Objective:CDH1 polymorphism has been suggested to be associated with susceptibility to gastric cancer (GC). However, relevant findings remain inconsistent across studies. This meta‑analysis was performed to evaluate the relationship between CDH1 -160C/A and -347G/GA polymorphisms and GC risk. Methods:Relevant studies were searched in PubMed, Web of Science, Google Scholar, Cochrane Library, Embase, CNKI, and Wanfang databases up to December 20, 2025. Pooled OR and 95% (95% CI) were calculated using fixed‑ or random‑effects models. Results:A total of 25 articles were included, involving 28 studies (4,836 cases and 6,187 controls) for the -160C/A polymorphism and 8 studies (1,201 cases and 1,611 controls) for the -347G/GA polymorphism. Overall, significant associations were identified between CDH1 polymorphisms and GC risk: -160C/A (recessive model: OR=1.28, 95% CI: 1.03-1.58; AA vs. CC: OR=1.28, 95% CI: 1.01-1.61); -347G/GA (G/GA vs. GG: OR=1.23, 95% CI: 1.04-1.44). In stratified analyses by histological type, the CDH1 -347G/GA polymorphism was associated with an elevated risk of diffuse‑type GC (G/GA vs. GG: OR=1.21, 95% CI: 1.01-1.62). Conclusions:This meta-analysis indicates that the two CDH1 promoter polymorphisms may contribute to GC susceptibility. Further large-scale and well-designed studies are needed to verify these results.

Objective:Caspase-8 (CASP8) is essential for apoptotic clearance of transformed cells and is encoded by the CASP8 gene. The CASP8 -652 6N del polymorphism (rs3834129) has been studied in relation to colorectal cancer (CRC) risk with conflicting outcomes. This meta-analysis aims to provide a consolidated assessment of the association between rs3834129 and susceptibility to CRC. Methods:Eligible case-control studies published up to January 2025 were systematically retrieved from PubMed, Web of Science, and China National Knowledge Infrastructure. For each study, the association of the CASP8 -652 6N del polymorphism with CRC risk was assessed using odds ratios (ORs) and 95% confidence intervals (CIs). Results:A total of 22 studies derived from 12 eligible articles involving 15,327 patients with CRC and 20,527 control subjects were enrolled in this meta-analysis. Collectively, the CASP8 -652 6N del variant correlated with reduced CRC risk under the heterozygote genetic model (OR=0.94, 95% CI: 0.89-0.99). When stratifying analyses according to ethnic background, comparable protective associations were detected within Asian populations. By contrast, no statistically meaningful link was identified between this polymorphism and CRC susceptibility among Caucasian individuals. Further stratification based on tumor site revealed no significant correlations for either colon cancer or rectal cancer subgroups. Conclusions:This meta-analysis provides evidence that the CASP8 -652 6N del polymorphism may be linked to a moderately decreased risk of CRC in Asian subjects.

BackgroundPreeclampsia is a severe hypertensive disorder with rising global prevalence. While machine learning (ML) models for predicting preeclampsia are increasingly published, existing evidence shows high heterogeneity, and the distinction between internal performance and external transferability remains unclear. ObjectiveThis study aims to evaluate the performance of ML models in predicting preeclampsia through a systematic review and meta-analysis, while also exploring their potential clinical application value, in order to specifically enhance the quality of future research and the predictive capability of the models. MethodsFollowing PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and PROSPERO registration, we searched PubMed, Web of Science, IEEE Xplore, and CNKI (China National Knowledge Infrastructure) for studies published through February 2025. We included studies using ML to predict preeclampsia in pregnant women. Bias was assessed using PROBAST (Prediction model Risk of Bias Assessment Tool). We calculated summary estimates using random-effects models and, crucially, computed 95% prediction intervals (PIs) to estimate performance in future clinical settings. Subgroup and meta-regression analyses were conducted to explore heterogeneity. ResultsIn total, 26 studies comprising 31 ML models were included. While the pooled area under the receiver operating characteristic curve was high at 0.91 (95% CI 0.87-0.92), extreme heterogeneity was observed (I2>99%). The 95% PI for sensitivity was wide (0.32-0.96), indicating that in some external settings, sensitivity could drop to 32%. Only 6 studies conducted external validation; in these, the pooled sensitivity decreased to 0.68, with a PI of 0.25-0.94.Subgroup analysis suggested that models incorporating laboratory biomarkers and neural networks outperformed others, though CIs overlapped. ConclusionsCurrent evidence suggests that a high area under the curve in ML models is more likely to reflect the “performance” of the model on the internal development dataset rather than its universal “effectiveness” and clinical utility in independent, diverse populations. The apparent performance exhibits significant contextual dependence. Future studies should conduct multicenter, prospective external validation and recalibration research to enhance transferability and reliability. Trial RegistrationPROSPERO CRD420251005830;https://www.crd.york.ac.uk/PROSPERO/view/CRD420251005830

