Peroxisome proliferator-activated receptor δ (PPARδ) is a critical regulator of energy metabolism in the heart. Here, we propose a mechanism that integrates two deleterious characteristics of heart failure, hypoxia and a metabolic shift toward glycolysis, involving the microRNA cluster miR-199a∼214 and PPARδ. We demonstrate that under hemodynamic stress, cardiac hypoxia activates DNM3os, a noncoding transcript that harbors the microRNA cluster miR-199a∼214, which shares PPARδ as common target. To address the significance of miR-199a∼214 induction and concomitant PPARδ repression, we performed antagomir-based silencing of both microRNAs and subjected mice to biomechanical stress to induce heart failure. Remarkably, antagomir-treated animals displayed improved cardiac function and restored mitochondrial fatty acid oxidation. Taken together, our data suggest a mechanism whereby miR-199a∼214 actively represses cardiac PPARδ expression, facilitating a metabolic shift from predominant reliance on fatty acid utilization in the healthy myocardium toward increased reliance on glucose metabolism at the onset of heart failure.

Talladega belt, southernmost Appalachians, provide insight into the timing and nature of pre-Alleghanian tectonism in this region. Low-grade metasedimentary rocks of the Talladega belt represent the outermost preserved portions of the southern Laurentian margin, thus recording the earliest orogenic events that affected the margin, in addition to later overprinting events. These rocks are structurally overlain by the Hillabee Greenstone metavolcanic sequence, from which metadacite yields an age of ‫4ע074‬ Ma (ion microprobe U-Pb zircon age). Hillabee geochemistry indicates formation in an arc or back-arc setting. We suggest correlation of the Hillabee Greenstone with 460-470-Ma arc-related rocks in the Dahlonega gold belt, which extends along strike with the Hillabee through Georgia and into North Carolina, and interpret the Hillabee as the southernmost volcanic expression of an Early-Middle Ordovician arc that formed outboard of Laurentia. Rocks of the Talladega belt, including the Hillabee, preserve a record of only one Paleozoic dynamothermal metamorphic event. 40 Ar/ 39 Ar dates are consistent with metamorphism following deposition of the youngest biostratigraphically dated unit, the Erin Slate, which contains early Mississippian Periastron plant fossils (360-350 Ma). Muscovite (closure temperature 350Њ-400ЊC) yields internally consistent ages between 334 and 320 Ma. Metamorphism of the Talladega belt, therefore, is constrained to the interval between 360 and 320 Ma. The pre-to synmetamorphic thrust contact between the Hillabee Greenstone and Talladega belt metasedimentary rocks must have formed after deposition of the Erin Slate at 360-350 Ma but before metamorphism of the Talladega belt (no later than ∼320 Ma). We propose that the Ordovician Hillabee-Dahlonega arc terrane first collided with the Laurentian continental margin between 360 and 320 Ma, with variations in timing of deformation and metamorphic character along the collision zone.

Biomarkers for primary or secondary risk prediction of cardiovascular disease (CVD) are urgently needed to improve individual treatment and clinical trial design. The vast majority of biomarker discovery studies has concentrated on plasma/serum as an easily accessible source. Although numerous markers have been identified, their added predictive value on top of traditional risk factors has been limited, as the biological specimen does not specifically reflect expression profiles related with CVD progression and because the signal is often diluted by marker release from other organs. In contrast to serum markers, circulating cells serve as indicators of the actual disease state due to their active role in the pathogenesis of CVD and are responsible for the majority of secreted biomarkers. Therefore, the CIRCULATING CELLS study was initiated, focusing on the cellular effectors of atherosclerosis in the circulation. In total, 714 patients with coronary artery disease (CAD) symptoms were included. Blood cell fractions (monocytes, T-lymphocytes, platelets, granulocytes, PBMC) of all individual patients were isolated and stored for analysis. Concomitantly, extensive flow cytometric characterization of these populations was performed. From each patient, a detailed clinical profile together with extensive questionnaires about medical history and life style was obtained. Various high-throughput -omics approaches (protein, mRNA, miRNA) are currently being undertaken. Data will be integrated with advanced bioinformatics for discovery and validation of secondary risk markers for adverse events. Overall, the CIRCULATING CELLS study grants the interesting possibility that it will both identify novel biomarkers and provide useful insights into the pathophysiology of CAD in patients.

BackgroundNext generation sequencing provides clinical research scientists with direct read out of innumerable variants, including personal, pathological and common benign variants. The aim of resequencing studies is to determine the candidate pathogenic variants from individual genomes, or from family-based or tumor/normal genome comparisons. Whilst the use of appropriate controls within the experimental design will minimize the number of false positive variations selected, this number can be reduced further with the use of high quality whole genome reference data to minimize false positives variants prior to candidate gene selection. In addition the use of platform related sequencing error models can help in the recovery of ambiguous genotypes from lower coverage data.DescriptionWe have developed a whole genome database of human genetic variations, Huvariome, determined by whole genome deep sequencing data with high coverage and low error rates. The database was designed to be sequencing technology independent but is currently populated with 165 individual whole genomes consisting of small pedigrees and matched tumor/normal samples sequenced with the Complete Genomics sequencing platform. Common variants have been determined for a Benelux population cohort and represented as genotypes alongside the results of two sets of control data (73 of the 165 genomes), Huvariome Core which comprises 31 healthy individuals from the Benelux region, and Diversity Panel consisting of 46 healthy individuals representing 10 different populations and 21 samples in three Pedigrees. Users can query the database by gene or position via a web interface and the results are displayed as the frequency of the variations as detected in the datasets. We demonstrate that Huvariome can provide accurate reference allele frequencies to disambiguate sequencing inconsistencies produced in resequencing experiments. Huvariome has been used to support the selection of candidate cardiomyopathy related genes which have a homozygous genotype in the reference cohorts. This database allows the users to see which selected variants are common variants (> 5% minor allele frequency) in the Huvariome core samples, thus aiding in the selection of potentially pathogenic variants by filtering out common variants that are not listed in one of the other public genomic variation databases. The no-call rate and the accuracy of allele calling in Huvariome provides the user with the possibility of identifying platform dependent errors associated with specific regions of the human genome.ConclusionHuvariome is a simple to use resource for validation of resequencing results obtained by NGS experiments. The high sequence coverage and low error rates provide scientists with the ability to remove false positive results from pedigree studies. Results are returned via a web interface that displays location-based genetic variation frequency, impact on protein function, association with known genetic variations and a quality score of the variation base derived from Huvariome...

No abstract