Chemical modifications are important for RNA function and metabolism. N4-acetylcytidine (ac4C) is critical for the translation and stability of mRNA. Although ac4C is found in RNA viruses, the detailed mechanisms through which ac4C affects viral replication are unclear. Here, we reported that the 5′ untranslated region of the enterovirus 71 (EV71) genome was ac4C modified by the host acetyltransferase NAT10. Inhibition of NAT10 and mutation of the ac4C sites within the internal ribosomal entry site (IRES) suppressed EV71 replication. ac4C enhanced viral RNA translation via selective recruitment of PCBP2 to the IRES and boosted RNA stability. Additionally, ac4C increased the binding of RNA-dependent RNA polymerase (3D) to viral RNA. Notably, ac4C-deficient mutant EV71 showed reduced pathogenicity in vivo. Our findings highlighted the essential role of ac4C in EV71 infection and provided insights into potential antiviral treatments.

Cell membrane surface tension has emerged as a pivotal biophysical factor governing cell behavior and fate. This review systematically delineates recent advances in techniques for cell membrane surface tension quantification, mechanosensing mechanisms, and regulatory roles of cell membrane surface tension in modulating major cellular processes. Micropipette aspiration, tether pulling, and newly developed fluorescent probes enable the measurement of cell membrane surface tension with spatiotemporal precision. Cells perceive cell membrane surface tension via conduits including mechanosensitive ion channels, curvature-sensing proteins (e.g. BAR domain proteins), and cortex-membrane attachment proteins (e.g. ERM proteins). Through membrane receptors like integrins, cells convert mechanical cues into biochemical signals. This conversion triggers cytoskeletal remodeling and extracellular matrix interactions in response to environmental changes. Elevated cell membrane surface tension suppresses cell spreading, migration, and endocytosis while facilitating exocytosis. Moreover, reduced cell membrane surface tension promotes embryonic stem cell differentiation and cancer cell invasion, underscoring cell membrane surface tension as a regulator of cell plasticity. Outstanding questions remain regarding cell membrane surface tension regulatory mechanisms and roles in tissue development/disease in vivo. Emerging tools to manipulate cell membrane surface tension with high spatiotemporal control in combination with omics approaches will facilitate the elucidation of cell membrane surface tension-mediated effects on signaling networks across various cell types/states. This will accelerate the development of cell membrane surface tension-based biomarkers and therapeutics for regenerative medicine and cancer. Overall, this review provides critical insights into cell membrane surface tension as a potent orchestrator of cell function, with broader impacts across mechanobiology.

Poly(ADP‐ribose) glycohydrolase (PARG) as a main enzyme hydrolyzing poly(ADP‐ribose) in eukaryotes, and its silencing can inhibit benzo(a)pyrene (BaP)‐induced carcinogenesis. A thorough understanding of the mechanism of PARG silenced inhibition of BaP‐induced carcinogenesis provides a new therapeutic target for the prevention and treatment of environmental hazard induced lung cancer. We found that the expression of several subtypes of the histone H2B was downregulated in BaP‐induced carcinogenesis via PARG silencing as determined by label‐free proteomics and confirmed by previous cell line‐ and mouse model‐based studies. Analysis using the GEPIA2 online tool indicated that the transcription levels of H2BFS, HIST1H2BD, and HIST1H2BK in lung adenocarcinoma (LUAD) tissues and squamous cell lung carcinoma (LUSC) tissues were higher than those in normal lung tissues, while the transcription levels of HIST1H2BH in LUSC tissues were higher than those in normal lung tissues. The expression levels of HIST1H2BB, HIST1H2BH, and HIST1H2BL were significantly different in different lung cancer (LC) stages. Moreover, the expression of H2BFS, HIST1H2BD, HIST1H2BJ, HIST1H2BK, HIST1H2BL, HIST1H2BO, HIST2H2BE, and HIST2H2BF was positively correlated with that of PARG in LC tissues. Analysis of the Kaplan‐Meier plotter database indicated that high H2B levels predicted low survival in all LC patients suggesting that H2B could be a new biomarker for determining the prognosis of the LC, and that its expression can be inhibited by PARG silencing in BaP‐induced carcinogenesis.

The BCRP/ABCG2 transporter, which mediates drug resistance in many types of cells, depends on energy provided by ATP hydrolysis. Here, a retrovirus encoding a shRNA targeting the ATP-binding domain of this protein was used to screen for highly efficient agents that could reverse drug resistance and improve cell sensitivity to drugs, thus laying the foundation for further studies and applications. To target the ATP-binding domain of BCRP/ABCG2, pLenti6/BCRPsi shRNA recombinant retroviruses, with 20 bp target sequences starting from the 270^th, 745^th and 939^th bps of the 6^th exon, were constructed and packaged. The pLenti6/BCRPsi retroviruses (V-BCRPi) that conferred significant knockdown effects were screened using a drug-sensitivity experiment and flow cytometry. The human choriocarcinoma cell line JAR, which highly expresses endogenous BCRP/ABCG2, was injected under the dorsal skin of a hairless mouse to initiate a JAR cytoma. After injecting V-BCRPi-infected JAR tumor cells into the dorsal skin of hairless mice, BCRP/ABCG2 expression in the tumor tissue was determined using immunohistochemistry, fluorescent quantitative RT-PCR and Western blot analyses. After intraperitoneal injection of BCRP/ABCG2-tolerant 5-FU, the tumor volume, weight change, and apoptosis rate of the tumor tissue were determined using in situ hybridization. V-BCRPi increased the sensitivity of the tumor histiocytes to 5-FU and improved the cell apoptosis-promoting effects of 5-FU in the tumor. The goal of the in vivo and in vitro studies was to screen for an RNA interference recombinant retrovirus capable of stably targeting the ATP-binding domain of BCRP/ABCG2 (V-BCRPi) to inhibit its function. A new method to improve the chemo-sensitivity of breast cancer and other tumor cells was discovered, and this method could be used for gene therapy and functional studies of malignant tumors.

