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991.
992.
Barrett DG Catalano JG Deaton DN Hassell AM Long ST Miller AB Miller LR Ray JA Samano V Shewchuk LM Wells-Knecht KJ Willard DH Wright LL 《Bioorganic & medicinal chemistry letters》2006,16(6):1735-1739
Starting from a potent pantolactone ketoamide cathepsin K inhibitor discovered from structural screening, conversion of the lactone scaffold to a pyrrolidine scaffold allowed exploration of the S(3) subsite of cathepsin K. Manipulation of P3 and P1' groups afforded potent inhibitors with drug-like properties. 相似文献
993.
Escherichia coli DNA adenine methyltransferase (Dam) plays essential roles in DNA replication, mismatch repair and gene regulation. The differential methylation by Dam of the two GATC sequences in the pap promoter regulates the expression of pili genes necessary for uropathogenic E.coli cellular adhesion. Dam processively methylates GATC sites in various DNA substrates, yet the two pap GATC sites are not processively methylated. We previously proposed that the flanking sequences surrounding the two pap GATC sites contribute to the enzyme's distributive methylation. We show here that replacement of the poorly methylated pap GATC sites with sites predicted to be processively methylated indeed results in an increase in Dam processivity. The increased processivity is due to a change in the methyltransfer kinetics and not the binding efficiency of Dam. A competition experiment in which the flanking sequences of only one pap GATC site were altered demonstrates that the GATC flanking sequences directly regulate the enzyme's catalytic efficiency. The GATC flanking sequences in Dam-regulated promoters in E.coli and other bacteria are similar to those in the pap promoter. Gene regulation from some of these promoters involves mechanisms and proteins that are quite different from those in the pap operon. Further, GATC sequences previously identified to remain unmethylated within the E.coli genome, but whose function remains largely unassigned, are flanked by sequences predicted to be poorly methylated. We conclude that the GATC flanking sequences may be critical for expression of pap and other Dam-regulated genes by affecting the activity of Dam at such sites and, thus, its processivity. A model is proposed, illustrating how the sequences flanking the GATC sites in Dam-regulated promoters may contribute to this epigenetic mechanism of gene expression, and how flanking sequences contribute to the diverse biological roles of Dam. 相似文献
994.
When plants are subjected to leaf canopy shade in forest understories or from neighboring plants, they not only experience reduced light quantity, but light quality in lowered red : far red light (R : FR). Growth and other developmental responses of plants in reduced R : FR can vary and are not consistent across species. We compared how an invasive liana, Celastrus orbiculatus, and its closely related native congener, C. scandens, responded to changes in the R : FR under controlled, simulated understory conditions. We measured a suite of morphological and growth attributes under control, neutral shading, and low R : FR light treatments. Celastrus orbiculatus showed an increase in height, aboveground biomass, and total leaf mass in reduced R : FR treatments as compared to the neutral shade, while C. scandens had increased stem diameter, single leaf area, and leaf mass to stem mass ratio. These differences provide a mechanistic understanding of the ability of C. orbiculatus to increase height and actively forage for light resources in forest understories, while C. scandens appears unable to forage for light and instead depends upon a light gap forming. The plastic growth response of C. orbiculatus in shaded conditions points to its success in forested habitats where C. scandens is largely absent. 相似文献
995.
