Promoting CO2 Electroreduction Over Nano-Socketed Cu/Perovskite Heterostructures via A-Site-Valence-Controlled Oxygen Vacancies.

Despite the intriguing potential, nano-socketed Cu/perovskite heterostructures for CO2 electroreduction (CO2 RR) are still in their infancy and rational optimization of their CO2 RR properties is lacking. Here, an effective strategy is reported to promote CO2 -to-C2+ conversion over nano-socketed Cu/perovskite heterostructures by A-site-valence-controlled oxygen vacancies. For the proof-of-concept catalysts of Cu/La0.3-x Sr0.6+x TiO3-δ (x from 0 to 0.3), their oxygen vacancy concentrations increase controllably with the decreased A-site valences (or the increased x values). In flow cells, their activity and selectivity for C2+ present positive correlations with the oxygen vacancy concentrations. Among them, the Cu/Sr0.9 TiO3-δ with most oxygen vacancies shows the optimal activity and selectivity for C2+ . And relative to the Cu/La0.3 Sr0.6 TiO3-δ with minimum oxygen vacancies, the Cu/Sr0.9 TiO3-δ exhibits marked improvements (up to 2.4 folds) in activity and selectivity for C2+ . The experiments and theoretical calculations suggest that the optimized performance can be attributed to the merits provided by oxygen vacancies, including the accelerated charge transfer, enhanced adsorption/activation of reaction species, and reduced energy barrier for C─C coupling. Moreover, when explored in a membrane-electrode assembly electrolyzer, the Cu/Sr0.9 TiO3-δ catalyst shows excellent activity, selectivity (43.9%), and stability for C2 H4 at industrial current densities, being the most effective perovskite-based catalyst for CO2 -to-C2 H4 conversion.

Aborted infection of human sodium taurocholate cotransporting polypeptide (hNTCP) expressing woodchuck hepatocytes with hepatitis B virus (HBV).

Due to the limited host range of HBV, research progress has been hindered by the absence of a suitable animal model. The natural history of woodchuck hepatitis virus (WHV) infection in woodchuck closely mirrors that of HBV infection in human, making this species a promising candidate for establishing both in vivo and in vitro HBV infection models. Therefore, this animal may be a valuable species to evaluate HBV vaccines and anti-HBV drugs. A significant milestone in HBV and hepatitis D virus (HDV) infection is the discovery of sodium taurocholate cotransporting polypeptide (NTCP) as the functional receptor. In an effort to enhance susceptibility to HBV infection, we introduced hNTCP into the woodchuck hepatocytes by multiple approaches including transduction of vLentivirus-hNTCP in woodchuck hepatocytes, transfection of p-lentivirus-hNTCP-eGFP plasmids into these cells, as well as transduction of vAdenovirus-hNTCP-eGFP. Encouragingly, our findings demonstrated the successful introduction of hNTCP into woodchuck hepatocytes. However, it was observed that these hNTCP-expressing hepatocytes were only susceptible to HDV infection but not HBV. This suggests the presence of additional crucial factors mediating early-stage HBV infection that are subject to stringent species-specific restrictions.

Cation-Radius-Controlled Sn-O Bond Length Boosting CO2 Electroreduction over Sn-Based Perovskite Oxides.

Despite the intriguing potential shown by Sn-based perovskite oxides in CO2 electroreduction (CO2 RR), the rational optimization of their CO2 RR properties is still lacking. Here we report an effective strategy to promote CO2 -to-HCOOH conversion of Sn-based perovskite oxides by A-site-radius-controlled Sn-O bond lengths. For the proof-of-concept examples of Ba1-x Srx SnO3 , as the A-site cation average radii decrease from 1.61 to 1.44 Å, their Sn-O bonds are precisely shortened from 2.06 to 2.02 Å. Our CO2 RR measurements show that the activity and selectivity of these samples for HCOOH production exhibit volcano-type trends with the Sn-O bond lengths. Among these samples, the Ba0.5 Sr0.5 SnO3 features the optimal activity (753.6 mA ⋅ cm-2 ) and selectivity (90.9 %) for HCOOH, better than those of the reported Sn-based oxides. Such optimized CO2 RR properties could be attributed to favorable merits conferred by the precisely controlled Sn-O bond lengths, e.g., the regulated band center, modulated adsorption/activation of intermediates, and reduced energy barrier for *OCHO formation. This work brings a new avenue for rational design of advanced Sn-based perovskite oxides toward CO2 RR.

