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921.
Naidu BN Sorenson ME Bronson JJ Pucci MJ Clark JM Ueda Y 《Bioorganic & medicinal chemistry letters》2005,15(8):2069-2072
The synthesis and antibacterial activity of a series of nocathiacin I derivatives (4-20) containing polar water solubilizing groups is described. Thiol-Michael adducts containing acidic polar groups have reduced antibacterial activity whereas those with basic polar groups have retained very good antibacterial activity. 相似文献
922.
Gustin DJ Sehon CA Wei J Cai H Meduna SP Khatuya H Sun S Gu Y Jiang W Thurmond RL Karlsson L Edwards JP 《Bioorganic & medicinal chemistry letters》2005,15(6):1687-1691
A novel series of competitive, reversible cathepsin S (CatS) inhibitors was discovered and optimized. The 4-(2-keto-1-benzimidazolinyl)-piperidin-1-yl moiety was found to be an effective replacement for the 4-arylpiperazin-1-yl group found in our earlier series of CatS inhibitors. This replacement imparted improved PK properties as well as decreased off-target activity. Optimization of the ketobenzimidazole moiety led to the discovery of the lead compound JNJ 10329670, which represents a novel class of selective, noncovalent, reversible, and orally bioavailable inhibitors of cathepsin S. 相似文献
923.
Clark LA 《Protein science : a publication of the Protein Society》2005,14(3):653-662
Two-chain aggregation simulations using minimalist models of proteins G, L, and mutants were used to investigate the fundamentals of protein aggregation. Mutations were selected to break up repeats of hydrophobic beads in the sequence while maintaining native topology and folding ability. Data are collected under conditions in which all chain types have similar folded populations and after equilibrating the separated chains to minimize competition between folding and aggregation. Folding cooperativity stands out as the best single-chain determinant under these conditions and for these simple models. It can be experimentally measured by the width of the unfolding transition during thermal denaturation and loosely related to population of intermediate-like states during folding. Additional measures of cooperativity and other properties such as radius of gyration fluctuations and patterning of hydrophobic residues are also examined. Initial contact system states with transition-state characteristics can be identified and are more expanded than average initial contact states. Two-chain minimalist model aggregates are considerably less structured than their native states and have minimal domain-swapping features. 相似文献
924.
Fawzi NL Chubukov V Clark LA Brown S Head-Gordon T 《Protein science : a publication of the Protein Society》2005,14(4):993-1003
We simulate the aggregation thermodynamics and kinetics of proteins L and G, each of which self-assembles to the same alpha/beta [corrected] topology through distinct folding mechanisms. We find that the aggregation kinetics of both proteins at an experimentally relevant concentration exhibit both fast and slow aggregation pathways, although a greater proportion of protein G aggregation events are slow relative to those of found for protein L. These kinetic differences are correlated with the amount and distribution of intrachain contacts formed in the denatured state ensemble (DSE), or an intermediate state ensemble (ISE) if it exists, as well as the folding timescales of the two proteins. Protein G aggregates more slowly than protein L due to its rapidly formed folding intermediate, which exhibits native intrachain contacts spread across the protein, suggesting that certain early folding intermediates may be selected for by evolution due to their protective role against unwanted aggregation. Protein L shows only localized native structure in the DSE with timescales of folding that are commensurate with the aggregation timescale, leaving it vulnerable to domain swapping or nonnative interactions with other chains that increase the aggregation rate. Folding experiments that characterize the structural signatures of the DSE, ISE, or the transition state ensemble (TSE) under nonaggregating conditions should be able to predict regions where interchain contacts will be made in the aggregate, and to predict slower aggregation rates for proteins with contacts that are dispersed across the fold. Since proteins L and G can both form amyloid fibrils, this work also provides mechanistic and structural insight into the formation of prefibrillar species. 相似文献
925.
