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Ethnopharmacological Relevance: Alzheimer's disease (AD) is a common type of neurodegenerative disease with the β-amyloid plaques (Aβ) deposition. Previously, Dengzhan Shengmai capsule (DZSM) has been shown to reduce the pathology associated with AD, but the underlying mechanism is unclear., Aim of Study: This study investigated the potential mechanisms of DZSM against AD., Materials and Methods: The six-month-old wild-type male mice and APP/PS1 double transgenic male mice were administered 0.9 % saline or DZSM for 8 weeks by gavage. Open field test, new object recognition test, and Morris Water maze test were used to assess spatial learning and memory. Aβ plaques in brains were visualized using ThT staining. Nissl staining, TUNEL staining, and western blot analyses were used to detect the neuronal function and apoptosis level. The superoxide dismutase (SOD), glutathione peroxidase assay kit (GSH-Px), and malondialdehyde (MDA) kits were performed to assess oxidative stress levels. Then, immunofluorescence and western blot analysis were applied to evaluate ER stress pathway protein levels. Finally, HT22 cells were treated by Aβ 1-42 with or without DZSM medicated serum. Cell viability was assessed using the CCK-8 assay, and western blot analysis was applied to evaluate ER stress pathway protein levels., Results: Open filed test, new object recognition test and Morris Water maze test showed that DZSM restored cognitive disorders in APP/PS1 mice. Immunohistochemistry and Thioflavin T staining results indicated that DZSM reduced Aβ plaques in the brain. Deeper and denser Nissl bodies were found in APP/PS1 mice after DZSM administration. Besides, APP/PS1 mice treated with DZSM showed a lower level of TUNEL and Bax/Bcl-2 ratio. DZSM improved the acetylcholine (ACh), choline acetyltransferase (ChAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activity while reducing acetylcholinesterase (AChE) and malondialdehyde (MDA) activity. In addition, the levels of ER stress pathway containing Phospho-PKR-like ER kinase (P-PERK), phosphorylate eukaryotic initiation factor 2 (P-eIF2α), activating transcription factor 4 (ATF4), glutamine-rich protein 1 (QRICH1), phosphorylate inositol-requiring protein 1α (P-IRE1α), the spliced form of X-box binding protein 1 (XBP1s), activating transcription factor-6 (ATF6) and C/EBP homologous binding protein (CHOP) were decreased by DZSM. CCK-8 results indicated that DZSM medicated serum played cytoprotective effects on Aβ 1-42 -induced HT22 cells. Western blot results suggested DZSM possibly inhibited ER stress pathways in Aβ 1-42 -induced HT22 cells., Conclusion: The potential protective mechanism of DZSM on cognitive impairment in AD might be related to ER stress pathways., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Chronic hepatitis B virus (HBV) infection is one of the major public health issues of ongoing global concern. Due to inadequate understanding of the HBV life cycle, there is a lack of effective drugs to cure chronic hepatitis B. During HBV replication, covalently closed circular DNA (cccDNA) serves as the template for viral replication and can be transcribed to produce five viral RNAs of 3.5, 2.4, 2.1 kb and 0.7 kb in length, which are translated to produce HBeAg, core protein, polymerase (P) protein, HBsAg and HBx proteins, respectively. Among them, the 3.5 kb pregenomic RNA (pgRNA) is also the template for viral reverse transcription. Polymerase protein recognizes and binds to the capsid assembly signal on the pgRNA to initiate capsid assembly and reverse transcription. Recent studies have revealed that the processes of splicing, nuclear export, stability, translation, and pgRNA encapsidation of HBV RNAs are regulated by a post-transcriptional regulatory network within the host cell and depend on unique post-transcriptional regulatory elements in the HBV RNA structure. The aim of this review is to overview the post-transcriptional regulatory mechanisms of HBV RNA and their applications in the study of HBV antiviral therapeutics, with the aim of providing new ideas for the development of new drugs targeting HBV RNA.

Objective: To investigate the hepatitis B surface antigen (HBsAg) clearance condition and its predictive factors after treatment with nucleos(t)ide analogues to pegylated interferon-α add-on therapy in patients with chronic hepatitis B. Methods: Patients with chronic hepatitis B who visited the First Affiliated Hospital of Zhengzhou University from 2018~2019 were prospectively enrolled. HBsAg≤ 1500 IU/mL, hepatitis B e antigen-negative, HBV DNA undetectable, received antiviral treatment with nucleos(t)ide analogues for at least one year, and pegylated interferon-α add-on therapy for 48 weeks were included. The primary endpoint of study was to determine the proportion of HBsAg clearance at 72 weeks. Concurrently, the predictive factors for HBsAg clearance were analyzed. Quantitative and qualitative data were analyzed using a t-test or non-parametric test and a Fisher's exact test. Results: A total of 38 cases were included in this study, of which 13 cases obtained HBsAg clearance at 48 weeks of therapy and another six cases obtained HBsAg clearance throughout the extended treatment period of 72 weeks, accounting for 50.00% of all enrolled patients. There was a significant difference in HBsAg dynamics between the HBsAg clearance group and the non-clearance group (P < 0.05). Univariate logistic regression analysis showed that patients' age, baseline, 12-and 24-week HBsAg levels, and early HBsAg reduction were predictive factors for HBsAg clearance at 72 weeks of treatment. Multivariate logistic regression analysis showed that age (OR = 1.311; P = 0.016; 95% confidence interval: 1.051~1.635) and HBsAg levels at 24 weeks of treatment (OR = 4.481; P = 0.004; 95% confidence interval: 1.634~12.290) were independent predictors for HBsAg clearance. Conclusion: Hepatitis B e antigen-negative, nucleos(t)ide analogue treated, HBsAg ≤ 1500 IU/mL, and HBV DNA undetectable, peg-IFNα add-on treatment for 48 weeks could promote HBsAg clearance in patients with chronic hepatitis B. Six of the sixteen cases (37.50%) who did not obtain HBsAg clearance at week 48 did so with the course of therapy extended to week 72. Hence, the optimal individualized treatment strategy should be customized according to the predictors rather than the fixed 48-week course. Age (≤ 38), baseline HBsAg level (≤2.86 log(10)IU/ml), HBsAg level at 24 weeks (≤ 0.92 log(10)IU/ml), and 12-week HBsAg decrease from baseline (≥ 0.67 log(10)IU/ml) indicate that patients are highly likely to obtain HBsAg clearance at the 72 weeks of combination therapy, in which the combined indicator based on HBsAg level ≤0.92 log(10)IU/ml at 24 weeks will identify 85.0% to 100.0% of patients with HBsAg clearance.

Objective: Lung cancer (LC) is the highest contributor to cancer-associated mortality worldwide. Approximately 85% of all LC incidences involve non-small cell LC (NSCLC). Unfortunately, owing to a significant lack of sensitive and robust bioindicators, most patient diagnoses occur at advanced stages of the disease, thereby resulting in extremely poor patient outcomes. Herein, we elucidated the role of interleukin-17A (IL-17A) among NSCLC patients., Materials and Methods: Circulating IL-17A content was measured using enzyme-linked immunosorbent assay (ELISA), and its diagnostic and prognostic abilities were assessed using the receiver operating characteristic (ROC) curve and Kaplan-Meier analysis, respectively., Results: Our analysis revealed that circulating IL-17A levels were significantly augmented among NSCLC vs. control samples. Moreover, based on our area under the curve (AUC) analysis, circulating IL-17A levels fared considerably better than the standard bioindicator carcinoembryonic antigen (CEA) in both testing and validation cohorts. Notably, we also revealed that the circulating IL-17A levels were accurately and reliably predicted in early-stage NSCLC patients. Besides, we demonstrated a strong correlation between elevated circulating IL-17A expression and worse prognosis among NSCLC patients., Conclusions: Herein, we demonstrated that circulating IL-17A levels can serve as reliable and potent diagnostic and prognostic bioindicators for NSCLC.

