AGEを介したSmad1とSmad3のリン酸化を介した新規相互作用は糖尿病性腎症の進展を制御する

Diabetic nephropathy (DN) is the major cause of end-stage renal failure and is associated with increased morbidity and mortality compared with other causes of renal diseases. We previously found that Smad1 plays a critical role in the development of DN both in vitro and in vivo. However, functional interaction between Smad1 and Smad3 signaling in DN is unclear. Here, we addressed the molecular interplay between Smad1 and Smad3 signaling under a diabetic condition by using Smad3-knockout diabetic mice. Extracellular matrix (ECM) protein overexpression and Smad1 activation were observed in the glomeruli of db/db mice but were suppressed in the glomeruli of Smad3+/−; db/db mice. Smad3 activation enhanced the phosphorylation of Smad1 C-terminal domain but decreased the phosphorylation of linker domain, thus regulating Smad1 activation in advanced glycation end product-treated mesangial cells (MCs). However, forced phosphorylation of the Smad1 linker domain did not affect Smad3 activation in MCs. Phosphorylation of the Smad1 linker domain increased in Smad3+/−; db/db mice and probucol-treated db/db mice, which was consistent with the attenuation of ECM overproduction. These results indicate that Smad3 expression and activation or probucol treatment alters Smad1 phosphorylation, thus suggesting new molecular mechanisms underlying DN development and progression

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

Carbachol-induced Suppression of Contraction Rhythm in Spontaneously Beating Cultured Cardiac Myocytes From Neonatal Rats

Nitric oxide (NO) and reactive oxygen species (ROS) are known to play various functional and pathophysiological roles as an intracellular messenger in the heart. In this study, we investigated whether the increased production of NO and/or ROS was involved in the cholinergic regulation of rhythmic contraction in spontaneously beating cultured cardiac myocytes from neonatal rats. Exposure of cultures to carbachol, an agonist of muscarinic acetylcholine receptors (mAchR), produced a dose-dependent decrease in the beat rate of cultured cardiac myocytes, and such a effect was significantly attenuated by pre-treatment with an NOS inhibitor, as well as an NO scavenger. In addition, exposure to an NO donor (SNAP) also decreased the beat rate dose-dependently. Carbachol- or SNAP-induced suppression of the contraction rhythm was significantly attenuated by co-treatment with 5-hydroxydecanoate (5-HD). In contrast, treatment with diazoxide decreased the beat rate dose-dependently. Carbachol treatment increased the intensity of 2',7'-dichlorodihydrofluorescein fluorescence, suggesting that the production of ROS was enhanced by the treatment. In addition, the carbachol- or diazoxide-induced suppression of contraction rhythm was attenuated by co-treatment with 2-mercaptopropionyl glycine, a scavenger of ROS. The present study has suggested that the mAchR-NO-mitoK ATP -ROS pathway is a factor responsible for carbachol-induced suppression of contraction rhythm in cultured cardiac myocytes.http://www.taylorandfrancisgroup.com

Determination of Seebeck coefficient originating from phonon-drag effect using Si single crystals at different carrier densities

Abstract The phonon-drag effect is useful for improving the thermoelectric performance, especially the Seebeck coefficient. Therefore, the phonon and electron transport properties of Si single crystals at different carrier densities were investigated, and the relationship between these properties and the phonon-drag effect was clarified. Phonon transport properties were determined using nanoindentation and spot-periodic heating radiation thermometry. The electron transport properties were determined based on the electrical conductivity of Si. The diffusive Seebeck coefficient derived from the electron transport properties was in good agreement with previous reports. However, the value of the phonon-drag Seebeck coefficient derived from the phonon transport properties is very low. This phenomenon suggests that phonons with a normal mean free path (MFP) do not contribute to the increase in the Seebeck coefficient; however, phonons with a long MFP and low frequency increase the Seebeck coefficient via the phonon-drag effect. Moreover, the phonon-drag effect was sufficiently pronounced even at 300 K and in the heavily doped region. These features are key in designing thermoelectric materials with enhanced performance derived from the phonon-drag effect

Surface Modification of Bi₂Te₃ Nanoplates Deposited with Tin, Palladium, and Tin/Palladium Using Electroless Deposition

Surface-modified nanoplate-shaped thermoelectric materials can achieve good thermoelectric performance. Herein, single-crystalline Bi2Te3 nanoplates with regular hexagonal shapes were prepared via solvothermal techniques. Surface modification was performed to deposit different metals onto the nanoplates using electroless deposition. Nanoparticle-shaped tin (Sn) and layer-shaped palladium (Pd) formed on the Bi2Te3 nanoplates via electroless deposition. For the sequential deposition of Sn and Pd, the surface morphology was mostly the same as that of the Sn-Bi2Te3 nanoplates. To assess the thermoelectric properties of the nanoplates as closely as possible, they were compressed into thin bulk shapes at 300 K. The Sn-Bi2Te3 and Sn/Pd-Bi2Te3 nanoplates exhibited the lowest lattice thermal conductivity of 1.1 W/(m·K), indicating that nanoparticle-shaped Sn facilitated the scattering of phonons. By contrast, the Pd-Bi2Te3 nanoplates exhibited the highest electrical conductivity. Thus, the highest power factor (15 μW/(m∙K2)) and dimensionless ZT (32 × 10−3) were obtained for the Pd-Bi2Te3 nanoplates. These thermoelectric properties were not as high as those of the sintered Bi2Te3 samples; however, this study revealed the effect of different metal depositions on Bi2Te3 nanoplates for improving thermoelectric performance. These findings offer venues for improving thermoelectric performance by sintering nanoplates deposited with appropriate metals