Analysis of magnetic characteristics of three-phase reactor made of grain-oriented silicon steel

Flux and iron loss distributions of three-phase reactor are analyzed using the finite element method considering 2-D B-H curves and iron losses in arbitrary directions which are measured up to high flux density. It is shown that the total iron loss of reactor yoke does not change so much by the yoke dimension, although the local iron loss is increased when the width of yoke is decreased. The experimental verification of flux and iron loss distributions are also carried out </p

Synthesis and post-polymerization reaction of end-clickable stereoregular polymethacrylates via termination of stereospecific living anionic polymerization

Poly(methyl methacrylate)s with high stereoregularity and clickable end-groups were synthesized via terminating reactions with α-(halomethyl)acrylates in stereospecific living anionic polymerization. The terminating reaction was efficient and tolerant to the reaction conditions to such an extent that almost quantitative end-functionalization was achieved in isotactic- and syndiotactic-specific polymerization systems. The terminating reactions were also achieved in polymerizations of vinyl methacrylate and trimethylsilyl methacrylate. For the polymerization of butyl acrylate, however, the termination efficiency was limited to less than 69%. Furthermore, the quantitative end-functionalization of the incorporated C[double bond, length as m-dash]C double bond at ω-end was achieved with various thiols catalyzed by Et3N. The base-catalysed thiol–ene reaction of the stereoregular poly(vinyl methacrylate) with a ω-end C[double bond, length as m-dash]C double bond selectively proceeded to retain vinyl ester functions, and the subsequent hydrolysis afforded ω-functional stereoregular poly(methacrylic acid). A combination of the terminating agent with a protected lithium amide afforded stereoregular poly(methyl methacrylates) with orthogonally clickable α- and ω-ends.ArticlePolymer Chemistry.6(7):1078-1087(2015)journal articl

Recommendations related to the analytical equivalence assessment of gene panel testing

Advances in cancer genome care over the past few years have included the development of gene panel testing for various biomarkers. This article summarizes issues and provides recommendations related to analytical performance evaluations for new oncology gene panels. The scope of these recommendations includes comprehensive genomic profiling assays related to gene panel testing that uses histological or serum specimens to detect gene mutations. As a research project of the Japan Agency for Medical Research and Development Research on Regulatory Science of Pharmaceuticals and Medical Devices, we convened the working group committee that consisted of more than 30 experts from academia, industry, and government. We have discussed the points that should be considered to allow maximal simplification of assessments using clinical specimens in evaluating accuracy and limit of detection in equivalence and analytical performance for three years. We provide recommendations specific to each type of gene mutation as well as to reference standards or specimens used for evaluations. In addition, in order to facilitate the discussion on the analytical performance of gene panel tests by multidisciplinary tumor boards of hospitals, the present recommendations also describe the items that companies are expected to provide information on in their packaging inserts and reports, and the items that are expected to be discussed by multidisciplinary tumor boards. Our working group document will be important for participants in multidisciplinary tumor boards including medical oncologists and genome scientists, and developers of gene panels not only in Japan but also in other countries

Novel Calcium-Binding Ablating Mutations Induce Constitutive RET Activity and Drive Tumorigenesis

がんゲノム医療のさらなる拡大へ向けた一歩 --コンピュータ解析で意義不明変異のなかに治療標的となる新たな遺伝子変異を発見--. 京都大学プレスリリース. 2022-09-29.Distinguishing oncogenic mutations from variants of unknown significance (VUS) is critical for precision cancer medicine. Here, computational modeling of 71, 756 RET variants for positive selection together with functional assays of 110 representative variants identified a three-dimensional cluster of VUSs carried by multiple human cancers that cause amino acid substitutions in the calmodulin-like motif (CaLM) of RET. Molecular dynamics simulations indicated that CaLM mutations decrease interactions between Ca²⁺ and its surrounding residues and induce conformational distortion of the RET cysteine-rich domain containing the CaLM. RET-CaLM mutations caused ligand-independent constitutive activation of RET kinase by homodimerization mediated by illegitimate disulfide bond formation. RET-CaLM mutants possessed oncogenic and tumorigenic activities that could be suppressed by tyrosine kinase inhibitors targeting RET. This study identifies calcium-binding ablating mutations as a novel type of oncogenic mutation of RET and indicates that in silico–driven annotation of VUSs of druggable oncogenes is a promising strategy to identify targetable driver mutations

