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581.
Six new indole alkaloids, viz., (3S)-3-cyanocoronaridine (2), (3S)-3-cyanoisovoacangine (3), conolobine A (5), conolobine B (6), conolidine (7), and (3R/3S)-3-ethoxyvoacangine (8), in addition to 36 known ones, were obtained from the stem-bark extract of the Malayan Tabernaemontana divaricata. The structures were determined by NMR and MS analysis. The CN-substituted alkaloids showed appreciable cytotoxicity towards the KB human oral epidermoid carcinoma cell-line. 相似文献
582.
Zhang KY Card GL Suzuki Y Artis DR Fong D Gillette S Hsieh D Neiman J West BL Zhang C Milburn MV Kim SH Schlessinger J Bollag G 《Molecular cell》2004,15(2):279-286
Phosphodiesterases (PDEs) comprise a family of enzymes that modulate the immune response, inflammation, and memory, among many other functions. There are three types of PDEs: cAMP-specific, cGMP-specific, and dual-specific. Here we describe the mechanism of nucleotide selectivity on the basis of high-resolution co-crystal structures of the cAMP-specific PDE4B and PDE4D with AMP, the cGMP-specific PDE5A with GMP, and the apo-structure of the dual-specific PDE1B. These structures show that an invariant glutamine functions as the key specificity determinant by a "glutamine switch" mechanism for recognizing the purine moiety in cAMP or cGMP. The surrounding residues anchor the glutamine residue in different orientations for cAMP and for cGMP. The PDE1B structure shows that in dual-specific PDEs a key histidine residue may enable the invariant glutamine to toggle between cAMP and cGMP. The structural understanding of nucleotide binding enables the design of new PDE inhibitors that may treat diseases in which cyclic nucleotides play a critical role. 相似文献
583.
Focal contacts as mechanosensors: externally applied local mechanical force induces growth of focal contacts by an mDia1-dependent and ROCK-independent mechanism 总被引:17,自引:0,他引:17
Riveline D Zamir E Balaban NQ Schwarz US Ishizaki T Narumiya S Kam Z Geiger B Bershadsky AD 《The Journal of cell biology》2001,153(6):1175-1186
The transition of cell-matrix adhesions from the initial punctate focal complexes into the mature elongated form, known as focal contacts, requires GTPase Rho activity. In particular, activation of myosin II-driven contractility by a Rho target known as Rho-associated kinase (ROCK) was shown to be essential for focal contact formation. To dissect the mechanism of Rho-dependent induction of focal contacts and to elucidate the role of cell contractility, we applied mechanical force to vinculin-containing dot-like adhesions at the cell edge using a micropipette. Local centripetal pulling led to local assembly and elongation of these structures and to their development into streak-like focal contacts, as revealed by the dynamics of green fluorescent protein-tagged vinculin or paxillin and interference reflection microscopy. Inhibition of Rho activity by C3 transferase suppressed this force-induced focal contact formation. However, constitutively active mutants of another Rho target, the formin homology protein mDia1 (Watanabe, N., T. Kato, A. Fujita, T. Ishizaki, and S. Narumiya. 1999. Nat. Cell Biol. 1:136-143), were sufficient to restore force-induced focal contact formation in C3 transferase-treated cells. Force-induced formation of the focal contacts still occurred in cells subjected to myosin II and ROCK inhibition. Thus, as long as mDia1 is active, external tension force bypasses the requirement for ROCK-mediated myosin II contractility in the induction of focal contacts. Our experiments show that integrin-containing focal complexes behave as individual mechanosensors exhibiting directional assembly in response to local force. 相似文献
584.
Glucocorticoid-inducible gene expression in rice 总被引:14,自引:0,他引:14
585.
586.
