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CD8+ T cells provide host protection against pathogens by differentiating into distinct effector and memory cell subsets, but how chromatin is site-specifically remodeled during their differentiation is unclear. Due to its critical role in regulating chromatin and enhancer accessibility through its nucleosome remodeling activities, we investigated the role of the canonical BAF (cBAF) chromatin remodeling complex in antiviral CD8+ T cells during infection. ARID1A, a subunit of cBAF, was recruited early after activation and established de novo open chromatin regions (OCRs) at enhancers. Arid1a deficiency impaired the opening of thousands of activation-induced enhancers, leading to loss of TF binding, dysregulated proliferation and gene expression, and failure to undergo terminal effector differentiation. Although Arid1a was dispensable for circulating memory cell formation, tissue-resident memory (Trm) formation was strongly impaired. Thus, cBAF governs the enhancer landscape of activated CD8+ T cells that orchestrates TF recruitment and activity and the acquisition of specific effector and memory differentiation states.

In the studies of the vulnerability of armored vehicles, the impact of high-velocity penetrators on liquid-filled container components is one of the critical concerns. The purpose of this study is to investigate the structural damage of the liquid-filled container subjected to shaped charge jet impact utilizing the Structural Arbitrary Lagrangian–Eulerian method in ANSYS/LS-DYNA. The numerical model is validated against available experimental data. The validation effort of the numerical model showed very good agreements with experiments in terms of radial shock wave and radial crater formation as a function of time. Using the validated model, the liquid pressure, the energy transfer as well as the influence of overmatch on the impact process were analyzed. The results indicate that the structural damage modes of containers under shaped charge jet impact include perforation and wall deformation. Perforation results from the penetration of the jet tip and tail, while wall deformation is caused by the high-velocity impact of the flowing liquid. In cases where the overmatch (OM) is equal to 1, the contribution of the tip to front and back wall perforation increment primarily depends on the impact velocity. In cases with OM less than 1, the "filtering effect" of the Rolled Homogeneous Armor (RHA) armor plate leads to the loss of the tail's contribution to front wall perforation. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to investigate the predictive value of Pan-Immune-Inflammation Value (PIV) combined with the PILE score for immunotherapy in patients with advanced non-small cell lung cancer (NSCLC) and to construct a nomogram prediction model to provide reference for clinical work. Patients and Methods: Patients with advanced NSCLC who received ICIs treatment in Qingdao Municipal Hospital from January 2019 to December 2021 were selected as the study subjects. The chi-square test, Kaplan-Meier survival analysis, and Cox proportional risk regression analysis were used to evaluate the prognosis. The results were visualized by a nomogram, and the performance of the model was judged by indicators such as the area under the subject operating characteristic curve (AUC) and C-index. The patients were divided into high- and low-risk groups by PILE score, and the prognosis of patients in different risk groups was evaluated. Results: Multivariate Cox regression analysis showed that immune-related adverse events (irAEs) were prognostic factors for overall survival (OS) improvement, and ECOG PS score ≥ 2, bone metastases before treatment, and high PIV expression were independent risk factors for OS. The C index of OS predicted by the nomogram model is 0.750 (95% CI: 0.677– 0.823), and the Calibration and ROC curves show that the model has good prediction performance. Compared with the low-risk group, patients in the high-risk group of PILE were associated with a higher inflammatory state and poorer physical condition, which often resulted in a poorer prognosis. Conclusion: PIV can be used as a prognostic indicator for patients with advanced NSCLC treated with ICIs, and a nomogram prediction model can be constructed to evaluate the survival prediction of patients, thus contributing to better clinical decision-making and prognosis assessment. [ABSTRACT FROM AUTHOR]

Fungal infection stimulates the canonical C-type lectin receptor (CLR) signaling pathway via activation of the tyrosine kinase Syk. Here we identify a crucial role for the tyrosine phosphatase SHP-2 in mediating CLR-induced activation of Syk. Ablation of the gene encoding SHP-2 (Ptpn11; called Shp-2 here) in dendritic cells (DCs) and macrophages impaired Syk-mediated signaling and abrogated the expression of genes encoding pro-inflammatory molecules following fungal stimulation. Mechanistically, SHP-2 operated as a scaffold, facilitating the recruitment of Syk to the CLR dectin-1 or the adaptor FcRγ, through its N-SH2 domain and a previously unrecognized carboxy-terminal immunoreceptor tyrosine-based activation motif (ITAM). We found that DC-derived SHP-2 was crucial for the induction of interleukin 1β (IL-1β), IL-6 and IL-23 and anti-fungal responses of the TH17 subset of helper T cells in controlling infection with Candida albicans. Together our data reveal a mechanism by which SHP-2 mediates the activation of Syk in response to fungal infection.

Ischemic postconditioning (PostC) and perconditioning (PerC) provide practical methods for protecting the heart against ischemia-reperfusion (I/R) injury, but their combined effects have not been studied in detail. Using an in vivo rat I/R model, we tested 1) whether additive effects were produced when local PostC was preceded by varying doses of remote PerC, and whether the optimal PostC+PerC regime is additive to local ischemic preconditioning (IPC), and 2) how combined PostC+PerC alters the activity of the reperfusion injury salvage kinase pathway. The optimal combination of PerC and PostC therapy was produced by PerC delivered with four cycles of 5 min of limb ischemia followed by 5-min reperfusion. This resulted in lower infarct size (22.56 [+ or -] 4.45%) compared with rats with PostC alone (29.39 [+ or -] 3.66%) and PerC alone (33.49 [+ or -] 5.81%) and complementary differences in the generation of reactive oxygen species and apoptotic signaling. However, this optimal combination of PostC+PerC resulted in protection similar to local IPC alone (18.8 [+ or -] 2.54%, P = 0.13), and when added to IPC there was no additional protection (19.62 [+ or -] 2.89%, P = 0.675). Akt and ERKI/2 phosphorylation was induced by PostC and PerC and maximally by combined PostC+PerC treatment, and protection was abolished by phosphatidylinositol 3-kinase or ERK1/2 inhibitors. This study shows that neither PostC nor a maximized 'dose' of PerC leads to optimal kinase signaling or cardioprotection compared with IPC alone. However, combined PostC+PerC may result in complementary effects on kinase signaling to recapitulate the effects of local IPC. Finally, combined PostC+PerC is not additive to IPC, suggesting that each works via a common pathway. apoptosis; ischemia-reperfusion; reactive oxygen species; survival kinase doi: 10.1152/ajpheart.01102.2009.