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204 results on '"Institut National de la Transfusion Sanguine [Paris] (INTS)"'

1. Insights into<scp>anti‐D</scp>formation in carriers of<scp>RhD</scp>variants through studies of<scp>3D</scp>intraprotein interactions

Author: Aline Floch, France Pirenne, Aurélie Barrault, Btissam Chami, Cécile Toly‐Ndour, Christophe Tournamille, Alexandre G. Brevern, IMRB - 'Transfusion et Maladies du Globule Rouge' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Etablissement Français du Sang [Créteil], Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Service de Médecine Fœtale [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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 de Paris (UP), Université de La Réunion (UR), Université des Antilles (UA), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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), and TOURNAMILLE, Christophe
Subjects: Tropocollagen, Heterozygote, RHD, Rho(D) Immune Globulin, homology modeling, Immunology, 030204 cardiovascular system & hematology, Epitope, Epitopes, 03 medical and health sciences, 0302 clinical medicine, Antigen, Pregnancy, intraprotein interactions, Extracellular, Humans, Immunology and Allergy, Homology modeling, Alleles, Retrospective Studies, Genetics, chemistry.chemical_classification, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Membrane Glycoproteins, biology, Point mutation, Blood Proteins, Hematology, antibody formation, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Transmembrane protein, 3. Good health, Amino acid, Amino Acid Substitution, chemistry, Structural Homology, Protein, RHCG, Mutation, biology.protein, Female, 030215 immunology
Abstract: International audience; Background: Many RhD variants associated with anti-D formation (partial D) in carriers exposed to the conventional D antigen carry mutations affecting extracellular loop residues. Surprisingly, some carry mutations affecting transmembrane or intracellular domains, positions not thought likely to have a major impact on D epitopes.Study design and methods: A wild-type Rh trimer (RhD1 RhAG2 ) was modeled by comparative modeling with the human RhCG structure. Taking trimer conformation, residue accessibility, and position relative to the lipid bilayer into account, we redefine the domains of the RhD protein. We generated models for RhD variants carrying one or two amino acid substitutions associated with anti-D formation in published articles (25 variants) or abstracts (12 variants) and for RHD*weak D type 38. We determined the extracellular substitutions and compared the interactions of the variants with those of the standard RhD.Results: The findings of the three-dimensional (3D) analysis were correlated with anti-D formation for 76% of RhD variants: 15 substitutions associated with anti-D formation concerned extracellular residues, and structural differences in intraprotein interactions relative to standard RhD were observed in the others. We discuss the mechanisms by which D epitopes may be modified in variants in which the extracellular residues are identical to those of standard RhD and provide arguments for the benignity of p.T379M (RHD*DAU0) and p.G278D (RHD*weak D type 38) in transfusion medicine.Conclusion: The study of RhD intraprotein interactions and the precise redefinition of residue accessibility provide insight into the mechanisms through which RhD point mutations may lead to anti-D formation in carriers.
Published: 2021

2. Lack of the multidrug transporter MRP4/ABCC4 defines the PEL-negative blood group and impairs platelet aggregation

Author: Gaël Nicolas, Thierry Peyrard, Mahmoud Mikdar, Slim Azouzi, Patrick Mayeux, Christine Bole-Feysot, Alexandra Willemetz, Olivier Hermine, Cédric Vrignaud, Marc Cloutier, Emilie-Fleur Gautier, Alexandre Raneri, Virginie Salnot, Maryse St-Louis, Caroline Le Van Kim, Jessica Constanzo-Yanez, Jean-Pierre Cartron, Gabriele Jedlitschky, Nancy Robitaille, Carole Éthier, Patricia Hermand, Patrick Nitschke, Yves Colin, colin, yves, Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Institut National de la Transfusion Sanguine [Paris] (INTS), Département Centre National de Référence pour les Groupes Sanguins [Paris], Plateforme protéomique 3P5 [Institut Cochin] (3P5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Medicine Greifswald, Héma-Québec [Québec], Héma-Québec [Montréal], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), and Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Blood Platelets, 0301 basic medicine, Platelet Aggregation, [SDV]Life Sciences [q-bio], Immunology, ATP-binding cassette transporter, ABCC4, Biology, Biochemistry, 03 medical and health sciences, Cyclic nucleotide, chemistry.chemical_compound, 0302 clinical medicine, Erythroid Cells, Antigen, hemic and lymphatic diseases, medicine, Humans, Gene, integumentary system, Impaired platelet aggregation, Cell Biology, Hematology, medicine.disease, Molecular biology, [SDV] Life Sciences [q-bio], Leukemia, Phenotype, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Blood Group Antigens, biology.protein, CRISPR-Cas Systems, Multidrug Resistance-Associated Proteins, BLOOD Commentary, Gene Deletion, K562 cells
Abstract: The rare PEL-negative phenotype is one of the last blood groups with an unknown genetic basis. By combining whole-exome sequencing and comparative global proteomic investigations, we found a large deletion in the ABCC4/MRP4 gene encoding an ATP-binding cassette (ABC) transporter in PEL-negative individuals. The loss of PEL expression on ABCC4-CRISPR-Cas9 K562 cells and its overexpression in ABCC4-transfected cells provided evidence that ABCC4 is the gene underlying the PEL blood group antigen. Although ABCC4 is an important cyclic nucleotide exporter, red blood cells from ABCC4null/PEL-negative individuals exhibited a normal guanosine 3′,5′-cyclic monophosphate level, suggesting a compensatory mechanism by other erythroid ABC transporters. Interestingly, PEL-negative individuals showed an impaired platelet aggregation, confirming a role for ABCC4 in platelet function. Finally, we showed that loss-of-function mutations in the ABCC4 gene, associated with leukemia outcome, altered the expression of the PEL antigen. In addition to ABCC4 genotyping, PEL phenotyping could open a new way toward drug dose adjustment for leukemia treatment.
Published: 2020

3. New αIIbβ3 variants in 28 Turkish Glanzmann patients; structural hypothesis for complex activation by residues variations in I-EGF domains

Author: Canan Albayrak, B Koc, Davut Albayrak, F Bianchi, Berkay Saraymen, Emine Zengin, Christophe Chenet, Mustafa Yavuz Köker, Musa Karakukcu, Bulent Zulfikar, Nazan Sarper, V. Jallu, R Petermann, Hüseyin Avcılar, A.G. de Brevern, Kocaeli University [Turkey], Ondokuz Mayis University (OMU), Istanbul University, Institut National de la Transfusion Sanguine [Paris] (INTS), Centre de Référence en Hémobiologie Péninatale (CNRHP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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 (UPC), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPC), The authors are grateful to Dr. William Vainchencker for helping in the manuscript redaction. This work was supported by a grant n° 96 (2014) from the 'Association Recherche et Transfusion' (ART) Paris, AGdB acknowledges 1) the French National Research Agency with grant ANR-19-CE17-0021 (BASIN), 2) to Indo-French Centre for the Promotion of Advanced Research/CEFIPRA for collaborative grant (number 5302-2), and 3) granted access to high-performance computing (HPC) resources at the French National Computing Centre CINES under grants no. A0040710426 and no. A0070710961 funded by the GENCI (Grand Equipement National de Calcul Intensif). Calculations were also performed on an SGI cluster granted by Conseil Régional Ile de France and INTS (SESAME Grant), France (n° 96, 2014)., and ANR-19-CE17-0021,BASIN,Cibler la voie IL-3 pour inhiber la fonction basophile en conditions inflammatoires(2019)
Subjects: Turkey, Fibrinogen receptor, Integrin, Integrin alpha2, Platelet Glycoprotein GPIIb-IIIa Complex, Molecular dynamics, Structural allostery, Integrin alpha-IIb beta-3, Humans, [CHIM]Chemical Sciences, Genetic variation, Allele, Gene, Hemostasis, Epidermal Growth Factor, biology, Platelet, Integrin beta3, Impaired platelet aggregation, Hematology, General Medicine, Transfection, Molecular biology, Phenotype, HEK293 Cells, RNA splicing, biology.protein, Glanzmann Thrombasthenia, Thrombasthenia
Abstract: Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder characterized by impaired platelet aggregation due to defects in integrin alpha IIb beta 3, a fibrinogen receptor. Platelet phenotypes and allelic variations in 28 Turkish GT patients are reported. Platelets alpha IIb beta 3 expression was evaluated by flow cytometry. Sequence analyzes of ITGA2B and ITGB3 genes allowed identifying nine variants. Non-sense variation effect on alpha IIb beta 3 expression was studied by using transfected cell lines. 3D molecular dynamics (MDs) simulations allowed characterizing structural alterations. Five new alleles were described. alpha IIb:p.Gly423Asp, p.Asp560Ala and p.Tyr784Cys substitutions impaired alpha IIb beta 3 expression. The alpha IIb:p.Gly128Val substitution allowed normal expression; however, the corresponding NM_000419.3:c.476G>T variation would create a cryptic donor splicing site altering mRNA processing. The beta 3:p.Gly540Asp substitution allowed alpha IIb beta 3 expression in HEK-293 cells but induced its constitutive activation likely by impairing alpha IIb and beta 3 legs interaction. The substitution alters the beta 3 I-EGF-3 domain flexibility as shown by MDs simulations. GT variations are mostly unique although the NM_000419.3:c.1752 + 2 T > C and NM_000212.2:c.1697 G > A variations identified in 4 and 8 families, respectively, might be a current cause of GT in Turkey. MD simulations suggested how some subtle structural variations in the beta 3 I-EGF domains might induce constitutive activation of alpha IIb beta 3 without altering the global domain structure.
Published: 2022

4. Dual role of EZH2 in megakaryocyte differentiation

Author: Rachel Petermann, Bruno Cassinat, Mathieu Vieira, Marie Cambot, William Vainchenker, Monika Wittner, Isabelle Plo, Philippe Dessen, Hana Raslova, Mira El Khoury, Najet Debili, Francesca Basso-Valentina, Valérie Edmond, Iléana Antony-Debré, Salwa BenAbdoulahab, Brahim Arkoun, Stefania Mazzi, Philippe Rameau, Virginie Dufour, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Plateforme de Bioinformatique [Gustave Roussy], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Microbiologie : Risques Infectieux, Université de Rennes (UR)-CHU Pontchaillou [Rennes]-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes - UFR d'Odontologie (UR Odontologie), Université de Rennes (UR)-Université de Rennes (UR), 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), Gamétogenèse et Qualité du Gamète - ULR 4308 (GQG), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université de Lille, Institut National de la Transfusion Sanguine [Paris] (INTS), Service de Biologie Cellulaire [Saint-Louis], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Faculté de Chirurgie Dentaire de Rennes-Faculté d'Odontologie-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), 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: Blood Platelets, Megakaryocyte differentiation, [SDV]Life Sciences [q-bio], Immunology, macromolecular substances, Biochemistry, Thrombopoiesis, Small hairpin RNA, Mice, 03 medical and health sciences, 0302 clinical medicine, Megakaryocyte, Downregulation and upregulation, medicine, Animals, Humans, Enhancer of Zeste Homolog 2 Protein, Cells, Cultured, 030304 developmental biology, 0303 health sciences, Gene knockdown, biology, Chemistry, Kinase, Cell Biology, Hematology, Platelets and Thrombopoiesis, Cell biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, biology.protein, RNA Interference, Transcriptome, PRC2, Megakaryocytes, Chromatin immunoprecipitation
Abstract: EZH2, the enzymatic component of PRC2, has been identified as a key factor in hematopoiesis. EZH2 loss-of-function mutations have been found in myeloproliferative neoplasms, particularly in myelofibrosis, but the precise function of EZH2 in megakaryopoiesis is not fully delineated. Here, we show that EZH2 inhibition by small molecules and short hairpin RNA induces megakaryocyte (MK) commitment by accelerating lineage marker acquisition without change in proliferation. Later in differentiation, EZH2 inhibition blocks proliferation and polyploidization and decreases proplatelet formation. EZH2 inhibitors similarly reduce MK polyploidization and proplatelet formation in vitro and platelet levels in vivo in a JAK2V617F background. In transcriptome profiling, the defect in proplatelet formation was associated with an aberrant actin cytoskeleton regulation pathway, whereas polyploidization was associated with an inhibition of expression of genes involved in DNA replication and repair and an upregulation of cyclin-dependent kinase inhibitors, particularly CDKN1A and CDKN2D. The knockdown of CDKN1A and to a lesser extent CDKN2D could partially rescue the percentage of polyploid MKs. Moreover, H3K27me3 and EZH2 chromatin immunoprecipitation assays revealed that CDKN1A is a direct EZH2 target and CDKN2D expression is not directly regulated by EZH2, suggesting that EZH2 controls MK polyploidization directly through CDKN1A and indirectly through CDKN2D.
Published: 2021

5. Clinical diversity and treatment results in tegumentary leishmaniasis

Author: Diana N. J. Lockwood, Jean-Pierre Gangneux, Romain Guery, Mark S. Bailey, Andreas Neumayr, Stephen L. Walker, Christophe Ravel, Pierre Buffet, Gundel Harms, Jan Clerinx, Gert Van der Auwera, Laurence Lachaud, Johannes Blum, Leo G. Visser, Sara Karlsson Söbirk, Aldert Bart, Pieter P. A. M. van Thiel, APH - Global Health, AII - Amsterdam institute for Infection and Immunity, Infectious diseases, AII - Infectious diseases, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital privé du Confluent [Nantes], University College London Hospitals (UCLH), London School of Hygiene and Tropical Medicine (LSHTM), Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health (BIH), James Cook University (JCU), Swiss Tropical and Public Health Institute [Basel], Universiteit van Amsterdam (UvA), Institut de recherche en santé, environnement et travail (Irset), 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 ), Institute of Tropical Medicine [Antwerp] (ITM), Lund University [Lund], Universiteit Leiden [Leiden], Hôpital Lapeyronie [Montpellier] (CHU), University of Basel (Unibas), 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 de Paris (UP), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Chard-Hutchinson, Xavier, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Humboldt University Of Berlin, 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 ), 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), and Universiteit Leiden
Subjects: Adult, Male, medicine.medical_specialty, Old World, Adolescent, [SDV]Life Sciences [q-bio], 030231 tropical medicine, RC955-962, Antiprotozoal Agents, Leishmaniasis, Cutaneous, law.invention, 03 medical and health sciences, Middle East, Young Adult, 0302 clinical medicine, Randomized controlled trial, Cutaneous leishmaniasis, law, Arctic medicine. Tropical medicine, Medicine, Humans, 030212 general & internal medicine, Young adult, Child, Aged, Leishmania, Travel, biology, business.industry, Transmission (medicine), Public Health, Environmental and Occupational Health, Leishmaniasis, Middle Aged, South America, medicine.disease, biology.organism_classification, Dermatology, 3. Good health, Europe, [SDV] Life Sciences [q-bio], Infectious Diseases, Africa, Female, Leishmania infantum, Public aspects of medicine, RA1-1270, business, Research Article
Abstract: Background Cutaneous leishmaniasis (CL) is frequent in travellers and can involve oro-nasal mucosae. Clinical presentation impacts therapeutic management. Methodology Demographic and clinical data from 459 travellers infected in 47 different countries were collected by members of the European LeishMan consortium. The infecting Leishmania species was identified in 198 patients. Principal findings Compared to Old World CL, New World CL was more frequently ulcerative (75% vs 47%), larger (3 vs 2cm), less frequently facial (17% vs 38%) and less frequently associated with mucosal involvement (2.7% vs 5.3%). Patients with mucosal lesions were older (58 vs 30 years) and more frequently immunocompromised (37% vs 3.5%) compared to patients with only skin lesions. Young adults infected in Latin America with L. braziliensis or L. guyanensis complex typically had an ulcer of the lower limbs with mucosal involvement in 5.8% of cases. Typically, infections with L. major and L. tropica acquired in Africa or the Middle East were not associated with mucosal lesions, while infections with L. infantum, acquired in Southern Europe resulted in slowly evolving facial lesions with mucosal involvement in 22% of cases. Local or systemic treatments were used in patients with different clinical presentations but resulted in similarly high cure rates (89% vs 86%). Conclusion/Significance CL acquired in L. infantum-endemic European and Mediterranean areas displays unexpected high rates of mucosal involvement comparable to those of CL acquired in Latin America, especially in immunocompromised patients. When used as per recommendations, local therapy is associated with high cure rates., Author summary Cutaneous and muco-cutaneous leishmaniasis (CL and MCL) are disfiguring diseases caused by a worldwide distributed parasite called Leishmania and its 20 species. Clinical manifestations span a wide continuum from single nodular lesion to disseminated form with mucosal involvement. No randomized clinical trial has ever been done exclusively in travellers and medical management is poorly evidence-based or based very predominantly on data obtained in endemic countries. Articles and reviews almost invariably propose a dichotomic view, with Old World CL described as a benign disease in contrast to New World CL strongly associated with destructive mucosal lesions. Our study is the first prospective clinical study providing a detailed description of the clinical presentation and risk of mucosal involvement in CL in several hundreds of patients, with frequent formal identification of the infecting Leishmania species. The harmonized data collection in patients infected in many transmission foci worldwide enabled direct comparisons of clinical patterns induced by different Leishmania species, and on the outcome following treatment with either local or systemic regimens. The study is based on an international harmonized data collection that allowed a wide capture of parasitologically confirmed cases. In striking contrast with previous assumptions, the study shows that CL acquired in Europe displays unexpected high rates of mucosal involvement comparable to those of CL acquired in Latin America, especially in immunocompromised travellers. It also shows that when used as per recommendations, local therapy is associated with high cure rates.
Published: 2021

6. Short in-Frame Insertions/Deletions in the Coding Sequence of the α-Globin Gene. Consequences of the 3D Structure and Resulting Phenotypes: Hb Choisy as an Example

Author: Alexandre G de Brevern, Henri Wajcman, Serge Pissard, Michael C. Marden, Celine Latouche, Jean Riou, Service de Biochimie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), IMRB - 'Transfusion et Maladies du Globule Rouge' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), 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 de Paris (UP), Institut National de la Transfusion Sanguine [Paris] (INTS), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Service de génétique [CHU Mondor], CHU Henri Mondor, 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 Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and de Brevern, Alexandre G.
Subjects: hemoglobin (Hb) variant, Hemoglobins, Abnormal, [SDV]Life Sciences [q-bio], Clinical Biochemistry, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, 0302 clinical medicine, INDEL Mutation, alpha-Globins, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, insertion/deletion (ins/del), Insertion deletion, Coding region, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Nucleotide, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Gene, Genetics (clinical), Sequence (medicine), chemistry.chemical_classification, Genetics, Base Sequence, molecular modeling, Biochemistry (medical), Nucleic acid sequence, Hematology, Phenotype, Protein Structure, Tertiary, [SDV] Life Sciences [q-bio], chemistry, 030220 oncology & carcinogenesis, Hemoglobin, a-Globin, 030215 immunology
Abstract: International audience; A small group of hemoglobin (Hb) variants result from 'in-frame' deletion/insertion (del/ins). We describe a new variant of this group (Hb Choisy), found on the α1 gene, which is the exact counterpart of a previously published deletional variant, Hb J-Biskra [codons 51-58 (or codons 52-59) (-24 bp) (-TCTGCCCAGGTTAAGGGCCACGGC); HBA1: c.157_180del (or HBA2)]. In Hb J-Biskra, the sequence Ser-Ala-Gln-Val-Lys-Gly-His-Gly located from positions α52(E1) to α59(E8) is deleted, while in Hb Choisy the same sequence (Ser-Ala-Gln-Val-Lys-Gly-His-Gly) is inserted at position α52(E1). The variant carrying the insertion appears to be less damaging than the one with the deletion. A possible explanation could be that the additional sequence is located in the C to E interhelical region, and is less disturbing to the general structure of the globin chain. This insertion/deletion (ins/del) is likely favored by the repetition, at an interval of 16 nucleotides, of an eight nucleotide sequence. Comparison of variants of this group, found in the HbVar database, shows that structural modifications resulting from insertions are frequently less damaging than that caused by deletions.
Published: 2018

7. The sickle cell trait affects contact dynamics and endothelial cell activation in Plasmodium falciparum-infected erythrocytes

Author: Dimitris Missirlis, Christine Lansche, Marilou Tétard, Anil K. Dasanna, Benjamin Fröhlich, Benoit Gamain, Ulrich S. Schwarz, Cecilia P. Sanchez, Katharina A. Quadt, Bernd Buchholz, Motomu Tanaka, Michael Lanzer, Institute of Biochemistry [ETH Zürich], Department of Biology [ETH Zürich] (D-BIOL), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich)-Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université de La Réunion (UR)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Transfusion Sanguine [Paris] (INTS), Universität Heidelberg [Heidelberg], Max-Planck-Institut für Chemische Physik fester Stoffe (CPfS), Max-Planck-Gesellschaft, Abteilung Parasitologie, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), and Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)
Subjects: 0301 basic medicine, Endothelium, [SDV]Life Sciences [q-bio], Cell, Medicine (miscellaneous), Biology, Article, General Biochemistry, Genetics and Molecular Biology, Membrane bending, 03 medical and health sciences, 0302 clinical medicine, parasitic diseases, medicine, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, lcsh:QH301-705.5, ComputingMilieux_MISCELLANEOUS, Sickle cell trait, Plasmodium falciparum, Adhesion, medicine.disease, biology.organism_classification, 3. Good health, Cell biology, Endothelial stem cell, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, 030104 developmental biology, medicine.anatomical_structure, Blood Disorder, lcsh:Biology (General), General Agricultural and Biological Sciences, 030217 neurology & neurosurgery
Abstract: Sickle cell trait, a common hereditary blood disorder, protects carriers from severe disease in infections with the human malaria parasite Plasmodium falciparum. Protection is associated with a reduced capacity of parasitized erythrocytes to cytoadhere to the microvascular endothelium and cause vaso-occlusive events. However, the underpinning cellular and biomechanical processes are only partly understood and the impact on endothelial cell activation is unclear. Here, we show, by combining quantitative flow chamber experiments with multiscale computer simulations of deformable cells in hydrodynamic flow, that parasitized erythrocytes containing the sickle cell haemoglobin displayed altered adhesion dynamics, resulting in restricted contact footprints on the endothelium. Main determinants were cell shape, knob density and membrane bending. As a consequence, the extent of endothelial cell activation was decreased. Our findings provide a quantitative understanding of how the sickle cell trait affects the dynamic cytoadhesion behavior of parasitized erythrocytes and, in turn, endothelial cell activation., Christine Lansche, Anil Dasanna et al. investigate the dynamic cytoadhesion behavior of erythrocytes infected with malaria parasite using quantitative flow chamber experiments and computer simulations. They find that parasitized erythrocytes have altered adhesion dynamics, mainly due to differences in cell shape, knob density and membrane bending.
Published: 2018

