7,852 research outputs found

    A novel small molecule target in human airway smooth muscle for potential treatment of obstructive lung diseases: a staged high-throughput biophysical screening

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    <p>Abstract</p> <p>Background</p> <p>A newly identified mechanism of smooth muscle relaxation is the interaction between the small heat shock protein 20 (HSP20) and 14-3-3 proteins. Focusing upon this class of interactions, we describe here a novel drug target screening approach for treating airflow obstruction in asthma.</p> <p>Methods</p> <p>Using a high-throughput fluorescence polarization (FP) assay, we screened a library of compounds that could act as small molecule modulators of HSP20 signals. We then applied two quantitative, cell-based biophysical methods to assess the functional efficacy of these molecules and rank-ordered their abilities to relax isolated human airway smooth muscle (ASM). Scaling up to the level of an intact tissue, we confirmed in a concentration-responsive manner the potency of the cell-based hit compounds.</p> <p>Results</p> <p>Among 58,019 compound tested, 268 compounds caused 20% or more reduction of the polarized emission in the FP assay. A small subset of these primary screen hits, belonging to two scaffolds, caused relaxation of isolated ASM cell <it>in vitro </it>and attenuated active force development of intact tissue <it>ex vivo</it>.</p> <p>Conclusions</p> <p>This staged biophysical screening paradigm provides proof-of-principle for high-throughput and cost-effective discovery of new small molecule therapeutic agents for obstructive lung diseases.</p

    Levels of Major and Minor Elements in Some Commercial Fruit Juices Available in Serbia

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    Purpose: To evaluate the macro- and micro-nutrient elements of some commercially available fruit juices in Serbia.Methods: Inductively coupled plasma optical emission spectrometry (ICP-OES) technique was employed for determination of the major and minor elements in samples of two different types of fruit juices - clear and cloudy.Results: Among macro-nutrient elements, potassium (K) had the highest content of 230.17 μg/g in samples of multivitamine cloudy juice. The content of K was higher in cloudy fruit juices than in clear fruit juices. The content of iron, which is among the group of trace elements, ranged from 2.237 to 5.911 μg/g in clear juices and 3.55 to 10.05 μg/g in cloudy fruit juices. Other trace elements followed the descending order copper &gt; zinc &gt; nickel in terms of their content. The presence of aluminum and cadmium in the tested samples of fruit juices can be toxic since they have no nutritional value, and hence may be treated as potential contaminants in these beverages.Conclusion: All the tested juices had some nutritional value for human health and the juices could be use as an additional source of these elements. The content of aluminium and cadmium are below levels permitted by national regulations.Keywords: Elements, Fruit juice, Inductively-coupled plasma optical emission spectrometry

    Development and Application of Ligand-Exchange Reaction Method for the Determination of Clonazepam

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    Purpose: This paper presents an improved kinetic-spectrophotometric procedure for determining clonazepam (CZP) in pharmaceutical formulations and human serum.Methods: The method is based on ligand-exchange reaction. The reaction was followed spectrophotometrically by measuring the rate of change of absorbance at 425 nm in ethanolic sodium hydroxide solution.Results: The optimum operating conditions for reagent concentrations and temperature were established. Linear calibration curve was obtained in the range of 0.32 - 4.10 &mu;g mL-1. The optimized conditions yielded a theoretical detection limit of 0.24 &mu;g mL-1 based on the 3.3So criterion, where S0 is standard deviation of the calibration line. The interference of certain drugs, foreign ions and amino acids on the reaction rate were studied in order to assess the selectivity of the method.Conclusion: The developed method is sensitive, accurate and reproducible and could be used for routine anlysis of clonazepam in pharmaceutical preparations and serum samples.Keywords: Clonazepam, Ligand-exchange reaction, Kinetic spectrometry, Validation, Pharmaceutical preparation, Human seru

    The structure of the infinite models in integer programming

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    The infinite models in integer programming can be described as the convex hull of some points or as the intersection of halfspaces derived from valid functions. In this paper we study the relationships between these two descriptions. Our results have implications for corner polyhedra. One consequence is that nonnegative, continuous valid functions suffice to describe corner polyhedra (with or without rational data)

