The Hydrodynamic Interaction in Polymer Solutions Simulated with Dissipative Particle Dynamics

We analyzed extensively the dynamics of polymer chains in solutions simulated with dissipative particle dynamics (DPD), with a special focus on the potential influence of a low Schmidt number of a typical DPD fluid on the simulated polymer dynamics. It has been argued that a low Schmidt number in a DPD fluid can lead to underdevelopment of the hydrodynamic interaction in polymer solutions. Our analyses reveal that equilibrium polymer dynamics in dilute solution, under a typical DPD simulation conditions, obey the Zimm model very well. With a further reduction in the Schmidt number, a deviation from the Zimm model to the Rouse model is observed. This implies that the hydrodynamic interaction between monomers is reasonably developed under typical conditions of a DPD simulation. Only when the Schmidt number is further reduced, the hydrodynamic interaction within the chains becomes underdeveloped. The screening of the hydrodynamic interaction and the excluded volume interaction as the polymer volume fraction is increased are well reproduced by the DPD simulations. The use of soft interaction between polymer beads and a low Schmidt number do not produce noticeable problems for the simulated dynamics at high concentrations, except that the entanglement effect which is not captured in the simulations.Comment: 27 pages, 13 page

Anabolic effects of IGF-1 signaling on the skeleton

This review focuses on the anabolic effects of IGF-1 signaling on the skeleton, emphasizing the requirement for IGF-1 signaling in normal bone formation and remodeling. We first discuss the genomic context, splicing variants, and species conservation of the IGF-1 locus. The modulation of IGF-1 action by growth hormone (GH) is then reviewed while also discussing the current model which takes into account the GH-independent actions of IGF-1. Next, the skeletal phenotypes of IGF-1-deficient animals are described in both embryonic and postnatal stages of development, which include severe dwarfism and an undermineralized skeleton. We then highlight two mechanisms by which IGF-1 exerts its anabolic action on the skeleton. Firstly, the role of IGF-1 signaling in the modulation of anabolic effects of parathyroid hormone (PTH) on bone will be discussed, presenting in vitro and in vivo studies that establish this concept and the proposed underlying molecular mechanisms involving Indian hedgehog (Ihh) and the ephrins. Secondly, the crosstalk of IGF-1 signaling with mechanosensing pathways will be discussed, beginning with the observation that animals subjected to skeletal unloading by hindlimb elevation are unable to mitigate cessation of bone growth despite infusion with IGF-1 and the failure of IGF-1 to activate its receptor in bone marrow stromal cell cultures from unloaded bone. Disrupted crosstalk between IGF-1 signaling and the integrin mechanotransduction pathways is discussed as one of the potential mechanisms for this IGF-1 resistance. Next, emerging paradigms on bone-muscle crosstalk are examined, focusing on the potential role of IGF-1 signaling in modulating such interactions. Finally, we present a future outlook on IGF research

Pressure Driven Flow of Polymer Solutions in Nanoscale Slit Pores

Polymer solutions subject to pressure driven flow and in nanoscale slit pores are systematically investigated using the dissipative particle dynamics approach. We investigated the effect of molecular weight, polymer concentration and flow rate on the profiles across the channel of the fluid and polymer velocities, polymers density, and the three components of the polymers radius of gyration. We found that the mean streaming fluid velocity decreases as the polymer molecular weight or/and polymer concentration is increased, and that the deviation of the velocity profile from the parabolic profile is accentuated with increase in polymer molecular weight or concentration. We also found that the distribution of polymers conformation is highly anisotropic and non-uniform across the channel. The polymer density profile is also found to be non-uniform, exhibiting a local minimum in the center-plane followed by two symmetric peaks. We found a migration of the polymer chains either from or towards the walls. For relatively long chains, as compared to the thickness of the slit, a migration towards the walls is observed. However, for relatively short chains, a migration away from the walls is observed.Comment: 11 pages, 13 figure

Actin and dynamin2 dynamics and interplay during clathrin-mediated endocytosis.