Gamma-Glutamyl Transpeptidase-to-Platelet ratio predicts liver fibrosis in patients with concomitant chronic hepatitis B and nonalcoholic fatty liver disease.

OBJECTIVES: The aim of this study was to compare the correlation of gamma-glutamyl transpeptidase-to-platelet ratio (GPR), aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis index-4 (FIB-4), and liver stiffness measurement (LSM) in the diagnosis of liver fibrosis, and perform a diagnostic value of GPR for predicting fibrosis in CHB patients with NAFLD. METHODS: A retrospective study was conducted on CHB patients concurrent with NAFLD between September 2019 and December 2020. They were divided into control group (LSM ≤ 9.7 kpa) and fibrosis group (LSM ≥ 9.8 kpa). Demographic data were collected; ALT, AST, and PLT were also detected. LSM was measured by transient elastography (TE). The GPR, APRI, and FIB-4 were calculated. The correlation between GPR, APRI, FIB-4, and LSM was compared. The accuracy of predicting liver fibrosis using GPR, APRI, and FIB-4 was assessed. RESULTS: Eighty-five CHB patients with NAFLD were enrolled. Multivariate analysis showed that age (p = 0.005), GGT (p = 0.001), and PLT (p = 0.013) were the independent risk factors for LSM. The GPR (p = 0.008), APRI (p = 0.001), and FIB-4 (p = 0.001) values in fibrosis group were higher than control group. Pearson linear correlation was used to analyze the correlations between LSM and GPR, APRI, and FIB-4. LSM was correlated with GPR, APRI, and FIB-4. The AUCs of GPR, APRI, and FIB4 were 0.805, 0.766, and 0.826 in assessing liver fibrosis, respectively. No significant differences in the areas of GPR were comparable to that of APRI and FIB-4. CONCLUSION: GPR has a good correlation with LSM in assessing liver fibrosis and can be used as a noninvasive index for the assessment of liver fibrosis in patients with concomitant CHB and NAFLD.

Diagnostic accuracy of red blood cell distribution width to platelet ratio for predicting liver fibrosis in patients with chronic hepatitis B: A meta-analysis / Precisión diagnóstica del ancho de distribución de glóbulos rojos a la proporción de plaquetas para predecir la fibrosis hepática en pacientes con hepatitis B crónica: un metaanálisis

Objective: This study aims to systematically review the performance of red blood cell distribution width to platelet ratio (RPR) in the diagnosis of significant or advanced fibrosis, and cirrhosis associated with hepatitis B virus (HBV). Methods: The relevant studies were comprehensively searched in English databases such as Web of Science, PubMed, EMBASE, Cochrane Library, as well as Chinese databases such as China National Knowledge Infrastructure, Wanfang Data from the inception to March 2021. Accuracy of RPR in diagnosing significant or advanced fibrosis and liver cirrhosis was assessed by area under the curve (AUC), pooled sensitivity and specificity, as well as positive and negative likelihood ratios. Stata 15.0 software was applied to analyze the data. Results: In total, 13 literature met the requirements, including patients with significant fibrosis (n=1890), advanced fibrosis (n=645), and cirrhosis (n=499). The prevalence rates of significant fibrosis, advanced fibrosis and cirrhosis were 49.31% (range: 17.25–84.21%), 37.07% (range: 9.60–58.20%) and 2.18% (range: 2.78–44.19%), respectively. The AUCs for predicting significant fibrosis, advanced fibrosis, and cirrhosis by RPR were 0.73 (95%CI: 0.69–0.76), 0.80 (95%CI: 0.77–0.84) and 0.80 (95%CI: 0.76–0.83), respectively. Conclusion: RPR is of some diagnostic value to the prediction of HBV-related significant fibrosis, advanced fibrosis and cirrhosis. This conclusion is urgently needed to be verified by further multi-center studies of large sample size and rigorous design.(AU)

