60 research outputs found
METAPHOR IN CREATING FEMALE IMAGES (BASED ON AMERICAN SONG FOLKLORE)
No full textThe article describes the use of metaphor in creating female images in American folk songs. The purpose of the author is to investigate how metaphor intensifies female image, which function in the text. Considering the fact that American folk songs are rich in stylistic devices, metaphor proves to be one of the best to evoke feelings and convey emotions in connection to the relevant image. It also appears to be a powerful interpretation means forming the background of the female image. The research results demonstrate that specific negative historical background can stimulate appearance of new metaphors especially in times of political crisis.The article describes the use of metaphor in creating female images in American folk songs. The purpose of the author is to investigate how metaphor intensifies female image, which function in the text. Considering the fact that American folk songs are rich in stylistic devices, metaphor proves to be one of the best to evoke feelings and convey emotions in connection to the relevant image. It also appears to be a powerful interpretation means forming the background of the female image. The research results demonstrate that specific negative historical background can stimulate appearance of new metaphors especially in times of political crisis
Efficient Solution-Phase Synthesis of 4,5,7-Trisubstituted Pyrrolo[3,2- d ]pyrimidines
No full textWe have developed an efficient and robust route to synthesize 4,5,7-trisubstituted pyrrolo[3,2-d]pyrimidines as potent kinase inhibitors. This solution-phase synthesis features a SNAr substitution reaction, cross-coupling reaction, one-pot reduction/reductive amination and N-alkylation reaction. These reactions occur rapidly with high yields and have broad substrate scopes. A variety of groups can be selectively introduced into the N5 and C7 positions of 4,5,7-trisubstituted pyrrolopyrimidines at a late stage of the synthesis, thereby providing a highly efficient approach to explore the structure-activity relationships of pyrrolopyrimidine derivatives. Four synthetic analogs have been profiled against a panel of 48 kinases and a new and selective FLT3 inhibitor 9 is identified
ФАКТОР РИНКОВИХ СИГНАЛІВ ДО ПІДВИЩЕННЯ ЯКОСТІ ПРОДУКЦІЇ В УКРАЇНІ
No full textThere had been conducted analysis in the present paper of problems of poor quality of domestic products in the of example grain production. It is substantiated profitableness of production with higher quality if the market conditions arerelevant. From this position dysfunctionsof modern Ukrainian grain market prospects for its regulationare outlined. The hypothesis of these studies was based on the assumption that in the basis of problem of poor quality of Ukrainian product is dysfunctional aspects of imperfect competitive environment, which was formed in the domestic market model. The objective of paper, accordingly, is to review the mentioned thesis on the example of domestic grain production. General of the above mentioned it can be conclusion that on the real grain market relationbetween quality and price has a completely different character than in the experimental conditions and determined by situational relationship between supply and demand. The main problem of low quality of domestic agricultural products are dysfunctional role of certain aspects of the market and market relations in Ukraine, where the effect gaining more social and economic importance in provocation of poor quality products due to lack of buyers requirements to its highest level. Hence, the solution to the problem of poor quality Ukrainian grain is also troubled field of complex optimization economic relations in agriculture, where the first actualized possibility of increasing the value added by processing and subsequent movement better grain products and further movement grainproductionsubcomplex. Obviously, in this chain formed the most effective incentives to increase the supply of grain quality. In view of the above it should be emphasized apparent ambiguity and lack of information about the actual state of the grain, as shown and author of the study. In Ukraine, the main buyers of grain traditionally harvesting of grain trading and processing enterprises, but grain quality indicators in these subjects over substantially different. Thus, the data suggest harvesting enterprises sentence structure products, while traders - reflect the demand of customers, mostly foreign. Thus, these traders primarily reflect the situation lack of demand for top quality grain as such, even if the country is also produced. These aspects can determine the nature of the so-called factor opportunistic behavior as a major potential causes by disfunctionalitymarket.У статті здійснено аналізування проблем низької якості вітчизняної продукції на прикладі виробництва зерна. Обґрунтовано вигідність виробництва продукції більш високої якості за умов наявності відповідних ринкових умов. Гіпотеза досліджень будувалася на припущенні про те, що в основі проблеми низької якості української продукції полягає дисфункціональні аспекти недосконалого конкурентного середовища, яке сформувалося у вітчизняній моделі ринку. З цієї позиції окреслено дисфункції сучасного українського ринку зерна та перспективи його регулювання
Efficient Solution-Phase Synthesis of 4,5,7-Trisubstituted Pyrrolo[3,2‑<i>d</i>]pyrimidines
No full textWe have developed an efficient and robust route to synthesize
4,5,7-trisubstituted
pyrrolo[3,2-d]pyrimidines as potent kinase inhibitors.
