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1. Identification of a new regulation pathway of EGFR and E-cadherin dynamics

Author: Jean-Christophe Gelly, Tamara Advedissian, Mireille Viguier, Frederique Deshayes, Véronique Proux-Gillardeaux, Charlotte Perin, IJM, CNRS, Université Paris Diderot, Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Proux-Gillardeaux, Véronique, Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Trafic membranaire et Division cellulaire - Membrane Traffic and Cell Division, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), 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), and This work was supported by Gefluc.
Subjects: Cellular differentiation, [SDV]Life Sciences [q-bio], Endocytic cycle, Regulator, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Epidermal homeostasis, Biochemistry, Mice, 0302 clinical medicine, Cell Movement, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Deficient mouse, HaCaT Cells, Receptor, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], ComputingMilieux_MISCELLANEOUS, Mice, Knockout, 0303 health sciences, Multidisciplinary, Chemistry, Dynamics (mechanics), Cell Differentiation, Cadherins, Cell biology, [SDV] Life Sciences [q-bio], ErbB Receptors, Molecular Docking Simulation, 030220 oncology & carcinogenesis, Phosphorylation, Medicine, Female, Intracellular, Signal Transduction, Galectins, Science, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Article, 03 medical and health sciences, In vivo, Antigens, CD, otorhinolaryngologic diseases, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene Silencing, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 030304 developmental biology, Cell Proliferation, Cell growth, Cadherin, Cell Membrane, Mice, Inbred C57BL, stomatognathic diseases, Epidermis, Epidermal thickening
Abstract: EGFR plays key roles in multiple cellular processes such as cell differentiation, cell proliferation, migration and epithelia homeostasis. Phosphorylation of the receptor, intracellular signaling and trafficking are major events regulating EGFR functions. Galectin-7, a soluble lectin expressed in epithelia such as the skin, has been shown to be involved in cell differentiation. Through this study we demonstrate that galectin-7 regulates EGFR function by a direct interaction with its extracellular domain hence modifying its downstream signaling and endocytic pathway. From observations in mice we focused on the molecular mechanisms deciphering the glycosylation dependent interaction between EGFR and galectin-7. Interestingly, we also revealed that galectin-7 is a direct binder of both EGFR and E-cadherin bridging them together. Strikingly this study not only deciphers a new molecular mechanism of EGFR regulation but also points out a novel molecular interaction between EGFR and E-cadherin, two major regulators of the balance between proliferation and differentiation.SUMMARYEGFR and E-cadherin are known to interact and to regulate epithelial homeostasis. In this study we unravel in the epidermis a new partner and regulator of EGFR which also binds E-cadherin reciprocally bridging their dynamics and functions.
Published: 2021

2. Splenic clearance of rigid erythrocytes as an inherited mechanism for splenomegaly and natural resistance to malaria

Author: Benoît Henry, Geoffroy Volle, Hilaire Akpovi, Laure Gineau, Camille Roussel, Papa Alioune Ndour, Félicien Tossou, Felipe Suarez, Friso Palstra, Aurélie Fricot, Charlotte Chambrion, Julien Solinc, Julie Nguyen, Mathilde Garé, Florentin Aussenac, Charles-Henry Cottart, Christine Keyser, Rafiou Adamou, Magali Tichit, David Hardy, Nadine Fievet, Jérôme Clain, André Garcia, David Courtin, Olivier Hermine, Audrey Sabbagh, Pierre Buffet, 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), Service des Maladies infectieuses et tropicales [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris] (IP)-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 Paris Cité (UPCité), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-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), Hôpital Bicêtre, Centre d’Etude et de Recherche sur les Pathologies Associéees à la Grossesse et à l’Enfance [Cotonou, Bénin] (CERPAGE), 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), Centre Interfacultaire de Formation et de Recherche en Environnement pour le Développement Durable [Cotonou, Benin] (CIFRED), Université d’Abomey-Calavi = University of Abomey Calavi (UAC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biologie, anthropologie, biométrie, épigénétique, lignées : De la diversité des populations à l'individu, de l'identification à l'identité (BABEL), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Neuropathologie expérimentale / Experimental neuropathology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP), This research was supported by a grant from Labex GR-Ex and from the National Geographic Society Committee for Research and Exploration (Grant 9804-15). The labex GR-Ex, reference ANR-11-LABX-0051 is funded by the program Investissements d'avenir of the French National Research Agency, reference ANR-11-IDEX-0005-02. It also received funding from IMEA (Institut de Médecine et d'Epidémiologie Appliquée) and IRD (Institut de Recherche pour le Développement), BH was supported by a grant from Région Ile de France (DIM Malinf, grant dim150030)., ANR-11-LABX-0051,GR-Ex,Biogenèse et pathologies du globule rouge(2011), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), Hardy, David, Biogenèse et pathologies du globule rouge - - GR-Ex2011 - ANR-11-LABX-0051 - LABX - VALID, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, and Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216)
Subjects: Falciparum, Genome-wide association study, Erythrocytes, Phosphoric Diester Hydrolases, [SDV]Life Sciences [q-bio], Plasmodium falciparum, Membrane Proteins, RNA-Binding Proteins, Anemia, General Medicine, Ethnic groups, General Biochemistry, Genetics and Molecular Biology, Immunity, Innate, Malaria, [SDV] Life Sciences [q-bio], Cohort Studies, DNA-Binding Proteins, Heritability, Immunoglobulin M, Splenomegaly, Humans, Malaria, Falciparum, Spleen
Abstract: In malaria-endemic areas, subjects from specific groups like Fulani have a peculiar protection against malaria, with high levels of IgM but also frequent anemia and splenomegaly. The mechanisms underlying this phenotype remain elusive. In Benin, West Africa, we measured the deformability of circulating erythrocytes in genetically distinct groups (including Fulani) living in sympatry, using ektacytometry and microsphiltration, a mimic of how the spleen clears rigid erythrocytes. Compared to non-Fulani, Fulani displayed a higher deformability of circulating erythrocytes, pointing to an enhanced clearance of rigid erythrocytes by the spleen. This phenotype was observed in individuals displaying markers of Plasmodium falciparum infection. The heritability of this new trait was high, with a strong multigenic component. Five of the top 10 genes selected by a population structure-adjusted GWAS, expressed in the spleen, are potentially involved in splenic clearance of erythrocytes (CHERP, MB, PALLD, SPARC, PDE10A), through control of vascular tone, collagen synthesis and macrophage activity. In specific ethnic groups, genetically-controlled processes likely enhance the innate retention of infected and uninfected erythrocytes in the spleen, explaining splenomegaly, anemia, cryptic intrasplenic parasite loads, hyper-IgM, and partial protection against malaria. Beyond malaria-related phenotypes, inherited splenic hyper-filtration of erythrocytes may impact the pathogenesis of other hematologic diseases.Research in contextEvidence before this studyThe genetic background of individuals influences their susceptibility to infectious diseases. Specific human groups, like the Fulani in Africa, react to malaria parasites (named Plasmodium) in a specific way. Upon infection, Fulani develop a grossly enlarged spleen, and high levels of anti-Plasmodium antibodies in their blood. They also carry smaller numbers of parasites in their blood, and thus are considered partially protected against malaria. The mechanisms underlying this natural protection, different from other natural protective mechanisms such as the sickle cell trait, are not well understood.Malaria impairs the deformability of red blood cells and the spleen is a key organ to controlling red blood cell quality. We have recently demonstrated that red blood cells containing live malaria parasites accumulate intensely in the spleen of subjects with long term exposure to these parasites. Enhanced retention of infected and uninfected red blood cells in the spleen would explain why the spleen is larger and why lower numbers of parasites are left in circulation. We thus explored whether the retention of infected and uninfected red blood cells could explain why Fulani are partially protected against malaria. Because it is unethical to perform spleen puncture or biopsies for research purposes, our explorations were indirect by carefully analyzing the properties of circulating red blood cells in a large number of subjects and by assessing whether observations could be explained by their genetic make-up.Added value of this studyIn more than 500 subjects, we confirmed the high frequency of large spleens in Fulani and, through 2 different methods, we demonstrated an enhanced deformability of their circulating red blood cells, that likely stems from the more efficient removal of the less deformable ones. This enhanced deformability was found to be inheritable based on carefully collected family links and refined analysis of genetic markers.Implications of all the available evidenceOur findings indicate that genes potentially driving the filtration of red blood cells by the spleen likely influence how subjects in specific groups in Africa and elsewhere react to malaria. While most previous hypotheses pointed to conventional immunological mechanisms as the trigger, we propose that a simple physiological mechanism that controls the quality of red blood cells may drive natural protection from malaria even before the intervention of immunological cells. A better understanding of these processes is of great importance in the context of malaria elimination efforts.These findings may also have an impact on the understanding of other red blood cell-related disorders, such as inherited red cell diseases, in which splenic filtration of abnormal red blood cells may precipitate splenic complications.
Published: 2022

3. Non-linearity of Metabolic Pathways Critically Influences the Choice of Machine Learning Model

Author: Ophélie Lo-Thong-Viramoutou, Philippe Charton, Xavier F. Cadet, Brigitte Grondin-Perez, Emma Saavedra, Cédric Damour, Frédéric Cadet, 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 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)-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)-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), Protein Engineering Accelerator [Paris] (PEACCEL), Energy Lab (ENERGY Lab), Université de La Réunion (UR), Instituto Nacional de Cardiologia Ignacio Chavez, and Charton, Philippe
Subjects: drug target identification, [SDV] Life Sciences [q-bio], Trypanosoma cruzi detoxification pathway, machine learning, non-linear modeling, Artificial Intelligence, [SDV]Life Sciences [q-bio], penicillin production, Entamoeba histolytica glycolysis pathway
Abstract: The use of machine learning (ML) in life sciences has gained wide interest over the past years, as it speeds up the development of high performing models. Important modeling tools in biology have proven their worth for pathway design, such as mechanistic models and metabolic networks, as they allow better understanding of mechanisms involved in the functioning of organisms. However, little has been done on the use of ML to model metabolic pathways, and the degree of non-linearity associated with them is not clear. Here, we report the construction of different metabolic pathways with several linear and non-linear ML models. Different types of data are used; they lead to the prediction of important biological data, such as pathway flux and final product concentration. A comparison reveals that the data features impact model performance and highlight the effectiveness of non-linear models (e.g., QRF: RMSE = 0.021 nmol·min−1 and R2 = 1 vs. Bayesian GLM: RMSE = 1.379 nmol·min−1 R2 = 0.823). It turns out that the greater the degree of non-linearity of the pathway, the better suited a non-linear model will be. Therefore, a decision-making support for pathway modeling is established. These findings generally support the hypothesis that non-linear aspects predominate within the metabolic pathways. This must be taken into account when devising possible applications of these pathways for the identification of biomarkers of diseases (e.g., infections, cancer, neurodegenerative diseases) or the optimization of industrial production processes.
Published: 2022
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4. 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

5. 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

6. Base-editing-mediated dissection of a γ-globin cis-regulatory element for the therapeutic reactivation of fetal hemoglobin expression

