Normalization of aortic function during arousal episodes in the hibernating ground squirrel

Hypothermia is commonly used to restrict organ damage during preservation of tissue, but does not offer complete protection. Organ damage after reperfusion/rewarming is amongst others caused by an impairment of vascular properties, particularly endothelium-dependent vasodilatation. We hypothesized that hibernating small animals, which frequently cycle through periods of deep cooling (torpor) and full rewarming (arousal), employ specific mechanisms to preserve vascular function after cooling and reperfusion. Therefore we measured contraction of aortic tissue of hibernating European ground squirrels after 24 h and 7 days of torpor, arousal (1.5 h) and in non-hibernating animals. To assess the role of nitric oxide (NO), experiments were performed in the absence and presence of the NO-synthesis inhibitor, L-NMMA (10(-4) M). Maximum contraction to phenylephrine and angiotensin 11 was doubled in 7-days torpid animals without a shift in EC50, compared to the other 3 groups. Maximum contraction to KCl was doubled in 7-days torpid animals compared to the arousal group and non-hibernating animals. Relaxation to acetylcholine (ACh) and sodium nitrite in phenylephrine precontracted rings did not differ between groups. In the presence of L-NMMA, the maximum of concentration-response curves for all three vasoconstrictors was increased by about 30% in the arousal group, but unaffected in other groups. L-NNMA completely inhibited ACh-induced relaxation in 24-h torpid animals and non-hibernating animals, but only partially in 7-days torpid animals and in the arousal group. From this we conclude that vascular adaptation proceeds during torpor. Further, increased contractility of aortic tissue during long torpor returns to normal within 1.5 hours of arousal, which is associated with an increased basal NO synthesis. In addition, involvement of NO in agonist-mediated relaxation differs between the various stages of hibernation. Thus, hibernating animals have effectively developed mechanisms to preserve vascular function after cooling and rewarming. (C) 2002 Elsevier Science Inc. All rights reserved

HNF1B and Endometrial Cancer Risk: Results from the PAGE study

We examined the association between HNF1B variants identified in a recent genome-wide association study and endometrial cancer in two large case-control studies nested in prospective cohorts: the Multiethnic Cohort Study (MEC) and the Women's Health Initiative (WHI) as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. A total of 1,357 incident cases of invasive endometrial cancer and 7,609 controls were included in the analysis (MEC: 426 cases/3,854 controls; WHI: 931cases/3,755 controls). The majority of women in the WHI were European American, while the MEC included sizable numbers of African Americans, Japanese and Latinos. We estimated the odds ratios (ORs) per allele and 95% confidence intervals (CIs) of each SNP using unconditional logistic regression adjusting for age, body mass index, and four principal components of ancestry informative markers. The combined ORs were estimated using fixed effect models. Rs4430796 and rs7501939 were associated with endometrial cancer risk in MEC and WHI with no heterogeneity observed across racial/ethnic groups (P≥0.21) or between studies (P≥0.70). The ORper allele was 0.82 (95% CI: 0.75, 0.89; P = 5.63×10−6) for rs4430796 (G allele) and 0.79 (95% CI: 0.73, 0.87; P = 3.77×10−7) for rs7501939 (A allele). The associations with the risk of Type I and Type II tumors were similar (P≥0.19). Adjustment for additional endometrial cancer risk factors such as parity, oral contraceptive use, menopausal hormone use, and smoking status had little effect on the results. In conclusion, HNF1B SNPs are associated with risk of endometrial cancer and that the associated relative risks are similar for Type I and Type II tumors

Phenome-Wide Association Study (PheWAS) for Detection of Pleiotropy within the Population Architecture using Genomics and Epidemiology (PAGE) Network

Using a phenome-wide association study (PheWAS) approach, we comprehensively tested genetic variants for association with phenotypes available for 70,061 study participants in the Population Architecture using Genomics and Epidemiology (PAGE) network. Our aim was to better characterize the genetic architecture of complex traits and identify novel pleiotropic relationships. This PheWAS drew on five population-based studies representing four major racial/ethnic groups (European Americans (EA), African Americans (AA), Hispanics/Mexican-Americans, and Asian/Pacific Islanders) in PAGE, each site with measurements for multiple traits, associated laboratory measures, and intermediate biomarkers. A total of 83 single nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) were genotyped across two or more PAGE study sites. Comprehensive tests of association, stratified by race/ethnicity, were performed, encompassing 4,706 phenotypes mapped to 105 phenotype-classes, and association results were compared across study sites. A total of 111 PheWAS results had significant associations for two or more PAGE study sites with consistent direction of effect with a significance threshold of p<0.01 for the same racial/ethnic group, SNP, and phenotype-class. Among results identified for SNPs previously associated with phenotypes such as lipid traits, type 2 diabetes, and body mass index, 52 replicated previously published genotype-phenotype associations, 26 represented phenotypes closely related to previously known genotype-phenotype associations, and 33 represented potentially novel genotype-phenotype associations with pleiotropic effects. The majority of the potentially novel results were for single PheWAS phenotype-classes, for example, for CDKN2A/B rs1333049 (previously associated with type 2 diabetes in EA) a PheWAS association was identified for hemoglobin levels in AA. Of note, however, GALNT2 rs2144300 (previously associated with high-density lipoprotein cholesterol levels in EA) had multiple potentially novel PheWAS associations, with hypertension related phenotypes in AA and with serum calcium levels and coronary artery disease phenotypes in EA. PheWAS identifies associations for hypothesis generation and exploration of the genetic architecture of complex traits

