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Synthetic challenges toward anomalous structures and electronic states often involve handling problems such as insolubility in common organic solvents and oxidative degradation under aerobic conditions. We designed benzo-annulated aza[n]helicenes, which benefit from both the suppressed elevation of highest occupied molecular orbital (HOMO) energies and high solubility due to hydrogen bonding with solvent molecules to overcome these challenges. This strategy enabled the synthesis of six new aza[n]helicenes ([n]AHs) of different lengths (n = 9-19) from acyclic precursors via one-pot intramolecular oxidative fusion reactions. The structures of all of the synthesized aza[n]helicenes were determined by X-ray diffraction (XRD) analysis, and their electrochemical potentials were measured by cyclic voltammetry. Among the synthesized aza[n]helicenes, [17]AH and [19]AH are the first heterohelicenes with a triple-layered helix. The noncovalent interaction (NCI) plots confirm the existence of an effective π-π interaction between the layers. The absorption and fluorescence spectra red-shifted as the helical lengths increased, without any distinct saturation points. The optical resolutions of N-butylated [9]AH, [11]AH, [13]AH, and [15]AH were accomplished, and their circular dichroism (CD) and circularly polarized luminescence (CPL) were measured. Thus, the structural, (chir)optical, and electrochemical properties of the aza[n]helicenes were comprehensively analyzed.
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OBJECTIVES: The predictive validity of disease-specific quality of life (QOL) remains unknown in patients with systemic lupus erythematosus (SLE), although disease-specific measures are equally or more responsive to changes than generic QOL. We aimed to examine the predictive validity of the Lupus patient-reported outcome (PRO) for damage accrual. METHODS: Patients with SLE and ≥2 measurements over time were included in Japanese nationwide multicentre registry (LUNA). The Lupus PRO questionnaire contains both health-related (HR) and non-HR-QOL measures. Damage accrual was evaluated using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). We examined the association between the Lupus-PRO score at baseline and longitudinal SDI scores using mixed-effects models adjusted for prognostic factors. RESULTS: Among 1295 patients, those with higher HR-QOL of Lupus PRO at baseline demonstrated a significantly lower increase in SDI (-0.005/year, 95% confidence interval [CI]: -0.007 to - 0.004, p < 0.001). According to the categorisation of HR-QOL based on tertile, a similar dose-dependent effect of HR-QOL on longitudinal SDI was identified (second vs first tertile category: -0.101/year, 95% CI: -0.172 to - 0.030; third tertile category: -0.211/year, 95% CI: -0.281 to - 0.142). Non-HR-QOL was not significantly associated with the SDI scores. Among the HR-QOL domains, cognition, procreation, and physical health were significantly associated with the total SDI scores over time. HR-QOL was associated with corticosteroid-dependent and -independent SDI scores. CONCLUSION: A higher HR-QOL of Lupus PRO was associated with a lower increase in SDI scores. Our findings imply the importance of disease-specific HR-QOL measurements in assessing prognosis.
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OBJECTIVES: To evaluate the effectiveness and safety of two different intravenous methylprednisolone (IVMP) pulse doses in patients with severe microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). METHODS: We emulated a target trial using observational data from the nationwide registry in Japan. Patients with severe glomerulonephritis or diffuse alveolar haemorrhage were selected and pseudo-randomised into three groups using propensity score-based overlap weighting as follows: non-IVMP, IVMP 0.5 g/day, and IVMP 1.0 g/day. The primary outcome was all-cause death, and the secondary outcomes were composite all-cause death and kidney failure, severe relapse, and serious infection from 2 to 48 weeks after treatment initiation. To estimate the treatment effects, the Cox proportional hazard model and Fine-Gray subdistribution hazard model were used. RESULTS: In this emulated target trial, of 201 eligible patients (MPA, 175; GPA, 26), 6 (2.8%) died, 4 (2.0%) had kidney failure, 11 (5.3%) had severe relapse, and 40 (19.8%) had severe infections. Hazard ratios (HR) for IVMP 0.5 g/day and IVMP 1.0 g/day pulse groups compared with non-IVMP pulse were as follows: all-cause death = 0.46 (95% confidence interval [95%CI]: 0.07-2.81) and 0.07 (95%CI: 0.01-0.41); all-cause death/kidney failure = 1.18 (95%CI: 0.26-5.31) and 0.59 (95%CI: 0.08-4.52); subdistribution HRs for severe relapse = 1.26 (95%CI: 0.12-13.70) and 3.36 (95%CI: 0.49-23.29); and serious infection = 1.88 (95%CI: 0.76-4.65) and 0.94 (95%CI: 0.28-3.13). CONCLUSIONS: IVMP 1.0 g/day pulse may improve 48-week mortality in patients with severe MPA/GPA.
