Distributed archive and single access system for accelerometric event data : a NERIES initiative

We developed a common access facility to homogeneously formatted accelerometric event data and to the corresponding sheet of ground motion parameters. This paper is focused on the description of the technical development of the accelerometric data server and the link with the accelerometric data explorer. The server is the third node of the 3-tier architecture of the distributed archive system for accelerometric data. The server is the link between the data users and the accelero- metric data portal. The server follows three main steps: (1) Reading and analysis of the end-user request; (2) Processing and converting data; and (3) Archiving and updating the accelerometric data explorer. This paper presents the description of the data server and the data explorer for accessing data

TP53 transcription factor for the NEDD9/HEF1/Cas-L gene: potential targets in Non-Small Cell Lung Cancer treatment

International audienceLung cancer is a serious public health problem. Although there has been significant progress in chemotherapy, non-small cell lung cancer is still resistant to current treatments, primarily because of the slow rate of cell development. It is thus important to find new molecules directed against targets other than proliferation agents. Considering the high proportion of mutant proteins in tumor cells, and the high rate of mutation of the TP53 gene in all cancers, and in NSCLC in particular, this gene is a perfect target. Certain new molecules have been shown to restore the activity of mutated p53 protein, for example PRIMA-1, which reactivates the His273 mutant p53. In a previous study, we presented triazine A190, a molecule with a cytostatic activity that blocks cells in the G1 phase and induces apoptosis. Here, we show that A190 not only restores mutant p53 activity, but also induces an overexpression of the NEDD9 gene, leading to apoptotic death. These findings might offer hope for the development of new targeted therapies, specific to tumor cells, which spare healthy cell

The hypothalamopituitary-adrenal axis and alcohol preference

Abstract Effects of alterations in stress hormones and their actions were investigated on alcohol preference, by intraperitoneal administration of RU38486 (a Type II glucocorticoid receptor antagonist, also given by the intracerebroventricular route), spironolactone (a Type I glucocorticoid receptor antagonist), metyrapone (a corticosterone synthesis inhibitor), corticosterone, adrenocorticotropin (ACTH1-39), or intracerebroventricular injection of corticotropin releasing factor (CRF) or a CRF antagonist (alpha-helical CRF9-41). Intracerebroventricular or intraperitoneal administration of RU38486 did not alter the alcohol consumption of mice with high preference for alcohol, or, on first administration, the intake of those with low alcohol preference. When given by repeated intraperitoneal injection however this drug prevented the increase in alcohol consumption seen in "low preference" mice after 3 weeks vehicle injections. Spironolactone did not alter alcohol preference when given by intracerebroventricular or intraperitoneal routes. Repeated, but not single, administration of metyrapone reduced alcohol preference in both high and low preference animals and prevented the increase from low alcohol preference caused by repeated vehicle injections. ACTH1-39 or corticosterone administered by single or repeated intraperitoneal injection, or CRF given i.c.v., did not alter alcohol preference, but the CRF antagonist, alpha-helical CRF9-41, caused a transient increase from low alcohol preference. Blood corticosterone concentrations prior to preference measurements did not correlate with the alcohol preference of the mice. The results indicate that delayed consequences of corticosterone acting on Type II glucocorticoid receptors may be involved in the increases in alcohol preference after injection stress. They also suggest that central actions of CRF may influence the low alcohol consumption of the low alcohol-preferring mice

Modelling the porewater chemistry of the Callovian–Oxfordian formation at a regional scale

International audienceIn ANDRA's studies to characterize the Callovian-Oxfordian formation, porewater chemistry is a key topic. Indeed, chemistry determines the durability of the repository materials (bentonite, concrete, metals, nuclear glass) and the speciation (and thus the mobility) of radionuclides. The method developed in the frame of the THERMOAR project enables the acquisition of a complete set of data from core samples to model the porewater chemistry. The method requires a detailed mineralogical study, a model of free-water/bound-water distribution, leaching experiments, adsorbed ion measurements, ion-exchange constant acquisition, and CO2 partial-pressure measurements. These experiments and measurements were done on samples from the site of the Meuse/Haute-Marne laboratory and from ANDRA's regional boreholes. The regional stability of a great number of parameters can be observed, except for a decrease of the Na and Cl concentration following a NE-SW axis passing through the laboratory. The water/rock equilibrium model makes it possible to calculate the chemical composition of interstitial waters of the formation

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article