Background. Gut barrier dysfunction with alterant mucosal permeability during sepsis is a challenge problem in clinical practice. Intestinal epithelial cells (IECs) are strongly involved in mucosal oxidative stress and inflammatory response. The current study aimed at investigating the effect of MitoQ, a mitochondrial targeted antioxidant, in the treatment of intestinal injury and its potential mechanism during sepsis. Methods. 30 minutes before sepsis induction by lipopolysaccharide (LPS) treatment, mice were treated with MitoQ. Intestinal histopathology, mucosal permeability, inflammatory cytokines, and mucosal barrier proteins were evaluated in the present study. Results. MitoQ pretreatment significantly decreased the levels of plasma diamine oxidase, D-lactate, and intestinal histological damage and markedly restored the levels of tight junction proteins (ZO-1 and occludin) following LPS challenge. Furthermore, MitoQ inhibited the LPS-induced intestinal oxidative stress and inflammatory response, evidenced by increased levels of intestinal superoxide dismutase and glutathione, and decreased levels of intestinal IL-1, IL-6, TNF-α, and nitric oxide levels. Mechanically, we found that MitoQ inhibited the oxidative stress via activating nuclear factor E2-related factor 2 (Nrf2) signaling pathway and its downstream antioxidant genes, including HO-1, NQO-1, and GCLM. Conclusions. MitoQ exerts antioxidative and anti-inflammatory effects against sepsis-associated gut barrier injury by promoting Nrf2 signaling pathway.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Understanding the influence of mutations in the SARS-CoV-2 gene on clinical outcomes is critical for treatment and prevention. Here, we analyzed all high-coverage complete SARS-CoV-2 sequences from GISAID database from January 1, 2020, to January 1, 2021, to mine the mutation hotspots associated with clinical outcome and developed a model to predict the clinical outcome in different epidemic strains. Exploring the cause of mutation based on RNA-dependent RNA polymerase (RdRp) and RNA-editing enzyme, mutation was more likely to occur in severe and mild cases than in asymptomatic cases, especially A > G, C > T, and G > A mutations. The mutations associated with asymptomatic outcome were mainly in open reading frame 1ab (ORF1ab) and N genes; especially R6997P and V30L mutations occurred together and were correlated with asymptomatic outcome with high prevalence. D614G, Q57H, and S194L mutations were correlated with mild and severe outcome with high prevalence. Interestingly, the single-nucleotide variant (SNV) frequency was higher with high percentage of nt14408 mutation in RdRp in severe cases. The expression of ADAR and APOBEC was associated with clinical outcome. The model has shown that the asymptomatic percentage has increased over time, while there is high symptomatic percentage in Alpha, Beta, and Gamma. These findings suggest that mutation in the SARS-CoV-2 genome may have a direct association with clinical outcomes and pandemic. Our result and model are helpful to predict the prevalence of epidemic strains and to further study the mechanism of mutation causing severe disease.

Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://www.youtube.com/watch?v=vyHEYxL16_M Background: Treatment of castration-resistant prostate cancer (CRPC) is an enormous challenge. As E2F transcription factor 1 (E2F1) is an essential factor in CRPC, this study investigated the genes and pathways controlled by E2F1 and their effects on cellular behavior in CRPC. Methods: In vitro assays were used to evaluate cellular proliferation, apoptosis, and behavior. Cellular expression was quantified by RNA sequencing (RNA-seq). Gene coexpression was assessed using the GeneMANIA database, and correlations were analyzed with the GEPIA server. Altered pathways of differentially expressed genes (DEGs) were revealed by functional annotation. Module analysis was performed using the STRING database and hub genes were filtered with the Cytoscape software. Some DEGs were validated by real-time quantitative PCR (RT-qPCR). Results: Knockdown of E2F1 significantly inhibited proliferation and accelerated apoptosis in PC3 cells but not in DU145 cells. Invasion and migration were reduced for both cell lines. A total of 1811 DEGs were identified in PC3 cells and 27 DEGs in DU145 cells exhibiting E2F1 knockdown. Ten overlapping DEGs, including TMOD2 and AIF1L, were identified in both knockdown cell lines and were significantly enriched for association with actin filament organization pathways. TMOD2 and KREMEN2 were genes co-expressed with E2F1; six overlapping DEGs were positively correlated with transcription factor E2F1. DEGs of the PC3 and DU145 groups were associated with multiple pathways. Five DEGs that overlapped between the two cell lines and three hub DEGs from PC3 cells were validated by RT-qPCR. Conclusion: The results of this study suggest that E2F1 has a critical role in regulating actin filaments, as indicated by the change in expression level of several genes, including TMOD2 and AIF1L, in CRPC. This extends our understanding of the cellular responses affected by E2F1 in CRPC.

BackgroundPhenomics provides new technologies and platforms as a systematic phenome-genome approach. However, few studies have reported on the systematic mining of shared genetics among clinical biochemical indices based on phenomics methods, especially in China. This study aimed to apply phenomics to systematically explore shared genetics among 29 biochemical indices based on the Fangchenggang Area Male Health and Examination Survey cohort.ResultA total of 1999 subjects with 29 biochemical indices and 709,211 single nucleotide polymorphisms (SNPs) were subjected to phenomics analysis. Three bioinformatics methods, namely, Pearson’s test, Jaccard’s index, and linkage disequilibrium score regression, were used. The results showed that 29 biochemical indices were from a network. IgA, IgG, IgE, IgM, HCY, AFP and B12 were in the central community of 29 biochemical indices. Key genes and loci associated with metabolism traits were further identified, and shared genetics analysis showed that 29 SNPs (P < 10− 4) were associated with three or more traits. After integrating the SNPs related to two or more traits with the GWAS catalogue, 31 SNPs were found to be associated with several diseases (P < 10− 8). Using ALDH2 as an example to preliminarily explore its biological function, we also confirmed that the rs671 (ALDH2) polymorphism affected multiple traits of osteogenesis and adipogenesis differentiation in 3 T3-L1 preadipocytes.ConclusionAll these findings indicated a network of shared genetics and 29 biochemical indices, which will help fully understand the genetics participating in biochemical metabolism.

Background Trachypithecus leucocephalus, the white-headed langur, is a critically endangered primate that is endemic to the karst mountains in the southern Guangxi province of China. Studying the genomic and transcriptomic mechanisms underlying its local adaptation could help explain its persistence within a highly specialized ecological niche. Results In this study, we used PacBio sequencing and optical assembly and Hi-C analysis to create a high-quality de novo assembly of the T. leucocephalus genome. Annotation and functional enrichment revealed many genes involved in metabolism, transport, and homeostasis, and almost all of the positively selected genes were related to mineral ion binding. The transcriptomes of 12 tissues from three T. leucocephalus individuals showed that the great majority of genes involved in mineral absorption and calcium signaling were expressed, and their gene families were significantly expanded. For example, FTH1 primarily functions in iron storage and had 20 expanded copies. Conclusions These results increase our understanding of the evolution of alkali tolerance and other traits necessary for the persistence of T. leucocephalus within an ecologically unique limestone karst environment.