Based on network pharmacology,molecular docking and experimental validation to reveal the potential molecular mechanism of quercetin for the treatment of diarrheal irritable bowel syndrome

Objective:To explore the potential mechanism of action of quercetin in the treatment of diarrhea irritable bowel syndrome(IBS-D).Methods:The potential targets of quercetin were obtained from the TCMSP,SwissTar-getPrediction,and BATMAN-TCM databases.The targets of IBS-D were obtained by searching the GeneCards database with"diarrhea irritable bowel syndrome"as the keyword,and the targets of quercetin and IBS-D were intersected.The PPI network was constructed by Cytoscape 3.7.1 software.The intersected targets were imported into the DAVID database for GO functional analysis and KEGG pathway enrichment analysis.The binding ability of quercetin to the core targets was observed using molecular docking.Based on this,we established an IBS-D rat model,administered quercetin for intervention,and experimentally validated the network pharmacology prediction results by HE staining and ELISA assay.Results:Network pharmacology analysis showed that TP53,TNF-α,AKT1,VEGF-A,IL-6 factors and MAPK,PI3K-Akt signaling pathway as the core targets and pathways of quercetin for the treatment of IBS-D.The results of animal experiments revealed that quercetin could inhibit the secretion of TP53,TNF-α,AKT1,VEGF-A,IL-1βand IL-6,reduce the inflammatory response and improve IBS-D.Conclusion:Quercetin could protect colon tissue by regulating the expression of TP53,TNF-α,AKT1,VEGF-A,IL-1βand IL-6,thereby treating IBS-D.

Dynamic coupled thermo-hydro-mechanical problem for heterogeneous deep-sea sediments under vibration of mining vehicle

Due to the influence of deep-sea environment,deep-sea sediments are usually heterogeneous,and their moduli of elasticity and density change as depth changes.Combined with the characteristics of deep-sea sediments,the thermo-hydro-mechanical coupling dynamic response model of heterogeneous saturated porous sediments can be established to study the influence of elastic modulus,density,frequency,and load amplitude changes on the model.Based on the Green-Lindsay generalized thermoelasticity theory and Darcy’s law,the thermo-hydro-mechanical coupled dynamic response model and governing equations of heterogeneous deep-sea sediments with nonlinear elastic modulus and density are established.The analytical solutions of dimensionless vertical displacement,vertical stress,excess pore water pressure,and temperature are obtained by means of normal modal analysis,which are depicted graphically.The results show that the changes of elastic modulus and density have few effects on vertical displacement,vertical stress,and temperature,but have great effects on excess pore water pressure.When the mining machine vibrates,the heterogeneity of deep-sea sediments has great influence on vertical displacement,vertical stress,and excess pore water pressure,but has few effects on temperature.In addition,the vertical displacement,vertical stress,and excess pore water pressure of heterogeneous deep-sea sediments change more gently.The variation trends of physical quantities for heterogeneous and homogeneous deep-sea sediments with frequency and load amplitude are basically the same.The results can provide theoretical guidance for deep-sea mining engineering construction.

Optimization of Fermentation Conditions for Cellulase Production from Camellia Seed Shell Using Response Surface Methodology

Objective] This study was conducted to optimize cameI ia seed sheI fer-mentation conditions for ceI uIase production by Trichoderma koningi using response surface methodoIogy. [Method] Fermentation conditions for ceI uIase production from Trichoderma koningi were optimized with response surface method （RSM） by taking carboxymethyI ceI uIase （CMCase） activity as a response indicator. Three factors that affecting CMCase activity were screened out using singIe factor test among pretreatment methods of raw material, nitrogen sources, initial pH values, inocuIum voIume, fermentation time and voIume of Iiquid medium, they were fermentation time, initial pH value, and voIume of Iiquid medium. The optimum conditions of fer-mentation and interaction of the three factors were determined through Box-Behnken design and regression analysis using Design-Expert software. [Result] Pretreatment of cameI ia seed sheI with alkaline was most conducive to CMCase production. The use of 0.2% （NH4）2SO4 as nitrogen source, inocuIum size of 5%, initial pH value of 5.8 and voIume of Iiquid medium at 22 mI were the best fermentation conditions for maximizing CMCase production by T. koningi from cameI ia seed sheI . Under these conditions, 179.15 U/mI of CMCase was obtalned after 5 d of fermentation, which was improved by 24.52% compared with the maximum CMCase activity of singIe factor test. [Conclusion] The resuIts wiI provide some references for use of cameI ia seed sheI and ceI uIase production.

Ultrastructure of stridulating organ of Xylotrechus rusticus L. (Coleoptera, Cerambycidae) and behavioral responses to alarm sounds

We used scanning electron microscope （SEM） to observe the ultrastructure of stridulating organs in Xylotrechus rusticus L. We com- pared the morphological structure and size of stridulating organs, the numbers of a tooth-like part used in stridulation and its presence in fe- males and males of this beetle. The alarm sound of X.. rusticus was re- corded first when it was stimulated, then we tested behavioral responses to this alarm sound. The alarm sound ofX. rusticus has a warning effect on conspecifics.

Advanced Glycation End Products Promote Differentiation of CD4^+ T Helper Cells toward Pro-inflammatory Response

This study investigated the effect of advanced glycation end products（AGEs） on differentiation of na ve CD4＋T cells and the role of the receptor of AGEs（RAGE） and peroxisome proliferator-activated receptors（PPARs） activity in the process in order to gain insight into the mechanism of immunological disorders in diabetes. AGEs were prepared by the reaction of bovine serum albumin（BSA） with glucose. Human na ve CD4＋T cells, enriched from blood of healthy adult volunteers with negative selection assay, were cultured in vitro and treated with various agents including AGEs, BSA, high glucose, PGJ2 and PD68235 for indicated time. In short hairpin（sh） RNA knock-down experiment, na ve CD4＋T cells were transduced with media containing shRNA-lentivirus generated from lentiviral packaging cell line, Lent-XTM293 T cells. Surface and intracellular cytokine stainings were used for examination of CD4＋T cell phenotypes, and real-time PCR and Western blotting for detection of transcription factor mRNA and protein expression, respectively. The suppressive function of regulatory T（Treg） cells was determined by a [3H]-thymidine incorporation assay. The results showed that AGEs induced higher pro-inflammatory Th1/Th17 cells differentiated from na ve CD4＋T cells than the controls, whereas did not affect anti-inflammatory Treg cells. However, AGEs eliminated suppressive function of Treg cells. In addition, AGEs increased RAGE mRNA expression in na ve CD4＋T cells, and RAGE knock-down by shRNA eliminated the effect of AGEs on the differentiation of CD4＋T cells and the reduction of suppressive function of Treg cells. Furthermore, AGEs inhibited the mRNA expression of PPARγ, not PPARα; PPARγ agonist, PGJ2, inhibited the effect of AGEs on na ve CD4＋T cell differentiation and reversed the AGE-reduced suppressive function of Treg cells; on the other hand, PPARγ antagonist, PD68235, attenuated the blocking effect of RAGE shRNA on the role of AGEs. It was concluded that AGEs may promote CD4＋T cells development toward pro-inflammatory state, which is associated with increased RAGE mRNA expression and reduced PPARγ activity. ＋

IL28B polymorphism as a predictor of antiviral response in chronic hepatitis C

AIM： To evaluate the effect of single nucleotide poly- morphisms of interleukin （IL）-28B, rs12979860 on progression and treatment response in chronic hepatitis C. METHODS： Patients （n = 64; 37 men, 27 women; mean age, 44 ＋ 12 years） with chronic hepatitis C, genotype 1, received treatment with peg-interferon plus ribavirin. Genotyping of rs12979860 was per- formed on peripheral blood DNA. Histopathological assessment of necroinflammatory grade and fibrosis stage were scored using the METAVIR system on a liver biopsy sample before treatment. Serum viral load, ami- notransferase activity, and insulin level were measured. Insulin resistance index, body mass index, waist/hip ratio, percentage of body fat and fibrosis progression rate were calculated. Applied dose of interferon and ribavirin, platelet and neutrophil count and hemoglobin level were measured. RESULTS： A sustained virological response （SVR） was significantly associated with IL28B polymorphism （CC vs -l-r allele： odds ratio （OR）, 25; CC vs CT allele： OR, 5.4）, inflammation activity （G 〈 1 vs G 〉 1： OR, 3.9）, fibrosis （F 〈 1 vs F 〉 1： OR, 5.9）, platelet count （〉 200 × 109/L vs 〈 200 ×109/L： OR, 4.7; OR in patients with genotype CT： 12.8）, fatty liver （absence vs presence of steatosis： OR, 4.8）, insulin resistance index （〈 2.5 vs 〉 2.5： OR, 3.9）, and baseline HCV viral load （〈 106 IU/mL vs 〉 106 IU/mL： OR, 3.0）. There was no association with age, sex, aminotransferases activity, body mass index, waist/hip ratio, or percentage body fat. There was borderline significance （P = 0.064） of increased fibrosis in patients with the I-I allele, and no differences in the insulin resistance index between groups of patients with CC, CT and -IF alleles （P = 0.12）. Spearman＇s rank correlation coefficient between insulin resistance and stage of fibrosis and body mass index was r = 0.618 and r = 0.605, respectively （P 〈 0.001）. Significant dif- ferences were found in the insulin resistance index （P = 0.01） between patients with and without steatosis. Patients with the C-I- allele and absence of a SVR had a higher incidence of requiring threshold dose reduction of interferon （P = 0.07）. CONCLUSION： IL28B variation is the strongest host factor not related to insulin resistance that determines outcome of antiviral therapy. Baseline platelet count predicts the outcome of antiviral therapy in CT allele patients.