8. HIV infection and placental malaria reduce maternal transfer of multiple antimalarial antibodies in Mozambican women

Author: Marta Vidal, David R. Cavanagh, M. Nelia Manaca, Raquel González, Esperança Sevene, Pau Cisteró, Chenjerai Jairoce, María Rupérez, John J. Aponte, Benoit Gamain, Evelina Angov, Carlota Dobaño, Arsenio Nhacolo, Reyes Balcells, James G. Beeson, Eusebio Macete, Miquel Vázquez-Santiago, Anifa Vala, Selena Alonso, Gemma Moncunill, Alfredo Mayor, Laura Fuente-Soro, Clara Menéndez, Ross L. Coppel, Ruth Aguilar, Gemma Ruiz-Olalla, Instituto de Salud Global - Institute For Global Health [Barcelona] (ISGlobal), Centro de Investigação em Saúde de Manhiça [Maputo, Mozambique] (CISM), Walter Reed Army Institute of Research, Monash University [Melbourne], 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 de Paris (UP), University of Edinburgh, Burnet Institute [Melbourne, Victoria], Eduardo Mondlane University, Gamain, Benoit, 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 Paris Cité (UPCité)
Subjects: 0301 basic medicine, cord blood antibodies, [SDV]Life Sciences [q-bio], Cord blood antibodies, Antibodies, Protozoan, HIV Infections, placental malaria, 0302 clinical medicine, Placental malaria, Pregnancy, 030212 general & internal medicine, Malaria, Falciparum, Child, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology, 3. Good health, [SDV] Life Sciences [q-bio], Infectious Diseases, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, Cord blood, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Antibody, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Microbiology (medical), Cord, [SDV.IMM] Life Sciences [q-bio]/Immunology, IgG, Plasmodium falciparum, 030106 microbiology, Antimalarials, 03 medical and health sciences, Placental transfer, Antigen, parasitic diseases, medicine, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, IgG subclasses, Maternal antibodies, business.industry, Infant, Transplacental, HIV, medicine.disease, biology.organism_classification, Malaria, placental transfer, maternal antibodies, Immunology, biology.protein, business
Abstract: Objectives: Maternal Plasmodium falciparum-specific antibodies may contribute to protect infants against severe malaria. Our main objective was to evaluate the impact of maternal HIV infection and placental malaria on the cord blood levels and efficiency of placental transfer of IgG and IgG subclasses. Methods: In a cohort of 341 delivering HIV-negative and HIV-positive mothers from southern Mozambique, we measured total IgG and IgG subclasses in maternal and cord blood pairs by quantitative suspension array technology against eight P. falciparum antigens: Duffy-binding like domains 3-4 of VAR2CSA from the erythrocyte membrane protein 1, erythrocyte-binding antigen 140, exported protein 1 (EXP1), merozoite surface proteins 1, 2 and 5, and reticulocyte-binding-homologue-4.2 (Rh4.2). We performed univariable and multivariable regression models to assess the association of maternal HIV infection, placental malaria, maternal variables and pregnancy outcomes on cord antibody levels and antibody transplacental transfer. Results: Maternal antibody levels were the main determinants of cord antibody levels. HIV infection and placental malaria reduced the transfer and cord levels of IgG and IgG1, and this was antigen-dependent. Low birth weight was associated with an increase of IgG2 in cord against EXP1 and Rh4.2. Conclusions: We found lower maternally transferred antibodies in HIV-exposed infants and those born from mothers with placental malaria, which may underlie increased susceptibility to malaria in these children. (C) 2021 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Published: 2021

9. ABCG2 Is Overexpressed on Red Blood Cells in Ph-Negative Myeloproliferative Neoplasms and Potentiates Ruxolitinib-Induced Apoptosis

Author: Slim Azouzi, Alexandre G. de Brevern, Tatiana Galochkina, Thierry Peyrard, Mégane Brusson, Sylvie Cochet, Bruno Cassinat, Ivan Nemazanyy, Ralfs Buks, Wassim El Nemer, Jean-Jacques Kiladjian, 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), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut National de la Transfusion Sanguine [Paris] (INTS), Hématopoïèse normale et pathologique : émergence, environnement et recherche translationnelle [Paris] ((UMR_S1131 / U1131)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre d'Investigations Cliniques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), and ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018)
Subjects: 0301 basic medicine, Ruxolitinib, Erythrocytes, Myeloid, ruxolitinib, Apoptosis, Tyrosine-kinase inhibitor, hydroxyurea, lcsh:Chemistry, 0302 clinical medicine, Polycythemia vera, hemic and lymphatic diseases, ATP Binding Cassette Transporter, Subfamily G, Member 2, JAK2V617F, lcsh:QH301-705.5, Spectroscopy, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Differentiation, General Medicine, Neoplasm Proteins, 3. Good health, Computer Science Applications, Leukemia, Haematopoiesis, medicine.anatomical_structure, 030220 oncology & carcinogenesis, embryonic structures, Stem cell, medicine.drug, animal structures, medicine.drug_class, ABCG2, [SDV.CAN]Life Sciences [q-bio]/Cancer, Diketopiperazines, Phosphatidylserines, Biology, Heterocyclic Compounds, 4 or More Rings, Article, Catalysis, Cell Line, Inorganic Chemistry, 03 medical and health sciences, Erythroid Cells, polycythemia vera, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Nitriles, medicine, Humans, Computer Simulation, Physical and Theoretical Chemistry, Myelofibrosis, Molecular Biology, Binding Sites, Myeloproliferative Disorders, Organic Chemistry, Interferon-alpha, medicine.disease, Pyrimidines, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Cancer research, Pyrazoles, sense organs, K562 Cells, red blood cells
Abstract: International audience; Myeloproliferative neoplasms (MPNs) are a group of disorders characterized by clonal expansion of abnormal hematopoietic stem cells leading to hyperproliferation of one or more myeloid lineages. The main complications in MPNs are high risk of thrombosis and progression to myelofibrosis and leukemia. MPN patients with high risk scores are treated by hydroxyurea (HU), interferon-α, or ruxolitinib, a tyrosine kinase inhibitor. Polycythemia vera (PV) is an MPN characterized by overproduction of red blood cells (RBCs). ABCG2 is a member of the ATP-binding cassette superfamily transporters known to play a crucial role in multidrug resistance development. Proteome analysis showed higher ABCG2 levels in PV RBCs compared to RBCs from healthy controls and an additional increase of these levels in PV patients treated with HU, suggesting that ABCG2 might play a role in multidrug resistance in MPNs. In this work, we explored the role of ABCG2 in the transport of ruxolitinib and HU using human cell lines, RBCs, and in vitro differentiated erythroid progenitors. Using stopped-flow analysis, we showed that HU is not a substrate for ABCG2. Using transfected K562 cells expressing three different levels of recombinant ABCG2, MPN RBCs, and cultured erythroblasts, we showed that ABCG2 potentiates ruxolitinib-induced cytotoxicity that was blocked by the ABCG2-specific inhibitor KO143 suggesting ruxolitinib intracellular import by ABCG2. In silico modeling analysis identified possible ruxolitinib-binding site locations within the cavities of ABCG2. Our study opens new perspectives in ruxolitinib efficacy research targeting cell types depending on ABCG2 expression and polymorphisms among patients.
Published: 2021
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10. Progress and Insights Toward an Effective Placental Malaria Vaccine

Author: Benoît Gamain, Arnaud Chêne, Nicola K. Viebig, Nicaise Tuikue Ndam, Morten A. Nielsen, 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 de Paris (UP), Institut National de la Transfusion Sanguine [Paris] (INTS), UniversitätsKlinikum Heidelberg, Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Institut de Recherche pour le Développement (IRD)-Université de Paris (UP), University of Copenhagen = Københavns Universitet (KU), Rigshospitalet [Copenhagen], Copenhagen University Hospital, 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), Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 261), Institut de Recherche pour le Développement (IRD)-Université Paris Cité (UPCité), University of Copenhagen = Københavns Universitet (UCPH), ANR-16-CE11-0014,STRUCT-4-PAM,Analyse structurale et fonctionnelle des processus adhésifs associés au paludisme gestationnel(2016), and Gamain, Benoit
Subjects: 0301 basic medicine, Placenta, [SDV]Life Sciences [q-bio], VAR2CSA, placental malaria, 0302 clinical medicine, Immunogenicity, Vaccine, vaccine, Immunology and Allergy, Medicine, 030212 general & internal medicine, Malaria, Falciparum, biology, Transmission (medicine), Malaria vaccine, 3. Good health, [SDV] Life Sciences [q-bio], Treatment Outcome, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, pregnancy, Antibody, medicine.symptom, lcsh:Immunologic diseases. Allergy, [SDV.IMM] Life Sciences [q-bio]/Immunology, Mini Review, Immunology, Plasmodium falciparum, Antigens, Protozoan, Host-Parasite Interactions, 03 medical and health sciences, [SDV.IMM.VAC] Life Sciences [q-bio]/Immunology/Vaccinology, Drug Development, Immunity, Malaria Vaccines, parasitic diseases, Animals, Humans, Pregnancy, business.industry, medicine.disease, biology.organism_classification, PfEMP1, Low birth weight, 030104 developmental biology, Pregnancy Complications, Parasitic, biology.protein, Immunization, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, lcsh:RC581-607, business, Malaria
Abstract: In areas where Plasmodium falciparum transmission is endemic, clinical immunity against malaria is progressively acquired during childhood and adults are usually protected against the severe clinical consequences of the disease. Nevertheless, pregnant women, notably during their first pregnancies, are susceptible to placental malaria and the associated serious clinical outcomes. Placental malaria is characterized by the massive accumulation of P. falciparum infected erythrocytes and monocytes in the placental intervillous spaces leading to maternal anaemia, hypertension, stillbirth and low birth weight due to premature delivery, and foetal growth retardation. Remarkably, the prevalence of placental malaria sharply decreases with successive pregnancies. This protection is associated with the development of antibodies directed towards the surface of P. falciparum-infected erythrocytes from placental origin. Placental sequestration is mediated by the interaction between VAR2CSA, a member of the P. falciparum erythrocyte membrane protein 1 family expressed on the infected erythrocytes surface, and the placental receptor chondroitin sulfate A. VAR2CSA stands today as the leading candidate for a placental malaria vaccine. We recently reported the safety and immunogenicity of two VAR2CSA-derived placental malaria vaccines (PRIMVAC and PAMVAC), spanning the chondroitin sulfate A-binding region of VAR2CSA, in both malaria-naïve and P. falciparum-exposed non-pregnant women in two distinct Phase I clinical trials (ClinicalTrials.gov, NCT02658253 and NCT02647489). This review discusses recent advances in placental malaria vaccine development, with a focus on the recent clinical data, and discusses the next clinical steps to undertake in order to better comprehend vaccine-induced immunity and accelerate vaccine development.
Published: 2021

11. Tolerance and humoral immune response to the yellow fever vaccine in sickle cell disease children treated with hydroxyurea: a multicentre prospective study

Author: Florence Missud, Berengere Koehl, F. Sorge, Valentine Brousse, Camille Aupiais, Laurent Holvoet, Assa Niakate, Nelly Schinckel, Marie-Hélène Odièvre, Pierre Mornand, Malika Benkerrou, Ghislaine Ithier, Albert Faye, Hôpital Robert Debré, 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), Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), HAL-SU, Gestionnaire, 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), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP)
Subjects: Male, paediatric, Adolescent, 030231 tropical medicine, Yellow fever vaccine, Anemia, Sickle Cell, immunization, 03 medical and health sciences, 0302 clinical medicine, Yellow Fever, haemoglobinopathy, medicine, Humans, Hydroxyurea, Prospective Studies, 030212 general & internal medicine, Child, Adverse effect, travel, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, business.industry, Immunogenicity, Vaccination, Yellow Fever Vaccine, hydroxycarbamide, Antibody titer, General Medicine, medicine.disease, Sickle cell anemia, Immunity, Humoral, 3. Good health, side effects, Immunization, Child, Preschool, Africa, Immunology, biology.protein, Female, Antibody, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract: Background Sickle cell disease (SCD) children are frequent travellers to countries where yellow fever (YF) is endemic, but there are no data regarding the safety and immunogenicity of the vaccine in such children treated with hydroxyurea (HU). The main objective of this study was to compare the tolerance and immune response to YF vaccination in SCD children treated or not with HU. Method SCD children Results Among the 52 SCD children vaccinated against YF, 17 (33%) were treated with HU. Only mild adverse events, mainly fever and local reaction, were observed in the HU group with a similar frequency in the non-HU group (57 and 35%, respectively, P = 0.30). YF antibody titres were measured in 15/17 patients in the HU group and 23/35 patients in the non-HU group after a median of 6.0 months (3.5–8.5) following vaccination. The geometric mean of YF antibody titre was similar in both groups. A protective antibody level was observed in 85% of the children in the HU group vs 100% in the non-HU group (P = 0.14), suggesting a lower effectiveness of the vaccine in patients on HU similarly to what has been described in patients on immune suppressive therapy for other vaccines. Conclusion YF vaccination seems to be safe and efficient in SCD children treated with HU. Considering the potential risk of severe complications in cases of YF while travelling in Africa for those patients, the benefit-to-risk ratio argues for YF vaccination in all SCD children. Control of a protective antibody titre may also be useful to ascertain an adequate response in those treated with HU.
Published: 2021

12. Downregulation of Mitochondrial TSPO Inhibits Mitophagy and Reduces Enucleation During Human Terminal Erythropoiesis

Author: Naomi Taylor, Claude Hattab, Suella Martino, Mariano A. Ostuni, Sophie D. Lefevre, Martina Moras, Pedro Gonzalez-Menendez, Jérôme Larghero, Sandrina Kinet, Caroline Le Van Kim, KARLI, Mélanie, 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), Institut National de la Transfusion Sanguine [Paris] (INTS), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hematopoïèse et Immunothérapie, Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CIC - Biotherapie - Saint Louis ((CIC-BT 301)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Subjects: Mitochondrion, MESH: Benzodiazepinones, MESH: Down-Regulation, lcsh:Chemistry, 0302 clinical medicine, MESH: RNA, Small Interfering, Mitophagy, Erythropoiesis, RNA, Small Interfering, lcsh:QH301-705.5, Spectroscopy, 0303 health sciences, Benzodiazepinones, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: Kinetics, biology, VDAC, Chemistry, Cell Differentiation, General Medicine, Computer Science Applications, Cell biology, Mitochondria, Phenotype, MESH: Receptors, GABA, 030220 oncology & carcinogenesis, enucleation, MESH: Cell Differentiation, MESH: Cell Nucleus, Voltage-dependent anion channel, MESH: Mitochondria, MESH: Mitophagy, Down-Regulation, PINK1, MESH: Phenotype, Catalysis, Article, Inorganic Chemistry, 03 medical and health sciences, Downregulation and upregulation, Receptors, GABA, Erythroblast, Translocator protein, Humans, Physical and Theoretical Chemistry, Molecular Biology, 030304 developmental biology, Cell Nucleus, MESH: Humans, MESH: Erythropoiesis, Organic Chemistry, Kinetics, lcsh:Biology (General), lcsh:QD1-999, biology.protein, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, TSPO1
Abstract: International audience; Translocator protein (TSPO) and voltage dependent anion channels (VDAC) are two proteins forming a macromolecular complex in the outer mitochondrial membrane that is involved in pleiotropic functions. Specifically, these proteins were described to regulate the clearance of damaged mitochondria by selective mitophagy in non-erythroid immortalized cell lines. Although it is well established that erythroblast maturation in mammals depends on organelle clearance, less is known about mechanisms regulating this clearance throughout terminal erythropoiesis. Here, we studied the effect of TSPO1 downregulation and the action of Ro5-4864, a drug ligand known to bind to the TSPO/VDAC complex interface, in ex vivo human terminal erythropoiesis. We found that both treatments delay mitochondrial clearance, a process associated with reduced levels of the PINK1 protein, which is a key protein triggering canonical mitophagy. We also observed that TSPO1 downregulation blocks erythroblast maturation at the orthochromatic stage, decreases the enucleation rate, and increases cell death. Interestingly, TSPO1 downregulation does not modify reactive oxygen species (ROS) production nor intracellular adenosine triphosphate (ATP) levels. Ro5-4864 treatment recapitulates these phenotypes, strongly suggesting an active role of the TSPO/VDAC complex in selective mitophagy throughout human erythropoiesis. The present study links the function of the TSPO/VDAC complex to the PINK1/Parkin-dependent mitophagy induction during terminal erythropoiesis, leading to the proper completion of erythroid maturation.
Published: 2020

13. Investigating the Product Profiles and Structural Relationships of New Levansucrases with Conventional and Non-Conventional Substrates

Author: Alexandre G. de Brevern, Tarun Jairaj Narwani, Salwa Karboune, Andrea Hill, de Brevern, Alexandre G., Department of Food Science and Agricultural Chemistry [Montréal], McGill University = Université McGill [Montréal, Canada], Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Institut National de la Transfusion Sanguine [Paris] (INTS), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Subjects: 0301 basic medicine, Gluconobacter oxydans, Sucrose, Novosphingobium, Protein Conformation, homology modeling, Gene Expression, Oligosaccharides, Vibrio natriegens, acceptor specificity, 01 natural sciences, Quantitative Biology - Quantitative Methods, Substrate Specificity, lcsh:Chemistry, chemistry.chemical_compound, Raffinose, lcsh:QH301-705.5, Spectroscopy, Quantitative Methods (q-bio.QM), chemistry.chemical_classification, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], biology, alcohol, Burkholderiaceae, General Medicine, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Recombinant Proteins, Computer Science Applications, Molecular Docking Simulation, Sphingomonadaceae, prebiotic, Protein Binding, Stereochemistry, levansucrase, Fructose, Catalysis, Article, Inorganic Chemistry, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Monosaccharide, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, fructooligosaccharide, Homology modeling, Amino Acid Sequence, Physical and Theoretical Chemistry, Molecular Biology, Vibrio, Binding Sites, 010405 organic chemistry, Organic Chemistry, Levansucrase, Biomolecules (q-bio.BM), biology.organism_classification, Acceptor, 0104 chemical sciences, Fructans, Kinetics, 030104 developmental biology, Enzyme, Prebiotics, chemistry, lcsh:Biology (General), lcsh:QD1-999, Quantitative Biology - Biomolecules, Hexosyltransferases, Structural Homology, Protein, FOS: Biological sciences, Biocatalysis, fructosylation, Sequence Alignment
Abstract: The synthesis of complex oligosaccharides is desired for their potential as prebiotics, and their role in the pharmaceutical and food industry. Levansucrase (LS, EC 2.4.1.10), a fructosyl-transferase, can catalyze the synthesis of these compounds. LS acquires a fructosyl residue from a donor molecule and performs a non-Lenoir transfer to an acceptor molecule, via &beta, (2&rarr, 6)-glycosidic linkages. Genome mining was used to uncover new LS enzymes with increased transfructosylating activity and wider acceptor promiscuity, with an initial screening revealing five LS enzymes. The product profiles and activities of these enzymes were examined after their incubation with sucrose. Alternate acceptor molecules were also incubated with the enzymes to study their consumption. LSs from Gluconobacter oxydans and Novosphingobium aromaticivorans synthesized fructooligosaccharides (FOSs) with up to 13 units in length. Alignment of their amino acid sequences and substrate docking with homology models identified structural elements causing differences in their product spectra. Raffinose, over sucrose, was the preferred donor molecule for the LS from Vibrio natriegens, N. aromaticivorans, and Paraburkolderia graminis. The LSs examined were found to have wide acceptor promiscuity, utilizing monosaccharides, disaccharides, and two alcohols to a high degree.
Published: 2020

