Cochin, France
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Mimoun S.,French National Institute for Agricultural Research | Andriamihaja M.,French National Institute for Agricultural Research | Chaumontet C.,French National Institute for Agricultural Research | Atanasiu C.,Hopital Avicenne | And 5 more authors.
Antioxidants and Redox Signaling | Year: 2012

Aims: Sulfide is released in the large intestine lumen by the microbiota and is an inhibitor of mitochondrial respiration and a genotoxic agent in colonocytes when present in excess. Deciphering how colonocytes metabolize sulfide is an important issue. Results: In this study, using the human colonic epithelial HT-29 Glc-/+ cells, we found that 50 μM sodium hydrogen sulfide represents the threshold of concentration above which respiration is decreased. The capacity of HT-29 Glc-/+ cells to oxidize lower concentration of sulfide was associated with the expression of transcripts corresponding to the enzymes of the sulfide oxidizing unit (SOU), that is, sulfide quinone reductase (SQR), dioxygenase ethylmalonic encephalopathy, and thiosulfate sulfur transferase (TST). Inhibition of cell O2 consumption by sulfide was reverted by zinc but not by calcium and iron. When the cells undergo either spontaneous or butyrate-induced differentiation, their capacity to oxidize sulfide was significantly increased. The expression levels of the genes corresponding to the enzymes of the SOU were not increased, whereas increased cellular maximal respiratory capacity and oxygen consumption by the dioxygenase were both measured. In human biopsies recovered from various parts of the large intestine, the three enzymes of the SOU were expressed. Innovation: SOU and cell respiratory capacity are crucial for sulfide detoxification in colonocytes. Conclusion: Sulfide oxidative capacity in the colonic mucosa is higher in differentiated than in proliferative epithelial cells. The cell respiratory capacity and SOU activity appear to represent major determinants allowing sulfide detoxification in colonic epithelial cells. © 2012 Mary Ann Liebert, Inc.


Pavlowsky A.,University of Paris Descartes | Pavlowsky A.,French Institute of Health and Medical Research | Pavlowsky A.,New York University | Pavlowsky A.,SUNY Downstate Medical Center | And 5 more authors.
Molecular Psychiatry | Year: 2012

Genetic causes of intellectual disability (ID) include mutations in proteins with various functions. However, many of these proteins are enriched in synapses and recent investigations point out their crucial role in the subtle regulation of synaptic activity and dendritic spine morphogenesis. Moreover, in addition to genetic data, functional and animal model studies are providing compelling evidence that supports the emerging unifying synapse-based theory for cognitive deficit. In this review, we highlight ID-related gene products involved in synaptic morphogenesis and function, with a particular focus on the emergent signaling pathways involved in synaptic plasticity whose disruption results in cognitive deficit. © 2012 Macmillan Publishers Limited All rights reserved.


Triyatni M.,U.S. National Institutes of Health | Triyatni M.,Hoffmann-La Roche | Berger E.A.,U.S. National Institutes of Health | Saunier B.,U.S. National Institutes of Health | And 3 more authors.
PLoS Pathogens | Year: 2011

Numerous constraints significantly hamper the experimental study of hepatitis C virus (HCV). Robust replication in cell culture occurs with only a few strains, and is invariably accompanied by adaptive mutations that impair in vivo infectivity/replication. This problem complicates the production and study of authentic HCV, including the most prevalent and clinically important genotype 1 (subtypes 1a and 1b). Here we describe a novel cell culture approach to generate infectious HCV virions without the HCV replication requirement and the associated cell-adaptive mutations. The system is based on our finding that the intracellular environment generated by a West-Nile virus (WNV) subgenomic replicon rendered a mammalian cell line permissive for assembly and release of infectious HCV particles, wherein the HCV RNA with correct 5′ and 3′ termini was produced in the cytoplasm by a plasmid-driven dual bacteriophage RNA polymerase-based transcription/amplification system. The released particles preferentially contained the HCV-based RNA compared to the WNV subgenomic RNA. Several variations of this system are described with different HCV-based RNAs: (i) HCV bicistronic particles (HCVbp) containing RNA encoding the HCV structural genes upstream of a cell-adapted subgenomic replicon, (ii) HCV reporter particles (HCVrp) containing RNA encoding the bacteriophage SP6 RNA polymerase in place of HCV nonstructural genes, and (iii) HCV wild-type particles (HCVwt) containing unmodified RNA genomes of diverse genotypes (1a, strain H77; 1b, strain Con1; 2a, strain JFH-1). Infectivity was assessed based on the signals generated by the HCV RNA molecules introduced into the cytoplasm of target cells upon virus entry, i.e. HCV RNA replication and protein production for HCVbp in Huh-7.5 cells as well as for HCVwt in HepG2-CD81 cells and human liver slices, and SP6 RNA polymerase-driven firefly luciferase for HCVrp in target cells displaying candidate HCV surface receptors. HCV infectivity was inhibited by pre-incubation of the particles with anti-HCV antibodies and by a treatment of the target cells with leukocyte interferon plus ribavirin. The production of authentic infectious HCV particles of virtually any genotype without the adaptive mutations associated with in vitro HCV replication represents a new paradigm to decipher the requirements for HCV assembly, release, and entry, amenable to analyses of wild type and genetically modified viruses of the most clinically significant HCV genotypes.


