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44 results on '"Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)"'

1. Primary osteomyelitis caused by an NDM-1-producing K. pneumoniae strain of the highly virulent sequence type 23

Author: Isabelle Podglajen, Nathalie Genel, Astrid Ramahefasolo, Fabrice Compain, Marie Gominet, Dominique Decré, David Lebeaux, Alexis Vandenberghe, Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Paris 5 (UPD5), 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), Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), HAL-UPMC, Gestionnaire, Service de microbiologie [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), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Paris Descartes - Paris 5 ( UPD5 ), Centre d'Immunologie et de Maladies Infectieuses ( CIMI ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP]
Subjects: 0301 basic medicine, Epidemiology, 030106 microbiology, Immunology, Virulence, Biology, Microbiology, 03 medical and health sciences, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Virology, Drug Discovery, medicine, Letter to the Editor, Sequence (medicine), [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [ SDV.MHEP.ME ] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Strain (chemistry), Osteomyelitis, K pneumoniae, General Medicine, medicine.disease, 3. Good health, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Infectious Diseases, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Parasitology
Abstract: International audience; Hypervirulent variant of Klebsiella pneumoniae (hvKP) is characterized by its hypermucoviscosity and its capacity to cause invasive community-acquired infections in previously healthy young individuals. The most common clinical presentation is a pyogenic liver abscess with metastatic spread, while various other invasive infections have been reported. Strains of hvKP belong predominantly to the capsular serotypes K1 and K22 and their genetic background seems to differ from that of multidrug-resistant (MDR) isolates. The most commonly encountered sequence types (STs) among hvKP include ST23 (associated with serotype K1), ST25, ST65, ST86, ST375 and the recently emerging ST380.
Published: 2017

2. Electrophilic RNA for Peptidyl-RNA Synthesis and Site-Specific Cross-Linking with tRNA-Binding Enzymes

Author: Tom Brown, Chloé Le Fournis, Matthieu Fonvielle, Nicolas Sakkas, Laura Iannazzo, Sébastien Cardon, Dominique Mengin-Lecreulx, Emmanuelle Braud, Delphine Patin, Mélanie Etheve-Quelquejeu, Michel Arthur, Afaf H. El-Sagheer, Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Chemistry Branch, Dept. of Science and Mathematics, Faculty of Petroleum and Mining Engineering, Suez Canal University, Suez, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques ( LCBPT - UMR 8601 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), and Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay
Subjects: Models, Molecular, Stereochemistry, [SDV]Life Sciences [q-bio], Lysine, Molecular Conformation, squarates, 010402 general chemistry, 01 natural sciences, Catalysis, Enzyme catalysis, chemistry.chemical_compound, Solid-phase synthesis, RNA modifications, RNA, Transfer, crosslinking, Fem transferases, chemistry.chemical_classification, [ SDV ] Life Sciences [q-bio], 010405 organic chemistry, RNA, General Medicine, General Chemistry, Aminoacyltransferases, TRNA binding, Uridine Diphosphate N-Acetylmuramic Acid, 0104 chemical sciences, Cross-Linking Reagents, Enzyme, chemistry, Transfer RNA, Peptidoglycan, post-functionalization, Peptides
Abstract: International audience; RNA functionalization is challenging due to the instability of RNA and the limited range of available enzymatic reactions. We developed a strategy based on solid phase synthesis and post-functionalization to introduce an electrophilic site at the 3' end of tRNA analogues. The squarate diester used as an electrophile enabled sequential amidation and provided asymmetric squaramides with high selectivity. The squaramate-RNAs specifically reacted with the lysine of UDP-MurNAc-pentapeptide, a peptidoglycan precursor used by the aminoacyl-transferase FemXWv for synthesis of the bacterial cell wall. The peptidyl-RNA obtained with squaramate-RNA and unprotected UDP-MurNAc-pentapeptide efficiently inhibited FemXWv . The squaramate unit also promoted specific cross-linking of RNA to the catalytic Lys of FemXWv but not to related transferases recognizing different aminoacyl-tRNAs. Thus, squaramate-RNAs provide specificity for cross-linking with defined groups in complex biomolecules due to its unique reactivity.
Published: 2016

3. Role of the motif SDN in the inhibition and substrate specificities of β-lactamases from mycobacteria

Author: Soroka, Daria, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris VI, Michel Arthur, Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE)
Subjects: Carbapénème, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Clavulanate, Mycobacterium abscessus, Avibactam, Mycobacterium tuberculosis, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Β-lactamases, Carbapenem
Abstract: Mycobacterium tuberculosis and Mycobacterium abscessus produce the β-lactamases BlaC and BlaMab that contribute to the intrinsic resistance of those bacteria to β-lactams. Our objective was to characterize the inhibition of these β-lactamases by avibactam and clavulanate in order to contribute to the development of new treatments. We have determined the inhibition and substrate profiles of BlaMab, as well as its crystal structure, revealing three major differences with BlaC. BlaMab is more active than BlaC with respect to hydrolysis of all β-lactams except cefoxitin, which is used for the treatment of infections due to M. abscessus. BlaC is inhibited irreversibly by clavulanate and inefficiently by avibactam. In contrast, BlaMab shows the opposite behavior involving hydrolysis of clavulanate and a rapid inhibition by avibactam. Structurally BlaC differs from BlaMab mainly by the replacement of the conserved motif SDN by SDG. The introduction of SDG in BlaMab and of SDN in BlaC revealed that this difference determines the inhibition profile of the β-lactamases. A single mutation can therefore lead to the emergence of resistance to the association of β-lactam with clavulanate or avibactam, but not to both associations. Thus, avibactam and clavulanate offer therapeutic alternatives in case of resistance to one of the two inhibitors. We have also investigated the β-lactam partners of clavulanate for the treatment of tuberculosis and showed that the structure of carbapenems could be optimized to enhance the inactivation of the targets and to reduce hydrolysis by BlaC.; Mycobacterium tuberculosis et Mycobacterium abscessus produisent les β-lactamases BlaC et BlaMab qui contribuent à la résistance intrinsèque de ces bactéries aux β-lactamines. Notre objectif est de caractériser l’inhibition de ces β-lactamases par l’avibactam et le clavulanate pour contribuer au développement de nouveaux traitements. Nous avons déterminé le profil de substrat et d’inhibition de BlaMab ainsi que sa structure cristalline, révélant trois différences majeures avec BlaC. BlaMab a une activité supérieure à celle de BlaC pour toutes les β-lactamines sauf la céfoxitine qui est utilisée pour les infections dues à M. abscessus. BlaC est inhibée irréversiblement par le clavulanate et inefficacement par l’avibactam alors que BlaMab présente le comportement inverse impliquant une hydrolyse du clavulanate et une inhibition très rapide par l’avibactam. La structure de BlaMab diffère de celle de BlaC principalement par le remplacement du motif conservé SDN par SDG. L’introduction de SDG dans BlaMab et de SDN dans BlaC a montré que cette différence détermine le profil d’inhibition des β-lactamases. Une seule mutation peut donc entraîner l’émergence d’une résistance aux combinaisons d’une β-lactamine avec le clavulanate ou l’avibactam mais pas avec les deux inhibiteurs. L’avibactam et le clavulanate offrent donc des alternatives thérapeutiques en cas de résistance à l’un des inhibiteurs. Nous nous sommes également intéressés aux β-lactamines partenaires du clavulanate, pour le traitement de la tuberculose et montrer que la structure des carbapénèmes pouvait être optimisée pour améliorer l’inactivation des cibles et diminuer l’hydrolyse par BlaC.
Published: 2016

4. Unusual substrate specificity of the peptidoglycan MurE ligase from Erysipelothrix rhusiopathiae

Author: Hélène Barreteau, Delphine Patin, Didier Blanot, Michel Arthur, Samo Turk, Stanislav Gobec, Jean-Luc Mainardi, Dominique Mengin-Lecreulx, Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Faculty of Pharmacy, University of Ljubljana, Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, food.ingredient, [SDV]Life Sciences [q-bio], Sequence alignment, Peptidoglycan, Erysipelothrix rhusiopathiae, medicine.disease_cause, l-alanine-adding enzyme, Biochemistry, Substrate Specificity, Microbiology, 03 medical and health sciences, chemistry.chemical_compound, Erysipelothrix, food, MurE, Escherichia coli, medicine, Homology modeling, Peptide Synthases, chemistry.chemical_classification, DNA ligase, biology, meso-diaminopimelate-adding enzyme, [ SDV ] Life Sciences [q-bio], General Medicine, biology.organism_classification, Amino acid, 030104 developmental biology, chemistry
Abstract: International audience; Erysipelothrix rhusiopathiae is a Gram-positive bacterium pathogenic to many species of birds and mammals, including humans. The main feature of its peptidoglycan is the presence of l-alanine at position 3 of the peptide stem. In the present work, we cloned the murE gene from E. rhusiopathiae and purified the corresponding protein as His6-tagged form. Enzymatic assays showed that E. rhusiopathiae MurE was indeed an l-alanine-adding enzyme. Surprisingly, it was also able, although to a lesser extent, to add meso-diaminopimelic acid, the amino acid found at position 3 in many Gram-negative bacteria, Bacilli and Mycobacteria. Sequence alignment of MurE enzymes from E. rhusiopathiae and Escherichia coli revealed that the DNPR motif that is characteristic of meso-diaminopimelate-adding enzymes was replaced by HDNR. The role of the latter motif in the interaction with l-alanine and meso-diaminopimelic acid was demonstrated by site-directed mutagenesis experiments and the construction of a homology model. The overexpression of the E. rhusiopathiae murE gene in E. coli resulted in the incorporation of l-alanine at position 3 of the peptide part of peptidoglycan.
Published: 2016

5. Association of the Pro12Ala and C1431T Variants ofPPARγ and Their Haplotypes with Susceptibility to Gestational Diabetes

Author: Barbara Heude, Jean-François Bedel, Jean-Marc Lacorte, Anne Forhan, Véronique Pelloux, Marie-Aline Charles, Karine Clément, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-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), Service d’Endocrinologie, Métabolisme et Prévention des Risques Cardio-Vasculaires [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie des maladies infectieuses et modélisation (ESIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), G. Liccardi, I. Annesi-Maesano 1, A. Salzillo, G. D'amato Liccardi G, Annesi-Maesano I, Salzillo A, D'Amato G. Collaboration, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Endocrinologie, Métabolisme et Prévention des Maladies Cardio-vasculaires [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en épidémiologie et santé des populations ( CESP ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'endocrinologie-métabolisme [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Epidémiologie des maladies infectieuses et modélisation ( ESIM ), and Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: MESH : DNA, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, MESH : Genotype, Type 2 diabetes, Biochemistry, Body Mass Index, MESH: Genotype, Cohort Studies, MESH: Pregnancy, 0302 clinical medicine, Endocrinology, Gene Frequency, Pregnancy, Odds Ratio, Medicine, MESH : Female, MESH : Gene Frequency, MESH: Genetic Variation, MESH: Cohort Studies, MESH: Genetic Association Studies, MESH: Diabetes, Gestational, 2. Zero hunger, 0303 health sciences, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, MESH: DNA, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, MESH : Adult, 3. Good health, Gestational diabetes, Female, MESH : PPAR gamma, Adult, medicine.medical_specialty, Genotype, MESH : Cohort Studies, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, MESH: Body Mass Index, 03 medical and health sciences, MESH : Genetic Variation, Diabetes mellitus, Internal medicine, MESH: Gene Frequency, Humans, MESH : Haplotypes, Genetic Association Studies, 030304 developmental biology, MESH: Humans, business.industry, MESH : Humans, Biochemistry (medical), Haplotype, Genetic Variation, MESH: Adult, MESH : Genetic Association Studies, MESH: Haplotypes, DNA, Odds ratio, medicine.disease, Obesity, MESH: Odds Ratio, PPAR gamma, MESH : Body Mass Index, MESH : Pregnancy, Diabetes, Gestational, MESH: PPAR gamma, Haplotypes, MESH : Odds Ratio, MESH : Diabetes, Gestational, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Female, Body mass index
Abstract: International audience; BACKGROUND: The protective role of the Ala allele in the Pro12Ala polymorphism of PPARγ on type 2 diabetes has been well established but not confirmed in the context of pregnancy, for gestational diabetes, a known predictor of later type 2 diabetes onset. Another PPARγ polymorphism, the C1431T, is in strong linkage disequilibrium with Pro12Ala and has been shown to be associated with body weight, but its association with diabetes is controversial. RESEARCH DESIGN AND METHODS: In 1708 women of the EDEN mother-child cohort, the PPARγ Pro12Ala and C1431T polymorphisms were genotyped and analyzed in association with maternal prepregnancy body mass index, obesity before pregnancy, and gestational diabetes, separately and also combined in haplotypes. RESULTS: The prevalence of obesity was significantly higher in mothers with the Ala/Ala genotype compared with carriers of the Pro allele (35 vs. 9%, P < 0.0001), but there was no cases of gestational diabetes in Ala/Ala mothers. Mothers homozygous for the T allele of C1431T were also more obese (24 vs. 9%, P = 0.035), and three times more had gestational diabetes (18 vs. 6%, P = 0.044). Frequencies of haplotypes for these two single-nucleotide polymorphisms differed significantly in mothers with and without gestational diabetes; in comparison with the Pro-C haplotype, the Pro-T haplotype conferred the highest risk [odds ratio (95% CI) = 1.89 (1.05-3.40)], and the Ala-C the lowest risk [odds ratio (95% CI) = 0.12 (0.52-1.70)]. CONCLUSIONS: These results from a haplotype analysis, show for the first time that genetic variations in the PPARγ gene could play a role in the susceptibility to develop gestational diabetes.
Published: 2011

6. Acyl acceptor recognition by Enterococcus faecium l,d-transpeptidase Ldtfm

Author: Jean-Emmanuel Hugonnet, Sébastien Triboulet, Cédric Laguri, Jean-Pierre Simorre, Michel Arthur, Catherine M. Bougault, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), U1138 equipe 12, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de biologie structurale (IBS - UMR 5075), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Laboratoire de Chimie et Biologie des Métaux ( LCBM - UMR 5249 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de biologie structurale ( IBS - UMR 5075 ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), 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), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: Ertapenem, Models, Molecular, Stereochemistry, Acylation, Enterococcus faecium, Peptidoglycan, beta-Lactams, Microbiology, Article, Substrate Specificity, chemistry.chemical_compound, Bacterial Proteins, Catalytic Domain, Binding site, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Binding Sites, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Active site, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, Acceptor, Anti-Bacterial Agents, 3. Good health, Molecular Docking Simulation, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Biochemistry, chemistry, Docking (molecular), Peptidyl Transferases, Mutagenesis, Site-Directed, biology.protein, Cysteine, [ SDV.BBM.BS ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM]
Abstract: Summary In Mycobacterium tuberculosis and ampicillin-resistant mutants of Enterococcus faecium, the classical target of β-lactam antibiotics is bypassed by l,d-transpeptidases that form unusual 3 → 3 peptidoglycan cross-links. β-lactams of the carbapenem class, such as ertapenem, are mimics of the acyl donor substrate and inactivate l,d-transpeptidases by acylation of their catalytic cysteine. We have blocked the acyl donor site of E. faecium l,d-transpeptidase Ldtfm by ertapenem and identified the acyl acceptor site based on analyses of chemical shift perturbations induced by binding of peptidoglycan fragments to the resulting acylenzyme. An nuclear magnetic resonance (NMR)-driven docking structure of the complex revealed key hydrogen interactions between the acyl acceptor and Ldtfm that were evaluated by site-directed mutagenesis and development of a cross-linking assay. Three residues are reported as critical for stabilisation of the acceptor in the Ldtfm active site and proper orientation of the nucleophilic nitrogen for the attack of the acylenzyme carbonyl. Identification of the catalytic pocket dedicated to the acceptor substrate opens new perspectives for the design of inhibitors with an original mode of action that could act alone or in synergy with β-lactams.
Published: 2015