14. Potent human broadly neutralizing antibodies to hepatitis B virus from natural controllers

Author: Camille Sureau, Verena Hehle, Oriane Fiquet, Cyril Planchais, Valérie Lorin, Marie-Louise Michel, Jordan D. Dimitrov, Helene Strick-Marchand, Nadege Pelletier, Stanislas Pol, Maxime Beretta, Hugo Mouquet, Thierry Hieu, Malika Ait-Goughoulte, James P. Di Santo, Andrea Stauffer, Marie-Noëlle Ungeheuer, Maryline Bourgine, Benjamin Vesin, Solen Morisse, BOURGINE, Maryline, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, Human Antibody Responses to Viruses - HUMANTIVIRUSES - - EC:FP7:ERC2014-01-01 - 2018-12-31 - 337146 - VALID, Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virologie Moléculaire et Vaccinologie / Molecular Virology and Vaccinology, Institut Pasteur [Paris] (IP), F. Hoffmann-La Roche [Basel], Immunité Innée - Innate Immunity, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), 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), Centre de Recherche Translationnelle - Center for Translational Science (CRT), H. Mouquet received core grants from the G5 Institut Pasteur Program, the Milieu Intérieur Program (ANR-10-LABX-69-01) and INSERM. This work was funded by Institut Roche. V. Hehle and M. Beretta were supported by postdoctoral fellowships from Roche. V. Hehle and T. Hieu were also supported by the European Research Council–Seventh Framework Program (ERC-2013-StG 337146). H. Strick-Marchand was supported by the Institut Pasteur and Agence Nationale de Recherches sur le Sida et les Hépatites Virales (2016-16365, 2019-19241)., We are grateful to members of the Center for Translational Sciences (Institut Pasteur), Cassandre Von Platen (Clinical core) for the preparation of the RAPIVIB protocol, and Gloria Morizot (Investigation Clinique et Accès aux Ressources Biologiques) for collecting biological samples and associated personal data. We also thank Sandrine Schmutz, Sophie Novault (UTechS CB, Center for Translational Sciences, Institut Pasteur), and Ayrin Kök for their technical help with single cell sorting, and Dr. J. Aguilar (Center for Genetic Engineering and Biotechnology, Havana, Cuba) for providing us with the purified adw HBsAg particles., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), European Project: 337146,EC:FP7:ERC,ERC-2013-StG,HUMANTIVIRUSES(2014), École Pratique des Hautes Études (EPHE), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), 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, HBsAg, MESH: Epitopes, MESH: Hepatitis B, Chronic, Immunology, MESH: Flow Cytometry, Viremia, medicine.disease_cause, Epitope, Virus, MESH: Antibodies, Neutralizing, MESH: Cross Reactions, 03 medical and health sciences, [SDV.IMM.VAC] Life Sciences [q-bio]/Immunology/Vaccinology, 0302 clinical medicine, MESH: B-Lymphocytes, medicine, Immunology and Allergy, MESH: Animals, MESH: Mice, Hepatitis B virus, MESH: Hepatitis B Vaccines, MESH: Humans, MESH: Hepatitis B, biology, MESH: Neutralization Tests, MESH: Enzyme-Linked Immunosorbent Assay, virus diseases, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Hepatitis B, medicine.disease, Virology, digestive system diseases, MESH: Hepatitis B Surface Antigens, 3. Good health, Vaccination, MESH: Hepatitis B virus, 030104 developmental biology, MESH: Immunologic Memory, biology.protein, 030211 gastroenterology & hepatology, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, Antibody
Abstract: International audience; Rare individuals can naturally clear chronic hepatitis B virus (HBV) infection and acquire protection from reinfection as conferred by vaccination. To examine the protective humoral response against HBV, we cloned and characterized human antibodies specific to the viral surface glycoproteins (HBsAg) from memory B cells of HBV vaccinees and controllers. We found that human HBV antibodies are encoded by a diverse set of immunoglobulin genes and recognize various conformational HBsAg epitopes. Strikingly, HBsAg-specific memory B cells from natural controllers mainly produced neutralizing antibodies able to cross-react with several viral genotypes. Furthermore, monotherapy with the potent broadly neutralizing antibody Bc1.187 suppressed viremia in vivo in HBV mouse models and led to post-therapy control of the infection in a fraction of animals. Thus, human neutralizing HBsAg antibodies appear to play a key role in the spontaneous control of HBV and represent promising immunotherapeutic tools for achieving HBV functional cure in chronically infected humans.
Published: 2020

15. The equilibrative nucleoside transporter ENT1 is critical for nucleotide homeostasis and optimal erythropoiesis

Author: Naomi Taylor, Yujin Zhang, Yang Xia, Marc Sitbon, Mahmoud Mikdar, Sylvia Sanquer, Cerina Chhuon, Pedro González-Menéndez, Narla Mohandas, Ida Chiara Guerrera, Anne-Claire Boschat, Slim Azouzi, Olivier Hermine, Thierry Peyrard, Sandrina Kinet, Yves Colin, Marion Serra, Xiaoli Cai, Caroline Le Van Kim, Abdoul Karim Dembele, 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), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre National de Référence pour les Groupes Sanguins (CNRGS), CNRGS, Hematopoïèse et Immunothérapie, Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), New York Blood Center, National Institutes of Health [Bethesda] (NIH), KARLI, Mélanie, 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), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Iron, Immunology, ABCC4, Biochemistry, Equilibrative Nucleoside Transporter 1, 03 medical and health sciences, chemistry.chemical_compound, Cyclic nucleotide, Mice, Red Cells, Iron, and Erythropoiesis, 0302 clinical medicine, medicine, Animals, Homeostasis, Humans, Cyclic adenosine monophosphate, Erythropoiesis, Cells, Cultured, Mice, Knockout, Adenosine transport, biology, Nucleosides, Equilibrative nucleoside transporter, Cell Biology, Hematology, Hematopoietic Stem Cells, Adenosine, Adenosine Monophosphate, Cell biology, [SDV] Life Sciences [q-bio], 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, biology.protein, Nucleoside, medicine.drug
Abstract: This is a related article to: Nucleoside ENTry modulates erythropoiesis (cf ci-dessous); International audience; Abstract The tight regulation of intracellular nucleotides is critical for the self-renewal and lineage specification of hematopoietic stem cells (HSCs). Nucleosides are major metabolite precursors for nucleotide biosynthesis and their availability in HSCs is dependent on their transport through specific membrane transporters. However, the role of nucleoside transporters in the differentiation of HSCs to the erythroid lineage and in red cell biology remains to be fully defined. Here, we show that the absence of the equilibrative nucleoside transporter (ENT1) in human red blood cells with a rare Augustine-null blood type is associated with macrocytosis, anisopoikilocytosis, an abnormal nucleotide metabolome, and deregulated protein phosphorylation. A specific role for ENT1 in human erythropoiesis was demonstrated by a defective erythropoiesis of human CD34+ progenitors following short hairpin RNA-mediated knockdown of ENT1. Furthermore, genetic deletion of ENT1 in mice was associated with reduced erythroid progenitors in the bone marrow, anemia, and macrocytosis. Mechanistically, we found that ENT1-mediated adenosine transport is critical for cyclic adenosine monophosphate homeostasis and the regulation of erythroid transcription factors. Notably, genetic investigation of 2 ENT1null individuals demonstrated a compensation by a loss-of-function variant in the ABCC4 cyclic nucleotide exporter. Indeed, pharmacological inhibition of ABCC4 in Ent1−/− mice rescued erythropoiesis. Overall, our results highlight the importance of ENT1-mediated nucleotide metabolism in erythropoiesis.
Published: 2020

16. PEPOP 2.0: new approaches to mimic non-continuous epitopes

Author: Liza Felicori, Franck Molina, Benedicte Jardin, Alexandre G. de Brevern, Violaine Moreau, Lionel Valera, Géraldine Lavigne, Vincent Demolombe, Ricardo Andrez Machado De Ávila, Aurélien Lebreton, Christophe Nguyen, Biochimie et Physiologie Moléculaire des Plantes (BPMP), Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Plateforme de Spectrométrie de Masse Protéomique - Mass Spectrometry Proteomics Platform (MSPP), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-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), Sys2Diag-Modélisation et Ingénierie des Systèmes Complexes Biologiques pour le Diagnostic (Sys2Diag), Centre National de la Recherche Scientifique (CNRS)-Alcediag, Laboratoire Agronomie et Environnement (LAE), Institut National de la Recherche Agronomique (INRA)-Université de Lorraine (UL), Sysdag, Sysdiag CNRS Bio-Rad UMR 3145, Cap Delta/Parc Euromédecine, Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), CNRS/Bio-Rad, Centre National de la Recherche Scientifique (CNRS), Lab-STICC_UBS_CACS_IAS, Laboratoire des sciences et techniques de l'information, de la communication et de la connaissance (Lab-STICC), École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie du cancer du foie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-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 la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), GRICH, Hichem, Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), and Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Protein surface, Computer science, IPP, [SDV]Life Sciences [q-bio], Peptide, medicine.disease_cause, Biochemistry, Epitope, Structural bioinformatics, Epitopes, Mice, 0302 clinical medicine, Structural Biology, Peptide design, [SDV.BV] Life Sciences [q-bio]/Vegetal Biology, lcsh:QH301-705.5, chemistry.chemical_classification, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], biology, Applied Mathematics, Immunogenicity, Methodology Article, A protein, Antibodies, Monoclonal, Antigenicity, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Computer Science Applications, [SDV] Life Sciences [q-bio], Molecular mimicry, 030220 oncology & carcinogenesis, lcsh:R858-859.7, Discontinuous epitope, DNA microarray, Antibody, Surface protein, Discontinuous and continuous epitope, Computational biology, lcsh:Computer applications to medicine. Medical informatics, 03 medical and health sciences, Protein Domains, medicine, Molecule, Animals, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Amino Acid Sequence, Binding site, Molecular Biology, 030304 developmental biology, Internet, Immune Sera, Computational Biology, Proteins, B-cell epitope, Ag-ab interaction, lcsh:Biology (General), chemistry, biology.protein, Peptides, Software
Abstract: Background Bioinformatics methods are helpful to identify new molecules for diagnostic or therapeutic applications. For example, the use of peptides capable of mimicking binding sites has several benefits in replacing a protein which is difficult to produce, or toxic. Using peptides is less expensive. Peptides are easier to manipulate, and can be used as drugs. Continuous epitopes predicted by bioinformatics tools are commonly used and these sequential epitopes are used as is in further experiments. Numerous discontinuous epitope predictors have been developed but only two bioinformatics tools have been proposed so far to predict peptide sequences: Superficial and PEPOP 2.0. PEPOP 2.0 can generate series of peptide sequences that can replace continuous or discontinuous epitopes in their interaction with their cognate antibody. Results We have developed an improved version of PEPOP (PEPOP 2.0) dedicated to answer to experimentalists’ need for a tool able to handle proteins and to turn them into peptides. The PEPOP 2.0 web site has been reorganized by peptide prediction category and is therefore better formulated to experimental designs. Since the first version of PEPOP, 32 new methods of peptide design were developed. In total, PEPOP 2.0 proposes 35 methods in which 34 deal specifically with discontinuous epitopes, the most represented epitope type in nature. Conclusion Through the presentation of its user-friendly, well-structured new web site conceived in close proximity to experimentalists, we report original methods that show how PEPOP 2.0 can assist biologists in dealing with discontinuous epitopes. Electronic supplementary material The online version of this article (10.1186/s12859-019-2867-5) contains supplementary material, which is available to authorized users.
Published: 2019

17. Positron emission tomography and magnetic resonance imaging in experimental human malaria to identify organ-specific changes in morphology and glucose metabolism: A prospective cohort study

Author: Rintis Noviyanti, Agatha M. Puspitasari, Papa Alioune Ndour, Nurjati Chairani Siregar, Benediktus Andries, Benoit Henry, Leo Leonardo, Dwi Apriyanti, Fabrice Chrétien, Bruce Russell, Nur I. Margyaningsih, Carmen Fernandez-Becerra, Aurélie Fricot, Matthias Marti, Nicholas M. Anstey, Tsin W. Yeo, Valentine Brousse, Labibah Qotrunnada, Ric N. Price, David Hardy, Pierre Buffet, Hernando A. del Portillo, Leily Trianty, Pak Prayoga, Enny Kenangalem, Elamaran Meibalan, Jeanne Rini Poespoprodjo, Innocent Safeukui, Putu A. I. Wardani, Tonia Woodberry, Steven Kho, Gabriela Minigo, Global and Tropical Health Division [Rocklands, Australia], Menzies School of Health Research [Australia], Charles Darwin University [Australia]-Charles Darwin University [Australia], Eijkman Institute for Molecular Biology [Jakarta], Papuan Health and Community Development Foundation [Timika, Papua Indonesia], Rumah Sakit Umum Daerah Kabupaten Mimika [Timika, Papua, Indonesia], 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), Neuropathologie expérimentale / Experimental neuropathology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), University of Notre Dame [Indiana] (UND), Instituto de Salud Global - Institute For Global Health [Barcelona] (ISGlobal), Institut d’Investigació Germans Trias i Pujol = Germans Trias i Pujol Research Institute (IGTP), Institució Catalana de Recerca i Estudis Avançats (ICREA), Harvard School of Public Health, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), University of Glasgow, University of Oxford, Mahidol University [Bangkok], University of Otago [Dunedin, Nouvelle-Zélande], Universitas Gadjah Mada, Universitas Indonesia (UI ), This work was supported by the Australian National Health and Medical Research Council (Program Grant #1037304, Fellowships to NA [#1042072 and #1135820], and ‘Improving Health Outcomes in the Tropical North (HOTNORTH): A multidisciplinary collaboration [#1131932], and the Australian Centre of Research Excellence in Malaria Elimination), the Paris Ile-de-France Region under « DIM Thérapie génique » and « DIM Maladies Infectieuses » initiatives (awarded to PAB and BH), the French Institut National de la Santé Et de la Recherche Médicale (INSERM), the University of Paris, the Laboratory of excellence GREx, the Bill and Melinda Gates Foundation (BMGF OPP1123683), and the « Sauver la Vie Foundation » (to PAB), the Wellcome Trust (Grant #099875 awarded to JRP and Senior Fellowship in Clinical Science awarded to RNP [#200909]), an Australian Government Postgraduate Award Scholarship and OzEMalaR Travel award (awarded to SK), a Royal Society Wolfson Research Merit award (awarded to MM), the Singapore National Medical Research Council (award to TWY [CSA INV 15nov007]), and the Australian Department of Foreign Affairs and Trade., We thank patients and relatives of patients in Indonesia and France for their participation and support, staff in the laboratory and operating theatre at RSUD hospital and French hospitals, Dr Daniel Lampah and Dr Freis Candrawati for clinical input, Dr Gregory Jouvion, Dr Sarah Auburn and Dr Jutta Marfurt for methodological and intellectual advice, Dr Grennady Wirjanata, Ms Aisah Resti Amelia and Mrs Magali Tichit for laboratory assistance, and Prof Yati Soenarto for facilitating the study. We are grateful to colleagues at the Timika Research Facility for their support., Hardy, David, Charles Darwin University-Charles Darwin University, 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), Institut Pasteur [Paris]-Université de Paris (UP), and University of Oxford [Oxford]
Subjects: Male, 0301 basic medicine, Plasmodium, Reticulocytes, Physiology, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Plasmodium vivax, Medical Conditions, 0302 clinical medicine, Reticulocyte, Animal Cells, Immune Physiology, Red Blood Cells, Medicine and Health Sciences, Blood and Lymphatic System Procedures, Prospective Studies, Asymptomatic Infections, Protozoans, biology, Malarial Parasites, Eukaryota, General Medicine, Middle Aged, Body Fluids, 3. Good health, [SDV] Life Sciences [q-bio], Blood, medicine.anatomical_structure, Splenectomy, Red pulp, Medicine, Female, Cellular Types, Anatomy, medicine.symptom, Research Article, Adult, Adolescent, 030231 tropical medicine, Bone Marrow Cells, Surgical and Invasive Medical Procedures, Spleen, Asymptomatic, Young Adult, 03 medical and health sciences, Parasite Groups, parasitic diseases, Malaria, Vivax, Parasitic Diseases, medicine, Humans, New Guinea, Blood Cells, Organisms, Biology and Life Sciences, Plasmodium falciparum, Cell Biology, Tropical Diseases, biology.organism_classification, medicine.disease, Parasitic Protozoans, Malaria, 030104 developmental biology, Indonesia, Immunology, Parasitology, Apicomplexa
Abstract: Background A very large biomass of intact asexual-stage malaria parasites accumulates in the spleen of asymptomatic human individuals infected with Plasmodium vivax. The mechanisms underlying this intense tropism are not clear. We hypothesised that immature reticulocytes, in which P. vivax develops, may display high densities in the spleen, thereby providing a niche for parasite survival. Methods and findings We examined spleen tissue in 22 mostly untreated individuals naturally exposed to P. vivax and Plasmodium falciparum undergoing splenectomy for any clinical indication in malaria-endemic Papua, Indonesia (2015 to 2017). Infection, parasite and immature reticulocyte density, and splenic distribution were analysed by optical microscopy, flow cytometry, and molecular assays. Nine non-endemic control spleens from individuals undergoing spleno-pancreatectomy in France (2017 to 2020) were also examined for reticulocyte densities. There were no exclusion criteria or sample size considerations in both patient cohorts for this demanding approach. In Indonesia, 95.5% (21/22) of splenectomy patients had asymptomatic splenic Plasmodium infection (7 P. vivax, 13 P. falciparum, and 1 mixed infection). Significant splenic accumulation of immature CD71 intermediate- and high-expressing reticulocytes was seen, with concentrations 11 times greater than in peripheral blood. Accordingly, in France, reticulocyte concentrations in the splenic effluent were higher than in peripheral blood. Greater rigidity of reticulocytes in splenic than in peripheral blood, and their higher densities in splenic cords both suggest a mechanical retention process. Asexual-stage P. vivax-infected erythrocytes of all developmental stages accumulated in the spleen, with non-phagocytosed parasite densities 3,590 times (IQR: 2,600 to 4,130) higher than in circulating blood, and median total splenic parasite loads 81 (IQR: 14 to 205) times greater, accounting for 98.7% (IQR: 95.1% to 98.9%) of the estimated total-body P. vivax biomass. More reticulocytes were in contact with sinus lumen endothelial cells in P. vivax- than in P. falciparum-infected spleens. Histological analyses revealed 96% of P. vivax rings/trophozoites and 46% of schizonts colocalised with 92% of immature reticulocytes in the cords and sinus lumens of the red pulp. Larger splenic cohort studies and similar investigations in untreated symptomatic malaria are warranted. Conclusions Immature CD71+ reticulocytes and splenic P. vivax-infected erythrocytes of all asexual stages accumulate in the same splenic compartments, suggesting the existence of a cryptic endosplenic lifecycle in chronic P. vivax infection. Findings provide insight into P. vivax-specific adaptions that have evolved to maximise survival and replication in the spleen., Dr. Anstey and co-authors found that P. vivax-infected immature reticulocytes and erythrocytes accumulate in the same splenic compartments, suggesting existence of a cryptic endosplenic lifecycle in chronic P. vivax infection that maximizes survival and replication in the spleen., Author summary Why was this study done? There is a surprisingly large biomass of intact Plasmodium vivax parasites in the spleen of people living in malaria endemic areas, greater than with Plasmodium falciparum. Why P. vivax accumulates so intensely in the spleen is not known. P. vivax requires very young red cells (immature reticulocytes) for invasion and replication. What did the researchers do and find? The accumulation of P. vivax and immature reticulocytes were evaluated in spleens from people undergoing splenectomy in malaria-endemic Papua. P. vivax parasites and immature reticulocytes accumulated in the same splenic compartments. All stages of P. vivax accumulated in the spleen at magnitudes unexplainable by replication occurring in the circulation alone, with the proportion of each stage in the spleen consistent with the duration in their lifecycle. What do these findings mean? Taking advantage of the large physiological splenic reservoir of immature reticulocytes, the majority of the P. vivax lifecycle can take place in the spleen in chronic malaria. Chronic vivax malaria should be considered predominantly an infection of the reticulocyte-rich spleen, with secondary involvement of the intravascular compartment. The spleen is not solely a compartment for parasite destruction and clearance. Specific adaptations have likely evolved to maximise P. vivax survival in the spleen.
Published: 2021

18. Band 3 phosphorylation induces irreversible alterations of stored red blood cells

Author: Marc Romana, Slim Azouzi, Caroline Le Van Kim, Nobuto Arashiki, Thierry Peyrard, Yves Colin, Wassim El Nemer, Yuichi Takakuwa, Pascal Amireault, Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Protéines de la membrane érythrocytaire et homologues non-érythroides, Université des Antilles et de la Guyane (UAG)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Transfusion Sanguine [Paris] (INTS), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Erythrocytes, Time Factors, Blood preservation, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Text mining, Anion Exchange Protein 1, Erythrocyte, Humans, 030212 general & internal medicine, Phosphorylation, Band 3, ComputingMilieux_MISCELLANEOUS, biology, business.industry, Chemistry, ANION EXCHANGE PROTEIN 1, Erythrocyte metabolism, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Protein multimerization, Biochemistry, Blood Preservation, biology.protein, Protein Multimerization, business
Abstract: International audience
Published: 2018