Gebser M.,University of Potsdam | Schaub T.,University of Potsdam | Thiele S.,University of Potsdam | Veber P.,Institute Cochin
Theory and Practice of Logic Programming | Year: 2011

We introduce an approach to detecting inconsistencies in large biological networks by using answer set programming. To this end, we build upon a recently proposed notion of consistency between biochemical/genetic reactions and high-throughput profiles of cell activity. We then present an approach based on answer set programming to check the consistency of large-scale data sets. Moreover, we extend this methodology to provide explanations for inconsistencies by determining minimal representations of conflicts. In practice, this can be used to identify unreliable data or to indicate missing reactions. © 2011 Cambridge University Press.


Saclier M.,French Institute of Health and Medical Research | Yacoub-Youssef H.,French Institute of Health and Medical Research | Yacoub-Youssef H.,French National Center for Scientific Research | Mackey A.L.,French National Center for Scientific Research | And 10 more authors.
Stem Cells | Year: 2013

Macrophages (MPs) exert either beneficial or deleterious effects on tissue repair, depending on their activation/ polarization state. They are crucial for adult skeletal muscle repair, notably by acting on myogenic precursor cells. However, these interactions have not been fully characterized. Here, we explored both in vitro and in vivo, in human, the interactions of differentially activated MPs with myogenic precursor cells (MPCs) during adult myogenesis and skeletal muscle regeneration. We showed in vitro that through the differential secretion of cytokines and growth factors, proinflammatory MPs inhibited MPC fusion while anti-inflammatory MPs strongly promoted MPC differentiation by increasing their commitment into differentiated myocytes and the formation of mature myotubes. Furthermore, the in vivo time course of expression of myogenic and MP markers was studied in regenerating human healthy muscle after damage. We observed that regenerating areas containing proliferating MPCs were preferentially associated with MPs expressing proinflammatory markers. In the same muscle, regenerating areas containing differentiating myogenin-positive MPCs were preferentially coupled to MPs harboring anti-inflammatory markers. These data demonstrate for the first time in human that MPs sequentially orchestrate adult myogenesis during regeneration of damaged skeletal muscle. These results support the emerging concept that inflammation, through MP activation, controls stem cell fate and coordinates tissue repair. © 2012 AlphaMed Press.


Devauchelle-Pensec V.,University of Western Brittany | Cagnard N.,University of Paris Descartes | Pers J.-O.,Brest University Hospital Center | Youinou P.,Brest University Hospital Center | And 3 more authors.
Arthritis and Rheumatism | Year: 2010

Objective. Primary Sjögren's syndrome (SS) is a complex disorder, in part due to B cell abnormalities. Although anti-B cell therapy is promising in primary SS, no treatment has yet been demonstrated to modify the disease course. This open-label study was undertaken to evaluate the efficacy of rituximab in primary SS and to investigate whether expression of specific genes is associated with efficacy of this treatment. Methods. Fifteen patients with primary SS were treated in an open-label trial. Salivary gland biopsy specimens were obtained, and total RNA was extracted and amplified. Microarray analysis with the Affymetrix Human Genome U133 Plus 2.0 Array was used to analyze >54,000 transcripts, and potential pathways were identified. Results. With gene expression data obtained before treatment, patients could be correctly classified in terms of whether they would be responders or nonresponders to rituximab. Gene pathway analysis demonstrated that the B cell signaling pathway was the most profoundly differentially expressed before treatment in the responders compared with nonresponders. Subclassification of patients based on the level of infiltration also demonstrated differential expression of genes belonging to the interferon (IFN) pathway between responders and nonresponders. Furthermore, unsupervised analysis based on gene expression modification before and after treatment allowed identification of 8 genes that were differentially expressed between responders and nonresponders, with the difference remaining significant after Bonferroni correction. Conclusion. Our results demonstrate the ability to elaborate a set of genes predictive of rituximab efficacy and highlight the importance of studying the differential expression of B cell and IFN pathway signaling molecules in relation to the response to anti-CD20 treatment. A randomized controlled study is currently ongoing to confirm these results. © 2010, American College of Rheumatology.


