Coupling Methodology within the Software Platform Alliances

CEA, ANDRA and EDF are jointly developing the software platform ALLIANCES which aim is to produce a tool for the simulation of nuclear waste storage and disposal repository. This type of simulations deals with highly coupled thermo-hydro-mechanical and chemical (T-H-M-C) processes. A key objective of Alliances is to give the capability for coupling algorithms development between existing codes. The aim of this paper is to present coupling methodology use in the context of this software platform.Comment: 7 page

Finite volume approximation of a diffusion-dissolution model and application to nuclear waste storage

International audienceThe study of two phase flow in porous media under high capillary pressures, in the case where one phase is incompressible and the other phase is gaseous, shows complex phenomena. We present in this paper a numerical approximation method, based on a two pressures formulation in the case where both phases are miscible, which is shown to also handle the limit case of immiscible phases. The space discretization is performed using a finite volume method, which can handle general grids. The efficiency of the formulation is shown on three numerical examples related tounderground waste disposal situations

Des esters arylboroniques aux arylnitrones (synthèse d'esters arylboroniques et nouvelle réaction d'arylation de nitrones cycliques)

Au cours de ce travail, nous nous sommes intéressés à la préparation d'esters arylboroniques issus de l'hexylène glycol et porteurs de substituants électroattracteurs. Nous avons d'abord étudié la borylation catalysée au palladium d'halogénures d'aryle pauvres en électrons par MPBH, substitut économique du PinBH. Il s'est avéré que MPBH était moins performant sur ce type de substrats que le PinBH. Nous nous sommes alors tournés vers une borylation par un échange iode/magnésium avec piégeage in situ par le borate MPBOiPr. Cette méthode nous a permis de boryler des iodures d'aryle pauvres en électrons, porteurs de groupes fonctionnels sensibles, de manière propre et sécurisée (pas d'accumulation de magnésien). Elle s'avère applicable à grande échelle (kilogramme). Ces esters arylboroniques ont ensuite été engagés dans des réactions d'addition sur des nitrones, sans succès. Cela nous a amené à développer une nouvelle réaction : l'arylation directe de nitrones cycliques par des halogénures d'aryle. Au cours de l'étude, nous avons démontré l'effet d'accélération de deux additifs introduits en quantité catalytique : un sel de cuivre et l'acide pivalique. Les réactions sont ainsi rapides et propres, et s'appliquent à des iodures, bromures ou chlorures (hétéro)aromatiques très variés. Pour finir, nous avons effectué une étude mécanistique qui nous a permis de proposer deux mécanismes, selon l'additif mis en jeu.The first part is focused on the preparation of arylboronic esters derived from hexylene glycol, and bearing electron withdrawing substituents. We studied the palladium catalyzed borylation of electron-poor aryl halides with MPBH, an economic substitute for PinBH. MPBH, however, was found less efficient than PinBH. Next, a borylation through iodine/magnesium exchange with in situ trapping by the borate MPBOiPr was developed. This method allowed the borylation of aryl iodides carrying electron withdrawing and sensitive substituents, cleanly and safely (no accumulation of organomagnesium species), and scale up was possible (kilogram scale). Our attempts to use these arylboronic esters in addition reaction onto nitrones were unsuccessful. This led us to develop a new reaction: the direct arylation of cyclic nitrones with aryl halides. The coupling is dramatically accelerated by catalytic amounts of either a copper salt or pivalic acid. The reactions are fast and clean, and various (hetero)aryl iodides, bromides and chlorides can be used. Last, a mechanistic study allowed us to propose a mechanism for each additive.SAVOIE-SCD - Bib.électronique (730659901) / SudocGRENOBLE1/INP-Bib.électronique (384210012) / SudocGRENOBLE2/3-Bib.électronique (384219901) / SudocSudocFranceF

