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151.
Javier de Vicente Robert T. Hendricks David B. Smith Jay B. Fell John Fischer Stacey R. Spencer Peter J. Stengel Peter Mohr John E. Robinson James F. Blake Ramona K. Hilgenkamp Calvin Yee George Adjabeng Todd R. Elworthy Jahari Tracy Elbert Chin Jim Li Beihan Wang Joe T. Bamberg Rebecca Stephenson Brian Xu 《Bioorganic & medicinal chemistry letters》2009,19(13):3642-3646
A new series of benzothiazine-substituted quinolinediones were evaluated as inhibitors of HCV polymerase NS5B. SAR studies on this series revealed a methyl sulfonamide group as a high affinity feature. Analogues with this group showed submicromolar potencies in the HCV cell based replicon assay. Pharmacokinetic and toxicology studies were also performed on a selected compound (34) to evaluate in vivo properties of this new class of inhibitors of HCV NS5B polymerase. 相似文献
152.
Calmodulin (CaM) binds to a domain near the C-terminus of the plasma membrane Ca2+-ATPase (PMCA), causing the release of this domain and relief of its autoinhibitory function. We investigated the kinetics of dissociation and binding of Ca2+-CaM with a 28-residue peptide [C28W(1b)] corresponding to the CaM-binding domain of isoform 1b of PMCA. CaM was labeled with a fluorescent probe on either the N-terminal domain at residue 34 or the C-terminal domain at residue 110. Formation of complexes of CaM with C28W(1b) results in a decrease in the fluorescence yield of the fluorophore, allowing the kinetics of dissociation or binding to be detected. Using a maximum entropy method, we determined the minimum number and magnitudes of rate constants required to fit the data. Comparison of the fluorescence changes for CaM labeled on the C-terminal or N-terminal domain suggests sequential and ordered binding of the C-terminal and N-terminal domains of CaM with C28W(1b). For dissociation of C28W(1b) from CaM labeled on the N-terminal domain, we observed three time constants, indicating the presence of two intermediate states in the dissociation pathway. However, for CaM labeled on the C-terminal domain, we observed only two time constants, suggesting that the fluorescence label on the C-terminal domain was not sensitive to one of the kinetic steps. The results were modeled by a kinetic mechanism in which an initial complex forms upon binding of the C-terminal domain of CaM to C28W(1b), followed by binding of the N-terminal domain, and then formation of a tight binding complex. Oxidation of methionine residues in CaM resulted in significant perturbations to the binding kinetics. The rate of formation of a tight binding complex was reduced, consistent with the poorer effectiveness of oxidized CaM in activating the Ca2+ pump. 相似文献
153.
Theresa M. Thieme Ramona Steri Ewgenij Proschak Alexander Paulke Gisbert Schneider Manfred Schubert-Zsilavecz 《Bioorganic & medicinal chemistry letters》2010,20(8):2469-2473
Peroxisome proliferator-activated receptor γ (PPARγ) is involved in glucose and lipid homeostasis. PPARγ agonists are in clinical use for the treatment of type 2 diabetes. Lately, a new class of selective PPARγ modulators (SPPARγMs) was developed, which are believed to show less side effects than full PPARγ agonists. We have previously shown that α-substitution of pirinixic acid, a moderate agonist of PPARα and PPARγ, leads to low micromolar active balanced dual agonists of PPARα and PPARγ. Herein we present modifications of pirinixic acid leading to subtype-selective PPARγ agonists and furthermore the development of a selective PPARγ modulator guided by molecular docking studies. 相似文献
154.
