965 research outputs found
Germline DNA Repair Gene Mutations in Young-onset Prostate Cancer Cases in the UK: Evidence for a More Extensive Genetic Panel
Background
Rare germline mutations in DNA repair genes are associated with prostate cancer (PCa) predisposition and prognosis.
Objective
To quantify the frequency of germline DNA repair gene mutations in UK PCa cases and controls, in order to more comprehensively evaluate the contribution of individual genes to overall PCa risk and likelihood of aggressive disease.
Design, setting, and participants
We sequenced 167 DNA repair and eight PCa candidate genes in a UK-based cohort of 1281 young-onset PCa cases (diagnosed at â¤60 yr) and 1160 selected controls.
Outcome measurements and statistical analysis
Gene-level SKAT-O and gene-set adaptive combination of p values (ADA) analyses were performed separately for cases versus controls, and aggressive (Gleason score âĽ8, n = 201) versus nonaggressive (Gleason score â¤7, n = 1048) cases.
Results and limitations
We identified 233 unique protein truncating variants (PTVs) with minor allele frequency <0.5% in controls in 97 genes. The total proportion of PTV carriers was higher in cases than in controls (15% vs 12%, odds ratio [OR] = 1.29, 95% confidence interval [CI] 1.01â1.64, p = 0.036). Gene-level analyses selected NBN (pSKAT-O = 2.4 Ă 10â4) for overall risk and XPC (pSKAT-O = 1.6 Ă 10â4) for aggressive disease, both at candidate-level significance (p < 3.1 Ă 10â4 and p < 3.4 Ă 10â4, respectively). Gene-set analysis identified a subset of 20 genes associated with increased PCa risk (OR = 3.2, 95% CI 2.1â4.8, pADA = 4.1 Ă 10â3) and four genes that increased risk of aggressive disease (OR = 11.2, 95% CI 4.6â27.7, pADA = 5.6 Ă 10â3), three of which overlap the predisposition gene set.
Conclusions
The union of the gene-level and gene-set-level analyses identified 23 unique DNA repair genes associated with PCa predisposition or risk of aggressive disease. These findings will help facilitate the development of a PCa-specific sequencing panel with both predictive and prognostic potential.
Patient summary
This large sequencing study assessed the rate of inherited DNA repair gene mutations between prostate cancer patients and disease-free men. A panel of 23 genes was identified, which may improve risk prediction or treatment pathways in future clinical practice
The Hubble Constant from Observations of the Brightest Red Giant Stars in a Virgo-Cluster Galaxy
The Virgo and Fornax clusters of galaxies play central roles in determining
the Hubble constant H_0. A powerful and direct way of establishing distances
for elliptical galaxies is to use the luminosities of the brightest red-giant
stars (the TRGB luminosity, at M_I = -4.2). Here we report the direct
observation of the TRGB stars in a dwarf elliptical galaxy in the Virgo
cluster. We find its distance to be 15.7 +- 1.5 Megaparsecs, from which we
estimate a Hubble constant of H_0 = 77 +- 8 km/s/Mpc. Under the assumption of a
low-density Universe with the simplest cosmology, the age of the Universe is no
more than 12-13 billion years.Comment: 12 pages, LaTeX, with 2 postscript figures; in press for Nature, July
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Markedly Divergent Tree Assemblage Responses to Tropical Forest Loss and Fragmentation across a Strong Seasonality Gradient
We examine the effects of forest fragmentation on the structure and composition of tree assemblages within three seasonal and aseasonal forest types of southern Brazil, including evergreen, Araucaria, and deciduous forests. We sampled three southernmost Atlantic Forest landscapes, including the largest continuous forest protected areas within each forest type. Tree assemblages in each forest type were sampled within 10 plots of 0.1 ha in both continuous forests and 10 adjacent forest fragments. All trees within each plot were assigned to trait categories describing their regeneration strategy, vertical stratification, seed-dispersal mode, seed size, and wood density. We detected differences among both forest types and landscape contexts in terms of overall tree species richness, and the