Sliding Mode Control for Markov Jump Singularly Perturbed Systems Under Piecewise Homogeneous Stochastic Communication Protocol.

This work involves the sliding mode control (SMC) issue for a class of Markov jump singularly perturbed systems (MJSPSs) under consideration of unmatched external disturbances and communication constraints. For the first time, the piecewise homogeneous Markov chain (MC) which depends on the system mode and the controller mode is applied to control the scheduling of stochastic communication protocol (SCP), so that the MCs in the system models, the controller and the SCP constitute a three-layer nonstationary Markov model (NMM). This model perfectly describes the different objects of the three MCs and reflects the mutual regulation among them. The critical issue is to devise an adaptive controller and a sliding surface (SS) simultaneously under SCP scheduling. By applying a standard singular sliding mode surface, an appropriate nonstationary SMC law is established to promise the accessibility of the SS and the stability of the closed-loop system (CLS), and meet the expected performance indicator. Further, using the mode-dependent Lyapunov function and piecewise homogeneous Markov model method, sufficient criteria are obtained. The specific expression of the control gain is obtained by matrix decoupling technology. Finally, a numerical simulation is furnished to testify the correctness of the conclusion.

Piglet growth performance improved by dietary supplementation of porous or nano particles of zinc oxide may be related to the gut microbiota.

Previous studies on porous or nano particles zinc oxide (ZnO) in the piglets have mainly focused on growth performance and intestinal inflammation, but have scarcely explored the efficacy on gut microbiota. In addition, the efficacy of nano particles ZnO, which is related to its product quality, remains undefined. This study aimed to determine the efficacy of dietary 500 mg/kg porous or nano particles ZnO on the growth performance and gut microbiota of the weaned piglets. A total of 128 weaned piglets were randomly assigned to the dietary groups: NC (basal diet), PC (basal diet + 3,000 mg/kg conventional ZnO), 500HiZ (basal diet + 500 mg/kg porous particles ZnO), and 500ZNP (basal diet + 500 mg/kg nano particles ZnO). Compared with the NC diet group, both 500HiZ and 500ZNP increased (P < 0.05) average daily feed intake (1 to 28 d) and average daily gain (1 to 28 d), and the 500ZNP tended to decrease feed to gain ratio (F:G ratio, 1 to 28 d) (P = 0.09). Both 500HiZ and 500ZNP decreased crypt depth of the ileum and increased claudin-2 in the duodenum and zonula occludens-1 in the ileum (P < 0.05). Moreover, both 500HiZ and 500ZNP decreased IL-1ß and tumor necrosis factor-α (TNF-α) in the jejunum and decreased TNF-α and IL-6 in the ileum (P < 0.05). Both 500HiZ and 500ZNP increased microbial ß-diversity index in the ileum and microbial α-diversity indices in the colon of piglets (P < 0.05). The probiotic genera Coprococcus (500ZNP) and Blautia (500HiZ) were positively correlated with the F:G ratio (1 to 28 d) in colon of piglets (P < 0.05). In addition, 500HiZ promoted mitochondrial fusion protein 1 (MFN1) and zinc transporter-1 (ZnT-1) in the jejunum (P < 0.05), whilst 500ZNP decreased MFN1 in the jejunum and ZnT-1 in the ileum (P < 0.05). In summary, both 500HiZ and 500ZNP improved the growth performance of piglets, which is likely via the genera Blautia and Coprococcus, respectively. Both 500HiZ and 500ZNP improved barrier function and inflammation of the intestine, and 500HiZ achieved better efficacy than 500ZNP on intestine mitochondrial functions.

A Cell Surface-Binding Antibody Atlas Nominates a MUC18-Directed Antibody-Drug Conjugate for Targeting Melanoma.