Response Surface Optimization for Process Parameters of LiFePO_4/C Preparation by Carbothermal Reduction Technology

A statistically based optimization strategy is used to optimize the carbothermal reduction technology for the synthesis of LiFePO4/C using LiOH,FePO4 and sucrose as raw materials.The experimental data for fitting the response are collected by the central composite rotatable design(CCD).A second order model for the discharge ca-pacity of LiFePO4/C is expressed as a function of sintering temperature,sintering time and carbon content.The ef-fects of individual variables and their interactions are studied by a statistical analysis(ANOVA).The results show that the linear effects and the quadratic effects of sintering temperature,carbon content and the interactions among these variables are statistically significant,while those effects of sintering time are insignificant.Response surface plots for spatial representation of the model illustrate that the discharge capacity depends on sintering temperature and carbon content more than sintering time.The model obtained gives the optimized reaction parameters of sinter-ing temperature at 652.0 ℃,carbon content of 34.33 g?mol-1 and 8.48 h sintering time,corresponding to a dis-charge capacity of 150.8 mA·h·g-1.The confirmatory test with these optimum parameters gives the discharge ca-pacity of 147.2 and 105.1 mA·h·g-1 at 0.5 and 5 C,respectively.

Treatment of chronic hepatitis delta virus with peg-interferon and factors that predict sustained viral response

AIM： To observe the efficacy of peg-interferon in the treatment of hepatitis delta virus （HDV） and to identify the factors that would be predictive of the sustained viral response （SVR）. METHODS： This prospective study was conducted in Medical Unit IV of the Liaquat University of Medi- cal and Health Sciences Hospital Jamshoro from June 2008 to September 2011. This study cohort included all patients of either sex who presented during this time with hepatitis B surface antigen positivity, hepa- titis B virus DNA 〉 20 000 IU/ml, serum glutamic py- ruvic transaminase （SGPT） 〉 2（upper limit of normal）, HDV-RNA positivity with fibrosis stage ≥ 2. Informed consent was obtained from each of these individuals. Patients were diagnosed with hepatitis D on the ba- sis of detectable viral antibodies and the presence of HDV-RNA in their serum. A liver biopsy was performed in all cases and fibrosis staging was performed in ac- cordance with the METAVIR scoring system. All eligible patients were administered peg-interferon at a weekly dosage of 1.5 μg/kg body weight for 48 wk. HDV-RNA was assayed at the end of this treatment period and again at 24 wk later. A biochemical response was de- termined by a normalization of SGPT at the end of the treatment or during follow up. The end of treatment response was defined by a HDV-RNA negative status. A sustained virological response was defined by unde- tectable serum HDV-RNA at six months after the end of treatment. RESULTS： Among the 277 patients enrolled in our present study, 238 completed a course of peg-interfer- on therapy of which 180 （75.6%） were male and 58 （24.4%） female. Biochemical responses were achieved in 122/238 （51.3%） patients. End of treatment re- sponses were achieved in 71/238 （29.8%） cases. A SVR was achieved in 70 of these patients （29.4%）. A strong association was found between the SVR and the end of treatment responses （P = 0.001）, biochemical responses （P = 0.001） and the degree of fibrosis （P = 0.002）. CONCLUSION： Peg-interferon therapy can induce re- mission in nearly one third of patients harboring HDV.

A central analgesic mechanism of acupuncture for migraine An ongoing functional MRI study

Shaoyang acupoints are the most frequently used in migraine treatment. However, the central anal- gesic mechanism remains poorly understood. Studies have demonstrated that single stimulus of the verum acupuncture in healthy subjects can induce significant connectivity or activity changes in pain- related central networks compared with sham acupuncture. However, these findings are not indicative of the central analgesic mechanism of acupuncture at Shaoyang acupoints. Thus, we recruited 100 migraine sufferers and randomly assigned them into five groups： Shaoyang uncommon acupoint, Shaoyang common acupoint, Yangming uncommon acupoint, non-acupoint control, and blank control groups. Subjects were subjected to evaluation of curative effects and functional MRI prior to and after 10 and 20 acupuncture treatments. All subjects were diagnosed by physicians and enrolled following clinical physical examination. Subjects were observed during 1-4 weeks after inclusion. At the fifth week, the first clinical evaluation and resting functional MRI were conducted. The Shaoyang uncom- mon acupoint, Shaoyang common acupoint, Yangming uncommon acupoint, and non-acupoint control grousp then were treated with acupuncture, five times per week, 20 times in total over 4 weeks. The second and third clinical evaluations and resting functional MRI screenings were conducted following 10 and 20 acupuncture treatments. The blank control group was observed during the 5 to 8 week pe- riod, followed by clinical evaluation and resting functional MRI. The aim of this study was to examine changes in brain functional activity and central networks in subjects with migraine undergoing acu- puncture at Shaoyang uncommon acupoints. This study provides a further explanation of the central analgesic mechanism by which acupuncture at Shaoyang acupoints treats migraine,

Physical mechanism of the compressive response of F-actin networks:significance of crosslinker unbinding events

A model of crosslinker unbinding is implemented in a highly coarse- grained granular model of F-actin cytoskeleton. We employ this specific granular model to study the mechanisms of the compressive responses of F-actin networks. It is found that the compressive response of F-actin cytoskeleton has dependency on the strain rate. The evolution of deformation energy in the network indicates that crosslinker unbinding events can induce the remodelling of F-actin cytoskele- ton in response to external loadings. The internal stress in F-actin cytoskeleton can efficiently dissipate with the help of crosslinker unbinding, which could lead to the soontaneous relaxation of living cells.

The dependence of response spectrum on the tectonic ambient shear stress field

It has been analyzed the influence of the tectonic ambient shear stress value on response spectrum based on the previous theory. Based on the prediction equation BJF94 presented by the famous American researchers, CLB20, a new prediction formula is proposed by us, where it is introduced the influence of tectonic ambient shear stress value on response spectrum. BJF94 is the prediction equation, which mainly depends on strong ground motion data from western USA, while the prediction equation SEA99 is based on the strong ground motion data from exten-sional region all over the world. Comparing these two prediction equations in detail, it is found that after BJF94′s prediction value lg(Y) minus 0.16 logarithmic units, the value is very close to SEA99′s one. This case demonstrates that lg(Y) in extensional region is smaller; the differences of prediction equation are mainly owe to the differences of tectonic ambient shear stress value. If the factor of tectonic ambient shear stress value is included into the pre-diction equation, and the magnitude is used seismic moment magnitude to express, which is universal used around the world, and the distance is used the distance of fault project, which commonly used by many people, then re-gional differences of prediction equation will become much less, even vanish, and it can be constructed the uni-versal prediction equation proper to all over the world. The error in the earthquake-resistant design in China will be small if we directly use the results of response spectrum of USA (e.g. BJF94 or SEA99).

A transient-enhanced NMOS low dropout voltage regulator with parallel feedback compensation

This paper presents a transient-enhanced NMOS low-dropout regulator （LDO） for portable applications with parallel feedback compensation. The parallel feedback structure adds a dynamic zero to get an adequate phase margin with a load current variation from 0 to 1 A. A class-AB error amplifier and a fast charging/discharging unit are adopted to enhance the transient performance. The proposed LDO has been implemented in a 0.35 μm BCD process. From experimental results, the regulator can operate with a minimum dropout voltage of 150 mV at a maximum 1 A load and IQ of 165 μA. Under the full range load current step, the voltage undershoot and overshoot of the proposed LDO are reduced to 38 mV and 27 mV respectively.

Proteomic approach for acute-phase proteins of hemolymph and muscles in Scylla serrata challenged by a pathogenic bacterium

Acute-phase response is documented to be a significant mechanism of innate immunity in vertebrates and invertebrates.In this study,proteomic methodologies were applied for different protein expressions in hemolymph of Scylla serrata challenged by Vibrio parahaemolyticus after immunization,and in muscles of the crabs separately chal-lenged by V.parahaemolyticus,V.anguillarum and Aeromonas hydrophila.Up-regulated cryptocyanin is documented in the hemolymph and up-regulated calexcitin,wingless(fragment)and tachykinin-related peptide in the muscle as acute-phase proteins.All the four altered proteins were responsible for bacterial stress,but cryptocyanin seemed to be a memory response protein against the chal-lenge by a live bacterium after immunization of the live cells.These up-regulated proteins can be indicative of an understanding of immunity of a crab.