Involvement of a Binuclear Species with the Re−C(O)O−Re Moiety in CO_2 Reduction Catalyzed by Tricarbonyl Rhenium(I) Complexes with Diimine Ligands: Strikingly Slow Formation of the Re−Re and Re−C(O)O−Re Species from Re(dmb)(CO)_3S (dmb = 4,4‘-Dimethyl-2,2‘-bipyridine, S = Solvent)

Excited-state properties of fac-[Re(dmb)(CO)_3(CH_3CN)]PF_6, [Re(dmb)(CO)_3]_2 (where dmb = 4,4‘-dimethyl-2,2‘-bipyridine), and other tricarbonyl rhenium(I) complexes were investigated by transient FTIR and UV−vis spectroscopy in CH_3CN or THF. The one-electron reduced monomer, Re(dmb)(CO)_3S (S = CH_3CN or THF), can be prepared either by reductive quenching of the excited states of fac-[Re(dmb)(CO)_3(CH_3CN)]PF_6 or by homolysis of [Re(dmb)(CO)_3]_2. In the reduced monomer's ground state, the odd electron resides on the dmb ligand rather than on the metal center. Re(dmb)(CO)_3S dimerizes slowly in THF, k_d = 40 ± 5 M^(-1) s^(-1). This rate constant is much smaller than those of other organometallic radicals which are typically 10^9 M^(-1) s^(-1). The slower rate suggests that the equilibrium between the ligand-centered and metal-centered radicals is very unfavorable (K ≈ 10^(-4)). The reaction of Re(dmb)(CO)_3S with CO_2 is slow and competes with the dimerization. Photolysis of [Re(dmb)(CO)_3]_2 in the presence of CO_2 produces CO with a 25−50% yield based on [Re]. A CO_2 bridged dimer, (CO)_3(dmb)Re−CO(O)−Re(dmb)(CO)_3 is identified as an intermediate. Both [Re(dmb)(CO)_3]_2(OCO_2) and Re(dmb)(CO)_3(OC(O)OH) are detected as oxidation products; however, the previously reported formato-rhenium species is not detected

ガボン キョウワコク ニオケル エボラ シュッケツネツ リュウコウ ト カンレン スル ブンカテキ ヨウイン

【目的】　1994～97年に3度のエボラ出血熱（以下EHF）流行が発生したガボン共和国において，流行状況とその対策，また背景にあると考えられる文化的要因について検討した。【方法】　1997年1月3度目のEHF流行期間中，米国およびガボンにおいて関係機関を訪問し情報を収集した。また，EHFが流行中のガボンのBooue村において，20歳以上男女計20人に対しEHFに関する知識および意識について，伝統治療士2人に対し患者の治療方法について，それぞれ訪問面接調査を実施した。【結果】　3回の流行はすべてチンパンジーやゴリラとの関連が疑われ，特に第二の流行では12人の死亡例が村の祭りのため死んだチンパンジーの皮を剥いで調理し食していた。スーダンやザイールでEHF流行を悪化させた要因である病院での汚染注射針の利用は早期に予防されていたが，家庭内における家族の患者との濃厚な接触，葬式における遺体への抱擁などの伝統的風習が本流行での重要な伝播要因となっていたと考えられる。　訪問面接調査の結果は，流行地の村でありながら3割以上はその疾病の名前さえ知らず，知っていてもそれがどのような病気でどのように伝播するかを回答できない者が多かった。住民の伝統治療士に対する信頼度は高いが，患者の両腕にナイフで傷をつけ血液を皮膚に擦りつけるなどの伝統的治療が感染伝播に寄与していることも推測された。【結論】　EHF流行の背景には文化的要因が強く関連している可能性が示唆された。今後国際的な感染症対策において，人類学・社会学など保健医療以外の分野との協力体制が重要になってくると思われる。【Objective】The Republic of Gabon experienced epidemics of Ebola hemorrhagic fever (EHF) three times between 1994 and 1997. This study aimed at exploring cultural factors related to the outbreaks.【Methods】We collected information about EHF epidemics from the Gabon Ministry of Health, district hospitals and other facilities and conducted in-depth interviews with 20 villagers and 2 traditional healers in the village where the third epidemic occurred.【Results】All three epidemics were supposed to have direct or indirect relationship with great apes, the victims having cooked or eaten chimpanzees meat. Although the reuse of syringes and needles in hospitals which had worsened past EHF outbreaks in Sudan and Zaire did not contribute to the outbreak in Gabon, traditional practices as family members remaining close to the patient to nurse him/her, and hugging and touching the dead at funerals were suspected to be crucial sources of infection. Interviews with traditional healers revealed that traditional treatment methods as cutting a patient\u27 skin with an unsterilized knife and appkling blood to the skin were risky and might have been contributory factors in the deaths of one traditionals healer and his assistant in the thir EHF outbreak. In one village where EHF had reached epidemic proportions, in-depth interviews were conducted with 2 traditional healers and 20 persons of mean age 33 (20～46) years with a sampling method of selecting every tenth household form the entrance. Even though they lived in a village suffering an EHF outbreak, only two thirds of them knew the name of the disease and about half of them could not explain what kind of thought it had been due to evil spirits; others responded the mosquitoes or patient\u27s sweat/saliva were the cause.【Conclusions】This study showed that cultural factors might be very crucial to EHF outbreaks in developing counties. Quick intervention with health education is needed to disseminate appropriate knowledge and persuade people that traditional practices could carry a high risk of infection

Genetic polymorphism of pleiotrophin is associated with pain experience in Japanese adults Case-control study

