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981.
Maria Angeles Martinez-Grau Isabel C. Gonzalez Valcarcel Julie V. Early Richard Klaus Gessner Candice Soares de Melo Eva Maria Martin de la Nava Aaron Korkegian Yulia Ovechkina Lindsay Flint Anisa Gravelle Jeff W. Cramer Prashant V. Desai Leslie J. Street Joshua Odingo Thierry Masquelin Kelly Chibale Tanya Parish 《Bioorganic & medicinal chemistry letters》2018,28(10):1758-1764
Despite increased research efforts to find new treatments for tuberculosis in recent decades, compounds with novel mechanisms of action are still required. We previously identified a series of novel aryl-oxadiazoles with anti-tubercular activity specific for bacteria using butyrate as a carbon source. We explored the structure activity relationship of this series. Structural modifications were performed in all domains to improve potency and physico-chemical properties. A number of compounds displayed sub-micromolar activity against M. tuberculosis utilizing butyrate, but not glucose as the carbon source. Compounds showed no or low cytotoxicity against eukaryotic cells. Three compounds were profiled in mouse pharmacokinetic studies. Plasma clearance was low to moderate but oral exposure suggested solubility-limited drug absorption in addition to first pass metabolism. The presence of a basic nitrogen in the linker slightly increased solubility, and salt formation optimized aqueous solubility. Our findings suggest that the 1,3,4-oxadiazoles are useful tools and warrant further investigation. 相似文献
982.
Jinhong Ren Tina L. Mistry Pin-Chih Su Shahila Mehboob Robel Demissie Leslie Wo-Mei Fung Arun K. Ghosh Michael E. Johnson 《Bioorganic & medicinal chemistry letters》2018,28(11):2074-2079
We have previously reported benzimidazole-based compounds to be potent inhibitors of FabI for Francisella tularensis (FtFabI), making them promising antimicrobial hits. Optically active enantiomers exhibit markedly differing affinities toward FtFabI. The IC50 of benzimidazole (?)-1 is ~100× lower than the (+)-enantiomer, with similar results for the 2 enantiomers. Determining the absolute configuration for these optical compounds and elucidating their binding modes is important for further design. Electronic circular dichroism (ECD) quantum calculations have become important in determining absolute configurations of optical compounds. We determined the absolute configuration of (?)/(+)-1 and (?)/(+)-2 by comparing experimental spectra and theoretical density functional theory (DFT) simulations of ECD spectra at the B3LYP/6-311+G(2d, p) level using Gaussian09. Comparison of experimental and calculated ECD spectra indicates that the S configuration corresponds to the (?)-rotation for both compounds 1 and 2, while the R configuration corresponds to the (+)-rotation. Further, molecular dynamics simulations and MM-GBSA binding energy calculations for these two pairs of enantiomers with FtFabI show much tighter binding MM-GBSA free energies for S-1 and S-2 than for their enantiomers, R-1 and R-2, consistent with the S configuration being the more active one, and with the ECD determination of the S configuration corresponding to (?) and the R configuration corresponding to (+). Thus, our computational studies allow us to assign (?) to (S)- and (+) to (R)- for compounds 1 and 2, and to further evaluate structural changes to improve efficacy. 相似文献
983.
Roger Magarey Leslie Newton Seung Cheon Hong Yu Takeuchi David Christie Catherine S. Jarnevich Lisa Kohl Martin Damus Steven I. Higgins Leah Millar Karen Castro Amanda West John Hastings Gericke Cook John Kartesz Anthony L. Koop 《Biological invasions》2018,20(3):679-694
This study compares four models for predicting the potential distribution of non-indigenous weed species in the conterminous U.S. The comparison focused on evaluating modeling tools and protocols as currently used for weed risk assessment or for predicting the potential distribution of invasive weeds. We used six weed species (three highly invasive and three less invasive non-indigenous species) that have been established in the U.S. for more than 75 years. The experiment involved providing non-U. S. location data to users familiar with one of the four evaluated techniques, who then developed predictive models that were applied to the United States without knowing the identity of the species or its U.S. distribution. We compared a simple GIS climate matching technique known as Proto3, a simple climate matching tool CLIMEX Match Climates, the correlative model MaxEnt, and a process model known as the Thornley Transport Resistance (TTR) model. Two experienced users ran each modeling tool except TTR, which had one user. Models were trained with global species distribution data excluding any U.S. data, and then were evaluated using the current known U.S. distribution. The influence of weed species identity and modeling tool on prevalence and sensitivity effects was compared using a generalized linear mixed model. Each modeling tool itself had a low statistical significance, while weed species alone accounted for 69.1 and 48.5% of the variance for prevalence and sensitivity, respectively. These results suggest that simple modeling tools might perform as well as complex ones in the case of predicting potential distribution for a weed not yet present in the United States. Considerations of model accuracy should also be balanced with those of reproducibility and ease of use. More important than the choice of modeling tool is the construction of robust protocols and testing both new and experienced users under blind test conditions that approximate operational conditions. 相似文献
984.
