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171.
Yogendra Patel Catherine A Heyward Michael RH White Douglas B Kell 《BMC systems biology》2011,5(1):32
Background
The similarity property principle has been used extensively in drug discovery to identify small compounds that interact with specific drug targets. Here we show it can be applied to identify the interactions of small molecules within the NF-κB signalling pathway. 相似文献172.
Jerome Deval Jin Hong Guangyi Wang Josh Taylor Lucas K. Smith Amy Fung Sarah K. Stevens Hong Liu Zhinan Jin Natalia Dyatkina Marija Prhavc Antitsa D. Stoycheva Vladimir Serebryany Jyanwei Liu David B. Smith Yuen Tam Qingling Zhang Martin L. Moore Rachel Fearns Sushmita M. Chanda Lawrence M. Blatt Julian A. Symons Leo Beigelman 《PLoS pathogens》2015,11(6)
Respiratory syncytial virus (RSV) causes severe lower respiratory tract infections, yet no vaccines or effective therapeutics are available. ALS-8176 is a first-in-class nucleoside analog prodrug effective in RSV-infected adult volunteers, and currently under evaluation in hospitalized infants. Here, we report the mechanism of inhibition and selectivity of ALS-8176 and its parent ALS-8112. ALS-8176 inhibited RSV replication in non-human primates, while ALS-8112 inhibited all strains of RSV in vitro and was specific for paramyxoviruses and rhabdoviruses. The antiviral effect of ALS-8112 was mediated by the intracellular formation of its 5''-triphosphate metabolite (ALS-8112-TP) inhibiting the viral RNA polymerase. ALS-8112 selected for resistance-associated mutations within the region of the L gene of RSV encoding the RNA polymerase. In biochemical assays, ALS-8112-TP was efficiently recognized by the recombinant RSV polymerase complex, causing chain termination of RNA synthesis. ALS-8112-TP did not inhibit polymerases from host or viruses unrelated to RSV such as hepatitis C virus (HCV), whereas structurally related molecules displayed dual RSV/HCV inhibition. The combination of molecular modeling and enzymatic analysis showed that both the 2''F and the 4''ClCH2 groups contributed to the selectivity of ALS-8112-TP. The lack of antiviral effect of ALS-8112-TP against HCV polymerase was caused by Asn291 that is well-conserved within positive-strand RNA viruses. This represents the first comparative study employing recombinant RSV and HCV polymerases to define the selectivity of clinically relevant nucleotide analogs. Understanding nucleotide selectivity towards distant viral RNA polymerases could not only be used to repurpose existing drugs against new viral infections, but also to design novel molecules. 相似文献
173.
Akl EA Gaddam S Mustafa R Wilson MC Symons A Grifasi A McGuigan D Schünemann HJ 《PloS one》2011,6(2):e16942
Background
The response rates to physician postal surveys remain modest. The primary objective of this study was to assess the effect of tracking responses on physician survey response rate (i.e., determining whether each potential participant has responded or not). A secondary objective was to assess the effects of day of mailing (Monday vs. Friday) on physician survey response rate.Methods
We conducted 3 randomized controlled trials. The first 2 trials had a 2×2 factorial design and tested the effect of day of mailing (Monday vs. Friday) and of tracking vs. no tracking responses. The third trial tested the effect of day of mailing (Monday vs. Friday). We meta-analyzed these 3 trials using a random effects model.Results
The total number of participants in the 3 trials was 1339. The response rate with tracked mailing was not statistically different from that with non-tracked mailing by the time of the first reminder (RR = 1.01 95% CI 0.84, 1.22; I2 = 0%). There was a trend towards lower response rate with tracked mailing by the time of the second reminder (RR = 0.91; 95% CI 0.78, 1.06; I2 = 0%). The response rate with mailing on Mondays was not statistically different from that with Friday mailing by the time of first reminder (RR = 1.01; 95% CI 0.87, 1.17; I2 = 0%), and by the time of the 2nd reminder (RR = 1.08; 95% CI 0.84, 1.39; I2 = 77%).Conclusions
Tracking response may negatively affect physicians'' response rate. The day of mailing does not appear to affect physicians'' response rate. 相似文献174.
