Serotype distribution and antibiotic resistance of Streptococcus pneumoniae isolates collected at a Chinese hospital from 2011 to 2013.

BACKGROUND: Streptococcus pneumoniae infections are a major cause of global morbidity and mortality, and the emergence of antibiotic-resistant Streptococcus pneumoniae strains has been increasingly reported. This study provides up-to-date information on bacterial serotype distribution and drug resistance from S. pneumoniae clinical isolates that could guide prevention and treatment strategies for pneumococcal disease in China. METHODS: A total of 94 S. pneumoniae isolates were collected from outpatients and inpatients at one Chinese hospital from 2011-2013. Drug susceptibility and resistance was determined by minimum inhibitory concentrations (MICs). Capsular serotypes were identified by the quellung reaction test and multiplex polymerase chain reaction. RESULTS: Fifteen serotypes were identified among the 94 S. pneumoniae clinical isolates that were collected. Prevalent serotypes were 19F (42.6 %), 19A (8.5 %), 3 (8.5 %), and 6B (7.4 %). Potential immunization coverage rates for the 7-, 10- and 13-valent pneumococcal polysaccharide conjugate vaccines were 59.6, 62.6, and 79.6 %, respectively. Resistance rates to tetracycline, erythromycin, and trimethoprim/sulfamethoxazole were 91.2, 80.2 and 63.8 %, respectively. Resistance rates to penicillin, amoxicillin, ceftriaxone, and cefotaxime were 47.3, 34.1, 19.8, and 18.7 %, respectively. In almost all cases, antimicrobial resistance of the S. pneumoniae isolates in patients five years or younger was higher than isolates collected from patients aged 51 years or older. CONCLUSION: Prevalent serotypes among the 94 S. pneumoniae clinical isolates were 19F, 19A, 3, and 6B. The 13-valent pneumococcal polysaccharide conjugate vaccine covered the majority of the serotypes identified in this sample. Drug resistance varied among different serotypes and age groups. Clinical precautions should be taken to avoid the development of multidrug resistance in this potential human pathogen.

Integrated model of ozone mass transfer and oxidation kinetic: Construction, solving and analysis.

Ozone-based advanced oxidation process (O3-AOPs) is rapidly evolving, but the surge of emerging pollutants brings new challenges for ozone oxidation research. Herein, we proposed a state-of-the-art model for simultaneously analyzing both ozone mass transfer and oxidation kinetics during ozone oxidation of emerging organic contaminants. The numerical solution and graphical representations of the integrated model were utilized to analyze the dynamics of ozone and pollutant concentration. An in-depth analysis of the integrated model revealed that the reaction rate constants in this present study were higher than previously reported apparent reaction rate constants, and catalysts were not always necessary. Finally, we developed an installable mobile application (APP) that allowed the simulation of the dynamic process for ozone oxidizing organic pollutants in the laboratory, which offered theoretical support for the selection of experimental conditions. The results of model simulation not only provide scientific explanations for counter-intuitive experimental phenomena, but also optimized experimental conditions to enhance ozone utilization.

Quercetin improves cerebral ischemia/reperfusion injury by promoting microglia/macrophages M2 polarization via regulating PI3K/Akt/NF-κB signaling pathway.

The modulation of microglial polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype shows promise as a therapeutic strategy for ischemic stroke. Quercetin, a natural flavonoid abundant in various plants, possesses anti-inflammatory, anti-apoptotic, and antioxidant properties. Nevertheless, its effect and underlying mechanism on microglia/macrophages M1/M2 polarization in the treatment of cerebral ischemia/reperfusion injury (CI/RI) remain poorly explored. In the current study, we observed that quercetin ameliorated neurological deficits, reduced infarct volume, decreased the number of M1 microglia/macrophages (CD16/32+/Iba1+), and enhanced the number of M2 microglia/macrophages (CD206+/Iba1+) after establishing the CI/RI model in rats. Subsequent in vivo and in vitro experiments indicated that quercetin downregulated M1 markers (CD86, iNOS, TNF-α, IL-1ß, and IL-6) and upregulated M2 markers (CD206, Arg-1, IL-10, and TGF-ß). Network pharmacology analysis and molecular docking revealed that the PI3K/Akt/NF-κB signaling pathway emerged as the core pathway. Western blot confirmed that quercetin upregulated the phosphorylation of PI3K and Akt, while alleviating the phosphorylation of IκBα and NF-κB both in vivo and in vitro. However, the PI3K inhibitor LY294002 reversed the effects of quercetin on M2 polarization and the expression of key proteins in the PI3K/Akt/NF-κB pathway in primary microglia after oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro. Collectively, our findings demonstrate that quercetin facilitates microglia/macrophages M2 polarization by modulating the PI3K/Akt/NF-κB signaling pathway in the treatment of CI/RI. These findings provide novel insights into the therapeutic mechanisms of quercetin in ischemic stroke.

Structure-guided engineering of transcriptional activator XYR1 for inducer-free production of lignocellulolytic enzymes in Trichoderma reesei.

The filamentous fungus Trichoderma reesei is widely used for the production of lignocellulolytic enzymes in industry. XYR1 is the major transcriptional activator of cellulases and hemicellulases in T. reesei. However, rational engineering of XYR1 for improved lignocellulolytic enzymes production has been limited by the lack of structure information. Here, alanine 873 was identified as a new potential target for the engineering of XYR1 based on its structure predicted by AlphaFold2. The mutation of this residue to tyrosine enabled significantly enhanced production of xylanolytic enzymes in the medium with cellulose as the carbon source. Moreover, xylanase and cellulase production increased by 56.7- and 3.3-fold, respectively, when glucose was used as the sole carbon source. Under both conditions, the improvements of lignocellulolytic enzyme production were higher than those in the previously reported V821F mutant. With the enriched hemicellulases and cellulases, the crude enzymes secreted by the A873Y mutant strain produced 51 % more glucose and 52 % more xylose from pretreated corn stover than those of the parent strain. The results provide a novel strategy for engineering the lignocellulolytic enzyme-producing capacity of T. reesei, and would be helpful for understanding the molecular mechanisms of XYR1 regulation.

Population pharmacokinetic modelling for enterohepatic circulation of mycophenolic acid in healthy Chinese and the influence of polymorphisms in UGT1A9.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Mycophenolic acid (MPA) undergoes enterohepatic circulation (EHC) in the body and several population models have been proposed to describe this process using sparse data. Recent studies in Whites have found that polymorphism in UGT1A9 could partly explain the large interindividual variability associated with the pharmacokinetics of MPA. WHAT THIS STUDY ADDS: A new population pharmacokinetic model for EHC combining MPA and its main glucuronide metabolite (MPAG) simultaneously was established based on physiological aspects of biliary excretion using intensive sampling data. Pharmacokinetic profiles of MPA and MPAG with the UGT1A9 polymorphism in healthy Chinese were characterized. AIMS To establish a population pharmacokinetic model that describes enterohepatic circulation (EHC) of mycophenolic acid (MPA) based on physiological considerations and to investigate the influence of polymorphisms of UGT1A9 on the pharmacokinetics of MPA. METHODS: Pharmacokinetic data were obtained from two comparative bioavailability studies of oral mycophenolic mofetil formulations. Nonlinear mixed effects modelling was employed to develop an EHC model including both MPA and its main glucuronide metabolite (MPAG) simultaneously. Demographic characteristics and UGT1A9 polymorphisms were screened as covariates. RESULTS: In total, 590 MPA and 589 MPAG concentration-time points from 42 healthy male volunteers were employed in this study. The chain compartment model included an intestinal compartment, a gallbladder compartment, a central and a peripheral compartment for MPA and a central compartment for MPAG. The typical population clearance (CL/F) estimates with its relative standard error for MPA and MPAG were 10.2 l h(-1) (5.7%) and 1.38 l h(-1) (6.9%), respectively. The amount of MPA recycled in the body was estimated to be 29.1% of the total amount absorbed. Covariate analysis showed that body weight was positively correlated with CL/F of MPA, intercompartment CL/F of MPA and distribution volume of MPA peripheral compartment. Polymorphisms of UGT1A9 did not show any effect on the pharmacokinetics of MPA and MPAG. The model evaluation tests indicated that the proposed model can describe the pharmacokinetic profiles of MPA and MPAG in healthy Chinese subjects. CONCLUSIONS: The proposed model may provide a valuable approach for planning future pharmacokinetic-pharmacodynamic studies and for designing proper dosage regimens of MPA.

Association of MDR1, CYP3A4*18B, and CYP3A5*3 polymorphisms with cyclosporine pharmacokinetics in Chinese renal transplant recipients.

