Instance nationale et multi-communauté de DIRAC pour France Grilles

DIRAC [DIRAC] [TSA-08] is a software framework for building distributed computing systems. It was primarily designed forthe needs of the LHCb [LHCb] Collaboration, and is now used by many other communities within EGI [EGI] as a primary wayof accessing grid resources. In France, dedicated instances of the service have been deployed in different locations toanswer specific needs. Building upon this existing expertise, France Grilles [FG] initiated last year a project to deploy anational, multi-community instance in order to share expertise and provide a consistent high-quality service. After describingDIRAC main aims and functionalities, this paper presents the motivations for such a project, as well as the wholeorganizational and technical process that led to the establishment of a production instance that already serves 13communities: astro.vo.eu-egee.org, biomed, esr, euasia, gilda, glast.org, prod.vo.eu-eela.eu, superbvo.org,vo.formation.idgrilles.fr, vo.france-asia.org, vo.france-grilles.fr, vo.msfg.fr and vo.mcia.fr

The PGM3 gene encodes the major phosphoribomutase in the yeast Saccharomyces cerevisiae

The phosphoglucomutases (PGM) Pgm1, Pgm2, and Pgm3 of the yeast Saccharomyces cerevisiae were tested for their ability to interconvert ribose-1-phosphate and ribose-5-phosphate. The purified proteins were studied in vitro with regard to their kinetic properties on glucose-1-phosphate and ribose-1-phosphate. All tested enzymes were active on both substrates with Pgm1 exhibiting only residual activity on ribose-1-phosphate. The Pgm2 and Pgm3 proteins had almost equal kinetic properties on ribose-1-phosphate, but Pgm2 had a 2000 times higher preference for glucose-1-phosphate when compared to Pgm3. The in vivo function of the PGMs was characterized by monitoring ribose-1-phosphate kinetics following a perturbation of the purine nucleotide balance. Only mutants with a deletion of PGM3 hyper-accumulated ribose-1-phosphate. We conclude that Pgm3 functions as the major phosphoribomutase in vivo. (C) 2012 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved

Mise en place d'un gestionnaire de données léger, pluridisciplinaire et national pour les données scientifiques

Mise en place d'un gestionnaire de données léger, pluridisciplinaire et national pour les données scientifique

Mise en place d'un gestionnaire de données léger, pluridisciplinaire et national pour les données scientifiques

Mise en place d'un gestionnaire de données léger, pluridisciplinaire et national pour les données scientifique

Chlordecone exposure and risk of prostate cancer.

International audiencePURPOSE: Determining whether environmental estrogens are associated with the risk of prostate cancer may have important implications for our general understanding of this disease. The estrogenic insecticide chlordecone was used extensively in the French West Indies, contaminating the population for more than 30 years. We analyzed the relationship between exposure to chlordecone and the risk of prostate cancer. PATIENTS AND METHODS: We investigated 623 men with prostate cancer and 671 controls. Exposure was analyzed according to case-control status, using either current plasma concentration or a cumulative exposure index based on years of exposure. We genotyped two single-nucleotide polymorphisms (rs3829125 and rs17134592) in the gene encoding chlordecone reductase. RESULTS: We found a significant increase in the risk of prostate cancer with increasing plasma chlordecone concentration (odds ratio [OR], 1.77; 95% CI, 1.21 to 2.58 for the highest tertile of values above the limit of detection [LD]; P trend = .002) and for cumulative exposure index (OR, 1.73; 95% CI, 1.04 to 2.88 for the highest quartile; P trend = .004). Stronger associations were observed among those with a positive family history of prostate cancer and among those who had lived in a Western country. The rs3829125 and rs17134592 allele variants were in complete linkage disequilibrium and were found at low frequency (0.04). Among subjects with plasma chlordecone concentrations above the LD, carriers of the allele variants had a higher risk of prostate cancer (OR, 5.23; 95% CI, 0.82 to 33.32). CONCLUSION: These findings support the hypothesis that exposure to environmental estrogens increases the risk of prostate cancer

Persistent organic pollutant exposure and thyroid function among 12-year-old children

International audienceIntroductionPolychlorobiphenyls (PCBs), organochlorine pesticides (OCPs) and per- and polyfluoroalkyl substances (PFASs) are persistent organic pollutants (POPs) having numerous toxicological properties, including thyroid endocrine disruption. Our aim was to assess the impact of POPs on thyroid hormones among 12-years children, while taking puberty into consideration MethodsExposure to 7 PCBs, 4 OCPs and 6 PFASs (in mu g/L), and free triiodothyronine (fT3, pg/mL), free thyroxine (fT4, ng/dL) and thyroid-stimulating hormones (TSH, mIU/L) were assessed through blood-serum measurements at age 12 in 249 boys and 227 girls of the PELAGIE mother-child cohort (France). Pubertal status was clinically rated using the Tanner stages. For each POP, associations were estimated using linear regression, adjusted for potential confounders.ResultsAmong boys, hexachlorobenzene and perfluorodecanoic acid were associated with decreased fT3 (log-scale; beta (95% Confidence Interval) =-0.07 (-0.12,-0.02) and beta=-0.03 (-0.06,-0.00) respectively). Intermediate levels of perfluorohexanesulfonic acid (PFHxS) and PCB180 were associated, respectively, with increased and decreased fT4. After stratification on pubertal status, PCBs and OCPs were associated with decreased TSH only in the more advanced Tanner stages (3, 4 and 5) and with decreased fT3 among early Tanner stages (1-2).Among girls, PFHxS was associated with decreased TSH (log-scale; beta=-0.15 (-0.29,-0.00)), and perfluorooctanoic acid was associated with decreased fT3 (beta 2nd_tercile=-0.06 (-0.10,-0.03) and beta 3rd_tercile=-0.04 (-0.08,-0.00), vs 1st tercile). Discussion / ConclusionThis cross-sectional study highlights associations between some POPs and thyroid function disruption, which appears consistent with the literature. Considering that the associations were sex-specific and moderated by pubertal status in boys, complex endocrine interactions are likely involved

