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排序方式: 共有247条查询结果,搜索用时 609 毫秒
21.
Jin J Wang Y Wang F Kerns JK Vinader VM Hancock AP Lindon MJ Stevenson GI Morrow DM Rao P Nguyen C Barrett VJ Browning C Hartmann G Andrew DP Sarau HM Foley JJ Jurewicz AJ Fornwald JA Harker AJ Moore ML Rivero RA Belmonte KE Connor HE 《Bioorganic & medicinal chemistry letters》2007,17(6):1722-1725
High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series that led to the identification of SB-649701 (1a), are described. 相似文献
22.
Replacing N-sulfo groups in heparin with N-arylacyl moieties has been shown to afford charge-reduced heparin derivatives that maintain affinity for select heparin-binding proteins. In this study 50% and 100% N-desulfonated heparins were selectively N-acylated with phenylacetic acid and four phenylacetic acid analogs where the phenyl ring was replaced by a heterocycle. Protein-binding studies reveal that structural differences in the ring systems of the N-acyl groups appended to heparin afford significant affects on affinity and selectivity for different heparin-binding proteins. 相似文献
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R Gon?alves LA Szmuchrowski LS Prado BP Couto JCQ Machado VO Damasceno JA Lamounier 《Biology of sport / Institute of Sport》2015,32(3):255-260
The aim of this study was to assess the suitability of body mass index, waist circumference, waist-to-height ratio and aerobic fitness as predictors of cardiovascular risk factor clustering in children. A cross-sectional study was conducted with 290 school boys and girls from 6 to 10 years old, randomly selected. Blood was collected after a 12-hour fasting period. Blood pressure, waist circumference (WC), height and weight were evaluated according to international standards. Aerobic fitness (AF) was assessed by the 20-metre shuttle-run test. Clustering was considered when three of these factors were present: high systolic or diastolic blood pressure, high low-density lipoprotein (LDL) cholesterol, high triglycerides, high plasma glucose, high insulin concentrations and low high-density lipoprotein (HDL) cholesterol. A ROC curve identified the cut-off points of body mass index (BMI), WC, waist-to-height ratio (WHtR) and AF as predictors of risk factor clustering. BMI, WC and WHR resulted in significant areas under the ROC curves, which was not observed for AF. The anthropometric variables were good predictors of cardiovascular risk factor clustering in both sexes, whereas aerobic fitness should not be used to identify cardiovascular risk factor clustering in these children. 相似文献
25.
David Gendron Anne-Marie Lemay Claudine Tremblay Laetitia JA Lai Anick Langlois émilie Bernatchez Nicolas Flamand Marie-Renée Blanchet Anthony S Don Ynuk Bossé élyse Bissonnette David Marsolais 《Respiratory research》2015,16(1)
Background
In vivo phosphorylation of sphingosine analogs with their ensuing binding and activation of their cell-surface sphingosine-1-phosphate receptors is regarded as the main immunomodulatory mechanism of this new class of drugs. Prophylactic treatment with sphingosine analogs interferes with experimental asthma by impeding the migration of dendritic cells to draining lymph nodes. However, whether these drugs can also alleviate allergic airway inflammation after its onset remains to be determined. Herein, we investigated to which extent and by which mechanisms the sphingosine analog AAL-R interferes with key features of asthma in a murine model during ongoing allergic inflammation induced by Dermatophagoides pteronyssinus.Methods
BALB/c mice were exposed to either D. pteronyssinus or saline, intranasally, once-daily for 10 consecutive days. Mice were treated intratracheally with either AAL-R, its pre-phosphorylated form AFD-R, or the vehicle before every allergen challenge over the last four days, i.e. after the onset of allergic airway inflammation. On day 11, airway responsiveness to methacholine was measured; inflammatory cells and cytokines were quantified in the airways; and the numbers and/or viability of T cells, B cells and dendritic cells were assessed in the lungs and draining lymph nodes.Results
AAL-R decreased airway hyperresponsiveness induced by D. pteronyssinus by nearly 70%. This was associated with a strong reduction of IL-5 and IL-13 levels in the airways and with a decreased eosinophilic response. Notably, the lung CD4+ T cells were almost entirely eliminated by AAL-R, which concurred with enhanced apoptosis/necrosis in that cell population. This inhibition occurred in the absence of dendritic cell number modulation in draining lymph nodes. On the other hand, the pre-phosphorylated form AFD-R, which preferentially acts on cell-surface sphingosine-1-phosphate receptors, was relatively impotent at enhancing cell death, which led to a less efficient control of T cell and eosinophil responses in the lungs.Conclusion
Airway delivery of the non-phosphorylated sphingosine analog, but not its pre-phosphorylated counterpart, is highly efficient at controlling the local T cell response after the onset of allergic airway inflammation. The mechanism appears to involve local induction of lymphocyte apoptosis/necrosis, while mildly affecting dendritic cell and T cell accumulation in draining lymph nodes. 相似文献26.
