The design of efficient and concentration‐insensitive metal‐free thermally activateddelayed fluorescence (TADF) materials is reported. Blue and green organic light‐emitting diodes (OLEDs) containing ...a hole‐transport layer, an undoped TADF emissive layer, and an electron‐transport layer achieve maximum external quantum efficiencies of 19%, which is comparable to the best doped OLEDs.
Systemic sclerosis (SSc) is a multisystem connective tissue disease characterized by three cardinal pathological features, such as autoimmunity/inflammation, vasculopathy and extensive organ ...fibrosis. Therefore, numerous interests have been put on the roles of immune cells, vascular cells (endothelial cells and pericytes/vascular smooth muscle cells) and interstitial fibroblasts as well as their precursors in the field of SSc research. However, recent studies with clinical samples and animal models have drawn much attention to the potential role of epithelial cells as a member of critical drivers and/or modifiers in the pathogenesis of SSc. Indeed, phenotypically altered epithelial cells possibly explain the selective organ fibrosis in the skin, esophagus and lung, the origin of autoimmunity and Köbner phenomenon-associated localized scleroderma-like lesions, the mechanisms of which had remained unknown in the canonical idea of SSc pathogenesis. This article overviews the recent progress in understanding the contribution of epithelial cells to the pathogenesis of SSc. Although further studies are required to confirm the potential role of epithelial cells in SSc development, this notion may provide us with a missing piece of the puzzle to solve the unanswered questions in the pathogenesis of SSc.
Sex differences in immune responses Takahashi, Takehiro; Iwasaki, Akiko
Science (American Association for the Advancement of Science),
2021-Jan-22, 2021-01-22, 20210122, Letnik:
371, Številka:
6527
Journal Article
Recenzirano
Biological sex differences in immunity potentially underlie male bias for severe COVID-19
Evidence increasingly indicates that male sex is a risk factor for more severe disease and death from ...COVID-19. Male bias in COVID-19 mortality is observed in nearly all countries with available sex-disaggregated data, and the risk of death in males is ∼1.7 times higher than in females (
1
). Aging is strongly associated with higher risk of death in both sexes, but at all ages above 30 years, males have a significantly higher mortality risk, rendering older males the most vulnerable group (
1
). Sex differences are intertwined with differences in gender roles socially and with behavioral factors, which also influence COVID-19 incidence and outcomes. However, there are also possible biological mechanisms of male sex bias that affect the severity of COVID-19, particularly with respect to immune responses.
Objective
Fli‐1, a potential predisposing factor for systemic sclerosis (SSc), is constitutively down‐regulated in the lesional skin of patients with SSc by an epigenetic mechanism. To investigate ...the impact of Fli‐1 deficiency on the induction of an SSc phenotype in various cell types, we generated bleomycin‐induced skin fibrosis in Fli‐1+/− mice and investigated the molecular mechanisms underlying its phenotypic alterations.
Methods
Messenger RNA (mRNA) levels and protein expression of target molecules were examined by quantitative reverse transcription–polymerase chain reaction and immunostaining. Transforming growth factor β (TGFβ) bioassay was used to evaluate the activation of latent TGFβ. The binding of Fli‐1 to the target gene promoters was assessed with chromatin immunoprecipitation.
Results
Bleomycin induced more severe dermal fibrosis in Fli‐1+/− mice than in wild‐type mice. Fli‐1 haploinsufficiency activated dermal fibroblasts via the up‐regulation of αvβ3 and αvβ5 integrins and activation of latent TGFβ. Dermal fibrosis in Fli‐1+/− mice was also attributable to endothelial‐to‐mesenchymal transition, which is directly induced by Fli‐1 deficiency and amplified by bleomycin. Th2/Th17‐skewed inflammation and increased infiltration of mast cells and macrophages were seen, partly due to the altered expression of cell adhesion molecules in endothelial cells as well as the induction of the skin chemokines. Fli‐1+/− mouse macrophages preferentially differentiated into an M2 phenotype upon stimulation with interleukin‐4 (IL‐4) or IL‐13.
Conclusion
Our findings provide strong evidence for the fundamental role of Fli‐1 deficiency in inducing SSc‐like phenotypic alterations in dermal fibroblasts, endothelial cells, and macrophages in a manner consistent with human disease.
