Clinical and genetic study of ABCB4 gene-related cholestatic liver disease in China: children and adults.

BACKGROUND: ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. The correlation between genotype and clinical phenotype still unclear. This study retrospectively analyzed the clinical and pathological characteristics of 23 patients with ABCB4 gene-related cholestatic liver diseases. Next-generation sequencing was used to identify the genetic causes. RESULTS: The 23 included patients (15 children and 8 adults) were diagnosed as progressive familial intrahepatic cholestasis type 3 (PFIC3), drug-induced liver injury (DILI), cirrhosis cholestasis, cirrhosis, and mild liver fibrosis. Nineteen patients underwent liver pathological examination of the liver, exhibiting fibrosis, small bile duct hyperplasia, CK7(+), Cu(+), bile duct deletion, and cirrhosis. Thirty ABCB4 variants were identified, including 18 novel variants. CONCLUSION: ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. Biallelic ABCB4 mutation carriers tended to severe PFIC3, which mostly occurs in children; while ABCB4 non-biallelic variants can lead to milder ICP, LACP, DILI or overlapping, mostly in adults. Thus, the ABCB4 genotype has a specific correlation with the phenotype, but there are exceptions. Non-biallelic null mutations can cause severe diseases. The mechanisms underlying this genetic phenotype require further investigation.

Development and Validation of a Machine Learning-Based Model Used for Predicting Hepatocellular Carcinoma Risk in Patients with Hepatitis B-Related Cirrhosis: A Retrospective Study.

Object: Our objective was to estimate the 5-year cumulative risk of HCC in patients with HBC by utilizing an artificial neural network (ANN). Methods: We conducted this study with 1589 patients hospitalized at Beijing Ditan Hospital of Capital Medical University and People's Liberation Army Fifth Medical Center. The training cohort consisted of 913 subjects from Beijing Ditan Hospital of Capital Medical University, while the validation cohort comprised 676 subjects from People's Liberation Army Fifth Medical Center. Through univariate analysis, we identified factors that independently influenced the occurrence of HCC, which were then used to develop the ANN model. To evaluate the ANN model, we assessed its predictive accuracy, discriminative ability, and clinical net benefit using metrics such as the area under the receiver operating characteristic curve (AUC), concordance index (C-index), calibration curves. Results: In total, we included nine independent risk factors in the development of the ANN model. Remarkably, the AUC of the ANN model was 0.880, significantly outperforming the AUC values of other existing models including mPAGE-B (0.719) (95% CI 0.670-0.768), PAGE-B (0. 710) (95% CI 0.660-0.759), FIB-4 (0.693) (95% CI 0.640-0.745), and Toronto hepatoma risk index (THRI) (0.705) (95% CI 0.654-0.756) (p<0.001 for all). The ANN model effectively stratified patients into low, medium, and high-risk groups based on their 5-year In the training cohort, the positive predictive value (PPV) for low-risk patients was 26.2% (95% CI 25.0-27.4), and the negative predictive value (NPV) was 98.7% (95% CI 95.2-99.7). For high-risk patients, the PPV was 54.7% (95% CI 48.6-60.7), and the NPV was 91.6% (95% CI 89.4-93.4). These findings were validated in the independent validation cohort. Conclusion: The ANNs model has good individualized prediction performance and may be helpful to evaluate the probability of the 5-year risk of HCC in patients with HBC.

Functional cure is associated with younger age in children undergoing antiviral treatment for active chronic hepatitis B.