Objective: To explore the relationship and dynamic changes between virological markers and hepatic pathological damage due to host anti-hepatitis B virus (HBV) immunity in the natural course of disease in chronic HBV infected patients. Methods: Two hundred and thirty-eight adult chronic HBV-infected patients who underwent liver biopsy from January 2016 to June 2022 in Taizhou Hospital, Zhejiang Province, were retrospectively selected. General clinical data such as age, gender, platelets, ALT, AST, albumin, HBV DNA, qHBsAg, HBeAg, and liver pathology diagnostic indexes such as the grade of liver necroinflammation and liver fibrotic stages of the patients were collected. The patients were grouped according to HBeAg status, and subgrouped according to different grades of liver necroinflammation and different HBV DNA loads. Statistical analyses were performed to compare the differences in HBV virologic marker levels between the groups, and the correlation between them and the indicators of hepatic inflammatory injury, such as ALT,AST, and the grade of liver necroinflammation in the patients. Results: The levels of HBV virological markers in HBeAg-positive patients with moderate or higher liver necroinflammatory grade (G≥2) were significantly lower than those with mild (no) liver necroinflammatory grade (G < 2) ( P < 0.01); whereas the opposite trend was observed in HBeAg-negative patients, with the levels of HBV DNA, and qHBsAg in the G≥2 subgroup being significantly higher than those in the G < 2 subgroup ( P < 0.01). Correspondingly, HBV DNA level and qHBsAg showed weak to moderately strong negative correlation with liver necroinflammatory grade and AST which was an indicator of hepatic inflammatory injury in HBeAg-positive patients ( P < 0.05); whereas in HBeAg-negative patients, they showed weak to moderately strong positive correlation with hepatic inflammatory activity and ALT, AST ( P < 0.001), in which qHBsAg showed only a weak positive correlation with patients' liver necroinflammatory grade ( P = 0.003). Further subgroup analyses of HBeAg-positive patients according to whether the HBV DNA level was > 2×10(6) IU/ml showed weak to moderate negative correlations between HBV virological markers and liver necroinflammatory grade as well as ALT and AST in the subgroup of patients with HBV DNA > 2×10(6) IU/ml ( P < 0.05); however, the negative correlation disappeared in patients who were still HBeAg positive and had HBV DNA ≤ 2×10(6) IU/ml. Moreover, HBV DNA and ALT, HBeAg and AST showed moderate positive correlation ( P < 0.05). Conclusion: We speculate that the activation of host anti-HBV immunity can efficiently inhibit HBV replication by targeting the infected hepatocytes, but only in the early phase of disease progression in HBeAg positive patients with HBV DNA high (> 2×10(6) IU/ml).

Objective: To explore carnosine dipeptidase 1 (CNDP1) potential value as a diagnostic and prognostic evaluator of hepatocellular carcinoma (HCC). Methods: A gene chip and GO analysis were used to screen the candidate marker molecule CNDP1 for HCC diagnosis. 125 cases of HCC cancer tissues, 85 cases of paracancerous tissues, 125 cases of liver cirrhosis tissues, 32 cases of relatively normal liver tissue at the extreme end of hepatic hemangioma, 66 cases from serum samples of HCC, and 82 cases of non-HCC were collected. Real-time fluorescent quantitative PCR, immunohistochemistry, western blot, and enzyme-linked immunosorbent assay were used to detect the differences in mRNA and protein expression levels of CNDP1 in HCC tissue and serum. Receiver operating characteristic (ROC) curves and Kaplan-Meier survival were used to analyze and evaluate the value of CNDP1 in the diagnosis and prognosis of HCC patients. Results: The expression level of CNDP1 was significantly reduced in HCC cancer tissues. The levels of CNDP1 were significantly lower in the cancer tissues and serum of HCC patients than those in liver cirrhosis patients and normal controls. ROC curve analysis showed that the area under the curve of serum CNDP1 in the diagnosis of HCC patients was 0.753 2 (95% CI 0.676-0.830 5), and the sensitivity and specificity were 78.79% and 62.5%, respectively. The combined detection of serum CNDP1 and serum alpha-fetoprotein (AFP) significantly improved the diagnostic accuracy (AUC = 0.820 6, 95% CI 0.753 5-0.887 8). The diagnostic sensitivity and specificity of serum CNDP1 for AFP-negative HCC patients were 73.68% and 68.75% (AUC = 0.793 1, 95% CI 0.708 8-0.877 4), respectively. In addition, the level of serum CNDP1 distinguished small liver cancer (tumor diameter < 3 cm) (AUC = 0.757 1, 95% CI 0.637 4-0.876 8). Kaplan-Meier survival analysis showed that CNDP1 was associated with a poor prognosis in HCC patients. Conclusion: CNDP1 may be a potential biomarker for the diagnostic and prognostic evaluation of HCC, and it has certain complementarity with serum AFP.

Alzheimer's disease (AD) is the most common type of dementia with an insidious onset and slow progression. Kai-Xin-San (KXS) has been reported to be effective in improving cognitive impairment in AD. However, the mechanism is still confused. In this study, we employed APP/PS1 mice to explore the neuroprotective mechanism of KXS. Forty-eight male APP/PS1 mice were randomly divided into model group, KXS groups (0.7, 1.4, and 2.8 g/kg/d, p.o.) and the wild-type mice were assigned to the normal control group ( n  = 12 in each group). Y-maze and novel object recognition tests were carried out after continuous intragastric administration for 2 months. The abilities of learning, memory, and new object recognition in the APP/PS1 mice were enhanced significantly after KXS treatment. KXS can reduce the deposition of Aβ 40 and Aβ 42 in APP/PS1 mice brain. KXS decreased the levels of serum inflammatory cytokines, tumor necrosis factor-α, interleukin-1β, and interleukin-6. KXS increased the activities of superoxide dismutase and glutathione peroxidase significantly, whereas it inhibited the contents of reactive oxygen species and malondialdehyde significantly. In addition, we also detected Wnt/β-catenin signaling related proteins, such as Wnt7a, β-catenin, low-density lipoprotein receptor-related protein 6 (LRP6), glycogen synthase kinase-3β (GSK-3β), nuclear factor kappa-B (NF-κB), postsynaptic density 95 (PSD95), microtubule associated protein-2 (MAP-2), and endoplasmic reticulum stress (IRE1 pathway) related proteins, such as inositol-requiring enzyme 1 (IRE1), phosphorylated IRE1(p-IRE1), spliced X-box-binding protein 1 (XBP1s), immunoglobulin binding protein (BIP), and protein disulfide isomerase (PDI) in the hippocampus. Results showed that KXS decreased the expression of GSK-3β, NF-kB, p-IRE1/IRE1 ratio, XBP1s, and BIP; increased the expression of Wnt7a, β-catenin, LRP6, PSD95, MAP2, and PDI. In conclusion, KXS improved cognitive impairment by activating Wnt/β-catenin signaling, inhibiting the IRE1/XBP1s pathway in APP/PS1 mice.

Ischemia stroke is thought to be one of the vascular risks associated with neurodegenerative diseases, such as Alzheimer's disease (AD). Hydroxysafflor yellow A (HSYA) has been reported to protect against stroke and AD, while the underlying mechanism remains unclear. In this study, SH-SY5Y cell model treated with oxygen-glucose deprivation/reperfusion (OGD/R) was used to explore the potential mechanism of HSYA. Results from cell counting kit-8 (CCK-8) showed that 10 μM HSYA restored the cell viability after OGD 2 hours/R 24 hours. HSYA reduced the levels of malondialdehyde and reactive oxygen species, while improved the levels of superoxide dismutase and glutathione peroxidase. Furthermore, apoptosis was inhibited, and the expression of brain-derived neurotrophic factor was improved after HSYA treatment. In addition, the expression levels of amyloid-β peptides (Aβ) and BACE1 were decreased by HSYA, as well as the expression levels of binding immunoglobulin heavy chain protein, PKR-like endoplasmic reticulum (ER) kinase pathway, and activating transcription factor 6 pathway, whereas the expression level of protein disulfide isomerase was increased. Based on these results, HSYA might reduce Aβ toxicity after OGD/R by interfering with apoptosis, oxidation, and neurotrophic factors, as well as relieving ER stress.