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OBJECTIVES: This study investigated the clinically relevant factors for headaches in patients with systemic lupus erythematosus (SLE) using a registry from a Japanese multicenter cohort. METHODS: This cross-sectional study analysed the clinical information of patients with SLE who experienced headache episodes using the Migraine Disability Assessment (MIDAS) questionnaire. Significant findings in the comparisons between patients with headache (HA patients) and those without headache (non-HA patients) and in the comparisons depending on the grades of headache-induced disability in daily life based on the MIDAS scores were evaluated. Multivariate logistic regression analyses were performed to identify the relevant factors for headache. RESULTS: We analyzed 369 patients (median age, 45 years; female, 90.8%), including 113 HA patients who were significantly younger than non-HA patients (p < .005). HA patients had significantly higher frequencies of photosensitivity, rashes, and mucosal ulcers than non-HA patients (p < .05). Age and photosensitivity were significantly associated with headache (odds ratio (OR) 0.93, 95% confidence interval (CI) 0.95-0.99; OR 2.11, 95% CI 1.29-3.49, respectively). In the HA patients, hypocomplementemia was significantly associated with a disability of more than mild grade (OR 2.89, 95% CI 1.14-7.74), while rash was significantly observed in those presenting with moderate and severe disability. CONCLUSION: This study suggests that photosensitivity is a relevant manifestation of headache in patients with SLE. Persistent hypocomplementemia can contribute to headache-induced disability in daily life, whereas a rash may be a dominant manifestation in patients presenting with moderate/severe headache-induced disability.
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Cefalea , Lupus Eritematoso Sistémico , Sistema de Registros , Humanos , Femenino , Estudios Transversales , Persona de Mediana Edad , Masculino , Adulto , Lupus Eritematoso Sistémico/complicaciones , Japón/epidemiología , Cefalea/etiología , Cefalea/epidemiología , Encuestas y Cuestionarios , Modelos Logísticos , Evaluación de la Discapacidad , Índice de Severidad de la Enfermedad , Análisis Multivariante , Factores de Edad , Trastornos por Fotosensibilidad/epidemiología , Trastornos por Fotosensibilidad/etiología , AncianoRESUMEN
Temperature-dependent plastic deformation behaviors of single crystals of quaternary and ternary equiatomic medium-entropy alloys (MEAs) belonging to the Cr-Mn-Fe-Co-Ni system were investigated in compression at temperatures in the range 9 K to 1373 K. Their critical resolved shear stresses (CRSSs) increase with decreasing temperature below room temperature. There is also a dulling of the temperature dependence of CRSS below 77 K due to dislocation inertial effects that we attribute to a decrease in the phonon drag coefficient. These behaviors were compared with those of previously investigated single crystals of the equiatomic Cr-Co-Ni and Cr-Fe-Co-Ni MEAs, and the equiatomic Cr-Mn-Fe-Co-Ni high-entropy alloy (HEA). The temperature dependence of CRSS and the apparent activation volumes below room temperature can be well described by conventional thermal activation theories of face-centered cubic (FCC) alloys. Above 673 K, there is a small increase in CRSS, which we believe is due to elastic interactions between solutes and mobile dislocations, the so-called Portevin-Le Chatelier (PL) effect. The CRSS at 0 K was obtained by extrapolation of fitted CRSS vs. temperature curves and compared with predictions from solid solution strengthening models of HEA and MEAs.
The novelty of our work entitled 'Analysis of the temperature-dependent plastic deformation of single crystals of quinary, quaternary and ternary equiatomic high- and medium-entropy alloys of the Cr-Mn-Fe-Co-Ni system' can be summarized as follows: The temperature dependences of CRSS were experimentally deduced from bulk single crystals of the six MEAs for the first time, so that fair comparison among the FCC HEA/MEAs is made.
