Copper-catalyzed silylation of aryl and alkenyl triflates with silylboronic esters avoiding base-mediated borylation.

Silylation of aryl and alkenyl triflates is found to occur readily with silylboronic esters as a silicon source under copper catalysis. The silyl moieties are exclusively installed into the organic frameworks through the preferential generation of a silylcopper species, wherein base-mediated direct borylation is totally suppressed. The combined use of tri-n-butylphosphine and 4,4'-diphenyl-2,2'-bipyridine as a ligand combination turned out to be indispensable for achieving the high catalytic activity.

Effects of interleukin-6 signal inhibition on Treg subpopulations and association of Tregs with clinical outcomes in rheumatoid arthritis.

OBJECTIVES: Anti-IL-6 receptor antibodies are clinically efficacious in the management of rheumatoid arthritis (RA) with an associated increase in regulatory T cells (Tregs); however, the role of functional Treg subsets has yet to be clarified. This study aimed to evaluate how functional Treg subsets are altered by IL-6 receptor blockade and to analyze the relationship between these Treg subsets and the clinical outcome of RA. METHODS: We collected frozen peripheral blood mononuclear cells (PBMCs) from 40 patients with RA who started tocilizumab (TCZ) with or without MTX and 11 healthy controls (HCs). We fractionated Tregs with flow cytometry based on markers of phenotype and function and measured the proportions of detailed Treg subsets sequentially from baseline to week 52. RESULTS: The proportions of resting Tregs (rTregs) and rTregs+activated Tregs (aTregs) were significantly lower in RA patients at baseline than in HCs. The proportions of all those CD127low Tregs, rTregs, aTregs, and rTregs+aTregs were significantly increased with TCZ treatment. In patients treated with TCZ without MTX, rTreg were increased. Patients with an increase in the proportion of rTregs at week 12 had significantly less arthritis flares during the observation period. CONCLUSIONS: Blocking IL-6 receptor with TCZ increased the proportion of rTregs, a functional Treg subpopulation. Patients with an early increase in rTregs showed a favorable treatment course, and this increase in rTregs may reflect molecular remission induced by IL-6 signal inhibition.

Ethynyl-B(dan) in [3+2] Cycloaddition and Larock Indole Synthesis: Synthesis of Stable Boron-Containing Heteroaromatic Compounds.

The cycloaddition of nitrile oxides with ethynyl-B(dan) (dan=naphthalene-1,8-diaminato) allowed the facile preparation of diverse isoxazolyl-B(dan) compounds, all of which displayed excellent protodeborylation-resistant properties. The dan-installation on the boron center proves vital to the high stability of the products as well as the perfect regioselectivity arising from hydrogen bond-directed orientation in the cycloaddition. The diminished boron-Lewis acidity of ethynyl-B(dan) also renders it amenable to azide-alkyne cycloaddition, Larock indole synthesis and related heteroannulations. The obtained boron-containing triazole, indoles, benzofuran and indenone exhibit sufficient resistance toward protodeborylation. Despite the commonly accepted transmetalation-inactive property derived from the diminished Lewis acidity, the synthesized heteroaryl-B(dan) compound was still found to be convertible to the oligoarene via sequential Suzuki-Miyaura coupling.

Selective S-Arylation of Sulfenamides with Arynes: Access to Sulfilimines.

Sulfilimines, the aza analogues of sulfoxides, are of increasing interest in medicinal and agrochemical research programs. However, the development of efficient routes for their synthesis has remained relatively unexplored. In this study, we report a transition metal-free, selective S-arylation reaction between sulfenamides and arynes, enabling the facile preparation of structurally diverse sulfilimines under mild and redox-neutral conditions in good yields. The application value of our method was further demonstrated by scale-up synthesis, downstream derivatization, and robustness screen.

Complexation-Triggered Fluctuation of π-Conjugation on an Antiaromatic Dicyanoanthracene Dianion.

