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

Activity Enhancement of a Carbon Electrode Material for Vanadium Redox Flow Battery by Electron-Beam Irradiation

The effective addition of surface oxygen groups, which are active sites for redox reactions, on carbon clothes as electrodes by electron beam irradiation in normal air which contains environmental humidity, dry air, or nitrogen atmosphere was carried out. The irradiation introduced 20 at% oxygen at the carbon surface as determined by X-ray photoelectron spectroscopy and the phenol-type hydroxyl group, the carboxylic group, etc., were detected by temperature-programmed desorption. Single-cell measurements indicated the current density at 1.3 V-IR-corrected of the irradiated electrode in normal air was 28% higher than that of the as-received electrode. Since double-layer capacitance between the as-received carbon cloth and irradiated carbon cloth in normal air was similar, the improvement of current density is attributed to the increase of surface oxygen groups. In addition, the radiation in both normal air and dry air improved electrochemical activity similarly. This result suggests the radiation-chemical reaction in this study is dominated by the oxidation reaction with ozone or nitrogen oxides (NOx), while in the meantime, the contribution of the hydroxyl radical from water is considered to be negligible

Spontaneous pleural aspergillosis in an immunocompetent young adult treated with minimally invasive surgery

Spontaneous cases of pleural aspergillosis in healthy adults are rare, and the optimal therapeutic approach has not been established. Here we report a rare case of spontaneous pleural aspergillosis in an otherwise healthy young adult. Two-stage surgery with decortication and cavernostomy, followed by systemic antifungal therapy, finally resulted in a successful resolution of his empyema without any serious complications. In young patients with good pulmonary compliance, less invasive procedures, such as thoracoscopic decortication and/or carvernotomy, is a potential treatment option

Bartter syndrome representing digenic-based salt-losing tubulopathies presumably accelerated by renal insufficiency

Bartter syndrome and Gitelman syndrome (GS) are autosomal recessive disorders usually caused by homozygous or compound heterozygous mutations in causative genes. In some patients, these two syndromes cannot be discriminated based on clinical features or mutation type; thus, a single disease concept, salt-losing tubulopathies (SLTs), has been used instead. Despite the existence of several SLT causative genes, cases of digenic heterozygous mutations in two different genes are extremely rare. Here, we report the case of a 36-year-old woman with renal insufficiency and hypokalemia caused by an SLT. To evaluate the SLT phenotype, we performed next-generation sequencing (NGS) with a gene panel including SLC12A3,SLC12A1, CLCNKB, and CLCNKA as well as laboratory examinations and diuretic loading tests. The results of the diuretic loading tests were consistent with a GS phenotype, while the NGS results showed that the patient had heterozygous mutations in SLC12A1 and CLCNKB. Both genes have been associated with BS,suggesting that the SLT was caused by digenic heterozygous mutations in two different genes. To date, only a few SLT cases caused by digenic heterozygous mutations in two different genes have been reported. The digenic SLT phenotype in the patient was presumably accelerated by moderate renal insufficiency

Discrimination of taste qualities among mouse fungiform taste bud cells

Multiple lines of evidence from molecular studies indicate that individual taste qualities are encoded by distinct taste receptor cells. In contrast, many physiological studies have found that a significant proportion of taste cells respond to multiple taste qualities. To reconcile this apparent discrepancy and to identify taste cells that underlie each taste quality, we investigated taste responses of individual mouse fungiform taste cells that express gustducin or GAD67, markers for specific types of taste cells. Type II taste cells respond to sweet, bitter or umami tastants, express taste receptors, gustducin and other transduction components. Type III cells possess putative sour taste receptors, and have well elaborated conventional synapses. Consistent with these findings we found that gustducin-expressing Type II taste cells responded best to sweet (25/49), bitter (20/49) or umami (4/49) stimuli, while all GAD67 (Type III) taste cells examined (44/44) responded to sour stimuli and a portion of them showed multiple taste sensitivities, suggesting discrimination of each taste quality among taste bud cells. These results were largely consistent with those previously reported with circumvallate papillae taste cells. Bitter-best taste cells responded to multiple bitter compounds such as quinine, denatonium and cyclohexamide. Three sour compounds, HCl, acetic acid and citric acid, elicited responses in sour-best taste cells. These results suggest that taste cells may be capable of recognizing multiple taste compounds that elicit similar taste sensation. We did not find any NaCl-best cells among the gustducin and GAD67 taste cells, raising the possibility that salt sensitive taste cells comprise a different population