Thieme R Rakosy-Tican E Gavrilenko T Antonova O Schubert J Nachtigall M Heimbach U Thieme T 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2008,116(5):691-700
Solanum tarnii, a wild diploid, tuber-bearing Mexican species belonging to the series Pinnatisecta is highly resistant to Potato virus Y (PVY) and Colorado potato beetle and shows a strong hypersensitive reaction to Phytophthora infestans. Therefore, it could be a potential source of resistance to pathogens for potato breeders. S. tarnii (2n = 2x = 24) is reproductively isolated from tetraploid Solanum tuberosum and hence difficult to include in potato breeding programmes. In this study, interspecific somatic hybrids were produced
for the first time by protoplast electrofusion of the cells of potato cv. Delikat (Solanum tuberosum L.) and Solanum tarnii. The hybrid nature of the regenerants was confirmed by simple sequence repeat (SSR) and amplified fragment length polymorphism
(AFLP) markers and by morphological analysis and flow cytometry. Selected somatic hybrids were successfully backcrossed with
cv. Delikat. Parental lines, primary somatic hybrids and BC1 progeny were assessed for resistance to PVY by mechanical inoculation, grafting and exposure to viruliferous aphid vectors
in the field, and resistance to late blight (P. infestans) by detached leaflet and whole tuber tests. The somatic hybrids showed no symptoms of viral infection and most of them displayed
high levels of resistance to foliage blight. The BC1 progenies were highly resistant to PVY and a few were resistant to foliage blight. Selected hybrids and BC1 clones were evaluated in the field for tuber quality and tuber yield. Some BC1 clones produced yields of good quality tubers. The results confirm that both the resistance to PVY and to late blight of
S. tarnii is expressed in somatic hybrids, and PVY resistance is transferred to BC1 progeny, whereas blight resistance is harder to transfer. Somatic hybridization again proved to be a valuable tool for producing
pre-breeding material with increased genetic diversity. 相似文献
155.
Patterson J Vineyard D Thomas-Wohlever J Behshad R Burke M Lee I 《Biochemistry》2004,43(23):7432-7442
Escherichia coli Lon, also known as protease La, is a serine protease that is activated by ATP and other purine or pyrimidine triphosphates. In this study, we examined the catalytic efficiency of peptide cleavage as well as intrinsic and peptide-stimulated nucleotide hydrolysis in the presence of hydrolyzable nucleoside triphosphates ATP, CTP, UTP, and GTP. We observed that the k(cat) of peptide cleavage decreases with the reduction in the nucleotide binding affinity of Lon in the following order: ATP > CTP > GTP approximately UTP. Compared to those of the other hydrolyzable nucleotide triphosphates, the ATPase activity of Lon is also the most sensitive to peptide stimulation. Collectively, our kinetic as well as tryptic digestion data suggest that both nucleotide binding and hydrolysis contribute to the peptidase turnover of Lon. The kinetic data that were obtained were further put into the context of the structural organization of Lon protease by probing the conformational change in Lon bound to the different nucleotides. Both adenine-containing nucleotides and CTP protect a 67 kDa fragment of Lon from tryptic digestion. Since this 67 kDa fragment contains the ATP binding pocket (also known as the alpha/beta domain), the substrate sensor and discriminatory (SSD) domain (also known as the alpha-helical domain), and the protease domain of Lon, we propose that the binding of ATP induces a conformational change in Lon that facilitates the coupling of nucleotide hydrolysis with peptide substrate delivery to the peptidase active site. 相似文献
156.
Patrizzia Mastromatteo-Alberga Fabiola Placeres-Uray Marcelo A. Alfonzo-González Ramona Gonzalez de Alfonzo Itala Lippo de Becemberg 《Journal of receptor and signal transduction research》2016,36(3):278-287
Muscarinic antagonists, via muscarinic receptors increase the cAMP/cGMP levels at bovine tracheal smooth muscle (BTSM) through the inhibition of phosphodiesterases (PDEs), displaying a similar behavior of vinpocetine (a specific-PDE1 inhibitor). The presence of PDE1 hydrolyzing both cyclic nucleotides in BTSM strips was revealed. Moreover, a vinpocetine and muscarinic antagonists inhibited PDE1 located at plasma membranes (PM) fractions from BTSM showing such inhibition, an M2AChR pharmacological profile. Therefore, a novel Ca2+/CaM dependent and vinpocetine inhibited PDE1 was purified and characterized at PM fractions from BTSM. This PDE1 activity was removed from PM fractions using a hypotonic buffer and purified some 38 fold using two columns (Q-Sepharose and CaM-agarose). This PDE1 was stimulated by CaM and inhibited by vinpocetine showing two bands in PAGE-SDS (56, 58?kDa) being the 58?kDa identified as PDE1A by Western blotts. This PDE1A activity was assayed with [3H]cGMP and [3H]cAMP exhibiting a higher affinity as Km (μM) for cGMP than cAMP but being close values with Vmax cAMP/cGMP ratio of 1.5. The co-factor Mg2+ showed similar K(A) (mM) for both cyclic nucleotides. Vinpocetine showed similar inhibition concentration 50% (IC50 of 4.9 and 4.6?μM) for cAMP and cGMP, respectively. CaM stimulated the cyclic nucleotides hydrolysis by PDE1A exhibiting similar activation constant as K(CaM), in nM range. The original finding was the identification and purification of a vinpocetine and muscarinic antagonist-inhibited and CaM-activated PM-bound PDE1A, linked to M2AChR. A model of this novel signal transducing cascade for the regulation of cyclic nucleotides levels at BTSM is proposed. 相似文献
157.
