Author: "Région Pays de la Loire" / Topic: 03 medical and health sciences - Searchworks@Jio Institute Digital Library Search Results

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108 results on '"Région Pays de la Loire"'

1. Discovery of a Small-Molecule Inhibitor of Interleukin 15: Pharmacophore-Based Virtual Screening and Hit Optimization

Author: Yannick Jacques, Monique Mathé-Allainmat, Laurence Arzel, Mike Maillasson, Erwan Mortier, Jacques Lebreton, Romy Vomiandry, Didier Dubreuil, Agnès Quéméner, Benoit Sicard, 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), Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation (CEISAM), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), This work was funded by the programs CIMATH2 (Ciblage Moléculaire et Applications Thérapeutiques 2) and PIRAMID (Protein‐protein Interactions in Rational Approaches for Medicinal Innovative Drugs) supported by La Région Pays de la Loire. R.V. was supported by a fellowship from La Région Pays de la Loire. We thank CHEM)Symbiose and IMPACT facilities for technical assistance., Bernardo, Elizabeth, 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), and Université de Nantes (UN)-Université de Nantes (UN)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, 01 natural sciences, Cell Line, Small Molecule Libraries, Mice, Structure-Activity Relationship, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Drug Discovery, medicine, Animals, Humans, Receptor, Cell Proliferation, Interleukin-15, Virtual screening, 010405 organic chemistry, Chemistry, Interleukin, Stereoisomerism, Triazoles, Small molecule, 0104 chemical sciences, 3. Good health, Cell biology, Interleukin-2 Receptor beta Subunit, Molecular Docking Simulation, 030104 developmental biology, Cytokine, Interleukin 15, Immunology, Phthalazines, Molecular Medicine, Pharmacophore, Databases, Chemical, CD8
Abstract: International audience; Interleukin (IL)-15 is a pleiotropic cytokine, which is structurally close to IL-2 and shares with it the IL-2 β and γ receptor (R) subunits. By promoting the activation and proliferation of NK, NK-T and CD8+ T cells, IL-15 plays important roles in innate and adaptative immunity. Moreover, the association of high levels of IL-15 expression with inflammatory and autoimmune diseases has led to the development of various antagonistic approaches targeting IL- 15. This study is an original approach aimed at discovering small-molecule inhibitors impeding IL-15/IL-15R interaction. A pharmacophore and docking-based virtual screening of compound libraries led to the selection of 240 high-scoring compounds, 36 of which were found to bind IL-15, to inhibit the binding of IL-15 to the IL-2Rβ chain and/or the proliferation of IL-15-dependent cells. One of them was selected as a hit, optimized by a structure-activity relationship approach, leading to the first small-molecule IL-15 inhibitor with sub-micromolar activity.
Published: 2017

2. Loss of vascular expression of nucleoside triphosphate diphosphohydrolase-1/CD39 in hypertension

Author: Antoine Caillon, Daniel Henrion, Ludovic Martin, Julie Favre, Daniele C. Nascimento, Jean Sévigny, Julie Tabiasco, Bernhard Ryffel, Jean Mérot, Charlotte Roy, Simon C. Robson, Gilles Kauffenstein, Yves Delneste, Anne-Laure Guihot, Euromov (EuroMov), Université de Montpellier (UM), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Physique et Physiologie Intégratives de l'Arbre Fruitier et Forestier (PIAF), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut National de la Recherche Agronomique (INRA), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Département de microbiologie-infectiologie et d’immunologie [Québec City, QC, Canada], Faculté de médecine de l'Université Laval [Québec] (ULaval), Biologie et physiologie moléculaire du vaisseau, Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-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), Unité de recherche de l'institut du thorax (ITX-lab), Division of Gastroenterology [Boston, MA, USA], Harvard University [Cambridge]-Harvard Medical School [Boston] (HMS)-Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS), Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Centre de recherche [CHU Québec, Canada], Medical Biology, Medicine / Université de Laval-Hôtel-Dieu de Québec [Canada]-CHU de Québec–Université Laval, MitoVasc Institute was supported by INSERM, CNRS, University of Angers, CHU of Angers, Région Pays de la Loire, Angers-Loire Métropole, and Département du Maine et Loire. CR was supported by grants from INSERM and Région Pays de la Loire., Bernardo, Elizabeth, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), 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-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP), Faculté de médecine de l'Université Laval (Québec) [Canada], Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), 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), and Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO)
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Vascular smooth muscle, Nucleotidase activity, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Myocytes, Smooth Muscle, [SDV.CAN]Life Sciences [q-bio]/Cancer, 030204 cardiovascular system & hematology, Proinflammatory cytokine, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigens, CD, Internal medicine, medicine, Animals, Ectonucleotidase, Endothelial dysfunction, Molecular Biology, ComputingMilieux_MISCELLANEOUS, CD39, Chemistry, Angiotensin II, Apyrase, Endothelial Cells, Arteries, Cell Biology, medicine.disease, 3. Good health, Mice, Inbred C57BL, ATP, 030104 developmental biology, Cytokine, Endocrinology, Hypertension, Original Article, Tumor necrosis factor alpha
Abstract: International audience; Ectonucleoside triphosphate diphosphohydrolase-1, the major vascular/immune ectonucleotidase, exerts anti-thrombotic and immunomodulatory actions by hydrolyzing extracellular nucleotides (danger signals). Hypertension is characterized by vascular wall remodeling, endothelial dysfunction, and immune infiltration. Here our aim was to investigate the impact of arterial hypertension on CD39 expression and activity in mice. Arterial expression of CD39 was determined by reverse transcription quantitative real-time PCR in experimental models of hypertension, including angiotensin II (AngII)-treated mice (1 mg/kg/day, 21 days), deoxycorticosterone acetate-salt mice (1% salt and uninephrectomy, 21 days), and spontaneously hypertensive rats. A decrease in CD39 expression occurred in the resistance and conductance arteries of hypertensive animals with no effect on lymphoid organs. In AngII-treated mice, a decrease in CD39 protein levels (Western blot) was corroborated by reduced arterial nucleotidase activity, as evaluated by fluorescent (etheno)-ADP hydrolysis. Moreover, serum-soluble ADPase activity, supported by CD39, was significantly decreased in AngII-treated mice. Experiments were conducted in vitro on vascular cells to determine the elements underlying this downregulation. We found that CD39 transcription was reduced by proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor alpha on vascular smooth muscle cells and by IL-6 and anti-inflammatory and profibrotic cytokine transforming growth factor beta 1 on endothelial cells. In addition, CD39 expression was downregulated by mechanical stretch on vascular cells. Arterial expression and activity of CD39 were decreased in hypertension as a result of both a proinflammatory environment and mechanical strain exerted on vascular cells. Reduced ectonucleotidase activity may alter the vascular condition, thus enhancing arterial damage, remodeling, or thrombotic events.
Published: 2018

3. TLR3 promotes MMP-9 production in primary human airway epithelial cells through Wnt/β-catenin signaling

Author: Royer, Pierre Joseph, Antoine, Martine, Cappello, Matteo, Souilamas, Redha, Ruiz, M., Sokolow, Youri, Vanden Eynden, Frédéric, Van Nooten, Guido, Barvais, Luc, Berré, Jacques, Brimioulle, Serge, De Backer, Daniel, Creteur, Jacques, Engelman, E., Huybrechts, Isabelle, Ickx, Brigitte, Preiser, T.J.C., Tuna, Tibel, Van Obbergh, Luc, Vancutsem, Nathalie, Vincent, Jean Louis, De Vuyst, Paul, Etienne, Isabelle, Féry, F., Jacobs, Frédérique, Knoop, Christiane, Vachiery, Jean-Luc, Van den Borne, Pleunie, Wellemans, Isabelle, Amand, G., Collignon, Laurent, Giroux, Martin, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service de pneumologie [Hôpital Foch], Hôpital Foch [Suresnes], Pôle Thorax et Vaisseaux [CHU Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), 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 [2016-2019] (UGA [2016-2019]), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Faculté de Médecine - Université de Nantes, CIC biothérapies CBT 0503 [Nantes], Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier universitaire de Nantes (CHU Nantes), This research program was supported by Vaincre la Mucoviscidose, Association Gregory Lemarchal, Agence de Biomédecine, INSERM, Région Pays de La Loire, Institut de Recherche en Santé Respiratoire des Pays de la Loire, Fonds de Recherche en Santé Respiratoire, Fondation du Souffle and Fondation pour la Recherche Médicale. This work was realized in the context of the IHU-Cesti project, the DHU Oncogreffe, the LabEX IGO and the Labex TRANSPLANTEX thanks to French government financial support managed by the National Research Agency via the 'Investment Into The Future'. The IHU-Cesti project is also supported by Nantes Métropole and Région Pays de la Loire., Degauque, Nicolas, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Dr SPOC, Paris
Subjects: Lipopolysaccharides, 0301 basic medicine, Chemokine, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], medicine.medical_treatment, CCL3, Respiratory Mucosa, 03 medical and health sciences, 0302 clinical medicine, Transforming Growth Factor beta, medicine, Humans, CXCL10, Wnt Signaling Pathway, Cells, Cultured, beta Catenin, lcsh:RC705-779, Toll-like receptor, biology, Chemistry, Research, Wnt signaling pathway, Receptor Cross-Talk, lcsh:Diseases of the respiratory system, respiratory system, Toll-Like Receptor 3, 3. Good health, Cell biology, 030104 developmental biology, Cytokine, Matrix Metalloproteinase 9, 030228 respiratory system, TLR4, biology.protein, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, Pneumologie, Chemokines
Abstract: Background: Airway epithelial cells (AEC) act as the first line of defence in case of lung infections. They constitute a physical barrier against pathogens and they participate in the initiation of the immune response. Yet, the modalities of pathogen recognition by AEC and the consequences on the epithelial barrier remain poorly documented. Method: We investigated the response of primary human AEC to viral (polyinosinic-polycytidylic acid, poly(I:C)) and bacterial (lipopolysaccharide, LPS) stimulations in combination with the lung remodeling factor Transforming Growth Factor-β (TGF-β). Results: We showed a strong production of pro-inflammatory cytokines (Interleukin (IL)-6, Tumor Necrosis Factor α, TNFα) or chemokines (CCL2, CCL3, CCL4, CXCL10, CXCL11) by AEC stimulated with poly(I:C). Cytokine and chemokine production, except CXCL10, was Toll Like Receptor (TLR)-3 dependent and although they express TLR4, we found no cytokine production after LPS stimulation. Poly(I:C), but not LPS, synergised with TGF-β for the production of matrix metalloproteinase-9 (MMP-9) and fibronectin. Mechanistic analyses suggest the secretion of Wnt ligands by AEC along with a degradation of the cellular junctions after poly(I:C) exposure, leading to the release of β-catenin from the cell membrane and stimulation of the Wnt/β-catenin pathway. Conclusion: Our results highlight the cross talk between TGF-β and TLR signaling in bronchial epithelium and its impact on the remodeling process., 0, SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2017

4. Interleukin-10 plays a key role in the modulation of neutrophils recruitment and lung inflammation during infection byStreptococcus pneumoniae

Author: Hernán F. Peñaloza, Pamela A. Nieto, Natalia Muñoz-Durango, María José Parga, Javiera Torres, Francisco J. Salazar-Echegarai, Manuel Álvarez-Lobos, Susan M. Bueno, Claudia A. Riedel, Alexis M. Kalergis, Departamento de Microbiologıa y Genetica Molecular [Santiago, Chile] (Facultad de Ciencias Biologicas), Pontificia Universidad Católica de Chile (UC), Departamento de Anatomia Patologica [Santiago, Chile] (Facultad de Medicina), Departamento de Gastroenterologıa [Santiago, Chile] (Facultad de Medicina), Departamento de Ciencias Biologicas [Santiago, Chile] (Facultad de Ciencias Biologicas y Facultad de Medicina), Universidad Andrés Bello [Santiago] (UNAB), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Departamento de Inmunologıa Clınica y Reumatologıa [Santiago, Chile] (Escuela de Medicina), This study was supported by the following grants: FONDO NACIONAL DE CIENCIA Y TECNOLOGIA DE CHILE (FONDECYT numbers 1140010, 1110604, 1100971, 1131012, 1150862 and 1110397), Millennium Institute on Immunology and Immunotherapy P09/016-F and Grant ‘Nouvelles Equipes-nouvelles thématiques’ from the La Région Pays De La Loire. HFP, PAN, NMD and MJP are supported by the Comision Nacional de Investigacion Cientıﬁca y Tecnologica (CONICYT). AMK is a Chaire De La Région Pays De La Loire, Chercheur Etranger D’excel-lence, France., and Le Bihan, Sylvie
Subjects: medicine.medical_treatment, Interleukin-1beta, Immunology, Inflammation, Biology, medicine.disease_cause, Pathogenesis, Sepsis, Interferon-gamma, Mice, 03 medical and health sciences, 0302 clinical medicine, neutrophils, Streptococcus pneumoniae, medicine, Animals, Immunology and Allergy, Lung, 030304 developmental biology, Mice, Knockout, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Tumor Necrosis Factor-alpha, bacterial infection, Brain, Original Articles, Pneumonia, Pneumococcal, medicine.disease, Bacterial Load, cytokines, Interleukin-10, respiratory tract diseases, 3. Good health, Mice, Inbred C57BL, Interleukin 10, Otitis, Cytokine, Neutrophil Infiltration, Pneumococcal pneumonia, systemic bacterial infection, medicine.symptom, lung inﬂammation, Spleen, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract: International audience; Streptococcus pneumoniae is a major aetiological agent of pneumonia worldwide, as well as otitis media, sinusitis, meningitis and sepsis. Recent reports have suggested that inﬂammation of lungs due to S. pneumoniae infection promotes bacterial dissemination and severe disease. However, the contribution of anti-inﬂammatory molecules to the pathogenesis of S. pneumoniae remains unknown. To elucidate whether the production of the anti-inﬂammatory cytokine interleukin-10 (IL-10) is beneﬁcial or detrimental for the host during pneumococcal pneumonia, we performed S. pneumoniae infections in mice lacking IL-10 (IL-10[-/-] mice). The IL-10/[-/-] mice showed increased mortality, higher expression of proinﬂammatory cytokines, and an exacerbated recruitment of neutrophils into the lungs after S. pneumoniae infection. However, IL-10[-/-] mice showed signiﬁcantly lower bacterial loads in lungs, spleen, brain and blood, when compared with mice that produced this cytokine. Our results support the notion that production of IL-10 during S. pneumoniae infection modulates the expression of pro-inﬂammatory cytokines and the inﬁltration of neutrophils into the lungs. This feature of IL-10 is important to avoid excessive inﬂammation of tissues and to improve host survival, even though bacterial dissemination is less efﬁcient in the absence of this cytokine.
Published: 2015

5. T Cells Promote Bronchial Epithelial Cell Secretion of Matrix Metalloproteinase-9 via a C-C Chemokine Receptor Type 2 Pathway: Implications for Chronic Lung Allograft Dysfunction

Author: Pain, Mallory, Royer, Pierre-Joseph, Loy, Jennifer, Girardeau, Aurore, Tissot, A., Lacoste, P., Roux, A., Reynaud-Gaubert, M., Kessler, R., Mussot, S., Dromer, C., Brugiere, O., Mornex, J. -F., Guillemain, R., Dahan, M., Knoop, C., Botturi, Karine, Pison, C., Danger, R., Brouard, S., Magnan, Antoine, Consortium, COLT, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CTG - Italcementi Group, Ciments CALCIA-Italcementi Group, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Service de Pneumologie, Nouvel Hôpital Civil Strasbourg, 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 [2016-2019] (UGA [2016-2019]), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Association Vaincre la Mucoviscidose, Agence de la Biomédecine, Fonds de Recherche en Santé Respiratoire, Fondation du Souffle, French government, Nantes Métropole and Région Pays de la Loire, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, ANR-10-IBHU-005, Agence Nationale de la Recherche, Association Gregory Lemarchal, Région Pays de La Loire, Institut de Recherche en Santé Respiratoire des Pays de la Loire, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Graft Rejection, Lung Diseases, Male, 0301 basic medicine, Chemokine, translational research/science, T-Lymphocytes, 030230 surgery, Matrix metalloproteinase, Chemokine receptor, Postoperative Complications, 0302 clinical medicine, lung transplantation/pulmonology, Risk Factors, Transforming Growth Factor beta, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Immunology and Allergy, Medicine, Pharmacology (medical), Longitudinal Studies, Epithelial cell differentiation, biology, Graft Survival, Middle Aged, Allografts, Prognosis, Matrix Metalloproteinase 9, Cytokines, Female, Lung Transplantation, Adult, Receptors, CCR2, Bronchi, Proinflammatory cytokine, 03 medical and health sciences, Immune system, Humans, Secretion, Transplantation, business.industry, rejection: chronic, Epithelial Cells, Transforming growth factor beta, 030104 developmental biology, lung (allograft) function/dysfunction, Chronic Disease, Immunology, biology.protein, business, bronchiolitis obliterans (BOS), Biomarkers, Follow-Up Studies
Abstract: International audience; Chronic lung allograft dysfunction (CLAD) is the major limitation of long-term survival after lung transplantation. CLAD manifests as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). Alloimmune reactions and epithelial-to-mesenchymal transition have been suggested in BOS. However, little is known regarding the role of allogenicity in epithelial cell differentiation. Primary human bronchial epithelial cells (BECs) were treated with activated T cells in the presence or absence of transforming growth factor (TGF)-beta. The expression of epithelial and mesenchymal markers was investigated. The secretion of inflammatory cytokines and matrix metalloproteinase (MMP)-9 was measured in culture supernatants and in plasma from lung transplant recipients (LTRs): 49 stable, 29 with BOS, and 16 with RAS. We demonstrated that C-C motif chemokine 2 secreted by T cells supports TGF-beta-induced MMP-9 production by BECs after binding to C-C chemokine receptor type 2. Longitudinal investigation in LTRs revealed a rise in plasma MMP-9 before CLAD onset. Multivariate analysis showed that plasma MMP-9 was independently associated with BOS (odds ratio [OR] = 6.19, p = 0.002) or RAS (OR = 3.9, p = 0.024) and predicted the occurrence of CLAD 12 months before the functional diagnosis. Thus, immune cells support airway remodeling through the production of MMP-9. Plasma MMP-9 is a potential predictive biomarker of CLAD.
Published: 2017

6. Antigen-specific single B cell sorting and expression-cloning from immunoglobulin humanized rats: a rapid and versatile method for the generation of high affinity and discriminative human monoclonal antibodies

