N6-Methyladenosine (m6A) modification is a crucial post-transcriptional regulatory mechanism and the most abundant and highly conserved RNA epigenetic modification in eukaryotes. Previous studies have indicated the involvement of m6A modification in various tissue regeneration processes, including liver regeneration. Vir-like m6A methyltransferase associated protein (VIRMA) is an m6A methyltransferase with robust methylation capability. However, its role in liver regeneration remains poorly understood. In this study, we generated liver-specific Virma knockout mice using the Cre-loxP system and investigated the biological functions of VIRMA in liver regeneration using both the Associating Liver Partition and Portal vein Ligation for Staged Hepatectomy (ALPPS) mouse model and the carbon tetrachloride (CCl₄) mouse model. The expression level of VIRMA was rapidly up-regulated after ALPPS surgery and gradually down-regulated during liver repair. Virma deficiency significantly impaired liver regeneration capacity and disrupted cell cycle progression. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) analysis revealed that Shq1 is an effective downstream target of VIRMA-mediated m6A modification. The upregulation of Shq1 enhanced the proliferation ability of cells, which was attenuated by the specific AKT inhibitor ipatasertib. Supplementation of Shq1 in vivo alleviated the liver cell proliferation inhibition caused by Virma deficiency. Furthermore, the m6A-binding protein heterogeneous nuclear ribonucleoprotein a2b1 (HNRNPA2B1) enhanced the mRNA stability of Shq1. Mechanistically, Virma deficiency resulted in decreased m6A modification on Shq1 mRNA, leading to reduced binding ability of m6A-binding protein HNRNPA2B1 with Shq1, thereby decreasing the mRNA stability of Shq1 and reducing its protein expression level. Downregulation of Shq1 inhibited the PI3K/AKT pathway, thereby suppressing cell proliferation and cell cycle progression, ultimately impeding liver regeneration. In summary, our results demonstrate that VIRMA plays a critical role in promoting liver regeneration by regulating m6A modification, providing valuable insights into the epigenetic regulation during liver regeneration.

The management of antibiotic-resistant, bacterial biofilm infections in skin wounds poses an increasingly challenging clinical scenario. Pseudomonas aeruginosa infection is difficult to eradicate because of biofilm formation and antibiotic resistance. In this study, we identified a new benzothiazole derivative compound, SN12 (IC₅₀ = 43.3 nmol/L), demonstrating remarkable biofilm inhibition at nanomolar concentrations in vitro. In further activity assays and mechanistic studies, we formulated an unconventional strategy for combating P. aeruginosa-derived infections by targeting the two-component (Gac/Rsm) system. Furthermore, SN12 slowed the development of ciprofloxacin and tobramycin resistance. By using murine skin wound infection models, we observed that SN12 significantly augmented the antibacterial effects of three widely used antibiotics-tobramycin (100-fold), vancomycin (200-fold), and ciprofloxacin (1000-fold)-compared with single-dose antibiotic treatments for P. aeruginosa infection in vivo. The findings of this study suggest the potential of SN12 as a promising antibacterial synergist, highlighting the effectiveness of targeting the two-component system in treating challenging bacterial biofilm infections in humans.

Objective:To compare the effects of non-invasive bi-level pressure triggering (BiPhasic tr) on oxygenation index (OI), partial pressure of oxygen and utilization rate of mechanical ventilation in premature infants with respiratory distress syndrome (RDS).Methods:The clinical data of 100 premature infants with RDS in Shantou Dafeng Hospital of Guangdong Province from March 2018 to May 2019 were retrospectively analyzed. Among them, 56 cases treated with nasal continuous positive airway pressure (nCPAP) were enrolled as control group, and 44 cases treated with BiPhasic tr were as observation group. The OI, arterial partial pressure of oxygen (PaO 2) and arterial partial pressure of carbon dioxide (PaCO 2) before and after respiratory support, duration of auxiliary ventilation, utilization rate of mechanical ventilation and incidence of complication were compared between 2 groups. Results:There were no statistical difference in PaO 2, PaCO 2 and OI before respiratory support between 2 groups ( P>0.05); the PaO 2, PaCO 2 and OI 1, 6, 12 and 24 h after respiratory support in 2 groups were significantly improved compared with those before respiratory support, and the improvement degree in observation group were significantly better than those in control group, and there were statistical differences ( P<0.05). The duration of auxiliary ventilation, utilization rate of mechanical ventilation, incidence of complication in observation group were significantly lower than those in control group: (52.41 ± 16.53) h vs. (57.42 ± 17.82) h, 11.36% (5/44) vs. 19.64% (11/56) and 15.91% (7/44) vs. 33.93% (19/56), and there were statistical differences ( P<0.05). Conclusions:BiPhasic tr can effectively improve the oxygenation state, reduce the use rate of mechanical ventilation and carbon dioxide retention, reduce the incidence of complications such as intraventricular hemorrhage and so on in the treatment of RDS premature infants.