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Jie Li Stephen C. Pak Linda P. O’Reilly Joshua A. Benson Yan Wang Tunda Hidvegi Pamela Hale Christine Dippold Michael Ewing Gary A. Silverman David H. Perlmutter 《PloS one》2014,9(1)
The classical form of α1-antitrypsin deficiency (ATD) is associated with hepatic fibrosis and hepatocellular carcinoma. It is caused by the proteotoxic effect of a mutant secretory protein that aberrantly accumulates in the endoplasmic reticulum of liver cells. Recently we developed a model of this deficiency in C. Elegans and adapted it for high-content drug screening using an automated, image-based array scanning. Screening of the Library of Pharmacologically Active Compounds identified fluphenazine (Flu) among several other compounds as a drug which reduced intracellular accumulation of mutant α1-antitrypsin Z (ATZ). Because it is representative of the phenothiazine drug class that appears to have autophagy enhancer properties in addition to mood stabilizing activity, and can be relatively easily re-purposed, we further investigated its effects on mutant ATZ. The results indicate that Flu reverses the phenotypic effects of ATZ accumulation in the C. elegans model of ATD at doses which increase the number of autophagosomes in vivo. Furthermore, in nanomolar concentrations, Flu enhances the rate of intracellular degradation of ATZ and reduces the cellular ATZ load in mammalian cell line models. In the PiZ mouse model Flu reduces the accumulation of ATZ in the liver and mediates a decrease in hepatic fibrosis. These results show that Flu can reduce the proteotoxicity of ATZ accumulation in vivo and, because it has been used safely in humans, this drug can be moved rapidly into trials for liver disease due to ATD. The results also provide further validation for drug discovery using C. elegans models that can be adapted to high-content drug screening platforms and used together with mammalian cell line and animal models. 相似文献
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The influence of ungulate grazers on nutrient cycling and ecosystem productivity in grasslands has been shown to differ with moisture, nutrient availability, and feedbacks between above- and belowground activities. We examined the movement of nitrogen (N), applied as (15NH4)2SO4, through both dry and mesic sites in the northern range of Yellowstone National Park to test the hypothesis that plants were more able to acquire added N in grazed relative to ungrazed sites. Previous studies showed enhanced N mineralization in grazed areas, and detritus removal by grazers was predicted to enhance early-season plant growth. Thirteen months after tracer addition, there were no differences in plant 15N as a function of grazing, but historically ungrazed sites retained more 15N in accumulated litter than at grazed sites. This result demonstrated the importance of detritus in regulating redistribution of incoming N and the role of grazers in this process. Site moisture status influenced 15N recovery in all pools—soils, microbial biomass, and plants—and greater plant 15N acquisition occurred in roots at dry relative to mesic sites. Understanding how grazers influence nutrient cycling at the landscape scale requires further investigation of interactions among soil moisture, plant production, litter accumulation, grazing intensity, and belowground processes. 相似文献
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H. Ait sir D. F. Ewing N. Fahmi G. Goethals G. Mackenzie G. Ronco 《Nucleosides, nucleotides & nucleic acids》2013,32(3-5):359-362
Abstract 1-O-Acetyl-3,5-di-O-benzoyl-2-deoxy-4-thio-α,β-D-ribofuranose and its 3-azido analogue have been prepared by an efficient route starting from L-arabinose. A key intermediate in this route is 2-deoxy-4,5-O-isopropylidene-L-erythro-pentose dibenzyl dithioacetal which is readily substituted in the 3-position thus offering extensive scope for the synthesis of 3-substituted 2-deoxy-4-thio-α,β-D-ribofuranoses and subsequent nucleoside derivatives. 相似文献
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Ross HA Lento GM Dalebout ML Goode M Ewing G McLaren P Rodrigo AG Lavery S Baker CS 《The Journal of heredity》2003,94(2):111-114
DNA Surveillance is a Web-based application that assists in the identification of the species and population of unknown specimens by aligning user-submitted DNA sequences with a validated and curated data set of reference sequences. Phylogenetic analyses are performed and results are returned in tree and table format summarizing the evolutionary distances between the query and reference sequences. DNA Surveillance is implemented with mitochondrial DNA (mtDNA) control region sequences representing the majority of recognized cetacean species. Extensions of the system to include other gene loci and taxa are planned. The service, including instructions and sample data, is available at http://www.dna-surveillance.auckland.ac.nz. 相似文献