Author: Laetitia Gautreau-Rolland, Melinda Moyon, Laure-Hélène Ouisse, Xavier Saulquin, Jonathan Visentin, Frank Halary, Marie-Claire Devilder, Roland Buelow, Marianne Brüggemann, Ignacio Anegon, Michael J. Osborn, Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Recombinant Antibody Technology Ltd. [Cambridge, UK], Babraham Bioscience Technologies Ltd [Cambridge, UK], Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Immunologie et Immunogénétique [Bordeaux], CHU Bordeaux [Bordeaux]-Hôpital Pellegrin - Bordeaux, Ligand Pharmaceuticals, This work was financially supported by the IHU-Cesti project funded by the « Investissements d'Avenir » French Government program, managed by the French National Research Agency (ANR) (ANR-10-IBHU-005). The IHU-Cesti project is also supported by Nantes Métropole and Région Pays de la Loire. This work was performed in the context of the Labex IGO and TEFOR projects which are also part of the « Investissements d’Avenir » French Government program managed by the ANR (ANR-11-LABX-0016-01 and ANRI I-INSB-0014), respectively. The work was also partially funded by Région Pays de la Loire through Biogenouest and by the IBiSA program., ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), Bernardo, Elizabeth, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, and Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID
Subjects: 0301 basic medicine, Tetramers, Human antibodies, medicine.drug_class, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Separation, Yeast display, Protein Engineering, Monoclonal antibody, Major histocompatibility complex, Polymerase Chain Reaction, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigen, medicine, Animals, Humans, Cloning, Molecular, Humanized rats, B cell, B-Lymphocytes, biology, Methodology Article, Immunogenicity, pMHC, Antibodies, Monoclonal, Cytofluorimetry, Molecular biology, Rats, 3. Good health, Cell biology, 030104 developmental biology, medicine.anatomical_structure, Immunoglobulin G, Expression cloning, biology.protein, Antibody, Biotechnology
Abstract: Background There is an ever-increasing need of monoclonal antibodies (mAbs) for biomedical applications and fully human binders are particularly desirable due to their reduced immunogenicity in patients. We have applied a strategy for the isolation of antigen-specific B cells using tetramerized proteins and single-cell sorting followed by reconstruction of human mAbs by RT-PCR and expression cloning. Results This strategy, using human peripheral blood B cells, enabled the production of low affinity human mAbs against major histocompatibility complex molecules loaded with peptides (pMHC). We then implemented this technology using human immunoglobulin transgenic rats, which after immunization with an antigen of interest express high affinity-matured antibodies with human idiotypes. Using rapid immunization, followed by tetramer-based B-cell sorting and expression cloning, we generated several fully humanized mAbs with strong affinities, which could discriminate between highly homologous proteins (eg. different pMHC complexes). Conclusions Therefore, we describe a versatile and more effective approach as compared to hybridoma generation or phage or yeast display technologies for the generation of highly specific and discriminative fully human mAbs that could be useful both for basic research and immunotherapeutic purposes. Electronic supplementary material The online version of this article (doi:10.1186/s12896-016-0322-5) contains supplementary material, which is available to authorized users.
Published: 2017

7. RORγt+ cells selectively express redundant cation channels linked to the Golgi apparatus

Author: Gaelle Beriou, Aurélie Lemoine, Melanie Lancien, Aurélie Moreau, Arnaud Nicot, Régis Josien, Jerome Martin, Elise Chiffoleau, Laurence Bouchet-Delbos, Géraldine Bienvenu, Thierry Cens, Maria-Cristina Cuturi, Pierre Charnet, Hans Jörg Fehling, Lucile Drujont, Cédric Louvet, Flora Guillot, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Institute of Immunology [Ulm], Universitätsklinikum Ulm - University Hospital of Ulm, Faculté de Médecine - Université de Nantes, Laboratoire d'Immunologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), The IHU-Cesti project is also supported by Nantes Métropole and région Pays de la Loire. Inserm-Région Pays de la Loire fellowship, Fondation Progreffe., ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), Centre de recherche en Biologie cellulaire de Montpellier (CRBM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Le Bihan, Sylvie, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, and Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID
Subjects: 0301 basic medicine, Encephalomyelitis, Autoimmune, Experimental, T cell, Biology, Article, 03 medical and health sciences, Mice, Downregulation and upregulation, RAR-related orphan receptor gamma, medicine, Animals, Humans, Psoriasis, Cells, Cultured, Orphan receptor, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Multidisciplinary, Experimental autoimmune encephalomyelitis, Innate lymphoid cell, Membrane Proteins, T-Lymphocytes, Helper-Inducer, Nuclear Receptor Subfamily 1, Group F, Member 3, medicine.disease, Colitis, Cell biology, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Intracellular, Cation channel activity, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, trans-Golgi Network
Abstract: Retinoid-related orphan receptor gamma t (RORγt) is a master transcription factor central to type 17 immunity involving cells such as T helper 17, group 3 innate lymphoid cells or IL-17-producing γδ T cells. Here we show that the intracellular ion channel TMEM176B and its homologue TMEM176A are strongly expressed in these RORγt+ cells. We demonstrate that TMEM176A and B exhibit a similar cation channel activity and mainly colocalise in close proximity to the trans-Golgi network. Strikingly, in the mouse, the loss of Tmem176b is systematically associated with a strong upregulation of Tmem176a. While Tmem176b single-deficiency has no effect on the course of experimental autoimmune encephalomyelitis, T cell or DSS-induced colitis, it significantly reduces imiquimod-induced psoriasis-like skin inflammation. These findings shed light on a potentially novel specific process linked to post-Golgi trafficking for modulating the function of RORγt+ cells and indicate that both homologues should be simultaneously targeted to clearly elucidate the role of this intracellular ion flow.
Published: 2016

8. Modulation of antigen processing by haem-oxygenase 1. Implications on inflammation and tolerance

Author: Sebastián A. Riquelme, Janyra A. Espinoza, Claudia A. Riedel, Alexis M. Kalergis, Susan M. Bueno, Leandro J. Carreño, Manuel Álvarez-Lobos, Juan Pablo Mackern-Oberti, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Departamento de Microbiologıa y Genetica Molecular [Santiago, Chile] (Facultad de Ciencias Biologicas), Pontificia Universidad Católica de Chile (UC), Department of Microbiology and Immunology [Bronx, NY, USA], Albert Einstein College of Medicine [New York], Institute of Medicine and Experimental Biology of Cuyo [Mendoza, Argentina] (IMBECU), Science and Technology Center [Mendoza, Argentina] (CCT)-National Council of Scientific and Technical Research [Mendoza, Argentina], Institute of Physiology [Mendoza, Argentina] (School of Medicine), National University of Cuyo [Mendoza, Argentina], Departamento de Gastroenterologıa [Santiago, Chile] (Facultad de Medicina), Departamento de Ciencias Biologicas [Santiago, Chile] (Facultad de Ciencias Biologicas y Facultad de Medicina), Universidad Andrés Bello - UNAB (CHILE), Departamento de Endocrinología [Santiago, Chile] (Facultad de Medicina), This study was supported by the following grants: FONDO NACIONAL DE CIENCIA Y TECNOLOGIA DE CHILE (FONDECYT numbers 1110397, 1131012, 1140010 and 1110604), Millennium Institute on Immunology and Immunotherapy P09/016-F and Grant ‘Nouvelles Equipesnouvelles thématiques’ from the La Région Pays De La Loire. SAR and JAE are supported by the Comision Nacional de Investigacion Cientıfica y Tecnologica (CONICYT). LJC is a Latin American Pew Fellow. AMK is a Chaire De La Région Pays De La Loire, Chercheur Etranger D’excellence, France., Le Bihan, Sylvie, and Universidad Andrés Bello [Santiago] (UNAB)
Subjects: 0301 basic medicine, CIENCIAS MÉDICAS Y DE LA SALUD, T-Lymphocytes, Immunology, Inmunología, Priming (immunology), Inflammation, Lymphocyte Activation, DENDRITIC CELLS, HAEM-OXYGENASE 1, Immunomodulation, 03 medical and health sciences, Immune system, Immunity, ANTIGEN PRESENTATION, medicine, cytokine, Immune Tolerance, Immunology and Allergy, Animals, Humans, dendritic cells, Review Articles, haem-oxygenase 1, Antigen Presentation, Carbon Monoxide, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Graft rejection, Antigen processing, business.industry, CARBON MONOXIDE, Haem Oxygenase, 3. Good health, CYTOKINE, Medicina Básica, 030104 developmental biology, Immune System Diseases, Drug Design, medicine.symptom, Endotoxic shock, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Heme Oxygenase-1
Abstract: Haem-oxygenase-1 (HO-1) is an enzyme responsible for the degradation of haem that can suppress inflammation, through the production of carbon monoxide (CO). It has been shown in several experimental models that genetic and pharmacological induction of HO-1, as well as non-toxic administration of CO, can reduce inflammatory diseases, such as endotoxic shock, type 1 diabetes and graft rejection. Recently, it was shown that the HO-1/CO system can alter the function of antigen-presenting cells (APCs) and reduce T-cell priming, which can be beneficial during immune-driven inflammatory diseases. The molecular mechanisms by which the HO-1 and CO reduce both APC- and T-cell-driven immunity are just beginning to be elucidated. In this article we discuss recent findings related to the immune regulatory capacity of HO-1 and CO at the level of recognition of pathogen-associated molecular patterns and T-cell priming by APCs. Finally, we propose a possible regulatory role for HO-1 and CO over the recently described mitochondria-dependent immunity. These concepts could contribute to the design of new therapeutic tools for inflammation-based diseases. Fil: Riquelme, Sebastián A.. Pontificia Universidad Católica de Chile; Chile Fil: Carreño, Leandro J.. Pontificia Universidad Católica de Chile; Chile Fil: Espinoza, Janyra A.. Pontificia Universidad Católica de Chile; Chile Fil: Mackern Oberti, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; Argentina Fil: Alvarez Lobos, Manuel M.. Pontificia Universidad Católica de Chile; Chile Fil: Riedel, Claudia. Universidad Andrés Bello; Chile Fil: Bueno, Susan M.. Pontificia Universidad Católica de Chile; Chile Fil: Kalergis, Alexis M.. Pontificia Universidad Católica de Chile; Chile
Published: 2016

9. Reconstructing pedigrees using probabilistic analysis of ISSR amplification

Author: Loïc Chaumont, Richard Pymar, Chaker Sbai, Valéry Malécot, Laboratoire Angevin de Recherche en Mathématiques (LAREMA), Université d'Angers (UA)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Horticulture et Semences (IRHS), Université d'Angers (UA)-Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), University College of London [London] (UCL), Physiologie, Environnement et Génétique pour l'Animal et les Systèmes d'Elevage [Rennes] (PEGASE), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Région des Pays de la Loire, This work was supported by MODEMAVE research project from the Région Pays de la Loire. Acces to molecular data was supported by both EUROGENI project, funded by Région Pays de la Loire (dynamiques de filière) and by BRIO project funded by same Région Pays de la Loire and the Fonds Unique Interministériel., AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA)-Université d'Angers (UA), AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA), Université d'Angers (UA)-AGROCAMPUS OUEST-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Dept Stat Sci, University College London (UCL), MODEMAVE research project from the Region Pays de la Loire, EUROGENI project - Region Pays de la Loire (dynamiques de filiere, BRIO project - Region Pays de la Loire + Fonds Unique Interministériel, Université d'Angers (UA)-AGROCAMPUS OUEST, and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: 0301 basic medicine, carte génétique, [SDV]Life Sciences [q-bio], [SDV.SA.AGRO]Life Sciences [q-bio]/Agricultural sciences/Agronomy, Pedigree chart, 92D25, 92D10, 60F15, gène marqueur, 01 natural sciences, 010104 statistics & probability, probabilistic model, Probabilistic method, Statistics, [SDV.IDA]Life Sciences [q-bio]/Food engineering, 10. No inequality, [SDV.SA.HORT]Life Sciences [q-bio]/Agricultural sciences/Horticulture, Cytisus, Probability measure, Mathematics, Cytisus scoparius, [SHS.SOCIO]Humanities and Social Sciences/Sociology, biology, Applied Mathematics, General Medicine, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics, [QFIN.ST]Quantitative Finance [q-fin]/Statistical Finance [q-fin.ST], interaction isolat cultivar, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Pedigree, Modeling and Simulation, [SDV.SA.SPA]Life Sciences [q-bio]/Agricultural sciences/Animal production studies, genetic mapping, General Agricultural and Biological Sciences, Mathematics - Probability, Statistics and Probability, law of reproduction, ems, gene frequency, [QFIN.RM]Quantitative Finance [q-fin]/Risk Management [q-fin.RM], [SDV.SA.SDS]Life Sciences [q-bio]/Agricultural sciences/Soil study, bcs, General Biochemistry, Genetics and Molecular Biology, [SDV.GEN.GPL]Life Sciences [q-bio]/Genetics/Plants genetics, 03 medical and health sciences, ISSR amplification, Law of reproduction, Gene frequency, [SDV.SA.STA]Life Sciences [q-bio]/Agricultural sciences/Sciences and technics of agriculture, FOS: Mathematics, Probabilistic analysis of algorithms, 0101 mathematics, Allele, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Quantitative Biology - Populations and Evolution, [QFIN.TR]Quantitative Finance [q-fin]/Trading and Market Microstructure [q-fin.TR], Allele frequency, Alleles, cytisus scoparius, matrice de parenté combinée, Models, Genetic, General Immunology and Microbiology, modèle probabiliste, Probability (math.PR), Populations and Evolution (q-bio.PE), Mathematics Subject Classification (2000): 92D25, 92D10, 60F15, Statistical model, [SDV.SA.AEP]Life Sciences [q-bio]/Agricultural sciences/Agriculture, economy and politics, biology.organism_classification, [SDV.BV.PEP]Life Sciences [q-bio]/Vegetal Biology/Phytopathology and phytopharmacy, diploïde, [MATH.MATH-PR]Mathematics [math]/Probability [math.PR], [SDV.BV.AP]Life Sciences [q-bio]/Vegetal Biology/Plant breeding, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, 030104 developmental biology, FOS: Biological sciences, [SDV.SA.STP]Life Sciences [q-bio]/Agricultural sciences/Sciences and technics of fishery, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.EE.IEO]Life Sciences [q-bio]/Ecology, environment/Symbiosis
Abstract: Data obtained from ISSR amplification may readily be extracted but only allows us to know, for each gene, if a specific allele is present or not. From this partial information we provide a probabilistic method to reconstruct the pedigree corresponding to some families of diploid cultivars. This method consists in determining for each individual what is the most likely couple of parent pair amongst all older individuals, according to some probability measure. The construction of this measure bears on the fact that the probability to observe the specific alleles in the child, given the status of the parents does not depend on the generation and is the same for each gene. This assumption is then justified from a convergence result of gene frequencies which is proved here. Our reconstruction method is applied to a family of 85 living accessions representing the common broom {\it Cytisus scoparius}., Comment: 5 figures
Published: 2015

10. Characterization of Dystrophin Deficient Rats: A New Model for Duchenne Muscular Dystrophy

Author: Laurent Tesson, Helicia Goubin, Jean-Baptiste Renaud, Thibaut Larcher, Caroline Le Guiner, Yan Cherel, Carine Giovannangeli, Corinne Huchet, Maeva Dutilleul, Ignacio Anegon, Gilles Toumaniantz, Anne De Cian, Lydie Guigand, Jean-Paul Concordet, Séverine Remy, Charlotte Boix, A. Lafoux, Virginie François, Virginie Thepenier, Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Atlantic Gene Therapies, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-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), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de Transplantation Urologie-Néphrologie (ITUN), Institut de Transplantation Urologie-Néphrologie ( ITUN), Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques (Inserm UMR 1089), Généthon, Structure et Instabilité des Génomes (STRING), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Région Pays de la Loire (Biogenouest), IBiSA program, Fondation Progreffe, TEFOR (Infrastructures d'Avenir du Gouvernement Français), Développement et Pathologie du Tissu Musculaire (DPTM), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Muséum national d'Histoire naturelle (MNHN)-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), Ecole Nationale Vétérinaire de Nantes-Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes (UN), APEX - Plate-forme d'expertise en anatomie pathologique pour la Recherche [Nantes] (PAnTher), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-INRA - Oniris (INRA UMR0703), Institut National de la Recherche Agronomique (INRA)-Institut National de la Recherche Agronomique (INRA), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Thérapie génique translationnelle pour les maladies neuromusculaires et de la rétine, Recherche et développement [Généthon, Evry] (R & D Généthon), Généthon [Evry], Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Région Pays de la Loire through Biogenouest, IBiSA program, Fondation Progreffe and TEFOR (Infrastructures d’Avenir of the French goverment), and the integrative genomic facility of Nantes for sequencing experiments., Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Unité de recherche de l'institut du thorax (ITX-lab), Le Bihan, Sylvie, and Lafoux, Aude
Subjects: Male, Pathology, Necrosis, myopathie de duchenne, Physiology, Duchenne muscular dystrophy, Gene Expression, Adipose tissue, Dystrophin, 0302 clinical medicine, Medicine and Health Sciences, Medicine, rat, Muscular dystrophy, Creatine Kinase, 0303 health sciences, Muscle Weakness, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Multidisciplinary, Ventricular Remodeling, biology, Dilated cardiomyopathy, Exons, Diaphragm (structural system), Neurology, Gene Targeting, Female, medicine.symptom, Research Article, Biotechnology, musculoskeletal diseases, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Science, Médecine humaine et pathologie, modèle d'analyse, 03 medical and health sciences, Genetics, Congenital Disorders, Animals, RNA, Messenger, Muscle, Skeletal, Molecular Biology, 030304 developmental biology, Base Sequence, business.industry, Myocardium, Biology and Life Sciences, Muscle weakness, Cell Biology, Muscular Dystrophy, Animal, medicine.disease, Fibrosis, Rats, Muscular Dystrophy, Duchenne, Disease Models, Animal, Mutation, biology.protein, Human health and pathology, business, mutant déficient, Gene Deletion, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; A few animal models of Duchenne muscular dystrophy (DMD) are available, large ones such as pigs or dogs being expensive and difficult to handle. Mdx (X-linked muscular dystrophy) mice only partially mimic the human disease, with limited chronic muscular lesions and muscle weakness. Their small size also imposes limitations on analyses. A rat model could represent a useful alternative since rats are small animals but 10 times bigger than mice and could better reflect the lesions and functional abnormalities observed in DMD patients. Two lines of Dmd mutated-rats (Dmd[mdx]) were generated using TALENs targeting exon 23. Muscles of animals of both lines showed undetectable levels of dystrophin by western blot and less than 5% of dystrophin positive fibers by immunohistochemistry. At 3 months, limb and diaphragm muscles from Dmd[mdx] rats displayed severe necrosis and regeneration. At 7 months, these muscles also showed severe fibrosis and some adipose tissue infiltration. Dmd[mdx] rats showed significant reduction in muscle strength and a decrease in spontaneous motor activity. Furthermore, heart morphology was indicative of dilated cardiomyopathy associated histologically with necrotic and fibrotic changes. Echocardiography showed significant concentric remodeling and alteration of diastolic function. In conclusion, Dmd[mdx] rats represent a new faithful small animal model of DMD.
Published: 2014