Isozyme Variation among Biological Species in the Gibberella fujikuroi Species Complex (Fusarium Section Liseola) 总被引:3,自引:0,他引:3
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Isozyme phenotypes were determined for 101 strains of Gibberella fujikuroi and 2 strains of Gibberella nygamai that represent seven biological species (mating populations) isolated from a variety of plant hosts in dispersed geographic locations. Fourteen enzymes were resolved in one or more of three buffer systems. Two of the enzymes, arylesterase and acid phosphatase, were polymorphic within two or more biological species and are suitable for intraspecific studies of population variation. Six enzymes, alcohol dehydrogenase, aspartate aminotransferase, glucose-6-phosphate dehydrogenase, mannitol dehydrogenase, phosphoglucomutase, and phosphogluconate dehydrogenase, were monomorphic in all of the isolates examined. The remaining six enzymes, fumarase, glucose phosphate isomerase, glutamate dehydrogenase (NADP), isocitrate dehydrogenase (NADP), malate dehydrogenase, and triose-phosphate isomerase, could potentially be used to distinguish the different biological species. Mating populations C and D are the most similar, since the mating population C isolates examined had the same isozyme phenotype as did a subset of the isolates in mating population D. Mating population E is the least similar to the other taxa examined. Unique isozyme phenotypes are present but are composed of banding patterns shared among the biological species. This finding supports the hypothesis that these biological species, with the possible exception of mating populations C and D, are reproductively isolated from one another and that no significant gene flow is occurring between them. Isozyme analysis is a useful method to distinguish these closely related biological species. Examination of isozyme phenotypes is more rapid than the present technique, which is based on sexual crosses; can be applied to strains that are not sexually fertile; and is more sensitive than traditional morphological characters, which cannot distinguish more than three or four morphological groups among the seven biological species. While emphasizing the discreteness of the mating populations as biological entities, our isozyme data also reaffirm the close genetic relationship among these groups. 相似文献
985.
Summary Evidence indicates that elongation factor-1 (EF-1), a ubiquitous and abundant protein factor involved in the first step of peptide elongation, is also associated with the cytoskeleton in a variety of organisms. Although the effects of these associations on EF-1's translational function have not been examined, the associations do appear to result in non-passive effects on the cytoskeleton. A carrot homolog of EF-1, pp 50, has been reported to interact with microtubules in vitro, inducing the formation of microtubule bundles that can be dissociated by Ca2+/calmodulin. The characterization of anti-pp 50 antibodies is reported here. Immunocytochemistry, using anti-pp 50 and anti-tubulin antibodies, was used to investigate the co-localization of pp 50 and microtubules in situ. In carrot protoplasts fixed after detergent lysis, at least a fraction of pp 50 appears to be associated with microtubules. Treatment of such protoplasts with amiprophos-methyl (APM) reduced both the presence of microtubules and the co-localizing pp 50-associated fluorescence. In taxol-treated protoplasts, increases in both microtubules and the colocalizing pp 50-associated fluorescence were observed. When carrot protoplasts were fixed prior to detergent extraction, confocal laser scanning microscopy likewise revealed co-localization. Furthermore, what is likely to be a fluorescence resonance energy transfer (FRET) between fluorochromes associated with anti-pp 50 and anti-tubulin reporters was observed, indicating that some pp 50 is intimately associated with microtubules. The in situ cytoarchitectural evidence is consistent with a function previously proposed for pp 50 based on in vitro experiments — that pp 50 is a plant microtubuleassociated protein (MAP) whose function can be modulated by a Ca2+/calmodulin signal transduction mechanism in plant cells.Abbreviations APM
amiprophos-methyl
- BSA
bovine serum albumin
- EF-1
elongation factor-1-alpha
- FRET
fluorescence resonance energy transfer
- MAP
microtubule-associated protein
- PBS
phosphate buffered saline
- SDS-PAGE
sodium dodecylsulfate polyacrylamide gel electrophoresis 相似文献
986.
987.
We have investigated the modulation of the intracellular calcium concentration ([Ca2+]i) in rat C6 glioma cells following their activation by the agonists 5-hydroxytryptamine·HCl (5-HT) and bradykinin, using single cell imaging of [Ca2+]i with the calcium-sensitive dye Fura-2. The majority of the signals observed involved release of calcium from intracellular stores, and after prolonged application of 5-HT, but not bradykinin, the cells exhibited oscillations in [Ca2+]i levels. These calcium oscillations were dependent on the presence of extracellular calcium, and were unaffected by the calcium channel antagonists nifedipine and verapamil. Caffeine, which in other cell types is able to release calcium from inositol trisphosphate-insentive stores, had very little effect on [Ca2+]i levels in C6 cells. On the other hand, bradykinin, although able to elevate [Ca2+]i probably by acting via the B2-receptor subtype, was unable to induce any calcium oscillations in these cells. 相似文献
988.
