Carbon monoxide: impact on remethylation/transsulfuration metabolism and its pathophysiologic implications

Carbon monoxide (CO) is a gaseous product generated by heme oxygenase (HO), which oxidatively degrades heme. While the stress-inducible HO-1 has well been recognized as an anti-oxidative defense mechanism under stress conditions, recent studies suggest that cancer cells utilize the reaction for their survival. HO-2, the constitutive isozyme, also plays protective roles as a tonic regulator for neurovascular function. Although protective roles of the enzyme reaction and CO have extensively been studied, little information is available on the molecular mechanisms by which the gas exerts its biological actions. Recent studies using metabolomics revealed that CO inhibits cystathionine β-synthase (CBS), which generates H2S, another gaseous mediator. The CO-dependent CBS inhibition may impact on the remethylation cycle and related metabolic pathways including the methionine salvage pathway and polyamine synthesis. This review focuses on the gas-responsive regulation of metabolic systems, particularly the remethylation and transsulfuration pathways, and their putative implications for cancer and ischemic diseases

Topological melting of the metastable skyrmion lattice in the chiral magnet Co9_9Zn9_9Mn2_2

In a $\beta$-Mn-type chiral magnet Co$_9$Zn$_9$Mn$_2$, we demonstrate that the magnetic field-driven collapse of a room temperature metastable topological skyrmion lattice passes through a regime described by a partial topological charge inversion. Using Lorentz transmission electron microscopy, the magnetization distribution was observed directly as the magnetic field was swept antiparallel to the original skyrmion core magnetization, i.e. negative magnetic fields. Due to the topological stability of skyrmions, a direct transition of the metastable skyrmion lattice to the equilibrium helical state is avoided for increasingly negative fields. Instead, the metastable skyrmion lattice gradually transforms into giant magnetic bubbles separated by $2\pi$ domain walls. Eventually these large structures give way to form a near-homogeneously magnetized medium that unexpectedly hosts a low density of isolated skyrmions with inverted core magnetization, and thus a total topological charge of reduced size and opposite sign compared with the initial state. A similar phenomenon has been observed previously in systems hosting ordered lattices of magnetic bubbles stabilized by the dipolar interaction and called "topological melting". With support from numerical calculations, we argue that the observed regime of partial topological charge inversion has its origin in the topological protection of the starting metastable skyrmion state.Comment: 9 pages, 4 figure

Clinical Characteristics and Outcomes in 314 Japanese Patients with Bacterial Endophthalmitis : A Multicenter Cohort Study from J-CREST

Bacterial endophthalmitis is an intraocular infection that causes rapid vison loss. Pathogens can infect the intraocular space directly (exogenous endophthalmitis (ExE)) or indirectly (endogenous endophthalmitis (EnE)). To identify predictive factors for the visual prognosis of Japanese patients with bacterial endophthalmitis, we retrospectively examined the bacterial endophthalmitis characteristics of 314 Japanese patients and performed statistics using these clinical data. Older patients, with significantly more severe clinical symptoms, were prevalent in the ExE group compared with the EnE group. However, the final best-corrected visual acuity (BCVA) was not significantly different between the ExE and EnE groups. Bacteria isolated from patients were not associated with age, sex, or presence of eye symptoms. Genus Streptococcus, Streptococcus pneumoniae, and Enterococcus were more prevalent in ExE patients than EnE patients and contributed to poor final BCVA. The presence of eye pain, bacterial identification, and poor BCVA at baseline were risk factors for final visual impairment

