Bringing self assessment home: repository profiling and key lines of enquiry within DRAMBORA

Digital repositories are a manifestation of complex organizational, financial, legal, technological, procedural, and political interrelationships. Accompanying each of these are innate uncertainties, exacerbated by the relative immaturity of understanding prevalent within the digital preservation domain. Recent efforts have sought to identify core characteristics that must be demonstrable by successful digital repositories, expressed in the form of check-list documents, intended to support the processes of repository accreditation and certification. In isolation though, the available guidelines lack practical applicability; confusion over evidential requirements and difficulties associated with the diversity that exists among repositories (in terms of mandate, available resources, supported content and legal context) are particularly problematic. A gap exists between the available criteria and the ways and extent to which conformity can be demonstrated. The Digital Repository Audit Method Based on Risk Assessment (DRAMBORA) is a methodology for undertaking repository self assessment, developed jointly by the Digital Curation Centre (DCC) and DigitalPreservationEurope (DPE). DRAMBORA requires repositories to expose their organization, policies and infrastructures to rigorous scrutiny through a series of highly structured exercises, enabling them to build a comprehensive registry of their most pertinent risks, arranged into a structure that facilitates effective management. It draws on experiences accumulated throughout 18 evaluative pilot assessments undertaken in an internationally diverse selection of repositories, digital libraries and data centres (including institutions and services such as the UK National Digital Archive of Datasets, the National Archives of Scotland, Gallica at the National Library of France and the CERN Document Server). Other organizations, such as the British Library, have been using sections of DRAMBORA within their own risk assessment procedures. Despite the attractive benefits of a bottom up approach, there are implicit challenges posed by neglecting a more objective perspective. Following a sustained period of pilot audits undertaken by DPE, DCC and the DELOS Digital Preservation Cluster aimed at evaluating DRAMBORA, it was stated that had respective project members not been present to facilitate each assessment, and contribute their objective, external perspectives, the results may have been less useful. Consequently, DRAMBORA has developed in a number of ways, to enable knowledge transfer from the responses of comparable repositories, and incorporate more opportunities for structured question sets, or key lines of enquiry, that provoke more comprehensive awareness of the applicability of particular threats and opportunities

Exposure to sixty minutes of hyperoxia upregulates myocardial humanins in patients with coronary artery disease - A pilot study

In experimental setting the concept of myocardial preconditioning by hyperoxia has been introduced and different intracellular protective mechanisms and their effects have been described. To study whether similar protective phenotype can be induced by hyperoxia also in humans, gene expression profile after hyperoxic exposure was analyzed. Adult patients were randomized to be ventilated with either FiO2 0.4 (n = 14) or 1.0 (n = 10) for 60 minutes before coronary artery bypass grafting. A tissue sample from the right atrial appendage was taken for gene analysis and expression profile analysis on genome wide level by RNA-seq analysis was applied. Exposure to > 96% oxygen for 60 minutes significantly changed the expression of 20 different genes, including upregulation of two different humanins - MTRNR2L2 and MTRNR2L8, and activated a "cell survival" network as detected by Ingenuity Pathway Analyses. We concluded that administration of > 96% oxygen for 1 hour changes gene expression in the myocardium of the patients with coronary artery disease and may enhance cell survival capability

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. Objective: To identify additional AAA risk loci using data from all available genome-wide association studies (GWAS). Methods and Results: Through a meta-analysis of 6 GWAS datasets and a validation study totalling 10,204 cases and 107,766 controls we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches we observed no new associations between the lead AAA SNPs and coronary artery disease, blood pressure, lipids or diabetes. Network analyses identified ERG, IL6R and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. Conclusions: The 4 new risk loci for AAA appear to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease

Plasma cortisol-linked gene networks in hepatic and adipose tissues implicate corticosteroid-binding globulin in modulating tissue glucocorticoid action and cardiovascular risk

