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排序方式: 共有349条查询结果,搜索用时 218 毫秒
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Balog Edward M.; Gallant Esther M. 《American journal of physiology. Cell physiology》1999,276(1):C128
Modulation of the L-type current by sarcoplasmicreticulum (SR) Ca2+ release hasbeen examined in patch-clamped mouse myotubes. Inhibition of SRCa2+ release by inclusion ofryanodine in the internal solution shifted the half-activating voltage(V0.5) of theL-type current from 1.1 ± 2.1 to 7.7 ± 1.7 mV. Rutheniumred in the internal solution shiftedV0.5 from 5.4 ± 1.9 to 3.2 ± 4.1 mV. Chelation of myoplasmic Ca2+ with1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraaceticacid perfusion shiftedV0.5 from 4.4 ± 1.7 to 3.5 ± 3.3 mV and increased the peak current.Extracellular caffeine (1 mM), which should enhance SRCa2+ release, significantlydecreased the peak Ca2+ current.In low (0.1 mM) internal EGTA, myotube contraction was abolished byinternal perfusion with ryanodine or ruthenium red, whereas addition ofcaffeine to the extracellular solution lowered the contractilethreshold, indicating that these modulators of SRCa2+ release had the expectedeffects on contraction. Therefore, SR Ca2+ release appears to modulatethe sarcolemmal L-type current, suggesting a retrograde communicationfrom the SR to the sarcolemmal L-type channels inexcitation-contraction coupling. 相似文献
23.
Gallant EM Hart J Eager K Curtis S Dulhunty AF 《American journal of physiology. Cell physiology》2004,286(4):C821-C830
Enhanced sensitivity to caffeine is part of the standard tests for susceptibility to malignant hyperthermia (MH) in humans and pigs. The caffeine sensitivity of skeletal muscle contraction and Ca2+ release from the sarcoplasmic reticulum is enhanced, but surprisingly, the caffeine sensitivity of purified porcine ryanodine receptor Ca2+-release channels (RyRs) is not affected by the MH mutation (Arg615Cys). In contrast, we show here that native malignant hyperthermic pig RyRs (incorporated into lipid bilayers with RyR-associated lipids and proteins) were activated by caffeine at 100- to 1,000-fold lower concentrations than native normal pig RyRs. In addition, the results show that the mutant ryanodine receptor channels were less sensitive to high-affinity activation by a peptide (CS) that corresponds to a part of the IIIII loop of the skeletal dihydropyridine receptor (DHPR). Furthermore, subactivating concentrations of peptide CS enhanced the response of normal pig and rabbit RyRs to caffeine. In contrast, the caffeine sensitivity of MH RyRs was not enhanced by the peptide. These novel results showed that in MH-susceptible pig muscles 1) the caffeine sensitivity of native RyRs was enhanced, 2) the sensitivity of RyRs to a skeletal IIIII loop peptide was depressed, and 3) an interaction between the caffeine and peptide CS activation mechanisms seen in normal RyRs was lost. calcium ion homeostasis; excitation-contraction coupling; ryanodine receptor polymorphisms; muscle contraction 相似文献
24.
Use of in-biofilm expression technology to identify genes involved in Pseudomonas aeruginosa biofilm development 下载免费PDF全文
Mature Pseudomonas aeruginosa biofilms form complex three-dimensional architecture and are tolerant of antibiotics and other antimicrobial compounds. In this work, an in vivo expression technology system, originally designed to study virulence-associated genes in complex mammalian environments, was used to identify genes up-regulated in P. aeruginosa grown to a mature (5-day) biofilm. Five unique cloned promoters unable to promote in vitro growth in the absence of purines after recovery from the biofilm environment were identified. The open reading frames downstream of the cloned promoter regions were identified, and knockout mutants were generated. Insertional mutation of PA5065, a homologue of Escherichia coli ubiB, was lethal, while inactivation of PA0240 (a porin homologue), PA3710 (a putative alcohol dehydrogenase), and PA3782 (a homologue of the Streptomyces griseus developmental regulator adpA) had no effect on planktonic growth but caused defects in biofilm formation in static and flowing systems. In competition experiments, mutants demonstrated reduced fitness compared with the parent strain, comprising less than 0.0001% of total biofilm cells after 5 days. Therefore, using in-biofilm expression technology, we have identified novel genes that do not affect planktonic growth but are important for biofilm formation, development, and fitness. 相似文献
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Gallant M Carrière MC Chateauneuf A Denis D Gareau Y Godbout C Greig G Juteau H Lachance N Lacombe P Lamontagne S Metters KM Rochette C Ruel R Slipetz D Sawyer N Tremblay N Labelle M 《Bioorganic & medicinal chemistry letters》2002,12(18):2583-2586
Potent and selective ligands for the human EP3 prostanoid receptor are described. Biaryl compounds bearing a tethered ortho substituted acidic moiety were identified as potent EP3 antagonists based on the SAR described herein. The binding affinity of key compounds on all eight human prostanoid receptors is reported. 相似文献
27.
