Search

Alopecia areata (AA) is a CD8+ T cell–mediated autoimmune disease characterized by nonscarring hair loss. Ivarmacitinib, which is a selective oral Janus kinase 1 inhibitor, may interrupt certain cytokine signaling implicated in the pathogenesis of AA. To evaluate the efficacy and safety of ivarmacitinib in adult patients with AA who have ≥25% scalp hair loss. Eligible patients were randomized 1:1:1:1 to receive ivarmacitinib 2, 4, or 8 mg once daily or placebo for 24 weeks. The primary end point was the percentage change from baseline in the Severity of Alopecia Tool score at week 24. A total of 94 patients were randomized. At week 24, the least squares mean difference in the percentage change from baseline in the Severity of Alopecia Tool score for ivarmacitinib 2, 4, and 8 mg and placebo groups were −30.51% (90% CI, −45.25, −15.76), −56.11% (90% CI, −70.28, −41.95), −51.01% (90% CI, −65.20, −36.82), and −19.87% (90% CI, −33.99, −5.75), respectively. Two serious adverse events—follicular lymphoma and COVID-19 pneumonia—were reported. A small sample size limits the generalizability of the results. Treatment with ivarmacitinib 4 and 8 mg doses in patients with moderate and severe AA for 24 weeks was efficacious and generally tolerated. [ABSTRACT FROM AUTHOR]

MicroRNA 165 and 166 (miR165/166) is composed of nine members and targets five members ( PHB , PHV , REV , ATHB8 and ATHB15 ) of the HD-ZIP III transcription factor family. Mutants generated by traditional methods could hardly reveal the overall functions of miR165/166 in plant development. In this study, the expressions of all miR165/166 members were simultaneously blocked by over-expressing STTM165/166-31 in Arabidopsis and tomato for functional dissection of miR165/166 family. Following a down-regulation of over 90% endogenous miR165/166, the target HD-ZIP III genes were correspondingly up-regulated in the STTM transgenic Arabidopsis and tomato plants. Notably, the STTM165/166-31 over-expressed Arabidopsis and tomato displayed pleiotropic effects on development which were not frequently observed in previously identified genetic mutants of either individual miR165/166 gene or any of the five target genes. Furthermore, the transgenic Arabidopsis showed increased IAA content and decreased IAA sensitivity accompanied by enhanced expressions of genes responsible for auxin biosynthesis and signaling, suggesting possible roles of auxin in mediation of miR165/166-regulated processes. Importantly, the transgenic Arabidopsis exhibited the improved behavior under salt stress. Overall, such diverse variations in plant development and physiological process revealed by STTM165/166 demonstrate a key role of miR165/166-mediated network in regulating plant development and responses to abiotic stresses. [ABSTRACT FROM AUTHOR]

[Display omitted] • A nonlocal multiaxial fatigue model leveraging artificial neural networks (ANN) is proposed to forecast the fretting fatigue life of dovetail joints. • This model demonstrates exceptional accuracy in predicting the fretting fatigue life of dovetail samples within a 1.5× limit band. • This accuracy stems from combining the representation capabilities of ANN approaches with the integration of physics or domain knowledge. Fretting fatigue of dovetail joints is of paramount importance for ensuring equipment safety, where the swift and precise estimation of their fatigue life is crucial. In this study, we present a nonlocal multiaxial fatigue model based on artificial neural networks (ANN) to tackle these challenges. Initially, the damage parameters were calculated using critical plane approaches (CPA) and theory of critical distance (TCD) analysis, and the fretting fatigue stress was computed. Subsequently, these parameters were integrated as input features in the ANN model to predict the fretting fatigue life of dovetail joints. The predicted results demonstrate that this proposed model can accurately predict the fretting fatigue life of dovetail samples within a 1.5× limit band. Furthermore, a comparative analysis with other ANN models inspired by previous researchers also supports this viewpoint. This capability stems from its integration of ANN representation capabilities with physics and domain knowledge, such as CPA/TCD methods and fretting fatigue stress analysis. This approach not only establishes a theoretical foundation for predicting the fretting fatigue life of dovetail samples but also showcases promising practical applications. [ABSTRACT FROM AUTHOR]

Abstract Objective Stem cell transplantation is a promising tool to treat burn injuries. However, the inflammatory microenvironment in damaged skin limits the efficiency of stem cell-based therapy via poorly understood mechanisms. The aim of our study is to explore the contribution and mechanism of Sirtuin-1 (Sirt1) in TNFα-mediated inflammatory stress in hair follicle stem cells (HFSCs). Methods Cellular viability was determined using the MTT assay, TUNEL staining, western blot analysis and LDH release assay. Adenovirus-loaded Sirt1 was transduced into HFSCs to overexpress Sirt1 in the presence of TNFα. Mitochondrial function was determined using JC-1 staining, mitochondrial ROS staining, immunofluorescence staining and western blotting. Results Sirt1 was downregulated in response to the TNFα treatment. Additionally, TNFα stress reduced the viability, mobility and proliferation of HFSCs, and these effects were reversed by the overexpression of Sirt1. At the molecular level, Sirt1 overexpression attenuated TNFα-mediated mitochondrial damage, as evidenced by increased mitochondrial energy metabolism, decreased mitochondrial ROS generation, stabilized mitochondrial potential and blockage of the mitochondrial apoptotic pathway. Furthermore, Sirt1 modulated mitochondrial homeostasis by activating the MAPK-ERK-Mfn2 axis; inhibition of this pathway abrogated the protective effects of Sirt1 on HFSC survival, migration and proliferation. Significance Based on our results, the inflammatory stress-mediated HFSC injury may be associated with a decrease in Sirt1 expression and subsequent mitochondrial dysfunction. Accordingly, strategies designed to enhance Sirt1 expression would be an effective approach to enhance the survival of HFSCs in the inflammatory microenvironment. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are currently emerged as important regulators in psoriasis. Psoriasis is characterized by hyperproliferation and impaired differentiation of keratinocytes in skin lesions. miR-194 is a well-known regulator of cell proliferation and differentiation. However, the role of miR-194 in psoriasis pathogenesis remains unclear. In this study we aimed to investigate the role of miR-194 in keratinocyte hyperproliferation and differentiation. We found that miR-194 was significantly downregulated in psoriasis lesional skin. Overexpression of miR-194 inhibited the proliferation and promoted the differentiation of primary human keratinocytes, whereas miR-194 suppression promoted the proliferation and inhibited their differentiation. Bioinformatic analysis predicted that the Grainyhead-like 2 (GRHL2) was a target gene of miR-194, which we further validated with a dual-luciferase reporter assay, real-time quantitative polymerase chain reaction (RT-qPCR), and Western blot analysis. The effect of miR-194 on cell proliferation and differentiation was significantly reversed by overexpression of GRHL2. Moreover, the expression of miR-194 and GRHL2 was inversely correlated in psoriasis lesional skin. Taken together, our results suggest that miR-194 inhibits the proliferation and promotes the differentiation of keratinocytes through targeting GRHL2. The downregulation of miR-194 expression may contribute to the pathogenesis of psoriasis and targeting miR-194 may represent a novel and potential therapeutic strategy for psoriasis. [ABSTRACT FROM AUTHOR]