Strategies that concurrently reactivate latent reservoirs and enhance immune-mediated clearance hold significant promise for achieving an HIV cure. Here, we developed hyperIL-15×sCD4-Fc (15×sCD4-Fc), a fusion protein that integrates latency reactivation, targeted immune engagement, and effector-mediated killing into a single molecule. This agent not only potently reverses HIV-1 latency in CD4+ T cells from people living with HIV-1 (PLWHs) through coordinated IL-15 receptor signaling and sCD4-mediated HIV-1 envelope (Env) engagement but also enhances the antigen-specific CD8+ T cell response in peripheral blood mononuclear cells (PBMCs) derived from PLWHs. Furthermore, 15×sCD4-Fc enables Env-specific elimination of reactivated latently infected cells by NK cells while preventing off-target cytotoxicity. In PBMCs from PLWHs, 15×sCD4-Fc reduced replication-competent HIV-1 DNA by 93.8%. In antiretroviral-treated HIV-1-infected humanized mice, the molecule demonstrated both safety and efficacy in diminishing the viral reservoir in lymphoid organs. This spatiotemporally coupled approach to reservoir exposure and immune recognition establishes a clinically viable strategy for clearing the HIV-1 reservoir.

Background: Patients with high-risk acute cholecystitis are challenging to manage because many cannot tolerate early surgery. Percutaneous transhepatic gallbladder drainage (PTGBD) is therefore commonly used; however, the clinical response after drainage is not always satisfactory. Reliable indicators for early identification of patients at risk of poor treatment response remain limited. Although inflammatory and nutritional biomarkers have shown potential value in risk stratification, their role in predicting response to PTGBD has not been fully clarified. Accordingly, this study aims to evaluate the predictive value of the preoperative C-reactive protein/albumin ratio (CAR) for poor treatment response in high-risk patients with acute cholecystitis undergoing PTGBD. Methods: Clinical data from 309 patients with high-risk acute cholecystitis who underwent PTGBD at our institution between January 2023 and January 2025 were retrospectively reviewed. Based on post-procedural treatment response, patients were categorized into a good response group (n = 231) and a poor response group (n = 78). Receiver operating characteristic (ROC) curve analysis was applied to assess the predictive performance of CAR. Multivariable logistic regression analysis was used to determine independent predictors of poor treatment response, and a predictive model was subsequently developed. Results: Seventy-eight patients (25.2%) developed poor treatment response. Preoperative CAR was higher in the poor response group than in the good response group [5.82 (3.65-8.96) vs 2.68 (1.35-4.52), p G 0.001]. ROC curve analysis showed that the area under the curve (AUC) of CAR for predicting poor treatment response was 0.812 (95% confidence interval (CI): 0.758-0.866), which was higher than that of C-reactive protein (CRP) (AUC = 0.756) and albumin (AUC = 0.718) (p G 0.05); the optimal cutoff value was 3.85, with a sensitivity of 74.4% and specificity of 76.2%. Multivariable logistic regression analysis showed that CAR >3.85 (odds ratio (OR) = 3.42, 95% CI: 1.89-6.18), TG18 Grade III (OR = 2.28, 95% CI: 1.26-4.12), time from onset to PTGBD >72 h (OR = 2.15, 95% CI: 1.18-3.92), diabetes mellitus (OR = 1.86, 95% CI: 1.04-3.33), and CCI >4 (OR = 1.92, 95% CI: 1.08-3.41) were independent risk factors for poor treatment response (all p G 0.05). The high CAR group (CAR >3.85) had longer time to temperature normalization, abdominal pain relief, and WBC normalization compared to the low CAR group (all p G 0.001). Conclusion: Preoperative CAR shows good performance in identifying high-risk acute cholecystitis patients who are more likely to experience an unfavorable response to PTGBD. A CAR value >3.85 is associated with an increased likelihood of poor treatment response and may assist clinicians in early risk stratification and treatment planning.