Author: Panagiotis Antoniou, Giulia Hardouin, Pierre Martinucci, Giacomo Frati, Tristan Felix, Anne Chalumeau, Letizia Fontana, Jeanne Martin, Cecile Masson, Megane Brusson, Giulia Maule, Marion Rosello, Carine Giovannangeli, Vincent Abramowski, Jean-Pierre de Villartay, Jean-Paul Concordet, Filippo Del Bene, Wassim El Nemer, Mario Amendola, Marina Cavazzana, Anna Cereseto, Oriana Romano, Annarita Miccio, Demokritos University of Thrace, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biodiversité et Biotechnologie Fongiques (BBF), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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 GR-Ex, Paris, France, University of Trento [Trento], National Research Council [Italy] (CNR), Institut Curie [Paris], Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Structure et Instabilité des Génomes (STRING), Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Equipe labellisée Ligue contre le Cancer, Muséum national d'Histoire naturelle (MNHN), Université Paris sciences et lettres (PSL), Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Département de Biothérapie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'investigation clinique Biothérapie [CHU Pitié-Salpêtrière] (CIC-BTi), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CIC AP-HP (hegp Ex-Broussais)/inserm, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre for Integrative Biology (CIBIO), University of Trento (CIBIO), Etablissement Français du Sang Provence-Alpes Côte-d'Azur et Corse (EFS), Généthon, Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Giovannangeli, Carine, Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), and Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: Multidisciplinary, [SDV]Life Sciences [q-bio], beta-Thalassemia, General Physics and Astronomy, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, General Chemistry, Anemia, Sickle Cell, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Hematopoietic Stem Cells, General Biochemistry, Genetics and Molecular Biology, [SDV] Life Sciences [q-bio], [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, gamma-Globins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Fetal Hemoglobin, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Sickle cell disease and β-thalassemia affect the production of the adult β-hemoglobin chain. The clinical severity is lessened by mutations that cause fetal γ-globin expression in adult life (i.e., the hereditary persistence of fetal hemoglobin). Mutations clustering ~200 nucleotides upstream of the HBG transcriptional start sites either reduce binding of the LRF repressor or recruit the KLF1 activator. Here, we use base editing to generate a variety of mutations in the −200 region of the HBG promoters, including potent combinations of four to eight γ-globin-inducing mutations. Editing of patient hematopoietic stem/progenitor cells is safe, leads to fetal hemoglobin reactivation and rescues the pathological phenotype. Creation of a KLF1 activator binding site is the most potent strategy – even in long-term repopulating hematopoietic stem/progenitor cells. Compared with a Cas9-nuclease approach, base editing avoids the generation of insertions, deletions and large genomic rearrangements and results in higher γ-globin levels. Our results demonstrate that base editing of HBG promoters is a safe, universal strategy for treating β-hemoglobinopathies.
Published: 2022

7. 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

8. Structural variations within proteins can be as large as variations observed across their homologues

Author: Narayanaswamy Srinivasan, Bernard Offmann, Iyanar Vetrivel, Frédéric Cadet, Alexandre G. de Brevern, 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, Unité de fonctionnalité et ingénierie de protéines (UFIP), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), 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), Dynamique des Structures et Interactions des Macromolécules Biologiques - Pôle de La Réunion (DSIMB Réunion), 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), PEACCEL, Molecular Biophysics Unit, Indian Institute of Science, Région Réunion and the Fond Social Européen, Conseil Regional des Pays de la Loire in the framework of GRIOTE project, 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), Université de La Réunion, Faculty of Sciences and Technology, Indo-French Centre for the Promotion of Advanced Research / CEFIPRA for collaborative grant (number 5302-2), Department of Biotechnology, Government of India, J.C. Bose National Fellow, ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), 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 Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Subjects: 0301 basic medicine, Structural alphabet, [SDV]Life Sciences [q-bio], Datasets as Topic, Molecular Dynamics Simulation, Molecular dynamics, Biochemistry, Mice, 03 medical and health sciences, Protein structural variation, Protein structure, Protein Domains, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Databases, Protein, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Bacteria, 030102 biochemistry & molecular biology, Chemistry, Proteins, General Medicine, Protein superfamily, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Nmr data, [SDV] Life Sciences [q-bio], 030104 developmental biology, Protein conformation, Structural Homology, Protein, Structural plasticity, Biophysics
Abstract: International audience; Understanding the structural plasticity of proteins is key to understanding the intricacies of their functions and mechanistic basis. In the current study, we analyzed the available multiple crystal structures of the same protein for the structural differences. For this purpose we used an abstraction of protein structures referred as Protein Blocks (PBs) that was previously established. We also characterized the nature of the structural variations for a few proteins using molecular dynamics simulations. In both the cases, the structural variations were summarized in the form of substitution matrices of PBs. We show that certain conformational states are preferably replaced by other specific conformational states. Interestingly, these structural variations are highly similar to those previously observed across structures of homologous proteins (r 2 =0.923) or across the ensemble of conformations from NMR data (r 2 =0.919). Thus our study quantitatively shows that overall trends of structural changes in a given protein are nearly identical to the trends of structural differences that occur in the topologically equivalent positions in homologous proteins. Specific case studies are used to illustrate the nature of these structural variations.
Published: 2019

9. Naive and memory CD4+ T cell subsets can contribute to the generation of human Tfh cells

Author: Jeger-Madiot, Raphaël, Vaineau, Romain, Heredia, Maud, Tchitchek, Nicolas, Bertrand, Lisa, Pereira, Mathias, Konza, Océane, Gouritin, Bruno, Hoareau-Coudert, Bénédicte, Corneau, Aurélien, Blanc, Catherine, Savier, Eric, Buffet, Pierre, Six, Adrien, Klatzmann, David, Moris, Arnaud, Graff-Dubois, Stéphanie, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Cytométrie Pitié-Salpêtrière (PASS-CYPS), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Service d'Imagerie et de Cytométrie [CHU Saint-Antoine] (UMS LUMIC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de Chirurgie Digestive, Hépato-Bilio-pancréatique et Transplantation Hépatique [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], 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), Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-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)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], 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)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Centre d'Immunologie et des Maladies Infectieuses (CIMI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), 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 National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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 Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], and Tchitchek, Nicolas
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], [SDV.IMM]Life Sciences [q-bio]/Immunology
Abstract: International audience; CD4 + T follicular helper cells (Tfh) promote B cell maturation and antibody production in secondary lymphoid organs. By using an innovative culture system based on splenocyte stimulation, we studied the dynamics of naive and memory CD4 + T cells during the generation of a Tfh cell response. We found that both naive and memory CD4 + T cells can acquire phenotypic and functional features of Tfh cells. Moreover, we show here that the transition of memory as well as naive CD4 + T cells into the Tfh cell profile is supported by the expression of pro-Tfh genes, including transcription factors known to orchestrate Tfh cell development. Using this culture system, we provide pieces of evidence that HIV infection differentially alters these newly identified pathways of Tfh cell generation. Such diversity in pathways of Tfh cell generation offers a new framework for the understanding of Tfh cell responses in physiological and pathological contexts.
Published: 2021

10. 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

11. Exposure to inorganic particles in paediatric sarcoidosis: the PEDIASARC study

Author: Véronique Houdouin, Catherine Cavalin, Antoine Deschildre, Jean-Marc Naccache, Catherine Chapelon-Abric, Céline Delestrain, Julien Haroche, Ralph Epaud, Ulrich Meinzer, Simon Chauveau, Fleur Cohen-Aubart, Mickaël Catinon, Florence Jeny, Odile Macchi, Sylvain Le Jeune, Hilario Nunes, Michel Vincent, Paul-André Rosental, Manon Brocvielle, Marie-Hélène Odièvre, Marie-Emeline Montagne, S. Mattioni, Dominique Valeyre, Karine Juvin, Annick Clement, Dominique Israël-Biet, A. Dossier, Nadia Nathan, Jacques Brouard, François Lionnet, Lucile Sesé, Rola Abou Taam, Christophe Delacourt, Marie Mittaine, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Recherche Interdisciplinaire en Sciences Sociales (IRISSO), Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Groupe de Recherche sur l'Adaptation Microbienne (GRAM 2.0), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service de Pneumologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Département de médecine interne et immunologie clinique [CHU Pitié-Salpêtrière] (DMIIC), CHU Pitié-Salpêtrière [AP-HP], Service de pneumologie [Avicenne], Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Pneumologie et allergologie pédiatriques [CHU Jeanne de Flandre, Lille], Hôpital Jeanne de Flandre [Lille], Université de Lille, Service de Pneumologie et d'Allergologie Pédiatriques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biomécanique cellulaire et respiratoire (BCR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Service de Pneumologie, soins intensifs (Pneumo - HEGP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Médecine Interne = Hôpital de jour de médecine [CHU Tenon], CHU Tenon [AP-HP], Centre d'études européennes et de politique comparée (Sciences Po, CNRS) (CEE), Sciences Po (Sciences Po)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de référence maladies rares des maladies pulmonaires rares de l’adulte (CHU Dijon) (CRMR des maladies pulmonaires rares de l’adulte), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hypoxie et Poumon : pneumopathologies fibrosantes, modulations ventilatoires et circulatoires (H&P), UFR SMBH-Université Sorbonne Paris Nord, 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), Centre d'histoire de Sciences Po (Sciences Po) (CHSP), Sciences Po (Sciences Po), Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Observatoire du Samu Social de Paris, CHU Necker - Enfants Malades [AP-HP], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre des maladies respiratoires rares Respirare [CHI Créteil], 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), AP-HP - Hôpital Bichat - Claude Bernard [Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de médecine interne [Avicenne], Centre de Référence pour les Maladies Rhumatologiques Auto-Immunes et Systémiques [CHU Necker] (RAISE), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de pneumologie [Hôpital Foch], Hôpital Foch [Suresnes], Groupe Hospitalier Paris Saint-Joseph (hpsj), Laboratoire interdisciplinaire d'évaluation des politiques publiques (Sciences Po) (LIEPP), Centre d'études de l'emploi et du travail (CEET), 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)-Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.)-Ministère du Travail, de l'Emploi et de la Santé, contract grant sponsor: European Research Council (ERC) / SILICOSISproject / Principal investigator: Paul-André Rosental, Contract grant number: ERC2011-ADG_20110406ˆProject ID: 295817. Statistical analysis: RespiFIL funds, European Project: 295449,EC:FP7:ERC,ERC-2011-ADG_20110406,DARTCH(2012), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), 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 Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université de Caen Normandie (UNICAEN), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Service de Médecine Interne [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'études européennes et de politique comparée (CEE), Centre d'histoire de Sciences Po (CHSP), Service de médecine interne et d'immunologie clinique [CHU Pitié-Salpêtrière], and Centre National de la Recherche Scientifique (CNRS)-Sciences Po (Sciences Po)
Subjects: Pulmonary and Respiratory Medicine, Adult, medicine.medical_specialty, paediatric interstitial lung disease, [SDV]Life Sciences [q-bio], [SHS]Humanities and Social Sciences, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Occupational Exposure, medicine, Humans, sarcoidosis, Occupational lung disease, Occupations, Child, Inorganic particles, 030304 developmental biology, 0303 health sciences, Median score, rare lung diseases, business.industry, Dust, Environmental exposure, Environmental Exposure, medicine.disease, 3. Good health, 030228 respiratory system, Metal dust, Talc, Sarcoidosis, business, occupational lung disease
Abstract: International audience; Inorganic antigens may contribute to paediatric sarcoidosis. Thirty-six patients matched with 36 healthy controls as well as a group of 21 sickle-cell disease (SCD) controls answered an environmental questionnaire. Patients' indirect exposure to inorganic particles, through coresidents' occupations, was higher than in healthy and SCD controls (median score: 2.5 (0.5-7) vs 0.5 (0-2), p=0.003 and 1 (0-2), p=0.012, respectively), especially for construction, exposures to metal dust, talc, abrasive reagents and scouring products. Wood or fossil energies heating were also linked to paediatric sarcoidosis. This study supports a link between mineral environmental exposure due to adult coresident occupations and paediatric sarcoidosis.
Published: 2021

