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Stat6 is known to drive macrophage M2 polarization. However, how macrophage polarization is fine-tuned by Stat6 is poorly understood. Here, we find that Lys383 of Stat6 is acetylated by the acetyltransferase CREB-binding protein (CBP) during macrophage activation to suppress macrophage M2 polarization. Mechanistically, Trim24, a CBP-associated E3 ligase, promotes Stat6 acetylation by catalyzing CBP ubiquitination at Lys119 to facilitate the recruitment of CBP to Stat6. Loss of Trim24 inhibits Stat6 acetylation and thus promotes M2 polarization in both mouse and human macrophages, potentially compromising antitumor immune responses. By contrast, Stat6 mediates the suppression of TRIM24 expression in M2 macrophages to contribute to the induction of an immunosuppressive tumor niche. Taken together, our findings establish Stat6 acetylation as an essential negative regulatory mechanism that curtails macrophage M2 polarization. Stat6 promotes M2 macrophage polarization. Here the authors characterize Trim24-CBP-Stat6 circuit regulating M2 macrophage polarization via Stat6 acetylation, and show it contributes to pro-tumorigenic macrophage activity in mice.

Chronic inflammation and an immunosuppressive microenvironment promote prostate cancer (PCa) progression and diminish the response to immune checkpoint blockade (ICB) therapies. However, it remains unclear how and to what extent these two events are coordinated. Here, we show that ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, functions downstream of inflammation-induced IKKβ activation to shape the immunosuppressive tumor microenvironment (TME). Prostate-specific deletion of Arid1a cooperates with Pten loss to accelerate prostate tumorigenesis. We identify polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) as the major infiltrating immune cell type that causes immune evasion and reveal that neutralization of PMN-MDSCs restricts the progression of Arid1a -deficient tumors. Mechanistically, inflammatory cues activate IKKβ to phosphorylate ARID1A, leading to its degradation via β-TRCP. ARID1A downregulation in turn silences the enhancer of A20 deubiquitinase, a critical negative regulator of NF-κB signaling, and thereby unleashes CXCR2 ligand-mediated MDSC chemotaxis. Importantly, our results support the therapeutic strategy of anti-NF-κB antibody or targeting CXCR2 combined with ICB for advanced PCa. Together, our findings highlight that the IKKβ/ARID1A/NF-κB feedback axis integrates inflammation and immunosuppression to promote PCa progression. The accumulation of myeloid derived suppressor cells (MDSC) has been associated with prostate cancer progression and castration resistance. Here the authors show that loss of ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, results in polymorphonuclear-MDSC infiltration and cooperates with Pten loss to accelerate prostate tumorigenesis.

IFN-γ-stimulated MHC class I (MHC-I) antigen presentation underlies the core of antitumor immunity. However, sustained IFN-γ signaling also enhances the programmed death ligand 1 (PD-L1) checkpoint pathway to dampen antitumor immunity. It remains unclear how these opposing effects of IFN-γ are regulated. Here, we report that loss of the histone dimethyltransferase WHSC1 impaired the antitumor effect of IFN-γ signaling by transcriptional downregulation of the MHC-I machinery without affecting PD-L1 expression in colorectal cancer (CRC) cells. Whsc1 loss promoted tumorigenesis via a non-cell-autonomous mechanism in an Apcmin/+ mouse model, CRC organoids, and xenografts. Mechanistically, we found that the IFN-γ/STAT1 signaling axis stimulated WHSC1 expression and, in turn, that WHSC1 directly interacted with NLRC5 to promote MHC-I gene expression, but not that of PD-L1. Concordantly, silencing Whsc1 diminished MHC-I levels, impaired antitumor immunity, and blunted the effect of immune checkpoint blockade. Patient cohort analysis revealed that WHSC1 expression positively correlated with enhanced MHC-I expression, tumor-infiltrating T cells, and favorable disease outcomes. Together, our findings establish a tumor-suppressive function of WHSC1 that relays IFN-γ signaling to promote antigen presentation on CRC cells and provide a rationale for boosting WHSC1 activity in immunotherapy.

