Objective Using healthy female reproductive-age rhesus macaques as the research subjects,we explored the correlation between menstrual cycle abnormalities and gut microbiota composition by using 16S rRNA metagenomic sequencing.Methods Twenty-seven healthy female rhesus macaques were divided into regular menstrual and irregular menstrual groups.Fecal samples were collected at follicular phase(FP),ovulation phase(OP)and luteal phase(LP)of the two groups.The structure and diversity of bacterial flora in different physiological periods were analyzed and compared between the two groups.Results At the phylum level,Firmicutes,Bacteroidetes,and Proteobacteria dominated the sample flora in the follicular,luteal,and ovulatory phases of the rhesus macaques in both the regular and irregular groups,with a combined percentage of more than 98% .At the genus level,the genus Prevotella_9,Ruminococcaceae_UCG-002,Lactobacillus,Prevotella_2,Phascolarctobacterium,Ruminococcaceae_UCG-005,Streptococcus,Blautia,Prevotellaceae_NK3B31_group,Rikenellaceae_RC9_gut_group were dominant.In the luteal phase the percentage of Firmicutes was higher in the regular group than in the irregular group,while the opposite was true for Bacteroidetes.Spirochaetes were higher in the regular group than in the irregular group at all 3 stages(P＜0.05).Conclusion There were some differences in intestinal microbial composition between the two groups of macaques with regular and irregular menstrual cycles,which provided some reference for the study of intestinal bacteria and ovulation disorders.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Fat accumulation "sensitizes" the liver to insult and leads to nonalcoholic steatohepatitis (NASH). G protein-coupled receptor 35 (GPR35) is involved in metabolic stresses, but its role in NAFLD is unknown. We report that hepatocyte GPR35 mitigates NASH by regulating hepatic cholesterol homeostasis. Specifically, we found that GPR35 overexpression in hepatocytes protected against high-fat/cholesterol/fructose (HFCF) diet-induced steatohepatitis, whereas loss of GPR35 had the opposite effect. Administration of the GPR35 agonist kynurenic acid (Kyna) suppressed HFCF diet-induced steatohepatitis in mice. Kyna/GPR35 induced expression of StAR-related lipid transfer protein 4 (STARD4) through the ERK1/2 signaling pathway, ultimately resulting in hepatic cholesterol esterification and bile acid synthesis (BAS). The overexpression of STARD4 increased the expression of the BAS rate-limiting enzymes cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and CYP8B1, promoting the conversion of cholesterol to bile acid. The protective effect induced by GPR35 overexpression in hepatocytes disappeared in hepatocyte STARD4-knockdown mice. STARD4 overexpression in hepatocytes reversed the aggravation of HFCF diet-induced steatohepatitis caused by the loss of GPR35 expression in hepatocytes in mice. Our findings indicate that the GPR35-STARD4 axis is a promising therapeutic target for NAFLD.

Grape (Vitis vinifera L.) in production is frequently exposed to inadequate light, which significantly affects its agronomic traits via inhibiting their physiological, metabolic and developmental processes. To explore the mechanism how the grape plants respond to the weak light stress, we used 'Yinhong' grape and examined their physiology-biochemistry characteristics and transcriptional profile under different levels of weak light stress. The results showed that grape seedlings upon low intensity shading treatments were not significantly affected. As the shading stress intensity was strengthened, the epidermis cells, palisade tissue, and spongy tissue in the leaves were thinner, the intercellular space between the palisade tissue and spongy tissue was larger compared with that of the control, and the activities of superoxide dismutase, catalase and peroxidase were decreased gradually. Additionally, the soluble protein content increased and the free proline content decreased gradually. Compared with the control, significant changes in plant photosynthetic characteristics and physiology-biochemistry characteristics were observed under high intensity of shading (80%). RNA-seq data showed that the differentially expressed genes between CK and T2, CK and T4, T2 and T4 were 13 913, 13 293 and 14 943, respectively. Most of the enrichment pathways were closely related with the plant's response to stress. Several signaling pathways in response to stress-resistance, e.g. JA/MYC2 pathway and MAPK signal pathway, were activated under weak light stress. The expression level of a variety of genes related to antioxidation (such as polyphenol oxidase and thioredoxin), photosynthesis (such as phytochrome) was altered under weak light stress, indicating that 'Yinhong' grape may activate the antioxidation related pathways to cope with reactive oxygen species (ROS). In addition, it may activate the expression of photosynthetic pigment and light reaction structural protein to maintain the photosynthesis activity. This research may help better understand the relevant physiological response mechanism and facilitate cultivation of grape seedlings under weak light.
Vitis/metabolism* ; Gene Expression Regulation, Plant ; Photosynthesis/genetics* ; Plant Leaves ; Light ; Seedlings/metabolism*