BACKGROUND AND AIMS: Functional cure is difficult to achieve using current antiviral therapies; moreover, limited data are available regarding treatment outcomes in children. This retrospective study aimed to assess the frequency of functional cure among children undergoing antiviral treatment for active chronic hepatitis B (CHB). METHODS: A total of 372 children aged 1-16 years, with active CHB were enrolled and underwent either nucleos(t)ide analog monotherapy or combination therapy with interferon-α (IFN-α) for 24-36 months. All children attended follow-up visits every 3 months. Functional cure was defined as evidence of hepatitis B virus (HBV) DNA loss, circulating hepatitis B e antigen (HBeAg) loss/seroconversion, and hepatitis B surface antigen (HBsAg) loss. RESULTS: After 36 months of antiviral treatment and/or follow-up visits, children with CHB aged 1- < 7 years exhibited higher rates of HBV DNA clearance, HBeAg seroconversion, and HBsAg loss than CHB children ≥ 7-16 years of age (93.75% versus [vs.] 86.21% [p < 0.0001]; 79.30% vs. 51.72% [p < 0.0001]; and 50.78% vs. 12.93% [p < 0.0001], respectively). Longitudinal investigation revealed more rapid dynamic reduction in HBV DNA, HBeAg, and HBsAg levels in children aged 1-7 years than in those aged ≥ 7-16 years with CHB. According to further age-stratified analysis, HBsAg loss rates were successively decreased in children with CHB who were 1- < 3, 3- < 7, 7- < 12, and 12-16 years of age (62.61% vs. 41.13% vs. 25.45% vs. 1.64%, respectively; p < 0.0001) at 36 months. In addition, baseline HBsAg level < 1,500 IU/mL was found to favor disease cure among these pediatric patients. No serious adverse events were observed throughout the study period. CONCLUSION: Results of the present study demonstrated that children aged 1- < 7 years, with active CHB can achieve a high functional cure rate by undergoing antiviral therapy compared to those aged ≥ 7 years, who undergo antiviral therapy. These data support the use of antiviral treatment at an early age in children with CHB. However, future prospectively randomized controlled trials are necessary to validate the findings of this study.

A review of studies on the implication of NLRP3 inflammasome for Parkinson's disease and related candidate treatment targets.

Parkinson's disease (PD) is a neurodegenerative disease for which the prevalence is second only to Alzheimer's disease (AD). This disease primarily affects people of middle and old age, significantly impacting their health and quality of life. The main pathological features include the degenerative nigrostriatal dopaminergic (DA) neuron loss and Lewy body (LB) formation. Currently, available PD medications primarily aim to alleviate clinical symptoms, however, there is no universally recognized therapy worldwide that effectively prevents, clinically treats, stops, or reverses the disease. Consequently, the evaluation and exploration of potential therapeutic targets for PD are of utmost importance. Nevertheless, the pathophysiology of PD remains unknown, and neuroinflammation mediated by inflammatory cytokines that prompts neuron death is fundamental for the progression of PD. The nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is a key complex of proteins linking the neuroinflammatory cascade in PD. Moreover, mounting evidence suggests that traditional Chinese medicine (TCM) alleviates PD by suppressing the NLRP3 inflammasome. This article aims to comprehensively review the available studies on the composition and activating mechanism of the NLRP3 inflammasome, along with its significance in PD pathogenesis and potential treatment targets. We also review natural products or synthetic compounds which reduce neuroinflammation via modulating NLRP3 inflammasome activity, aiming to identify new targets for future PD diagnosis and treatment through the exploration of NLRP3 inhibitors. Additionally, this review offers valuable references for developing new PD treatment methods.

Functional Cure of Chronic Hepatitis B with Antiviral Treatment in Children having High-level Viremia and Normal or Mildly Elevated Serum Aminotransferase.