OBJECTIVE: The objective of this study was to retrospectively evaluate the effects of MDR1, CYP3A4*18B, and CYP3A5*3 genetic polymorphisms on cyclosporine A (CsA) pharmacokinetics in Chinese renal transplant patients during the first month after transplantation. METHODS: A total of 103 renal transplant recipients receiving CsA were genotyped for MDR1 (C1236T, G2677T/A, and C3435T), CYP3A4*18B, and CYP3A5*3. The predose and 2-h postdose concentrations of CsA (C(0) and C(2), respectively) were determined by fluorescence polarization immunoassay, and their relationships with corresponding genotypes and haplotypes were investigated. RESULTS: Patients with a CYP3A4*1/*1 genotype were found to have a higher dose-adjusted concentration compared with those with CYP3A4*18B/*18B, as follows: for C(2), 19.3% (P = 0.008) during days 8-15, 35.2% (P = 0.008) during days 16-30, and for C(0), 39.7% (P = 0.012) during days 16-30. The dose-adjusted C(0) was higher in patients with MDR1 1236CC compared with those with 1236TT in the first month postoperation. The dose-adjusted C(0) in patients with the CYP3A5*3/*3 genotype was 25.5% and 30.7% higher than those with the wild-type genotype during days 8-15 (P = 0.011) and days 16-30 (P = 0.015), respectively. Haplotype analysis revealed that the dose-adjusted C(0) was higher in the first month following surgery in carriers of haplotype MDR1 CAC than in noncarriers. Polymorphisms of MDR1 and CYP3A5*3 did not affect dose-adjusted C(2.) CONCLUSION: The data suggests that the CYP3A4*18B genotype affects CsA pharmacokinetics during the first month following surgery in Chinese renal transplant recipients. Patients with CYP3A4*18B alleles may require higher doses of CsA to reach the target levels. Large prospective studies may be needed to further explore the impact of MDR1 and CYP3A5*3 polymorphisms on CsA pharmacokinetics in renal transplant recipients.

[Effect of MDR1 polymorphic expression on oral disposition of cyclosporine A].

AIM: To determine the relationship between C3435T mutation in exon 26 of the human multidrug resistant 1 gene and cyclosporine (CsA) pharmacokinetic (PK) parameters among healthy Chinese volunteers by nonlinear mixed effect model (NONMEM). METHODS: Twenty healthy subjects were given orally a single dose of 500 mg CsA in microemulsion solution. Blood CsA concentrations were measured with HPLC and the genotype for the C3435T polymorphism of MDR1 gene was determined with the PCR and restriction fragment length polymorphism. The results were further confirmed by sequencing. NONMEM was performed to assess the effect of genotype on CsA PK profile. RESULTS: MDR1 C3435T genotype was identified as the best predictor of CsA systemic exposure. The relative bioavailability of CsA was 40% higher in subjects who carried at least one 3435C allele compared to that of TT type individuals in the study population. CONCLUSION: The MDR1 C3435T genotype offers a potential basis of mechanism to explain inter-subject differences in CsA oral bioavailability.

[Changes of alkaline phosphatase sugar chains in hepatocellular carcinoma tissue].

OBJECTIVE: To investigate the changes of sugar chain structures of alkaline phosphatase (ALP) in hepatoma tissue and its relation to the invasiveness of hepatocellular carcinoma (HCC). METHODS: The binding ratios of ALP from 9 normal liver tissues, 16 hepatoma tissues and 16 noncancerous tissues surrounding hepatoma were analysed by affinity chromatography on various lectin columns including leukoagglutinating phytohemagglutinin (L-PHA), lentil lectin (LCA), Datura stramonium agglutinin (DSA), erythroagglutinating phytohemagglutinin (E-PHA) and Sambucus nigra bark agglutinin (SNA). RESULTS: The binding ratios of ALP on L-PHA (22.94%+/-5.30%), DSA (55.97%+/-13.72%), LCA (38.16%+/-8.87%), E-PHA (11.56%+/-4.81%) and SNA (69.80%+/-13.71%) in HCC tissues were significantly increased (P<0.01) compared with that in normal liver tissues (L-PHA 5.89%+/-2.75%, DSA 36.20%+/-11.58%, LCA 17.90%+/-6.71%, E-PHA 5.38%+/-2.20%, SNA 57.32%+/-11.27%), respectively. t values between the two groups were 8.94, 3.64, 5.94, 3.62 and 2.32, respectively. L-PHA-binding ratio (25.84%+/-4.67%) of ALP in HCC with invasiveness was significantly higher than that (18.10%+/-3.64%) without invasiveness (t=3.71, P<0.01). CONCLUSION: The changes of ALP sugar chain structures occur in HCC tissue. b1-6 branching sugar chain structure of ALP is related to the invasiveness of HCC.