Chronic hepatitis B caused by hepatitis B virus (HBV) infection is a global public health issue. Antiviral therapy for chronic HBV infection plays a critical role, and the goal of antiviral therapy is mainly defined by virological, serological, and biochemical parameters. As the two types of antiviral drugs approved for marketing, both interferon and nucleos(t)ide analogues can alleviate liver inflammation and liver fibrosis and reduce the incidence rates of liver cirrhosis and hepatocellular carcinoma. However, the ideal goal of antiviral therapy is functional cure, which significantly improves the long-term outcome of chronic hepatitis B. The limitation of current treatment is that it can inhibit HBV replication, but cannot clear the virus, with low serological clearance rates of HBeAg and HBsAg. Development of new drugs with the goal of functional cure and evaluation of the synergistic and combined effects of existing drugs are important directions for HBV treatment and development.

Objective:To understand the effectiveness and safety sofosbuvir/velpatasvir (SOF/VEL) combination ±ribavirin in the treatment of chronic hepatitis C virus (HCV) infection in China.Methods:A total of 96 Chinese adults with chronic HCV infection who were treated with SOF/VEL combination ± ribavirin for 12 weeks between July 2018 and February 2020 were selected. HCV RNA, routine blood test, liver, kidney and coagulation function, abdominal Color Doppler ultrasound or CT and liver stiffness were detected at baseline, 4 weeks of treatment, end of treatment and 12 weeks of follow-up. Adverse events and laboratory abnormalities during the treatment were recorded. A t-test was used to compare the measurement data between the two groups, and the analysis of variance was used for multiple group comparison.Results:A total of 93 cases (96.9%) achieved sustained virological response (SVR12), of which 3 cases had relapsed. 88 cases (91.7%, 88/96) had achieved rapid virological response (RVR). 96 cases (100%) had achieved virological response by the end of treatment (EOT). In patients with decompensated liver cirrhosis, the average baseline Child-Pugh score and Model for End-Stage Liver Disease score was 7.4±1.0, and 11.4±1.7, respectively. Among them, 12 cases of the SOF/VEL combined with RBV treatment had achieved SVR12 (100%) at 12 weeks, while only 3 of the 5 cases of single-tablet regimen of SOF/VEL had achieved SVR12 (60%). There was no significant difference between creatinine levels and baseline during or 12 weeks after treatment. The incidence of adverse events in patients with chronic hepatitis C and compensated cirrhosis was 6.3% (5/79), while that in patients with decompensated cirrhosis was 35.3% (6/17). The most common adverse events were hyperbilirubinemia, fatigue and anemia. There were no serious adverse events, deaths or discontinuation of treatment due to adverse events.Conclusion:SOF/VEL combination ± ribavirin in the treatment of various common genotypes of chronic hepatitis C, compensated cirrhosis, decompensated cirrhosis and hepatocellular carcinoma has higher SVR12 in China, and the tolerance and safety are good.

Objective: To investigate the clinical effect of 156-week telbivudine sequential therapy in HBeAg-positive chronic hepatitis B patients with suboptimal response to pegylated interferon-α-2a (Peg-IFN-α-2a) therapy. Methods: A total of 35 HBeAg-positive CHB patients with HBV DNA < 500 IU/ml who were treated with Peg-IFN-α-2a for 48 weeks and did not experience seroconversion of HBeAg were given telbivudine sequential therapy for 156 weeks. HBeAg clearance rate, HBeAg seroconversion rate, HBV DNA clearance rate, safety, and drug resistance rate were analyzed. The t-test was used for the analysis of continuous data and the chi-square test was used for the analysis of categorical data. A multivariate Cox regression analysis was used to identify the influencing factors for HBeAg seroconversion. Results: Telbivudine sequential therapy achieved an ideal HBeAg seroconversion rate of 87.88% with good tolerability and low drug resistance. The HBeAg clearance rate and HBeAg seroconversion rate increased over the time of treatment and were 45.45% and 45.45%, respectively, at 24 weeks and 93.94% and 87.88%, respectively, at 156 weeks. No patient had virologic breakthrough or HBsAg clearance during treatment. The multivariate Cox regression analysis showed that baseline HBsAg level (hazard ratio [HR] = 0.404, P = 0.003) and > 0.5 lg IU/ml reduction in HBeAg at 24 weeks (HR = 2.196, P = 0.048) were predictive factors for HBeAg seroconversion at 156 weeks. Conclusions In HBeAg-positive CHB patients with suboptimal response to Peg-IFN-α-2a therapy, 156-week telbivudine sequential therapy has a good clinical effect and can be used as an optimal regimen for such patients.

