A random testing approach using pushdown automata

International audienceSince finite automata are in general strong abstractions of systems, many test cases which are automata traces generated uniformly at ran-dom, may be un-concretizable. This paper proposes a method extending the abovementioned testing approach to pushdown systems providing finer abstractions. Using combinatorial techniques guarantees the uniformity of generated traces. In addition, to improve the quality of the test suites, the combination of coverage criteria with random testing is investigated. The method is illustrated within both structural and model-based testing contexts

L'acacia au Sénégal

Cette présentation propose une revue bibliographique de certains aspects de la nodulation des acacias, en particulier en ce qui concerne la diversité des rhizobiums qui leur sont associés, au regard de la taxonomie générale des rhizobiums, et développe plus en détails les derniers résultats obtenus au Sénégal dans ce domaine. (Résumé d'auteur

Nod factors thin-layer chromatography profiling as a tool to characterize symbiotic specificity of rhizobial strains : application to Sinorhizobium saheli, S. teranga, and Rhizobium sp. strains isolated from Acacia and Sesbania

Rhizobia isolated from #Acacia or #Sesbania belong to several taxonomic groups, including the newly described species #Sinorhizobium saheli, #Sinorhizobium teranga, and the so-called cluster U. A collection of strains belonging to these different groups was analyzed in order to determine whether the host range of a strain could be correlated with various molecular nodulation determinants. Nodulation tests showed that, independently of their taxonomic position, all the strains isolated from the same plant genus exhibited a similar host range, which was different for #Sesbania and #Acacia isolates. The fact that #S. teranga strains nodulate either #Acacia or #Sesbania led us to subdivide this species into biovars #acaciae and #sesbaniae. Thin-layer chromatography (TLC) analysis of the Nod factors synthesized by overproducing strains showed that strains isolated from the same plant genus exhibited similar TLC profiles and profiles of #Acacia and #Sesbania symbionts were easily distinguishable, #Acacia strains producing, in particular, sulfated molecules. In contrast, no correlation could be established between the host range of a strain and its plasmid content, the nature of the nod gene inducers or the presence of DNA sequences homologous to specific nod genes. We thus propose that Nod factor TLC profiling may be used as an easy and powerful tool for the classification of rhizobial strains on the basis of their symbiotic properties. (Résumé d'auteur

L'acacia au Sénégal

L'intérêt agronomique et écologique des rhizobiums repose essentiellement sur leurs propriétés symbiotiques. Il est donc capital de pouvoir apprécier la diversité des souches sur la base de leur pouvoir de nodulation. L'objectif de ce travail est de proposer une nouvelle approche, alternative aux tests de nodulation, permettant de classer les souches en fonction de leur spécificité symbiotique. Au cours des premières étapes de l'interaction rhizobium-légumineuses, les rhizobiums excrètent des molécules signal, appelées facteurs Nod, qui jouent un rôle déterminant dans l'infection et la nodulation des plantes-hôtes. Leur utilisation potentielle comme marqueur de la spécificité de nodulation a été évaluée à partir de l'étude d'une collection de souches isolées d'#Acacia et de #Sesbania au Sénégal. L'analyse chromatographique des facteurs Nod de ces souches a montré que les profils chromatographiques sont parfaitement corrélés à la fois à la structure chimique des facteurs Nod et à la spécificité d'hôte des souches, et plus particulièrement à la plante d'isolement. Une telle méthode de caractérisation globale des facteurs Nod pourrait donc être utilisée pour la caractérisation symbiotique des rhizobiums, en particulier pour l'étude taxonomique, l'étude de la biodiversité des souches ou pour le contrôle des inoculums. (Résumé d'auteur

Molecular study of the perforin gene in familial hematological malignancies

Perforin gene (PRF1) mutations have been identified in some patients diagnosed with the familial form of hemophagocytic lymphohistiocytosis (HLH) and in patients with lymphoma. The aim of the present study was to determine whether patients with a familial aggregation of hematological malignancies harbor germline perforin gene mutations. For this purpose, 81 unrelated families from Tunisia and France with aggregated hematological malignancies were investigated. The variants detected in the PRF1 coding region amounted to 3.7% (3/81). Two of the three variants identified were previously described: the p.Ala91Val pathogenic mutation and the p.Asn252Ser polymorphism. A new p.Ala 211Val missense substitution was identified in two related Tunisian patients. In order to assess the pathogenicity of this new variation, bioinformatic tools were used to predict its effects on the perforin protein structure and at the mRNA level. The segregation of the mutant allele was studied in the family of interest and a control population was screened. The fact that this variant was not found to occur in 200 control chromosomes suggests that it may be pathogenic. However, overexpression of mutated PRF1 in rat basophilic leukemia cells did not affect the lytic function of perforin differently from the wild type protein

The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations

International audienceBACKGROUND:Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers.METHODS:Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort.RESULTS:For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, P trend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort P trend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98).CONCLUSIONS:These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers

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

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