (ICE), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Zentrum für Biosystemanalyse, Albert-Ludwigs-Universität Freiburg, This study was supported by CNRS, the European Commission (FP7-LUPA, GA-201370). R. Zechner and R. Zimmermann were supported by the FWF F30 SFB Lipotox, Z136 Wittgenstein, the GEN-AU project GOLD by the Austrian Ministry of Science and Research and FFG. I.H. was supported by the NIRK Network (German BMBF 01GM0904)., European Project: 201370,EC:FP7:HEALTH,FP7-HEALTH-2007-A,LUPA(2008), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Institut de Génomique d'Evry ( IG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Trousseau [APHP], Unité de Dermatologie, VetAgro Sup ( VAS ), Centre d'Etude du Polymorphisme Humain ( CEPH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Fondation Jean Dausset, European Project : 201370,EC:FP7:HEALTH,FP7-HEALTH-2007-A,LUPA ( 2008 ), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universität Heidelberg [Heidelberg] = Heidelberg University, Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), De Villemeur, Hervé, and Unravelling the molecular basis of common complex human disorders using the dog as a model system - LUPA - - EC:FP7:HEALTH2008-01-01 - 2012-06-30 - 201370 - VALID
Subjects: Male, MESH : Molecular Sequence Data, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Base Sequence, medicine.disease_cause, 0403 veterinary science, MESH: Dogs, MESH: INDEL Mutation, MESH: Lipase, MESH : Dogs, INDEL Mutation, Congenital ichthyosis, Missense mutation, MESH : Female, MESH: Animals, MESH: Codon, Nonsense, Cells, Cultured, Skin, Genetics, 0303 health sciences, Mutation, 04 agricultural and veterinary sciences, Lamellar ichthyosis, MESH : Adult, MESH : Lipase, MESH : Dermatologic Agents, MESH : Codon, Nonsense, MESH: Ichthyosis, Lamellar, Codon, Nonsense, Female, MESH : Genome-Wide Association Study, MESH: Cells, Cultured, Adult, 040301 veterinary sciences, MESH : Male, Nonsense mutation, Molecular Sequence Data, Mutation, Missense, ALOX12B, Golden Retriever, Genes, Recessive, MESH: Nitrendipine, Biology, 03 medical and health sciences, Dogs, MESH: Skin, MESH : Cells, Cultured, medicine, MESH : Skin, Animals, Humans, Indel, MESH : INDEL Mutation, MESH: Genes, Recessive, 030304 developmental biology, MESH: Mutation, Missense, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, Nitrendipine, MESH : Humans, MESH : Ichthyosis, Lamellar, MESH : Genes, Recessive, MESH: Adult, Lipase, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, medicine.disease, MESH : Nitrendipine, MESH: Male, MESH: Dermatologic Agents, MESH: Genome-Wide Association Study, MESH : Base Sequence, MESH : Animals, Dermatologic Agents, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, [ SDV.MHEP.DERM ] Life Sciences [q-bio]/Human health and pathology/Dermatology, MESH: Female, MESH : Mutation, Missense, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, Ichthyosis, Lamellar, Genome-Wide Association Study
Abstract: International audience; Ichthyoses comprise a heterogeneous group of genodermatoses characterized by abnormal desquamation over the whole body, for which the genetic causes of several human forms remain unknown. We used a spontaneous dog model in the golden retriever breed, which is affected by a lamellar ichthyosis resembling human autosomal recessive congenital ichthyoses (ARCI), to carry out a genome-wide association study. We identified a homozygous insertion-deletion (indel) mutation in PNPLA1 that leads to a premature stop codon in all affected golden retriever dogs. We subsequently found one missense and one nonsense mutation in the catalytic domain of human PNPLA1 in six individuals with ARCI from two families. Further experiments highlighted the importance of PNPLA1 in the formation of the epidermal lipid barrier. This study identifies a new gene involved in human ichthyoses and provides insights into the localization and function of this yet uncharacterized member of the PNPLA protein family.
