Effects of ranolazine on right ventricular function, fluid dynamics, and metabolism in patients with precapillary pulmonary hypertension: insights from a longitudinal, randomized, double-blinded, placebo controlled, multicenter study

IntroductionRight ventricular (RV) function is a major determinant of outcome in patients with precapillary pulmonary hypertension (PH). We studied the effect of ranolazine on RV function over 6 months using multi-modality imaging and biochemical markers in patients with precapillary PH (groups I, III, and IV) and RV dysfunction [CMR imaging ejection fraction (EF) < 45%] in a longitudinal, randomized, double-blinded, placebo-controlled, multicenter study of ranolazine treatment.MethodsEnrolled patients were assessed using cardiac magnetic resonance (CMR) imaging, 11C-acetate and 18-F-FDG positron emission tomography (PET), and plasma metabolomic profiling, at baseline and at the end of treatment.ResultsTwenty-two patients were enrolled, and 15 patients completed all follow-up studies with 9 in the ranolazine arm and 6 in the placebo arm. RVEF and RV/Left ventricle (LV) mean glucose uptake were significantly improved after 6 months of treatment in the ranolazine arm. Metabolomic changes in aromatic amino acid metabolism, redox homeostasis, and bile acid metabolism were observed after ranolazine treatment, and several changes significantly correlated with changes in PET and CMR-derived fluid dynamic measurements.DiscussionRanolazine may improve RV function by altering RV metabolism in patients with precapillary PH. Larger studies are needed to confirm the beneficial effects of ranolazine

J-shaped relationship between waist circumference and subsequent risk for Type 2 diabetes: An 8-year follow-up of relatively lean Japanese individuals

金沢大学医薬保健研究域医学系金沢医科大学健康増進予防医学（公衆衛生学）Aims This study investigated the relationship between waist circumference and the subsequent incidence of Type 2 diabetes and the association with insulin resistance and pancreatic B-cell function in relatively lean Japanese individuals. Methods The study participants were 3992 employees (2533 men and 1459 women, aged 35-55 years) of a metal-products factory in Japan. The incidence of diabetes was determined in annual medical examinations during an 8-year follow-up. We calculated age- and sex-adjusted hazard ratios (HRs) according to the sex-specific quintile of waist circumference at baseline. Differences in baseline insulin resistance [homeostatis model assessment (HOMA)-IR] and pancreatic B-cell function (HOMA-B) were compared between participants who developed diabetes and those who did not. Results During the follow-up, 218 participants developed diabetes. Age- and sex-adjusted HRs across the quintiles of waist circumference were 1.78, 1.00 (reference), 1.59, 3.11 and 3.30, respectively (P for trend, < 0.0001). The HR for the lowest quintile was significantly higher than that for the second quintile. Among participants with waist circumference of the lowest quintile, HOMA-B was lower in those who developed diabetes than in those who did not [33.1 (24.1-45.0) vs. 54.3 (37.9-74.6) median (interquartile range), P < 0.0001], but HOMA-IR did not differ between these groups. Conclusions There was a J-shaped relationship between waist circumference and subsequent risk for Type 2 diabetes in relatively lean Japanese individuals; lower pancreatic B-cell function may also increase the risk of diabetes in very lean Japanese people. © 2009 Diabetes UK

Optimal Estimation of Ion-Channel Kinetics from Macroscopic Currents

Markov modeling provides an effective approach for modeling ion channel kinetics. There are several search algorithms for global fitting of macroscopic or single-channel currents across different experimental conditions. Here we present a particle swarm optimization(PSO)-based approach which, when used in combination with golden section search (GSS), can fit macroscopic voltage responses with a high degree of accuracy (errors within 1%) and reasonable amount of calculation time (less than 10 hours for 20 free parameters) on a desktop computer. We also describe a method for initial value estimation of the model parameters, which appears to favor identification of global optimum and can further reduce the computational cost. The PSO-GSS algorithm is applicable for kinetic models of arbitrary topology and size and compatible with common stimulation protocols, which provides a convenient approach for establishing kinetic models at the macroscopic level

Variation among 532 genomes unveils the origin and evolutionary history of a global insect herbivore