19. Investigation of the impact of PTMs on the protein backbone conformation

Author: Tarun Jairaj Narwani, Pierrick Craveur, Alexandre G. de Brevern, Joseph Rebehmed, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), The SCRIPPS Research Institute (SCRIPPS), University of California [Los Angeles] (UCLA), University of California-University of California, Institut National de la Transfusion Sanguine [Paris] (INTS), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Department of Computer Science and Mathematics [Lebanese American University] (CSM/SAS/LAU), Lebanese American University (LAU), the Ministry of Research (France), University de Paris, University Paris Diderot, Sorbonne, Paris Cité (France), National Institute for Blood Transfusion (INTS, France), National Institute for Health and Medical Research (INSERM, France), French National Computing Centre CINES under grant no. c2013037147 by the GENCI (Grand Equipement National de Calcul Intensif)., Indo-French Centre for the Promotion of Advanced Research / CEFIPRA for collaborative grant (number 5302-2)., Calculations were also performed on an SGI cluster granted by Conseil Régional Ile de France and INTS (SESAME Grant), ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), ANR-10-CD2I-0014,NaturaDyRe,Réactions d'oxydation biocatalysées efficaces pour la synthèse de composés naturels ou énantiopurs(2010), de Brevern, Alexandre G., Université de Paris - - Université de Paris2018 - ANR-18-IDEX-0001 - IDEX - VALID, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, Chimie Durable – Industries – Innovation - Réactions d'oxydation biocatalysées efficaces pour la synthèse de composés naturels ou énantiopurs - - NaturaDyRe2010 - ANR-10-CD2I-0014 - CD2I - VALID, The Scripps Research Institute [La Jolla, San Diego], and Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: 0301 basic medicine, Models, Molecular, Glycosylation, Protein Conformation, Entropy, Clinical Biochemistry, N-glycosylation, Proteomics, Quantitative Biology - Quantitative Methods, Biochemistry, liver carboxylesterase, Carboxylesterase, Protein structure, N-linked glycosylation, Peptide bond, deformability, Databases, Protein, renin endopeptidase, Quantitative Methods (q-bio.QM), [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], biology, Chemistry, phosphorylation, Methylation, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], mobility, rigidity, statistics, Phosphorylation, actin, cyclin-dependent kinase 2 (CDK2), Computational biology, 03 medical and health sciences, Endopeptidases, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Actin, 030102 biochemistry & molecular biology, Organic Chemistry, Cyclin-dependent kinase 2, Cyclin-Dependent Kinase 2, Proteins, Biomolecules (q-bio.BM), Actins, 030104 developmental biology, Quantitative Biology - Biomolecules, FOS: Biological sciences, biology.protein, methylation, Protein Processing, Post-Translational
Abstract: International audience; Post-Translational Modifications (PTMs) are known to play a critical role in the regulation of the protein functions. Their impact on protein structures, and their link to disorder regions have already been spotted on the past decade. Nonetheless, the high diversity of PTMs types, and the multiple schemes of protein modifications (multiple PTMs, of different types, at different time, etc) make difficult the direct confrontation of PTM annotations and protein structures data.We so analyzed the impact of the residue modifications on the protein structures at local level. Thanks to a dedicated structure database, namely PTM-SD, a large screen of PTMs have been done and analyze at a local protein conformation levels using the structural alphabet Protein Blocks (PBs). We investigated the relation between PTMs and the backbone conformation of modified residues, of their local environment, and at the level of the complete protein structure. The two main PTM types (N-glycosylation and phosphorylation) have been studied in non-redundant datasets, and then, 4 different proteins were focused, covering 3 types of PTMs: N-glycosylation in renin endopeptidase and liver carboxylesterase, phosphorylation in cyclin-dependent kinase 2 (CDK2), and methylation in actin. We observed that PTMs could either stabilize or destabilize the backbone structure, at a local and global scale, and that these effects depend on the PTM types.
Published: 2019

20. Impact of Hemoglobin S Trait on Cell Surface Antibody Recognition of Plasmodium falciparum-Infected Erythrocytes in Pregnancy-Associated Malaria

Author: Murielle Lohezic, Jacqueline Milet, Anaïs Merckx, Marilou Tétard, Emeline Brossier, Luc Denoyel, Margaux Chauvet, Jocelyne Roman, Benoit Gamain, Florentin Aussenac, Nicaise Tuikue Ndam, Adrian J. F. Luty, Marion Hanny, Damien Pineau, Gilles Cottrell, Florence Migot-Nabias, Institute of Biochemistry [ETH Zürich], Department of Biology [ETH Zürich] (D-BIOL), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Institut de Recherche pour le Développement (IRD), Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Institut de Recherche pour le Développement (IRD)-Université de Paris (UP), Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 261), Institut de Recherche pour le Développement (IRD)-Université Paris Cité (UPCité), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich)-Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), Mère et enfant face aux infections tropicales (MERIT - UMR_D 216), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université de La Réunion (UR)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Transfusion Sanguine [Paris] (INTS)
Subjects: 0301 basic medicine, Thalassemia, [SDV]Life Sciences [q-bio], 030106 microbiology, Population, Cell surface antibody binding, VAR2CSA, Major Articles, 03 medical and health sciences, 0302 clinical medicine, parasitic diseases, pregnancy-associated malaria, Medicine, 030212 general & internal medicine, hemoglobin S, education, ComputingMilieux_MISCELLANEOUS, education.field_of_study, Sickle cell trait, Pregnancy-associated malaria, biology, business.industry, Plasmodium falciparum, medicine.disease, biology.organism_classification, 3. Good health, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Oncology, Immunology, biology.protein, Hemoglobin, Antibody, business, Malaria, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Background. Sickle cell trait (HbAS) confers partial protection against malaria by reducing the adhesion of Plasmodium falciparum-infected erythrocytes to host receptors, but little is known about its potential protection against placental malaria. Methods. Using flow cytometry, we assessed the recognition of HbAA and HbAS VAR2CSA-expressing infected erythrocytes, by plasma from 159 Beninese pregnant women with either HbAA (normal) or HbAS. Using multivariate linear models adjusted for gravidity, parasite infection at delivery, glucose-6-phosphate dehydrogenase deficiency, and α-thalassemia carriage, we observed significantly reduced cell surface antibody binding of HbAS-infected erythrocytes by plasma from HbAS compared with HbAA women (P < 10-3). Results. The difference in cell surface antibody binding was only observed when infected erythrocytes and plasma were associated according to the same hemoglobin genotype. Similar levels of VAR2CSA-specific antibody were measured by enzyme-linked immunosorbent assay in the 2 groups, suggesting that the altered interaction between VAR2CSA and HbAS women's antibodies could reflect abnormal display of VAR2CSA on HbAS erythrocytes. Conclusions. Our data stress the need for assessments of erythrocyte disorders such as the sickle cell trait in a population group when studying immunological responses to P falciparum.
Published: 2019

21. Preclinical immunogenicity and safety of the cGMP-grade placental malaria vaccine PRIMVAC

Author: Anna Guadall, Nicola K. Viebig, Stéphane Gangnard, Arnaud Chêne, Nicolas Havelange, Odile Leroy, Benoit Gamain, Hervé Ginisty, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université de La Réunion (UR)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Transfusion Sanguine [Paris] (INTS), GTP Technol, Prologue Biotech, European Vaccine Initiative [Heidelberg, Germany], UniversitätsKlinikum Heidelberg [Germany], Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), and UniversitätsKlinikum Heidelberg
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Heterologous, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Antigen, medicine, Good manufacturing practice, ComputingMilieux_MISCELLANEOUS, biology, Malaria vaccine, business.industry, Immunogenicity, General Medicine, medicine.disease, 3. Good health, Clinical trial, 030104 developmental biology, 030220 oncology & carcinogenesis, Immunology, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, business, Malaria
Abstract: Background VAR2CSA is the lead antigen for developing a vaccine that would protect pregnant women against placental malaria. A multi-system feasibility study has identified E. coli as a suitable bacterial expression platform allowing the production of recombinant VAR2CSA-DBL1x-2x (PRIMVAC) to envisage a prompt transition to current Good Manufacturing Practice (cGMP) vaccine production. Methods Extensive process developments were undertaken to produce cGMP grade PRIMVAC to permit early phase clinical trials. PRIMVAC stability upon storage was assessed over up to 3 years. A broad toxicology investigation was carried out in rats allowing meanwhile the analysis of PRIMVAC immunogenicity. Findings We describe the successful cGMP production of 4. 65 g of PRIMVAC. PRIMVAC drug product was stable and potent for up to 3 years upon storage at −20 °C and showed an absence of toxicity in rats. PRIMVAC adjuvanted with Alhydrogel® or GLA-SE was able to generate antibodies able to recognize VAR2CSA expressed at the surface of erythrocytes infected with different strains. These antibodies also inhibit the interaction of the homologous NF54-CSA strain and to a lower extend of heterologous strains to CSA. Interpretation This work paved the way for the clinical development of an easily scalable low cost effective vaccine that could protect against placental malaria and prevent an estimated 10,000 maternal and 200,000 infant deaths annually. Fund This work was supported by a grant from the Bundesministerium fur Bildung und Forschung (BMBF), Germany through Kreditanstalt fur Wiederaufbau (KfW) (Reference No: 202060457) and through funding from Irish Aid, Department of Foreign Affairs and Trade, Ireland.
Published: 2019

22. Differential patterns of IgG subclass responses to Plasmodium falciparum antigens in relation to malaria protection and RTS,S vaccination

Author: Carlota Dobaño, Rebeca Santano, Marta Vidal, Alfons Jiménez, Chenjerai Jairoce, Itziar Ubillos, David Dosoo, Ruth Aguilar, Nana Aba Williams, Núria Díez-Padrisa, Aintzane Ayestaran, Clarissa Valim, Kwaku Poku Asante, Seth Owusu-Agyei, David Lanar, Virander Chauhan, Chetan Chitnis, Sheetij Dutta, Evelina Angov, Benoit Gamain, Ross L. Coppel, James G. Beeson, Linda Reiling, Deepak Gaur, David Cavanagh, Ben Gyan, Augusto J. Nhabomba, Joseph J. Campo, Gemma Moncunill, Department of Immunology and Infectious Diseases (IID), Harvard T.H. Chan School of Public Health, U.S. Military Malaria Vaccine Program, Walter Reed Army Institute of Research-Division of Malaria Vaccine Development, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Department of Immunology and Infectious Diseases, Harvard School of Public Health, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université de La Réunion (UR)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Transfusion Sanguine [Paris] (INTS)
Subjects: 0301 basic medicine, Male, [SDV]Life Sciences [q-bio], Adaptive Immunity, Subclass, 0302 clinical medicine, antibody, vaccine, Immunology and Allergy, ComputingMilieux_MISCELLANEOUS, Original Research, biology, Vaccination, Acquired immune system, protection, 3. Good health, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Antibody, lcsh:Immunologic diseases. Allergy, plasmodium falciparum, Immunology, Plasmodium falciparum, malaria, Malària, Antigens, Protozoan, 03 medical and health sciences, Antigen, IgG subclass, children, Malaria Vaccines, parasitic diseases, medicine, Humans, naturally acquired immunity, RTS,S, Infant, biology.organism_classification, medicine.disease, Malaria, 030104 developmental biology, Immunoglobulin G, biology.protein, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, lcsh:RC581-607, 030215 immunology
Abstract: Naturally acquired immunity (NAI) to Plasmodium falciparum malaria is mainly mediated by IgG antibodies but the subclasses, epitope targets and effector functions have not been unequivocally defined. Dissecting the type and specificity of antibody responses mediating NAI is a key step toward developing more effective vaccines to control the disease. We investigated the role of IgG subclasses to malaria antigens in protection against disease and the factors that affect their levels, including vaccination with RTS,S/AS01E. We analyzed plasma and serum samples at baseline and 1 month after primary vaccination with RTS,S or comparator in African children and infants participating in a phase 3 trial in two sites of different malaria transmission intensity: Kintampo in Ghana and Manhiça in Mozambique. We used quantitative suspension array technology (qSAT) to measure IgG1−4 responses to 35 P. falciparum pre-erythrocytic and blood stage antigens. Our results show that the pattern of IgG response is predominantly IgG1 or IgG3, with lower levels of IgG2 and IgG4. Age, site and RTS,S vaccination significantly affected antibody subclass levels to different antigens and susceptibility to clinical malaria. Univariable and multivariable analysis showed associations with protection mainly for cytophilic IgG3 levels to selected antigens, followed by IgG1 levels and, unexpectedly, also with IgG4 levels, mainly to antigens that increased upon RTS,S vaccination such as MSP5 and MSP1 block 2, among others. In contrast, IgG2 was associated with malaria risk. Stratified analysis in RTS,S vaccinees pointed to novel associations of IgG4 responses with immunity mainly involving pre-erythrocytic antigens upon RTS,S vaccination. Multi-marker analysis revealed a significant contribution of IgG3 responses to malaria protection and IgG2 responses to malaria risk. We propose that the pattern of cytophilic and non-cytophilic IgG antibodies is antigen-dependent and more complex than initially thought, and that mechanisms of both types of subclasses could be involved in protection. Our data also suggests that RTS,S efficacy is significantly affected by NAI, and indicates that RTS,S vaccination significantly alters NAI.
Published: 2019

23. RTS,S/AS01E immunization increases antibody responses to vaccine-unrelated Plasmodium falciparum antigens associated with protection against clinical malaria in African children: a case-control study

Author: Núria Díez-Padrisa, Chenjerai Jairoce, Nana Aba Williams, Benoit Gamain, Ben Gyan, James G. Beeson, Alfons Jiménez, Evelina Angov, Kwaku Poku Asante, Rebeca Santano, Deepak Gaur, Ruth Aguilar, Aintzane Ayestaran, Clarissa Valim, Ross L. Coppel, David Dosoo, Seth Owusu-Agyei, Joseph J. Campo, David E. Lanar, Itziar Ubillos, Marta Vidal, David R. Cavanagh, Augusto Nhabomba, Virander S. Chauhan, Sheetij Dutta, Carlota Dobaño, Gemma Moncunill, Chetan E. Chitnis, Universitat de Barcelona (UB), Centro de Investigação em Saúde de Manhiça [Maputo, Mozambique] (CISM), University of Ghana, Kintampo Health Research Centre, Ghana, CIBER de Epidemiología y Salud Pública (CIBERESP), Walter Reed Army Institute of Research, International Centre for Genetic Engineering and Biotechnology [New Delhi] (ICGEB), Biologie de Plasmodium et Vaccins - Malaria Parasite Biology and Vaccines, Institut Pasteur [Paris], Jawaharlal Nehru University (JNU), Department of Immunology and Infectious Diseases (IID), Harvard T.H. Chan School of Public Health, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Monash University [Melbourne], University of Edinburgh, The Macfarlane Burnet Institute for Medical Research and Public Health [Melbourne], Funding was obtained from the NIH-NIAID (R01AI095789), PATH Malaria Vaccine Initiative (MVI), Ministerio de Economía y Competitividad (Instituto de Salud Carlos III, PI11/00423 and PI14/01422), and EVIMalaR and AGAUR-Catalonia (2014 SGR991). GM was a recipient of a Sara Borrell—ISCIII fellowship (CD010/00156) and had the support of the Department of Health, Catalan Government (SLT006/17/00109). ISGlobal is a member of the CERCA Program, Generalitat de Catalunya., Biologie de Plasmodium et Vaccins, Department of Immunology and Infectious Diseases, Harvard School of Public Health, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université de La Réunion (UR)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Transfusion Sanguine [Paris] (INTS), Institut Pasteur [Paris] (IP), and Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)
Subjects: Male, lcsh:Medicine, Antibodies, Protozoan, 0302 clinical medicine, Pre-erythrocytic antigens, antibody, RTS,S, Medicine, 030212 general & internal medicine, Malaria, Falciparum, Child, Children, Protection, biology, Malaria vaccine, Vaccination, General Medicine, Acquired immune system, protection, 3. Good health, Blood-stage antigens, Child, Preschool, Female, Infants, Research Article, Naturally acquired immunity, Plasmodium falciparum, malaria, Malària, Àfrica, Antigens, Protozoan, RTS, 03 medical and health sciences, Immune system, Antigen, parasitic diseases, Malaria Vaccines, Humans, Antibody, Maternal antibodies, business.industry, lcsh:R, Infant, biology.organism_classification, medicine.disease, Malaria, maternal antibodies, Case-Control Studies, Immunology, Africa, Antibody Formation, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, business, Vaccine, 030217 neurology & neurosurgery
Abstract: Background Vaccination and naturally acquired immunity against microbial pathogens may have complex interactions that influence disease outcomes. To date, only vaccine-specific immune responses have routinely been investigated in malaria vaccine trials conducted in endemic areas. We hypothesized that RTS,S/A01E immunization affects acquisition of antibodies to Plasmodium falciparum antigens not included in the vaccine and that such responses have an impact on overall malaria protective immunity. Methods We evaluated IgM and IgG responses to 38 P. falciparum proteins putatively involved in naturally acquired immunity to malaria in 195 young children participating in a case-control study nested within the African phase 3 clinical trial of RTS,S/AS01E (MAL055 NCT00866619) in two sites of different transmission intensity (Kintampo high and Manhiça moderate/low). We measured antibody levels by quantitative suspension array technology and applied regression models, multimarker analysis, and machine learning techniques to analyze factors affecting their levels and correlates of protection. Results RTS,S/AS01E immunization decreased antibody responses to parasite antigens considered as markers of exposure (MSP142, AMA1) and levels correlated with risk of clinical malaria over 1-year follow-up. In addition, we show for the first time that RTS,S vaccination increased IgG levels to a specific group of pre-erythrocytic and blood-stage antigens (MSP5, MSP1 block 2, RH4.2, EBA140, and SSP2/TRAP) which levels correlated with protection against clinical malaria (odds ratio [95% confidence interval] 0.53 [0.3–0.93], p = 0.03, for MSP1; 0.52 [0.26–0.98], p = 0.05, for SSP2) in multivariable logistic regression analyses. Conclusions Increased antibody responses to specific P. falciparum antigens in subjects immunized with this partially efficacious vaccine upon natural infection may contribute to overall protective immunity against malaria. Inclusion of such antigens in multivalent constructs could result in more efficacious second-generation multistage vaccines. Electronic supplementary material The online version of this article (10.1186/s12916-019-1378-6) contains supplementary material, which is available to authorized users.
Published: 2019

24. Prediction of the intestinal resistome by a three-dimensional structure-based method

Author: Willem van Schaik, Kevin Weiszer, Nicolas Maziers, Hervé M. Blottière, Luis Máiz, Nicolas Pons, Fernando Baquero, S. Dusko Ehrlich, Bruno Fantin, José L. Martínez, Amine Ghozlane, Julien Tap, Malbert R. C. Rogers, Pierre Leonard, Rob J. L. Willems, Anne-Sophie Alvarez, Florence Haimet, Etienne Ruppé, Sara Hernando-Amado, Victoire de Lastours, Alexandre G. de Brevern, Tiphaine Goulenok, Ingrid Wieder, Xinglin Zhang, Antoine Andremont, Trinidad Cuesta, Véronique Léjard, Jean-Michel Batto, Aline Letur, Nawal Amor, Joël Doré, Val F. Lanza, Teresa M. Coque, Florence Levenez, Irene Clares, Sean Kennedy, MetaGenoPolis, Institut National de la Recherche Agronomique (INRA), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Biomics, Centre de Recherche et Innovation Technologique (CITECH), Institut Pasteur [Paris] (IP)-Institut Pasteur [Paris] (IP), Centro Nacional de Biotecnología [Madrid] (CNB-CSIC), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Instituto Ramon y Cajal de Investigacion Sanitaria [Madrid, Spain] (IRYCIS), Universidad de Alcalá - University of Alcalá (UAH), CIBER de Epidemiología y Salud Pública (CIBERESP), Hospital Universitario Ramón y Cajal [Madrid], Service de Médecine Interne [AP-HP, CHU Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Bactériologie [AP-HP Hôpital Bichat-Claude Bernard], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University Medical Center [Utrecht], University of Birmingham [Birmingham], 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), King‘s College London, The project was funded in part by the European Union Seventh Framework Programme (FP7-HEALTH-2011-single-stage) under grant agreement number 282004, EvoTAR. IRYCIS authors acknowledge the European Development Regional Fund ‘A way to achieve Europe’ for co-founding the Spanish R&D National Plan 2012–2019 Work (PI15-0512), CIBER (CIBERESP, CB06/02/0053) and the Government of Madrid (InGeMICS- B2017/BMD-3691). V.F.L. was further funded by a Research Award Grant 2016 of the European Society for Clinical Microbiology and Infectious Diseases., The authors are grateful to the GENOTOUL (Toulouse, France), GENOUEST (Rennes, France), ABIMS (Roscoff, France), MIGALE (Jouy-en-Josas) and TGCC-GENCI (Institut Curie) calculation clusters. The authors also thank B. Perichon (Institut Pasteur, Paris, France) for providing ARD sequences from Acinetobacter baumannii, P. Siguier (CNRS, Toulouse, France) for helping the search of insertion sequences with ISfinder, J. Guglielmini (Institut Pasteur, Paris, France) for his assistance in finding conjugative elements, S. Volant (Institut Pasteur, Paris, France) for the design of the statistical model in SHAMAN, T. Jové (University of Limoges, France) for his assistance in finding integrons, M. Petitjean (IAME Research Center, Paris, France) for her assistance in bioinformatic analyses, and F. Plaza-Oñate and M. Almeida for their help with MSPs., European Project: 282004,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,EVOTAR(2011), European Commission, Instituto de Salud Carlos III, Comunidad de Madrid, European Society of Clinical Microbiology and Infectious Diseases, Kennedy, Sean, Evolution and Transfer of Antibiotic Resistance - EVOTAR - - EC:FP7:HEALTH2011-10-01 - 2015-09-30 - 282004 - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Institut Pasteur [Paris], Biocomputing Unit [Madrid], 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: ARDS, Protein Conformation, microbiome, Drug resistance, Antimicrobial resistance, Applied Microbiology and Biotechnology, MESH: Anti-Bacterial Agents/pharmacology, MESH: Intestines/microbiology, bacteria, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], Genetics, MESH: Protein Conformation, 0303 health sciences, antibiotic-resistance genes, MESH: Gastrointestinal Microbiome/genetics, tool, alignment, Anti-Bacterial Agents, 3. Good health, MESH: Bacteria/drug effects, Intestines, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Enterotype, reveals, MESH: Bacterial Proteins/chemistry, Microbiology (medical), reservoir, Immunology, MESH: Bacteria/genetics, Biology, MESH: beta-Lactamases/chemistry, MESH: Bacterial Proteins/genetics, Microbiology, beta-Lactamases, web, Bacterial genetics, 03 medical and health sciences, models, Antibiotic resistance, Bacterial Proteins, Drug Resistance, Bacterial, medicine, Microbiome, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, 030304 developmental biology, 030306 microbiology, Cell Biology, medicine.disease, Gastrointestinal Microbiome, Resistome, Computational biology and bioinformatics, MESH: beta-Lactamases/genetics, MESH: Drug Resistance, Bacterial/genetics, MESH: Bacteria/classification, identification, Mobile genetic elements, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: The intestinal microbiota is considered to be a major reservoir of antibiotic resistance determinants (ARDs) that could potentially be transferred to bacterial pathogens via mobile genetic elements. Yet, this assumption is poorly supported by empirical evidence due to the distant homologies between known ARDs (mostly from culturable bacteria) and ARDs from the intestinal microbiota. Consequently, an accurate census of intestinal ARDs (that is, the intestinal resistome) has not yet been fully determined. For this purpose, we developed and validated an annotation method (called pairwise comparative modelling) on the basis of a three-dimensional structure (homology comparative modelling), leading to the prediction of 6,095 ARDs in a catalogue of 3.9 million proteins from the human intestinal microbiota. We found that the majority of predicted ARDs (pdARDs) were distantly related to known ARDs (mean amino acid identity 29.8%) and found little evidence supporting their transfer between species. According to the composition of their resistome, we were able to cluster subjects from the MetaHIT cohort (n = 663) into six resistotypes that were connected to the previously described enterotypes. Finally, we found that the relative abundance of pdARDs was positively associated with gene richness, but not when subjects were exposed to antibiotics. Altogether, our results indicate that the majority of intestinal microbiota ARDs can be considered intrinsic to the dominant commensal microbiota and that these genes are rarely shared with bacterial pathogens., The project was funded in part by the European Union Seventh Framework Programme (FP7-HEALTH-2011-single-stage) under grant agreement number 282004, EvoTAR. IRYCIS authors acknowledge the European Development Regional Fund ‘A way to achieve Europe’ for co-founding the Spanish R&D National Plan 2012–2019 Work (PI15-0512), CIBER (CIBERESP; CB06/02/0053) and the Government of Madrid (InGeMICS- B2017/BMD-3691). V.F.L. was further funded by a Research Award Grant 2016 of the European Society for Clinical Microbiology and Infectious Diseases.
Published: 2019