Background: Serum protein induced by vitamin K absence or antagonist-II (PIVKA-II) is a promising biomarker for hepatocellular carcinoma (HCC) surveillance., Aim: To identify the contributing factors related to the abnormal elevation of PIVKA-II level and assess their potential influence on the performance of PIVKA-II in detecting HCC., Methods: This study retrospectively enrolled in 784 chronic liver disease (CLD) patients and 267 HCC patients in Mengchao Hepatobiliary Hospital of Fujian Medical University from April 2016 to December 2019. Logistic regression and the area under the receiver operating characteristic curve (AUC) were used to evaluate the influencing factors and diagnostic performance of PIVKA-II for HCC, respectively., Results: Elevated PIVKA-II levels were independently positively associated with alcohol-related liver disease, serum alkaline phosphatase (ALP), and total bilirubin (TBIL) for CLD patients and aspartate aminotransferase (AST) and tumor size for HCC patients (all P < 0.05). Serum PIVKA-II were significantly lower in patients with viral etiology, ALP ≤ 1 × upper limit of normal (ULN), TBIL ≤ 1 × ULN, and AST ≤ 1 × ULN than in those with nonviral disease and abnormal ALP, TBIL, or AST (all P < 0.05), but the differences disappeared in patients with early-stage HCC. For patients with TBIL ≤ 1 × ULN, the AUC of PIVKA-II was significantly higher compared to that in patients with TBIL > 1 × ULN (0.817 vs 0.669, P = 0.015), while the difference between ALP ≤ 1 × ULN and ALP > 1 × ULN was not statistically significant (0.783 vs 0.729, P = 0.398). These trends were then more prominently perceived in subgroups of patients with viral etiology and HBV alone., Conclusion: Serum PIVKA-II has better performance in detecting HCC at an early stage for CLD patients with normal serum TBIL., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Recently, several phase I and phase II clinical trials of antisense oligodeoxynucleotides (ASOs) targeting to the commonly shared conserved sequences of HBV transcripts brought us some promising results. Particularly in the report of phase IIb clinical trial of Bepirovirsen (GSK3228836), approximately 9-10% patients with low baseline serum HBsAg (> 100 IU/ml & < 3 000 IU/ml) achieved functional cure after 24 weeks' of Bepirovirsen treatment. After reviewing the results of other clinical trials, one would be impressed to know that ALG-020572 (Aligos), RO7062931 (Roche) and GSK3389404 (GSK) all failed to sufficiently suppress serum HBsAg expression though the hepatocyte-targeted delivery of these ASOs were enhanced via N-acetyl galactosamine conjugation. Bepirovirsen enabled some patients to achieve sustained disappearance of serum HBsAg. The analysis of its distribution in different tissues of patients after drug administration showed that only a few fractions of ASOs entered liver tissues and far fewer eventually entered hepatocytes. Taking into consideration that only a few hepatocytes could be expected positive for HBsAg staining among these participants with low serum HBsAg level. We suspect that the mechanistic contribution of ASOs declining the serum HBsAg is not only via directly acting on the HBV transcripts in hepatocytes, but also via entering non-parenchymal cells such as Kupffer cells and resulting in stimulation and activation of innate immunity. Eventually the serum HBsAg declines in most participants and even disappears in a small fraction of patients with low baseline HBsAg level, via attack the infected hepatocytes evidenced by the aberrant elevation of ALT. Nevertheless, the functional cure of CHB remains a challenging issue and more efforts are needed.

Nucleoside/Nucleotide analogues (NAs) are widely used for the antiviral treatment of chronic hepatitis B (CHB), however, it is difficult to achieve serum hepatitis B surface antigen (HBsAg) loss with NAs therapy. In recent years, several prospective trails have reported that HBsAg loss (functional cure or clinical cure) also occurs in a small number of hepatitis B e antigen (HBeAg) negative CHB patients who discontinued long-term treatment with NAs. Accordingly, the "stop-to-cure" strategy is proposed. Although the mechanism has not been fully elucidated, the known factors related to serum HBsAg loss with NAs withdrawal include HBV genotype, duration of NAs treatment, serum HBsAg and HBV RNA levels at end-of-treatment, and ethnic differences. In the review, we discuss the best time to stop NAs therapy, the potential markers for predicting relapse after cessation of NAs and the possible mechanism of "stop-to-cure" in HBeAg-negative CHB patients, and propose some suggestions on the time of retreatment.

Objective: To better understand and revise the natural history and disease progression of chronic hepatitis B virus (HBV) infection through analysis of a single-center large-scale cohort of indivi-duals with chronic HBV infection., Methods: Patients with chronic HBV infection who had undergone liver biopsy in the Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital from January 2014 to October 2020 were retrospectively recruited. Based on patient's hepatitis B e antigen (HBeAg) states and pathologic diagnosis, they were categorized into four disease progression statuses (or phases according to the old-terminology in the updated guidelines of chronic hepatitis B (CHB), such as European Association for the Study of the Liver (EASL) 2017, Clinical Practice Guidelines on the Management of Hepatitis B Virus Infection: HBeAg-positive chronic HBV infection (immune tolerance), HBeAg-positive CHB (immune active HBeAg positive), HBeAg-negative chronic HBV infection (inactive carrier), and HBeAg-negative CHB (immune reactive HBeAg negative). Then the demographic, laboratory tests and liver histological results of the patients in different disease progression stages were compared. Age differences between the two groups were evaluated using Mann-Whitney U test., Results: A total of 760 eligible patients with a median age of 29 (interquartile range: 16-39) years were enrolled. Among them, 197 were underage individuals (age < 18 years) and 563 were adults; and 456 were males and 304 females. According to the pathological diagnosis, the patients were classified, and in each of the above four natural disease phases there were 173, 329, 95, and 163 individuals, respectively. Further comparison of the ages of the patients of the four disease progression statuses revealed that patients of HBeAg-negative CHB had a median age at 37 years, which was reasonably higher than those with HBeAg-positive CHB in immune active phase (37 vs . 24 years, P < 0.001), but was relatively younger than those with HBeAg-negative chronic HBV infection (37 vs . 39 years, P = 0.240)., Conclusion: According to this study, it could be speculated that HBeAg-negative CHB patients probably not all reactivate from individuals of HBeAg-negative chronic HBV infection. Instead, certain HBeAg-negative CHB patients may also come from HBeAg-positive CHB patients who have undergone HBeAg clearance or seroconversion and still remain in the immune active state.

Since April 2022, severe acute hepatitis of unknown origin in children has spread to 35 countries and regions around the world, and more than 1 010 cases have been reported. Since the severe acute hepatitis of unknown origin involves a wide range of areas and has a high rate, it is critical to identify the etiology and establish effective preventive, diagnostic and therapeutic measures as soon as possible. This study discusses the possible mechanisms and countermeasures of the severe acute hepatitis of unknown origin in children. It speculates that the occurrence of the recent severe acute hepatitis might be related to adenovirus, adeno-associated virus infection, and the COVID-19 epidemic, while the difference in HLA polymorphism among different races might be related to the fact that reported cases were more common in Europe and the United States. Based on the currently available evidence, it can be preliminarily judged that the risk of large-scale outbreak of severe acute hepatitis of unknown origin in children would be low in China, but the persistent awareness and vigilance of the etiology is still needed.

Direct-acting antivirals (DAAs) can strongly inhibit the replication of hepatitis C virus (HCV) and effectively clear the infection, but it may cause hepatitis B virus (HBV) reactivation, leading to severe liver damage and fulminate hepatitis in patients with HCV/HBV coinfection. In this review, we summarized the different replication process of HCV and HBV in infected hepatocytes and consequent innate immune response, and then discussed the molecular mechanism and clinical significance of HBV reactivation, and put forward the clinical precaution.

Covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) is the template for HBV replication. Currently, there is a lack of therapeutic drugs that directly target cccDNA. Therefore, blocking cccDNA supplements as fast as possible and reducing the existing cccDNA is the key to achieving a complete cure of chronic hepatitis B. Previous studies have suggested that cccDNA had a long half-life, but a recent study showed that it only took a few months to update cycle of cccDNA pool, and its number was much less than previously predicted. In the future, with the advent of new antiviral drugs that can completely inhibit HBV replication, it is expected that the cccDNA pool will be completely cleared due to its supplement complete blockade, so as to achieve virological cure of chronic hepatitis B.