7. Serine/threonine protein phosphatase-mediated control of the peptidoglycan cross-linking L,D-transpeptidase pathway in Enterococcus faecium

Author: Jean-Luc Mainardi, Nathalie Josseaume, Emmanuelle Sacco, Michel Arthur, Mélanie Cortes, Louis B. Rice, Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Brown University, Service de Microbiologie [CHU GeorgesPompidou], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), and HAL UPMC, Gestionnaire
Subjects: Phosphatase, Enterococcus faecium, Peptidoglycan, Biology, [ SDV.MP.BAC ] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Pentapeptide repeat, Microbiology, Dephosphorylation, Serine, 03 medical and health sciences, chemistry.chemical_compound, Bacterial Proteins, Virology, Phosphoprotein Phosphatases, Protein phosphorylation, Protein kinase A, 030304 developmental biology, 0303 health sciences, Peptidoglycan glycosyltransferase, 030306 microbiology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, QR1-502, chemistry, Biochemistry, Peptidoglycan Glycosyltransferase, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Research Article
Abstract: The last step of peptidoglycan polymerization involves two families of unrelated transpeptidases that are the essential targets of β-lactam antibiotics. d,d-transpeptidases of the penicillin-binding protein (PBP) family are active-site serine enzymes that use pentapeptide precursors and are the main or exclusive cross-linking enzymes in nearly all bacteria. However, peptidoglycan cross-linking is performed mainly by active-site cysteine l,d-transpeptidases that use tetrapeptides in Mycobacterium tuberculosis, Clostridium difficile, and β-lactam-resistant mutants of Enterococcus faecium. We have investigated reprogramming of the E. faecium peptidoglycan assembly pathway by a switch from pentapeptide to tetrapeptide precursors and bypass of PBPs by l,d-transpeptidase Ldtfm. Mutational alterations of two signal transduction systems were necessary and sufficient for activation of the l,d-transpeptidation pathway, which is essentially cryptic in wild-type strains. The first one is a classical two-component regulatory system, DdcRS, that controls the activity of Ldtfm at the substrate level. As previously described, loss of DdcS phosphatase activity leads to production of the d,d-carboxypeptidase DdcY and conversion of the pentapeptide into the tetrapeptide substrate of Ldtfm. Here we show that full bypass of PBPs by Ldtfm also requires increased Ser/Thr protein phosphorylation resulting from impaired activity of phosphoprotein phosphatase StpA. This enzyme negatively controlled the level of protein phosphorylation both by direct dephosphorylation of target proteins and by dephosphorylation of its cognate kinase Stk. In combination with production of DdcY, increased protein phosphorylation by this eukaryotic-enzyme-like Ser/Thr protein kinase was sufficient for activation of the l,d-transpeptidation pathway in the absence of mutational alteration of peptidoglycan synthesis enzymes., IMPORTANCE The mechanism of acquisition of high-level ampicillin resistance involving bypass of the penicillin-binding proteins (PBPs) by l,d-transpeptidase Ldtfm was incompletely understood, as production of tetrapeptide precursors following transcriptional activation of the ddc locus by the DdcRS two-component regulatory system was necessary but not sufficient for full activation of the l,d-transpeptidation pathway. Here, we identified the release of a negative control of Ser/Thr protein phosphorylation mediated by phosphatase StpA as the additional factor essential for ampicillin resistance. Thus, bypass of PBPs by Ldtfm requires the modification of signal transduction regulatory systems without any gain of function by mutational alteration of peptidoglycan biosynthetic enzymes. In contrast, previously characterized mechanisms of antibiotic resistance involve horizontal gene transfer and mutational alteration of drug targets. Activation of the l,d-transpeptidation pathway reported in this study is an unprecedented mechanism of emergence of a new metabolic pathway since it involved the recruitment of preexisting functions following modifications of regulatory circuits.
Published: 2014

8. Specificity determinants for the two tRNA substrates of the cyclodipeptide synthase AlbC from Streptomyces noursei

Author: Matthieu Fonvielle, Mireille Moutiez, Emmanuel Favry, Isabelle Jacques, Michel Arthur, Muriel Gondry, Pascal Belin, Jérôme Seguin, Service d’Ingénierie Moléculaire des Protéines, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), HAL UPMC, Gestionnaire, Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), and Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: RNA, Transfer, Leu, RNA, Transfer, Amino Acyl, 01 natural sciences, Streptomyces, Substrate Specificity, [PHYS] Physics [physics], 03 medical and health sciences, RNA, Transfer, Phe, Bacterial Proteins, Genetics, Binding site, Peptide Synthases, 030304 developmental biology, [PHYS]Physics [physics], 0303 health sciences, [ PHYS ] Physics [physics], Binding Sites, biology, ATP synthase, 010405 organic chemistry, Nucleic Acid Enzymes, Substrate (chemistry), biology.organism_classification, 0104 chemical sciences, Streptomyces noursei, Biochemistry, Transfer RNA, Helix, biology.protein, Leucine
Abstract: International audience; Cyclodipeptide synthases (CDPSs) use two aminoacyl-tRNA substrates in a sequential ping-pong mechanism to form a cyclodipeptide. The crystal structures of three CDPSs have been determined and all show a Rossmann-fold domain similar to the catalytic domain of class-I aminoacyl-tRNA synthetases (aaRSs). Structural features and mutational analyses however suggest that CDPSs and aaRSs interact differently with their tRNA substrates. We used AlbC from Streptomyces noursei that mainly produces cyclo(l-Phe-l-Leu) to investigate the interaction of a CDPS with its substrates. We demonstrate that Phe-tRNA Phe is the first substrate accommodated by AlbC. Its binding to AlbC is dependent on basic residues located in the helix ␣4 that form a basic patch at the surface of the protein. AlbC does not use all of the Leu-tRNA Leu isoacceptors as a second substrate. We show that the G 1-C 72 pair of the acceptor stem is essential for the recognition of the second substrate. Substitution of D163 located in the loop ␣6–␣7 or D205 located in the loop ␤6–␣8 affected Leu-tRNA Leu isoacceptors specificity, suggesting the involvement of these residues in the binding of the second substrate. This is the first demonstration that the two substrates of CDPSs are accommodated in different binding sites.
Published: 2014

9. Colicin M, a peptidoglycan lipid-II-degrading enzyme: potential use for antibacterial means?

Author: Delphine Patin, Dominique Mengin-Lecreulx, Thierry Touzé, Aurélie Barnéoud-Arnoulet, Roland Lloubès, Ahmed Bouhss, Didier Blanot, Michel Arthur, Hélène Barreteau, Denis Duché, Emmanuelle Sacco, Meriem El Ghachi, Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Enveloppes Bactériennes et Antibiotiques, Département Microbiologie (Dpt Microbio), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Institut de biochimie et biophysique moléculaire et cellulaire (IBBMC), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Laboratoire d'ingénierie des systèmes macromoléculaires (LISM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Enveloppes Bactériennes et Antibiotiques (ENVBAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Département Microbiologie ( Dpt Microbio ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Institut de biochimie et biophysique moléculaire et cellulaire ( IBBMC ), Université Paris-Sud - Paris 11 ( UP11 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), Laboratoire d'ingénierie des systèmes macromoléculaires ( LISM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Enveloppes Bactériennes et Antibiotiques ( ENVBAC )
Subjects: Models, Molecular, Isomerase activity, Protein Conformation, Colicins, Peptidoglycan, Biology, medicine.disease_cause, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Protein structure, Bacteriocin, Bacteriocins, Antibiosis, medicine, Escherichia coli, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, 0303 health sciences, Lipid II, 030306 microbiology, Periplasmic space, Uridine Diphosphate N-Acetylmuramic Acid, Anti-Bacterial Agents, chemistry, Colicin
Abstract: International audience; Colicins are proteins produced by some strains of Escherichia coli to kill competitors belonging to the same species. Among them, ColM (colicin M) is the only one that blocks the biosynthesis of peptidoglycan, a specific bacterial cell-wall polymer essential for cell integrity. ColM acts in the periplasm by hydrolysing the phosphoester bond of the peptidoglycan lipid intermediate (lipid II). ColM cytotoxicity is dependent on FkpA of the targeted cell, a chaperone with peptidylprolyl cis-trans isomerase activity. Dissection of ColM was used to delineate the catalytic domain and to identify the active-site residues. The in vitro activity of the isolated catalytic domain towards lipid II was 50-fold higher than that of the full-length bacteriocin. Moreover, this domain was bactericidal in the absence of FkpA under conditions that bypass the import mechanism (FhuA-TonB machinery). Thus ColM undergoes a maturation process driven by FkpA that is not required for the activity of the isolated catalytic domain. Genes encoding proteins with similarity to the catalytic domain of ColM were identified in pathogenic strains of Pseudomonas and other genera. ColM acts on several structures of lipid II representative of the diversity of peptidoglycan chemotypes. All together, these data open the way to the potential use of ColM-related bacteriocins as broad spectrum antibacterial agents.
Published: 2012

10. Characterization of colicin M and its orthologs targeting bacterial cell wall peptidoglycan biosynthesis

Author: Delphine Patin, Meriem El Ghachi, Ahmed Bouhss, Michel Arthur, Mark A. Brooks, Thierry Touzé, Dominique Mengin-Lecreulx, Hélène Barreteau, Denis Duché, Emmanuelle Sacco, Fabien Gérard, Roland Lloubès, Aurélie Barnéoud-Arnoulet, Herman van Tilbeurgh, Didier Blanot, Enveloppes Bactériennes et Antibiotiques, Département Microbiologie (Dpt Microbio), 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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'ingénierie des systèmes macromoléculaires (LISM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de biochimie et biophysique moléculaire et cellulaire (IBBMC), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Enveloppes Bactériennes et Antibiotiques (ENVBAC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Département Microbiologie ( Dpt Microbio ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'ingénierie des systèmes macromoléculaires ( LISM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de biochimie et biophysique moléculaire et cellulaire ( IBBMC ), Université Paris-Sud - Paris 11 ( UP11 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ), and Enveloppes Bactériennes et Antibiotiques ( ENVBAC )
Subjects: Microbiology (medical), Models, Molecular, Lysis, Immunology, Colicins, Peptidoglycan, Biology, medicine.disease_cause, Microbiology, Bacterial cell structure, Substrate Specificity, Cell wall, 03 medical and health sciences, chemistry.chemical_compound, Bacteriocin, Bacteriocins, Cell Wall, Pseudomonas, medicine, Escherichia coli, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Pharmacology, chemistry.chemical_classification, 0303 health sciences, 030306 microbiology, Uridine Diphosphate N-Acetylmuramic Acid, Protein Structure, Tertiary, Enzyme, chemistry, Biochemistry, Colicin
Abstract: International audience; For a long time, colicin M was known for killing susceptible Escherichia coli cells by interfering with cell wall peptidoglycan biosynthesis, but its precise mode of action was only recently elucidated: this bacterial toxin was demonstrated to be an enzyme that catalyzes the specific degradation of peptidoglycan lipid intermediate II, thereby provoking the arrest of peptidoglycan synthesis and cell lysis. The discovery of this activity renewed the interest in this colicin and opened the way for biochemical and structural analyses of this new class of enzyme (phosphoesterase). The identification of a few orthologs produced by pathogenic strains of Pseudomonas further enlarged the field of investigation. The present article aims at reviewing recently acquired knowledge on the biology of this small family of bacteriocins.
Published: 2012

11. Enzyme structural plasticity and the emergence of broad-spectrum antibiotic resistance

Author: Isabelle Broutin, Frédérique Maurice, Frédéric Dardel, Isabelle Podglajen, Ekkehard Collatz, Philippe Benas, Laboratoire de cristallographie et RMN biologiques (LCRB - UMR 8015), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de cristallographie et RMN biologiques ( LCRB - UMR 8015 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)
Subjects: Models, Molecular, Scientific Report, Biology, medicine.disease_cause, Biochemistry, 03 medical and health sciences, Antibiotic resistance, Transition state analog, Acetyltransferases, Ciprofloxacin, Genetics, medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Gene, Amikacin, 030304 developmental biology, 0303 health sciences, Molecular Structure, 030306 microbiology, Mechanism (biology), Aminoglycoside, Pathogenic bacteria, Drug Resistance, Multiple, 3. Good health, Acetyltransferase, Mobile genetic elements, Gentamicins, Crystallization
Abstract: The emergence of multi-resistant pathogenic bacteria is a worldwide health issue. Recently, clinical variants of a single antibiotic-modifying acetyltransferase, AAC(6')-Ib-a variant of aminoglycoside 6'-N-acetyltransferase-have been identified that confer extended resistance to most aminoglycosides and, more surprisingly, to structurally unrelated fluoroquinolones. The corresponding gene is carried by mobile genetic elements and is present in most multi-resistant pathogenic strains, hence making it a serious threat to current therapies. Here, we report the crystal structures of both narrow- and broad-spectrum resistance variants of this enzyme, which reveal the structural basis for the emergence of extended resistance. The active site shows an important plasticity and has adapted to new substrates by a large-scale gaping process. We have also obtained co-crystals with both substrates, and with a simple transition state analogue, which provides new clues for the design of inhibitors of this resistance mechanism.
Published: 2007

12. Identification of the L,D-transpeptidases responsible for attachment of the Braun lipoprotein to Escherichia coli peptidoglycan

Author: Martine Fourgeaud, Dominique Mengin-Lecreulx, Sébastien Petit-Frère, Laurent Gutmann, Michel Arthur, Samuel Bellais, Jean-Luc Mainardi, Arul Marie, Lionel Dubost, Sophie Magnet, Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de chimie et biochimie des substances naturelles, Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), 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), Enveloppes Bactériennes et Antibiotiques (ENVBAC), Département Microbiologie (Dpt Microbio), 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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), This work was supported by the European Community (COBRA, contract LSHM-CT-2003- 503335, 6th PCRD), the National Institute of Allergy and Infectious Diseases (Grant R01 AI45626), and the Fondation pour la Recherche Médicale., Lecerf, Maxime, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Chimie et Biochimie des Substances Naturelles, Centre National de la Recherche Scientifique ( CNRS ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Enveloppes Bactériennes et Antibiotiques ( ENVBAC ), Département Microbiologie ( Dpt Microbio ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), and Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS )
Subjects: MESH : Escherichia coli, MESH : Molecular Sequence Data, MESH: Peptidyl Transferases, Genomics and Proteomics, Mutant, MESH: Escherichia coli Proteins, MESH: Amino Acid Sequence, medicine.disease_cause, chemistry.chemical_compound, MESH : Peptidoglycan, 0303 health sciences, biology, MESH : Peptides, MESH: Escherichia coli, MESH: Peptides, MESH: Peptidoglycan, MESH : Amino Acid Sequence, MESH : Escherichia coli Proteins, Escherichia coli Proteins, MESH: Lipoproteins, Enterobacteriaceae, Biochemistry, Lipoproteins, Molecular Sequence Data, MESH : Lipoproteins, Peptidoglycan, Microbiology, 03 medical and health sciences, MESH : Peptidyl Transferases, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Bacteriology, Escherichia coli, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, 030304 developmental biology, MESH: Molecular Sequence Data, 030306 microbiology, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, chemistry, Peptidyl Transferases, bacteria, Peptides, Bacteria, Enterococcus faecium, Lipoprotein
Abstract: The l , d -transpeptidase Ldt fm catalyzes peptidoglycan cross-linking in β-lactam-resistant mutant strains of Enterococcus faecium . Here, we show that in Escherichia coli Ldt fm homologues are responsible for the attachment of the Braun lipoprotein to murein, indicating that evolutionarily related domains have been tailored to use muropeptides or proteins as acyl acceptors in the l , d -transpeptidation reaction.
Published: 2007