11. High throughput quantitative phenotyping of plant resistance using chlorophyll fluorescence image analysis

Author: Charles Manceau, Céline Rousseau, Marie-Agnès Jacques, Etienne Belin, Jacky Guillaumes, Romain Berruyer, Frédéric Fabre, Tristan Boureau, David Rousseau, Edouard Bove, Institut de Recherche en Horticulture et Semences (IRHS), AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA)-Université d'Angers (UA), Laboratoire d'Ingéniérie des Systèmes Automatisés (LISA), Université d'Angers (UA), Station de Pathologie Végétale (AVI-PATHO), Institut National de la Recherche Agronomique (INRA), Laboratoire de la santé des végétaux, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), This work was supported by Angers Loire Métropole, Conseil Général Département de Maine-et-Loire and Région Pays de la Loire (Phenotic) and by Institut National de la Recherche Agronomique and Région Pays de la Loire., Université d'Angers (UA)-Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Unité de Pathologie Végétale (PV), Boureau, Tristan, BMC, Ed., Laboratoire de santé des végétaux (LSV Angers), Laboratoire de la santé des végétaux (LSV), and Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)
Subjects: 0106 biological sciences, [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, détection de la maladie, fluorescence chlorophyllienne, Plant Science, Bioinformatics, 01 natural sciences, pixel, résistance des plantes aux agents pathogènes, Contrast (vision), Segmentation, logiciel r, Throughput (business), Chlorophyll fluorescence, media_common, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 0303 health sciences, [SDV.SA] Life Sciences [q-bio]/Agricultural sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], résistance quantitative, mise au point de technique, Thresholding, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Agricultural sciences, automatisation, Biotechnology, notation des maladies, media_common.quotation_subject, Biology, analyse d'image, Image (mathematics), 03 medical and health sciences, Genetics, Cluster analysis, imagerie quantitative, 030304 developmental biology, modélisation, bactérie phytopathogène, Pixel, business.industry, imagerie in vivo, méthode de quantification, Methodology, Pattern recognition, phaseolus vulgaris, maladie des plantes, Artificial intelligence, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, xanthomonas fuscans, Sciences agricoles, 010606 plant biology & botany
Abstract: Background: In order to select for quantitative plant resistance to pathogens, high throughput approaches that can precisely quantify disease severity are needed. Automation and use of calibrated image analysis should provide more accurate, objective and faster analyses than visual assessments. In contrast to conventional visible imaging, chlorophyll fluorescence imaging is not sensitive to environmental light variations and provides single-channel images prone to a segmentation analysis by simple thresholding approaches. Among the various parameters used in chlorophyll fluorescence imaging, the maximum quantum yield of photosystem II photochemistry (Fv/Fm) is well adapted to phenotyping disease severity. Fv/Fm is an indicator of plant stress that displays a robust contrast between infected and healthy tissues. In the present paper, we aimed at the segmentation of Fv/Fm images to quantify disease severity., Results: Based on the Fv/Fm values of each pixel of the image, a thresholding approach was developed to delimit diseased areas. A first step consisted in setting up thresholds to reproduce visual observations by trained raters of symptoms caused by Xanthomonas fuscans subsp. fuscans (Xff) CFBP4834-R on Phaseolus vulgaris cv. Flavert. In order to develop a thresholding approach valuable on any cultivars or species, a second step was based on modeling pixel-wise Fv/Fm-distributions as mixtures of Gaussian distributions. Such a modeling may discriminate various stages of the symptom development but over-weights artifacts that can occur on mock-inoculated samples. Therefore, we developed a thresholding approach based on the probability of misclassification of a healthy pixel. Then, a clustering step is performed on the diseased areas to discriminate between various stages of alteration of plant tissues. Notably, the use of chlorophyll fluorescence imaging could detect pre-symptomatic area. The interest of this image analysis procedure for assessing the levels of quantitative resistance is illustrated with the quantitation of disease severity on five commercial varieties of bean inoculated with Xff CFBP4834-R., Conclusions: In this paper, we describe an image analysis procedure for quantifying the leaf area impacted by the pathogen. In a perspective of high throughput phenotyping, the procedure was automated with the software R downloadable at http://www.r-project.org/. The R script is available at http://lisa.univ-angers.fr/PHENOTIC/telechargements.html.
Published: 2013

12. Carbon monoxide decreases endosome-lysosome fusion andinhibits soluble antigen presentation by dendritic cells to tcells

Author: Alexis M. Kalergis, Claudia A. Riedel, Susan M. Bueno, Claudia M. Cortés, Séverine Remy, Thomas Simon, Virginie Tardif, Cédric Louvet, Leandro J. Carreño, Marcelo Hill, Jean Marie Bach, Sebastián A. Riquelme, Ignacio Anegon, Christine Chauveau, Philippe Blancou, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN), Millenium Institute of Immunology and Immunotherapy, Pontificia Universidad Católica de Chile (UC), Universidad Andrés Bello [Santiago] (UNAB), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Departamento de Reumatologia, La Région Pays de la Loire through the 'Chaire d’excellence program'., IMBIO program., Agence de la Biomédecine., Ministère de la Recherche., Fondation CENTAURE., Fondation Progreffe., Grant 'Nouvelles Equipes-nouvelles thématiques' from the La Région Pays De La Loire., INSERM CDD grant., ECOS France-Chile grant., Millennium Institute on Immunology and Immunotherapy from Chile (P09/016-F)., École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), and Le Bihan, Sylvie
Subjects: CD4-Positive T-Lymphocytes, Lipopolysaccharides, Endosome, Ovalbumin, Immunology, Antigen presentation, Mice, Transgenic, Endosomes, Lymphocyte Activation, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Antigen, MHC class I, Immunology and Allergy, Animals, Cells, Cultured, 030304 developmental biology, 0303 health sciences, MHC class II, Antigen Presentation, Carbon Monoxide, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Cross-presentation, biology, Antigen processing, Histocompatibility Antigens Class I, Histocompatibility Antigens Class II, Membrane Proteins, Dendritic Cells, Endocytosis, Cell biology, Mice, Inbred C57BL, biology.protein, Lysosomes, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Heme Oxygenase-1, 030215 immunology
Abstract: International audience; Heme oxygenase-1 (HO-1) inhibits immune responses and inflammatory reactions via the catabolism of heme into carbon monoxide (CO), Fe 2+ , and biliverdin. We have previously shown that either induction of HO-1 or treatment with exogenous CO inhibits LPS-induced maturation of dendritic cells (DCs) and protects in vivo and in vitro antigen-specific inflammation. Here, we evaluated the capacity of HO-1 and CO to regulate antigen presentation on MHC class I and MHC class II molecules by LPS-treated DCs. We observed that HO-1 and CO treatment significantly inhibited the capacity of DCs to present soluble antigens to T cells. Inhibition was restricted to soluble OVA protein, as no inhibition was observed for antigenic OVA-derived peptides, bead-bound OVA protein, or OVA as an endogenous antigen. Inhibition of soluble antigen presentation was not due to reduced antigen uptake by DCs, as endocytosis remained functional after HO-1 induction and CO treatment. On the contrary, CO significantly reduced the efficiency of fusion between late endosomes and lysosomes and not by phagosomes and lysosomes. These data suggest that HO-1 and CO can inhibit the ability of LPS-treated DCs to present exogenous soluble antigens to naïve T cells by blocking antigen trafficking at the level of late endosome-lysosome fusion.
Published: 2013

13. Cell-free circulating epimarks in cancer monitoring

Author: Gwenola Bougras-Cartron, Dominique Heymann, Jean-Sebastien Frenel, François M. Vallette, Pierre-François Cartron, Joséphine Briand, Manon Duforestel, Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), 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), Niches & Epigenetics of Tumors Network [Nantes] (Cancéropôle Grand Ouest), Epigénétique - Santé - AgroAlimentaire - Végétal - Mer - Environnement - Nutrition [Nantes] (EpiSAVMEN), Consortium de la Recherche en Epigénétique de la Région Pays de la Loire [Nantes], Service d'Oncologie Médicale Thoracique et Digestive [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), LabEX IGO Immunothérapie Grand Ouest, M Duforestel was supported by a fellowship from EpiSAVMEN/REGION PAYS DE LA LOIRE. J Briand was supported by a fellowship from EpiSAVMEN/REGION PAYS DE LA LOIRE and ‘EN AVANT LA VIE’, a French association that fights against glioma., 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), Nantes Université (Nantes Univ), and Bernardo, Elizabeth
Subjects: Cancer Research, RNA, Untranslated, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell free, Drug resistance, Biology, Circulating Tumor DNA, Epigenesis, Genetic, cfc-DNA, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Blood circulating, Neoplasms, Biomarkers, Tumor, Genetics, Extracellular, medicine, Humans, cancer, Epigenetics, Analysis method, 030304 developmental biology, 0303 health sciences, epigenetics, biomarkers, Cancer, DNA Methylation, cfc-ncRNA, medicine.disease, cfc-nucleosomes, Nucleosomes, 3. Good health, Histone Code, 030220 oncology & carcinogenesis, Cancer research, Cell-Free Nucleic Acids, Intracellular
Abstract: International audience; Cancer numbers increasing, cases heterogeneity and the drug resistance emergence have pushed scientists to search for innovative solutions for patients and epimutations can be one. Methylated DNA, modified nucleosomes and noncoding RNAs are found in all cells, including tumor cells. They are intracellular actors but also have intercellular communication roles, being released in extracellular environment and in different body fluids. Here, we reviewed current literature on the use of these blood circulating epimarks in cancer monitoring. What stands out is that epimarkers must be considered as 'real time' images of the tumor, and can be isolated without invasive methods. In the future, the real challenge lies in the development of specific, sensitive, fast and clinically applicable detection and analysis methods of epimarkers.
Published: 2020

14. Epigenetic protein complexes: the adequate candidates for the use of a new generation of epidrugs in personalized and precision medicine in cancer

Author: Laurent Bretaudeau, Mathilde Cheray, Pierre-François Cartron, Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), 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), Epigénétique - Santé - AgroAlimentaire - Végétal - Mer - Environnement - Nutrition [Nantes] (EpiSAVMEN), Consortium de la Recherche en Epigénétique de la Région Pays de la Loire [Nantes], LabEX IGO Immunothérapie Grand Ouest, Niches & Epigenetics of Tumors Network [Nantes] (Cancéropôle Grand Ouest), Toxicology Unit [Stockholm, Sweden] (Institute of Environmental Medicine), Karolinska Institutet [Stockholm], LB4 Biotech [Nantes, France], Bernardo, Elizabeth, 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), and Nantes Université (Nantes Univ)
Subjects: 0301 basic medicine, Cancer Research, high resolution DNA methylation, (epigenetic player/protein-X disruptor), [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, protein–protein interactions, Biology, Bioinformatics, Epigenesis, Genetic, Protein–protein interaction, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Neoplasms, Genetics, medicine, Humans, high selective drug, Epigenetics, epidrugs, Precision Medicine, epigenetics, business.industry, Cancer, personalized medicine, DNA Methylation, Precision medicine, medicine.disease, Response to treatment, 3. Good health, DNMT inhibitors, 030104 developmental biology, Mechanism of action, Drug development, Multiprotein Complexes, 030220 oncology & carcinogenesis, Personalized medicine, medicine.symptom, business
Abstract: International audience; Until recently, drug development in oncology was focused on treating most patients for a specific cancer type without taking in account the heterogeneity between these patients in term of response to treatment. Therefore, this type of broad treatment approach excludes the treatment of patient not responding to disease-specific common drugs. In this review, we focus on the different types of epigenetic drugs currently used as DNA methylation inhibitor agents and their limits in patient care due to their lack of specificity. We also highlight the emergence of a new type of epidrug with higher target specificity due to their original mechanism of action: the disruption of protein complexes involved in the epigenetic modifications.
Published: 2020

15. Modulation of the Activity and Regioselectivity of a Glycosidase: Development of a Convenient Tool for the Synthesis of Specific Disaccharides

Author: Sylvain Tranchimand, Vincent Ferrieres, Franck Daligault, Olivier Tasseau, Yari Cabezas-Pérusse, 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), Unité de fonctionnalité et ingénierie de protéines (UFIP), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), We are grateful to the Ministère de l’enseignement supérieur et de la recherche for financial support. The authors are also grateful to the GlycoOuest network, supported by the Région Bretagne and the Région Pays de la Loire and the Agence Nationale de la Recherche (ANR SynBioLeish)., ANR-10-BLAN-0718,SynBioLeish,Synthèse biocatalysée d'oligosaccharides leishmaniens en vue d'applications diagnostiques et thérapeutiques (Biocatalysis - Medical applications - Carbohydrates - Leishmania)(2010), 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, Glycosylation, Molecular model, Glycoside Hydrolases, Kinetics, Pharmaceutical Science, Organic chemistry, 010402 general chemistry, Disaccharides, 01 natural sciences, Article, Analytical Chemistry, Substrate Specificity, 03 medical and health sciences, Hydrolysis, QD241-441, galactofuranoside, Drug Discovery, [CHIM]Chemical Sciences, Glycoside hydrolase, Physical and Theoretical Chemistry, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Regioselectivity, Glycosidic bond, Combinatorial chemistry, molecular dynamics, 0104 chemical sciences, chemistry, Chemistry (miscellaneous), Docking (molecular), Yield (chemistry), Molecular Medicine, mutagenesis, transglycosylation
Abstract: The synthesis of disaccharides, particularly those containing hexofuranoside rings, requires a large number of steps by classical chemical means. The use of glycosidases can be an alternative to limit the number of steps, as they catalyze the formation of controlled glycosidic bonds starting from simple and easy to access building blocks, the main drawbacks are the yields, due to the balance between the hydrolysis and transglycosylation of these enzymes, and the enzyme-dependent regioselectivity. To improve the yield of the synthesis of β-d-galactofuranosyl-(1→X)-d-mannopyranosides catalyzed by an arabinofuranosidase, in this study we developed a strategy to mutate, then screen the catalyst, followed by a tailored molecular modeling methodology to rationalize the effects of the identified mutations. Two mutants with a 2.3 to 3.8-fold increase in transglycosylation yield were obtained, and in addition their accumulated regioisomer kinetic profiles were very different from the wild-type enzyme. Those differences were studied in silico by docking and molecular dynamics, and the methodology revealed a good predictive quality in regards with the regioisomer profiles, which is in good agreement with the experimental transglycosylation kinetics. So, by engineering CtAraf51, new biocatalysts were enabled to obtain the attractive central motif from the Leishmania lipophosphoglycan core with a higher yield and regioselectivity.
Published: 2021

16. Rethinking Alkylating(-Like) Agents for Solid Tumor Management

Author: Bénédicte Lelièvre, Emmanuel Garcion, Philippe Lecomte, Elodie Vauleon, Hélène Lajous, Université de Liège, Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), 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), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CRLCC Eugène Marquis (CRLCC), PL-BIO 2014-2020, Molecular Programmation, La Région Pays-de-la-Loire, Institut National de la Santé et de la Recherche Médicale (INSERM, University of Angers (Angers, France), Fonds de la Recherche Scientifique’ (F.R.S.-FNRS)., 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), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Jonchère, Laurent
Subjects: 0301 basic medicine, synergies, Bioactive molecules, cisplatin, [SDV.CAN]Life Sciences [q-bio]/Cancer, Toxicology, 03 medical and health sciences, Drug Delivery Systems, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, local treatment, Neoplasms, alkylating agents, medicine, Humans, Solid tumor, Cytotoxicity, Antineoplastic Agents, Alkylating, Pharmacology, Cisplatin, business.industry, Drug Synergism, solid tumors, nanomedicine, 3. Good health, 030104 developmental biology, Systemic toxicity, Treatment Schedule, Drug delivery, Cancer research, Nanomedicine, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: International audience; Although old molecules, alkylating agents and platinum derivatives are still widely used in the treatment of various solid tumors. However, systemic toxicity and cellular resistance mechanisms impede their efficacy. Innovative strategies, including local administration, optimization of treatment schedule/dosage, synergistic combinations, and the encapsulation of bioactive molecules in smart, multifunctional drug delivery systems, have shown promising results in potentiating anticancer activity while circumventing such hurdles. Furthermore, questioning of the old paradigm according to which nuclear DNA is the critical target of their anticancer activity has shed light on subcellular alternative and neglected targets that obviously participate in the mediation of cytotoxicity or resistance. Thus, rethinking of the use of these pivotal antineoplastic agents appears critical to improve clinical outcomes in the management of solid tumors.
Published: 2019

17. Plant low‐K responses are partly due to Ca prevalence and the low‐K biomarker putrescine does not protect from Ca side effects but acts as a metabolic regulator

Author: Emmanuelle Lamade, Jing Cui, Guillaume Tcherkez, Marlène Davanture, Michel Zivy, Australian National University (ANU), Research School of Biology, ANU Joint College of Science, Génétique Quantitative et Evolution - Le Moulon (Génétique Végétale) (GQE-Le Moulon), AgroParisTech-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Plateforme d'Analyse Protéomique de Paris Sud Ouest (PAPPSO), Agrosystèmes Biodiversifiés (UMR ABSys), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Centre International de Hautes Etudes Agronomiques Méditerranéennes - Institut Agronomique Méditerranéen de Montpellier (CIHEAM-IAMM), Centre International de Hautes Études Agronomiques Méditerranéennes (CIHEAM)-Centre International de Hautes Études Agronomiques Méditerranéennes (CIHEAM)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Département Performances des systèmes de production et de transformation tropicaux (Cirad-PERSYST), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Institut de Recherche en Horticulture et Semences (IRHS), Université d'Angers (UA)-AGROCAMPUS OUEST, and G.T. acknowledge the financial support of the Région Pays de la Loire and Angers Loire Métropole via the grant Connect Talent Isoseed.
Subjects: 0106 biological sciences, 0301 basic medicine, sunflower, Proteome, Nitrogen, Physiology, Metabolite, [SDV]Life Sciences [q-bio], Carence en substance nutritive, chemistry.chemical_element, Plant Science, Calcium, Photosynthesis, Plant Roots, 01 natural sciences, Acclimatization, Fertilisation, 03 medical and health sciences, chemistry.chemical_compound, proteomics, Hydroxyde de calcium, putrescine, protéomique, 2. Zero hunger, calcium, Catabolism, potassium, Assimilation (biology), metabolomics, Plant Leaves, 030104 developmental biology, F61 - Physiologie végétale - Nutrition, Biochemistry, chemistry, Assimilation, Putrescine, Helianthus, Biomarkers, Pyruvate kinase, 010606 plant biology & botany, F04 - Fertilisation
Abstract: International audience; Potassium (K) deficiency is a rather common situation which impacts negatively on biomass, photosynthesis and N assimilation, making K fertilization often unavoidable. Effects of K deficiency have been investigated for several decades and recently, progress has been made in identifying metabolomics signatures thereby offering potential to monitor the K status of crops in the field. However, effects of low K conditions could also be due to the antagonism with other nutrients like calcium (Ca) and the well-known biomarker of K deficiency, putrescine, could be a response to Ca/K imbalance rather than K deficiency per se. To sort this out, we carried out experiments in sunflower grown at either low or high K, at high or low Ca, with or without putrescine added to the nutrient solution. Using metabolomics and proteomics analysis, we show that a significant part of the low-K response such as lower photosynthesis and N assimilation, is due to calcium and can be suppressed by low Ca conditions. Putrescine addition tends to restore photosynthesis and N assimilation but unlike low-Ca, does not suppress but aggravates the impact of low-K conditions on catabolism, including the typical fall-over in pyruvate kinase. We conclude that (i) the effects of K deficiency on key metabolic processes can be partly alleviated by the use of low Ca and not only by K fertilization, and (ii) in addition to its role as a metabolite, putrescine participates in acclimation to low K via the regulation of the content in enzymes involved in carbon primary metabolism.
Published: 2021

18. Investigating Major Recurring Campylobacter jejuni Lineages in Luxembourg Using Four Core or Whole Genome Sequencing Typing Schemes

