318 research outputs found
Role of Varicella Zoster virus ORF9p in the secondary egress : importance of its interaction with the cellular Adaptin Protein-1.
Seismic structure and activity of the north-central Lesser Antilles subduction zone from an integrated approach: similarities with the Tohoku forearc
The 300 km long north-central segment of the Lesser Antilles subduction zone, including Martinique and Guadeloupe islands has been the target of a specific approach to the seismic structure and activity by a cluster of active and passive offshore-onshore seismic experiments coordinated within the ¿Thales was right¿ proposal to the European Union action (Laigle et al., Tectonophys., in rev.) The top of the subducting plate can be followed under the wide accretionary wedge by a dense grid of dip- and strike-lines of multichannel reflection seismics. This reveals the hidden updip limit of the contact of the upper plate crustal backstop thrust onto the slab. Two OBS refraction seismic profiles constrained a 26 km large crustal thickness from the volcanic arc throughout the forearc domain (Kopp et al., EPSL, 2011). These new observations imply a three times larger width of the potential interplate seismogenic zone under the marine domain of the Caribbean plate with respect to a regular intra-oceanic subduction zone, in the common assumption that the upper plate Moho contact on the slab is a proxy of its downdip limit. Towards larger depth under the mantle corner, the top of the slab imaged from the conversions of teleseismic body-waves and the locations of earthquakes from the dense temporary array of 80 OBS and land seismometers appears with kinks which increase the dip from 10-20° under the forearc domain, to 60° on the segment from 70 km depth down to under the volcanic arc. There, at 140 km depth just north of Martinique the 2007 M 7.4 earthquake, largest for half a century, was accompanied by an increased seismic activity over the whole depth range, which provides a new focused image thanks to the OBS and land deployments. A double-planed dipping slab seismicity is thus now resolved, as originally discovered in Tohoku ( NE Japan) and since in some other subduction zones. Other types of seismic activity uniquely observed in Tohoku, are resolved now here, such as ¿supraslab¿ earthquakes with normal-faulting focal mechanisms reliably located in the mantle corner and ¿deep flat-thrust¿ earthquakes at 45 km depth on the interplate fault under the Caribbean plate forearc mantle. None such types of seismicity should occur under the paradigm of a regular peridotitic mantle of the upper plate which is serpentinized by the fluids provided from the dehydrating slab beneath, and which is commonly considered as limiting the downward extent of the interplate seismic coupling. If the upper plate here comprised lithospheric segments related to the earlier formation of the Caribbean oceanic plateau by the material advection from a mantle plume, it could then be underlain by a correspondingly modified, heterogeneous mantle, which may impose regions of stick-slip behaviour on the interplate under the mantle corner among stable-gliding areas. The Tohoku 2011 M9 earthquake was unexpected not only in its slip reaching to the trench, but also in its slip reaching far under the mantle corner against the serpentinization decoupling paradigm, and its structural setting may be revisited for resolving corresponding structural heterogeneityPeer Reviewe
A multi-site campaign to measure solar-like oscillations in Procyon. II. Mode frequencies
We have analyzed data from a multi-site campaign to observe oscillations in
the F5 star Procyon. The data consist of high-precision velocities that we
obtained over more than three weeks with eleven telescopes. A new method for
adjusting the data weights allows us to suppress the sidelobes in the power
spectrum. Stacking the power spectrum in a so-called echelle diagram reveals
two clear ridges that we identify with even and odd values of the angular
degree (l=0 and 2, and l=1 and 3, respectively). We interpret a strong, narrow
peak at 446 muHz that lies close to the l=1 ridge as a mode with mixed
character. We show that the frequencies of the ridge centroids and their
separations are useful diagnostics for asteroseismology. In particular,
variations in the large separation appear to indicate a glitch in the
sound-speed profile at an acoustic depth of about 1000 s. We list frequencies
for 55 modes extracted from the data spanning 20 radial orders, a range
comparable to the best solar data, which will provide valuable constraints for
theoretical models. A preliminary comparison with published models shows that
the offset between observed and calculated frequencies for the radial modes is
very different for Procyon than for the Sun and other cool stars. We find the
mean lifetime of the modes in Procyon to be 1.29 +0.55/-0.49 days, which is
significantly shorter than the 2-4 days seen in the Sun.Comment: accepted for publication in Ap
Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly.
International audienceThe genetic causes of malformations of cortical development (MCD) remain largely unknown. Here we report the discovery of multiple pathogenic missense mutations in TUBG1, DYNC1H1 and KIF2A, as well as a single germline mosaic mutation in KIF5C, in subjects with MCD. We found a frequent recurrence of mutations in DYNC1H1, implying that this gene is a major locus for unexplained MCD. We further show that the mutations in KIF5C, KIF2A and DYNC1H1 affect ATP hydrolysis, productive protein folding and microtubule binding, respectively. In addition, we show that suppression of mouse Tubg1 expression in vivo interferes with proper neuronal migration, whereas expression of altered Îł-tubulin proteins in Saccharomyces cerevisiae disrupts normal microtubule behavior. Our data reinforce the importance of centrosomal and microtubule-related proteins in cortical development and strongly suggest that microtubule-dependent mitotic and postmitotic processes are major contributors to the pathogenesis of MCD
PĂ©rigord black truffle genome uncovers evolutionary origins and mechanisms of symbiosis
LetterInternational audienceThe PĂ©rigord black truffle ( Vittad.) and the Piedmont white truffle dominate today's truffle market. The hypogeous fruiting body of is a gastronomic delicacy produced by an ectomycorrhizal symbiont endemic to calcareous soils in southern Europe. The worldwide demand for this truffle has fuelled intense efforts at cultivation. Identification of processes that condition and trigger fruit body and symbiosis formation, ultimately leading to efficient crop production, will be facilitated by a thorough analysis of truffle genomic traits. In the ectomycorrhizal , the expansion of gene families may have acted as a 'symbiosis toolbox'. This feature may however reflect evolution of this particular taxon and not a general trait shared by all ectomycorrhizal species. To get a better understanding of the biology and evolution of the ectomycorrhizal symbiosis, we report here the sequence of the haploid genome of , which at 125âmegabases is the largest and most complex fungal genome sequenced so far. This expansion results from a proliferation of transposable elements accounting for 58% of the genome. In contrast, this genome only contains 7,500 protein-coding genes with very rare multigene families. It lacks large sets of carbohydrate cleaving enzymes, but a few of them involved in degradation of plant cell walls are induced in symbiotic tissues. The latter feature and the upregulation of genes encoding for lipases and multicopper oxidases suggest that degrades its host cell walls during colonization. Symbiosis induces an increased expression of carbohydrate and amino acid transporters in both and , but the comparison of genomic traits in the two ectomycorrhizal fungi showed that genetic predispositions for symbiosis 'the symbiosis toolbox' evolved along different ways in ascomycetes and basidiomycete
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 HRâ=â0.85, 95% CI 0.80-0.90, Pâ=â3.9Ă10â8). 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
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 Ă 10-20), ER-negative BC (P=1.1 Ă 10-13), BRCA1-associated BC (P=7.7 Ă 10-16) and triple negative BC (P-diff=2 Ă 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 Ă 10-3) and ABHD8 (P<2 Ă 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 3âČ-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
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
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 FANCMâ/â 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
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 = 2.7Ă10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4Ă10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4Ă10-8, 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
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