13. Specificity of L,D-transpeptidases from gram-positive bacteria producing different peptidoglycan chemotypes

Author: Jean-Emmanuel Hugonnet, Jean-Luc Mainardi, Martine Fourgeaud, Arul Marie, Vanessa Delfosse, Louis B. Rice, Ana Arbeloa, Michel Arthur, Sophie Magnet, Lionel Dubost, Claudine Mayer, Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Laboratoire de Chimie et Biochimie des Substances Naturelles, Centre National de la Recherche Scientifique ( CNRS ), Medical and Research Services, Louis Stokes Cleveland Veterans Affairs Medical Center, ACI Microbiologie 2003' from the Fonds National de la Science (Grant ACIM-4-9), the European Community (COBRA, contract LSHM-CT-2003-503335, 6th PCRD), the National Institute of Allergy and Infectious Diseases (Grant R01 AI45626), and the Fondation pour la Recherche Médicale., Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire de chimie et biochimie des substances naturelles, and Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Peptidyl Transferases, Penicillin binding proteins, MESH: Sequence Homology, Amino Acid, Bacillus subtilis, MESH : Drug Resistance, Bacterial, Diaminopimelic Acid, Biochemistry, Pentapeptide repeat, Substrate Specificity, chemistry.chemical_compound, Cell Wall, Enterococcus faecalis, MESH : Bacterial Proteins, MESH : Diaminopimelic Acid, MESH : Enterococcus faecalis, MESH: Bacterial Proteins, MESH : Peptidoglycan, chemistry.chemical_classification, MESH: Penicillin-Binding Proteins, 0303 health sciences, biology, MESH : Substrate Specificity, MESH: Peptidoglycan, MESH : Bacillus subtilis, Glycopeptide, MESH : Sequence Homology, Amino Acid, Amino acid, Cysteine Endopeptidases, MESH: Oligopeptides, MESH : Cysteine Endopeptidases, Oligopeptides, MESH : Oligopeptides, MESH: Enterococcus faecalis, Stereochemistry, Gram-positive bacteria, Peptidoglycan, MESH : Penicillin-Binding Proteins, 03 medical and health sciences, MESH: Cell Wall, Bacterial Proteins, Species Specificity, MESH : Peptidyl Transferases, MESH: Drug Resistance, Bacterial, Drug Resistance, Bacterial, MESH: Species Specificity, MESH: Diaminopimelic Acid, MESH : Species Specificity, Penicillin-Binding Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, MESH : Cell Wall, Tetrapeptide, Sequence Homology, Amino Acid, 030306 microbiology, Cell Biology, MESH: Bacillus subtilis, biology.organism_classification, chemistry, Peptidyl Transferases, MESH: Substrate Specificity, MESH: Cysteine Endopeptidases
Abstract: International audience; We report here the first direct assessment of the specificity of a class of peptidoglycan cross-linking enzymes, the L,D-transpeptidases, for the highly diverse structure of peptidoglycan precursors of Gram-positive bacteria. The lone functionally characterized member of this new family of active site cysteine peptidases, Ldt(fm) from Enterococcus faecium, was previously shown to bypass the D,D-transpeptidase activity of the classical penicillin-binding proteins leading to high level cross-resistance to glycopeptide and beta-lactam antibiotics. Ldt(fm) homologues from Bacillus subtilis (Ldt(Bs)) and E. faecalis (Ldt(fs)) were found here to cross-link their cognate disaccharide-peptide subunits containing meso-diaminopimelic acid (mesoDAP(3)) and L-Lys(3)-L-Ala-L-Ala at the third position of the stem peptide, respectively, instead of L-Lys(3)-d-iAsn in E. faecium. Ldt(fs) differed from Ldt(fm) and Ldt(Bs) by its capacity to hydrolyze the L-Lys(3)-D-Ala(4) bond of tetrapeptide (L,D-carboxypeptidase activity) and pentapeptide (L,D-endopeptidase activity) stems, in addition to the common cross-linking activity. The three enzymes were specific for their cognate acyl acceptors in the cross-linking reaction. In contrast to Ldt(fs), which was also specific for its cognate acyl donor, Ldt(fm) tolerated substitution of L-Lys(3)-D-iAsn by L-Lys(3)-L-Ala-L-Ala. Likewise, Ldt(Bs) tolerated substitution of mesoDAP(3) by L-Lys(3)-D-iAsn and L-Lys(3)-L-Ala-L-Ala in the acyl donor. Thus, diversification of the structure of peptidoglycan precursors associated with speciation has led to a parallel evolution of the substrate specificity of the L,D-transpeptidases affecting mainly the recognition of the acyl acceptor. Blocking the assembly of the side chain could therefore be used to combat antibiotic resistance involving L,D-transpeptidases.
Published: 2007

14. The Enterococcus hirae Mur-2 enzyme displays N-acetylglucosaminidase activity

Author: Stéphane Mesnage, Sophie Magnet, Catherine Eckert, Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Lecerf, Maxime, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), and Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP )
Subjects: MESH : Molecular Sequence Data, MESH: Acetylglucosaminidase, MESH: Catalytic Domain, MESH: Amino Acid Sequence, Tandem mass spectrometry, Biochemistry, Mass Spectrometry, Substrate Specificity, chemistry.chemical_compound, Structural Biology, Enterococcus hirae, Catalytic Domain, chemistry.chemical_classification, 0303 health sciences, MESH : Substrate Specificity, biology, MESH : Amino Acid Sequence, MESH : Catalytic Domain, N-acetylglucosaminidase, MESH: Enterococcus, CAZy, Molecular Sequence Data, Biophysics, Article, 03 medical and health sciences, MESH : Mass Spectrometry, MESH : Acetylglucosaminidase, Acetylglucosaminidase, Hydrolase, Genetics, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Glycosyl, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, 030304 developmental biology, MESH: Mass Spectrometry, MESH: Molecular Sequence Data, 030306 microbiology, Autolysin, MESH : Enterococcus, Cell Biology, biology.organism_classification, Enzyme, chemistry, Enterococcus, MESH: Substrate Specificity
Abstract: International audience; Enterococcus hirae produces two autolytic enzymes named Mur-1 and Mur-2, both previously described as N-acetylmuramidases. We used tandem mass spectrometry to show that Mur-2 in fact displays N-acetylglucosaminidase activity. This result reveals that Mur-2 and its counterparts studied to date, which are members of glycosyl hydrolase family 73 from the CAZy (Carbohydrate-Active enZyme) database, display the same catalytic activity.
Published: 2007

15. Aslfm, the D-aspartate ligase responsible for the addition of D-aspartic acid onto the peptidoglycan precursor of Enterococcus faecium

Author: Raymond Legrand, Samuel Bellais, Laurent Gutmann, Lionnel Dubost, J.-L. Mainardi, Jean van Heijenoort, Louis B. Rice, Michel Arthur, Jean-Emmanuel Hugonnet, Jean-Paul Brouard, Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de chimie et biochimie des substances naturelles, Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Institut de biochimie et biophysique moléculaire et cellulaire (IBBMC), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Aventis Pharma, the Medical and Research Services, Louis Stokes Cleveland Veterans Affairs Medical Center, Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Chimie et Biochimie des Substances Naturelles, Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut de biochimie et biophysique moléculaire et cellulaire ( IBBMC ), Université Paris-Sud - Paris 11 ( UP11 ) -Centre National de la Recherche Scientifique ( CNRS ), and Arthur, Michel
Subjects: Enterococcus faecium, Molecular Sequence Data, Aspartate racemase, Peptidoglycan, Biochemistry, Enterococcus faecalis, Substrate Specificity, Ligases, chemistry.chemical_compound, Adenosine Triphosphate, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Molecular Biology, Peptide sequence, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Isomerases, chemistry.chemical_classification, DNA ligase, biology, Sequence Homology, Amino Acid, D-Aspartic Acid, Cell Biology, biology.organism_classification, Molecular biology, Amino acid, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Enzyme, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, chemistry, Amino Acid Substitution, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases
Abstract: D-aspartate ligase has remained the last unidentified peptide bond-forming enzyme in the peptidoglycan assembly pathway of Gram-positive bacteria. Here we show that a two-gene cluster of Enterococcus faecium encodes aspartate racemase (Racfm) and ligase (Aslfm) for incorporation of D-Asp into the side chain of the peptidoglycan precursor. Aslfm was identified as a new member of the ATP-grasp protein superfamily, which includes a diverse set of enzymes catalyzing ATP-dependent carboxylate-amine ligation reactions. Aslfm specifically ligated the beta-carboxylate of D-Asp to the epsilon-amino group of L-Lys in the nucleotide precursor UDP-N-acetylmuramyl-pentapeptide. D-iso-asparagine was not a substrate of Aslfm, indicating that the presence of this amino acid in the peptidoglycan of E. faecium results from amidation of the alpha-carboxyl of D-Asp after its addition to the precursor. Heterospecific expression of the genes encoding Racfm and Aslfm in Enterococcus faecalis led to production of stem peptides substituted by D-Asp instead of L-Ala2, providing evidence for the in vivo specificity and function of these enzymes. Strikingly, sequencing of the cross-bridges revealed that substitution of L-Ala2 by D-Asp is tolerated by the d,d-transpeptidase activity of the penicillin-binding proteins both in the acceptor and in the donor substrates. The Aslfm ligase appears as an attractive target for the development of narrow spectrum antibiotics active against multiresistant E. faecium.
Published: 2006

16. Novel mechanism of resistance to glycopeptide antibiotics in Enterococcus faecium

Author: Arul Marie, J.-C. Quincampoix, Jean-Emmanuel Hugonnet, Louis B. Rice, Laurent Gutmann, Julie Cremniter, Nathalie Josseaume, Lionel Dubost, Jean-Luc Mainardi, Michel Arthur, Lecerf, Maxime, Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire de chimie et biochimie des substances naturelles, Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Medical and Research Services, Louis Stokes Cleveland Veterans Affairs Medical Center, This work was supported by the European Community (COBRA, contract LSHM-CT-2003-503335, 6th PCRD), the National Institute of Allergy and Infectious Diseases (Grant R01 AI45626), and the Fondation pour la Recherche Médicale., Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Laboratoire de Chimie et Biochimie des Substances Naturelles, and Centre National de la Recherche Scientifique ( CNRS )
Subjects: Cytoplasm, MESH : Muramoylpentapeptide Carboxypeptidase, Enterococcus faecium, MESH : Models, Biological, Muramoylpentapeptide Carboxypeptidase, MESH : Drug Resistance, Bacterial, Biochemistry, Substrate Specificity, Muramoylpentapeptide carboxypeptidase, chemistry.chemical_compound, polycyclic compounds, Peptide bond, MESH: Enterococcus faecium, MESH : Anti-Bacterial Agents, MESH : Enterococcus faecium, MESH: Peptide Fragments, MESH : Peptidoglycan, Alanine, 0303 health sciences, MESH: Microbial Sensitivity Tests, MESH : Substrate Specificity, MESH: Peptidoglycan, Hydrolysis, Glycopeptides, MESH: Amino Acid Substitution, Glycopeptide, Anti-Bacterial Agents, Cross-Linking Reagents, MESH: Muramoylpentapeptide Carboxypeptidase, MESH: Hydrolysis, MESH : Cross-Linking Reagents, MESH : Cytoplasm, MESH : Glycopeptides, Stereochemistry, MESH: Alanine, MESH: Cross-Linking Reagents, Microbial Sensitivity Tests, Peptidoglycan, Biology, beta-Lactams, Models, Biological, Article, 03 medical and health sciences, MESH : Amino Acid Substitution, MESH : beta-Lactams, MESH : Hydrolysis, MESH: beta-Lactams, MESH: Anti-Bacterial Agents, Glycosyltransferase, Drug Resistance, Bacterial, MESH: Drug Resistance, Bacterial, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, 030304 developmental biology, MESH: Glycopeptides, 030306 microbiology, MESH: Cytoplasm, MESH : Peptide Fragments, MESH: Models, Biological, Cell Biology, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, Peptide Fragments, chemistry, Amino Acid Substitution, biology.protein, MESH: Substrate Specificity, MESH : Microbial Sensitivity Tests, MESH : Alanine, Bacteria
Abstract: International audience; Glycopeptides and beta-lactams are the major antibiotics available for the treatment of infections due to Gram-positive bacteria. Emergence of cross-resistance to these drugs by a single mechanism has been considered as unlikely because they inhibit peptidoglycan polymerization by different mechanisms. The glycopeptides bind to the peptidyl-D-Ala(4)-D-Ala(5) extremity of peptidoglycan precursors and block by steric hindrance the essential glycosyltransferase and D,D-transpeptidase activities of the penicillin-binding proteins (PBPs). The beta-lactams are structural analogues of D-Ala(4)-D-Ala(5) and act as suicide substrates of the D,D-transpeptidase module of the PBPs. Here we have shown that bypass of the PBPs by the recently described beta-lactam-insensitive L,D-transpeptidase from Enterococcus faecium (Ldt(fm)) can lead to high level resistance to glycopeptides and beta-lactams. Cross-resistance was selected by glycopeptides alone or serially by beta-lactams and glycopeptides. In the corresponding mutants, UDP-MurNAc-pentapeptide was extensively converted to UDP-MurNAc-tetrapeptide following hydrolysis of D-Ala(5), thereby providing the substrate of Ldt(fm). Complete elimination of D-Ala(5), a residue essential for glycopeptide binding, was possible because Ldt(fm) uses the energy of the L-Lys(3)-D-Ala(4) peptide bond for cross-link formation in contrast to PBPs, which use the energy of the D-Ala(4)-D-Ala(5) bond. This novel mechanism of glycopeptide resistance was unrelated to the previously identified replacement of D-Ala(5) by D-Ser or D-lactate.
Published: 2006

17. Functional analysis of AtlA, the major N-acetylglucosaminidase of Enterococcus faecalis

Author: Catherine Eckert, Michel Arthur, Maxime Lecerf, Stéphane Mesnage, Lionel Dubost, Lecerf, Maxime, Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire de chimie et biochimie des substances naturelles, Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Laboratoire de Chimie et Biochimie des Substances Naturelles, and Centre National de la Recherche Scientifique ( CNRS )
Subjects: MESH : Escherichia coli, MESH: Acetylglucosaminidase, medicine.disease_cause, law.invention, MESH: Recombinant Proteins, chemistry.chemical_compound, law, Tandem Mass Spectrometry, Enterococcus faecalis, MESH : Bacterial Proteins, Threonine, MESH : Enterococcus faecalis, MESH: Bacterial Proteins, MESH : Peptidoglycan, 0303 health sciences, medicine.diagnostic_test, MESH: Escherichia coli, MESH: Peptidoglycan, Recombinant Proteins, Biochemistry, Recombinant DNA, MESH : Tandem Mass Spectrometry, MESH: Enterococcus faecalis, MESH : Recombinant Proteins, Proteolysis, Peptidoglycan, Biology, Microbiology, 03 medical and health sciences, Bacterial Proteins, MESH : Acetylglucosaminidase, Acetylglucosaminidase, medicine, Escherichia coli, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, MESH: Humans, 030306 microbiology, MESH : Humans, MESH: Tandem Mass Spectrometry, biology.organism_classification, Proteinase K, Molecular biology, Enzymes and Proteins, Enzyme assay, chemistry, biology.protein
Abstract: The major peptidoglycan hydrolase of Enterococcus faecalis , AtlA, has been identified, but its enzyme activity remains unknown. We have used tandem mass spectrometry analysis of peptidoglycan hydrolysis products obtained using the purified protein to show that AtlA is an N -acetylglucosaminidase. To gain insight into the regulation of its enzyme activity, the three domains of AtlA were purified alone or in combination following expression of truncated forms of the atlA gene in Escherichia coli or partial digestion of AtlA by proteinase K. The central domain of AtlA was catalytically active, but its activity was more than two orders of magnitude lower than that of the complete protein. Partial proteolysis of AtlA was detected in vivo: zymograms of E. faecalis extracts revealed two catalytically active protein bands of 62 and 72 kDa that were both absent in extracts from an atlA null mutant. Limited digestion of AtlA by proteinase K in vitro suggested that the proteolytic cleavage of AtlA in E. faecalis extracts corresponds to the truncation of the N-terminal domain, which is rich in threonine and glutamic acid residues. We show that the truncation of the N-terminal domain from recombinant AtlA has no impact on enzyme activity. The C-terminal domain of the protein, which contains six LysM modules bound to highly purified peptidoglycan, was required for optimal enzyme activity. These data indicate that AtlA is not produced as a proenzyme and that control of the AtlA glucosaminidase activity is likely to occur at the level of LysM-mediated binding to peptidoglycan.
Published: 2006