De-etiolation involves a number of phenotypic changes as the plants shift from a dark-grown (etiolated) to a light-grown (de-etiolated)
morphology. Whilst these light-induced, morphological changes are thought to be mediated by plant hormones, the precise mechanism/s
are not yet fully understood. Here we provide further direct evidence that gibberellins (GAs) may play an important role in
de-etiolation, because a similar light-induced reduction in bioactive GA levels was detected in barley (Hordeum vulgare L.), Arabidopsis (Arabidopsis thaliana L.), and pea (Pisum sativum L.). This is indicative of a highly conserved, negative-regulatory role for GAs in de-etiolation, in a range of taxonomically
diverse species. In contrast, we found no direct evidence of a reduction in brassinosteroid (BR) levels during de-etiolation
in any of these species.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
175.
During the preparation of sodium 3,5-dibromo-4-nitrosobenzenesulphonate (DBNBS) of high purity for electron paramagnetic resonance (EPR) spin-trapping purposes, it was found that the material synthesised as part of the present study differed significantly from some commercially available samples of DBNBS. A thorough chemical characterisation of the contents of the various samples led to the conclusion that the preparations synthesised in the present study, as well as one of four commercially available samples, contained essentially pure DBNBS and had efficient spin-trapping activity. In contrast, the remaining three commercially available samples contained almost exclusively sodium 3,5-dibromo-4-nitrobenzenesulphonate, i.e. a one-oxygen oxidation product of DBNBS, and had little spin-trapping activity. The two compounds were readily separated by reverse-phase high performance liquid chromatography (HPLC). It was further found that the quality of DBNBS preparations may be determined by NMR spectrometry, IR spectrometry, fast atom bombardment-mass spectrometry (FAB-MS) and EPR spectrometry. In particular, UV-Visible spectroscopy may be used to determine A 308 /A 280 , which should be greater than 1.8 for a high purity DBNBS preparation. 相似文献
176.
Symons M 《Current biology : CB》2000,10(14):R535-R537
Interaction of cells with the extracellular matrix influences various aspects of cellular behavior. A recent study shows that cell-substrate adhesion is necessary for effective coupling of the small GTPase Rac to its effector PAK. 相似文献
177.
Auxin inhibition of decapitation-induced branching is dependent on graft-transmissible signals regulated by genes Rms1 and Rms2 总被引:7,自引:0,他引:7
Decapitation-induced axillary bud outgrowth is a vital mechanism whereby shoots are able to continue normal growth and development. In many plants, including wild-type garden pea (Pisum sativum L.), this process can be inhibited by exogenous auxin. Using the ramosus (rms) increased branching mutants of pea, we present evidence that this response to auxin is dependent on graft-transmissible substance(s) regulated by the genes Rms1 and Rms2. The response to exogenous auxin is massively diminished in decapitated rms1 and rms2 mutant plants. However, basipetal auxin transport is not reduced in intact or decapitated mutants. Grafting rms1 or rms2 shoots onto wild-type rootstocks restored the auxin response, indicating that Rms1 and Rms2 gene action in the rootstock is sufficient to enable an auxin response in mutant shoots. We conclude that Rms1 and Rms2 act in the rootstock and shoot to control levels of mobile substance(s) that interact with exogenous auxin in the inhibition of bud outgrowth after decapitation. At least for rms1, the reduced auxin response is unlikely to be due to an inability of auxin to decrease xylem sap cytokinin content, as this is already low in intact rms1 plants. Consequently, we have genetic evidence that auxin action in decapitated plants depends on at least one novel long-distance signal. 相似文献
178.
