Sepsis-associated encephalopathy (SAE) is a critical neurological complication of sepsis and represents a crucial factor contributing to high mortality and adverse prognosis in septic patients. This study explored the contribution of NAT10-mediated messenger RNA (mRNA) acetylation in cognitive dysfunction associated with SAE, utilizing a cecal ligation and puncture (CLP)-induced SAE mouse model. Our findings demonstrate that CLP significantly upregulates NAT10 expression and mRNA acetylation in the excitatory neurons of the hippocampal dentate gyrus (DG). Notably, neuronal-specific Nat10 knockdown improved cognitive function in septic mice, highlighting its critical role in SAE. Proteomic analysis, RNA immunoprecipitation, and real-time qPCR identified GABA B R1 as a key downstream target of NAT10. Nat10 deletion reduced GABA B R1 expression, and subsequently weakened inhibitory postsynaptic currents in hippocampal DG neurons. Further analysis revealed that microglia activation and the release of inflammatory mediators lead to the increased NAT10 expression in neurons. Microglia depletion with PLX3397 effectively reduced NAT10 and GABA B R1 expression in neurons, and ameliorated cognitive dysfunction induced by SAE. In summary, our findings revealed that after CLP, NAT10 in hippocampal DG neurons promotes GABA B R1 expression through mRNA acetylation, leading to cognitive dysfunction.

Necroptosis plays a double-edged sword role in necroptotic cancer cell death and tumor immune escape. How cancer orchestrates necroptosis with immune escape and tumor progression remains largely unclear. We found that RIP3, the central activator of necroptosis, was methylated by PRMT1 methyltransferase at the amino acid of RIP3 R486 in human and the conserved amino acid R479 in mouse. The methylation of RIP3 by PRMT1 inhibited the interaction of RIP3 with RIP1 to suppress RIP1-RIP3 necrosome complex, thereby blocking RIP3 phosphorylation and necroptosis activation. Moreover, the methylation-deficiency RIP3 mutant promoted necroptosis, immune escape and colon cancer progression due to increasing tumor infiltrated myeloid-derived immune suppressor cells (MDSC), while PRMT1 reverted the immune escape of RIP3 necroptotic colon cancer. Importantly, we generated a RIP3 R486 di-methylation specific antibody (RIP3 ADMA ). Clinical patient samples analysis revealed that the protein levels of PRMT1 and RIP3 ADMA were positively correlated in cancer tissues and both of them predicted the longer patient survival. Our study provides insights into the molecular mechanism of PRMT1-mediated RIP3 methylation in the regulation of necroptosis and colon cancer immunity, as well as reveals PRMT1 and RIP3 ADMA as the valuable prognosis markers of colon cancer.

Gastric cancer(GC)is the third most common cause of cancer death globally and a large portion of patients are diagnosed at advanced stages with cancer invasion and metastasis1,2.However,the mechanisms underlying the invasion and metastasis of GC remain to be delineated.ZYX plays critical roles in cell mobility via cytoskeleton regu-lation in various cell types.

Background Gut microbiota is associated with the progression of brain tumors. However, the alterations in gut microbiota observed during glioma growth and temozolomide (TMZ) therapy remain poorly understood. Methods C57BL/6 male mice were implanted with GL261 glioma cells. TMZ/sodium carboxymethyl cellulose (SCC) was administered through gavage for five consecutive days (from 8 to 12 days after implantation). Fecal samples were collected before (T0) and on days 7 (T1), 14 (T2), and 28 (T3) after implantation. The gut microbiota was analyzed using 16S ribosomal DNA sequencing followed by absolute and relative quantitation analyses. Results Nineteen genera were altered during glioma progression with the most dramatic changes in Firmicutes and Bacteroidetes phyla. During glioma growth, Lactobacillus abundance decreased in the early stage (T1) and then gradually increased (T2, T3); Intestinimonas abundance exhibited a persistent increase; Anaerotruncus showed a transient increase (T2) and then a subsequent decrease (T3). Similar longitudinal changes in Intestinimonas and Anaerotruncus abundance were observed in TMZ-treated mice, but the decrease of Anaerotruncus at T3 in the TMZ-treated group was less than that in the vehicle-treated group. No significant change in Lactobacillus was observed after TMZ treatment. Additionally, compared to vehicle control, TMZ treatment led to an enrichment in Akkermansia and Bifidobacterium. Conclusion Glioma development and progression altered the composition of gut microbiota. Induction of Akkermansia and Bifidobacterium as well as the prevention of the reduction in Anaerotruncus may contribute to the anti-tumor effect of TMZ. This study helps to reveal the association between levels of specific microbial species in the gut and the anti-tumor effect of TMZ.

Glioblastoma multiforme (GBM) is characterized by highly invasive growth, which leads to extensive infiltration and makes complete tumor excision difficult. Since cytoskeleton proteins are related to leading processes and cell motility, and through analysis of public GBM databases, we determined that an actin-interacting protein, zyxin ( ZYX ), may involved in GBM invasion. Our own glioma cohort as well as the cancer genome atlas (TCGA), Rembrandt, and Gravendeel databases consistently showed that increased ZYX expression was related to tumor progression and poor prognosis of glioma patients. In vitro and in vivo experiments further confirmed the oncogenic roles of ZYX and demonstrated the role of ZYX in GBM invasive growth. Moreover, RNA-seq and mass-spectrum data from GBM cells with or without ZYX revealed that stathmin 1 ( STMN1 ) was a potential target of ZYX . Subsequently, we found that both mRNA and protein levels of STMN1 were positively regulated by ZYX . Functionally, STMN1 not only promoted invasion of GBM cells but also rescued the invasion repression caused by ZYX loss. Taken together, our results indicate that high ZYX expression was associated with worse prognosis and highlighted that the ZYX - STMN1 axis might be a potential therapeutic target for GBM.

