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Mechanism of PTC124 activity in cell-based luciferase assays of nonsense codon suppression 总被引:1,自引:0,他引:1 下载免费PDF全文
Douglas S. Auld Natasha Thorne William F. Maguire James Inglese 《Proceedings of the National Academy of Sciences of the United States of America》2009,106(9):3585-3590
High-throughput screening (HTS) assays used in drug discovery frequently use reporter enzymes such as firefly luciferase (FLuc) as indicators of target activity. An important caveat to consider, however, is that compounds can directly affect the reporter, leading to nonspecific but highly reproducible assay signal modulation. In rare cases, this activity appears counterintuitive; for example, some FLuc inhibitors, acting through posttranslational Fluc reporter stabilization, appear to activate gene expression. Previous efforts to characterize molecules that influence luciferase activity identified a subset of 3,5-diaryl-oxadiazole-containing compounds as FLuc inhibitors. Here, we evaluate a number of compounds with this structural motif for activity against FLuc. One such compound is PTC124 {3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid}, a molecule originally identified in a cell-based FLuc assay as having nonsense codon suppression activity [Welch EM, et al., Nature (2007) 447:87–91]. We find that the potency of FLuc inhibition for the tested compounds strictly correlates with their activity in a FLuc reporter cell-based nonsense codon assay, with PTC124 emerging as the most potent FLuc inhibitor (IC50 = 7 ± 1 nM). However, these compounds, including PTC124, fail to show nonsense codon suppression activity when Renilla reniformis luciferase (RLuc) is used as a reporter and are inactive against the RLuc enzyme. This suggests that the initial discovery of PTC124 may have been biased by its direct effect on the FLuc reporter, implicating firefly luciferase as a molecular target of PTC124. Our results demonstrate the value of understanding potential interactions between reporter enzymes and chemical compounds and emphasize the importance of implementing the appropriate control assays before interpreting HTS results. 相似文献
994.
Natasha Nazarali Cheryl M. Glazebrook Digby Elliott 《Journal of autism and developmental disorders》2009,39(10):1401-1411
Two experiments explored how individuals with and without autism plan and reprogram movements. Participants were given partial
or complete information regarding the location of the upcoming manual movement. In Experiment 1, direct information specified
the hand or direction of the upcoming movement. These results replicated previous reports that participants with autism utilize
advance information to prepare their movements in the same manner as their chronologically age matched peers. Experiment 2
examined how individuals respond to an unexpected change in the movement requirements. Participants received advance information
about the hand and direction of the upcoming movement. On 20% of the trials participants needed to adjust either the hand or direction they
had prepared. Overall, the individuals with autism had difficulty reprogramming already planned movements, particularly if
a different effector was required. 相似文献
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Kimberly S. Chiew BSc Heather Shepherd BA Dip HE † Janette Vardy MD PhD FRACP ‡ Martin H.N. Tattersall MA MSc MD FRCP FRACP § Phyllis N. Butow BA PhD Dip Ed MClin Psych MPH ¶ Natasha B. Leighl MD MMSc FRCPC 《Health expectations》2008,11(1):35-45
Objective Treatment decisions in advanced breast cancer are complex, with enhanced quality of life and survival among important treatment goals. Patients with metastatic breast cancer face the decision of whether or not to have chemotherapy, and many wish to be involved in this decision. We report the development and evaluation of a decision aid (DA) designed to assist patients facing this treatment decision. Design and sample Women with metastatic breast cancer (n = 17) and medical oncologists in Australia and Canada (n = 7) were invited to evaluate the DA. Intervention A DA was developed for patients with hormone‐resistant metastatic breast cancer considering chemotherapy. The DA presented options of supportive care, with or without chemotherapy. Potential benefits and side effects of different chemotherapy regimens, and evidence‐based prognostic estimates were described, and a values clarification exercise included. Main outcome measures Patient questionnaires evaluating information and decision involvement preferences, attitudes toward the DA and oncologist feedback regarding attitudes toward the DA. Results Seventeen patients participated; fifteen desired as much information about their illness as possible; sixteen wished to be actively involved in the decision‐making process. The majority rated the DA as highly acceptable, clear and informative, and would recommend it to others facing this treatment decision. Conclusion This is the first DA for patients with advanced metastatic breast cancer considering chemotherapy. A randomized trial is underway to evaluate its role in clinical decision‐making. 相似文献
996.