Author: Morgane Nennig, Ann-Katrin Llarena, Malte Herold, Joël Mossong, Christian Penny, Serge Losch, Odile Tresse, Catherine Ragimbeau, Fonds National de la Recherche - FnR [sponsor], RFI Food for Tomorrow of Région Pays de la Loire - France [sponsor], Laboratoire National de Santé [research center], and INRAE - Oniris (France) [research center]
Subjects: 0301 basic medicine, Microbiology (medical), Microbiologie [F11] [Sciences du vivant], Lineage (evolution), 030106 microbiology, Immunology, Population, lcsh:QR1-502, typing schemes, core genome MLST, medicine.disease_cause, Microbiology, Campylobacter jejuni, lcsh:Microbiology, 03 medical and health sciences, clones, medicine, Microbiology [F11] [Life sciences], Typing, education, Genotyping, Whole genome sequencing, Genetics, whole genome sequencing, education.field_of_study, biology, Campylobacter, whole genome MLST, WGS typing scheme comparison, biology.organism_classification, 030104 developmental biology, Infectious Diseases, recurring genotypes, Multilocus sequence typing
Abstract: Campylobacter jejuni is the leading cause of bacterial gastroenteritis, which has motivated the monitoring of genetic profiles circulating in Luxembourg since 13 years. From our integrated surveillance using a genotyping strategy based on an extended MLST scheme including gyrA and porA markers, an unexpected endemic pattern was discovered in the temporal distribution of genotypes. We aimed to test the hypothesis of stable lineages occurrence by implementing whole genome sequencing (WGS) associated with comprehensive and internationally validated schemes. This pilot study assessed four WGS-based typing schemes to classify a panel of 108 strains previously identified as recurrent or sporadic profiles using this in-house typing system. The strain collection included four common lineages in human infection (N = 67) initially identified from recurrent combination of ST-gyrA-porA alleles also detected in non-human samples: veterinary (N = 19), food (N = 20), and environmental (N = 2) sources. An additional set of 19 strains belonging to sporadic profiles completed the tested panel. All the strains were processed by WGS by using Illumina technologies and by applying stringent criteria for filtering sequencing data; we ensure robustness in our genomic comparison. Four typing schemes were applied to classify the strains: (i) the cgMLST SeqSphere+ scheme of 637 loci, (ii) the cgMLST Oxford scheme of 1,343 loci, (iii) the cgMLST INNUENDO scheme of 678 loci, and (iv) the wgMLST INNUENDO scheme of 2,795 loci. A high concordance between the typing schemes was determined by comparing the calculated adjusted Wallace coefficients. After quality control and analyses with these four typing schemes, 60 strains were confirmed as members of the four recurrent lineages regardless of the method used (N = 32, 12, 7, and 9, respectively). Our results indicate that, regardless of the typing scheme used, epidemic or endemic signals were detected as reflected by lineage B (ST2254-gyrA9-porA1) in 2014 or lineage A (ST19-gyrA8-porA7), respectively. These findings support the clonal expansion of stable genomes in Campylobacter population exhibiting a multi-host profile and accounting for the majority of clinical strains isolated over a decade. Such recurring genotypes suggest persistence in reservoirs, sources or environment, emphasizing the need to investigate their survival strategy in greater depth.
Published: 2021

19. High neutralizing potency of swine glyco-humanized polyclonal antibodies against SARS-CoV-2

Author: Dominique Blanchard, Melody Paulus, Gwénaëlle Evanno, Roberto Bruzzone, Matthieu Ledure, Sophie Brouard, Irina Lagutina, Sophie Conchon, Emanuele Cozzi, Roberto Duchi, Cesare Galli, Juliette Rousse, Bernard Vanhove, Elsa Lheriteau, Laurent Vacher, Apolline Salama, Romain Oger, Pierre-Joseph Royer, Andrea Perota, Nadine Gervois, Marc Bouillet, Yannick Jacques, Odile Duvaux, Ray T.Y. So, Jean-Marie Bach, Jean-Paul Soulillou, Chris Ka Pun Mok, Carine Ciron, Philippe Delahaut, Xenothera [Nantes, France], Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), 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), Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Université de Nantes (UN)-Université de Nantes (UN), Avantea [Cremona, Italy], CER Groupe Marloie, The University of Hong Kong (HKU), University Hospital of Padua, Immuno-Endocrinologie Cellulaire et Moléculaire (IECM), Université de Nantes (UN)-Ecole Nationale Vétérinaire de Nantes-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Bpifrance, Xenothera, Société d'Accélération et Transfert de Technologie Ouest Valorisation, Région Pays de la Loire, 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), CER Groupe, Azienda Ospedale Università di Padova = Hospital-University of Padua (AOUP), Université de Nantes (UN)-Ecole Nationale Vétérinaire de Nantes-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Bernardo, Elizabeth
Subjects: 0301 basic medicine, pig, Swine, Spike, Antibodies, Viral, medicine.disease_cause, SARS‐CoV‐2, Epitope, Animals, Genetically Modified, chemistry.chemical_compound, 0302 clinical medicine, Neuraminic acid, Immunology and Allergy, polyclonal antibodies, Research Articles, Coronavirus, Covid-19, SARS-CoV-2, Galactosyltransferases, 3. Good health, Spike Glycoprotein, Coronavirus, Research Article|Basic, Antibody, medicine.drug_class, Immunology, Immunity to infection, Heterologous, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Monoclonal antibody, Article, 03 medical and health sciences, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigen, COVID‐19, medicine, Animals, Humans, Basic, COVID-19 Serotherapy, Immunization, Passive, Antibodies, Neutralizing, Virology, HEK293 Cells, 030104 developmental biology, chemistry, Polyclonal antibodies, Sialic Acids, biology.protein, 030215 immunology
Abstract: Heterologous polyclonal antibodies might represent an alternative to the use of convalescent plasma or monoclonal antibodies (mAbs) in coronavirus disease (COVID‐19) by targeting multiple antigen epitopes. However, heterologous antibodies trigger human natural xenogeneic antibody responses particularly directed against animal‐type carbohydrates, mainly the N‐glycolyl form of the neuraminic acid (Neu5Gc) and the α1,3‐galactose, potentially leading to serum sickness or allergy. Here, we immunized cytidine monophosphate‐N‐acetylneuraminic acid hydroxylase and α1,3‐galactosyl‐transferase (GGTA1) double KO pigs with the Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spike receptor binding domain to produce glyco‐humanized polyclonal neutralizing antibodies lacking Neu5Gc and α1,3‐galactose epitopes. Animals rapidly developed a hyperimmune response with anti‐SARS‐CoV‐2 end‐titers binding dilutions over one to a million and end‐titers neutralizing dilutions of 1:10 000. The IgG fraction purified and formulated following clinical Good Manufacturing Practices, named XAV‐19, neutralized spike/angiotensin converting enzyme‐2 interaction at a concentration, GGTA1/CMAH double KO pigs produced high titers of XAV‐19, an anti‐SARS‐Cov‐2 RBD glyco‐humanized polyclonal antibody. XAV‐19 is presented with a high complement activation and a high neutralization potency in vitro and in cell‐based neutralization assays. XAV‐19 does not interact with human Fc gamma receptors, preventing Fc‐dependent enhancement or immune cells skewing.
Published: 2021

20. Otoferlin gene editing in sheep via CRISPR-assisted ssODN-mediated Homology Directed Repair

Author: Laurent Tesson, Vanessa Chenouard, Martina Crispo, Ignacio Anegon, F. Cuadro, Jean-Marie Heslan, P.C. dos Santos-Neto, Alejo Menchaca, M Gantier, A. P. Mulet, Aude Guiffes, M Souza-Neves, Instituto de Reproducción Animal Uruguay [Montevideo, Uruguay], Fundación IRAUy, Transgenic and Experimental Animal / Animales Transgénicos y de Experimentación [Montevideo], Institut Pasteur de Montevideo, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Transgenesis Rat ImmunoPhenomic facility [Nantes] (TRIP platform - Inserm U1064 - CRTI), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Plate-forme GenoCellEdit [Nantes] (PF-GCE - Inserm 1064 - CRTI), This work received support from the Uruguayan National Research Agency (ANII, Uruguay). Some activities were funded by 'TEFOR' project («Investissements d’Avenir» French Government program, managed by the French National Research Agency, ANRII-INSB-0014) and the IHU-Cesti project (ANR-10-IBHU-005) which both are part of the «Investissements d’Avenir» French Government program managed by the ANR, the IHU-Cesti project is also supported by Nantes Métropole and Région Pays de la Loire. Part of this work was realized in the context of the Labex IGO project (ANR-11-LABX-0016-01)., ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), Le Bihan, Sylvie, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, and Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID
Subjects: Male, Microinjections, [SDV]Life Sciences [q-bio], lcsh:Medicine, Biology, Article, Homology directed repair, 03 medical and health sciences, Exon, 0302 clinical medicine, Genome editing, OTOF, Animals, CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats, lcsh:Science, Gene, 030304 developmental biology, Subgenomic mRNA, Gene Editing, Genetics, 0303 health sciences, Sheep, Multidisciplinary, Cas9, lcsh:R, Membrane Proteins, Recombinational DNA Repair, 3. Good health, Experimental models of disease, [SDV] Life Sciences [q-bio], Oligodeoxyribonucleotides, 030220 oncology & carcinogenesis, Mutation, Genetic engineering, Female, lcsh:Q, CRISPR-Cas Systems
Abstract: Different mutations of the OTOF gene, encoding for otoferlin protein expressed in the cochlear inner hair cells, induces a form of deafness that is the major cause of nonsyndromic recessive auditory neuropathy spectrum disorder in humans. We report the generation of the first large animal model of OTOF mutations using the CRISPR system associated with different Cas9 components (mRNA or protein) assisted by single strand oligodeoxynucleotides (ssODN) to induce homology-directed repair (HDR). Zygote microinjection was performed with two sgRNA targeting exon 5 and 6 associated to Cas9 mRNA or protein (RNP) at different concentrations in a mix with an ssODN template targeting HDR in exon 5 containing two STOP sequences. A total of 73 lambs were born, 13 showing indel mutations (17.8%), 8 of which (61.5%) had knock-in mutations by HDR. Higher concentrations of Cas9-RNP induced targeted mutations more effectively, but negatively affected embryo survival and pregnancy rate. This study reports by the first time the generation of OTOF disrupted sheep, which may allow better understanding and development of new therapies for human deafness related to genetic disorders. These results support the use of CRISPR/Cas system assisted by ssODN as an effective tool for gene editing in livestock.
Published: 2020

21. Acibenzolar-S-methyl and resistance quantitative trait loci complement each other to control apple scab and fire blight

Author: Matthieu Gaucher, Juliette Bénéjam, Marie-Noëlle Brisset, Laure Perchepied, Elisa Ravon, Charles-Eric Durel, Institut de Recherche en Horticulture et Semences (IRHS), Université d'Angers (UA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), INRAE, and Région Pays de la Loire : QTLstim project
Subjects: 0106 biological sciences, 0301 basic medicine, Population, Plant Science, Quantitative trait locus, 01 natural sciences, Intrinsic resistance, Crop, 03 medical and health sciences, chemistry.chemical_compound, Erwinia amylovora, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, education, 2. Zero hunger, education.field_of_study, Resistance (ecology), biology, Venturia 30 inaequalis, fungi, Venturia inaequalis, food and beverages, biology.organism_classification, [SDV.BV.PEP]Life Sciences [q-bio]/Vegetal Biology/Phytopathology and phytopharmacy, Horticulture, 030104 developmental biology, chemistry, Malus domestica, Apple scab, Fire blight, induced defense, Acibenzolar-S-methyl, Agronomy and Crop Science, 010606 plant biology & botany
Abstract: International audience; Diversifying disease control methods is a key strategy to sustainably reduce pesticides. Plant genetic resistance has long been used to create resistant varieties. Plant resistance inducers (PRI) are also considered to promote crop health, but their effectiveness is partial and can vary according to the environment and the plant genotype. We investigated the putative interaction between intrinsic (genetic) and PRI-induced resistance in apple when affected by scab and fire blight diseases. A large F1 mapping population was challenged by each disease after a pre-treatment with acibenzolar-S-methyl (ASM) and compared with the water control. Apple scab and fire blight resistance quantitative trait loci (QTLs) were detected in both conditions and compared. ASM exhibited a strong effectiveness in reducing both diseases. When combined, QTL-controlled and ASM-induced resistance acted complementarily to reduce the symptoms from 85% to 100% depending on the disease. In our conditions, resistance QTLs were only slightly or rarely affected by ASM treatment, despite their probable implication in various stages of the resistance build-up. Implications of these results are discussed considering already known results, the underlying mechanisms, cross-protection of both types of resistance against pathogen adaptation, and practical application in orchard conditions.
Published: 2020

22. Non‐targeted 13 C metabolite analysis demonstrates broad re‐orchestration of leaf metabolism when gas exchange conditions vary

Author: Anis M. Limami, Cyril Abadie, Guillaume Tcherkez, Julie Lalande, Institut de Recherche en Horticulture et Semences (IRHS), Université d'Angers (UA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Australian National University - Joint College of Sciences, (ANU), and Région Pays de la Loire and Angers Loire Métropole via the research grant Connect Talent Isoseed.
Subjects: 0106 biological sciences, 0301 basic medicine, photorespiration, Physiology, day respiration, isotopic labelling, Plant Science, 01 natural sciences, 03 medical and health sciences, Metabolomics, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, photosynthesis, Chemistry, Assimilation (biology), Metabolism, metabolomics, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Citric acid cycle, Metabolic pathway, 030104 developmental biology, gas-exchange, Carboxylation, Biochemistry, Photorespiration, Phosphoenolpyruvate carboxykinase, 010606 plant biology & botany
Abstract: International audience; It is common practice to manipulate CO2 and O2 mole fraction during gas-exchange experiments to suppress or exacerbate photorespiration, or simply carry out CO2 response curves. In doing so, it is implicitly assumed that metabolic pathways otherthan carboxylation and oxygenation are altered minimally. In the past few years, targeted metabolic analyses have shown that this assumption is incorrect, with changes in the tricarboxylic acid cycle, anaplerosis (phosphoenolpyruvate carboxylation), and nitrogen or sulphur assimilation. However, this problem has never been tackled systematically using non-targeted analyses to embrace all possible affected metabolic pathways. Here, we exploited combined NMR, GC–MS, and LC–MS data and conducted non-targeted analyses on sunflower leaves sampled at different O2/CO2 ratios in a gas exchange system. The statistical analysis of nearly 4,500 metabolic features not only confirms previous findings on anaplerosis or S assimilation, but also reveals significant changes in branched chain amino acids, phenylpropanoid metabolism, or adenosine turn-over. Noteworthy, all of these pathways involve CO2assimilation or liberation and thus affect net CO2 exchange. We conclude that manipulating CO2 and O2 mole fraction has a broad effect on metabolism, and this must be taken into account to better understand variations in carboxylation (anaplerotic fixa-tion) or apparent day respiration.
Published: 2020

23. Serine 165 Phosphorylation of SHARPIN regulates the Activation of NF-κB

Author: Nicolas Bidère, Charles Pineau, An Thys, Emmanuelle Com, Audrey Gayraud, Clotilde C. N. Renaud, Tiphaine Douanne, Franck Vérité, Julie Gavard, Kilian Trillet, Yannic Danger, Sara Rosińska, Régis Lavigne, Luc Antigny, Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Etablissement français du sang [Rennes] (EFS Bretagne), Institut de recherche en santé, environnement et travail (Irset), 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 ), Proteomics Core Facility (Protim), Université de Rennes (UR)-Plateforme Génomique Santé Biogenouest®, Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), 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), Centre Intégré d'Oncologie Nantes/Angers, Gavard, Julie, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Fondation pour la Recherche Médicale, Fondation de France, Fondation ARC contre le Cancer, Ligue nationale contre le cancer comités de Loire-Atlantique, Maine et Loire, Vendée, Région Pays de la Loire et Nantes Métropole, INCa-DGOS-Inserm_12558, SIRIC ILIAD, Nantes Métropole, Biogenouest, ANR-16-IDEX-0007, Agence Nationale de la Recherche, Infrastructures en Biologie Santé et Agronomie, Conseil Régional de Bretagne, International Program for Scientific Cooperation, ANR-16-IDEX-0007,NExT (I-SITE),NExT (I-SITE)(2016), 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), 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 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Plateforme Génomique Santé Biogenouest®, 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), Chard-Hutchinson, Xavier, and NExT (I-SITE) - - NExT (I-SITE)2016 - ANR-16-IDEX-0007 - IDEX - VALID
Subjects: Programmed cell death, [SDV]Life Sciences [q-bio], Mutant, Immunology, SHARPIN, Article, Serine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Ubiquitin, LUBAC, NF-kappaB, lcsh:Science, Receptor, Molecular Biology, 030304 developmental biology, 0303 health sciences, biology, Chemistry, phosphorylation, NF-κB, Cell Biology, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, biology.protein, Phosphorylation, lcsh:Q, Tumor necrosis factor alpha
Abstract: Summary The adaptor SHARPIN composes, together with the E3 ligases HOIP and HOIL1, the linear ubiquitin chain assembly complex (LUBAC). This enzymatic complex catalyzes and stamps atypical linear ubiquitin chains onto substrates to modify their fate and has been linked to the regulation of the NF-κB pathway downstream of most immunoreceptors, inflammation, and cell death. However, how this signaling complex is regulated is not fully understood. Here, we report that a portion of SHARPIN is constitutively phosphorylated on the serine at position 165 in lymphoblastoid cells and can be further induced following T cell receptor stimulation. Analysis of a phosphorylation-resistant mutant of SHARPIN revealed that this mark controls the linear ubiquitination of the NF-κB regulator NEMO and allows the optimal activation of NF-κB in response to TNFα. These results identify an additional layer of regulation of the LUBAC and unveil potential strategies to modulate its action., Graphical abstract, Highlights • Part of SHARPIN is constitutively phosphorylated on S165 in lymphoblastoid cells • SHARPIN S165 phosphorylation governs TNFα-mediated linear ubiquitination of NEMO • Mutation of S165 hinders NF-κB activation, Molecular Biology; Immunology; Cell Biology
Published: 2020

24. From 1957 to Nowadays: A Brief History of Epigenetics

Author: Eric Hervouet, Paul Peixoto, Aurélien A. Sérandour, Pierre-François Cartron, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), EPIgenetics and GENe EXPression Technical Plateform (EPIGENExp), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), 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), Apoptose et progression tumorale (ICO, Saint-Herblain), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, Cancéropôle Grand-Ouest [Bretagne-Centre-Pays de Loire], EpiSAVMEN Network (Région Pays de la Loire) [Saint-Herblain], LabEX IGO Immunothérapie Grand Ouest, École Centrale de Nantes (ECN), DImaCell Platform, Université Bourgogne Franche-Comté [COMUE] (UBFC), Bernardo, Elizabeth, 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), Nantes Université (Nantes Univ), Dispositif Inter-régional d'Imagerie Cellulaire [Dijon] (DImaCell), Procédés Alimentaires et Microbiologiques (PAM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ingénierie et biologie cellulaire et tissulaire (IBCT (ex IFR133)), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Agroécologie [Dijon], and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: Epigenomics, History, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, History, 21st Century, Catalysis, Epigenesis, Genetic, Inorganic Chemistry, lcsh:Chemistry, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Epitranscriptomics, histones, Animals, Humans, Epigenetics, Physical and Theoretical Chemistry, Molecular Biology, lcsh:QH301-705.5, Spectroscopy, 030304 developmental biology, Cognitive science, 0303 health sciences, DNA methylation, epigenetics, Organic Chemistry, General Medicine, History, 20th Century, Computer Science Applications, lcsh:Biology (General), lcsh:QD1-999, 030220 oncology & carcinogenesis, Identification (biology), history, epitranscriptomics, Protein Processing, Post-Translational
Abstract: International audience; Due to the spectacular number of studies focusing on epigenetics in the last few decades, and particularly for the last few years, the availability of a chronology of epigenetics appears essential. Indeed, our review places epigenetic events and the identification of the main epigenetic writers, readers and erasers on a historic scale. This review helps to understand the increasing knowledge in molecular and cellular biology, the development of new biochemical techniques and advances in epigenetics and, more importantly, the roles played by epigenetics in many physiological and pathological situations.
Published: 2020

