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971.
KY Hostetler GD Kini JR Beadle KA Aldern MF Gardner R Border R Kumar L Barshak CN Sridhar CJ Wheeler DD Richman 《Canadian Metallurgical Quarterly》1996,31(1-2):59-67
Phosphonoformate (PFA) effectively inhibits viral polymerases but is relatively ineffective in virus-infected cells in tissue culture. A lipid prodrug of phosphonoformate was synthesized by coupling the phosphonate residue of phosphonoformate to the sn-3 hydroxyl of 1-O-octadecyl-sn-glycerol. This prodrug, 1-O-octadecyl-sn-glycero-3-phosphonoformate (ODG-PFA), was 93-fold more active than phosphonoformate in cells infected with the AD169 strain of cytomegalovirus (CMV), and 111-147-fold more active in cells infected with three human clinical isolates of CMV. The compound was also 44-fold more active in human immunodeficiency virus-1 (HIV-1) infected cells and 43-fold more active in cells infected with herpes simplex virus (HSV). Studies of the mechanisms of increased antiviral activity indicate that 1-O-octadecyl-sn-glycero-3-[14C]phosphonoformate is taken up more extensively than the free drug by the host MRC-5 human lung fibroblasts. Intracellular enzymes convert 1-O-octadecyl-sn-glycero-3-phosphonoformate to phosphonoformate. This conversion does not occur in the tissue culture medium containing fetal bovine serum (FBS) or in MRC-5-conditioned medium. In view of its greatly increased in vitro potency and selectivity, 1-O-octadecyl-sn-glycero-3-phosphonoformate may be useful in treating viral diseases. 相似文献
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974.
The effect of embryo fibroblasts on the growth of erythroid colony-forming cells in vitro (CFU-e) from mouse bone marrow was investigated. First, the maintenance of CFU-e number in suspension culture was assayed. CFU-e recovered from suspension culture fell rapidly to values below 30% of the initial number. When erythropoietin (EP) was added, the initial decline during the first day was followed by a rise to 80%. In cultures supplemented with irradiated fibroblasts, the number of CFU-e did not show an abortive fall, but there was a slight increase during 3 days of culturing. The influence of fibroblasts on the colony-forming ability of CFU-e was studied in a semisolid culture system composed of an agar underlayer and a methylcellulose overlayer. The number of erythroid colonies scored after 5 days of culture in the presence of different levels of EP was proportional to the number of added fibroblasts and the colony size (depending on the number of fibroblasts) increased to macroscopic dimensions. Fibroblasts alone, without EP, induced colony formation by CFU-e if added in concentrations of 1 X 10(5) or higher. EP was not detectable in medium conditioned by the fibroblasts. These data indicate that fibroblasts may stimulate erythroid colony formation (in the absence of EP) and enhance the colony-forming ability of CFU-e in the presence of EP. From these results, it is suggested that fibroblasts exert proliferation activating effects on CFU-e target cells. 相似文献
975.
Names of cities were shock associated and then embedded in material presented to the nonattended channel in a dichotic listening and shadowing situation. Despite earlier claims of differential responding to city names in the absence of awareness, no such differential responding was found. A test for conditioning following the dichotic listening task found that the subjects had been conditioned. Postexperimental interviews found that the subjects were aware of the city-shock contingency and had expected to be shocked during the dichotic listening task. Comparisons are made with other studies of galvanic skin responses to unattended words. 相似文献
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Glutamate (Glu), the major excitatory neurotransmitter in the nervous system, is toxic to neurons when it accumulates at high concentrations in the extracellular space. Even though Glu is a mixed agonist, capable of activating N-methyl-D-aspartate (NMDA) receptors and non-NMDA receptors, in many preparations Glu neurotoxicity is prevented by selective blockade of NMDA receptors. In cultures of hippocampal neurons, treatment with 500 microM Glu for 30 min killed more than 90% of the neurons. The simultaneous addition of the selective NMDA agonist methyl-10,11-dihydro-5-H-dibenzocyclo-hepten-5,10-imine (MK-801) reduced the cell loss to less than 30%. However, when Glu was combined with either diazoxide or cyclothiazide, two thiazides which dramatically diminish rapid Glu desensitization, MK-801 was no longer very protective and neuronal loss exceeded 80%. However, the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), in combination with MK-801, was able to prevent most Glu neurotoxicity in the presence of these thiazides. These experiments show that there are circumstances under which Glu neurotoxicity is produced by overactivation of non-NMDA receptors. Our observations offer a possible explanation for the recent finding that blockade of non-NMDA receptors is much more beneficial than NMDA receptor blockade in protecting the brain in some in vivo models of global ischemia. 相似文献
980.
We have studied the role of DNA polymerase III, encoded in S. cerevisiae by the CDC2 gene, in the repair of yeast nuclear DNA. It was found that the repair of MMS-induced single-strand breaks is defective in the DNA polymerase III temperature-sensitive mutant cdc2-1 at the restrictive temperature (37 degrees C), but is not affected at the permissive temperature (23 degrees C). Under conditions where only a small number of lesions was introduced into DNA (80% survival), the repair of MMS-induced damage could also be observed in the mutant at the restrictive temperature, although with low efficiency. When the quantity of lesions increased (50% survival or less), the repair of single-strand breaks was blocked. At the same time we observed a high rate of reversion in the meth, his and trp loci of the cdc2-1 mutant under restrictive conditions. The results presented suggest that DNA polymerase III is involved in the repair of MMS-induced lesions in yeast DNA and that the cdc2-1 mutation affects the proofreading activity of this polymerase. 相似文献