Golgi protein 73 (GP73) is a transmembrane protein on the Golgi apparatus and can be cut and released into the blood. In recent years, an increasing number of clinical studies have shown that the elevated serum GP73 level is closely related to liver diseases. And thus GP73 is expected to be used as a new serum marker for assessing progress of chronic liver diseases. Herein, the clinical application of serum GP73 in chronic hepatitis, liver fibrosis, liver cirrhosis and hepatocellular carcinoma with different etiologies was reviewed based on available literatures; and a research outlook in this field is made.

The first-line nucleos(t)ide analogs (NAs) based antiviral drugs can effectively inhibit HBV replication and slow down the progression of chronic hepatitis B. However, about 20% of patients receiving standard NAs antiviral therapy will still develop low-level viremia (LLV). Therefore, understanding the occurrence mechanism of LLV will help to optimize antiviral treatment regimens and improve the prognosis of patients with chronic hepatitis B. This article systematically summarizes the possible mechanisms of LLV occurrence, and the important factor of NAs failure. Taking into account the unique limitations of NAs competitive inhibition of virus replication, weakening host's immune response is not enough to directly eliminate infected hepatocytes. This makes it difficult to achieve a complete virological response in some patients with the active compensatory proliferation of residual infected hepatocytes and the accompanying effective removal or dilution of covalent, closed, circular DNA (cccDNA) pools. Therefore, it is speculated that activating host immunity can eliminate infected liver cells and may be more conducive to address LLV.

Hepatitis B virus (HBV) is an important pathogen that causes different liver diseases such as viral hepatitis and liver cirrhosis. HBV pregenomic RNA (pgRNA) plays a crucial role in HBV life cycle, which is not only the translation template of core (C) and polymerase (P), but also the template of reverse transcription. The ratio of P protein to core protein is tightly regulated. Since P and core are both translated by pgRNA and the open reading frame (ORF) of P is located downstream of the ORF of core, how to initiate P protein translation is a key scientific question. Previous studies suggest that P can be translated through different mechanisms, such as leaky scanning and reinitiation. In this review, we summarized the proposed mechanisms relevant to the translation of polymerase from HBV pgRNA through literature review and derivation.

The cytotoxic effect targeting hepatitis B virus (HBV) infected hepatocytes from virus-specific cytotoxic T cells and the neutralizing antibodies secreted by virus-specific B cells play an important role in the immune control and elimination of HBV. In patients with chronic hepatitis B, the liver immune microenvironment usually presents a suppression state, and virus-specific immune cells are mostly exhausted. Studies on the interaction between HBV and host immunity during infection, especially the influence of various viral proteins on immune cell function, will contribute to understanding the mechanism of the chronicity of HBV infection, disease progression, and optimization of immunotherapy against HBV. The review summarized the suppressive effects of HBV viral proteins on the host innate immunity and adaptive immune system, to help us understanding the mechanism(s) relevant to the observation that a CHB patient with HBeAg loss and lower HBsAg level is more likley achieving functionall cure. and expect to provide new sights for accelerate virus clearance and achieve functional cure of chronic hepatitis B, by removing the HBV viral proteins and consequently, liberting host immune from suppression state.

Schistosomiasis is a parasitic helminth disease that can cause organ lesions leading to health damage. During a schistosome infection, schistosome eggs can flow into the liver along the portal vein. Numerous inflammatory cells gather around the eggs, causing granulomas and fibrosis in the liver. In this process, many molecules are involved in the initiation and regulation of the fibrous scar formation. However, the precise molecular mechanisms responsible for the progression of granuloma formation and fibrosis initiation caused by schistosome infection have not been extensively studied. In this study, C57BL/6 wild-type mice and Stat3 flox/flox Alb-Cre mice were infected with cercariae of Schistosoma japonicum Liver injury, effector molecule levels, and RNA transcriptome resequencing of liver tissue were detected at 4, 5, and 6 weeks postinfection. We investigated the role of STAT3 (signal transducer and activator of transcription 3) in Schistosoma -induced liver injury in mice. After 6 weeks postinfection, there was obvious liver fibrosis. A sustained pathological process (inflammation, oxidative stress, proliferation, and apoptosis) occurred in S. japonicum -induced liver fibrosis initiation. Meanwhile, we observed activation of the STAT3 pathway in hepatic injury during S. japonicum infection by RNA transcriptome resequencing. Liver deficiency of phospho-STAT3 alleviated infection-induced liver dysfunction, hepatic granuloma formation, and fibrosis initiation. It also promoted STAT3-dependent apoptosis and reduced liver inflammation, oxidative stress, and proliferation. Our results suggest that STAT3 signal pathway and its mediating inflammation, oxidative stress, proliferation, and apoptosis are involved in S. japonicum -induced liver injury and may be a new potential guideline for the treatment of schistosomiasis., (Copyright © 2021 American Society for Microbiology.)

Chronic hepatitis B (CHB) poses a serious threat to the health of the Chinese people. Viral markers are of great significance during antiviral therapy and research and development of innovative drugs. However, traditional serovirological markers such as HBV DNA and hepatitis B surface antigen (HBsAg) have certain limitations in assessing the efficacy of antiviral treatment and accurately reflecting the transcriptional activity of covalently closed circular DNA (cccDNA). In recent years, the role of new viral markers such as HBV RNA, hepatitis B core-related antigen (HBcrAg) and quantitative anti-hepatitis B core protein (qAnti-HBc) have attracted more and more attention because of accurately reflecting the transcription activity of cccDNA, determining the therapeutic effect and predicting the risk of recurrence after drug discontinuation. This article briefly introduces the application of new and old markers in various stages of antiviral therapy in CHB patients, and combines the application of new viral markers in the evaluation of drug efficacy, and expounds its possible role in the research and development of new antiviral therapy.

Objective: To investigate the clinical and diagnostic value of liver stiffness measurement (LSM) for the evaluation and comparison of aspartate aminotransferas/platelet ratio index (APRI), fibrosis 4 indexes (FIB-4) and NAFLD fibrosis score (NFS) with liver fibrosis staging in relation to nonalcoholic fatty liver disease (NAFLD). Methods: 103 cases with NAFLD who met the inclusion criteria confirmed by liver biopsy were selected for retrospective analysis. The results of serological tests and LSM were recorded. The APRI, FIB-4 and NFS were calculated. The accuracy and applicability of four liver fibrosis models in the diagnosis of liver fibrosis in NAFLD patients were compared with the receiver operating characteristic curve (ROC), and the diagnostic cut-off value of LSM was established. Results: Varying degrees of LSM, APRI, FIB-4 and NFS had shown positive correlations with the increasing degree of liver fibrosis. Among them, LSM was positively correlated with the degree of liver fibrosis, and the correlation coefficient was r = 0.727, P < 0.0001. Consistent with this, the area under the receiver operating characteristic curve, sensitivity, and specificity of LSM diagnosis of liver fibrosis in different stages was significantly higher than APRI, FIB-4 and NFS. Area under receiver operating characteristic curve of LSM was 0.862 and 0.928 for significant liver fibrosis ( f ≥ 2), and advanced liver fibrosis ( f ≥ 3). Conclusion: LSM has a good diagnostic exclusion value for NAFLD-induced fibrosis, and its sensitivity and specificity are better than APRI, FIB-4 and NFS.

