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101.
Ta-Hsien Lin Horng-Dar Lin Jeng-Ling Yang Vladimir R. Kaberdin Sue Lin-Chao Tai-huang Huang 《Journal of biomolecular structure & dynamics》2013,31(4):677-685
Abstract We have synthesized two RNA fragments: a 42-mer corresponding to the full loop I sequence of the loop I region of ColE1 antisense RNA (RNA I), plus three additional Gs at the 5′-end, and a 31-mer which has 11 5′-end nucleotides (G(-2)-U9) deleted. The secondary structure of the 42-mer, deduced from one- and two-dimensional NMR spectra, consists of a stem of 11 base-pairs which contains a U-U base-pair and a bulged C base, a 7 nucleotide loop, and a single-stranded 5′ end of 12 nucleotides. The UV-melting study of the 42-mer further revealed a multi-step melting behavior with transition temperatures 32°C and 71°C clearly discernible. In conjunction with NMR melting study the major transition at 71°C is assigned to the overall melting of the stem region and the 32°C transition is assigned to the opening of the loop region. The deduced secondary structure agrees with that proposed for the intact RNA I and provides structural bases for understanding the specificity of RNase E. 相似文献
102.
103.
Joseph M. Hyser Budi Utama Sue E. Crawford James R. Broughman Mary K. Estes 《Journal of virology》2013,87(24):13579-13588
Rotavirus nonstructural protein 4 (NSP4) induces dramatic changes in cellular calcium homeostasis. These include increased endoplasmic reticulum (ER) permeability, resulting in decreased ER calcium stores and activation of plasma membrane (PM) calcium influx channels, ultimately causing a 2- to 4-fold elevation in cytoplasmic calcium. Elevated cytoplasmic calcium is absolutely required for virus replication, but the underlying mechanisms responsible for calcium influx remain poorly understood. NSP4 is an ER-localized viroporin, whose activity depletes ER calcium, which ultimately leads to calcium influx. We hypothesized that NSP4-mediated depletion of ER calcium activates store-operated calcium entry (SOCE) through activation of the ER calcium sensor stromal interaction molecule 1 (STIM1). We established and used a stable yellow fluorescent protein-expressing STIM1 cell line (YFP-STIM1) as a biosensor to assess STIM1 activation (puncta formation) by rotavirus infection and NSP4 expression. We found that STIM1 is constitutively active in rotavirus-infected cells and that STIM1 puncta colocalize with the PM-localized Orai1 SOCE calcium channel. Expression of wild-type NSP4 activated STIM1, resulting in PM calcium influx, but an NSP4 viroporin mutant failed to induce STIM1 activation and did not activate the PM calcium entry pathway. Finally, knockdown of STIM1 significantly reduced rotavirus yield, indicating STIM1 plays a critical role in virus replication. These data demonstrate that while rotavirus may ultimately activate multiple calcium channels in the PM, calcium influx is predicated on NSP4 viroporin-mediated activation of STIM1 in the ER. This is the first report of viroporin-mediated activation of SOCE, reinforcing NSP4 as a robust model to understand dysregulation of calcium homeostasis during virus infections. 相似文献
104.
Steven Rockman Lorena E. Brown Ian G. Barr Brad Gilbertson Sue Lowther Anatoly Kachurin Olga Kachurina Jessica Klippel Jesse Bodle Martin Pearse Deborah Middleton 《Journal of virology》2013,87(6):3053-3061
In preparing for the threat of a pandemic of avian H5N1 influenza virus, we need to consider the significant delay (4 to 6 months) necessary to produce a strain-matched vaccine. As some degree of cross-reactivity between seasonal influenza vaccines and H5N1 virus has been reported, this was further explored in the ferret model to determine the targets of protective immunity. Ferrets were vaccinated with two intramuscular inoculations of trivalent inactivated split influenza vaccine or subcomponent vaccines, with and without adjuvant, and later challenged with a lethal dose of A/Vietnam/1203/2004 (H5N1) influenza virus. We confirmed that vaccination with seasonal influenza vaccine afforded partial protection against lethal H5N1 challenge and showed that use of either AlPO4 or Iscomatrix adjuvant with the vaccine resulted in complete protection against disease and death. The protection was due exclusively to the H1N1 vaccine component, and although the hemagglutinin contributed to protection, the dominant protective response was targeted toward the neuraminidase (NA) and correlated with sialic acid cleavage-inhibiting antibody titers. Purified heterologous NA formulated with Iscomatrix adjuvant was also protective. These results suggest that adjuvanted seasonal trivalent vaccine could be used as an interim measure to decrease morbidity and mortality from H5N1 prior to the availability of a specific vaccine. The data also highlight that an inducer of cross-protective immunity is the NA, a protein whose levels are not normally monitored in vaccines and whose capacity to induce immunity in recipients is not normally assessed. 相似文献
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106.
