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Nina Boiko Volodymyr Kucher Benjamin A. Eaton James D. Stockand 《The Journal of biological chemistry》2013,288(13):9418-9427
The voltage-gated K+ (Kv) channel blocker 4-aminopyridine (4-AP) is used to target symptoms of the neuroinflammatory disease multiple sclerosis (MS). By blocking Kv channels, 4-AP facilitates action potential conduction and neurotransmitter release in presynaptic neurons, lessening the effects of demyelination. Because they conduct inward Na+ and Ca2+ currents that contribute to axonal degeneration in response to inflammatory conditions, acid-sensing ion channels (ASICs) contribute to the pathology of MS. Consequently, ASICs are emerging as disease-modifying targets in MS. Surprisingly, as first demonstrated here, 4-AP inhibits neuronal degenerin/epithelial Na+ (Deg/ENaC) channels, including ASIC and BLINaC. This effect is specific for 4-AP compared with its heterocyclic base, pyridine, and the related derivative, 4-methylpyridine; and akin to the actions of 4-AP on the structurally unrelated Kv channels, dose- and voltage-dependent. 4-AP has differential actions on distinct ASICs, strongly inhibiting ASIC1a channels expressed in central neurons but being without effect on ASIC3, which is enriched in peripheral sensory neurons. The voltage dependence of the 4-AP block and the single binding site for this inhibitor are consistent with 4-AP binding in the pore of Deg/ENaC channels as it does Kv channels, suggesting a similar mechanism of inhibition in these two classes of channels. These findings argue that effects on both Kv and Deg/ENaC channels should be considered when evaluating the actions of 4-AP. Importantly, the current results are consistent with 4-AP influencing the symptoms of MS as well as the course of the disease because of inhibitory actions on Kv and ASIC channels, respectively. 相似文献
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Richard Swartz Loyd West Iouri Boiko Anais Malpica Calum MacAulay Anita Carraro Martial Guillaud Dennis Cox Michele Follen 《Analytical cellular pathology》2003,25(4):193-200
This is a methodological study exploring the use of quantitative histopathology applied to the cervix to discriminate between normal and cancerous (consisting of adenocarcinoma and adenocarcinoma in situ) tissue samples. The goal is classifying tissue samples, which are populations of cells, from measurements on the cells. Our method uses one particular feature, the IODs-Index, to create a tissue level feature. The specific goal of this study is to find a threshold for the IODs-Index that is used to create the tissue level feature. The main statistical tool is Receiver Operating Characteristic (ROC) curve analysis. When applied to the data, our method achieved promising results with good estimated sensitivity and specificity for our data set. The optimal threshold for the IODs-Index was found to be 2.12. 相似文献
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Construction of a fusion protein carrying antigenic determinants of enteric clostridial toxins 总被引:1,自引:0,他引:1
Clostridium difficile and Clostridium perfringens type A are infectious agents of enteric diseases. The main virulence factors of these microorganisms include toxins A and B of C. difficile (ToxA and ToxB) and enterotoxin of C. perfringens (Cpe). In this study genetic constructions have been created for the expression of ToxA, ToxB and Cpe fragments either as individual components or as a hybrid multidomain (ToxA-ToxB-Cpe) protein. Rabbit monospecific sera raised against individual peptides reacted with the chimeric product indicating that the corresponding antigenic determinants were correctly expressed on the hybrid molecule. Furthermore, mice immunized with the fusion protein produced antibodies specific to each of the three separate components. These data suggest that the constructed three-domain molecule could be used in future studies for development of a vaccine against enteric clostridial diseases. 相似文献
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Rostyslav R. Panchuk Natalia M. Boiko Maxim D. Lootsik Rostyslav S. Stoika 《Central European Journal of Biology》2007,2(1):71-86
The main goal of this study was to evaluate if specific cytokine expression in the NK/Ly lymphoma cells might be involved
in development of intoxication in the tumor-bearing animals. RT-PCR analysis was used to study an expression of mRNA coding
for IL-1α, IL-6, TNF-α, TNF-β and VEGF. ELISA was used to evaluate IL-6 and IFN-γ concentration in the ascitic fluid. Cytomorphological investigation of tumor cells was done after standard Romanovsky-Giemsa
staining, and chromatin staining was performed with hematoxyline and neutral red. Lactate dehydrogenase and acid phosphatase
release from tumor cells was estimated. It was revealed that the level of mRNA coding for VEGF and IL-6 was significant in
