Thermal Square Planar-to-Octahedral Transformation of Nickel(II) Complexes Containing 2-Aminobenzimidazole in the Solid Phase

Thermal reactions of the complexes, [Ni(abi)4]X2·nH2O (abi, 2-aminobenzimidazole; X, Cl, Br, I, NO3, ClO4, or 1/2SO4; n, 3 for chloride and bromide, 1 for nitrate, and 0 for others) were investigated. Distinct color changes from orange to green were observed in the three complexes of chloride, bromide, and nitrate upon heating. It was found from the changes in absorption and far-IR spectra and magnetic susceptibilities under the thermal reactions that the complexes undergo transformation from square planar to tetragonally distorted octahedral structures, involving an increase in the coordination number from four to six. No such transformation could be found in the corresponding iodide, perchlorate, and sulfate. The effect of the introduced amino group on the structural conversion reactions of the abi complexes is discussed as compared with the corresponding benzimidazole complexes, [Ni(bimd)4]X2, which underwent transformation from square planar to octahedral structure upon heating when X is I or NO3

新規シアノ架橋複核金属錯体の設計・開発およびそのロタキサンの合成

金沢大学医教育学部シアノソース側の錯体の合成に手間取り、現在のところ、目的のシアノ架橋複核金属錯体の合成には成功していない。しかしながら、当初はシアノ架橋を受ける側の錯体として設計・開発したいくつかのニッケル(II)及び銅(II)錯体において、以下に述べるような興味深い性質が確認できた。(1)トロボロンあるいはヒノキチオールとN-あるいはN、N\u27-メチル置換エチレンジアミン類を含む混合配位子ニッケル(II)及び銅(II)錯体を多数合成し、主にそのソルバトクロミズムについて明かにした。これらの錯体は溶媒の極性に関わりなく溶解して多様なソルバトクロミズムを示すとともに、それらの電子スペクトルが溶媒の極性についての一つのパラメーターを与えることを明かにした。(2)1-ベンジル-1,2-エタンジアミン(bezen)を含むニッケル(II)錯体(trans-[Ni(H_2O)_2(benzen)_2]X_2:X=Cl,Br,or NO_3)の固相熱化学反応を検討したところ、deaquation-anationによりいずれの塩ともに、シス-アニオノ錯体へと変化することがわかった。合成が難しいとされているシス体の生成には、かさ高い置換基を持ち、しかも対称性の低くなるモノ置換体ジアミンが適していることを明かにした。(3)光学活性なジアミン類を含むニッケル(II)錯体(trans-[Ni(H_2O)_2(diamine)_2]X_2:X=Cl,Br,or NO_3)の固相熱化学反応を検討したところ、シス-アニオノ錯体に変化する例が数多く見られた。これは対応するジアミンのラセミ体を含む同型の錯体の場合と大きく異なっていた。シス錯体の生成にはジアミンの光学活性種が有利であるとともに、ラセミ体を用いた時のジアクア錯体は、trans-[Ni(H_2O)_2(d-diamine)(l-diamine)1X_2の構造を持つことが明かとなった。(1) Mixed copper (II) chelates of the type [Cu (trop/hino) (diamine)] ClO_4 were prepared with a tropolonato or hinokitiolato ligand (trop/hino) and N,N-dimethyl, N,N\u27-dimethyl, N,N,N\u27-trimethyl or N,N,N\u27, N\u27-tetramethyl-ethylenediamine. These chelates were generally similar to the corresponding beta-diketonato chelates, in particular with respect to their characteristic solvatochromism, i.e., the shifts of their d-d bands to the red with increasing DN (donor number) of the solvent.(2) Eleven mixed-ligand chelates of Ni (II) containing a molecule of N,N-di-, N,N,N\u27-tri-, or N,N,N\u27, N\u27-tetramethyl-ethylenediamine, and a tropolone (trop) or hinokitiolate (hino) ligand, were prepared, and their electronic spectra in solid state and in various organic solvents were studied. Most systems studied were green, containing octahedral chelate species [Ni (trop/hino) (diamine) (H_2O/Solvent)_2]^+ or [Ni (NO_3) (trop/hino) (diamine)], but some were red, containing square planar [Ni (trop/hino) (diamine)]^+, an equilibrium between the octahedral and square planar species was sometimes observed in solutions. Strong spectral resemblances with the corresponding diamine-beta-diketonate chelates of Ni (II) were observed.(3) The solid-phase thermal reactions of trans-diaquabis (diamine) nickel (II) complexes (trans- [Ni (diamine)_2 (H_2O)_2] X_2) were investigated by means of TG/DTA and DSC,and high-temperature electronic spectrometry, where the diamine is an optically active diamine such as (1S,2S) -1,2-diphenyl-1,2-ethanediamine, (1R,2R) -1,2-cyclo-hexanediamine, or (S) -4-methyl-1,2-pentanediamine, and X is Cl^-, Br^-, or NO_3^-. Several complexes were peculiarly transformed into cis- [NiX_2 (diamine)_2] upon thermal deaquation-anation, and then isomerized to trans- [NiX_2(dimaine)_2] upon further heating. The results were in contrast to the reactions of the complexes with the coresponding racemic diamines which underwent a simple deaquation-anation, retaining an original trans configuration. The differences must come from a slight difference in the conformation of diamine ligands between trans- [Ni (R-diamine) (S-diamine) (H_2O)_2]X_2 which is obtained for the rac-diamines and trans- [Ni (R- or S-diamine)_2 (H_2O)_2]X_2 which is obtained for the optically active diamines.研究課題/領域番号:07640741, 研究期間(年度):1995 – 1997出典：研究課題「新規シアノ架橋複核金属錯体の設計・開発およびそのロタキサンの合成」課題番号07640741（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-07640741/076407411997kenkyu_seika_hokoku_gaiyo/）を加工して作

