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61.
TJ Stout D Tondi M Rinaldi D Barlocco P Pecorari DV Santi ID Kuntz RM Stroud BK Shoichet MP Costi 《Canadian Metallurgical Quarterly》1999,38(5):1607-1617
Thymidylate synthase is an attractive target for antiproliferative drug design because of its key role in the synthesis of DNA. As such, the enzyme has been widely targeted for anticancer applications. In principle, TS should also be a good target for drugs used to fight infectious disease. In practice, TS is highly conserved across species, and it has proven to be difficult to develop inhibitors that are selective for microbial TS enzymes over the human enzyme. Using the structure of TS from Lactobacillus casei in complex with the nonsubstrate analogue phenolphthalein, inhibitors were designed to take advantage of features of the bacterial enzyme that differ from those of the human enzyme. Upon synthesis and testing, these inhibitors were found to be up to 40-fold selective for the bacterial enzyme over the human enzyme. The crystal structures of two of these inhibitors in complex with TS suggested the design of further compounds. Subsequent synthesis and testing showed that these second-round compounds inhibit the bacterial enzyme at sub-micromolar concentrations, while the human enzyme was not inhibited at detectable levels (selectivities of 100-1000-fold or greater). Although these inhibitors share chemical similarities, X-ray crystal structures reveal that the analogues bind to the enzyme in substantially different orientations. Site-directed mutagenesis experiments suggest that the individual inhibitors may adopt multiple configurations in their complexes with TS. 相似文献
62.
Brian Shelmadine Matt Cooke Thomas Buford Geoffrey Hudson Liz Redd Brian Leutholtz Darryn S Willoughby 《Journal of the International Society of Sports Nutrition》2009,6(1):16
Purpose
This study determined the effects of 28 days of heavy resistance exercise combined with the nutritional supplement, NO-Shotgun?, on body composition, muscle strength and mass, markers of satellite cell activation, and clinical safety markers. 相似文献63.
64.
This experiment examined the effect of a child's age on his or her interpretation of an act of interpersonal violence on television. One hundred eighty-four children in 2 age groups were randomly assigned to 1 of 4 viewing conditions in which they watched a violent video clip. The clips depicted identical violent acts; however, punishment (yes/no) of the violent act and provocation (yes/no) for the violent act were manipulated to create the 4 conditions. Following the video clip, children were asked to judge whether the act was right or wrong and why. They then engaged in a test of their willingness to choose aggression as a solution to a hypothetical interpersonal conflict. As predicted, younger children thought that unpunished violence was more right than punished violence. Older children thought that provoked violence was more right than unprovoked violence, although this result only approached significance. Children's willingness to choose a violent story ending to a hypothetical interpersonal conflict was related to their experimental condition for older children but not for younger children. 相似文献
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Measurement of maintenance performance is done on the basis of component history data in which service sojourns are distinguished according to whether they terminate in corrective or preventive maintenance. From the viewpoint of data analysis, corrective and preventive maintenance constitute competing failure nudes. This article examines ways to assess maintenance performance without introducing statistical assumptions, then introduces a plausible statistical model for describing the interaction of preventive and corrective maintenance, and finally illustrates these with examples from the Nordic TUD data system. 相似文献
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69.
C. Jiang M. Driffield E. L. Bradley P. K. T. Oldring P. Cooke L. Castle J. T. Guthrie 《Journal of Coatings Technology and Research》2009,6(4):437-444
A methyl ethyl ketone oxime-blocked isocyanate was used as a crosslinking agent in the curing of polyester–polyurethane (PEPU)
can coatings. The completeness of cure was assessed from the amount of residual (un-reacted) isophorone diisocyanate (IPDI)
trimer that was presented in the coating after curing. This amount of residual trimer depended strongly on the temperature
at which the curing was undertaken and time given for curing. The degree of cure was also assessed, correlating with the reduced
IPDI trimer migration potential. The amount of residual IPDI trimer that was extractable from a typical PEPU coating rose
markedly (15- to 20-fold) if the wet coating was aged up to 6 months before use. The presence of a TiO2 pigment increased the aging effect. An aluminum flake pigment had an even greater effect. The TiO2 pigment increased aging by different degrees according to the type of surface modification that had been applied to the pigment.
The grade having the greatest alumina content, as a result of surface modification, gave the greatest aging. The undesirable
effects of aging were counteracted by the addition of more catalyst to the aged coating just before the coating was used to
coat panels. Deactivation of the acidic polymerization catalyst system (based on organotin compounds) is thought to be the
cause of this aging. These findings have allowed improvements to be made to the specifications of the pigments and the catalysts
used, with respect to the consistent industrial production of low migration coatings. 相似文献
70.
Roger Cooke 《Reliability Engineering & System Safety》2008,93(5):775-777