TIPE2 deficiency prolongs mouse heart allograft survival by facilitating immature DCs-induced Treg generation.

It has been reported that deletion of tumor necrosis factor-α-induced protein-8 like 2 (TNFAIP8L2, TIPE2) facilitates the activation of T-cell receptors. However, the role of TIPE2 in T-cell-mediated acute transplant rejection remains unclear. To illustrate the underlying cellular mechanisms, we transplanted BALB/c hearts into C57BL/6 wild-type (WT) or C57BL/6 mice deficient for TIPE2 (TIPE2-/-) and found that TIPE2-/- recipient mice showed significantly prolonged survival of heart allografts and suppressed maturation of CD11c+ dendritic cells (DCs), which largely abolished the activation and proliferation of alloreactive T cells and their cytotoxic activity. TIPE2-/- DCs increased CD4+CD25+Foxp3+CD127- regulatory T cells (Tregs)generation, likely by inhibiting DCs maturation and CD80 and CD86 expression. Administration of anti-CD25 abolished the allograft survival induced by TIPE2 deficiency. Moreover, TIPE2 deficiency increased IL-10 production in T cells and in recipient serum and allografts. Mechanistic studies revealed that TIPE2-/- restrained the maturation of DCs via inhibition of PI3K/AKT phosphorylation during alloantigen stimulation. Taken together, TIPE2 deficiency in recipient mice inhibited acute rejection by increasing Tregs generated by immature DCs. Thus, TIPE2 could be a therapeutic target for suppressing rejection in organ transplantation.

Curriculum Reinforcement Learning Based on K-Fold Cross Validation.

With the continuous development of deep reinforcement learning in intelligent control, combining automatic curriculum learning and deep reinforcement learning can improve the training performance and efficiency of algorithms from easy to difficult. Most existing automatic curriculum learning algorithms perform curriculum ranking through expert experience and a single network, which has the problems of difficult curriculum task ranking and slow convergence speed. In this paper, we propose a curriculum reinforcement learning method based on K-Fold Cross Validation that can estimate the relativity score of task curriculum difficulty. Drawing lessons from the human concept of curriculum learning from easy to difficult, this method divides automatic curriculum learning into a curriculum difficulty assessment stage and a curriculum sorting stage. Through parallel training of the teacher model and cross-evaluation of task sample difficulty, the method can better sequence curriculum learning tasks. Finally, simulation comparison experiments were carried out in two types of multi-agent experimental environments. The experimental results show that the automatic curriculum learning method based on K-Fold cross-validation can improve the training speed of the MADDPG algorithm, and at the same time has a certain generality for multi-agent deep reinforcement learning algorithm based on the replay buffer mechanism.

Case report: Gastric carcinoma with SMARCA4 deficient: two cases report and literature review.

SMARCA4-deficient gastric carcinoma has been reported sporadically since 2016. Only 29 patients have been reported; nevertheless, it is aggressive and highly malignant with poor outcomes. It has an immunohistochemical phenotype showing loss of SMARCA4 expression and can be accompanied by codeletion of other switch/sucrose non-fermentable chromatin-remodeling complex subunits. Microscopically, it displays high-grade undifferentiated histological morphology with rhabdoid cell differentiation. Rarely does the tumor contain a purely or partly adenocarcinoma component. Here, we report two cases to demonstrate these unusual morphologies analyzed using morphological and immunohistochemical techniques. In addition, there is a lack of research on the classification of these morphologies. Therefore, our report will aid the diagnosis and classification of SMARCA4-deficient gastric carcinoma.

Correlations between iodine uptake, invasive CT features and pleural invasion in adenocarcinomas with pleural contact.