Objective: To explore and analyze the possible mechanism of liver injury in patients with coronavirus disease 2019 (novel coronavirus pneumonia, NCP). Methods: The correlation between ALT, AST and other liver enzyme changes condition and NCP patients' disease status reported in the literature was comprehensively analyzed. ACE2 expression in liver tissue for novel coronavirus was analyzed based on single cell sequencing (GSE115469) data. RNA-Seq method was used to analyze Ace2 expression and transcription factors related to its expression in liver tissues at various time-points after hepatectomy in mouse model of acute liver injury with partial hepatectomy. t -test or Spearman rank correlation analysis was used for statistical analysis. Results: ALT and AST were abnormally elevated in some patients with novel coronavirus infection, and the rate and extent of ALT and AST elevation in severe NCP patients were higher than those in non-severe patients. Liver tissue results of single cell sequencing and immunohistochemistry showed that ACE2 was only expressed in bile duct epithelial cells of normal liver tissues, and very low in hepatocytes. In a mouse model of acute liver injury with partial hepatectomy, Ace2 expression was down-regulated on the first day, but it was elevated up to twice of the normal level on the third day, and returned to normal level on seventh day when the liver recovered and hepatocyte proliferation stopped. Whether this phenomenon suggests that the bile duct epithelial cells with positive expression of Ace2 participate in the process of liver regeneration after partial hepatectomy deserves further study. In RNA-Seq data, 77 transcription factors were positively correlated with the expression of Ace2 ( r > 0.2, FDR < 0.05), which were mainly enriched in the development, differentiation, morphogenesis and cell proliferation of glandular epithelial cells. Conclusion: We assumed that in addition to the over activated inflammatory response in patients with NCP, the up-regulation of ACE2 expression in liver tissue caused by compensatory proliferation of hepatocytes derived from bile duct epithelial cells may also be the possible mechanism of liver tissue injury caused by 2019 novel coronavirus infection.

Children with Down's syndrome (DS) might exhibit disrupted brain functional connectivity in the motor and prefrontal cortex. To inspect the alterations in brain activation and functional connectivity for children with DS, the functional near-infrared spectroscopy (fNIRS) method was applied to examine the brain activation difference in the motor and prefrontal cortex between the DS and typically developing (TD) groups during a fine motor task. In addition, small-world analysis based on graph theory was also carried out to characterize the topological organization of functional brain networks. Interestingly, behavior data demonstrated that the DS group showed significantly long reaction time and low accuracy as compared to the TD group ( p < 0.05 ). More importantly, significantly reduced brain activations in the frontopolar area, the pre-motor, and the supplementary motor cortex ( p < 0.05 ) were identified in the DS group compared with the TD group. Meanwhile, significantly high global efficiency ( E g ) and short average path length ( L p ) were also detected for the DS group. This pilot study illustrated that the disrupted connectivity of frontopolar area, pre-motor, and supplementary motor cortex might be one of the core mechanisms associated with motor and cognitive impairments for children with DS. Therefore, the combination of the fNIRS technique with functional network analysis may pave a new avenue for improving our understanding of the neural mechanisms of DS., (Copyright © 2020 Xu, Lu, Wang, Hu, Zhang, Chen, Armada-da-Silva and Yuan.)

Objective: To establish and evaluate diagnostic efficacy and applicability of serum Golgi protein (GP) 73 based non-invasive diagnostic model with other conventional serological indicators for compensated stage hepatitis B cirrhosis. Methods: 666 cases with chronic hepatitis B (CHB) who had visited to the Fifth Medical Center of People's Liberation Army General Hospital from January 2010 to December 2017 were selected as the study subjects, and were classified according to compensated stage cirrhosis into clinical and pathological diagnosis group based on whether or not the liver histological examination was performed. A diagnostic model of compensated stage hepatitis B cirrhosis in the clinical diagnosis group was established. The current clinically used diagnostic model of liver cirrhosis, aspartate aminotransferase/platelet ratio index (APRI), fibrosis index (FIB)-4 and liver stiffness measurement (LSM) were compared. Eventually, the diagnostic model was verified step by step by pathological diagnosis group. Results: The area under the receiver operating characteristic curve (AUC) of GP73 and APRI, FIB-4, and LSM for cirrhosis patients in the clinical diagnosis group were 0.842, 0.857, 0.864, and 0.832, respectively. The diagnostic efficiency of the four indicators were of similar ( P value > 0.05). A diagnostic model of compensated stage hepatitis B cirrhosis (GAPA) using logistic regression analysis was established: LogitP = 1/ [1 + exp (1.614-0.054 × GP73-0.045 × Age + 0.030 × PLT-0.015 × ALP)]. The AUC of the model was as high as 0.940 and the optimal cut-off value were 0.41. The corresponding diagnostic sensitivity and specificity were 0.92 and 0.82, respectively. The diagnostic efficiency was better than that of APRI, FIB-4, LSM and GP73 alone ( P < 0.05). The AUC of GAPA was 0.877 in the pathological diagnosis group, which was similar to the diagnostic efficacy of LSM (0.891) and FIB-4 (0.847) ( P > 0.1), but still superior to that of APRI (0.811) and GP73 alone (0.780) ( P < 0.001). Conclusion: GAPA, a diagnostic model for compensated stage hepatitis B cirrhosis established in this study, has a good diagnostic efficacy in both the clinical and pathological diagnosis group, and has certain auxiliary diagnostic value in the areas where resources are relatively scarce or where LSM has not been developed.

Hepatocellular carcinoma (HCC) is a common malignant tumor in China, and most of the patients have a background of chronic HBV infection. Nucleos(t)ide drugs (NAs) are currently recommended by major guidelines as a first-line treatments for chronic hepatitis B. However, it is still clinically possible to observe that some patients who have acquired virological response (HBV DNA below the lower detection limit) after NAS treatment progress to HCC, and its mechanism of development is still unclear. In this review, the mechanism relevant to HCC progression in treatment of chronic hepatitis B patients with NAs is analyzed mainly from the aspects of gene integration and persistent inflammatory injury.

Chronic heart failure affects myocardial energy metabolism and cardiac function. Puerarin has been reported to improve cardiac function through regulation of energy metabolism in mice with myocardial infarction. The aim of the current study was to determine whether puerarin can improve body weight and reduce inflammation and apoptosis in rats with chronic heart failure. Rats were divided into three groups: Puerarin, PBS and sham group. Transverse aortic constriction was performed to induce chronic heart failure in the puerarin an PBS groups. Cardiac function, apoptosis and inflammation were evaluated following a 4-week treatment in rats with chronic heart failure. The results demonstrated that puerarin significantly increased the survival rate of rats and improved cardiac function compared with the PBS group. In addition, puerarin decreased lactate dehydrogenase and succinate dehydrogenase activity compared with the PBS group. Puerarin treatment increased the expression levels of glucose transporter type 4 and decreased the expression levels of CD36. Additionally, puerarin decreased the levels inflammatory factors, including tumor necrosis factor α, interleukin (IL)-1β and IL-6 in serum and myocardial tissue compared with the PBS group. Puerarin upregulated peroxisome proliferator-activated receptor α (PPARα) and its downstream target genes nuclear respiratory factor 1, FOS proto-oncogene, YY1 transcription factor, acetyl-coenzyme A carboxylase a, Fas cell surface death receptor, L-type pyruvate kinase and acetyl-coenzyme A dehydrogenase medium chain in myocardial cells from rats with chronic heart failure. These results demonstrated that puerarin inhibited apoptosis and inflammation in myocardial cells via the PPARα pathway. In conclusion, the present study indicated that puerarin may exhibit antiapoptotic and anti-inflammatory activity through the PPARα pathway in rats with chronic heart failure., (Copyright: © He et al.)

Hepatitis B virus (HBV) infection continues to be a major public health issue worldwide. HBsAg loss is associated with functional remission and improved long-term outcome, and is considered to be a 'functional cure' (also referred to as clinical or immunologic cure) for chronic hepatitis B. This ideal goal of therapy can be achieved using optimized combination regimens with direct-acting antivirals [eg nucleos(t)ide analogues (NAs)] and immunomodulators [eg pegylated interferon alpha2a (Peg-IFN)] in selected patients with chronic hepatitis B. Among different combination therapies currently available, those with NA lead-in followed by Peg-IFN in virally suppressed patients has been demonstrated to be effective. This review provides an updated overview of the evidence supporting the use of combination therapies and summarizes expert consensus on the roadmap to attain functional cure for chronic hepatitis B patients., (© 2019 John Wiley & Sons Ltd.)