density and species richness of different functional groups in terms of regeneration strategy, seed dispersal mode and woody density. Overall, evergreen forest fragments exhibited the largest deviations from continuous forest plots in assemblage structure. Evergreen, Araucaria and deciduous forests diverge in the functional composition of tree floras, particularly in relation to regeneration strategy and stress tolerance. By supporting a more diversified light-demanding and stress-tolerant flora with reduced richness and abundance of shade-tolerant, old-growth species, both deciduous and Araucaria forest tree assemblages are more intrinsically resilient to contemporary human-disturbances, including fragmentation-induced edge effects, in terms of species erosion and functional shifts. We suggest that these intrinsic differences in the direction and magnitude of responses to changes in landscape structure between forest types should guide a wide range of conservation strategies in restoring fragmented tropical forest landscapes worldwide
Study of behaviour on simulated daylight ageing of artistsÂż acrylic and poly(vinyl acetate) paint films
[EN] This work proposes a multi-method approach that combines advanced microscopy (SEM/EDX, AFM) and spectroscopy (UV-vis and FTIR) techniques. This approach not only characterises the behaviour of the additives of two commercial poly(vinyl acetate) (PVAc) and acrylic emulsion paints but also simultaneously characterises the changes in chemical composition and morphology observed in the paint films as a result of ageing due to the paints being exposed to an intense source of simulated daylight. In parallel, a series of mechanical tests were performed that correlate the chemical changes in composition and the changes observed in the films' mechanical properties. This work was a comparative study between both types of acrylic and PVAc paints. The results obtained are of great interest for the modern paint conservation field as they provide valuable information on the mid- and long-term behaviours of these synthetic paints.Financial support is gratefully acknowledged from the Spanish "I+D+I MICINN" project CTQ2008-06727-C03-01/BQU supported by ERDEF funds and from the "Generalitat Valenciana" I+D project ACOMP/2009/171 and the AP2006-3223 project ascribed to the Predoctoral Stages Programme of Universitary Researchers in Spanish Universities and Research Centres from the Spanish Ministry of Science and Innovation (MICINN). The authors wish to thank Mr. Manuel Planes i Insausti and Dr. Jose Luis Moya Lopez, the technical supervisors responsible for the Electron Microscopy Service at the Polytechnic University of Valencia.Domenech Carbo, MT.; Silva, MF.; Aura Castro, E.; Fuster LĂłpez, L.; KrĂśner ., SU.; MartĂnez BazĂĄn, ML.; Mas BarberĂ , X.... (2011). Study of behaviour on simulated daylight ageing of artistsÂż acrylic and poly(vinyl acetate) paint films. Analytical and Bioanalytical Chemistry. 399:2921-2937. https://doi.org/10.1007/s00216-010-4294-3S2921293739
Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease
Background
Prostate cancer (PrCa) demonstrates a heterogeneous clinical presentation ranging from largely indolent to lethal. We sought to identify a signature of rare inherited variants that distinguishes between these two extreme phenotypes.
Methods
We sequenced germline whole exomes from 139 aggressive (metastatic, age of diagnosisâ<â60) and 141 non-aggressive (low clinical grade, age of diagnosis âĽ60) PrCa cases. We conducted rare variant association analyses at gene and gene set levels using SKAT and Bayesian risk index techniques. GO term enrichment analysis was performed for genes with the highest differential burden of rare disruptive variants.
Results
Protein truncating variants (PTVs) in specific DNA repair genes were significantly overrepresented among patients with the aggressive phenotype, with BRCA2, ATM and NBN the most frequently mutated genes. Differential burden of rare variants was identified between metastatic and non-aggressive cases for several genes implicated in angiogenesis, conferring both deleterious and protective effects.
