Prospective study of lung function and abdominal aortic aneurysm risk: The Atherosclerosis Risk in Communities study

Abstract Background and aims No prospective study has investigated whether individuals with respiratory impairments, including chronic obstructive pulmonary disease (COPD) and restrictive lung disease (RLD), are at increased risk of abdominal aortic aneurysm (AAA). We aimed to prospectively investigate whether those respiratory impairments are associated with increased AAA risk. Methods In 1987–1989, the Atherosclerosis Risk in Communities (ARIC) study followed 14,269 participants aged 45–64 years, without a history of AAA surgery, through 2011. Participants were classified into four groups, “COPD” [forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <lower limit of normal (LLN)], “RLD” (FEV1/FVC ≥ LLN and FVC < LLN), “respiratory symptoms with normal spirometry” (without RLD or COPD), and “normal” (without respiratory symptoms, RLD or COPD, reference group). Results During the 284,969 person-years of follow-up, 534 incident AAA events were documented. In an age, sex, and race-adjusted proportional hazards model, individuals with respiratory impairments had a significantly higher risk of AAA than the normal reference group. After adjustment for AAA risk factors, including smoking status and pack-years of smoking, AAA risk was no longer significant in the respiratory symptoms with normal spirometry group [HR (95% CI), 1.25 (0.98–1.60)], but was still increased in the other two groups [RLD: 1.45 (1.04–2.02) and COPD: 1.66 (1.34–2.05)]. Moreover, continuous measures of FEV1/FVC, FEV1 and FVC were associated inversely with risk of AAA. Conclusions In the prospective population-based cohort study, obstructive and restrictive spirometric patterns were associated with increased risk of AAA independent of smoking, suggesting that COPD and RLD may increase the risk of AAA. Highlights • No prospective study has examined the association between lung function and abdominal aortic aneurysm (AAA). • We examined this association using a prospective population-based study in the US. • Chronic obstructive pulmonary disease (COPD) and restrictive diseases patterns were associated with increased AAA risk. • This study suggested COPD and restrictive lung diseases may increase AAA risk

Functional expression of thiocyanate hydrolase is promoted by its activator protein, P15K

AbstractThiocyanate hydrolase (SCNase) is a cobalt-containing enzyme with a post-translationally modified cysteine ligand, γCys131-SO2H. When the SCNase α, β and γ subunits were expressed in Escherichia coli, the subunits assembled to form a hetero-dodecamer, (αβγ)4, like native SCNase but exhibited no catalytic activity. Metal analysis indicated that SCNase was expressed as an apo-form irrespective of the presence of cobalt in the medium. On the contrary, SCNase co-expressed with P15K, encoded just downstream of SCNase genes, in cobalt-enriched medium under the optimized condition (SCNase(+P15K)) possessed 0.86 Co atom/αβγ trimer and exhibited 78% of the activity of native SCNase. SCNase(+P15K) showed a UV–Vis absorption peak characteristic of the SCNase cobalt center. About 70% of SCNase(+P15K) had the γCys131-SO2H modification. These results indicate that SCNase(+P15K) is the active holo-SCNase. P15K is likely to promote the functional expression of SCNase probably by assisting the incorporation of cobalt ion

Overexpression of a Minimal Domain of Calpastatin Suppresses IL-6 Production and Th17 Development via Reduced NF-κB and Increased STAT5 Signals

Calpain, a calcium-dependent cysteine protease, is reportedly involved in the pathophysiology of autoimmune diseases such as rheumatoid arthritis (RA). In addition, autoantibodies against calpastatin, a natural and specific inhibitor of calpain, are widely observed in RA. We previously reported that E-64-d, a membrane-permeable cysteine protease inhibitor, is effective in treating experimental arthritis. However, the exact role of the calpastatin-calpain balance in primary inflammatory cells remains unclear. Here we investigated the effect of calpain-specific inhibition by overexpressing a minimal functional domain of calpastatin in primary helper T (Th) cells, primary fibroblasts from RA patients, and fibroblast cell lines. We found that the calpastatin-calpain balance varied during Th1, Th2, and Th17 development, and that overexpression of a minimal domain of calpastatin (by retroviral gene transduction) or the inhibition of calpain by E-64-d suppressed the production of IL-6 and IL-17 by Th cells and the production of IL-6 by fibroblasts. These suppressions were associated with reductions in RORγt expression and STAT3 phosphorylation. Furthermore, inhibiting calpain by silencing its small regulatory subunit (CPNS) suppressed Th17 development. We also confirmed that overexpressing a minimal domain of calpastatin suppressed IL-6 by reducing NF-κB signaling via the stabilization of IκBα, without affecting the upstream signal. Moreover, our findings indicated that calpastatin overexpression suppressed IL-17 production by Th cells by up-regulating the STAT5 signal. Finally, overexpression of a minimal domain of calpastatin suppressed IL-6 production efficiently in primary fibroblasts derived from the RA synovium. These findings suggest that inhibiting calpain by overexpressing a minimal domain of calpastatin could coordinately suppress proinflammatory activities, not only those of Th cells but also of synovial fibroblasts. Thus, this strategy may prove viable as a candidate treatment for inflammatory diseases such as RA

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

パン酵母(Saccharomyces cerevisiae)ミトコンドリアのリボソーム蛋白質遺伝子の構造と発現に関する研究

博士（学術）神戸大

Oxidative removal of soluble divalent manganese ion by chlorine in the presence of superfine powdered activated carbon

Here, we examined the removal of soluble divalent manganese (Mn(II)) by combination treatment with superfine powdered activated carbon (SPAC) and free chlorine in a membrane filtration pilot plant and batch experiments. Removal rates >95 % were obtained with 3 mg/L SPAC, 1 mg/L chlorine, and a contact time of 4 min, meeting practical performance standards. Mn(II) was found to be oxidized and precipitated on the surface of the activated carbon particles by chlorine. The Mn(II) removal rate was fitted to pseudo-first-order reaction kinetics, and the rate coefficient changed in inverse proportion to as-is particle size, but not to true particle size. The rate coefficient was independent of both Mn(II) concentration, except at high Mn(II) concentration, and the chlorine concentrations tested. The rate-determining step of Mn(II) removal was confirmed to be external-film mass transfer, not chemical oxidation. Activated carbon was found to have a catalytic effect on the oxidation of Mn(II), but the effect was minimal for conventionally sized activated carbon. However, Mn(II) removal at feasible rates for practical application can be expected when the activated carbon particle diameter is reduced to several micrometers. Activated carbon with a particle size of around 1–2 μm may be the most appropriate for Mn(II) removal because particles below this size were aggregated, resulting in reduced removal efficiency

Determination of sea ice concentration from AVHRR visible and near infrared imagery

Sea ice concentrations are determined from the visible and near infrared albedo of the AVHRR imagery. One method uses only one channel data to interpolate the ice concentration between 0 and 100% corresponding to the open water and the snow cover, respectively. This method yieds an uncertainty owing to the variation of albedo by the surface condition change. Another method uses two-channel data to derive not only the ice concentration but also the ice surface condition and can eliminate uncertainties involved in the first method. The ice surface condition is expressed by "snow coverage". Air photographs are compared with the satellite data. They are helpful to discuss the surface condition of sea ice. Time variations of the concentration and surface condition of summer sea ice are discussed