Ulcerative colitis (UC) is a chronic, nonspecific inflammatory bowel disease (IBD) characterized by complicated and relapsing inflammation in the gastrointestinal tract. SM934 is a water-soluble ...artemisinin analogue that shows anti-inflammatory and immuno-regulatory effects. In this study, we investigated the effects of SM934 on UC both in vivo and in vitro. A mouse model of colitis was established in mice by oral administration of 5% dextran sulfate sodium (DSS). SM934 (3, 10 mg/kg per day, ig) was administered to the mice for 10 days. After the mice were sacrificed, colons, spleens and mesenteric lymph nodes (MLNs) were collected for analyses. We showed that SM934 administration restored DSS-induced body weight loss, colon shortening, injury and inflammation scores. Furthermore, SM934 administration significantly decreased the disease activity index (DAI), histopathological scores, and myeloperoxidase (MPO) activities in colonic tissues. Moreover, SM934 administration dose-dependently decreased the mRNA and protein levels of DSS-induced pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α), and the percentage of macrophages and neutrophils in colon tissues. The effects of SM934 on LPS-stimulated RAW 264.7 cells and THP-1-derived macrophages were examined in vitro. Treatment with SM934 (0.8, 8, 80 μmol/L) dose-dependently decreased the production of pro-inflammatory mediators in LPS-stimulated RAW264.7 cells and THP-1-derived macrophages via inhibiting activation of the NF-κB signaling. Our results reveal the protective effects of SM934 on DSS-induced colitis can be attributed to its suppressing effects on neutrophils and macrophages and its inhibitory role in the NF-κB signaling, suggests that SM934 might be a potential effective drug for ulcerative colitis.
In order to improve the position high-precision synchronization performance of multi-motor synchronous control, a multi-motor position synchronization control method based on non-singular fast ...terminal sliding mode control (NFTSMC) combined with an improved deviation coupling control structure (Improved Deviation Coupling Control(IDCC), NFTSMC+IDCC). Firstly, this paper designs a sliding mode controller using a non-singular fast terminal sliding mode surface with a Permanent Magnet Synchronous Motor (PMSM) as the control object. Secondly, the deviation coupling is improved to enhance the coupling between multiple motors and achieve position synchronization. Finally, the simulation results show that the total error of multi-motor position synchronization under NFTSMC control is 0.553r in the simulation of multi-motor synchronization control under the same working conditions, which is 2.873r and 1.772r less than that of SMC and FTSMC in terms of speed error, and the anti-disturbance performance is 83.68% and 76.22% higher than that of both of them, respectively. In the subsequent simulation of the improved multi-motor position synchronization structure, the total error of the multi-motor position is in the range of 0.56r-0.58r at three speeds, which is much smaller than the synchronization error under the Ring Coupling Control (RCC) structure and Deviation Coupling Control (DCC) structure, showing a better The synchronization error is much smaller than that of the RCC structure and DCC structure, which shows better position synchronization performance. Therefore, the multi-motor position synchronization control method proposed in this paper has a good position synchronization effect and achieves the control effect of small displacement error and fast convergence of the multi-motor position synchronization control system after being disturbed, the control performance is significantly improved.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Anti-angiogenic therapy combined with chemotherapy could improve the outcomes of patients with platinum-resistant ovarian cancer. Apatinib is an oral tyrosine kinase inhibitor that selectively ...inhibits VEGF receptor 2. We assessed the efficacy and safety of the combination therapy of apatinib and oral etoposide, considering the potential advantage of home administration without hospital admission, in patients with platinum-resistant or platinum-refractory ovarian cancer.