18. Anatomie de la rétine

Author: Laurent Jonet, Francine Behar-Cohen, Patricia Lassiaz, Emmanuelle Gelize, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Métabolisme et physiologie rénale (CRC - UMR_S 1138), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), and Université Paris Descartes - Paris 5 (UPD5)
Subjects: 0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Philosophy, [SDV]Life Sciences [q-bio], 030221 ophthalmology & optometry, General Medicine, Molecular biology, General Biochemistry, Genetics and Molecular Biology
Abstract: International audience; La neurorétine est une unité fonctionnelle du système nerveux central assurant la conversion d’un signal lumineux en un influx nerveux. D’origine neuroectodermique, dérivée du diencéphale, la neurorétine est un tissu stratifié, composé de six types de cellules neuronales (deux types de photorécepteurs : les cônes et les bâtonnets ; les cellules horizontales, bipolaires, amacrines et ganglionnaires) et de trois types de cellules gliales (les cellules gliales de Müller, les astrocytes et les cellules microgliales). La neurorétine repose sur l’épithélium pigmentaire rétinien, l’ensemble constituant la rétine. L’existence des barrières hémato-rétiniennes interne et externe et des jonctions intra-rétiniennes rend compte de la finesse de la régulation des échanges de la rétine avec la circulation et au sein de la rétine elle-même. La zone centrale de la rétine humaine, la macula, zone hautement spécialisée pour assurer l’acuité visuelle, présente des spécificités anatomiques. Les méthodes d’imagerie récentes permettent d’enrichir nos connaissances sur les caractéristiques anatomiques et fonctionnelles de la rétine, qui restent encore imparfaitement décrites.
Published: 2020

19. Comparison Between ESC and Duke Criteria for the Diagnosis of Prosthetic Valve Infective Endocarditis

Author: Mainardi, Jean-Luc, Fernandez-Gerlinger, Marie-Paule, Hagège, Albert, Casalta, Anne Claire, Casalta, Jean Paul, Philip, Mary, Tessonier, Laetitia, Mancini, Julien, Mainardi, Jl, Fernandez-Gerlinger, MP, Lussato, David, Attias, David, Cammilleri, Serge, Weinmann, Pierre, Hagege, A, Arregle, Florent, Martel, Hélène, Oliver, Leopold, Camoin, Laurence, Casalta, AC, Casalta, JP, Gouriet, Frederique, Riberi, Alberto, Lepidi, Hubert, Raoult, Didier, Drancourt, Michel, Habib, Gilbert, Département de Cardiologie [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service de médecine nucléaire [Marseille], Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Biostatistique et technologies de l'information et de la communication (BioSTIC) - [Hôpital de la Timone - APHM] (BiosTIC ), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre cardiologique du Nord (CCN), Médecine nucléaire [CHU 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 cardiologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Guedj, Eric, 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de microbiologie, 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)-Université Paris Descartes - Paris 5 (UPD5), 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), Institut Hospitalier Universitaire Méditerranée Infection (IHU AMU), Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bichat, Institut universitaire de formation des maîtres - Nord-Pas-de-Calais (IUFM Nord-Pas-de-Calais), Université d'Artois (UA), Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Infectieuses Tropicales Emergentes (URMITE), and INSB-INSB-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48
Subjects: [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Cardiology, 030204 cardiovascular system & hematology, valve disease, Duke criteria, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Fluorodeoxyglucose F18, Predictive Value of Tests, Positron Emission Tomography Computed Tomography, medicine, Endocarditis, Humans, Radiology, Nuclear Medicine and imaging, guidelines, ComputingMilieux_MISCELLANEOUS, Prosthetic valve, nuclear imaging, Reproducibility, medicine.diagnostic_test, business.industry, Reproducibility of Results, medicine.disease, Confidence interval, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Positron emission tomography, Infective endocarditis, Heart Valve Prosthesis, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Radiopharmaceuticals, Cardiology and Cardiovascular Medicine, Nuclear medicine, business, Kappa, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Objectives: The primary objective was to assess the value of the European Society of Cardiology (ESC) criteria, including 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in prosthetic valve infective endocarditis (PVE). Secondary objectives were: 1) to assess the reproducibility of 18F-FDG-PET/CT; 2) to compare its diagnostic value with that of echocardiography; and 3) to assess the diagnostic value of the presence of a diffuse splenic uptake BACKGROUND: 18F-FDG PET/CT has been added as a major criterion in the ESC 2015 infective endocarditis (IE) guidelines, but the benefit of the ESC criteria has not been prospectively compared with the conventional Duke criteria.Methods: Between 2014 and 2017, 175 patients with suspected PVE were prospectively included in 3 French centers. After exclusion of patients with uninterpretable 18F-FDG PET/CT, 115 patients were evaluated, including 91 definite and 24 rejected IE, as defined by an expert consensus.Results: Cardiac uptake by 18F-FDG PET/CT was observed in 67 of 91 patients with definite PVE and 6 with rejected IE (sensitivity 73.6% [95% confidence interval (CI): 63.3% to 82.3%], specificity 75% [95% CI: 53.3% to 90.2%]). The ESC 2015 classification increased the sensitivity of Duke criteria from 57.1% (95% CI: 46.3% to 67.5%) to 83.5% (95% CI: 74.3% to 90.5%) (p < 0.001), but decreased its specificity from 95.8% (95% CI: 78.9% to 99.9%) to 70.8% (95% CI: 48.9% to 87.4%). Intraobserver reproducibility of 18F-FDG PET/CT was good (kappa = 0.84) but interobserver reproducibility was less satisfactory (kappa = 0.63). A diffuse splenic uptake was observed in 24 (20.3%) patients, including 23 (25.3%) of definite PVE, and only 1 (4.2%) rejected PVE (p = 0.024).Conclusions: 18F-FDG PET/CT is a useful diagnostic tool in suspected PVE, and explains the greater sensitivity of ESC criteria than Duke criteria. However, 18F-FDG PET/CT also presents with important limitations concerning its feasibility, specificity, and reproducibility. Our study describes for the first time a new endocarditis criterion, that is, the presence of a diffuse splenic uptake on 18F-FDG PET/CT.
Published: 2020

20. Ionpair-π interactions favor cell penetration of arginine/tryptophan-rich cell-penetrating peptides

Author: Astrid Walrant, Natpasit Chaianantakul, Isabel D. Alves, Françoise Illien, Antonio Frontera, Sandrine Sagan, Sophie Lecomte, Sébastien Cardon, Manjula Pallerla, Claudia Girardet, Antonio Bauzá, Fabienne Burlina, University of Cambridge [UK] (CAM), Departament de Quimica, Universitat des Illes Balears, Chimie et Biologie des Membranes et des Nanoobjets (CBMN), Université Sciences et Technologies - Bordeaux 1-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Centre National de la Recherche Scientifique (CNRS), Analyse, Interactions Moléculaires et Cellulaires (LBM-E2), Laboratoire des biomolécules (LBM UMR 7203), Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Département de cardiologie, CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Institut National de la Santé et de la Recherche Médicale (INSERM)-Chimie Moléculaire de Paris Centre (FR 2769), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universitat de les Illes Balears (UIB), Université de Bordeaux (UB)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Naresuan University, École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-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)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chimie Moléculaire de Paris Centre (FR 2769), Université Pierre et Marie Curie - Paris 6 (UPMC)-ESPCI ParisTech-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-ESPCI ParisTech-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: 0301 basic medicine, Chinese Hamster Ovary, Isothermal Titration Calorimetry, Arginine, CHO, [SDV]Life Sciences [q-bio], POPG, Peptide, Cell-Penetrating Peptides, Attenuated Total Reflection Fourier Transformed Infra Red, 01 natural sciences, Biochemistry, DFT, DSC, Cell membrane, Cricetinae, Lipid membrane, Lipid bilayer, Internalization, Glycosaminoglycans, media_common, Cell-penetrating-peptide, chemistry.chemical_classification, GAG, 0303 health sciences, cell-penetrating-peptide / ionpair-pi interaction / glycosaminoglycan / lipid membrane / tryptophan / arginine Abbreviations ART-FTIR, Differential Scanning Calorimetry, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Tryptophan, [CHIM.MATE]Chemical Sciences/Material chemistry, Endocytosis, Protein Transport, Membrane, medicine.anatomical_structure, Thermodynamics, DMPG, media_common.quotation_subject, 1-palmitoyl-2, Biophysics, CHO Cells, 010402 general chemistry, Cell-Penetrating Peptide, 03 medical and health sciences, Cricetulus, medicine, Animals, Humans, Amino Acid Sequence, 030304 developmental biology, Ionpair-pi interaction, Cell Membrane, Isothermal titration calorimetry, Cell Biology, ITC, 0104 chemical sciences, 030104 developmental biology, Glycosaminoglycan, Cell-penetrating peptide, Density functional theory, CPP, 2-dimyristoyl sn-glycero-3-phospho-(1'-rac- glycerol)
Abstract: Cell-penetrating peptides (CPPs) internalization can occur both by endocytosis and direct translocation through the cell membrane. These different entry routes suggest that molecular partners at the plasma membrane, phospholipids or glycosaminoglycans (GAGs), bind CPPs with different affinity or selectivity. The analysis of sequence-dependent interactions of CPPs with lipids and GAGs should lead to a better understanding of the molecular mechanisms underlying their internalization. CPPs are short sequences generally containing a high number of basic arginines and lysines and sometimes aromatic residues, in particular tryptophans. Tryptophans are crucial residues in membrane-active peptides, because they are important for membrane interaction. Membrane-active peptides often present facial amphiphilicity, which also promote the interaction with lipid bilayers. To study the role of Trp and facial amphiphilicity in cell interaction and penetration of CPPs, a nonapeptide series containing only Arg, Trp or D-Trp residues at different positions was designed. Our quantitative study indicates that to maintain/increase the uptake efficiency, Arg can be advantageously replaced by Trp in the nonapeptides. The presence of Trp in oligoarginines increases the uptake in cells expressing GAGs at their surface, when it only compensates for the loss of Arg and maintains similar peptide uptake in GAG-deficient cells. In addition, we show that facial amphiphilicity is not required for efficient uptake of these nonapeptides. Thermodynamic analyses point towards a key role of Trp that highly contributes to the binding enthalpy of complexes formation. Density functional theory (DFT) analysis highlights that salt bridge-π interactions play a crucial role for the GAG-dependent entry mechanisms.
Published: 2019

21. Peptidoglycan potentiates the membrane disrupting effect of the carboxyamidated form of DMS-DA6, a Gram-positive selective antimicrobial peptide isolated from Pachymedusa dacnicolor skin

Author: Cardon, Sébastien, Sachon, Emmanuelle, Carlier, Ludovic, Drujon, Thierry, Walrant, Astrid, Alemán-Navarro, Estefanía, Martínez-Osorio, Verónica, Guianvarc'H, Dominique, Sagan, Sandrine, Fleury, Yannick, Marquant, Rodrigue, Piesse, Christophe, Rosenstein, Yvonne, Auvynet, Constance, Lacombe, Claire, Analyse, Interactions Moléculaires et Cellulaires (LBM-E2), Laboratoire des biomolécules (LBM UMR 7203), Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Equipe de Chimie Organique et Biologie Structurale (ECOBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA), University of Cambridge [UK] (CAM), Synthèse, Structure et Fonction de Molécules Bioactives (SSFMB), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Universitaire de Biodiversité et Ecologie Microbienne (LUBEM), Université de Brest (UBO), Peptides, glycoconjugués et métaux en biologie (LBM-E1), Ingénierie des protéines, PCR, Interaction Moléculaires [IBPS] (IBPS-IPIM), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Protéines : biochimie structurale et fonctionnelle (PBSF), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-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)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chimie Moléculaire de Paris Centre (FR 2769), Université Pierre et Marie Curie - Paris 6 (UPMC)-ESPCI ParisTech-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-ESPCI ParisTech-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Département de Chimie - ENS Paris, and École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Magnetic Resonance Spectroscopy, Polymers, Staphylococcus, [SDV]Life Sciences [q-bio], Enterococcus faecium, lcsh:Medicine, Pathology and Laboratory Medicine, Biochemistry, Medicine and Health Sciences, Staphylococcus Aureus, lcsh:Science, Materials, Phospholipids, Skin, Antimicrobials, Circular Dichroism, Gram Positive Bacteria, Eukaryota, Drugs, Drug Synergism, Lipids, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Bacterial Pathogens, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Chemistry, Macromolecules, Medical Microbiology, Physical Sciences, Vertebrates, Frogs, Anura, Pathogens, Cellular Structures and Organelles, Research Article, Materials Science, Microbial Sensitivity Tests, Peptidoglycan, Microbiology, Amphibian Proteins, Amphibians, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Microbial Control, Animals, Humans, Vesicles, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Microbial Pathogens, Pharmacology, Membranes, Bacteria, lcsh:R, Organisms, Biology and Life Sciences, Bacteriology, Cell Biology, Peptidoglycans, Polymer Chemistry, A549 Cells, Antibacterials, lcsh:Q, Antimicrobial Cationic Peptides
Abstract: International audience; The occurrence of nosocomial infections has been on the rise for the past twenty years. Notably, infections caused by the Gram-positive bacteria Staphylococcus aureus represent a major clinical problem, as an increase in antibiotic multi-resistant strains has accompanied this rise. There is thus a crucial need to find and characterize new antibiotics against Gram-positive bacteria, and against antibiotic-resistant strains in general. We identified a new der-maseptin, DMS-DA6, produced by the skin of the Mexican frog Pachymedusa dacnicolor, with specific antibacterial activity against Gram-positive bacteria. This peptide is particularly effective against two multiple drug-resistant strains Enterococcus faecium BM4147 and Staphylococcus aureus DAR5829, and has no hemolytic activity. DMS-DA6 is naturally produced with the C-terminal carboxyl group in either the free or amide forms. By using Gram-positive model membranes and different experimental approaches, we showed that both forms of the peptide adopt an α-helical fold and have the same ability to insert into, and to disorganize a membrane composed of anionic lipids. However, the bactericidal capacity of DMS-DA6-NH 2 was consistently more potent than that of DMS-DA6-OH. Remarkably, rather than resulting from the interaction with the negatively charged lipids of the membrane, or from a more stable conformation towards proteolysis, the increased capacity to permeabi-lize the membrane of Gram-positive bacteria of the carboxyamidated form of DMS-DA6 was found to result from its enhanced ability to interact with peptidoglycan. PLOS ONE | https://doi.org/10.1371/journal.pone.
Published: 2018