This solution-phase synthesis features a SNAr substitution
reaction, cross-coupling reaction, one-pot reduction/reductive amination
and N-alkylation reaction. These reactions occur
rapidly with high yields and have broad substrate scopes. A variety
of groups can be selectively introduced into the N5 and C7 positions
of 4,5,7-trisubstituted pyrrolopyrimidines at a late stage of the
synthesis, thereby providing a highly efficient approach to explore
the structure–activity relationships of pyrrolopyrimidine derivatives.
Four synthetic analogs have been profiled against a panel of 48 kinases
and a new and selective FLT3 inhibitor 9 is identified
Development of a High-Throughput Screening Assay to Identify Inhibitors of the Lipid Kinase PIP5K1C
No full textPhosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) regulate a variety of cellular processes including signaling through G protein-coupled receptors (GPCRs), endocytosis, exocytosis, and cell migration. These lipid kinases synthesize phosphatidylinositol 4,5-bisphosphate (PIP2) from phosphatidylinositol 4-phosphate [PI(4)P]. Since small molecule inhibitors of these lipid kinases did not exist, molecular and genetic approaches were predominantly used to study PIP5K1 regulation of these cellular processes. Moreover, standard radioisotope-based lipid kinase assays cannot be easily adapted for high-throughput screening. Here, we report a novel high-throughput microfluidic mobility shift assay to identify inhibitors of PIP5K1C. This assay utilizes fluorescently labeled phosphatidylinositol 4-phosphate as the substrate and recombinant human PIP5K1C. Our assay exhibited high reproducibility, had a calculated ATP Km of 15 µM, performed with z’ values >0.7, and was used to screen a kinase-focused library of ~4,700 compounds. From this screen, we identified several potent inhibitors of PIP5K1C, including UNC3230, a compound that we recently found can reduce nociceptive sensitization in animal models of chronic pain. This novel assay will allow continued drug discovery efforts for PIP5K1C and can be easily adapted to screen additional lipid kinases
Cholecystokinin (CCK) antagonists: (R)-tryptophan-based hybrid antagonists of high affinity and selectivity for CCK-A receptors
No full textRetraction: A High-Throughput Screening-Compatible Strategy for the Identification of Inositol Pyrophosphate Kinase Inhibitors.
No full textPharmacological tools-'chemical probes'-that intervene in cell signaling cascades are important for complementing genetically-based experimental approaches. Probe development frequently begins with a high-throughput screen (HTS) of a chemical library. Herein, we describe the design, validation, and implementation of the first HTS-compatible strategy against any inositol phosphate kinase. Our target enzyme, PPIP5K, synthesizes 'high-energy' inositol pyrophosphates (PP-InsPs), which regulate cell function at the interface between cellular energy metabolism and signal transduction. We optimized a time-resolved, fluorescence resonance energy transfer ADP-assay to record PPIP5K-catalyzed, ATP-driven phosphorylation of 5-InsP7 to 1,5-InsP8 in 384-well format (Z' = 0.82 ± 0.06). We screened a library of 4745 compounds, all anticipated to be membrane-permeant, which are known-or conjectured based on their structures-to target the nucleotide binding site of protein kinases. At a screening concentration of 13 μM, fifteen compounds inhibited PPIP5K >50%. The potency of nine of these hits was confirmed by dose-response analyses. Three of these molecules were selected from different structural clusters for analysis of binding to PPIP5K, using isothermal calorimetry. Acceptable thermograms were obtained for two compounds, UNC10112646 (Kd = 7.30 ± 0.03 μM) and UNC10225498 (Kd = 1.37 ± 0.03 μM). These Kd values lie within the 1-10 μM range generally recognized as suitable for further probe development. In silico docking data rationalizes the difference in affinities. HPLC analysis confirmed that UNC10225498 and UNC10112646 directly inhibit PPIP5K-catalyzed phosphorylation of 5-InsP7 to 1,5-InsP8; kinetic experiments showed inhibition to be competitive with ATP. No other biological activity has previously been ascribed to either UNC10225498 or UNC10112646; moreover, at 10 μM, neither compound inhibits IP6K2, a structurally-unrelated PP-InsP kinase. Our screening strategy may be generally applicable to inhibitor discovery campaigns for other inositol phosphate kinases
CAPN2: A Target Enabling Package
No full textCAPN2 mediates neurodegenerative effect through cleavage of a range of proteins linked to tau hyperphosphorylation (GSK-3β), higher levels of Aβ (NCX3), or poor memory (CPEB3). Inhibiting calpain-2 might reduce cleavage of these proteins and reverse its neurodegenerative effect. This aim of this TEP is to produce reagents to allow for further analysis of CAPN2 as a potential target for AD treatment.This document is version 1 of the CAPN2 TEP
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