Published: 2011
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47. A Place to Hide in the Home-Cage Decreases Yolk Androgen Levels and Offspring Emotional Reactivity in Japanese Quail

Author: Kurt Kotrschal, Sophie Lumineau, Marie-Annick Richard-Yris, Erich Möstl, Aline Bertin, Vanessa Guesdon, Laureline Formanek, Cécilia Houdelier, Ethologie animale et humaine (EthoS), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Konrad Lorenz Forschungsstelle Grünau, Universität Wien, Department of Biomedical Sciences, Medical Biochemistry, University of Veterinary Medicine [Vienna] (Vetmeduni), Foundation Fyssen, FWF (Fonds zur Förderung der Wissenschaftlichen Forschung: The Austrian Science Fund) Project P 18601-017, Normandie Université (NU)-Normandie Université (NU)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0106 biological sciences, TESTOSTERONE LEVELS, Animal Evolution, AMONG-CLUTCH VARIATION, Emotions, Physiology, réaction émotionnelle, lcsh:Medicine, DEVELOPMENTAL STRESS, Territoriality, Social Environment, 01 natural sciences, comportement animal, stress, Cognition, Testosterone, lcsh:Science, Animal Management, Multidisciplinary, GALLUS-DOMESTICUS, biology, Behavior, Animal, Animal Behavior, 05 social sciences, Agriculture, Animal Models, COTURNIX-COTURNIX-JAPONICA, Egg Yolk, Quail, Androgens, Female, CORTICOSTERONE LEVELS, Research Article, medicine.medical_specialty, food.ingredient, Offspring, Science Policy, acceptabilité, Cognitive Neuroscience, Animal Types, SPARROW PASSER-DOMESTICUS, MATERNAL TESTOSTERONE, Coturnix, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Environment, STEROID-HORMONES, Animal Welfare, 010603 evolutionary biology, BIEN-ETRE ANIMAL, food, Model Organisms, Internal medicine, biology.animal, Animal welfare, Yolk, medicine, caille japonaise, Animal Physiology, Animals, 0501 psychology and cognitive sciences, 050102 behavioral science & comparative psychology, Androstenedione, comportement social, Biology, Ecosystem, ENVIRONMENTAL ENRICHMENT, coturnix coturnix japonica, Evolutionary Biology, Behavior, Animal, lcsh:R, Bioethics, biology.organism_classification, Animal Cognition, Organismal Evolution, Endocrinology, Crowding, oeuf, Animal Studies, Veterinary Science, lcsh:Q, Zoology, Neuroscience
Abstract: International audience; An animal's emotional responses are the result of its cognitive appraisal of a situation. This appraisal is notably influenced by the possibility of an individual to exert control over an aversive event. Although the fact that environment controllability decreases emotional responses in animals is well established, far less is known about its potential trans-generational effects. As the levels of avian yolk hormones can vary according to the mother's environment, we hypothesized that housing environment of mothers would modulate the quality of her eggs and in turn her offspring's behaviour. Two groups of female japanese quail were constituted: a group that had access to a place to hide in their home-cage (Hd, n = 20) and a group that had nowhere to hide (NoHd, n = 20) when stressed. Both groups were submitted to daily human disturbances for a twenty-day-period. Hd females produced eggs with both less testosterone and androstenedione than did NoHd females. The emotional and social reactivity of Hd female's offspring were lower and their growth wes slower than those of NoHd females' offspring. Our results show that a minor difference in housing environment had substantial effects on eggs and offspring. The presence of a shelter probably helped quail to cope with daily human disturbances, producing less reactive offspring. This transgenerational effect caused by an opportunity to hide could lead to applications in care of laboratory animals, conservation biology and animal welfare.
Published: 2011
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48. LipA, a tyrosine and lipid phosphatase involved in the virulence of Listeria monocytogenes

Author: Didier Soulat, Renate Kastner, Pascale Cossart, Elisabeth Kernbauer, Cristel Archambaud, Olivier Dussurget, Thomas Decker, University of Vienna [Vienna], Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), USC2020, Inst Natl Rech Agron, Interactions Bactéries-Cellules (UIBC), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Vienna, Austrian Science Fund (FWF) [P 20522-B05], Institut Pasteur [GPH9], Inserm, INRA, ANR [ANR-06-PATHO-011-01], ERC [233348], Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-06-PATH-0011,SPATELIS,Spatio-temporal analysis of Listeria-host protein interactions(2006), and European Project: 233348,EC:FP7:ERC,ERC-2008-AdG,MODELIST(2009)
Subjects: [SDV]Life Sciences [q-bio], PROTEIN, Protein tyrosine phosphatase, medicine.disease_cause, Mice, INFECTION, Listeriosis, Tyrosine, POSTTRANSLATIONAL MODIFICATIONS, 0303 health sciences, biology, IN-VITRO TRANSCRIPTION, PHOSPHOINOSITIDE METABOLISM, MYCOBACTERIUM-TUBERCULOSIS, HOST-CELLS, BACTERIAL PATHOGENESIS, IMMUNE-RESPONSES, III SECRETION, Bacterial Infections, 3. Good health, Infectious Diseases, Biochemistry, Lipid phosphatase activity, Virulence Factors, Blotting, Western, Immunology, Phosphatase, Virulence, Enzyme-Linked Immunosorbent Assay, Hemolytic Plaque Technique, Listeria infection, Microbiology, Cell Line, 03 medical and health sciences, Bacterial Proteins, Listeria monocytogenes, medicine, Animals, 030304 developmental biology, 030306 microbiology, Macrophages, biology.organism_classification, medicine.disease, Mice, Inbred C57BL, Listeria, Parasitology, Protein Tyrosine Phosphatases
Abstract: Intracellular bacterial pathogens manipulate host cell functions by producing enzymes that stimulate or antagonize signal transduction. The Listeria monocytogenes genome contains a gene, lmo1800 , encoding a protein with a conserved motif of conventional tyrosine phosphatases. Here, we report that the lmo1800 -encoded protein LipA is secreted by Listeria and displays tyrosine as well as lipid phosphatase activity in vitro . Bacteria lacking LipA are severely attenuated in virulence in vivo , thus revealing a so-far-undescribed enzymatic activity involved in Listeria infection.