22. Rôle du motif SDN dans l'inhibition et l'activité des β-lactamases des mycobactéries

Author: Soroka, Daria, STAR, ABES, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris VI, and Michel Arthur
Subjects: Carbapénème, Clavulanate, Mycobacterium abscessus, Avibactam, Mycobacterium tuberculosis, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Β-lactamases, Carbapenem, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM]
Abstract: Mycobacterium tuberculosis and Mycobacterium abscessus produce the β-lactamases BlaC and BlaMab that contribute to the intrinsic resistance of those bacteria to β-lactams. Our objective was to characterize the inhibition of these β-lactamases by avibactam and clavulanate in order to contribute to the development of new treatments. We have determined the inhibition and substrate profiles of BlaMab, as well as its crystal structure, revealing three major differences with BlaC. BlaMab is more active than BlaC with respect to hydrolysis of all β-lactams except cefoxitin, which is used for the treatment of infections due to M. abscessus. BlaC is inhibited irreversibly by clavulanate and inefficiently by avibactam. In contrast, BlaMab shows the opposite behavior involving hydrolysis of clavulanate and a rapid inhibition by avibactam. Structurally BlaC differs from BlaMab mainly by the replacement of the conserved motif SDN by SDG. The introduction of SDG in BlaMab and of SDN in BlaC revealed that this difference determines the inhibition profile of the β-lactamases. A single mutation can therefore lead to the emergence of resistance to the association of β-lactam with clavulanate or avibactam, but not to both associations. Thus, avibactam and clavulanate offer therapeutic alternatives in case of resistance to one of the two inhibitors. We have also investigated the β-lactam partners of clavulanate for the treatment of tuberculosis and showed that the structure of carbapenems could be optimized to enhance the inactivation of the targets and to reduce hydrolysis by BlaC., Mycobacterium tuberculosis et Mycobacterium abscessus produisent les β-lactamases BlaC et BlaMab qui contribuent à la résistance intrinsèque de ces bactéries aux β-lactamines. Notre objectif est de caractériser l’inhibition de ces β-lactamases par l’avibactam et le clavulanate pour contribuer au développement de nouveaux traitements. Nous avons déterminé le profil de substrat et d’inhibition de BlaMab ainsi que sa structure cristalline, révélant trois différences majeures avec BlaC. BlaMab a une activité supérieure à celle de BlaC pour toutes les β-lactamines sauf la céfoxitine qui est utilisée pour les infections dues à M. abscessus. BlaC est inhibée irréversiblement par le clavulanate et inefficacement par l’avibactam alors que BlaMab présente le comportement inverse impliquant une hydrolyse du clavulanate et une inhibition très rapide par l’avibactam. La structure de BlaMab diffère de celle de BlaC principalement par le remplacement du motif conservé SDN par SDG. L’introduction de SDG dans BlaMab et de SDN dans BlaC a montré que cette différence détermine le profil d’inhibition des β-lactamases. Une seule mutation peut donc entraîner l’émergence d’une résistance aux combinaisons d’une β-lactamine avec le clavulanate ou l’avibactam mais pas avec les deux inhibiteurs. L’avibactam et le clavulanate offrent donc des alternatives thérapeutiques en cas de résistance à l’un des inhibiteurs. Nous nous sommes également intéressés aux β-lactamines partenaires du clavulanate, pour le traitement de la tuberculose et montrer que la structure des carbapénèmes pouvait être optimisée pour améliorer l’inactivation des cibles et diminuer l’hydrolyse par BlaC.
Published: 2016

23. Nocardia pseudobrasiliensis as an Emerging Cause of Opportunistic Infection after Allogeneic Hematopoietic Stem Cell Transplantation

Author: Emilie Catherinot, Marc Lecuit, David Lebeaux, Felipe Suarez, Olivier Lortholary, Nicolas Degand, J.-L. Mainardi, Marie-Thérèse Rubio, Fanny Lanternier, Isabelle Podglajen, 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), Service des Maladies infectieuses et tropicales [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Foch [Suresnes], 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), Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microorganismes et Barrières de l'Hôte (Equipe avenir), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Référence des Mycoses invasives et antifongiques - Mycologie moléculaire (CNRMA), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), We thank Blandine Rammaert, Jean-Paul Viard, Sylvain Poiree, and Louis Puybasset for their clinical assistance in the care of this patient., DIAKITE, andrée, Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Opportunistic infection, [SDV]Life Sciences [q-bio], medicine.medical_treatment, MESH: Microscopy, Fluorescence, Case Reports, Hematopoietic stem cell transplantation, Nocardia, MESH: Carbapenems, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 030212 general & internal medicine, Tomography, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, MESH: Microbial Sensitivity Tests, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: Middle Aged, medicine.diagnostic_test, MESH: Tomography, Nocardiosis, Hematopoietic Stem Cell Transplantation, Middle Aged, Anti-Bacterial Agents, 3. Good health, [SDV] Life Sciences [q-bio], [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Nocardia Infections, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.IMM]Life Sciences [q-bio]/Immunology, Radiography, Thoracic, Nocardia Infections, Bronchoalveolar Lavage Fluid, Microbiology (medical), [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Pneumonia, Bacterial, MESH: Nocardia, Microbial Sensitivity Tests, Opportunistic Infections, Biology, Microbiology, 03 medical and health sciences, MESH: Anti-Bacterial Agents, Drug Resistance, Bacterial, MESH: Drug Resistance, Bacterial, Pneumonia, Bacterial, medicine, Humans, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Hematopoietic Stem Cell Transplantation, MESH: Humans, MESH: Bronchoalveolar Lavage Fluid, 030306 microbiology, MESH: Opportunistic Infections, MESH: Radiography, Thoracic, medicine.disease, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Male, Transplantation, Pneumonia, Bronchoalveolar lavage, Carbapenems, Microscopy, Fluorescence, Immunology, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: We report the case of a 55-year-old man who exhibited a nodular pneumonia 4 months after an allogeneic hematopoietic stem cell transplantation. Culture of the bronchoalveolar lavage fluid revealed Nocardia pseudobrasiliensis . This recently described carbapenem-resistant species should be included in the differential diagnosis of fungal infection in this setting.
Published: 2010

24. Idiosyncratic features in tRNAs participating in bacterial cell wall synthesis

Author: Nathalie Josseaume, Lionel Dubost, Claudine Mayer, Jean-Marc Valery, Jean-Emmanuel Hugonnet, Stéphane Mesnage, Mélanie Etheve-Quelquejeu, Maryline Chemama, Michel Arthur, Antoine P. Maillard, Matthieu Fonvielle, Patricia Busca, Arul Marie, Régis Villet, Structure bactérienne et résistance aux antibiotiques (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Pathogenèse bactérienne et réponses cellulaires (PBRC), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de chimie et biochimie des substances naturelles, Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Molécules de Communication et Adaptation des Micro-Organismes (MCAM), Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Krebs Inst, University of Sheffield [Sheffield], Université Paris Diderot - Paris 7 (UPD7), Synthèse, Structure et Fonction de Molécules Bioactives (SSFMB), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École Pratique des Hautes Études (EPHE), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Chimie et Biochimie des Substances Naturelles, Centre National de la Recherche Scientifique (CNRS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Models, Molecular, Base pair, [SDV]Life Sciences [q-bio], Molecular Sequence Data, RNA, Transfer, Ala, Peptidoglycan, Wobble base pair, MESH: Base Sequence, Biology, 03 medical and health sciences, chemistry.chemical_compound, MESH: Cell Wall, Cell Wall, Genetics, Transferase, Nucleotide, Peptide Synthases, MESH: RNA, Transfer, Ala, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, MESH: Molecular Sequence Data, Bacteria, Base Sequence, Nucleic Acid Enzymes, MESH: Peptidoglycan, 030306 microbiology, Mutagenesis, MESH: Peptide Synthases, Amino acid, MESH: Bacteria, MESH: Mutagenesis, Site-Directed, chemistry, Biochemistry, Transfer RNA, Mutagenesis, Site-Directed, MESH: Uridine Diphosphate N-Acetylmuramic Acid, MESH: Models, Molecular
Abstract: International audience; The FemX(Wv) aminoacyl transferase of Weissella viridescens initiates the synthesis of the side chain of peptidoglycan precursors by transferring l-Ala from Ala-tRNA(Ala) to UDP-MurNAc-pentadepsipeptide. FemX(Wv) is an attractive target for the development of novel antibiotics, since the side chain is essential for the last cross-linking step of peptidoglycan synthesis. Here, we show that FemX(Wv) is highly specific for incorporation of l-Ala in vivo based on extensive analysis of the structure of peptidoglycan. Comparison of various natural and in vitro-transcribed tRNAs indicated that the specificity of FemX(Wv) depends mainly upon the sequence of the tRNA although additional specificity determinants may include post-transcriptional modifications and recognition of the esterified amino acid. Site-directed mutagenesis identified cytosines in the G1-C72 and G2-C71 base pairs of the acceptor stem as critical for FemX(Wv) activity in agreement with modeling of tRNA(Ala) in the catalytic cavity of the enzyme. In contrast, semi-synthesis of Ala-tRNA(Ala) harboring nucleotide substitutions in the G3-U70 wobble base pair showed that this main identity determinant of alanyl-tRNA synthetase is non-essential for FemX(Wv). The different modes of recognition of the acceptor stem indicate that specific inhibition of FemX(Wv) could be achieved by targeting the distal portion of tRNA(Ala) for the design of substrate analogues.
Published: 2007

25. Genome wide association study identifies KCNMA1contributing to human obesity

Author: David Brodin, Anders Hamsten, Ferdinand M. van't Hooft, Ingrid Dahlman, Sébastien Czernichow, Thorkild I. A. Sørensen, Oluf Pedersen, Hong Jiao, Torben Hansen, Tomas Axelsson, Johan Hoffstedt, Johannes Hebebrand, Peter Arner, Karin Dahlman-Wright, Juha Kere, Béatrice Dubern, Karine Clément, Department of Biosciences and Nutrition, Karolinska Institutet [Stockholm], Clinical Research Centre, Karolinska University Hospital [Stockholm], Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Unité de Recherche en Epidémiologie Nutritionnelle ( UREN ), Université Paris 13 ( UP13 ) -Institut National de la Recherche Agronomique ( INRA ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Cardiovascular Genetics Group, Karolinska Institutet [Stockholm]-Atherosclerosis Research Unit-Department of Medicine Solna, Department of Medical Sciences, Uppsala University-Molecular Medicine-Science for Life Laboratory, Hagedorn Research Institute, Gentofte, Center of Basic Metabolic Research, Faculty of Health Sciences-University of Copenhagen ( KU ), Institute for Preventive Medicine, Copenhagen University Hospital-Center for Health and Society, Department of Child and Adolescent Psychiatry, Universität Duisburg-Essen [Essen], Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), This project was supported by grants from AFA (PA), the Swedish Heart and Lung Foundation (PA, AHA), the Swedish Research Council (PA, AHA, ID), Novo Nordic Foundation (ID), Swedish Diabetes Association (PA), the Knut and Alice Wallenberg Foundation and the Stockholm County Council (project 56218, AHA)., Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), BMC, Ed., Department of Biosciences and Nutrition [Karolinska Insitutet, Sueden] (BioNut), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-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 Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Universität Duisburg-Essen = University of Duisburg-Essen [Essen], and Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Medizin, Genome-wide association study, Susceptibility Locus, Bioinformatics, FTO gene, Body Mass Index, Cohort Studies, 0302 clinical medicine, Germany, ADULT OBESITY, EXTREME OBESITY, Genetics(clinical), Large-Conductance Calcium-Activated Potassium Channel alpha Subunits, Genetics (clinical), 2. Zero hunger, 0303 health sciences, education.field_of_study, Obesity Gene, Allelic Association, COMMON VARIANTS, Middle Aged, Obesity, Morbid, FAT MASS, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, France, CHILDHOOD OBESITY, METABOLIC TRAITS, Research Article, medicine.medical_specialty, lcsh:Internal medicine, NON-REPLICATION, lcsh:QH426-470, Population, EARLY-ONSET, BODY-MASS INDEX, FTO GENE, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Childhood obesity, 03 medical and health sciences, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Genetics, ddc:61, Humans, Genetic Predisposition to Disease, ddc:610, Medizinische Fakultät » Universitätsklinikum Essen » LVR-Klinikum Essen » Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Obesity, education, lcsh:RC31-1245, Alleles, 030304 developmental biology, Sweden, Genome, Human, Odds ratio, medicine.disease, Morbid Obesity, lcsh:Genetics, Endocrinology, Case-Control Studies, Body mass index, Genome-Wide Association Study
Abstract: Background Recent genome-wide association (GWA) analyses have identified common single nucleotide polymorphisms (SNPs) that are associated with obesity. However, the reported genetic variation in obesity explains only a minor fraction of the total genetic variation expected to be present in the population. Thus many genetic variants controlling obesity remain to be identified. The aim of this study was to use GWA followed by multiple stepwise validations to identify additional genes associated with obesity. Methods We performed a GWA analysis in 164 morbidly obese subjects (BMI:body mass index > 40 kg/m2) and 163 Swedish subjects (> 45 years) who had always been lean. The 700 SNPs displaying the strongest association with obesity in the GWA were analyzed in a second cohort comprising 460 morbidly obese subjects and 247 consistently lean Swedish adults. 23 SNPs remained significantly associated with obesity (nominal P< 0.05) and were in a step-wise manner followed up in five additional cohorts from Sweden, France, and Germany together comprising 4214 obese and 5417 lean or population-based control individuals. Three samples, n = 4133, were used to investigate the population-based associations with BMI. Gene expression in abdominal subcutaneous adipose tissue in relation to obesity was investigated for14 adults. Results Potassium channel, calcium activated, large conductance, subfamily M, alpha member (KCNMA1) rs2116830*G and BDNF rs988712*G were associated with obesity in five of six investigated case-control cohorts. In meta-analysis of 4838 obese and 5827 control subjects we obtained genome-wide significant allelic association with obesity for KCNMA1 rs2116830*G with P = 2.82 × 10-10 and an odds ratio (OR) based on cases vs controls of 1.26 [95% C.I. 1.12-1.41] and for BDNF rs988712*G with P = 5.2 × 10-17and an OR of 1.36 [95% C.I. 1.20-1.55]. KCNMA1 rs2116830*G was not associated with BMI in the population-based samples. Adipose tissue (P = 0.0001) and fat cell (P = 0.04) expression of KCNMA1 was increased in obesity. Conclusions We have identified KCNMA1 as a new susceptibility locus for obesity, and confirmed the association of the BDNF locus at the genome-wide significant level.
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26. Japanese encephalitis virus expands regulatory T cells by increasing the expression of PD-L1 on dendritic cells

Author: Gupta, Nimesh, Hegde, Pushpa, Lecerf, Maxime, Nain, Minu, Kaur, Manpreet, Kalia, Manjula, Vrati, Sudhanshu, Bayry, Jagadeesh, Lacroix-Desmazes, Sébastien, Kaveri, Srini, Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Translational Health Science and Technology Institute [Faridabad] (THSTI), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Sorbonne Paris Cité (USPC), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bayry, Jagadeesh, Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE)
Subjects: [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2014