Pleural contact in lung cancers does not always imply pleural invasion (PI). This study was designed to determine whether specific invasive CT characteristics or iodine uptake can aid in the prediction of PI. The sample population comprised patients with resected solid lung adenocarcinomas between April 2019 and May 2022. All participants underwent a contrast enhanced spectral CT scan. Two proficient radiologists independently evaluated the CT features and iodine uptake. Logistic regression analyses were employed to identify predictors for PI, via CT features and iodine uptake. To validate the improved diagnostic efficiency, accuracy analysis and ROC curves were subsequently used. A two-tailed P value of less than 0.05 was considered statistically significant. We enrolled 97 consecutive patients (mean age, 61.8 years ± 10; 48 females) in our study. The binomial logistic regression model revealed that a contact length > 10 mm (OR 4.80, 95% CI 1.92, 11.99, p = 0.001), and spiculation sign (OR 2.71, 95% CI 1.08, 6.79, p = 0.033) were independent predictors of PI, while iodine uptake was not. Enhanced sensitivity (90%) and a greater area under the curve (0.73) were achieved by integrating the two aforementioned CT features in predicting PI. We concluded that the combination of contact length > 10 mm and spiculation sign can enhance the diagnostic performance of PI.

TIPE2 knockout reduces myocardial cell damage by inhibiting IFN-γ-mediated ferroptosis.

Acute rejection of the transplanted heart is mediated by oxidative programmed cell death through the synergistic effects of the innate and adaptive immune systems. However, the role of ferroptosis, a newly discovered form of oxidative cell death, has not been widely evaluated. Tumor necrosis factor-α-induced protein-8 like 2 (TNFAIP8L2), also known as TIPE2, is required for maintaining immune homeostasis. To characterize the role of TIPE2 in mediating heart allografts, BALB/c hearts were transplanted into C57BL/6 wild-type (WT) and TIPE2-/- recipient mice. In TIPE2-/- recipient mice, allograft injury in BALB/c allograft hearts was significantly reduced through the inhibition of allograft ferroptosis. On day 3 and day 6 post-transplantation, the numbers of CD3+, CD4+, and CD8+ cells among splenocytes and draining lymph node cells were significantly decreased, and the activation of CD4+ and CD8+ cells in grafts was decreased in TIPE2-/- recipient mice compared with WT mice. Moreover, CD4+ and CD8+ T cells in TIPE2-/- recipient mice were characterized by deficient capacities for interferon-γ (IFN-γ) production through the TBK1 signaling axis and increased glutathione peroxidase 4 (GPX4). In cell experiments, treatment with IFN-γ enhanced ferroptosis-specific lipid peroxidation in myocardial cells and correlated inversely with GPX4 expression. Mechanistically, IFN-γ administration decreased the expression of GPX4 by inhibiting MEK/ERK phosphorylation. In summary, our findings demonstrated that TIPE2 deficiency inhibits T-cell production of IFN-γ to reduce ferroptosis in allografts by restraining lipid peroxidation.

Identification of Essential Tumor-Infiltrating Immune Cells and Relevant Genes in Left-Sided and Right-Sided Colon Cancers.

BACKGROUNDS: Colorectal cancer is the third most prevalent cancer worldwide. A right-sided colon cancer patient typically has a worse prognosis than one who has a left-sided colon cancer. There is an unclear understanding of how left-sided colon cancer differs from right-sided colon cancer in tumor-infiltrating immune cells (TIICs) and relevant genes. METHODS: The Cancer Genome Atlas provided RNA-seq data and clinical information regarding colon adenocarcinoma. We conducted a single-sample gene set enrichment analysis (ssGSEA) to quantify the level of 24 immune cells infiltrating the tissues. Based on an analysis of univariate Cox regression, immune cell types associated with survival were identified. Weighted gene co-expression network analysis (WGCNA) was used to identify hub genes related to location and critical immune cells. Based on the Search Tool for the Retrieval of Interacting Genes (STRING), interaction potential was predicted among the hub genes. Hub genes that influence outcomes through immune infiltration were identified using the least absolute shrinkage and selection operator (LASSO). Then, we used the TISIDB database (a repository portal for tumor-immune system interactions) to validate the correlation between hub genes and immune cell infiltration. Finally, immunohistochemical assays were conducted to determine the levels of proteins expressed by critical TIICs and cancer cells. RESULTS: Colon cancers on the right side of the body had higher levels of myeloid-derived suppressor cells (MDSCs) than on the left side. There were three key genes: LCP1, ITGB2, and IKZF1. It was found that their expression was linked to poor prognosis and an increased level of MDSC infiltration. An immunohistochemical study confirmed these findings. CONCLUSIONS: There is a higher rate of MDSC infiltration in right-sided colon cancer when compared with left-sided colon cancer. COAD outcomes are associated with changes in MDSC infiltration, and therefore LCP1, ITGB2, and IKZF1 may be novel targets for immunotherapy.