Background and Aims: There is a lack of data supporting the notion that antiviral treatments can benefit children with chronic hepatitis B (CHB) having high viremia and normal or mildly elevated serum alanine aminotransferase (ALT) levels. We aimed to analyze the efficacy of antiviral treatments in children with CHB and explore the factors associated with functional cure. Methods: Forty-eight children with CHB having high viremia and normal or mildly elevated serum ALT levels were screened in this real-world study. Thirty-two children received either interferon-alpha (IFN-α) monotherapy, IFN-α therapy with a nucleoside analog (NA) add-on, or IFN-α and NA combination therapy. The 16 children in the control group did not receive antiviral treatment. All 48 children were available for follow-up assessments for the entire 36-month study period. We identified a functional cure with respect to hepatitis B virus (HBV) DNA loss, loss /seroconversion of circulating hepatitis B e antigen (HBeAg), and loss of hepatitis B surface antigen (HBsAg) with or without seroconversion. Cox regression analysis was employed to evaluate the factors that may have influenced the functional cure. Results: After 36 months, the cumulative functional cure rate was 56.25% (18/32) in the treated group and 0% (0/16) in the control group (p<0.001). In the treated group, the serum HBV DNA levels declined rapidly at the end of a 6-month visit and the cured children achieved a loss rate of 100% (18/18) within 16 months of beginning treatment, compared with 64.29% (9/14) of the uncured children (p<0.001). The rates of HBeAg seroconversion were significantly higher among the cured children than among the uncured children (p<0.001). All 16 children in the control group maintained high levels of serum HBV DNA and were positive for both serum HBeAg and HBsAg during the entire 36 months of the study period. Functional cure was associated with younger ages (1-6 vs. 7-14 years, p=0.013), CD8+ T lymphocyte counts (p=0.013), and B lymphocyte counts (p=0.003). No serious adverse events were observed. Conclusions: Antiviral treatment achieved a functional cure of CHB in a high proportion of children having high-level viremia and normal or mildly elevated ALT levels. Younger age and high peripheral lymphocyte counts were associated with this functional cure.

Cdk5 phosphorylation-dependent C9orf72 degradation promotes neuronal death in Parkinson's disease models.

AIMS: Chromosome 9 open reading frame 72 (C9orf72) is one of the most dazzling molecules in neurodegenerative diseases, albeit that its role in Parkinson's disease (PD) remains unknown. This article aimed to explore the potential mechanism of C9orf72 involved in the pathogenesis of PD. METHODS: The expression and phosphorylation levels of C9orf72 were examined by Western blotting, RT-PCR, and immunoprecipitation using PD models. Multiple bioinformatics software was used to predict the potential phosphorylation sites of C9orf72 by Cdk5, followed by verification of whether Cdk5-inhibitor ROSCOVITINE could reverse the degradation of C9orf72 in PD. By constructing the sh-C9orf72-knockdown adenovirus and overexpressing the FLAG-C9orf72 plasmid, the effects of C9orf72 knockdown and overexpression, respectively, were determined. A short peptide termed Myr-C9orf72 was used to verify whether interfering with Cdk5 phosphorylation at the Ser9 site of the C9orf72 protein could alleviate autophagy disorder, neuronal death, and movement disorder in PD models. RESULTS: The expression level of the C9orf72 protein was significantly reduced, albeit the mRNA expression was not changed in the PD models. Moreover, the phosphorylation level was enhanced, and its reduction was mainly degraded by the ubiquitin-proteasome pathway. The key nervous system kinase Cdk5 directly phosphorylated the S9 site of the C9orf72 protein, which promoted the degradation of the C9orf72 protein. The knockdown of C9orf72 aggravated autophagy dysfunction and increased neuronal loss and motor dysfunction in substantia nigra neurons of PD mice. The overexpression of C9orf72 alleviated autophagy dysfunction in PD neurons. Specifically, interference with Cdk5 phosphorylation at the S9 site of C9orf72 alleviated autophagy dysfunction, neuronal death, and motor dysfunction mediated by C9orf72 protein degradation during PD. CONCLUSIONS: Cumulatively, our findings illustrate the importance of the role of C9orf72 in the regulation of neuronal death during PD progression via the Cdk5-dependent degradation.

Equilibrative nucleoside transporter 3 promotes the progression of hepatocellular carcinoma by regulating the AKT/mTOR signaling pathway.

Equilibrative nucleoside transporter 3 (ENT3) belongs to the solute carrier family 29. Nucleoside transporters encoded by ENT3 play an important role in the uptake of nucleosides, nucleobases, and their nucleoside analogs, as well as participate in and regulate several physiological activities. However, no study has so far reported the role of ENT3 in hepatocellular carcinoma (HCC). We employed bioinformatics to analyze the expression, prognosis, and mechanism of ENT3 in HCC, as well as verified the same through biological experiments including cell proliferation, cell migration and invasion, and cell cycle and apoptosis, along with the detection of the AKT/mTOR protein expression in the pathway by Western blotting. ENT3 was widely and highly expressed in pan-cancer and upregulated in HCC. The upregulated ENT3 was related to the poor prognosis and clinical features in HCC patients. ENT3 knockdown inhibited cell proliferation, migration, and invasion and promoted cell apoptosis. ENT3 knockdown reduced the p-AKT and p-mTOR protein phosphorylation level, inhibited p-p70S6K1 and increased the p-4EBP1-the downstream effector of the AKT/mTOR pathway-protein phosphorylation level. Our study findings demonstrated that the expression of ENT3 was upregulated in HCC, which represents a poor prognosis. Thus, ENT3 promotes the progression of HCC through the AKT/mTOR signaling pathway.