27. Epac contributes to cardiac hypertrophy and amyloidosis induced by radiotherapy but not fibrosis

Author: Wolfgang Dörr, Marie-Catherine Vozenin, Pascal Fenoglietto, Carine Strup-Perrot, Marianne Mazevet, Marie-Michèle Germaini, Céline Bourgier, André Bridier, Eric Deutsch, Thi-Hong-Van To, L. Calmels, A.M. Gomez, Virginie Monceau, Julia Haagen, David Azria, Benoit Petit, Brigitte Escoubet, Anna Llach, Eric Morel, Sophie Gourgou, Radiothérapie moléculaire (UMR 1030), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Signalisation et physiopathologie cardiaque, Université Paris-Sud - Paris 11 (UP11)-IFR141-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Val d'Aurelle - Paul Lamarque, Département de radiothérapie [Gustave Roussy], Institut Gustave Roussy (IGR), Laboratoire de Radiopathologie et de Thérapies Expérimentales (IRSN/PRP-HOM/SRBE/LRTE), Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Département de radiothérapie, Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Association pour la Recherche sur le Cancer, ARCEuropean Commission, EC FP7-Fission-2007-3.1.1Laboratoire d'Excellence en Recherche sur le MÃ©dicament et l'Innovation ThÃ©rapeutique, LERMITInstitut National de la SantÃ© et de la Recherche MÃ©dicale, Inserm ANR-10-LABX-33, U1030Fondation pour la Recherche MÃ©dicale, FRM, and Laboratoire de Radiopathologie et Thérapies Expérimentales [IRSN, Fontenay-aux-Roses] (PRP-HOM - SRBE)
Subjects: Male, Pathology, medicine.medical_specialty, MMP2, RHOA, [SDV]Life Sciences [q-bio], Population, Breast Neoplasms, Cardiomegaly, Muscle hypertrophy, Pericarditis, Mice, Fibrosis, medicine, Animals, Guanine Nucleotide Exchange Factors, Humans, Radiology, Nuclear Medicine and imaging, Myocytes, Cardiac, education, Radiation Injuries, education.field_of_study, biology, business.industry, Amyloidosis, Heart, Hematology, medicine.disease, 3. Good health, Rats, CTGF, Mice, Inbred C57BL, Oncology, biology.protein, Calcium, Female, business
Abstract: International audience; Background Cardiac toxicity is a side-effect of anti-cancer treatment including radiotherapy and this translational study was initiated to characterize radiation-induced cardiac side effects in a population of breast cancer patients and in experimental models in order to identify novel therapeutic target. Methods The size of the heart was evaluated in CO-HO-RT patients by measuring the Cardiac-Contact-Distance before and after radiotherapy (48 months of follow-up). In parallel, fibrogenic signals were studied in a severe case of human radiation-induced pericarditis. Lastly, radiation-induced cardiac damage was studied in mice and in rat neonatal cardiac cardiomyocytes. Results In patients, time dependent enhancement of the CCD was measured suggesting occurrence of cardiac hypertrophy. In the case of human radiation-induced pericarditis, we measured the activation of fibrogenic (CTGF, RhoA) and remodeling (MMP2) signals. In irradiated mice, we documented decreased contractile function, enlargement of the ventricular cavity and long-term modification of the time constant of decay of Ca2+ transients. Both hypertrophy and amyloid deposition were correlated with the induction of Epac-1; whereas radiation-induced fibrosis correlated with Rho/CTGF activation. Transactivation studies support Epac contribution in hypertrophy stimulation and showed that radiotherapy and Epac displayed specific and synergistic signals. Conclusion Epac-1 has been identified as a novel regulator of radiation-induced hypertrophy and amyloidosis but not fibrosis in the heart. © 2014 Elsevier Ireland Ltd. All rights reserved.
Published: 2014

28. Association between melanocortin-4 receptor mutations and eating behaviors in obese patients: a case-control study

Author: Sébastien Czernichow, J Le Beyec, Karine Clément, F Bellisle, M Valette, Christine Poitou, Claire Carette, Serge Hercberg, Emmanuelle Kesse-Guyot, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Centre de Recherche en Nutrition Humaine, Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), foundation NRJ- Institute de France and Programme Hospitalier de Recherche Clinique (APHP), University Paris 13, Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Leptin, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), Receptors, Cell Surface, eating disorders, Gene mutation, eating behavior, medicine.disease_cause, Body Mass Index, Eating, 03 medical and health sciences, 0302 clinical medicine, binge eating, Surveys and Questionnaires, Internal medicine, MC4R mutations, medicine, Humans, Obesity, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, Mutation, Nutrition and Dietetics, melanocortin-4 receptor, Binge eating, business.industry, Case-control study, Feeding Behavior, Middle Aged, 3. Good health, Melanocortin 4 receptor, Endocrinology, Case-Control Studies, Receptor, Melanocortin, Type 4, Female, Melanocortin, medicine.symptom, Energy Intake, business, Body mass index, 030217 neurology & neurosurgery, Dietary Carbohydrates
Abstract: International audience; Melanocortin-4 receptor (MC4R) gene mutations are involved in the leptin-melanocortin pathways that control food intake. The effect of these mutations on eating behavior phenotypes is still debated. To determine the association between functional MC4R mutations and eating behaviors, dietary intake and physical activity, we sequenced the MC4R gene in 4653 obese adults. Among them, 19 adults carriers of functional MC4R mutation were matched on age, sex and body mass index with two randomly-paired controls without MC4R mutation (n = 57). We found that eating behaviors and physical activity did not differ between groups. In particular, cases were not at increased risk of binge eating disorders. Subjects carriers of MC4R mutation reported a higher proportion of dietary carbohydrates intakes (43.2 +/- 7.1 and 39.2 +/- 8.1% of total energy intake, respectively, P = 0.048) and a lower proportion of dietary lipids (34.3 +/- 6.7 and 38.5 +/- 6.7% of total energy intake, respectively, P = 0.018). In conclusion, mutation carriers differ from controls by a higher consumption of carbohydrates counterbalanced by a lower consumption of lipids expressed as percentage of total energy intake. However, functional MC4R mutations do not have a higher risk of compulsive eating contrary to what was previously suggested.
Published: 2014

29. Clinical and Autoimmune Profile of Scleroderma Patients from Western India

Author: Anjali Rajadhyaksha, Maxime Lecerf, Srinivas V. Kaveri, Pallavi Pandit, Prathamesh Surve, Vandana Pradhan, Jagadeesh Bayry, Kanjaksha Ghosh, Milind Y Nadkar, Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Sorbonne Paris Cité (USPC), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bayry, Jagadeesh, and Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE)
Subjects: medicine.medical_specialty, Pathology, lcsh:Diseases of the musculoskeletal system, Article Subject, Immunology, Disease, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Scleroderma, Serology, Rheumatology, Internal medicine, medicine, Clinical significance, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, skin and connective tissue diseases, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, ComputingMilieux_MISCELLANEOUS, integumentary system, biology, business.industry, Autoantibody, medicine.disease, Dermatology, 3. Good health, biology.protein, lcsh:RC925-935, Antibody, business, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, Rheumatism, Research Article
Abstract: Background. Systemic sclerosis (SSc, scleroderma) is a disorder characterized by fibrosis of skin and visceral organs. Pathogenesis of scleroderma is complex and is incompletely understood as yet. Autoantibodies in SSc represent a serologic hallmark which have clinical relevance, with diagnostic and prognostic potential.Objectives. To study distribution of clinical manifestations and to identify frequency of autoantibodies among subtypes of scleroderma patients from Western India.Methodology. One hundred and ten scleroderma patients were clinically classified according to the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria. All these patients were in active stage of disease. Clinical manifestations were recorded at the time of presentation. Autoantibodies were tested in them by indirect immunofluorescence test and ELISA. Immunoglobulin levels were estimated by nephelometer. These parameters were further correlated with clinical presentation of the disease.Results. Scleroderma patients had M : F ratio of 1 : 10 where mean age at evaluation was34.7±10.7years and a mean disease duration was43.7±35months. Clinical subtypes showed that 45 patients (40.9%) had diffused cutaneous (dcSSc) lesions, 32 patients (29.1%) had limited cutaneous (lcSSc) lesions, and 33 patients (30%) had other autoimmune overlaps. The overall frequency of ANA in SSc patients studied was 85.5%. The frequency of anti-Scl70, anti-centromere, anti-endothelial cell antibodies (AECA), and anti-keratinocyte antibodies (AKA) was 62.7%, 22.7%, 30%, and 40.9%, respectively. Anti-Scl70 antibodies were significantly high (75.6% versus 46.9%) among dcSSc patients (P<0.0115) whereas anti-centromere antibodies were significantly high (9% versus 38%) among lcSSc patients when these two subtypes were compared (P<0.0044).Conclusion. This study supports that there are geoepidemiological variations among scleroderma patients for their clinical presentation, autoantibody profile, and immune parameters across the country.
Published: 2014

30. Quality of life after Roux-en-Y gastric bypass and changes in body mass index and obesity-related comorbidities

Author: C. Ciangura, L. Capuron, Chantal Julia, C. Poitou, Jean-Luc Bouillot, Jean-Michel Oppert, A. Basdevant, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Université Pierre et Marie Curie - Paris 6 (UPMC), Nutrition et Neurobiologie intégrée (NutriNeuro), Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1-Centre National de la Recherche Scientifique (CNRS), Hôpital Ambroise Paré [AP-HP], Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-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 Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1 (UB)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Time Factors, Cross-sectional study, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Comorbidity, bypass gastrique de type Roux-en-Y, Body Mass Index, 0302 clinical medicine, Endocrinology, Quality of life, Weight loss, Surveys and Questionnaires, Longitudinal Studies, 030212 general & internal medicine, 2. Zero hunger, education.field_of_study, Remission Induction, General Medicine, Middle Aged, humanities, Obesity, Morbid, 3. Good health, Treatment Outcome, post-surgery follow-up, surveillance postopératoire, Hypertension, Female, France, medicine.symptom, Adult, medicine.medical_specialty, Roux-en-Y gastric bypass, Population, Gastric Bypass, 030209 endocrinology & metabolism, qualité de vie, 03 medical and health sciences, Sleep Apnea Syndromes, Internal medicine, Weight Loss, Internal Medicine, medicine, Humans, education, Dyslipidemias, obésité morbide, business.industry, nutritional and metabolic diseases, medicine.disease, Obesity, morbid obesity, Cross-Sectional Studies, Knee pain, Diabetes Mellitus, Type 2, quality of life, Physical therapy, business, Body mass index
Abstract: International audience; Aim Dynamics of improvement in health-related quality of life (QoL) after bariatric surgery have never been fully assessed, and neither has the potential influence of body mass index (BMI) and comorbidity modification. The objective of this study was to investigate early and medium-term changes in QoL following Roux-en-Y gastric bypass (RYGB), and their relationship to BMI and comorbidity variations. Methods A total of 71 obese subjects (80% women, mean age 42.1 ± 11.2 years, mean baseline BMI 47.6 ± 6.2 kg/m2) undergoing RYGB filled in QoL questionnaires (SF-36) before and 3, 6 and 12 months after surgery. QoL was assessed using repeated-measures Anova, with associations between its changes and changes in BMI and comorbidities (diabetes, hypertension, dyslipidaemia, sleep apnoea, knee pain) assessed by mixed-effects models. Results Physical QoL scales (physical component summary, PCS) significantly increased over time (from 38.9 ± 9.3 to 52.6 ± 7.9; P < 0.001) as did other physical SF-36 scales (all P < 0.001), whereas mental QoL summary scale did not vary significantly (from 45.7 ± 9.5 to 48.6 ± 11.5; P = 0.072). Major changes in QoL occurred at 3 months after surgical intervention to reach values comparable to those in the general population. PCS was mostly associated with changes in either BMI or comorbidity status except for diabetes, dyslipidaemia and sleep apnoea. Conclusion Results show that improvements in physical QoL after RYGB are observed as early as 3 months after intervention, and are independently associated with weight loss and improvements in comorbidities.; Objectifs La cinétique de l’amélioration de la qualité de vie liée à la santé (QdV) après chirurgie bariatrique n’a pas été bien étudiée, de même que l’influence potentielle des modifications de l’indice de masse corporelle (IMC) ou des comorbidités associées à l’obésité. L’objectif de cette étude était d’analyser la cinétique à court et moyen terme de la QdV et ses relations avec les modifications de l’IMC et des comorbidités dans un échantillon de patients qui avaient bénéficié d’un bypass gastrique de type Roux-en-Y (BPGRY). Méthodes Soixante et onze patients obèses (80 % de femmes, âge moyen 42,1 ± 11,2 ans, IMC moyen préopératoire 47,6 ± 6,2 kg/m2) qui avaient bénéficié d’un BPGRY ont rempli un questionnaire de QdV (SF-36) en préopératoire et à trois, six et 12 mois postopératoires. Les modifications de QdV ont été analysées par Anova pour mesures répétées et les associations entre les modifications de la QdV et les modifications de l’IMC ou des comorbidités (diabète, hypertension artérielle, dyslipidémie, syndrome d’apnées du sommeil, gonalgies) ont été analysées par des modèles mixtes. Résultats La composante physique résumée de la QdV (PCS) augmentait significativement avec le temps (de 38,9 ± 9,3 à 52,6 ± 7,9, P < 0,001), de même que les autres échelles de QdV physique (tous les P < 0,001) alors que la composante mentale résumée (MCS) n’augmentait pas significativement (de 45,7 ± 9,5 à 48,6 ± 11,5, P = 0,072). Les modifications les plus importantes de la QdV avaient lieu dès trois mois postopératoires, et rejoignaient des valeurs comparables à celles de la population générale. La PCS était associée aux modifications de l’IMC et des comorbidités, excepté pour le diabète, la dyslipidémie ou le syndrome d’apnées du sommeil. Conclusions Nos résultats montrent que l’amélioration de la QdV physique après BPGRY est observée dès le troisième mois après l’intervention, et est associée de manière indépendante à la perte de poids et à l’amélioration des comorbidités.
Published: 2013

31. Distinctive unhealthy eating pattern in free-living middle-aged hypertensives when compared with dyslipidemic or overweight patients

Author: Emmanuelle Kesse-Guyot, Joël Ménard, Pilar Galan, Pierre Meneton, Serge Hercberg, Léopold Fezeu, Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-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 Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), U557, Institut National de la Santé et de la Recherche Médicale (INSERM), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Université Paris Nord (Paris 13), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA)
Subjects: Blood Glucose, Male, Physiology, [SDV]Life Sciences [q-bio], Blood Pressure, 030204 cardiovascular system & hematology, Overweight, Body Mass Index, 0302 clinical medicine, Surveys and Questionnaires, 030212 general & internal medicine, adherence, physician, food and beverages, drug treatment, Middle Aged, 3. Good health, clinical practice, su vi max cohort, Female, France, medicine.symptom, Cardiology and Cardiovascular Medicine, guideline, management, Risk, recommendation, medicine.medical_specialty, hypertension, antioxidant vitamin, free-living patients, 03 medical and health sciences, Internal medicine, Environmental health, Dietary Carbohydrates, Internal Medicine, medicine, Humans, overweight, In patient, Aged, Dyslipidemias, business.industry, dyslipidemia, Feeding Behavior, life style, blood pressure control, medicine.disease, Diet, Endocrinology, Unhealthy eating, Energy Intake, business, dietary intake, Dyslipidemia
Abstract: International audience; Objective:To evaluate habitual dietary intakes in patients with established hypertension, dyslipidemia and/or overweight.Methods:A national sample of 6167 French free-living patients, aged 45-65 years, in whom daily food and nutrient intakes (24-h records) and clinical status were regularly monitored between 1994 and 2002.Results:For each disorder, affected patients have reduced fat and energy intakes compared with nonaffected participants after adjustment for confounding factors. In addition, after further adjustment for energy intake, dyslipidemic patients eat less cheeses, sweets, eggs and appetizers, whereas overweight patients eat less bread and sweets, more yoghurts, vegetables, meats and poultries in comparison to their nonaffected counterparts. By contrast, hypertensive patients drink more wines and less milk, eat less yoghurts, fruits and vegetables, more processed meats than participants without hypertension. Nutrient intakes also reflect these distinctive eating patterns as shown by reduced carbohydrate intake and increased protein and mineral intakes in overweight patients and increased alcohol intake and decreased mineral intakes in hypertensives when compared with nonaffected participants. Among affected patients, antihypertensive and hypolipidemic drug treatments are not associated with additional differences in daily food and nutrient intakes except eggs that are consumed in smaller amounts by treated dyslipidemic patients.Conclusion:Hypertensive patients maintain an unhealthy eating pattern that tends to perpetuate their disorder in contrast to dyslipidemic or overweight patients who adopt more protective diets. The origin of this behavioural difference and poor adherence to practice guidelines between hypertensives and other cardiovascular risk patients needs to be investigated.
Published: 2013