Clathrin-mediated endocytosis (CME) involves the recruitment of numerous proteins to sites on the plasma membrane with prescribed timing to mediate specific stages of the process. However, how choreographed recruitment and function of specific proteins during CME is achieved remains unclear. Using genome editing to express fluorescent fusion proteins at native levels and live-cell imaging with single-molecule sensitivity, we explored dynamin2 stoichiometry, dynamics, and functional interdependency with actin. Our quantitative analyses revealed heterogeneity in the timing of the early phase of CME, with transient recruitment of 2-4 molecules of dynamin2. In contrast, considerable regularity characterized the final 20 s of CME, during which ∼26 molecules of dynamin2, sufficient to make one ring around the vesicle neck, were typically recruited. Actin assembly generally preceded dynamin2 recruitment during the late phases of CME, and promoted dynamin recruitment. Collectively, our results demonstrate precise temporal and quantitative regulation of the dynamin2 recruitment influenced by actin polymerization

Long-term clinical consequences of acute kidney injury in the HIV-infected

To evaluate the long-term consequences of acute kidney injury (AKI) in human immunodeficiency virus (HIV)-infected persons, we studied 17,325 patients in a national HIV registry during their first hospitalization. We determined the association of AKI with risk for heart failure, cardiovascular events, end-stage renal disease (ESRD), and mortality beginning 90 days after discharge. Based on AKI Network criteria, 2453 had stage 1; 273 had stage 2 or 3; and 334 had dialysis-requiring AKI. Over a mean follow-up period of 5.7 years, 333 had heart failure, 673 had cardiovascular diseases (CVDs), 348 developed ESRD, and 8405 deaths occurred. In multivariable-adjusted analyses, AKI stage 1 was associated with death and ESRD, but not heart failure or other CVD. Dialysis-requiring AKI had much stronger and significant associations with increased risk for long-term ESRD, and death in addition to heart failure and cardiovascular events. When AKI was reclassified to account for recovery, stage 1 with recovery was still associated with death, but not ESRD. Thus, in this national sample of HIV-infected persons, we found the clinical repercussions of AKI appear to extend beyond the hospital setting contributing to excess cardiovascular risks, ESRD, and mortality. Additionally, AKI affected almost one of six patients with HIV who survived at least 90 days following discharge

Racial/Ethnic Patterns in Prostate Cancer Outcomes in an Active Surveillance Cohort

Introduction. Concern regarding overtreatment of prostate cancer (CaP) is leading to increased attention on active surveillance (AS). This study examined CaP survivors on AS and compared secondary treatment patterns and overall survival by race/ethnicity. Methods. The study population consisted of CaP patients self-classified as black or white followed on AS in the Center for Prostate Disease Research (CPDR) multicenter national database between 1989 and 2008. Secondary treatment included radical prostatectomy (RP), external beam radiation therapy or brachytherapy (EBRT-Br), and hormone therapy (HT). Secondary treatment patterns and overall survival were compared by race/ethnicity. Results. Among 886 eligible patients, 21% were black. Despite racial differences in risk characteristics and secondary treatment patterns, overall survival was comparable across race. RP following AS was associated with the longest overall survival. Conclusion. Racial disparity in overall survival was not observed in this military health care beneficiary cohort with an equal access to health care

Vitamin D-responsive SGPP2 variants associated with lung cell expression and lung function