Bifidobacterium animalis A12, a Probiotic Strain That Promotes Glucose and Lipid Metabolism, Improved the Texture and Aroma of the Fermented Sausage.

Bifidobacterium animalis A12 was used for the development of fermented sausage. The growth activity, tolerance, and enzyme activity of B. animalis A12 and its contribution to the texture and flavour of fermented sausages were evaluated. Additionally, the sensory texture, flavour components, and amino acid nutrients during the fermentation process were assessed. B. animalis had high tolerance to NaCl and nitrite, and B. animalis A12 had protease and lipase activities. The pH value of sausage fermented with B. animalis A12 was lower than that of sausage fermented without any fermentation strain. Hexanal, heptanal, decanal, cis-2-decanal, and 4-methoxy-benzaldehyde are the unique aldehydes flavour components of fermented sausages in the A12 group. The highest content of volatile flavour substances and amino acids, and the color and texture characteristics of fermented sausage in the experimental group at 18 h were better than those at other times. These results suggest that B. animalis A12 has the potential to be used as a starter culture for im-proving flavour and texture in fermented sausage.

Succinate dehydrogenase complex subunit C: Role in cellular physiology and disease.

Succinate dehydrogenase complex subunit C (SDHC) is a subunit of mitochondrial complex II (MCII), which is also known as succinate dehydrogenase (SDH) or succinate: ubiquinone oxidoreductase. Mitochondrial complex II is the smallest respiratory complex in the respiratory chain and contains four subunits. SDHC is a membrane-anchored subunit of SDH, which connects the tricarboxylic acid cycle and the electron transport chain. SDH regulates several physiological processes within cells, plays an important role in generating energy to maintain normal cell growth, and is involved in apoptosis. Currently, SDHC is generally recognized as a tumor-suppressor gene. SDHC mutations can cause oxidative damage in the body. It is closely related to the occurrence and development of cancer, neurodegenerative diseases, and aging-related diseases. Here, we review studies on the structure, biological function, related diseases of SDHC, and the mev-1 Animal Model of SDHC Mutation and its potential use as a therapeutic target of certain human diseases.

Cdk5 phosphorylation-induced SIRT2 nuclear translocation promotes the death of dopaminergic neurons in Parkinson's disease.

NAD-dependent protein deacetylase Sirtuin 2 (SIRT2), which regulates several cellular pathways by deacetylating multiple substrates, has been extensively studied in the context of Parkinson's disease (PD). Although several studies based on the MPTP model of PD show that SIRT2 deletion can protect against dopaminergic neuron loss, the precise mechanisms of SIRT2-mediated neuronal death have largely remained unknown. Here, we show that SIRT2 knockout can effectively ameliorate anomalous behavioral phenotypes in transgenic mouse models of PD. Importantly, in both cellular and animal models of PD, it was observed that SIRT2 translocates from the cytoplasm to the nucleus. Further, the nuclear translocation of SIRT2 promotes neuronal death. Moreover, the cyclin-dependent kinase 5 (Cdk5)-mediated phosphorylation of SIRT2 at the Ser331 and Ser335 sites appears to be necessary for such nuclear translocation. Taken together, the results provide insights into the mechanisms involved in the regulation of neuronal death during PD progression via the Cdk5-dependent nuclear-cytoplasmic shuttling of SIRT2.

The utility of hierarchical genetic testing in paediatric liver disease.