Objetivo: Este estudio tiene como objetivo revisar sistemáticamente la capacidad del cociente entre el ancho de distribución de los glóbulos rojos y el recuento plaquetario (RPR) para discriminar en pacientes con infección crónica por virus de la hepatitis B la existencia de fibrosis significativa, avanzada y cirrosis. Métodos: Se realizaron búsquedas exhaustivas de los estudios relevantes en bases de datos en inglés, como Web of Science, PubMed, EMBASE y Cochrane Library, así como en bases de datos chinas, como China National Knowledge Infrastructure y Wanfang Data, desde el inicio hasta marzo de 2021. La precisión de RPR en el diagnóstico de fibrosis avanzada y cirrosis hepática se evaluó mediante el área bajo la curva, la sensibilidad y la especificidad combinadas, así como las razones de probabilidad positiva y negativa. Se aplicó el software Stata 15.0 para analizar los datos. Resultados: Un total de 13 publicaciones cumplieron con los requisitos, incluyendo pacientes con fibrosis significativa (n=1.890), fibrosis avanzada (n=645) y cirrosis (n=499). Las tasas de prevalencia de fibrosis significativa, fibrosis avanzada y cirrosis fueron del 49,31% (rango: 17,25-84,21), 37,07% (rango: 9,60-58,20) y 2,18% (rango: 2,78-44,19), respectivamente. El área bajo la curva para predecir fibrosis significativa, fibrosis avanzada y cirrosis por RPR fue 0,73 (IC 95%: 0,69-0,76), 0,80 (IC 95%: 0,77-0,84) y 0,80 (IC 95%: 0,76-0,83), respectivamente. Conclusión: La RPR tiene algún valor diagnóstico para la predicción de fibrosis significativa relacionada con el virus de la hepatitis B, fibrosis avanzada y cirrosis. Y esta conclusión debe ser verificada con urgencia mediante más estudios multicéntricos de gran tamaño de muestra y diseño riguroso.(AU)

Diagnostic accuracy of red blood cell distribution width to platelet ratio for predicting liver fibrosis in patients with chronic hepatitis B: A meta-analysis.

OBJECTIVE: This study aims to systematically review the performance of red blood cell distribution width to platelet ratio (RPR) in the diagnosis of significant or advanced fibrosis, and cirrhosis associated with hepatitis B virus (HBV). METHODS: The relevant studies were comprehensively searched in English databases such as Web of Science, PubMed, EMBASE, Cochrane Library, as well as Chinese databases such as China National Knowledge Infrastructure, Wanfang Data from the inception to March 2021. Accuracy of RPR in diagnosing significant or advanced fibrosis and liver cirrhosis was assessed by area under the curve (AUC), pooled sensitivity and specificity, as well as positive and negative likelihood ratios. Stata 15.0 software was applied to analyze the data. RESULTS: In total, 13 literature met the requirements, including patients with significant fibrosis (n=1890), advanced fibrosis (n=645), and cirrhosis (n=499). The prevalence rates of significant fibrosis, advanced fibrosis and cirrhosis were 49.31% (range: 17.25-84.21%), 37.07% (range: 9.60-58.20%) and 2.18% (range: 2.78-44.19%), respectively. The AUCs for predicting significant fibrosis, advanced fibrosis, and cirrhosis by RPR were 0.73 (95%CI: 0.69-0.76), 0.80 (95%CI: 0.77-0.84) and 0.80 (95%CI: 0.76-0.83), respectively. CONCLUSION: RPR is of some diagnostic value to the prediction of HBV-related significant fibrosis, advanced fibrosis and cirrhosis. This conclusion is urgently needed to be verified by further multi-center studies of large sample size and rigorous design.

Simultaneous or Prior Activation of Intrahepatic Type I Interferon Signaling Leads to Hepatitis B Virus Persistence in a Mouse Model.