14 Abstract 15 Background: Various risk factors influence obesity differently, and 16 environmental endocrine disruption may increase the occurrence of obesity. 17 However, most of the previous studies have considered only a unitary 18 exposure or a set of similar exposures instead of mixed exposures, BKMR model, despite no statistically significant difference in the overall 41 association between the chemical mixtures and the outcome (obesity or 42 BMI z-score), there was nonetheless an increasing trend. 2,5-DCP and 43 MEP were found to be positively associated with the outcome (obesity or 44 BMI z-score), while fixing other chemicals at their median 45 concentrations. 46 Conclusion: Comparing the three statistical models, we found that 47 2,5-DCP and MEP may play an important role in obesity. Considering the 48 advantages and disadvantages of the three statistical models, our study 49 confirms the necessity to combine different statistical models on obesity 50 when dealing with mixed exposures. 51

Background: Various risk factors influence obesity differently, and too much environmental endocrine disruption may increase the occurrence of obesity. However, most of the previous studies have considered only a unitary exposure or a set of similar exposures instead of mixed exposures, which entail complicated interactions. We utilized three statistical models to evaluate the interactions between mixed chemicals to analyze the association between 13 different chemical exposures and obesity in children and adolescents. Methods: We fitted the generalized linear regression, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) to analyze the association between the mixed exposures and obesity in the participants aged 6-19 in the National Health and Nutrition Examination Survey (NHANES) 2005–2010. Results: In the logistic regression model, 2,5-dichlorophenol (2,5-DCP) (P = 0.001), monoethyl phthalate (MEP) (P = 0.005), and mono-isobutyl phthalate (MiBP) (P = 0.023) were found to be positively associated with obesity, while methylparaben (MeP) (P = 0.011) was negatively associated with obesity. In the multivariable linear regression, MEP was the only chemical found to be associated with the body mass index (BMI) z-score (P = 0.003). In the WQS regression model, the WQS index had a significant association (P = 0.001) with the outcome in the obesity model, in which 2,5-DCP (weighted 0.35), 2,4,6-trichlorophenol (2,4,6-TCP) (weighted 0.16), MEP (weighted 0.14), and MiBP (weighted 0.12) all had relatively high weights. In the BKMR model, despite no statistically significant difference in the overall association between the chemical mixtures and the outcome (obesity or BMI z-score), there was nonetheless an increasing trend. 2,5-DCP, MEP, and MiBP were found to be positively associated with obesity, while fixing other chemicals at their median concentrations. Conclusion: Comparing the three statistical models, we found that 2,5-DCP, MEP, and MiBP may play an important role in the 13 exposures. Considering the advantages and disadvantages of the three statistical models, our study confirms the necessity to combine different statistical models on obesity when dealing with mixed exposures.

Primary glial and neuronal tumors of the ovary or peritoneum are rare neuroectodermal-type tumors similar to their counterparts in the central nervous system. We retrospectively reviewed 11 cases. These cases included 4 ependymomas, 6 astrocytic tumors, and 1 neurocytoma. Patients’ age ranged from 9 to 50 years (mean, 26 y; median, 24 y). All ependymal tumors with detailed clinical history (n=3) were not associated with any other ovarian neoplasm. In contrast, all astrocytic tumors were associated with immature teratoma (n=4), mature cystic teratoma (n=1), or mixed germ cell tumor (n=1). The neurocytoma arose in association with mature teratomatous components in a patient with a history of treated mixed germ cell tumor. Immunohistochemical staining showed that 7 of 7 ependymal and astrocytic tumors (100%) were positive for glial fibrillary acidic protein, and 2 of 2 ependymomas (100%) were positive for both estrogen and progesterone receptors. The neurocytoma was positive for synaptophysin and negative for S100 protein, glial fibrillary acidic protein, and SALL4. No IDH1-R132H mutation was detected in 2 of 2 (0%) astrocytomas by immunohistochemistry. Next-generation sequencing was performed on additional 2 ependymomas and 2 astrocytomas but detected no mutations in a panel of 50 genes that included IDH1, IDH2, TP53, PIK3CA, EGFR, BRAF, and PTEN. Follow-up information was available for 8 patients, with the follow-up period ranging from 4 to 59 months (mean, 15 mo; median, 8.5 mo), of which 3 had no evidence of disease and 5 were alive with disease. In conclusion, primary glial and neuronal tumors of the ovary can arise independently or in association with other ovarian germ cell tumor components. Pathologists should be aware of these rare tumors and differentiate them from other ovarian neoplasms. Even though an IDH1 or IDH2 mutation is found in the majority of WHO grade II and III astrocytomas, and in secondary glioblastomas arising from them, such mutations were not identified in our series, suggesting that these tumors are molecularly different from their central nervous system counterparts despite their morphologic and immunophenotypic similarities.