32. Human epicardial adipose tissue induces fibrosis of the atrial myocardium through the secretion of adipo-fibrokines

Author: Anne Dutour, Valeria Guglielmi, Karine Clément, Elise Balse, Stéphane N. Hatem, Aurélie Cotillard, Nicolas Venteclef, Fabrice Atassi, Bénédicte Gaborit, Pascal Leprince, Julien Amour, Institut de Cardiométabolisme et Nutrition - Institute of Cardiometabolism and Nutrition, Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-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), Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Fondation de France, Fondacoeur Association, Assistance Publique-Hopitaux de Paris (APHP), European Commission (Collaborative Project ADAPT) [HEALTH-F2-2008-201100], Assistance Publique-Hopitaux de Marseille (Programme Hospitalier de Recherche Clinique), National Agency of Research (Adipofib), Fondation de La Recherche Medicale, Fondation Leducq 'Structural Alterations in the Myocardium and the Substrate for Cardiac Fibrillation', European Union (EUTRAF), French National Agency through the national program 'Investissements d'avenir' [ANR-10-IAHU-05], ProdInra, Migration, Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), 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 Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, medicine.medical_specialty, Settore MED/09 - Medicina Interna, Cells, [SDV]Life Sciences [q-bio], Subcutaneous Fat, Adipose tissue, Adipokines, Fibrosis, Internal medicine, Myocardial fibrosis, Epicardial adipose tissue, Atrial Fibrillation, Medicine, Animals, Humans, Secretion, Heart Atria, Atrium (heart), Neutralizing antibody, Cells, Cultured, Cultured, biology, business.industry, Myocardium, Atrial fibrillation, Atrial Remodeling, Atrial fibrosis, Activin A, Middle Aged, medicine.disease, 3. Good health, Peripheral, Activins, Rats, [SDV] Life Sciences [q-bio], Adipose Tissue, Female, Matrix Metalloproteinase 8, medicine.anatomical_structure, Endocrinology, biology.protein, cardiovascular system, Cardiology and Cardiovascular Medicine, business
Abstract: International audience; Aims Recent studies have reported a relationship between the abundance of epicardial adipose tissue (EAT) and the risk of cardiovascular diseases including atrial fibrillation (AF). However, the underlying mechanisms are unknown. The aim of this study was to examine the effects of the secretome of human EAT on the histological properties of the myocardium. Methods and results Samples of EAT and subcutaneous adipose (SAT), obtained from 39 patients undergoing coronary bypass surgery, were analysed and tested in an organo-culture model of rat atria to evaluate the fibrotic properties of human fat depots. The EAT secretome induced global fibrosis (interstitial and peripheral) of rat atria in organo-culture conditions. Activin A was highly expressed in EAT compared with SAT and promoted atrial fibrosis, an effect blocked using neutralizing antibody. In addition, Activin A levels were enhanced in patients with low left-ventricular function. In sections of human atrial and ventricular myocardium, adipose and myocardial tissues were in close contact, together with fibrosis. Conclusion This study provides the first evidence that the secretome from EAT promotes myocardial fibrosis through the secretion of adipo-fibrokines such as Activin A.
Published: 2012

33. Locally expressed IGF1 propeptide improves mouse heart function in induced dilated cardiomyopathy by blocking myocardial fibrosis and SRF-dependent CTGF induction

Author: Melissa Touvron, Brigitte Escoubet, Mathias Mericskay, Aude Angelini, Luciane Lamotte, Maria Paola Santini, Nadia Rosenthal, Dominique Daegelen, David Tuil, Jean-François Decaux, Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Signalisation et physiopathologie cardiovasculaire (UMRS1180), Institut National de la Santé et de la Recherche Médicale (INSERM), MicrodB, Euro-Mediterranean Center on Climate Change (CMCC), Groupe Myologie, Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cardiomyopathy, Dilated, Serum Response Factor, Longevity, lcsh:Medicine, Mice, lcsh:Pathology, Animals, Humans, Myocytes, Cardiac, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Insulin-Like Growth Factor I, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, Inflammation, Myocardium, lcsh:R, Connective Tissue Growth Factor, Heart, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Fibrosis, Mice, Mutant Strains, Gene Expression Regulation, Organ Specificity, Heart Function Tests, cardiovascular system, Peptides, lcsh:RB1-214, Research Article
Abstract: SUMMARY Cardiac fibrosis is critically involved in the adverse remodeling accompanying dilated cardiomyopathies (DCMs), which leads to cardiac dysfunction and heart failure (HF). Connective tissue growth factor (CTGF), a profibrotic cytokine, plays a key role in this deleterious process. Some beneficial effects of IGF1 on cardiomyopathy have been described, but its potential role in improving DCM is less well characterized. We investigated the consequences of expressing a cardiac-specific transgene encoding locally acting IGF1 propeptide (muscle-produced IGF1; mIGF1) on disease progression in a mouse model of DCM [cardiac-specific and inducible serum response factor (SRF) gene disruption] that mimics some forms of human DCM. Cardiac-specific mIGF1 expression substantially extended the lifespan of SRF mutant mice, markedly improved cardiac functions, and delayed both DCM and HF. These protective effects were accompanied by an overall improvement in cardiomyocyte architecture and a massive reduction of myocardial fibrosis with a concomitant amelioration of inflammation. At least some of the beneficial effects of mIGF1 transgene expression were due to mIGF1 counteracting the strong increase in CTGF expression within cardiomyocytes caused by SRF deficiency, resulting in the blockade of fibroblast proliferation and related myocardial fibrosis. These findings demonstrate that SRF plays a key role in the modulation of cardiac fibrosis through repression of cardiomyocyte CTGF expression in a paracrine fashion. They also explain how impaired SRF function observed in human HF promotes fibrosis and adverse cardiac remodeling. Locally acting mIGF1 efficiently protects the myocardium from these adverse processes, and might thus represent a therapeutic avenue to counter DCM.
Published: 2012

34. Health Effects of Artificial Light

Author: Mattsson, M.O., Jung, Th., Proykova, A., Behar-Cohen, F., Zissis, Georges, de Gruijl, F., Ferguson, J., Hansen, J., Moseley, H., Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Descartes - Paris 5 (UPD5), Lumière et Matière (LAPLACE-LM), LAboratoire PLasma et Conversion d'Energie (LAPLACE), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), IZA, Institute for the Study of Labor, CIREQ, Centre Interuniversitaire de Recherche en Economie Quantitative, CIRANO - Montréal, Department of Economics, Concordia University, and Concordia University [Montreal]
Subjects: [SPI]Engineering Sciences [physics]
Abstract: International audience
Published: 2012

35. Melanocortin-4 Receptor Mutations and Polymorphisms Do Not Affect Weight Loss after Bariatric Surgery

Author: Karine Clément, Johanne Le Beyec, Marion Valette, Christine Poitou, Jean-Luc Bouillot, Sébastien Czernichow, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Hôpital Ambroise Paré [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)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), foundation NRJ - Institute de France, University Paris 13, Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-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 Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and ProdInra, Migration
Subjects: medicine.medical_specialty, [SDV]Life Sciences [q-bio], lcsh:Medicine, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Clinical nutrition, Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Weight loss, medicine, SNP, lcsh:Science, 030304 developmental biology, 0303 health sciences, Mutation, Multidisciplinary, lcsh:R, Case-control study, medicine.disease, Obesity, 3. Good health, Surgery, [SDV] Life Sciences [q-bio], Melanocortin 4 receptor, lcsh:Q, medicine.symptom
Abstract: International audience; Bariatric surgery is the most effective long term weight-loss therapy for severe and morbidly obese patients. Melanocortin-4 Receptor (MC4R) mutations, the most frequent known cause of monogenic obesity, affect the regulation of energy homeostasis. The impact of such mutations on weight loss after bariatric surgery is still debated. The objective is to determine the impact of MC4R status on weight loss in obese subjects over one year after bariatric surgery. A total of 648 patients, who were referred to bariatric surgery in a single clinical nutrition department, were genotyped for their MC4R status. The following four groups were categorized: functional MC4R mutations, MC4R single nucleotide polymorphisms (SNPs): Val103Ile (V103L) and Ile251Leu (I251L), MC4R variant rs17782313 (downstream of MC4R) and MC4R SNP A-178C on the promoter. Each patient was matched with two randomly paired controls without mutation. Matching factors were age, sex, baseline weight and type of surgery procedure (Roux-en-Y gastric bypass and adjustable gastric banding). We compared weight loss between cases and controls at 3, 6 and 12 months after surgery. Among 648 patients, we identified 9 carriers of functional MC4R mutations, 10 carriers of MC4R V103L and I251L SNPs, 7 carriers of the rs17792313 variant and 22 carriers of the A-178C SNP. Weight loss at 3, 6 and 12 months did not differ between cases and controls, whatever the MC4R mutations. This is the first case-control study to show that MC4R mutations and polymorphisms do not affect weight loss and body composition over one year after bariatric surgery.
Published: 2012

36. Mechanisms of action of ceramide in different muscle cell lines

Author: Khoury, R., Turban, S., Loiseau, Nicolas, Stretton, C., Lasnier, F., Hundal, H., Ferre, P., Hajduch, E., Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Edinburgh, Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), University of Dundee, ProdInra, Migration, Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)
Subjects: [SDV] Life Sciences [q-bio], lignée musculaire, céramides, [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS, insuline
Abstract: National audience
Published: 2011

37. Impact of the environment in the development of diabetic GK rat pancreas, ex vivo approach

Author: Calderari, Sophie, Pardanaud, L., Corvol, P., Larger, E., Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Angiogénèse embryonnaire et pathologique, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Société Francophone du Diabète (SFD). FRA., Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ProdInra, Migration
Subjects: [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience
Published: 2011

38. Rare melanocortin-3 receptor mutations with in vitro functional consequences are associated with human obesity

Author: Monica Mencarelli, Patrick Tounian, Anna Maria Di Blasio, Chantal Simon, Serge Hercberg, Lina Benajiba, Béatrice Dubern, Pilar Galan, Antonio Liuzzi, Mariantonella Tagliaferri, Maura Rinaldi, Rohia Alili, Karine Clément, Sabrina Maestrini, Mol Biol Lab, Brazilian Agricultural Research Corporation (Embrapa), Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Istituto Auxologico Italiano, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Université Paris Nord (Paris 13), Mécanisme Moléculaire du Diabète (MMD), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg (UNISTRA), Ile de France, Institut Benjamin Delessert and Guigoz, Paris, Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), and 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 Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, [SDV]Life Sciences [q-bio], CHILDREN, MC4R, medicine.disease_cause, 0302 clinical medicine, Child, Genetics (clinical), Genetics, 0303 health sciences, Mutation, General Medicine, Middle Aged, Phenotype, Melanocortin 3 receptor, 3. Good health, PREVALENCE, Melanocortin 4 receptor, FAT MASS, Receptor, Melanocortin, Type 4, Female, GENE VARIANTS, medicine.symptom, Receptor, Melanocortin, Type 3, Adult, medicine.medical_specialty, Adolescent, 030209 endocrinology & metabolism, Biology, White People, Young Adult, 03 medical and health sciences, EARLY-ONSET OBESITY, Melanocortin receptor, Internal medicine, medicine, Humans, Obesity, Molecular Biology, Gene, POLYMORPHISMS, 030304 developmental biology, FRAMESHIFT MUTATION, Body Weight, medicine.disease, BODY-MASS INDEX, HEK293 Cells, Endocrinology, INTRACELLULAR RETENTION, Weight gain
Abstract: International audience; In contrast to the melanocortin 4 receptor, the possible role of the melanocortin 3 receptor (MC3R) in regulating body weight is still debated. We have previously reported three mutations in the MC3R gene showing association with human obesity, but these results were not confirmed in a study of severe obese North American adults. In this study, we evaluated the entire coding region of MC3R in 839 severely obese subjects and 967 lean controls of Italian and French origin. In vitro functional analysis of the mutations detected was also performed. The total prevalence of rare MC3R variants was not significantly different in obese subjects when compared with controls (P = 0.18). However, the prevalence of mutations with functional alterations was significantly higher in the obese group (P = 0.022). In conclusions, the results of this large study demonstrate that in the populations studied functionally significant MC3R variants are associated with obesity supporting the current hypothesis that rare variants might have a stronger impact on the individual susceptibility to gain weight. They also underline the importance of detailed in vitro functional studies in order to prove the pathogenic effect of such variants. Further investigations in larger cohorts will be needed in order to define the specific phenotypic characteristics potentially correlated with reduced MC3R signalling
Published: 2011

39. Relationship between adiposity, emotional status and eating behaviour in obese women: role of inflammation

Author: Sophie Layé, Karine Clément, A. Basdevant, V Frochot, D. Machaux-Tholliez, C. Poitou, Lucile Capuron, Jean-Luc Bouillot, Nutrition et Neurobiologie intégrée (NutriNeuro), Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1 (UB)-Centre National de la Recherche Scientifique (CNRS)
Subjects: medicine.medical_specialty, Neurotic Disorders, [SDV]Life Sciences [q-bio], Adipokine, Bariatric Surgery, Body Mass Index, Extraversion, Psychological, 03 medical and health sciences, 0302 clinical medicine, Adipokines, Weight loss, Diabetes mellitus, Internal medicine, Surveys and Questionnaires, medicine, Humans, Affective Symptoms, Applied Psychology, 030304 developmental biology, Adiposity, 2. Zero hunger, Inflammation, Psychiatric Status Rating Scales, 0303 health sciences, biology, business.industry, Interleukin-6, C-reactive protein, Feeding Behavior, Middle Aged, medicine.disease, Neuroticism, Obesity, Obesity, Morbid, Psychiatry and Mental health, Endocrinology, C-Reactive Protein, biology.protein, Anxiety, Female, medicine.symptom, business, Body mass index, 030217 neurology & neurosurgery, Biomarkers, Follow-Up Studies
Abstract: BackgroundObesity is characterized by chronic low-grade inflammation that may lead to emotional distress and behavioural symptoms. This study assessed the relationship between adiposity, low-grade inflammation, eating behaviour and emotional status in obese women awaiting gastric surgery and investigated the effects of surgery-induced weight loss on this relationship.MethodA total of 101 women with severe or morbid obesity awaiting gastric surgery were recruited. Assessments were performed before and at 1 year post-surgery and included the measurement of neuroticism and extraversion using the revised Neuroticism–Extraversion–Openness personality inventory (NEO-PI-R) and eating behaviour using the Three-Factor Eating Questionnaire (TFEQ). Blood samples were collected for the measurement of serum inflammatory markers [interleukin-6 (IL-6), high-sensitive C-reactive protein (hsCRP)] and adipokines (leptin, adiponectin).ResultsAt baseline, body mass index (BMI) was positively correlated with inflammatory markers and adipokines. Regression analyses adjusting for age and diabetes revealed that baseline concentrations of IL-6 and hsCRP were associated with the depression and anxiety facets of neuroticism, with higher inflammation predicting higher anxiety and depression. This association remained significant after adjusting for BMI. Gastric surgery induced significant weight loss, which correlated with reduced inflammation. After controlling for BMI variations, decreases in inflammatory markers, notably hsCRP, were associated with reduced anxiety and TFEQ-cognitive restraint scores.ConclusionsThese findings indicate strong associations between adiposity, inflammation and affectivity in obese subjects and show that surgery-induced weight loss is associated concomitantly with reduced inflammation and adipokines and with significant improvement in emotional status and eating behaviour. Inflammatory status appears to represent an important mediator of emotional distress and psychological characteristics of obese individuals.
Published: 2010

