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We report epidemiologic, laboratory, and clinical findings for 7 patients with 2019 novel coronavirus disease in a 2-family cluster. Our study confirms asymptomatic and human-to-human transmission through close contacts in familial and hospital settings. These findings might also serve as a practical reference for clinical diagnosis and medical treatment.

We found that a subset of signal transducer and activator of transcription 3 (STAT3) translocated into mitochondria in phagocytes, including macrophages isolated from individuals with sepsis. However, the role of mitochondrial STAT3 in macrophages remains unclear. To investigate the function of mitochondrial STAT3 , we generated inducible mitochondrial STAT3 knock-in mice. A cytokine array analysis, a CBA analysis, flow cytometry, immunofluorescence staining and quantification and metabolic analyses were subsequently performed in an LPS-induced sepsis model. Single-cell RNA sequencing, a microarray analysis, metabolic assays, mass spectrometry and ChIP assays were utilized to gain insight into the mechanisms of mitochondrial STAT3 in metabolic reprogramming in LPS-induced sepsis. We found that mitochondrial STAT3 induced NF-κB nuclear localization and exacerbated LPS-induced sepsis in parallel with a metabolic switch from mainly using glucose to an increased reliance on fatty acid oxidation (FAO). Moreover, mitochondrial STAT3 abrogated carnitine palmitoyl transferase 1a (CPT1a) ubiquitination and degradation in LPS-treated macrophages. Meanwhile, an interaction between CPT1a and ubiquitin-specific peptidase 50 (USP50) was observed. In contrast, knocking down USP50 decreased CPT1a expression and FAO mediated by mitochondrial STAT3. The ChIP assays revealed that NF-κB bound the USP50 promoter. Curcumin alleviated LPS-mediated sepsis by suppressing the activities of mitochondrial STAT3 and NF-κB. Our findings reveal that mitochondrial STAT3 could trigger FAO by inducing CPT1a stabilization mediated by USP50 in macrophages, at least partially.

During chronic hepatitis B virus (HBV) infection, hepatic fibrosis is a serious pathological condition caused by virus-induced liver damage. The activation of hepatic stellate cells (HSCs) is a central event in the occurrence and progression of liver fibrosis. Although accumulating evidence has shown that HBV directly stimulates HSC activation, whether the virus infects and replicates in HSCs remains controversial. Inflammation is one of the obvious characteristics of chronic HBV infection, and it has been demonstrated that persistent inflammation has a predominant role in triggering and maintaining liver fibrosis. In particular, the regulation of HSC activation by HBV-related hepatocytes via various inflammatory modulators, including TGF-β and CTGF, in a paracrine manner has been reported. In addition to these inflammation-related molecules, several inflammatory cells are essential for the progression of HBV-associated liver fibrosis. Monocytes, macrophages, Th17 cells, NK cells, as well as NKT cells, participate in the modulation of HBV-related liver fibrosis by interacting with HSCs. This review summarizes current findings on the effects of HBV and the relevant molecular mechanisms involved in HSC activation. Because HSC activation is essential for liver fibrosis, targeting HSCs is an attractive therapeutic strategy to prevent and reverse hepatic fibrosis induced by HBV infection. EnVSpHEvp1vJ1E4tL-_AS1 Video abstract

As a small DNA virus, hepatitis B virus (HBV) plays a pivotal role in the development of various liver diseases, including hepatitis, cirrhosis, and liver cancer. Among the molecules encoded by this virus, the HBV X protein (HBX) is a viral transactivator that plays a vital role in HBV replication and virus-associated diseases. Accumulating evidence so far indicates that pattern recognition receptors (PRRs) are at the front-line of the host defense responses to restrict the virus by inducing the expression of interferons and various inflammatory factors. However, depending on HBX, the virus can control PRR signaling by modulating the expression and activity of essential molecules involved in the toll-like receptor (TLR), retinoic acid inducible gene I (RIG-I)-like receptor (RLR), and NOD-like receptor (NLR) signaling pathways, to not only facilitate HBV replication, but also promote the development of viral diseases. In this review, we provide an overview of the mechanisms that are linked to the regulation of PRR signaling mediated by HBX to inhibit innate immunity, regulation of viral propagation, virus-induced inflammation, and hepatocarcinogenesis. Given the importance of PRRs in the control of HBV replication, we propose that a comprehensive understanding of the modulation of cellular factors involved in PRR signaling induced by the viral protein may open new avenues for the treatment of HBV infection.