It remains controversial how interferon (IFN) response contributes to hepatitis B virus (HBV) control and pathogenesis. A previous study identified that hydrodynamic injection (HI) of type I IFN (IFN-I) inducer polyinosinic-poly(C) [poly(I·C)] leads to HBV clearance in a chronic HBV mouse model. However, recent studies have suggested that premature IFN-I activation in the liver may facilitate HBV persistence. In the present study, we investigated how the early IFN-I response induces an immunosuppressive signaling cascade and thus causes HBV persistence. We performed HI of the plasmid adeno-associated virus (pAAV)/HBV1.2 into adult BALB/c mice to establish an adult acute HBV replication model. Activation of the IFN-I signaling pathway following poly(I·C) stimulation or murine cytomegalovirus (MCMV) infection resulted in subsequent HBV persistence. HI of poly(I·C) with the pAAV/HBV1.2 plasmid resulted in not only the production of IFN-I and the anti-inflammatory cytokine interleukin-10 (IL-10) but also the expansion of intrahepatic regulatory T cells (Tregs), Kupffer cells (KCs), and myeloid-derived suppressor cells (MDSCs), all of which impaired the T cell response. However, when poly(I·C) was injected at day 14 after the HBV plasmid injection, it significantly enhanced HBV-specific T cell responses. In addition, interferon-alpha/beta receptor (IFNAR) blockade rescued T cell response by downregulating IL-10 expression and decreasing Treg and KC expansion. Consistently, Treg depletion or IL-10 blockade also controlled HBV replication. IMPORTANCE IFN-I plays a double-edged sword role during chronic HBV infection. Here, we identified that application of IFN-I at different time points causes contrast outcomes. Activation of the IFN-I pathway before HBV replication induces an immunosuppressive signaling cascade in the liver and consequently caused HBV persistence, while IFN-I activation post HBV infection enhances HBV-specific T cell responses and thus promotes HBV clearance. This result provided an important clue to the mechanism of HBV persistence in adult individuals.

High-throughput chromosome conformation capture-based analysis of higher-order chromatin structure in nasopharyngeal carcinoma.

BACKGROUND: Firstly, we aimed to compare the differences of higher-order chromatin structure between nasopharyngeal carcinoma (NPC) and normal nasopharyngeal tissues. The second objective was to analyze the specific chromatin interaction site of NPC and the NPC-related genes regulated by this interaction site. METHODS: We included 6 NPC patients and 6 healthy controls to obtain the sequencing results of highest-throughput chromosome conformation capture (Hi-C) technique, followed by further analysis of the specific chromatin interaction sites in NPC. RESULTS: We found an abnormal ultra-long distance interaction site on the chromosome 7p in the CNE210 sample, which was caused by a fusion gene SEPT7P2-PSPH. Additionally, a significant interaction site between chromosome 8q and 3p was revealed in the samples CNE25, CNE29, and CNE211, which was the interaction between 1.5 kb downstream of ASAP1 and 0.8 kb upstream of CTNNB1 gene. Further quantitative polymerase chain reaction (qPCR) revealed that ASAP1 and CTNNB1 genes were more highly expressed in CNE25, CNE29, and CNE211 than in the Np group, preliminarily indicating that this interaction site was likely related to the high expression of ASAP1 and CTNNB1 in NPC. CONCLUSIONS: Through Hi-C analysis, we analyzed the specific chromatin interaction sites associated with NPC, and found the chromosomal translocation and chromatin interaction sites associated with NPC based on statistical analysis. This study has certain guiding significance for in-depth study of the mechanism of NPC occurrence and development.

Impact of the Gut Microbiome on the Progression of Hepatitis B Virus Related Acute-on-Chronic Liver Failure.

The relationship between the progression of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) and the gut microbiota is poorly understood, and an HBV-ACLF-related microbiome has yet to be identified. In this study alterations in the fecal microbiome of 91 patients with HBV-ACLF (109 stool samples), including a cohort of nine patients at different stages of HBV-ACLF, were determined by high-throughput 16S rDNA sequencing. The operational taxonomic units and Shannon indexes indicated that the diversity and abundance of the gut microbiome significantly decreased with the progression of HBV-ACLF (p <0.05). The relative abundance of the Bacteroidetes phylum in the microbiome was significantly reduced, whereas the abundance of potentially pathogenic bacteria, such as Veilonella, Streptococcus, Enterococcus, and Klebsiella, was highly enriched in the HBV-ACLF group compared with the healthy control group. The abundance of Bacteroidetes was negatively correlated with the level of serum alpha fetoprotein, and the abundance of Veilonella was positively correlated with serum total bilirubin (TBIL). Furthermore, the abundance of Coprococcus was significantly negatively correlated with the level of serum TBIL and the international normalized ratio and positively correlated with prothrombin time activity. Our findings suggest that the gut microbiota plays an important role in the development of HBV-ACLF.

[Analysis of the Types of Thalassemia Gene Mutations in Nanping Area of Fujian, China].