Recent advances in targeted therapy and immunotherapy have substantially improved the treatment of melanoma. However, therapeutic strategies are still needed for unresponsive or treatment-relapsed patients with melanoma. To discover antibody-drug conjugate (ADC)-tractable cell surface targets for melanoma, we developed an atlas of melanoma cell surface-binding antibodies (pAb) using a proteome-scale antibody array platform. Target identification of pAbs led to development of melanoma cell killing ADCs against LGR6, TRPM1, ASAP1, and MUC18, among others. MUC18 was overexpressed in both tumor cells and tumor-infiltrating blood vessels across major melanoma subtypes, making it a potential dual-compartment and universal melanoma therapeutic target. AMT-253, an MUC18-directed ADC based on topoisomerase I inhibitor exatecan and a self-immolative T moiety, had a higher therapeutic index compared with its microtubule inhibitor-based counterpart and favorable pharmacokinetics and tolerability in monkeys. AMT-253 exhibited MUC18-specific cytotoxicity through DNA damage and apoptosis and a strong bystander killing effect, leading to potent antitumor activities against melanoma cell line and patient-derived xenograft models. Tumor vasculature targeting by a mouse MUC18-specific antibody-T1000-exatecan conjugate inhibited tumor growth in human melanoma xenografts. Combination therapy of AMT-253 with an antiangiogenic agent generated higher efficacy than single agent in a mucosal melanoma model. Beyond melanoma, AMT-253 was also efficacious in a wide range of MUC18-expressing solid tumors. Efficient target/antibody discovery in combination with the T moiety-exatecan linker-payload exemplified here may facilitate discovery of new ADC to improve cancer treatment. SIGNIFICANCE: Discovery of melanoma-targeting antibodies using a proteome-scale array and use of a cutting-edge linker-payload system led to development of a MUC18-targeting antibody-exatecan conjugate with clinical potential for treating major melanoma subtypes.

Effects of Dietary L-Theanine on Growth Performance, Antioxidation, Meat Quality, and Intestinal Microflora in White Feather Broilers With Acute Oxidative Stress.

In order to reduce the negative effects caused by oxidative stress on broilers, it is particularly important to find ways to alleviate oxidative stress. As a natural plant extract, L-theanine has a variety of biological effects, such as improving antioxidant capacity, promoting growth, and enhancing immunity and antitumor. This trial evaluated the effects of dietary supplementation of L-theanine on growth performance, antioxidation, meat quality, and intestinal microflora in 817 White Feather Broilers. A total of 108 21-day-old 817 broilers with similar body weight (BW) were randomly divided into three groups with six replicates per group and six chickens within each replicate. The three groups were corn-soybean-based diet (NC group); basal diet plus drinking water with 30 mg hydrocortisone/kg (PC group); and basal diet supplemented with 400 mg L-theanine/kg plus drinking water with 30 mg hydrocortisone/kg (LT group). Compared with the NC group, from 21 to 24 days of age, the PC and LT groups had decreased BW, average daily gain (ADG), and average daily feed intake (ADFI), and increased feed to gain ratio (F/G; p < 0.05). At 24 days of age, the LT group had improved superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in serum as compared to the NC group (p < 0.05). The LT group broilers also had significantly higher concentrations of malondialdehyde (MDA) in serum and liver (p < 0.05). On the 42nd days, the PC group had lower PH45min (p < 0.05) than the NC and LT groups and higher cooking loss and shear force (p < 0.05). Moreover, the villi height of the PC group was significantly lower in jejunum than the NC group (p < 0.05). The LT group had a higher ZO-1 content in duodenum than the NC and PC groups (p < 0.05). The activity of GSH-Px in the liver of the LT group was increased than in the PC group (p < 0.05). The relative abundance of Firmicutes in the LT group was significantly higher than in the NC and PC groups (p < 0.05). These results suggested that the effects of acute oxidative stress on growth performance and meat quality of broilers are continuous, and dietary supplementation of L-theanine could improve the growth performance and meat quality, enhance the intestinal mucosal barrier and antioxidant capacity, and improve the composition of the intestinal flora of broilers caused by acute oxidative stress.

An array of 60,000 antibodies for proteome-scale antibody generation and target discovery.

Antibodies are essential for elucidating gene function. However, affordable technology for proteome-scale antibody generation does not exist. To address this, we developed Proteome Epitope Tag Antibody Library (PETAL) and its array. PETAL consists of 62,208 monoclonal antibodies (mAbs) against 15,199 peptides from diverse proteomes. PETAL harbors binders for a great multitude of proteins in nature due to antibody multispecificity, an intrinsic antibody feature. Distinctive combinations of 10,000 to 20,000 mAbs were found to target specific proteomes by array screening. Phenotype-specific mAb-protein pairs were found for maize and zebrafish samples. Immunofluorescence and flow cytometry mAbs for membrane proteins and chromatin immunoprecipitation-sequencing mAbs for transcription factors were identified from respective proteome-binding PETAL mAbs. Differential screening of cell surface proteomes of tumor and normal tissues identified internalizing tumor antigens for antibody-drug conjugates. By finding high-affinity mAbs at a fraction of current time and cost, PETAL enables proteome-scale antibody generation and target discovery.