BACKGROUND & AIMS: Genetic factors underlie a substantial proportion of paediatric liver diseases. Hereditary liver diseases have considerable genetic heterogeneity and variable clinical manifestations, which bring great challenges to clinical and molecular diagnoses. In this study, we investigated a group of paediatric patients with varying degrees of liver dysfunction using a hierarchical genetic testing strategy. METHODS: We first applied a panel encompassing 166 known causal genes of liver disease. We then used exome sequencing (ES) in those patients whose cases remained undiagnosed to identify the genetic aetiology of their symptoms. RESULTS: In total, we enrolled 131 unrelated paediatric patients with liver disease of Chinese Han ethnicity. We first applied targeted gene sequencing of 166 genes to all patients and yielded a diagnostic rate of 35.9% (47 of 131). Eighty-four patients who remained undiagnosed after target gene sequencing were subjected to ES. As a result, eight (8/84, 9.5%) of them obtained molecular diagnoses, including four patients suspected of abnormal bilirubin metabolism and four idiopathic cases. Non-typical genetic findings, including digenic inheritance and dual molecular diagnosis, were also identified. Through a comprehensive assessment of novel candidate variants of uncertain disease association, 11 patients of the remaining undiagnosed patients were able to obtain likely molecular diagnoses. CONCLUSIONS: Our study presents evidence for the diagnostic utility of sequential genetic testing in a cohort of patients with paediatric liver disease. Our findings expand the understanding of the phenotypic and mutational spectrum underlying this heterogeneous group of diseases.

Research Progress of Collapse Response Mediator Proteins in Neurodegenerative Diseases.

Collapse response mediator proteins (CRMPs) are a family of cytoplasmic phosphorylated proteins, and the mechanism of action has always been the research focus of neurological diseases. Previous studies on the CRMPs family have revealed that CRMPs mediate the growth and development of neuronal cytoskeleton through different signaling pathways in the body. It plays an important role in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and spinocerebellar ataxia, which has attracted the attention of researchers. This article reviews the recent literature on the biological characteristics and mechanisms of CRMPs in different neurodegenerative diseases.

Socioeconomic and environmental factors of poverty in China using geographically weighted random forest regression model.

Correlations between socioeconomic factors and poverty in regression models do not reflect actual relationships, especially when data exhibit patterns of spatial heterogeneity. Spatial regression models can estimate the relationships between socioeconomic factors and poverty in defined geographical areas, explaining the imbalanced distribution of poverty, but the relationships between these factors and poverty are not always linear however, and conventional simple linear local regression models do not accurately capture these nonlinear relationships. To fill this gap, we used a local regression method, geographically weighted random forest regression (GW-RFR), that integrates a spatial weight matrix (SWM) and random forest (RF). The GW-RFR evaluates the spatial variations in the nonlinear relationships between variables. A county-level poverty data set of China was employed to estimate the performance of the GW-RFR against the random forest (RF). In this poverty application, the value of [Formula: see text] was 0.128 higher than that of the RF, the NRMSE value was 1.6% lower than the RF, and the MAE value was 0.295 lower than the RF. These results showed that the relationship between poverty factors and poverty varies with space at the county level in China, and the GW-RFR was suitable for dealing with nonlinear relationships in local regression analysis.

Inhibition of the TLR/NF-κB Signaling Pathway and Improvement of Autophagy Mediates Neuroprotective Effects of Plumbagin in Parkinson's Disease.

A naphthoquinone molecule known as plumbagin (PL), which has a wide range of pharmacological properties including antitumor, antioxidation, anti-inflammation, and neuroprotective effects, is extracted from the roots of the medicinal herb Plumbago zeylanica L. Plumbagin has been studied for its potential to treat Parkinson's disease (PD). However, its effectiveness and mechanism are still unknown. This study intends to evaluate plumbagin's effectiveness against PD in vitro and in vivo. Plumbagin partially repaired the loss of dopaminergic neurons in the nigral substantia nigra and the resulting behavioural impairment caused by MPTP or MPTP/probenecid in mice. Furthermore, plumbagin treatment significantly inhibited the TLR/NF-κB pathways. It reduced the TNF-α, IL-6, and IL-1ß mRNA expression in PD mice induced by MPTP or MPTP/probenecid, which was consistent with the findings in the inflammatory model of BV2 cells induced by MPP+ or LPS. In addition, plumbagin treatment enhanced the microtubule-associated protein 1 light chain 3 beta (LC3) LC3-II/LC3-I levels while decreasing the p-mTOR and p62 protein accumulation in PD mice induced by MPTP or MPTP/probenecid, which was similar to the results obtained from the experiments in SH-SY5Y and PC12 cells induced by MPP+. Consequently, our results support the hypothesis that plumbagin, by promoting autophagy and inhibiting the activation of the TLR/NF-κB signaling pathway, is a promising treatment agent for treating Parkinson's disease (PD). However, to confirm plumbagin's anti-PD action more thoroughly, other animal and cell PD models must be used in future studies.

