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

Mechanism of enhanced optical second-harmonic generation in the conducting pyrochlore-type Pb2_{2}Ir2_{2}O7−x_{7-x} oxide compound

The structural, electronic, and optical properties of pyrochlore-type Pb$_{2}$Ir$_{2}$O$_{6}$O'$_{0.55}$, which is a metal without spatial inversion symmetry at room temperature, were investigated. Structural analysis revealed that the structural distortion relevant to the breakdown of the inversion symmetry is dominated by the Pb-O' network but is very small in the Ir-O network. At the same time, gigantic second-harmonic generation signals were observed, which can only occur if the local environment of the Ir 5$d$ electrons features broken inversion symmetry. First-principles electronic structure calculations reveal that the underlying mechanism for this phenomenon is the induction of the noncentrosymmetricity in the Ir 5$d$ bands by the strong hybridization with O' 2$p$ orbitals. Our results stimulate theoretical study of inversion-broken iridates, where exotic quantum states such as a topological insulator and Dirac semimetal are anticipated

カンイガタ ジキシキ ショクジ レキホウ シツモンヒョウ（BDHQ） オ モチイタ ガイライ トウニョウビョウ エイヨウ シドウ タイショウシャ チュウシュツホウ ニカンスル ケントウ

【背景】地域に開かれた無床診療所には、管理栄養士はほとんど常勤しておらず、栄養指導が必要な生活習慣 病患者に対する指導でさえも十分に実施できていない現状がある。また、糖尿病栄養指導対象者抽出については、医 師の主観（治療歴、患者背景、患者の性格等）や血液検査値等の客観的指標のみを参考にしており、必ずしも食事調 査結果に基づいた抽出をしている訳ではない。そのため、実際に食習慣が乱れており、糖尿病栄養指導の必要性が高 い患者に対して効率良く栄養指導ができているとは言い難い。 【目的】無床診療所における外来糖尿病患者の治療効果を向上させるため、BDHQ から得られた食事調査結果を活 用した新しい外来糖尿病栄養指導対象者抽出法を確立すること。 【方法】M 医院（大阪府阪南市）に通院している2 型糖尿病患者のうち、研究の趣旨に同意が得られた109 名（男 性77 名、女性32 名、平均年齢64.7±7.4 歳）にBDHQ を実施し、ある1 日の平均的な「栄養素摂取量」を算出し た。次いで当該患者カルテの検査値（HbA1c、クレアチニン等）を記録し、食事調査結果と組み合わせた栄養指導 対象者抽出基準を検討した。 【結果および考察】糖尿病食事療法のうち、栄養基準が大きく変化する糖尿病性腎症第3 期B に該当する患者は、 109 名中25 名であった。このうち、BDHQ から得られたたんぱく質摂取量が1.0g/kg 標準体重/日を上まっている 患者は17 名であり、特にこれらの患者は管理栄養士による詳細な栄養指導を受ける必要性が高いことが考えられる。 BDHQ は集団での妥当性はある程度証明されているが、個人での妥当性は証明されていない。そのため得られた結 果の解釈には慎重な配慮を要する。しかし、少なくとも今回のように、無床診療所において管理栄養士による詳細な 栄養指導を受ける必要性があるか否かを大雑把に判定するような目的には最適であろうと考えられた。Purpose: To improve therapeutic efficacy of ambulatory patients with diabetes in non-bed clinics and to establish a new method of identifying subjects at risk of diabetes related complications using a dietary survey obtained from a brief self administered diet history questionnaire（BDHQ）. Methods: Among patients with type 2 diabetes attending M clinic（Osaka, Japan）, 109 gave informed consent（male 77, female 32, mean age 64.7 ± 7.4 years）. A BDHQ was administered to calculate the average “nutrient intake” per day. The test results in the patients’ medical records（HbA1c, creatinine, etc.） were recorded. The criteria for identifying patients requiring nutritional guidance were also examined in conjunction with the dietary surveys. Results: For 25 of the participants, their nutritional standards put them at risk of third phase B diabetic nephropathy. Of these, the protein intake of 17, as calculated from the BDHQ, was >1.0 g/kg/day. It was considered essential that these patients receive detailed nutritional guidance from registered dietitians. Although the relevance of administering group BDHQ is to some extent proved, the benefit for the individual has not been demonstrated. The interpretation of the results must, therefore, be viewed with caution. However, there are indicators that suggest detailed nutritional guidance by registered dietitians at non bed clinics would be advisable. Keywords: Non bed Clinic, I

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