HYDRAM : système informatique d'aide à la décision dans l'aménagement des eaux, planification des HYDro-AMénagements

La complexité croissante des systèmes d'eau en Guadeloupe, notamment pour l'irrigation, et la forte variabilité spatio-temporelle des précipitations ont conduit l'ORSTOM à proposer l'élaboration d'un outil d'aide à la décision dans l'aménagement des eaux. Une des originalités du logiciel réside dans la construction interactive des systèmes permettant d'envisager facilement différents scénarios de développement. En se basant sur la confrontation des besoins et des ressources, l'outil permet de simuler le fonctionnement hydrologique des aménagements et de fournir des analyses synthétiques des résultats. Le choix de la conception et programmation par objets autorise toutes les extensions nécessaires pour envisager les multiples facettes d'une gestion rationnelle des ressources en eau. (Résumé d'auteur

UV-induced formation of the thymine-thymine pyrimidine (6-4) pyrimidone photoproduct - a DFT study of the oxetane intermediate ring opening

International audienceThe mechanism by which the hypothetical oxetane/azetidine intermediate formed during the photochemical process leading to pyrimidine (6-4) pyrimidone photoproducts when DNA is submitted to UV radiation opens is investigated computationally by DFT using a 5′-TT-3′ dinucleoside monophosphate as a structural model. First, the feasibility of an intramolecular mechanism involving one proton transfer inducing opening of the oxetane ring is examined. It results in a very high Gibbs energy of activation (+166 kJ mol−1) and quite a low Gibbs energy of reaction (−35 kJ mol−1). The protonation state of the phosphate group is shown to have little effect while the bulk effect of an aqueous environment modeled by the Polarizable Continuum Model method lowers slightly the activation barrier (by about 10-20 kJ mol−1), not enough to explain the fact that the oxetane intermediate is not observed experimentally. Then the catalytic effect of water molecules on the reaction pathway is studied by including either 1 or 2 assisting water molecules in the chemical system. The resulting activation barrier is considerably lowered and in the most favorable situation - a phosphate group deprotonated and 2 assisting water molecules - the Gibbs energy activation is as low as +44 kJ mol−1 and the Gibbs energy of reaction is quite favorable: −79 kJ mol−1, suggesting that in biological systems the oxetane ring opening process proceeds with explicit intervention of water molecules from the environment

Molecular Interactions From the Density Functional Theory for Chemical Reactivity: The Interaction Energy Between Two-Reagents

Reactivity descriptors indicate where a reagent is most reactive and how it is most likely to react. However, a reaction will only occur when the reagent encounters a suitable reaction partner. Determining whether a pair of reagents is well-matched requires developing reactivity rules that depend on both reagents. This can be achieved using the expression for the minimum-interaction-energy obtained from the density functional reactivity theory. Different terms in this expression will be dominant in different circumstances; depending on which terms control the reactivity, different reactivity indicators will be preferred

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Un nouveau descripteur de la réactivité chimique : étude théorique et applications à la sélectivité de quelques réaction chimiques

The prediction of the reactivity and the selectivity of a chemical process is critical. Conceptual Density Functional Theory (Conceptual DFT) is the theoretical framework in which all the global and local indexes aiming to describe the chemical reactivity have been rationalized. The description of a chemical process in terms of derivatives of the electronic energy with respect of either the number of electron (N) or the external potential [v(r)], provides a definition of each index. In this work a new dual descriptor that characterizes the variations of the absolute hardness when the external potential changes have been proposed. It has been regarded through three different theoretical points of view: its relations with the Fukui functions; its links with the covalent interaction energy; and finally its compliance with the Principle of Maximum Hardness. It appears from the three studies that the sign of the descriptor is able to characterize the electrophilic/nucleophilic behavior of a molecular site. Finally, the descriptor has been tested through of some classical organic reactions. All the predictions are in agreement with the experimental results.La prédiction de la réactivité et de la sélectivité d'un processus chimique est cruciale. La théorie de la fonctionnelle de la densité électronique conceptuelle est le cadre théorique dans lequel tous les indices locaux et globaux qui décrivent la réactivité chimique ont été rationalisés. La description d'un processus chimique en terme de dérivées de l'énergie électronique par rapport au nombre d'électrons, ou au potentiel externe fournit une définition à chaque descripteur. Dans ce travail, un nouveau descripteur dual qui caractérise les variations de la dureté lorsque le potentiel externe est modifié, est défini. Il a été étudié à travers trois différentes théories : ses relations avec les fonctions de Fukui, ses relations avec la contribution covalente à l'énergie d'interaction et sa relation avec le principe de dureté maximum. Il apparaît dans les trois cas que le signe du descripteur permet de caractériser le comportement électrophile ou nucléophile d'un site moléculaire. Ce descripteur a finalement été testé à l'aide de différentes réactions classiques en chimie organique. Toutes ses prédictions sont en accord avec les résultats expérimentaux

