Integration of Women Veterans into VA Quality Improvement Research Efforts: What Researchers Need to Know

The Department of Veterans Affairs (VA) and other federal agencies require funded researchers to include women in their studies. Historically, many researchers have indicated they will include women in proportion to their VA representation or pointed to their numerical minority as justification for exclusion. However, women’s participation in the military—currently 14% of active military—is rapidly changing veteran demographics, with women among the fastest growing segments of new VA users. These changes will require researchers to meet the challenge of finding ways to adequately represent women veterans for meaningful analysis. We describe women veterans’ health and health-care use, note how VA care is organized to meet their needs, report gender differences in quality, highlight national plans for women veterans’ quality improvement, and discuss VA women’s health research. We then discuss challenges and potential solutions for increasing representation of women veterans in VA research, including steps for implementation research

Resolving the ancestry of Austronesian-speaking populations

There are two very different interpretations of the prehistory of Island Southeast Asia (ISEA), with genetic evidence invoked in support of both. The “out-of-Taiwan” model proposes a major Late Holocene expansion of Neolithic Austronesian speakers from Taiwan. An alternative, proposing that Late Glacial/postglacial sea-level rises triggered largely autochthonous dispersals, accounts for some otherwise enigmatic genetic patterns, but fails to explain the Austronesian language dispersal. Combining mitochondrial DNA (mtDNA), Y-chromosome and genome-wide data, we performed the most comprehensive analysis of the region to date, obtaining highly consistent results across all three systems and allowing us to reconcile the models. We infer a primarily common ancestry for Taiwan/ISEA populations established before the Neolithic, but also detected clear signals of two minor Late Holocene migrations, probably representing Neolithic input from both Mainland Southeast Asia and South China, via Taiwan. This latter may therefore have mediated the Austronesian language dispersal, implying small-scale migration and language shift rather than large-scale expansion

APOE Genotype-Function Relationship: Evidence of −491 A/T Promoter Polymorphism Modifying Transcription Control but Not Type 2 Diabetes Risk

BACKGROUND: The apolipoprotein E gene (APOE) coding polymorphism modifies the risks of Alzheimer's disease, type 2 diabetes, and coronary heart disease. Aside from the coding variants, single nucleotide polymorphism (SNP) of the APOE promoter has also been shown to modify the risk of Alzheimer's disease. METHODOLOGY/PRINCIPAL FINDINGS: In this study we investigate the genotype-function relationship of APOE promoter polymorphism at molecular level and at physiological level: i.e., in transcription control of the gene and in the risk of type 2 diabetes. In molecular studies, the effect of the APOE -491A/T (rs449647) polymorphism on gene transcription was accessed by dual-luciferase reporter gene assays. The -491 A to T substitution decreased the activity (p<0.05) of the cloned APOE promoter (-1017 to +406). Using the -501 to -481 nucleotide sequence of the APOE promoter as a 'bait' to screen the human brain cDNA library by yeast one-hybrid system yielded ATF4, an endoplasmic reticulum stress response gene, as one of the interacting factors. Electrophoretic-mobility-shift assays (EMSA) and chromatin immuno-precipitation (ChIP) analyses further substantiated the physical interaction between ATF4 and the APOE promoter. Over-expression of ATF4 stimulated APOE expression whereas siRNA against ATF4 suppressed the expression of the gene. However, interaction between APOE promoter and ATF4 was not -491A/T-specific. At physiological level, the genotype-function relationship of APOE promoter polymorphism was studied in type 2 diabetes. In 630 cases and 595 controls, three APOE promoter SNPs -491A/T, -219G/T (rs405509), and +113G/C (rs440446) were genotyped and tested for association with type 2 diabetes in Hong Kong Chinese. No SNP or haplotype association with type 2 diabetes was detected. CONCLUSIONS/SIGNIFICANCE: At molecular level, polymorphism -491A/T and ATF4 elicit independent control of APOE gene expression. At physiological level, no genotype-risk association was detected between the studied APOE promoter SNPs and type 2 diabetes in Hong Kong Chinese

Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy.

BACKGROUND: Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM). METHODS: To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency. RESULTS: We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM. CONCLUSION: Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies. FUNDING: This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L'Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US)

Dynamic probe selection for studying microbial transcriptome with high-density genomic tiling microarrays

<p>Abstract</p> <p>Background</p> <p>Current commercial high-density oligonucleotide microarrays can hold millions of probe spots on a single microscopic glass slide and are ideal for studying the transcriptome of microbial genomes using a tiling probe design. This paper describes a comprehensive computational pipeline implemented specifically for designing tiling probe sets to study microbial transcriptome profiles.</p> <p>Results</p> <p>The pipeline identifies every possible probe sequence from both forward and reverse-complement strands of all DNA sequences in the target genome including circular or linear chromosomes and plasmids. Final probe sequence lengths are adjusted based on the maximal oligonucleotide synthesis cycles and best isothermality allowed. Optimal probes are then selected in two stages - sequential and gap-filling. In the sequential stage, probes are selected from sequence windows tiled alongside the genome. In the gap-filling stage, additional probes are selected from the largest gaps between adjacent probes that have already been selected, until a predefined number of probes is reached. Selection of the highest quality probe within each window and gap is based on five criteria: sequence uniqueness, probe self-annealing, melting temperature, oligonucleotide length, and probe position.</p> <p>Conclusions</p> <p>The probe selection pipeline evaluates global and local probe sequence properties and selects a set of probes dynamically and evenly distributed along the target genome. Unique to other similar methods, an exact number of non-redundant probes can be designed to utilize all the available probe spots on any chosen microarray platform. The pipeline can be applied to microbial genomes when designing high-density tiling arrays for comparative genomics, ChIP chip, gene expression and comprehensive transcriptome studies.</p