Conclusions
Inherited PTVs in several DNA repair genes distinguish aggressive from non-aggressive PrCa cases. Furthermore, inherited variants in genes with roles in angiogenesis may be potential predictors for risk of metastases. If validated in a larger dataset, these findings have potential for future clinical application
Size and frequency of natural forest disturbances and the Amazon forest carbon balance
types: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.Copyright Š 2014 Macmillan Publishers Limited. All rights reserved.This is an open-access articleForest inventory studies in the Amazon indicate a large terrestrial carbon sink. However, field plots may fail to represent forest mortality processes at landscape-scales of tropical forests. Here we characterize the frequency distribution of disturbance events in natural forests from 0.01âha to 2,651âha size throughout Amazonia using a novel combination of forest inventory, airborne lidar and satellite remote sensing data. We find that small-scale mortality events are responsible for aboveground biomass losses of ~1.7âPgâCây(-1) over the entire Amazon region. We also find that intermediate-scale disturbances account for losses of ~0.2âPgâCây(-1), and that the largest-scale disturbances as a result of blow-downs only account for losses of ~0.004âPgâCây(-1). Simulation of growth and mortality indicates that even when all carbon losses from intermediate and large-scale disturbances are considered, these are outweighed by the net biomass accumulation by tree growth, supporting the inference of an Amazon carbon sink.NASA Earth System Science Fellowship (NESSF
Galaxies appear simpler than expected
Galaxies are complex systems the evolution of which apparently results from
the interplay of dynamics, star formation, chemical enrichment, and feedback
from supernova explosions and supermassive black holes. The hierarchical theory
of galaxy formation holds that galaxies are assembled from smaller pieces,
through numerous mergers of cold dark matter. The properties of an individual
galaxy should be controlled by six independent parameters including mass,
angular-momentum, baryon-fraction, age and size, as well as by the accidents of
its recent haphazard merger history. Here we report that a sample of galaxies
that were first detected through their neutral hydrogen radio-frequency
emission, and are thus free of optical selection effects, shows five
independent correlations among six independent observables, despite having a
wide range of properties. This implies that the structure of these galaxies
must be controlled by a single parameter, although we cannot identify this
parameter from our dataset. Such a degree of organisation appears to be at odds
with hierarchical galaxy formation, a central tenet of the cold dark matter
paradigm in cosmology.Comment: 26 pages, 14 figure
Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV
The performance of muon reconstruction, identification, and triggering in CMS
has been studied using 40 inverse picobarns of data collected in pp collisions
at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection
criteria covering a wide range of physics analysis needs have been examined.
For all considered selections, the efficiency to reconstruct and identify a
muon with a transverse momentum pT larger than a few GeV is above 95% over the
whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4,
while the probability to misidentify a hadron as a muon is well below 1%. The
efficiency to trigger on single muons with pT above a few GeV is higher than
90% over the full eta range, and typically substantially better. The overall
momentum scale is measured to a precision of 0.2% with muons from Z decays. The
transverse momentum resolution varies from 1% to 6% depending on pseudorapidity
for muons with pT below 100 GeV and, using cosmic rays, it is shown to be
better than 10% in the central region up to pT = 1 TeV. Observed distributions
of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO
Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at â s = 8 TeV with the ATLAS detector
Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fbâ1 of â s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente
Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV
The performance of muon reconstruction, identification, and triggering in CMS
has been studied using 40 inverse picobarns of data collected in pp collisions
at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection
criteria covering a wide range of physics analysis needs have been examined.
For all considered selections, the efficiency to reconstruct and identify a
muon with a transverse momentum pT larger than a few GeV is above 95% over the
whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4,
while the probability to misidentify a hadron as a muon is well below 1%. The
efficiency to trigger on single muons with pT above a few GeV is higher than
90% over the full eta range, and typically substantially better. The overall
momentum scale is measured to a precision of 0.2% with muons from Z decays. The
transverse momentum resolution varies from 1% to 6% depending on pseudorapidity
for muons with pT below 100 GeV and, using cosmic rays, it is shown to be
better than 10% in the central region up to pT = 1 TeV. Observed distributions
of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO
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