Desglycinamide-(ARG8)-vasopressin in five trials with memory-disturbed patients

A series of five consecutive clinical trials were performed in which the neuropeptide desglycinamide‐(Arg8)‐vasopressin (DGAVP) was administered to human subjects suffering from cognitive and memory complaints. The patients selected for the study were carefully screened with the aid of neuropsychological assessment procedures. The trials were conducted according to a structured design in which the variables ‘dose’, ‘route of administration’, ‘treatment schedule’, ‘diagnostic group’, and ‘severity of deficit’ were varied from trial to trial in order to find optimal conditions for the possible expression of a peptide effect. The results indicate a statistically significant effect of DGAVP on word list learning in patients with mild brain trauma, suggesting that learning performance and memory retrieval are improved after peptide treatment in these patients. Patients with more severe brain trauma did not respond to peptide treatment. Some DGAVP effects, e.g. increased speed of memory search, were observed in patients with age‐associated memory deficits

VPH-HF: A software framework for the execution of complex subject-specific physiology modelling workflows

Computational medicine more and more requires complex orchestrations of multiple modelling & simulation codes, written in different programming languages and with different computational requirements, which when validated need to be run many times on large cohorts of patients. The aim of this paper is to present a new open source software, the VPH Hypermodelling Framework (VPH-HF). The VPH-HF overcomes the limitations of most workflow execution environments by supporting both Taverna and Muscle2; the addition of Muscle2 support makes possible the execution of very complex orchestrations that include strongly-coupled models. The overhead that the VPH-HF imposes in exchange for this is small, and tends to be flat regardless of the complexity and the computational cost of the hypermodel being executed. We recommend the use of the VPH-HF to orchestrate any hypermodel with an execution time of 200 s or higher, which would confine the VPH-HF overhead to less than 10%. The VPH-HF also provide an automatic caching system over the execution of every hypomodel, which may provide considerable speed-up when the orchestration is run repeatedly over large numbers of patients or within stochastic frameworks, and the input sets are properly binned. The caching system also makes it easy to form large input set/output set databases required to develop reduced-order models, and the framework offers the possibility to dynamically replace single models in the orchestration with reduced-order versions built from cached results, an essential feature when the orchestration of multiple models produces a combinatory explosion of the computational cost

Association of Cancer Susceptibility Variants with Risk of Multiple Primary Cancers: The Population Architecture using Genomics and Epidemiology Study

Multiple primary cancers account for ~16% of all incident cancers in the U.S.. While genome-wide association studies (GWAS) have identified many common genetic variants associated with various cancer sites, no study has examined the association of these genetic variants with risk of multiple primary cancers (MPC)

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

MicroRNAs in Diabetic Nephropathy: From Biomarkers to Therapy

Recent estimates suggest that 1 in 12 of the global population suffers from diabetes mellitus. Approximately 40 % of those affected will go on to develop diabetes-related chronic kidney disease or diabetic nephropathy (DN). DN is a major cause of disability and premature death. Existing tests for prognostic purposes are limited and can be invasive, and interventions to delay progression are challenging. MicroRNAs (miRNAs) are a recently described class of molecular regulators found ubiquitously in human tissues and bodily fluids, where they are highly stable. Alterations in miRNA expression profiles have been observed in numerous diseases. Blood and tissue miRNAs are already established cancer biomarkers, and cardiovascular, metabolic and immune disease miRNA biomarkers are under development. Urinary miRNAs represent a potential novel source of non-invasive biomarkers for kidney diseases, including DN. In addition, recent data suggest that miRNAs may have therapeutic applications. Here, we review the utility of miRNAs as biomarkers for the early detection and progression of DN, assess emerging data on miRNAs implicated in DN pathology and discuss how the data from both fields may contribute to the development of novel therapeutic agents

Genetic analyses of diverse populations improves discovery for complex traits

Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry1–3. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific4–10. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations11,12. Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States—where minority populations have a disproportionately higher burden of chronic conditions13—the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities. © 2019, The Author(s), under exclusive licence to Springer Nature Limited

The isolation and characterization of the promoter of the human type 1 inositol 1,4,5-trisphosphate receptor

In humans, at least three types of inositol (1,4,5)-trisphosphate receptor (IP3R) are present. The gene encoding type 1 IP3R (IP3R-I) is expressed in all cell types, although expression predominates in Purkinje cells. To study the regulation of the human IP3R-I gene, we isolated and characterized a 2.1-kb 5' flanking region. In transient expression assays using a rat cell line, analysis of various deletion mutants demonstrated that a fragment of only 86 bp 5' of the putative tsp displayed a promoter activity similar to that of the 2.1-kb fragment. Also, we compared the sequence of the human IP3R-T promoter with the sequence of the mouse IP3R-I promoter. Considerable sequence homology is present in four distinct domains, which include several conserved putative binding sites for transcription factors. Further, we demonstrate a decrease in the activity of the isolated human IP3R-I promoter and of the endogenous IP3R-I promoter after 48 h of treatment with retinoic acid. Analysis of deletion constructs of the human promoter indicates that the decreased promoter activity in response to retinoic acid is likely to be mediated by a conserved AP-2 binding site. (C) 1998 Elsevier Science B.V