Benzo(a)pyrene inhibits the role of the bioturbator Tubifex tubifex in river sediment biogeochemistry

International audienceThe interactions between invertebrates and micro-organisms living in streambed sediments often play key roles in the regulation of nutrient and organic matter fluxes in aquatic ecosystems. However, benthic sedi- ments also constitute a privileged compartment for the accumulation of persistent organic pollutants such as PAHs or PCBs that may affect the diversity, abundance and activity of benthic organisms. The objective of this study was to quantify the impact of sediment contamination with the PAH benzo(a)pyrene on the in- teraction between micro-organisms and the tubificid worm, Tubifex tubifex, which has been recognized as a major bioturbator in freshwater sediments. Sedimentary microcosms (slow filtration columns) contaminated or not with benzo(a)pyrene (3 tested concentrations: 0, 1 and 5 mg kg−1) at the sediment surface were in- cubated under laboratory conditions in the presence (100 individuals) or absence of T. tubifex. Although the surface sediment contaminations with 1 mg kg−1 and 5 mg kg−1 of benzo(a)pyrene did not affect tubificid worm survival, these contaminations significantly influenced the role played by T. tubifex in biogeochemical processes. Indeed, tubificid worms stimulated aerobic respiration, denitrification, dehydrogenase and hydrolytic activities of micro-organisms in uncontaminated sediments whereas such effects were inhibited in sediments polluted with benzo(a)pyrene. This inhibition was due to contaminant-induced changes in bioturbation (and especially bio-irrigation) activities of worms and their resulting effects on microbial processes. This study reveals the importance of sublethal concentrations of a contaminant on ecological processes in river sediments through affecting bioturbator-microbe interactions. Since they affect microbial processes involved in water purification processes, such impacts of sublethal concentrations of pollutants should be more often considered in ecosystem health assessment

An Optimized Workflow for the Discovery of New Antimicrobial Compounds Targeting Bacterial RNA Polymerase Complex Formation

Bacterial resistance represents a major health problem worldwide and there is an urgent need to develop first-in-class compounds directed against new therapeutic targets. We previously developed a drug-discovery platform to identify new antimicrobials able to disrupt the protein-protein interaction between the beta' subunit and the sigma(70) initiation factor of bacterial RNA polymerase, which is essential for transcription. As a follow-up to such work, we have improved the discovery strategy to make it less time-consuming and more cost-effective. This involves three sequential assays, easily scalable to a high-throughput format, and a subsequent in-depth characterization only limited to hits that passed the three tests. This optimized workflow, applied to the screening of 5360 small molecules from three synthetic and natural compound libraries, led to the identification of six compounds interfering with the beta'-sigma(70) interaction, and thus was capable of inhibiting promoter-specific RNA transcription and bacterial growth. Upon supplementation with a permeability adjuvant, the two most potent transcription-inhibiting compounds displayed a strong antibacterial activity against Escherichia coli with minimum inhibitory concentration (MIC) values among the lowest (0.87-1.56 mu M) thus far reported for beta'-sigma PPI inhibitors. The newly identified hit compounds share structural feature similarities with those of a pharmacophore model previously developed from known inhibitors

Prescription de médicaments potentiellement inappropriés chez la personne âgée : étude rétrospective à l'officine avec proposition de suivi de la pharmacothérapie basée sur un entretien de bilan de médication

REIMS-BU Santé (514542104) / SudocSudocFranceF

N1- and N7-substituted sibiriline derivatives and their use as inhibitor of cellular necroptosis.

The present invention relates to new N1-and N7-substituted sibiriline derivatives of the following general formula (I): (I) or a pharmaceutically acceptable salt and/or solvate thereof, notably for use as drug, in particular for use as inhibitor of cellular necroptosis. The present invention also relates to a pharmaceutical composition comprising such a compound and processes to prepare such a compound. The present invention also encompasses the use of a compound of the general formula (I) for organs preservation

N1- and N7-substituted sibiriline derivatives and their use as inhibitor of cellular necroptosis.