Objective: To investigate the optimal treatment regimen for patients with HBeAg-positive chronic hepatitis B (CHB) after suboptimal response to 24 weeks of pegylated interferon (Peg-IFN) α-2a. Methods: A total of 188 patients with HBeAg-positive CHB who had suboptimal response to 24 weeks of Peg-IFN α-2a were randomly divided into entecavir group (n = 93) and telbivudine group (n = 95). The two groups received entecavir 0.5 mg/d and telbivudine 0.6 g/d, respectively, for 208 weeks. After 208 weeks of treatment, the following indices were assessed: HBeAg clearance rate and seroconversion rate, hepatitis B virus (HBV) DNA clearance rate (HBV DNA < 500 IU/ml), safety, and drug resistance rate. The data were subjected to intention-to-treat (ITT) analysis and per protocol (PP) analysis. Univariate and multivariate logistic regression analyses were performed for the drugs used and baseline characteristics in patients with or without HBeAg seroconversion, and stratification analysis was performed based on the baseline HBeAg level. Results: Six cases in the entecavir group and four cases in the telbivudine group did not complete the treatment. Sequential entecavir and telbivudine were well tolerated and safe for all patients. There was a significant difference in HBV DNA clearance rate at 52 weeks of treatment between the entecavir group and the telbivudine group (ITT analysis: 93.55% [87/93] vs 77.89% [74/95], χ ² = 9.363, P = 0.002; PP analysis: 93.10% [81/87] vs 76.92% [70/91], χ ² = 9.049, P = 0.003). The suppression rates of HBV DNA at 208 weeks of treatment were 95.70% (89/93) vs 92.63% (88/95) (ITT analysis) and 95.40% (83/87) vs 92.31% (84/91) (PP analysis). There was a significant difference in HBeAg seroconversion rate at 208 weeks of treatment between the entecavir group and the telbivudine group (ITT analysis: 38.71% [36/93] vs 62.11% [59/95], χ ² = 10.290, P = 0.001; PP analysis: 41.38% [36/87] vs 64.84% [59/91], χ ² = 9.833, P = 0.002). Univariate and multivariate logistic regression analyses suggested that sequential use of telbivudine, male sex, and the baseline level of HBeAg were significantly associated with HBeAg seroconversion at 208 weeks of treatment (P = 0.003, hazard ratio [HR] = 0.386; P = 0.009, HR = 0.303; P = 0.001, HR = 3.502). Conclusion For patients with HBeAg-positive CHB after suboptimal response to 24 weeks of Peg-IFNα-2a, sequential use of telbivudine is the optimal treatment regimen according to the baseline level of HBeAg (baseline guidance). The incidence of HBeAg seroconversion during 208 weeks of sequential treatment can be significantly increased according to the HBeAg decline curve in early treatment (24 weeks) and 104 weeks (response guidance).

Objective To investigate the efficacy and safety of 104-week sequential therapy with telbivudine or entecavir in HBeAg-positive chronic hepatitis B (CHB) patients with suboptimal responses to 24-week pegylated interferon-α-2a (PEG-IFN-α-2a) therapy.Methods A total of 130 HBeAg-positive CHB patients with HBV DNA ≥ 5.0 lg IU/ml and a reduction in HBsAg quantitation ＜ 1 lg IU/ml compared with baseline who received PEG-IFN-α-2a therapy for 24 weeks were enrolled and randomly divided into telbivudine group and entecavir group,and 5 of them were lost.HBeAg clearance rate and seroconversion rate,HBV DNA clearance rate,safety,and drug resistance rate at week 104 were observed.The t-test,chi-square test,or multivariate Cox regression analysis were used for statistical analysis of different types of data.Results At week 104 of treatment,HBV DNA clearance rate showed no significant difference between the telbivudine group and entecavir group (P =0.363),and the telbivudine group had significantly higher HBeAg clearance rate and HBeAg seroconversion rate than the entecavir group (HBeAg clearance rate:61.29％ vs 23.81％,P ＜ 0.01;HBeAg seroconversion rate:51.61％ vs 19.05％,P ＜ 0.01).Male sex and telbivudine therapy were baseline predictors of HBeAg seroconversion.The multivariate Cox regression analysis (Forward LR,a =0.05) showed that the presence or absence of HBeAg seroconversion at week 104 was significantly associated with male sex (HR =4.917),a reduction in HBsAg ＞ 0.5 lg IU/ml at week 12 of treatment compared baseline (HR =3.514),and a reduction in HBeAg ＞ 1 lg COI at week 12 of treatment compared baseline (HR =8.651).Conclusion In HBeAg-positive CHB patients with suboptimal responses to 24-week PEG-IFNα-2a therapy,the sequential therapy with telbivudine helps achieve better HBeAg clearance rate and seroconversion rate compared with the sequential therapy with entecavir and can be used as a therapeutic regimen for such patients.A reduction in HBeAg ＞ 1 lg COI at week 12 of treatment compared baseline can be used as a predictive factor for HBeAg seroconversion at week 104.

