96 research outputs found

    Oxidant-NO dependent gene regulation in dogs with type I diabetes: impact on cardiac function and metabolism

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    <p>Abstract</p> <p>Background</p> <p>The mechanisms responsible for the cardiovascular mortality in type I diabetes (DM) have not been defined completely. We have shown in conscious dogs with DM that: <it>1</it>) baseline coronary blood flow (CBF) was significantly decreased, <it>2</it>) endothelium-dependent (ACh) coronary vasodilation was impaired, and <it>3</it>) reflex cholinergic NO-dependent coronary vasodilation was selectively depressed. The most likely mechanism responsible for the depressed reflex cholinergic NO-dependent coronary vasodilation was the decreased bioactivity of NO from the vascular endothelium. The goal of this study was to investigate changes in cardiac gene expression in a canine model of alloxan-induced type 1 diabetes.</p> <p>Methods</p> <p>Mongrel dogs were chronically instrumented and the dogs were divided into two groups: one normal and the other diabetic. In the diabetic group, the dogs were injected with alloxan monohydrate (40-60 mg/kg iv) over 1 min. The global changes in cardiac gene expression in dogs with alloxan-induced diabetes were studied using Affymetrix Canine Array. Cardiac RNA was extracted from the control and DM (n = 4).</p> <p>Results</p> <p>The array data revealed that 797 genes were differentially expressed (P < 0.01; fold change of at least ±2). 150 genes were expressed at significantly greater levels in diabetic dogs and 647 were significantly reduced. There was no change in eNOS mRNA. There was up regulation of some components of the NADPH oxidase subunits (gp91 by 2.2 fold, P < 0.03), and down-regulation of SOD1 (3 fold, P < 0.001) and decrease (4 - 40 fold) in a large number of genes encoding mitochondrial enzymes. In addition, there was down-regulation of Ca<sup>2+ </sup>cycling genes (ryanodine receptor; SERCA2 Calcium ATPase), structural proteins (actin alpha). Of particular interests are genes involved in glutathione metabolism (glutathione peroxidase 1, glutathione reductase and glutathione S-transferase), which were markedly down regulated.</p> <p>Conclusion</p> <p>our findings suggest that type I diabetes might have a direct effect on the heart by impairing NO bioavailability through oxidative stress and perhaps lipid peroxidases.</p

    Quiescence and γH2AX in neuroblastoma are regulated by ouabain/Na,K-ATPase

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    Cellular quiescence is a state of reversible proliferation arrest that is induced by anti-mitogenic signals. The endogenous cardiac glycoside ouabain is a specific ligand of the ubiquitous sodium pump, Na,K-ATPase, also known to regulate cell growth through unknown signalling pathways. To investigate the role of ouabain/Na,K-ATPase in uncontrolled neuroblastoma growth we used xenografts, flow cytometry, immunostaining, comet assay, real-time PCR, and electrophysiology after various treatment strategies. The ouabain/Na,K-ATPase complex induced quiescence in malignant neuroblastoma. Tumour growth was reduced by >50% when neuroblastoma cells were xenografted into immune-deficient mice that were fed with ouabain. Ouabain-induced S-G2 phase arrest, activated the DNA-damage response (DDR) pathway marker γH2AX, increased the cell cycle regulator p21Waf1/Cip1 and upregulated the quiescence-specific transcription factor hairy and enhancer of split1 (HES1), causing neuroblastoma cells to ultimately enter G0. Cells re-entered the cell cycle and resumed proliferation, without showing DNA damage, when ouabain was removed. Conclusion: These findings demonstrate a novel action of ouabain/Na,K-ATPase as a regulator of quiescence in neuroblastoma, suggesting that ouabain can be used in chemotherapies to suppress tumour growth and/or arrest cells to increase the therapeutic index in combination therapies

    Quantitative impacts of regenerative vibration and abrasive wheel eccentricity on surface grinding dynamic performance

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    In grinding, regenerative vibration and forced vibration due to grinding wheel eccentric rotation are main excited-vibration sources that interact with grinding material removal mechanism. In the paper, instantaneous undeformed chip thickness in down-grinding cutting phase may consist of two components, i.e. linear kinetic thickness and nonlinear dynamic thickness. Considering abrasive grit-workpiece interaction in the grinding contact zone, the grinding vibration system is presented by a new set of differential equations of two degrees of freedom (DOF) with a close-loop feedback control system models. Conventional grinding control parameters, including wheel spindle speed, work-speed in feed direction and radial cutting depth, are often regarded as linear constants in many existing simplified models. When considering time delay, they can be transferred to nonlinear variables, so the capability of prediction and the accuracy of solution of the grit-workpiece dynamic performance are improved. Based on quantitative comparison of force and vibration magnitudes, the influence of the eccentric rotation of abrasive wheel and the negative rake angle of working grit cutting edges on grinding performance are demonstrated in the paper. © 2018 Springer-Verlag London Ltd., part of Springer Natur

    Saving Human Lives: What Complexity Science and Information Systems can Contribute

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    We discuss models and data of crowd disasters, crime, terrorism, war and disease spreading to show that conventional recipes, such as deterrence strategies, are often not effective and sufficient to contain them. Many common approaches do not provide a good picture of the actual system behavior, because they neglect feedback loops, instabilities and cascade effects. The complex and often counter-intuitive behavior of social systems and their macro-level collective dynamics can be better understood by means of complexity science. We highlight that a suitable system design and management can help to stop undesirable cascade effects and to enable favorable kinds of self-organization in the system. In such a way, complexity science can help to save human lives.Comment: 67 pages, 25 figures; accepted for publication in Journal of Statistical Physics [for related work see http://www.futurict.eu/
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