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Primary biliary cholangitis (PBC) is a cholestatic autoimmune liver disease characterized by autoreactive T cell response against intrahepatic small bile ducts. Here, we use Il12b-/-Il2ra-/- mice (DKO mice) as a model of autoimmune cholangitis and demonstrate that Cd8a knockout or treatment with an anti-CD8α antibody prevents/reduces biliary immunopathology. Using single-cell RNA sequencing analysis, we identified CD8+ tissue-resident memory T (Trm) cells in the livers of DKO mice, which highly express activation- and cytotoxicity-associated markers and induce apoptosis of bile duct epithelial cells. Liver CD8+ Trm cells also upregulate the expression of several immune checkpoint molecules, including PD-1. We describe the development of a chimeric antigen receptor to target PD-1-expressing CD8+ Trm cells. Treatment of DKO mice with PD-1-targeting CAR-T cells selectively depleted liver CD8+ Trm cells and alleviated autoimmune cholangitis. Our work highlights the pathogenic role of CD8+ Trm cells and the potential therapeutic usage of PD-1-targeting CAR-T cells.

Adrenocortical carcinoma (ACC) is a malignant carcinoma with an extremely poor prognosis, and its pathogenesis remains to be understood to date, necessitating further investigation. This study aims to discover biomarkers and potential therapeutic agents for ACC through bioinformatics, enhancing clinical diagnosis and treatment strategies. Differentially expressed genes (DEGs) between ACC and normal adrenal cortex were screened out from the GSE19750 and GSE90713 datasets available in the GEO database. An online Venn diagram tool was utilized to identify the common DEGs between the two datasets. The identified DEGs were subjected to functional assessment, pathway enrichment, and identification of hub genes by performing the protein-protein interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The differences in the expressions of hub genes between ACC and normal adrenal cortex were validated at the GEPIA2 website, and the association of these genes with the overall patient survival was also assessed. Finally, on the QuartataWeb website, drugs related to the identified hub genes were determined. A total of 114 DEGs, 10 hub genes, and 69 known drugs that could interact with these genes were identified. The GO and KEGG analyses revealed a close association of the identified DEGs with cellular signal transduction. The 10 hub genes identified were overexpressed in ACC, in addition to being significantly associated with adverse prognosis in ACC. Three genes and the associated known drugs were identified as potential targets for ACC treatment. [ABSTRACT FROM AUTHOR]

Perovskites exhibit considerable potential as catalysts for various applications, yet their performance modulation in the carbon dioxide reduction reaction (CO2RR) remains underexplored. In this study, we report a strategy to enhance the electrocatalytic carbon dioxide (CO2) reduction activity via Ce-doped La2CuO4 (LCCO) and Sr-doped La2CuO4 (LSCO) perovskite oxides. Specifically, compared to pure phase La2CuO4 (LCO), the Faraday efficiency (FE) for CH4 of LCCO at −1.4 V vs. RHE (reversible hydrogen electrode) is improved from 38.9% to 59.4%, and the FECO2RR of LSCO increased from 68.8% to 85.4%. In situ attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy spectra results indicate that the doping of A-site ions promotes the formation of *CHO and *HCOO, which are key intermediates in the production of CH4, compared to the pristine La2CuO4. X-ray photoelectron spectroscopy (XPS), electron paramagnetic resonance (EPR), and double-layer capacitance (Cdl) outcomes reveal that heteroatom-doped perovskites exhibit more oxygen vacancies and higher electrochemical active surface areas, leading to a significant improvement in the CO2RR performance of the catalysts. This study systematically investigates the effect of A-site ion doping on the catalytic activity center Cu and proposes a strategy to improve the catalytic performance of perovskite oxides. [ABSTRACT FROM AUTHOR]

Objective To summarize the key elements and shortcomings of relevant policies in the field of mental health in China, so as to provide reference for the formulation and improvement of follow-up policies in the field of mental health in China. Methods Using NVivollPlus software and content analysis method, a two-dimensional analysis framework of "policy tool-policy object" was constructed to quantitatively analyze 141 relevant policy texts in the field of mental health at the national level from 1999 to 2023 in China. Results China has paid growing attention to mental health, and the National Health Commission, the Ministry of Education, and the Ministry of Civil Affairs were the core departments of policy formulation. The internal structure of supply-oriented policy tools was out of balance, and the application of environmental policy tools was insufficient. Demand-based policy tools were the least used, accounting for 49.96%, 28.36%, and 21.68%, respectively. The policy object was concentrated in the whole system, health system, and education system, accounting for 32.81%, 24.59%, and 21.94%, respectively. Conclusion It is suggested that the policy design balance the structure of policy tools, increase the supply of resources, apply strategies and measures, strengthen mental health education and promotion, strengthen community grass-roots mental health services, and standardize the development of social mental health service institutions so as to improve mental health and mental hygiene policy system. [ABSTRACT FROM AUTHOR]

The flow softening behaviors of a nickel-based superalloy with δ phase are investigated by hot compression tests over wide ranges of deformation temperature and strain rate. Electron backscattered diffraction (EBSD), optical microscopy (OM), and scanning electron microscopy (SEM) are employed to study the flow softening mechanisms of the studied superalloy. It is found that the flow softening behaviors of the studied superalloy are sensitive to deformation temperature and strain rate. At high strain rate and low deformation temperature, the obvious flow softening behaviors occur. With the increase of deformation temperature or decrease of strain rate, the flow softening degree becomes weaken. At high strain rate (1s−1), the flow softening is mostly induced by the plastic deformation heating and flow localization. However, at low strain rate domains (0.001-0.01s−1), the effects of deformation heating on flow softening are slight. Moreover, the flow softening at low strain rates is mainly induced by the discontinuous dynamic recrystallization and the dissolution of δ phase (Ni3Nb).