South-to-north migration preceded the advent of intensive farming in the Maya region

This is the final version. Available on open access from Nature Research via the DOI in this recordData availability: The aligned sequences have been deposited in the European Nucleotide Archive database under accession code PRJEB49391. The processed genotype data used in analysis are available online on the Nature Communications website as Supplementary Data 9.The genetic prehistory of human populations in Central America is largely unexplored leaving an important gap in our knowledge of the global expansion of humans. We report genome-wide ancient DNA data for a transect of twenty individuals from two Belize rock-shelters dating between 9,600-3,700 calibrated radiocarbon years before present (cal. BP). The oldest individuals (9,600-7,300 cal. BP) descend from an Early Holocene Native American lineage with only distant relatedness to present-day Mesoamericans, including Mayan-speaking populations. After ~5,600 cal. BP a previously unknown human dispersal from the south made a major demographic impact on the region, contributing more than 50% of the ancestry of all later individuals. This new ancestry derived from a source related to present-day Chibchan speakers living from Costa Rica to Colombia. Its arrival corresponds to the first clear evidence for forest clearing and maize horticulture in what later became the Maya region.Alphawood FoundationNational Science Foundation (NSF)National Institutes of Health (NIH)John Templeton FoundationPaul G. Allen Family Foundatio

Increased Serum and Musculotendinous Fibrogenic Proteins following Persistent Low-Grade Inflammation in a Rat Model of Long-Term Upper Extremity Overuse.

We examined the relationship between grip strength declines and muscle-tendon responses induced by long-term performance of a high-repetition, low-force (HRLF) reaching task in rats. We hypothesized that grip strength declines would correlate with inflammation, fibrosis and degradation in flexor digitorum muscles and tendons. Grip strength declined after training, and further in weeks 18 and 24, in reach limbs of HRLF rats. Flexor digitorum tissues of reach limbs showed low-grade increases in inflammatory cytokines: IL-1β after training and in week 18, IL-1α in week 18, TNF-α and IL-6 after training and in week 24, and IL-10 in week 24, with greater increases in tendons than muscles. Similar cytokine increases were detected in serum with HRLF: IL-1α and IL-10 in week 18, and TNF-α and IL-6 in week 24. Grip strength correlated inversely with IL-6 in muscles, tendons and serum, and TNF-α in muscles and serum. Four fibrogenic proteins, TGFB1, CTGF, PDGFab and PDGFbb, and hydroxyproline, a marker of collagen synthesis, increased in serum in HRLF weeks 18 or 24, concomitant with epitendon thickening, increased muscle and tendon TGFB1 and CTGF. A collagenolytic gelatinase, MMP2, increased by week 18 in serum, tendons and muscles of HRLF rats. Grip strength correlated inversely with TGFB1 in muscles, tendons and serum; with CTGF-immunoreactive fibroblasts in tendons; and with MMP2 in tendons and serum. Thus, motor declines correlated with low-grade systemic and musculotendinous inflammation throughout task performance, and increased fibrogenic and degradative proteins with prolonged task performance. Serum TNF-α, IL-6, TGFB1, CTGF and MMP2 may serve as serum biomarkers of work-related musculoskeletal disorders, although further studies in humans are needed

Environmental and vegetation controls on the spatial variability of CH4 emission from wet-sedge and tussock tundra ecosystems in the Arctic

Aims Despite multiple studies investigating the environmental controls on CH4 fluxes from arctic tundra ecosystems, the high spatial variability of CH4 emissions is not fully understood. This makes the upscaling of CH4 fluxes from plot to regional scale, particularly challenging. The goal of this study is to refine our knowledge of the spatial variability and controls on CH4 emission from tundra ecosystems. Methods CH4 fluxes were measured in four sites across a variety of wet-sedge and tussock tundra ecosystems in Alaska using chambers and a Los Gatos CO2 and CH4 gas analyser. Results All sites were found to be sources of CH4, with northern sites (in Barrow) showing similar CH4 emission rates to the southernmost site (ca. 300 km south, Ivotuk). Gross primary productivity (GPP), water level and soil temperature were the most important environmental controls on CH4 emission. Greater vascular plant cover was linked with higher CH4 emission, but this increased emission with increased vascular plant cover was much higher (86 %) in the drier sites, than the wettest sites (30 %), suggesting that transport and/or substrate availability were crucial limiting factors for CH4 emission in these tundra ecosystems. Conclusions Overall, this study provides an increased understanding of the fine scale spatial controls on CH4 flux, in particular the key role that plant cover and GPP play in enhancing CH4 emissions from tundra soils