Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction (HARP-2) trial : study protocol for a randomized controlled trial

Acute lung injury (ALI) is a common devastating clinical syndrome characterized by life-threatening respiratory failure requiring mechanical ventilation and multiple organ failure. There are in vitro, animal studies and pre-clinical data suggesting that statins may be beneficial in ALI. The Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial is a multicenter, prospective, randomized, allocation concealed, double-blind, placebo-controlled clinical trial which aims to test the hypothesis that treatment with simvastatin will improve clinical outcomes in patients with ALI

Outcomes among HIV-1 Infected Individuals First Starting Antiretroviral Therapy with Concurrent Active TB or Other AIDS-Defining Disease

Background: Tuberculosis (TB) is common among HIV-infected individuals in many resource-limited countries and has been associated with poor survival. We evaluated morbidity and mortality among individuals first starting antiretroviral therapy (ART) with concurrent active TB or other AIDS-defining disease using data from the “Prospective Evaluation of Antiretrovirals in Resource-Limited Settings” (PEARLS) study. Methods: Participants were categorized retrospectively into three groups according to presence of active confirmed or presumptive disease at ART initiation: those with pulmonary and/or extrapulmonary TB (“TB” group), those with other non-TB AIDS-defining disease (“other disease”), or those without concurrent TB or other AIDS-defining disease (“no disease”). Primary outcome was time to the first of virologic failure, HIV disease progression or death. Since the groups differed in characteristics, proportional hazard models were used to compare the hazard of the primary outcome among study groups, adjusting for age, sex, country, screening CD4 count, baseline viral load and ART regimen. Results: 31 of 102 participants (30%) in the “TB” group, 11 of 56 (20%) in the “other disease” group, and 287 of 1413 (20%) in the “no disease” group experienced a primary outcome event (p = 0.042). This difference reflected higher mortality in the TB group: 15 (15%), 0 (0%) and 41 (3%) participants died, respectively (p<0.001). The adjusted hazard ratio comparing the “TB” and “no disease” groups was 1.39 (95% confidence interval: 0.93–2.10; p = 0.11) for the primary outcome and 3.41 (1.72–6.75; p<0.001) for death. Conclusions: Active TB at ART initiation was associated with increased risk of mortality in HIV-1 infected patients

WormBase: a comprehensive resource for nematode research

WormBase (http://www.wormbase.org) is a central data repository for nematode biology. Initially created as a service to the Caenorhabditis elegans research field, WormBase has evolved into a powerful research tool in its own right. In the past 2 years, we expanded WormBase to include the complete genomic sequence, gene predictions and orthology assignments from a range of related nematodes. This comparative data enrich the C. elegans data with improved gene predictions and a better understanding of gene function. In turn, they bring the wealth of experimental knowledge of C. elegans to other systems of medical and agricultural importance. Here, we describe new species and data types now available at WormBase. In addition, we detail enhancements to our curatorial pipeline and website infrastructure to accommodate new genomes and an extensive user base

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

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

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A&gt;T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Culex pipiens development is greatly influenced by native bacteria and exogenous yeast

Culex pipiens is the most cosmopolitan mosquito of the Pipiens Assemblage. By studying the nature of interactions between this species and microorganisms common to its breeding environment we can unravel important pitfalls encountered during development. We tested the survival rate of larval stages, pupae and adults of a Cx. pipiens colony exposed to a variety of microorganisms in laboratory conditions and assessed the transmission to offspring (F1) by those organisms that secured development up to adulthood. Three complementary experiments were designed to: 1) explore the nutritional value of yeasts and other microorganisms during Cx. pipiens development; 2) elucidate the transstadial transmission of yeast to the host offspring; and 3) to examine the relevance of all these microorganisms in female choice for oviposition-substratum. The yeast Saccharomyces cerevisiae proved to be the most nutritional diet, but despite showing the highest survival rates, vertical transmission to F1 was never confirmed. In addition, during the oviposition trials, none of the gravid females was attracted to the yeast substratum. Notably, the two native bacterial strains, Klebsiella sp. and Aeromonas sp., were the preferred oviposition media, the same two bacteria that managed to feed neonates until molting into 2nd instar larvae. Our results not only suggest that Klebsiella sp. or Aeromonas sp. serve as attractants for oviposition habitat selection, but also nurture the most fragile instar, L1, to assure molting into a more resilient stage, L2, while yeast proves to be the most supportive diet for completing development. These experiments unearthed survival traits that might be considered in the future development of strategies of Cx. pipiens control. These studies can be extended to other members of the Pipiens Assemblag

