Increased Activity of 2',5'-Oligoadenylate Synthetase in Peripheral Blood Mononuclear Cells of Patients with Major Depressive Disorder

The aim of this study was to measure the activity of 2',5'-oligoadenylate synthetase (2',5'AS) which is mainly induced by interferon (IFN)-α and -β in patients with major depression and evaluate its relationship to the disease. 2',5'AS activity of 23 patients (male = 11, female = 12) with major depression and of 29 normal control subjects (male = 15, female = 14) was measured in peripheral blood mononuclear cells (PBMCs) by radioassay. The mean 2',5'AS activity in the PBMCs of the patients and that of the control subjects were 1.10 ± 0.69% and 0.72 ± 0.51%, respectively. The activity in the patients was statistically higher than that of the control subjects (P = 0.03). These results imply some abnormality in the IFN-2',5'AS system of patients with major depression

Cardiovascular events in Japanese asymptomatic patients with type 2 diabetes: a 1-year interim report of a J-ACCESS 2 investigation using myocardial perfusion imaging

金沢大学医薬保健研究域医学系Purpose Diabetic patients have a high risk for cardiovascular events. The role of myocardial perfusion imaging was investigated in asymptomatic diabetic patients to evaluate short-term prognosis in a Japanese population. Methods A total of 506 asymptomatic patients ≥50 years of age who had carotid artery maximum intima-media thickness ≥1.1 mm, urinary albumin excretion of ≥30 mg/g creatinine, with additional criteria of abdominal obesity, low HDL cholesterol, high triglyceride level, and hypertension were enrolled and followed up over a 3-year period. Gated SPECT with stress-rest protocol was performed and analyzed by summed defect scores and QGS software. One-year cardiovascular events were analyzed. Results Myocardial ischemia was observed in 17% of patients, and abnormal perfusion findings of ischemia and/or scar were observed in 32% of patients. By the end of the 1-year follow-up, 33 (6.5%) cardiovascular events occurred including 6 all-cause deaths. Patients with summed stress score (SSS) >8 had a higher incidence of either death or cardiovascular events. Event-free survival rates for SSS 0–3, 4–8, 9–13, and ≥14 were 0.96, 0.95, 0.82, and 0.76, respectively. Multivariate Cox regression analysis showed that significant variables were SSS, history of cerebrovascular accident, and electrocardiographic abnormality at rest. Conclusion The 1-year interim summary showed that cardiovascular events were significantly higher in patients with SPECT abnormality, although hard cardiac event rate was relatively low. Targeted treatment strategy is required for asymptomatic but potentially high-risk diabetic patients

Expression of excess receptors and negative feedback control of signal pathways are required for rapid activation and prompt cessation of signal transduction

Cellular signal transduction is initiated by the binding of extracellular ligands to membrane receptors. Receptors are often expressed in excess, and cells are activated when a small number of receptors bind ligands. Intracellular signal proteins are act

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

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

Association between serum oxytocin levels and depressive state in community‐dwelling older adults: A cross‐sectional study

Abstract Aim Identifying peripheral biomarkers related to the prevention or modification of unhealthy mental conditions in older adults would be extremely beneficial. This study aimed to evaluate serum oxytocin levels in older adults living in a rural community and their association with cognitive function, anxiety, depressive state, and well‐being. Methods This survey was conducted between November 2016 and September 2017 in Kurokawa‐cho, Imari, Saga Prefecture, Japan, among people aged ≥65 years. Blood samples were collected from the participants for serum oxytocin level analysis, which was performed using peptide enzyme immunoassay. Participants underwent neuropsychological assessments, including the Mini‐Mental State Examination, Clinical Dementia Rating, Frontal Assessment Battery, State‐Trait Anxiety Inventory, 15‐item Geriatric Depression Scale, and 17‐item Philadelphia Geriatric Center Morale Scale. We examined the association between serum oxytocin levels and neuropsychological assessment results. Results Out of 94 participants, 25 were men and 69 were women, with mean ages of 78.24 ± 3.85 years and 78.10 ± 5.43 years, respectively. Serum oxytocin levels were negatively associated with 15‐item Geriatric Depression Scale scores. Additionally, nondepressive state/depressive state was classified by the 15‐item Geriatric Depression Scale (cut‐off 5/6). Logistic regression analysis showed that higher serum oxytocin levels tended to be associated with a less depressive state at that time. Conclusions Serum oxytocin levels may be associated with depressive state in adults aged ≥65 years