25. Unexpected macrophage-independent dyserythropoiesis in Gaucher disease

Author: Olivier Hermine, Nadia Belmatoug, Nelly Reihani, Thierry Billette de Villemeur, Christian Rose, Yves Colin-Aronovicz, Mélanie Franco, Caroline Le Van Kim, Jean-Benoît Arlet, Michael Dussiot, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpitaux Universitaires Paris Nord Val de Seine, Université catholique de Lille - Faculté de médecine et de maïeutique (UCL FMM), Université catholique de Lille (UCL), Biologie Intégrée du Globule Rouge ( BIGR ), Institut National de la Transfusion Sanguine [Paris] ( INTS ) -Université Paris Diderot - Paris 7 ( UPD7 ) -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 ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Université catholique de Lille - Faculté de médecine et de maïeutique ( UCL FMM ), Université catholique de Lille ( UCL ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université de La Réunion (UR)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Transfusion Sanguine [Paris] (INTS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP]
Subjects: Erythrocyte Indices, Male, 0301 basic medicine, Ineffective erythropoiesis, Erythroblasts, Anemia, Cellular differentiation, Biology, medicine.disease_cause, Immunophenotyping, Colony-Forming Units Assay, 03 medical and health sciences, Reticulocyte, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, medicine, Humans, Erythropoiesis, Child, Erythroid Precursor Cells, Cell Proliferation, Gaucher Disease, Macrophages, Cell Differentiation, Articles, Hematology, medicine.disease, Coculture Techniques, 3. Good health, Phenotype, 030104 developmental biology, medicine.anatomical_structure, Child, Preschool, Immunology, Female, Glucocerebrosidase, Biomarkers, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Gaucher disease is a rare inherited disease caused by a deficiency in glucocerebrosidase leading to lipid accumulation in cells of mononuclear-macrophage lineage known as Gaucher cells. Visceral enlargement, bone involvement, mild anemia and thrombocytopenia are the major manifestations of Gaucher disease. We have previously demonstrated that the red blood cells from patients exhibit abnormal properties, which indicates a new role in Gaucher disease pathophysiology. To investigate whether erythroid progenitors are affected, we examined the in vitro erythropoiesis from the peripheral CD34+ cells of patients and controls. CD34− cells were differentiated into macrophages and co-cultivated with erythroblasts. We showed an accelerated differentiation of erythroid progenitors without maturation arrest from patients compared to controls. This abnormal differentiation persisted in the patients when the same experiments were performed without macrophages, which strongly suggested that dyserythropoiesis in Gaucher disease is secondary to an inherent defect in the erythroid progenitors. The accelerated differentiation was associated with reduced cell proliferation. As a result, less mature erythroid cells were generated in vitro in the Gaucher disease cultures compared to the control. We then compared the biological characteristics of untreated patients according to their anemic status. Compared to the non-anemic group, the anemic patients exhibit higher plasma levels of growth differentiation factor-15, a marker of ineffective erythropoiesis, but they had no indicators of hemolysis and similar reticulocyte counts. Taken together, these results demonstrated an unsuspected dyserythropoiesis that was independent of the macrophages and could participate, at least in part, to the basis of anemia in Gaucher disease.
Published: 2016

26. Holding the Nucleosome Together: A Quantitative Description of the DNA–Histone Interface in Solution

Author: Brigitte Hartmann, Romain Retureau, Christophe Oguey, Ahmad Elbahnsi, Marc Baaden, Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie théorique [Paris] (LBT (UPR_9080)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut de biologie physico-chimique (IBPC (FR_550)), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Laboratoire de Physique Théorique et Modélisation (LPTM - UMR 8089), Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), ANR-11-LABX-0011,DYNAMO,Dynamique des membranes transductrices d'énergie : biogénèse et organisation supramoléculaire.(2011), Université Paris Diderot - Paris 7 (UPD7)-Institut de biologie physico-chimique (IBPC), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Dynamique des Structures et Interactions des Macromolécules Biologiques - Pôle de La Réunion (DSIMB Réunion), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université de La Réunion (UR)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université de La Réunion (UR)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Transfusion Sanguine [Paris] (INTS), Université de Cergy Pontoise (UCP), and Université Paris-Seine-Université Paris-Seine-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Static Electricity, Molecular Dynamics Simulation, 01 natural sciences, Histones, 03 medical and health sciences, Molecular dynamics, chemistry.chemical_compound, 0103 physical sciences, Nucleosome, Physical and Theoretical Chemistry, Topology (chemistry), 010304 chemical physics, biology, Chemistry, Superhelix, DNA, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Nucleosomes, Computer Science Applications, Chromatin, Solutions, 030104 developmental biology, Histone, Helix, Biophysics, biology.protein
Abstract: International audience; The nucleosome is the fundamental unit of eukaryotic genome packaging in the chromatin. In this complex, the DNA wraps around eight histone proteins to form a superhelical double helix. The resulting bending, stronger than anything observed in free DNA, raises the question of how such a distortion is stabilized by the proteic and solvent environments. In this work, the DNA-histone interface in solution was exhaustively analyzed from nucleosome structures generated by molecular dynamics. An original Voronoi tessellation technique, measuring the topology of interacting elements without any empirical or subjective adjustment, was used to characterize the interface in terms of contact area and occurrence. Our results revealed an interface more robust than previously known, combining extensive, long-lived nonelectrostatic and electrostatic interactions between DNA and both structured and unstructured histone regions. Cation accumulation makes the proximity of juxtaposed DNA gyres in the superhelix possible by shielding the strong electrostatic repulsion of the charged phosphate groups. Overall, this study provides new insights on the nucleosome cohesion, explaining how DNA distortions can be maintained in a nucleoprotein complex.
Published: 2018

27. Human erythrocytes release ATP by a novel pathway involving VDAC oligomerization independent of pannexin-1

Author: Irene Marginedas-Freixa, Pablo J. Schwarzbaum, Isabelle Mouro-Chanteloup, Caroline Le Van Kim, María Florencia Leal Denis, François Hallé, Sophie D. Lefevre, Frédéric Bihel, Cora Lilia Alvarez, Claude Hattab, Martina Moras, Mariano A. Ostuni, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Universidad de Buenos Aires [Buenos Aires] (UBA), Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Laboratoire d'Innovation Thérapeutique (LIT), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC), Protéines de la membrane érythrocytaire et homologues non-érythroides, Université des Antilles et de la Guyane (UAG)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Transfusion Sanguine [Paris] (INTS), BIHEL, Frédéric, and Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Erythrocytes, CIENCIAS MÉDICAS Y DE LA SALUD, Voltage-dependent anion channel, purl.org/becyt/ford/3.5 [https], lcsh:Medicine, Nerve Tissue Proteins, EXTRACELLULAR ATP, Ligands, Models, Biological, Connexins, Article, Polymerization, 03 medical and health sciences, Adenosine Triphosphate, Receptors, GABA, Adenine nucleotide, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, Voltage-Dependent Anion Channels, Translocase, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, lcsh:Science, Protein Kinase C, Protein kinase C, Multidisciplinary, biology, VDAC, Kinase, Chemistry, lcsh:R, Adenine Nucleotide Translocator 1, PANNEXIN 1, Membrane transport, Cyclic AMP-Dependent Protein Kinases, ANT, Otras Ciencias Médicas, Kinetics, 030104 developmental biology, biology.protein, Biophysics, Calcium, purl.org/becyt/ford/3 [https], lcsh:Q, Protein Multimerization, NUCLEOTIDASES, Intracellular
Abstract: We previously demonstrated that the translocase protein TSPO2 together with the voltage-dependentanion channel (VDAC) and adenine nucleotide transporter (ANT) were involved in a membrane transportcomplex in human red blood cells (RBCs). Because VDAC was proposed as a channel mediating ATPrelease in RBCs, we used TSPO ligands together with VDAC and ANT inhibitors to test this hypothesis.ATP release was activated by TSPO ligands, and blocked by inhibitors of VDAC and ANT, while it wasinsensitive to pannexin-1 blockers. TSPO ligand increased extracellular ATP (ATPe) concentration by 24?59% over the basal values, displaying an acute increase in [ATPe] to a maximal value, which remainedconstant thereafter. ATPe kinetics were compatible with VDAC mediating a fast but transient ATPefflux. ATP release was strongly inhibited by PKC and PKA inhibitors as well as by depleting intracellularcAMP or extracellular Ca2+, suggesting a mechanism involving protein kinases. TSPO ligands favouredVDAC polymerization yielding significantly higher densities of oligomeric bands than in unstimulatedcells. Polymerization was partially inhibited by decreasing Ca2+ and cAMP contents. The present resultsshow that TSPO ligands induce polymerization of VDAC, coupled to activation of ATP release by asupramolecular complex involving VDAC, TSPO2 and ANT. Fil: Marginedas Freixa, Irene. Université Paris Diderot - Paris 7; Francia. Institut National de la Transfusion Sanguine; . Université de la Réunion; Francia. Université des Antilles; Francia Fil: Alvarez, Cora Lilia. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Biodiversidad y Biología Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentina Fil: Moras, Martina. Institut National de la Transfusion Sanguine; . Université des Antilles; Francia. Université Paris Diderot - Paris 7; Francia. Université de la Réunion; Francia Fil: Leal Denis, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Analítica y Fisicoquímica. Cátedra de Química Analítica; Argentina Fil: Hattab, Claude. Université de la Réunion; Francia. Université Paris Diderot - Paris 7; Francia. Université des Antilles; Francia. Institut National de la Transfusion Sanguine; Fil: Halle, François. University of Strasbourg; Francia Fil: Bihel, Frédéric. Université de Strasbourg; Francia Fil: Mouro Chanteloup, Isabelle. Université des Antilles; Francia. Institut National de la Transfusion Sanguine; . Université de la Réunion; Francia. Université Paris Diderot - Paris 7; Francia Fil: Lefevre, Sophie Denise. Université Paris Diderot - Paris 7; Francia. Université des Antilles; Francia. Université de la Réunion; Francia. Institut National de la Transfusion Sanguine; Fil: Le Van Kim, Caroline. Université des Antilles; Francia. Université de la Réunion; Francia. Institut National de la Transfusion Sanguine; . Université Paris Diderot - Paris 7; Francia Fil: Schwarzbaum, Pablo Julio. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentina Fil: Ostuni, Mariano. Université Paris Diderot - Paris 7; Francia. Université de la Réunion; Francia. Université des Antilles; Francia. Institut National de la Transfusion Sanguine
Published: 2018

28. Characterization of a new human monoclonal antibody directed against the Vel antigen

Author: Sophie Danard, Y. Danger, F. Vérité, Vanessa Gringoire, P. Riou, G. Semana, T. Peyrard, Etablissement français du sang [Rennes] (EFS Bretagne), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-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 ), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Université de Rennes (UR)-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 ), and Jonchère, Laurent
Subjects: 0301 basic medicine, medicine.drug_class, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, Biology, Monoclonal antibody, Vel blood group antigen, Flow cytometry, Serology, 03 medical and health sciences, 0302 clinical medicine, Western blot, Antigen, medicine, Humans, medicine.diagnostic_test, Antibodies, Monoclonal, Membrane Proteins, SMIM1, Hematology, General Medicine, Molecular biology, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Monoclonal, Blood Group Antigens, biology.protein, Female, human monoclonal antibody, Antibody, Clone (B-cell biology)
Abstract: International audience; BACKGROUND AND OBJECTIVES: The Vel blood group antigen is a poorly characterized high-prevalence antigen. Until now, anti-Vel antibodies have been observed in only alloimmunized Vel-negative individuals. In this study, we aimed to establish a human hybridoma cell line secreting the first anti-Vel monoclonal antibody (mAb), clone SpG213Dc. MATERIALS AND METHODS: Peripheral blood lymphocytes from a French Vel-negative woman with anti-Vel in her plasma were transformed with Epstein-Barr virus and then hybridized with the myeloma cell line Sp2/O-Ag14 using the polyethylene glycol (PEG) method. A specific anti-Vel mAb was successfully produced and was extensively characterized by serological, flow cytometry and Western blot analyses. RESULTS: One human anti-Vel-secreting clone was produced and the secreted anti-Vel mAb (SpG213Dc) was examined. The specificity of the SpG213Dc mAb was assessed by its reactivity against a panel of nine genotyped RBCs including, respectively, three Vel-negative and six Vel-positive (three wild-type homozygous and three heterozygous) samples using flow cytometry method. Vel-positive RBCs were specifically stained and were subsequently used to perform Western blot and immunoprecipitation analysis of the Vel antigen. CONCLUSION: Serological characterization of the new monoclonal anti-Vel SpG213Dc showed a heterogeneous level of expression of the Vel antigen on the different RBCs. Our results suggest that the mAb SpG213Dc can be reliably used as a blood grouping reagent, thus allowing the mass-scale phenotyping of blood donors to strengthen rare blood banks with Vel-negative RBC units
Published: 2015

29. Association between oxidative stress and vascular reactivity in children with sickle cell anaemia and sickle haemoglobin C disease

Author: Olivier Hue, Vincent Pialoux, Stéphane Jumet, Sophie Antoine, Vanessa Tarer, Maryse Etienne-Julan, Marc Romana, Philippe Connes, Marie-Dominique Hardy-Dessources, Marie Petras, Berenike Möckesch, Cyril Martin, Benoit Tressières, Sarah Skinner, Keyne Charlot, Lydia Divialle-Doumdo, Université des Antilles (Pôle Guadeloupe), Université des Antilles (UA), Dynamique des Structures et Interactions des Macromolécules Biologiques - Pôle de La Réunion (DSIMB Réunion), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université de La Réunion (UR)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université de La Réunion (UR)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Transfusion Sanguine [Paris] (INTS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université de La Réunion (UR)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Transfusion Sanguine [Paris] (INTS), Protéines de la membrane érythrocytaire et homologues non-érythroides, Université des Antilles et de la Guyane (UAG)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Adaptation, Climat Tropical, Exercice et Santé (ACTES), Unité Transversale de la Drépanocytose, CHU Pointe-à-Pitre/Abymes [Guadeloupe], Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM ), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM), Centre d'Investigation Clinique Antilles-Guyane (CIC - Antilles Guyane), Université des Antilles et de la Guyane (UAG)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Service d'Orthopédie et de Traumatologie, Université des Antilles et de la Guyane (UAG)-CHU Pointe-à-Pitre/Abymes [Guadeloupe], Pharmacogénétique et abords thérapeutiques des maladies héréditaires, Université des Antilles et de la Guyane (UAG)-Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Hôpital Ricou, CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles et de la Guyane (UAG), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), and CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française]-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles et de la Guyane (UAG)
Subjects: Male, 0301 basic medicine, Antioxidant, medicine.medical_treatment, medicine.disease_cause, vascular function, Antioxidants, chemistry.chemical_compound, 0302 clinical medicine, Malondialdehyde, Laser-Doppler Flowmetry, Child, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, Endothelin-1, biology, Glutathione peroxidase, Nitrotyrosine, Hematology, Blood Viscosity, Haemolysis, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Advanced Oxidation Protein Products, Catalase, Female, haemolysis, medicine.medical_specialty, Adolescent, Anemia, Sickle Cell, Nitric Oxide, Hemolysis, Nitric oxide, Fingers, 03 medical and health sciences, Internal medicine, medicine, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, Microcirculation, Oxidative Stress, 030104 developmental biology, Endocrinology, chemistry, Case-Control Studies, Immunology, biology.protein, sickle cell disease, Hemoglobin SC Disease, Oxidative stress, 030215 immunology
Abstract: International audience; Oxidative stress and haemolysis-associated nitric oxide (NO) depletion plays a crucial role in the development of vasculopathy in sickle cell anaemia (SS). However it remains unknown whether oxidative stress and haemolysis levels influence vascular function in patients with sickle haemoglobin C disease (SC). Microvascular response to heat (using Laser Doppler flowmetry on finger), oxidative stress biomarkers, NO metabolites, endothelin-1 and haematological parameters were compared between patients with SS and SC. Vascular function, oxidative and nitrosative markers were also measured in healthy (AA) children. SS and SC had increased plasma advanced oxidation protein products (AOPP), malondialdehyde, plasma antioxidant activities and NO end products, compared to AA. SC had lower catalase activity compared to AA and SS. Haemolytic rate, glutathione peroxidase and nitrotyrosine concentrations were significantly increased in children with SS compared to SC and AA. SS and SC had impaired microvascular reactivity compared to AA. In SS, the plateau phase of the response to local thermal heating was negatively associated with nitrotyrosine and AOPP. No association between vascular function parameters and oxidative stress markers was observed in SC. Mild haemolysis in SC, compared to SS, may limit oxidative and nitrosative stress and could explain the better preserved microvascular function in this group.
Published: 2017

30. Bioinformatic analysis of the protein/DNA interface

Author: Daniel Svozil, Jiří Černý, Bohdan Schneider, Alexandre G. de Brevern, Agnel Praveen Joseph, Jean-Christophe Gelly, de Brevern, Alexandre G., Institute of Biotechnology AS CR, Laboratory of Informatics and Chemistry, Institute of Chemical Technology [Prague] (ICT), GR-Ex, Laboratoire d'Excellence, GR-Ex, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Czech-France collaboration Barrande [MEB021032], BIOCEV CZ.1.05/1.1.00/02.0109 from the ERDF, [P305/ 80 12/1801] from the Czech Science Foundation, and institutional [AV0Z50520701], supported by [MSM 6046137302 to D.S. and P.Č.], and supported by the Ministry of Research (France), University Paris Diderot, Sorbonne Paris Cité (France), National Institute of Blood Transfusion (INTS, France), National Institute of Health and Medical Research (INSERM, France) and 'Investissements d'avenir', Laboratories of Excellence GR-Ex (France) (to J.C.G. and A.G.dB.). Funding for open access charge: Czech Science Foundation and Academy of Sciences of the Czech Republic.
Subjects: Models, Molecular, Protein Conformation, DNA interface, Crystal structure, Plasma protein binding, Pentapeptide repeat, chemistry.chemical_compound, 0302 clinical medicine, structural alphabet: Protein Blocks, MESH: Protein Conformation, Protein structure, Structural Biology, Structural motif, Conformational isomerism, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], Genetics, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], MESH: DNA, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], DNA-Binding Proteins, MESH: Nucleic Acid Conformation, Naked DNA, Data Interpretation, Statistical, MESH: Phosphates, MESH: Models, Molecular, Protein Binding, MESH: Computational Biology, Stereochemistry, Biophysics, Biology, DNA-binding protein, Phosphates, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Water, MESH: Protein Binding, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Transcription factor, 030304 developmental biology, Computational Biology, Water, DNA structure, DNA, Base (topology), Crystallography, chemistry, protein structures, Nucleic acid, Nucleic Acid Conformation, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], DNA interactions, protein, MESH: Data Interpretation, Statistical, 030217 neurology & neurosurgery, MESH: DNA-Binding Proteins
Abstract: Despite extensive studies of the geometry of protein/DNA interfaces the understanding of the affinity and specificity of the protein/DNA interactions remains elusive. We present a novel approach to geometric analysis of protein/nucleic acid interfaces that is based on classification of their local conformations. Protein structures are divided into a series of pentapeptide fragments and each is assigned one of 16 conformers or ‘protein blocks’ [de Brevern et al. Proteins 41, 271 (2000)]. Similarly, each DNA step (unit [base]sugar-phosphate-sugar[base]) is assigned one of ∼20 DNA conformers [Svozil et al. NAR 36, 3690 (2008)]. Significantly, local structures classified into distinct conformers can be represented by symbols so that they can be analyzed more easily than complicated 3D objects. Size of the fragments used for the classification allows analysis of structural features of the interface at a scale intermediate between too detailed interatomic contacts on one side and too crude protein motifs (helix-turn-helix, Zn-finger, ...) on the other. We will present correlations between protein and DNA conformers at their interface from more than 15 hundred protein/DNA crystal structures broken by various criteria of the analyzed structures as protein functional classification, e.g. in GO or Pfam or by crystallographic properties, resolution or overall structure quality.Acknowledgments. This work was supported by Czech-France collaboration Barrande (MEB021032) and Czech Science Foundation (P305/10/2184).
Published: 2013