Background: Vitamin D is associated with lung health in epidemiologic studies, but mechanisms mediating observed associations are poorly understood. This study explores mechanisms for an effect of vitamin D in lung through an in vivo gene expression study, an expression quantitative trait loci (eQTL) analysis in lung tissue, and a population-based cohort study of sequence variants. Methods: Microarray analysis investigated the association of gene expression in small airway epithelial cells with serum 25(OH)D in adult non-smokers. Sequence variants in candidate genes identified by the microarray were investigated in a lung tissue eQTL database, and also in relation to cross-sectional pulmonary function in the Health, Aging, and Body Composition (Health ABC) study, stratified by race, with replication in the Framingham Heart Study (FHS). Results: 13 candidate genes had significant differences in expression by serum 25(OH)D (nominal p < 0.05), and a genome-wide significant eQTL association was detected for SGPP2. In Health ABC, SGPP2 SNPs were associated with FEV1 in both European- and African-Americans, and the gene-level association was replicated in European-American FHS participants. SNPs in 5 additional candidate genes (DAPK1, FSTL1, KAL1, KCNS3, and RSAD2) were associated with FEV1 in Health ABC participants. Conclusions: SGPP2, a sphingosine-1-phosphate phosphatase, is a novel vitamin D-responsive gene associated with lung function. The identified associations will need to be followed up in further studies

Toward an Artificial Golgi: Redesigning the Biological Activities of Heparan Sulfate on a Digital Microfluidic Chip

Using digital microfluidics, recombinant enzyme technology, and magnetic nanoparticles, we have created a functional prototype of an artificial Golgi organelle. Analogous to the natural Golgi, which is responsible for the enzymatic modification of glycosaminoglycans immobilized on proteins, this artificial Golgi enzymatically modifies glycosaminoglycans, specifically heparin sulfate (HS) chains immobilized onto magnetic nanoparticles. Sulfo groups were transferred from adenosine 3′-phosphate 5′-phosphosulfate to the 3-hydroxyl group of the D-glucosamine residue in an immobilized HS chain using D-glucosaminyl 3-O-sulfotransferase. After modification, the nanoparticles with immobilized HS exhibited increased affinity for fluorescently labeled antithrombin III as detected by confocal microscopy. Since the biosynthesis of HS involves an array of specialized glycosyl transferases, epimerase, and sulfotransferases, this approach should mimic the synthesis of HS in vivo. Furthermore, our method demonstrates the feasibility of investigating the effects of multi-enzyme systems on the structure of final glycan products for HS-based glycomic studies

Uromodulin concentrations are not associated with incident CKD among persons with coronary artery disease

<p>Abstract</p> <p>Background</p> <p>A common variant of the UMOD gene was linked with prevalent chronic kidney disease (CKD) in large, genomics consortia. One community-based study found that urine concentrations of the uromodulin protein forecast risk of incident CKD. This study within persons with known coronary artery disease (CAD) evaluated whether uromodulin concentrations could distinguish CKD risk.</p> <p>Methods</p> <p>In the Heart and Soul Study, the UMOD snp (12917707) was genotyped in 879 individuals with baseline creatinine clearance (CrCl) measured from a 24-hour urine collection. Uromodulin protein was measured from stored urine specimens among a subset of 120 participants, balanced by genotype. Incident CKD cases (N = 102) were defined by an initial CrCl > 70 ml/min and a 5-year follow-up CrCl <60 ml/min; controls (N = 94) were matched on age, sex, and race.</p> <p>Results</p> <p>Among 527 self-described White participants with DNA, 373 (71%) were homozygous for the dominant allele (G/G), 133 (25%) were heterozygous (G/T) and only 21 (4%) were homozygous for the minor allele (T/T). The T/T genotype had an approximately 11 ml/min higher CrCl than the other 2 groups, but this difference did not reach statistical significance (p = 0.20). The T/T genotype had significantly lower uromodulin levels than the common G/G genotype, and the G/T genotype had intermediate levels. However, uromodulin concentrations were similar between cases and controls (44 vs. 48 mg/dL, p = 0.88).</p> <p>Conclusions</p> <p>This study among a cohort of persons with established CAD found no association between urine uromodulin and incident CKD, although UMOD genotype was associated with urine uromodulin concentrations.</p

Drug-gene interactions of antihypertensive medications and risk of incident cardiovascular disease: a pharmacogenomics study from the CHARGE consortium

Background Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals. Methods Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases). Results Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction &gt; 5.0×10−8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD