Abstract Background: Acid-sensing ion channel 1a (ASIC1a) plays a critical role in physiological and pathological processes. To further elucidate the biological functions of ASICs and their relationships with disease occurrence and development, it is advantageous to investigate and develop additional regulatory factors for ASICs. Methods: In this study, cation exchange chromatography was used to separate seven chromatographic components from Naja naja atra venom. Capillary electrophoresis was employed to detect that Ⅶ peak component containing a main protein Ⅶ-2, which could bind to ASIC1a. The analgesic effects of Ⅶ-2 protein were determined using hot plate methods, and ASIC1a expression in spinal cord tissue from rats with inflammatory pain was detected using western blot. Results: The purified Ⅶ-2 protein named Naja naja atra venom-Ⅶ-2 (NNAV-Ⅶ-2) was obtained by Sephadex G-50 gel filtration, which exhibited a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis with a molecular weight of 6.7 kD. Remarkably, the NNAV-Ⅶ-2 protein demonstrated a significant analgesic effect and downregulated ASIC1a expression in the spinal cord tissue of rats with inflammatory pain. Conclusions: The analgesic mechanism of the NNAV-Ⅶ-2 protein may be associated with its binding to ASIC1a, consequently downregulating ASIC1a expression in neural tissues. Background Acidsensing Acid sensing ASICa ASIC (ASIC1a processes development Methods study venom Ⅶ2, Ⅶ2 2, 2 Ⅶ- methods blot Results venomⅦ2 venom-Ⅶ- NNAVⅦ2 NNAV (NNAV-Ⅶ-2 G50 G 50 G-5 filtration sulfatepolyacrylamide sulfate polyacrylamide 67 6 7 6. kD Remarkably NNAV-Ⅶ- Conclusions tissues venomⅦ venom-Ⅶ NNAVⅦ (NNAV-Ⅶ- G5 5 G- NNAV-Ⅶ venom- (NNAV-Ⅶ NNAV- (NNAV- (NNAV

Abstract Voriconazole increases tacrolimus blood concentration significantly when coadministrated. The recommendation of reducing tacrolimus to 1/3 in voriconazole package insert seems not to be satisfactory in clinical practice. In vitro studies demonstrated that the magnitude of inhibition depends on the concentration of voriconazole, while voriconazole exposure is determined by the genotype status of CYP2C19. CYP2C19 gene polymorphism challenges the management of drug-drug interactions(DDIs) between voriconazole and tacrolimus. This work aimed to predict the impact of CYP2C19 polymorphism on the DDIs by using physiologically based pharmacokinetics (PBPK) models. The precision of the developed voriconazole and tacrolimus models was reasonable by evaluating the pharmacokinetic parameters fold error, such as AUC0-24, Cmax and tmax. Voriconazole increased tacrolimus concentration immediately in all population. The simulated duration of DDIs disappearance after voriconazole withdrawal were 146h, 90h and 66h in poor metabolizers (PMs), intermediate metabolizers (IMs) and extensive metabolizers(EMs), respectively. The developed and optimized PBPK models in this study can be applied to assit the dose adjustment for tacrolimus with and without voriconazole. coadministrated 13 1 3 1/ practice CYPC CYP C CYP2C1 drugdrug drug interactionsDDIs interactions interactions(DDIs (PBPK error AUC024, AUC024 AUC AUC0 24, 24 AUC0-24 tmax population 146h h PMs, PMs , (PMs) IMs (IMs metabolizersEMs, metabolizersEMs EMs metabolizers(EMs) respectively CYP2C AUC02 2 AUC0-2 (PMs metabolizers(EMs AUC0-

RESUMO Introdução: O algoritmo genético é um dos mais importantes modelos matemáticos teóricos para simulação de desenvolvimento biológico. É amplamente utilizado em muitos campos, tais como engenharia, medicina e economia. Objetivo: Utilizar o algoritmo genético como base de um modelo matemático para otimização no programa de aptidão nos estudantes do ensino médio. Método: Adota-se o método de seleção por competição para eleger o cruzamento aleatório da probabilidade de crossover masculino com grande semelhança para gerar uma nova população. Um algoritmo genético foi proposto para ajustar a probabilidade de crossover e mutação dinâmica de acordo com a aptidão física, visando resolver o problema das alterações dinâmicas. Efetua-se uma análise comparativa entre os resultados das equações diferenciais não-lineares e o algoritmo de Levenberg-Marquardt de quarta ordem. Resultados: O aperfeiçoamento do algoritmo foi obtido após a análise do processo de operação e estruturação do algoritmo genético tradicional, a aplicação do modelo matemático revelou melhora na precisão do modelo de movimento estabelecido pelo algoritmo genético. Conclusão: O esquema de otimização do aprimoramento físico foi testado e verificado por um algoritmo genético provando que os resultados da pesquisa possuem praticabilidade teórica.Nível de evidência II; Estudos Terapêuticos - Investigação de Resultados.

ABSTRACT Introduction: The genetic algorithm is one of the essential theoretical mathematical models for simulating biological development. It is widely used in many fields such as engineering, medicine, and economics. Objective: Use the genetic algorithm as a mathematical model basis for optimization in the high school students’ aptitude program. Methods: The selection method by competition is adopted to elect the random crossover of male crossover probability with high similarity to generate a new population. A genetic algorithm was proposed to adjust the crossover probability and dynamic mutation according to fitness, aiming to solve the problem of dynamic changes. A comparative analysis is performed between the nonlinear differential equations and the Levenberg–Marquardt method algorithm. Results: The algorithm improvement was obtained after analyzing the operation process and structuring of the traditional genetic algorithm; the mathematical model application revealed improvement in the motion accuracy model established by the genetic algorithm. Conclusion: The physical enhancement optimization scheme was tested and verified by a genetic algorithm and proves the research results hold theoretical feasibility. Evidence Level II; Therapeutic Studies – Investigating the results.

RESUMEN Introducción: El algoritmo genético es uno de los modelos matemáticos teóricos más importantes para la simulación del desarrollo biológico. Se utiliza ampliamente en muchos campos como la ingeniería, la medicina y la economía. Objetivo: Utilizar el algoritmo genético como base de un modelo matemático de optimización en el programa de aptitud para estudiantes de secundaria. Método: Se adopta el método de selección por competencia para elegir el cruce aleatorio de probabilidad de crossover masculino con alta similitud para generar una nueva población. Se propuso un algoritmo genético para ajustar la probabilidad de cruce y la mutación dinámica en función de la aptitud, con el fin de resolver el problema de los cambios dinámicos. Se realiza un análisis comparativo entre los resultados de las ecuaciones diferenciales no lineales y el algoritmo de Levenberg-Marquardt de cuarto orden. Resultados: La mejora del algoritmo se obtuvo tras el análisis del proceso de funcionamiento y estructuración del algoritmo genético tradicional, la aplicación del modelo matemático reveló la mejora de la precisión del modelo de movimiento establecido por el algoritmo genético. Conclusión: El esquema de optimización de la mejora física se probó y verificó mediante un algoritmo genético, demostrando que los resultados de la investigación tienen viabilidad teórica. Nivel de evidencia II; Estudios terapéuticos - Investigación de resultados.

Abstract This study aimed to investigate the potential of a novel preparation strategy for glycosylated hydrolysate by liquid fermentation in order to provide a high-quality glycosylated hydrolysate. Protein solubility, surface hydrophobicity and antioxidant activity were evaluated. The results of Fourier transform infrared spectra demonstrated the occurrence of glycosylation reaction. The results of Fluorescence emission spectroscope revealed the decrease of tertiary conformation stability. Circular dichroism spectra revealed significant decrease in α-helix and increase in β-sheet and random coil by glycosylation reaction. In comparison with zein hydrolysate, glycosylated hydrolysate had lower surface hydrophobicity but higher in solubility and in vitro digestibility due to glycosylation. Glycosylated hydrolysate presented higher ABTS (2,2'-Azinobis [3-ethylbenzothiazoline-6-sulfonic acid]-diammonium salt) and superoxide radicals scavenging activities as well as Cu2+ chelating capacity. It is concluded that the glycosylation confer an open structure and modified properties of zein, and glycosylated hydrolysate is a potential ingredient with better hydration and antioxidant activities than zein hydrolysate.

Abstract The potential astringency of eight grape cultivars was evaluated based on polyphenol/protein binding. The parameters such as weights, sizes, total phenols, flavanols and tannins of different grape tissues were determined, and the polyphenol/protein binding was analyzed by SDS-PAGE and spectroscopy. The Cabernet Sauvignon had the highest skin proportion, while the Blue French had the highest seed proportion. The Blue French seeds had the highest total phenolic content, while the Cabernet Sauvignon skins had the highest total phenolic content. SDS-PAGE showed that the seed extracts had a better affinity than skin extracts for saliva proteins, but fluorescence spectra demonstrated that the interactions of skin polyphenols with protein were more complex. These results may provide some useful information on grape potential astringency’s evaluation and wine-making in China.

Abstract INTRODUCTION: Based on reports, infection with Mycobacterium tuberculosis is believed to induce the development of antibodies that are considered to be biological indicators for the diagnosis of some other diseases. However, conflicting results have been published regarding the presence of antineutrophil cytoplasmic antibodies (ANCAs) in patients with tuberculosis. We aim to study the seroprevalence of ANCA in a population of Chinese patients with tuberculosis, which may lead to the misdiagnosis of vasculitic disorders. METHODS: The study was conducted from January 2016 to May 2017 to evaluate the presence of ANCA in 103 Chinese patients using indirect immunofluorescent assay. An enzyme-linked immunosorbent assay was performed for anti-myeloperoxidase (MPO) and anti-proteinase 3 (PR3) detection. RESULTS: Perinuclear ANCA (p-ANCA) was detected in 4.8% (5/103) of patients, whereas cytoplasmic ANCA (c-ANCA) was not detected; 1.9% (2/103) of patients with tuberculosis was positive for anti-MPO antibodies, and none had anti-PR3 antibodies. Both anti-MPO-positive patients were diagnosed with ANCA-associated vasculitides. CONCLUSIONS: ANCA positivity may be more related to vasculitis and immunological disorders than to a M. tuberculosis infection. Therefore, to improve diagnostic accuracy, patients with M. tuberculosis who are ANCA positive should be investigated for concurrent diseases, including the effects of drugs. Therefore, even in tuberculosis epidemic area, ANCA seropositivity, detected by ELISA, is still more suggestive of ANCA-associated vasculitides.

Summary Objective: The aim of this study was to assess the efficacy and safety of ceftazidime-avibactam in the treatment of complicated intra-abdominal infections (CIAIs) and complicated urinary tract infections (CUTIs) with meta-analysis method. Method: We included six randomized clinical trials identified from Medline, Embase, Cochrane Library, “ISRCTN Register” and “ClinicalTrials.gov” which compared ceftazidime-avibactam with comparison group. The meta-analysis was performed using Review Manager software version 5.3. Results: Ceftazidime-avibactam versus active comparisons demonstrated a statistically significant higher rate of microbiological response success on microbiological evaluable populations at the test-of-cure visit (95CI 1.10-2.38, p=0.02) and late-follow-up visit (95CI 1.09-2.23, p=0.02) for the treatment of CUTIs. Ceftazidime-avibactam versus active comparisons demonstrated a statistically significant higher rate of microbiological response success on EME populations at the test-of-cure visit (95CI 1.08-4.27, p=0.03) and late-follow-up visit (OR=1.75, 95CI 1.33-2.29, p<0.0001) for the treatment of CUTIs. Similar results were obtained at the late-follow-up visit (OR = 1.58, 95CI 1.26-1.97, p<0.0001) on microbiologically modified intent-to-treat (mMITT) populations for the treatment of CUTIs. We can find better eradication rates for E. coli and Klebsiella pneumoniae based on mMITT populations. In terms of AEs, SAEs and mortality, ceftazidime-avibactam had a safety and tolerability profile broadly similar to the comparison group. Conclusion: This meta-analysis provides evidence of the efficacy of ceftazidime-avibactam as a potential alternative for the treatment of patients with CUTIs, and CIAIs.

Background: The impact of enteral nutrition (EN) on surgical risk in Crohn's disease (CD) patients suffering from spontaneous intra-abdominal abscess (IAA) was evaluated. Methods: CD patients diagnosed with spontaneous IAA from 2008 to 2015 were included in the study. The impact of EN on surgical risk was evaluated using both univariate and multivariate analyses. Results: A total of 87 patients were enrolled, 66 (75.9%) were male. The mean age at the development of an abscess was 30.2 ± 10.1 years and the median duration of illness from CD diagnosis until the development of an abscess was three (2-6) years. After a median follow-up of 1.9 (1.1-2.9) years, surgical intervention was performed in 42 patients (48.3%). Patients treated with EN were less likely to require surgical intervention (26.1% vs 56.3%, p = 0.01). Multivariate analysis showed that EN was an independent protective factor for the risk of surgery with a hazard ratio of 0.27 (95% confidence interval: 0.11-0.65, p = 0.004) after adjusting for abdominal pain, history of abdominal surgery, concomitant intestinal stenosis and prior use of antibiotics within three months. Conclusions: Surgical intervention is common for CD patients with IAA. Appropriate application of EN may help obviate the need for surgical treatment.