31. JAK2V617F activates Lu/BCAM-mediated red cell adhesion in polycythemia vera through an EpoR-independent Rap1/Akt pathway

Author: Marie-Paule Wautier, Wassim El Nemer, Marie Cambot, Bruno Cassinat, Maria De Grandis, Jean-Luc Wautier, Christine Chomienne, Yves Colin, Caroline Le Van Kim, Protéines de la membrane érythrocytaire et homologues non-érythroides, Université des Antilles et de la Guyane (UAG)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), GR-Ex, Laboratoire d'Excellence, Institut National de la Transfusion Sanguine [Paris] (INTS), Unite de Biologie Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hématologie -Immunologie -Cibles thérapeutiques, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and The work was funded by the Institut National de la Santé et de la Recherche Médicale (Inserm), the Institut National de la Transfusion Sanguine (INTS), and a grant from Région Île-de-France (SESAME 2007 no. F-08-1104/R). The PhD student, Maria De Grandis, was funded by the Ministère de l'Enseignement Supérieur et de la Recherche at the Ecole Doctorale B3MI.
Subjects: Male, MESH: Signal Transduction, Erythrocytes, MESH: rap1 GTP-Binding Proteins, MESH: Polycythemia Vera, Biochemistry, MESH: Janus Kinase 2, Mice, MESH: Aged, 80 and over, 0302 clinical medicine, Receptors, Erythropoietin, MESH: Animals, Phosphorylation, Polycythemia Vera, Aged, 80 and over, MESH: Aged, 0303 health sciences, MESH: Middle Aged, Janus kinase 2, biology, Cell adhesion molecule, MESH: Erythrocytes, rap1 GTP-Binding Proteins, MESH: Laminin, Hematology, Middle Aged, Lutheran Blood-Group System, MESH: Lutheran Blood-Group System, 030220 oncology & carcinogenesis, MESH: Cell Adhesion Molecules, Female, Signal Transduction, Immunology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Cell Line, MESH: Cell Adhesion, 03 medical and health sciences, BCAM, Cell Adhesion, Animals, Humans, MESH: Receptors, Erythropoietin, Cell adhesion, MESH: Mice, Protein kinase B, PI3K/AKT/mTOR pathway, Aged, 030304 developmental biology, MESH: Humans, MESH: Phosphorylation, MESH: Proto-Oncogene Proteins c-akt, Akt/PKB signaling pathway, Cell Biology, Janus Kinase 2, Molecular biology, MESH: Male, MESH: Cell Line, Erythropoietin receptor, biology.protein, Laminin, Cell Adhesion Molecules, Proto-Oncogene Proteins c-akt, MESH: Female
Abstract: Polycythemia vera (PV) is characterized by an increased RBC mass, spontaneous erythroid colony formation, and the JAK2V617F mutation. PV is associated with a high risk of mesenteric and cerebral thrombosis. PV RBC adhesion to endothelial laminin is increased and mediated by phosphorylated erythroid Lu/BCAM. In the present work, we investigated the mechanism responsible for Lu/BCAM phosphorylation in the presence of JAK2V617F using HEL and BaF3 cell lines as well as RBCs from patients with PV. High levels of Rap1-GTP were found in HEL and BaF3 cells expressing JAK2V617F compared with BaF3 cells with wild-type JAK2. This finding was associated with increased Akt activity, Lu/BCAM phosphorylation, and cell adhesion to laminin that were inhibited by the dominant-negative Rap1S17N or by the specific Rap1 inhibitor GGTI-298. Surprisingly, knocking-down EpoR in HEL cells did not alter Akt activity or cell adhesion to laminin. Our findings reveal a novel EpoR-independent Rap1/Akt signaling pathway that is activated by JAK2V617F in circulating PV RBCs and responsible for Lu/BCAM activation. This new characteristic of JAK2V617F could play a critical role in initiating abnormal interactions among circulating and endothelial cells in patients with PV.
Published: 2013

32. Insights into Brain Glycogen Metabolism

Author: Thibaut Léger, Gary Woffendin, Ahmed Haouz, Angélique Cocaign, Cécile Mathieu, Jean-Michel Camadro, Jean-Marie Dupret, Catherine Etchebest, Ximing Xu, Romain Duval, Fernando Rodrigues-Lima, Inès Li de la Sierra-Gallay, Université Sorbonne Paris Cité (USPC), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Thermo Fisher Scientific, GR-Ex, Laboratoire d'Excellence, GR-Ex, Université Paris Diderot - Paris 7 - UFR Sciences du Vivant (UPD7 UFR Sciences du Vivant), Université Paris Diderot - Paris 7 (UPD7), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), French Ministry of Research (Ecole Doctorale BioSPC), Région Ile de France (DIM), China Scholarship Council, University Paris Diderot, CNRS, Institut Pasteur, Université Sorbonne Paris Cité ( USPC ), Biologie Fonctionnelle et Adaptative ( BFA ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Institut Jacques Monod ( IJM ), UFR Sciences du Vivant [Paris] ( SDV ), Université Paris Diderot - Paris 7 ( UPD7 ), Biologie Intégrée du Globule Rouge ( BIGR ), and Institut National de la Transfusion Sanguine [Paris] ( INTS ) -Université Paris Diderot - Paris 7 ( UPD7 ) -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 )
Subjects: 0301 basic medicine, crystal structure, Glycogenolysis, glycogen metabolism, Biochemistry, Isozyme, Lafora disease (Lafora progressive myoclonic epilepsy, brain functions, Glycogen debranching enzyme, 03 medical and health sciences, chemistry.chemical_compound, Glycogen phosphorylase, 0302 clinical medicine, energy metabolism, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Phosphorylase kinase, Glycogen synthase, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, ComputingMilieux_MISCELLANEOUS, biology, Glycogen, MELF), Cell Biology, allosteric regulation, 030104 developmental biology, Allosteric enzyme, chemistry, brain metabolism, glycogen, biology.protein, 030217 neurology & neurosurgery
Abstract: International audience; Brain glycogen metabolism plays a critical role in major brain functions such as learning or memory consolidation. However, alteration of glycogen metabolism and glycogen accumulation in the brain contributes to neurodegeneration as observed in Lafora disease. Glycogen phosphorylase (GP), a key enzyme in glycogen metabolism, catalyzes the rate-limiting step of glyco-gen mobilization. Moreover, the allosteric regulation of the three GP isozymes (muscle, liver, and brain) by metabolites and phosphorylation, in response to hormonal signaling, fine-tunes glycogenolysis to fulfill energetic and metabolic requirements. Whereas the structures of muscle and liver GPs have been known for decades, the structure of brain GP (bGP) has remained elusive despite its critical role in brain glycogen metabolism. Here, we report the crystal structure of human bGP in complex with PEG 400 (2.5 A ˚) and in complex with its allos-teric activator AMP (3.4 A ˚). These structures demonstrate that bGP has a closer structural relationship with muscle GP, which is also activated by AMP, contrary to liver GP, which is not. Importantly, despite the structural similarities between human bGP and the two other mammalian isozymes, the bGP structures reveal molecular features unique to the brain isozyme that provide a deeper understanding of the differences in the activation properties of these allosteric enzymes by the allosteric effector AMP. Overall, our study further supports that the distinct structural and regulatory properties of GP isozymes contribute to the different functions of muscle, liver, and brain glycogen.
Published: 2016

33. Association of adenylyl cyclase 6 rs3730070 polymorphism and hemolytic level in patients with sickle cell anemia

Author: Nathalie Lemonne, Vanessa Tarer, Laura Brudey, Séverine Ferdinand, Kizzy-Clara Cita, Philippe Connes, Maryse Etienne-Julan, Jacques Elion, Benoit Tressières, Marc Romana, Observatoire Régional de la Santé de la Guadeloupe, Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Centre d'investigation clinique Antilles-Guyane (CIC - Antilles Guyane), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU de la Martinique [Fort de France]-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Laboratory of Excellence GR-Ex 'The red cell: from genesis to death', PRES Sorbonne Paris Cité, Unité Transversale de la Drépanocytose, CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Hôpital Ricou, Centre de référence maladies rares pour la drépanocytose aux Antilles-Guyane, CHU Pointe-à-Pitre/Abymes [Guadeloupe], Insern, UMR 763, Hôpital Robert Debré, Université Paris Diderot - Paris 7 (UPD7), Université des Antilles et de la Guyane (UAG), Hôpital Ricou-CHU Pointe-à-Pitre/Abymes [Guadeloupe], Dynamique des Structures et Interactions des Macromolécules Biologiques - Pôle de La Réunion (DSIMB Réunion), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM), Centre d'Investigation Clinique Antilles-Guyane (CIC - Antilles Guyane), Université des Antilles et de la Guyane (UAG)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Service d'Orthopédie et de Traumatologie, CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles et de la Guyane (UAG), Protéines de la membrane érythrocytaire et homologues non-érythroides, Université des Antilles et de la Guyane (UAG)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université de La Réunion (UR)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université de La Réunion (UR)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Transfusion Sanguine [Paris] (INTS), and Université des Antilles et de la Guyane (UAG)-CHU Pointe-à-Pitre/Abymes [Guadeloupe]
Subjects: Adult, Male, 0301 basic medicine, Adenosine, Adolescent, [SDV]Life Sciences [q-bio], Anemia, Sickle Cell, Biology, Polymorphism, Single Nucleotide, Hemolysis, Adenylyl cyclase, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Adenosine deaminase, alpha-Thalassemia, Lactate dehydrogenase, medicine, Humans, Child, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Hemolytic Index, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Biology, Hematology, Adenosine pathway, medicine.disease, Sickle cell anemia, 3. Good health, Cross-Sectional Studies, 030104 developmental biology, chemistry, Immunology, biology.protein, Molecular Medicine, Female, Adenosine A2B receptor, Adenylyl Cyclases, 030215 immunology, medicine.drug
Abstract: International audience; A recent study suggested that adenosine signaling pathway could promote hemolysis in patients with sickle cell anemia (SCA). This signaling pathway involves several gene coding enzymes for which variants have been described. In this study, we analyzed the genotype-phenotype relationships between functional polymorphisms or polymorphisms associated with altered expression of adenosine pathway genes, namely adenosine deaminase (ada; rs73598374), adenosine A2b receptor (adora2b; rs7208480), adenylyl cyclase6 (adcy6; rs3730071, rs3730070, rs7300155), and hemolytic rate in SCA patients. One hundred and fifty SCA patients were genotyped for adcy6, ada, and adora2b variants as well as alpha-globin gene, a genetic factor known to modulate hemolytic rate. Hematological and biochemical data were obtained at steady-state. Lactate dehydrogenase, aspartate aminotransferase, reticulocytes and total bilirubin were used to calculate a hemolytic index. Genotype-phenotype relationships were investigated using parametric tests and multivariate analysis. SCA patients carrying at least one allele of adcy6 rs3730070-G exhibited lower hemolytic rate than non-carriers in univariate analysis (p=0.006). The presence of adcy6 rs3730070-G variant was associated with a decreased hemolytic rate in adjusted model for age and alpha-thalassemia (p=0.032). Our results support a protective effect of adcy6 rs3730070-G variant on hemolysis in SCA patients.
Published: 2016

34. Effects of Poloxamer 188 on red blood cell membrane properties in sickle cell anaemia

Author: Bruno Le Pioufle, Miklos Rabai, Mickaël Marin, Philippe Connes, Barbara Sandor, Sophie D. Lefevre, Anaïs Mozar, Nathalie Lemonne, Olivier Français, Caroline Le Van Kim, Claudine Lapoumeroulie, Wassim El Nemer, Physiopathologie et traitement des maladies du foie, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Paul Brousse, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université de La Réunion (UR)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Transfusion Sanguine [Paris] (INTS), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Unité Transversale de la Drépanocytose, CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Hôpital Ricou, ESIEE Paris, Bio-MIcroSystèmes et BioSensors (SATIE-BIOMIS), Systèmes d'Information et d'Analyse Multi-Echelles (SIAME), Systèmes et Applications des Technologies de l'Information et de l'Energie (SATIE), École normale supérieure - Rennes (ENS Rennes)-Université Paris-Sud - Paris 11 (UP11)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Cachan (ENS Cachan)-Université Gustave Eiffel (UNIV GUSTAVE EIFFEL)-École normale supérieure - Rennes (ENS Rennes)-Université Paris-Sud - Paris 11 (UP11)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Cachan (ENS Cachan)-Université Gustave Eiffel (UNIV GUSTAVE EIFFEL)-Systèmes et Applications des Technologies de l'Information et de l'Energie (SATIE), Université Paris-Seine-Université Paris-Seine-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Cachan (ENS Cachan)-Université Gustave Eiffel (UNIV GUSTAVE EIFFEL), Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM ), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM), Dynamique des Structures et Interactions des Macromolécules Biologiques - Pôle de La Réunion (DSIMB Réunion), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université de La Réunion (UR)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université de La Réunion (UR)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Transfusion Sanguine [Paris] (INTS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Paul Brousse-Université Paris-Sud - Paris 11 (UP11), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), École normale supérieure - Cachan (ENS Cachan)-Université Paris-Sud - Paris 11 (UP11)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-École normale supérieure - Rennes (ENS Rennes)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Cachan (ENS Cachan)-Université Paris-Sud - Paris 11 (UP11)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-École normale supérieure - Rennes (ENS Rennes)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre National de la Recherche Scientifique (CNRS)-Systèmes et Applications des Technologies de l'Information et de l'Energie (SATIE), Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)
Subjects: Erythrocyte Aggregation, Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], Blood viscosity, Cell, Anemia, Sickle Cell, Poloxamer, 030204 cardiovascular system & hematology, Biology, Erythrocyte aggregation, 03 medical and health sciences, 0302 clinical medicine, Cell Adhesion, medicine, Humans, Clinical severity, Cell adhesion, ComputingMilieux_MISCELLANEOUS, Erythrocyte Membrane, Hematology, Blood Viscosity, 3. Good health, Red blood cell, 030104 developmental biology, medicine.anatomical_structure, Membrane, Immunology, Female
Abstract: Vaso-occlusive crisis (VOC) is the main acute complication in sickle cell anaemia (SS) and several clinical trials are investigating different drugs to improve the clinical severity of SS patients. A phase III study is currently exploring the profit of Velopoloxamer in SS during VOCs. We analysed, in-vitro, the effect of poloxamer (P188) on red blood cell (RBC) properties by investigating haemorheology, mechanical and adhesion functions using ektacytometry, microfluidics and dynamic adhesion approaches, respectively. We show that poloxamer significantly reduces blood viscosity, RBC aggregation and adhesion to endothelial cells, supporting the beneficial use of this molecule in SS therapy.
Published: 2016

35. Red blood cell nitric oxide synthase modulates red blood cell deformability in sickle cell anemia

Author: Marijke Grau, Marie-Dominique Hardy-Dessources, Wilhelm Bloch, Marc Romana, Anaïs Mozar, Philippe Connes, Bianca Collins, Nathalie Lemonne, Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Laboratory of Excellence GR-Ex 'The red cell: from genesis to death', PRES Sorbonne Paris Cité, Université des Antilles et de la Guyane (UAG), Unité Transversale de la Drépanocytose, Hôpital Ricou-CHU Pointe-à-Pitre/Abymes [Guadeloupe], Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université de La Réunion (UR)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université de La Réunion (UR)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Transfusion Sanguine [Paris] (INTS), and CHU Pointe-à-Pitre/Abymes [Guadeloupe]
Subjects: Male, medicine.medical_specialty, Erythrocytes, Physiology, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Anemia, Sickle Cell, 030204 cardiovascular system & hematology, Nitric Oxide, Nitric oxide, Wortmannin, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Physiology (medical), Internal medicine, Erythrocyte Deformability, medicine, Erythrocyte deformability, Humans, biology, Nitrotyrosine, Insulin, Sickle cell disease, red blood cell rheology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, hemic and immune systems, Hematology, Immunohistochemistry, 3. Good health, Nitric oxide synthase, Red blood cell, Oxidative Stress, medicine.anatomical_structure, Endocrinology, chemistry, biology.protein, Female, Sodium nitroprusside, Cardiology and Cardiovascular Medicine, 030215 immunology, medicine.drug, circulatory and respiratory physiology
Abstract: International audience; Sickle cell anemia (SCA) is an inherited red blood cells (RBC) disorder characterized by significantly decreased RBC deformability. The present study aimed to assess whether modulation of RBC Nitric Oxide Synthase (RBC-NOS) activation could affect RBC deformability in SCA.Blood of twenty-five SCA patients was treated for 1 hour at 37°C with Phosphate Buffered Saline (PBS) or PBS containing 1% of Dimethylsulfoxyde as control, L-arginine or N(5)-(1-Iminoethyl)-L-ornithine (L-NIO) to directly stimulate or inhibit RBC-NOS, insulin or wortmannin to indirectly stimulate or inhibit RBC-NOS through their effects on the PI3 Kinase/Akt pathway, and sodium nitroprusside (SNP) and 2-(4-Carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) as NO donor and NO scavenger, respectively. RBC deformability was measured by ektacytometry at 3 Pa.RBC deformability significantly increased after insulin treatment and significantly decreased after L-NIO and wortmannin incubation. The other conditions did not affect deformability. Significantly increased nitrotyrosine levels, a marker of enhanced free radical generation, were detected by immunohistochemistry in SNP and insulin treated samples.These data suggest that RBC deformability of SCA can be modulated by RBC-NOS activity but also that oxidative stress may impair effectiveness of RBC-NOS produced NO.
Published: 2016

36. The tumoral A genotype of the MGMT rs34180180 single-nucleotide polymorphism in aggressive gliomas is associated with shorter patients’ survival

Author: Bruno M. Costa, Jean-Louis Kemeny, Pierre Verrelle, Catherine Vaurs-Barrière, Afonso A. Pinto, Bruno Pereira, Lucie Karayan-Tapon, Mélanie Müller-Barthélémy, Franck Court, Julian Biau, Anne Fogli, Philippe Arnaud, Emmanuel Chautard, Toufic Khalil, Service de Biochimie et Génétique Moléculaire [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Génétique, Reproduction et Développement (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Faculté de Médecine - Clermont-Ferrand, Université d'Auvergne - Clermont-Ferrand I (UdA), Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Biostatistiques [CHU Clermont-Ferrand], Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Laboratoire de pathologie, Service de Neurochirurgie [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Gabriel Montpied [Clermont-Ferrand], Institut National de la Transfusion Sanguine [Paris] (INTS), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service de Neurochirurgie [CHU Clermont-Ferrand], Service de Biochimie Médicale et Biologie Moléculaire [CHU Clermont-Ferrand], Génétique, Reproduction et Développement - Clermont Auvergne ( GReD ), IFR79-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Université d'Auvergne - Clermont-Ferrand I ( UdA ), Génétique, reproduction et développement ( GReD ), Université Blaise Pascal - Clermont-Ferrand 2 ( UBP ) -Université d'Auvergne - Clermont-Ferrand I ( UdA ) -IFR79-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Biostat Unit, Centre Hospitalier Universitaire de Clermont-Ferrand, Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), CHU Clermont-Ferrand-Hôpital Gabriel Montpied, Institut National de la Transfusion Sanguine [Paris] ( INTS ), Centre Jean Perrin, CRLCC Jean Perrin, [et.al.], and Universidade do Minho
Subjects: Adult, Male, Cancer Research, Methyltransferase, IDH1, Genotype, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Kaplan-Meier Estimate, Biology, Bioinformatics, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Glioma, medicine, Humans, Promoter Regions, Genetic, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, DNA Modification Methylases, neoplasms, ComputingMilieux_MISCELLANEOUS, Proportional Hazards Models, Retrospective Studies, Temozolomide, Brain Neoplasms, Tumor Suppressor Proteins, Promoter, General Medicine, Methylation, DNA Methylation, Prognosis, medicine.disease, digestive system diseases, 3. Good health, DNA Repair Enzymes, CpG site, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030220 oncology & carcinogenesis, Cancer research, Female, Polymorphism, Restriction Fragment Length, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract: Malignant gliomas are the most common primary brain tumors. Grade III and IV gliomas harboring wild-type IDH1/2 are the most aggressive. In addition to surgery and radiotherapy, concomitant and adjuvant chemotherapy with temozolomide (TMZ) significantly improves overall survival (OS). The methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter is predictive of TMZ response and a prognostic marker of cancer outcome. However, the promoter regions the methylation of which correlates best with survival in aggressive glioma and whether the promoter methylation status predictive value could be refined or improved by other MGMT-associated molecular markers are not precisely known. In a cohort of 87 malignant gliomas treated with radiotherapy and TMZ-based chemotherapy, we retrospectively determined the MGMT promoter methylation status, genotyped single nucleotide polymorphisms (SNPs) in the promoter region and quantified MGMT mRNA expression level. Each of these variables was correlated with each other and with the patients' OS. We found that methylation of the CpG sites within MGMT exon 1 best correlated with OS and MGMT expression levels, and confirmed MGMT methylation as a stronger independent prognostic factor compared to MGMT transcription levels. Our main finding is that the presence of only the A allele at the rs34180180 SNP in the tumor was significantly associated with shorter OS, independently of the MGMT methylation status. In conclusion, in the clinic, rs34180180 SNP genotyping could improve the prognostic value of the MGMT promoter methylation assay in patients with aggressive glioma treated with TMZ., ARC -Fondation ARC pour la Recherche sur le Cancer(EML20120904843)
Published: 2016

