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91.
Effect of External and Internal pH Changes on K and Cl Conductances in the Muscle Fiber Membrane of a Giant Barnacle 总被引:5,自引:3,他引:2 下载免费PDF全文
S. Hagiwara R. Gruener H. Hayashi H. Sakata A. D. Grinnell 《The Journal of general physiology》1968,52(5):773-792
The membrane potential and conductance of the giant muscle fiber of a barnacle (Balanus nubilus Darwin) were analyzed in relation to changes in the external (3.5–10.0) and the internal (4.7–9.6) pH, under various experimental conditions. A sharp increase in membrane conductance, associated with a large increase in conductance to Cl ions, was observed when the external pH was lowered to values below 5.0. The ratio of Cl to K conductance in normal barnacle saline is between –1/7 at pH 7.7, whereas at pH 4.0 the ratio is about 6–9. The behavior of the membrane in response to pH changes in a Cl-depleted muscle fiber shows that the K conductance decreases with decreasing external pH for the whole range of pH examined. A steep increase in Cl conductance is also observed when the internal pH of the fiber is lowered below 5.0. The K to Cl conductance ratio increases with increasing internal pH in a manner very similar to that found when the external pH is raised above 5.0. These facts suggest that the membrane is amphoteric with positive and negative fixed charge groups having dissociation constants such that at pH greater than 5, negative groups predominate and cations permeate more easily than anions, while at lower pH positive groups predominate, facilitating the passage of anions through the membrane. 相似文献
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P21-activated kinase 1: convergence point in PDGF- and LPA-stimulated collagen matrix contraction by human fibroblasts 总被引:4,自引:0,他引:4 下载免费PDF全文
Fibroblast three-dimensional collagen matrix culture provides a tissue-like model that can be used to analyze cell form and function. The physiological agonists platelet-derived growth factor (PDGF) and lysophosphatidic acid (LPA) both stimulate human fibroblasts to contract floating collagen matrices. In this study, we show that the PDGF and LPA signaling pathways required for matrix contraction converge on p21-activated kinase 1 (PAK1) and its downstream effector cofilin1 and that contraction depends on cellular ruffling activity, rather than on the protrusion and retraction of cellular dendritic extensions. We also show that, depending on the agonist, different Rho effectors cooperate with PAK1 to regulate matrix contraction, Rho kinase in the case of PDGF and mDia1 in the case of LPA. These findings establish a unified framework for understanding the cell signaling pathways involved in fibroblast contraction of floating collagen matrices. 相似文献
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Frederick Grinnell Hidekazu Fukamizu Pamela Pawelek Shigenori Nakagawa 《Experimental cell research》1989,181(2):483-491
Human foreskin fibroblasts were cultured for up to 6 weeks in medium supplemented with ascorbic acid. During this time, the cells produced an extensive new connective tissue matrix in which the accumulated collagen (mostly type I) amounted to about 0.25 mg/10(6) cells. The matrix was highly differentiated as shown by complete processing of procollagen to collagen alpha-chains and covalent crosslinking of the collagen. Alignment of collagen fibrils occurred as the fibrils were deposited between cells, and binding of adjacent fibrils to the cell surface appeared to hold the fibrils in register. Groups of aligned fibrils were subdivided into bundles by cell-surface folds. If beta-aminopropionitrile was added to the medium, collagen crosslinking was inhibited, but not collagen synthesis or fibril bundle organization. If ascorbic acid was omitted from the culture medium, the extensive new connective tissue matrix was not produced. Our results indicate that fibroblasts in long-term cultures supplemented with ascorbic acid produce a connective tissue matrix with many in vivo-like properties including supermolecular organization of collagen. 相似文献
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Julie E. Pickett Kunihiko Nagakura Anna R. Pasternak Steven G. Grinnell Susruta Majumdar Jason S. Lewis Gavril W. Pasternak 《Bioorganic & medicinal chemistry letters》2013,23(15):4347-4350
Standard radioiodination methods lack site-selectivity and either mask charges (Bolton-Hunter) or involve oxidative reaction conditions (chloramine-T). Opioid peptides are very sensitive to certain structural modifications, making these labeling methods untenable. In our model opioid peptide, α-neoendorphin, we replaced a tyrosyl hydroxyl with an iodine, and in cell lines stably expressing mu, delta, or kappa opioid receptors, we saw no negative effects on binding. We then optimized a repurposed Sandmeyer reaction using copper(I) catalysts with non-redoxing/non-nucleophilic ligands, bringing the radiochemical yield up to around 30%, and site-selectively incorporated radioactive iodine into this position under non-oxidizing reaction conditions, which should be broadly compatible with most peptides. The 125I- and 131I-labeled versions of the compound bound with high affinity to opioid receptors in mouse brain homogenates, thus demonstrating the general utility of the labeling strategy and of the peptide for exploring opioid binding sites. 相似文献
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Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis 总被引:7,自引:0,他引:7
Isermann B Vinnikov IA Madhusudhan T Herzog S Kashif M Blautzik J Corat MA Zeier M Blessing E Oh J Gerlitz B Berg DT Grinnell BW Chavakis T Esmon CT Weiler H Bierhaus A Nawroth PP 《Nature medicine》2007,13(11):1349-1358
Data providing direct evidence for a causative link between endothelial dysfunction, microvascular disease and diabetic end-organ damage are scarce. Here we show that activated protein C (APC) formation, which is regulated by endothelial thrombomodulin, is reduced in diabetic mice and causally linked to nephropathy. Thrombomodulin-dependent APC formation mediates cytoprotection in diabetic nephropathy by inhibiting glomerular apoptosis. APC prevents glucose-induced apoptosis in endothelial cells and podocytes, the cellular components of the glomerular filtration barrier. APC modulates the mitochondrial apoptosis pathway via the protease-activated receptor PAR-1 and the endothelial protein C receptor EPCR in glucose-stressed cells. These experiments establish a new pathway, in which hyperglycemia impairs endothelial thrombomodulin-dependent APC formation. Loss of thrombomodulin-dependent APC formation interrupts cross-talk between the vascular compartment and podocytes, causing glomerular apoptosis and diabetic nephropathy. Conversely, maintaining high APC levels during long-term diabetes protects against diabetic nephropathy. 相似文献
100.
Simultaneous targeting of multiple disease mediators by a dual-variable-domain immunoglobulin 总被引:3,自引:0,他引:3
Wu C Ying H Grinnell C Bryant S Miller R Clabbers A Bose S McCarthy D Zhu RR Santora L Davis-Taber R Kunes Y Fung E Schwartz A Sakorafas P Gu J Tarcsa E Murtaza A Ghayur T 《Nature biotechnology》2007,25(11):1290-1297
For complex diseases in which multiple mediators contribute to overall disease pathogenesis by distinct or redundant mechanisms, simultaneous blockade of multiple targets may yield better therapeutic efficacy than inhibition of a single target. However, developing two separate monoclonal antibodies for clinical use as combination therapy is impractical, owing to regulatory hurdles and cost. Multi-specific, antibody-based molecules have been investigated; however, their therapeutic use has been hampered by poor pharmacokinetics, stability and manufacturing feasibility. Here, we describe a generally applicable model of a dual-specific, tetravalent immunoglobulin G (IgG)-like molecule--termed dual-variable-domain immunoglobulin (DVD-Ig)--that can be engineered from any two monoclonal antibodies while preserving activities of the parental antibodies. This molecule can be efficiently produced from mammalian cells and exhibits good physicochemical and pharmacokinetic properties. Preclinical studies of a DVD-Ig protein in an animal disease model demonstrate its potential for therapeutic application in human diseases. 相似文献