Hodous BL Geuns-Meyer SD Hughes PE Albrecht BK Bellon S Caenepeel S Cee VJ Chaffee SC Emery M Fretland J Gallant P Gu Y Johnson RE Kim JL Long AM Morrison M Olivieri PR Patel VF Polverino A Rose P Wang L Zhao H 《Bioorganic & medicinal chemistry letters》2007,17(10):2886-2889
A novel class of selective Tie-2 inhibitors was derived from a multi-kinase inhibitor 1. By reversing the amide connectivity and incorporating aminotriazine or aminopyridine hinge-binding moieties, excellent Tie-2 potency and KDR selectivity could be achieved with 3-substituted terminal aryl rings. X-ray co-crystal structure analysis aided inhibitor design. This series was evaluated on the basis of potency, selectivity, and rat pharmacokinetic parameters. 相似文献
28.
Kan Chen Wanlu Cao Juan Li Dave Sprengers Pratika Y Hernanda Xiangdong Kong Luc JW van der Laan Kwan Man Jaap Kwekkeboom Herold J Metselaar Maikel P Peppelenbosch Qiuwei Pan 《Molecular medicine (Cambridge, Mass.)》2015,21(1):792-802
As uncontrolled cell proliferation requires nucleotide biosynthesis, inhibiting enzymes that mediate nucleotide biosynthesis constitutes a rational approach to the management of oncological diseases. In practice, however, results of this strategy are mixed and thus elucidation of the mechanisms by which cancer cells evade the effect of nucleotide biosynthesis restriction is urgently needed. Here we explored the notion that intrinsic differences in cancer cell cycle velocity are important in the resistance toward inhibition of inosine monophosphate dehydrogenase (IMPDH) by mycophenolic acid (MPA). In short-term experiments, MPA treatment of fast-growing cancer cells effectively elicited G0/G1 arrest and provoked apoptosis, thus inhibiting cell proliferation and colony formation. Forced expression of a mutated IMPDH2, lacking a binding site for MPA but retaining enzymatic activity, resulted in complete resistance of cancer cells to MPA. In nude mice subcutaneously engrafted with HeLa cells, MPA moderately delayed tumor formation by inhibiting cell proliferation and inducing apoptosis. Importantly, we developed a lentiviral vector–based Tet-on label-retaining system that enables to identify, isolate and functionally characterize slow-cycling or so-called label-retaining cells (LRCs) in vitro and in vivo. We surprisingly found the presence of LRCs in fast-growing tumors. LRCs were superior in colony formation, tumor initiation and resistance to MPA as compared with fast-cycling cells. Thus, the slow-cycling compartment of cancer seems predominantly responsible for resistance to MPA. 相似文献
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Simard D Leblanc Y Berthelette C Zaghdane MH Molinaro C Wang Z Gallant M Lau S Thao T Hamel M Stocco R Sawyer N Sillaots S Gervais F Houle R Lévesque JF 《Bioorganic & medicinal chemistry letters》2011,21(2):841-845
A new class of 7-azaindole analogs of MK-7246 as potent and selective CRTH2 antagonists is reported. The SAR leading to the identification of the optimal azaindole regioisomer as well as the pharmacokinetics and off-target activities of the most potent antagonists are disclosed. 相似文献