25. Identification and Quantification of a Phytotoxic Metabolite from Alternaria dauci

Author: Luis M. Peña-Rodríguez, Martha Leyte-Lugo, Pascal Richomme, Pascal Poupard, Centro de Investigacion Cientifica de Yucatan (CICY), Substances d'Origine Naturelle et Analogues Structuraux (SONAS), Université d'Angers (UA), Institut de Recherche en Horticulture et Semences (IRHS), Université d'Angers (UA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Région Pays de la Loire, and SEP-CONACYT-ANUIES-ECOS-NORD (México-France) collaborative Project No. 276520.
Subjects: 0106 biological sciences, Alternaria leaf blight, Metabolite, [SDV]Life Sciences [q-bio], Pharmaceutical Science, Secondary Metabolism, 01 natural sciences, Analytical Chemistry, chemistry.chemical_compound, phytotoxins, α-acetylorcinol, Drug Discovery, Pastinaca, 0303 health sciences, biology, Nicotiana alata, Alternaria, food and beverages, p-hydroxybenzoic acid, Daucus carota, Horticulture, Chemistry (miscellaneous), Metabolome, Molecular Medicine, acetylorcinol, Article, lcsh:QD241-441, 03 medical and health sciences, Tagetes, Alternaria dauci, lcsh:Organic chemistry, otorhinolaryngologic diseases, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Physical and Theoretical Chemistry, Piperazine, 030304 developmental biology, Toxins, Biological, Organic Chemistry, fungi, biology.organism_classification, [SDV.BV.PEP]Life Sciences [q-bio]/Vegetal Biology/Phytopathology and phytopharmacy, Plant Leaves, chemistry, Salicylic acid, 010606 plant biology & botany
Abstract: Alternaria dauci is the causal agent of Alternaria leaf blight (ALB) in carrot (Daucus carota) crops around the world. However, to date, A. dauci has received limited attention in its production of phytotoxic metabolites. In this investigation, the bioassay-guided isolation of the extract from liquid cultures of A. dauci resulted in the isolation of two metabolites identified as &alpha, acetylorcinol (1) and p-hydroxybenzoic acid (2), based on their spectroscopic data and results from chemical correlation reactions. Testing of both metabolites in different assays showed an important phytotoxic activity for p-hydroxybenzoic acid (2) when tested in the leaf-spot assay on parsley (Petroselinum crispum), in the leaf infiltration assay on tobacco (Nicotiana alata) and marigold (Tagetes erecta), and in the immersion assay on parsley and parsnip (Pastinaca sativa) leaves. Quantification of the two metabolites in the crude extract of A. dauci kept at different times showed that p-hydroxybenzoic acid (2) is one of the first metabolites to be synthesized by the pathogen, suggesting that this salicylic acid derivative could play an important role in the pathogenicity of the fungus.
Published: 2020

26. Comparison of Stomaching versus Rinsing for Recovering Bacterial Communities from Rainbow Trout (Oncorhynchus mykiss) Fillets

Author: Catherine Magras, Albert Rossero, Agnès Bouju-Albert, Hervé Prévost, Nicolas Helsens, Ségolène Calvez, Sécurité des Aliments (SECALIM), Ecole Nationale Vétérinaire de Nantes-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biologie, Epidémiologie et analyse de risque en Santé Animale (BIOEPAR), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and European Union and the 'Région Pays de la Loire' (RFI 'Food for Tomorrow' call for proposals 2016—contract 34000656—PhD grant to Nicolas Helsens
Subjects: [SDV]Life Sciences [q-bio], Microbiology, 03 medical and health sciences, Rainbow trout fillets, Recovery method, Animals, Food science, Rinsing, DNA extraction, Volume concentration, 030304 developmental biology, 0303 health sciences, biology, Bacteria, 030306 microbiology, Chemistry, Stomaching, Fish fillet, Bacterial recovery, biology.organism_classification, Bacterial communities, Fresh fish, Oncorhynchus mykiss, Rainbow trout, Brochothrix thermosphacta, Food Science, Brochothrix
Abstract: International audience; The use of high-throughput methods allows a better characterization of food-related bacterial communities. However, such methods require large amounts of high-quality bacterial DNA, which may be a challenge when dealing with a complex matrix that has a low concentration of bacteria, such as fresh fish fillets. Therefore, the choice of method used to recover bacteria from a food matrix in a cost-effective way is critical, yet little information is available on the performance of commonly used methods. We assessed the recovery capacity of two such methods: stomaching and mechanical rinsing. The efficiency of the methods was evaluated through quantitative recovery and compatibility with end-point quantitative PCR (qPCR). Fresh rainbow trout (Oncorhynchus mykiss) fillets were inoculated with a bacterial marker, Brochothrix thermosphacta, at different concentrations (7.52 to 1.52 log CFU/g). The fillets were processed by one of the two methods, and the recovery of the marker in the suspensions was assessed by plate counting and qPCR targeting B. thermosphacta-rpoC. The same analyses were performed on six noninoculated fresh fillets. Stomaching and mechanical rinsing allowed efficient and repeatable recovery of the bacterial communities from the 42 inoculated fillets. No significant differences in recovery ratios were observed between the marker enumerated in the inoculation suspensions and in the corresponding recovery suspensions after rinsing and stomaching. However, the stomaching method allowed too many particles to pass through the filters bag, making necessary a limiting supplementary filtration step. As a consequence, only the rinsing recovery method allowed proper PCR quantification of the inoculated B. thermosphacta. The mean recovered bacterial level of the fillets was approximately 3 log CFU/g. It seems more relevant and cost-effective to recover the endogenous bacterial microbiota of a fish fillet structure using the rinsing method rather than the stomaching method.
Published: 2020

27. Seed Germination in Oil Palm (Elaeis guineensis Jacq.): A Review of Metabolic Pathways and Control Mechanisms

Author: Jing Cui, Guillaume Tcherkez, Emmanuelle Lamade, Research School of Biology [Canberra, Australia], Australian National University (ANU), Performance des systèmes de culture des plantes pérennes (UPR Système de pérennes), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Département Performances des systèmes de production et de transformation tropicaux (Cirad-PERSYST), Institut de Recherche en Horticulture et Semences (IRHS), Université d'Angers (UA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Région Pays de la Loire and Angers Loire Métropole via the research grant Connect Talent, and Isoseed. J. C. was supported by an Australia Awards PhD Scholarship.
Subjects: 0106 biological sciences, 0301 basic medicine, F62 - Physiologie végétale - Croissance et développement, Review, Arecaceae, Elaeis guineensis, 01 natural sciences, oil palm, lcsh:Chemistry, Gene Expression Regulation, Plant, Canola, skin and connective tissue diseases, lcsh:QH301-705.5, Spectroscopy, Plant Proteins, 2. Zero hunger, food and beverages, General Medicine, Computer Science Applications, Horticulture, haustorium, Germination, Seeds, Palm, Metabolic Networks and Pathways, congenital, hereditary, and neonatal diseases and abnormalities, food.ingredient, education, lipid remobilization, Biology, Catalysis, Inorganic Chemistry, Crop, 03 medical and health sciences, food, Métabolisme, Palm oil, F03 - Production et traitement des semences, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Physical and Theoretical Chemistry, Molecular Biology, Organic Chemistry, 15. Life on land, biology.organism_classification, Germination des graines, [SDV.BV.PEP]Life Sciences [q-bio]/Vegetal Biology/Phytopathology and phytopharmacy, body regions, Metabolic pathway, [SDV.BV.AP]Life Sciences [q-bio]/Vegetal Biology/Plant breeding, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, germination, Dormancy, seed, metabolism, 010606 plant biology & botany
Abstract: International audience; Oil palm is an oil-producing crop of major importance at the global scale. Oil palm mesocarp lipids are used for myriads industrial applications, and market demand has been growing for decades. In addition, oil palm seeds are oleaginous, and the oil extracted therefrom can be used for several purposes, from food to cosmetics. As such, there is a huge need in oil palm seeds to maintain the global cohort of more than 2 billion trees. However, oil palm seed germination is a rather difficult process, not only to break dormancy, but also because it is long and often reaches lower-than-expected germination rates. Surprisingly, despite the crucial importance of germination for oil palm plantation management, our knowledge is still rather limited, in particular about germinating oil palm seed metabolism. The present review incorporates different pieces of information that have been obtained in the past few years, in oil palm and in other palm species, in order to provide an overview of germination metabolism and its control. Further insights can also be gained from other oleaginous model plants, such as Arabidopsis or canola, however, palm seeds have peculiarities that must be accounted for, to gain a better understanding of germinating seed metabolism.
Published: 2020

28. ScreenSeed as a novel high throughput seed germination phenotyping method

Author: Marie-Hélène Wagner, Pierre Cordier, Sylvie Ducournau, Sophie Aligon, Edwin Grappin, Nicolas Merieux, Dominique Job, Philippe Grappin, EffiSciency, ScreenSeed, GIP GEVES SNES ANGERS (GIP GEVES SNES ANG), Institut de Recherche en Horticulture et Semences (IRHS), Université d'Angers (UA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Microbiologie, adaptation et pathogénie (MAP), Centre National de la Recherche Scientifique (CNRS)-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, Génomique fonctionnelle des Champignons Phytopathogènes (GFCP), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), and The regional program 'Objectif Végétal, Research, Education and Innovation in Pays de la Loire', supported by the French Région Pays de la Loire, Angers Loire Métropole and theEur opean Régional Development Fund
Subjects: 0106 biological sciences, 0301 basic medicine, Plant genetics, [SDV]Life Sciences [q-bio], Science, Plant physiology, Arabidopsis, Germination, Biology, 01 natural sciences, Article, 03 medical and health sciences, Statistical analyses, Visual scoring, Plant development, Radicle, Image Processing, Computer-Assisted, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Throughput (business), Multidisciplinary, food and beverages, Repeatability, [SDV.BV.PEP]Life Sciences [q-bio]/Vegetal Biology/Phytopathology and phytopharmacy, Horticulture, 030104 developmental biology, Plant stress responses, Seeds, Medicine, Plant biotechnology, Plant sciences, 010606 plant biology & botany
Abstract: A high throughput phenotyping tool for seed germination, the ScreenSeed technology, was developed with the aim of screening genotype responsiveness and chemical drugs. This technology was presently used with Arabidopsis thaliana seeds to allow characterizing seed samples germination behavior by incubating seeds in 96-well microplates under defined conditions and detecting radicle protrusion through the seed coat by automated image analysis. This study shows that this technology provides a fast procedure allowing to handle thousands of seeds without compromising repeatability or accuracy of the germination measurements. Potential biases of the experimental protocol were assessed through statistical analyses of germination kinetics. Comparison of the ScreenSeed procedure with commonly used germination tests based upon visual scoring displayed very similar germination kinetics.
Published: 2020

29. Maternal Protein Restriction in Rats Alters the Expression of Genes Involved in Mitochondrial Metabolism and Epitranscriptomics in Fetal Hypothalamus

Author: Simon Guignard, Patricia Parnet, Isabelle Grit, Dimitri Meistermann, Valérie Amarger, Morgane Frapin, Valentine Suzanne Moullé, Vincent Paillé, Institut des Maladies de l'Appareil Digestif, Université de Nantes (UN), Centre de Recherche en Nutrition Humaine Ouest [UNIV Nantes] (CRNHO), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), INRAE, Région Pays de la Loire and the Fondation pour la Recherche Médicale (ARF20170938730)., and Le Bihan, Sylvie
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Hypothalamus, lcsh:TX341-641, Biology, Mitochondrion, Energy homeostasis, Article, Transcriptome, Fetal Development, 03 medical and health sciences, transcriptomics, 0302 clinical medicine, Fetus, fetal brain, Pregnancy, Diet, Protein-Restricted, Animals, protein restriction, Gene, Progenitor, 2. Zero hunger, Nutrition and Dietetics, differentiation, Maternal Nutritional Physiological Phenomena, Cell biology, Mitochondria, Rats, [SDV] Life Sciences [q-bio], neurogenesis, 030104 developmental biology, Mitochondrial respiratory chain, Female, epitranscriptomics, lcsh:Nutrition. Foods and food supply, 030217 neurology & neurosurgery, Food Science, maternal nutrition
Abstract: International audience; Fetal brain development is closely dependent on maternal nutrition and metabolic status. Maternal protein restriction (PR) is known to be associated with alterations in the structure and function of the hypothalamus, leading to impaired control of energy homeostasis and food intake. The objective of this study was to identify the cellular and molecular systems underlying these effects during fetal development. We combined a global transcriptomic analysis on the fetal hypothalamus from a rat model of maternal PR with in vitro neurosphere culture and cellular analyses. Several genes encoding proteins from the mitochondrial respiratory chain complexes were overexpressed in the PR group and mitochondrial metabolic activity in the fetal hypothalamus was altered. The level of the N6-methyladenosine epitranscriptomic mark was reduced in the PR fetuses, and the expression of several genes involved in the writing/erasing/reading of this mark was indeed altered, as well as genes encoding several RNA-binding proteins. Additionally, we observed a higher number of neuronal-committed progenitors at embryonic day 17 (E17) in the PR fetuses. Together, these data strongly suggest a metabolic adaptation to the amino acid shortage, combined with the post-transcriptional control of protein expression, which might reflect alterations in the control of the timing of neuronal progenitor differentiation.
Published: 2020

30. Analysis of the Targets and Glycosylation of Monoclonal IgAs From MGUS and Myeloma Patients

Author: Adrien Bosseboeuf, Célia Seillier, Nicolas Mennesson, Sophie Allain-Maillet, Maeva Fourny, Anne Tallet, Eric Piver, Philippe Lehours, Francis Mégraud, Laureline Berthelot, Jean Harb, Edith Bigot-Corbel, Sylvie Hermouet, 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), Laboratoire de Biochimie [CHU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie du cancer du foie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2, Laboratoire de Bactériologie, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Université de Nantes (UN)-Université de Nantes (UN), Laboratoire de Biochimie [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Département d'Hématologie [CHU Nantes], The Ligue Nationale contre le Cancer, the Cancéropôle Grand Ouest and Région Pays de la Loire and Région Centre (2015–2016), and Janssen USA., Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Le Bihan, Sylvie, 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)
Subjects: 0301 basic medicine, Male, hepatitis C virus, Epstein-Barr Virus Infections, Herpesvirus 4, Human, Glycosylation, lysoglucosylceramide (LGL-1), [SDV]Life Sciences [q-bio], Hepacivirus, medicine.disease_cause, Monoclonal Gammopathy of Undetermined Significance, Cohort Studies, Epstein–Barr virus, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Immunology and Allergy, Antigens, Viral, Multiple myeloma, Original Research, Aged, 80 and over, Viral Core Proteins, Antibodies, Monoclonal, Middle Aged, Hepatitis C, 3. Good health, [SDV] Life Sciences [q-bio], multiple myeloma, Monoclonal, Female, Epstein–Barr virus nuclear antigen 1, lcsh:Immunologic diseases. Allergy, Hepatitis C virus, Immunology, infectious antigens, monoclonal gammopathy of undetermined significance (MGUS), Glucosylceramides, Virus, 03 medical and health sciences, sialylation, Antigen, medicine, monoclonal immunoglobulin A (IgA), Humans, Aged, business.industry, medicine.disease, Immunoglobulin A, 030104 developmental biology, Epstein-Barr Virus Nuclear Antigens, business, lcsh:RC581-607, Monoclonal gammopathy of undetermined significance, 030215 immunology
Abstract: International audience; Previous studies showed that monoclonal immunoglobulins G (IgGs) of “monoclonal gammopathy of undetermined significance” (MGUS) and myeloma were hyposialylated, thus presumably pro-inflammatory, and for about half of patients, the target of the monoclonal IgG was either a virus—Epstein–Barr virus (EBV), other herpes viruses, hepatitis C virus (HCV)—or a glucolipid, lysoglucosylceramide (LGL1), suggesting antigen-driven disease in these patients. In the present study, we show that monoclonal IgAs share these characteristics. We collected 35 sera of patients with a monoclonal IgA (6 MGUS, 29 myeloma), and we were able to purify 25 of the 35 monoclonal IgAs (6 MGUS, 19 myeloma). Monoclonal IgAs from MGUS and myeloma patients were significantly less sialylated than IgAs from healthy volunteers. When purified monoclonal IgAs were tested against infectious pathogens and LGL1, five myeloma patients had a monoclonal IgA that specifically recognized viral proteins: the core protein of HCV in one case, EBV nuclear antigen 1 (EBNA-1) in four cases (21.1%of IgA myeloma). Monoclonal IgAs from three myeloma patients reacted against LGL1. In summary, monoclonal IgAs are hyposialylated and as described for IgG myeloma, significant subsets (8/19, or 42%) of patients with IgA myeloma may have viral or self (LGL1) antigen-driven disease.
Published: 2020

31. TAK1 lessens the Activity of the Paracaspase MALT1 during T cell Receptor Signaling

Author: Nicolas Bidère, Julie Gavard, Carolina Alves Nicolau, Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), 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), L’Héma-NexT [UNIV Nantes] (i-Site NexT), Université de Nantes (UN), Microenvironnement des niches tumorales [UNIV Tours] (CNRS GDR 3697 MicroNiT), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, This research was funded by an International Program for Scientific Cooperation (PICS, CNRS), Fondation ARC contre le Cancer (JG, NB), Ligue nationale contre le cancer comités de Loire-Atlantique, Maine et Loire,Vendée (JG, NB), Région Pays de la Loire et Nantes Métropole under Connect Talent Grant (JG), the National Research Agency under the Programme d’Investissements d’Avenir (ANR-16-IDEX-0007), and by the SIRIC ILIAD (INCa-DGOS-Inserm_12558). CAN holds a postdoctoral fellowship from Fondation de France. Team projects are funded by Equipe Labellisée Fondation pour la Recherche Médicale (FRM DEQ20180339184)., Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), 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), Microenvironnement des niches tumorales (CNRS GDR 3697 Micronit ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Bernardo, Elizabeth
Subjects: 0301 basic medicine, TAK1, Immunology, Receptors, Antigen, T-Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Lymphocyte Activation, NF-κB, Jurkat Cells, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, CBM complex, Humans, Gene silencing, Phosphorylation, Transcription factor, Adaptor Proteins, Signal Transducing, B-Lymphocytes, MALT1, NF-kappa B, Paracaspase, MAP Kinase Kinase Kinases, Signaling, Neoplasm Proteins, Cell biology, 030104 developmental biology, chemistry, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Multiprotein Complexes, Lymphocyte, Signal transduction, Signal Transduction, Transcription Factors, 030215 immunology
Abstract: International audience; The CARMA1-BCL10-MALT1 (CBM) complex couples antigen receptors to the activation of Nuclear Factor κB (NF-κB) transcription factors in T/B lymphocytes. Within this signalosome, the MALT1 paracaspase serves dual roles: it is a crucial adaptor for signal transduction to NF-κB signaling, and a protease that shapes NF-κB activity and lymphocyte activation. Although a subtle choreography of ubiquitination and phosphorylation orchestrate the CBM, how precisely this complex and MALT1 enzyme are regulated continue to be elucidated. Here, we report that the chemical inhibition or the siRNA-based silencing of transforming growth factor beta-activated kinase 1 (TAK1), a known partner of the CBM complex required for NF-κB activation, enhanced the processing of MALT1 substrates. We further show that the assembly of the CBM as well as the ubiquitination of MALT1 was augmented when TAK1 was inhibited. Thus, TAK1 may initiate a negative feedback loop to finely tune the CBM complex activity.
Published: 2020

32. Stable and Local Reservoirs of Mycobacterium ulcerans Inferred from the Nonrandom Distribution of Bacterial Genotypes, Benin