Chinese herb extract improves liver steatosis by promoting the expression of high molecular weight adiponectin in NAFLD rats.

High molecular weight (HMW) adiponectin (APN) is closely correlated with the development of fatty liver and is modulated by the Akt/forkhead box protein O1 (FOXO1) pathway through disulfide­bond A oxidoreductase­like protein (DsbA­L). The Chinese herb extract, QSHX, is used to treat liver diseases. The present study investigated the effects of QSHX on non­alcoholic fatty liver disease (NAFLD) and its underlying mechanism. A rat model of NAFLD was established by feeding of a high­fat and high­sugar diet for 20 weeks. From week 13, the rats were administered with QSHX, or saline as a control, for 8 weeks. The liver function, blood fat and plasma APN were measured using a radioimmunoassay. The hepatic tissue score was measured following staining for pathology. The expression and activities of Akt, FOXO1, DsbA­L and HMW APN in the adipose tissue and primary adipocytes of the rats were measured using western blot analysis. It was found that QSHX significantly decreased the body weight, liver index, and serum levels of aspartate aminotransferase, alanine aminotransferase and triglyceride; and increased the serum level of APN in the NAFLD rats. Following 8 weeks of treatment with QSHX, the hepatic steatosis in the liver tissue improved and the score of hepatic steatosis was significantly decreased. The results of the western blot analysis indicated that QSHX promoted the expression of DsbA­L and HMW APN, and reduced the expression levels of phosphorylated FOXO1 and FOXO1 in adipose tissue and primary adipocytes. It was concluded that QSHX reduced hepatic steatosis by promoting the expression of HMW APN and DsbA­L, which may have been induced by inhibiting the activation and expression of FOXO1 in adipocytes.

Transcriptomic and proteomic analysis of human hepatic stellate cells treated with natural taurine.

The aim of this study was to investigate the differential expression of genes and proteins between natural taurine (NTau)­treated hepatic stellate cells (HSCs) and control cells as well as the underlying mechanism of NTau in inhibiting hepatic fibrosis. A microculture tetrazolium (MTT) assay was used to analyze the proliferation of NTau­treated HSCs. Flow cytometry was performed to compare the apoptosis rate between NTau-treated and non­treated HSCs. Proteomic analysis using a combination of 2-dimensional gel electrophoresis (2DE) and mass spectrometry (MS) was conducted to identify the differentially expressed proteins. Microarray analysis was performed to investigate the differential expression of genes and real-time polymerase chain reaction (PCR) was used to validate the results. The experimental findings obtained demonstrated that NTau decreased HSC proliferation, resulting in an increased number of cells in the G0/G1 phase and a reduced number of cells in the S phase. Flow cytometric analysis showed that NTau-treated HSCs had a significantly increased rate of apoptosis when compared with the non­treated control group. A total of 15 differentially expressed proteins and 658 differentially expressed genes were identified by 2DE and MS, and microarray analysis, respectively. Gene ontology (GO) functional analysis indicated that these genes and proteins were enriched in the function clusters and pathways related to cell proliferation, cellular apoptosis and oxidation. The transcriptome and proteome analyses of NTau-treated HSCs demonstrated that NTau is able to significantly inhibit cell proliferation and promote cell apoptosis, highlighting its potential therapeutic benefits in the treatment of hepatic fibrosis.

Entecavir versus lamivudine for the treatment of chronic hepatitis B: a systematic review.

The aim of this study was to systematically review the efficacy and safety of entecavir versus lamivudine for the treatment of chronic hepatitis B (CHB). A computerized search of The Cochrane Library (CENTRAL, Issue 5, 2011), MEDLINE (PubMed, 1978-June 2011), EMbase (1974-June 2011) and CNKI (1978-June 2011) databases was conducted. In addition, a manual search was made of the references of the included studies and relevant articles. The searches were restricted to studies published in Chinese or English from the time the database was created to June 2011. Studies were selected according to prespecified inclusion and exclusion criteria and then subjected for quality assessment and data extraction. Meta-analysis was performed using the statistical software (RevMan 5.1.1) provided by the Cochrane Collaboration. A total of 8 studies, all of which were randomized clinical trials (RCTs), involving 2178 patients with CHB were included. Subgroup analyses by treatment duration were conducted. The quality of the evidence was classified as moderate by the GRADED approach for all the included RCTs. Meta-analysis showed the following. Entecavir was associated with significantly improved liver histology, compared with lamivudine (RR 1.16, 95, CI [1.07, 1.26], P=0.0004). Patients were significantly more likely to experience HBV-DNA loss and have normalized ALT levels when treated with entecavir versus lamivudine for either 48 or 96 weeks (RR 1.65, 95, CI [1.37, 1.98], P<0.00001; RR 1.15, 95, CI [1.11, 1.20], P<0.00001, respectively). There were no statistically significant differences in the proportion of patients who achieved HBeAg loss or HBeAg seroconversion, or who developed adverse events between entecavir and lamivudine treatments (RR 1.03, 95, CI [0.83, 1.26], P=0.81; RR 0.92, 95, CI [0.75, 1.12], P=0.39; RR 1.09, 95, CI [0.92, 1.30], P=0.31, respectively). Current clinical evidence suggests that despite of short- or long-term use, entecavir appears to be more effective than lamivudine in reducing serum HBV-DNA load, improving liver histology, and normalizing ALT in patients with CHB. However, the probability for patients to experience HBeAg loss or HBeAg seroconversion, or the risk for adverse events seems to be similar between entecavir and lamivudine regimens.