OBJECTIVE: To investigation the types and frequencies of thalassemia gene mutations in pregnant population in Nanping area of Fujian Province, so as to provide a basis for prevention and control of birth children with moderate and severe thalassaemia in this area. METHODS: The genotyping of α and ß thalassemia was performed using the gap-PCR (gap-PCR) technique combined with reverse dot blot (RDB). The genotyping test was performed by Gap-PCR for three rare deficient thalassemia. The cases with negative detection were further detected by Sanger sequencing method, so as to identify rare α or ß thalassemia mutation. RESULTS: 1120 specimens were genotyped for thalassemia, out of them 547 thalassemia genes were determined. The detection rate was 48.8% (547/1120). 340 specimens were diagnosed as α thalassemia, and the detection rate was 30.6%, including 266 cases of --SEA/αα, 44 cases of -α3.7/αα, 12 cases of -α4.2/αα, 8 cases of ααQS/αα,. 3 cases of Hb H disease ( 2 cases of --SEA/-α3.7, 1 case of --SEA/-α4.2), 2 cases of ααCS/αα, 2 cases of ααWS/αα, 1 case of -α3.7/-α3.7, and 1 case of -α3.7/ααQS. Also, they contain 11 cases of rare α thalassemia, 8 kinds of rare types of α thalassemia mutations in combination, such as 4 cases of ααIVS-II-55 (T→G) in α1/αα, 1 case of ααIVS-I-62 (C→T) in α1/αα, 1 case of ααCD106（CTG→GTG）in α2/αα, 1 case of ααHBA2:c.-24C>G/αα, 1 case of ααIVS-II-55 (T→G) in α1/ααIVS-II-55 (T→G) in α1, 1 case of ααIVS-II-55 (T→G) in α1/ααIVS-II-119 (G;+CTCGGCCC) in α2, 1 case of ααIVS-II-88 (G→A) in α2/αα, and 1 case of --THAI/αα. Among them, 5 α mutation sites were first reported, namely ααIVS-I-62 (C→T) in α1, ααIVS-II-55 (T→G) in α1, ααIVS-II-119 (G; +CTCGGCCC ) in α2, ααIVS-II-88 (G→A) in α2 and ααCD106 (CTG→GTG) in α2; 2 α thalassemia mutation sites: ααHBA2: c.-24C>G and --THAI were detected again in the Chinese population, respectively. 188 specimens were diagnosed as ß thalassemia with a detection rate of 16.8%. Among them, 68 cases of ßIVS-II-654/ßN, 47 cases of ßCD41-42/ßN, 20 cases of ßCD17/ßN, 17 cases of ß-28/ßN, 7 cases of ßCD27-28/ßN, 7 cases of ßE/ßN, 3 cases of ßCD71-72/ßN and 2 cases of ßCD43/ßN. And 17 cases were diagnosed as rare ß thalassemia, 8 kinds of rare types were ß thalassemia mutations in combination. There were 4 cases of ßIVS-II-81 (C→T)/ßN, 3 cases of ßHb J-Bangkok/ßN, 3 cases of ßHb New York/ßN, 2 cases of ß-96 (G→T)/ßN, 2 cases of ßIVS-II-806 (G→C)/ßN, 1 case of ßCodons 8/9/ßN, 1 case of ßHb G-Coushatta/ßN, 1 case of ßIVS-II-827 (A→T)/ßN. Among them, 3 ß thalassemia mutation sites were reported for the first time, namely ß-96 (G→T), ßIVS-II-806 (G→C) and ßIVS-II-827 (A→T); it was found that in the Chinese population as ßCodons 8/9, ßHb G-Coushatta, ßHb J-Bangkok, ßHb New York, and ßIVS-II-81 (C→T), respectively. 19 cases were diagnosed as αß-complex thalassemia, out of which 15 types of thalassemia mutation combinations were detected. They contain 2 cases of rare αß-complex thalassemia, which are ααIVS-II-55 (T→G)/αα complex ßIVS-II-81 (C→T)/ßN, ααIVS-II-65 (G→A) in α1/αα complex ßHb G-Coushatta/ßN. CONCLUSION: The types of thalassemia gene mutations in Nanping area of Fujian province are genetically heterogeneous. The prevention and control strategies of thalassaemia in this area should be based on the prevention and treatment of common α thalassemia and ß thalassaemia. And the attention should be paid to the types of rare and unknown gene mutations using screening and testing method.