Published: 2011
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49. Habituation to humans affects yolk steroid levels and offspring phenotype in quail

Author: Kurt Kotrschal, Aline Bertin, Alexandra Kuchar, Katharina Hirschenhauser, Cécilia Houdelier, Marie-Annick Richard-Yris, Erich Möstl, Sophie Lumineau, Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), Ethologie animale et humaine (EthoS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Department of Biomedical Sciences, Institute of Biochemistry, University of Veterinary Medicine, Konrad Lorenz Forschungsstelle Grünau, Universität Wien, Department of Behavioural Biology, University of Vienna [Vienna], Foundation Fyssen, FWF Project P 18601-017, Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Normandie Université (NU)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0106 biological sciences, medicine.medical_specialty, food.ingredient, Eggs' quality, Offspring, Maternal effects, Coturnix japonica, Yolk steroids, [SDV]Life Sciences [q-bio], Emotions, Coturnix, Growth, Social Environment, 010603 evolutionary biology, 01 natural sciences, Behavioral Neuroscience, Endocrinology, food, Internal medicine, biology.animal, Yolk, medicine, Animals, 0501 psychology and cognitive sciences, Testosterone, Human disturbances, 050102 behavioral science & comparative psychology, Androstenedione, Habituation, Gonadal Steroid Hormones, Habituation, Psychophysiologic, Progesterone, Behavior, biology, Endocrine and Autonomic Systems, Hatching, 05 social sciences, Egg Proteins, Maternal effect, Quail, Phenotype, Oviparity, embryonic structures, Androgens, Female, Arousal
Abstract: In the field as well as in the laboratory, human-generated stress responses are reduced in adult animals previously habituated to humans in comparison to non-habituated individuals. In birds, yolk steroid levels vary with maternal environment and condition. We tested the hypothesis that the experience of female birds with humans could affect yolk steroids levels and offspring phenotype. Two groups of Japanese quail, one habituated to humans (H) and a second non-habituated (NH), were exposed daily to brief human disturbances. We analysed egg quality, offspring growth, and offspring emotional reactivity. NH females produced eggs with less androgens (testosterone and androstenedione) and more immunoreactive progesterone compared to birds habituated to humans. NH females produced eggs with less yolk, heavier shell and chicks hatching later and being smaller as compared to habituated individuals. A lower emotional reactivity was found in young of NH females compared to young of H females. Thus, human disturbance of the mother triggered different effects on chick phenotype depending on previous experience of mother birds with humans. In addition, we describe for the first time the influence of environmental stimuli on yolk immunoreactive progesterone levels. Our results show that a relatively minor difference in behavioral habituation may have substantial effects on eggs and offspring. This has obvious implications for keeping and handling laboratory animals, for conservation biology and for animal welfare.