12. 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

13. Hierarchical Structure of Protein Sequence

Author: Yuri P. Kozmin, Alexandre G. de Brevern, Alexei N. Nekrasov, Anastasia A. Anashkina, Sergey V. Kozyrev, Rustam H. Ziganshin, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry (IBCh RAS), Russian Academy of Sciences [Moscow] (RAS), Steklov Mathematical Institute [Moscow] (SMI), 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 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)-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), Engelhardt Institute of Molecular Biology (ISTC), ANR-19-CE17-0021,BASIN,Cibler la voie IL-3 pour inhiber la fonction basophile en conditions inflammatoires(2019), Université Paris Cité, Equipe HAL, and Cibler la voie IL-3 pour inhiber la fonction basophile en conditions inflammatoires - - BASIN2019 - ANR-19-CE17-0021 - AAPG2019 - VALID
Subjects: 0301 basic medicine, Models, Molecular, Protein Conformation, QH301-705.5, Structure (category theory), Computational biology, hierarchy, Pentapeptide repeat, Catalysis, Article, Inorganic Chemistry, 03 medical and health sciences, protein sequence, Protein structure, Protein sequencing, Humans, Hierarchical organization, biochemistry, Supersecondary structure, Physical and Theoretical Chemistry, protein structure, ANIS method, Biology (General), Databases, Protein, Molecular Biology, QD1-999, Spectroscopy, Mathematics, Sequence, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, 030102 biochemistry & molecular biology, Hierarchy (mathematics), Basis (linear algebra), Organic Chemistry, Proteins, super secondary structure, General Medicine, Computer Science Applications, Chemistry, 030104 developmental biology, Algorithms, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Most non-communicable diseases are associated with dysfunction of proteins or protein complexes. The relationship between sequence and structure has been analyzed for a long time, and the analysis of the sequences organization in domains and motifs remains an actual research area. Here, we propose a mathematical method for revealing the hierarchical organization of protein sequences. The method is based on the pentapeptide as a unit of protein sequences. Employing the frequency of occurrence of pentapeptides in sequences of natural proteins and a special mathematical approach, this method revealed a hierarchical structure in the protein sequence. The method was applied to 24,647 non-homologous protein sequences with sizes ranging from 50 to 400 residues from the NRDB90 database. Statistical analysis of the branching points of the graphs revealed 11 characteristic values of y (the width of the inscribed function), showing the relationship of these multiple fragments of the sequences. Several examples illustrate how fragments of the protein spatial structure correspond to the elements of the hierarchical structure of the protein sequence. This methodology provides a promising basis for a mathematically-based classification of the elements of the spatial organization of proteins. Elements of the hierarchical structure of different levels of the hierarchy can be used to solve biotechnological and medical problems.
Published: 2021

14. Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24

Author: Jennifer Cullen, Brandon A. Mahal, Maria Elena Martinez, Robin J. Leach, Brent S. Rose, Marie-Élise Parent, Catherine M. Tangen, Pascal Blanchet, Tyler M. Seibert, Jong Y. Park, Jennifer J. Hu, Geraldine Cancel-Tassin, Rosalind A. Eeles, Chun Chieh Fan, Esther M. John, Roshan Karunamuni, James L. Mohler, Jack A. Taylor, Melinda C. Aldrich, Artitaya Lophatananon, Luc Multigner, Ole A. Andreassen, Thérèse Truong, Marc Romana, Florence Menegaux, Ian M. Thompson, Laurent Brureau, Kenneth Muir, Olivier Cussenot, Dana C. Crawford, Adam S. Kibel, Gyorgy Petrovics, Asona Lui, Elizabeth T. H. Fontham, Bettina F. Drake, Jeannette T. Bensen, Ian G. Mills, William S. Bush, Hui-Yi Lin, Zsofia Kote-Jarai, Wesley K. Thompson, Maureen Sanderson, Anders M. Dale, Wei Zheng, Jay H. Fowke, Phyllis J. Goodman, William J. Blot, Minh-Phuong Huynh-Le, Collaborators, UKGPCS, Consortium, PRACTICAL, University of California [San Diego] (UC San Diego), University of California, The institute of cancer research [London], Centre de Recherche pour les Pathologies Prostatiques [Paris] (CeRePP), Sorbonne Université (SU), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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 ), CHU Pointe-à-Pitre/Abymes [Guadeloupe], 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), This study was funded in part by grants from the University of California (#C21CR2060), the United States National Institute of Health/National Institute of Biomedical Imaging and Bioengineering (#K08EB026503), the Research Council of Norway (#223273), KG Jebsen Stiftelsen, and South East Norway Health Authority., University of California (UC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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 ), 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: Male, Multifactorial Inheritance, Cancer Research, Urology, Genetic genealogy, 030232 urology & nephrology, Black People, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Polymorphism, Single Nucleotide, Risk Assessment, White People, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Genotype, Genetic variation, Humans, Medicine, Genetic Predisposition to Disease, 1000 Genomes Project, Prostate cancer risk, Proportional hazards model, business.industry, Prostatic Neoplasms, 3. Good health, Oncology, Case-Control Studies, 030220 oncology & carcinogenesis, Relative risk, business, Chromosomes, Human, Pair 8, Demography
Abstract: Background We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ. Materials and methods Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC. Results CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings. Conclusion We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.
Published: 2021

15. Characterisation of Asp669Tyr Piezo1 cation channel activity in red blood cells: an unexpected phenotype

Author: Véronique Picard, Guillaume Bouyer, Martin Figeac, Judith Bruge, Claude Preudhomme, Morgane Nudel, Wassim El Nemer, David Monedero Alonso, Christian Rose, Laurent Peres, Shéhérazade Sebda, Stéphane Egée, Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), 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), Hôpital Claude Huriez [Lille], CHU Lille, Plateforme de génomique fonctionnelle et structurelle [Lille], Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Université de Lille, Droit et Santé, Service d'Hématologie biologique [AP-HP Hôpital Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris Sud-Paris Saclay, 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'Hématologie Biologique, Centre de biologie Pathologie PM Degand, Université catholique de Lille (UCL), Bouyer, Guillaume, Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, 0303 health sciences, Chemistry, PIEZO1, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], medicine.disease, Phenotype, Red cell membrane, 03 medical and health sciences, 0302 clinical medicine, Hereditary stomatocytosis, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Biophysics, medicine, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Cation transport, Cation channel activity, ComputingMilieux_MISCELLANEOUS, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, 030304 developmental biology, 030215 immunology
Abstract: International audience
Published: 2021

16. Dépistage néonatal de la drépanocytose en France

Author: Valentine Brousse, Malika Benkerrou, Bichr Allaf, 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), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Novartis Pharma, 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 de Paris (UP), Hôpital Robert Debré, 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), and Sciences, EDP
Subjects: Gynecology, medicine.medical_specialty, business.industry, [SDV]Life Sciences [q-bio], General Medicine, General Biochemistry, Genetics and Molecular Biology, 3. Good health, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Medicine, business, 030215 immunology
Abstract: International audience; Le dépistage néonatal de la drépanocytose, la plus fréquente des maladies rares en France, a permis, entre 1984 et 2019, l’identification de 9 260 nouveau-nés atteints de drépanocytose (dont 586 en 2019) et de 180 687 hétérozygotes AS. Ce dépistage a permis la mise en œuvre précoce de mesures prophylactiques chez ces enfants, grâce à un tissu sanitaire et social structuré. Depuis que ce dépistage est organisé, on a pu observer, dès l’âge pédiatrique, une diminution majeure de la mortalité et de la morbidité de la drépanocytose, qui concerne notamment les complications infectieuses invasives, anémiques et neuro-vasculaires. En métropole, ce dépistage garde la particularité d’être ciblé vers les nouveau-nés dont les parents sont originaires de régions à risque. La fréquence croissante de la drépanocytose (1/1 303 nouveau-nés identifiés en 2019 contre 1/2 089 en 2009) et l’augmentation de la fréquence des hétérozygotes plaident aujourd’hui pour un dépistage systématique étendu à tous les nouveau-nés et pour une meilleure information sur cette maladie, devenue un enjeu majeur de santé publique.
Published: 2021

17. 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

18. 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

19. A Review of the Literature Organized Into a New Database: RHeference

Author: Aline Floch, Stéphane Téletchéa, Christophe Tournamille, Alexandre G. de Brevern, France Pirenne, 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), 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 Paris Cité (UPCité), Unité de fonctionnalité et ingénierie de protéines (UFIP), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Université des Antilles (UA), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), 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 TOURNAMILLE, Christophe
Subjects: Databases, Factual, Computer science, Clinical Biochemistry, Data loss, 030204 cardiovascular system & hematology, computer.software_genre, Set (abstract data type), Database, 03 medical and health sciences, 0302 clinical medicine, RH blood group, Immunogenetics, Humans, Architecture, Alleles, Complement (set theory), Rh-Hr Blood-Group System, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Biochemistry (medical), Hematology, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Data access, Phenotype, Blood Group Antigens, Data architecture, computer, 030215 immunology, RHD gene
Abstract: International audience; Hundreds of articles containing heterogeneous data describe D variants or add to the knowledge of known alleles. Data can be difficult to find despite existing online blood group resources and genetic and literature databases. We have developed a modern, elaborate database for D variants, thanks to an extensive literature search with meticulous curation of 387 peer-reviewed articles and 80 abstracts from major conferences and other sources. RHeference contains entries for 710 RHD alleles, 11 RHCE alleles, 30 phenotype descriptions (preventing data loss from historical sources), 35 partly characterized alleles, 3 haplotypes, and 16 miscellaneous entries. The entries include molecular, phenotypic, serological, alloimmunization, haplotype, geographical, and other data, detailed for each source. The main characteristics are summarized for each entry. The sources for all information are included and easily accessible through doi and PMID links. Overall, the database contains more than 10,000 individual pieces of data. We have set up the database architecture based on our previous expertise on database setup and biocuration for other topics, using modern technologies such as the Django framework, BioPython, Bootstrap, and Jquery. This architecture allows an easy access to data and enables simple and complex queries: combining multiple mutations, keywords, or any of the characteristics included in the database. RHeference provides a complement to existing resources and will continue to grow as our knowledge expands and new articles are published. The database url is http://www.rheference.org/.
Published: 2021

20. 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

21. Sickle Cell Maculopathy: Microstructural Analysis Using OCTA and Identification of Genetic, Systemic, and Biological Risk Factors

Author: Malik Acomat, Kevin Zuber, Philippe Connes, Thierry David, Laurence Beral, Selim Farès, Marc Romana, Coralie Zorobabel, Maryse Etienne-Julan, Elise Boulanger-Scemama, Sophie Hajjar, 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), CHU Pointe-à-Pitre/Abymes [Guadeloupe], 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 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]), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Université des Antilles (UA), and CCSD, Accord Elsevier
Subjects: Male, genetic structures, Hemoglobins, Abnormal, Hemoglobin, Sickle, Cell, Visual Acuity, Multimodal Imaging, 0302 clinical medicine, Risk Factors, Genotype, Fluorescein Angiography, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Biological risk factors, Hemoglobin C, Blood Coagulation Disorders, Middle Aged, 3. Good health, Prothrombin ratio, medicine.anatomical_structure, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, 030220 oncology & carcinogenesis, Female, Tomography, Optical Coherence, Adult, medicine.medical_specialty, Adolescent, Macular ischemia, Anemia, Sickle Cell, Hemolysis, Young Adult, 03 medical and health sciences, Retinal Diseases, Ophthalmology, medicine, Humans, In patient, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, business.industry, Retinal Vessels, Optical coherence tomography angiography, medicine.disease, eye diseases, Cross-Sectional Studies, 030221 ophthalmology & optometry, Maculopathy, sense organs, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Purpose To identify genetic, systemic, and biological factors associated with the occurrence of sickle cell maculopathy (SCM). To evaluate microvascular macular alterations using optical coherence tomography angiography (OCTA) in sickle cell disease (SCD). Design Cross-sectional study. Methods One hundred fifty-one eyes of 78 adult SCD patients (43 HbSS, 30 HbSC, 4 S/β+, and 1 HbS Lepore) and 40 eyes of 20 healthy controls underwent spectral-domain optical coherence tomography (SDOCT) and OCTA using Spectralis HRA+OCT (Heidelberg Engineering, Heidelberg, Germany). We analyzed the occurrence of SCM, the foveal avascular zone (FAZ) area, and the severity of macular ischemia and studied their relationships with genetic, systemic, and biological parameters using multivariate logistic regression analysis. Results Maculopathy occurred in 66 eyes (44%), and more frequently in HbSS patients (71%, P = .004). Multivariate analysis identified HbSS genotype and lower prothrombin ratio (PR) as independently associated with SCM (P = .01). Proliferative sickle cell retinopathy was also associated with SCM (P = .02). FAZ enlargement was associated with higher lactate dehydrogenase level (P = .02). Macular ischemia was more severe in patients with lower hemoglobin level (P = .004) and lower PR (P = .01). No flow areas were identified with OCTA even in eyes with no macular thinning (36 eyes, 42%) and appeared more frequently in the temporal superior subfield (36%). Conclusions HbSS genotype, abnormal coagulation and hemolysis increase the risk of SCM. OCTA provides valuable criteria to identify potential risk factors of SCM. OCTA also improves detection of early microvascular changes before the onset of macular thinning.
Published: 2021