Genome-wide association meta-analysis (GWAMA) by the Cortisol Network (CORNET) consortium identified genetic variants spanning the SERPINA6/SERPINA1 locus on chromosome 14 associated with morning plasma cortisol, cardiovascular disease (CVD), and SERPINA6 mRNA expression encoding corticosteroid-binding globulin (CBG) in the liver. These and other findings indicate that higher plasma cortisol levels are causally associated with CVD; however, the mechanisms by which variations in CBG lead to CVD are undetermined. Using genomic and transcriptomic data from The Stockholm Tartu Atherosclerosis Reverse Networks Engineering Task (STARNET) study, we identified plasma cortisol-linked single-nucleotide polymorphisms (SNPs) that are trans-associated with genes from seven different vascular and metabolic tissues, finding the highest representation of trans-genes in the liver, subcutaneous fat, and visceral abdominal fat, [false discovery rate (FDR) = 15%]. We identified a subset of cortisol-associated trans-genes that are putatively regulated by the glucocorticoid receptor (GR), the primary transcription factor activated by cortisol. Using causal inference, we identified GR-regulated trans-genes that are responsible for the regulation of tissue-specific gene networks. Cis-expression Quantitative Trait Loci (eQTLs) were used as genetic instruments for identification of pairwise causal relationships from which gene networks could be reconstructed. Gene networks were identified in the liver, subcutaneous fat, and visceral abdominal fat, including a high confidence gene network specific to subcutaneous adipose (FDR = 10%) under the regulation of the interferon regulatory transcription factor, IRF2. These data identify a plausible pathway through which variation in the liver CBG production perturbs cortisol-regulated gene networks in peripheral tissues and thereby promote CVD

Cardiometabolic risk loci share downstream cis- and trans-gene regulation across tissues and diseases

Genome-wide association studies (GWAS) have identified hundreds of cardiometabolic disease (CMD) risk loci. However, they contribute little to genetic variance, and most downstream gene-regulatory mechanisms are unknown. We genotyped and RNA-sequenced vascular and metabolic tissues from 600 coronary artery disease patients in the Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task study (STARNET). Gene expression traits associated with CMD risk single-nucleotide polymorphism (SNPs) identified by GWAS were more extensively found in STARNET than in tissue- and disease-unspecific gene-tissue expression studies, indicating sharing of downstream cis-/trans-gene regulation across tissues and CMDs. In contrast, the regulatory effects of other GWAS risk SNPs were tissue-specific; abdominal fat emerged as an important gene-regulatory site for blood lipids, such as for the low-density lipoprotein cholesterol and coronary artery disease risk gene PCSK9 STARNET provides insights into gene-regulatory mechanisms for CMD risk loci, facilitating their translation into opportunities for diagnosis, therapy, and prevention.</p

Correction to: Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits

Erratum for Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits. [BMC Med Genomics. 2019

A Study of Pi Aquarii During a Quasi-normal Star Phase: Refined Fundamental Parameters and Evidence for Binarity

We present the results of recent multicolor photometric and high-resolution spectroscopic observations of the bright Be star Pi Aquarii. Observational data collected from the literature were used to study the star's variations over the last four decades. The star is identified with the IR sources F22227+0107 in the IRAS Faint Point Source catalog and MSX5_G066.0066-44.7392 in the MSX catalog. The variations in near-IR brightness of Pi Aqr are found to be among the largest reported for Be stars. Since 1996, the star has shown only weak signs of circumstellar emission, which has allowed us to refine the fundamental stellar parameters: A_V=0.15 mag., T_eff=24000K, log g=3.9, and M_V=-2.95 mag. A weak emission component of the H-alpha line has been detected during the recent quasi-normal star phase. From analysis of the H-alpha line profiles, we find anti-phased radial velocity variations of the emission component and the photospheric absorption, with a period of 84.1 days and semi-amplitudes of 101.4 and 16.7 km/s, respectively. This result suggests that Pi Aqr may be a binary system consisting of stars with masses of M_1 sin^{3}i = 12.4 M_sun, M_2 sin^{3}i = 2.0 M_sun. We also estimate the orbital inclination angle to be between 50 and 75 degrees. We suggest that the photometric, spectroscopic, and polarimetric variations observed during the second half of the 20th century may be due to variable mass transfer between the binary components.Comment: 26 pages (including 8 figs, 2 tables), accepted by Ap

A mechanistic framework for cardiometabolic and coronary artery diseases

Coronary atherosclerosis results from the delicate interplay of genetic and exogenous risk factors, principally taking place in metabolic organs and the arterial wall. Here we show that 224 gene-regulatory coexpression networks (GRNs) identified by integrating genetic and clinical data from patients with (n = 600) and without (n = 250) coronary artery disease (CAD) with RNA-seq data from seven disease-relevant tissues in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study largely capture this delicate interplay, explaining &gt;54% of CAD heritability. Within 89 cross-tissue GRNs associated with clinical severity of CAD, 374 endocrine factors facilitated inter-organ interactions, primarily along an axis from adipose tissue to the liver (n = 152). This axis was independently replicated in genetically diverse mouse strains and by injection of recombinant forms of adipose endocrine factors (EPDR1, FCN2, FSTL3 and LBP) that markedly altered blood lipid and glucose levels in mice. Altogether, the STARNET database and the associated GRN browser (http://starnet.mssm.edu) provide a multiorgan framework for exploration of the molecular interplay between cardiometabolic disorders and CAD