The formation of Lewis pairs is an important chemical concept. Recently, the complexation of Lewis acidic tris(pentafluorophenyl)borane with Lewis basic moieties and subsequent reduction has emerged as a fascinating strategy for designing novel reactions and structures. The impact of the complexation and subsequent reduction of antiaromatic systems bearing Lewis base moieties has been investigated. We found how Lewis adduct formation stabilizes an antiaromatic system consisting of 9,10-dicyanoanthracene and tris(pentafluorophenyl)borane by using synthesis, X-ray crystallography, spectroscopic analysis, and quantum chemical calculations.

Efficient one-pot synthesis of dan-substituted organo- and silyl-boron compounds.

Direct, transition metal-free B(dan)-installation into organic frameworks has been developed. Heteroaryl-H bonds were transformable into the respective heteroaryl-B(dan) bonds through deprotonation. The resulting heteroaryl-B(dan) compounds, which are otherwise difficult to access, can undergo the direct Suzuki-Miyaura coupling. The method was demonstrated to apply to a silicon nucleophile, giving Lewis acidity-diminished stable silyl-B(dan) and -B(aam) in one pot.

Computed ammonia affinity for evaluating Lewis acidity of organoboronates and organoboronamides.

Lewis acidity of organoboronates [B(pin), B(neop), B(cat), B(eg), B(nad)] and organoboronamides [B(dan), B(aam), B(mdan)] has been found to be unifiedly evaluated by computed ammonia affinity (AA), while other methods [LUMO energies, global electrophilicity index (GEI), fluoride ion affinity (FIA)] were only partially applicable. The relationships between the AA values and such structural characters including the B-X bond lengths, the X-B-X angles, and the changes in the B-X bond lengths in the formation of the ammonia adducts were also described.

Longitudinal monitoring of circulating immune cell phenotypes in anti-neutrophil cytoplasmic antibody-associated vasculitis.

Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a necrotizing multiorgan autoimmune disease that affects small- to medium-sized blood vessels. Despite the improvements in treatments, half of the patients with AAV still experience disease relapses. In this review, we focus on peripheral leukocyte properties and phenotypes in patients with AAV. In particular, we explore longitudinal changes in circulating immune cell phenotypes during the active phase of the disease and treatment. The numbers and phenotypes of leukocytes in peripheral blood were differs between AAV and healthy controls, AAV in active versus inactive phase, AAV in treatment responders versus non-responders, and AAV with and without severe infection. Therefore, biomarkers detected in peripheral blood immune cells may be useful for longitudinal monitoring of disease activity in AAV.

Distinct gene signatures of monocytes and B cells in patients with giant cell arteritis: a longitudinal transcriptome analysis.

BACKGROUND: Giant cell arteritis (GCA) is a primary large-vessel vasculitis (LVV) of unknown origin. Its management is a challenge due to the late onset of disease symptoms and frequent relapse; therefore, clarifying the pathophysiology of GCA is essential to improving treatment. This study aimed to identify the transition of molecular signatures in immune cells relevant to GCA pathogenesis by analyzing longitudinal transcriptome data in patients. METHODS: We analyzed the whole blood transcriptome of treatment-naive patients with GCA, patients with Takayasu arteritis (TAK), age-matched, old healthy controls (HCs), and young HCs. Characteristic genes for GCA were identified, and the longitudinal transition of those genes was analyzed using cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT). RESULTS: Repeated measures analysis of variance revealed 739 differentially expressed genes among all patients and HCs. Of the 739 genes, 15 were characteristically upregulated and 36 were downregulated in patients with GCA compared to those with TAK and HCs. Pathway enrichment analysis showed that downregulated genes in GCA were associated with B cell activation. CIBERSORT analysis revealed that upregulation of "M0-macrophages" and downregulation of B cells were characteristic of GCA. Upregulation of "M0-macrophages" reflects the activation of monocytes in GCA toward M0-like phenotypes, which persisted under 6 weeks of treatment. Combined treatment with prednisolone and an interleukin-6 receptor antagonist normalized molecular profiles more efficiently than prednisolone monotherapy. CONCLUSIONS: Gene signatures of monocyte activation and B cell inactivation were characteristic of GCA and associated with treatment response.

Longitudinal monitoring of circulating immune cell phenotypes in large vessel vasculitis.