22. 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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23. 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

24. 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

25. Neuropathic Pain in Children with Sickle Cell Disease: The Hidden Side of the Vaso-Occlusive Crisis

Author: Malika Benkerrou, Anne-Françoise Thiollier, Enora Le Roux, Bérengère Koehl, Jeanne Sigalla, Sophie Dugue, Artemis Toumazi, Laurent Holvoet, Nathalie Duparc Alegria, Hôpital Robert Debré, Centre d'Investigation Clinique 1426 (CIC 1426), 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), Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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 Gestionnaire, Hal Sorbonne Université
Subjects: medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, pediatrics, [SDV]Life Sciences [q-bio], DN-4, Disease, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, hemic and lymphatic diseases, medicine, Prospective cohort study, neuropathic pain, vaso-occlusive crisis, business.industry, lcsh:RJ1-570, lcsh:Pediatrics, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Nociception, 030220 oncology & carcinogenesis, Pediatrics, Perinatology and Child Health, Neuropathic pain, Morphine, sickle cell disease, business, Vaso-occlusive crisis, 030217 neurology & neurosurgery, medicine.drug
Abstract: International audience; The majority of hospitalizations of patients with sickle cell disease (SCD) are related to painful vaso-occlusive crises (VOCs). Although the pain of VOC is classically nociceptive, neuropathic pain (NP) has also been demonstrated in SCD patients. The aim of our study is to specify the prevalence of NP during VOCs in SCD children using a dedicated scale and to measure its characteristics. We performed a prospective study that included SCD children hospitalized for an acute VOC. The presence of NP was sought with the DN4 scale on the second and fourth days of hospitalization. A total of 54 SCD children were included in the study. Overall, 41% of the patients (n = 22) experienced neuropathic pain during the VOC, mostly at an early stage (Day 2). The median age, the sex ratio, the location of the pain, and the morphine consumption were similar for patients with and without NP. Our study shows that neuropathic pain is very common during VOCs in SCD children. The absence of identified risk factors should prompt us to be vigilant regardless of the patient’s age, sex, and clinical presentation. View Full-Text
Published: 2021

26. African-specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer

Author: Ian M. Thompson, Roshan Karunamuni, Elizabeth T.H. Fontham, Tyler M. Seibert, Jennifer J. Hu, Jong Y. Park, Phyllis J. Goodman, Ian G. Mills, Luc Multigner, James L. Mohler, Jack A. Taylor, Anders M. Dale, Wei Zheng, Chun Fan, Bettina F. Drake, Jeannette T. Bensen, Florence Menegaux, Supriya Srivastava, Laurent Brureau, Wesley K. Thompson, Hui Yi Lin, Jay H. Fowke, Maureen Sanderson, Zsofia Kote-Jarai, Rosalind A. Eeles, Geraldine Cancel-Tassin, William Blot, Minh-Phuong Huynh-Le, Catherine M. Tangen, Melinda C. Aldrich, Olivier Cussenot, Gyorgy Petrovics, Ole A. Andreassen, Thérèse Truong, Jennifer Cullen, Robin J. Leach, Esther M. John, Artitaya Lophatananon, Pascal Blanchet, Marc Romana, Kenneth Muir, William S. Bush, Marie-Élise Parent, Dana C. Crawford, Adam S. Kibel, University of California [San Diego] (UC San Diego), University of California (UC), Healthlytix [San Diego], The Royal Marsden, The institute of cancer research [London], University of Manchester [Manchester], University of Warwick [Coventry], Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Vanderbilt University School of Engineering [Nashville] (VUSE), GeneDx [Gaithersburg, MD, USA], Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Washington University in Saint Louis (WUSTL), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, H. Lee Moffitt Cancer Center and Research Institute, Louisiana State University (LSU), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), National Institute of Environmental Health Sciences [Durham] (NIEHS-NIH), National Institutes of Health [Bethesda] (NIH), 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 ), 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), The University of Texas at San Antonio (UTSA), Stanford University, Vanderbilt University [Nashville], Case Western Reserve University [Cleveland], eResearch Collaboratory [Quebec City], McGill University = Université McGill [Montréal, Canada], University of Miami Leonard M. Miller School of Medicine (UMMSM), School of Medicine, Dentistry and Biomedical Sciences [Belfast], Queen's University [Belfast] (QUB), University of Oslo (UiO), KG Jebsen Stiftelsen, National Institute of Biomedical Imaging and BioengineeringUnited States Department of Health and Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Biomedical Imaging and Bioengineering (NIBIB) [K08EB026503], Research Council of NorwayResearch Council of Norway [223273], South East Norway Health Authority, U.S. Department of DefenseUnited States Department of Defense [W81XWH-13-1-0391], Chard-Hutchinson, Xavier, collaborators, UKGPCS, Consortium, PRACTICAL, University of California, 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), 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: Male, Cancer Research, Multifactorial Inheritance, Genotyping Techniques, [SDV]Life Sciences [q-bio], Age at diagnosis, Genome-wide association study, Prostate cancer, 0302 clinical medicine, Genotype, genome wide association study, 0303 health sciences, education.field_of_study, genotypic ancestry, Age Factors, Middle Aged, prostate cancer, Hazard, [SDV] Life Sciences [q-bio], Oncology, 030220 oncology & carcinogenesis, polygenic risk, Genetic genealogy, Population, Black People, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, SDG 3 - Good Health and Well-being, medicine, genomics, Humans, Genetic Predisposition to Disease, education, Proportional Hazards Models, 030304 developmental biology, Genetic association, health disparities, Models, Genetic, Proportional hazards model, business.industry, African, Prostatic Neoplasms, medicine.disease, Case-Control Studies, business, Demography
Abstract: IntroductionPolygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46), showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify SNPs that might improve performance in this population.Material and MethodsAnonymized genotypic data were obtained from the PRACTICAL consortium for 6,253 men with African genetic ancestry. Ten iterations of a ten-fold cross-validation search were conducted, to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African were compared using the same cross-validated approach.ResultsThree SNPs (rs76229939, rs74421890, and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47 to 4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65 to 0.53).ConclusionsWe identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans and Asians. A strategy of building on established statistical models might benefit ancestral groups generally under-represented in genome-wide association studies.
Published: 2021

27. A microfluidic device to statistically determine the distribution of sickle red cell subpopulations using bioimpedance

Author: Bruno Le Pioufle, Emile Martincic, Valentine Brousse, Wassim El Nemer, Maria A. Lizarralde-Iragorri, Olivier Français, Jean Roman, Tieying Xu, Le Pioufle, Bruno, Institut Jean Le Rond d'Alembert (DALEMBERT), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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 Nanosciences et de Nanotechnologies (C2N), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Electronique, Systèmes de communication et Microsystèmes (ESYCOM), 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)-Université Gustave Eiffel, Université Paris-Saclay, Laboratoire Lumière, Matière et Interfaces (LuMIn), CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), 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 Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre National de la Recherche Scientifique (CNRS)-Université Gustave Eiffel
Subjects: education.field_of_study, Red Cell, Bioimpedance, Population, Microfluidics, Cell subpopulations, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Sickle cell subpopulations, Statistical single cell analysis, Microfluidic, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Distribution (pharmacology), Statistical analysis, education, Biomedical engineering
Abstract: International audience; Bioimpedance measurements using microfluidic systems play an increasingly important role in cell analysis. In this paper, a microfluidic device mimicking the vasculature, in particular blood microcapillaries, and equipped with electrodes for bioimpedance sensing is described. Red blood cells, from patients suffering from sickle cell disease, were analyzed and discriminated in this device according to the physical parameters. The statistical position of different subpopulations on the Gaussian distribution of the whole sickle cell population was analyzed. A discrimination between sickle cell subpopulations, related to different density states, was achieved.
Published: 2021

28. Rapid clearance of storage-induced micro-erythrocytes alters transfusion recovery

Author: Madeleine Casimir, Benoit Henry, Camille Roussel, François Paye, Mickael Marin, Safi Dokmak, Alexandre Morel, Papa Alioune Ndour, Steven L. Spitalnik, Alain Sauvanet, Michael Dussiot, Philippe Roingeard, Pierre Buffet, Martin Colard, Geoffroy Volle, Caroline Le Van Kim, Yves Colin, Anaïs Martinez, Olivier Hermine, Eldad A. Hod, Sonia Georgeault, Aurélie Fricot-Monsinjon, Mallorie Depond, Pascal Amireault, Charlotte Chambrion, Gestionnaire, HAL Sorbonne Université 5, 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), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d’Hépatologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de chirurgie générale et digestive [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Plateforme des Microscopies, Université de Tours (UT), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Columbia University [New York], 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université de Tours, and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, mice, Immunology, Echinocyte, Spleen, 030204 cardiovascular system & hematology, Biochemistry, perfusion, Andrology, 03 medical and health sciences, 0302 clinical medicine, Blood product, retail clinics, Medicine, 030212 general & internal medicine, transfusion, business.industry, Quality assessment, concentrate dosage form, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Biology, Hematology, macrophages, medicine.anatomical_structure, spleen, business, Perfusion, Ex vivo, Clearance
Abstract: Permanent availability of red blood cells (RBCs) for transfusion depends on refrigerated storage, during which morphologically altered RBCs accumulate. Among these, a subpopulation of small RBCs, comprising type III echinocytes, spheroechinocytes, and spherocytes and defined as storage-induced microerythrocytes (SMEs), could be rapidly cleared from circulation posttransfusion. We quantified the proportion of SMEs in RBC concentrates from healthy human volunteers and assessed correlation with transfusion recovery, investigated the fate of SMEs upon perfusion through human spleen ex vivo, and explored where and how SMEs are cleared in a mouse model of blood storage and transfusion. In healthy human volunteers, high proportion of SMEs in long-stored RBC concentrates correlated with poor transfusion recovery. When perfused through human spleen, 15% and 61% of long-stored RBCs and SMEs were cleared in 70 minutes, respectively. High initial proportion of SMEs also correlated with high retention of RBCs by perfused human spleen. In the mouse model, SMEs accumulated during storage. Transfusion of long-stored RBCs resulted in reduced posttransfusion recovery, mostly due to SME clearance. After transfusion in mice, long-stored RBCs accumulated predominantly in spleen and were ingested mainly by splenic and hepatic macrophages. In macrophage-depleted mice, splenic accumulation and SME clearance were delayed, and transfusion recovery was improved. In healthy hosts, SMEs were cleared predominantly by macrophages in spleen and liver. When this well-demarcated subpopulation of altered RBCs was abundant in RBC concentrates, transfusion recovery was diminished. SME quantification has the potential to improve blood product quality assessment. This trial was registered at www.clinicaltrials.gov as #NCT02889133.
Published: 2021