The present invention relates to new N1-and N7-substituted sibiriline derivatives of the following general formula (I): (I) or a pharmaceutically acceptable salt and/or solvate thereof, notably for use as drug, in particular for use as inhibitor of cellular necroptosis. The present invention also relates to a pharmaceutical composition comprising such a compound and processes to prepare such a compound. The present invention also encompasses the use of a compound of the general formula (I) for organs preservation

Reactions of dicarbanion equivalents generated from complexation of 1,3-dienes on Ti(II) moiety

International audienc

La répartition des compétences entre juridictions administratives et judiciaires à l'égard des litiges touchant les personnels des services publics

La question de la juridiction compétente à l'égard des litiges relatifs aux personnels des services publics a donné lieu, depuis près d'un demi-siècle, à une jurisprudence fort complexe. La règle posée par le législateur dans l'article L 511-1 al. 7 du Code du travail, selon laquelle ces personnels, lorsqu'ils sont employés dans les conditions du droit privé, relèvent de la compétence des conseils des prud'hommes, explique la complexité du problème. Il résulte simplement de l'article précité que les conseils des prud'hommes statuent sur les litiges individuels opposant les personnels des services publics à leurs employeurs, lorsqu'ils sont employés dans les conditions du droit privé ; mais, encore faut-il déterminer au préalable si l'on est en présence d'une relation de droit privé ou de droit public. L'étude se donne d'abord pour objet de mettre en évidence ce type de disparités, de bien cerner leurs implications pratiques et de proposer des pistes de solutions en vue d'une simplification du droit applicable. Elle se propose également d'essayer de mesurer quel est, en pratique, le degré de connaissance réelle des règles juridiques applicables, tant par les personnels que par les gestionnaires des services et, de manière plus générale, de déterminer quelles sont les difficultés concrètes, liées à la compétence juridictionnelle, qui se posent à l'intérieur des services. L'objectif est d'apporter un éclairage sur la question de la détermination du juge compétent sur un double plan : celui de l'état du droit positif et celui de l'application effective de ce droit

La répartition des compétences entre juridictions administratives et judiciaires à l'égard des litiges touchant les personnels des services publics

La question de la juridiction compétente à l'égard des litiges relatifs aux personnels des services publics a donné lieu, depuis près d'un demi-siècle, à une jurisprudence fort complexe. La règle posée par le législateur dans l'article L 511-1 al. 7 du Code du travail, selon laquelle ces personnels, lorsqu'ils sont employés dans les conditions du droit privé, relèvent de la compétence des conseils des prud'hommes, explique la complexité du problème. Il résulte simplement de l'article précité que les conseils des prud'hommes statuent sur les litiges individuels opposant les personnels des services publics à leurs employeurs, lorsqu'ils sont employés dans les conditions du droit privé ; mais, encore faut-il déterminer au préalable si l'on est en présence d'une relation de droit privé ou de droit public. L'étude se donne d'abord pour objet de mettre en évidence ce type de disparités, de bien cerner leurs implications pratiques et de proposer des pistes de solutions en vue d'une simplification du droit applicable. Elle se propose également d'essayer de mesurer quel est, en pratique, le degré de connaissance réelle des règles juridiques applicables, tant par les personnels que par les gestionnaires des services et, de manière plus générale, de déterminer quelles sont les difficultés concrètes, liées à la compétence juridictionnelle, qui se posent à l'intérieur des services. L'objectif est d'apporter un éclairage sur la question de la détermination du juge compétent sur un double plan : celui de l'état du droit positif et celui de l'application effective de ce droit

Structural determination and kinetic analysis of the Transketolase from Vibrio vulnificus reveal unexpected cooperative behavior

International audienceVibrio vulnificus (vv) is a multidrug-resistant human bacterial pathogen whose prevalence is expected to increase over the years. Transketolases (TK), transferases catalyzing two reactions of the non-oxidative branch of the pentose-phosphate pathway and therefore linked to several crucial metabolic pathways, are potential targets for new drugs against this pathogen. Here, the vvTK is crystallized and its structure is solved at 2.1 Å. A crown of 6 histidyl residues is observed in the active site and expected to participate in the thiamine pyrophosphate (cofactor) activation. Docking of fructose-6-phosphate and ferricyanide used in the activity assay, suggests that both substrates can bind vvTK simultaneously. This is confirmed by steady-state kinetics showing a sequential mechanism, on the contrary to the natural transferase reaction which follows a substituted mechanism. Inhibition by the I38-49 inhibitor (2-(4-ethoxyphenyl)-1-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine) reveals for the first time a cooperative behavior of a TK and docking experiments suggest a previously undescribed binding site at the interface between the pyrophosphate and pyridinium domains