This study aimed to access hepatitis B virus (HBV) reactivation and its effect on survival in HBV-related hepatocarcinoma (HCC) patients who underwent transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs). In this single-center retrospective study, we enrolled 119 HBV-related unresectable advanced HCC patients receiving TACE combined with TKIs plus ICIs. Risk factors for HBV reactivation were analyzed by logistic regression. Kaplan-Meier method was applied to draw the survival curve, and log-rank test was used to compare survival between patients with and without HBV reactivation. A total of 12 patients (10.1%) encountered HBV reactivation in our study, of which only 4 patients received antiviral prophylaxis. The incidence of HBV reactivation was 1.8% (1/57) in patients with detectable baseline HBV DNA and 4.2% (4/95) in patients with antiviral prophylaxis respectively. Lack of prophylactic antiviral treatment (OR=0.047, 95%CI 0.008-0.273, =0.001) and undetectable HBV DNA (OR=0.073, 95%CI 0.007-0.727, =0.026) were independent risk factors for HBV reactivation. The median survival time (MST) for all patients was 22.4 months. No survival difference was observed in patients with or without HBV reactivation. (MST: undefined vs 22.4 months, log-rank test: =0.614). HBV reactivation could occur in HBV-related HCC patients who treated with TACE in combination with TKIs plus ICIs. Before and during the combination treatment, it is necessary to routinely monitor HBV DNA and to take effective prophylactic antiviral therapy.

As a ubiquitous second messenger, calcium (Ca2+) can interact with numerous cellular proteins to regulate multiple physiological processes and participate in a variety of diseases, including hepatitis B virus (HBV) infection, which is a major cause of hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. In recent years, several studies have demonstrated that depends on the distinct Ca2+ channels on the plasma membrane, endoplasmic reticulum, as well as mitochondria, HBV can elevate cytosolic Ca2+ levels. Moreover, within HBV-infected cells, the activation of intracellular Ca2+ signaling contributes to viral replication via multiple molecular mechanisms. Besides, the available evidence indicates that targeting Ca2+ signaling by suitable pharmaceuticals is a potent approach for the treatment of HBV infection. In the present review, we summarized the molecular mechanisms related to the elevation of Ca2+ signaling induced by HBV to modulate viral propagation and the recent advances in Ca2+ signaling as a potential therapeutic target for HBV infection. DjLUUGPzDA8N3DHK7ahUq9 Video Abstract

This study aimed to determine whether nonalcoholic fatty liver disease (NAFLD) influences the functional cure of nucleos(t)ide analogues (NAs)-treated chronic hepatitis B (CHB) patients in combination with pegylated interferon (PEG-IFN) therapy. A retrospective analysis was conducted on CHB patients treated with nucleos(t)ide analogues (NAs) who received PEG-IFN combination therapy at a single center. Patients were stratified into a CHB group and a CHB-NAFLD group based on the presence of fatty liver comorbidity. The primary endpoint was the difference in hepatitis B virus surface antigen (HBsAg) seroclearance rates between the two groups, and the secondary endpoint was the differences in biochemical parameters and adverse events. A total of 158 NAs-treated CHB patients were enrolled, comprising 91 CHB -only patients and 67 CHB-NAFLD patients. After 48 weeks of PEG-IFN therapy, 20.9% of patients achieved HBsAg seroclearance. Before and after propensity score matching (PSM), differences in cumulative HBsAg seroclearance probability between groups were non-significant (25.3% . 14.9% , = 0.121; 32.4% . 13.5%, = 0.063). Similarly, cumulative hepatitis B e antigen (HBeAg) seroconversion incidence showed no intergroup differences before and after PSM ( = 0.618 and = 0.954, respectively). Logistic regression analysis indicated that baseline HBeAg status was independently associated with HBsAg seroclearance. Further analysis confirmed that NAFLD did not significantly affect HBsAg loss, regardless of HBeAg status, both before and after PSM ( > 0.05). Moreover, the NAFLD group exhibited higher rates of abnormal alanine aminotransferase (ALT) at weeks 24 and 48 the CHB-only group (31.9% . 12.3%, = 0.009; 70.8% . 47.4%, = 0.007). However, ALT normalization rates 24 weeks post-treatment showed no significant difference (88.9% . 77.2%, = 0.074). NAFLD does not affect the achievement of functional cure with PEG-IFN therapy in NAs-treated chronic hepatitis B patients. However, CHB patients with NAFLD show a reduced likelihood of ALT normalization during treatment.