29. Impact of protein dynamics on secondary structure prediction

Author: Alexandre G. de Brevern, 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)-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 CCSD, Accord Elsevier
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Molecular Dynamics Simulation, Protein secondary structure prediction, Biochemistry, Stability (probability), Protein Structure, Secondary, 03 medical and health sciences, Molecular dynamics, Protein structure, Sequence Analysis, Protein, Databases, Protein, Protein secondary structure, Mathematics, Potential impact, 030102 biochemistry & molecular biology, Protein Stability, Protein dynamics, Computational Biology, Proteins, General Medicine, [SDV] Life Sciences [q-bio], 030104 developmental biology, Biological system, Algorithms, Software, DSSP (hydrogen bond estimation algorithm)
Abstract: Protein 3D structures support their biological functions. As the number of protein structures is negligible in regards to the number of available protein sequences, prediction methodologies relying only on protein sequences are essential tools. In this field, protein secondary structure prediction (PSSPs) is a mature area, and is considered to have reached a plateau. Nonetheless, proteins are highly dynamical macromolecules, a property that could impact the PSSP methods. Indeed, in a previous study, the stability of local protein conformations was evaluated demonstrating that some regions easily changed to another type of secondary structure. The protein sequences of this dataset were used by PSSPs and their results compared to molecular dynamics to investigate their potential impact on the quality of the secondary structure prediction. Interestingly, a direct link is observed between the quality of the prediction and the stability of the assignment to the secondary structure state. The more stable a local protein conformation is, the better the prediction will be. The secondary structure assignment not taken from the crystallized structures but from the conformations observed during the dynamics slightly increase the quality of the secondary structure prediction. These results show that evaluation of PSSPs can be done differently, but also that the notion of dynamics can be included in development of PSSPs and other approaches such as de novo approaches.
Published: 2020

30. 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

31. Human erythroid differentiation requires VDAC1-mediated mitochondrial clearance

Author: Naomi Taylor, Martina Moras, Claude Hattab, Pedro Gonzalez-Menendez, Sandrina Kinet, Claudio Marcelo Fader, Michael Dussiot, Mariano A. Ostuni, Jérôme Larghero, Caroline Le Van Kim, Sophie D. Lefevre, MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut National de la Transfusion Sanguine [Paris] (INTS), 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), 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), Hematopoïèse et Immunothérapie, Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Universidad Nacional de Cuyo [Mendoza] (UNCUYO), Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), 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), National Institutes of Health [Bethesda] (NIH), The authors would like to thank Mrs Corentine Chrysostome et Mr Abdellah Nait for their secretarial and technical assistance, respectively. We acknowledge the Cell Sorting facility of the Institut Imagine, the ImagoSeine core facility of the Institut Jacques Monod, member of IBiSA and France-BioImaging (ANR-10-INBS-04) infrastructure, the Laboratory of Excellence GR-Ex (Grant ANR-11-LABX-0051) and the Guests Researcher program from Paris Diderot University. Martina Moras is funded by the European Union’s Horizon 2020 2 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 665850, the Club du Globule Rouge et du Fer (CGRF) and Société Française d’Hématologie (SFH). Pedro Gonzalez-Menendez is founded by the CLARIN-COFUND program from the Principado de Asturias and the European Union., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-11-LABX-0051,GR-Ex,Biogenèse et pathologies du globule rouge(2011), Hopital Saint-Louis [AP-HP] (AP-HP), and National Cancer Institute [Bethesda] (NCI-NIH)
Subjects: Programmed cell death, Erythroblasts, [SDV]Life Sciences [q-bio], Apoptosis, Mitochondrion, Article, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Erythroblast, hemic and lymphatic diseases, Organelle, Mitophagy, Animals, Humans, Erythropoiesis, 030304 developmental biology, Mammals, 0303 health sciences, [SHS.STAT]Humanities and Social Sciences/Methods and statistics, Chemistry, Voltage-Dependent Anion Channel 1, Cell Differentiation, hemic and immune systems, Hematology, Mitochondria, Cell biology, 030220 oncology & carcinogenesis, VDAC1, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, circulatory and respiratory physiology
Abstract: Erythroblast maturation in mammals is dependent on organelle clearance throughout terminal erythropoiesis. We studied the role of the outer mitochondrial membrane protein voltage-dependent anion channel-1 (VDAC1) in human terminal erythropoiesis. We show that short hairpin (shRNA)-mediated downregulation of VDAC1 accelerates erythroblast maturation. Thereafter, erythroblasts are blocked at the orthochromatic stage, exhibiting a significant decreased level of enucleation, concomitant with an increased cell death. We demonstrate that mitochondria clearance starts at the transition from basophilic to polychromatic erythroblast, and that VDAC1 downregulation induces the mitochondrial retention. In damaged mitochondria from non-erythroid cells, VDAC1 was identified as a target for Parkin-mediated ubiquitination to recruit the phagophore. Here, we showed that VDAC1 is involved in phagophore’s membrane recruitment regulating selective mitophagy of still functional mitochondria from human erythroblasts. These findings demonstrate for the first time a crucial role for VDAC1 in human erythroblast terminal differentiation, regulating mitochondria clearance.
Published: 2020

32. Identification of flux checkpoints in a metabolic pathway through white-box, grey-box and black-box modeling approaches

Author: Lo-Thong, Ophélie, Charton, Philippe, Cadet, Xavier F., Grondin-Perez, Brigitte, Saavedra, Emma, Damour, Cédric, Cadet, Frédéric, 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), Dynamique des Structures et Interactions des Macromolécules Biologiques - Pôle de La Réunion (DSIMB Réunion), 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)-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), Artificial Intelligence Department [Paris], Protein Engineering Accelerator [Paris] (PEACCEL), Laboratoire d'Energétique, d'Electronique et Procédés (LE2P), Université de La Réunion (UR), Instituto Nacional de Cardiología Ignacio Chávez [Mexico, Mexique], OLT is supported by a PhD grant from the Region Reunion and European Union (FEDER) under European Operational Program FEDER REUNION –2014/2020 file number 20171389, tiers 216275., 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), Bodescot, Myriam, 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)-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)-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 Energy Lab (ENERGY Lab)
Subjects: Science, Entamoeba histolytica, [SCCO.COMP]Cognitive science/Computer science, Models, Theoretical, Models, Biological, Article, Physical Phenomena, Kinetics, [SCCO.COMP] Cognitive science/Computer science, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Machine learning, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Medicine, Computational models, Computer Simulation, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Glycolysis, Metabolic Networks and Pathways, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, ComputingMilieux_MISCELLANEOUS
Abstract: International audience; Metabolic pathway modeling plays an increasing role in drug design by allowing better understanding of the underlying regulation and controlling networks in the metabolism of living organisms. However, despite rapid progress in this area, pathway modeling can become a real nightmare for researchers, notably when few experimental data are available or when the pathway is highly complex. Here, three different approaches were developed to model the second part of glycolysis of E. histolytica as an application example, and have succeeded in predicting the final pathway flux: one including detailed kinetic information (white-box), another with an added adjustment term (grey-box) and the last one using an artificial neural network method (black-box). Afterwards, each model was used for metabolic control analysis and flux control coefficient determination. The first two enzymes of this pathway are identified as the key enzymes playing a role in flux control. This study revealed the significance of the three methods for building suitable models adjusted to the available data in the field of metabolic pathway modeling, and could be useful to biologists and modelers.
Published: 2020

33. Management and prevention of anemia (acute bleeding excluded) in adult critical care patients

Author: Yoann Launey, Michaël Piagnerelli, Sylvain Ausset, Antoine Kimmoun, Frédéric Pène, L. Velly, Hafid Ait-Oufella, Olivier Huet, Matthieu Legrand, Hervé Quintard, Gerald Chanques, Cécile Aubron, Armand Mekontso Dessap, Pierre Buffet, Thomas Lescot, Sigismond Lasocki, Département d'Anesthésie-Réanimation [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Soins Intensifs [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [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)-Sorbonne Université (SU), Unité de soins intensifs [Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Ecoles Militaires de Santé de Lyon-Bron (ESA), 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), CHRU Brest - Département d'Anesthésie Réanimation (CHU - BREST - DAR), UFR Médecine [Brest], Université de Brest (UBO), Service d'Anesthésie Réanimation [Rennes], CHU Pontchaillou [Rennes], University of California [San Francisco] (UC San Francisco), University of California (UC), Hôpital Henri Mondor, Université libre de Bruxelles (ULB), Hôpital Pasteur [Nice] (CHU), Assistance Publique - Hôpitaux de Marseille (APHM), Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), PRES Université Nantes Angers Le Mans (UNAM), Hôpital Cochin [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 de Bretagne Occidentale - UFR Médecine et Sciences de la Santé (UBO UFR MSS), University of California [San Francisco] (UCSF), University of California, Hôpital de la Timone [CHU - APHM] (TIMONE), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Service de Réanimation Médicale [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Herrada, Anthony, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Hôpital d'instruction des Armées Percy, Service de Santé des Armées, Nutrition, Métabolismes et Cancer (NuMeCan), 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), Université Paris Diderot - Paris 7 (UPD7), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, MESH: Anemia, Blood transfusion, medicine.medical_treatment, Review, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, 0302 clinical medicine, 030202 anesthesiology, Medicine, 030212 general & internal medicine, education.field_of_study, lcsh:Medical emergencies. Critical care. Intensive care. First aid, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Anemia, General Medicine, Hematology, 3. Good health, Blood, MESH: Critical Illness, Economie, Public Health and Health Services, MESH: Hemorrhage, medicine.medical_specialty, Iron, Population, Clinical Sciences, Context (language use), MESH: Blood Transfusion, Guidelines, 03 medical and health sciences, MESH: Critical Care, Clinical Research, Severity of illness, Intensive care medicine, education, Erythropoietin, MESH: Humans, business.industry, 030208 emergency & critical care medicine, MESH: Adult, Evidence-based medicine, Guideline, lcsh:RC86-88.9, Phlebotomy, medicine.disease, Anesthesiology and Pain Medicine, MESH: Erythrocyte Transfusion, business
Abstract: Objective: Anemia is very common in critical care patients, on admission (affecting about two-thirds of patients), but also during and after their stay, due to repeated blood loss, the effects of inflammation on erythropoiesis, a decreased red blood cell life span, and haemodilution. Anemia is associated with severity of illness and length of stay. Methods: A committee composed of 16 experts from four scientific societies, SFAR, SRLF, SFTS and SFVTT, evaluated three fields: (1) anemia prevention, (2) transfusion strategies and (3) non-transfusion treatment of anemia. Population, Intervention, Comparison, and Outcome (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Analysis of the literature and formulation of recommendations were then conducted according to the GRADE® methodology. Results: The SFAR–SRLF guideline panel provided ten statements concerning the management of anemia in adult critical care patients. Acute haemorrhage and chronic anemia were excluded from the scope of these recommendations. After two rounds of discussion and various amendments, a strong consensus was reached for ten recommendations. Three of these recommendations had a high level of evidence (GRADE 1±) and four had a low level of evidence (GRADE 2±). No GRADE recommendation could be provided for two questions in the absence of strong consensus. Conclusions: The experts reached a substantial consensus for several strong recommendations for optimal patient management. The experts recommended phlebotomy reduction strategies, restrictive red blood cell transfusion and a single-unit transfusion policy, the use of red blood cells regardless of storage time, treatment of anaemic patients with erythropoietin, especially after trauma, in the absence of contraindications and avoidance of iron therapy (except in the context of erythropoietin therapy)., SCOPUS: re.j, info:eu-repo/semantics/published
Published: 2020