The diamondback moth, Plutella xylostella is a cosmopolitan pest that has evolved resistance to all classes of insecticide, and costs the world economy an estimated US $4-5 billion annually. We analyse patterns of variation among 532 P. xylostella genomes, representing a worldwide sample of 114 populations. We find evidence that suggests South America is the geographical area of origin of this species, challenging earlier hypotheses of an Old-World origin. Our analysis indicates that Plutella xylostella has experienced three major expansions across the world, mainly facilitated by European colonization and global trade. We identify genomic signatures of selection in genes related to metabolic and signaling pathways that could be evidence of environmental adaptation. This evolutionary history of P. xylostella provides insights into transoceanic movements that have enabled it to become a worldwide pest.Minsheng You … Simon W. Baxter … Christopher M. Ward … et al

Structural insights into Ca2+-activated long-range allosteric channel gating of RyR1

Ryanodine receptors (RyRs) are a class of giant ion channels with molecular mass over 2.2 mega-Daltons. These channels mediate calcium signaling in a variety of cells. Since more than 80% of the RyR protein is folded into the cytoplasmic assembly and the remaining residues form the transmembrane domain, it has been hypothesized that the activation and regulation of RyR channels occur through an as yet uncharacterized long-range allosteric mechanism. Here we report the characterization of a Ca2+-activated open-state RyR1 structure by cryo-electron microscopy. The structure has an overall resolution of 4.9 angstrom and a resolution of 4.2 angstrom for the core region. In comparison with the previously determined apo/closed-state structure, we observed long-range allosteric gating of the channel upon Ca2+ activation. In-depth structural analyses elucidated a novel channel-gating mechanism and a novel ion selectivity mechanism of RyR1. Our work not only provides structural insights into the molecular mechanisms of channel gating and regulation of RyRs, but also sheds light on structural basis for channel-gating and ion selectivity mechanisms for the six-transmembrane-helix cation channel family.Strategic Priority Research Program of Chinese Academy of Sciences [XDB08030202]; National Basic Research Program (973 Program); Ministry of Science &amp; Technology of China [2012CB917200, 2014CB910700]; National Natural Science Foundation of China [31270768]; Ministry of Education of China (111 Program China)SCI(E)PubMed中国科技核心期刊(ISTIC)[email protected]; [email protected]

Long-Term Exposure to Low-Level PM2.5 and Mortality: Investigation of Heterogeneity by Harmonizing Analyses in Large Cohort Studies in Canada, United States, and Europe.

BACKGROUND: Studies across the globe generally reported increased mortality risks associated with particulate matter with aerodynamic diameter ≤2.5μm (PM2.5) exposure with large heterogeneity in the magnitude of reported associations and the shape of concentration-response functions (CRFs). We aimed to evaluate the impact of key study design factors (including confounders, applied exposure model, population age, and outcome definition) on PM2.5 effect estimates by harmonizing analyses on three previously published large studies in Canada [Mortality-Air Pollution Associations in Low Exposure Environments (MAPLE), 1991-2016], the United States (Medicare, 2000-2016), and Europe [Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE), 2000-2016] as much as possible. METHODS: We harmonized the study populations to individuals 65+ years of age, applied the same satellite-derived PM2.5 exposure estimates, and selected the same sets of potential confounders and the same outcome. We evaluated whether differences in previously published effect estimates across cohorts were reduced after harmonization among these factors. Additional analyses were conducted to assess the influence of key design features on estimated risks, including adjusted covariates and exposure assessment method. A combined CRF was assessed with meta-analysis based on the extended shape-constrained health impact function (eSCHIF). RESULTS: More than 81 million participants were included, contributing 692 million person-years of follow-up. Hazard ratios and 95% confidence intervals (CIs) for all-cause mortality associated with a 5-μg/m3 increase in PM2.5 were 1.039 (1.032, 1.046) in MAPLE, 1.025 (1.021, 1.029) in Medicare, and 1.041 (1.014, 1.069) in ELAPSE. Applying a harmonized analytical approach marginally reduced difference in the observed associations across the three studies. Magnitude of the association was affected by the adjusted covariates, exposure assessment methodology, age of the population, and marginally by outcome definition. Shape of the CRFs differed across cohorts but generally showed associations down to the lowest observed PM2.5 levels. A common CRF suggested a monotonically increased risk down to the lowest exposure level. https://doi.org/10.1289/EHP12141

FIM OBSERVATION OF IRON PARTICLES IN Cu - 1.5 wt % Fe ALLOY

Fe particles of fcc structure in Cu matrix are observed and they are found to be stable at low temperatures. The bcc Fe particles are observed in plastically deformed specimens and the orientation relationship between the particle and the matrix is examined by FIM images