Objective: The aim of this article is to compare the efficacy and safety of doripenem for bacterial infections. Methods: We included six randomized clinical trials identified from PubMed and Embase up to July 31, 2014. The included trials compared efficacy and safety of doripenem for complicated intra-abdominal infections, complicated urinary tract infection, nosocomial pneumonia, and acute biliary tract infection. The meta-analysis was carried on by the statistical software of Review Manager, version 5.2. Results: Compared with empirical antimicrobial agents on overall treatment efficacy, doripenem was associated with similar clinical and microbiological treatment success rates (for the clinical evaluable population, odds ratio [OR] = 1.26, 95% confidence interval [CI] 0.93-1.69, p = 0.13; for clinical modified intent-to-treatment population, OR = 0.88, 95% CI 0.55-1.41, p = 0.60; for microbiology evaluable population, OR = 1.16, 95% CI 0.90-1.50, p = 0.26; for microbiological modified intent-to-treatment (m-mITT), OR = 0.98, 95% CI 0.81-1.20, p = 0.87). We compared incidence of adverse events and all-cause mortality to analyze treatment safety. The outcomes suggested that doripenem was similar to comparators in terms of incidence of adverse events and all-cause mortality on modified intent-to-treatment population (for incidence of AEs, OR = 1.10, 95% CI 0.90-1.35, p = 0.33; for all-cause mortality, OR = 1.08, 95% CI 0.77-1.51, p = 0.67). In nosocomial pneumonia and ventilator-associated pneumonia treatment, doripenem was not inferior to other antibacterial agents in terms of efficacy and safety. Conclusion: From this meta-analysis, we can conclude that doripenem is as valuable and well-tolerated than empirical antimicrobial agents for complicated intra-abdominal infections, complicated urinary tract infection, acute biliary tract infection and nosocomial pneumonia treatment.

Genetic variation and evolutionary demography of the shrimp Fenneropenaeus chinensis were investigated using sequence data of the complete mitochondrial control region (CR). Fragments of 993 bp of the CR were sequenced for 93 individuals from five localities over most of the species' range in the Yellow Sea and the Bohai Sea. There were 84 variable sites defining 68 haplotypes. Haplotype diversity levels were very high (0.95 ± 0.03-0.99 ± 0.02) in F. chinensis populations, whereas those of nucleotide diversity were moderate to low (0.66 ± 0.36%-0.84 ± 0.46%). Analysis of molecular variance and conventional population statistics (F ST) revealed no significant genetic structure throughout the range of F. chinensis. Mismatch distribution, estimates of population parameters and neutrality tests revealed that the significant fluctuations and shallow coalescence of mtDNA genealogies observed were coincident with estimated demographic parameters and neutrality tests, in implying important past-population size fluctuations or range expansion. Isolation with Migration (IM) coalescence results suggest that F. chinensis, distributed along the coasts of northern China and the Korean Peninsula (about 1000 km apart), diverged recently, the estimated time-split being 12,800 (7,400-18,600) years ago.

Fructus Schisandrae sinensis Baill, a traditional Chinese medicine, used as tonic and sedative, has been shown at the beginning of 70's to lower the elevated serum glutamic-pyruvic transaminase (SGPT) levels of patients suffering from chronic viral hepatitis. Durign past 20 years, a series of neolignans have been isolated and identified as effective principles. Pharmacological studies revealed that they increased liver protein and glicogen synthesis, antagonized liver injuries from CCl4 and thioacetamide. The mechanism of SGPT lowering was considered as a hepato-protective and membrane stabilize action, although inhibition of the activity of liver GPT may also be existed. It was found that some principles of Schisandrae have an inducing effect on hepatic microsomal drug-metabolizing enzynme system P-450, thus explained their anti-toxic, anti-carcinogenic and anti-mutagenic effects. A synthetic derivative compound of Schisandrin called DDB has most of the above mentioned actions now used widely in Chine as a hepato-protective drug with high effectiveness in normalizing liver functions and very low side effects. From Schisandrin to synthesized DDB, pointed out a successful way in the development of new drugs from natural products.

Traditional Chinese medicine always pays close attention to the strengthening of the patient"s general resitence against illness, ther are many Chinese herbs used for thousands of years are considered as tonics. Animal experiments and modern clinica; trails have shown that quite a number herbs are immunologically active, and most of the tonics are excellent immunomodulating agents, such as polysaccharides or saponins isolated from Astragalus mongholicus, Acanthopanax senticosus and Panax notoginseng, which stimulated mactophages, promoted antibody formation, actived complement and increased T lymphocyte proliferation. Moreover, some of them were proved to be anti-irradiative and protected animals from liver intoxications. On the other hand, some anti-inflammative or anti-pyretic hervs such as Tripterygium wilfordii, Aconitum and Artemiasiae species were proved to have immunosuppressive principles, some of them were now used clinically for the treatment of rheumatoid arthritis, chronic nephritis, systemic lupus erythematosis and various skin disorders. Pharmacological studies revealed that they have depressant effect on most of the humoral-immunity but not on the cell-mediated immunity. Some of them stimulated adrenal cortex functions and prolonged the survival time of transplanted allograft tissues.