A review of the cost of cardiovascular disease 总被引:1,自引:0,他引:1
Jean-Eric Tarride Morgan Lim Marie DesMeules Wei Luo Natasha Burke Daria O��Reilly James Bowen Ron Goeree 《The Canadian journal of cardiology》2009,25(6):e195-e202
In Canada, 74,255 deaths (33% of all deaths) in 2003 were due to cardiovascular disease (CVD). As one of the most costly diseases, CVD represents a major economic burden on health care systems. The purpose of the present study was to review the literature on the economic costs of CVD in Canada and other developed countries (United States, Europe and Australia) published from 1998 to 2006, with a focus on Canada. Of 1656 screened titles and abstracts, 34 articles were reviewed including six Canadian studies and 17 American studies. While considerable variation was observed among studies, all studies indicated that the costs of treating CVD-related conditions are significant, outlining a convincing case for CVD prevention programs. 相似文献
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Anindya Chanda Ludmila V. Roze Suil Kang Katherine A. Artymovich Glenn R. Hicks Natasha V. Raikhel Ana M. Calvo John E. Linz 《Proceedings of the National Academy of Sciences of the United States of America》2009,106(46):19533-19538
Eukaryotes have evolved highly conserved vesicle transport machinery to deliver proteins to the vacuole. In this study we show that the filamentous fungus Aspergillus parasiticus employs this delivery system to perform new cellular functions, the synthesis, compartmentalization, and export of aflatoxin; this secondary metabolite is one of the most potent naturally occurring carcinogens known. Here we show that a highly pure vesicle-vacuole fraction isolated from A. parasiticus under aflatoxin-inducing conditions converts sterigmatocystin, a late intermediate in aflatoxin synthesis, to aflatoxin B1; these organelles also compartmentalize aflatoxin. The role of vesicles in aflatoxin biosynthesis and export was confirmed by blocking vesicle-vacuole fusion using 2 independent approaches. Disruption of A. parasiticus vb1 (encodes a protein homolog of AvaA, a small GTPase known to regulate vesicle fusion in A. nidulans) or treatment with Sortin3 (blocks Vps16 function, one protein in the class C tethering complex) increased aflatoxin synthesis and export but did not affect aflatoxin gene expression, demonstrating that vesicles and not vacuoles are primarily involved in toxin synthesis and export. We also observed that development of aflatoxigenic vesicles (aflatoxisomes) is strongly enhanced under aflatoxin-inducing growth conditions. Coordination of aflatoxisome development with aflatoxin gene expression is at least in part mediated by Velvet (VeA), a global regulator of Aspergillus secondary metabolism. We propose a unique 2-branch model to illustrate the proposed role for VeA in regulation of aflatoxisome development and aflatoxin gene expression. 相似文献
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Richard L. Doty Jonathan Treem Isabelle Tourbier Natasha Mirza 《Pharmacology, biochemistry, and behavior》2009,94(2):312-318
Taste disturbance is a common, but poorly understood, side effect of a large number of medications. This double-blind study examined the frequency, intensity, and quality of taste disturbances related to the widely used hypnotic sleep aid eszopiclone (ESZ; Lunesta®), as well as their associations with age, sex, body mass index (BMI), time of day, phenyl thiocarbamide (PTC) taste sensitivity, and ESZ saliva and blood levels. Sixty six percent of 24 female subjects and 53% of 15 male subjects reported dysgeusic sensations, mostly bitter/metallic, during the drug administration (respective placebo figures 17% and 7%). No meaningful relationships were found between the frequency or the intensity of the sensations and age, BMI, or PTC taste sensitivity. Dysgeusia was more intense and longer lasting in women than in men, stronger in the morning than in the evening, and positively correlated with drug plasma and saliva levels. In women, intensity ratings decreased across treatment days. Taste test measures were marginally, at best, influenced by ESZ. This study demonstrates, for the first time, that the dysgeusia associated with ESZ is systemically influenced by a number of factors, including sex, time since drug administration, and both blood and saliva levels of the drug. 相似文献
1000.