Background: Previous studies reported that reduced gray matter volume (GMV) was associated with violent-related behaviors. However, the previous studies were conducted on adults and no study has studied the association between GMV and violent behaviors on adolescents. The purpose of the study was to investigate GMV's effects in adolescent violent offenders based on a Chinese Han population, which can address the problem of possible confounding factors in adult studies., Methods: We recruited 30 male adolescent violent offenders and 29 age- and sex-matched healthy controls (HCs). Differences in both whole-brain and GMV were evaluated using voxel-based morphometry (VBM). We assessed the accuracy of VBM using the receiver operating characteristic curve (ROC) and discriminant analysis., Results: Compared with HCs, the male adolescent offenders showed significantly reduced GMV in five cortical and subcortical brain regions, including the olfactory cortex, amygdala, middle temporal gyrus and inferior parietal lobe in the left hemisphere, as well as the right superior temporal gyrus. Both ROC curve and discriminate analyses showed that these regions had relatively high sensitivities (58.6%-89.7%) and specificities (58.1%-74.2%) with 76.7% classification accuracy., Conclusions: Our results indicated that reduced volume in the frontal-temporal-parietal-subcortical circuit may be closely related to violent behaviors in male adolescents, which might be an important biomarker for detecting violent behaviors in male adolescents., Competing Interests: The authors declare there are no competing interests.

Objective: To determine whether single-stranded guided RNA (gRNA) and Cas9 protein exist in the exosome secreted by cells transfected with CRISPR/Cas9 expression plasmid. Furthermore, to explore whether CRISPR/Cas9 system can edit target genes of peripheral cells through the intercellular transmission of exosomes. Methods: (1) The CRISPR/Cas9 expression plasmid was transfected into HuH7 cells. The supernatant was collected and the exosomes were concentrated and purified by differential centrifugation. The morphology and particle size of exosomes were determined by electronic microscopy and Malvern laser scatter granulometry. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were used to detect the levels of gRNA and Cas9 protein. (2) HuH7 cells transfected with pBB4.5 1.2×HBV and HBV specific CRISPR/Cas9 expression plasmids were co-cultured. After 2 days, HBV DNA was extracted and sequenced by PCR. Results: There were not only full-length gRNA and Cas9 protein in the exosomes of Huh7 cells transfected with CRISPR / Cas9 expression plasmid. In addition, gene-editing functions were delivered between the cells to achieve the destruction of HBV genome of surrounding cells. Conclusion: The CRISPR-Cas9 gene-editing system has the potential to deliver exosomes between cells via carrying functional gRNA and Cas9 proteins. This phenomenon hints that we are in the process of using the CRISPR/Cas9 system for gene therapy. Therefore, it is necessary to consider the potential effects of exosomes-carried gRNA and Cas9 proteins on the surrounding cells of the distal tubules.

Type VI secretion system (T6SS) is described as a macromolecular secretion machine that is utilized for bacterial competition. The gene clusters encoding T6SS are composed of core tss genes and tag genes. However, the clusters differ greatly in different pathogens due to the great changes accumulated during the long-term evolution. In this work, we identified a novel hypothetical periplasmic protein designated as AsaA which is encoded by the first gene of the T6SS cluster in the genus Acinetobacter. By constructing asaA mutant, we delineated its relative contributions to bacterial competition and secretion of T6SS effector Hcp. Subsequently, we studied the localization of AsaA and potential proteins that may have interactions with AsaA. Our results showed that AsaA in Acinetobacter baumannii (A. baumannii) localized in the bacterial periplasmic space. Results based on bacterial two-hybrid system and protein pull-down assays indicated that it was most likely to affect the assembly or stability of T6SS by interacting with the T6SS core protein TssM. Collectively, our findings of AsaA is most likely a key step in understanding of the T6SS functions in A. baumannii.

Objective: To explore the expression and clinical significance of chemokine CXCL10 and CXCR3 in hepatocellular carcinoma (HCC)., Methods: The expression and prognostic of CXCL10 and CXCR3 in HCC tumor tissues and non-tumor tissues were analyzed in two different publicly available databases the Cancer Genome Atlas (TCGA) and Liver Cancer Institute (LCI). In addition, quantitative real-time PCR (qPCR) was used to detect the mRNA expression of CXCL10 and CXCR3 in 45 HCC clinical samples with HBV infection background. Pearson correlation and Spearman rank correlation were used to determine the correlation between the expression level of CXCL10 and CXCR3 in tumor and non-tumor tissues., Results: In TCGA database, the expression of CXCL10 in HCC tumor tissues was significantly higher than that in non-tumor tissues (nonpaired samples: 3.379±2.081 vs. 2.213±2.274, P<0.001; paired samples: 3.159±2.267 vs. 2.213±2.274, P=0.018). Similarly in LCI datebase (7.625±1.683 vs. 7.287±1.328, P=0.009). And higher CXCL10 expression was significantly associated with a better prognosis in the patients with HCC both in TCGA and LCI database (P=0.107, P=0.002). In TCGA database, the expression of CXCR3 in HCC tumor tissues was significantly higher than that in non-tumor tissues (nonpaired samples: -0.906±1.697 vs. -1.978±1.629, P<0.001; paired samples: -1.329±1.732 vs. -1.978±1.629, P=0.037), while lower in LCI database (3.989±0.339 vs. 4.074±0.309, P=0.003). In both databases, higher CXCR3 expression was significantly associated with a better prognosis in the HCC patients (P=0.004, P=0.014). Furthermore, in TCGA database, the expression level of CXCL10 and CXCR3 was positively correlated both in HCC tumor tissues and matched non-tumor tissues (r=0.584, P<0.001; r=0.776, P<0.001). The qPCR assay showed that the expression of CXCL10 in HBV-related HCC tumor tissues was significantly higher than those in normal liver tissues [0.479(0.223, 1.094) vs. 0.131(0.106, 0.159), P=0.010], and the expression in HBV-related non-tumor tissues was also significantly higher than those in normal liver tissues [0.484(0.241, 0.846) vs. 0.131(0.106, 0.159), P<0.001]. The same was true as CXCR3 [0.011(0.006, 0.019) vs. 0.002(0.001, 0.004), P=0.004; 0.016(0.011, 0.021) vs. 0.002(0.001, 0.004), P<0.001]. However there was no significant difference of CXCL10 and CXCR3 between tumor tissues and matched non-tumor tissues (P=1.000, P=0.374)., Conclusion: Expression of CXCL10 was up-regulated in HCC tissues, expression of CXCR3 was down-regulated in HBV-related HCC tissues, and the higher expression of both genes was correlated with better overall survival in HCC patients.

Hepatitis B virus (HBV) infection remains to be a serious public health problem in China. There used to be a high prevalence of HBV infection in China, which resulted in a large number of HBV susceptible and post-infected population. Single anti-HBc positive usually indicates post HBV infection and its prevalence is particularly high among people over 40 years old, some of whom may be occult hepatitis B virus infection (OBI). The clinical diagnosis of OBI is difficult and easily missed. Since OBI may cause chronic liver disease progression and even lead to cirrhosis and hepatocellular carcinoma eventually, and more importantly, patients with OBI may leed to HBV reactivation when the immune function decreases or immunosuppressive therapy is performed, the accurate identify of OBI is of particular importance. Moreover, OBI is the potential source of HBV infection, which may transmit through blood transfusion, organ transplantation and mother-to-child transmission. In view of this situation, we reviewed the mechanism, prevalence and definition of OBI, and proposed a determination system for replication-competent HBV DNA based on our understanding of the updated OBI definition. It is expected to be beneficial for OBI diagnosis, treatment and management.

Background: Our aim was to evaluate the prognostic value of the number of lymph nodes examined (eLNs) in patients with node-negative gastric cancer (GC) and further to adjust the American Joint Committee on Cancer (AJCC) 8th staging system based on the number of eLNs., Methods: Node-negative GC patients diagnosed during 1988-2015 from the Surveillance, Epidemiology, and End Results (SEER) database were included. On the basis of a primary cohort of 4159 node-negative GC patients, we built the adjusted AJCC 8th staging system, which was then internally validated by a bootstrap method, and externally validated with an independent cohort of 5565 node-negative GC patients., Results: The median number of eLNs was 10. For the training set, the optimal eLNs thresholds were determined to be 9 for node-negative GC patients. The adjusted AJCC 8th staging system for node-negative GC patients based on the number of eLNs had a significantly higher Harrell's concordance index than the initial AJCC 8th staging system (C-index, 0.635 versus 0.616; P < 0.001). Thus, the adjusted AJCC 8th staging system had superior prognostic stratification. Similar results were found in the validation set., Conclusions: For node-negative GC patients in the United States, the adjusted AJCC 8th staging system based on the number of eLNs predicted survival more accurately and discriminatively.