Unveiling the Impact of Morphine on Tamoxifen Metabolism in Mice in vivo

Background- Tamoxifen is used to treat breast cancer and cancer recurrences. After administration, tamoxifen is converted into two more potent antitumor compounds, 4OH-tamoxifen and endoxifen by the CYP3A4/5 and 2D6 enzymes in human. These active compounds are inactivated by the same UDP-glucuronosyltransferases isoforms as those involved in the metabolism of morphine. Importantly, cancer-associated pain can be treated with morphine, and the common metabolic pathway of morphine and tamoxifen suggests potential clinically relevant interactions. Methods- Mouse liver microsomes were used to determine the impact of morphine on 4OH-tamoxifen metabolism in vitro. For in vivo experiments, female mice were first injected with tamoxifen alone and then with tamoxifen and morphine. Blood was collected, and LC-MS/MS was used to quantify tamoxifen, 4OH-tamoxifen, N-desmethyltamoxifen, endoxifen, 4OH-tamoxifen-glucuronide and endoxifen-glucuronide. Results- In vitro, we found increased Km values for the production of 4OH-tamoxifen-glucuronide in the presence of morphine, suggesting an inhibitory effect on 4OH-tamoxifen glucuronidation. Conversely, in vivo morphine treatment decreased 4OH-tamoxifen levels in the blood while dramatically increasing the formation of inactive metabolites 4OH-tamoxifen-glucuronide and endoxifen-glucuronide. Conclusions- Our findings emphasize the need for caution when extrapolating results from in vitro metabolic assays to in vivo drug metabolism interactions. Importantly, morphine strongly impacts tamoxifen metabolism in mice. It suggests that tamoxifen efficiency could be reduced when both drugs are co-administered in a clinical setting, e.g. to relieve pain in breast cancer patients. Further studies are needed to assess the potential for tamoxifen-morphine metabolic interactions in humans

Inflammatory cytokines and biofilm production sustain Staphylococcus aureus outgrowth and persistence: A pivotal interplay in the pathogenesis of Atopic Dermatitis

Individuals with Atopic dermatitis (AD) are highly susceptible to Staphylococcus aureus colonization. However, the mechanisms driving this process as well as the impact of S. aureus in AD pathogenesis are still incompletely understood. In this study, we analysed the role of biofilm in sustaining S. aureus chronic persistence and its impact on AD severity. Further we explored whether key inflammatory cytokines overexpressed in AD might provide a selective advantage to S. aureus. Results show that the strength of biofilm production by S. aureus correlated with the severity of the skin lesion, being significantly higher (P < 0.01) in patients with a more severe form of the disease as compared to those individuals with mild AD. Additionally, interleukin (IL)-β and interferon γ (IFN-γ), but not interleukin (IL)-6, induced a concentration-dependent increase of S. aureus growth. This effect was not observed with coagulase-negative staphylococci isolated from the skin of AD patients. These findings indicate that inflammatory cytokines such as IL1-β and IFN-γ, can selectively promote S. aureus outgrowth, thus subverting the composition of the healthy skin microbiome. Moreover, biofilm production by S. aureus plays a relevant role in further supporting chronic colonization and disease severity, while providing an increased tolerance to antimicrobials

Mof-associated complexes have overlapping and unique roles in regulating pluripotency in embryonic stem cells and during differentiation

The histone acetyltransferase (HAT) Mof is essential for mouse embryonic stem cell (mESC) pluripotency and early development. Mof is the enzymatic subunit of two different HAT complexes, MSL and NSL. The individual contribution of MSL and NSL to transcription regulation in mESCs is not well understood. Our genome-wide analysis show that i) MSL and NSL bind to specific and common sets of expressed genes, ii) NSL binds exclusively at promoters, iii) while MSL binds in gene bodies. Nsl1 regulates proliferation and cellular homeostasis of mESCs. MSL is the main HAT acetylating H4K16 in mESCs, is enriched at many mESC-specific and bivalent genes. MSL is important to keep a subset of bivalent genes silent in mESCs, while developmental genes require MSL for expression during differentiation. Thus, NSL and MSL HAT complexes differentially regulate specific sets of expressed genes in mESCs and during differentiation

