The rollercoaster ride to anti-cancer antibodies Weiner, Louis M; Carter, Paul
Nature biotechnology,
200305, 2003-May, 2003-5-00, 20030501, Letnik:
21, Številka:
5
Journal Article, Conference Proceeding
Recenzirano
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Harrison discussed the play "The Black Star Line" by Charles Smith, which offers an untutored view of Marcus Garvey's Back-to-Africa Movement in the 1920s.
With this information, the facility maintenance team can schedule corrective action to bring the equipment back into normal energy usage parameters. There are a wide variety of potential issues that ...can create abnormal energy consumption without a known mechanical problem. Motor faults A good FDD system will look at the realtime operating status of all the motors in a facility and determine if they are operating as designed, or in an unnatural state such as continuously running.
Background: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase, the activity of which is inhibited by a variety of extracellular stimuli including insulin, growth factors, cell ...specification factors and cell adhesion. Consequently, inhibition of GSK-3 activity has been proposed to play a role in the regulation of numerous signalling pathways that elicit pleiotropic cellular responses. This report describes the identification and characterisation of potent and selective small molecule inhibitors of GSK-3.
Results: SB-216763 and SB-415286 are structurally distinct maleimides that inhibit GSK-3α in vitro, with
K
is of 9 nM and 31 nM respectively, in an ATP competitive manner. These compounds inhibited GSK-3β with similar potency. However, neither compound significantly inhibited any member of a panel of 24 other protein kinases. Furthermore, treatment of cells with either compound stimulated responses characteristic of extracellular stimuli that are known to inhibit GSK-3 activity. Thus, SB-216763 and SB-415286 stimulated glycogen synthesis in human liver cells and induced expression of a β-catenin-LEF/TCF regulated reporter gene in HEK293 cells. In both cases, compound treatment was demonstrated to inhibit cellular GSK-3 activity as assessed by activation of glycogen synthase, which is a direct target of this kinase.
Conclusions: SB-216763 and SB-415286 are novel, potent and selective cell permeable inhibitors of GSK-3. Therefore, these compounds represent valuable pharmacological tools with which the role of GSK-3 in cellular signalling can be further elucidated. Furthermore, development of similar compounds may be of use therapeutically in disease states associated with elevated GSK-3 activity such as non-insulin dependent diabetes mellitus and neurodegenerative disease.
Growers frequently are concerned about the response of corn (Zea mays L.) to planting date. Early planting of corn is recommended because full-season hybrids utilize the entire growing season, ...achieve physiological maturity before a killing frost, and start to dry, thereby increasing profit through reduced drying costs. The objective was to evaluate the influence of planting date and hybrid maturity on corn grain yield and harvest moisture in Wisconsin. Two or three corn hybrids ranging in relative maturity from 80 to 115 d were planted between 19 April and 22 June at six locations in Wisconsin from 1991 to 1994. In southern Wisconsin locations, the optimum planting date for grain yield of full- and shorter-season hybrids ranged between 1 and 7 May, and was still at 95% of optimum between 9 and 18 May. In northern Wisconsin, the optimum planting date for grain yield of hybrids ranged between 8 and 14 May, and was still at 95% of optimum between 15 and 23 May. Grain yield did not change much when corn was planted between 24 April and 8 May. Grain yield of corn planted after 8 May in southern Wisconsin declined at the rate of 0.5 to 1.1% d(-1) over the next 2 wk, accelerating to 1.3 to 1.9% d(-1) and 2.0 to 2.8% d(-1) over the next two 2-wk periods. Grain yield of corn planted after 8 May in northern Wisconsin declined at the rate of 0.2 to 1.7% d(-1) over the next 2 wk, accelerating to 1.7 to 2.2% d(-1) and 3.2 to 3.8% d(-1) over the next two 2-wk periods. The decision to begin planting corn early should be based on soil temperature and field conditions. After 20 April, planting of full-season hybrids should proceed as rapidly as field conditions allow. The date to switch from full-season to shorter-season hybrids depends on numerous factors, including corn price and drying costs, but generally occurs by mid-May in southern and by late May in northern Wisconsin.
We have examined the plasticity of the antigen-combining site of a high-affinity antibody. In phage-displayed Fab libraries, selected CDR positions and one FR position of the humanized anti-Her2 ...antibody hu4D5 were substituted with all 20 amino acids. Antigen-binding selections were used to enrich for high-affinity variants, and a large number of sequences were obtained prior to convergence of the selected pool to a small set of clones. As expected, sequence variability of the antigen-binding site is overall diminished compared to known IgG sequences; however, certain positions retain much higher variability than others. The sequence variability map of the hu4D5 binding site is compared with a map derived from previous alanine-scanning of the antibody. Affinities of soluble Fab fragments for antigen confirm that multiple variants were selected with high affinity for antigen, including one variant with a single point mutation that was about threefold improved in affinity compared to the parental hu4D5. Interestingly, this mutation is one of the most radical in terms of changing side-chain chemistry (Trp for Asp) and occurs at the most plastic site as calculated by the Wu–Kabat variability coefficient. Thus variability mapping yields information about the antibody–antigen interaction that is useful and complementary to that obtained by alanine scanning mutagenesis.
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