37. Polymorphisms of Estrogen Metabolism-Related Genes and Prostate Cancer Risk in Two Populations of African Ancestry

Author: E. Emeville, Luc Multigner, Dieudonne Moningo, Simon Lufuma, Marc Romana, Séverine Ferdinand, Augustin Punga, Laurent Brureau, Pascal Blanchet, ROMANA, marc, 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 ), Service d’Urologie [CHU de Pointe à Pitre], CHU Pointe-à-Pitre/Abymes [Guadeloupe], Université des Antilles (UA), Service d’Urologie [Kinshasa, Congo], Cliniques Universitaires de Kinshasa [Congo], Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), PhD fellowship, Ligue Contre le Cancer, French National Health Directorate, 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 ), and Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, Oncology, Heredity, Enzyme Metabolism, lcsh:Medicine, Biochemistry, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Geographical locations, Prostate cancer, 0302 clinical medicine, Cancer screening, Genotype, Medicine and Health Sciences, Ethnicities, French People, Glucuronosyltransferase, Aromatase, Enzyme Chemistry, lcsh:Science, Guadeloupe, Aged, 80 and over, Genetics, Multidisciplinary, biology, Prostate Cancer, Prostate Diseases, Steroid 17-alpha-Hydroxylase, Middle Aged, 3. Good health, Genetic Mapping, 030220 oncology & carcinogenesis, Cytochrome P-450 CYP1B1, Democratic Republic of the Congo, Cancer Screening, Research Article, rs4680, Adult, medicine.medical_specialty, West Indies, Urology, Black People, Variant Genotypes, [SDV.CAN]Life Sciences [q-bio]/Cancer, Catechol O-Methyltransferase, Polymorphism, Single Nucleotide, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Cancer Detection and Diagnosis, medicine, Humans, Genetic Predisposition to Disease, Allele, Alleles, Genetic Association Studies, Aged, Caribbean, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], lcsh:R, Case-control study, Prostatic Neoplasms, Cancers and Neoplasms, Biology and Life Sciences, Estrogens, Odds ratio, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Hormones, Genitourinary Tract Tumors, 030104 developmental biology, Case-Control Studies, People and Places, North America, Enzymology, biology.protein, [SDV.GEN.GPO] Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Population Groupings, lcsh:Q, Africans
Abstract: International audience; BACKGROUND: Estrogens are thought to play a critical role in prostate carcinogenesis. It has been suggested that polymorphisms of genes encoding enzymes involved in estrogen metabolism are risk factors for prostate cancer. However, few studies have been performed on populations of African ancestry, which are known to have a high risk of prostate cancer.OBJECTIVE: We investigated whether functional polymorphisms of CYP17, CYP19, CYP1B1, COMT and UGT1A1 affected the risk of prostate cancer in two different populations of African ancestry.METHODS: In Guadeloupe (French West Indies), we compared 498 prostate cancer patients and 565 control subjects. In Kinshasa (Democratic Republic of Congo), 162 prostate cancer patients were compared with 144 controls. Gene polymorphisms were determined by the SNaPshot technique or short tandem repeat PCR analysis. Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI).RESULTS: The AA genotype and the A allele of rs4680 (COMT) appeared to be inversely associated with the risk of prostate cancer in adjusted models for both Afro-Caribbean and native African men. For the A allele, a significant inverse association was observed among cases with low-grade Gleason scores and localized clinical stage, in both populations.CONCLUSIONS: These preliminary results support the hypothesis that polymorphisms of genes encoding enzymes involved in estrogen metabolism may modulate the risk of prostate cancer in populations of African ancestry.
Published: 2016

38. Progressive structure-based alignment of homologous proteins: Adopting sequence comparison strategies

Author: Alexandre G. de Brevern, Narayanaswamy Srinivasan, Agnel Praveen Joseph, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Molecular Biophysics Unit, Indian Institute of Science, and French Ministry of Research, University of Paris Diderot - Paris 7, Sorbone Paris Cité, French National Institute for Blood Transfusion (INTS), French Institute for Health and Medical Research (INSERM), Indian Department of Biotechnology, CEFIPRA/IFCPAR for collaborative grant (number 3903-E).
Subjects: Models, Molecular, Protein Conformation, MESH: Sequence Homology, Amino Acid, 0206 medical engineering, Structural alignment, MESH: Sequence Alignment, structure conservation, Sequence alignment, 02 engineering and technology, Biology, Biochemistry, 03 medical and health sciences, MESH: Protein Conformation, Protein Data Bank, anchor-based alignment, MESH: Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, protein structure comparison, Homology modeling, Loop modeling, Alignment-free sequence analysis, 030304 developmental biology, 0303 health sciences, Multiple sequence alignment, Sequence Homology, Amino Acid, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Proteins, protein structure mining, General Medicine, computer.file_format, Protein superfamily, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Crystallography, Protein Blocks, structural alphabet, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Sequence Alignment, Algorithm, computer, MESH: Models, Molecular, 020602 bioinformatics
Abstract: International audience; Comparison of multiple protein structures has a broad range of applications in the analysis of protein structure, function and evolution. Multiple structure alignment tools (MSTAs) are necessary to obtain a simultaneous comparison of a family of related folds. In this study, we have developed a method for multiple structure comparison largely based on sequence alignment techniques. A widely used Structural Alphabet named Protein Blocks (PBs) was used to transform the information on 3D protein backbone conformation as a 1D sequence string. A progressive alignment strategy similar to CLUSTALW was adopted for multiple PB sequence alignment (mulPBA). Highly similar stretches identified by the pairwise alignments are given higher weights during the alignment. The residue equivalences from PB based alignments are used to obtain a three dimensional fit of the structures followed by an iterative refinement of the structural superposition. Systematic comparisons using benchmark datasets of MSTAs underlines that the alignment quality is better than MULTIPROT, MUSTANG and the alignments in HOMSTRAD, in more than 85% of the cases. Comparison with other rigid-body and flexible MSTAs also indicate that mulPBA alignments are superior to most of the rigid-body MSTAs and highly comparable to the flexible alignment methods.
Published: 2012

39. TSPO ligands stimulate ZnPPIX transport and ROS accumulation leading to the inhibition of P. falciparum growth in human blood

Author: C Le van Kim, Arnaud Chêne, Jean-Jacques Lacapère, Benoit Gamain, Claude Hattab, Irene Marginedas-Freixa, François Hallé, Mariano A. Ostuni, Frédéric Bihel, Stéphane Egée, Martine Schmitt, Anne Cueff, Sophie D. Lefevre, M Cambot, Guillaume Bouyer, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Innovation Thérapeutique (LIT), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC), Bouyer, Guillaume, Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)
Subjects: 0301 basic medicine, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Erythrocytes, Cellular differentiation, Protoporphyrins, Endogeny, Antigens, CD34, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Ligands, Mass Spectrometry, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Protein Isoforms, Voltage-Dependent Anion Channels, Receptor, chemistry.chemical_classification, Multidisciplinary, biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Differentiation, Glutathione, 3. Good health, Cell biology, Biochemistry, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Gene isoform, Voltage-dependent anion channel, Plasmodium falciparum, Article, 03 medical and health sciences, Erythroid Cells, Receptors, GABA, Translocator protein, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Animals, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Parasites, Amino Acid Sequence, RNA, Messenger, Reactive oxygen species, Gene Expression Profiling, Erythrocyte Membrane, Biological Transport, biology.organism_classification, 030104 developmental biology, chemistry, biology.protein, Reactive Oxygen Species
Abstract: After invading red blood cells (RBCs), Plasmodium falciparum (Pf) can export its own proteins to the host membrane and activate endogenous channels that are present in the membrane of RBCs. This transport pathway involves the Voltage Dependent Anion Channel (VDAC). Moreover, ligands of the VDAC partner TranSlocator PrOtein (TSPO) were demonstrated to inhibit the growth of the parasite. We studied the expression of TSPO and VDAC isoforms in late erythroid precursors, examined the presence of these proteins in membranes of non-infected and infected human RBCs, and evaluated the efficiency of TSPO ligands in inhibiting plasmodium growth, transporting the haem analogue Zn-protoporphyrin-IX (ZnPPIX) and enhancing the accumulation of reactive oxygen species (ROS). TSPO and VDAC isoforms are differentially expressed on erythroid cells in late differentiation states. TSPO2 and VDAC are present in the membranes of mature RBCs in a unique protein complex that changes the affinity of TSPO ligands after Pf infection. TSPO ligands dose-dependently inhibited parasite growth, and this inhibition was correlated to ZnPPIX uptake and ROS accumulation in the infected RBCs. Our results demonstrate that TSPO ligands can induce Pf death by increasing the uptake of porphyrins through a TSPO2–VDAC complex, which leads to an accumulation of ROS.
Published: 2015

40. αIIbβ3 integrin: new allelic variants in Glanzmann thrombasthenia, effects onITGA2BandITGB3mRNA splicing, expression, and structure-function

Author: Jenny Goudemand, Nathalie Hézard, Alexandre G. de Brevern, Vincent Jallu, Simon Panzer, Marie-Francoise Torchet, Cécile Kaplan, Mathilde Dusseaux, Laboratoire d'immunologie plaquettaire, Institut National de la Transfusion Sanguine [Paris] (INTS), Department of Blood Group Serology and Transfusion Medicine, Medizinische Universität Wien = Medical University of Vienna, Centre des Hémophiles, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Reims Champagne-Ardenne (URCA), Hôpital cardiologique, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and The work done by M. Dusseaux was supported by a grant from Novo Nordisk
Subjects: MESH: Integrin beta3, Fibrinogen receptor, DNA Mutational Analysis, Mutant, Integrin alpha2, MESH: Base Sequence, 030204 cardiovascular system & hematology, medicine.disease_cause, MESH: Receptors, Fibrinogen, Exon, MESH: Structure-Activity Relationship, 0302 clinical medicine, Chlorocebus aethiops, Missense mutation, MESH: Animals, MESH: DNA Mutational Analysis, ITGB3, Genetics (clinical), Genetics, 0303 health sciences, Mutation, alphaIIbbeta3, MESH: Alternative Splicing, Integrin beta3, MESH: Gene Expression Regulation, MESH: Thrombasthenia, MESH: COS Cells, ITGA2B, COS Cells, RNA splicing, Thrombasthenia, Molecular Sequence Data, MESH: Integrin alpha2, Biology, Structure-Activity Relationship, 03 medical and health sciences, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene, Alleles, 030304 developmental biology, MESH: Molecular Sequence Data, MESH: Humans, Base Sequence, MESH: Alleles, Alternative splicing, MESH: Cercopithecus aethiops, Molecular biology, Alternative Splicing, Receptors, Fibrinogen, Gene Expression Regulation, Protein structure modeling, Glanzmann
Abstract: International audience; Glanzmann thrombasthenia (GT) is an autosomal recessive inherited bleeding disorder characterized by an impaired platelet aggregation due to defects in integrin alphaIIbbeta3 (ITGA2B, ITGB3), a fibrinogen receptor. Mutations from 24 GT patients and two carriers of various origins, Caucasian, North-African and Asian were characterized. Promoter and exon sequences of alphaIIb and beta3 genes were amplified and directly sequenced. Among 29 identified mutations, 17 new allelic variants resulting from nonsense, missense and deletion/insertion mutations were described. RNA alterations were evaluated by using Web servers. The alphaIIb p.S926L, p.V903F, and beta3 p.C38Y, p.M118R, p.G221D substitutions prevented complex expression at the surface of COS-7 cells by altering the alphaIIb or the beta3 subunit structure. As shown by free energy analyses applied on the resolved structure of alphaIIbbeta3 and structural modeling of the mutant, the p.K253M substitution of beta3 helped to define a key role of the K253 in the interaction of the alphaIIb beta-propeller and the beta3 beta-I domains. finally, the alphaIIb p.Q595H substitution allowed cell surface expression of the complex but its corresponding c.2800G>T mutation is predicted to alter normal RNA splicing. In conclusion, our study yielded the discovery of 17 new GT allelic variants, revealed the key role of K253 of alphaIIb for the alphaIIbbeta3 complex formation and provides an additional example of an apparently missense mutation causing a splicing defect.
Published: 2010

41. Splenic retention of Plasmodium falciparum gametocytes to block the transmission of malaria

Author: Bruno Le Pioufle, Vicky M. Avery, Inês F. Amado, Pierre Buffet, Papa Alioune Ndour, Caroline Le Van Kim, Catherine Lavazec, John P. Holleran, Olivier Français, Julien Duez, Wassim El Nemer, Nathalie Chartrel, Pascal Amireault, Sasdekumar Loganathan, Sylvie Garcia, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Eskitis Institute for Drug Discovery, Griffith University [Brisbane], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Transfusion Sanguine [Paris] (INTS), Bio-MIcroSystèmes et BioSensors (SATIE-BIOMIS), Systèmes d'Information et d'Analyse Multi-Echelles (SIAME), Systèmes et Applications des Technologies de l'Information et de l'Energie (SATIE), École normale supérieure - Cachan (ENS Cachan)-Université Paris-Sud - Paris 11 (UP11)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-École normale supérieure - Rennes (ENS Rennes)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Cachan (ENS Cachan)-Université Paris-Sud - Paris 11 (UP11)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-École normale supérieure - Rennes (ENS Rennes)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre National de la Recherche Scientifique (CNRS)-Systèmes et Applications des Technologies de l'Information et de l'Energie (SATIE), Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], This work was supported by the Bill and Melinda Gates Foundation [OPP1043892], the 'Agence Nationale de la Recherche' [ANR-10-IAHU-01, ANR-11-LABX-0051, ANR-11-IDEX-0005-02] and by a grant from 'HRA Pharma Laboratoires Paris', ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), Centre d'Immunologie et de Maladies Infectieuses ( CIMI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Griffith University Australia, Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Transfusion Sanguine [Paris] ( INTS ), Bio-MIcroSystèmes et BioSensors ( SATIE-BIOMIS ), Systèmes d'Information et d'Analyse Multi-Echelles ( SIAME ), Systèmes et Applications des Technologies de l'Information et de l'Energie ( SATIE ), École normale supérieure - Cachan ( ENS Cachan ) -Université Paris-Sud - Paris 11 ( UP11 ) -École normale supérieure - Rennes ( ENS Rennes ) -Université de Cergy Pontoise ( UCP ), Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux ( IFSTTAR ) -École normale supérieure - Cachan ( ENS Cachan ) -Université Paris-Sud - Paris 11 ( UP11 ) -École normale supérieure - Rennes ( ENS Rennes ) -Université de Cergy Pontoise ( UCP ), Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux ( IFSTTAR ) -Systèmes et Applications des Technologies de l'Information et de l'Energie ( SATIE ), Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux ( IFSTTAR ), ANR-11-IDEX-0005-02 ,USPC : Projet Université Sorbonne Paris Cité,Initiatives d’excellence - Laboratoire d’excellence INFLAMEX, Systèmes d'Information et d'Analyse Multi-Echelles (SATIE-SIAME), Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Cachan (ENS Cachan)-Université Paris-Sud - Paris 11 (UP11)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-École normale supérieure - Rennes (ENS Rennes)-Université de Cergy Pontoise (UCP), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Rennes (ENS Rennes)-Université Paris-Sud - Paris 11 (UP11)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Cachan (ENS Cachan)-Université Gustave Eiffel (UNIV GUSTAVE EIFFEL)-École normale supérieure - Rennes (ENS Rennes)-Université Paris-Sud - Paris 11 (UP11)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Cachan (ENS Cachan)-Université Gustave Eiffel (UNIV GUSTAVE EIFFEL)-Systèmes et Applications des Technologies de l'Information et de l'Energie (SATIE), and Université Paris-Seine-Université Paris-Seine-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Cachan (ENS Cachan)-Université Gustave Eiffel (UNIV GUSTAVE EIFFEL)
Subjects: [ SDV.MP.PAR ] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Erythrocytes, [SDV]Life Sciences [q-bio], Plasmodium falciparum, Models, Biological, Antimalarials, Automation, Mice, 03 medical and health sciences, chemistry.chemical_compound, Microtiter plate, In vivo, parasitic diseases, Image Processing, Computer-Assisted, Gametocyte, Animals, Pharmacology (medical), [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Enzyme Inhibitors, Malaria, Falciparum, Biologic Response Modifiers, Oxazoles, Parasite Egg Count, 030304 developmental biology, Pharmacology, 0303 health sciences, biology, [ SDV ] Life Sciences [q-bio], 030306 microbiology, Macrophages, Anopheles, Microfluidic Analytical Techniques, Flow Cytometry, biology.organism_classification, Virology, Microspheres, In vitro, 3. Good health, Cell biology, Infectious Diseases, chemistry, Erythrocyte Count, Marine Toxins, Marine toxin, Filtration, Spleen, Calyculin
Abstract: Plasmodium falciparum is transmitted from humans to Anopheles mosquito vectors via the sexual erythrocytic forms termed gametocytes. Erythrocyte filtration through microsphere layers (microsphiltration) had shown that circulating gametocytes are deformable. Compounds reducing gametocyte deformability would induce their splenic clearance, thus removing them from the blood circulation and blocking malaria transmission. The hand-made, single-sample prototype for microsphiltration was miniaturized to a 96-well microtiter plate format, and gametocyte retention in the microsphere filters was quantified by high-content imaging. The stiffening activity of 40 pharmacological compounds was assessed in microtiter plates, using a small molecule (calyculin) as a positive control. The stiffening activity of calyculin was assessed in spleen-mimetic microfluidic chips and in macrophage-depleted mice. Marked mechanical retention (80% to 90%) of mature gametocytes was obtained in microplates following exposure to calyculin at concentrations with no effect on parasite viability. Of the 40 compounds tested, including 20 antimalarials, only 5 endoperoxides significantly increased gametocyte retention (1.5- to 2.5-fold; 24 h of exposure at 1 μM). Mature gametocytes exposed to calyculin accumulated in microfluidic chips and were cleared from the circulation of macrophage-depleted mice as rapidly as heat-stiffened erythrocytes, thus confirming results obtained using the microsphiltration assay. An automated miniaturized approach to select compounds for their gametocyte-stiffening effect has been established. Stiffening induces gametocyte clearance both in vitro and in vivo . Based on physiologically validated tools, this screening cascade can identify novel compounds and uncover new targets to block malaria transmission. Innovative applications in hematology are also envisioned.
Published: 2015

42. Construction and validation of an atomic model for bacterial TSPO from electron microscopy density, evolutionary constraints, and biochemical and biophysical data

Author: Catherine Etchebest, Mariano A. Ostuni, Konrad Hinsen, Aurore Vaitinadapoule, Jean-Jacques Lacapère, Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), and Frapart, Isabelle
Subjects: Models, Molecular, Molecular Sequence Data, Biophysics, Protoporphyrins, Rhodobacter sphaeroides, Biology, Transporter, Ligands, Biochemistry, Protein Structure, Secondary, chemistry.chemical_compound, Bacterial Proteins, Atomic model, Amino Acid Sequence, Conserved Sequence, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], chemistry.chemical_classification, Binding Sites, Cryoelectron Microscopy, Cell Biology, Ligand (biochemistry), biology.organism_classification, Isoquinolines, Transmembrane protein, Amino acid, Translocase 18kDa, Transmembrane domain, Monomer, Cholesterol, chemistry, Membrane protein, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Protein Multimerization, Carrier Proteins, Crystallization, Sequence Alignment, Protein Binding
Abstract: International audience; The 18kDa protein TSPO is a highly conserved transmembrane protein found in bacteria, yeast, animals and plants. TSPO is involved in a wide range of physiological functions, among which the transport of several molecules. The atomic structure of monomeric ligand-bound mouse TSPO in detergent has been published recently. A previously published low-resolution structure of Rhodobacter sphaeroides TSPO, obtained from tubular crystals with lipids and observed in cryo-electron microscopy, revealed an oligomeric structure without any ligand. We analyze this electron microscopy density in view of available biochemical and biophysical data, building a matching atomic model for the monomer and then the entire crystal. We compare its intra- and inter-molecular contacts with those predicted by amino acid covariation in TSPO proteins from evolutionary sequence analysis. The arrangement of the five transmembrane helices in a monomer of our model is different from that observed for the mouse TSPO. We analyze possible ligand binding sites for protoporphyrin, for the high-affinity ligand PK 11195, and for cholesterol in TSPO monomers and/or oligomers, and we discuss possible functional implications.
Published: 2014