Systemic sclerosis (SSc), or scleroderma, is a multisystem autoimmune disorder characterized by vasculopathy and fibrosis in the skin and internal organs, most frequently in the esophagus and lungs. ...Hitherto, studies on SSc pathogenesis centered on immune cells, vascular cells, and fibroblasts. Although dysregulated keratinocytes in SSc have been recently reported, the contribution of epithelial cells to pathogenesis remains unexplored. In this study, we demonstrated the induction of SSc-like molecular phenotype in keratinocytes by gene silencing of transcription factor Friend leukemia virus integration 1 (Fli1), the deficiency of which is implicated in SSc pathogenesis. Keratin 14-expressing epithelial cell-specific
knockout mice spontaneously developed dermal and esophageal fibrosis with epithelial activation. Furthermore, they developed remarkable autoimmunity with interstitial lung disease derived from thymic defects with down-regulation of autoimmune regulator (Aire). Importantly, Fli1 directly regulated Aire expression in epithelial cells. Collectively, epithelial Fli1 deficiency might be involved in the systemic autoimmunity and selective organ fibrosis in SSc. This study uncovers unidentified roles of dysregulated epithelial cells in SSc pathogenesis.
Systemic sclerosis‐associated interstitial lung disease (SSc‐ILD) is the most frequent cause of death for SSc but there is still no sufficient treatment available. Although cyclophosphamide (CYC) ...therapy is a common treatment which has shown statistical efficacy against SSc‐ILD to date, its effects are temporary and not enough. Rituximab (RTX), the anti‐CD20 monoclonal antibody, has recently shown efficacy in many autoimmune diseases. In SSc‐ILD, RTX is also considered to be one of the novel treatment candidates. However, studies of SSc‐ILD in Japanese treated with RTX have only a few case reports. Therefore, in this study, we retrospectively compared nine patients treated with RTX and 30 patients treated with CYC to investigate the efficacy of RTX treatment for Japanese anti‐topoisomerase I‐positive SSc‐ILD patients. At the 24‐month evaluation, the improvement rates of percent predicted of forced vital capacity and percent predicted of diffusing capacity of the lung carbon monoxide in the RTX‐treated group were significantly higher than those in the CYC‐treated group (20.6 ± 8.8% vs 1.1 ± 3.9%; P < 0.05 and 34.0 ± 6.0% vs −1.5 ± 2.8%; P < 0.01, respectively). In addition, skin thickness scores also showed a marked improvement from 13.5 points before the start of treatment to 5.8 points after 24 months by RTX therapy (P < 0.05). These results suggest that RTX treatment is more effective for Japanese SSc‐ILD patients than CYC treatment. In the future, it is expected that large‐scale clinical trials will show the usefulness of RTX treatment for SSc‐ILD.
A new series of luminescent 1,4-diazatriphenylene (ATP) derivatives with various peripheral donor units, including phenoxazine, 9,9-dimethylacridane and 3-(diphenylamino)carbazole, is synthesized and ...characterized as thermally activated delayed fluorescence (TADF) emitters. The influence of the donor substituents on the electronic and photophysical properties of the materials is investigated by theoretical calculations and experimental spectroscopic measurements. These ATP-based molecules with donor-acceptor-donor (D-A-D) structures can reduce the singlet-triplet energy gap (0.04-0.26 eV) upon chemical modification of the ATP core, and thus exhibit obvious TADF characteristics in solution and doped thin films. As a demonstration of the potential of these materials, organic light-emitting diodes containing the D-A-D-structured ATP derivatives as emitters are fabricated and tested. External electroluminescence quantum efficiencies above 12% and 8% for green- and sky-blue-emitting devices, respectively, are achieved.
In obese patients with type 2 diabetes, insulin delivery to and insulin-dependent glucose uptake by skeletal muscle are delayed and impaired. The mechanisms underlying the delay and impairment are ...unclear. We demonstrate that impaired insulin signaling in endothelial cells, due to reduced Irs2 expression and insulin-induced eNOS phosphorylation, causes attenuation of insulin-induced capillary recruitment and insulin delivery, which in turn reduces glucose uptake by skeletal muscle. Moreover, restoration of insulin-induced eNOS phosphorylation in endothelial cells completely reverses the reduction in capillary recruitment and insulin delivery in tissue-specific knockout mice lacking Irs2 in endothelial cells and fed a high-fat diet. As a result, glucose uptake by skeletal muscle is restored in these mice. Taken together, our results show that insulin signaling in endothelial cells plays a pivotal role in the regulation of glucose uptake by skeletal muscle. Furthermore, improving endothelial insulin signaling may serve as a therapeutic strategy for ameliorating skeletal muscle insulin resistance.
► Insulin delivery to the skeletal muscle is delayed and impaired in obesity ► Impaired endothelial insulin signaling causes attenuation of insulin delivery ► Restoration of endothelial insulin signaling restores insulin delivery ► Improving endothelial insulin signaling may serve as a novel therapeutic strategy
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