Abstract Chronic hepatitis B virus (HBV) infection (CHB) progresses through distinct clinical phases characterized by dynamic immune responses and changes in intrahepatic gene expression. While hepatic transcriptomes have been studied, hepatic microRNA (miRNA) profiles across the natural history of CHB remain poorly defined. In this study, we aimed to characterize hepatic miRNA expression and its association with liver cell composition across CHB phases. Liver biopsies from 43 treatment-naïve CHB patients across four clinical phases, immune tolerance (IT), immune active (IA), inactive carrier (IC), and HBeAg-negative hepatitis (ENH), were analyzed using miRNA microarrays and mRNA sequencing. Hepatic cell composition was inferred using CIBERSORT and expression of 92 cell-type marker genes. Differentially expressed miRNAs were identified by Mann–Whitney U test, and clustering and correlation analyses were performed to assess associations with immune and liver cell markers. Consistent with previous studies, immune cell infiltration varied by phase, peaking in IA and ENH phases. Sixty-five miRNAs were significantly differentially expressed (|log₂FC| > 0.585), including immune-associated miRNAs such as miR-155-5p, miR-150-5p, and miR-142-5p. Twenty-two miRNAs elevated in IA phase were associated with macrophage and T cell markers. Hepatocyte-enriched miRNAs (e.g., miR-122-5p, miR-192-5p) remained highly expressed across all phases. Clustering analysis identified five miRNA expression patterns, with immune-associated clusters upregulated in IA and ENH phases. Correlation analysis confirmed strong associations between immune-phase miRNAs and αβ T cell markers. Overall, these findings indicate that hepatic miRNA profiles are largely stable across CHB phases, with immune cell infiltration associated with selective miRNA changes, particularly in IA and ENH phases.

Background:Frailty is frequently observed in patients with inflammatory bowel disease (IBD) and is strongly associated with adverse clinical outcomes. This study aimed to develop a risk prediction model for frailty in IBD patients by integrating three key indicators: systemic immune-inflammation index (SII), albumin (Alb), and fibrinogen (FIB). The objective was to establish an early identification approach for frailty and contribute to reducing the disease burden. Methods:Among the 344 patients diagnosed with IBD, 61 were identified as frail. Factors that exhibited significant differences in univariate analysis were incorporated into a multivariable binary logistic regression model to identify independent predictors of frailty in IBD patients. Receiver operating characteristic (ROC) curves were generated to evaluate the predictive efficacy of SII, Alb, and FIB in the occurrence of frailty. A nomogram prediction model was developed, and its performance was assessed using the concordance index (C-index) and calibration curves. Results:The incidence of frailty in the training and validation sets was 17.8% and 17.6%, respectively. Multivariable binary logistic regression analysis indicated that a high Pittsburgh Sleep Quality Index (PSQI) score, elevated SII, increased FIB levels, and reduced Alb levels were significant risk factors for frailty in IBD patients. ROC analysis for both the training and validation sets demonstrated that the predictive ability of the combined serological and demographic indicators was superior to that of any single indicator, with area under the curve (AUC) values of 0.906 and 0.904, respectively. The C-index of the nomogram model in the training set was 0.917, confirming its strong predictive performance in both datasets. Conclusion:Preoperative serological testing provides an effective method for predicting frailty in IBD patients. The frailty risk prediction model developed in this study demonstrated high predictive accuracy and serve as a valuable tool for the clinical assessment of frailty risk in IBD patients.