43. Coarse-Grained Simulations of the HIV-1 Matrix Protein Anchoring: Revisiting Its Assembly on Membrane Domains

Author: Laurent Chaloin, Nicolas Floquet, Patrick F.J. Fuchs, Cyril Favard, Jean Martinez, Landry Charlier, Delphine Muriaux, Maxime Louet, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université de La Réunion (UR)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université de La Réunion (UR)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Transfusion Sanguine [Paris] (INTS)
Subjects: Phosphatidylinositol 4,5-Diphosphate, Vesicle-associated membrane protein 8, HIV Antigens, Molecular Sequence Data, Biophysics, Molecular Dynamics Simulation, Biology, gag Gene Products, Human Immunodeficiency Virus, 7. Clean energy, Cell membrane, Viral envelope, medicine, Humans, Amino Acid Sequence, Lipid bilayer, Myristoylation, Host cell membrane, Membranes, Viral matrix protein, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Cell Membrane, Membrane, medicine.anatomical_structure, Biochemistry, Protein Binding
Abstract: International audience; In the accepted model for human immunodeficiency virus preassembly in infected host cells, the anchoring to the intracellular leaflet of the membrane of the matrix domain (MA) that lies at the N-terminus of the viral Gag protein precursor appears to be one of the crucial steps for particle assembly. In this study, we simulated the membrane anchoring of human immunodeficiency virus-1 myristoylated MA protein using a coarse-grained representation of both the protein and the membrane. Our calculations first suggest that the myristoyl group could spontaneously release from its initial hydrophobic pocket before MA protein interacts with the lipid membrane. All-atom simulations confirmed this possibility with a related energy cost estimated to be ∼5 kcal.mol−1. The phosphatidylinositol (4,5) bisphosphate (PI(4,5)P2) head binds preferentially to the MA highly basic region as described in available NMR data, but interestingly without flipping of its 2′ acyl chain into the MA protein. Moreover, MA was able to confine PI(4,5)P2 lipids all around its molecular surface after having found a stable orientation at the membrane surface. Our results suggest that this orientation is dependent on Myr anchoring and that this confinement induces a lateral segregation of PI(4,5)P2 in domains. This is consistent with a PI(4,5)P2 enrichment of the virus envelope as compared to the host cell membrane.
Published: 2014

44. Structure-Affinity Properties of a High-Affinity Ligand of FKBP12 Studied by Molecular Simulations of a Binding Intermediate

Author: Lilian Olivieri, Fabrice Gardebien, GARDEBIEN, Fabrice, Dynamique des Structures et Interactions des Macromolécules Biologiques - Pôle de La Réunion (DSIMB Réunion), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), and Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: lcsh:Medicine, Tacrolimus Binding Protein 1A, Molecular Dynamics Simulation, Biology, Ligands, 010402 general chemistry, Bioinformatics, Biochemistry, 01 natural sciences, Protein Structure, Secondary, Structure-Activity Relationship, 03 medical and health sciences, Molecular dynamics, Protein structure, Biochemical Simulations, Intermediate state, Biomacromolecule-Ligand Interactions, Binding site, lcsh:Science, 030304 developmental biology, 0303 health sciences, Binding Sites, Multidisciplinary, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Ligand, Hydrogen bond, lcsh:R, Intermolecular force, Biology and Life Sciences, Computational Biology, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 0104 chemical sciences, Crystallography, Intramolecular force, lcsh:Q, Protein Binding, Research Article
Abstract: International audience; With a view to explaining the structure-affinity properties of the ligands of the protein FKBP12, we characterized a binding intermediate state between this protein and a high-affinity ligand. Indeed, the nature and extent of the intermolecular contacts developed in such a species may play a role on its stability and, hence, on the overall association rate. To find the binding intermediate, a molecular simulation protocol was used to unbind the ligand by gradually decreasing the biasing forces introduced. The intermediate was subsequently refined with 17 independent stochastic boundary molecular dynamics simulations that provide a consistent picture of the intermediate state. In this state, the core region of the ligand remains stable, notably because of the two anchoring oxygen atoms that correspond to recurrent motifs found in all FKBP12 ligand core structures. Besides, the non-core regions participate in numerous transient intermolecular and intramolecular contacts. The dynamic aspect of most of the contacts seems important both for the ligand to retain at least a part of its configurational entropy and for avoiding a trapped state along the binding pathway. Since the transient and anchoring contacts contribute to increasing the stability of the intermediate, as a corollary, the dissociation rate constant k {1 of this intermediate should be decreased, resulting in an increase of the affinity constant K a. The present results support our previous conclusions and provide a coherent rationale for explaining the prevalence in high-affinity ligands of (i) the two oxygen atoms found in carbonyl or sulfonyl groups of dissimilar core structures and of (ii) symmetric or pseudo-symmetric mobile groups of atoms found as non-core moieties. Another interesting aspect of the intermediate OPEN ACCESS Citation: Olivieri L, Gardebien F (2014) Structure-Affinity Properties of a High-Affinity Ligand of FKBP12 Studied by Molecular Simulations of a Binding Intermediate. PLoS ONE 9(12): e114610.
Published: 2014

45. Ultradeep Pyrosequencing and Molecular Modeling Identify Key Structural Features of Hepatitis B Virus RNase H, a Putative Target for Antiviral Intervention

Author: Jean-Michel Pawlotsky, Georgios Germanidis, Christophe Rodriguez, Juliette Hayer, Christophe Combet, Fabien Zoulim, Gilbert Deléage, Bases moléculaires et structurales des systèmes infectieux ( BMSSI ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Centre National de Référence Virus des hépatites B, C et Delta, Institut National de la Transfusion Sanguine [Paris] ( INTS ) -Assistance publique - Hôpitaux de Paris (AP-HP), Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Pathology Clinic, Aristotle University of Thessaloniki-Papageorgiou General Hospital, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service Hépatologie, Hospices Civils de Lyon ( HCL ), J.H. received a doctoral fellowship from the Ministère de l'Enseignement Supérieur et de la Recherche (contract 0012). C.R. received a doctoral fellowship from the National Agency for Research on AIDS and Viral Hepatitis (ANRS). This work was supported by the Finovi Foundation (contract 051274 2010-2011), Fondation pour la Recherche Médicale (FRM), and the ANRS. Sequence data analyses and molecular modeling were performed on the PRABI computing platform (contract GIS-IBiSA 2009-2011)., Bases moléculaires et structurales des systèmes infectieux (BMSSI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut National de la Transfusion Sanguine [Paris] (INTS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Guellaen, Georges
Subjects: Models, Molecular, Hepatitis B virus, Genotype, Immunology, Population, Molecular Sequence Data, Ribonuclease H, Biology, medicine.disease_cause, Microbiology, Antiviral Agents, Hepatitis B virus PRE beta, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Virology, Vaccines and Antiviral Agents, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, RNase H, education, Gene, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Genetics, 0303 health sciences, education.field_of_study, Sequence Homology, Amino Acid, RNA, High-Throughput Nucleotide Sequencing, digestive system diseases, 3. Good health, HBx, chemistry, Insect Science, biology.protein, 030211 gastroenterology & hepatology, DNA
Abstract: Last-generation nucleoside/nucleotide analogues are potent against hepatitis B virus (HBV) and have a high barrier to resistance. However, delayed responses have been observed in patients previously exposed to other drugs of the same class, long-term resistance is possible, and cure of infection cannot be achieved with these therapies, emphasizing the need for alternative therapeutic approaches. The HBV RNase H represents an interesting target because its enzyme activity is essential to the HBV life cycle. The goal of our study was to characterize the structure of the HBV RNase H by computing a 3-dimensional molecular model derived from E. coli RNase H and analyzing 2,326 sequences of all HBV genotypes available in public databases and 958,000 sequences generated by means of ultradeep pyrosequencing of sequences from a homogenous population of 73 treatment-naive patients infected with HBV genotype D. Our data revealed that (i) the putative 4th catalytic residue displays unexpected variability that could be explained by the overlap of the HBx gene and has no apparent impact on HBV replicative capacity and that (ii) the C-helix-containing basic protrusion, which is required to guide the RNA/DNA heteroduplex into the catalytic site, is highly conserved and bears unique structural properties that can be used to target HBV-specific RNase H inhibitors without cross-species activity. The model shows substantial differences from other known RNases H and paves the way for functional and structural studies as a prerequisite to the development of new inhibitors of the HBV cell cycle specifically targeting RNase H activity.
Published: 2014

46. Genome-wide detection of sRNA targets with rNAV

Author: Patricia Thebault, Isabelle Dutour, Amine Ghozlane, Romain Bourqui, Jonathan Dubois, Laboratoire Bordelais de Recherche en Informatique (LaBRI), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB), Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bourqui, Romain, Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)
Subjects: 0303 health sciences, business.industry, [INFO.INFO-DS]Computer Science [cs]/Data Structures and Algorithms [cs.DS], 030302 biochemistry & molecular biology, [INFO.INFO-DS] Computer Science [cs]/Data Structures and Algorithms [cs.DS], Genomics, Computational biology, Biology, Data science, Genome, Domain (software engineering), 03 medical and health sciences, Data visualization, Tree view, Transfer RNA, Functional activity, Area navigation, business, 030304 developmental biology
Abstract: International audience; The central dogma in molecular biology postulated that 'DNA makes RNA makes protein', however this dogma has been recently extended to integrate new biological activities involving small non- coding RNAs, called sRNAs. Accordingly, an increasing attention has been given to these molecules over the last decade and related experimental works have shown a wide range of functional activ- ities for these molecules. In this paper, we present rNAV (for rna NAVigator), a new tool for the visual exploration and analysis of sRNA-mediated regulatory networks. rNAV has been designed to help bioinformaticians and biologists to identify, from list of thou- sands of predictions, pertinent and reasonable sRNAs and target candidates for carrying out experimental validations. We propose a list of dedicated algorithms and interaction tools that facilitate the exploration of such networks. These algorithms can be gathered into pipelines which can then be saved and reuse over several sessions. To support exploration awareness, rNAV also provides an exploration tree view that allows to navigate through the steps of the analysis but also to select the -sub-networks to visualize and compare. These comparisons are facilitated by the integration of multiple and fully linked views. We demonstrate the usefulness of our approach by a case study on Escherichia coli bacteria performed by domain experts.
Published: 2013

47. Structural Model of the Anion Exchanger 1 (SLC4A1) and Identification of Transmembrane Segments Forming the Transport Site

Author: Hélène Guizouarn, Catherine Etchebest, Damien Barneaud-Rocca, Institut de Biologie Valrose (IBV), 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 National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université de La Réunion (UR)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université de La Réunion (UR)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Transfusion Sanguine [Paris] (INTS)
Subjects: Anions, Models, Molecular, Bicarbonate, Inorganic chemistry, Molecular Sequence Data, Bicarbonate transporter protein, Lithium, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Xenopus laevis, Protein structure, stomatognathic system, Membrane Biology, Anion Exchange Protein 1, Erythrocyte, Animals, Humans, Point Mutation, Homology modeling, Amino Acid Sequence, Sulfhydryl Compounds, Molecular Biology, Band 3, Ion channel, 030304 developmental biology, 0303 health sciences, Binding Sites, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], 030302 biochemistry & molecular biology, Cell Membrane, Sodium, Cell Biology, Transmembrane protein, Protein Structure, Tertiary, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], stomatognathic diseases, chemistry, Symporter, biology.protein, Biophysics, Mutagenesis, Site-Directed, Oocytes, Potassium, Female
Abstract: The anion exchanger 1 (AE1), a member of bicarbonate transporter family SLC4, mediates an electroneutral chloride/bicarbonate exchange in physiological conditions. However, some point mutations in AE1 membrane-spanning domain convert the electroneutral anion exchanger into a Na+ and K+ conductance or induce a cation leak in a still functional anion exchanger. The molecular determinants that govern ion movement through this transporter are still unknown. The present study was intended to identify the ion translocation pathway within AE1. In the absence of a resolutive three-dimensional structure of AE1 membrane-spanning domain, in silico modeling combined with site-directed mutagenesis experiments was done. A structural model of AE1 membrane-spanning domain is proposed, and this model is based on the structure of a uracil-proton symporter. This model was used to design cysteine-scanning mutagenesis on transmembrane (TM) segments 3 and 5. By measuring AE1 anion exchange activity or cation leak, it is proposed that there is a unique transport site comprising TM3–5 and TM8 that should function as an anion exchanger and a cation leak. Background: There is still no high resolution three-dimensional structure available for the membrane-spanning domain of anion exchanger 1 (AE1). Results: A three-dimensional model of AE1 membrane-spanning domain has been generated in silico and experimentally assessed. Conclusion: Transmembrane segments forming AE1 transport site have been identified. Significance: This is the first three-dimensional model of AE1 membrane-spanning domain based on a cation symporter.
Published: 2013

48. Evolution study of the Baeyer-Villiger monooxygenases enzyme family: functional importance of the highly conserved residues

Author: Véronique de Berardinis, Véronique Alphand, Alexandre G. de Brevern, Joseph Rebehmed, GR-Ex, Laboratoire d'Excellence, GR-Ex, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Institut des Sciences Moléculaires de Marseille (ISM2), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), The Ministry of Research (France) The University Paris Diderot, Sorbonne Paris Cite (France) The National Institute of Blood Transfusion (INTS, France) The National Institute of Health and Medical Research (INSERM, France) The Laboratories of Excellence, GR-Ex (France) The National Center for Atomic Research (CEA,France) University d'Aix-Marseille (France) The National Center for Scientific Research (CNRS,France) high performance computing (HPC) resources at the French National Computing Center CINES under grant no. 2012-c2012076930 funded by the GENCI (Grand Equipement National de Calcul Intensif)., Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Génomique métabolique (UMR 8030), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), and de Brevern, Alexandre G.
Subjects: Threonine, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, ketones, phylogeny, 01 natural sciences, Biochemistry, Conserved sequence, Mixed Function Oxygenases, Protein structure, esters, Rhodococcus, [INFO.INFO-BT]Computer Science [cs]/Biotechnology, lactones, Conserved Sequence, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], chemistry.chemical_classification, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [CHIM.ORGA]Chemical Sciences/Organic chemistry, enentioselectivity, [CHIM.CATA] Chemical Sciences/Catalysis, General Medicine, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Amino acid, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, [SDV.TOX] Life Sciences [q-bio]/Toxicology, [SDV.TOX]Life Sciences [q-bio]/Toxicology, sequence alignment, Flavin-Adenine Dinucleotide, Stereochemistry, Sequence alignment, Biology, 010402 general chemistry, stereoselectivity, 03 medical and health sciences, Pseudomonas, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, protein structure, 030304 developmental biology, function, Binding Sites, [CHIM.CATA]Chemical Sciences/Catalysis, Monooxygenase, interactions, [CHIM.ORGA] Chemical Sciences/Organic chemistry, 0104 chemical sciences, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Enzyme binding, [INFO.INFO-BT] Computer Science [cs]/Biotechnology, chemistry, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Function (biology), NADP
Abstract: International audience; Baeyer-Villiger monooxygenases (BVMOs) catalyze the transformation of linear and cyclic ketones into their corresponding esters and lactones by introducing an oxygen atom into a C-C bond. This bioreaction has numerous advantages compared to its chemical version; it does not induce the use of potentially harmful reagents (i.e., green chemistry) and displays significant better enantio- and regio-selectivity. New potential BVMOs were searched using sequence homology for type I BVMO proteins. 116 new sequences were identified as new putative BVMOs respecting the defined selection criteria. Multiple sequence alignments were carried out on the selected sequences to study the conservation of structurally and/or functionally important amino acids during evolution. Type I BVMO signature motif was found to be conserved in 94.8% of the sequences. We noticed also the highly conserved - but previously unnoticed - Threonine 167 (93.1%), located in the signature motif; this position could be added in the pattern used to characterize specific Type I enzymes. Amino acids at the vicinity of the FAD and NADPH cofactors were found also to be highly conserved and the details of the interactions were emphasized. Interestingly, residues at the enzyme binding site were found less conserved in terms of sequence evolution, leading sometimes to some important amino acid changes. These behaviors could explain the enzyme selectivity and specificity for different ligands.
Published: 2013

49. VLDP web server: a powerful geometric tool for analysing protein structures in their environment

Author: Alexandre G. de Brevern, Jeremy Esque, Sylvain Leonard, Christophe Oguey, Laboratoire de Physique Théorique et Modélisation (LPTM - UMR 8089), Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), GR-Ex, Laboratoire d'Excellence, GR-Ex, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Ministry of Research (France) The University Paris Diderot, Sorbonne Paris Cite (France) The National Institute of Blood Transfusion (INTS, France) The National Institute of Health and Medical Research (INSERM, France) The Laboratories of Excellence, GR-Ex (France) The University of Cergy-Pontoise (France) The National Center for Scientific Research (CNRS,France), de Brevern, Alexandre G., and Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)
Subjects: Models, Molecular, Web server, MESH: Amino Acids, Protein Conformation, Voronoi, protein accessibility, Biology, Bioinformatics, computer.software_genre, 01 natural sciences, tessellations, Set (abstract data type), 03 medical and health sciences, MESH: Software, Protein structure, MESH: Protein Conformation, 0103 physical sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, MESH: Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 030304 developmental biology, Delaunay, Internet, 0303 health sciences, amino acids, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Tessellation, 010304 chemical physics, Delaunay triangulation, Proteins, Articles, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Visualization, MESH: Internet, protein structures, Laguerre polynomials, protein volume, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Voronoi diagram, computer, Algorithm, Software, MESH: Models, Molecular
Abstract: International audience; Protein structures are an ensemble of atoms determined experimentally mostly by X-ray crystallography or Nuclear Magnetic Resonance. Studying 3D protein structures is a key point for better understanding protein function at a molecular level. We propose a set of accurate tools, for analysing protein structures, based on the reliable method of Voronoi-Laguerre tessellations. The Voronoi Laguerre Delaunay Protein web server (VLDPws) computes the Laguerre tessellation on a whole given system first embedded in solvent. Through this fine description, VLDPws gives the following data: (i) Amino acid volumes evaluated with high precision, as confirmed by good correlations with experimental data. (ii) A novel definition of inter-residue contacts within the given protein. (iii) A measure of the residue exposure to solvent that significantly improves the standard notion of accessibility in some cases. At present, no equivalent web server is available. VLDPws provides output in two complementary forms: direct visualization of the Laguerre tessellation, mostly its polygonal molecular surfaces; files of volumes; and areas, contacts and similar data for each residue and each atom. These files are available for download for further analysis. VLDPws can be accessed at http://www.dsimb.inserm.fr/dsimb_tools/vldp.
Published: 2013

50. PRR repeats in the intracellular domain of KISS1R are important for its export to cell membrane.: PRR repeats in intracellular domain of KISSIR

Author: Anne Marie Guedj, Lucie Chevrier, Nicolas de Roux, Alexandre G. de Brevern, Jérôme Leprince, Eva Hernandez, Hubert Vaudry, Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), GR-Ex, Laboratoire d'Excellence, GR-Ex, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service des Maladies Métaboliques et Endocriniennes, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), INSERM UMR676, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Laboratoire de Biochimie, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré
Subjects: DNA Mutational Analysis, Gene Expression, MESH: Receptors, G-Protein-Coupled, MESH: Base Sequence, MESH: Hypogonadism, Receptors, G-Protein-Coupled, 0302 clinical medicine, Endocrinology, Protein structure, Chlorocebus aethiops, Receptors, MESH: Obesity, MESH: Animals, MESH: Molecular Dynamics Simulation, MESH: Proline-Rich Protein Domains, MESH: DNA Mutational Analysis, Structural motif, Original Research, MESH: Genetic Association Studies, Genetics, 0303 health sciences, variants, COS cells, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Transport protein, Cell biology, MESH: COS Cells, Protein Transport, 030220 oncology & carcinogenesis, MESH: HEK293 Cells, COS Cells, Proline-Rich Protein Domains, structural alphabet, Isolated hypogonadotropic hypogonadism, MESH: Protein Transport, MESH: Gene Expression, Molecular Sequence Data, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Molecular Dynamics Simulation, 03 medical and health sciences, G-Protein-Coupled, male, Insertional, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Obesity, protein structure, Molecular Biology, Genetic Association Studies, 030304 developmental biology, Polyproline helix, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, Hypogonadism, Cell Membrane, HEK 293 cells, Heterozygote advantage, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, medicine.disease, MESH: Cercopithecus aethiops, MESH: Male, Mutagenesis, Insertional, HEK293 Cells, MESH: Mutagenesis, Insertional, Mutagenesis, adolescent, MESH: HeLa Cells, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], HeLa Cells, Receptors, Kisspeptin-1, MESH: Cell Membrane
Abstract: The National Institute of Health and Medical Research (INSERM, France) The Ministry of Research (France) The University Paris Diderot, Sorbonne Paris Cite (France) The National Institute of Blood Transfusion (INTS, France) The Laboratories of Excellence, GR-Ex (France); International audience; Inactivating mutations of KISS-1 receptor (KISS1R) have been recently described as a rare cause of isolated hypogonadotropic hypogonadism transmitted as a recessive trait. Few mutations have been described, and the structure-function relationship of KISS1R remains poorly understood. Here, we have taken advantage of the discovery of a novel mutation of KISS1R to characterize the structure and function of an uncommon protein motif composed of 3 proline-arginine-arginine (PRR) repeats located within the intracellular domain. A heterozygous insertion of 1 PRR repeat in-frame with 3 PRR repeats leading to synthesis of a receptor bearing 4 PRR repeats (PRR-KISS1R) was found in the index case. Functional analysis of PRR-KISS1R showed a decrease of the maximal response to kisspeptin stimulation, associated to a lower cell surface expression without modification of total expression. PRR-KISS1R exerts a dominant negative effect on the synthesis of the wild-type (WT)-KISS1R. This effect was due to the nature of inserted residues but also to the difference of the length of the intracellular domain between PRR-KISS1R and WT-KISS1R. A molecular dynamic analysis showed that the additional PRR constrained this arginine-rich region into a polyproline type II helix. Altogether, this study shows that a heterozygous insertion in KISS1R may lead to hypogonadotropic hypogonadism by a dominant negative effect on the WT receptor. An additional PRR repeat into a proline-arginine-rich motif can dramatically changed the conformation of the intracellular domain of KISS1R and its probable interaction with partner proteins.
Published: 2013

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