MSI2 deficiency in ILC3s attenuates DSS-induced colitis by affecting the intestinal microbiota.

Background: The etiology and pathogenesis of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are generally believed to be related to immune dysfunction and intestinal microbiota disorder. However, the exact mechanism is not yet fully understood. The pathological changes associated with dextran sodium sulfate (DSS)-induced colitis are similar to those in human UC. As a subgroup of the innate immune system, group 3 innate lymphoid cells (ILC3s) are widely distributed in the lamina propria of the intestinal mucosa, and their function can be regulated by a variety of molecules. Musashi2 (MSI2) is a type of evolutionarily conserved RNA-binding protein that maintains the function of various tissue stem cells and is essential for postintestinal epithelial regeneration. The effect of MSI2 deficiency in ILC3s on IBD has not been reported. Thus, mice with conditional MSI2 knockout in ILC3s were used to construct a DSS-induced colitis model and explore its effects on the pathogenesis of IBD and the species, quantity and function of the intestinal microbiota. Methods: Msi2flox/flox mice (Msi2fl/fl ) and Msi2flox/floxRorcCre mice (Msi2ΔRorc ) were induced by DSS to establish the IBD model. The severity of colitis was evaluated by five measurements: body weight percentage, disease activity index, colon shortening degree, histopathological score and routine blood examination. The species, quantity and function of the intestinal microbiota were characterized by high-throughput 16S rRNA gene sequencing of DNA extracted from fecal samples. Results: MSI2 was knocked out in the ILC3s of Msi2ΔRorc mice. The Msi2ΔRorc mice exhibited reductions in body weight loss, the disease activity index, degree of colon shortening, tissue histopathological score and immune cells in the peripheral blood compared to those of Msi2fl/fl mice after DSS administration. The 16S rRNA sequencing results showed that the diversity of the intestinal microbiota in DSS-treated Msi2ΔRorc mice changed, with the abundance of Firmicutes increasing and that of Bacteroidetes decreasing. The linear discriminant analysis effect size (LEfSe) approach revealed that Lactobacillaceae could be the key bacteria in the Msi2ΔRorc mouse during the improvement of colitis. Using PICRUST2 to predict the function of the intestinal microbiota, it was found that the functions of differential bacteria inferred by modeling were mainly enriched in infectious diseases, immune system and metabolic functions. Conclusions: MSI2 deficiency in ILC3s attenuated DSS-induced colonic inflammation in mice and affected intestinal microbiota diversity, composition, and function, with Lactobacillaceae belonging to the phylum Firmicutes possibly representing the key bacteria. This finding could contribute to our understanding of the pathogenesis of IBD and provide new insights for its clinical diagnosis and treatment.

RNA-seq analyses of Marine Medaka (Oryzias melastigma) reveals salinity responsive transcriptomes in the gills and livers.