Influence of Fuzheng Huayu Tablet on mental state and social function of patients with post-hepatitis B liver cirrhosis.

OBJECTIVE: To observe the influence of Fuzheng Huayu Tablet on mental state and social activity of patients with post-hepatitis B liver cirrhosis (LC-HB). METHODS: Adopting grouped randomized double-blinded control method, 180 LC-HB patients in 3 research centers were distributed to 2 groups, the treated group and the control group, 90 in each group. Patients in the treated group were administered with FZHYT; while those in the control group treated with conventional therapy combined with placebo, the course for all patients were 6 months. Their mental state and social activity were evaluated before treatment, after 3 months' treatment and at terminal of the 6-month therapeutic course by estimating with Zung self-rating anxiety scale (SAS), self-rating depression scale (SDS) and social deficit screening scale (SDSS). Additionally, the basic demographic materials, liver function, cirrhosis index, hepatic and splenic images, blood coagulation function, etc. in the patients were tested and compared as well. RESULTS: As compared with before treatment, the normal rate of SAS and SDS scores increased and the social deficit rate decreased in the treated group significantly after treatment, showing statistical significance (P<0.05 or P<0.01); while in the control group, change was only shown in the social deficit (P<0.01), inter-group comparisons after treatment showed significant differences in all the three indexes (P<0.05 or P<0.01). Additionally, after treatment, levels of liver function, cirrhosis, blood coagulation function and splenomegaly in the treated group were all improved significantly P<0.05 or P<0.01), and the improvements were better than those in the control group (P<0.01) in levels of total bilirubin (TBIL), albumin (ALB), type IV collagen (IV-C), prothrombin time (PT), prothrombin activity (PTA). CONCLUSION: Most patients of LC-HB have mental disturbance and social activity deficit, which could definitely be improved by intervention with Chinese FZHYT.

Effects of the Ganning formula on liver fibrosis in patients with chronic hepatitis B.

OBJECTIVE: To investigate the clinical efficacy and safety of the Ganning formula for the treatment of liver fibrosis in patients with chronic hepatitis B. METHODS: In a multicenter, randomized, controlled clinical trial, 150 patients with liver fibrosis secondary to hepatitis B virus (HBV) infection were randomly assigned in equal numbers to receive either the Ganning formula (a Chinese herbal decoction; active treatment group) or oral entecavir (control group) for two 3-month courses. Patients were monitored for any treatment-induced changes in liver function test parameters (ALT, AST, and GGT), liver fibrosis markers (LN, HA, IV-C, and PCIII), HBV DNA level, hepatosplenic imaging, quality of life scores, or psychological and social functioning scores. Patients were also observed for any adverse effects. RESULTS: After treatment, patients in both groups experienced significant improvements in liver function, HBV DNA load, hepatosplenic B-mode ultrasonography, quality of life, and psychological and social functioning (P < 0.05 or P < 0.01). Patients receiving the Ganning formula achieved greater improvements in HA, IV-C, quality of life, and psychological and social functioning compared with those on entecavir (P < 0.05 or P < 0.01). There were no abnormal changes in blood tests, urine, feces, renal function, or electrocardiogram. Additionally, no adverse effects were observed in any patients in either group. CONCLUSIONS: The Ganning formula appears to have the potential to inhibit liver fibrosis and therefore improve liver function by inhibiting HBV replication in patients with chronic hepatitis B. Additionally, this formula is helpful in improving quality of life and psychological and social functioning.