Objective: To investigate the correlation between serum protein level of insulin growth factor 1 (IGF-1) and the degree of liver fibrosis in patients with chronic hepatitis C (CHC) combined with type 2 diabetes mellitus (T2DM)., Methods: The cases are divided into four groups. Then serum levels of IFG-1, alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatitis C virus (HCV) RNA, and HCV genotypes were detected simultaneously in patients with hepatitis C, liver stiffness measurement (LSM) was measured by transient elastography, and aspartate aminotransferase platelet ratio (APRI) score was determined., Results: There was no significant difference between CHC with T2DM group and CHC group in diabetes family history (P > 0.05), but the difference between the two groups were significantly lower than that of T2DM group ( P < 0.05). The levels of fasting insulin and homeostatic model assessment of insulin resistance (HOMA-IR) in CHC group with T2DM group were significantly higher than those in the other two groups ( P < 0.05), while the IGF-1 RNA and the serum protein level in the two groups were significantly lower than those in the CHC group, and were lower than those in the control group ( P < 0.05). The level of serum IGF-1 was negatively correlated with HOMA-IR, LSM, and APRI score in CHC with T2DM group ( r = -0.71, -0.75, and -0.69; P < 0.01)., Conclusion: The degree of hepatic fibrosis in patients with CHC combined with T2DM was higher than that in non-T2DM patients with CHC, which was mainly related to insulin resistance (IR) induced by 1b genotype HCV infection. IR can lead to impaired synthesis of IGF-1, and the degree of damage has a corresponding relationship with hepatic fibrosis., (© 2018 Wiley Periodicals, Inc.)

Objective: To investigate the prognostic value of albumin/globulin ratio on postoperative survival outcomes in patients with hepatocellular carcinoma. Methods: Data of 630 patients with HCC, who underwent surgical resection from February 2009 to July 2013, were retrospectively analyzed. Patients were divided into low-value group (A/G < 1.5, defined as L group) and high-value group (A/G≥1.5, defined as H group), and their distribution characteristics were observed with the normal A/G threshold value. Independent risk factors' affecting survival and prognosis was analyzed with univariate and multivariate Cox's regression model. Survival trend of all patients with low-value and high-value groups in A, B and C of Barcelona stage (BCLC stage) were analyzed using the Kaplan-Meier method. Results: Multivariate analysis showed that preoperative A/G ratio ( P = 0.007), alpha-fetoprotein ( P < 0.001), gamma-glutamyltransferase ( P = 0.006), RBC ( P = 0.014), international normalized ratio ( P = 0.009), preoperative BCLC staging ( P < 0.001) and number of tumors ( P = 0.003), and intraoperative blood transfusion ( P < 0.001) were independent prognostic factors affecting long-term survival in HCC patients. The median overall survival time in-group L was 15 months, significantly lower than that in group H of 42 months ( P < 0.001). Stratified analysis showed that the short-term survival advantage of patients with high A / G value was limited to those with Barcelona stage A ( P < 0.001), and disappeared in patients with Barcelona stage B and C ( P > 0.05). The long-term survival advantage existed in patients with Barcelona stage A ( P < 0.001), B ( P < 0.05), and disappeared in C ( P > 0.05). Conclusion: Preoperative albumin/globulin ratio can predict postoperative prognosis and survival, and direct towards the treatment for early stage of HCC and thus representing as an indicator of high clinical value.

Accumulated neuroimaging evidence shows that the dorsal lateral prefrontal cortex (dlPFC) is activated during emotion anticipation. The aim of this work is to examine the brain connectivity and activation differences in dlPFC between the positive, neutral and negative emotion anticipation by using functional near-infrared spectroscopy (fNIRS). The hemodynamic responses were first assessed for all subjects during the performance of various emotion anticipation tasks. And then small-world analysis was performed, in which the small-world network indicators including the clustering coefficient, average path length, average node degree, and measure of small-world index were calculated for the functional brain networks associated with the positive, neutral and negative emotion anticipation, respectively. We discovered that compared to negative and neutral emotion anticipation, the positive one exhibited enhanced brain activation in the left dlPFC. Although the functional brain networks for the three emotion anticipation cases manifested the small-world properties regarding the clustering coefficient, average path length, average node degree, and measure of small-world index, the positive one showed significantly higher clustering coefficient and shorter average path length than those from the neutral and negative cases. Consequently, the small-world network indicators and brain activation in dlPPC were able to distinguish well between the positive, neutral and negative emotion anticipation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Accumulating evidence shows that the dorsal lateral prefrontal cortex (dlPFC) is implicated in personality traits. In this study, resting-state functional near infrared spectroscopy (fNIRS) combined with small-world analysis was utilized to examine the relationship between the network properties of dlPFC and personality traits., Methods: Thirty college students (aged between 20 and 29) were recruited from the University of Macau campus, whose personality scores were accessed with the NEO-FFT questionnaire. Graph theory combined with resting-state fNIRS data was used to quantify the network properties of dlPFC, whereas Pearson correlation analysis was performed to generate the relationship between the small-world indicators and personality scores., Results: Compared to matched random networks, the resting-state brain networks exhibited a larger clustering coefficient (C p , 0.1-0.66), shorter characteristic path length (L p , 0.1-0.66), and higher global (E g , 0.1-0.66) and local efficiency (E loc , 0.1-0.65). In particular, conscientiousness (r = -0.63) and neuroticism (r = 0.40) respectively showed negative and positive correlation with the L p ., Conclusions: The resting-state functional brain networks in dlPFC exhibited the small-world properties. In addition, participants with higher conscientiousness scores showed a shorter L p ., (© 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Liver cirrhosis is the end-stage change of chronic liver diseases with various causative factors. The accurate diagnosis of liver cirrhosis in an early stage is very important for the timely treatment and prognosis of patients. A liver biopsy test is the gold standard for the diagnosis of liver cirrhosis; but its use is limited in clinical practices due to its invasive nature. The conventional non-invasive measures (APRI, FIB-4 and LSM) for diagnosis of liver cirrhosis could not fulfill the needs. Therefore, finding a new serological marker of liver cirrhosis has become a research hotspot. Based on literature review and our own results, we suggest that serum GP73 as the most potential serum marker for liver cirrhosis diagnosis. This review briefly introduces the application of serum GP73 in the diagnosis of liver cirrhosis and the potential mechanism relevant to its involvement in the development of liver cirrhosis.

Neuroimaging studies have revealed that insomnia is characterized by aberrant neuronal connectivity in specific brain regions, but the topological disruptions in the white matter (WM) structural connectivity networks remain largely unknown in insomnia. The current study uses diffusion tensor imaging (DTI) tractography to construct the WM structural networks and graph theory analysis to detect alterations of the brain structural networks. The study participants comprised 30 healthy subjects with insomnia symptoms (IS) and 62 healthy subjects without IS. Both the two groups showed small-world properties regarding their WM structural connectivity networks. By contrast, increased local efficiency and decreased global efficiency were identified in the IS group, indicating an insomnia-related shift in topology away from regular networks. In addition, the IS group exhibited disrupted nodal topological characteristics in regions involving the fronto-limbic and the default-mode systems. To our knowledge, this is the first study to explore the topological organization of WM structural network connectivity in insomnia. More importantly, the dysfunctions of large-scale brain systems including the fronto-limbic pathways, salience network and default-mode network in insomnia were identified, which provides new insights into the insomnia connectome. Topology-based brain network analysis thus could be a potential biomarker for IS.

Recent neuroimaging studies revealed that the dominant frequency of neural oscillations is brain-region-specific and can vary with frequency-specific reorganization of brain networks during cognition. In this study, we examined the dominant frequency in low-frequency neural oscillations represented by oxygenated hemoglobin measurements after the hemodynamic response function (HRF) deconvolution. Twenty-nine healthy college subjects were recruited to perform a serial finger tapping task at the frequency of 0.2 Hz. Functional near-infrared spectroscopy (fNIRS) was applied to record the hemodynamic signals over the primary motor cortex, supplementary motor area (SMA), premotor cortex, and prefrontal area. We then explored the low frequency steady-state brain response (lfSSBR), which was evoked in the motor systems at the fundamental frequency (0.2 Hz) and its harmonics (0.4, 0.6, and 0.8 Hz). In particular, after HRF deconvolution, the lfSSBR at the frequency of 0.4 Hz in the SMA was identified as the dominant frequency. Interestingly, the domain frequency exhibited the correlation with behavior data such as reaction time, indicating that the physiological implication of lfSSBR is related to the brain anatomy, stimulus frequency and cognition. More importantly, the HRF deconvolution showed its capability for recovering signals probably reflecting neural-level events and revealing the physiological meaning of lfSSBR.