This study investigates the association of platelet count (PLT), mean platelet volume (MPV), and platelet distribution width (PDW) with liver fibrosis and hepatic inflammatory activity in nonalcoholic fatty liver disease (NAFLD) and evaluate their noninvasive biomarker potential. This retrospective case-control study included 117 biopsy-confirmed NAFLD patients and 108 healthy controls. NAFLD patients were stratified by METAVIR scoring system fibrosis stage (F0-F4) and inflammatory activity grade (A0-A3). Platelet parameters, biochemical markers, and fibrosis markers were compared. Correlations were assessed using Spearman analysis, and multivariate logistic regression identified independent risk factors. NAFLD patients had lower PLT and higher MPV/PDW levels than controls (all P < .05). PLT negatively correlated with fibrosis stage (r = -0.640) and inflammatory grade (r = -0.556), while MPV (fibrosis: r = 0.523; inflammation: r = 0.319) and PDW (fibrosis: r = 0.417; inflammation: r = 0.440) showed positive correlations (all P < .01). Decreased PLT, increased MPV, PDW, alanine aminotransferase, aspartate aminotransferase, and procollagen type III N-terminal peptide were independent risk factors for fibrosis progression. Increased PDW, alanine aminotransferase, total cholesterol, hyaluronic acid, and procollagen type III N-terminal peptide were independent risk factors for inflammatory exacerbation (all P < .05). Altered platelet parameters (decreased PLT, increased MPV/PDW) in NAFLD patients correlate with, and independently predict, the severity of liver fibrosis and inflammation. These routine hematological indices show promise as noninvasive biomarkers for NAFLD assessment, warranting further prospective validation.

OBJECTIVE:Patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) are characterized by severe liver function impairment, coagulation disorder, and multiple organ function impairment. The aim of this study was to explore the predictive value of antithrombin Ⅲ activity to the prognosis of HBV-ACLF patients.METHODS:A total of 186 HBV-ACLF patients were included in the analysis, and the baseline clinical data of patients were recorded to analyze the risk factors affecting the 30-day survival outcome of patients. Bacterial infection, sepsis, and hepatic encephalopathy were observed in ACLF patients. Antithrombin Ⅲ activity and serum cytokine levels were determined.RESULTS:The antithrombin Ⅲ activity of ACLF patients in the death group was significantly lower than that in the survival group, and antithrombin Ⅲ activity was independent factors affecting the 30-day outcome. The areas under the receiver operation characteristic (ROC) curve of antithrombin Ⅲ activity to predict the 30-day mortality of ACLF was 0.799. Survival analysis showed that the mortality of patients with antithrombin Ⅲ activity less than 13% was significantly increased. Patients with bacterial infection and sepsis had lower antithrombin Ⅲ activity than those without infection. Antithrombin Ⅲ activity was positively correlated with platelet count, fibrinogen, interferon (IFN)-γ, interleukin (IL)-13, IL-1β, IL-4, IL-6, tumor necrosis factor-α, IL-23, IL-27, and IFN-α, but negatively correlated with C-reactive protein, D dimer, total bilirubin, and creatinine levels.CONCLUSION:As a natural anticoagulant, antithrombin Ⅲ can be regarded as a marker of inflammation and infection in patients with HBV-ACLF, and as a predictor of survival outcome in patients with ACLF.

Chronic hepatitis B is a major health problem worldwide, with more than 250 million chronic carriers. Hepatitis B virus interferes with the host innate immune system so as to evade elimination via almost all of its constituent proteins; nevertheless, the function of HBsAg with respect to immune escape remains unclear. This study aimed to determine the role HBsAg plays in assisting HBV to escape from immune responses. We found that HBsAg suppressed the activation of the nuclear factor kappa B (NF-кB) pathway, leading to downregulation of innate immune responses. HBsAg interacted with TAK1 and TAB2 specifically, inhibiting the phosphorylation and polyubiquitination of TAK1 and the K63-linked polyubiquitination of TAB2. Autophagy is a major catabolic process participating in many cellular processes, including the life cycle of HBV. We found that HBsAg promoted the autophagic degradation of TAK1 and TAB2 via the formation of complexes with TAK1 and TAB2, resulting in suppression of the NF-κB pathway. The expression of TAK1, TAB2, and the translocation of NF-κB inversely correlated with HBsAg levels in clinical liver tissues. Taken together, our findings suggest a novel mechanism by which HBsAg interacts with TAK1-TAB2 complex and suppresses the activation of NF-κB signaling pathway via reduction of the post-translational modifications and autophagic degradation.