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OBJECTIVES: To investigate the association between decreased serum IgG levels caused by remission-induction immunosuppressive therapy of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and the development of severe infections. METHODS: We conducted a retrospective cohort study of patients with new-onset or severe relapsing AAV enrolled in the J-CANVAS registry, which was established at 24 referral sites in Japan. The minimum serum IgG levels up to 24 weeks and the incidence of severe infection up to 48 weeks after treatment initiation were evaluated. After multiple imputations for all explanatory variables, we performed the multivariate analysis using a Fine-Gray model to assess the association between low IgG (the minimum IgG levels <500 mg/dl) and severe infections. In addition, the association was expressed as a restricted cubic spline (RCS) and analysed by treatment subgroups. RESULTS: Of 657 included patients (microscopic polyangiitis, 392; granulomatosis with polyangiitis, 139; eosinophilic granulomatosis with polyangiitis, 126), 111 (16.9%) developed severe infections. The minimum serum IgG levels were measured in 510 patients, of whom 77 (15.1%) had low IgG. After multiple imputations, the confounder-adjusted hazard ratio of low IgG for the incidence of severe infections was 1.75 (95% confidence interval: 1.03-3.00). The RCS revealed a U-shaped association between serum IgG levels and the incidence of severe infection with serum IgG 946 mg/dl as the lowest point. Subgroup analysis showed no obvious heterogeneity between treatment regimens. CONCLUSION: Regardless of treatment regimens, low IgG after remission-induction treatment was associated with the development of severe infections up to 48 weeks after treatment initiation.
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Agammaglobulinemia , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Síndrome de Churg-Strauss , Granulomatosis con Poliangitis , Poliangitis Microscópica , Humanos , Granulomatosis con Poliangitis/tratamiento farmacológico , Estudios Retrospectivos , Agammaglobulinemia/inducido químicamente , Quimioterapia de Inducción , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Poliangitis Microscópica/tratamiento farmacológico , Inmunoglobulina G/uso terapéutico , Anticuerpos Anticitoplasma de NeutrófilosRESUMEN
OBJECTIVES: To identify the optimal dose of intravenous cyclophosphamide (IVCY) for induction therapy for anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: We retrospectively assessed patients with AAV who received IVCY every 2-3 weeks during the remission induction phase. The associations of the IVCY dose with infection-free survival and relapse-free survival were analysed using a Cox regression model. We compared patients in three categories: very low-dose (VLD), low-dose (LD), and conventional dose (CD) (<7.5 mg/kg, 7.5-12.5 mg/kg, and >12.5 mg/kg, respectively). The non-linear association between IVCY dose and the outcomes were also evaluated. RESULTS: Of the 80 patients (median age 72 years), 12, 42, and 26 underwent the VLD, LD, and CD regimens, respectively, of whom 4, 3, and 7 developed infection or died. The adjusted hazard ratios for infection or death were 4.3 (95% confidence interval (CI) 0.94-19.8) for VLD and 5.1 (95% CI 1.21-21.3) for CD, compared with LD. We found the hazard ratio for infection or death increased when the initial IVCY dose exceeded 9 mg/kg. Relapse-free survival did not differ clearly. CONCLUSION: Low-dose IVCY (7.5-12.5 mg/kg) may result in fewer infections and similar relapse rates compared with the conventional regimen (>12.5 mg/kg).
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Oxidative fusion reaction of cyclic heteroaromatic pentads consisting of pyrrole and thiophene gave closed-heterohelicene monomers and dimers depending on the oxidation conditions. Specifically, oxidation with [bis(trifluoroacetoxy)iodo]benzene (PIFA) gave closed-[7]helicene dimers connected at the ß-position of one of the pyrrole units with remarkably elongated C-C bonds of about 1.60â Å. Although this bond was intact against thermal and physical activations, homolytic bond dissociation took place in DMSO upon irradiation with UV light to give the corresponding monomers. Thus, interconversion between the closed-helicene monomer and dimer was achieved. The optically pure dimer was photo-dissociated into the monomers associated with a turn-on of circularly polarized luminescence (CPL).
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A pentabenzopentaaza[10]circulene has been synthesized as the largest fully conjugated hetero[n]circulene via a fold-in oxidative fusion reaction of an ortho-phenylene-bridged cyclic pyrrole pentamer. This circulene takes a saddle-distorted structure with bond lengths of the central ten-membered-ring in the range of 1.455-1.493â Å. Relatively broad absorption and fluorescence spectra were observed, which reflects its flexible structure, in accordance with the low-temperature NMR spectra and theoretical calculations. The energy barrier for saddle-to-saddle interconversion was estimated to be quite small (≈3â kcal mol-1 ).