TREM-1 multimerization is essential for its activation on monocytes and neutrophils

The triggering receptor expressed on myeloid cells-1 (TREM-1) is a receptor expressed on innate immune cells. By promoting the amplification of inflammatory signals that are initially triggered by Toll-like receptors (TLRs), TREM-1 has been characterized as a major player in the pathophysiology of acute and chronic inflammatory diseases, such as septic shock, myocardial infarction, atherosclerosis, and inflammatory bowel diseases. However, the molecular events leading to the activation of TREM-1 in innate immune cells remain unknown. Here, we show that TREM-1 is activated by multimerization and that the levels of intracellular Ca2+release, reactive oxygen species, and cytokine production correlate with the degree of TREM-1 aggregation. TREM-1 activation on primary human monocytes by LPS required a two-step process consisting of upregulation followed by clustering of TREM-1 at the cell surface, in contrast to primary human neutrophils, where LPS induced a rapid cell membrane reorganization of TREM-1, which confirmed that TREM-1 is regulated differently in primary human neutrophils and monocytes. In addition, we show that the ectodomain of TREM-1 is able to homooligomerize in a concentration-dependent manner, which suggests that the clustering of TREM-1 on the membrane promotes its oligomerization. We further show that the adapter protein DAP12 stabilizes TREM-1 surface expression and multimerization. TREM-1 multimerization at the cell surface is also mediated by its endogenous ligand, a conclusion supported by the ability of the TREM-1 inhibitor LR12 to limit TREM-1 multimerization. These results provide evidence for ligand-induced, receptor-mediated dimerization of TREM-1. Collectively, our findings uncover the mechanisms necessary for TREM-1 activation in monocytes and neutrophils

Bi-decadal changes in nutrient concentrations and ratios in marine coastal ecosystems: the case of the Arcachon bay, France

Large amounts of nutrients have been released to the coastal ecosystems during the 20th century. Since then, management policies have been implemented and these amounts decreased in the economically developed countries. We examined the bi-decadal changes in nutrients (nitrate + nitrite, ammonium, orthophosphate and silicic acid) in the Arcachon bay, a semi-enclosed lagoon that hosts one of the largest but declining seagrass meadow in Europe. Seven sites have been sampled for nutrients and biogeochemical parameters during twenty years at low and/or high tide. In addition, continental and climatic data as well as hydro-climatic indices were used. Dynamic linear models were used to assess the bi-decadal changes in nutrient concentrations and ratios, their seasonality, and the bi-decadal changes of their potential drivers. Partial least square path modeling were used to investigate the relationships between potential abiotic drivers and nutrients. During the study period, the concentration of N and Si nutrients increased whereas the concentration of orthophosphate decreased, leading to deep changes in nutrient ratios. Clear relationships between abiotic drivers (local climate, continental inputs and the bay hydrodynamism) and N, P and Si nutrients were highlighted. However, the bi-decadal change in nutrient concentrations and ratios was mainly ascribed to the seagrass meadow decline through direct (less nutrient consumption) and indirect (increase in phytoplankton biomass) processes. Changes in temperature and wind direction may also influenced the nutrients concentrations through processes of remineralisation and flushing time, respectively. This study illustrates (1) the top-down control of seagrass on the nutrients concentrations and stoichiometry, and (2) the competition between primary producers (seagrass vs phytoplankton) for their nutrients resource

New hormone receptor-positive breast cancer mouse cell line mimicking the immune microenvironment of anti-PD-1 resistant mammary carcinoma

Background Progress in breast cancer (BC) research relies on the availability of suitable cell lines that can be implanted in immunocompetent laboratory mice. The best studied mouse strain, C57BL/6, is also the only one for which multiple genetic variants are available to facilitate the exploration of the cancer-immunity dialog. Driven by the fact that no hormone receptor-positive (HR+) C57BL/6-derived mammary carcinoma cell lines are available, we decided to establish such cell lines.Methods BC was induced in female C57BL/6 mice using a synthetic progesterone analog (medroxyprogesterone acetate, MPA) combined with a DNA damaging agent (7,12-dimethylbenz[a]anthracene, DMBA). Cell lines were established from these tumors and selected for dual (estrogen+progesterone) receptor positivity, as well as transplantability into C57BL/6 immunocompetent females.Results One cell line, which we called B6BC, fulfilled these criteria and allowed for the establishment of invasive estrogen receptor-positive (ER+) tumors with features of epithelial to mesenchymal transition that were abundantly infiltrated by myeloid immune populations but scarcely by T lymphocytes, as determined by single-nucleus RNA sequencing and high-dimensional leukocyte profiling. Such tumors failed to respond to programmed cell death-1 (PD-1) blockade, but reduced their growth on treatment with ER antagonists, as well as with anthracycline-based chemotherapy, which was not influenced by T-cell depletion. Moreover, B6BC-derived tumors reduced their growth on CD11b blockade, indicating tumor sustainment by myeloid cells. The immune environment and treatment responses recapitulated by B6BC-derived tumors diverged from those of ER+ TS/A cell-derived tumors in BALB/C mice, and of ER– E0771 cell-derived and MPA/DMBA-induced tumors in C57BL/6 mice.Conclusions B6BC is the first transplantable HR+ BC cell line derived from C57BL/6 mice and B6BC-derived tumors recapitulate the complex tumor microenvironment of locally advanced HR+ BC naturally resistant to PD-1 immunotherapy