A hnRNPA2B1 agonist effectively inhibits HBV and SARS-CoV-2 omicron in vivo.

The twenty-first century has already recorded more than ten major epidemics or pandemics of viral disease, including the devastating COVID-19. Novel effective antivirals with broad-spectrum coverage are urgently needed. Herein, we reported a novel broad-spectrum antiviral compound PAC5. Oral administration of PAC5 eliminated HBV cccDNA and reduced the large antigen load in distinct mouse models of HBV infection. Strikingly, oral administration of PAC5 in a hamster model of SARS-CoV-2 omicron (BA.1) infection significantly decreases viral loads and attenuates lung inflammation. Mechanistically, PAC5 binds to a pocket near Asp49 in the RNA recognition motif of hnRNPA2B1. PAC5-bound hnRNPA2B1 is extensively activated and translocated to the cytoplasm where it initiates the TBK1-IRF3 pathway, leading to the production of type I IFNs with antiviral activity. Our results indicate that PAC5 is a novel small-molecule agonist of hnRNPA2B1, which may have a role in dealing with emerging infectious diseases now and in the future.

Uncertainty analysis of vehicle-pedestrian accident reconstruction based on unscented transformation.

In order to investigate the sensitivity of parameters and analyze the uncertainty of reconstructed results in traffic accident, the impact of correlations between parameters on accident reconstruction results was taken into account using uncertainty analysis. Based on unscented transformation (UT), a parameter sensitivity analysis method and an efficient uncertainty analysis method in accident reconstruction were proposed. Sensitivity analysis was performed through the sigma point sets generated by the UT method. A first-order response surface model was constructed to analyze the sensitivity of accident reconstruction parameters combined with regression analysis, which is more flexible and controllable than the general experimental design. For the uncertainty analysis of the reconstructed results, the other methods have been used to demonstrate the validity of the proposed method, including the first second-order method of moments (FOSM), the uncertainty theory, and the Monte Carlo (MC) methods, through analyzing the numerical and real-world cases. The results show that the presented method has high accuracy, significantly reduces the computational burden, and does not depend on the distribution type of variables. When considering the effect of the correlation between parameters of the vehicle-pedestrian crash on accident reconstruction results, the results show that the correlation coefficient between random variables had a much more significant impact on the standard deviation of vehicle speed than on the mean value of vehicle speed. Regardless of negative or positive correlations, the relative error of standard deviation of vehicle speed increased continuously as the correlation increased, reaching 52%. The proposed method is effective and reliable for vehicle collision accident reconstruction under uncertainty and correlation, which can provide more comprehensive information in accident reconstruction.

Mannan-binding lectin deficiency augments hepatic endoplasmic reticulum stress through IP3R-controlled calcium release.

The aberrant release of endoplasmic reticulum (ER) calcium leads to the disruption of intracellular calcium homeostasis, which is associated with the occurrence of ER stress and closely related to the pathogenesis of liver damage. Mannan-binding lectin (MBL) is a soluble calcium-dependent protein synthesized primarily in hepatocytes and is a pattern recognition molecule in the innate immune system. MBL deficiency is highly prevalent in the population and has been reported to be associated with susceptibility to several liver diseases. We here showed that genetic MBL ablation strongly sensitized mice to ER stress-induced liver injury. Mechanistic studies established that MBL directly interacted with ER-resident chaperone immunoglobulin heavy chain binding protein (BiP), and MBL deficiency accelerated the separation of PKR-like ER kinase (PERK) from BiP during hepatic ER stress. Moreover, MBL deficiency led to enhanced activation of the PERK-C/EBP-homologous protein (CHOP) pathway and initiates an inositol 1,4,5-trisphosphate receptor (IP3R)-mediated calcium release from the ER, thereby aggravating the hepatic ER stress response. Our results demonstrate an unexpected function of MBL in ER calcium homeostasis and ER stress response, thus providing new insight into the liver injury related to ER stress in patients with MBL deficiency.

Omega­3 polyunsaturated fatty acids inhibit IL­11/STAT3 signaling in hepatocytes during acetaminophen hepatotoxicity.

Omega­3 polyunsaturated fatty acids (n­3 PUFAs) exert a negative effect on IL­6 production in several liver disorders, including cirrhosis, acute liver failure and fatty liver disease. However, its effect on the production of IL­11, another important IL­6 family cytokine, remains unclear. IL­11 was found to be significantly elevated in acetaminophen (APAP)­induced liver damage. The aim of the present study was to investigate whether and how n­3 PUFAs modulate IL­11 production during APAP­induced liver injury. For that purpose, wild­type (WT) and fat­1 transgenic mice were intraperitoneally injected with APAP to induce liver injury. Serum was collected for ELISA and alanine aminotransferase assay. The hepatocytes of APAP­injected mice were isolated for reverse transcription­quantitative PCR and western blot analyses. For the in vitro study, primary hepatocytes isolated from WT or fat­1 mice were stimulated with APAP. The results revealed that both endogenous and exogenous n­3 PUFAs significantly aggravated APAP­induced liver damage via the downregulation of STAT3 signaling. Notably, n­3 PUFAs inhibited IL­11 expression, but not IL­6 expression in hepatocytes during the APAP challenge. Furthermore, it was demonstrated that limited phosphorylation of ERK1/2 and Fos­â€‹like­1 (Fra­1) expression are responsible for the n­3 PUFA­mediated inhibitory effect on IL­11 production in APAP­treated hepatocytes. It was concluded that n­3 PUFAs inhibit IL­11 production and further STAT3 activation in hepatocytes during APAP­induced liver injury. Therefore, ERK1/2­mediated Fra­1 expression is responsible for the effect of n­3 PUFAs on IL­11 expression.