    Chaos in the Gauge/Gravity Correspondence

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    We study the motion of a string in the background of the Schwarzschild black hole in AdS_5 by applying the standard arsenal of dynamical systems. Our description of the phase space includes: the power spectrum, the largest Lyapunov exponent, Poincare sections and basins of attractions. We find convincing evidence that the motion is chaotic. We discuss the implications of some of the quantities associated with chaotic systems for aspects of the gauge/gravity correspondence. In particular, we suggest some potential relevance for the information loss paradox.Comment: 29 pages, 11 figure

    Loss of heterozygosity in multistage carcinogenesis of esophageal carcinoma at high-incidence area in Henan Province, China

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    Aim: Microsatellites are the repeated DNA sequences scattered widely within the genomes and closely linked with many important genes. This study was designed to characterize the changes of microsatellite DNA loss of heterozygosity (LOH) in esophageal carcinogenesis. Methods: Allelic deletions in 32 cases of matched precancerous, cancerous and normal tissues were examined by syringe microdissection under an anatomic microscope and microsatellite polymorphism analysis using 15 polymorphic markers on chromosomes 3p, 5q, 6p, 9p, 13q, 17p, 17q and 18q. Results: Microsatellite DNA LOH was observed in precancerous and cancerous tissues, except D9S1752. The rate of LOH increased remarkably with the lesions progressed from basal cell hyperplasia (BCH) to squamous cell carcinoma (SCC) (P60%). LOH loci were different in precancerous and cancerous tissues. LOH in D3S1234 and TP53 was the common event in different lesions from the same patients. Conclusion: Microsatellite DNA LOH occurs in early stage of human esophageal carcinogenesis, even in BCH. With the lesion progressed, gene instability increases, the accumulation of this change may be one of the important mechanisms driving precancerous lesions to cancer. © 2005 The WJG Press and Elsevier Inc. All rights reserved.published_or_final_versio

    Early-Time Energy Loss in a Strongly-Coupled SYM Plasma

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    We carry out an analytic study of the early-time motion of a quark in a strongly-coupled maximally-supersymmetric Yang-Mills plasma, using the AdS/CFT correspondence. Our approach extracts the first thermal effects as a small perturbation of the known quark dynamics in vacuum, using a double expansion that is valid for early times and for (moderately) ultrarelativistic quark velocities. The quark is found to lose energy at a rate that differs significantly from the previously derived stationary/late-time result: it scales like T^4 instead of T^2, and is associated with a friction coefficient that is not independent of the quark momentum. Under conditions representative of the quark-gluon plasma as obtained at RHIC, the early energy loss rate is a few times smaller than its late-time counterpart. Our analysis additionally leads to thermally-corrected expressions for the intrinsic energy and momentum of the quark, in which the previously discovered limiting velocity of the quark is found to appear naturally.Comment: 39 pages, no figures. v2: Minor corrections and clarifications. References added. Version to be published in JHE

    Defining an olfactory receptor function in airway smooth muscle cells

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    Pathways that control, or can be exploited to alter, the increase in airway smooth muscle (ASM) mass and cellular remodeling that occur in asthma are not well defined. Here we report the expression of odorant receptors (ORs) belonging to the superfamily of G-protein coupled receptors (GPCRs), as well as the canonical olfaction machinery (G olf and AC3) in the smooth muscle of human bronchi. In primary cultures of isolated human ASM, we identified mRNA expression for multiple ORs. Strikingly, OR51E2 was the most highly enriched OR transcript mapped to the human olfactome in lung-resident cells. In a heterologous expression system, OR51E2 trafficked readily to the cell surface and showed ligand selectivity and sensitivity to the short chain fatty acids (SCFAs) acetate and propionate. These endogenous metabolic byproducts of the gut microbiota slowed the rate of cytoskeletal remodeling, as well as the proliferation of human ASM cells. These cellular responses in vitro were found in ASM from non-asthmatics and asthmatics, and were absent in OR51E2-deleted primary human ASM. These results demonstrate a novel chemo-mechanical signaling network in the ASM and serve as a proof-of-concept that a specific receptor of the gut-lung axis can be targeted to treat airflow obstruction in asthma.open0
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