DEAD/H-box helicases are an essential protein family with a conserved motif containing unique amino acid sequences (Asp-Glu-Ala-Asp/His). Current evidence indicates that DEAD/H-box helicases regulate RNA metabolism and innate immune responses. In recent years, DEAD/H-box helicases have been reported to participate in the development of a variety of diseases, including hepatitis B virus (HBV) infection, which is a significant risk factor for hepatic fibrosis, cirrhosis, and liver cancer. Furthermore, emerging evidence suggests that different DEAD/H-box helicases play vital roles in the regulation of viral replication, based on the interaction of DEAD/H-box helicases with HBV and the modulation of innate signaling pathways mediated by DEAD/H-box helicases. Besides these, HBV can alter the expression and activity of DEAD/H-box helicases to facilitate its biosynthesis. More importantly, current investigation suggests that targeting DEAD/H-box helicases with appropriate compounds is an attractive treatment strategy for the virus infection. In this review, we delineate recent advances in molecular mechanisms relevant to the interplay of DEAD/H-box helicase and HBV and the potential of targeting DEAD/H-box helicase to eliminate HBV infection.

Sirtuins (SIRTs) are well-known histone deacetylases that are capable of modulating various cellular processes in numerous diseases, including the infection of hepatitis B virus (HBV), which is one of the primary pathogenic drivers of liver cirrhosis and hepatocellular carcinoma. Mounting evidence reveals that HBV can alter the expression levels of all SIRT proteins. In turn, all SIRTs regulate HBV replication via a cascade of molecular mechanisms. Furthermore, several studies suggest that targeting SIRTs using suitable drugs is a potential treatment strategy for HBV infection. Here, we discuss the molecular mechanisms associated with SIRT-mediated upregulation of viral propagation and the recent advances in SIRT-targeted therapy as potential therapeutic modalities against HBV infection.

Combination therapy with pegylated interferon α-2a (PEG-IFN α-2a) and nucleoside analogue (NA) has been shown to improve liver histology in patients with chronic hepatitis B (CHB) and hepatic fibrosis. PEG-IFN α-2a effectiveness was assessed in NA-treated CHB patients with advanced fibrosis/compensated cirrhosis. This retrospective multicenter study included NA-treated CHB patients with advanced fibrosis/compensated cirrhosis. Patients received 48-week PEG-IFN α-2a plus 24-week follow-up. The primary endpoint was liver fibrosis status 24 weeks post-treatment. A total of 102 patients were enrolled in the study, including 35 and 67 baseline HBeAg-positive and HBeAg-negative CHB patients, respectively. At the end of PEG-IFN α-2a treatment, a total of 18 (17.6%) patients achieved HBsAg loss, and 23 (65.7%) achieved HBeAg loss. Sixty-nine patients completed the comparison of liver fibrosis and cirrhosis before and after treatment, of whom 16 (23.2%) experienced progression of liver fibrosis or cirrhosis, 32 (46.4%) experienced liver fibrosis reversal, and 21 (30.4%) remained stable. Penalized logistic regression analysis demonstrated that GPR (Intercept = -1.200; Coefficients = 0.102) and GGT levels (Intercept = -1.198; Coefficients = 0.048) at 24 weeks of PEG-IFN α-2a treatment were independent predictors of fibrosis progression. Among these, GPR at 24 weeks exhibited the highest predictive value (Corrected AUC = 0.805). Approximately one-fifth of the NA-treated CHB patients with advanced liver fibrosis and compensated cirrhosis experienced progression of liver fibrosis after PEG-IFN α-2a treatment. The GPR at 24 weeks of treatment was an independent predictive factor for the progression of liver fibrosis in this population.