To investigate the bearing characteristics of super-long and large-diameter cast-in-place piles with combined pile-end and pile-side post-grouting, double-load-box self-balanced static-load tests were conducted on two such piles of the Yellow River Bridge Project on Jiaoping Expressway both before and after grouting. This study aims to provide technical insights for the design and construction of similar pile foundations. The test results indicate that, after grouting, the ultimate bearing capacities of test piles SZ1 and SZ2 increased by 123.1% and 72.8%, respectively, with a significant reduction in pile top settlement under the same load level. Under each load level, the axial force of the pile shaft reaches its maximum near the upper load box, presenting a triangular distribution curve. Furthermore, the side frictions of SZ1 and SZ2 enhanced by 87.73% and 83.59%, respectively, after grouting, while their ultimate end resistances are improved by 362.6% and 120.6%. These findings demonstrate that post-grouting effectively optimizes the mechanical properties of the pile–soil interface and enhances the structural stiffness of the surrounding soil. Specifically, the grout hardens at the pile end, solidifies the sediment there, increases the density of the pile-end soil layer, and improves the bearing rigidity of the bearing stratum. This research validates the effectiveness of the combined pile-end and pile-side post-grouting technology in improving the bearing performance of super-long and large-diameter cast-in-place piles, providing valuable technical support for the safe and efficient construction of the Yellow River Bridge on the Jiaoping Expressway and similar engineering projects.

Analyzing the propeller aerodynamic performance is of vital importance for research and improvement of unmanned aerial vehicles. This paper presents the design requirements for a propeller for rotorcraft unmanned aerial vehicles and an analysis of a model for calculating propeller aerodynamic performance. Based on blade element momentum theory, the aerodynamic force of a blade element is analyzed and used. The symmetric airfoil NACA 0012 is used as an example to verify the validity of the model. An experimental system for propeller aerodynamic performance is designed and built to test the aerodynamic performance of six types of the propeller from a single manufacturer (APC). Data-processing software is also developed to draw curves and perform single-step calculations of three propellers’ parameters: airfoil resistance power, induced velocity, and efficiency. The results of the experiment indicate that both the thrust and torque of the propeller increase with rotational speed, propeller diameter, and propeller pitch. The research is of great significance to select more suitable propellers for unmanned aerial vehicles and the further improvement of the performance of unmanned aerial vehicles’ dynamical system.

T follicular helper (Tfh) cells are crucial for regulating autoimmune inflammation and protective immunity against viral infection. However, the molecular mechanism controlling Tfh cell differentiation is poorly understood. Here, through two mixed bone marrow chimeric experiments, we identified Peli1, a T cell-enriched E3 ubiquitin ligase, as an intrinsic regulator that inhibits Tfh cell differentiation. Peli1 deficiency significantly promoted c-Rel-mediated inducible T-cell costimulator (ICOS) expression, and PELI1 mRNA expression was negatively associated with ICOS expression on human CD4+ T cells. Mechanistically, increased ICOS expression on Peli1-KO CD4+ T cells enhanced the activation of PI3K-AKT signaling and thus suppressed the expression of Klf2, a transcription factor that inhibits Tfh differentiation. Therefore, reconstitution of Klf2 abolished the differences in Tfh differentiation and germinal center reaction between WT and Peli1-KO cells. As a consequence, Peli1-deficient CD4+ T cells promoted lupus-like autoimmunity but protected against H1N1 influenza virus infection in mouse models. Collectively, our findings established Peli1 as a critical negative regulator of Tfh differentiation and indicated that targeting Peli1 may have beneficial therapeutic effects in Tfh-related autoimmunity or infectious diseases.

Myeloid derived suppressor cells (MDSC) in the liver microenvironment protects against the inflammation-induced liver injury in fulminant hepatitis (FH). However, the molecular mechanism through which MDSC is recruited into the inflamed liver remain elusive. Here we identified a protein kinase Tpl2 as a critical mediator of MDSC recruitment into liver during the pathogenesis of /LPS-induced FH. Loss of Tpl2 dramatically suppressed MDSC mobilization into liver, leading to exaggerated local inflammation and increased FH-induced mortality. Mechanistically, although the protective effect of Tpl2 for FH-induced mortality was dependent on the presence of MDSC, Tpl2 neither directly targeted myeloid cells nor T cells to regulate FH pathogenesis, but functioned in hepatocytes to mediate the induction of MDSC-attracting chemokine CXCL1 and CXCL2 through modulating IL-25 (also known as IL-17E) signaling. As a consequence, increased MDSC in the inflamed liver specifically restrained the local proliferation of infiltrated pathogenic CD4 T cells, and thus protected against the inflammation-induced acute liver failure. Together, our findings established Tpl2 as a critical mediator of MDSC recruitment and highlighted the therapeutic potential of Tpl2 for the treatment of FH.