Author: Télésphore Yao Brou, Estelle Marion, Ronald Gnimavo, Marie Kempf, Alban Besnard, Céline Bris, Roch Christian Johnson, Clement Coudereau, Fida Khater, Sara Eyangoh, Marie Robbe-Saule, ATOMycA (CRCINA-ÉQUIPE 6), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-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), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Université d’Abomey-Calavi = University of Abomey Calavi (UAC), Fondation Raoul Follereau [Paris], Maison de la Télédétection, Centre de diagnostic et de traitement de la lèpre et de l’Ulcère de Buruli Madeleine et Raoul Follereau [Pobè, Bénin], Centre Pasteur du Cameroun, Réseau International des Instituts Pasteur (RIIP), Fondation Raoul FollereauINSERMAgence Nationale de la Recherche Région Pays de la Loire, ANR-11-CEPL-0007,EXTRA-MU,Etudes multidisciplinaires de l'Expansion et de la Transmission de Mycobacterium ulcerans liées aux changements environnementaux(2011), KEMPF, Marie, Changements Environnementaux Planétaires et Sociétés - Etudes multidisciplinaires de l'Expansion et de la Transmission de Mycobacterium ulcerans liées aux changements environnementaux - - EXTRA-MU2011 - ANR-11-CEPL-0007 - CEP&S - VALID, 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), and Université d’Abomey-Calavi (UAC)
Subjects: Buruli ulcer, Stable and Local Reservoirs of Mycobacterium ulcerans Inferred from the Nonrandom Distribution of Bacterial Genotypes, Benin, Epidemiology, lcsh:Medicine, Distribution (economics), 0302 clinical medicine, Genotype, Benin, 030212 general & internal medicine, bacteria, 2. Zero hunger, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], biology, Ecology, genetic diversity, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Phylogeography, Infectious Diseases, Mycobacterium ulcerans, Water Microbiology, geospatial model, DNA, Bacterial, Microbiology (medical), 030231 tropical medicine, Nigeria, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, mutational profiling, medicine, Humans, lcsh:RC109-216, Genotyping, 030304 developmental biology, Disease Reservoirs, Genetic diversity, business.industry, Research, lcsh:R, Tropical disease, 15. Life on land, medicine.disease, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, tuberculosis and other mycobacteria, genotyping, genomic analysis, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, business
Abstract: International audience; Mycobacterium ulcerans is the causative agent of Buruli ulcer, a neglected tropical disease found in rural areas of West and Central Africa. Despite the ongoing efforts to tackle Buruli ulcer epidemics, the environmental reservoir of its pathogen remains elusive, underscoring the need for new approaches to improving disease prevention and management. In our study, we implemented a local-scale spatial clustering model and deciphered the genetic diversity of the bacteria in a small area of Benin where Buruli ulcer is endemic. Using 179 strain samples from West Africa, we conducted a phylogeographic analysis combining whole-genome sequencing with spatial scan statistics. The 8 distinct genotypes we identified were by no means randomly spread over the studied area. Instead, they were divided into 3 different geographic clusters, associated with landscape characteristics. Our results highlight the ability of M. ulcerans to evolve independently and differentially depending on location in a specific ecologic reservoir.
Published: 2020

33. Characterization of Rat ILCs Reveals ILC2 as the Dominant Intestinal Subset

Author: Ahmed Abidi, Thomas Laurent, Gaëlle Bériou, Laurence Bouchet-Delbos, Cynthia Fourgeux, Cédric Louvet, Raja Triki-Marrakchi, Jeremie Poschmann, Régis Josien, Jérôme Martin, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Tunis - El Manar II, Université de Tunis El Manar (UTM), École Centrale de Nantes (ECN), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire d’Immunologie, Centre d’Immunomonitorage Nantes Atlantique (CIMNA), Centre hospitalier universitaire de Nantes (CHU Nantes), This work was realized in the context of IHU-CESTI project that received French government financial support managed by the National Research Agency (ANR). This work was also supported by the Région Pays de la Loire. AA was supported by a FrenchTunisian PHU-UTIQUE grant from the 2015 Hubert Curien program (CMCU N◦15G0809)., ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), Le Bihan, Sylvie, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, and University of Tunis El Manar
Subjects: Male, 0301 basic medicine, lcsh:Immunologic diseases. Allergy, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, innate lymphoid cells, Cell Count, Biology, Flow cytometry, ILC2, Rats, Sprague-Dawley, Mice, 03 medical and health sciences, Th2 Cells, 0302 clinical medicine, Intestinal mucosa, medicine, Animals, Humans, Immunology and Allergy, Mesenteric lymph nodes, rat, Lymphocytes, Intestinal Mucosa, Receptor, skin and connective tissue diseases, intestine, Cells, Cultured, Original Research, medicine.diagnostic_test, Innate lymphoid cell, Flow Cytometry, Phenotype, Immunity, Innate, Lymphocyte Subsets, Rats, Cell biology, Peyer Patch, [SDV] Life Sciences [q-bio], body regions, 030104 developmental biology, medicine.anatomical_structure, Cytokine, secondary lymphoid organs, Cytokines, lcsh:RC581-607, 030215 immunology
Abstract: International audience; Innate lymphoid cells (ILCs) are tissue-resident lymphocytes that lack antigen-specific receptors and exhibit innate effector functions such as cytokine production that play an important role in immediate responses to pathogens especially at mucosal sites. Mouse and human ILC subsets have been extensively characterized in various tissues and in blood. In this study, we present the first characterization of ILCs and ILC subsets in rat gut and secondary lymphoid organs using flow cytometry and single cell RNA sequencing. Our results show that phenotype and function of rat ILC subsets are conserved as compared to human and mouse ILCs. However, and in contrast to human and mouse, our study unexpectedly revealed that ILC2 and not ILC3 was the dominant ILC subset in the rat intestinal lamina propria. ILC2 predominance in the gut was independent of rat strain, sex or housing facility. In contrast, ILC3 was the predominant ILC subset in mesenteric lymph nodes and Peyer patches. In conclusion, our study demonstrates that in spite of highly conserved phenotype and function between mice, rat and humans, the distribution of ILC subsets in the intestinal mucosa is dependent on the species likely in response to both genetic and environmental factors.
Published: 2020

34. A glance into the evolution of template-free protein structure prediction methodologies

Author: Frédéric Cadet, Ramanathan Sowdhamini, Bernard Offmann, Surbhi Dhingra, OFFMANN, Bernard, Unité de fonctionnalité et ingénierie de protéines (UFIP), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Tata Institute for Fundamental Research (TIFR), National Centre for Biological Sciences [TIFR] (NCBS), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Université de La Réunion - Faculté des Sciences et Technologies (FST), Université de La Réunion (UR), Région Pays de la Loire, projet GRIOTE, Conseil Régional de La Réunion and Fonds Social Européen, PhD scholarship tier 234275, convention DIRED/20161451, and Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université de Paris (UP)
Subjects: 0301 basic medicine, Models, Molecular, ab-initio, Protein Folding, template-free modelling, Computer science, Protein Conformation, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Ab initio, Machine learning, computer.software_genre, Biochemistry, Quantitative Biology - Quantitative Methods, Field (computer science), 03 medical and health sciences, Protein structure, CASP, Databases, Protein, Quantitative Methods (q-bio.QM), Structure (mathematical logic), Template free, 030102 biochemistry & molecular biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], business.industry, Computational Biology, Proteins, Biomolecules (q-bio.BM), General Medicine, Protein structure prediction, artificial intelligence, protein structure prediction, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, [CHIM.THEO] Chemical Sciences/Theoretical and/or physical chemistry, 030104 developmental biology, Quantitative Biology - Biomolecules, FOS: Biological sciences, Artificial intelligence, business, computer, Algorithms
Abstract: Prediction of protein structures using computational approaches has been explored for over two decades, paving a way for more focused research and development of algorithms in comparative modelling, ab intio modelling and structure refinement protocols. A tremendous success has been witnessed in template-based modelling protocols, whereas strategies that involve template-free modelling still lag behind, specifically for larger proteins (> 150 a.a.). Various improvements have been observed in ab initio protein structure prediction methodologies overtime, with recent ones attributed to the usage of deep learning approaches to construct protein backbone structure from its amino acid sequence. This review highlights the major strategies undertaken for template-free modelling of protein structures while discussing few tools developed under each strategy. It will also briefly comment on the progress observed in the field of ab initio modelling of proteins over the course of time as seen through the evolution of CASP platform., 17 pages, 1 figure, 1 table
Published: 2020

35. Simultaneous exploration of nutrients and pollutants in human milk and their impact on preterm infant growth: An integrative cross-platform approach

Author: Marie-Cécile Alexandre-Gouabau, Jean-Philippe Antignac, German Cano-Sancho, Dominique Darmaun, Yann Guitton, Anne-Lise Royer, Thomas Moyon, Bruno Le Bizec, Jean-Christophe Rozé, Clair-Yves Boquien, Hélène Billard, Laboratoire d'étude des Résidus et Contaminants dans les Aliments (LABERCA), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre hospitalier universitaire de Nantes (CHU Nantes), European Milk Bank Association [Milan, Italie] (EMBA), Région Pays-de-la-Loire, France, (2011–2012), and Fonds Européen de Développement Economique et Régional (FEDER, France, Grant 38395, Project 6226, 2013–2015)
Subjects: Exposome, Biomarkers Nutrients, Breast milk, Pilot Projects, 010501 environmental sciences, Biology, 01 natural sciences, Biochemistry, 03 medical and health sciences, Child Development, 0302 clinical medicine, Nutrient, Environmental health, Bayesian multivariate linear regression, Humans, 030212 general & internal medicine, Infant Nutritional Physiological Phenomena, 0105 earth and related environmental sciences, General Environmental Science, 2. Zero hunger, Pollutant, Milk, Human, Confounding, Infant, Newborn, Infant, Preterm infants, Nutrients, Growth model, [SDE.ES]Environmental Sciences/Environmental and Society, 3. Good health, Risk-benefit assessment, Persistent pollutants, Environmental Pollutants, Molecular Profile, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Infant, Premature
Abstract: International audience; Early nutritional management including fortified human breastmilk is currently recommended to fulfil the energy demands and counterbalance risks associated to preterm birth. However, little is known about the potential adverse effects of exposure to persistent organic pollutants (POPs) carried in human milk on preterm infant growth. We conducted a pilot study proving the application of an integrative analytical approach based on mass spectrometry (MS) coupled to advanced statistical models, favouring the comprehensive molecular profiling to support the identification of multiple biomarkers. We applied this workflow in the frame of a preterm infants’ cohort to explore environmental determinants of growth. The combination of high resolution gas and liquid chromatography MS platforms generated a large molecular profile, including 102 pollutants and nutrients (targeted analysis) and 784 metabolites (non-targeted analysis). Data analysis consisted in a preliminary examination of associations between the signatures of POPs and the normalised growth of preterm infants, using multivariate linear regression adjusting for known confounding variables. A second analysis aimed to identify multidimensional biomarkers using a multiblock algorithm allowing the integration of multiple datasets in the growth model of preterm infants. The preliminary results did not suggest an impairment of preterm growth associated to the milk concentrations of POPs. The multiblock approach however revealed complex interrelated molecular networks of POPs, lipids, metabolites and amino acids in breastmilk associated to preterm infant growth, supporting the high potential of biomarkers exploration of this proposed workflow. Whereas the present study intended to identify simultaneously pollutant and nutrient exposure profiles associated to early preterm infant growth, this workflow may be easily adapted and applied to other matrices (e.g. serum) and research settings, favouring the functional exploration of environmental determinants of complex and multifactorial diseases.
Published: 2020

36. Urine-derived cells provide a readily accessible cell type for feeder-free mRNA reprogramming

Author: Laurent David, Léa Flippe, Amandine Caillaud, Quentin Francheteau, Karim Si-Tayeb, Sebastian Knöbel, Anne Gaignerie, A Derevier, M Rousselle, V Forest-Choquet, N Lefort, F Chaubron, Aurore Girardeau, Caroline Chariau, Valentin François-Campion, Nathalie Gaborit, Plate-forme Cellules souches pluripotentes induites - iPSC [Nantes] (CHU Nantes/INSERM/CNRS-IFR Santé François Bonamy), 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)-Structure Fédérative de Recherche en Santé François Bonamy (SFR RSFB), IPS Platform [Paris], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), LabEx IGO 'Immunotherapy, Graft, Oncology' [Nantes], Institut Clinident [Aix en Provence], Miltenyi Biotec GmbH [Bergisch Gladbach, Germany], Région Pays de la Loire., The national project CHOPIN (CHolesterol Personalized INnovation)., ANR-14-CE16-0026,StemHepTher,Validation pré-clinique des hépatocytes dérivés de cellules souches pluripotentes pour la biothérapie hépatique(2014), ANR-16-RHUS-0007,CHOPIN,CHOPIN(2016), Le Bihan, Sylvie, Appel à projets générique - Validation pré-clinique des hépatocytes dérivés de cellules souches pluripotentes pour la biothérapie hépatique - - StemHepTher2014 - ANR-14-CE16-0026 - Appel à projets générique - VALID, CHOPIN - - CHOPIN2016 - ANR-16-RHUS-0007 - RHUS - VALID, Unité de recherche de l'institut du thorax (ITX-lab), LabEX IGO Immunothérapie Grand Ouest, and Nantes Université (Nantes Univ)
Subjects: 0301 basic medicine, Cell type, Somatic cell, Cellular differentiation, Induced Pluripotent Stem Cells, lcsh:Medicine, Biology, Urine, Cell Line, 03 medical and health sciences, Humans, RNA, Messenger, Induced pluripotent stem cell, lcsh:Science, Dental Pulp, Messenger RNA, Multidisciplinary, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, lcsh:R, Translation (biology), Cell Differentiation, Fibroblasts, Cellular Reprogramming, 3. Good health, Cell biology, 030104 developmental biology, Cell culture, lcsh:Q, Reprogramming, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Over a decade after their discovery, induced pluripotent stem cells (iPSCs) have become a major biological model. The iPSC technology allows generation of pluripotent stem cells from somatic cells bearing any genomic background. The challenge ahead of us is to translate human iPSCs (hiPSCs) protocols into clinical treatment. To do so, we need to improve the quality of hiPSCs produced. In this study we report the reprogramming of multiple patient urine-derived cell lines with mRNA reprogramming, which, to date, is one of the fastest and most faithful reprogramming method. We show that mRNA reprogramming efficiently generates hiPSCs from urine-derived cells. Moreover, we were able to generate feeder-free bulk hiPSCs lines that did not display genomic abnormalities. Altogether, this reprogramming method will contribute to accelerating the translation of hiPSCs to therapeutic applications.
Published: 2018

37. Pharmacology of Recombinant Adeno-associated Virus Production

Author: Magalie Penaud-Budloo, Nathalie Clement, Achille François, Eduard Ayuso, JAULIN, Nicolas, Démonstrateurs - Consortium préindustriel des vecteurs de thérapie génique - - PGT2010 - ANR-10-DPBS-0001 - DPBS - VALID, Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques (Inserm UMR 1089), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Powell Gene Therapy [Gainesville, FL, USA], Department of Pediatrics [Gainesville, FL, USA], University of Florida [Gainesville] (UF)-University of Florida [Gainesville] (UF), Financial support to E.A.’s laboratory was provided by INSERM, University of Nantes, CHU of Nantes, Fondation d’Entreprises pour la Thérapie Génique en Pays de la Loire, and Région Pays de la Loire and Pre-industrial gene therapy consortium (Agence Nationale de la Recherche-investissements d’avenir, grant number 10-DPBS-0001)., ANR-10-DPBS-0001,PGT,Consortium préindustriel des vecteurs de thérapie génique(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)
Subjects: 0301 basic medicine, lcsh:QH426-470, viral vectors, [SDV]Life Sciences [q-bio], Genetic enhancement, viruses, quality controls, Biology, medicine.disease_cause, impurities, Article, law.invention, Viral vector, 03 medical and health sciences, Plasmid, law, Genetics, medicine, lcsh:QH573-671, Molecular Biology, Adeno-associated virus, lcsh:Cytology, AAV, Virology, gene therapy, [SDV] Life Sciences [q-bio], lcsh:Genetics, manufacturing, 030104 developmental biology, Herpes simplex virus, Helper virus, Recombinant DNA, Molecular Medicine, Homologous recombination
Abstract: International audience; Recombinant adeno-associated viral (rAAV) vectors have been used in more than 150 clinical trials with a good safety profile and significant clinical benefit in many genetic diseases. In addition, due to their ability to infect non-dividing and dividing cells and to serve as efficient substrate for homologous recombination, rAAVs are being used as a tool for gene-editing approaches. However, manufacturing of these vectors at high quantities and fulfilling current good manufacturing practices (GMP) is still a challenge, and several technological platforms are competing for this niche. Herein, we will describe the most commonly used upstream methods to produce rAAVs, paying particular attention to the starting materials (input) used in each platform and which related impurities can be expected in final products (output). The most commonly found impurities in rAAV stocks include defective particles (i.e., AAV capsids that do contain the therapeutic gene or are not infectious), residual proteins from host cells and helper viruses (adenovirus, herpes simplex virus, or baculoviruses), and illegitimate DNA from plasmids, cells, or helper viruses that may be encapsidated into rAAV particles. Given the role that impurities may play in immunotoxicity, this article reviews the impurities inherently associated with each manufacturing platform.
Published: 2018

38. Intestinal multicellular organoids to study colorectal cancer

Author: Veerle Melotte, Maria M. Alves, Maxime M. Mahe, Robert M.W. Hofstra, Musa Idris, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Erasmus University Medical Center [Rotterdam] (Erasmus MC), The Enteric Nervous System in gut and brain disorders [U1235] (TENS), 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), Cincinnati Children's Hospital Medical Center, 'New Team' grant (BOGUS to MM) from the Bioregate Regenerative Medicine Cluster, University of Nantes and Région Pays de la Loire, ANR-17-CE14-0021,SyNEDI,Rôle du Système Nerveux Entérique sur le Développement Intestinal chez l'Homme.(2017), MAHE, Maxime, and Rôle du Système Nerveux Entérique sur le Développement Intestinal chez l'Homme. - - SyNEDI2017 - ANR-17-CE14-0021 - AAPG2017 - VALID
Subjects: HUMAN COLON, Cancer Research, Colorectal cancer, EPITHELIUM, DIVERSITY, [SDV.CAN]Life Sciences [q-bio]/Cancer, MICROENVIRONMENT, DISEASE, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, SDG 3 - Good Health and Well-being, Genetics, Organoid, Humans, Medicine, Induced pluripotent stem cell, neoplasms, 030304 developmental biology, 0303 health sciences, Tumor microenvironment, business.industry, Modeling, PLATFORM, Treatment options, Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, digestive system diseases, 3. Good health, Intestines, Organoids, Multicellular organism, DIFFERENTIATION, Oncology, 030220 oncology & carcinogenesis, Cancer research, Colorectal Neoplasms, business, PLURIPOTENT STEM-CELLS
Abstract: International audience; Modeling colorectal cancer (CRC) using organoids has burgeoned in the last decade, providing enhanced in vitro models to study the development and possible treatment options for this type of cancer. In this review, we describe both normal and CRC intestinal organoid models and their utility in the cancer research field. Besides highlighting studies that develop epithelial CRC organoid models, i.e. organoids without tumor microenvironment (TME) cellular components, we emphasize on the need for TME in CRC modeling, to help reduce translational disparities in this area. Also, we discuss the utilization of CRC organoids derived from pluripotent stem cells, as well as their potential to be used in cancer research. Finally, limitations and challenges in the current CRC organoids field, are discussed.
Published: 2021