Colorectal cancer is the third most prevalent type of cancer in the United States. Early diagnosis of lymph node metastases is essential to improve the prognosis for patients with colorectal cancer. Therefore, the present study aimed to screen genetic markers, including single nucleotide polymorphisms (SNPs), copy number variations (CNVs) and mRNA expression, associated with lymph node metastases in patients with colorectal cancer to enable an early diagnosis. Targeted next-generation sequencing was applied to capture SNPs and CNVs in tumor-related candidate genes within tumor tissues from 39 colorectal cancer patients; reverse transcription-quantitative polymerase chain reaction was used to detect the specific mRNA level of tumor-related candidate genes, including vascular endothelial growth factor C, cyclin-A2, Interleukin-2, ATP-binding cassette sub-family G member 2, epidermal growth factor (EGF) and nuclear factor kappa B subunit 1 (NFKB1) on chromosome 4. The SNPs in solute carrier family 28 member 3 (SLC28A3), breast cancer 1 (BRCA1), ribonucleotide reductase regulators subunit M2 (RRM2), PMS1 homolog 2 (PMS2), cytidine deaminase (CDA), epoxide hydrolase 1 (EPHX1), heterogenous ribonucleoprotein particle-associated with lethal yellow (RALY), Siglec-3 (CD33), B cell lymphoma 10 (BCL10), ETS variant 1 (ETV1), macrophage stimulating 1 receptor 1 (MST1R), lysine methyltransferase 2B (KMT2B), B cell lymphoma 2 (BCL2), U6 small nuclear RNA-associated Sm-like protein 3 (LSM3), thyroid transcription factor 1 (TTF1) and mitogen-activated protein 3 kinase 1 (MAP3K1) were significantly associated with lymphatic metastasis (P<0.05). EGF and NFKB1 were both observed to be significantly downregulated in the lymph node metastases group (P<0.05). Although no association between CNVs and lymph node metastases in patients with colorectal cancer was observed in the present study, SNPs in SLC28A3, BRCA1, RRM2, PMS2, CDA, EPHX1, RALY, CD33, BCL10, ETV1, MST1R, KMT2B, BCL2, LSM3, TTF1 and MAP3K1 were significantly associated with colorectal cancer. Downregulation of EGF and NFKB1 was also identified to be associated with lymph node metastases in colorectal cancer. The findings of the current study provide a scientific basis for the clinical inspection of lymphatic metastasis and prognosis prediction, intervention and guidance therapy for patients with colorectal cancer.

Background: Blood inflammatory status is closely associated with tuberculosis (TB) progression. Emerging inflammatory indices from different leukocyte subtypes have become a prognostic hotspot for various diseases, yet their application in TB prognosis remains limited. This study aims to assess the impact of inflammatory status on TB patients’ prognosis and its potential as a prognostic indicator to optimize prognostic assessment and therapeutic strategies.Methods: This study included 4027 TB patients admitted to a tuberculosis-designated hospital in Shenzhen from January 2017 to December 2022. Patients were classified into three inflammatory statuses (Q1-Q3) based on each index’s level. We conducted Cox regression and restricted cubic splines (RCS) analyses to evaluate the association between inflammatory status and unfavorable outcome, subgroup analyses to understand heterogeneous associations among subpopulations, and receiver operating characteristic (ROC) analyses to evaluate the prognostic performance of inflammatory status on TB treatment outcomes.Results: During 48991.79 person-months of follow-up involving 4027 patients, 225 unfavorable outcomes occurred. Multivariable Cox regression indicated that the Q3 levels of CAR, CLR, dNLR, NLR, SII, and SIRI increased the risk of unfavorable outcome by 45%-99% (HR: 1.45-1.99, all P0.050), and nonlinear for MLR, NLR, and PNI (all P for nonlinear<0.050). Subgroup analyses identified heterogeneous associations across age, sex, BMI, comorbidities, and drug resistance (all P for interaction<0.050), with attenuated risk effects of CAR, CLR, dNLR, and SII in patients aged 30-60 years, male, BMI≥24.0 kg/m², smokers, retreatment cases, and those with tumor. ROC analysis demonstrated stable predictive performances of inflammatory status (AUC: 0.785–0.804 at 6-month, 0.781–0.793 at 9-month, and 0.762–0.773 at 12-month), and the combination of the inflammatory status significantly optimized the prognostic performance of the basic model (9-month AUC: 0.811 vs 0.780, P=0.024; 12-month AUC: 0.794 vs 0.758, P=0.013).Conclusion: Pretreatment blood inflammatory status effectively predicts the treatment outcome of TB patients. Our findings hold significant clinical value for TB patient management and warrant prospective evaluation in future studies.