Local influence of boundary conditions on a confined supercooled colloidal liquid

We study confined colloidal suspensions as a model system which approximates the behavior of confined small molecule glass-formers. Dense colloidal suspensions become glassier when confined between parallel glass plates. We use confocal microscopy to study the motion of confined colloidal particles. In particular, we examine the influence particles stuck to the glass plates have on nearby free particles. Confinement appears to be the primary influence slowing free particle motion, and proximity to stuck particles causes a secondary reduction in the mobility of free particles. Overall, particle mobility is fairly constant across the width of the sample chamber, but a strong asymmetry in boundary conditions results in a slight gradient of particle mobility.Comment: For conference proceedings, "Dynamics in Confinement", Grenoble, March 201

Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction

Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD

Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole-genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n = 109,122 individuals. We identified 59 sentinel variants (p < 5 × 10−9) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated that the independent signals colocalized with cell-type-specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes

Enhanced cardiac phosphoinositide 3-kinase (p110α) using gene therapy attenuates cardiac remodeling in type 2 diabetic mice

Diabetic cardiomyopathy is a distinct form of heart disease that represents a major cause of death and disability in diabetic patients, particularly the more prevalent type-2 diabetic population. In the current study, we investigated administration of recombinant adeno-associated viral vectors carrying a constitutively-active PI3K(p110α) construct (rAAV6-caPI3K) at a clinically-relevant time point attenuates diabetic cardiomyopathy in a pre-clinical type-2 diabetes (T2D) model. T2D was induced by a combination of high-fat diet and low-dose streptozotocin, and confirmed by increased body weight, hyperglycemia, and impaired glucose tolerance. After 18 weeks of untreated diabetes, impaired left ventricular (LV) systolic dysfunction was evident, as confirmed by echocardiography. A single tail vein injection of rAAV6-caPI3K gene therapy was then administered. Mice were followed for an additional 8 weeks before end-point. Administration of cardiac targeted rAAV6-caPI3K attenuates diabetes-induced cardiac remodeling by limiting cardiac fibrosis and cardiomyocyte hypertrophy. The diabetes-induced LV systolic dysfunction was reversed with rAAV6-caPI3K as demonstrated by improved fractional shortening and velocity of circumferential fiber shortening. This cardioprotection occurred in combination with reduced LV ROS levels and an associated decrease in markers of endoplasmic reticulum stress. Together, the findings demonstrate that cardiac-selective increases in PI3K(p110α), via rAAV6-caPI3K, attenuates diabetic cardiomyopathy in a mouse model of T2D.Darnel Prakoso, Miles J. De Blasio, Mitchel Tate, Helen Kiriazis, Daniel G. Donner, Hongwei Qian ... et al

Interactive Effects of Dietary Copper, Water Copper, and Eimeria spp. Infection on Growth, Water Intake, and Plasma and Liver Copper Concentrations of Poults

The effects of dietary Cu, water Cu, and coccidial infection on poult growth performance and selected tissue mineral concentrations were investigated in a 10-d experiment using 200 5-d-old Nicholas toms (five replicates of 5 poults each; initial weight = 85 g). Uninfected and coccidiosis-infected (Eimeria meleagrimitis, Eimeria dispersa, Eimeria adenoeides, and Eimeria gallopavonis; cocci) poults were assigned to two levels of dietary Cu [Basal (B) and B + 204 mg Cu/kg diet on Days 1 to 10] and two levels of water Cu (0 and 103 mg Cu/kg water on Days 6 to 10). Dietary Cu and water Cu (main effects) did not affect (P \u3e .10) gain, feed intake, gain:feed, water intake, hemoglobin, hematocrit, or liver Fe and Zn concentrations. Dietary Cu and water Cu increased (P \u3c .03) liver and plasma Cu concentrations. The combination of dietary Cu and water Cu increased plasma Cu more than the sum of the Cu additions (dietary Cu by water Cu, P \u3c .08). Coccidial infection reduced (P \u3c .07) gain, feed intake, gain:feed, water intake, and hemoglobin, and increased (P \u3c .02) liver Zn. Water Cu reduced water intake in uninfected poults but increased water intake in coccidiosis-infected poults (water Cu by cocci, P \u3c .07). Water Cu increased hemoglobin in uninfected poults but decreased hemoglobin in coccidiosis-infected poults (water Cu by cocci, P \u3c .07). Water Cu increased plasma Cu and liver Cu more in coccidiosis-infected poults than in uninfected poults (water Cu by cocci, P \u3c .02).(ABSTRACT TRUNCATED AT 250 WORDS