Our aim was to describe the incidence and predictors of stroke in patients who have heart failure without atrial fibrillation (AF).
We pooled 2 contemporary heart failure trials, the Controlled ...Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza cardiaca-Heart Failure trial (GISSI-HF). Of the 9585 total patients, 6054 did not have AF. Stroke occurred in 165 patients (4.7%) with AF and in 206 patients (3.4%) without AF (rates 16.8/1000 patient-years and 11.1/1000 patient-years, respectively). Using Cox proportional-hazards models, we identified the following independent predictors of stroke in patients without AF (ranked by χ(2) value): age (hazard ratio, 1.34; 95% confidence interval, 1.18-1.63 per 10 years), New York Heart Association class (1.60, 1.21-2.12 class III/IV versus II), diabetes mellitus treated with insulin (1.87, 1.22-2.88), body mass index (0.74, 0.60-0.91 per 5 kg/m(2) up to 30), and previous stroke (1.81, 1.19-2.74). N-terminal pro B-type natriuretic peptide (available in 2632 patients) was also an independent predictor of stroke (hazard ratio, 1.31; 1.11-1.57 per log unit) when added to this model. With the use of a risk score formulated from these predictors, we found that patients in the upper third of risk had a rate of stroke that approximated the risk in patients with AF.
A small number of demographic and clinical variables identified a subset of patients who have heart failure without AF at a high risk of stroke.
EMU is an efficient and scalable model to simulate bulk musculoskeletal motion with heterogenous materials. First, EMU requires no model reductions, or geometric coarsening, thereby producing results ...visually accurate when compared to an FEM simulation. Second, EMU is efficient and scales much better than state‐of‐the‐art FEM with the number of elements in the mesh, and is more easily parallelizable. Third, EMU can handle heterogeneously stiff meshes with an arbitrary constitutive model, thus allowing it to simulate soft muscles, stiff tendons and even stiffer bones all within one unified system. These three key characteristics of EMU enable us to efficiently orchestrate muscle activated skeletal movements. We demonstrate the efficacy of our approach via a number of examples with tendons, muscles, bones and joints.
EMU is an efficient and scalable model to simulate bulk musculoskeletal motion with heterogenous materials.
Drosophila melanogaster is unique among animal models because it has a fully defined synthetic diet available to study nutrient-gene interactions. However, use of this diet is limited to adult ...studies due to impaired larval development and survival. Here, we provide an adjusted formula that reduces the developmental period, restores fat levels, enhances body mass, and fully rescues survivorship without compromise to adult lifespan. To demonstrate an application of this formula, we explored pre-adult diet compositions of therapeutic potential in a model of an inherited metabolic disorder affecting the metabolism of branched-chain amino acids. We reveal rapid, specific, and predictable nutrient effects on the disease state consistent with observations from mouse and patient studies. Together, our diet provides a powerful means with which to examine the interplay between diet and metabolism across all life stages in an animal model.
Unravelling regulatory programs governed by transcription factors (TFs) is fundamental to understanding biological systems. TFCat is a catalog of mouse and human TFs based on a reliable core ...collection of annotations obtained by expert review of the scientific literature. The collection, including proven and homology-based candidate TFs, is annotated within a function-based taxonomy and DNA-binding proteins are organized within a classification system. All data and user-feedback mechanisms are available at the TFCat portal (http://www.tfcat.ca).
Microfluidics, a technology characterized by the engineered manipulation of fluids at the submillimetre scale, has shown considerable promise for improving diagnostics and biology research. Certain ...properties of microfluidic technologies, such as rapid sample processing and the precise control of fluids in an assay, have made them attractive candidates to replace traditional experimental approaches. Here we analyse the progress made by lab-on-a-chip microtechnologies in recent years, and discuss the clinical and research areas in which they have made the greatest impact. We also suggest directions that biologists, engineers and clinicians can take to help this technology live up to its potential.
Genome-wide association studies (GWAS) have identified >500 common variants associated with quantitative metabolic traits, but in aggregate such variants explain at most 20-30% of the heritable ...component of population variation in these traits. To further investigate the impact of genotypic variation on metabolic traits, we conducted re-sequencing studies in >6,000 members of a Finnish population cohort (The Northern Finland Birth Cohort of 1966 NFBC) and a type 2 diabetes case-control sample (The Finland-United States Investigation of NIDDM Genetics FUSION study). By sequencing the coding sequence and 5' and 3' untranslated regions of 78 genes at 17 GWAS loci associated with one or more of six metabolic traits (serum levels of fasting HDL-C, LDL-C, total cholesterol, triglycerides, plasma glucose, and insulin), and conducting both single-variant and gene-level association tests, we obtained a more complete understanding of phenotype-genotype associations at eight of these loci. At all eight of these loci, the identification of new associations provides significant evidence for multiple genetic signals to one or more phenotypes, and at two loci, in the genes ABCA1 and CETP, we found significant gene-level evidence of association to non-synonymous variants with MAF<1%. Additionally, two potentially deleterious variants that demonstrated significant associations (rs138726309, a missense variant in G6PC2, and rs28933094, a missense variant in LIPC) were considerably more common in these Finnish samples than in European reference populations, supporting our prior hypothesis that deleterious variants could attain high frequencies in this isolated population, likely due to the effects of population bottlenecks. Our results highlight the value of large, well-phenotyped samples for rare-variant association analysis, and the challenge of evaluating the phenotypic impact of such variants.