Fernandes F Chen K Ehrlich LS Jin J Chen MH Medina GN Symons M Montelaro R Donaldson J Tjandra N Carter CA 《Traffic (Copenhagen, Denmark)》2011,12(4):438-451
Phosphatidylinositol 4,5-biphosphate [PI(4,5)P(2) ], the predominant phosphoinositide (PI) on the plasma membrane, binds the matrix (MA) protein of human immunodeficiency virus type 1 (HIV-1) and equine infectious anemia virus (EIAV) with similar affinities in vitro. Interaction with PI(4,5)P(2) is critical for HIV-1 assembly on the plasma membrane. EIAV has been shown to localize in internal compartments; hence, the significance of its interaction with PI(4,5)P(2) is unclear. We therefore investigated the binding in vitro of other PIs to EIAV MA and whether intracellular association with compartments bearing these PIs was important for assembly and release of virus-like particles (VLPs) formed by Gag. In vitro, EIAV MA bound phosphatidylinositol 3-phosphate [PI(3)P] with higher affinity than PI(4,5)P(2) as revealed by nuclear magnetic resonance (NMR) spectra upon lipid titration. Gag was detected on the plasma membrane and in compartments enriched in phosphatidylinositol 3,5-biphosphate [PI(3,5)P(2) ]. Treatment of cells with YM201636, a kinase inhibitor that blocks production of PI(3,5)P(2) from PI(3)P, caused Gag to colocalize with aberrant compartments and inhibited VLP release. In contrast to HIV-1, release of EIAV VLPs was not significantly diminished by coexpression with 5-phosphatase IV, an enzyme that specifically depletes PI(4,5)P(2) from the plasma membrane. However, coexpression with synaptojanin 2, a phosphatase with broader specificity, diminished VLP production. PI-binding pocket mutations caused striking budding defects, as revealed by electron microscopy. One of the mutations also modified Gag-Gag interaction, as suggested by altered bimolecular fluorescence complementation. We conclude that PI-mediated targeting to peripheral and internal membranes is a critical factor in EIAV assembly and release. 相似文献
179.
GM Symons YJ Chua JJ Ross LJ Quittenden NW Davies JB Reid 《Journal of experimental botany》2012,63(13):4741-4750
In contrast to climacteric fruits, where ethylene is known to be pivotal, the regulation of ripening in non-climacteric fruits is not well understood. In the non-climacteric strawberry (Fragaria anannassa), auxin and abscisic acid (ABA) are thought to be important, but the roles of other hormones suggested to be involved in fruit development and ripening are not clear. Here changes in the levels of indole-3-acetic acid (IAA), ABA, GA(1), and castasterone from anthesis to fully ripened fruit are reported. The levels of IAA and GA(1) rise early in fruit development before dropping to low levels prior to colour accumulation. Castasterone levels are highest at anthesis and drop to very low levels well before ripening commences, suggesting that brassinosteroids do not play an important role in ripening in strawberry. ABA levels are low at anthesis and gradually rise through development and ripening. The synthetic auxin, 1-naphthaleneacetic acid (NAA), can delay ripening, but the application of GA(3), the gibberellin biosythesis inhibitor paclobutrazol, and ABA had no significant effect. IAA and ABA levels are higher in the developing achenes than in the receptacle tissue and may be important for receptacle enlargement and ripening, and seed maturation, respectively. Contrary to a recent report, the biologically active GA(4) was not detected. The pattern of changes in the levels of the hormones are different from those reported in another well studied non-climateric fruit, grape, suggesting that a single consistent pattern of hormone changes does not occur in this group of fruit during ripening. 相似文献
180.
Rusk N Le PU Mariggio S Guay G Lurisci C Nabi IR Corda D Symons M 《Current biology : CB》2003,13(8):659-663
Synaptojanin 2 is a ubiquitously expressed polyphosphoinositide phosphatase that displays a high degree of homology in its catalytic domains with synaptojanin 1 [1,2]. Neurons of synaptojanin 1-deficient mice display an increase in clathrin-coated vesicles and delayed reentry of recycling vesicles into the fusion-competent vesicle pool, but no defects in early steps of endocytosis [3,4]. Here we show that inhibition of synaptojanin 2 expression via small interfering (si) RNA causes a strong defect in clathrin-mediated receptor internalization in a lung carcinoma cell line. This inhibitory phenotype is rescued by overexpression of wild-type synaptojanin 2, but not of wild-type synaptojanin 1 or mutant synaptojanin 2 that is deficient in 5'-phosphatase activity. In addition, electron-microscopic analysis shows that synaptojanin 2 depletion causes a decrease in clathrin-coated pits and vesicles. These results suggest a role for synaptojanin 2 in clathrin-coated pit formation and imply that lipid hydrolysis is required at an early stage of clathrin-mediated endocytosis. Taken together, our results also indicate that synaptojanin 2 is functionally distinct from synaptojanin 1. 相似文献