Giant cell arteritis (GCA) and Takayasu arteritis (TAK) are two types of primary large vessel vasculitis (LVV). LVV is an intractable, rare disease with a high relapse rate. Disease progression in asymptomatic patients is an important issue in the clinical management of LVV. Useful biomarkers associated with clinical phenotypes, disease activity, and prognosis may be present in peripheral blood. In this review, we focused on peripheral leukocyte counts, surface markers, functions, and gene expression in LVV patients. In particular, we explored longitudinal changes in circulating immune cell phenotypes during the active phase of the disease and during treatment. The numbers and phenotypes of leukocytes in the peripheral blood were different between LVV and healthy controls, GCA and TAK, LVV in active versus treatment phases, and LVV in treatment responders versus non-responders. Therefore, biomarkers obtained from peripheral blood immune cells may be useful for longitudinal monitoring of disease activity in LVV.

Self-Regulated Pathway-Dependent Chirality Control of Silver Nanoclusters.

Imparting chirality affords additive values, functions and responsiveness in molecular systems including nanoscale materials. Here, we report pathway-dependent chirality control in silver nanoclusters (NCs). The use of enantiomeric ligand, α-dihydrolipoic acid (DHLA), for the synthesis of Ag NCs leads to the preferential formation of one-handed chiral Ag29 (DHLA)12 NCs with intrinsic chirality in the exterior shell composed of a silver-dithiolate framework. Small Lewis base molecules such as pyridine bind to silver atoms in the shell of NC as a guest. The guest binding reverses the relative stability between the right- and left-handed NCs upon a steric interaction with the chiral ligand DHLA in the exterior shell in a kinetic manner, leading to unprecedented chirality inversion in the synthesis of NCs. This mechanism is further extended to the self-regulation or self-replication of chirality through interNC interactions dependent on the concentration in the synthesis of NCs.

A stable silylborane with diminished boron Lewis acidity.

A new dimethyl(phenyl)silylborane having a naphthalene-1,8-diaminato (dan) substituent on the boron center, PhMe2Si-B(dan), was synthesized. Owing to the diminished boron Lewis acidity, it is highly stable toward air. Synthetic application of the silylborane to catalytic silylboration and silylation of alkynes is also described.

Bone fragility via degradation of bone quality featured by collagen/apatite micro-arrangement in human rheumatic arthritis.

Although increased bone fragility is a well-recognized consequence in patients with rheumatoid arthritis (RA), the essential cause of degenerate bone strength remains unknown. This study aimed to determine factors contributing to bone dysfunction in RA by focusing on the bone matrix micro-arrangement, based on the preferential orientation of collagen and the related apatite c-axis as a bone quality index. The classical understanding of RA is limited to its severe pathological conditions associated with inflammation-induced bone loss. This study examined periarticular proximal tibiae from RA patients as compared with osteoarthritis (OA) patients as controls. Bone tissue material strength was disrupted in the RA group compared with the control. Collagen/apatite micro-arrangement and vBMD were significantly lower in the RA group, and the rate of decrease in apatite c-axis orientation (-45%) was larger than that in vBMD (-22%). Multiple regression analysis showed that the degree of apatite c-axis orientation (ß = 0.52, p = 1.9 × 10-2) significantly contributed to RA-induced bone material impairment as well as vBMD (ß = 0.46, p = 3.8 × 10-2). To the best of our knowledge, this is the first report to demonstrate that RA reduces bone material strength by deteriorating the micro-arrangement of collagen/apatite bone matrix, leading to decreased fracture resistance. Our findings represent the significance of bone quality-based analysis for precise evaluation and subsequent therapy of the integrity and soundness of the bone in patients with RA.

