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51.
Dane D. Jensen Cody B. Godfrey Christian Niklas Meritxell Canals Martina Kocan Daniel P. Poole Jane E. Murphy Farzad Alemi Graeme S. Cottrell Christoph Korbmacher Nevin A. Lambert Nigel W. Bunnett Carlos U. Corvera 《The Journal of biological chemistry》2013,288(32):22942-22960
TGR5 is a G protein-coupled receptor that mediates bile acid (BA) effects on energy balance, inflammation, digestion, and sensation. The mechanisms and spatiotemporal control of TGR5 signaling are poorly understood. We investigated TGR5 signaling and trafficking in transfected HEK293 cells and colonocytes (NCM460) that endogenously express TGR5. BAs (deoxycholic acid (DCA), taurolithocholic acid) and the selective agonists oleanolic acid and 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N, 5-dimethylisoxazole-4-carboxamide stimulated cAMP formation but did not induce TGR5 endocytosis or recruitment of β-arrestins, as assessed by confocal microscopy. DCA, taurolithocholic acid, and oleanolic acid did not stimulate TGR5 association with β-arrestin 1/2 or G protein-coupled receptor kinase (GRK) 2/5/6, as determined by bioluminescence resonance energy transfer. 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N, 5-dimethylisoxazole-4-carboxamide stimulated a low level of TGR5 interaction with β-arrestin 2 and GRK2. DCA induced cAMP formation at the plasma membrane and cytosol, as determined using exchange factor directly regulated by cAMP (Epac2)-based reporters, but cAMP signals did not desensitize. AG1478, an inhibitor of epidermal growth factor receptor tyrosine kinase, the metalloprotease inhibitor batimastat, and methyl-β-cyclodextrin and filipin, which block lipid raft formation, prevented DCA stimulation of ERK1/2. Bioluminescence resonance energy transfer analysis revealed TGR5 and EGFR interactions that were blocked by disruption of lipid rafts. DCA stimulated TGR5 redistribution to plasma membrane microdomains, as localized by immunogold electron microscopy. Thus, TGR5 does not interact with β-arrestins, desensitize, or traffic to endosomes. TGR5 signals from plasma membrane rafts that facilitate EGFR interaction and transactivation. An understanding of the spatiotemporal control of TGR5 signaling provides insights into the actions of BAs and therapeutic TGR5 agonists/antagonists. 相似文献
52.
Mani K Belting M Ellervik U Falk N Svensson G Sandgren S Cheng F Fransson LA 《Glycobiology》2004,14(5):387-397
We have previously reported that the heparan sulfate-priming glycoside 2-(6-hydroxynaphthyl)-beta-D-xylopyranoside selectively inhibits growth of transformed or tumor-derived cells. To investigate the specificity of this xyloside various analogs were synthesized and tested in vitro. Selective growth inhibition was dependent on the presence of a free 6-hydroxyl in the aglycon. Because cells deficient in heparan sulfate synthesis were insensitive to the xyloside, we conclude that priming of heparan sulfate synthesis was required for growth inhibition. In growth-inhibited cells, heparan sulfate chains primed by the active xyloside were degraded to products that contained anhydromannose and appeared in the nuclei. Hence the degradation products were generated by nitric oxide-dependent cleavage. Accordingly, nitric oxide depletion reduced nuclear localization of the degradation products and counteracted the growth-inhibitory effect of the xyloside. We propose that 2-(6-hydroxynaphthyl)-beta-D-xylopyranoside entered cells and primed synthesis of heparan sulfate chains that were subsequently degraded by nitric oxide into products that accumulated in the nucleus. In vivo experiments demonstrated that the xyloside administered subcutaneously, perorally, or intraperitoneally was adsorbed and made available to tumor cells located subcutaneously. Treatment with the xyloside reduced the average tumor load by 70-97% in SCID mice. The present xyloside may serve as a lead compound for the development of novel antitumor strategies. 相似文献
53.
Niklas KJ Molina-Freaner F Tinoco-Ojanguren C Hogan CJ Paolillo DJ 《American journal of botany》2003,90(5):663-674
We examined the hypothesis that the procumbent growth habit of the rare, columnar cactus Stenocereus eruca is in part the result of a diminution of the mechanical properties of stem tissues by comparing the properties of S. eruca plants with those of the putatively closely related semi-erect shrub S. gummosus. Intact stems and surgically removed anatomically comparable regions of the stems of both species were tested in bending and tension to determine their Young's modulus and breaking stress. A computer program was used to evaluate the contribution of each region to the capacity of entire stems to resist bending forces. Our analyses indicate that the principal stiffening agent in the stems of both species is a peripheral tissue complex (= epidermis and collenchyma in the primary plant body) that has a significantly higher tensile breaking stress and greater extensibility for S. gummosus than that of S. eruca. Computer simulations indicate that the wood of either species contributes little to bending stiffness, except in very old portions of S. gummosus stems, because of its small volume and central location in the stem. These and other observations are interpreted to support the hypothesis that S. eruca evolved a procumbent growth habit as the result of manifold developmental alterations some of which reduced the capacity of tissues to support the weight of stems. 相似文献
54.