Background Non-small cell lung cancer (NSCLC) is one of the predominant malignancies globally. Percutaneous thermal ablation (PTA) has gained widespread use among NSCLC patients, with the potential to elicit immune responses but limited therapeutic efficacies for advanced-stage disease. T-helper type 9 (Th9) cells are a subset of CD4 + effector T cells with robust and persistent anti-tumor effects. This study proposes to develop PTA-Th9 cell integrated therapy as a potential strategy for NSCLC treatment. Methods The therapeutic efficacies were measured in mice models with subcutaneously transplanted, recurrence, or lung metastatic tumors. The tumor microenvironments (TMEs) were evaluated by flow cytometry. The cytokine levels were assessed by ELISA. The signaling molecules were determined by quantitative PCR and Western blotting. The translational potential was tested in the humanized NSCLC patient-derived xenograft (PDX) model. Results We find that PTA combined with adoptive Th9 cell transfer therapy substantially suppresses tumor growth, recurrence, and lung metastasis, ultimately extending the survival of mice with NSCLC grafts, outperforming both PTA and Th9 cell transfer monotherapy. Analysis of TMEs indicates that combinatorial therapy significantly augments tumor-infiltrating Th9 cells, boosts anti-tumor effects of CD8 + T cells, and remodels tumor immunosuppressive microenvironments. Moreover, combinatorial therapy significantly strengthens the regional and circulation immune response of CD8 + T cells in mice with tumor lung metastasis and induces peripheral CD8 + T effector memory cells in mice with tumor recurrence. Mechanically, PTA reinforces the anti-tumor ability of Th9 cells primarily through upregulating interleukin (IL)-1β and subsequently activating the downstream STAT1/IRF1 pathway, which could be effectively blocked by intercepting IL-1β signaling. Finally, the enhanced therapeutic effect of combinatorial therapy is validated in humanized NSCLC PDX models. Conclusions Collectively, this study demonstrates that combinatorial therapy displays robust and durable anti-tumor efficacy and excellent translational potential, offering excellent prospects for translation and emerging as a promising approach for NSCLC treatment.

Camellia nitidissima is an endangered species. This species contains two varieties. Here, we report on the chloroplast genomes of C. nitidissima var. nitidissima from Fangcheng (GenBank accession MT157617) and Nanning (MT157618), as well as one sample of C. nitidissima var. microcarpa (MT157619) from Nanning. The total chloroplast genomes of C. nitidissima var. nitidissima Fangcheng and Nanning samples are 156,596 bp and 157,567 bp in length, respectively. C. nitidissima var. microcarpa (MT157619) genome is 157,407 bp in length. The three samples possess GC contents of 37.3%, 128 genes, comprising 86 protein-coding genes, 34 tRNA genes, and 8 rRNA genes.

In this study, we report on the complete chloroplast genomes of Camellia perpetua and Camellia indochinensis for the first time. The complete chloroplast genome of C. perpetua is 156,804 bp in length and is comprised of two inverted repeat (IR) regions (25,996 bp each), a large single copy (LSC) region (86,570 bp), and a small single copy (SSC) region (18,242 bp). The chloroplast genome of C. perpetua harbors 86 protein-coding genes, 28 tRNA genes, and eight rRNA genes, with an overall GC content of 37.32%. The chloroplast genome of C. indochinensis showed similar characteristics as that of C. perpetua. The total length of C. indochinensis chloroplast genome is 156,571 bp, which includes 26,053 bp each of the two IR regions, 86,246 bp of the LSC region, and 18,219 bp of the SSC region. C. indochinensis chloroplast genome contains 85 protein-coding genes, 28 tRNA genes, and eight rRNA genes, with an overall GC content of 37.34%. Furthermore, a phylogenetic tree was constructed using the chloroplast genome sequences of the two species, and their phylogenetic positions were determined.