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Faith MS Berkowitz RI Stallings VA Kerns J Storey M Stunkard AJ 《Obesity (Silver Spring, Md.)》2006,14(1):131-138
Objective: Eating in the absence of hunger (EAH) may be a behavioral trait through which obesity‐promoting genes promote positive energy balance. The primary aim of this study was to compare children born at high vs. low risk for obesity with respect to EAH at 5 years of age. Research Methods and Procedures: This was an observational investigation of families enrolled in the University of Pennsylvania and The Children's Hospital of Philadelphia's Infant Growth Study. Five‐year‐old children born at high (N = 28) or low (N = 25) risk for obesity on the basis of maternal prepregnancy body weight were evaluated at a hospital‐based laboratory. Children consumed 11 snack foods ad libitum after consuming an ad libitum dinner and reporting fullness. Parents reported on snack foods at home and their own eating styles. Nutritive sucking at 3 months of age was evaluated by computerized apparatus. Results: EAH in high‐risk boys (mean ± standard error = 326 ± 66 kJ] was more than twice that of low‐risk boys (mean ± standard error = 151 ± 39 kJ), p = 0.03. Among girls, there was a trend for EAH to be associated with increased parental limitations on daughter snack food consumption at home (p = 0.06). EAH was unrelated to 3‐month sucking behavior. Discussion: Genes that promote childhood obesity may partially exert their influence through EAH, an effect that was limited to boys born at risk for obesity. The unique influences of genes and home environment on this trait should be disaggregated in subsequent studies. 相似文献
29.
The signal produced by fluorescence in situ hybridization (FISH) often is inconsistent among cells and sensitivity is low. Small DNA targets on the chromatin are difficult to detect. We report here an improved nick translation procedure for Texas red and Alexa Fluor 488 direct labeling of FISH probes. Brighter probes can be obtained by adding excess DNA polymerase I. Using such probes, a 30 kb yeast transgene, and the rp1, rp3 and zein multigene clusters were clearly detected. 相似文献
30.
Aldred KJ McPherson SA Wang P Kerns RJ Graves DE Turnbough CL Osheroff N 《Biochemistry》2012,51(1):370-381
Bacillus anthracis, the causative agent of anthrax, is considered a serious threat as a bioweapon. The drugs most commonly used to treat anthrax are quinolones, which act by increasing the levels of DNA cleavage mediated by topoisomerase IV and gyrase. Quinolone resistance most often is associated with specific serine mutations in these enzymes. Therefore, to determine the basis for quinolone action and resistance, we characterized wild-type B. anthracis topoisomerase IV, the GrlA(S81F) and GrlA(S81Y) quinolone-resistant mutants, and the effects of quinolones and a related quinazolinedione on these enzymes. Ser81 is believed to anchor a water-Mg(2+) bridge that coordinates quinolones to the enzyme through the C3/C4 keto acid. Consistent with this hypothesized bridge, ciprofloxacin required increased Mg(2+) concentrations to support DNA cleavage by GrlA(S81F) topoisomerase IV. The three enzymes displayed similar catalytic activities in the absence of drugs. However, the resistance mutations decreased the affinity of topoisomerase IV for ciprofloxacin and other quinolones, diminished quinolone-induced inhibition of DNA religation, and reduced the stability of the enzyme-quinolone-DNA ternary complex. Wild-type DNA cleavage levels were generated by mutant enzymes at high quinolone concentrations, suggesting that increased drug potency could overcome resistance. 8-Methyl-quinazoline-2,4-dione, which lacks the quinolone keto acid (and presumably does not require the water-Mg(2+) bridge to mediate protein interactions), was more potent than quinolones against wild-type topoisomerase IV and was equally efficacious. Moreover, it maintained high potency and efficacy against the mutant enzymes, effectively inhibited DNA religation, and formed stable ternary complexes. Our findings provide an underlying biochemical basis for the ability of quinazolinediones to overcome clinically relevant quinolone resistance mutations in bacterial type II topoisomerases. 相似文献