Background: The impact of the influenza A (H1N1) and SARS-CoV-2 virus on the development of autoimmune hepatitis has not been described previously. Methods: In this case series, we evaluated the dynamic changes in liver function of three patients with autoimmune hepatitis who presented with viral infection (two with the H1N1 and one with the SARS-CoV-2 virus) during the recent COVID-19 outbreak. Result: Patient 1 was a 68-year-old woman with a history of hepatitis of unknown origin before being infected with the H1N1 virus. Autoimmune hepatitis with an exacerbation of liver injury was diagnosed during the infection. Patient 2 was a 48-year-old woman with pre-existing autoimmune hepatitis. Despite being on immunosuppressant therapy (using glucocorticoids), liver injury recurred with elevated total bilirubin and gamma-glutamyl transferase levels post H1N1 infection. Patient 3 was a 61-year-old woman with probable autoimmune hepatitis. Liver injury recurred with a flare in alanine transaminase/aspartate transaminase levels post SARS-CoV-2 infection, in spite of the patient being on liver protection therapy (using ursodeoxycholic acid). Conclusion: The case series raises the possibility that COVID-19 or influenza induced pneumonia triggers the progression of autoimmune hepatitis.

Induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, the COVID-19 pandemic has caused a serious crisis for healthcare systems worldwide. COVID-19 vaccine coverage has increased in many countries, but the COVID-19 epidemic has rapidly expanded, with a daily increase of 30,390 COVID-19 cases and 9,761 deaths since August 12, 2021. This article provides a brief overview of growing concerns about a rebound of the COVID-19 pandemic caused by the Delta variant and public health epidemic control measures that have recently been relaxed. As of August 13, 2021, 465,679 cases of COVID-19 due to the Delta variant of SARS-CoV-2 have been detected in over 120 countries. Epidemic control measures were relaxed in some areas, such as allowing large gatherings and improper criteria for ending self-isolation. Even in China, where the epidemic was tightly controlled with strict non-pharmaceutical interventions (NPIs), new COVID-19 cases, and asymptomatic cases in particular, spiked in the first 13 days of August. More importantly, most of those cases were local, while most of the cases accounting for the previous increase were imported. Therefore, relaxed epidemic control measures and asymptomatic infections possibly caused by the Delta variant of SARS-CoV-2 may increase the risk of virus transmission. Accordingly, suggestions for COVID-19 containment, such as encouraging vaccination of the general population, using Internet of Things technology (loT) to reduce the possibility of contact with the asymptomatic infected, and enhancing disease surveillance, have been offered here.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a serious public health burden. As the COVID-19 epidemic in China would coincide with a seasonal outbreak of influenza, there were serious concerns about whether influenza would be aggravated by the SARS-CoV-2 infection and COVID-19 pandemic. This article provides a brief overview of the impacts of the COVID-19 epidemic on influenza activity in China. The percentage of positive influenza tests decreased during the COVID-19 pandemic. During the first stage of the COVID-19 outbreak, the percentage of positive influenza tests reached to a peak of 47.7%. At the second stage, the percentage of positive influenza tests was dramatically decreased from 40.4% to 14.0%. Thereafter, it remains at a low level of less than 6.2%. In addition, the possible causes of this phenomenon have been summarized, including prevention and control measures and ecological competition. Lastly, this article suggests that the public health approach to preventing COVID-19 may also help to control other respiratory infectious diseases. Public health measures need to be maintained even in the later stages of the COVID-19 epidemic.

Acute-on-chronic liver failure (ACLF) is an acute syndrome accompanied with decompensation of cirrhosis, organ failure with high 28-day mortality rate. Systemic inflammation is the main feature of ACLF, and poor outcome is closely related with exacerbated systemic inflammatory responses. It is well known that severe systemic inflammation is an important event in chronic hepatitis B (CHB)-ACLF, which eventually leads to liver injury. However, the initial CHB-ACLF events are unclear; moreover, the effect of these events on host immunity as well as that of immune imbalance on CHB-ACLF progression are unknown. Here, we investigate the initial events of ACLF progression, discuss possible mechanisms underlying ACLF progression, and provide a new model for ACLF prediction and treatment. We review the characteristics of ACLF, and consider its plausible immune predictors and alternative treatment strategies.