Dexamethasone alters F-actin architecture and promotes cross-linked actin network formation in human trabecular meshwork tissue 总被引:7,自引:0,他引:7
Clark AF Brotchie D Read AT Hellberg P English-Wright S Pang IH Ethier CR Grierson I 《Cell motility and the cytoskeleton》2005,60(2):83-95
Elevated intraocular pressure is an important risk factor for the development of glaucoma, a leading cause of irreversible blindness. This ocular hypertension is due to increased hydrodynamic resistance to the drainage of aqueous humor through specialized outflow tissues, including the trabecular meshwork (TM) and the endothelial lining of Schlemm's canal. We know that glucocorticoid therapy can cause increased outflow resistance and glaucoma in susceptible individuals, that the cytoskeleton helps regulate aqueous outflow resistance, and that glucocorticoid treatment alters the actin cytoskeleton of cultured TM cells. Our purpose was to characterize the actin cytoskeleton of cells in outflow pathway tissues in situ, to characterize changes in the cytoskeleton due to dexamethasone treatment in situ, and to compare these with changes observed in cell culture. Human ocular anterior segments were perfused with or without 10(-7) M dexamethasone, and F-actin architecture was investigated by confocal laser scanning microscopy. We found that outflow pathway cells contained stress fibers, peripheral actin staining, and occasional actin "tangles." Dexamethasone treatment caused elevated IOP in several eyes and increased overall actin staining, with more actin tangles and the formation of cross-linked actin networks (CLANs). The actin architecture in TM tissues was remarkably similar to that seen in cultured TM cells. Although CLANs have been reported previously in cultured cells, this is the first report of CLANs in tissue. These cytoskeletal changes may be associated with increased aqueous humor outflow resistance after ocular glucocorticoid treatment. 相似文献
926.
Clark JB Rice L Sadiq T Brittain E Song L Wang J Gerber DA 《Biochemical and biophysical research communications》2005,329(1):337-344
The success of hepatocellular therapies using stem or progenitor cell populations is dependent upon multiple factors including the donor cell, microenvironment, and etiology of the liver injury. The following experiments investigated the impact of TGF-beta1 on a previously described population of hepatic progenitor cells (HPC). The majority of the hepatic progenitor cells were resistant to endogenously produced TGF-beta1's proapoptotic and anti-proliferative effects unlike more well-differentiated cellular populations (e.g., mature hepatocytes). Surprisingly, in vitro TGF-beta1 supplementation significantly inhibited de novo hepatic progenitor cell colony formation possibly via an indirect mechanism(s). Therefore despite the HPC's direct resistance to supplemental TGF-beta1, this cytokine's inhibitory effect on colony formation could have a potential negative impact on the use of these cells as a therapy for patients with liver disease. 相似文献
927.
Transposons are one means that nature has used to introduce new genetic material into chromosomes of organisms from every kingdom. They have been extensively used in prokaryotic and lower eukaryotic systems, but until recently there was no transposon that had significant activity in vertebrates. The Sleeping Beauty (SB) transposon system was developed to direct the integration of precise DNA sequences into chromosomes. The SB system was derived from salmonid sequences that had been inactive for more than 10 million years. SB transposons have been used for two principle uses – as a vector for transgenesis and as a method for introducing various trap vectors into (gene-trap) or in the neighborhood of (enhancer-trap) genes to identify their functions. Results of these studies show that SB-mediated transgenesis is more efficient than that by injection of simple plasmids and that expression of transgenesis is stable and reliable following passage through the germline. 相似文献
928.
Patients with systemic autoimmune diseases usually produce high levels of antibodies to self-antigens (autoantigens). The
repertoire of common autoantigens is remarkably limited, yet no readily understandable shared thread links these apparently
diverse proteins. Using computer prediction algorithms, we have found that most nuclear systemic autoantigens are predicted
to contain long regions of extreme structural disorder. Such disordered regions would generally make poor B cell epitopes
and are predicted to be under-represented as potential T cell epitopes. Consideration of the potential role of protein disorder
may give novel insights into the possible role of molecular mimicry in the pathogenesis of autoimmunity. The recognition of
extreme autoantigen protein disorder has led us to an explicit model of epitope spreading that explains many of the paradoxical
aspects of autoimmunity – in particular, the difficulty in identifying autoantigen-specific helper T cells that might collaborate
with the B cells activated in systemic autoimmunity. The model also explains the experimentally observed breakdown of major
histocompatibility complex (MHC) class specificity in peptides associated with the MHC II proteins of activated autoimmune
B cells, and sheds light on the selection of particular T cell epitopes in autoimmunity. Finally, the model helps to rationalize
the relative rarity of clinically significant autoimmunity despite the prevalence of low specificity/low avidity autoantibodies
in normal individuals. 相似文献
929.
930.