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Park Y Fujioka M Kobayashi M Jaynes JB Datta S 《Development (Cambridge, England)》2001,128(10):1899-1909
Development of a multicellular organism requires precise coordination of cell division and cell type determination. The selector homeoprotein Even skipped (Eve) plays a very specific role in determining cell identity in the Drosophila embryo, both during segmentation and in neuronal development. However, studies of gene expression in eve mutant embryos suggest that eve regulates the embryonic expression of the vast majority of genes. We present here genetic interaction and phenotypic analysis showing that eve functions in the trol pathway to regulate the onset of neuroblast division in the larval CNS. Surprisingly, Eve is not detected in the regulated neuroblasts, and culture experiments reveal that Eve is required in the body, not the CNS. Furthermore, the effect of an eve mutation can be rescued both in vivo and in culture by the hormone ecdysone. These results suggest that eve is required to produce a trans-acting factor that stimulates cell division in the larval brain. 相似文献
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Naturally occurring antimicrobial peptides have been discovered in both plants and animals. Many of these peptides demonstrate impaired activity or cytotoxicity when applied exogenously. Synthetically engineered antimicrobial peptides have been designed to increase potency and activity against bacteria and fungus yet remain noncytotoxic. The antimicrobial peptide D2A21 (Demegel) has already demonstrated significant activity in vitro against many common hospital pathogens. The purpose of this study was to evaluate the effects of D2A21 in an in vivo infected burn-wound model, examining both quantitative cultures of the wound and survival of the animal. Forty-four Wistar rats were subjected to a 23 percent total body surface area scald burn. Pseudomonas aeruginosa was administered topically with 108 organisms and wounds were then evaluated at day 1, 2, or 3 for eschar and subeschar muscle quantitative culture. The experimental group was treated daily with 1.5% topical D2A21. The control group was treated with control gel. A second group of Wistar rats (n = 14) were burned and given a 107 inoculum of the same Pseudomonas and evaluated to 14 days for survival and weight changes. This group was subdivided into rats receiving either topical D2A21 or control base daily. The quantitative biopsy results demonstrated that D2A21-treated wounds had no bacterial growth in burn eschar at day 2 or 3, whereas control animals demonstrated growth at greater than 105 organisms by day 2. Subeschar muscle cultures also demonstrated significantly less bacterial invasion compared with controls on each day tested. D2A21-treated animals had an 85.7 percent survival compared with 0 percent survival in controls. Furthermore, the D2A21-treated groups demonstrated maintenance of body weights, whereas controls had significant weight loss with time. In conclusion, D2A21 demonstrates significant antibacterial activity against Pseudomonas, sterilizing burn eschar and decreasing subeschar bacterial load, allowing for a markedly significant improvement in survival in this infected burn-wound model. 相似文献
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Sakya SM Hou X Minich ML Rast B Shavnya A DeMello KM Cheng H Li J Jaynes BH Mann DW Petras CF Seibel SB Haven ML 《Bioorganic & medicinal chemistry letters》2007,17(4):1067-1072
The structure-activity relationship toward canine COX-1 and COX-2 in vitro whole blood activity of 4-hydrogen versus 4-cyano substituted 5-aryl or 5-heteroatom substituted N-phenyl versus N-2-pyridyl sulfone pyrazoles is discussed. The differences between the pairs of compounds with the 4-nitrile pyrazole derivatives having substantially improved in vitro activity are highlighted for both COX-2 and COX-1. This difference in activity may be due to the contribution of the hydrogen bond of the 4-cyano group with Ser 530 as shown by our molecular modeling studies. In addition, our model suggests a potential contribution from hydrogen bonding of the pyridyl nitrogen to Tyr 355 for the increased activity over the phenyl sulfone analogs. 相似文献
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Boundaries of loop domains (insulators): Determinants of chromosome form and function in multicellular eukaryotes
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Insulators can block the action of enhancers on promoters and the spreading of repressive chromatin, as well as facilitating specific enhancer-promoter interactions. However, recent studies have called into question whether the activities ascribed to insulators in model transgene assays actually reflect their functions in the genome. The Drosophila even skipped (eve) gene is a Polycomb (Pc) domain with a Pc-group response element (PRE) at one end, flanked by an insulator, an arrangement also seen in other genes. Here, we show that this insulator has three major functions. It blocks the spreading of the eve Pc domain, preventing repression of the adjacent gene, TER94. It prevents activation of TER94 by eve regulatory DNA. It also facilitates normal eve expression. When Homie is deleted in the context of a large transgene that mimics both eve and TER94 regulation, TER94 is repressed. This repression depends on the eve PRE. Ubiquitous TER94 expression is “replaced” by expression in an eve pattern when Homie is deleted, and this effect is reversed when the PRE is also removed. Repression of TER94 is attributable to spreading of the eve Pc domain into the TER94 locus, accompanied by an increase in histone H3 trimethylation at lysine 27. Other PREs can functionally replace the eve PRE, and other insulators can block PRE-dependent repression in this context. The full activity of the eve promoter is also dependent on Homie, and other insulators can promote normal eve enhancer-promoter communication. Our data suggest that this is not due to preventing promoter competition, but is likely the result of the insulator organizing a chromosomal conformation favorable to normal enhancer-promoter interactions. Thus, insulator activities in a native context include enhancer blocking and enhancer-promoter facilitation, as well as preventing the spread of repressive chromatin. 相似文献
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Sakya SM Shavnya A Cheng H Li C Rast B Li J Koss DA Jaynes BH Mann DW Petras CF Seibel SB Haven ML Lynch MP 《Bioorganic & medicinal chemistry letters》2008,18(3):1042-1045
Structure-activity relationship (SAR) studies of novel 5-alkyl and 5-aryl/heteroaryl substituted 1,2,4-triazoles are described. The in vitro activity is compared to the pyrazole class of compounds with analogous side chains to delineate the contribution of the triazole ring nitrogen in binding to the active site. Both series are quite potent and selective in the canine whole blood (CWB) COX-2 assay, suggesting the increased binding contribution of the hydrophobic side chains. 相似文献