Role of interleukin-6 in bone destruction and bone repair in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common inflammatory form of arthritis leading to the progressive bone and joint destruction. Many factors are closely involved in the pathology of RA, in particular bone-related cells and inflammatory cytokines such as TNF-α and interleukin-6 (IL-6). Because RA patients with progressive bone destruction experience accelerated deterioration of their quality of life, inhibition of disease progression and joint destruction has become an important clinical goal. Recent studies have also found that drug intervention targeting proinflammatory cytokines such as IL-6 results in bone repair in addition to suppression of bone and joint destruction, and these results suggest the potential for new therapeutic goals. Regarding the relationship between IL-6 and bone destruction, essential roles of osteoclasts have been reported over many years; however, more recent studies have explored the relationship of IL-6 with osteoblasts and osteocytes. In this review, we highlight the perspectives of basic and clinical research, adding new findings on the relationships between IL-6 and bone-related cells associated with inflammation, and the possibility of bone repair by blocking IL-6.

Interleukin-1 pathway in active large vessel vasculitis patients with a poor prognosis: a longitudinal transcriptome analysis.

OBJECTIVES: Large vessel vasculitis (LVV) is characterised by a high relapse rate. Because accurate assessment of the LVV disease status can be difficult, an accurate prognostic marker for initial risk stratification is required. We conducted a comprehensive longitudinal investigation of next-generation RNA-sequencing data for patients with LVV to explore useful biomarkers associated with clinical characteristics. METHODS: Key molecular pathways relevant to LVV pathogenesis were identified by examining the whole blood RNA from patients with LVV and healthy controls (HCs). The data were examined by pathway analysis and weighted gene correlation network analysis (WGCNA) to identify functional gene sets that were differentially expressed between LVV patients and HCs, and associated with clinical features. We then compared the expression of the selected genes during week 0, week 6, remission and relapse. RESULTS: The whole-transcriptome gene expression data for 108 samples obtained from LVV patients (n = 27) and HCs (n = 12) were compared. The pathway analysis and WGCNA revealed that molecular pathway related to interleukin (IL)-1 was significantly upregulated in LVV patients compared with HCs, which correlated with the positron emission tomography vascular activity score, a disease-extent score based on the distribution of affected arteries. Further analysis revealed that the expression levels of genes in the IL-1 signalling pathway remained high after conventional treatment and were associated with disease relapse. CONCLUSION: Upregulation of the IL-1 signalling pathway was a characteristic of LVV patients and was associated with the extent of disease and a poor prognosis.

Borylation and Stannylation Reactions with Tuning of Lewis Acidity.

A B(dan) moiety (dan=naphthalene-1,8-diaminato) of diminished boron-Lewis acidity has efficiently been installed into organic frameworks by three-component carboboration of alkenes under copper catalysis, where a Cu-B(dan) species, generated by chemoselective σ-bond metathesis between a copper catalyst and an unsymmetrical diboron [(pin)B-B(dan)], acts as a key intermediate. The Cu-B(dan) species has also turned out to serve as a B(dan) nucleophile to afford various dan-substituted organoboranes via borylative substitution of carbon electrophiles. Furthermore, borylation reactions with another Lewis acidity-diminished boron unit, B(aam) (aam=anthranilamidato), have become feasible by use of (pin)B-B(aam) or H-B(aam). The resulting dan/aam-substituted organoboranes have been demonstrated to undergo direct cross-coupling without prior acidic deprotection, regardless of their diminished boron-Lewis acidity. Synthesis of diverse organostannanes based upon copper-catalyzed carbostannylation and borylstannylation, in which Lewis acidity increment of a tin center facilitates the progress in some cases, have also been described.

Association of Health Literacy with the Implementation of Exercise during the Declaration of COVID-19 State of Emergency among Japanese Community-Dwelling Old-Old Adults.

Health literacy is important for promoting and maintaining good health in old-old adults. It may influence the implementation of exercise in the coronavirus disease epidemic. The present cross-sectional study investigated the association of each dimension of health literacy with the implementation of exercise during the declaration of a state of emergency due to coronavirus disease in community-dwelling old-old adults. We collected data from 483 community-dwelling old-old adults (52.8% women) aged between 77 and 99 years who participated in a mail survey. Participants were divided into exercise or nonexercise groups based on the implementation of exercise during the declaration of a state of emergency. Health literacy was assessed using a 14-item health literacy scale. There were 327 (67.7%) participants in the exercise group and 156 (32.3%) in the nonexercise group. A significantly higher score of health literacy was observed in the exercise group than in the nonexercise group (communicative health literacy score = 14.0 ± 3.6 vs. 12.7 ± 3.8, p = 0.001). In a multivariate logistic regression model adjusted for potential confounders, high communicative health literacy scores were significantly associated with the implementation of exercise during the declaration of a state of emergency (odds ratio = 1.88, 95% confidence interval = 1.20-2.93). Approximately two-thirds of community-dwelling old-old adults implement exercise during the declaration of a state of emergency. High communicative health literacy was associated with the implementation of exercise during this period.