Pilot study of a novel multi-functional noninvasive prenatal test on fetus aneuploidy, copy number variation, and single-gene disorder screening.

BACKGROUND: The noninvasive prenatal testing (NIPT) has been successfully used in the clinical screening of fetal trisomy 13, 18, and 21 in the last few years and researches on detecting sub-chromosomal copy number variations (CNVs) and monogenic diseases are also in progress. To date, multiple tests are needed in order to complete a full set of fetus disorder screening, which is costly and time consuming. Therefore, an integrated 3-in-1 NIPT approach will be in great demand by routine clinical practice in the near future. METHODS: We designed a target capture sequencing panel with an associate bioinformatics pipeline to create a novel multi-functional NIPT method and we evaluated its performance by testing 22 clinical samples containing aneuploidy, CNV, and single-gene disorder. Chromosomal aneuploidy and CNV were detected based on the Z-value approach, whereas single-gene disorder was identified by using the "pseudo-tetraploid" model to estimate the best-suited genotype for each locus. RESULTS: The performance of this newly constructed 3-in-1 system was promising. We achieved a 100% detection rate for chromosomal aneuploidies (7/7), a 100% diagnosis rate for fetus CNVs larger than 20 Mb (3/3), and an 86.4% accuracy for single-gene disorder screening (19/22). CONCLUSION: For the first time, we showed that it is possible to use just a single NIPT test to detect three distinct types of fetus disorder and laid a foundation for developing a cheaper, faster, and multi-functional NIPT method in the future.

Pre-Activation of Toll-Like Receptor 2 Enhances CD8+ T-Cell Responses and Accelerates Hepatitis B Virus Clearance in the Mouse Models.

Toll-like receptors (TLRs) play a crucial role in activation of innate immunity, which is essential for inducing effective adaptive immune responses. Our previous studies have shown that toll-like receptor 2 (TLR2) is required to induce effective virus-specific T-cell responses against hepatitis B virus (HBV) in vivo. However, the contribution of TLR2 activation to adaptive immunity and HBV clearance remains to be clarified. In this study, we explored the hydrodynamic injection (HI) mouse models for HBV infection and examined how the TLR2 agonist Pam3CSK (P3C) influences HBV control and modulates HBV-specific T-cell response if applied in vivo. We found that TLR2 activation by P3C injection leads to the rapid but transient production of serum proinflammatory factors interleukin-6 and tumor necrosis factor-α and activation of CD8+ T cells in vivo. Then, the anti-HBV effect and HBV-specific T-cell immunity were investigated by TLR2 activation in the mouse models for persistent or acute HBV infections using HBV plasmids pAAV-HBV1.2 and pSM2, respectively. Both P3C application at early stage and pre-activation promoted HBV clearance, while only TLR2 pre-activation enhanced HBV-specific T-cell response in the liver. In the mouse model for acute HBV infection, P3C application had no significant effect on HBV clearance though P3C significantly enhanced the HBV-specific T-cell response. Collectively, TLR2 pre-activation enhances HBV-specific T-cell responses and accelerates HBV clearance in HI mouse models. Thus, the modulation of host immune status by TLR2 agonists may be explored for immunotherapeutic strategies to control HBV infection.

Local Stimulation of Liver Sinusoidal Endothelial Cells with a NOD1 Agonist Activates T Cells and Suppresses Hepatitis B Virus Replication in Mice.

Functional maturation of liver sinusoidal endothelial cells (LSECs) induced by a NOD1 ligand (diaminopimelic acid [DAP]) during viral infection has not been well defined. Thus, we investigated the role of DAP-stimulated LSEC maturation during hepatitis B virus (HBV) infection and its potential mechanism in a hydrodynamic injection (HI) mouse model. Primary LSECs were isolated from wild-type C57BL/6 mice and stimulated with DAP in vitro and in vivo and assessed for the expression of surface markers as well as for their ability to promote T cell responses via flow cytometry. The effects of LSEC maturation on HBV replication and expression and the role of LSECs in the regulation of other immune cells were also investigated. Pretreatment of LSECs with DAP induced T cell activation in vitro. HI-administered DAP induced LSEC maturation and subsequently enhanced T cell responses, which was accompanied by an increased production of intrahepatic cytokines, chemokines, and T cell markers in the liver. The HI of DAP significantly reduced the HBsAg and HBV DNA levels in the mice. Importantly, the DAP-induced anti-HBV effect was impaired in the LSEC-depleted mice, which indicated that LSEC activation and T cell recruitment into the liver were essential for the antiviral function mediated by DAP application. Taken together, the results showed that the Ag-presenting ability of LSECs was enhanced by DAP application, which resulted in enhanced T cell responses and inhibited HBV replication in a mouse model.

