Concerted Regulation of cGMP and cAMP Phosphodiesterases in Early Cardiac Hypertrophy Induced by Angiotensin II

Left ventricular hypertrophy leads to heart failure and represents a high risk leading to premature death. Cyclic nucleotides (cAMP and cGMP) play a major role in heart contractility and cyclic nucleotide phosphodiesterases (PDEs) are involved in different stages of advanced cardiac diseases. We have investigated their contributions in the very initial stages of left ventricular hypertrophy development. Wistar male rats were treated over two weeks by chronic infusion of angiotensin II using osmotic mini-pumps. Left cardiac ventricles were used as total homogenates for analysis. PDE1 to PDE5 specific activities and protein and mRNA expressions were explored

Mild replication stress causes chromosome mis-segregation via premature centriole disengagement

Replication stress, a hallmark of cancerous and pre-cancerous lesions, is linked to structuralchromosomal aberrations. Recent studies demonstrated that it could also lead to numericalchromosomal instability (CIN). The mechanism, however, remains elusive. Here, we showthat inducing replication stress in non-cancerous cells stabilizes spindle microtubules andfavours premature centriole disengagement, causing transient multipolar spindles that lead tolagging chromosomes and micronuclei. Premature centriole disengagement depends on theG2 activity of the Cdk, Plk1 and ATR kinases, implying a DNA-damage induced deregulationof the centrosome cycle. Premature centriole disengagement also occurs spontaneously insome CIN+cancer cell lines and can be suppressed by attenuating replication stress. Finally,we show that replication stress potentiates the effect of the chemotherapeutic agent taxol, byincreasing the incidence of multipolar cell divisions. We postulate that replication stress incancer cells induces numerical CIN via transient multipolar spindles caused by prematurecentriole disengagement

Design et Transmédia : le croisement des disciplines de SHS

Cette dixième livraison de la revue RFSIC propose un dossier Design et Transmédia. Ce dossier est important car il s’inscrit délibérément dans le croisement de notre discipline avec un autre secteur : le Design. Il est vrai que tous les objets communiquent, particulièrement les objets construits, comme ceux de l’architecture, parfois au sens le plus trivial du terme. Que l’on pense, par exemple, à la tour Burj Khalifa à Dubaï. Comme à l’hôtel Bellagio à Las Vegas, la société WET Design a installé un système de fontaines qui s’animent lors des spectacles façon son et lumière. Toutes les demi-heures à partir de 18 h, ces fontaines se mettent à danser, sur une longueur de 275 mètres et sur une hauteur pouvant atteindre 150 mètres. Le spectacle est différent à chaque fois par ses mouvements, ses couleurs et ses musiques : un air d’opéra interprété par Andrea Bocelli, un chant oriental ou une chanson swahili… [en savoir +

Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel

International audienceTo date, most BC GWASs have been performed Background Polygenic risk score (PRS), calculated in individuals of European (EUR) ancestry, and based on genome-wide association studies (GWASs), the generalisation of EUR-based PRS to other can improve breast cancer (BC) risk assessment. populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. Methods We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. Results In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). Conclusions Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women

Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry.

BACKGROUND: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. METHODS: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. RESULTS: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10-6) and AC058822.1 (P = 1.47 × 10-4), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C. CONCLUSIONS: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10-5), demonstrating the importance of diversifying study cohorts