Mitochondrial DNA Copy Number and Incident Heart Failure: The Atherosclerosis Risk in Communities (ARIC) Study

Heart failure (HF) is a leading clinical and public health concern because of its high prevalence and poor prognosis. It is thus critical to identify novel risk factors for developing HF. Mitochondrial DNA copy number (mtDNA-CN), an indirect biomarker of mitochondrial dysfunction, is associated with atherosclerotic cardiovascular disease endpoints, cardiovascular risk factors, all-cause mortality, and sudden cardiac death. The association between mtDNA-CN and the risk of incident HF, however, is unknown. We examined this association in the Atherosclerosis Risk in Communities (ARIC) cohort

A Genome-wide Association Study Discovers 46 Loci of the Human Metabolome in the Hispanic Community Health Study/Study of Latinos

Variation in levels of the human metabolome reflect changes in homeostasis, providing a window into health and disease. The genetic impact on circulating metabolites in Hispanics, a population with high cardiometabolic disease burden, is largely unknown. We conducted genome-wide association analyses on 640 circulating metabolites in 3,926 Hispanic Community Health Study/Study of Latinos participants. The estimated heritability for 640 metabolites ranged between 0%–54% with a median at 2.5%. We discovered 46 variant-metabolite pairs (p value < 1.2 × 10−10, minor allele frequency ≥ 1%, proportion of variance explained [PEV] mean = 3.4%, PEVrange = 1%–22%) with generalized effects in two population-based studies and confirmed 301 known locus-metabolite associations. Half of the identified variants with generalized effect were located in genes, including five nonsynonymous variants. We identified co-localization with the expression quantitative trait loci at 105 discovered and 151 known loci-metabolites sets. rs5855544, upstream of SLC51A, was associated with higher levels of three steroid sulfates and co-localized with expression levels of SLC51A in several tissues. Mendelian randomization (MR) analysis identified several metabolites associated with coronary heart disease (CHD) and type 2 diabetes. For example, two variants located in or near CYP4F2 (rs2108622 and rs79400241, respectively), involved in vitamin E metabolism, were associated with the levels of octadecanedioate and vitamin E metabolites (gamma-CEHC and gamma-CEHC glucuronide); MR analysis showed that genetically high levels of these metabolites were associated with lower odds of CHD. Our findings document the genetic architecture of circulating metabolites in an underrepresented Hispanic/Latino community, shedding light on disease etiology

Modelling spectral and timing properties of accreting black holes: the hybrid hot flow paradigm

The general picture that emerged by the end of 1990s from a large set of optical and X-ray, spectral and timing data was that the X-rays are produced in the innermost hot part of the accretion flow, while the optical/infrared (OIR) emission is mainly produced by the irradiated outer thin accretion disc. Recent multiwavelength observations of Galactic black hole transients show that the situation is not so simple. Fast variability in the OIR band, OIR excesses above the thermal emission and a complicated interplay between the X-ray and the OIR light curves imply that the OIR emitting region is much more compact. One of the popular hypotheses is that the jet contributes to the OIR emission and even is responsible for the bulk of the X-rays. However, this scenario is largely ad hoc and is in contradiction with many previously established facts. Alternatively, the hot accretion flow, known to be consistent with the X-ray spectral and timing data, is also a viable candidate to produce the OIR radiation. The hot-flow scenario naturally explains the power-law like OIR spectra, fast OIR variability and its complex relation to the X-rays if the hot flow contains non-thermal electrons (even in energetically negligible quantities), which are required by the presence of the MeV tail in Cyg X-1. The presence of non-thermal electrons also lowers the equilibrium electron temperature in the hot flow model to <100 keV, making it more consistent with observations. Here we argue that any viable model should simultaneously explain a large set of spectral and timing data and show that the hybrid (thermal/non-thermal) hot flow model satisfies most of the constraints.Comment: 26 pages, 13 figures. To be published in the Space Science Reviews and as hard cover in the Space Sciences Series of ISSI - The Physics of Accretion on to Black Holes (Springer Publisher

Best Practices and Joint Calling of the HumanExome BeadChip: The CHARGE Consortium

Genotyping arrays are a cost effective approach when typing previously-identified genetic polymorphisms in large numbers of samples. One limitation of genotyping arrays with rare variants (e.g., minor allele frequency [MAF] <0.01) is the difficulty that automated clustering algorithms have to accurately detect and assign genotype calls. Combining intensity data from large numbers of samples may increase the ability to accurately call the genotypes of rare variants. Approximately 62,000 ethnically diverse samples from eleve

Metamorphosis and Taxonomy of Andreev Bound States

We analyze the spatial and energy dependence of the local density of states in a SNS junction. We model our system as a one-dimensional tight-binding chain which we solve exactly by numerical diagonalization. We calculate the dependence of the Andreev bound states on position, phase difference, gate voltage, and coupling with the superconducting leads. Our results confirm the physics predicted by certain analytical approximations, but reveal a much richer set of phenomena beyond the grasp of these approximations, such as the metamorphosis of the discrete states of the normal link (the normal bound states) into Andreev bound states as the leads become superconducting.Comment: 23 pages, 15 figure

Radiation therapy and photodynamic therapy for biliary tract and ampullary carcinomas

