Markers for obese and non-obese Type 2 diabetes identified using whole blood metabolomics

Definitive differences in blood metabolite profiles between obese and non-obese Type 2 diabetes (T2D) have not been established. We performed an LC–MS-based non-targeted metabolomic analysis of whole blood samples collected from subjects classified into 4 types, based on the presence or absence of obesity and T2D. Of the 125 compounds identified, 20, comprising mainly nucleobases and glucose metabolites, showed significant increases or decreases in the T2D group. These included cytidine, UDP-glucuronate, UMP, 6-phosphogluconate, and pentose-phosphate. Among those 20 compounds, 11 enriched in red blood cells (RBCs) have rarely been studied in the context of diabetes, indicating that RBC metabolism is more extensively disrupted than previously known. Correlation analysis revealed that these T2D markers include 15 HbA1c-associated and 5 irrelevant compounds that may reflect diabetic conditions by a different mechanism than that of HbA1c. In the obese group, enhanced protein and fatty acid catabolism causes increases in 13 compounds, including methylated or acetylated amino acids and short-chain carnitines. Our study, which may be considered a pilot investigation, suggests that changes in blood metabolism due to obesity and diabetes are large, but essentially independent.journal articl

Improvement of drill system for the third deep ice coring project around Dome Fuji, Antarctica - Focusing on selection of drilling fluids -

The Tenth Symposium on Polar Science/Ordinary sessions: [OM] Polar Meteorology and Glaciology, Wed. 4 Dec. / Entrance Hall (1st floor) , National Institute of Polar Researc

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Co thickness dependence of structural and magnetic properties in spin quantum cross devices utilizing stray magnetic fields

We investigate the Co thickness dependence of the structural and magnetic properties of Co thin-film electrodes sandwiched between borate glasses in spin quantum cross (SQC) devices that utilize stray magnetic fields. We also calculate the Co thickness dependence of the stray field between the two edges of Co thin-film electrodes in SQC devices using micromagnetic simulation. The surface roughness of Co thin films with a thickness of less than 20 nm on borate glasses is shown to be as small as 0.18 nm, at the same scanning scale as the Co film thickness, and the squareness of the hysteresis loop is shown to be as large as 0.96-1.0. As a result of the establishment of polishing techniques for Co thin-film electrodes sandwiched between borate glasses, we successfully demonstrate the formation of smooth Co edges and the generation of stray magnetic fields from Co edges. Theoretical calculation reveals that a strong stray field beyond 6 kOe is generated when the Co thickness is greater than 10 nm at a junction gap distance of 5 nm. From these experimental and calculation results, it can be concluded that SQC devices with a Co thickness of 10-20 nm can be expected to function as spin-filter devices

Markers for obese and non-obese Type 2 diabetes identified using whole blood metabolomics

Definitive differences in blood metabolite profiles between obese and non-obese Type 2 diabetes (T2D) have not been established. We performed an LC–MS-based non-targeted metabolomic analysis of whole blood samples collected from subjects classified into 4 types, based on the presence or absence of obesity and T2D. Of the 125 compounds identified, 20, comprising mainly nucleobases and glucose metabolites, showed significant increases or decreases in the T2D group. These included cytidine, UDP-glucuronate, UMP, 6-phosphogluconate, and pentose-phosphate. Among those 20 compounds, 11 enriched in red blood cells (RBCs) have rarely been studied in the context of diabetes, indicating that RBC metabolism is more extensively disrupted than previously known. Correlation analysis revealed that these T2D markers include 15 HbA1c-associated and 5 irrelevant compounds that may reflect diabetic conditions by a different mechanism than that of HbA1c. In the obese group, enhanced protein and fatty acid catabolism causes increases in 13 compounds, including methylated or acetylated amino acids and short-chain carnitines. Our study, which may be considered a pilot investigation, suggests that changes in blood metabolism due to obesity and diabetes are large, but essentially independent

Transient, Tunable Expression of NTCP and BSEP in MDCKII Cells for Kinetic Delineation of the Rate-Determining Process and Inhibitory Effects of Rifampicin in Hepatobiliary Transport of Taurocholate

In predicting the hepatic elimination of compounds, the extended clearance concept has proven useful. Yet, its experimental proof was scarce partly due to the lack of models with the controlled expression of transporters. Here, the uptake and efflux transporters [NTCP (SLC10A1) and BSEP (ABCB11), respectively] were doubly and transiently expressed in MDCKII cells by electroporation-based transfection (with the BSEP plasmid amount varied and with the NTCP plasmid fixed), achieving the activity levels of NTCP and BSEP comparable to those of sandwich cultured human hepatocytes. The biliary excretion clearance for taurocholate increased proportionally to the BSEP expression level. Under the same conditions, the basal-to-apical transcellular clearance of taurocholate displayed an initial increase, and a subsequent plateau, indicating that the basolateral uptake of taurocholate became rate-limiting. The doubly transfected MDCKII cells were also used to kinetically analyze the inhibitory effects of rifampicin on BSEP and NTCP. The obtained results showed a bell-shaped profile for cell-to-medium concentration ratios over a range of rifampicin concentrations, which were quantitatively captured by kinetic modeling based on the extended clearance concept. The present study highlights the utility of the transient, tunable transporter expression system in delineating the rate-determining process and providing mechanistic insights into intracellular substrate accumulation. (C) 2020 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.Y

Structural and magnetic properties of Ni78Fe22 thin films sandwiched between low-softening-point glasses and application in spin devices

We investigate the structural and magnetic properties of Ni78Fe22 thin films sandwiched between low softening-point (LSP) glasses, which can be used in spin quantum cross (SQC) devices utilizing stray magnetic fields generated from magnetic thin-film edges. We also calculate the stray magnetic field generated between the two edges of Ni78Fe22 thin-film electrodes in SQC devices and discuss the applicability to spin-filter devices. Using the established fabrication technique, we successfully demonstrate the formation of LSP-glass/Ni78Fe22/LSP-glass structures with smooth and clear interfaces. The coercivity of the Ni78Fe22 thin films is enhanced from 0.9 to 103 Oe by increasing the applied pressure from 0 to 1.0 MPa in the thermal pressing process. According to the random anisotropy model, the enhancement of the coercivity is attributed to the increase in the crystal grain size. The stray magnetic field is also uniformly generated from the Ni78Fe22 thin-film edge in the direction perpendicular to the cross section of the LSP-glass/Ni78Fe22/LSP-glass structures. Theoretical calculation reveals that a high stray field of approximately 5 kOe is generated when the distance between two edges of the Ni78Fe22 thin-film electrodes is less than 5 nm and the thickness of Ni78Fe22 is greater than 20 nm. These experimental and calculation results indicate that Ni78Fe22 thin films sandwiched between LSP glasses are useful as electrodes for SQC devices, serving as spin-filter devices