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N,N'-Diarylated tetrabenzotetraaza[8]circulenes 3 a and 3 b were synthesized in good yields by a reaction sequence involving oxidation of tetrabenzodiazadithia[8]circulene 5-Oct and SN Ar reaction with aniline derivatives. The obtained aza[8]circulenes 3 a and 3 b were easily oxidized to give their radical cations 3 a+ and 3 b+ , which are highly stable under ambient conditions. X-ray diffraction analysis of radical cation 3 a+ showed a face-to-face dimer arrangement with an interplanar separation of 3.320â Å. The spin density of 3 a+ was calculated to be delocalized over the whole circulene π-systems with spin-spin exchange integral (J=-144â cm-1 ) in the dimeric part. These radical cations displayed far red-shifted absorption bands reaching to 2000â nm. Thus this study has proved the hetero[8]circulene scaffold to be a new entry of promising electronics and spin materials.
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Fibroblasts play crucial roles in the pathogenesis of rheumatoid arthritis (RA). Accumulation of fibroblasts in the synovial tissues characterizes the pathology of RA. Understanding how fibroblasts accumulate could lead to discovery of new therapeutic targets in RA treatment, while current antirheumatic therapies still have problems in efficacy and safety. In this regard, several studies have revealed cellular origins of fibroblasts in fibrotic tissues in murine models of organ fibrosis. Some studies employed lineage tracing, which bring generally convincing results, using transgenic mice. They demonstrated that resident fibroblasts, pericytes, mesenchymal stem cells, epithelial cells, endothelial cells and bone-marrow-derived and circulating cells can be cellular origins of fibroblasts in organ fibrotic tissues. In this review, we summarize and discuss available evidence for the origins of fibroblasts accumulating in the arthritic synovial tissues and organ fibrotic tissues.
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Artritis Reumatoide/patología , Fibroblastos/patología , Membrana Sinovial/patología , Animales , Fibrosis , HumanosRESUMEN
Synovial fibroblasts play crucial roles in inflammation and joint destruction in rheumatoid arthritis (RA). How they accumulate in the RA joints remains unclear. This study was conducted to discern whether cellular influx from the outside of the joints and local proliferation are responsible for synovial fibroblast accumulation in an animal model of RA. We found that synovial fibroblasts were identified as GFP+ cells using collagen type I alpha 2 (Col1a2)-GFP transgenic reporter mice. Then, bone marrow transplantation and parabiosis techniques were utilized to study the cellular influx. Irradiated wild-type mice were transplanted with bone marrow from Col1a2-GFP mice. Col1a2-GFP and wild-type mice were conjoined for parabiosis. The transplanted mice and the parabionts were subjected to collagen antibody-induced arthritis (CAIA). We found no GFP+ cells in the hyperplastic synovial tissues from the transplanted mice with CAIA and from the wild-type parabionts with CAIA. Furthermore, normal and CAIA synovial tissues from Col1a2-GFP mice and from fluorescent ubiquitination-based cell cycle indicator (Fucci) transgenic mice, in which cells in S/G2/M phases of the cell cycle express Azami-Green, were studied for Ki67, a cellular proliferation marker, and vimentin, a fibroblast marker, expression. The percentages of Ki67+/GFP+ and Azami-Green+/vimentin+ cells in the CAIA synovial tissues were higher than those in the untreated synovial tissues (34% vs. 0.40% and 19% vs. 0.26%, respectively). These findings indicate that local fibroblast proliferation but not cellular influx is responsible for the synovial hyperplasia in CAIA. Suppression of proliferation of the local synovial fibroblasts should be a promising treatment for RA.