In this phase 2, single-arm, prospective study, we recruited patients aged 18–70 years with platinum-resistant or platinum-refractory ovarian cancer at the Sun Yat-sen University Cancer Center (China). The treatment consisted of apatinib at an initial dose of 500 mg once daily on a continuous basis, and oral etoposide at a dose of 50 mg once daily on days 1–14 of a 21-day cycle. Oral etoposide was administered for a maximum of six cycles. Treatment was continued until disease progression, patient withdrawal, or unacceptable toxic effects. The primary endpoint was the proportion of patients achieving an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1. We used Simon's two-stage design, and analysed efficacy in the intention-to-treat and per-protocol populations. Safety analyses included enrolled patients who had received at least one dose of study medication, but excluded those without any safety data. This study is registered with ClinicalTrials.gov, number NCT02867956.
Between Aug 10, 2016, and Nov 9, 2017, we screened 38 and enrolled 35 patients. At the data cutoff date (Dec 31, 2017), 20 (57%) patients had discontinued the study, and 15 (43%) patients remained on treatment. Objective responses were achieved in 19 (54%; 95% CI 36·6–71·2) of 35 patients in the intention-to-treat population and in 19 (61%; 42·2–78·2) of 31 patients in the per-protocol population. The most common grade 3 or 4 adverse events were neutropenia (17 50%), fatigue (11 32%), anaemia (ten 29%), and mucositis (eight 24%). Serious adverse events were reported in two patients who were admitted to hospital (one patient had anaemia and anorexia; the other patient had increased ascites due to disease progression). No treatment-related deaths were recorded.
The combination of apatinib with oral etoposide shows promising efficacy and manageable toxicities in patients with platinum-resistant or platinum-refractory ovarian cancer, and further study in phase 3 trials is warranted.
None.
Tomato bacterial wilt caused by Ralstonia solanacearum bacterium is a severe problem in Southern China, where relatively high environmental temperatures commonly prevails during the crop seasons. ...Previous research has indicated that bacterial wilt disease incidence generally increases during the warm months of summer leading to reduced tomato yield. Moreover, the efficacy of bio-organic fertilizers (BOFs)-organic compost fortified with pathogen-suppressive bacteria-is often lost during the periods of high environmental temperatures. Here we studied if the disease incidence could be reduced and the BOF performance enhanced by simply preponing and postponing the traditional seedling transplantation times to avoid tomato plant development during periods of high environmental temperature. To this end, a continuous, two-year field experiment was conducted to evaluate the performance of BOF in two traditional (late-spring LS and early-autumn EA) and two alternative (early-spring ES and late-autumn LA) crop seasons. We found that changing the transplantation times reduced the mean disease incidence from 33.9% (LS) and 54.7% (EA) to 11.1% (ES) and 7.1% (LA), respectively. Reduction in disease incidence correlated with the reduction in R. Solanacearum pathogen density in the tomato plant rhizosphere and stem base. Applying BOF during alternative transplantation treatments improved biocontrol efficiency from 43.4% (LS) and 3.1% (EA) to 67.4% (ES) and 64.8% (LA). On average, the mean maximum air temperatures were positively correlated with the disease incidence, and negatively correlated with the BOF biocontrol efficacy over the crop seasons. Crucially, even though preponing the transplantation time reduced the tomato yield in general, it was still economically more profitable compared to LS season due to reduced crop losses and relatively higher market prices. Preponing and postponing traditional tomato transplantation times to cooler periods could thus offer simple but effective way to control R. solanacearum disease outbreaks.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Base composition asymmetry and gene orientation bias are two common genomic structures in bacterial genomes. Here, correlation coefficients between nucleotide disparities and coding sequence (CDS) ...skew have been calculated, which provides insights into their relationship from an individual genome perspective. Consequently, we find GC and RY disparities correlate significantly with CDS skew, since around 60% of the bacterial genomes under study have correlation coefficients > 0.9. Then, we present a model for quantitative assessment of nucleotide disparity and CDS skew in which a numerical index R2 is used for evaluation. We find that skew curves with higher R2 perform better on the prediction of replication origins in bacteria.