Genetic factors play a role in individual differences in pain experience. Here, we performed a genome-wide association study (GWAS) to identify novel loci regulating pain processing. We conducted a 2-stage GWAS and the candidate single-nucleotide polymorphisms (SNPs) association study on pain experience using an exploratory cohort of patients with cancer pain. The confirmatory cohort comprised of participants from the general population with and without habitual use of analgesic medication. In the exploratory cohort, we evaluated pain intensity using a numerical rating scale, recorded daily opioid dosages, and calculated pain reduction rate. In the confirmatory cohort, pain experience was defined as habitual nonsteroidal anti-inflammatory drug usage. Using linear regression models, we identified candidate SNP in the exploratory samples, and tested the association between phenotype and experienced pain in the confirmatory samples. We found 1 novel SNP (rs11764598)—located on the gene encoding for pleiotrophin on chromosome 7—that passed the genome-wide suggestive significance at 20% false discovery rate (FDR) correction in the exploratory samples of patients with cancer pain (P = 1.31 × 10-7, FDR = 0.101). We confirmed its significant association with daily analgesic usage in the confirmatory cohort (P = .028), although the minor allele affected pain experience in an opposite manner. We identified a novel genetic variant associated with pain experience. Further studies are required to validate the role of pleiotrophin in pain processing

Polymorphisms and Body Mass Index Across Life Course

Background: Obesity is a reported risk factor for various health problems. Genome-wide association studies (GWASs) have identified numerous independent loci associated with body mass index (BMI). However, most of these have been focused on Europeans, and little evidence is available on the genetic effects across the life course of other ethnicities. Methods: We conducted a cross-sectional study to examine the associations of 282 GWAS-identified single nucleotide polymorphisms with three BMI-related traits, current BMI, BMI at 20 years old (BMI at 20), and change in BMI (BMI change), among 11,586 Japanese individuals enrolled in the Japan Multi-Institutional Collaborative Cohort study. Associations were examined using multivariable linear regression models. Results: We found a significant association (P < 0.05/282 = 1.77 × 10−4) between BMI and 11 polymorphisms in or near FTO, BDNF, TMEM18, HS6ST3, and BORCS7. The trend was similar between current BMI and BMI change, but differed from that of the BMI at 20. Among the significant variants, those on FTO were associated with all BMI traits, whereas those on TMEM18 and HS6SR3 were only associated with BMI at 20. The association of FTO loci with BMI remained, even after additional adjustment for dietary energy intake. Conclusions: Previously reported BMI-associated loci discovered in Europeans were also identified in the Japanese population. Additionally, our results suggest that the effects of each loci on BMI may vary across the life course and that this variation may be caused by the differential effects of individual genes on BMI via different pathways

A genome-wide association study on meat consumption in a Japanese population : the Japan Multi-Institutional Collaborative Cohort study

Recent genome-wide association studies (GWAS) on the dietary habits of the Japanese population have shown that an effect rs671 allele was inversely associated with fish consumption, whereas it was directly associated with coffee consumption. Although meat is a major source of protein and fat in the diet, whether genetic factors that influence meat-eating habits in healthy populations are unknown. This study aimed to conduct a GWAS to find genetic variations that affect meat consumption in a Japanese population. We analysed GWAS data using 14 076 participants from the Japan Multi-Institutional Collaborative Cohort (J-MICC) study. We used a semi-quantitative food frequency questionnaire to estimate food intake that was validated previously. Association of the imputed variants with total meat consumption per 1000 kcal energy was performed by linear regression analysis with adjustments for age, sex, and principal component analysis components 1–10. We found that no genetic variant, including rs671, was associated with meat consumption. The previously reported single nucleotide polymorphisms that were associated with meat consumption in samples of European ancestry could not be replicated in our J-MICC data. In conclusion, significant genetic factors that affect meat consumption were not observed in a Japanese population

Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals

Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci (P<5 × 10–8) including eight novel loci. Of these, missense variants of SESN2 and PNPLA3 were predicted to be damaging to the function of these proteins; another five loci—TMEM18, TM4SF4, MXD3-LMAN2, PSORS1C1-PSORS1C2, and HNF4A—are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, LINC01578, is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout

A Genome-wide Association Study on Confection Consumption in a Japanese Population- The Japan Multi-Institutional Collaborative Cohort study.

Differences in individual eating habits may be influenced by genetic factors, in addition to cultural, social, or environmental factors. Previous studies suggested that genetic variants within sweet taste receptor genes family were associated with sweet taste perception and the intake of sweet foods. The aim of this study was to conduct a genome-wide association study (GWAS) to find genetic variations that affect confection consumption in a Japanese population. We analyzed GWAS data on sweets consumption using 14,073 participants from the Japan Multi-Institutional Collaborative Cohort study. We used a semi-quantitative food frequency questionnaire to estimate food intake that was validated previously. Association of the imputed variants with sweets consumption was performed by linear regression analysis with adjustments for age, sex, total energy intake and principal component analysis components 1 to 3. Furthermore, the analysis was repeated adjusting for alcohol intake (g/day) in addition to the above-described variables. We found 418 single nucleotide polymorphisms (SNPs) located in 12q24 that were associated with sweets consumption. SNPs with the 10 lowest P-values were located on nine genes including at the BRAP, ACAD10, and ALDH2 regions on 12q24.12-13. After adjustment for alcohol intake, no variant was associated with sweets intake with genome-wide significance. In conclusion, we found a significant number of SNPs located on 12q24 genes that were associated with sweets intake before adjustment for alcohol intake. However, all of them lost statistical significance after adjustment for alcohol intake

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