Effets du chargement et de la microstructure sur la propagation de fissures dans le plan transverse d'un bois résineux

Cette étude a pour objectif d'analyser et de modéliser finement la propagation de fissure dans le plan transverse d'un bois résineux. Il s'agit de prendre en compte le caractère fortement hétérogène et anisotrope du bois (succession radiale des cernes de croissance) dans le cheminement des fissures. Les critères de rupture sont construits en conséquence. Le caractère naturel du matériau ainsi que la complexité du phénomène étudié oblige à recourir à la simulation numérique pour confronter et valider les critères proposés. Plusieurs expériences de propagation avec différentes orientations du chargement par rapport aux directions naturelles du bois sous chargement statique ainsi que sous chargement dynamique ont été menés. Les résultats obtenus montrent que l'on reproduit convenablement les chemins de propagation observés. En revanche les modèles proposés ne sont pas encore capables de reproduire les fissurations multiples souvent présentes expérimentalement

In Vivo Evolution of Bacterial Resistance in Two Cases of Enterobacter aerogenes Infections during Treatment with Imipenem

International audienceInfections caused by multidrug resistant (MDR) bacteria are a major concern worldwide. Changes in membrane permeability, including decreased influx and/or increased efflux of antibiotics, are known as key contributors of bacterial MDR. Therefore, it is of critical importance to understand molecular mechanisms that link membrane permeability to MDR in order to design new antimicrobial strategies. In this work, we describe genotype-phenotype correlations in Enterobacter aerogenes, a clinically problematic and antibiotic resistant bacterium. To do this, series of clinical isolates have been periodically collected from two patients during chemotherapy with imipenem. The isolates exhibited different levels of resistance towards multiple classes of antibiotics, consistently with the presence or the absence of porins and efflux pumps. Transport assays were used to characterize membrane permeability defects. Simultaneous genome-wide analysis allowed the identification of putative mutations responsible for MDR. The genome of the imipenem-susceptible isolate G7 was sequenced to closure and used as a reference for comparative genomics. This approach uncovered several loci that were specifically mutated in MDR isolates and whose products are known to control membrane permeability. These were omp35 and omp36, encoding the two major porins; rob, encoding a global AraC-type transcriptional activator; cpxA, phoQ and pmrB, encoding sensor kinases of the CpxRA, PhoPQ and PmrAB two-component regulatory systems, respectively. This report provides a comprehensive analysis of membrane alterations relative to mutational steps in the evolution of MDR of a recognized nosocomial pathogen

Exome sequencing identifies germline variants in DIS3 in familial multiple myeloma

[Excerpt] Multiple myeloma (MM) is the third most common hematological malignancy, after Non-Hodgkin Lymphoma and Leukemia. MM is generally preceded by Monoclonal Gammopathy of Undetermined Significance (MGUS) [1], and epidemiological studies have identified older age, male gender, family history, and MGUS as risk factors for developing MM [2]. The somatic mutational landscape of sporadic MM has been increasingly investigated, aiming to identify recurrent genetic events involved in myelomagenesis. Whole exome and whole genome sequencing studies have shown that MM is a genetically heterogeneous disease that evolves through accumulation of both clonal and subclonal driver mutations [3] and identified recurrently somatically mutated genes, including KRAS, NRAS, FAM46C, TP53, DIS3, BRAF, TRAF3, CYLD, RB1 and PRDM1 [3,4,5]. Despite the fact that family-based studies have provided data consistent with an inherited genetic susceptibility to MM compatible with Mendelian transmission [6], the molecular basis of inherited MM predisposition is only partly understood. Genome-Wide Association (GWAS) studies have identified and validated 23 loci significantly associated with an increased risk of developing MM that explain ~16% of heritability [7] and only a subset of familial cases are thought to have a polygenic background [8]. Recent studies have identified rare germline variants predisposing to MM in KDM1A [9], ARID1A and USP45 [10], and the implementation of next-generation sequencing technology will allow the characterization of more such rare variants. [...]French National Cancer Institute (INCA) and the Fondation Française pour la Recherche contre le Myélome et les Gammapathies (FFMRG), the Intergroupe Francophone du Myélome (IFM), NCI R01 NCI CA167824 and a generous donation from Matthew Bell. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank the Association des Malades du Myélome Multiple (AF3M) for their continued support and participation. Where authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organizatio

A unique peptide deformylase platform to rationally design and challenge novel active compounds

International audiencePeptide deformylase (PDF) is considered an excellent target to develop antibiotics. We have performed an extensive characterization of a new PDF from the pathogen Streptococcus agalactiae, showing properties similar to other known PDFs. S. agalactiae PDF could be used as PDF prototype as it allowed to get complete sets of 3-dimensional, biophysical and kinetic data with virtually any inhibitor compound. Structure-activity relationship analysis with this single reference system allowed us to reveal distinct binding modes for different PDF inhibitors and the key role of a hydrogen bond in potentiating the interaction between ligand and target. We propose this protein as an irreplaceable tool, allowing easy and relevant fine comparisons between series, to design, challenge and validate novel series of inhibitors. As proof-of-concept, we report here the design and synthesis of effective specific bacterial PDF inhibitors of an oxadiazole series with potent antimicrobial activity against a multidrug resistant clinical isolate

Features of the G7 genome.

<p>CDS, coding sequences; ICE, integrative and conjugative element; IS, insertion sequence. * Data refer to the chromosome only, except when plasmids are indicated.</p

Hoechst 33342 influx into <i>E</i>. <i>aerogenes</i> strains.

<p>Strains were grown in LB broth and cells were harvested at the beginning of the stationary phase. Cells were washed, resuspended in PPB pH 7.0, and the H33342 influx was assayed in the presence of 50 μM CCCP. A. Chemical structure of H33342. B. Kinetics of H33342 influx. AU, arbitrary units. C. Total accumulation in <i>E</i>. <i>aerogenes</i> isolates after normalization to that of strain ATCC15038. All values are means of at least three independent experiments.</p

Summary of genome analysis.

<p>Summary of genome analysis.</p