Un nouveau descripteur de la réactivité chimique : étude théorique et applications à la sélectivité de quelques réaction chimiques

The prediction of the reactivity and the selectivity of a chemical process is critical. Conceptual Density Functional Theory (Conceptual DFT) is the theoretical framework in which all the global and local indexes aiming to describe the chemical reactivity have been rationalized. The description of a chemical process in terms of derivatives of the electronic energy with respect of either the number of electron (N) or the external potential [v(r)], provides a definition of each index. In this work a new dual descriptor that characterizes the variations of the absolute hardness when the external potential changes have been proposed. It has been regarded through three different theoretical points of view: its relations with the Fukui functions; its links with the covalent interaction energy; and finally its compliance with the Principle of Maximum Hardness. It appears from the three studies that the sign of the descriptor is able to characterize the electrophilic/nucleophilic behavior of a molecular site. Finally, the descriptor has been tested through of some classical organic reactions. All the predictions are in agreement with the experimental results.La prédiction de la réactivité et de la sélectivité d'un processus chimique est cruciale. La théorie de la fonctionnelle de la densité électronique conceptuelle est le cadre théorique dans lequel tous les indices locaux et globaux qui décrivent la réactivité chimique ont été rationalisés. La description d'un processus chimique en terme de dérivées de l'énergie électronique par rapport au nombre d'électrons, ou au potentiel externe fournit une définition à chaque descripteur. Dans ce travail, un nouveau descripteur dual qui caractérise les variations de la dureté lorsque le potentiel externe est modifié, est défini. Il a été étudié à travers trois différentes théories : ses relations avec les fonctions de Fukui, ses relations avec la contribution covalente à l'énergie d'interaction et sa relation avec le principe de dureté maximum. Il apparaît dans les trois cas que le signe du descripteur permet de caractériser le comportement électrophile ou nucléophile d'un site moléculaire. Ce descripteur a finalement été testé à l'aide de différentes réactions classiques en chimie organique. Toutes ses prédictions sont en accord avec les résultats expérimentaux

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International audienc

Probing Interstand CrossLinks Impact on DNA Structure by Classical Molecular Dynamics Simulations

National audienceInterstrands cross-links are highly cytotoxic oxidatively-generated DNA damages. They result from abasic sites (Ap) reaction with a purine on the facing strand of the double-helix. The aldehyde group of the abasic site condenses with the exocyclic amino group of the purine, leading to a covalent adduct, bonding the two strands.This type of lesions is very deleterious for cells since it avoids the strands separation during DNA replication, leading to apoptosis [1]. The feasability of such lesions has been prooved [2,3], with high yields (15-70%) reported for the formation of Ap-Adenine cross linking [4]. These observations suggest that B-helix is flexible enough to allow the two reactants to approach and react, despite the mechanical constraints that it could induce.We investigated the structural impact of these interstrands cross-links in 21 base pair oligonucleotides, generating 100ns molecular dynamics simulations. Structural analysis on these conformationnal sampling allowed us to probe the effect of such lesions on the double-helix. This study showed strong structural rearrangements in the double-helix, presenting two stable conformations, both with π-stacking modifications of the surrounding nucleobases and C33 exclusion, the difference between the two relying on the T12 exclusion.[1] Formation and Repair of Interstrand Cross- Links in DNA (Noll et al.), Chem. Rev. 106, 277-301 (2006).[2] Scope and Mechanism of Interstrand Cross-Link Formation by the C4’-Oxidized Abasic Site (Sczepanski et al.), J. Am. Chem. Soc. 131, 11132-11139 (2009).[3] Oxidation of the sugar moiety of DNA by ionizing radiation or bleomycin could induce the formation of a cluster DNA lesion (Regulus et al.), Proc. Natl. Acad. Sci. U.S.A 104, 14032-14037 (2007).[4] Interstrand DNA-DNA cross-link formation between adenine residues and abasic sites in duplex DNA (Price et al.), J. Am. Chem. Soc. 136, 3483-3490 (2014)