This study assessed the effectiveness, adverse events, patient adherence, and costs of modified dual therapy compared with bismuth-containing quadruple therapy for treating Helicobacter pylori ...infection in Chinese patients. We also sought to determine whether modified dual therapy could be used as an alternative first-line treatment for H. pylori infection.
A total of 232 H. pylori-infected, treatment-naive patients were enrolled in this open-label, randomized controlled clinical trial. Patients were randomly allocated into 2 groups: the 14-day modified dual therapy group and the bismuth-containing quadruple therapy group. Eradication rates, drug-related adverse events, patient compliance, and drug costs were compared between the 2 groups.
The modified dual therapy group achieved eradication rates of 87.9%, 91.1%, and 91.1% as determined by the intention-to-treat, per-protocol, and modified intention-to-treat analyses, respectively. The eradication rates were similar compared with the bismuth-containing quadruple therapy group: 89.7%, 91.2%, and 90.4%. In addition, modified dual therapy ameliorated variations in the CYP2C19, IL-1B-511, and H. pylori VacA genotypes. There were no significant differences in the compliance rates between the 2 groups. The modified dual therapy group exhibited significantly less overall side effects compared with the bismuth-containing quadruple therapy group (P < 0.001). Furthermore, the cost of medications in the modified dual therapy was lower compared with that in the bismuth-containing quadruple therapy.
Modified dual therapy at high dose and administration frequency is equally effective and safer and less costly compared with bismuth-containing quadruple therapy.
What is known and objective
Mycophenolate mofetil, an ester prodrug of mycophenolic acid (MPA), is widely used to prevent graft rejection after kidney transplantation. The pharmacokinetic (PK) of MPA ...has been extensively studied, which revealed a high degree of variability. An integrated population PK (PopPK) model of MPA and its main metabolite mycophenolic acid glucuronide (MPAG) was developed using the adult patients who underwent kidney transplant and were administered oral mycophenolate mofetil combined with tacrolimus.
Methods
In total, 917 MPA and 740 MPAG concentrations in191 adult patients were analysed via nonlinear mixed‐effects modelling. The concentration‐time data were adequately described using a chain compartment model, including central and peripheral compartments for MPA and a central compartment for MPAG. Stepwise forward inclusion and backward elimination procedures were used to investigate the effects of genetic polymorphisms, including in UGT1A8, UGT1A9, UGT2B7, ABCB1, ABCC2, ABCG2, SLCO1B1, SLCO1B3, and HNF1α.
Results and discussion
These genetic polymorphisms in metabolic enzymes and transporters have no obvious impact on the PK of MPA in adult patients who underwent kidney transplant and were co‐treated with tacrolimus. The post‐transplant time, serum albumin, and creatinine clearance were identified as significant covariates affecting the PK of MPA and MPAG, which should be considered in the clinical use of mycophenolate mofetil.
What is new and conclusion
We established a PopPK model of MPA and MPAG in Chinese adult patients who underwent kidney transplant and were co‐treated with tacrolimus. Genetic polymorphisms in metabolic enzymes and transporters showed no obvious impact on MMF PK. A model‐informed dosing strategy was proposed by the established model, and MMF dose adjustment should be based on ALB levels and the post‐transplantation time.
Population PK model of MPA and MPAG was established in Chinese adult renal transplant patients who co‐treated with tacrolimus. MMF dosing strategy based on albumin levels and the post‐transplantation time was proposed by the established model.
Abstract
DNA replication begins at replication origins in all three domains of life. Identification and characterization of replication origins are important not only in providing insights into the ...structure and function of the replication origins but also in understanding the regulatory mechanisms of the initiation step in DNA replication. The Z-curve method has been used in the identification of replication origins in archaeal genomes successfully since 2002. Furthermore, the Web servers of Ori-Finder and Ori-Finder 2 have been developed to predict replication origins in both bacterial and archaeal genomes based on the Z-curve method, and the replication origins with manual curation have been collected into an online database, DoriC. Ori-Finder system and DoriC database are currently used in the research field of DNA replication origins in prokaryotes, including: (i) identification of oriC regions in bacterial and archaeal genomes; (ii) discovery and analysis of the conserved sequences within oriC regions; and (iii) strand-biased analysis of bacterial genomes.