ObjectiveTo investigate the factors influencing the liver histological features in chronic hepatitis B virus (HBV) infection patients with low alanine transaminase (ALT) levels by analyzing the relationship of serum hepatitis B surface antigen (HBsAg) level with liver inflammation grade and fibrosis stage. MethodsA total of 511 HBV infection patients admitted to our hospital from December 2010 to December 2013 were studied. The liver histological features, serum HBsAg level, and HBV DNA copy number were examined. Comparison of categorical data between different groups was made by chi-square test, comparison of continuous data following the normal distribution was made by t test, and comparison of continuous data not following the normal distribution was made by Kruskal-Wallis H test. The relationship of serum HBsAg level with liver inflammation grade and fibrosis stage was determined by Spearman′s rank correlation analysis. ResultsAll patients showed different degrees of hepatic histological abnormalities. The group aged more than or equal to 40 years had significantly lower HBeAg positive rate, HBsAg level, and HBV DNA copy number compared with the group aged less than 40 years (χ2=86.8, P＜0000 1; t=2.99, P=0.003; t=7.25, P＜0.000 1). The groups with different ages had significant differences in liver inflammation grade and fibrosis stage (χ2=70.03, P＜0.000 1; χ2=61.92, P＜0.000 1). The Spearman′s rank correlation analysis indicated that in both HBeAg-positive and -negative patients HBsAg level was negatively correlated with liver inflammation grade (r=-0.245, P＜0.000 1; r=-1.51, P=0019) and fibrosis stage (r=-0.153, P=0.012; r=-0.181, P=0.005). ConclusionAge is one of the important factors influencing the liver histological progression in chronic HBV infection patients with low ALT levels. HBsAg level is negatively correlated with liver inflammation grade and fibrosis stage in chronic HBV infection patients with low ALT levels, so it could be used as an important non-invasive indicator for the liver histological status in these patients.

Objective To investigate the characteristics and risk factors of thyroid dysfunction induced after interferon therapy in patients with chronic viral hepatitis.Methods The clinical data of 96 chronic viral hepatitis patients received interferon therapy were analyzed retrospectively.Serological markers of thyroid function and thyroid autoantibodies changes were observed,and were followed up for 1 year after treatment.Logistic regression analysis was performed to evaluate risk factors of thyroid dysfunction.Results Among the 96 cases,84 cases didn't develop thyroid dysfunction after interferon therapy(normal group),and 12 cases developed thyroid dysfunction after interferon therapy (abnormal group),the incidence was 12.5％ (12/96),there were 5 cases of Hashimoto's thyroiditis,3 cases of Graves disease,3 cases of destructive thyroiditis,and 1 case of non-autoimmune hypothyroidism.The time to develop thyroid dysfunction was 2-7 (3.8 ± 1.9) months after treatment,the duration of thyroid dysfunction was 1-11 (4.2 ± 0.9) months.Five patients received endocrine therapy,and 2 patients stopped interferon therapy.All patients regained normal thyroid function during 1-year followup after end of treatment.Multivariate Logistic regression analysis showed that female gender (OR =3.767) and anti-thyroid peroxidase antibodies (OR =1.117) were the independent risk factors for thyoid dysfunction.Conclusions Hashimoto's thyroiditis,Graves disease,destructive thyroiditis and non-autoimmune hypothyroidism are the main types of thyroid dysfunction induced after interferon therapy in patients with chronic viral hepatitis.The thyroid function and thyroid autoantibodies should be closely monitored during treatment in patients with chronic viral hepatitis receiving interferon therapy,especially in female and patients who have thyroid autoantibodies.