Background and Aim The apolipoprotein C3 (APOC3) polymorphism has been reported to predispose to non-alcoholic fatty liver disease (NAFLD). However, the results remain inconclusive. This meta-analysis aimed to provide insights into the association between APOC3 polymorphisms and NAFLD risk. Methods Studies with terms “NALFD” and “APOC3” were retrieved from PubMed, Web of Science, CNKI and Wanfang databases up to August 1, 2019. Pooled odds ratio (OR) and 95% confidence interval (95% CI) for the association of APOC3 polymorphisms and NAFLD risk were calculated using fixed and random-effects models. Results A total of twelve studies from eleven articles were included. Of them, eight studies (1750 cases and 2181 controls) reported the strong association of variant rs2854116 with NAFLD and six studies (1523 cases and 1568 controls) found the association of rs2854117 polymorphism with NAFLD. Overall, a statistically significant association between rs2854116 polymorphism of APOC3 gene and NAFLD risk was found only under dominant model. However, association of rs2854117 polymorphism with NAFLD risk was not detected under all four genetic models. In sub-group analysis of NAFLD subjects based on country, no association among them in China was detected. Besides, four studies analyze the association between the two polymorphisms and clinical characteristics in all subjects or NAFLD patients, and we also failed detect any association between the wild carriers and variant carriers. Conclusion The meta-analyses suggests that the rs2854116 polymorphism but not rs2854117 polymorphism in APOC3 gene might be a risk factor for NAFLD among Asians. That is, individuals with CT+CC genotype have higher risk of developing NAFLD. However, studies with sufficient sample size are needed for the further validation.

Background: A critical issue is to identify COVID-19 patients early who develop severe pneumonia. Understanding the relationship of the laboratory parameters and radiological features of COVID-19 patients may improve the diagnosis of severe pneumonia.Methods: A retrospective analysis was performed on 55 confirmed COVID-19 patients included mild, moderate, and severe cases. The kinetic of clinical characteristics of these groups were compared. Blood parameters and CT values, estimated by chest CT scan, in 23 COVID-19 patients were analyzed. Bayesian inference was used to quantify the trend of major parameters.Findings: Principal Component Analysis indicated that higher Neutrophil to Lymphocyte Ratio and lower lymphocyte counts contributed most to disease severity among all variables. Neutrophil counts were dramatically increased while lymphocyte counts were lower in severe COVID-19 patients during disease compared to the other two groups. Neutrophilia occurred in 6 of 8 severe COVID-19 patients at 7 to 19 days after symptom onset. In severe cases, neutrophilia or lymphopenia coincided with the enlargement or consolidation of existing lesions or with the appearance of new lesions. There was a clear trend of increasing neutrophil counts parallel to increasing CT values of lung lesions during progressing pneumonia. Lymphocyte counts showed a clear decreasing trend inversely to CT values.Interpretation: Neutrophilia and lymphopenia occurred coincidently with progressing lung lesions in severe COVID-19 patients about 7 days after symptom onset, indicating their vital role in lung injury associated with SARS-CoV-2 infection. Funding Statement: This work was supported by the foundation of Wuxi Medical Development Discipline for Infectious Disease (FZXK006) and Wuxi Young Medical Talents (Q201743), Health and Science Bureau of Wuxi (MS201731, CSE31N1712). Declaration of Interests: All authors disclose that there are no conflicts of interest.Ethics Approval Statement: A written informed consent was obtained from all patients from the Fifth People's Hospital, Wuxi, China. The study was approved by the Ethics Committee of the Fifth People's Hospital, Wuxi (NO.2020-006-1).

The influenza virus nonstructural protein 1 (NS1) is a nonstructural protein that plays a major role in antagonizing host interferon responses during infection. However, a clear role for the NS1 protein in epigenetic modification has not been established. In this study, NS1 was found to regulate the expression of some key regulators of JAK-STAT signaling by inhibiting the DNA methylation of their promoters. Furthermore, DNA methyltransferase 3B (DNMT3B) is responsible for this process. Upon investigating the mechanisms underlying this event, NS1 was found to interact with DNMT3B but not DNMT3A, leading to the dissociation of DNMT3B from the promoters of the corresponding genes. In addition, the interaction between NS1 and DNMT3B changed the localization of DNMT3B from the nucleus to the cytosol, resulting in K48-linked ubiquitination and degradation of DNMT3B in the cytosol. We conclude that NS1 interacts with DNMT3B and changes its localization to mediate K48-linked polyubiquitination, subsequently contributing to the modulation of the expression of JAK-STAT signaling suppressors.IMPORTANCE The nonstructural protein 1 (NS1) of the influenza A virus (IAV) is a multifunctional protein that counters cellular antiviral activities and is a virulence factor. However, the involvement of NS1 in DNA methylation during IAV infection has not been established. Here, we reveal that the NS1 protein binds the cellular DNMT3B DNA methyltransferase, thereby inhibiting the methylation of the promoters of genes encoding suppressors of JAK-STAT signaling. As a result, these suppressor genes are induced, and JAK-STAT signaling is inhibited. Furthermore, we demonstrate that the NS1 protein transports DNMT3B to the cytoplasm for ubiquitination and degradation. Thus, we identify the NS1 protein as a potential trigger of the epigenetic deregulation of JAK-STAT signaling suppressors and illustrate a novel mechanism underlying the regulation of host immunity during IAV infection.