大都市団地居住高齢者の社会関係と生活ニーズ充足のためのソーシャルサポート ─ライフコースとケアリング関係の視点からの分析─

本研究の目的は,ライフコースとケアリング関係の視点から,大都市団地居住高齢者の社会関係と生活ニーズ充足のためのソーシャルサポートとの関連を分析し,地域包括ケアの課題を検討することである。東京都A 市B 団地居住高齢者429 名への訪問調査を2011 年5-6 月に実施した(有効N=196 名,有効回答率:46.0%)。主な結果として,1)生活ニーズのある人(全体の1 割弱)の2-4 割に支援者がおらず,有支援者の2 割弱が家事,買い物,ゴミだし,当番の場合に近所の人を担い手としてあげた(複数回答),2)困りごとの相談相手がいない人は2 割弱で,男性の方が女性よりいない割合が高い,3)ロジスティック回帰分析の結果,独居,男性,近隣ネットワークが小さい方が相談者がいない確率が高いことがわかった。独居や男性など既存の社会ネットワークを活用したソーシャルサポートの活用可能性が乏しいグループには適切な支援策が必要であることが示唆された。小規模調査の限界もあるが,団地居住高齢者の多様な社会関係とソーシャルサポートの現状をふまえての地域包括ケアの課題があきらかになった。The purpose of this study is two-fold: 1) to examine the association between social relationships and support for meeting the daily life needs of elderly people in an urban housing complex from the lifecourse and caring-relations perspectives and 2) to discuss the challenges of community comprehensive care. Structured home-visit interviews were conducted among 429 elderly people at Housing Complex B in City A, in the Tokyo Metropolitan area, from May to June, 2011. Valid responses were obtained from 196 persons, for a response rate of 46.0%. The results are as follows: 1) among the elderly who had daily-life needs (less than ten percent of total respondents), twenty percent relied on neighbors for doing housework, shopping, taking out garbage, and performing duties in the housing complex (multiple answer); 2) less than twenty percent of respondents had no one they could turn to for advice regarding their day-to-day difficulties; and 3) as a result of logistic regression analysis, single people, males, and respondents with small networks of neighbors were found to be less likely than couples, females, and those with large networks of neighbors to have anyone to turn to for advice. Our findings indicate thatit is necessary to have an appropriate support system for those who have limited support available in their existing social network (e.g. single people, males). In spite of the limitation of a small sample, we could clarify some of the challenges for community comprehensive care for elderly people by considering the diverse social relations and social support available to them in a housing complex

産後うつとボンディングの関連の経産による変化: 子どもの健康と環境に関する全国調査からの経時的な結果より

富山大学・富医薬博乙77号・土田 暁子・2020/11/25関連論文Tsuchida A, Hamazaki K, Matsumura K, Miura K, Kasamatsu H, Inadera H; Japan Environment and Children\u27s Study (JECS) Group. Changes in the association between postpartum depression and mother-infant bonding by parity: Longitudinal results from the Japan Environment and Children\u27s Study. J Psychiatr Res. 2019 Mar;110:110-116. doi: 10.1016/j.jpsychires.2018.11.022. Epub 2018 Nov 28. PMID: 30616158.富山大

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

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome.

X chromosomes are unusual in many regards, not least of which is their nonrandom gene content. The causes of this bias are commonly discussed in the context of sexual antagonism and the avoidance of activity in the male germline. Here, we examine the notion that, at least in some taxa, functionally biased gene content may more profoundly be shaped by limits imposed on gene expression owing to haploid expression of the X chromosome. Notably, if the X, as in primates, is transcribed at rates comparable to the ancestral rate (per promoter) prior to the X chromosome formation, then the X is not a tolerable environment for genes with very high maximal net levels of expression, owing to transcriptional traffic jams. We test this hypothesis using The Encyclopedia of DNA Elements (ENCODE) and data from the Functional Annotation of the Mammalian Genome (FANTOM5) project. As predicted, the maximal expression of human X-linked genes is much lower than that of genes on autosomes: on average, maximal expression is three times lower on the X chromosome than on autosomes. Similarly, autosome-to-X retroposition events are associated with lower maximal expression of retrogenes on the X than seen for X-to-autosome retrogenes on autosomes. Also as expected, X-linked genes have a lesser degree of increase in gene expression than autosomal ones (compared to the human/Chimpanzee common ancestor) if highly expressed, but not if lowly expressed. The traffic jam model also explains the known lower breadth of expression for genes on the X (and the Z of birds), as genes with broad expression are, on average, those with high maximal expression. As then further predicted, highly expressed tissue-specific genes are also rare on the X and broadly expressed genes on the X tend to be lowly expressed, both indicating that the trend is shaped by the maximal expression level not the breadth of expression per se. Importantly, a limit to the maximal expression level explains biased tissue of expression profiles of X-linked genes. Tissues whose tissue-specific genes are very highly expressed (e.g., secretory tissues, tissues abundant in structural proteins) are also tissues in which gene expression is relatively rare on the X chromosome. These trends cannot be fully accounted for in terms of alternative models of biased expression. In conclusion, the notion that it is hard for genes on the Therian X to be highly expressed, owing to transcriptional traffic jams, provides a simple yet robustly supported rationale of many peculiar features of X's gene content, gene expression, and evolution