Reversible Rail Shear Apparatus Applied to the Study of Woven Laminate Shear Behavior

The multitude of in-plane shear tests existing in the literature seems to demonstrate the complexity of developing a test adapted to all experimental works. In a general framework of investigation of translaminar cracks in thin laminates, a test able to reproduce a pure in-plane shear loading was required. The laminate studied is notably employed as helicopter blade skin, and cyclic torsion induced by aerodynamic load involves cyclic in-plane shear. This particular application established some specifications for the test needed to carry out this study. To comply with them, an original technological solution has been developed from a three-rail shear test apparatus. This paper describes the resulting “reversible rail shear test” solution and its application to the study of in-plane shear behavior of a thin glass-epoxy laminate. The results concern plain and notched coupons under quasi-static loading, and crack growth tests under cyclic loading

The full-scale avalanche test site, Lautaret, France

The Lautaret full-scale avalanche test site in the southern French Alps has been used by IRSTEA (Cemagref) Research Institute since 1973. Over the recent years two avalanche paths are used to release small to medium avalanches 3 or 4 times each winter. Avalanche flows are generally dense, whether wet or dry, sometimes with a powder part. Main path n°2 (track length 800 m) is dedicated to avalanche dynamics. Within the flow of the avalanche, flow height and vertical profiles of pressure and velocity are measured along a 3.5 m tripod. The snow volume released in the starting zone is quantified by a differential analysis of laser scanning measurements set before and after triggering. A high rate positioning of the avalanche along the track is determined from terrestrial oblique photogrammetry. Above the dense layer, the saltation layer and the powder part are characterized by particles and air fluxes measurements. In path n°1 smaller in size, medium-size avalanches (track length 500 m) make this track of particular interest for experiments on structures. A macroscopic sensor-structure is set nearly 150 m downhill from the starting zone, that is, in the area where avalanches generally reach their maximum velocity. It consists is a one square-meter plate supported by a 3.5 m high steel cantilever fixed in the ground, facing the avalanche. Impact pressures are reconstructed from the cantilever deformations, while avalanche velocity is measured from optical sensors. Seismic signals generated by avalanches of those 2 paths are recorded by a 3-axial broadband seismometer. Around those experimental devices dedicated to the understanding of avalanche physics, a national and international partnership has been developed from years to years, including INSA de Lyon, CNRS and Université Joseph Fourier (France), Aalto University (Finland), Nagoya University (Japan), Boku University (Austria), IGEMA (Bolivia), OGS (Italy)PublishedGrenoble, France3.8. Geofisica per l'ambienteope

Expression and implication of clusterin in left ventricular remodeling after myocardial infarction

International audienceBACKGROUND: Left ventricular remodeling (LVR) after myocardial infarction is associated with an increased risk of heart failure and death. In spite of a modern therapeutic approach, LVR remains relatively frequent and difficult to predict in clinical practice. Our aim was to identify new biomarkers of LVR and understand their involvement in its development.METHODS AND RESULTS:Proteomic analysis of plasma from the REVE-2 study (Remodelage Ventriculaire)-a study dedicated to the analysis of LVR which included 246 patients after a first anterior myocardial infarction-identified increased plasma levels of CLU (clusterin) in patients with high LVR. We used a rat model of myocardial infarction to analyze CLU expression in the LV and found a significant increase that was correlated with LVR parameters. We found increased CLU expression and secretion in primary cultures of rat neonate cardiomyocytes hypertrophied by isoproterenol. Silencing of CLU in hypertrophied neonate cardiomyocytes induced a significant decrease in cell size, ANP (atrial natriuretic peptide), and BNP (B-type natriuretic peptide) expression, associated with a decreased ERK (extracellular signal-regulated kinase) 1/2 activity, suggesting a prohypertrophic role of CLU. We then confirmed a significant increase of both intracellular p-CLU (precursor form of CLU) and m-CLU (mature form of CLU) in failing human hearts. Finally, the circulating levels of CLU (secreted form) were increased in patients with chronic heart failure who died from cardiovascular cause during a 3-year follow-up (n=99) compared with survivors (n=99).CONCLUSIONS: Our results show for the first time that plasma CLU levels are associated with LVR post-myocardial infarction, have in part a cardiac origin, and are a predictor of early death in heart failure patients

The high-mobility bended n-channel silicon nanowire transistor

This work demonstrates a method for incorporating strain in silicon nanowire gate-all-around (GAA) n-MOSFETs by oxidation-induced bending of the nanowire channel and reports on the resulting improvement in device performance. The variation in strain measured during processing is discussed. The strain profile in silicon nanowires is evaluated by Raman spectroscopy both before device gate stack fabrication (tensile strains of up to 2.5% are measured) and by measurement through the polysilicon gate on completed electrically characterized devices. Drain current boosting in bended n-channels is investigated as a function of the transistor operation regime, and it is shown that the enhancement depends on the effective electrical field. The maximum observed electron mobility enhancement is on the order of 100% for a gate bias near the threshold voltage. Measurements of stress through the full gate stack and experimental device characteristics of the same transistor reveal a stress of 600 MPa and corresponding improvements of the normalized drain current, normalized transconductance, and low-field mobility by 34% (at maximum gate overdrive), 50% (at g max), and 53%, respectively, compared with a reference nonstrained device at room temperature. Finally, it is found that, at low temperatures, the low-field mobility is much higher in bended devices, compared with nonbended devices

Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy.

OBJECTIVE: To improve the genetic diagnosis of dominant optic atrophy (DOA), the most frequently inherited optic nerve disease, and infer genotype-phenotype correlations. METHODS: Exonic sequences of 22 genes were screened by new-generation sequencing in patients with DOA who were investigated for ophthalmology, neurology, and brain MRI. RESULTS: We identified 7 and 8 new heterozygous pathogenic variants in SPG7 and AFG3L2. Both genes encode for mitochondrial matricial AAA (m-AAA) proteases, initially involved in recessive hereditary spastic paraplegia type 7 (HSP7) and dominant spinocerebellar ataxia 28 (SCA28), respectively. Notably, variants in AFG3L2 that result in DOA are located in different domains to those reported in SCA28, which likely explains the lack of clinical overlap between these 2 phenotypic manifestations. In comparison, the SPG7 variants identified in DOA are interspersed among those responsible for HSP7 in which optic neuropathy has previously been reported. CONCLUSIONS: Our results position SPG7 and AFG3L2 as candidate genes to be screened in DOA and indicate that regulation of mitochondrial protein homeostasis and maturation by m-AAA proteases are crucial for the maintenance of optic nerve physiology

Alteration of ribosome function upon 5-fluorouracil treatment favors cancer cell drug-tolerance.

Mechanisms of drug-tolerance remain poorly understood and have been linked to genomic but also to non-genomic processes. 5-fluorouracil (5-FU), the most widely used chemotherapy in oncology is associated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNA pathways. Here, we show that 5-FU treatment leads to the production of fluorinated ribosomes exhibiting altered translational activities. 5-FU is incorporated into ribosomal RNAs of mature ribosomes in cancer cell lines, colorectal xenografts, and human tumors. Fluorinated ribosomes appear to be functional, yet, they display a selective translational activity towards mRNAs depending on the nature of their 5'-untranslated region. As a result, we find that sustained translation of IGF-1R mRNA, which encodes one of the most potent cell survival effectors, promotes the survival of 5-FU-treated colorectal cancer cells. Altogether, our results demonstrate that "man-made" fluorinated ribosomes favor the drug-tolerant cellular phenotype by promoting translation of survival genes

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