生物学最新文献

Cirrhosis is a form of end-stage liver disease characterized by extensive hepatic fibrosis and loss of liver parenchyma. It is most commonly the result of long-term alcohol abuse in the United States. Large animal models of cirrhosis, as well as of one of its common long-term sequelae, HCC, are needed to study novel and emerging therapeutic interventions. In the present study, liver fibrosis was induced in the Oncopig cancer model, a large animal HCC model, via intrahepatic, intra-arterial ethanol infusion. Liver sections from five fibrosis induced and five age-matched controls were harvested for RNA-seq (mRNA and lncRNA), small RNA-seq (miRNA), and reduced representation bisulfite sequencing (RRBS; DNA methylation). Single- and multi-omic analysis was performed to investigate the transcriptomic and epigenomic mechanisms associated with fibrosis deposition in this model. A total of 3,439 genes, 70 miRNAs, 452 lncRNAs, and 7,715 methylation regions were found to be differentially regulated through individual single-omic analysis. Pathway analysis indicated differentially expressed genes were associated with collagen synthesis and turnover, hepatic metabolic functions such as ethanol and lipid metabolism, and proliferative and anti-proliferative pathways including PI3K and BAX/BCL signaling pathways. Multi-omic latent variable analysis demonstrated significant concordance with the single-omic analysis. lncRNA's associated with UHRF1BP1L and S1PR1 genes were found to reliably discriminate the two arms of the study. These genes were previously implicated in human cancer development and vasculogenesis, respectively. These findings support the validity and translatability of this model as a useful preclinical tool in the study of alcoholic liver disease and its treatment.

Chronic kidney and urinary tract diseases, including glomerulonephritis, nephrotic syndrome, and chronic kidney disease (CKD), present significant global health challenges. Recent studies suggest a complex interplay between infectious pathogens and immune-mediated kidney damage. This study employs Generalized Summary data-based Mendelian Randomization (GSMR) to explore causal relationships between pathogen-derived antibodies and major urinary and kidney diseases.We conducted a two-sample MR analysis using summary statistics from large-scale Genome-Wide Association Studies (GWAS) to assess associations between 46 pathogen-specific antibodies and seven urinary system diseases. We utilized robust statistical methods, including inverse variance weighting, to ascertain causal effects while controlling for potential confounders.Significant associations were identified between several pathogen-specific antibodies and disease risk. Notably, Epstein-Barr virus (EBNA-1) antibody levels were inversely associated with glomerulonephritis and nephrotic syndrome, indicating a potential protective effect. Conversely, Anti-Merkel cell polyomavirus IgG seropositivity was linked to increased risks of CKD and glomerulonephritis. Additionally, immune-mediated mechanisms were highlighted, with certain antibodies exhibiting dual roles as risk factors or protective agents.This study underscores the complex role of pathogen antibodies in the pathogenesis of kidney and urinary tract diseases, revealing significant implications for future research and potential therapeutic strategies. The findings advocate for further investigation into specific pathogen interactions with the immune system, aiming to inform targeted interventions.

Cervical cancer is a leading cause of cancer-related deaths, with cervical squamous cell carcinoma (CSCC) accounting for a majority of cases. Circular RNAs (circRNAs) have been repeatedly suggested as crucial effectors in modulating the development of multiple malignancies. The expression of circ_0002762 was predicted to be high in CSCC tissues in GEO dataset, but the functional role and underlying regulatory mechanism of circ_0002762 in CSCC was unclear. By series of functional assays and mechanism assays, supported by bioinformatics analysis, reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) analysis and western blot assays, we identified that circ_0002762 aberrantly up-regulated in CSCC, promoting CSCC cell migration and invasion. Mechanically, circ_0002762 was transcriptionally activated by Fork head box A1 (FOXA1). Moreover, the involvement of nuclear factor kappa B (NF-kB) signalling in circ_0002762 regulation mechanism in CSCC cells was ascertained. Additionally, circ_0002762, predominantly accumulated in cell cytoplasm, was proved to recruit Mov10 RISC complex RNA helicase (MOV10) to enhance RelA mRNA stability, thus affecting CSCC cell migration and invasion. In summary, FOXA1-mediated circ_0002762 up-regulation could enhance the migratory and invasive abilities of CSCC cells via the MOV10/RelA/NF-kB pathway.