Objectives: Conduct disorder (CD) is characterized by the violation of the rights of others or basic social rules and a repetitive, persistent pattern of antisocial and aggressive behaviors. A large number of functional and structural neuroimaging studies have identified widely abnormalities in specific brain regions in CD, but the alterations in the topological organization of functional networks among them remain largely unknown., Methods: Resting-state functional magnetic resonance imaging was applied to investigate the intrinsic functional connectivity in 18 pure CD patients and eighteen typically developing healthy controls. We first constructed the functional networks and then examined the CD-related alteration in topology properties using graph theoretical analysis., Results: Both the CD group and healthy controls exhibited small-world topology. However, the CD group showed decreased global and local efficiency. Changes in the nodal characteristics in CD group were found predominantly in the default-mode network, visual, and striatum regions. In addition, altered fronto-limbic-striatum network topology was found to have a relationship with clinical scores., Conclusions: Our findings indicate the altered nodal topology of brain functional connectivity networks in CD., Significance: The results provide unequivocal evidence of a topological disruption in the brain networks that suggest some possible pathophysiological mechanisms underlying CD., Competing Interests: CONFLICTS OF INTEREST The authors have declared that no potential conflicts of interest.

Decades ago, it was proposed that Na transport in cardiac myocytes is modulated by large changes in cytoplasmic Na concentration within restricted subsarcolemmal spaces. Here, we probe this hypothesis for Na/K pumps by generating constitutive transsarcolemmal Na flux with the Na channel opener veratridine in whole-cell patch-clamp recordings. Using 25 mM Na in the patch pipette, pump currents decay strongly during continuous activation by extracellular K (τ, ∼2 s). In contradiction to depletion hypotheses, the decay becomes stronger when pump currents are decreased by hyperpolarization. Na channel currents are nearly unchanged by pump activity in these conditions, and conversely, continuous Na currents up to 0.5 nA in magnitude have negligible effects on pump currents. These outcomes are even more pronounced using 50 mM Li as a cytoplasmic Na congener. Thus, the Na/K pump current decay reflects mostly an inactivation mechanism that immobilizes Na/K pump charge movements, not cytoplasmic Na depletion. When channel currents are increased beyond 1 nA, models with unrestricted subsarcolemmal diffusion accurately predict current decay (τ ∼15 s) and reversal potential shifts observed for Na, Li, and K currents through Na channels opened by veratridine, as well as for Na, K, Cs, Li, and Cl currents recorded in nystatin-permeabilized myocytes. Ion concentrations in the pipette tip (i.e., access conductance) track without appreciable delay the current changes caused by sarcolemmal ion flux. Importantly, cytoplasmic mixing volumes, calculated from current decay kinetics, increase and decrease as expected with osmolarity changes (τ >30 s). Na/K pump current run-down over 20 min reflects a failure of pumps to recover from inactivation. Simulations reveal that pump inactivation coupled with Na-activated recovery enhances the rapidity and effectivity of Na homeostasis in cardiac myocytes. In conclusion, an autoregulatory mechanism enhances cardiac Na/K pump activity when cytoplasmic Na rises and suppresses pump activity when cytoplasmic Na declines., (© 2017 Lu and Hilgemann.)

Conduct disorder (CD) is a developmental disorder defined by a repetitive and persistent display of antisocial and aggressive behaviors that violates the rights of others or basic social rules. Recently, resting-state functional magnetic resonance imaging (rsfMRI) has been widely adopted to investigate the altered intrinsic neural activities and the disrupted endogenous brain connectivity of CD. In this study, functional connectivity density (FCD) mapping, a newly developed ultrafast voxel-wise method based on rsfMRI, was applied for the first time to examine the changes in the brain functional connectivity in CD at the voxel level. We assessed the differences in FCD between eighteen male adolescents with CD and eighteen typically-developing (TD) individuals. Then, the identified brain regions in which CD patients and healthy controls exhibited significant difference in FCD were extracted to calculate the correlations between measures of FCD values and clinical data. We discovered that compared to healthy controls, CD patients showed increased short-range FCD in the default-mode network including the bilateral posterior cingulate cortex (PCC) and the bilateral precuneus (PCUN). More importantly, increased short-range FCD values in the bilateral PCC, the bilateral PCUN, and increased long-range FCD values in the left MCC showed significant correlations with the impulsivity. Overall, these results suggested that the FCD abnormalities in CD patients occurred in brain regions known to be involved in cognition, emotion and visual perception., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Insomnia is one of the most common health complaints, with a high prevalence of 30~50% in the general population. In particular, neuroimaging research has revealed that widespread dysfunctions in brain regions involved in hyperarousal are strongly correlated with insomnia. However, whether the topology of the intrinsic connectivity is aberrant in insomnia remains largely unknown. In this study, resting-state functional magnetic resonance imaging (rsfMRI) in conjunction with graph theoretical analysis, was used to construct functional connectivity matrices and to extract the attribute features of the small-world networks in insomnia. We examined the alterations in global and local small-world network properties of the distributed brain regions that are predominantly implicated in the frontostriatal network between 30 healthy subjects with insomnia symptoms (IS) and 62 healthy subjects without insomnia symptoms (NIS). Correlations between the small-world properties and clinical measurements were also generated to identify the differences between the two groups. Both the IS group and the NIS group exhibited a small-worldness topology. Meanwhile, the global topological properties didn't show significant difference between the two groups. By contrast, participants in the IS group showed decreased regional degree and efficiency in the left inferior frontal gyrus (IFG) compared with subjects in the NIS group. More specifically, significantly decreased nodal efficiency in the IFG was found to be negatively associated with insomnia scores, whereas the abnormal changes in nodal betweenness centrality of the right putamen were positively correlated with insomnia scores. Our findings suggested that the aberrant topology of the salience network and frontostriatal connectivity is linked to insomnia, which can serve as an important biomarker for insomnia.

Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in infected hepatocytes is the main cause of off-therapy viral rebound. The half-life of cccDNA is only 33-50 days, so the conversion of newly synthesized rcDNA to cccDNA in the nucleus is essential for the maintenance of cccDNA pool in infected hepatocytes. Though not directly targeting the existing cccDNA, current nucleos(t)ide analogues (NAs) may exhaust the cccDNA reservoir by blocking the rcDNA formation. Indeed, a prolonged consolidation therapy post loss of serum HBV DNA can achieve sustained remission and thus safe drug discontinuation in a small proportion of chronic hepatitis B (CHB) patients. In recent studies, we and others have demonstrated that it is the serum HBV RNA that reflects the cccDNA activity in infected hepatocytes, particularly among the patients on NAs. Here we suggest that instead of measuring serum HBV DNA only, simultaneous measurement of both viral DNA and RNA would improve the accuracy to reflect the cccDNA activity; therefore, the virological response should be redefined as consistent loss (less than the lower limit of detection) of both serum HBV DNA and RNA, which indicates the safety of drug discontinuation. Accumulating evidence has suggested that for the CHB patients with lower serum HBsAg, switch-to or add-on pegylated interferon (Peg-IFN) treatment would result in loss of serum HBsAg in a relatively large proportion of CHB patients. Since serum HBV RNA is an ideal biomarker to reflect the intrahepatic cccDNA activity, for the patients with a serum HBsAg level lower than 1 500 IU/ml after long-term NAs treatment, the serum HBV RNA should be measured. If serum HBV RNA is detected, peg-IFN should be added on; if serum HBV RNA is not detected, NAs treatment should be switched to peg-IFN treatment. We believe the therapy based on serum HBV RNA would make the functional cure of CHB (serum HBsAg loss or even conversion to anti-HBs) more efficient.