Regards d’économiste sur les défis de la santé dans les pays en voie de développement

« Nos sociétés industrielles, socialistes ou capitalistes, sont des sociétés économiques. L’économie est la forme essentielle du monde moderne et les problèmes économiques sont nos préoccupations principales. Pourtant, le vrai sens de la vie est ailleurs. Tous le savent. Tous l’oublient. Pourquoi ? » (J-P. Dupuis et P. Dumouchel, L’enfer des choses). Le sentiment qui se dégage aujourd’hui de l’abondante littérature sur la mondialisation est que le développement est redevenu, après quelques a..

Simulations and Experiments of a Nonlinear Aircraft Braking System With Physical Dispersion

International audienceThis paper deals with the simulation of nonlinear vibration induced by friction in an aircraft braking system. Experimental tests reveal that in similar experimental conditions the mechanism can generate vibrations of various amplitudes. The aim of this study is to simulate the behavior of the brake by taking into account the dispersion of parameters, which produce the variability of the response. A nonlinear model of the brake is presented. The time-history response is obtained by integration of the full set of nonlinear dynamic equations. Based on experimental results, the dispersions of the coefficient of friction and of the damping configuration are introduced. Monte Carlo simulations are performed and show a very good agreement with the experimental results

Liability in Software Engineering: Overview of the LISE Approach and Illustration on a Case Study

© ACM – 2010. This is the authors' pre-version of the work. It is posted here by permission of ACM for your personal use. Not for redistribution. The definitive version was published in the Proceedings of the 32nd ACM/IEEE international Conference on Software Engineering (ICSE'10) - Volume 1 – 978-1-60558-719-6/10/05 – (May 2-8 – 2010) http://doi.acm.org/10.1145/1806799.1806823LISE is a multidisciplinary project involving lawyers and computer scientists with the aim to put forward a set of methods and tools to (1) define software liability in a precise and unambiguous way and (2) establish such liability in case of incident. This report provides an overview of the overall approach taken in the project based on a case study. The case study illustrates a situation where, in order to reduce legal uncertainties, the parties to a contract wish to include in the agreement specific clauses to define as precisely as possible the share of liabilities between them for the main types of failures of the system

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Common breast cancer susceptibility alleles are associated with tumor subtypes in BRCA1 and BRCA2 mutation carriers : results from the Consortium of Investigators of Modifiers of BRCA1/2.

Abstract Introduction Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. Methods We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. Results The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. Conclusions The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers

Nonlinear transient vibrations and coexistences of multi-instabilities induced by friction in an aircraft braking system

International audienceFriction-induced vibration is still a cause for concern in a wide variety of mechanical systems, because it can lead to structural damage if high vibration levels are reached. Another effect is the noise produced that can be very unpleasant for end-users, thereby making it a major problem in the field of terrestrial transport. In this work the case of an aircraft braking system is examined. An analytical model with polynomial nonlinearity in the contact between rotors and stators is considered. Stability analysis is commonly used to evaluate the capacity of a nonlinear system to generate friction-induced vibrations. With this approach, the effects of variations in the system parameters on stability can be easily estimated. However, this technique does not give the amplitude of the vibrations produced. The integration of the full set of nonlinear dynamic equations allows computing the time-history response of the system when vibration occurs. This technique, which can be time-consuming for a model with a large number of degrees of freedom (dof), is nevertheless necessary in order to calculate the transient-state behavior of the system. The use of a continuous wavelet transform (CWT) is very suitable for the detailed analysis of the transient response. In this paper, the possibilities of coexistence of several instabilities at the same time will be examined. It will be shown that the behavior of the brake can be very complex and cannot be predicted by stability analysis alone

Guaranteed Characterization of Capture Basins of Nonlinear State-Space Systems

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Lysine Trimethylation in Planktonic and Pellicle Modes of Growth in Acinetobacter baumannii

International audienceOver the past 30 years, Acinetobacter baumannii has been described as an important nosocomial pathogen due to frequent ventilator-associated infections. Many biological processes of A. baumannii remain elusive, such as the formation of an air-liquid biofilm (pellicle). Several studies demonstrated the importance of post-translational modifications (PTM) in A. baumannii physiology. Here, we investigated K-trimethylation in A. baumannii ATCC 17978 in planktonic and pellicle modes using proteomic analysis. To identify the most high-confidence K-trimethylated peptides, we compared different sample preparation methods (i.e. Strong cation exchange, antibody-capture) and processing software (i.e. different database search engines). We identified, for the first time, 84 K-trimethylated proteins, many of which are involved in DNA and protein synthesis (HupB, RplK), transporters (Ata, AdeB) or lipid metabolism processes (FadB, FadD). In comparison with previous studies, several identical lysine residues were observed acetylated or trimethylated, indicating the presence of proteoforms and potential PTM cross-talks. This is the first large-scale proteomic study of trimethylation in A. baumannii and will be an important resource for the scientific community (availability in Pride repository under accession PXD035239)