Up to now, more and more predicted results by Ori-Finder system were supported by subsequent experiments, and Ori-Finder system has been used to identify the replication origins in > 100 newly sequenced prokaryotes in their genome reports. In addition, the data in DoriC database have been widely used in the large-scale analyses of replication origins and strand bias in prokaryotic genomes. Here, we review the development of Ori-Finder system and DoriC database as well as their applications. Some future directions and aspects for extending the application of Ori-Finder and DoriC are also presented.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•The generalized Bloch condition is used for the calculation.•The half-metallic properties of Mo0.75Mn0.25S2 monolayer are found.•The dispersion relation of the spin-spiral energy E(q⇀) for ...Mo0.75Mn0.25S2 is obtained.•The exchange coupling coefficient Ji (i=1, 2, 3, 4) is obtained through the Heisenberg interaction (HBI) model.•The next-nearest-neighbor interaction exchange coupling coefficient J2 is found to be nonnegligible.
We use first-principles method to investigate the crystal structure, electronic structure and magnetic properties of Mn-doped MoS2 monolayer (Mo0.75Mn0.25S2). The spin-up electron states exhibit metallic properties, while the spin-down electron states exhibit insulating properties, which indicates the half-metallic properties of Mo0.75Mn0.25S2 monolayer. The doping of Mn atoms leads to the strong ferromagnetism of the system with the coupling between dopant Mn 3d orbitals via Mo 4d and S 3p states. Under the generalized Bloch condition, we explore the dispersion relation of Mo0.75Mn0.25S2 between the spin-spiral energy E(q⇀) and the wave vector q⇀. The exchange coupling coefficient Ji (i=1,2,3,4) is obtained through the Heisenberg interaction (HBI) model. It is found that although the first nearest-neighbor J1 plays an important role, the second-nearest-neighbor interaction exchange coupling coefficient J2 is non-negligible.
Aim： To investigate the action of isothiafludine （NZ-4）, a derivative of bis-heterocycle tandem pairs from the natural product leucamide A, on the replication cycle of hepatitis B virus （HBV） in ...vitro and in vivo. Methods： HBV replication cycle was monitored in HepG2.2.15 cells using qPCR, qRT-PCR, and Southern and Northern blotting. HBV protein expression and capsid assembly were detected using Western blotting and native agarose gel electrophoresis analysis. The interaction of pregenomic RNA （pgRNA） and the core protein was investigated by RNA immunoprecipitation. To evaluate the anti-HBV effect of NZ-4 in vivo, DHBV-infected ducks were orally administered NZ-4 （25, 50 or 100 mg.k~l{1-1） for 15 d. Results： NZ-4 suppressed intracellular HBV replication in HepG2.2.15 cells with an IC~o value of 1.33 pmol/L, whereas the compound inhibited the cell viability with an IC5o value of 50.4 pmol/L. Furthermore, NZ-4 was active against the replication of various drug- resistant HBV mutants, including 3TC/ETV-dual-resistant and ADV-resistant HBV mutants. NZ-4 （5, 10, and 20 pmol/L） concentration- dependently reduced the encapsidated HBV pgRNA, resulting in the assembly of replication-deficient capsids in HepG2.2.15 cells. Oral administration of NZ-4 dose-dependently inhibited DHBV DNA replication in the DHBV-infected ducks. Conclusion： NZ-4 inhibits HBV replication by interfering with the interaction between pgRNA and HBcAg in the capsid assembly process thus increasing the replication-deficient HBV capsids. Such mechanism of action might provide a new therapeutic strategy to combat H BV infection.
PDF