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Artritis Reumatoide/patología , Fibroblastos/patología , Membrana Sinovial/patología , Animales , Artritis Reumatoide/inmunología , Movimiento Celular/inmunología , Proliferación Celular , Fibroblastos/inmunología , Hiperplasia/inmunología , Hiperplasia/patología , Masculino , Ratones , Membrana Sinovial/inmunologíaAsunto(s)
Enfermedades Cardiovasculares , Dieta Mediterránea , Lupus Eritematoso Sistémico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Estudios Transversales , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Lupus Eritematoso Sistémico/complicaciones , Factores de RiesgoRESUMEN
Peptidoglycan (PGN) is a major component of bacterial cell wall and is recognized as a potent immunostimulant. The PGN in the cell envelope of Mycobacterium Tuberculosis has been shown to possess several unique characteristics including the presence of N-glycolyl groups (in addition to N-acetyl groups) in the muramic acid residues, and amidation of the free carboxylic acid of d-Glu or of meso-DAP in the peptide chains. Using a newly developed, highly stereoselective, chemoenzymatic approach for the synthesis of meso-DAP in peptide stems, we successfully synthesized for the first time, a series of Mycobacterium PGN fragments that include both mono- and disaccharides of MurNGlyc or 1,6-anhydro-MurNGlyc, as well as peptide-amidated variants. The ability of these PGN fragments to stimulate the immune system through activation of human Nod1 and Nod2 was examined. The PGN fragments were found to modulate immune stimulation, specifically, amidation at the d-Glu and meso-DAP in the peptide stem strongly reduced hNod1 activation. This effect was dependent on modification position. Additionally, N-glycolyl (instead of acetyl) of muramic acid was associated with slightly reduced human Nod1 and Nod2 stimulatory capabilities.
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Ácido Diaminopimélico/farmacología , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/inmunología , Mycobacterium tuberculosis/química , Peptidoglicano/inmunología , Ácido Diaminopimélico/química , Ácido Diaminopimélico/metabolismo , Células HEK293 , Humanos , Conformación Molecular , Mycobacterium tuberculosis/inmunología , Proteína Adaptadora de Señalización NOD1/antagonistas & inhibidores , Proteína Adaptadora de Señalización NOD1/inmunología , Proteína Adaptadora de Señalización NOD2/antagonistas & inhibidores , Proteína Adaptadora de Señalización NOD2/inmunología , Peptidoglicano/biosíntesis , Peptidoglicano/química , Relación Estructura-ActividadRESUMEN
Benzo-annulated aza[9]helicene ([9]AH) and thia[9]helicene ([9]TH) were prepared as novel π-extended heterohelicenes. [9]TH showed a quite short fluorescence lifetime of â¼0.3 ns and intense phosphorescence at low temperature that were attributed to its larger spin-orbit coupling and faster intersystem crossing between pseudo-degenerate S1/2 and triplet states.
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A benzannulated double aza[9]helicene 1 was successfully synthesized via a one-pot oxidative fusion reaction. 1 was derivatized to N-alkylated double aza[9]helicene 1-Et and 1-Bu, whose structures were determined by X-ray diffraction analysis. 1-Et and 1-Bu exhibited red-shifted absorption and fluorescence spectra compared to single aza[9]helicene. The double aza[9]helicenes were expected to have two different conformers. Consistent with solid-state structure, the chiral-isomer was estimated to be more stable by 16â kcal/mol relative to meso-isomer. Indeed, enantiomers of 1-Et and 1-Bu were optically resolved by HPLC and showed mirror-imaged CD and CPL spectra with the CPL brightness up to 19.2â M-1cm-1 for 1-Bu.
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Oral administration of the food-derived antioxidant amino acid ergothioneine (ERGO) results in its efficient distribution in the brain and enhances cognitive function. However, effect of ERGO deficiency on cognitive impairment and the underlying mechanisms remain unknown. We revealed that cognitive function and hippocampal neurogenesis were lower in mice fed an ERGO-free diet than in those fed the control diet. Furthermore, ERGO supplementation to achieve the control diet ERGO levels reversed these effects and restored ERGO concentrations in the plasma and hippocampus. The ERGO-induced recovery of cognitive function and hippocampal neurogenesis was blocked by inhibiting the neurotrophic factor receptor tropomyosin receptor kinase B (TrkB), with a concomitant reduction in hippocampal phosphorylated TrkB, suggesting the involvement of TrkB in these events in mice. Phosphorylated TrkB was also detected in extracellular vesicles (EVs) derived from serum of volunteers who had been orally administered placebo or ERGO-containing tablets. Importantly, the ratio of serum EV-derived phosphorylated TrkB was significantly higher in the ERGO-treated group than in the placebo-treated group and was positively correlated with both serum ERGO concentrations and several cognitive domain scores from Cognitrax. Altogether, TrkB phosphorylation is involved in ERGO-induced cognitive enhancement in mice, and TrkB phosphorylation levels in serum EVs may quantitatively represent ERGO-induced cognitive enhancement in humans.