Study Design of a Phase II Clinical Trial to Assess the Efficacy and Safety of Eperisone in Japanese Type 2 Diabetes Patients with Risk and Non-risk Alleles of CDKAL1

Genetic variation in Cdk5 Regulatory Associated Protein 1-Like 1 (CDKAL1) is associated with the development of type 2 diabetes (T2D). Dysfunction of CDKAL1 impairs the translation of proinsulin, which leads to glucose intolerance. Eperisone, an antispasmodic agent, has been shown to ameliorate glucose intolerance in Cdkal1-deficient mice. We have launched a phase II clinical study to investigate the potential anti-diabetic effect of eperisone in T2D patients carrying risk or non-risk alleles of CDKAL1. The primary endpoint is the change of hemoglobin A1c (HbA1c) levels. We also examined whether the efficacy of eperisone in T2D patients is associated with CDKAL1 activity

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

What is artificial endocrine pancreas? Mechanism and history

The artificial endocrine pancreas is a feedback control instrument that regulates insulin delivery on a minute-by-minute basis according to measured blood glucose levels. Only one type of bedside-type artificial endocrine pancreas is now available in Japan: STG-22 (Nikkiso Co. Ltd., Japan). In the insulin infusion algorithm, insulin is infused on the basis of its proportional and derivative actions, to blood glucose concentrations with a constant time delay. The bedside-type artificial endocrine pancreas has been proven to be useful not only as a therapeutic tool for diabetes mellitus, but also as an elegant research tool for investigating the pathophysiology of the disease, by using the euglycemic hyperinsulinemic glucose clamp technique. The wearable type of closed-loop system has been developed recently. The breakthrough is the establishment of a needle-type glucose sensor. The development of closed-loop glycemic control systems that enable long-term physiological regulation has focused on implantable devices. Much effort has been expended to realize these devices

コウジンセイ センイ ホキョウ モルタル デ ダンメン セキソウ ホキョウ オ ホドコシタ テッキン コンクリートリョウ ニ タイスル レンゾク センイ シート ノ マゲホキョウ コウカ ノ カイゼン ニ カンスル ジッケンテキ ケンキュウ

In this study, analytical and experimental investigations were conducted to clarify the effect of clad reinforcement by polyethylene fiber reinforced mortar (PEFRM) on flexural characteristics of reinforced concrete (RC) beams strengthened with polyethylene fiber sheets. High-performance polyethylene fibers (PEF) were used for making the PEFRM with high tensile strength. The PEFRM-cladding was performed on the tensile side of the RC beam. The RC beams strengthened with the PEFRM-cladding and the sheets were tested under pure bending. As a result, it was shown that the PEFRM-cladding has a remarkable effect on an improvement of flexural reinforcement by the sheets of the RC beam

The impact of Ca2+/calmodulin-dependent protein kinase II on insulin gene expression in MIN6 cells

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is expressed in insulin-secretingβ cells. However, the effects of CaMKII on insulin synthesis are unknown. AlthoughSer133 phosphorylation of cyclic AMP-responsive element-binding (CREB) typicallyincreases CREB transcriptional activity, CaMKII phosphorylates CREB at Ser142 andat Ser133 to exert a dominant inhibitory effect. Our objective was to characterize therole of CaMKII in insulin gene expression. In MIN6 cells, insulin gene promoteractivity was significantly down-regulated by wild-type (WT) CaMKIIδ2, but wassignificantly upregulated after small interfering RNA (siRNA) knockdown of CaMKIIδexpression. These results were independent of glucose concentrations and membranedepolarization. Insulin mRNA levels were also decreased by WT CaMKIIδ2 andincreased by CaMKIIδ siRNA. Downregulation of insulin gene promoter activity byWT CaMKIIδ2 was partly mediated via cyclic AMP-responsive element 2. WTCaMKIIδ2 significantly increased CREB phosphorylation at Ser142 and significantly decreased binding to CREB binding protein (CBP), whereas kinase dead CaMKIIδ2 didnot. Our results indicate that CaMKIIδ2 downregulates insulin gene expression bySer142 phosphorylation of CREB and reducing binding of CREB to CBP