Published: 2008
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50. In vivo reinsertion of excised episomes by the V(D)J recombinase: a potential threat to genomic stability

Author: Bertrand Montpellier, Bertrand Nadel, Pierre Ferrier, Immo Prinz, Olivier Cabaud, Jean-Marc Navarro, Elodie Vachez, Katrina Vanura, Trang Le, Rodrig Marculescu, Sandrine Roulland, Ulrich Jäger, Salvatore Spicuglia, Division of Hematology, Medizinische Universität Wien = Medical University of Vienna, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the grant ID20010 from the Centre of Molecular Medicine (Austrian Academy of Science), the grant P13984 from the Fonds zur Förderung der Wissenschaftlichen Forschung (FWF), the Austrian GEN-AU GZ 200.136/1-VI/1/2005 project, the grant INE2003114116 from la Fondation pour la Recherche Médicale (FRM), a grant from Le Conseil Général des Bouches du Rhône, and institutional grants from Institut National de la Santé et de la Recherche Médicale (INSERM) and Centre National De La Recherche Scientifique (CNRS). Work in the BN lab is supported by the AVENIR2003 grant from INSERM. The PF lab is supported by specific grants from the Association pour la Recherche sur le Cancer (ARC grant 3275) and the Foundation Princesse Grace de Monaco. BN is a recipient of a Contrat d'Interface INSERM/Assistance Publique-Hôpitaux de Marseille. BM is a recipient of a fellowship from la Ligue Nationale Contre le Cancer., Haon, Marie Laure, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
Subjects: Genome instability, [SDV.IMM] Life Sciences [q-bio]/Immunology, QH301-705.5, Chromosomal translocation, Biology, medicine.disease_cause, Genome, Polymerase Chain Reaction, General Biochemistry, Genetics and Molecular Biology, Genomic Instability, Translocation, Genetic, 03 medical and health sciences, Mice, 0302 clinical medicine, Recombinase, medicine, Animals, Leukemia-Lymphoma, Adult T-Cell, MESH: Animals, MESH: Leukemia-Lymphoma, Adult T-Cell, Biology (General), VDJ Recombinases, MESH: Mice, Cells, Cultured, 030304 developmental biology, Genetics, Recombination, Genetic, 0303 health sciences, MESH: VDJ Recombinases, General Immunology and Microbiology, General Neuroscience, MESH: Genomic Instability, Synapsis, MESH: Polymerase Chain Reaction, Gene rearrangement, MESH: Translocation, Genetic, 3. Good health, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Recombination, Genetic, General Agricultural and Biological Sciences, Carcinogenesis, Ex vivo, 030215 immunology, Research Article, MESH: Cells, Cultured
Abstract: It has long been thought that signal joints, the byproducts of V(D)J recombination, are not involved in the dynamics of the rearrangement process. Evidence has now started to accumulate that this is not the case, and that signal joints play unsuspected roles in events that might compromise genomic integrity. Here we show both ex vivo and in vivo that the episomal circles excised during the normal process of receptor gene rearrangement may be reintegrated into the genome through trans-V(D)J recombination occurring between the episomal signal joint and an immunoglobulin/T-cell receptor target. We further demonstrate that cryptic recombination sites involved in T-cell acute lymphoblastic leukemia–associated chromosomal translocations constitute hotspots of insertion. Eventually, the identification of two in vivo cases associating episomal reintegration and chromosomal translocation suggests that reintegration events are linked to genomic instability. Altogether, our data suggest that V(D)J-mediated reintegration of episomal circles, an event likely eluding classical cytogenetic screenings, might represent an additional potent source of genomic instability and lymphoid cancer., Author Summary Lymphoid cells recognize billions of pathogens as a result of gene rearrangements that generate pathogen-specific B- and T-cell receptors. This genetic reshuffling, called V(D)J recombination, occasionally misfires and damages genomic integrity. When such aberrations dysregulate proto-oncogenes, cancer ensues. It has become increasingly clear that multiple oncogenes acting in different cellular pathways can cooperate to cause cancer. Nevertheless, in the case of T-cell acute lymphoblastic leukemia, about a third of cases display oncogene activation in the absence of identified aberration, suggesting the presence of additional mechanisms of chromosomal alteration. In the hunt for such mechanisms, episomal circles (DNA segments that are excised during V(D)J recombination) have recently drawn attention. Moreover, signal joints, short sequences formed after gene rearrangements, once considered harmless, now appear to take part in events that might compromise genomic integrity. Using ex vivo recombination assays and genetically modified mice, we demonstrate that episomal circles may be reintegrated into the genome through recombination occurring between the episomal signal joints and a T-cell receptor target. Furthermore, we show that cryptic recombination sites located in the vicinity of oncogenes constitute hotspots of episomal insertion. Altogether, our results suggest that reintegration of excised episomal circles constitute a potential source of genomic instability and cancer in leukemia and lymphoma., Episomal DNA circles are the by-products of immunoreceptor gene rearrangements in lymphoid cells. Episomal circles can be reintegrated into the genome by trans-V(D)J recombination and cause oncogene deregulation.
Published: 2007
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