<Symposium> Regional Geography and Area Studies Reconsidered Discussion

地誌学とエリアスタディ : 現状と課

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

Blocking of snow/water slurry flow in pipeline caused by compression-strengthening of snow column

In earlier works by the present authors, two systems for sustainable energy were proposed: (i) a system for urban snow removal in winter and storage for air conditioning in summer, applied to Nagaoka City, which suffers heavy snow fall every winter, and (ii) a district cooling system utilizing latent heat of ice to reduce the size of storage reservoir and transportation pipeline system. In these systems, the hydraulic conveying of snow or ice through pump-and-pipeline is the key technique to be developed, since characteristics of snow (ice)/ water slurry is largely different from those of conventional non-cohesive solid particle slurries. In this study, the blocking of pipeline of snow/water slurry is investigated experimentally. While the blocking of conventional slurry occurs due to deposition of heavy particles at low flow velocity or arching of large rigid particles, that of snow/water slurry is caused by a compressed plug of snow formed due to cohesive nature of snow particles. This is because the strength of snow plug formed at a high resistance piping element, such as an orifice, becomes higher when the compression velocity is lower, resulting in a solid-like plug filling the whole channel upstream the elemen

Left Ventricular End-Systolic Volume Is a Reliable Predictor of New-Onset Heart Failure with Preserved Left Ventricular Ejection Fraction

Background. Left ventricular (LV) ejection fraction (EF) and LV volumes were reported to have prognostic efficacy in cardiac diseases. In particular, the end-systolic volume index (LVESVI) has been featured as the most reliable prognostic indicator. However, such efficacy in patients with LVEF ≥ 50% has not been elucidated. Methods. We screened the patients who received cardiac catheterization to evaluate coronary artery disease concomitantly with both left ventriculography and LV pressure recording using a catheter-tipped micromanometer and finally enrolled 355 patients with LVEF ≥ 50% and no history of heart failure (HF) after exclusion of the patients with severe coronary artery stenosis requiring early revascularization. Cardiovascular death or hospitalization for HF was defined as adverse events. The prognostic value of LVESVI was investigated using a Cox proportional hazards model. Results. A univariable analysis demonstrated that age, log BNP level, tau, peak − dP/dt, LVEF, LV end-diastolic volume index (LVEDVI), and LVESVI were associated with adverse events. A correlation analysis revealed that LVESVI was significantly associated with log BNP level (r = 0.356, p<0.001), +dP/dt (r = −0.324, p<0.001), −dP/dt (r = 0.391, p<0.001), and tau (r = 0.337, p<0.001). Multivariable analysis with a stepwise procedure using the variables with statistical significance in the univariable analysis revealed that aging, an increase in BNP level, and enlargement of LVESVI were significant prognostic indicators (age: HR: 1.071, 95% CI: 1.009–1.137, p=0.024; log BNP : HR : 1.533, 95% CI: 1.090–2.156, p=0.014; LVESVI : HR : 1.051, 95% CI: 1.011–1.093, p=0.013, respectively). According to the receiver-operating characteristic curve analysis for adverse events, log BNP level of 3.23 pg/ml (BNP level: 25.3 pg/ml) and an LVESVI of 24.1 ml/m2 were optimal cutoff values (BNP : AUC : 0.753, p<0.001, LVESVI : AUC : 0.729, p<0.001, respectively). Conclusion. In patients with LVEF ≥ 50%, an increased LVESVI is related to the adverse events. LV contractile performance even in the range of preserved LVEF should be considered as a role of a prognostic indicator

Single nucleotide polymorphism leads to daptomycin resistance causing amino acid substitution-T345I in MprF of clinically isolated MRSA strains.

Daptomycin (DAP) is one of the most potent antibiotics used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. Due to an increase in its administration for combating MRSA infections, DAP non-susceptible (DAP-NS) MRSA strains have recently been reported in clinical settings. The presence of single nucleotide polymorphisms (SNPs) in the multiple peptide resistance factor (mprF) gene is the most frequently reported cause for the evolution of DAP-NS MRSA strains; however, there are some variations of SNPs that could lead to DAP-NS. In this study, we used two clinical MRSA strains, including DAP susceptible (DAP-S) and DAP-NS, isolated from the same patient at different time points. We introduced T345I SNP to mprF of the DAP-S MRSA strain using the gene exchange method with pIMAY vector. Further, we investigated the phenotype of the mutant strain, including drug susceptibility, cell surface positive charge, and growth speed. The mutant strain exhibited (i) resistance to DAP, (ii) up-regulation of positive surface charge, (iii) slower growth speed, and (iv) thickened cell walls. Hence, the SNP in mprF may have caused an up-regulation in MprF function, with a subsequent increase in positive surface charge. Cumulatively, these results demonstrated that the T345I amino acid substitution in mprF represents one of the primary causes of DAP-NS in MRSA strains