Brønsted-acid sites are introduced via –OSO
3
H groups on the coordinatively unsaturated ZrO
2
nodes of UiO-66 metal organic frameworks (MOFs). Such groups create strong Brønsted acidic sites that ...are active for cyclohexanol and ethanol dehydration (in liquid organic phase and gas phase, respectively). The intrinsic activity of Brønsted acid sites at nodes increased by increasing the concentration of sulfur, which is attributed to a shift from isolated µ
3
− OSO
3
H to two groups (µ
3
− OSO
3
H)
2
interacting via hydrogen bonding. For cyclohexanol dehydration, the relatively low activation enthalpies and negative transition entropies point to an E2 elimination mechanism, similar to dehydration with MFI zeolites in organic solvents. Our results, show that the catalytic activity can be manipulated via the functionalization of zirconia nodes of the MOF framework.
A comprehensive analysis of the H3O+ and H2O structure in the first solvation shell about Cl− in aqueous HCl solutions is reported from X-ray absorption fine structure (XAFS) measurements. Results ...show increasing degree of contact ion pairing between Cl− and H3O+ as the HCl concentration increases from 6.0 m, 10.0 m, and finally 16.1 m HCl (acid concentrations are expressed as molality or mole HCl/1000 g water). At the highest acid concentration there are on average, approximately 1.6 H3O+ ions and 4.2 H2O’s in the first shell about Cl−. The structure of the Cl−/H3O+ contact ion pair is distinctly different from that of the H2O structure about Cl−. The Cl−O bond length (2.98 Å) for Cl−/H3O+ is approximately 0.16 Å shorter than the Cl−/H2O bond. The bridging proton resides at an intermediate position between Cl and O at 1.60 Å from the Cl− and approximately 1.37 Å from the O of the H3O+. The bridging-proton structure of this contact ion pair, (Cl−H−OH2), is similar to the structure of the water Zundel ion, (H2O−H−OH2 +). In both cases there is a shortened Cl−O or O−O bond, and the intervening proton bond distances are substantially longer than for the covalent bonds of either HCl or H2O. A detailed structural analysis of the aqueous chloride species, Cl−/(H2O) n , was also completed as part of this study in order to understand the relative importance of various XAFS photoelectron scattering paths. For aqueous Cl− the measured Cl−O and Cl−H distances of 3.14 Å and 2.23 Å, respectively, are in excellent agreement with earlier neutron and X-ray diffraction results. Overall, these results significantly improve our understanding of the interaction of H3O+ with Cl−. The results are of interest to fundamental physical chemistry and they have important consequences in biochemical, geochemical, and atmospheric processes.
With an incidence of ~1 in 800 births, Down syndrome (DS) is the most common chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a ...triplication of chromosome 21 (HSA21), the genes encoded from HSA21 that directly contribute to cognitive deficits remain incompletely understood. Here, we found that the HSA21-encoded chromatin effector, BRWD1, was upregulated in neurons derived from iPS cells from an individual with Down syndrome and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued deficits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes.
Retinoblastoma is a rare childhood cancer of the developing retina. Most retinoblastomas initiate with biallelic inactivation of the RB1 gene through diverse mechanisms including point mutations, ...nucleotide insertions, deletions, loss of heterozygosity and promoter hypermethylation. Recently, a novel mechanism of retinoblastoma initiation was proposed. Gallie and colleagues discovered that a small proportion of retinoblastomas lack RB1 mutations and had MYCN amplification 1. In this study, we identified recurrent chromosomal, regional and focal genomic lesions in 94 primary retinoblastomas with their matched normal DNA using SNP 6.0 chips. We also analyzed the RB1 gene mutations and compared the mechanism of RB1 inactivation to the recurrent copy number variations in the retinoblastoma genome. In addition to the previously described focal amplification of MYCN and deletions in RB1 and BCOR, we also identified recurrent focal amplification of OTX2, a transcription factor required for retinal photoreceptor development. We identified 10 retinoblastomas in our cohort that lacked RB1 point mutations or indels. We performed whole genome sequencing on those 10 tumors and their corresponding germline DNA. In one of the tumors, the RB1 gene was unaltered, the MYCN gene was amplified and RB1 protein was expressed in the nuclei of the tumor cells. In addition, several tumors had complex patterns of structural variations and we identified 3 tumors with chromothripsis at the RB1 locus. This is the first report of chromothripsis as a mechanism for RB1 gene inactivation in cancer.
PDF