The purpose of radiation therapy for unresectable biliary tract cancer is to prolong survival or prolong stent patency, and to provide palliation of pain. For unresectable bile duct cancer, there are a number of studies showing that radiation therapy is superior to the best supportive care. Although radiation therapy is used in many institutions, no large randomized controlled trials (RCTs) have been performed to date and the evidence level supporting the superiority of this treatment is low. Because long-term relief of jaundice is difficult without using biliary stenting, a combination of radiation therapy and stent placement is commonly used. As radiation therapy, external-beam radiation therapy is usually performed, but combined use of intraluminal brachytherapy with external beam radiation therapy is more useful for making the treatment more effective. There are many reports demonstrating improved response rates as well as extended survival and time to recurrence achieved by this combination therapy. Despite the low level of the evidence, this combination therapy is performed at many institutions. It is expected that multiinstitutional RCTs will be carried out. Unresectable gallbladder cancer with a large focus is usually extensive, and normal organs with high radio sensitivity exist contiguously with it. Therefore, only limited anticancer effects are to be expected from external beam radiation therapy for this type of cancer. The number of reports on ampullary cancer is small and the role of radiation therapy in this cancer has not been established. Combination treatment for ampullary cancer consists of either a single use of intraoperative radiation therapy, postoperative external beam radiation therapy or intraluminal brachytherapy, or a combination of two or three of these therapies. Intraoperative radiation therapy is superior in that it enables precise irradiation to the target site, thereby protecting adjacent highly radiosensitive normal tissues from irradiation. There are reports showing extended survival, although not significant, in groups undergoing intraoperative or postoperative radiation therapy compared with groups without radiation therapy. To date, there are no reports of large RCTs focusing on the significance of radiation therapy as a postoperative adjuvant treatment, so its usefulness as a postoperative adjuvant treatment is not proven. An alternative treatment is photodynamic therapy. There is an RCT demonstrating that, in unresectable bile duct cancer, extended survival and improved quality of life (QOL) have been achieved through a combination of photodynamic therapy and biliary stenting, compared with biliary stenting alone. Results from large RCTs are desired

Forest Biodiversity Assessment in Peruvian Andean Montane Cloud Forest

Cloud forests are unusual and fragile habitats, being one of the least studied and least understood ecosystems. The tropical Andean dominion is considered one of the most significant places in the world as rega rds biological diversity, with a very high level of endemism. The biodiversity was analysed in an isolated remnant area of a tropical montane cloud forest known as the ?Bosque de Neblina de Cuyas?, in the North of the Peruvian Andean range. Composition, structure and dead wood were measured or estimated. The values obtained were compared with other cloud forests. The study revealed a high level of forest biodiversity, although the level of biodiversity differs from one area to another: in the inner areas, where human pressure is almost inexistent, the biodiversity values increase. The high species richness and the low dominance among species bear testimony to this montane cloud forest as a real enclave of biodiversity

Functionally oriented analysis of cardiometabolic traits in a trans-ethnic sample

Interpretation of genetic association results is difficult because signals often lack biological context. To generate hypotheses of the functional genetic etiology of complex cardiometabolic traits, we estimated the genetically determined component of gene expression from common variants using PrediXcan (1) and determined genes with differential predicted expression by trait. PrediXcan imputes tissue-specific expression levels from genetic variation using variant-level effect on gene expression in transcriptome data. To explore the value of imputed genetically regulated gene expression (GReX) models across different ancestral populations, we evaluated imputed expression levels for predictive accuracy genome-wide in RNA sequence data in samples drawn from European-Ancestry and African-Ancestry populations and identified substantial predictive power using European-derived models in a non-European target population.We then tested the association of GReX on 15 cardiometabolic traits including blood lipid levels, body mass index, height, blood pressure, fasting glucose and insulin, RR interval, fibrinogen level, factor VII level and white blood cell and platelet counts in 15 755 individuals across three ancestry groups, resulting in 20 novel gene-phenotype associations reaching experiment-wide significance across ancestries. In addition, we identified 18 significant novel gene-phenotype associations in our ancestry-specific analyses. Top associations were assessed for additional support via query of S-PrediXcan (2) results derived from publicly available genome-wide association studies summary data. Collectively, these findings illustrate the utility of transcriptome-based imputation models for discovery of cardiometabolic effect genes in a diverse dataset

Methylome-wide association study of central adiposity implicates genes involved in immune and endocrine systems

Aim: We conducted a methylome-wide association study to examine associations between DNA methylation in whole blood and central adiposity and body fat distribution, measured as waist circumference, waist-to-hip ratio and waist-to-height ratio adjusted for body mass index, in 2684 African-American adults in the Atherosclerosis Risk in Communities study. Materials & methods: We validated significantly associated cytosine-phosphate-guanine methylation sites (CpGs) among adults using the Women's Health Initiative and Framingham Heart Study participants (combined n = 5743) and generalized associations in adolescents from The Raine Study (n = 820). Results & conclusion: We identified 11 CpGs that were robustly associated with one or more central adiposity trait in adults and two in adolescents, including CpG site associations near TXNIP, ADCY7, SREBF1 and RAP1GAP2 that had not previously been associated with obesity-related traits

Meta-analysis of exome array data identifies six novel genetic loci for lung function

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P<2·8x10-7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs (SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU. Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease