Wounding induces suberin deposition, relevant gene expressions and changes of endogenous phytohormones in Chinese yam (Dioscorea opposita) tubers.

Wounds on Chinese yam (Dioscorea opposita ) tubers can ocurr during harvest and handling, and rapid suberisation of the wound is required to prevent pathogenic infection and desiccation. However, little is known about the causal relationship among suberin deposition, relevant gene expressions and endogenous phytohormones levels in response to wounding. In this study, the effect of wounding on phytohormones levels and the expression profiles of specific genes involved in wound-induced suberisation were determined. Wounding rapidly increased the expression levels of genes, including PAL , C4H , 4CL , POD , KCSs , FARs , CYP86A1 , CYP86B1 , GPATs , ABCGs and GELPs , which likely involved in the biosynthesis, transport and polymerisation of suberin monomers, ultimately leading to suberin deposition. Wounding induced phenolics biosynthesis and being polymerised into suberin poly(phenolics) (SPP) in advance of suberin poly(aliphatics) (SPA) accumulation. Specifically, rapid expression of genes (e.g. PAL , C4H , 4CL , POD ) associated with the biosynthesis and polymerisation of phenolics, in consistent with SPP accumulation 3days after wounding, followed by the massive accumulation of SPA and relevant gene expressions (e.g. KCSs , FARs , CYP86A1 /B1 , GPATs , ABCGs , GELPs ). Additionally, wound-induced abscisic acid (ABA) and jasmonic acid (JA) consistently correlated with suberin deposition and relevant gene expressions indicating that they might play a central role in regulating wound suberisation in yam tubers.

Serum cytokine change profile associated with HBsAg loss during combination therapy with PEG-IFN-α in NAs-suppressed chronic hepatitis B patients.

Objective: The aim of this study was to explore the profile of cytokine changes during the combination therapy with pegylated interferon alpha (PEG-IFN-α) and its relationship with HBsAg loss in nucleos(t)ide analogs (NAs)-suppressed chronic hepatitis B patients. Methods: Seventy-six patients with chronic hepatitis B with HBsAg less than 1,500 IU/ml and HBV DNA negative after receiving ≥ 1-year NAs therapy were enrolled. Eighteen patients continued to take NAs monotherapy (the NAs group), and 58 patients received combination therapy with NAs and PEG-IFN-α (the Add-on group). The levels of IFNG, IL1B, IL1RN, IL2, IL4, IL6, IL10, IL12A, IL17A, CCL2, CCL3, CCL5, CXCL8, CXCL10, TNF, and CSF2 in peripheral blood during treatment were detected. Results: At week 48, 0.00% (0/18) in the NAs group and 25.86% (15/58) in the Add-on group achieved HBsAg loss. During 48 weeks of combined treatment, there was a transitory increase in the levels of ALT, IL1RN, IL2, and CCL2. Compared to the NAs group, CXCL8 and CXCL10 in the Add-on group remain higher after rising, yet CCL3 showed a continuously increasing trend. Mild and early increases in IL1B, CCL3, IL17A, IL2, IL4, IL6, and CXCL8 were associated with HBsAg loss or decrease >1 log, while sustained high levels of CCL5 and CXCL10 were associated with poor responses to Add-on therapy at week 48. Conclusions: The serum cytokine change profile is closely related to the response to the combination therapy with PEG-IFN-α and NAs, and may help to reveal the mechanism of functional cure and discover new immunological predictors and new therapeutic targets.

Systematic Comparison of Structural Characterization of Polysaccharides from Ziziphus Jujuba cv. Muzao.

To investigate the structural information differences of Ziziphus Jujuba cv. Muzao polysaccharides, ten samples were successfully extracted from aqueous and alkaline solutions, prepared via DEAE-Sepharose Fast Flow through different eluents and Sephacryl S-300 columns, and systematically analyzed. Their characteristics were studied and then compared using chemical testing, high-performance gel permeation chromatography (HPGPC), gas chromatography (GC), methylation analysis, and NMR spectroscopy. The data achieved demonstrated that different jujube polysaccharide fractions possessed different structural characteristics, and most of them belonged to pectic polysaccharides. Overall, the structural information difference of jujube polysaccharides was preliminarily illuminated, which could not only promote the potential application of Z. Jujuba cv. Muzao polysaccharides but also provide an effective way to analyze the structures of polysaccharides from other genera jujube fruit.

Development and Validation of a nomogram for forecasting survival of alcohol related hepatocellular carcinoma patients.

Background: With the increasing incidence and prevalence of alcoholic liver disease, alcohol-related hepatocellular carcinoma has become a serious public health problem worthy of attention in China. However, there is currently no prognostic prediction model for alcohol-related hepatocellular carcinoma. Methods: The retrospective analysis research of alcohol related hepatocellular carcinoma patients was conducted from January 2010 to December 2014. Independent prognostic factors of alcohol related hepatocellular carcinoma were identified by Lasso regression and multivariate COX proportional model analysis, and the nomogram model was constructed. The reliability and accuracy of the model were assessed using the concordance index(C-Index), receiver operating characteristic (ROC) curve and calibration curve. Evaluate the clinical benefit and application value of the model through clinical decision curve analysis (DCA). The prognosis was assessed by the Kaplan-Meier (KM) survival curve. Results: In sum, 383 patients were included in our study. Patients were stochastically assigned to training cohort (n=271) and validation cohort (n=112) according to 7:3 ratio. The predictors included in the nomogram were splenectomy, platelet count (PLT), creatinine (CRE), Prealbumin (PA), mean erythrocyte hemoglobin concentration (MCHC), red blood cell distribution width (RDW) and TNM. Our nomogram demonstrated excellent discriminatory power (C-index) and good calibration at 1-year, 3-year and 5- year overall survival (OS). Compared to TNM and Child-Pugh model, the nomogram had better discriminative ability and higher accuracy. DCA showed high clinical benefit and application value of the model. Conclusion: The nomogram model we established can precisely forcasting the prognosis of alcohol related hepatocellular carcinoma patients, which would be helpful for the early warning of alcohol related hepatocellular carcinoma and predict prognosis in patients with alcoholic hepatocellular carcinoma.

Effect of inulin on the pasting and retrogradation characteristics of three different crystalline starches and their interaction mechanism.

At present, there are hardly any studies about the effect of inulin (IN) on the physicochemical properties and structures of different crystalline starches. In this study, three different crystalline starches (wheat, potato, and pea starch) were compounded with natural IN, and its pasting, retrogradation, and structural characteristics were investigated. Then, the potential mechanism of interaction between IN and starch was studied. The results showed that there were some differences in the effects of IN on the three different crystalline starch. Pasting experiments showed that the addition of IN not only increased pasting viscosity but also decreased the values of setback and breakdown. For wheat starch and pea starch, IN reduced their peak viscosity from 2,515 cP, 3,035 cP to 2,131 cP and 2,793 cP, respectively. Retrogradation experiment dates demonstrated that IN delayed gelatinization of all three starches. IN could reduce the enthalpy of gelatinization and retrogradation to varying degrees and inhibit the retrogradation of starch. Among them, it had a better inhibitory effect on potato starch. The addition of IN reduced the retrogradation rate of potato starch from 38.45 to 30.14%. Fourier-transform infrared spectroscopy and interaction force experiments results showed that IN interacted with amylose through hydrogen bonding and observed the presence of electrostatic force in the complexed system. Based on the above, experimental results speculate that the mechanism of interaction between IN and three crystalline starches was the same, and the difference in physicochemical properties was mainly related to the ratio of amylose to amylopectin in different crystalline starches. These findings could enrich the theoretical system of the IN with starch compound system and provide a solid theoretical basis for further applications.

Effect of annealing using plasma-activated water on the structure and properties of wheat flour.

In this study, wheat flour (WF) was modified by annealing (ANN) using plasma-activated water (PAW) for the first time. Compared with WF and DW-WF, the results of scanning electron microscopy (SEM) and particle-size analysis showed that the granule structure of wheat starch in PAW-WF was slightly damaged, and the particle size of PAW-WF was significantly reduced. The results of X-ray diffraction and Fourier transforming infrared spectroscopy indicated that PAW-ANN could reduce the long-range and short-range order degrees of wheat starch and change the secondary structure of the protein in WF, in which the content of random coils and α-helices was significantly increased. In addition, the analysis of solubility, viscosity, and dynamic rheological properties showed that PAW-ANN improved the solubility and gel properties of WF and decreased its viscosity properties and short-term regeneration. PAW-ANN, as a green modification technology, has the potential for further application in WF modification, as well as in the production of flour products.

Pradefovir Treatment in Patients With Chronic Hepatitis B: Week 24 Results From a Multicenter, Double-Blind, Randomized, Noninferiority, Phase 2 Trial.

BACKGROUND: Pradefovir is a liver-targeted prodrug of adefovir, a nucleoside/nucleotide analogue with antiviral activity against hepatitis B virus (HBV) DNA polymerase. This phase 2 study compared the efficacy and safety of oral pradefovir (30, 45, 60, or 75 mg) versus tenofovir disoproxil fumarate (TDF; 300 mg) and aimed to identify the most appropriate dose of pradefovir for the forthcoming phase 3 study. METHODS: Treatment-naive and experienced (not on treatment >6 months) patients with chronic hepatitis B were eligible. RESULTS: A total of 240 participants were randomized and treated in the study (48 per group). Approximately 80% were hepatitis B e antigen (HBeAg) positive, and 10% had liver cirrhosis. The reductions from baseline in HBV DNA levels achieved at week 24 were 5.40, 5.34, 5.33, and 5.40 log10 IU/mL, with pradefovir doses of 30-, 45-, 60-, and 75-mg, respectively, compared with 5.12 log10 IU/mL with TDF. However, HBeAg loss was attained by more participants who received 45-, 60-, or 75-mg pradefovir than by those receiving TDF (12%, 6%, and 9% vs 3%). The TDF group exhibited a more significant increase in serum creatinine than the pradefovir 30- and 45-mg groups, and serum phosphate levels were comparable among all groups. Most adverse events (AEs) were mild (grade 1). No treatment-related severe AEs were reported. Overall, AEs and laboratory abnormalities were comparable to those in the TDF group. CONCLUSIONS: Pradefovir and TDF exhibited comparable reductions in HBV DNA levels. All treatments were safe and well tolerated. CLINICAL TRIALS REGISTRATION: NCT00230503 and China Drug Trials CTR2018042.

Prediction of biochemical nonresolution in patients with chronic drug-induced liver injury: A large multicenter study.

BACKGROUND AND AIMS: To clarify high-risk factors and develop a nomogram model to predict biochemical resolution or biochemical nonresolution (BNR) in patients with chronic DILI. APPROACH AND RESULTS: Retrospectively, 3655 of 5326 patients with chronic DILI were enrolled from nine participating hospitals, of whom 2866 underwent liver biopsy. All of these patients were followed up for over 1 year and their clinical characteristics were retrieved from electronic medical records. The endpoint was BNR, defined as alanine aminotransferase or aspartate aminotransferase >1.5× upper limit of normal or alkaline phosphatase >1.1× ULN, at 12 months from chronic DILI diagnosis. The noninvasive high-risk factors for BNR identified by multivariable logistic regression were used to establish a nomogram, which was validated in an independent external cohort. Finally, 19.3% (707 of 3655) patients presented with BNR. Histologically, with the increase in liver inflammation grades and fibrosis stages, the proportion of BNR significantly increased. The risk of BNR was increased by 21.3-fold in patients with significant inflammation compared to none or mild inflammation (p < 0.001). Biochemically, aspartate aminotransferase and total bilirubin, platelets, prothrombin time, sex, and age were associated with BNR and incorporated to construct a nomogram model (BNR-6) with a concordance index of 0.824 (95% CI, 0.798-0.849), which was highly consistent with liver histology. These results were successfully validated both in the internal cohort and external cohort. CONCLUSIONS: Significant liver inflammation is a robust predictor associated with biochemical nonresolution. The established BNR-6 model provides an easy-to-use approach to assess the outcome of chronic DILI.

Response Stratification in the First-Line Combined Immunotherapy of Hepatocellular Carcinoma at Genomic, Transcriptional and Immune Repertoire Levels.

BACKGROUND: Immunotherapy combined with VEGF inhibitor has become the new first-line therapy for advanced or metastatic hepatocellular carcinoma (HCC). However, the biomarkers for response and prognosis stratification of HCC first-line combined immunotherapy have not been clarified. METHODS: Here, we obtained the genomic alteration data from pre-therapeutic samples of 103 HCC patients using a 605-gene NGS test, and obtained the transcriptional and T cell receptor (TCR) diversity data from 18 patients who underwent the first-line combined immunotherapy using RNAseq and TCR sequencing, respectively. Patients received sorafenib/sintilimab or lenvatinib/sintilimab combined first-line therapy and the response was assessed at 3-6 cycles of therapy. RESULTS: No stratification of response was found in high-frequency key driver gene mutations, including TP53 and TERT. However, significantly higher ratio of progression (PD) was found in patients carrying MDM4 amplification. Similarly, FGF/3/4/19 amplifications could also result in high ratio of PD. The mRNA and lncRNA levels of eight genes related to hepatic metabolism and immune microenvironment exhibited significant differences between PR/SD and PD group, including DGKI, TNFSF14, CHST4, ACTIN1, PFKP, SLC51B, LCK and ERN1, suggesting stratification of response. Furthermore, moderate correlation was identified between the stratification genes (CHST4, SLC51B and ERN1) and immune factors (TIGIT, CD34, ICAM1, CCL5, CXCL9 and CXCL10), suggesting potential roles of these factors in immunoregulation. Strong linear correlation was found between any two of the three indexes for TCR CDR3 diversity, including Shannon-Wiener Index, Simpson index and evenness. However, no significant difference was found in the three indexes between the PR/SD and PD group, suggesting no stratification of response by these indexes. CONCLUSION: We identified several potential biomarkers for response stratification in the first-line combined immunotherapy. MDM4 was capable of predicting disease progression, and a panel mRNA and lncRNA of eight genes may also predict the response. Further validation is needed to verify these biomarkers.

Metabolomic Analysis Reveals the Therapeutic Effects of MBT1805, a Novel Pan-Peroxisome Proliferator-Activated Receptor Agonist, on α-Naphthylisothiocyanate-Induced Cholestasis in Mice.

Background and Aims: Therapeutic drugs that are used to treat cholestatic liver disease are limited; however, the results of clinical trials on primary biliary cholangitis treatment targeting peroxisome proliferator-activated receptors (PPARs) are encouraging. In this study, we aimed to identify the effects of MBT1805, a novel balanced PPARα/γ/δ agonist, on cholestasis induced by α-naphthylisothiocyanate (ANIT) and elucidate the underlying mechanisms through untargeted and bile acid-targeted metabolomic analysis. Methods: Levels of serum biochemical indicators (transaminase, aspartate transaminase, alkaline phosphatase, and total bilirubin) and liver histopathology were analyzed to evaluate the therapeutic effects of MBT1805 on ANIT-induced cholestasis in C57BL/6 mice. Untargeted and bile acid-targeted metabolomic analysis of liver tissues was performed using ultrahigh-performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-MC/MC). qRT-PCR and Western blot analysis were carried out to measure the expression of key enzymes and transporters regulating bile acid synthesis, biotransformation, and transport. Results: MBT1805 significantly improved abnormal levels of liver biochemical indicators and gallbladder enlargement induced by ANIT. Histopathological analysis showed that MBT1805 effectively relieved ANIT-induced necrosis, vacuolation, and inflammatory infiltration. Untargeted metabolomic analysis identified 27 metabolites that were involved in the primary biliary acid biosynthesis pathway. In addition, bile acid-targeted metabolomics showed that MBT1805 could alleviate the abnormal bile acid content and composition induced by ANIT. Furthermore, qRT-PCR and Western blot results confirmed that MBT1805 could effectively regulate bile acid synthesis, biotransformation, and transport which helps relieve cholestasis. Conclusions: MBT1805 is a potential candidate drug for cholestasis, with a balanced PPARα/γ/δ activation effect.

[Expression of thymidylate synthase in salivary adenoid myoepithelial cells and its clinical significance].

OBJECTIVE: To evaluate the expression of thymidylate synthase (TS) in myoepithelial cells (MECs) of salivary adenoid tissues and explore its clinical significance. METHODS: Immunohistochemical staining EnVision method was used to detect the expression of TS, P63, Calponin, CK5/6 and S-100 in 32 salivary gland specimens, including 10 non-neoplastic and salivary inflammation specimens, 11 mixed tumor specimens, 5 basal cell carcinoma specimens and 6 adenoid cyst carcinoma specimens. The specificity and sensitivity of TS as a specific molecular marker of salivary muscle epithelial cells were evaluated in comparison with P63, Calponin, CK5/6 and S-100. RESULTS: The expression pattern of TS in all the salivary gland tissue specimens was identical with that of p63. TS and P63 both showed strong immunohistochemical expressions in MECs of salivary adenoid tissue specimens. Calponin, CK5/6, and S-100 showed cytoplasmic/membranous expressions in the MECs. In addition, TS exhibited weak or moderate cytoplasmic expression in a few salivary gland epithelial cells, cancer cells and scattered stromal cells, with negative expression in the cell nuclei. The expression of TS in the MECs of all the salivary adenoid specimens was highly consistent with those of P63, Calponin, CK5/6 and S-100 (P>0.05) Except for CK5/6 expression in Salivary inflammation and Salivary gland specimens. Kappa>0.75. The specificity and sensitivity of TS as a molecular marker of MECs were both 100%. CONCLUSIONS: TS is a new specific marker of MECs for differential diagnosis of salivary gland tumors.

Thymidylate synthase (TS) immunostaining in the diagnosis of the myoepithelial cells, basal cells, stratified epithelium cells, and associated tumors.

BACKGROUND: Thymidylate synthase (TS) is an important prognostic biomarker for resistance to 5FU-based adjuvant chemotherapy. Recently, we found that TS was specifically expressed in the nucleus of the myoepithelial cell (MEC), basal cell (BC), transitional epithelial cell (TEC), squamous epithelial cell (SEC), and associated tumor using immunostaining. This prompted us to examine whether TS could be used as a diagnostic biomarker for MEC, BC, TEC, SEC, and associated tumors. METHODS: Formalin-fixed, paraffin-embedded specimens from 186 cases of tumors were immunostaining for expression of TS and p63. The diagnostic capability of TS as a reliable diagnostic marker was evaluated and compared with the expression of p63. RESULTS: TS exhibited a strong specific and stable nuclear immunoreactivity in all specimens including MEC, BC, TEC, and SEC when compared with p63. Notably, a variable degree of TS cytoplasmic positive immunoreactivity was observed in 58.3% of squamous-cell carcinoma (SQCC), 37.5% of basal cell carcinoma (BCC), 44.4% transitional-cell carcinomas (TCC), 41.7% mixed tumor (MT) and 56.5% of adenocarcinoma (ADC) specimens. CONCLUSIONS: In addition to being used as a strong prognostic factor for 5-FU resistance, TS also serves as a promising putative diagnostic marker for identifying MEC, BC, SEC, and TEC from GEC, and for distinguishing SQCC, BCC, TCC, and MT from ADC.

[Generation of a novel HBeAg transgenic mice using CRISPR/Cas9 technique].

OBJECTIVE: To generate a new strain of HBeAg transgenic mice using CRISPR/Cas9 technique. METHODS: Hepatitis B virus (HBV) HBeAg gene was cloned and inserted in the pliver-HBeAg expression frame at the site of Rosa26 gene using CRISPR/Cas9 and homologous recombination techniques to construct the pliver-HBeAg expression vector containing HBeAg gene. The linear DNA fragment containing HBeAg gene was obtained by enzyme digestion. Cas9 mRNA, gRNA and the donor vector were microinjected into fertilized eggs of C57BL/6J mice, which were then transplanted into the uterus of C57BL/6J female surrogate mice to obtain F0 generation mice. The F0 generation mice were identified by long fragment PCR to obtain F0 transgenic mice with HBeAg gene. The positive F0 generation mice were bred with wild-type C57BL/6J mice to produce the F1 mice, which were identified by PCR and sequencing. The positive F1 transgenic mice carrying HBeAg gene were backcrossed until the homozygous offspring transgenic mice were obtained. The genotypes of the offspring mice were identified. The expressions of HBeAg and HBeAb in the heterozygous and homozygous HBeAg transgenic mice were detected by automatic chemiluminescence immunoassay, immune colloidal gold technique and immunohistochemistry method. RESULTS: A total of 56 F0 mice were obtained, and 2 of them carried homologous recombined HBeAg gene. Six positive F1 mice were obtained, from which 22 homozygous and 29 heterozygous F2 generation HBeAg transgenic mice were obtained. High concentration of HBeAg protein was detected in the peripheral blood of all the positive HBeAg transgenic mice without HBeAb expression. HBeAg expression was detected in the hepatocytes of HBeAg transgenic mice. CONCLUSIONS: We obtained a new strain of HBeAg transgenic mice with stable expression of HBeAg in the hepatocytes and immune tolerance to HBeAg using CRISPR/Cas9 technique, which provide a new animal model for studying HBV.

Thymidylate Synthase, a New Myoepithelial Biomarker for Breast Lesions.

Background. The identification of myoepithelial cells (MECs) can facilitate the differential diagnosis of breast lesions. We previously found thymidylate synthase (TS) expression in the nuclei of MECs in breast tissues, which prompted us to investigate the usefulness of TS as a sensitive and specific biomarker in the differential diagnosis of breast lesions, similar to other MEC biomarkers (ie, tumor protein [P63] and cluster of differentiation 10 [CD10]). Methods. Immunohistochemistry for TS, P63, and CD10 was performed on paraffin sections from 189 breast specimens. Results. The results showed the intensity of the immunoreactive TS signal to be comparable with that of P63 in the nuclei of MECs. Furthermore, the nuclei of MECs stained strongly for TS and P63 in normal breast tissues (obtained adjacent to invasive breast lesions), benign breast lesions, and carcinoma in situ, whereas the cytoplasm of MECs stained strongly for CD10. The immunoreactive TS signal in the cytoplasm of MECs was variable in 22 out of 32 (65.6%) cases of invasive breast carcinoma and 4 out of 20 cases (20.0%) of ductal carcinoma in situ. We found no immunoreactive TS signal in the nuclei of luminal and stromal cells in breast lesions, although there was a weak positive signal in the cytoplasm of luminal and stromal cells. Conclusions. TS is a sensitive and specific MEC biomarker in the differential diagnosis of breast lesions.

[Calcium channel blocker diltizem transiently inhibits migration and up-regulates metadherin expression in hepatocellular carcinoma cells in vitro].

OBJECTIVE: To investigate the effect of calcium channel blocker diltizem in reversing multi-drug resistance (MDR) and on metadherin expression in hepatocellular carcinoma cells and explore the molecular mechanism. METHODS: Hepatocellular carcinoma MHCC97H and 7402 cells were treated with diltiazem hydrochloride, a calcium channel blocker (0, 25, 50, 100, 200, and 400 µmol/L), for 12, 24, or 48 h. Wound healing assay was employed to assess the changes in the mobility and migration of the cells following the treatments, and the changes in the expression levels of metadherin mRNA and protein and P-gp protein were determined using RT-PCR and immunocytochemistry. RESULTS: Diltiazem hydrochloride could transiently inhibit the migration and movement of MHCC97H and 7402 cells in vitro in a time-and concentration-dependent manner (P < 0.05). Diltiazem hydrochloride at different concentrations also transiently up-regulated the expressions of metadherin mRNA and protein but did not inhibit the expression of P-gp protein in MHCC97H and 7402 cells. CONCLUSIONS: Calcium channel blocker can transiently inhibit the migration of hepatocellular carcinoma cells in vitro and up-regulate the expression of metadherin mRNA and protein through a feedback mechanism, suggesting the potential risk of calcium channel blockers for promoting tumor progression during the treatment of malignant tumors.

A 9­lncRNA risk score system for predicting the prognosis of patients with hepatitis B virus­positive hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and can be induced by hepatitis B virus (HBV) infection. The aim of the present study was to screen prognosis­associated long noncoding RNAs (lncRNAs) and construct a risk score system for the disease. The RNA­sequencing data of patients with HCC (including 100 HCC samples and 26 normal samples) were extracted from The Cancer Genome Atlas (TCGA) database. In addition, GSE55092, GSE19665 and GSE10186 datasets were downloaded from the Gene Expression Omnibus database. Combined with weighted gene co­expression network analysis, the identification and functional annotation of stable modules was performed. Using the MetaDE package, the consensus differentially expressed RNAs (DE­RNAs) were analyzed. To construct a risk score system, prognosis­associated lncRNAs and the optimal lncRNA combination were separately analyzed by survival and penalized packages. Finally, pathway enrichment analysis for the nodes in an lncRNA­mRNA network was conducted via Gene Set Enrichment Analysis. A total of four stable modules and 3,051 consensus DE­RNAs were identified. The stable modules were significantly associated with the histological grades of HCC, tumor, node and metastasis stage, pathological stage, recurrence and exposure to radiation therapy. A 9­lncRNA optimal combination [DiGeorge syndrome critical region gene 9, glucosidase, ß, acid 3 (GBA3), HLA complex group 4, N­acetyltransferase 8B, neighbor of breast cancer 1 gene 2, prostate androgen­regulated transcript 1, ret finger protein like 1 antisense RNA 1, solute carrier family 22 member 18 antisense and T­cell leukemia/lymphoma 6] was selected from the 14 prognosis­associated lncRNAs, and was further supported by the validation dataset, GSE10186. The lncRNA­mRNA co­expression network revealed lncRNA GBA3 as a positive regulator of phosphoenolpyruvate carboxykinase 2, an important enzyme in the metabolic pathway of gluconeogenesis. A risk score system was established based on the optimal 9 lncRNAs, which may be valuable for predicting the prognosis of patients with HBV­positive HCC and improving understanding of mechanisms associated with the pathogenesis of this disease. On the contrary, a larger, independent cohort of patients is required to further validate the risk­score system.

Novel hypolipidemic conjugates of fatty acid and bile acid with lysine for linkage.

Novel fatty acid-bile acid conjugates (1a-1k) were designed and synthesized by coupling of the fatty acids to the 3-OH of bile acids using lysine for linkage. In the conjugates, the 24-COOH of the bile acids was kept intact to preserve liver-specific recognition. The ability of the newly synthesized conjugates (at 100 mg/kg dosage) to reduce total cholesterol (TC) and triglyceride (TG) levels in mice fed with high-fat diet (HFD) was evaluated. Conjugates of stearic acid with cholic acid and palmitic acid with ursodeoxycholic acid (at dosages of 50, 100, and 200 mg/kg) were further evaluated to determine their ability to reduce aspartate aminotransferase (AST), alanine aminotransferase (ALT), TC, and TG levels in mice fed with HFD. All conjugates showed potent hypolipidemic activity. Further investigation revealed that compounds 1c and 1 g not only dose-dependently reduced serum levels of TC and TG, but also inhibited the elevation of serum AST and ALT levels in mice fed with HFD. Thus, compounds 1c and 1 g are promising hypolipidemic agents with hepatocyte protective effects against HFD-induced liver damage.

Assessing the Performance of GPS Precise Point Positioning Under Different Geomagnetic Storm Conditions during Solar Cycle 24.

The geomagnetic storm, which is an abnormal space weather phenomenon, can sometimes severely affect GPS signal propagation, thereby impacting the performance of GPS precise point positioning (PPP). However, the investigation of GPS PPP accuracy over the global scale under different geomagnetic storm conditions is very limited. This paper for the first time presents the performance of GPS dual-frequency (DF) and single-frequency (SF) PPP under moderate, intense, and super storms conditions during solar cycle 24 using a large data set collected from about 500 international GNSS services (IGS) stations. The global root mean square (RMS) maps of GPS PPP results show that stations with degraded performance are mainly distributed at high-latitude, and the degradation level generally depends on the storm intensity. The three-dimensional (3D) RMS of GPS DF PPP for high-latitude during moderate, intense, and super storms are 0.393 m, 0.680 m and 1.051 m, respectively, with respect to only 0.163 m on quiet day. RMS errors of mid- and low-latitudes show less dependence on the storm intensities, with values less than 0.320 m, compared to 0.153 m on quiet day. Compared with DF PPP, the performance of GPS SF PPP is inferior regardless of quiet or disturbed conditions. The degraded performance of GPS positioning during geomagnetic storms is attributed to the increased ionospheric disturbances, which have been confirmed by our global rate of TEC index (ROTI) maps. Ionospheric disturbances not only lead to the deteriorated ionospheric correction but also to the frequent cycle-slip occurrence. Statistical results show that, compared with that on quiet day, the increased cycle-slip occurrence are 13.04%, 56.52%, and 69.57% under moderate, intense, and super storms conditions, respectively.

A novel liver-targeted nitric oxide donor UDCA-Thr-NO protects against cirrhosis and portal hypertension.

Portal hypertension (PHT) is a common liver disease that is closely related to cirrhosis and has a high morbidity and mortality. The present study aimed to probe the efficacy of a novel nitric oxide (NO)-releasing agent with NO linked to ursodeoxycholic acid (UDCA) through threonine (UDCA-Thr-NO) as a liver-targeted therapy for cirrhosis and PHT. After intraperitoneal treatment of dimethyl nitrosamine-induced cirrhotic rats for 3 or 4 weeks, UDCA-Thr-NO could prevent ascites formation and reduce portal pressure instead of carotid artery pressure, when compared with UDCA or compound embryonic bovine liver extract tablets. Biochemical analysis of the rat sera also revealed that UDCA-Thr-NO improved the levels of alanine aminotransferase and total bilirubin and reduced the level of hydroxyproline (P < 0.05). Colorimetric analysis of the liver tissue by staining hematoxylin-eosin (HE) and Sirius red (SR) showed that UDCA-Thr-NO could improve pathological changes and reduce liver collagen deposition and intrahepatic resistance without affecting systemic circulation. It was concluded that UDCA-Thr-NO had a protective effect on liver injury and could be utilized to improve cirrhosis and PHT.

A New Real-Time Cycle Slip Detection and Repair Method under High Ionospheric Activity for a Triple-Frequency GPS/BDS Receiver.

Cycle slip detection and repair is a prerequisite for high-precision global navigation satellite system (GNSS)-based positioning. With the modernization and development of GNSS systems, more satellites are available to transmit triple-frequency signals, which allows the introduction of additional linear combinations and provides new opportunities for cycle slip detection and repair. In this paper, we present a new real-time cycle slip detection and repair method under high ionospheric activity for undifferenced Global Positioning System (GPS)/BeiDou Navigation Satellite System (BDS) triple-frequency observations collected with a single receiver. First, three optimal linearly independent geometry-free pseudorange minus phase combinations are selected to correctly and uniquely determine the cycle slips on the original triple-frequency carrier phase observations. Then, a second-order time-difference algorithm is employed for the pseudorange minus phase combinations to mitigate the impact of between-epoch ionospheric residuals on cycle slip detection, which is especially beneficial under high ionospheric activity. The performance of the approach is verified with static GPS/BDS triple-frequency observations that are collected with a 30 s sampling interval under active ionospheric conditions, and observations are manually inserted with simulated cycle slips. The results show that the method can correctly detect and repair cycle slips at a resolution as small as 1 cycle. Moreover, kinematic data collected from car-driven and airborne experiments are also processed to verify the performance of the method. The experimental results also demonstrate that the method is effective in processing kinematic data.