Willems L.,University of Paris Descartes | Tamburini J.,University of Paris Descartes | Chapuis N.,University of Paris Descartes | Lacombe C.,University of Paris Descartes | And 3 more authors.
Current Oncology Reports | Year: 2012

The mammalian target of rapamycin (mTOR) and the phosphoinositide 3-kinase (PI3K) signaling pathways are commonly deregulated in cancers and promote cellular growth, proliferation, and survival. mTOR is part of two complexes, mTORC1 and mTORC2, with different biochemical structures and substrates specificity. PI3K/AKT activation may result from genetic hits affecting different components of the pathway, whereas the mechanisms leading to constitutive mTORC1 activation remain globally unknown. The connections between the PI3K and mTOR kinases are multiple and complex, including common substrates, negative feedback loops, or direct activation mechanisms. Firstgeneration allosteric mTOR inhibitors (eg, rapamycin) are mainly active on mTORC1 and mostly display cytostatic anti-tumor activity. Recently, second-generation catalytic mTOR inhibitors targeting both mTOR complexes 1 and 2 have been developed. Some of them also inhibit class IA PI3K. Here, we highlight recent data generated with these new inhibitors against cancer cells and their potential as anticancer drugs. © 2012 Springer Science+Business Media, LLC.


Wang S.,The University of Oklahoma Health Sciences Center | Dale G.L.,The University of Oklahoma Health Sciences Center | Song P.,The University of Oklahoma Health Sciences Center | Viollet B.,Institute Cochin | And 3 more authors.
Journal of Biological Chemistry | Year: 2010

AMP-activated protein kinase (AMPK) is an energy sensor essential for maintaining cellular energy homeostasis. Here, we report that AMPKα1 is the predominant isoform of AMPK in murine erythrocytes and mice globally deficient in AMPKα1 (AMPKα1-/-), but not in those lacking AMPKα2, and the mice had markedly enlarged spleens with dramatically increased proportions of Ter119-positive erythroid cells. Blood tests revealed significantly decreased erythrocyte and hemoglobin levels with increased reticulocyte counts and elevated plasma erythropoietin concentrations in AMPKα1-/- mice. The life span of erythrocytes from AMPKα1-/- mice was less than that in wild-type littermates, and the levels of reactive oxygen species and oxidized proteins were significantly increased in AMPKα1-/- erythrocytes. In keeping with the elevated oxidative stress, treatment of AMPKα1-/- mice with the antioxidant, tempol, resulted in decreased reticulocyte counts and improved erythrocyte survival. Furthermore, the expression of Foxo3 and reactive oxygen species scavenging enzymes was significantly decreased in erythroblasts from AMPKα1-/- mice. Collectively, these results establish an essential role for AMPKα1 in regulating oxidative stress and life span in erythrocytes. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


Miralles F.,University Paris Diderot | Miralles F.,Institute Cochin
Journal of Molecular Evolution | Year: 2010

Previous studies have reported a positive correlation between the GC content of the double-stranded regions of structural RNAs and the optimal growth temperature (OGT) in prokaryotes. These observations led to the hypothesis that natural selection favors an increase in GC content to ensure the correct folding and the structural stability of the molecule at high temperature. To date these studies have focused mainly on ribosomal and transfer RNAs. Therefore, we addressed the question of the relationship between GC content and OGT in a different and universally conserved structural RNA, the RNA component of the signal recognition particle (SRP). To this end we generated the secondary structures of SRP-RNAs for mesophilic, thermophilic, and hyperthermophilic bacterial and archaeal species. The analysis of the GC content in the stems and loops of the SRP-RNA of these organisms failed to detect a relationship between the GC contents in the stems of this structural RNA and the growth temperature of bacteria. By contrast, we found that in archaea the GC content in the stem regions of SRP-RNA is highest in hyperthermophiles, intermediate in thermophiles, and lower in mesophiles. In these organisms, we demonstrated a clear positive correlation between the GC content of the stem regions of their SRP-RNAs and their OGT. This correlation was confirmed by a phylogenetic nonindependence analysis. Thus we conclude that in archaea the increase in GC content in the stem regions of SRP-RNA is an adaptation response to environmental temperature.


Hanoune J.,Institute Cochin
Medecine Therapeutique Medecine de la Reproduction, Gynecologie et Endocrinologie | Year: 2013

As far as one can go, a constant literary theme has always been the future of reproduction. A few examples are here analyzed, from various steps of our history, mythological, scientist, and finally modern with the surge of feminism.

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