Outcome of hospitalised heart failure in Japan and the United Kingdom stratified by plasma N-terminal pro-B-type natriuretic peptide

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Background: Mortality subsequent to a hospitalisation for heart failure is reported to be much lower in Japan than in the United Kingdom (UK). This could reflect differences in disease severity or in management. Accordingly, we directly compared patient backgrounds and outcomes between Japan and UK. Methods: Consecutive patients admitted to academic hospitals in the UK and Japan with heart failure had a common set of variables, including plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), collected during admission. Mortality during hospitalisations, at 90 and 180 days was recorded and stratified by quintile of NT-proBNP. Results: Overall, 935 patients were enrolled; 197 from UK and 738 from Japan. Median (interquartile range) age [UK: 78 (71–88) vs. Japan: 78 (70–84) years; p = 0.947], glomerular filtration rate [UK: 49 (34–68) vs. Japan: 49 (33–65) ml/min/1.73 m2; p = 0.209] and plasma NT-proBNP [UK: 4957 (2278–10,977) vs. Japan: 4155 (1972–9623) ng/l; p = 0.186] were similar, but systolic blood pressure was lower in the UK [118 (105–131) vs. 137 (118–159) mmHg; p < 0.001]. Patients with a higher plasma NT-proBNP had a worse prognosis in both countries; in-hospital and post-discharge mortality rates were higher in the UK even after adjusting for prognostic variables including NT-proBNP. Conclusions: This analysis suggests that either unobserved differences in patient characteristics or differences in care (formal or informal) rather than greater heart failure severity may account for the worse outcome of heart failure in the UK compared to Japan

Subcellular localization of glucocorticoid receptor protein in the human kidney glomerulus

Subcellular localization of glucocorticoid receptor protein in the human kidney glomerulus.BackgroundThe detailed mechanisms of glucocorticoid action in idiopathic nephrotic syndrome and progressive glomerulonephritides have not been clearly elucidated. The pharmacological actions of glucocorticoids are mediated by their binding to an intracellular protein, the glucocorticoid receptor (GR). The determination of GR localization in normal glomerular cells is essential to elucidate the mechanisms of glucocorticoid action in various glomerular diseases.MethodsWe carried out an immunoblot examination using antihuman GR-specific antibody and homogenates of isolated normal human glomeruli and mesangial cells in culture. Immunohistochemical examinations were also performed on normal human kidney specimens at light and electron microscopic levels. The nuclear translocation of GRs elicited by ligand binding was further investigated by confocal laser-scanning microscopic inspection of freshly isolated glomeruli and mesangial cells cultured with dexamethasone.ResultsAn immunoblot examination demonstrated the presence of a 94 kDa protein, a molecular weight consistent with that of GRs, in the homogenates of glomeruli and cultured mesangial cells. By light microscopic examination, GRs were strongly detected in the nucleus and moderately in the cytoplasm of all glomerular cells, parietal and visceral epithelial cells, endothelial cells, and mesangial cells. By electron microscopic examination, the nuclear GRs of all glomerular cells were found to be diffusely distributed in the euchromatin. Additionally, the immunofluorescence intensities of nuclear GRs in isolated glomeruli and mesangial cells in culture became more intense by the addition of dexamethasone.ConclusionsOur findings suggest that all subsets of human glomerular cells definitely express the GR protein, which potentially undergoes translocation by glucocorticoids