Increasing salinity levels in marine and estuarine ecosystems greatly influence developmental, physiological and molecular activities of inhabiting fauna. Marine medaka (Oryzias melastigma), a euryhaline research model, has extraordinary abilities to survive in a wide range of aquatic salinity. To elucidate how marine medaka copes with salinity differences, the responses of Oryzias melastigma after being transferred to different salt concentrations [0 practical salinity units (psu), 15 psu, 30 psu (control), 45 psu] were studied at developmental, histochemical and transcriptome levels in the gill and liver tissues. A greater number of gills differentially expressed genes (DEG) under 0 psu (609) than 15 psu (157) and 45 psu (312), indicating transcriptomic adjustments in gills were more sensitive to the extreme hypotonic environment. A greater number of livers DEGs were observed in 45 psu (1,664) than 0 psu (87) and L15 psu (512), suggesting that liver was more susceptible to hypertonic environment. Further functional analyses of DEGs showed that gills have a more immediate response, mainly in adjusting ion balance, immune and signal transduction. In contrast, DEGs in livers were involved in protein synthesis and processing. We also identified common DEGs in both gill and liver and found they were mostly involved in osmotic regulation of amino sugar and nucleotide sugar metabolism and steroid biosynthesis. Additionally, salinity stresses showed no significant effects on most developmental and histochemical parameters except increased heartbeat with increasing salinity and decreased glycogen after transferred from stable conditions (30 psu) to other salinity environments. These findings suggested that salinity-stress induced changes in gene expressions could reduce the effects on developmental and histochemical parameters. Overall, this study provides a useful resource for understanding the molecular mechanisms of fish responses to salinity stresses.

miR-539 activates the SAPK/JNK signaling pathway to promote ferropotosis in colorectal cancer by directly targeting TIPE.

Colorectal cancer (CRC) is a common tumor that harms human health with a high recurrence rate. It has been reported that the expression of microRNA-539 (miR-539) is low in several types of cancer, including CRC. Tumor necrosis factor (TNF)-α-induced protein 8 (TNFAIP8/TIPE) is highly expressed in CRC and promotes the proliferation, migration and angiogenesis of CRC. However, the relationship between miR-539 and TIPE and the mechanisms by which they regulate the proliferation of CRC remain to be explored. We aimed to investigate the functions and mechanisms of miR-539 in CRC proliferation. Functionally, miR-539 can bind to and regulate the expression of TIPE, and miR-539 activates SAPK/JNK to downregulate the expression of glutathione peroxidase 4 (GPX4) and promote ferroptosis. Our data reveal the novel role of miR-539 in regulating ferroptosis in CRC via activation of the SAPK/JNK axis, providing new insight into the mechanism of abnormal proliferation in CRC and a novel potential therapeutic target for advanced CRC.

The acute toxic effects of hexavalent chromium on the liver of marine medaka (Oryzias melastigma).

Chromium is toxic to marine animals and can cause damage to many of their organs, including the liver. To test the toxicity of chromium on marine organisms, we exposed the liver of the marine medaka (Oryzias melastigma) with hexavalent chromium [Cr(VI)]. Our results show that Cr enrichment in the liver demonstrates a positive correlation to the exposure concentration. With the increase of Cr(VI) concentration, pathological changes including nuclear migration, cell vacuolization, blurred intercellular gap, nuclear condensation, become noticeable. To further study changes in gene expression in the liver after Cr(VI) exposure, we used RNA-seq to compare expression profiles before and after Cr(VI) exposure. After acute Cr(VI) exposure (2.61 mg/l) for 96 h, 5862 transcripts significantly changed. It is the first time that the PPAR pathway was found to respond sensitively to Cr(VI) exposure in fish. Finally, combined with other published study, we found that there may be some difference between Cr(VI) toxicity in seawater fish and freshwater fish, due to degree of oxidative stress, distribution patterns and detailed Cr(VI) toxicological mechanisms. Not only does our study explore the mechanisms of Cr(VI) toxicity on the livers of marine medaka, it also points out different Cr(VI) toxicity levels and potential mechanisms between seawater fish and freshwater fish.