Modeling and practical fixed-time attitude tracking control of a paraglider recovery system.

The mathematical modeling and the control problem of the paraglider recovery system (PRS) are investigated in this paper. A 9-degree-of-freedom dynamic model describing the paraglider recovery control system is modeled including the inside relative rotation, the apparent mass, and the payload's time-varying inertia. On the basis of the attitude tracking error system, a novel practical fixed-time attitude tracking control approach is then proposed. The attitude tracking error is governed to converge into the small regions of the origin with a fixed-time convergence rate. Moreover, this rate is independent of any initial states. Simulation results are finally presented to illustrate the PRS performance obtained from the proposed control scheme.

A comprehensive overview of PPM1A: From structure to disease.

PPM1A (magnesium-dependent phosphatase 1 A, also known as PP2Cα) is a member of the Ser/Thr protein phosphatase family. Protein phosphatases catalyze the removal of phosphate groups from proteins via hydrolysis, thus opposing the role of protein kinases. The PP2C family is generally considered a negative regulator in the eukaryotic stress response pathway. PPM1A can bind and dephosphorylate various proteins and is therefore involved in the regulation of a wide range of physiological processes. It plays a crucial role in transcriptional regulation, cell proliferation, and apoptosis and has been suggested to be closely related to the occurrence and development of cancers of the lung, bladder, and breast, amongst others. Moreover, it is closely related to certain autoimmune diseases and neurodegenerative diseases. In this review, we provide an insight into currently available knowledge of PPM1A, including its structure, biological function, involvement in signaling pathways, and association with diseases. Lastly, we discuss whether PPM1A could be targeted for therapy of certain human conditions.

Assessment of liver fibrosis by transient elastography in young children with chronic hepatitis B virus infection.

BACKGROUND: This study aimed to compare the diagnostic accuracy of transient elastography (TE) and biopsy for the detection of liver fibrosis in children with chronic hepatitis B (CHB). METHODS: This single-center prospective study included 157 CHB children aged 0-6 years. All patients underwent liver stiffness measurement (LSM) by TE and liver biopsy, separated by an interval of less than 1 week. RESULTS: The LSM, aspartate aminotransferase-platelet ratio index (APRI), and fibrosis-4 index (FIB-4) were positively correlated with activity grade and fibrosis stage in CHB children. The areas under the receiver operating characteristic curves (AUCs) of LSM for identifying significant (F ≥ 2) and advanced (F ≥ 3) fibrosis were 0.732 and 0.941, respectively. The cut-off values, specificity, and sensitivity for significant fibrosis were 5.6 kPa, 75.7%, and 67.4%, respectively; the corresponding values for advanced fibrosis were 6.9 kPa, 91.5%, and 81.3%, respectively. Compared to LSM, the overall diagnostic performances of APRI and FIB-4 for significant and advanced fibrosis were suboptimal, with low AUCs and sensitivity. Since LSM, platelet, and Log10 (hepatitis B surface antigen) were independent factors associated with the fibrosis stage (F < 2 and F ≥ 2), they were used to formulate the "LPS" index for the prediction of F ≥ 2. The AUC of LPS (for F ≥ 2) was higher than that of LSM (0.792 vs. 0.732, p < 0.05), and had an improved sensitivity (76.6% vs. 67.4%). CONCLUSIONS: TE is a promising technology for the diagnosis of advanced fibrosis in CHB children aged 0-6 years.