Mortality after admission for heart failure in the UK compared with Japan

Objective Mortality amongst patients hospitalised for heart failure (HHF) in Western and Asian countries may differ, but this has not been investigated using individual patient-level data (IPLD). We sought to remedy this through rigorous statistical analysis of HHF registries and variable selection from a systematic literature review.Methods and results IPLD from registries of HHF in Japan (n=3781) and the UK (n=894) were obtained. A systematic literature review identified 23 models for predicting outcome of HHF. Five variables appearing in 10 or more reports were strongly related to prognosis (systolic blood pressure, serum sodium concentration, age, blood urea nitrogen and creatinine). To compare mortality in the UK and Japan, variables were imputed in a propensity model using inverse probability of treatment weighting (IPTW) and IPTW with logistic regression (doubly robust IPTW). Overall, patients in the UK were sicker and in-patient and post-discharge mortalities were greater, suggesting that the threshold for hospital admission was higher. Covariate-adjusted in-hospital mortality was similar in the UK and Japan (IPTW OR: 1.14, 95% CI 0.70 to 1.86), but 180-day postdischarge mortality was substantially higher in the UK (doubly robust IPTW OR: 2.33, 95% CI 1.58 to 3.43).Conclusions Despite robust methods to adjust for differences in patient characteristics and disease severity, HHF patients in the UK have roughly twice the mortality at 180 days compared with those in Japan. Similar analyses should be done using other data sets and in other countries to determine the consistency of these findings and identify factors that might inform healthcare policy and improve outcomes

Robust and highly efficient hiPSC generation from patient non-mobilized peripheral blood-derived CD34+ cells using the auto-erasable Sendai virus vector

Background: Disease modeling with patient-derived induced pluripotent stem cells (iPSCs) is a powerful tool forelucidating the mechanisms underlying disease pathogenesis and developing safe and effective treatments. Patientperipheral blood (PB) cells are used for iPSC generation in many cases since they can be collected with minimuminvasiveness. To derive iPSCs that lack immunoreceptor gene rearrangements, hematopoietic stem and progenitorcells (HSPCs) are often targeted as the reprogramming source. However, the current protocols generally requireHSPC mobilization and/or ex vivo expansion owing to their sparsity at the steady state and low reprogrammingefficiencies, making the overall procedure costly, laborious, and time-consuming.Methods: We have established a highly efficient method for generating iPSCs from non-mobilized PB-derivedCD34+ HSPCs. The source PB mononuclear cells were obtained from 1 healthy donor and 15 patients and werekept frozen until the scheduled iPSC generation. CD34+ HSPC enrichment was done using immunomagnetic beads,with no ex vivo expansion culture. To reprogram the CD34+-rich cells to pluripotency, the Sendai virus vectorSeVdp-302L was used to transfer four transcription factors: KLF4, OCT4, SOX2, and c-MYC. In this iPSC generationseries, the reprogramming efficiencies, success rates of iPSC line establishment, and progression time wererecorded. After generating the iPSC frozen stocks, the cell recovery and their residual transgenes, karyotypes, T cellreceptor gene rearrangement, pluripotency markers, and differentiation capability were examined.Results：We succeeded in establishing 223 iPSC lines with high reprogramming efficiencies from 15 patients with 8 different disease types. Our method allowed the rapid appearance of primary colonies (~ 8 days), all of which were expandable under feeder-free conditions, enabling robust establishment steps with less workload. After thawing, the established iPSC lines were verified to be pluripotency marker-positive and of non-T cell origin. A majority of the iPSC lines were confirmed to be transgene-free, with normal karyotypes. Their trilineage differentiation capability was also verified in a defined in vitro assay.Conclusion：This robust and highly efficient method enables the rapid and cost-effective establishment of transgene-free iPSC lines from a small volume of PB, thus facilitating the biobanking of patient-derived iPSCs and their use for the modeling of various diseases

Nurturing a gender-responsive approach to climate-smart agriculture in Guinayangan, Quezon

Coconut-based farming systems in Guinayangan, Quezon offer special opportunities for achieving multiple objectives, including carbon sequestration, economic empowerment of women and reduction of risks from variable and extreme weather. This info note discusses the gender-based role inequalities within coconut-based farming systems that can be addressed through agroforestry-based, climate-smart agriculture that features small livestock, fruit trees and root and tuber crops as understory crops. Numerous Climate-Smart Villages, spread across the municipality of Guinayangan, now serve as proof of concept, providing evidence that climate-smart agriculture based on agroforestry interventions are gender sensitive