34. Analysis of Protein Disorder Predictions in the Light of a Protein Structural Alphabet

Author: Alexandre G. de Brevern, 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), Ministry of Research (France)., University of Paris, University Paris Diderot, Sorbonne Paris Cité (France)., French National Computing Centre CINES under grant no. A0070710961 by the GENCI (Grand Equipement National de Calcul Intensif)., Conseil Régional Ile de France. INTS (SESAME Grant)., University of La Réunion, Réunion Island (France)., National Institute for Health and Medical Research (INSERM, France)., National Institute for Blood Transfusion (INTS, France)., Indo-French Centre for the Promotion of Advanced Research/CEFIPRA: 5302-2., French National Computing Centre CINES under grant no. c2013037147 by the GENCI (Grand Equipement National de Calcul Intensif)., French National Computing Centre CINES under grant no. A0010707621 by the GENCI (Grand Equipement National de Calcul Intensif)., French National Computing Centre CINES under grant no. A0040710426 by the GENCI (Grand Equipement National de Calcul Intensif)., ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), ANR-19-CE17-0021,BASIN,Cibler la voie IL-3 pour inhiber la fonction basophile en conditions inflammatoires(2019), 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, Cibler la voie IL-3 pour inhiber la fonction basophile en conditions inflammatoires - - BASIN2019 - ANR-19-CE17-0021 - AAPG2019 - VALID, 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 Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Subjects: protein blocks, Protein Conformation, Computer science, Entropy, lcsh:QR1-502, Rigidity (psychology), Molecular Dynamics Simulation, Biochemistry, lcsh:Microbiology, 03 medical and health sciences, Molecular dynamics, intrinsic disorder regions, Protein structure, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Statistical physics, Databases, Protein, Molecular Biology, 030304 developmental biology, Flexibility (engineering), 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Continuum (topology), Communication, protein flexibility, 030302 biochemistry & molecular biology, Atom (order theory), intrinsic disorder proteins, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], mobility, molecular dynamics, Characterization (materials science), Intrinsically Disordered Proteins, nuclear magnetic resonance, Order (biology), protein structures, alpha-Synuclein, X-ray structures
Abstract: International audience; Intrinsically-disordered protein (IDP) characterization was an amazing change of paradigm in our classical sequence-structure-function theory. Moreover, IDPs are over-represented in major disease pathways and are now often targeted using small molecules for therapeutic purposes. This has had created a complex continuum from order-that encompasses rigid and flexible regions-to disorder regions; the latter being not accessible through classical crystallographic methodologies. In X-ray structures, the notion of order is dictated by access to resolved atom positions, providing rigidity and flexibility information with low and high experimental B-factors, while disorder is associated with the missing (non-resolved) residues. Nonetheless, some rigid regions can be found in disorder regions. Using ensembles of IDPs, their local conformations were analyzed in the light of a structural alphabet. An entropy index derived from this structural alphabet allowed us to propose a continuum of states from rigidity to flexibility and finally disorder. In this study, the analysis was extended to comparing these results to disorder predictions, underlying a limited correlation, and so opening new ideas to characterize and predict disorder.
Published: 2020

35. 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

36. 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

37. Characterization of red blood cell microcirculatory parameters using a bioimpedance microfluidic device

Author: Emile Martincic, Valentine Brousse, Olivier Français, Jean Roman, Tieying Xu, Bruno Le Pioufle, Jean-Pierre Lefevre, Maria A. Lizarralde-Iragorri, Rasta Ghasemi, Wassim El Nemer, 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)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre National de la Recherche Scientifique (CNRS)-Université Gustave Eiffel-CY Cergy Paris Université (CY)-École normale supérieure - Cachan (ENS Cachan)-Université Paris-Sud - Paris 11 (UP11)-École normale supérieure - Rennes (ENS Rennes)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre National de la Recherche Scientifique (CNRS)-Université Gustave Eiffel-CY Cergy Paris Université (CY)-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)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre National de la Recherche Scientifique (CNRS)-Université Gustave Eiffel-CY Cergy Paris Université (CY)-École normale supérieure - Cachan (ENS Cachan)-Université Paris-Sud - Paris 11 (UP11)-École normale supérieure - Rennes (ENS Rennes)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre National de la Recherche Scientifique (CNRS)-Université Gustave Eiffel-CY Cergy Paris Université (CY), 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 d'Alembert (IDA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Photophysique et Photochimie Supramoléculaires et Macromoléculaires (PPSM), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), Centre de Nanosciences et de Nanotechnologies (C2N), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut National de la Transfusion Sanguine [Paris] (INTS), Electronique, Systèmes de communication et Microsystèmes (ESYCOM), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre National de la Recherche Scientifique (CNRS)-Université Gustave Eiffel, École normale supérieure - Cachan (ENS Cachan)-Université Paris-Sud - Paris 11 (UP11)-École normale supérieure - Rennes (ENS Rennes)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre National de la Recherche Scientifique (CNRS)-Université Gustave Eiffel-CY Cergy Paris Université (CY), Université Paris-Saclay, Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), Laboratoire Lumière, Matière et Interfaces (LuMIn), CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), Systèmes d'Information et d'Analyse Multi-Echelles (SATIE-SIAME), École normale supérieure - Rennes (ENS Rennes)-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)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay)-Université Gustave Eiffel-CY Cergy Paris Université (CY)-École normale supérieure - Rennes (ENS Rennes)-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)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay)-Université Gustave Eiffel-CY Cergy Paris Université (CY), 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), 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)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Centre National de la Recherche Scientifique (CNRS)-Université Gustave Eiffel, and Le Pioufle, Bruno
Subjects: 0301 basic medicine, Erythrocytes, [SPI.NANO] Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics, Microfluidics, Cell, lcsh:Medicine, Transit time, Anemia, Sickle Cell, Article, Microcirculation, Hereditary spherocytosis, 03 medical and health sciences, 0302 clinical medicine, Lab-On-A-Chip Devices, Electric Impedance, medicine, Humans, [SPI.NANO]Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics, lcsh:Science, Multidisciplinary, Red Cell, Chemistry, lcsh:R, medicine.disease, Red blood cell, Microelectrode, Biosensors, 030104 developmental biology, medicine.anatomical_structure, lcsh:Q, Biomedical engineering, 030215 immunology
Abstract: This paper describes the use of a microfluidic device comprising channels with dimensions mimicking those of the smallest capillaries found in the human microcirculation. The device structure, associated with a pair of microelectrodes, provides a tool to electrically measure the transit time of red blood cells through fine capillaries and thus generate an electrical signature for red blood cells in the context of human erythroid genetic disorders, such as sickle cell disease or hereditary spherocytosis, in which red cell elasticity is altered. Red blood cells from healthy individuals, heated or not, and red blood cells from patients with sickle cell disease or hereditary spherocytosis where characterized at a single cell level using our device. Transit time and blockade amplitude recordings were correlated with microscopic observations, and analyzed. The link between the electrical signature and the mechanical properties of the red blood cells is discussed in the paper, with greater transit time and modified blockade amplitude for heated and pathological red blood cells as compared to those from healthy individuals. Our single cell-based methodology offers a new and complementary approach to characterize red cell mechanical properties in human disorders under flow conditions mimicking the microcirculation.
Published: 2020

38. 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

39. CX3CL1 homo-oligomerization drives cell-to-cell adherence

Author: Jean-Jacques Lacapère, Patricia Hermand, Claude Hattab, Elodie Desuzinges-Mandon, Christophe Combadière, Frederic Pincet, Julie Guellec, Audrey Coens, Anass Jawhari, Soria Iatmanen-Harbi, Patrick F.J. Fuchs, Mariano A. Ostuni, Noëlline Guillou, Philippe Deterre, Emeline Saindoy, Olivier Lequin, 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), Immunologie et Embryologie Moléculaires (IEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-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), CALIXAR, 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), Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire de Spectroscopies et Structures Biomoléculaires (LSSBM) (EA3305), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Yale University School of Medicine, EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Yale School of Medicine [New Haven, Connecticut] (YSM), and Deterre, Philippe
Subjects: Molecular model, [SDV.IMM] Life Sciences [q-bio]/Immunology, lcsh:Medicine, Peptide, CHO Cells, Article, Cell Line, 03 medical and health sciences, 0302 clinical medicine, Cricetulus, Single-molecule biophysics, Chlorocebus aethiops, Animals, Humans, Cell adhesion, lcsh:Science, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Multidisciplinary, COS cells, Chemistry, Cell adhesion molecule, Chemokine CX3CL1, lcsh:R, Fluorescence recovery after photobleaching, Membrane Proteins, Membrane structure and assembly, Single-molecule experiment, Transmembrane protein, 3. Good health, HEK293 Cells, COS Cells, Biophysics, [SDV.IMM]Life Sciences [q-bio]/Immunology, lcsh:Q, Biological fluorescence, 030217 neurology & neurosurgery
Abstract: International audience; During inflammatory response, blood leukocytes adhere to the endothelium. This process involves numerous adhesion molecules, including a transmembrane chemokine, CX3CL1, which behaves as a molecular cluster. How this cluster assembles and whether this association has a functional role remain unknown. The analysis of CX3CL1 clusters using native electrophoresis and single molecule fluorescence kinetics shows that CX3CL1 is a homo-oligomer of 3 to 7 monomers. Fluorescence recovery after photobleaching assays reveal that the CX3CL1-transmembrane domain peptide self-associates in both cellular and acellular lipid environments, while its random counterpart (i.e. peptide with the same residues in a different order) does not. This strongly indicates that CX3CL1 oligomerization is driven by its intrinsic properties. According to the molecular modeling, CX3CL1 does not associate in compact bundles but rather with monomers linearly assembled side by side. Finally, the CX3CL1 transmembrane peptide inhibits both the CX3CL1 oligomerization and the adhesive function, while its random counterpart does not. This demonstrates that CX3CL1 oligomerization is mandatory for its adhesive potency. Our results provide a new direction to control CX3CL1-dependent cellular adherence in key immune processes. The migration of blood leukocytes to damaged tissues is the first step of the inflammation process and involves a sequence of coordinated interactions between leukocytes and endothelial cells 1-3. The chemotactic cytokines called chemokines that primarily attract leukocytes, are central to the physiological and pathological inflamma-tory processes 4-6. Chemokines trigger leukocyte activation and their firm adhesion to the inflamed endothelium, mainly through integrins 7-9. Two members of the chemokine family are exceptions: CXCL16 and CX3CL1. In addition to their chemokine domain (CD), these two chemokines possess three domains: a mucin-like stalk, a transmembrane (TM) domain, and a cytosolic tail 10,11. When interacting with their cognate receptors (CXCR6 and CX3CR1, respectively), these chemokines induce cell-cell adhesion 12. CXCL16 and CX3CL1 can also be cleaved by metalloproteinases, such as ADAM10 and ADAM17 13-15 , to produce a soluble form with chemotactic functions. The CX3CL1 chemokine, with its unique CX3CR1 receptor 16 , is involved in adherence to the endothelium of the inflammatory monocyte population (CD14 hi CD16-CX3CR1 + CCR2 + in humans, Ly6C hi CX3CR1 + CCR2 + in mice) 12,17-20 likely through interaction with platelets 21,22. This chemokine is also involved in the recruitment of NK lymphocytes 23,24 and in lymphocyte survival as in allergic diseases 25 , as well as in monocytic 26,27 and neuronal survival 28-31. An additional function of the CX3CR1-CX3CL1 pair is the regulation of the patrolling behavior and the margination of monocytes in blood vessels 32,33 or their adherence to the bone marrow 34. The CX3CL1 chemokine is also involved in cytoadhesion of red blood cells infected with the malaria parasite Plasmodium
Published: 2020