EMSY promoted the growth and migration of ovarian cancer cells.

Epithelial ovarian cancer is one of the most common and aggressive diseases among the female reproductive organ malignancies, and the molecular mechanism underlying this disease remains largely unknown. EMSY, a binding partner of BRCA2, has been reported to be amplified in ovarian cancer. However, the expression pattern and biological functions of EMSY in the progression of ovarian cancer are not fully understood. In this study, it was found that the expression of EMSY was significantly elevated in ovarian cancer samples compared to their adjacent normal tissues. Moreover, overexpression of EMSY promoted the growth and migration of ovarian cancer cells, while knocking down the expression of EMSY inhibited the growth, migration, and tumorigenesis of ovarian cancer cells in vitro and in vivo. Mechanistically, EMSY was found to interact with beta-catenin and activate beta-catenin/TCF signaling. Our study demonstrated that EMSY played an oncogenic role in the progression of ovarian cancer cells and EMSY might be a promising target for the treatment.

Poly(I:C) treatment leads to interferon-dependent clearance of hepatitis B virus in a hydrodynamic injection mouse model.

UNLABELLED: We have previously shown that poly(I:C) activates murine hepatic cells to produce interferon (IFN) and suppresses hepatitis B virus (HBV) replication in vitro. Therefore, we addressed whether poly(I:C) is able to induce the clearance of HBV in vivo. The chronic HBV replication mouse model was established by the hydrodynamic injection (HI) of pAAV-HBV1.2 into the tail veins of wild-type and IFN-α/ßR-, IFN-γ-, and CXCR3-deficient C57BL/6 mice. Fourteen days post-HI of pAAV-HBV1.2, mice were administered poly(I:C) by intraperitoneal injection, intramuscular injection, or HI. Only treatment of poly(I:C) by HI led to HBV clearance in wild-type C57BL/6 mice. Serum HBsAg disappeared within 40 days postinfection (dpi) in mice that received poly(I:C) by HI, and this was accompanied by the appearance of anti-HBs antibodies. HBV-specific T-cell and antibody responses were significantly enhanced by HI of poly(I:C). HBV replication intermediates and HBcAg-positive hepatocytes were eliminated in the liver. HI of poly(I:C) induced the production of IFNs in mice and enhanced the levels of cytokines, IFN-stimulated genes, and T-cell markers in the liver. Importantly, poly(I:C)-induced HBV clearance was impaired in IFN-α/ßR-, IFN-γ-, and CXCR3-deficient mice, indicating that the induction of type I IFN and the stimulation and recruitment of T cells into the liver are essential for HBV clearance in this model. Taken together, the application of poly(I:C) by HI into the liver enhances innate and adaptive immune responses and leads to HBV clearance in an HBV mouse model, implicating the potential of intrahepatic Toll-like receptor 3 (TLR3) activation for the treatment of chronic hepatitis B patients. IMPORTANCE: It has become well accepted that immunomodulation is a potentially useful approach to treat chronic viral infection. Recently, combinations of antiviral treatment and therapeutic vaccinations were evaluated for therapies of chronic hepatitis B virus (HBV) infection. Activation of the innate immune branch may also be important for viral control and contributes to HBV clearance. Our present study demonstrated that hepatic TLR3 activation led to clearance of hepatitis B virus in an HBV mouse model. For the first time, we showed that HBV clearance in this model is dependent not only on type I interferon (IFN) but also on type II IFN, indicating a coordinated action of innate and adaptive immune responses. T-cell recruitment appeared to be critical for the success of TLR3-mediated antiviral action. These findings implicate the potential of intrahepatic TLR3 activation for the treatment of chronic HBV infection.

Establishment and application of hepatitis B virus persistent replication model in IFNAR(-/-) mouse.