39. Nanomedicine as a potent strategy in melanoma tumor microenvironment

Author: Vincent Pautu, Catherine Passirani, Elise Lepeltier, Daniela Leonetti, Nicolas Clere, Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Endothelium Radiobiology and Targeting (CRCINA-ÉQUIPE 14), 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), The authors would like to thanks the Région Pays de la Loire and the Erasmus Mundus program for the financing of the Ph D programm of Vincent Pautu., Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Endothelium radiobiology and targeting (CRCINA - Département ONCO - Equipe 14), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-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 de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-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 de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Bernardo, Elizabeth, 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: 0301 basic medicine, Skin Neoplasms, medicine.drug_class, [SDV.CAN]Life Sciences [q-bio]/Cancer, Drug resistance, Monoclonal antibody, Metastasis, 03 medical and health sciences, Drug Delivery Systems, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Animals, Humans, Melanoma, Pharmacology, Targeting, Tumor microenvironment, Nanotheranostics, business.industry, Antibodies, Monoclonal, medicine.disease, 3. Good health, Nanomedicine, 030104 developmental biology, Formulation, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Nanotherapies, Drug delivery, Immunology, Cancer research, Nanoparticles, Skin cancer, business
Abstract: International audience; Melanoma originated from melanocytes is the most aggressive type of skin cancer. Despite considerable progresses in clinical treatment with the discovery of BRAF or MEK inhibitors and monoclonal antibodies, the durability of response to treatment is often limited to the development of acquired resistance and systemic toxicity. The limited success of conventional treatment highlights the importance of understanding the role of melanoma tumor microenvironment in tumor developement and drug resistance. Nanoparticles represent a promising strategy for the development of new cancer treatments able to improve the bioavailability of drugs and increase their penetration by targeting specifically tumors cells and/or tumor environment. In this review, we will discuss the main influence of tumor microenvironment in melanoma growth and treatment outcome. Furthermore, third generation loaded nanotechnologies represent an exciting tool for detection, treatment, and escape from possible mechanism of resistance mediated by tumor microenvironment, and will be highlighted in this review.
Published: 2017

40. Investigation of Phospholipase Cγ1 Interaction with SLP76 Using Molecular Modeling Methods for Identifying Novel Inhibitors

Author: Neha Tripathi, Mickael Jean, Patrick Legembre, Adèle D. Laurent, Iyanar Vetrivel, Stéphane Téletchéa, Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation (CEISAM), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Unité de fonctionnalité et ingénierie de protéines (UFIP), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), CRLCC Eugène Marquis (CRLCC), Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), PLBIO-2018, Institut National Contre le Cancer (INCa), Mim-Breg, Région Pays de la Loire, CE15-0027, Agence Nationale de la Recherche, 2017-2019 (PL), Fondation ARC pour la Recherche sur le Cancer, Université de Nantes (UN)-Université de Nantes (UN)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-17-CE15-0027,FASILE,Impact du CD95L, dans la dysfonction des lymphocytes T exprimant l'IL-17 au cours du lupus(2017), and Jonchère, Laurent
Subjects: Molecular model, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], pharmacophore mapping, Computational biology, Phospholipase, Phospholipase C gamma, Article, Catalysis, SH3 domain, lcsh:Chemistry, Inorganic Chemistry, phospholipase C gamma 1, 03 medical and health sciences, 0302 clinical medicine, Protein Domains, medicine, Humans, Enzyme Inhibitors, Physical and Theoretical Chemistry, lcsh:QH301-705.5, Molecular Biology, Spectroscopy, 030304 developmental biology, 0303 health sciences, Virtual screening, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Drug discovery, Chemistry, Organic Chemistry, General Medicine, molecular docking, virtual screening, SLP76, molecular dynamics, 3. Good health, Computer Science Applications, Molecular Docking Simulation, lcsh:Biology (General), lcsh:QD1-999, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Ritonavir, Pharmacophore, Peptides, Protein Binding, medicine.drug
Abstract: The enzyme phospholipase C gamma 1 (PLC&gamma, 1) has been identified as a potential drug target of interest for various pathological conditions such as immune disorders, systemic lupus erythematosus, and cancers. Targeting its SH3 domain has been recognized as an efficient pharmacological approach for drug discovery against PLC&gamma, 1. Therefore, for the first time, a combination of various biophysical methods has been employed to shed light on the atomistic interactions between PLC&gamma, 1 and its known binding partners. Indeed, molecular modeling of PLC&gamma, 1 with SLP76 peptide and with previously reported inhibitors (ritonavir, anethole, daunorubicin, diflunisal, and rosiglitazone) facilitated the identification of the common critical residues (Gln805, Arg806, Asp808, Glu809, Asp825, Gly827, and Trp828) as well as the quantification of their interaction through binding energies calculations. These features are in agreement with previous experimental data. Such an in depth biophysical analysis of each complex provides an opportunity to identify new inhibitors through pharmacophore mapping, molecular docking and MD simulations. From such a systematic procedure, a total of seven compounds emerged as promising inhibitors, all characterized by a strong binding with PLC&gamma, 1 and a comparable or higher binding affinity to ritonavir (∆Gbind &lt, &minus, 25 kcal/mol), one of the most potent inhibitor reported till now.
Published: 2019

41. Immunophenotype of a Rat Model of Duchenne's Disease and Demonstration of Improved Muscle Strength After Anti-CD45RC Antibody Treatment

Author: Laure-Hélène Ouisse, Séverine Remy, Aude Lafoux, Thibaut Larcher, Laurent Tesson, Vanessa Chenouard, Carole Guillonneau, Lucas Brusselle, Nadège Vimond, Karl Rouger, Yann Péréon, Alexis Chenouard, Christèle Gras-Le Guen, Cécile Braudeau, Régis Josien, Corinne Huchet, Ignacio Anegon, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Unité de Biotechnologie, Biocatalyse et Biorégulation (U3B), Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Institut National de la Recherche Agronomique (INRA), Atlantic Gene Therapies, Clinique Médicale et Service d'Urgences Pédiatriques, Hôpital Mère-Enfant, Centre hospitalier universitaire de Nantes (CHU Nantes), Thérapie génique translationnelle pour les maladies neuromusculaires et de la rétine, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biogenouest and the TEFOR, Nantes Métropole and Région Pays de la Loire, Anegon, Ignacio, Développement et Pathologie du Tissu Musculaire (DPTM), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, Le Bihan, Sylvie, and Institut National de la Recherche Agronomique (INRA)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)
Subjects: 0301 basic medicine, T-Lymphocytes, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Immune tolerance, Treg, tolerance, muscle injury, dystrophin, immunosuppression, knockout rats, nucleases, 0302 clinical medicine, Immunophenotyping, TALEN, Immunology and Allergy, Medicine, Muscular dystrophy, Original Research, biology, Antibodies, Monoclonal, Immunosuppression, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Prednisolone, Cytokines, medicine.symptom, Dystrophin, medicine.drug, lcsh:Immunologic diseases. Allergy, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Immunology, Inflammation, 03 medical and health sciences, Internal medicine, Animals, Muscle Strength, Muscle, Skeletal, business.industry, Macrophages, Skeletal muscle, medicine.disease, Rats, Muscular Dystrophy, Duchenne, Disease Models, Animal, 030104 developmental biology, Endocrinology, biology.protein, Leukocyte Common Antigens, lcsh:RC581-607, business, Spleen, 030215 immunology
Abstract: International audience; Corticosteroids (CS) are standard therapy for the treatment of Duchenne's muscular dystrophy (DMD). Even though they decrease inflammation, they have limited efficacy and are associated with significant side effects. There is therefore the need for new protolerogenic treatments to replace CS. Dystrophin-deficient rats (Dmd mdx ) closely resemble the pathological phenotype of DMD patients. We performed the first Immunophenotyping of Dmd mdx rats and showed leukocyte infiltration in skeletal and cardiac muscles, which consisted mostly of macrophages and T cells including CD45RChigh T cells. Muscles of DMD patients also contain elevated CD45RChigh T cells. We treated Dmd mdx rats with an anti-CD45RC MAb used in previous studies to deplete CD45RChigh T cells and induce immune tolerance in models of organ transplantation. Treatment of young Dmd mdx rats with anti-CD45RC MAb corrected skeletal muscle strength and was associated with depletion of CD45RChigh T cells with no side effects. Treatment of young Dmd mdx rats with prednisolone resulted in increase in skeletal muscle strength but also severe growth retardation. In conclusion, anti-CD45RC MAb treatment has potential in the treatment of DMD and might eventually result in reduction or elimination of CS use.
Published: 2019

42. Early Identification of Chronic Lung Allograft Dysfunction: The Need of Biomarkers

Author: Adrien Tissot, Richard Danger, Johanna Claustre, Antoine Magnan, Sophie Brouard, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service de pneumologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de transplantation urologie-néphrologie (ITUN), Service Hospitalier Universitaire Pneumologie-Physiologie [CHU Grenoble Alpes] (Pôle Thorax et Vaisseaux), Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), The IHU-Cesti project is also supported by Nantes Métropole and Région Pays de la Loire. JC was supported by Fondation du souffle and Fonds Agir pour les maladies chroniques grants., Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-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 [Grenoble] (CHU), Unité de recherche de l'institut du thorax (ITX-lab), and Le Bihan, Sylvie
Subjects: lcsh:Immunologic diseases. Allergy, 0301 basic medicine, Graft Rejection, medicine.medical_specialty, medicine.medical_treatment, Immunology, Review, 03 medical and health sciences, 0302 clinical medicine, blood, medicine, lung transplantation, Immunology and Allergy, Lung transplantation, Animals, Humans, Routine clinical practice, Respiratory function, BOS, Intensive care medicine, Lung, Lung function, chronic lung allograft dysfunction, Immunity, Cellular, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, bronchoalveolar lavage fluid, business.industry, High mortality, Allografts, 3. Good health, Immunity, Humoral, 030104 developmental biology, medicine.anatomical_structure, Biomarker (medicine), biomarker, lcsh:RC581-607, business, Airway, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Biomarkers, 030215 immunology, RAS
Abstract: International audience; A growing number of patients with end-stage lung disease have benefited from lung transplantation (LT). Improvements in organ procurement, surgical techniques and intensive care management have greatly increased short-term graft survival. However, long-term outcomes remain limited, mainly due to the onset of chronic lung allograft dysfunction (CLAD), whose diagnosis is based on permanent loss of lung function after the development of irreversible lung lesions. CLAD is associated with high mortality and morbidity, and its exact physiopathology is still only partially understood. Many researchers and clinicians have searched for CLAD biomarkers to improve diagnosis, to refine the phenotypes associated with differential prognosis and to identify early biological processes that lead to CLAD to enable an early intervention that could modify the inevitable degradation of respiratory function. Donor-specific antibodies are currently the only biomarkers used in routine clinical practice, and their significance for accurately predicting CLAD is still debated. We describe here significant studies that have highlighted potential candidates for reliable and non-invasive biomarkers of CLAD in the fields of imaging and functional monitoring, humoral immunity, cell-mediated immunity, allograft injury, airway remodeling and gene expression. Such biomarkers would improve CLAD prediction and allow differential LT management regarding CLAD risk.
Published: 2019

43. Paracaspase MALT1 regulates glioma cell survival by controlling endo-lysosome homeostasis

Author: Nicolas Bidère, Tiphaine Douanne, Elizabeth Harford-Wright, An Thys, Ying Li, Clément Maghe, Carolina Alves Nicolau, Jean-Sebastien Frenel, Gwennan André-Grégoire, Julie Gavard, Kilian Trillet, Kathryn A Jacobs, Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), 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), Integrated Center for Oncology [Angers] (ICO), School of Life Sciences [Beijing, China], Tsinghua University [Beijing] (THU), This research was funded by Fondation pour la Recherche Medicale (Equipe labellisée DEQ20180339184), Fondation ARC contre le Cancer (JG PJA20171206146), Ligue nationale contre le cancer comités de Loire-Atlantique, Maine et Loire, Vendée, Ille-et-Vilaine (JG, NB), Région Pays de la Loire et Nantes Métropole under Connect Talent Grant (JG), and SIRIC ILIAD INCa-DGOS-Inserm_12558. KAJ received PhD fellowships from Nantes Métropole and Fondation ARC, TD received PhD fellowship from Nantes Métropole, GAG and AT hold postdoctoral fellowships from Fondation de France and Fondation ARC, respectively., 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), and Bernardo, Elizabeth
Subjects: Male, Apoptosis, Lymphocyte Activation, Mice, 0302 clinical medicine, glioma, Tumor Cells, Cultured, Homeostasis, 0303 health sciences, Gene knockdown, Mice, Inbred BALB C, Membranes & Traf- ficking, General Neuroscience, TOR Serine-Threonine Kinases, RNA-Binding Proteins, Articles, Paracaspase, Middle Aged, 3. Good health, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Neoplastic Stem Cells, lysosome, mTOR, Female, Autophagy & Cell Death, Signal Transduction, Programmed cell death, protease Subject Categories Cancer, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Endosomes, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Glioma, Lysosome, medicine, Biomarkers, Tumor, Animals, Humans, Molecular Biology, PI3K/AKT/mTOR pathway, 030304 developmental biology, Aged, Cell Proliferation, General Immunology and Microbiology, MALT1, Autophagy, medicine.disease, Xenograft Model Antitumor Assays, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Proteolysis, Cancer research, Lysosomes, 030217 neurology & neurosurgery
Abstract: International audience; Glioblastoma is one of the most lethal forms of adult cancer with a median survival of around 15 months. A potential treatment strategy involves targeting glioblastoma stem-like cells (GSC), which constitute a cell autonomous reservoir of aberrant cells able to initiate, maintain, and repopulate the tumor mass. Here, we report that the expression of the paracaspase mucosa-associated lymphoid tissue l (MALT1), a protease previously linked to antigen receptor-mediated NF-jB activation and B-cell lymphoma survival, inversely correlates with patient probability of survival. The knockdown of MALT1 largely impaired the expansion of patient-derived stem-like cells in vitro, and this could be recapitulated with pharmacological inhibitors, in vitro and in vivo. Blocking MALT1 protease activity increases the endo-lysosome abundance, impairs autophagic flux, and culminates in lysosomal-mediated cell death, concomitantly with mTOR inactiva-tion and dispersion from endo-lysosomes. These findings place MALT1 as a new druggable target involved in glioblastoma and unveil ways to modulate the homeostasis of endo-lysosomes.
Published: 2019

44. Fruit and Leaf Response to Different Source–Sink Ratios in Apple, at the Scale of the Fruit-Bearing Branch

Author: Mickaël Delaire, Gerhard Buck-Sorlin, Christian leMorvan, Emna Bairam, Unité de recherche Plantes et Systèmes de Culture Horticoles (PSH), Institut National de la Recherche Agronomique (INRA), Institut de Recherche en Horticulture et Semences (IRHS), Université d'Angers (UA)-Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Région Pays de la Loire 2012-2016., and AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA)-Université d'Angers (UA)
Subjects: 0106 biological sciences, 0301 basic medicine, Plant Science, 01 natural sciences, Sink (geography), Carbon assimilation, functional- structural plant modeling, Cultivar, feuille végétal, source–sink ratio, [SDV.SA.HORT]Life Sciences [q-bio]/Agricultural sciences/Horticulture, Original Research, geography.geographical_feature_category, Vegetal Biology, defoliation, Microbiology and Parasitology, croissance des plantes, analyse de système, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics, Microbiologie et Parasitologie, Agricultural sciences, Horticulture, pomme, espèce modèle, port de la végétation, Shoot, Bio-informatique, Malus x domestica Borkh, utilisation du temps, Bioinformatics, functional-structural plant modeling, apple, Biology, lcsh:Plant culture, Photosynthesis, 03 medical and health sciences, Girdling, lcsh:SB1-1110, photosynthèse, arbre fruitier, source-sink ratio, Source sink, geography, photosynthesis, branch, fruit growth, 15. Life on land, 030104 developmental biology, Source strength, expression pattern, malus domestica borkh, Biologie végétale, Sciences agricoles, 010606 plant biology & botany
Abstract: International audience; Apple fruit growth is the result of several factors: inherent demand (relative sink strength) of the fruit (defined by the demands for cell division and expansion growth, etc.), carbon assimilation by the source leaves (source strength), and the resulting allocation to the organ in question. It is thus a complex process involving source-sink interactions. In the present study, we designed an experimental system in which parts of fruit-bearing branches of two apple cultivars ("Fuji" and "Ariane") were isolated from the rest of the tree by girdling and then subjected to specific pruning and fruit removal treatments to create a wide range of global (branch-level) source-sink ratios. We monitored not only fruit kinetics but also photosynthesis as a response to light in leaves of the three different shoot types (i.e., the rosette, the bourse, and the vegetative shoots) to 1) study the impact of source-sink distance on carbon partitioning between fruits within the same branch and 2) to investigate the impact of source/sink ratio on fruit growth and leaf photosynthetic activity. Our results indicate 1) no significant differences among lateral fruits belonging to different ranks, and this independent of source availability; 2) that a modification of the source/sink ratio seems to be compensated by an alteration of the photosynthetic rate of leaves, with stronger and weaker values obtained for lower and higher ratios, respectively. Moreover, our results seem to suggest that two growing sinks together will upregulate photosynthesis rate more strongly than one growing sink does on its own, and this with the same leaf area per fruit. These results are discussed, and some hypotheses are put forward to explain them.
Published: 2019

45. Stability of the adeno-associated virus 8 reference standard material

Author: Frédéric Broucque, Magalie Penaud-Budloo, Katell Harrouet, Susan M. D'Costa, Mohammed Bouzelha, Martin Lock, Richard O. Snyder, Véronique Blouin, Sandy Douthe, Eduard Ayuso, Sylvie Saleun, Oumeya Adjali, Sushma Ogram, Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques (Inserm UMR 1089), 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), Brammer Bio [Alachua, FL, USA], Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA] (Perelman School of Medicine), University of Pennsylvania [Philadelphia], Financial support to E.A.’s laboratory was provided by INSERM, University of Nantes, CHU of Nantes, Fondation d’Entreprises pour la Thérapie Génique en Pays de la Loire, and Région Pays de la Loire and Pre-industrial gene therapy consortium (Agence Nationale de la Recherche - Investissements d’Avenir, grant number 10-DPBS-0001)., ANR-10-DPBS-0001,PGT,Consortium préindustriel des vecteurs de thérapie génique(2010), University of Pennsylvania, JAULIN, Nicolas, and Démonstrateurs - Consortium préindustriel des vecteurs de thérapie génique - - PGT2010 - ANR-10-DPBS-0001 - DPBS - VALID
Subjects: 0301 basic medicine, Serotype, [SDV]Life Sciences [q-bio], Genetic Vectors, Biology, medicine.disease_cause, Virus Replication, Virus, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Dosing, Vector (molecular biology), Molecular Biology, Reference standards, Adeno-associated virus, Cryopreservation, Protein Stability, Dependovirus, Reference Standards, Virology, 3. Good health, [SDV] Life Sciences [q-bio], Titer, 030104 developmental biology, HEK293 Cells, Capsid, 030220 oncology & carcinogenesis, Practice Guidelines as Topic, Molecular Medicine, Capsid Proteins
Abstract: International audience; Adeno-associated virus (AAV) vectors are extensively used for gene therapy clinical trials. Accurate and standardized titration methods are essential for characterizing and dosing AAV-based drugs and thus to assess their safety and efficacy. To this end, the Reference Standard Materials (RSM) working group generated standards for AAV serotype 2 and serotype 8. The AAV8RSM (ATCC® VR-1816™) was deposited to the American Type Culture Collection in 2014 and is available to the scientific community. Here, three independent laboratories of the RSM working group provide stability data of the AAV8RSM 2 years after the initial characterization and after container relabeling performed at the ATCC. The AAV8RSM showed constant titers across experimental conditions: 1.48 ± 0.62 × 1012 vector genome (vg)/ml, 9.38 ± 11.4 × 108 infectious units (IU)/ml and 5.76 ± 2.39 × 1011 total particles (p)/ml as determined by qPCR, TCID50 and ELISA, respectively. Additionally, the AAV8RSM capsid protein integrity assessed by SDS-PAGE was equivalent to the original analyses. In conclusion, the AAV8RSM titers remained stable for two years under appropriate storage conditions (
Published: 2018