the lymphoma cells. The level of VEGF mRNA was initially high and did not change during tumor progression, while the level
of expression of IL6 mRNA was low at the initial stages of tumor growth and markedly increased (up to 5-fold) at the terminal
stages. The obtained data on IL-6 mRNA expression were confirmed by ELISA, which showed more than 6-fold increase (from 90
to 570 pg/ml) in the IL-6 concentration in the ascitic fluid at late stages of NK/Ly tumor development. On the contrary to
IL-6, concentration of IFN-γ in the ascitic fluid was very high at early stages of tumor development (1,000 pg/ml) and it markedly decreased (up to 30-fold,
30 pg/ml) at the terminal stages of tumor development. The high levels of IL-6 mRNA in tumor cells and IL-6 content in extracellular
medium correlated with cell deterioration, as revealed by cytomorphologic study and the release of intracellular enzymes into
extracellular medium. We suggest that an enhanced production and release of IL-6 by lymphoma cells can cause intoxication
and exhaustion of the organism observed at terminal stages of tumor growth. 相似文献
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V. A. Tarasov M. A. Makhotkin E. F. Shin N. V. Boiko M. G. Tyutyakina I. E. Chikunov A. V. Naboka A. N. Mashkarina A. A. Kirpii D. G. Matishov 《Doklady. Biochemistry and biophysics》2016,467(1):99-101
It was first shown that DNA damage induction in mitomycin C-treated HeLa cells leads to a change in the selection of 5p and 3p microRNA duplex strands in the formation of the RNA-induced silencing complex (RISC). 相似文献
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Rainbow tags: a visual tag system for recombinant protein expression and purification 总被引:1,自引:0,他引:1
Visualization systems for tracking proteins are standard experimental tools in most areas of biological research apart from protein purification. Here, we have sought to plug this gap by producing red and yellow visual tags using the heme-binding domain of mosquito cytochrome b5 and the flavin mononucleotide (FMN)-binding domain of human P450 reductase. Tests with colorless glutathione-S-transferase (GST) show them to be simple and effective tools for visually identifying correctly folded protein and tracking protein molecules through protein expression and purification. Furthermore, the characteristic absorbance signatures of the colored tags can be used to quantify protein concentrations directly, which allows purification to be linked to colorimetric detection. This technology, which we call Rainbow Tagging, facilitates expression and downstream processing of recombinant proteins, paving the way for the development of automated high-throughput protein expression systems. 相似文献
10.
Almsherqi ZA McLachlan CS Slocinska MB Sluse FE Navet R Kocherginsky N Kostetski I Shi DY Liu SL Mossop P Deng Y 《Cell research》2006,16(3):297-305
Cardiogenic shock is the leading cause of death among patients hospitalized with acute myocardial infarction (MI).Understanding the mechanisms for acute pump failure is therefore important.The aim of this study is to examine in anacute MI dog model whether mitochondrial bio-energetic function within non-ischemic wall regions are associated withpump failure.Anterior MI was produced in dogs via ligation of left anterior descending (LAD) coronary artery,thatresulted in an infract size of about 30% of the left ventricular wall.Measurements of hemodynamic status,mitochondrialfunction,free radical production and mitochondrial uncoupling protein 3 (UCP3) expression were determined over 24h period.Hemodynamic measurements revealed a>50% reduction in cardiac output at 24 h post infarction when com-pared to baseline.Biopsy samples were obtained from the posterior non-ischemic wall during acute infarction.ADP/Oratios for isolated mitochondria from non-ischemic myocardium at 6 h and 24 h were decreased when compared to theADP/O ratios within the same samples with and without palmitic acid (PA).GTP inhibition of (PA)-stimulated state 4respiration in isolated mitochondria from the non-ischemic wall increased by 7% and 33% at 6 h and 24 h post-infarctionrespectively when compared to sham and pre-infarction samples.This would suggest that the mitochondria are uncoupledand this is supported by an associated increase in UCP3 expression observed on western blots from these same biopsysamples.Blood samples from the coronary sinus measured by electron paramagnetic resonance (EPR) methods showedan increase in reactive oxygen species (ROS) over baseline at 6 h and 24 h post-infarction.In conclusion,mitochondrialbio-energetic ADP/O ratios as a result of acute infarction are abnormal within the non-ischemic wall.Mitochondria ap-pear to be energetically uncoupled and this is associated with declining pump function.Free radical production may beassociated with the induction of uncoupling proteins in the mitochondria. 相似文献