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Improved purification of potato tuber invertase was achieved by utilizing a form of affinity chromatography between the enzyme and Concanavalin A (Con A) bound to Sepharose. Twenty-fold increases in specific activity were routinely obtained with this step and the enzyme was purified 190-fold over that found in the crude homogenate. The Con A-Sepharose chromatography step gave a greater purification than any other step in the invertase isolation procedure. There was up to 170% recovery of the activity loaded onto the column. α-Methyl-d-mannoside, sucrose, d-glucose and d-fructose eluted the enzyme from the Con A-Sepharose column with similar recoveries, although the volume of eluent required varied with the sugar. This unusually high recovery of invertase activity was obtained with some batches of tubers but not with others. There was evidence to suggest that the high recovery, or activation, may be due to the release of an inhibitor from the enzyme in the presence of Con A-Sepharose. Adsorption of invertase to Con A-Sepharose could be eliminated by incubation of the enzyme with α-mannosidase and β-glucosidase, indicating that potato tuber invertase is a glycoprotein. Proteinaceous inhibitor purification was improved by treatment of the tuber extract at low pH. 相似文献
68.
Superoxide removal and radiation protection in bacteria 总被引:4,自引:0,他引:4
Previous work with procaryotic cells has identified one kind of lethal damage from ionizing radiation which occurs only within a specific range of low O2 concentrations, about 10(-6) to 10(-4) M. Within this range, protection can occur in three ways: through the enzymatic decomposition of hydrogen peroxide (H2O2) by added catalase, through the enzymatic degradation of superoxide anion radicals (.O2-) by added superoxide dismutase (SOD), and through scavenging hydroxyl radicals (.OH) by various additives. These results indicate that three radiolytic products, H2O2, .OH, and .O2- (and/or the conjugate acid, the perhydroxyl radical, .HO2) are involved in this single kind of radiation-induced damage. Although the radiolytic productions of H2O2 and .O2- are strongly enhanced in higher O2 concentrations, neither enzyme protects when these air-equilibrated bacteria are irradiated. These experiments address this apparent contradiction and focus on the specific issue of why the addition of SOD protects at low but not at high O2 concentrations. We propose that, at a given O2 concentration, .O2- (and/or .HO2) may either react (with some cellular component?) to cause damage or react (with itself) to form hydrogen peroxide (H2O2). The specific O2 concentration during irradiation would determine the relative rates of these competing reactions and therefore the O2 concentration itself would establish whether or not we will observe damage from .O2-. 相似文献
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Protective efficacy of IgM monoclonal antibodies in experimental group B streptococcal infection is a function of antibody avidity 总被引:6,自引:0,他引:6
S H Pincus A O Shigeoka A A Moe L P Ewing H R Hill 《Journal of immunology (Baltimore, Md. : 1950)》1988,140(8):2779-2785
We have produced and characterized six mAb directed against group B streptococci (GBS). All antibodies are IgM. We have previously shown that some of these antibodies are highly protective in the treatment of experimental infections in neonatal rats, whereas others do not appear to have any protective efficacy. Using an ELISA, we demonstrate the specificity of both protective and nonprotective antibodies. Two antibodies, binding different epitopes, are directed against antigenic structures present on all GBS; two are specific for type III carbohydrate determinants; one binds to a protein Ag present on all type I and II GBS; and one appears to bind to type Ia GBS only. Quantitative absorption assays provide evidence that the difference between protective antibodies and nonprotective antibodies is the avidity that the antibody demonstrates for the epitope recognized on the surface of the bacteria; 10 to 15 times as much protective antibody binds to GBS as does nonprotective antibody. Direct binding experiments with radiolabeled antibody confirm this conclusion. 相似文献