40. Modelling of Metabolic Pathways for Biomolecule Production in Cell-Free Systems

Author: Ajjolli Nagaraja, Anamya, Energy Lab (ENERGY Lab), Université de La Réunion (UR), 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 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)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Université de la Réunion, Brigitte Grondin-Perez, Frédéric Cadet, Philippe Charton, and STAR, ABES
Subjects: Artificial neural network, Biomolécules, Apprentissage automatique, Modélisation cinétique, Biomolecule, Kinetic modelling, Pathway optimisation, Réseau neuronal artificiel, Machine learning, Cell-free systems, Modélisation des voies métaboliques, Malate synthesis, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Metabolic pathway modelling, Systèmes acellulaires, Optimisation des voies, Synthèse du malate, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: Cell-free systems (CFS) are emerging as a powerful platform for biomanufacturing. The optimisation of the cell-free system is important to achieve maximum yield. The experimental optimisation is time-consuming and expensive. Different kinds of modelling emerged in the last decades, helping to optimise the pathway of interest in a shorter time at a low cost. In this study, we tested two approaches: systemic through the implementation of neural networks, and analytical through the use of differential equations. In the first step, an artificial neural network model was built to predict the flux through the pathway, and in the second step, a new methodology termed GC-ANN was developed to select optimum and cost-efficient enzyme balances for higher flux. This approach showed unexpected betterment of flux estimation, up to 63%. In the third step, a kinetic model was built and estimation of kinetic parameters for selected enzymes was achieved to replicate experimental conditions. Finally, linked to one of the most demanding chemicals, malate synthesis pathway was successfully modelled in the cell-free system. Even though many studies have been performed, biomanufacturing has not yet been possible for malate. The combination of the cell-free system and modelling could help achieve the biomanufacturing of malate. Overall, this thesis explores different mathematical modelling approaches, and their limits, for optimising metabolic pathways., Les systèmes acellulaires sont en train de devenir une puissante plateforme de biofabrication. L'optimisation de systèmes acellulaires est importante pour obtenir un rendement maximal. L'optimisation expérimentale, en laboratoire humide, est longue et coûteuse. Différents types de modélisations permettant d'optimiser la voie d'intérêt, en un temps plus court et à moindre coût, sont apparus au cours des dernières décennies. Dans cette étude, nous avons testé deux approches : systémique à travers la mise en œuvre de réseaux de neurones, et analytique à travers l™utilisation d™équations différentielles. Dans une première étape, un modèle à réseau de neurones artificiels a été construit pour prédire le flux de métabolites à travers la voie. Dans une seconde étape, une nouvelle méthodologie, appelée GC-ANN, a été développée pour sélectionner des équilibres enzymatiques optimaux, et rentables, pour des valeurs de flux plus élevées. Cette approche a permis une amélioration inattendue du flux, jusqu'à 63%, validée in vitro. Dans une troisième étape, un modèle cinétique a été construit, et l™estimation des paramètres cinétiques pour les enzymes sélectionnées a été réalisée, afin de reproduire les conditions expérimentales. Enfin, liée à l'un des produits chimiques les plus exigeants en termes de production, la voie de synthèse du malate a été modélisée avec succès dans un système acellulaires. Même si de nombreuses études ont été réalisées, la biofabrication a grande échelle n'est pas encore possible pour le malate. La combinaison du système acellulaire et de la modélisation pourrait aider à réaliser la bioproduction du malate. De manière plus générale, cette thèse explore différentes approches de modélisations mathématiques, et leurs limites, pour l'optimisation de voies métaboliques.
Published: 2020

41. Data set of intrinsically disordered proteins analysed at a local protein conformation level

Author: Melarkode Vattekatte, Akhila, Narwani, Tarun Jairaj, Floch, Aline, Maljković, Mirjana, Bisoo, Soubika, Shinada, Nicolas Ken, Kranjc, Agata, Gelly, Jean-Christophe, Srinivasan, Narayanaswamy, Mitić, Nenad, de Brevern, Alexandre, 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), Université de La Réunion - Faculté des Sciences et Technologies (FST), Université de La Réunion (UR), 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 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)-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 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), University of Belgrade [Belgrade, Serbie] (Faculty of Mathematics), 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), Discngine S.A.S [Paris], SBX corp, Molecular Biophysics Unit, Indian Institute of Science, 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)-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), 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 Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), University of Belgrade [Belgrade], Molecular Biophysics Unit [Bangalore, India] (IISc), Indian Institute of Science [Bangalore] (IISc Bangalore), de Brevern, Alexandre G., and Univ, Réunion
Subjects: PDB, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Structural alphabet, Entropy, [SDV]Life Sciences [q-bio], Local protein conformation, lcsh:Computer applications to medicine. Medical informatics, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV] Life Sciences [q-bio], Biochemistry, Genetics and Molecular Biology, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, lcsh:R858-859.7, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein disorder, Ensembles, lcsh:Science (General), lcsh:Q1-390
Abstract: Intrinsic Disorder Proteins (IDPs) have become a hot topic since their characterisation in the 90s. The data presented in this article are related to our research entitled “A structural entropy index to analyse local conformations in Intrinsically Disordered Proteins” published in Journal of Structural Biology [1]. In this study, we quantified, for the first time, continuum from rigidity to flexibility and finally disorder. Non-disordered regions were also highlighted in the ensemble of disordered proteins. This work was done using the Protein Ensemble Database (PED), which is a useful database collecting series of protein structures considered as IDPs. The data set consists of a collection of cleaned protein files in classical pdb format that can be readily used as an input with most automatic analysis software. The accompanying data include the coding of all structural information in terms of a structural alphabet, namely Protein Blocks (PBs). An entropy index derived from PBs that allows apprehending the continuum between protein rigidity to flexibility to disorder is included, with information from secondary structure assignment, protein accessibility and prediction of disorder from the sequences. The data may be used for further structural bioinformatics studies of IDPs. It can also be used as a benchmark for evaluating disorder prediction methods. Keywords: Protein disorder, PDB, Ensembles, Entropy, Local protein conformation, Structural alphabet
Published: 2020

42. αII‐spectrin controls calcium‐regulated exocytosis in neuroendocrine chromaffin cells through N-WASP interaction

Author: Houy, Sebastien, Nicolas, Gaël, Momboisse, Fanny, Malacombe, Magali, Bader, Marie‐france, Vitale, Nicolas, Lecomte, Marie‐christine, Ory, Stéphane, Gasman, Stephane, Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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), 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), Université des Antilles (UA), and Ory, Stéphane
Subjects: spectrin, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], N-WASP, exocytosis, PC12 and chromaffin cells
Abstract: International audience; Besides a fundamental structural role at the plasma membrane, spectrin-and actin-based skeletons have been proposed to participate in various processes including vesicular trafficking. Neuroendocrine cells release hormones and neuropeptides through calcium-regulated exocytosis, a process that is coordinated by a fine remodeling of the actin cytoskeleton. We describe here that calcium-regulated exocytosis is impaired in chromaffin and PC12 cells with reduced αII-spectrin expression levels. Using yeast two-hybrid screening, we show that neuronal Wiskott-Aldrich Syndrome protein (N-WASP) is a partner of the αII-spectrin SH3 domain and demonstrate that secretagogue-evoked N-WASP recruitment at cell periphery is blocked in the absence of αII-spectrin. Additionally, experiments performed with ectopically expressed αII-spectrin mutant unable to bind N-WASP indicated that the interaction between SH3 domain and N-WASP is pivotal for neuroendocrine secretion. Our results extend the list of spectrin interactors and strengthen the idea that αII-spectrin is an important scaffold protein that gathers crucial actin-related players of the exo-cytic machinery.
Published: 2020

43. Transient association between proteins elicits alteration of dynamics at sites far away from interfaces

Author: Himani Tandon, Narayanaswamy Srinivasan, Alexandre G. de Brevern, Molecular Biophysics Unit [Bangalore, India] (MBU), Indian Institute of Science, 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), Indo-French Centre for the Promotion of Advanced Research / CEFIPRA for collaborative grant (number 5302-2), DBT-COE, Ministry of Human Resource Development, DST-FIST, UGC Center for Advanced Study, Bioinformatics and Computational Biology centre support from DBT, DBT-IISc Partnership Program, ANR-18-IDEX-0001, ANR-11- LABX-0051, ANR-11-IDEX- 0005-02, and de Brevern, Alexandre G.
Subjects: Association (object-oriented programming), [SDV]Life Sciences [q-bio], Allosteric regulation, protein-protein interactions, Molecular Dynamics Simulation, MESH: Deoxyribonucleases, Type I Site-Specific, Protein–protein interaction, functional analysis, 03 medical and health sciences, Protein structure, Structural Biology, Protein Interaction Mapping, MESH: Protein Binding, Humans, MESH: Molecular Dynamics Simulation, protein structure, skin and connective tissue diseases, MESH: Allosteric Site, Molecular Biology, 030304 developmental biology, 0303 health sciences, allostery, MESH: Humans, Chemistry, Protein dynamics, MESH: Cyclophilin A, 030302 biochemistry & molecular biology, Dynamics (mechanics), MESH: Protein Interaction Mapping, Deoxyribonucleases, Type I Site-Specific, bioinformatics, Protein tertiary structure, [SDV] Life Sciences [q-bio], Structural change, normal mode analysis, protein dynamics, Biophysics, sense organs, Cyclophilin A, Allosteric Site, Protein Binding
Abstract: Proteins are known to undergo structural changes upon binding to partner proteins. However, the prevalence, extent, location, and function of change in protein dynamics due to transient protein-protein interactions is not well documented. Here, we have analyzed a dataset of 58 protein-protein complexes of known three-dimensional structure and structures of their corresponding unbound forms to evaluate dynamics changes induced by binding. Fifty-five percent of cases showed significant dynamics change away from the interfaces. This change is not always accompanied by an observed structural change. Binding of protein partner is found to alter inter-residue communication within the tertiary structure in about 90% of cases. Also, residue motions accessible to proteins in unbound form were not always maintained in the bound form. Further analyses revealed functional roles for the distant site where dynamics change was observed. Overall, the results presented here strongly suggest that alteration of protein dynamics due to binding of a partner protein commonly occurs.
Published: 2020

44. Discrete analysis of camelid variable domains: sequences, structures, and in-silico structure prediction: Sequence-structure characteristics of VHH domains

Author: Melarkode Vattekatte, Akhila, Shinada, Nicolas Ken, Narwani, Tarun, Noël, Floriane, Bertrand, Olivier, Meyniel, Jean-Philippe, Malpertuy, Alain, Gelly, Jean-Christophe, Cadet, Frédéric, De Brevern, Alexandre, Université de La Réunion - Faculté des Sciences et Technologies (FST), Université de La Réunion (UR), 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), 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)-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), 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), Services and solutions for Research Informatics [Paris] (Discngine), Discngine S.A.S [Paris], Institut National de la Transfusion Sanguine [Paris] (INTS), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), ISoft, Atragene (Atragene), Atragene, GR-Ex, Laboratoire d'Excellence, GR-Ex, PEACCEL, Ministry of Research (France)., University Paris Diderot, Sorbonne, Paris Cité (France)., Discngine, Paris, France., ANRT, France., Conseil Régional de la Réunion., The European Social Fund EU (ESF)., French National Computing Centre CINES under grant no. A0010707621 by the GENCI (Grand Equipement National de Calcul Intensif)., French National Computing Centre CINES under grant no. A0040710426 by the GENCI (Grand Equipement National de Calcul Intensif)., University of La Réunion, Réunion Island (France)., National Institute for Blood Transfusion (INTS, France)., National Institute for Health and Medical Research (INSERM, France)., Indo-French Centre for the Promotion of Advanced Research/CEFIPRA: 5302-2., ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), and ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011)
Subjects: Frameworks, Structural alphabet, [SDV]Life Sciences [q-bio], complementarity determining regions, Bioinformatics Keywords Secondary structure, Sequence structure relationship, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, secondary structure, Subjects Biochemistry, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], nanobodies, Antibodies
Abstract: International audience; Antigen binding by antibodies requires precise orientation of the complementarity- determining region (CDR) loops in the variable domain to establish the correct contact surface. Members of the family Camelidae have a modified form of immunoglobulin gamma (IgG) with only heavy chains, called Heavy Chain only Antibodies (HCAb). Antigen binding in HCAbs is mediated by only 3 CDR loops from the single variable domain (VHH) at the N-terminus of each heavy chain. This feature of the VHH, along with other important features, e.g. easy expression, small size, thermo-stability and hydrophilicity, made them promising candidates for therapeutics and diagnostics. Thus, to design better VHH domains, it is important to thoroughly understand their sequence and structure characteristics and relationships. In this study sequence, characteristics of VHH have been analysed in depth, along with their structural features using innovative approaches, namely a structural alphabet. An elaborate summary of various studies proposing structural models of VHHs showed diversity in the algorithms used. Finally, a case study to elucidate the differences in structural models from single and multiple templates is presented. In this case study, along with the above-mentioned aspects of VHH, an exciting view of various factors in structure prediction of VHH, like template framework selection, is also discussed.
Published: 2020