Variability of RNA quality extracted from biofilms of foodborne pathogens using different kits impacts mRNA quantification by qPCR

The biofilm formation by foodborne pathogens is known to increase the problem related with surface disinfection procedure in the food processing environment and consequent transmission of these pathogens into the population. Messenger RNA has been increasingly used to understand the action and the consequences of disinfectants in the virulence on such biofilms. RNA quality is an important requirement for any RNA-based analysis since the quality can impair the mRNA quantification. Therefore, we evaluated five different RNA extraction kits using biofilms of the foodborne pathogens Listeria monocytogenes, Escherichia coli, and Salmonella enterica. The five kits yielded RNA with different quantities and qualities. While for E. coli the variability of RNA quality did not affect the quantification of mRNA, the same was not true for L. monocytogenes or S. enterica. Therefore, our results indicate that not all kits are suitable for RNA extraction from bacterial biofilms, and thus, the selection of RNA extraction kit is crucial to obtain accurate and meaningful mRNA quantification.AF and JCB acknowledge the financial support of individual grants SFRH/BD/62359/2009 and SFRH/BD/66250/2009, respectively. The authors acknowledge the gift of bacterial strains to Joana Azeredo and Maria Olivia Pereira.

Effectiveness of Chitosan against Mature Biofilms Formed by Food Related Bacteria

Chitosan has proven antimicrobial properties against planktonic cell growth. Little is known, however, about its effects on already established biofilms. Oriented for application in food industry disinfection, the effectiveness of both medium molecular weight (MMW) chitosan and its enzymatically hydrolyzed product was tested against mature biofilms of four pathogenic strains, Listeria monocytogenes, Bacillus cereus, Staphylococcus aureus and Salmonella enterica, and a food spoilage species, Pseudomonas fluorescens. Unexpectedly, log reductions were in some cases higher for biofilm than for planktonic cells. One hour exposure to MMW chitosan (1% w/v) caused a 6 log viable cell reduction on L. monocytogenes monospecies mature biofilms and reduced significantly (3–5 log reductions) the attached population of the other organisms tested, except S. aureus. Pronase-treated chitosan was more effective than MMW chitosan on all tested microorganisms, also with the exception of S. aureus, offering best results (8 log units) against the attached cells of B. cereus. These treatments open a new possibility to fight against mature biofilms in the food industry

Effect of systemic transplantation of bone marrow-derived mesenchymal stem cells on neuropathology markers in APP/PS1 Alzheimer mice

Mesenchymal stem cells (MSC) have recently attracted interest as a potential basis for a cell based therapy of AD. We investigated the putative immune-modulatory effects in neuroinflammation of systemic transplantation of MSC into APP/PS1 transgenic mice.10(6) MSC were injected into APP/PS1 mice via the tail vein and histological analysis was performed for microglia and amyloid (pE3-A[beta]) plaque numbers, glial distribution and pE3-A[beta] plaque size. In addition, a biochemical analysis by qPCR for pro-inflammatory, chemoattractant and neurotrophic factors was performed.MSC co-localized with pE3-A[beta] plaques. The effects of transplantation on microglia-associated pathology could be observed after 28 hours. Animals showed a reduction in microglial numbers in the cortex and in size. Gene expression was reduced for TNF-[alpha], IL-6, MCP-1, and for NGF, in MSC recipients. Also, we investigated for the first time and found no changes in expression of IL-10, CCR5, BDNF, VEGF and IFN[gamma]. PTGER2 expression levels were increased in the hippocampus but were reduced in the cortex of MSC recipients. While there were no transplant-related changes in pE3-A[beta] plaque numbers, a reduction in the size of pE3-A[beta] plaques was observed in the hippocampus of transplant recipients.This is the first study to show reduction in pE3-A[beta] plaque size. pE3-A[beta] plaques have gained attention as potential key participants in AD due to their increased aggregation propensity, the possibility for the initial seeding event, resistance against degradation and neurotoxicity. These findings support the hypothesis that MSC-transplants may affect AD pathology via an immune modulatory function that includes an effect on microglial cells