40. The protective role of transferrin in Müller glial cells after iron-induced toxicity

Author: Emilie, Picard, Isabelle, Fontaine, Laurent, Jonet, Florian, Guillou, Francine, Behar-Cohen, Yves, Courtois, Jean-Claude, Jeanny, Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Physiologie de la reproduction et des comportements [Nouzilly] ( PRC ), Institut National de la Recherche Agronomique ( INRA ) -Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Descartes - Paris 5 (UPD5), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), 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), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-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 National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), and ProdInra, Migration
Subjects: Cell Survival, Iron, [SDV]Life Sciences [q-bio], rétine, Mice, Transgenic, souris, [INFO] Computer Science [cs], retine, Retina, fer, Mice, Animals, Humans, [INFO]Computer Science [cs], RNA, Messenger, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Cells, Cultured, Apoproteins/metabolism, Culture Media, Gene Expression Regulation/drug effects, Iron/toxicity, Mice, Inbred C57BL, Neuroglia/cytology, Neuroglia/drug effects, RNA, Messenger/genetics, RNA, Messenger/metabolism, Retina/cytology, Retina/drug effects, Transferrin/genetics, Transferrin/metabolism, Transferrin, stress oxydant, mus musculus, [SDV] Life Sciences [q-bio], Gene Expression Regulation, [ SDV.MHEP.OS ] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, animal transgénique, cellule gliale, SOURIS TRANSGENIQUE, Apoproteins, humain, Neuroglia, transferrine, Research Article
Abstract: International audience; Purpose: Transferrin (Tf) expression is enhanced by aging and inflammation in humans. We investigated the role of transferrin in glial protection. Methods: We generated transgenic mice (Tg) carrying the complete human transferrin gene on a C57Bl/6J genetic background. We studied human (hTf) and mouse (mTf) transferrin localization in Tg and wild-type (WT) C57Bl/6J mice using immunochemistry with specific antibodies. Muller glial (MG) cells were cultured from explants and characterized using cellular retinaldehyde binding protein (CRALBP) and vimentin antibodies. They were further subcultured for study. We incubated cells with FeCl3-nitrilotriacetate to test for the iron-induced stress response; viability was determined by direct counting and measurement of lactate dehydrogenase (LDH) activity. Tf expression was determined by reverse transcriptase-quantitative PCR with human- or mouse-specific probes. hTf and mTf in the medium were assayed by ELISA or radioimmunoassay (RIA), respectively. Results: mTf was mainly localized in retinal pigment epithelium and ganglion cell layers in retina sections of both mouse lines. hTf was abundant in MG cells. The distribution of mTf and hTf mRNA was consistent with these findings. mTf and hTf were secreted into the medium of MG cell primary cultures. Cells from Tg mice secreted hTf at a particularly high level. However, both WT and Tg cell cultures lose their ability to secrete Tf after a few passages. Tg MG cells secreting hTf were more resistant to iron-induced stress toxicity than those no longer secreted hTf. Similarly, exogenous human apo-Tf, but not human holo-Tf, conferred resistance to iron-induced stress on MG cells from WT mice. Conclusions: hTf localization in MG cells from Tg mice was reminiscent of that reported for aged human retina and age-related macular degeneration, both conditions associated with iron deposition. The role of hTf in protection against toxicity in Tg MG cells probably involves an adaptive mechanism developed in neural retina to control iron-induced stress.
Published: 2008

41. Observatoires régionaux du pneumocoque : épidémiologie et résistance aux antibiotiques des souches de Streptococcus pneumoniae isolées en France en 2007

Author: Thierry Fosse, Laurent Gutmann, Michel Brun, Henri Bonnabau, Jeanne Maugein, Marie-Cécile Ploy, Michel Vergnaud, Christine Segonds, Hubert Chardon, Bernadette Grignon, Gérard Chabanon, Pierre-Yves Donnio, André Pechinot, Agnes Lepoutre, Micheline Roussel-Delvallez, Regine Baraduc, Farida Hamdad, Marie Kempf, Alain Ros, Jacques Croizé, Alain Gravet, Philippe Dupont, Tahar Hadou, Jean-Louis Koeck, Veronique Vernet-Garnier, Marie-Claude Demachy, Philippe Lanotte, Marie-Laure Joly-Guillou, Josette Raymond, Emmanuelle Varon, Laurent Gibel, Groupe d'Étude des Interactions Hôte-Pathogène (GEIHP), Université d'Angers (UA), CHU Clermont-Ferrand, Service de l'Information Médicale et de l'Évaluation [CHU Limoges] (SIME), CHU Limoges, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier d'Aix en Provence [Aix-en-Provence] (CHIAP ), Laboratoire de bactériologie, CHU Grenoble, Laboratoire de Virologie [Rennes] = Virology [Rennes], CHU Pontchaillou [Rennes], 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), Bactériologie-Hygiène, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital Cimiez [Nice] (CHU), Centre Hospitalier de Mulhouse, site du Hasenrain (Mulhouse), Hôpital Bretonneau, Service Bactériologie, Virologie, CHU Bordeaux [Bordeaux], CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Biologie moléculaire et cellulaire des microorganismes (EA3175), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Limoges (UNILIM), Centre national de Référence des Streptocoques (CNR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Cochin [AP-HP], Service de Microbiologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Bactériologie, Virologie, Hygiène [CHU Limoges], Institut de Veille Sanitaire (INVS), Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre de Référence du Pneumocoque, 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), CHU Toulouse [Toulouse], 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 ), Université Nice Sophia Antipolis (... - 2019) (UNS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Department of Microbiology, and Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)
Subjects: 0303 health sciences, 2007 epidemiology, 030306 microbiology, surveillance network, [SDV]Life Sciences [q-bio], Biochemistry (medical), Résistance aux antibiotiques, 3. Good health, Analytical Chemistry, 03 medical and health sciences, Medical Laboratory Technology, épidémiologie 2007, 0302 clinical medicine, Streptococcus pneumoniae, 030225 pediatrics, antimicrobial resistance, France, réseau de surveillance
Abstract: International audience; RésuméLes observatoires régionaux du pneumocoque (ORP), créés à partir de 1995, participent aux côtés du Centre national de référence des pneumocoques et de l’Institut de veille sanitaire à la surveillance étroite de l’évolution de la résistance du pneumocoque aux antibiotiques. En 2007, les 23 ORP français ont étudié la sensibilité aux antibiotiques et le sérogroupe de 5 302 souches de pneumocoque isolées de liquides céphalo-rachidiens (LCR), d’hémocultures, de pus d’otite moyenne aiguë, de liquides pleuraux de l’enfant et de l’adulte (≥ 16 ans) ainsi que de certains échantillons pulmonaires de l’adulte (≥ 16 ans). L’étude a montré que 38,2 % des souches étaient de sensibilité diminuée à la pénicilline (PSDP), 19,3 % à l’amoxicilline et 10,5 % au céfotaxime. Le pourcentage de PSDP différait selon les régions, allant de 29 % en Alsace à 50 % à Paris Ile-de-France Ouest. Il était plus élevé chez l’enfant (50,2 %) que chez l’adulte (33,7 %) et variait selon le prélèvement (enfant/adulte) : hémocultures (27,8 %/32,5 %), LCR (33,7 %/34,6 %), pus d’otite moyenne aiguë (60,2 %/27,5 %), liquides pleuraux (50 %/31 %). Les PSDP étaient souvent multirésistants avec en particulier un pourcentage élevé de résistance à l’érythromycine (84,2 % contre 12,7 % pour les pneumocoques sensibles à la pénicilline). Enfin, le sérogroupe majoritairement rencontré était le sérogroupe 19 (25,2 % des isolats).
Published: 2008

42. Specificity of L,D-transpeptidases from gram-positive bacteria producing different peptidoglycan chemotypes

Author: Magnet, Sophie, Arbeloa, Ana, Mainardi, Jean-Luc, Hugonnet, Jean-Emmanuel, Fourgeaud, Martine, Dubost, Lionel, Marie, Arul, Delfosse, Vanessa, Mayer, Claudine, Rice, Louis, Arthur, Michel, Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire de chimie et biochimie des substances naturelles, Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN), Medical and Research Services, Louis Stokes Cleveland Veterans Affairs Medical Center, and ACI Microbiologie 2003' from the Fonds National de la Science (Grant ACIM-4-9), the European Community (COBRA, contract LSHM-CT-2003-503335, 6th PCRD), the National Institute of Allergy and Infectious Diseases (Grant R01 AI45626), and the Fondation pour la Recherche Médicale.
Subjects: MESH: Enterococcus faecalis, MESH: Penicillin-Binding Proteins, MESH: Peptidyl Transferases, MESH: Sequence Homology, Amino Acid, MESH: Peptidoglycan, MESH: Bacillus subtilis, MESH: Cell Wall, MESH: Drug Resistance, Bacterial, MESH: Oligopeptides, MESH: Species Specificity, MESH: Diaminopimelic Acid, MESH: Substrate Specificity, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Bacterial Proteins, MESH: Cysteine Endopeptidases
Abstract: International audience; We report here the first direct assessment of the specificity of a class of peptidoglycan cross-linking enzymes, the L,D-transpeptidases, for the highly diverse structure of peptidoglycan precursors of Gram-positive bacteria. The lone functionally characterized member of this new family of active site cysteine peptidases, Ldt(fm) from Enterococcus faecium, was previously shown to bypass the D,D-transpeptidase activity of the classical penicillin-binding proteins leading to high level cross-resistance to glycopeptide and beta-lactam antibiotics. Ldt(fm) homologues from Bacillus subtilis (Ldt(Bs)) and E. faecalis (Ldt(fs)) were found here to cross-link their cognate disaccharide-peptide subunits containing meso-diaminopimelic acid (mesoDAP(3)) and L-Lys(3)-L-Ala-L-Ala at the third position of the stem peptide, respectively, instead of L-Lys(3)-d-iAsn in E. faecium. Ldt(fs) differed from Ldt(fm) and Ldt(Bs) by its capacity to hydrolyze the L-Lys(3)-D-Ala(4) bond of tetrapeptide (L,D-carboxypeptidase activity) and pentapeptide (L,D-endopeptidase activity) stems, in addition to the common cross-linking activity. The three enzymes were specific for their cognate acyl acceptors in the cross-linking reaction. In contrast to Ldt(fs), which was also specific for its cognate acyl donor, Ldt(fm) tolerated substitution of L-Lys(3)-D-iAsn by L-Lys(3)-L-Ala-L-Ala. Likewise, Ldt(Bs) tolerated substitution of mesoDAP(3) by L-Lys(3)-D-iAsn and L-Lys(3)-L-Ala-L-Ala in the acyl donor. Thus, diversification of the structure of peptidoglycan precursors associated with speciation has led to a parallel evolution of the substrate specificity of the L,D-transpeptidases affecting mainly the recognition of the acyl acceptor. Blocking the assembly of the side chain could therefore be used to combat antibiotic resistance involving L,D-transpeptidases.
Published: 2007

43. L,D-transpeptidation in Gram-positive Bacteria

Author: Magnet, Sophie, Arbeloa, Ana, Mainardi, Jean-Luc, Hugonnet, Jean-Emmanuel, Fourgeaud, Martine, Dubost, Lionel, Marie, Arul, Delfosse, Vanessa, Mayer, Claudine, Rice, Louis, Arthur, Michel, Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire de chimie et biochimie des substances naturelles, Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Medical and Research Services, Louis Stokes Cleveland Veterans Affairs Medical Center, ACI Microbiologie 2003' from the Fonds National de la Science (Grant ACIM-4-9), the European Community (COBRA, contract LSHM-CT-2003-503335, 6th PCRD), the National Institute of Allergy and Infectious Diseases (Grant R01 AI45626), and the Fondation pour la Recherche Médicale., and Lecerf, Maxime
Subjects: MESH: Enterococcus faecalis, MESH: Penicillin-Binding Proteins, MESH: Peptidyl Transferases, MESH: Sequence Homology, Amino Acid, MESH: Peptidoglycan, MESH: Bacillus subtilis, MESH: Cell Wall, MESH: Drug Resistance, Bacterial, MESH: Oligopeptides, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Species Specificity, MESH: Diaminopimelic Acid, MESH: Substrate Specificity, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Bacterial Proteins, MESH: Cysteine Endopeptidases
Abstract: International audience; We report here the first direct assessment of the specificity of a class of peptidoglycan cross-linking enzymes, the L,D-transpeptidases, for the highly diverse structure of peptidoglycan precursors of Gram-positive bacteria. The lone functionally characterized member of this new family of active site cysteine peptidases, Ldt(fm) from Enterococcus faecium, was previously shown to bypass the D,D-transpeptidase activity of the classical penicillin-binding proteins leading to high level cross-resistance to glycopeptide and beta-lactam antibiotics. Ldt(fm) homologues from Bacillus subtilis (Ldt(Bs)) and E. faecalis (Ldt(fs)) were found here to cross-link their cognate disaccharide-peptide subunits containing meso-diaminopimelic acid (mesoDAP(3)) and L-Lys(3)-L-Ala-L-Ala at the third position of the stem peptide, respectively, instead of L-Lys(3)-d-iAsn in E. faecium. Ldt(fs) differed from Ldt(fm) and Ldt(Bs) by its capacity to hydrolyze the L-Lys(3)-D-Ala(4) bond of tetrapeptide (L,D-carboxypeptidase activity) and pentapeptide (L,D-endopeptidase activity) stems, in addition to the common cross-linking activity. The three enzymes were specific for their cognate acyl acceptors in the cross-linking reaction. In contrast to Ldt(fs), which was also specific for its cognate acyl donor, Ldt(fm) tolerated substitution of L-Lys(3)-D-iAsn by L-Lys(3)-L-Ala-L-Ala. Likewise, Ldt(Bs) tolerated substitution of mesoDAP(3) by L-Lys(3)-D-iAsn and L-Lys(3)-L-Ala-L-Ala in the acyl donor. Thus, diversification of the structure of peptidoglycan precursors associated with speciation has led to a parallel evolution of the substrate specificity of the L,D-transpeptidases affecting mainly the recognition of the acyl acceptor. Blocking the assembly of the side chain could therefore be used to combat antibiotic resistance involving L,D-transpeptidases.
Published: 2007

44. Insulinemia and inflammatory markers might predict different responses of obese subjects under the same hypocaloric diet intervention

Author: Kong, I., Wuillemin, P., Hajduch, F., Bastard, J., Fellahi, S., Basdevant, A., Jean-Daniel ZUCKER, Dore, J., Rizkalla, S., Clement, K., CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Tenon [AP-HP], Centre de Recherche en Nutrition Humaine, Unité de recherche d'Écologie et Physiologie du Système Digestif (UEPSD), Institut National de la Recherche Agronomique (INRA), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: obesity, prediction of weight loss, [SDV]Life Sciences [q-bio], fecal bacteria, hypocaloric diet, ComputingMilieux_MISCELLANEOUS
Abstract: International audience

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