Enterovirus 71 (EV71) induces significantly elevated levels of cytokines and chemokines, leading to local or systemic inflammation and severe complications. As shown in our previous study, microRNA (miR) 302c regulates influenza A virus–induced IFN expression by targeting NF-κB-inducing kinase. However, little is known about the role of the miR-302 cluster in EV71-mediated proinflammatory responses. In this study, we found that the miR-302 cluster controls EV71-induced cytokine expression. Further studies demonstrated that karyopherin α2 (KPNA2) is a direct target of the miR-302 cluster. Interestingly, we also found that EV71 infection upregulates KPNA2 expression by downregulating miR-302 cluster expression. Upon investigating the mechanisms behind this event, we found that KPNA2 intracellularly associates with JNK1/JNK2 and p38, leading to translocation of those transcription factors from the cytosol into the nucleus. In EV71-infected patients, miR-302 cluster expression was downregulated and KPNA2 expression was upregulated compared with controls, and their expression levels were closely correlated. Taken together, our work establishes a link between the miR-302/ KPNA2 axis and EV71-induced cytokine expression and represents a promising target for future antiviral therapy.

Little data is available on the evaluation of the occurrence rates of Epstein-Barr virus (EBV) in saliva and relationship with highly active antiretroviral therapy (HAART) use in HIV/AIDS patients in China. We conducted a retrospective cohort study of EBV serological tests for HIV/AIDS patients who were treated in the hospitals for infectious diseases in Wuxi and Shanghai, China from May 2016 to April 2017. The EBV-seropositive samples were identified by ELISA. EBV-specific primers and probes were used for the quantitative detection of viral DNA from saliva via quantitative real-time polymerase chain reaction. CD4 cell counts of the HIV/AIDS patients were detected by a flow cytometry. A total of 372 HIV/AIDS patients were ultimately selected and categorized for this retrospective cohort study. For EBV IgG and IgM, the HIV/AIDS HAART use (H) and non-HAART use (NH) groups had significantly higher seropositive rates than the HIV-negative control group. The HIV/AIDS (NH) group had the highest seropositive rate (IgG, 94.27%; IgM, 68.98%) and the highest incidence of EBV reactivation or infection. For salivary EBV DNA-positive rates and quantities, the HIV/AIDS (H) (73.69%) and the HIV/AIDS (NH) (100%) groups showed significantly higher values than the HIV-negative control group (35.79%, > twofold). Further, the salivary EBV DNA-negative population had significantly higher CD4 cell counts than the EBV DNA-positive population in the HIV/AIDS (H) group and the HIV/AIDS (NH) groups. Thus, HAART use is beneficial in decreasing the EBV salivary shedding in HIV/AIDS patients and indirectly decreases EBV transmission risk.

During influenza A virus (IAV) infection, cytokine storms play a vital and critical role in clinical outcomes. We have previously reported that microRNA (miR)-302c regulates IAV-induced IFN expression by targeting the 3′-UTR of nuclear factor κB (NF-κB)–inducing kinase. In the current study, we found that miR-302a, another member of the miR-302 cluster, controls the IAV-induced cytokine storm. According to results from cell-based and knockout mouse models, IAV induces a cytokine storm via interferon regulatory factor-5 (IRF-5). We also found that IAV infection up-regulates IRF-5 expression and that IRF-5 in turn promotes IAV replication. Furthermore, we observed that IRF-5 is a direct target of miR-302a, which down-regulated IRF-5 expression by binding its 3′-UTR. Moreover, IAV increased IRF-5 expression by down-regulating miR-302a expression. Interestingly, miR-302a inhibited IAV replication. In IAV-infected patients, miR-302a expression was down-regulated, whereas IRF-5 expression was up-regulated. Taken together, our work uncovers and defines a signaling pathway implicated in an IAV-induced cytokine storm.