Social interaction trajectories and all-cause mortality in older adults: the Otassha study

IntroductionThis longitudinal study aimed to identify aging trajectory patterns of social interaction by sex and determine the association between these patterns and all-cause mortality.MethodsParticipants were 4,065 community-dwelling older adults (1849 men) in Japan, aged 65–89 years, who responded twice or more to a mail survey conducted between 2012 and 2020. Social interaction was examined through the frequency of face-to-face and non-face-to-face contact with non-resident family and friends. The aging trajectories of the social interaction scores were identified using group-based trajectory modeling.ResultsTwo groups were identified among both men and women. Among men with high-frequency interaction, a rapid decrease in the frequency of social interaction was observed after 80 years of age. Conversely, among women, the frequency tended to remain the same, even after 80 years of age. The social interaction score among those aged 65 years in the low-frequency group was approximately 4 points for men and 6 points for women. Among men, no decrease was observed; however, it tended to decline after 85 years of age among women. Among men, the factors associated with the low-frequency group were instrumental activities of daily living score, perceived financial status, and social participation, while among women, they were self-rated health and social participation. The adjusted hazard ratio in the low-frequency group for all-cause mortality was 1.72 (95% confidence interval, 1.27–1.72) for men and 1.45 (95% confidence interval, 0.98–2.14) for women.DiscussionIn the low-frequency group, men had a higher risk of all-cause mortality than women. Daily social interaction from mid-age is important to reduce the risk of social isolation and all-cause mortality in later life

Higher Serum Brain-Derived Neurotrophic Factor Levels Are Associated With a Lower Risk of Cognitive Decline: A 2-Year Follow Up Study in Community-Dwelling Older Adults

ObjectiveTo assess the relationship of serum brain-derived neurotrophic factor (BDNF) levels with the subsequent short-term decline in cognitive functioning in community-dwelling older adults.DesignTwo-year prospective, observational study.Setting and ParticipantsThe study included 405 adults aged 65–84 years, initially free of a dementia diagnosis who were living in Tokyo, Japan.MethodsParticipants underwent health assessments at baseline (2011) and follow-up (2013). Serum BDNF levels and scores from the Montreal Cognitive Assessment-Japanese version (MoCA-J) were systematically measured. Logistic regression was used to estimate the odds of cognitive decline between baseline and follow-up assessments in the full MoCA-J scale (operationally defined as a decrease of two or more points), as well as in MoCA-J subscales (decline of one or more points in a specific subscale), as a function of serum BDNF level, adjusting for baseline demographics, prevalent chronic diseases, and baseline cognitive scores.ResultsAmong individuals who performed worse on the full MoCA-J at baseline (i.e., scores in the bottom quartile [≤21], which is consistent with a mild cognitive impairment status), but not among those who performed better (top 3 quartiles), those with highest baseline serum BDNF levels (top quartile) had lower odds of subsequent decline in the full MoCA-J scale than those with lowest (bottom quartile); i.e., odds ratio (OR): 0.10 (95% confidence interval [CI]: 0.02–0.62; p = 0.013). Regarding MoCA-J subscales, adjusted odds of decline in the executive function subscale, but not in the other five subscales, were substantially low among those with highest baseline serum BDNF levels (top quartile), as compared to those with the lowest (bottom quartile), i.e., OR: 0.27 (95% CI:0.13–0.60; p < 0.001).Conclusion and ImplicationsHigher serum BDNF levels were associated with a lower risk of decline in cognitive function in a sample of community-dwelling older Japanese adults. Risk varied across cognitive subdomains and according to baseline cognition. This warrants further research to evaluate the added-value of serum BDNF in health promotion initiatives directed toward cognitive decline prevention in community-dwelling older adults

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

Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis

Funder: Research Committee on Intractable Vasculitides; The Ministry of Health, Labour and Welfare of Japan.Objectives: Evaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial. Methods: Patients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m2) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse. Results: 188 patients were studied: 95/188 (51%) men, median age 59 years (range 19–89), prior disease duration 5.0 years (range 0.4–34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activity item, and 54/188 (29%) received the higher dose glucocorticoid regimen. 171/188 (90%) patients achieved remission by 4 months. Only six patients (3.2% of the study population) did not achieve disease control at month 4. Four patients died in the induction phase due to pneumonia (2), cerebrovascular accident (1), and active vasculitis (1). 41 severe adverse events occurred in 27 patients, including 13 severe infections. Conclusions: This large prospective cohort of patients with relapsing AAV treated with rituximab in conjunction with glucocorticoids demonstrated a high level of efficacy for the reinduction of remission in patients with AAV who have relapsed, with a similar safety profile to previous studies

Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis

Funder: Research Committee on Intractable Vasculitides; The Ministry of Health, Labour and Welfare of Japan.Objectives: Evaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial. Methods: Patients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m2) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse. Results: 188 patients were studied: 95/188 (51%) men, median age 59 years (range 19–89), prior disease duration 5.0 years (range 0.4–34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activity item, and 54/188 (29%) received the higher dose glucocorticoid regimen. 171/188 (90%) patients achieved remission by 4 months. Only six patients (3.2% of the study population) did not achieve disease control at month 4. Four patients died in the induction phase due to pneumonia (2), cerebrovascular accident (1), and active vasculitis (1). 41 severe adverse events occurred in 27 patients, including 13 severe infections. Conclusions: This large prospective cohort of patients with relapsing AAV treated with rituximab in conjunction with glucocorticoids demonstrated a high level of efficacy for the reinduction of remission in patients with AAV who have relapsed, with a similar safety profile to previous studies