Severe dengue often presents as shock syndrome with enhanced vascular permeability and plasma leakage into tissue spaces. In vitro studies have documented the role of Src family kinases (SFKs) and RhoA-kinases (ROCK) in dengue virus serotype 2 (DENV2)-induced endothelial permeability. Here, we show that the FDA-approved SFK inhibitors Bosutinib, Vandetanib and Ponatinib, as well as the ROCK inhibitors, Netarsudil and Ripasudil significantly inhibit DENV2-induced endothelial permeability. In cultured telomerase immortalized human microvascular endothelial cells (HMEC-1), treatment with these inhibitors reduced the phosphorylation of VE-Cadherin, Src and myosin light chain 2 (MLC2) proteins that were upregulated during DENV2 infection. It also prevented the loss of VE-Cadherin from the inter-endothelial cell junctions induced by viral infection. In in-vivo studies using DENV2-infected AG129 IFN receptor-α/β/γ deficient mice, ponatinib, when administered 24 h post-infection onwards, demonstrated significant benefits in improving body weight, clinical outcomes, and survival rates. While all virus-infected, untreated mice died by day-10 post-infection, 80% of the ponatinib-treated mice survived, and approximately 60% were still alive at the end of the 15-day observation period. The treatment also significantly reduced disease severity factors such as vascular leakage, thrombocytopenia; mRNA transcript levels of proinflammatory cytokines such as IL-1β and TNF-α; and restored liver function. Comparable effects were observed even when ponatinib treatment was initiated after symptom onset. The results highlight ponatinib as an effective therapeutic option in severe dengue; and also a similar potential for other FDA- approved SFK and ROCK inhibitors.

Porcine deltacoronavirus (PDCoV) is increasingly prevalent in newborn piglets with diarrhea. With the development of research on the virus and the feasibility of PDCoV cross-species transmission, the biosafety and the development of pig industry have been greatly affected. In this study, a PDCoV strain CH/LNFX/2022 was isolated from diarrheal newborn piglets at a farm in China. A genome-wide based phylogenetic analysis suggests that 97.5% to 99.2% homology existed in the whole genomes of other strains. Five amino acid mutations are seen for the first time in the S protein. By constructing 3D models, it was found that the S1-NTD/CTD and S2-HR-C regions produced structural alterations. Protein functional analysis showed that the structural changes of the three regions changed the epitope of S protein, the O-GalNAc glycosylation site and the 3C-like protease cleavage site. In addition, oral administration of 10⁷ TCID₅₀ CH/LNFX/2022 to newborn piglets successfully reproduced obvious clinical signs of piglets, such as diarrhea and dehydration. Meanwhile, PDCoV antigen was detected by immunofluorescence in the small intestine, and microscopic lesions and intestinal mucosal barrier destruction were detected by histological observation and scanning electron microscopy. Our study confirmed that porcine coronavirus strains increased pathogenicity through evolution, damaged the intestinal barrier of newborn piglets, and caused diarrhea in pigs. This study provided the candidate strains and theoretical basis for establishing the prevention and control system of vaccine and diagnostic methods for piglet diarrhea.

In this paper, we establish a compartmental model in which the transmission rate is associated with the fear of being infected by COVID-19. We provide a detailed analysis of the epidemic model and established results for the existence of a positively invariant set. The expression of the basic reproduction number $R_0$ is characterized. It is shown that the disease-free equilibrium (DFE) is globally asymptotically stable if $R_0<1$, and the system exhibits a forward bifurcation if $R_0=1$. When $R_0>1$, the system is uniformly persistent, the DFE is unstable and there exists a unique and globally asymptotic stable endemic equilibrium (EE). We fit unknown parameters using the reported data in Canada from September 1 to October 10, 2021, and carry out sensitivity analysis. The quantitative analysis of the model with awareness demonstrates the significance of reducing the transmission rate and enhancing public protective awareness.