The type I interferon and IFNAR play an important role in hepatitis B virus (HBV) infection and anti-HBV therapy. However, its mechanism of action is still poorly understood. To gain more insights into the role of type I interferon and type I interferon receptor (IFNAR) in HBV infection, we established an HBV persistent replication IFNAR knockout (IFNAR(-/-)) mouse model and preliminarily applied this model. At first, the progeny of IFNAR(-/-) mouse was reproduced. Then hydrodynamic injection with pAAV/HBV1.2 plasmid was conducted to establish the persistent HBV replication IFNAR(-/-) mouse model. At last, we applied this model to evaluate the effect of nucleoside analogues entecavir (ETV) on HBV replication. It was found that there was no difference in the serum HBsAg and HBeAg levels and HBcAg expression in the liver tissue between the ETV treated groups and normal saline (NS) treated group, but the serum HBV DNA levels were significantly suppressed 10, 25, 40 and 55 days after the ETV treatment [P=0.035, P=0.00, P=0.149 and P=0.084, IFNAR knockout (KO) control group vs. C57BL/6 ETV groups, respectively; P=0.081, P=0.001, P=0.243 and P=0.147, IFNAR KO control group vs. IFNAR KO ETV groups, respectively]. Interestingly, there was no difference in serum HBV DNA levels between the ETV treated IFNAR(-/-) and C57BL/6 mice. This result suggests that HBV suppression during ETV treatments doesn't depend on type I interferon and IFNAR. Collectively, persistent HBV replication IFNAR(-/-) mouse model that we established is a useful and convenient tool to detect the function of the type I interferon and IFNAR in HBV infection and anti-HBV treatments.

Chronic HBV carrier's acceptance of regular surveilling program in China.

Long-term compliance with regular surveillance is important for the prevention and timely management of chronic hepatitis B (CHB). However, there are no researches focusing on the compliance of hepatitis B virus infected patients in regular surveillance so far. The purpose of our study was to investigate the outpatient compliance with long-term regular surveillance in China. Data of 3257 CHB outpatients was pooled and analyzed to assess the outpatient's compliance with the long-term regular surveillance plan. In all outpatients, the non-follow-up and the follow-up group accounted for 73.2% and 26.8%, respectively. Among the follow-up outpatient's, only 48.9% received ongoing-follow-up and 51.1% were finally lost to follow-up; the median length of visiting duration was 25 months; and the predictive 1-, 2-, 3-, 4- and 5-year ongoing follow-up rate was 72.7%, 52.5%, 42.4%, 33.8%, and 26.3%, respectively. In conclusion, our survey proved that the regular long-term surveillance on Chinese chronic HBV carrier is difficult to be fully implemented. A large proportion of outpatients do not receive routine follow-up and are at risk of treatment delay due to various social reasons.

[Toll-like receptor dependent innate immune responses by primary mouse hepatocytes and its control of HBV replication].

OBJECTIVE: This report aims to investigate the Toll-like receptor (TLR) signaling pathways and induced antiviral activity in hepatocytes. METHODS: We isolated primary hepatocytes from wild-type C57BL/6 mice and examined the expression of TLR by realtime RT-PCR. Hepatocytes were stimulated with TLR 1-9 agonists and the supernatants were harvested. The secretion of cytokines were tested by ELISA. The antiviral effectors in supernatants were assayed via virus protection assay (in EMCV system) and the control of HBV replication were assessed via Southern blotting (in HBV system). RESULTS: We demonstrated that hepatocytes expressed TLR1-9. In accordance with these TLR expression profiles, hepatocytes responded to all TLR ligands by producing inflammatory cytokines (TNF-α or IL-6), to TLR -1,-3,-7 and -9 ligands by producing type I IFN (IFN-α or IFN-ß). Only TLR 3 and TLR 7 agonists could stimulate the production of high amounts of antiviral mediators by hepatocytes in virus protection assay. By contrast, supernatants from TLR1, -3 and -4 directly stimulated hepatocytes and TLR 3, -7 and -9 transfected hepatocytes were able to potently suppress HBV replication. CONCLUSION: Primary hepatocytes display a unique TLR signaling pathway and can control HBV replication after stimulation by TLR agonists in mice. It may be helpful for the development of TLR-based therapeutic approaches against hepatotropic virus.