Meigs JB Dupuis J Liu C O'Donnell CJ Fox CS Kathiresan S Gabriel SB Larson MG Yang Q Herbert AG Wilson PW Feng D Tofler GH Cupples LA 《Obesity (Silver Spring, Md.)》2006,14(5):753-758
Elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1) increase risk for type 2 diabetes. The PAI-1 4G/5G polymorphism is a major genetic determinant of plasma PAI-1 levels, with 4G/4G homozygotes having elevated PAI-1 levels relative to 5G allele carriers. These observations suggest the hypothesis that the PAI-1 4G/5G polymorphism could be a genetic risk factor for diabetes. We tested this hypothesis among 2169 participants of the Framingham Offspring Study followed for seven examinations over 26 years for 216 cases of type 2 diabetes. PAI-1 4G/4G homozygotes (genotype frequency, 27.4%) were not at significantly (p > 0.05) increased risk of incident diabetes compared with 5G allele carriers and did not have elevated levels of diabetes-related quantitative traits including BMI, fasting plasma glucose, or fasting insulin. In proportional hazards regression models accounting for correlation among siblings, with the 5G/5G genotype as the referent, the hazard ratio for incident diabetes for 4G/5G carriers was 0.93 (95% confidence interval, 0.68 to 1.28) and for 4G/4G carriers was 1.20 (95% confidence interval, 0.83 to 1.92). Results were not altered by further adjustment for sex or levels of BMI, triglycerides, or PAI-1. We conclude that the PAI-1 4G/5G polymorphism is not an important genetic risk factor for type 2 diabetes in this community-based sample. Elevated PAI-1 levels may be associated with an increased risk for diabetes as a marker for underlying endothelial dysfunction rather than by a direct effect of genetically mediated elevated levels. 相似文献
996.
Abstract The existence of a direct link between intensity of sexual selection and mating-system type is widely accepted. However, the quantification of sexual selection has proven problematic. Several measures of sexual selection have been proposed, including the operational sex ratio (OSR), the breeding sex ratio (BSR), and the opportunity for sexual selection (I(mates)). For a wild population of pronghorn (Antilocapra americana), we calculated OSR and BSR. We estimated I(mates) from census data on the spatial and temporal distribution of receptive females in rut and from a multigenerational genetic pedigree. OSR and BSR indicated weak sexual selection on males, but census and pedigree I(mates) suggested stronger sexual selection on males than on females. OSR and BSR correlated with census but not pedigree estimates of I(mates), and census I(mates) did not correlate with pedigree estimates. This suggests that the behavioral mating system, as deduced from the spatial and temporal distribution of females, does not predict the genetic mating system of pronghorn. The differences we observed between estimators were primarily due to female mate sampling and choice and to the sex ratio. For most species, behavioral data are not perfectly accurate and therefore will be an insufficient alternative to using multigenerational pedigrees to quantify sexual selection. 相似文献
997.
The present study tests the hypothesis that skin on the plantar surface of the foot absorbs oxygen (O(2)) when immersed in water that has a high dissolved O(2) content. Healthy male and female subjects (24.2 ± 1.4 years) soaked each foot in tap water (1.7 ± 0.1 mg O(2)·L(-1); 30.7 ± 0.3 °C) or O(2)-infused water (50.2 ± 1.7 mg O(2)·L(-1); 32.1 ± 0.5 °C) for up to 30 min in 50 different experiments. Transcutaneous oximetry and near infrared spectroscopy were used to evaluate changes in skin PO(2), oxygenated haemoglobin, and cytochrome oxidase aa(3) that resulted from treatment. Compared with the tap water condition, tissue oxygenation index was 3.5% ± 1.3% higher in feet treated for 30 min with O(2)-infused water. This effect persisted after treatment, as skin PO(2) was higher in feet treated with O(2)-infused water at 2 min (237 ± 9 vs. 112 ± 5 mm HG) and 15 min (131 ± 1 vs. 87 ± 4 mm HG) post-treatment. When blood flow to the foot was occluded for 5 min, feet resting in O(2)-infused water maintained a 3-fold higher O(2) consumption rate than feet treated with tap water (9.1 ± 1.4 vs. 3.0 ± 1.0 μL·100 g(-1)·min(-1)). We estimate that skin absorbs 4.5 mL of O(2)·m(-2)·min(-1) from O(2)-infused water. Thus, skin absorbs appreciable amounts of O(2) from O(2)-infused water. This finding may prove useful and assist development of treatments targeting skin diseases with ischemic origin. 相似文献
998.
999.
1000.
Kui Shen Yuan Qi Nan Song Chunqiao Tian Shara D Rice Michael J Gabrin Stacey L Brower William Fraser Symmans Joyce A O’Shaughnessy Frankie A Holmes Lina Asmar Lajos Pusztai 《BMC medical genomics》2012,5(1):1-8