Rufus B. Sage Andrew N. Hoodless Chris M. Hewson Sue Wilson Chris Le Clare John H. Marchant 《Bird Study》2013,60(4):409-420
Capsule Repeated counts of fledged broods can provide a useful estimate of breeding success for most common woodland birds. Aims To assess the efficacy of comparing fledged-brood survey data with territory mapping using simple mark–recapture analysis techniques to provide an estimate of breeding success for common woodland birds that does not involve finding nests. Methods Three observers undertook territory mapping surveys of adults, followed by counts of fledged broods four times a week during May–July 2007 in two 15 ha woods each, both in southern England. Using known fledging to maturity periods, these counts were used to calculate daily detection probabilities for broods of ubiquitous species. These enabled fledged brood territory occupancy probabilities (i.e. brood to territory ratios) to be estimated that take account of the possibility that broods were present but missed by surveys. Results Of the 19 species found in all six woods, mean daily detection probability estimates for fledged broods of 17 species ranged from 0.17 to 0.50 with significant variation between woods for 12 species, but within region/observer for four species. The mean probability of detecting a brood at least once was over 75% using four visits per week and over 50% using two visits. Only for Great Spotted Woodpeckers Dendrocopos major and Garden Warblers Sylvia borin was the fledging period too short and the daily detection probability too low to provide a reasonable estimate of the territory occupancy probability. Conclusion Daily detection probabilities for fledged broods of most common woodland birds were sufficiently high to enable useable estimates of fledged-brood territory occupancy probabilities to be made based on a survey programme involving two or three visits per week between late May and the end June. The method used may have application as a means of providing a relatively easily derived productivity index for woodland bird monitoring programmes or for research studies. 相似文献
107.
Scott J. Gratz Alexander M. Cummings Jennifer N. Nguyen Danielle C. Hamm Laura K. Donohue Melissa M. Harrison Jill Wildonger Kate M. O’Connor-Giles 《Genetics》2013,194(4):1029-1035
We have adapted a bacterial CRISPR RNA/Cas9 system to precisely engineer the Drosophila genome and report that Cas9-mediated genomic modifications are efficiently transmitted through the germline. This RNA-guided Cas9 system can be rapidly programmed to generate targeted alleles for probing gene function in Drosophila. 相似文献
108.
Graciela B. Arhancet Daniel P. Walker Sue Metz Yvette M. Fobian Steven E. Heasley Jeffrey S. Carter John R. Springer Darin E. Jones Michael J. Hayes Alexander F. Shaffer Gina M. Jerome Michael T. Baratta Ben Zweifel William M. Moore Jaime L. Masferrer Michael L. Vazquez 《Bioorganic & medicinal chemistry letters》2013,23(4):1114-1119
Inhibition of mPGES-1, the terminal enzyme in the arachidonic acid/COX pathway to regulate the production of pro-inflammatory prostaglandin PGE2, is considered an attractive new therapeutic target for safe and effective anti-inflammatory drugs. The discovery of a novel series of orally active, selective benzoxazole piperidinecarboxamides as mPGES-1 inhibitors is described. Structure–activity optimization of lead 5 with cyclohexyl carbinols resulted in compound 12, which showed excellent in vitro potency and selectivity against COX-2, and reasonable pharmacokinetic properties. Further SAR studies of the benzoxazole ring substituents lead to a novel series of highly potent compounds with improved PK profile, including 23, 26, and 29, which were effective in a carrageenan-stimulated guinea pig air pouch model of inflammation. Based on its excellent in vitro and in vivo pharmacological, pharmacokinetic and safety profile and ease of synthesis, compound 26 (PF-4693627) was advanced to clinical studies. 相似文献
109.
Nguyen The Tung To Dao Cuong Tran Manh Hung Jeong Hyung Lee Mi Hee Woo Jae Sue Choi Jaewang Kim Sung Ho Ryu Byung Sun Min 《Bioorganic & medicinal chemistry letters》2013,23(5):1428-1432
Four new lanostane triterpenes, butyl lucidenate P (1), butyl lucidenate D2 (2), butyl lucidenate E2 (3) and butyl lucidenate Q (4) along with 11 known compounds (5–15) were isolated from the fruiting bodies of Ganoderma lucidum. Their chemical structures were established mainly by 1D and 2D NMR techniques and mass spectrometry. Their anti-inflammatory activity was evaluated against LPS-induced NO production in macrophage RAW 264.7 cells. Compounds 1, 3, 4, 9, 10 and 15 showed inhibitory potency with IC50 values of 7.4, 6.4, 4.3, 9.4, 9.2 and 4.5 μM, respectively. Compounds 1, 3 and 15 dose-dependently reduced the LPS-induced iNOS expressions. Preincubation of cell with 1, 3 and 15 significantly suppressed LPS-induced expression of COX-2 protein. 相似文献
110.
Sajiv K. Nair Jean J. Matthews Stephan J. Cripps Hengmiao Cheng Jacqui E. Hoffman Christopher Smith Stanley Kupchinsky Michael Siu Wendy D. Taylor Yong Wang Theodore O. Johnson Klaus R. Dress Martin P. Edwards Sue Zhou Natilie A. Hosea Amy LaPaglia Ping Kang Arturo Castro Deepak Dalvie 《Bioorganic & medicinal chemistry letters》2013,23(8):2344-2348
N-(Pyridin-2-yl) arylsulfonamides 1 and 2 (PF-915275) were identified as potent inhibitors of 11β-hydroxysteroid dehydrogenase type 1. A screen for bioactivation revealed that these compounds formed glutathione conjugates. This communication presents the results of a risk benefit analysis carried out to progress 2 (PF-915275) to a clinical study and the strategies used to eliminate reactive metabolites in this series of inhibitors. Based on the proposed mechanism of bioactivation and structure–activity relationships, design efforts led to N-(pyridin-2-yl) arylsulfonamides such as 18 and 20 that maintained potent 11β-hydroxysteroid dehydrogenase type 1 activity, showed exquisite pharmacokinetic profiles, and were negative in the reactive metabolite assay. 相似文献