Physical state of the extracellular matrix regulates the structure and molecular composition of cell-matrix adhesions 总被引:11,自引:0,他引:11
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Katz BZ Zamir E Bershadsky A Kam Z Yamada KM Geiger B 《Molecular biology of the cell》2000,11(3):1047-1060
This study establishes that the physical state of the extracellular matrix can regulate integrin-mediated cytoskeletal assembly and tyrosine phosphorylation to generate two distinct types of cell-matrix adhesions. In primary fibroblasts, alpha(5)beta(1) integrin associates mainly with fibronectin fibrils and forms adhesions structurally distinct from focal contacts, independent of actomyosin-mediated cell contractility. These "fibrillar adhesions" are enriched in tensin, but contain low levels of the typical focal contact components paxillin, vinculin, and tyrosine-phosphorylated proteins. However, when the fibronectin is covalently linked to the substrate, alpha(5)beta(1) integrin forms highly tyrosine-phosphorylated, "classical" focal contacts containing high levels of paxillin and vinculin. These experiments indicate that the physical state of the matrix, not just its molecular composition, is a critical factor in defining cytoskeletal organization and phosphorylation at adhesion sites. We propose that molecular organization of adhesion sites is controlled by at least two mechanisms: 1) specific integrins associate with their ligands in transmembrane complexes with appropriate cytoplasmic anchor proteins (e.g., fibronectin-alpha(5)beta(1) integrin-tensin complexes), and 2) physical properties (e.g., rigidity) of the extracellular matrix regulate local tension at adhesion sites and activate local tyrosine phosphorylation, recruiting a variety of plaque molecules to these sites. These mechanisms generate structurally and functionally distinct types of matrix adhesions in fibroblasts. 相似文献
587.
A Delaminated Defect‐Rich ZrO2 Hierarchical Nanowire Photocathode for Efficient Photoelectrochemical Hydrogen Evolution
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An efficient way to combat the energy crisis and the greenhouse gas effect of fossil fuels is the production of hydrogen fuel from solar‐driven water splitting reaction. Here, this study presents a p‐type ZrO2 nanoplate‐decorated ZrO2 nanowire photocathode with a high photoconversion efficiency that makes it potentially viable for commercial solar H2 production. The composition of oxygen vacancy defects, low charge carrier transport property, and high specific surface area of these as‐grown hierarchical nanowires are further improved by an hydrofluoric acid (HF) treatment, which causes partial delamination and produces a thin amorphous ZrO2 layer on the surface of the as‐grown nanostructured film. The presence of different types of oxygen vacancies (neutral, singly charged, and doubly charged defects) and their compositional correlation to the Zrx+ oxidation states (4 > x > 2) are found to affect the charge transfer process, the p‐type conductivity, and the photocatalytic activity of the ZrO2 nanostructured film. The resulting photocathode provides the highest overall photocurrent (?42.3 mA cm?2 at 0 V vs reversible hydrogen electrode (RHE)) among all the photocathodes reported to date, and an outstanding 3.1% half‐cell solar‐to‐hydrogen conversion efficiency with a Faradaic efficiency of 97.8%. Even more remarkable is that the majority of the photocurrent (69%) is produced in the visible light region. 相似文献
588.
589.
Keith R. Hornberger Dan M. Berger Andrew P. Crew Hanqing Dong Andrew Kleinberg An-Hu Li Matthew R. Medeiros Mark J. Mulvihill Kam Siu James Tarrant Jing Wang Felix Weng Victoria L. Wilde Mark Albertella Mark Bittner Andrew Cooke Michael J. Gray Paul Maresca Brianna Tokar 《Bioorganic & medicinal chemistry letters》2013,23(16):4517-4522
The discovery and potency optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. Micromolar hits taken from high-throughput screening were optimized for biochemical and cellular mechanistic potency to ~10 nM, as exemplified by compound 12az. Application of structure-based drug design aided by co-crystal structures of TAK1 with inhibitors significantly shortened the number of iterations required for the optimization. 相似文献
590.
Baritaki S Katsman A Chatterjee D Yeung KC Spandidos DA Bonavida B 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(8):5441-5453