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

Correction: Furukawa et al. Long-Term Soft-Food Rearing in Young Mice Alters Brain Function and Mood-Related Behavior. <i>Nutrients</i> 2023, <i>15</i>, 2397

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Mesoscopic hierarchic polarization structure in relaxor ferroelectrics Pb[(Mg1/3Nb2/3)1-xTix]O3

Mesoscopic polarization structures such as polar nanoregions and polarization domain walls are the key factors that connecting microscopic fundamental polarization structures with macroscopic practical dielectric properties. Snapshot observation of domain in the relaxor-ferroelectrics PMN-x%PT just vicinity of morphotropic phase boundary region was performed by use of 7 ps single shot soft X-ray laser pulse. A self-assembled evolution of oblique polarization domain was observed in PMN-27.8%PT under the sample temperature decreased with thermal equilibrium condition. Based on energetic discussion, anti-phase shift of domain wall pairs keeping with flat boundaries was proposed for the dielectric response. A sharp enhancement in dielectric response at the vicinity of morphotropic phase boundary region reported previously was recognized as an evidence for hierarchic nature of the present oblique polarization domain wall

Erythritol Can Inhibit the Expression of Senescence Molecules in Mouse Gingival Tissues and Human Gingival Fibroblasts

Oral aging causes conditions including periodontal disease. We investigated how the sugar alcohol erythritol, which has anti-caries effects, impacts aging periodontal tissues and gingival fibroblasts in mice and humans in vivo and in vitro. Mice were classified into three groups: control groups of six-week-old (YC) and eighteen-month-old mice (AC) and a group receiving 5% w/w erythritol water for 6 months (AE). After rearing, RNA was extracted from the gingiva, and the levels of aging-related molecules were measured using PCR. Immunostaining was performed for the aging markers p21, γH2AX, and NF-κB p65. p16, p21, γH2AX, IL-1β, and TNFα mRNA expression levels were higher in the gingiva of the AC group than in the YC group, while this enhanced expression was significantly suppressed in AE gingiva. NF-κB p65 expression was high in the AC group but was strongly suppressed in the AE group. We induced senescence in cultured human gingival fibroblasts using H2O2 and lipopolysaccharide before erythritol treatment, which reduced elevated senescence-related marker (p16, p21, SA-β-gal, IL-1β, and TNFα) expression levels. Knockdown of PFK or PGAM promoted p16 and p21 mRNA expression, but erythritol subsequently rescued pyruvate production. Overall, intraoral erythritol administration may prevent age-related oral mucosal diseases

DNA Cross-Link Repair Protein SNM1A Interacts with PIAS1 in Nuclear Focus Formation

The yeast SNM1/PSO2 gene specifically functions in DNA interstrand cross-link (ICL) repair, and its role has been suggested to be separate from other DNA repair pathways. In vertebrates, there are three homologs of SNM1 (SNM1A, SNM1B, and SNM1C/Artemis; SNM1 family proteins) whose functions are largely unknown. We disrupted each of the SNM1 family genes in the chicken B-cell line DT40. Both SNM1A- and SNM1B-deficient cells were sensitive to cisplatin but not to X-rays, whereas SNM1C/Artemis-deficient cells exhibited sensitivity to X-rays but not to cisplatin. SNM1A was nonepistatic with XRCC3 (homologous recombination), RAD18 (translesion synthesis), FANCC (Fanconi anemia), and SNM1B in ICL repair. SNM1A protein formed punctate nuclear foci depending on the conserved SNM1 (metallo-β-lactamase) domain. PIAS1 was found to physically interact with SNM1A, and they colocalized at nuclear foci. Point mutations in the SNM1 domain, which disrupted the interaction with PIAS1, led to mislocalization of SNM1A in the nucleus and loss of complementation of snm1a cells. These results suggest that interaction between SNM1A and PIAS1 is required for ICL repair

Relationship between weight loss and regular dental management of older adults residing in long-term care facilities : a 1-year multicenter longitudinal study

Purpose This study aimed to determine the association between home visits by a dentist and regular oral hygiene management by a dental hygienist (regular dental management: RDM) and weight loss among older adults in long-term care facilities. Methods A total of 468 older residents from 26 Japanese long-term care facilities participated in two surveys in 2018 and 2019. Participants were divided into two groups based on their diet during the baseline survey (regular diet, n = 256; dysphagia diet, n = 212). Participants with a regular diet were further divided into those who exhibited a weight loss >= 5% over 1 year (weight loss group: n = 77) and those with a weight loss < 5% (consistent weight group: n = 179). The explanatory variables were age, sex, baseline weight, Barthel index, and clinical dementia rating, as well as the patients' medical history of pneumonia, stroke, diabetes, and depression (which is reportedly associated with weight). Additionally, a Poisson regression with robust standard error, was carried out to analyze the explanatory variables, namely the prevalence of RDM noted during the study and functional teeth (which seemed to affect weight loss). Results A multivariate analysis revealed that older residents' lack of RDM, clinical dementia assessment, and their history of pneumonia (prevalence rate ratio: 0.35, 95% confidence interval 0.24-0.95) were all significantly associated with weight loss when on a regular diet. Conclusion Thus, weight loss and RDM were related to each other. Weight loss may be suppressed by incorporating RDMs during the early nursing care for older residents on regular diets. Key summary pointsAim This study aimed to clarify the relationship between weight loss and regular dental management among older adults in long-term care facilities through a 1-year, multicenter longitudinal study. Findings The absence of regular dental management among older residents in long-term care facilities (who follow regular diets) was associated with weight loss and malnourishment. Message Regular dental care procedures among older residents (who follow regular diets) in long-term care facilities may reduce weight loss and prevent malnutrition