Sara Borin Stefano Ventura Fulvia Tambone Francesca Mapelli Florence Schubotz Lorenzo Brusetti Barbara Scaglia Luigi P. D'Acqui Bjørn Solheim Silvia Turicchia Ramona Marasco Kai‐Uwe Hinrichs Franco Baldi Fabrizio Adani Daniele Daffonchio 《Environmental microbiology》2010,12(2):293-303
During primary colonization of rock substrates by plants, mineral weathering is strongly accelerated under plant roots, but little is known on how it affects soil ecosystem development before plant establishment. Here we show that rock mineral weathering mediated by chemolithoautotrophic bacteria is associated to plant community formation in sites recently released by permanent glacier ice cover in the Midtre Lovénbreen glacier moraine (78°53′N), Svalbard. Increased soil fertility fosters growth of prokaryotes and plants at the boundary between sites of intense bacterial mediated chemolithotrophic iron‐sulfur oxidation and pH decrease, and the common moraine substrate where carbon and nitrogen are fixed by cyanobacteria. Microbial iron oxidizing activity determines acidity and corresponding fertility gradients, where water retention, cation exchange capacity and nutrient availability are increased. This fertilization is enabled by abundant mineral nutrients and reduced forms of iron and sulfur in pyrite minerals within a conglomerate type of moraine rock. Such an interaction between microorganisms and moraine minerals determines a peculiar, not yet described model for soil genesis and plant ecosystem formation with potential past and present analogues in other harsh environments with similar geochemical settings. 相似文献
158.
Ramona A. Cole William A. Haber William N. Setzer 《Biochemical Systematics and Ecology》2007,35(12):877-886
The leaf essential oils of seven species of Eugenia from Monteverde, Costa Rica (Eugenia austin-smithii, Eugenia cartagensis, Eugenia haberi, Eugenia monteverdensis, Eugenia zuchowskiae, Eugenia sp. A aff. haberi, and Eugenia sp. B aff. oerstediana) have been obtained by hydrodistillation and analyzed by GC–MS. The seven species were compared to determine the similarities and differences among their volatile chemical compositions. The major component in each of the seven species was as follows: E. austin-smithii and E. cartagensis was trans-2-hexenal, E. haberi and E. zuchowskiae was -pinene, E. monteverdensis was linalool, Eugenia sp. A was zingiberene, and Eugenia sp. B was 1,8-cineole. The following six components were present in all seven species: -copaene, β-caryophyllene, -humulene, δ-cadinene, trans-nerolidol, and torreyol. The complex array and differing abundances of these compounds among the Eugenia species studied suggest that they may provide useful characters in understanding the phylogenetic relationships among closely related species. 相似文献
159.
160.
Dr. Fary M. Cachelin Ramona M. Rebeck Grace H. Chung Elizabeth Pelayo 《Obesity (Silver Spring, Md.)》2002,10(3):158-166
Objective: Obesity is most common in the United States among women of ethnic minority groups (black and Hispanic). Researchers have hypothesized that these subcultures are more accepting of overweight figures. The purpose of this study was to examine body image and body size assessments in a large community sample of men and women. Research Methods and Procedures: Participants were 801 women and 428 men: 23% Asian, 45% Hispanic, 17% black, and 15% white. The figure rating scale was used to rate: body dissatisfaction, attractive male and female shapes, acceptable female size, and perceptions of underweight to obese female figures. Results: Controlling for age, education, and body weight, no ethnic differences were found for men. Asian women reported less body dissatisfaction than the other groups. Women were more dissatisfied with their size than men and chose thinner female figures as attractive and acceptable. Discussion: Ethnicity, independent of age, education, and body weight, does not influence preference for female and male shapes or tolerance for obesity. 相似文献