Perceived declining physical and cognitive fitness during the COVID-19 state of emergency among community-dwelling Japanese old-old adults.

AIM: Perceived health status, including physical and cognitive fitness, will be negatively associated with future health conditions among old-old adults. The coronavirus disease 2019 (COVID-19) pandemic has caused sudden changes in lifestyle. Thus, this study examined the associations of participation in an exercise class before the COVID-19 pandemic and the exercise habits and disruption to the rhythms of daily life during the COVID-19 state of emergency with perceived declining physical and cognitive fitness among community-dwelling old-old adults. METHODS: In July 2020, we carried out a mail survey of community-dwelling old-old adults aged between 77 and 99 years in Bibai, Hokkaido, Japan, to determine their perceived declining physical and cognitive fitness during the COVID-19 state of emergency. RESULTS: Of the 774 responders, 339 (43.8%) participants reported a decline in physical fitness, whereas 259 (33.5%) perceived declining cognitive fitness during the COVID-19 state of emergency. In a multivariate logistic regression model adjusted for potential confounders, exercise habits during the COVID-19 state of emergency were significantly associated with a lower perception of declining physical fitness. Disruption to the rhythms of daily life during the COVID-19 state of emergency was significantly associated with a higher perception of declining physical and cognitive fitness. CONCLUSIONS: Approximately half and more than one-third of community-dwelling old-old adults perceived declining physical and cognitive fitness, respectively, during the COVID-19 state of emergency. During this period, exercise habits were positively correlated with perceived health status among old-old adults, whereas disruption to the rhythms of daily life was negatively correlated. Geriatr Gerontol Int 2021; 21: 364-369.

Transition metal-free B(dan)-installing reaction (dan: naphthalene-1,8-diaminato): H-B(dan) as a B(dan) electrophile.

H-B(dan) was demonstrated to serve as a B(dan) electrophile, despite its highly diminished boron-Lewis acidity, leading to direct and transition metal-free approach to R-B(dan) of high synthetic utility upon treatment with Grignard reagents. Iterative cross-coupling of 5-bromo-2-pyridyl-B(dan), synthesized by the present method, was also achieved.

Enantioseparation and chiral induction in Ag29 nanoclusters with intrinsic chirality.

The optical activity of a metal nanocluster (NC) is induced either by an asymmetric arrangement of constituents or by a dissymmetric field of a chiral ligand layer. Herein, we unveil the origin of chirality in Ag29 NCs, which is attributed to the intrinsically chiral atomic arrangement. The X-ray crystal structure of a Ag29(BDT)12(TPP)4 NC (BDT: 1,3-benzenedithiol; TPP: triphenylphosphine) manifested the presence of intrinsic chirality in the outer shell capping the icosahedral achiral Ag13 core. The enantiomers of the Ag29(BDT)12(TPP)4 NC are separated by high-performance liquid chromatography (HPLC) using a chiral column for the first time, showing mirror-image circular dichroism (CD) spectra. The CD spectra are reproduced by time-dependent density functional theory (TDDFT) calculations based on enantiomeric Ag29 models with achiral 1,3-propanedithiolate ligands. The mechanism of chiral induction in the synthesis of Ag29(DHLA)12 (DHLA: α-dihydrolipoic acid) NCs with a chiral ligand system is further discussed with the aid of DFT calculations. The use of the enantiomeric DHLA ligand preferentially leads to a one-handed atomic arrangement which is more stable than the opposite one, inducing the enantiomeric excess in the population of intrinsically chiral Ag29 NCs with CD activity.