45. A Machine Learning Approach for Efficient Selection of Enzyme Concentrations and Its Application for Flux Optimization

Author: Nagaraja, Anamya, Charton, Philippe, Cadet, Xavier, Fontaine, Nicolas, Delsaut, Mathieu, Wiltschi, Birgit, Voit, Alena, Offmann, Bernard, Damour, Cédric, Grondin-Perez, Brigitte, Cadet, Frédéric, Laboratoire d'Energétique, d'Electronique et Procédés (LE2P), Université de La Réunion (UR), 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), 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), Dynamique des Structures et Interactions des Macromolécules Biologiques - Pôle de La Réunion (DSIMB Réunion), 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)-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), Protein Engineering Accelerator [Paris] (PEACCEL), Austrian Center of Industrial Biotechnology (ACIB), Technical University of Vienna [Vienna] (TU WIEN)-GmBH c/o Institute of Chemical Engineering, Unité de fonctionnalité et ingénierie de protéines (UFIP), Université de Nantes - Faculté des Sciences et des Techniques, Université de Nantes (UN)-Université de Nantes (UN)-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), 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), Vienna University of Technology (TU Wien)-GmBH c/o Institute of Chemical Engineering, Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), 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 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: lcsh:Chemistry, machine learning, lcsh:QD1-999, Quantitative Biology::Molecular Networks, flux optimization, cell-free systems, [SDV]Life Sciences [q-bio], lcsh:TP1-1185, synthetic biology, glycolysis, metabolic pathways optimization, lcsh:Chemical technology, artificial neural network
Abstract: The metabolic engineering of pathways has been used extensively to produce molecules of interest on an industrial scale. Methods like gene regulation or substrate channeling helped to improve the desired product yield. Cell-free systems are used to overcome the weaknesses of engineered strains. One of the challenges in a cell-free system is selecting the optimized enzyme concentration for optimal yield. Here, a machine learning approach is used to select the enzyme concentration for the upper part of glycolysis. The artificial neural network approach (ANN) is known to be inefficient in extrapolating predictions outside the box: high predicted values will bump into a sort of &ldquo, glass ceiling&rdquo, In order to explore this &ldquo, space, we developed a new methodology named glass ceiling ANN (GC-ANN). Principal component analysis (PCA) and data classification methods are used to derive a rule for a high flux, and ANN to predict the flux through the pathway using the input data of 121 balances of four enzymes in the upper part of glycolysis. The outcomes of this study are i. in silico selection of optimum enzyme concentrations for a maximum flux through the pathway and ii. experimental in vitro validation of the &ldquo, out-of-the-box&rdquo, fluxes predicted using this new approach. Surprisingly, flux improvements of up to 63% were obtained. Gratifyingly, these improvements are coupled with a cost decrease of up to 25% for the assay.
Published: 2020

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

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

47. Discrete analysis of camelid variable domains: sequences, structures, and in-silico structure prediction

Author: Melarkode Vattekatte, Akhila, Shinada, Nicolas Ken, Narwani, Tarun, Noël, Floriane, Bertrand, Olivier, Meyniel, Jean-Philippe, Malpertuy, Alain, Gelly, Jean-Christophe, Cadet, Frédéric, de Brevern, Alexandre, 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, Université de La Réunion - Faculté des Sciences et Technologies (FST), Université de La Réunion (UR), 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), 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), 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), Services and solutions for Research Informatics [Paris] (Discngine), Discngine S.A.S [Paris], Institut National de la Transfusion Sanguine [Paris] (INTS), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), ISoft, Atragene (Atragene), Atragene, GR-Ex, Laboratoire d'Excellence, GR-Ex, PEACCEL, Ministry of Research (France)., University Paris Diderot, Sorbonne, Paris Cité (France)., Discngine, Paris, France., ANRT, France., Conseil Régional de la Réunion., The European Social Fund EU (ESF)., French National Computing Centre CINES under grant no. A0010707621 by the GENCI (Grand Equipement National de Calcul Intensif)., French National Computing Centre CINES under grant no. A0040710426 by the GENCI (Grand Equipement National de Calcul Intensif)., University of La Réunion, Réunion Island (France)., National Institute for Blood Transfusion (INTS, France)., National Institute for Health and Medical Research (INSERM, France)., Indo-French Centre for the Promotion of Advanced Research/CEFIPRA: 5302-2., ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), and ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011)
Subjects: [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV]Life Sciences [q-bio], complementarity determining regions, Bioinformatics Keywords Secondary structure, secondary structure, Subjects Biochemistry, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], nanobodies, [SDV] Life Sciences [q-bio], frameworks, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, antibodies, structural alphabet, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, sequence structure relationship
Abstract: International audience; Antigen binding by antibodies requires precise orientation of the complementarity- determining region (CDR) loops in the variable domain to establish the correct contact surface. Members of the family Camelidae have a modified form of immunoglobulin gamma (IgG) with only heavy chains, called Heavy Chain only Antibodies (HCAb). Antigen binding in HCAbs is mediated by only 3 CDR loops from the single variable domain (VHH) at the N-terminus of each heavy chain. This feature of the VHH, along with other important features, e.g. easy expression, small size, thermo-stability and hydrophilicity, made them promising candidates for therapeutics and diagnostics. Thus, to design better VHH domains, it is important to thoroughly understand their sequence and structure characteristics and relationships. In this study sequence, characteristics of VHH have been analysed in depth, along with their structural features using innovative approaches, namely a structural alphabet. An elaborate summary of various studies proposing structural models of VHHs showed diversity in the algorithms used. Finally, a case study to elucidate the differences in structural models from single and multiple templates is presented. In this case study, along with the above-mentioned aspects of VHH, an exciting view of various factors in structure prediction of VHH, like template framework selection, is also discussed.
Published: 2020

48. Oxidative stress activates red cell adhesion to laminin in sickle cell disease

Author: Maria Alejandra, Lizarralde-Iragorri, Sophie D, Lefevre, Sylvie, Cochet, Sara, El Hoss, Valentine, Brousse, Anne, Filipe, Michael, Dussiot, Slim, Azouzi, Caroline, Le Van Kim, Fernando, Rodrigues-Lima, Olivier, Français, Bruno, Le Pioufle, Thomas, Klei, Robin, van Bruggen, Wassim, El Nemer, 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), Service de pédiatrie générale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Electronique, Systèmes de communication et Microsystèmes (ESYCOM), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre National de la Recherche Scientifique (CNRS)-Université Gustave Eiffel, Institut d'Alembert (IDA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), Université Paris-Saclay, Laboratoire Lumière, Matière et Interfaces (LuMIn), CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), Sanquin Research, University of Amsterdam [Amsterdam] (UvA), 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 Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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)-Université Gustave Eiffel, Le Pioufle, Bruno, and AII - Inflammatory diseases
Subjects: Sickle Cell Disease, Erythrocytes, [SPI.NANO] Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics, Red Cells, hemic and immune systems, Red Cell Adhesion, Anemia, Sickle Cell, Lutheran Blood-Group System, Article, Hemoglobinopathies, Oxidative Stress, hemic and lymphatic diseases, Cell Adhesion, Humans, Laminin, [SPI.NANO]Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics, Cell Adhesion Molecules
Abstract: International audience; Vaso-occlusive crises are the hallmark of sickle cell disease (SCD). They are believed to occur in two steps, starting with adhesion of deformable low-dense red blood cells (RBCs), or other blood cells such as neutrophils, to the wall of post-capillary venules, followed by trapping of the denser RBCs or leukocytes in the areas of adhesion because of reduced effective lumen-diameter. In SCD, RBCs are heterogeneous in terms of density, shape, deformability and surface proteins, which accounts for the differences observed in their adhesion and resistance to shear stress. Sickle RBCs exhibit abnormal adhesion to laminin mediated by Lu/BCAM protein at their surface. This adhesion is triggered by Lu/BCAM phosphorylation in reticulocytes but such phosphorylation does not occur in mature dense RBCs despite firm adhesion to laminin. In this study, we investigated the adhesive properties of sickle RBC subpopulations and addressed the molecular mechanism responsible for the increased adhesion of dense RBCs to laminin in the absence of Lu/BCAM phosphorylation. We provide evidence for the implication of oxidative stress in post-translational modifications of Lu/BCAM that impact its distribution and cis-interaction with glycophorin C at the cell surface activating its adhesive function in sickle dense RBCs.
Published: 2020

49. A structural entropy index to analyse local conformations in intrinsically disordered proteins: IDP PBs

Author: Melarkode Vattekatte, Akhila, Narwani, Tarun Jairaj, Floch, Aline, Maljković, Mirjana, Bisoo, Soubika, Shinada, Nicolas, Kranjc, Agata, Gelly, Jean-Christophe, Srinivasan, Narayanaswamy, Mitić, Nenad, de Brevern, Alexandre, 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, Institut National de la Transfusion Sanguine [Paris] (INTS), Université de La Réunion - Faculté des Sciences et Technologies (FST), Université de La Réunion (UR), 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), 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 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)-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)-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 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), University of Belgrade, Faculty of Mathematics, Molecular Biophysics Unit, Indian Institute of Science, Discngine S.A.S [Paris], Ministry of Research (France)., University Paris Diderot, Sorbonne, Paris Cité (France)., Discngine, Paris, France., ANRT, France., Conseil Régional de la Réunion., The European Social Fund EU (ESF)., French National Computing Centre CINES under grant no. c2013037147 by the GENCI (Grand Equipement National de Calcul Intensif)., French National Computing Centre CINES under grant no. A0010707621 by the GENCI (Grand Equipement National de Calcul Intensif)., French National Computing Centre CINES under grant no. A0040710426 by the GENCI (Grand Equipement National de Calcul Intensif)., Conseil Régional Ile de France. INTS (SESAME Grant)., University of La Réunion, Réunion Island (France)., National Institute for Blood Transfusion (INTS, France)., National Institute for Health and Medical Research (INSERM, France)., Indo-French Centre for the Promotion of Advanced Research/CEFIPRA: 5302-2., ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), and ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011)
Subjects: flexibility, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], rigidity, protein structures, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, structural alphabet, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, entropy, Condensed Matter::Disordered Systems and Neural Networks, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM]
Abstract: International audience; Sequence – structure – function paradigm has been revolutionized by the discovery of disordered regions and disordered proteins more than two decades ago. While the definition of rigidity is simple with X-ray structures, the notion of flexibility is linked to high experimental B-factors. The definition of disordered regions is more complex as in these same X-ray structures; it is associated to the position of missing residues. Thus a continuum so seems to exist between rigidity, flexibility and disorder. However, it had not been precisely described. In this study, we used an ensemble of disordered proteins (or regions) and, we applied a structural alphabet to analyse their local conformation. This structural alphabet, namely Protein Blocks, had been efficiently used to highlight rigid local domains within flexible regions and so discriminates deformability and mobility concepts. Using an entropy index derived from this structural alphabet, we underlined its interest to measure these local dynamics, and to quantify, for the first time, continuum states from rigidity to flexibility and finally disorder. We also highlight non-disordered regions in the ensemble of disordered proteins in our study.
Published: 2020

50. 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

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