Leslie A. Carter §John K. Belknap ‡§John C. Crabbe †‡ Aaron Janowsky 《Journal of neurochemistry》1995,64(1):213-219
Abstract: The effects of ethanol, glycine, and spermidine on the specific binding of [3H]MK-801 were characterized in Triton-treated membranes prepared from the hippocampus and cortex of ethanol-withdrawal seizure-prone (WSP) and -resistant (WSR) mice. Glycine, an allosteric agonist at the NMDA receptor-linked ion channel complex, caused an increase in specific [3H]MK-801 binding to hippocampal membrane preparations. There were no significant differences in EC50 values between the selected lines for the effect of glycine (WSP, 391.7 ± 48.4 nM; WSR, 313.4 ± 77 nM) in the presence of 10 µM NMDA or in the maximal response to the agonist (WSP, 1.75 ± 0.26 pmol/mg of protein; WSR, 1.67 ± 0.22 pmol/mg of protein). The EC50 values for the spermidine-induced increase in [3H]MK-801 binding in membranes from hippocampus in the absence (WSP, 11.7 ± 0.83 µM; WSR, 9.98 ± 1.29 µM) or in the presence of 10 µM glycine and 10 µM NMDA (WSP, 2.1 ± 0.35 µM; WSR, 2.37 ± 0.42 µM) also did not differ. Similar results were obtained in cortical membranes. Saturation isotherms indicated that there was no difference in the density of [3H]MK-801 binding sites, or in their affinity for the radioligand, between the mouse lines. In addition, administration of ethanol by inhalation (24 h) to WSP and WSR mice did not cause an increase in the density of [3H]MK-801 binding sites, and there was no difference in the density or affinity of binding sites between the mouse lines. Withdrawal from ethanol (6 h), which causes an increase in the severity of handling-induced convulsions in WSP mice, also did not alter the binding site density or affinity for radioligand. The results suggest that the characteristics of the NMDA receptor-linked ion channel complex in the tissue preparations described here do not differ in WSP and WSR mice. Thus, genetic differences in seizure susceptibility during ethanol withdrawal can be dissociated from the total density of hippocampal or cortex NMDA receptors under activating conditions. 相似文献
989.
Cold-shock induction of a family of TIP1-related proteins associated with the membrane in Saccharomyces cerevisiae 总被引:3,自引:0,他引:3
TIP1 is the first known cold-shock-and heat-shock-induced gene in Saccharomyces cerevisiae. Here it is demonstrated that a TIP1 homologue, TIR1, which had been previously cloned as SRP1 (serine-rich protein), is strongly induced by a downshift in growth temperature from 30 to 10°C. We further cloned TIR2, which is transcribed at a low basal level but is increased strongly by cold shock and, to a lesser extent, by heat shock. The predicted protein sequence of TIR2 demonstrates remarkable homology to T1R1 (72.2%) and is also homologous with TIP1 (49%). TIP1, TIR1 and TIR2 are rich in both serine and alanine residues and each contains serine-rich tandem repeats. The proteins contain putative N-terminal signal peptides as well as hydro-phobic C-terminal sequences, indicating that the proteins may be membrane bound. The predicted protein sequences are also consistent with extensive O-mannosylation as well as glycosyl-phosphatidyl inositol (GPI) membrane anchoring. Cell fractionation analysis as well as studies using a yeast strain that is conditionally deficient in glycosylation demonstrate that TIP1 is a heavily modified membrane-associated protein. Single, double combinations and triple mutants were created and none demonstrated any obvious phenotype, indicating that this family of genes is not essential for normal growth. 相似文献
990.
Tail-flagging and other antipredator signals in white-tailed deer: new data and synthesis 总被引:3,自引:1,他引:2
We present a series of predictions concerning the costs andbenefits of antipredator behavior in ungulates and then testthem with data on white-tailed deer reacting to a human on foot.Costs of tail-flagging were apparently low and no data supportedthe idea that flagging serves as a warning signal to conspecifics,in either this or in other studies. Flagging deer fled at greaterspeeds than nonflaggers, indicating that flagging could possiblysignal prey's ability to escape. Dropping the tail at the endof the flight may additionally have made deer inconspicuous.Snorting did not appear directed at conspecifics, and comparativedata suggest that it signals that the predator has been detected.In contrast, foot-stamping was effective in alerting other deerto the observer's presence. Deer may have bounded to clear obstaclesalong their flight path. These preliminary data indicate thatseveral aspects of antipredator behavior in white-tailed deermay be pursuit-deterrent signals, and they therefore highlightthe necessity of observing natural predators' reactions to signalsgiven by deer in future studies. 相似文献