Population substructure in Finland and Sweden revealed by the use of spatial coordinates and a small number of unlinked autosomal SNPs

Abstract Background Despite several thousands of years of close contacts, there are genetic differences between the neighbouring countries of Finland and Sweden. Within Finland, signs of an east-west duality have been observed, whereas the population structure within Sweden has been suggested to be more subtle. With a fine-scale substructure like this, inferring the cluster membership of individuals requires a large number of markers. However, some studies have suggested that this number could be reduced if the individual spatial coordinates are taken into account in the analysis. Results We genotyped 34 unlinked autosomal single nucleotide polymorphisms (SNPs), originally designed for zygosity testing, from 2044 samples from Sweden and 657 samples from Finland, and 30 short tandem repeats (STRs) from 465 Finnish samples. We saw significant population structure within Finland but not between the countries or within Sweden, and isolation by distance within Finland and between the countries. In Sweden, we found a deficit of heterozygotes that we could explain by simulation studies to be due to both a small non-random genotyping error and hidden substructure caused by immigration. Geneland, a model-based Bayesian clustering algorithm, clustered the individuals into groups that corresponded to Sweden and Eastern and Western Finland when spatial coordinates were used, whereas in the absence of spatial information, only one cluster was inferred. Conclusion We show that the power to cluster individuals based on their genetic similarity is increased when including information about the spatial coordinates. We also demonstrate the importance of estimating the size and effect of genotyping error in population genetics in order to strengthen the validity of the results.</p

Association Patterns in Saproxylic Insect Networks in Three Iberian Mediterranean Woodlands and Their Resistance to Microhabitat Loss

The assessment of the relationship between species diversity, species interactions and environmental characteristics is indispensable for understanding network architecture and ecological distribution in complex networks. Saproxylic insect communities inhabiting tree hollow microhabitats within Mediterranean woodlands are highly dependent on woodland configuration and on microhabitat supply they harbor, so can be studied under the network analysis perspective. We assessed the differences in interacting patterns according to woodland site, and analysed the importance of functional species in modelling network architecture. We then evaluated their implications for saproxylic assemblages’ persistence, through simulations of three possible scenarios of loss of tree hollow microhabitat. Tree hollow-saproxylic insect networks per woodland site presented a significant nested pattern. Those woodlands with higher complexity of tree individuals and tree hollow microhabitats also housed higher species/interactions diversity and complexity of saproxylic networks, and exhibited a higher degree of nestedness, suggesting that a higher woodland complexity positively influences saproxylic diversity and interaction complexity, thus determining higher degree of nestedness. Moreover, the number of insects acting as key interconnectors (nodes falling into the core region, using core/periphery tests) was similar among woodland sites, but the species identity varied on each. Such differences in insect core composition among woodland sites suggest the functional role they depict at woodland scale. Tree hollows acting as core corresponded with large tree hollows near the ground and simultaneously housing various breeding microsites, whereas core insects were species mediating relevant ecological interactions within saproxylic communities, e.g. predation, competitive or facilitation interactions. Differences in network patterns and tree hollow characteristics among woodland sites clearly defined different sensitivity to microhabitat loss, and higher saproxylic diversity and woodland complexity showed positive relation with robustness. These results highlight that woodland complexity goes hand in hand with biotic and ecological complexity of saproxylic networks, and together exhibited positive effects on network robustness.The research Projects I+D CGL2011-23658 y CGL2012-31669 of the Spanish Minister of Science provided economic support

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Large-scale patterns of turnover and basal area change in Andean forests

General patterns of forest dynamics and productivity in the Andes Mountains are poorly characterized. Here we present the first large-scale study of Andean forest dynamics using a set of 63 permanent forest plots assembled over the past two decades. In the North-Central Andes tree turnover (mortality and recruitment) and tree growth declined with increasing elevation and decreasing temperature. In addition, basal area increased in Lower Montane Moist Forests but did not change in Higher Montane Humid Forests. However, at higher elevations the lack of net basal area change and excess of mortality over recruitment suggests negative environmental impacts. In North-Western Argentina, forest dynamics appear to be influenced by land use history in addition to environmental variation. Taken together, our results indicate that combinations of abiotic and biotic factors that vary across elevation gradients are important determinants of tree turnover and productivity in the Andes. More extensive and longer-term monitoring and analyses of forest dynamics in permanent plots will be necessary to understand how demographic processes and woody biomass are responding to changing environmental conditions along elevation gradients through this century