Immune cell infiltration into adipose tissue (AT) is a key factor in type 2 diabetes (T2DM). However, research on the impact of fat distribution on immune cells and immune responses in women is still lacking. This study used enrichment, protein-protein interaction network, immune cell infiltration, and correlation analysis to compare the similarities and differences between the transcriptome data of visceral AT (VAT) and subcutprotein-proteinaneous AT (SAT) obtained from the omprehensive database of gene expression in women with non-T2DM and T2DM. DEGs with the same biological function in two types of ATs often exhibited different expression trends. SharedVAT-specific and SAT-specific hub genes were mainly associated with transcription factors, monocyte-macrophage markers, and chemokines, respectively. Immune cells affected by both AT types included monocytes, granulocytes, T and B lymphocytes, and NK cells. VAT affected more immune cells, mainly myeloid cells. Shared hub genes in VAT correlated positively with M1 macrophages, suggesting pro-inflammatory effects, while those in SAT correlated negatively with M1 macrophages and lymphocytes, suggesting anti-inflammatory effects. This study provides a theoretical basis for further understanding the correlation between AT and T2DM in women.

Transfer RNA (tRNA) is one of the most abundant RNA types in cells, acting as an adaptor to bridge the genetic information in mRNAs with the amino acid sequence in proteins. Both tRNAs and small fragments processed from them play many nonconventional roles in addition to translation. tRNA molecules undergo various types of chemical modifications to ensure the accuracy and efficiency of translation and regulate their diverse functions beyond translation. In this review, we discuss the biogenesis and molecular mechanisms of tRNA modifications, including major tRNA modifications, writer enzymes, and their dynamic regulation. We also summarize the state-of-the-art technologies for measuring tRNA modification, with a particular focus on 2'-O-methylation (Nm), and discuss their limitations and remaining challenges. Finally, we highlight recent discoveries linking dysregulation of tRNA modifications with genetic diseases.

We studied the viromes of three dominant mosquito species in Wenzhou, a coastal city in Zhejiang Province, using metavirome sequencing, with 18 viral families identified. Viral sequences were verified by RT-PCR. The JEV E gene was most closely related to the 1988 Korean strain. DENV sequences were most closely related to the 1997 Australian strain. CHIKV-E1-1 was most closely related to the 1983 Senegal strain and belonged to West African genotype CHIKV. Remarkably, this is the first time that a West African genotype of CHIKV has been detected in Zhejiang Province. Mutations in the CHIKV-E1-1 protein A226V may increase infectivity in Ae. albopictus. Three non-conservative mutations of CHIKV-E1-1 (D45H, D70H and V290D) may have an impact on the function. In conclusion, our study reveals the diversity of mosquito-borne viruses and potential emerging outbreaks in the southeast coastal region of China, providing new perspectives for mining the ecological characterization of other important arboviruses.

Objectives: Bone remodeling imbalance contributes to osteoporosis. Though current medications enhance osteoblast involvement in bone formation, the underlying pathways remain unclear. This study was aimed to explore the pathways involved in bone formation by osteoblasts, we investigate the protective role of glycolysis and N6-methyladenosine methylation (m6A) against oxidative stress-induced impairment of osteogenesis in MC3T3-E1 cells.

Methods: We utilized a concentration of 200 μM hydrogen peroxide (H₂O₂) to establish an oxidative damage model of MC3T3-E1 cells. Subsequently, we examined the alterations in the m6A methyltransferases (METTL3, METTL14), glucose transporter proteins (GLUT1, GLUT3) and validated m6A methyltransferase overexpression in vitro and in an osteoporosis model. The osteoblast differentiation and osteogenesis-related molecules and serum bone resorption markers were measured by biochemical analysis, Alizarin Red S staining, Western blot and ELISA.

Results: H₂O₂ treatment inhibited glycolysis and osteoblast differentiation in MC3T3-E1 cells. However, when METTL14 was overexpressed, these changes induced by H₂O₂ could be mitigated. Our findings indicate that METTL14 promotes GLUT3 expression via YTHDF1, leading to the modulation of various parameters in the H₂O₂-induced model. Similar positive effects of METTL14 on osteogenesis were observed in an ovariectomized mouse osteoporosis model.

Discussion: METTL14 could serve as a potential therapeutic approach for enhancing osteoporosis treatment.