Niklas KJ 《American journal of botany》2003,90(4):515-525
Morphogenesis (the development of organic form) requires signal-trafficking and cross-talking across all levels of organization to coordinate the operation of metabolic and genomic networked systems. Many biologists are currently converging on the pictorial conventions of computer scientists to render biological signaling as logic circuits supervising the operation of one or more signal-activated metabolic or gene networks. This approach can redact and simplify complex morphogenetic phenomena and allows for their aggregation into diagrams of larger, more "global" networked systems. This conceptualization is discussed in terms of how logic circuits and signal-activated subsystems work, and it is illustrated for examples of increasingly more complex morphogenetic phenomena, e.g., auxin-mediated cell expansion, entry into the mitotic cell cycle phases, and polar/lateral intercellular auxin transport. For each of these phenomena, a posited circuit/subsystem diagram draws rapid attention to missing components, either in the logic circuit or in the subsystem it supervises. These components must be identified experimentally if each of these basic phenomena is to be fully understood. Importantly, the power of the circuit/subsystem approach to modeling developmental phenomena resides not in its pictorial appeal but in the mathematical tools that are sufficiently strong to reveal and quantify the synergistics of networked systems and thus foster a better understanding of morphogenesis. 相似文献
55.
56.
The O-polysaccharide from Vibrio cholerae O6 was isolated from the LPS by mild-acid hydrolysis and has been investigated by sugar and methylation analysis and NMR spectroscopy. The polysaccharide was also depolymerized with aqueous hydrofluoric acid to give the repeating unit and multiples thereof. The O-polysaccharide had the following tetrasaccharide repeating unit. Two O-acetyl groups are present, one of them making the GlcNAc residue fully substituted and the steric crowding considerable at the branching residue. 相似文献
57.
Sommer I Zien A von Ohsen N Zimmer R Lengauer T 《Bioinformatics (Oxford, England)》2002,18(6):802-812
MOTIVATION: We present an extensive evaluation of different methods and criteria to detect remote homologs of a given protein sequence. We investigate two associated problems: first, to develop a sensitive searching method to identify possible candidates and, second, to assign a confidence to the putative candidates in order to select the best one. For searching methods where the score distributions are known, p-values are used as confidence measure with great success. For the cases where such theoretical backing is absent, we propose empirical approximations to p-values for searching procedures. RESULTS: As a baseline, we review the performances of different methods for detecting remote protein folds (sequence alignment and threading, with and without sequence profiles, global and local). The analysis is performed on a large representative set of protein structures. For fold recognition, we find that methods using sequence profiles generally perform better than methods using plain sequences, and that threading methods perform better than sequence alignment methods. In order to assess the quality of the predictions made, we establish and compare several confidence measures, including raw scores, z-scores, raw score gaps, z-score gaps, and different methods of p-value estimation. We work our way from the theoretically well backed local scores towards more explorative global and threading scores. The methods for assessing the statistical significance of predictions are compared using specificity--sensitivity plots. For local alignment techniques we find that p-value methods work best, albeit computationally cheaper methods such as those based on score gaps achieve similar performance. For global methods where no theory is available methods based on score gaps work best. By using the score gap functions as the measure of confidence we improve the more powerful fold recognition methods for which p-values are unavailable. AVAILABILITY: The benchmark set is available upon request. 相似文献
58.
We show that explicit mathematical and biological relationships exist among the scaling exponents and the allometric constants (α and β, respectively) of log–log linear tree‐community size frequency distributions, plant density NT, and minimum, maximum and average stem diameters (Dmin, Dmax, and , respectively). As individuals grow in size and Dmax increases, NT is predicted to decrease as reflected by a decrease in the numerical value of α and an increase in the value of β. Our derivations further show that NT decreases as increases even if Dmin or Dmax remain unchanged. Because Dmax and the age of the largest individuals in a community are correlated, albeit weakly, we argue that the interdependent relationships among the numerical values of α, β, NT, and shed light on the extent to which communities have experienced recent global disturbance. These predicted relationships receive strong statistical support using two large datasets spanning a broad spectrum of tree‐dominated communities. 相似文献
59.
Angiogenic synergism,vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2 总被引:18,自引:0,他引:18
Cao R Bråkenhielm E Pawliuk R Wariaro D Post MJ Wahlberg E Leboulch P Cao Y 《Nature medicine》2003,9(5):604-613
The establishment of functional and stable vascular networks is essential for angiogenic therapy. Here we report that a combination of two angiogenic factors, platelet-derived growth factor (PDGF)-BB and fibroblast growth factor (FGF)-2, synergistically induces vascular networks, which remain stable for more than a year even after depletion of angiogenic factors. In both rat and rabbit ischemic hind limb models, PDGF-BB and FGF-2 together markedly stimulated collateral arteriogenesis after ligation of the femoral artery, with a significant increase in vascularization and improvement in paw blood flow. A possible mechanism of angiogenic synergism between PDGF-BB and FGF-2 involves upregulation of the expression of PDGF receptor (PDGFR)-alpha and PDGFR-beta by FGF-2 in newly formed blood vessels. Our data show that a specific combination of angiogenic factors establishes functional and stable vascular networks, and provides guidance for the ongoing clinical trials of angiogenic factors for the treatment of ischemic diseases. 相似文献
60.
Victoria L. Wyckelsma Tomas Venckunas Peter J. Houweling Maja Schlittler Volker M. Lauschke Chrystal F. Tiong Harrison D. Wood Niklas Ivarsson Henrikas Paulauskas Nerijus Eimantas Daniel C. Andersson Kathryn N. North Marius Brazaitis Håkan Westerblad 《American journal of human genetics》2021,108(3):446-457