46. Agricultural landscapes and the Loire River influence the genetic structure of the marbled newt in Western France

Author: Jean-Marc Costanzi, Quentin Le Petitcorps, Francis Isselin-Nondedeu, Pierre Grillet, Pascal Mège, Olivier Lourdais, Sophie Morin-Pinaud, Agathe Legrand, François Varenne, Audrey Trochet, Alexandre Boissinot, Damien Picard, Sandra Guérin, Faculty of Technology, Natural Sciences and Maritime Sciences [Norway], University of South-Eastern Norway (USN), Département de Biologie UFR Sciences - Université d'Angers [France], Université d'Angers (UA), Centre d'Études Biologiques de Chizé - UMR 7372 (CEBC), Université de La Rochelle (ULR)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Cités, Territoires, Environnement et Sociétés (CITERES), Centre National de la Recherche Scientifique (CNRS)-Université de Tours (UT), Centre d’Ecologie Fonctionnelle et Evolutive (CEFE), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Université Paul-Valéry - Montpellier 3 (UPVM)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut de Recherche pour le Développement (IRD [France-Sud]), Evolution et Diversité Biologique (EDB), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Station d'écologie théorique et expérimentale (SETE), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), LPO Vendée, LPO, Pierre Grillet, Unité Avifaune migratrice, Direction de la Recherche et de l’Expertise (ONCFS France], Office National de la Chasse et de la Faune Sauvage (ONCFS), Région Pays de la Loire, Centre Beautour, Chinon SNB project (stratégie nationale pour la biodiversité 2011, French minister of ecology), Office National de la Chasse et de la Faune Sauvage (Pôle Bocage et Faune Sauvage) and Nouvelle-Aquitaine Region, ONF-Centre Val de Loire, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université de La Rochelle (ULR), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Université Paul-Valéry - Montpellier 3 (UM3)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-École pratique des hautes études (EPHE)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), ONCFS - Office National de la Chasse et de la Faune Sauvage, Centre National de la Recherche Scientifique (CNRS)-Université de Tours, Institut National de la Recherche Agronomique (INRA)-La Rochelle Université (ULR)-Centre National de la Recherche Scientifique (CNRS), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Université Paul-Valéry - Montpellier 3 (UPVM)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Observatoire Midi-Pyrénées (OMP), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)
Subjects: 0106 biological sciences, 0301 basic medicine, Biodiversité et Ecologie, Science, Triturus marmoratus, Loire River, 010603 evolutionary biology, 01 natural sciences, Biodiversity and Ecology, 03 medical and health sciences, DAPC Results, Discriminant Analysis Of Principal Components (DAPC), Isolation by distance, Multidisciplinary, biology, Ecology, Marbled Newt, Fragmentation (computing), 15. Life on land, biology.organism_classification, Large Crop Fields, 030104 developmental biology, Geography, Genetic distance, Genetic structure, [SDE]Environmental Sciences, Medicine, Biological dispersal, Conservation biology, Arable land
Abstract: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Amphibians are particularly sensitive to landscape fragmentation. Potential barriers between breeding sites can negatively infuence the dispersal of individuals and increase genetic structure between populations. In this study, we genotyped 10 microsatellites for 334 marbled newts (Triturus marmoratus) at 11 diferent locations in Western France. Samples were collected in diferent regions with contrasting agricultural landscapes (low and high proportion of arable land in the north and south, respectively). We found a strong genetic structure between the northern and southern sampling sites. Isolation by distance was recorded after 62km, but within the northern region, little or no genetic structure was detected over large distances (up to 114km). Genetic structure at shorter distance (43km) was found between sites situated in landscapes with larger amounts of arable lands. A signifcant positive relationship was found between the pairwise genetic distance (Fst) between sites and the amount of arable land together with the distance between sites. Our results suggest that the Loire River might act as a corridor for the marbled newt, while arable land might act as a barrier. Finally, although a large city is located between sampling sites, no efect was detected on population structure.
Published: 2018

47. Anti-CD28 Antibody and Belatacept Exert Differential Effects on Mechanisms of Renal Allograft Rejection

Author: Jeremy Hervouet, Karine Renaudin, David Minault, Nicolas Poirier, Sabrina Pengam, Steven Nedellec, Caroline Mary, Vianney Charpy, Véronique Nerrière-Daguin, Julien Branchereau, Stéphanie Le Bas-Bernardet, Bernard Vanhove, Simon Ville, Alexis Chenouard, Gilles Blancho, Flora Coulon, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Effimune SAS [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Cellular and Tissular Imaging Core Facility of Nantes (MicroPICell), Université de Nantes (UN), IHU-Cesti, région Pays de la Loire et Nantes Métropole., ANR: ANR-10-IBHU005, Le Bihan, Sylvie, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, and ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010)
Subjects: lymphocytes, Graft Rejection, 0301 basic medicine, Regulatory T cell, medicine.medical_treatment, kidney transplantation, chemical and pharmacologic phenomena, 030230 surgery, Biology, acute rejection, Belatacept, Antibodies, immunology, Abatacept, Mice, 03 medical and health sciences, 0302 clinical medicine, CD28 Antigens, medicine, Animals, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, immunosuppression, CD28, hemic and immune systems, General Medicine, Tacrolimus, 3. Good health, Basic Research, 030104 developmental biology, Cytokine, medicine.anatomical_structure, Nephrology, Immunology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Immunosuppressive Agents, CD80, Papio, medicine.drug, Allotransplantation
Abstract: International audience; Belatacept is a biologic that targets CD80/86 and prevents its interaction with CD28 and its alternative ligand, cytotoxic T lymphocyte antigen 4 (CTLA-4). Clinical experience in kidney transplantation has revealed a high incidence of rejection with belatacept, especially with intensive regimens, suggesting that blocking CTLA-4 is deleterious. We performed a head to head assessment of FR104 (n=5), a selective pegylated Fab9 antibody fragment antagonist of CD28 that does not block the CTLA-4 pathway, and belatacept (n=5) in kidney allotransplantation in baboons. The biologics were supplemented with an initial 1-month treatment with low-dose tacrolimus. In cases of acute rejection, animals also received steroids. In the belatacept group, four of five recipients developed severe, steroid-resistant acute cellular rejection, whereas FR104-treated animals did not. Assessment of regulatory T cell-specific demethylated region methylation status in 1-month biopsy samples revealed a nonsignificant trend for higher regulatory T cell frequencies in FR104-treated animals. Transcriptional analysis did not reveal significant differences in Th17 cytokines but did reveal higher levels of IL-21, the main cytokine secreted by CD4 T follicular helper (Tfh) cells, in belatacept-treated animals. In vitro, FR104 controlled the proliferative response of human preex-isting Tfh cells more efficiently than belatacept. In mice, selective CD28 blockade also controlled Tfh memory cell responses to KLH stimulation more efficiently than CD80/86 blockade. Our data reveal that selective CD28 blockade and belatacept exert different effects on mechanisms of renal allograft rejection, particularly at the level of Tfh cell stimulation.
Published: 2016

48. IL-9 promotes the survival and function of human melanoma-infiltrating CD4+CD8+double-positive T cells

Author: Nathalie Labarrière, Yves Delneste, Nadine Gervois, Romain Oger, Houssem Benlalam, Diane Raingeard de la Blétière, Tiphaine Parrot, Amir Khammari, Laurence Preisser, Mathilde Allard, Anne Coutolleau, Juliette Desfrançois, Philippe Guardiola, Brigitte Dréno, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Plateforme SNP, Transcriptome & Epigénomique, PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Plateforme CYTOCELL Nantes (CRCINA-CYTOCELL), 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), GMP Unit of Cellular Therapy, Centre hospitalier universitaire de Nantes (CHU Nantes), Unit of Skin Cancer, Canceropole Grand Ouest, Région Pays de la Loire, ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), 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), Bernardo, Elizabeth, and Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID
Subjects: CD4-Positive T-Lymphocytes, Cytotoxicity, Immunologic, 0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, Cell Survival, Immunology, Gene Expression, [SDV.CAN]Life Sciences [q-bio]/Cancer, Apoptosis, CD8-Positive T-Lymphocytes, Biology, Lymphocyte Activation, 03 medical and health sciences, Interleukin 21, Lymphocytes, Tumor-Infiltrating, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, T-Lymphocyte Subsets, Humans, Immunology and Allergy, Cytotoxic T cell, Interleukin 9, Melanoma, Cells, Cultured, Receptors, Interleukin-9, Interleukin-9, Degranulation, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, T lymphocyte, 3. Good health, Granzyme B, 030104 developmental biology, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, CD8
Abstract: International audience; We previously demonstrated an accumulation of tumor-reactive CD4 + CD8 + double positive (DP) T cells within melanoma-infiltrating lymphocytes, supporting their role in the regulation of anti-tumor immune responses. Similarly to their CD8 + counterparts, intra-tumor DP T cells are MHC class-I restricted but differed by a limited lytic activity against autologous melanoma cells. Based on these observations and to further characterize DP T cells, both populations were compared at the transcriptional level. Our results revealed the overexpression of the IL-9 receptor (IL-9R) by DP T cells and prompted us to investigate the impact of IL-9 on their biology. We show that IL-9 favors DP T-cell survival by protecting them from apoptosis and by promoting their proliferation. In addition, IL-9 enhances their ability to produce cytokines and increased their levels of granzyme B/perforin as well as degranulation capacity, leading to a strengthened cytotoxic activity against melanoma cells. Taken together, the IL-9R high DP T-cell population could be a new preferential target for IL-9, which could take part in their retention within the melanoma infiltrate while also favoring their anti-tumor activity. More generally, our results extend the pleiotropic effects of IL-9 to IL-9R-expressing intra-tumor T cells, which could further potentiate anti-tumor immune responses. Keywords: CD4 + CD8 + double-positive T lymphocyte r IL-9R r IL-9 r Melanoma r TIL Additional supporting information may be found in the online version of this article at the publisher's web-site
Published: 2016

49. Ester Cross-Link Profiling of the Cutin Polymer of Wild-Type and Cutin Synthase Tomato Mutants Highlights Different Mechanisms of Polymerization

Author: Nathalie Geneix, Christophe Rothan, Bénédicte Bakan, Cédric Gaillard, Jean-Philippe Mauxion, Didier Marion, Johann Petit, Cécile Bres, Michèle Dalgalarrondo, Glenn Philippe, Lukas Schreiber, Rochus Franke, Unité de recherche sur les Biopolymères, Interactions Assemblages (BIA), Institut National de la Recherche Agronomique (INRA), Laboratoire de l'intégration, du matériau au système (IMS), Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), Biologie du fruit et pathologie (BFP), Université Sciences et Technologies - Bordeaux 1-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA), Rheinische Friedrich-Wilhelms-Universität Bonn, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1, and Région Pays de la Loire
Subjects: Glycerol, 0106 biological sciences, 0301 basic medicine, Polymers, Physiology, Polyesters, [SDV]Life Sciences [q-bio], Alcohol, Plant Science, Cutin, 01 natural sciences, Polymerization, Membrane Lipids, 03 medical and health sciences, chemistry.chemical_compound, Solanum lycopersicum, Genetics, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Organic chemistry, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Plant Proteins, chemistry.chemical_classification, Esterification, Chemistry, Fatty Acids, fungi, Cross-link, food and beverages, Esters, Lipase, Articles, Polymer, Polyester, 030104 developmental biology, Monomer, Ethyl Methanesulfonate, Fruit, Mutation, 010606 plant biology & botany
Abstract: International audience; Cuticle function is closely related to the structure of the cutin polymer. However, the structure and formation of this hydrophobic polyester of glycerol and hydroxy/epoxy fatty acids has not been fully resolved. An apoplastic GDSL-lipase known as CUTIN SYNTHASE1 (CUS1) is required for cutin deposition in tomato (Solanum lycopersicum) fruit exocarp. In vitro, CUS1 catalyzes the self-transesterification of 2-monoacylglycerol of 9(10),16-dihydroxyhexadecanoic acid, the major tomato cutin monomer. This reaction releases glycerol and leads to the formation of oligomers with the secondary hydroxyl group remaining nonesterified. To check this mechanism in planta, a benzyl etherification of nonesterified hydroxyl groups of glycerol and hydroxy fatty acids was performed within cutin. Remarkably, in addition to a significant decrease in cutin deposition, mid-chain hydroxyl esterification of the dihydroxyhexadecanoic acid was affected in tomato RNA interference and ethyl methanesulfonate-cus1 mutants. Furthermore, in these mutants, the esterification of both sn-1,3 and sn-2 positions of glycerol was impacted, and their cutin contained a higher molar glycerol-to-dihydroxyhexadecanoic acid ratio. Therefore, in planta, CUS1 can catalyze the esterification of both primary and secondary alcohol groups of cutin monomers, and another enzymatic or nonenzymatic mechanism of polymerization may coexist with CUS1-catalyzed polymerization. This mechanism is poorly efficient with secondary alcohol groups and produces polyesters with lower molecular size. Confocal Raman imaging of benzyl etherified cutins showed that the polymerization is heterogenous at the fruit surface. Finally, by comparing tomato mutants either affected or not in cutin polymerization, we concluded that the level of cutin cross-linking had no significant impact on water permeance.
Published: 2015

50. New Insights into the Epigenetic Activities of Natural Compounds

Author: Christophe Blanquart, Michael S. Christodoulou, Daumantas Matulis, Fabien Fontaine-Vive, Judit Ovádi, Melita Vidaković, Maija Lahtela-Kakkonen, Nadine Martinet, Stéphane Poulain, Muriel Cuendet, Alain Burger, Vaida Linkuvienė, Danielle Passarella, Ruta navakauskiene, Benoît Y. Michel, Jessica Marinello, Saulius Klimašauskas, Department of Molecular Biology [Beograd, Serbia], University of Beograd [Serbia], Department of Pharmacy and Biotechnology [Bologna, Italy], University of Bologna [Italy], School of Pharmacy [Kuopio, Finland] (Faculty of Health Sciences), University of Eastern Finland, Department of Biothermodynamics and Drug Design [Vilnius, Lithuania], Vilnius University [Lithuania], Institut de Chimie de Nice (ICN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Department of Molecular Cell Biology [Vilnius, Lithuania] (Institute of Biochemistry), Vilnius University [Vilnius]-Life Sciences Center [Vilnius, Lithuania], Dipartimento di Scienze Farmaceutiche [Milano, Italy], Università degli Studi di Milano [Milano] (UNIMI), Dipartimento di Chimica [Milano, Italy], Department of Biological DNA Modification [Vilnius, Lithuania] (Institute of Biotechnology), Vilnius University [Vilnius], Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), 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), School of Pharmaceutical Sciences [Geneva, Switzerland], Université de Lausanne (UNIL)-Université de Genève (UNIGE), Institute of Enzymology [Budapest], Research Centre for Natural Sciences, Hungarian Academy of Sciences (MTA)-Hungarian Academy of Sciences (MTA), Centre des ressources biologiques - CRB [CHU Nantes] ( Institut de biologie), Centre hospitalier universitaire de Nantes (CHU Nantes), Melita Vidakovic was the recipient of the exchange program PAVEL SAVIC from the French and the Serbian Ministries of foreign affairs. This work was also supported by INSERM, CNRS, Région Pays de la Loire, the ‘Institut de recherche en santé respiratoire des Pays de la Loire’ and the ‘Ligue Contre le Cancer (committees of Morbihan, Sarthe, Vendée et Loire-Atlantique) : ARSMESO44. Ruta Navakauskienė is thankful for partial funding of this work by the Research Council of Lithuania (Project No. SEN-12/2015)., Bernardo, Elizabeth, Université Nice Sophia Antipolis (1965 - 2019) (UNS), Università degli Studi di Milano = University of Milan (UNIMI), 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), Université de Lausanne = University of Lausanne (UNIL)-Université de Genève = University of Geneva (UNIGE), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Milano [Milano], Mort cellulaire immunogénique appliquée aux traitements du mésothéliome (CRCINA - Département INCIT - Equipe 4), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-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 de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-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 de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)
Subjects: ddc:615, 0303 health sciences, biology, Chemistry, 010401 analytical chemistry, [SDV.CAN]Life Sciences [q-bio]/Cancer, Methylation, 01 natural sciences, 0104 chemical sciences, 03 medical and health sciences, Histone H3, Histone, DNA demethylation, Biochemistry, [SDV.CAN] Life Sciences [q-bio]/Cancer, Histone methylation, DNA methylation, biology.protein, Epigenetics, Histone deacetylase, 030304 developmental biology
Abstract: Background: With their varied pharmacophores, natural products are interesting tools to open the drug discovery pipeline. Several plant secondary metabolites belong to our diet and have conflictual documented epigenetic activities which need clarification. Methods: Seventy-one different natural products plus 17 controls were assembled for screening. First localized DNA methylation (DNAm) was studied on a stretch of the Retinoic Acid Receptor geneRAR followed then by a wider measure of all genomic 5 methylated Cytosine (5mC) by High Performance Liquid Chromatography tandem Mass Spectrometry (HPLC-MS/MS). DNA Methyl Transferase 1 (DNMT1) enzymatic activity was measured for selected compounds. Levels of Histone H3 trimethylation at lysine 9 and 27 (me3H3K9 and me3H3K27) were measured by Western blot. Global histone deacetylase inhibition (HDAC) was assayed first via a Bioluminescent Resonance Energy Transfer-based (BRET) assay and then with enzymatic fluorescence based-assays for HDAC class 1: 1, 2 and 3. As for HDAC6 inhibition, it was measured by Western blot screening. Sirtuine 2 (Sirt) inhibition was assessed first by a thermal shift assay and then by enzymatic assays for Sirt 1 and 2 using the SIRTainty™ Class III HDAC assay. Results: Several compounds decreased RAR methylation levels; but only Curcumin and (-) -Epigallocatechin gallate (EGCG) inhibited the DNMT1 catalytic activity; most other compounds worked probably, as S-Adenosyl-L-homocysteine (SAH) producers, with different potency under the assay conditions used here. Localized DNA demethylation was not mirrored by the global measure of 5mC levels. D-Glucuronic acid and anthraquinones decreased the level of me3H3K9 and 27 by un-deciphered mechanisms. When screening for HDAC class 1 inhibition, most flavonoids were emissive for enzymatic assays (excitation (Exec) = 340-360 nm and emission (Em) =440-465 nm). It was also the case when screening for Sirt activity by thermal shift (Exec= 365 nm and Em= 460 nm). This was overrun by the SIRTainty™ Class III HDAC (Exec= 420 nm and Em= 450 nm) assays by opposition to the FLUOR DE LYS® HDAC assay (Exec=360 nm and Em=460 nm). Within such limitations, we found that alkaloids like Brucine and Papaverin and anthraquinones are new epigenetic modifiers; this opens the epigenetic chemical space. Conclusions: To study diversity compound libraries, high through-put alpha screens are used at first. To study DNAm, they have large pitfalls. Indeed, finding unmethylated RARalleles does not indicate what a given compound is doing at the level of the entire genome for a given lapse of time and a given dose of compound. The measure of the DNMT1 enzymatic activity is not useful since most natural compounds are not direct enzymatic inhibitors. When studying histone methylation, Western blot is laborious but remains a cheap functional assay when several histone methylases (KDMs) or demethylases could be at the basis of histones methylation level decreases. Genome reversible epigenetic modifications remain desirable targets for nutrition oriented preventive strategies. However, reliable HDAC inhibition assays remain necessary before claiming that flavanols have true HDAC modulating activities.
Published: 2018

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108 results on '"Région Pays de la Loire"'

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