The role of mediator complex subunit 19 in human diseases.

Mediator is an evolutionarily conserved multi-protein complex that mediates the interaction between different proteins as a basic linker in the transcription mechanism of eukaryotes. It interacts with RNA polymerase II and participates in the process of gene expression. Mediator complex subunit 19 or regulation by oxygen 3, or lung cancer metastasis-related protein 1 is located at the head of the mediator complex; it is a multi-protein co-activator that induces the transcription of RNA polymerase II by DNA transcription factors. It is a tumor-related gene that plays an important role in transcriptional regulation, cell proliferation, and apoptosis and is closely related to the occurrence and development of the cancers of the lung, bladder, skin, etc. Here, we used the structure of mediator complex subunit 19 to review its role in tumor progression, fat metabolism, drug therapy, as well as the novel coronavirus, which has attracted much attention at present, suggesting that mediator complex subunit 19 has broad application in the occurrence and development of clinical diseases. As a tumor-related gene, the role and mechanism of mediator complex subunit 19 in the regulation of tumor growth could be of great significance for the diagnosis, prognosis, and treatment of mediator complex subunit 19 -related tumors.

Integrated Protein-Protein Interaction and Weighted Gene Co-expression Network Analysis Uncover Three Key Genes in Hepatoblastoma.

Hepatoblastoma (HB) is the most common liver tumor in the pediatric population, with typically poor outcomes for advanced-stage or chemotherapy-refractory HB patients. The objective of this study was to identify genes involved in HB pathogenesis via microarray analysis and subsequent experimental validation. We identified 856 differentially expressed genes (DEGs) between HB and normal liver tissue based on two publicly available microarray datasets (GSE131329 and GSE75271) after data merging and batch effect correction. Protein-protein interaction (PPI) analysis and weighted gene co-expression network analysis (WGCNA) were conducted to explore HB-related critical modules and hub genes. Subsequently, Gene Ontology (GO) analysis was used to reveal critical biological functions in the initiation and progression of HB. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that genes involved in cell cycle phase transition and the PI3K/AKT signaling were associated with HB. The intersection of hub genes identified by both PPI and WGCNA analyses revealed five potential candidate genes. Based on receiver operating characteristic (ROC) curve analysis and reports in the literature, we selected CCNA2, CDK1, and CDC20 as key genes of interest to validate experimentally. CCNA2, CDK1, or CDC20 small interfering RNA (siRNA) knockdown inhibited aggressive biological properties of both HepG2 and HuH-6 cell lines in vitro. In conclusion, we identified CCNA2, CDK1, and CDC20 as new potential therapeutic biomarkers for HB, providing novel insights into important and viable targets in future HB treatment.

microRNA-125a targets MAVS and TRAF6 to modulate interferon signaling and promote HCV infection.

Hepatitis C virus (HCV) can cause chronic lifelong infections in humans, resulting in sustained hepatic inflammation, liver cirrhosis, and hepatocellular carcinoma. The clearance of HCV infections is dependent upon effective and coordinated innate and adaptive antiviral immune responses. However, HCV has evolved a range of strategies that enable it to evade or overcome the host immune response, enabling the virus to persist in susceptible hosts through mechanisms that remain to be fully clarified. Herein, we describe a novel mechanism whereby HCV can evade immune surveillance by activating microRNA (miR)-125a. Hepatocytes upregulate miR-125a following HCV infection, and serum from HCV-infected patients similarly exhibits the upregulation of this miRNA. We found that miR-125a is able to target and suppress the expression of two key genes associated with the interferon (IFN) signaling pathway - mitochondrial antiviral signaling (MAVS) and TNF receptor-associated factor 6 (TRAF6). Disrupting the expression of these genes can in turn compromise type I IFN responses to HCV. Together, our data reveal that HCV infection results in the upregulation of miR-125a, which negatively regulates IFN signaling via inhibiting the expression of MAVS and TRAF6, thereby enabling the virus to evade innate antiviral immunity. Targeting this pathway may thus represent an efficient approach to treating HCV and bolstering antiviral immune responses in infected patients.