A compendium and functional characterization of mammalian genes involved in adaptation to Arctic or Antarctic environments

Many mammals are well adapted to surviving in extremely cold environments. These species have likely accumulated genetic changes that help them efficiently cope with low temperatures. It is not known whether the same genes related to cold adaptation in one species would be under selection in another species. The aims of this study therefore were: to create a compendium of mammalian genes related to adaptations to a low temperature environment; to identify genes related to cold tolerance that have been subjected to independent positive selection in several species; to determine promising candidate genes/pathways/organs for further empirical research on cold adaptation in mammals

The Role of Applied Epidemiology Methods in the Disaster Management Cycle

Disaster epidemiology (i.e., applied epidemiology in disaster settings) presents a source of reliable and actionable information for decision-makers and stakeholders in the disaster management cycle. However, epidemiological methods have yet to be routinely integrated into disaster response and fully communicated to response leaders. We present a framework consisting of rapid needs assessments, health surveillance, tracking and registries, and epidemiological investigations, including risk factor and health outcome studies and evaluation of interventions, which can be practiced throughout the cycle. Applying each method can result in actionable information for planners and decision-makers responsible for preparedness, response, and recovery. Disaster epidemiology, once integrated into the disaster management cycle, can provide the evidence base to inform and enhance response capability within the public health infrastructure

Phosphorylation of p130Cas initiates Rac activation and membrane ruffling

<p>Abstract</p> <p>Background</p> <p>Non-receptor tyrosine kinases (NTKs) regulate physiological processes such as cell migration, differentiation, proliferation, and survival by interacting with and phosphorylating a large number of substrates simultaneously. This makes it difficult to attribute a particular biological effect to the phosphorylation of a particular substrate. We developed the Functional Interaction Trap (FIT) method to phosphorylate specifically a single substrate of choice in living cells, thereby allowing the biological effect(s) of that phosphorylation to be assessed. In this study we have used FIT to investigate the effects of specific phosphorylation of p130Cas, a protein implicated in cell migration. We have also used this approach to address a controversy regarding whether it is Src family kinases or focal adhesion kinase (FAK) that phosphorylates p130Cas in the trimolecular Src-FAK-p130Cas complex.</p> <p>Results</p> <p>We show here that SYF cells (mouse fibroblasts lacking the NTKs Src, Yes and Fyn) exhibit a low level of basal tyrosine phosphorylation at focal adhesions. FIT-mediated tyrosine phosphorylation of NTK substrates p130Cas, paxillin and FAK and cortactin was observed at focal adhesions, while FIT-mediated phosphorylation of cortactin was also seen at the cell periphery. Phosphorylation of p130Cas in SYF cells led to activation of Rac1 and increased membrane ruffling and lamellipodium formation, events associated with cell migration. We also found that the kinase activity of Src and not FAK is essential for phosphorylation of p130Cas when the three proteins exist as a complex in focal adhesions.</p> <p>Conclusion</p> <p>These results demonstrate that tyrosine phosphorylation of p130Cas is sufficient for its localization to focal adhesions and for activation of downstream signaling events associated with cell migration. FIT provides a valuable tool to evaluate the contribution of individual components of the response to signals with multiple outputs, such as activation of NTKs.</p

Measurements of the neutron electric to magnetic form factor ratio GEn/GMn via the ^2H(\vec{e},e'\vec{n})^1H reaction to Q^2 = 1.45 (GeV/c)^2

We report values for the neutron electric to magnetic form factor ratio, GEn/GMn, deduced from measurements of the neutron's recoil polarization in the quasielastic 2H(\vec{e},e'\vec{n})1H reaction, at three Q^2 values of 0.45, 1.13, and 1.45 (GeV/c)^2. The data at Q^2 = 1.13 and 1.45 (GeV/c)^2 are the first direct experimental measurements of GEn employing polarization degrees of freedom in the Q^2 > 1 (GeV/c)^2 region and stand as the most precise determinations of GEn for all values of Q^2.Comment: 41 pages, 33 figures, submitted to Phys. Rev. C, archival paper for R. Madey et al., Phys. Rev. Lett. 91, 122002 (2003

Measurements of GEn/GMn from the ^2H(vec{e},e'vec{n})^1H Reaction to Q^2=1.45 (GeV/c)^2

We report new measurements of the ratio of the electric form factor to the magnetic form factor of the neutron, GEn/GMn, obtained via recoil polarimetry from the quasielastic ^2H(vec{e},e'vec{n})^1H reaction at Q^2 values of 0.45, 1.13, and 1.45 (GeV/c)^2 with relative statistical uncertainties of 7.6 and 8.4% at the two higher Q^2 points, which were not reached previously via polarization measurements. Scale and systematic uncertainties are small.Comment: 5 pages, 4 figures, 2 table

Convergent genetic and expression data implicate immunity in Alzheimer's disease

Background Late–onset Alzheimer's disease (AD) is heritable with 20 genes showing genome wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease we extended these genetic data in a pathway analysis. Methods The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (p = 3.27×10-12 after multiple testing correction for pathways), regulation of endocytosis (p = 1.31×10-11), cholesterol transport (p = 2.96 × 10-9) and proteasome-ubiquitin activity (p = 1.34×10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected p 0.002 – 0.05). Conclusions The immune response, regulation of endocytosis, cholesterol transport and protein ubiquitination represent prime targets for AD therapeutics

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

The impact of supplementary immunization activities on the epidemiology of measles in Tianjin, China

Objectives: China has repeatedly used supplemental immunization activities (SIAs) to work towards measles elimination, but it is unknown if the SIAs are reaching non-locals – migrants from rural to urban areas. This study characterized temporal trends in measles incidence by local and non-local residency and evaluated the impact of SIAs on measles incidence in Tianjin, China. Methods: Daily measles case-counts were tabulated separately by residency. These two datasets were combined so that each day had two observations. Poisson regression was conducted using generalized estimating equations with an exchangeable working correlation structure to estimate rate ratios (RRs). Results: There were 12 465 measles cases in Tianjin over the 10-year period. The rate of measles was higher in non-locals than locals before the 2008 SIA (RR 3.60, 95% confidence interval (CI) 3.27–3.96), but this attenuated to a RR of 1.22 between the 2008 and 2010 SIAs (95% CI 1.02–1.45). Following the 2010 SIA, non-locals had a lower rate of measles (RR 0.78, 95% CI 0.69–0.87). Conclusions: The disparity in measles incidence between locals and non-locals was reduced following two SIAs. Sustained public health interventions will be needed to maintain low measles incidence among non-locals given the ongoing migration of people throughout China