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Regulation of AMPA Receptor Currents by Mitochondrial ATP Sensitive K+ Channels in Anoxic Turtle NeuronsZivkovic, George 31 December 2010 (has links)
Mammalian neurons rapidly undergo excitotoxic cell death during anoxia, while neurons from the anoxia-tolerant painted turtle can survive without oxygen for hours without apparent damage. An anoxia-mediated decrease in AMPA receptor currents are an important part of the turtle’s natural defence however the mechanism underlying it is unknown. Here I investigate a mechanism that involves activation of a mitochondrial KATP channel that subsequently signals a decrease in AMPAR currents. Whole-cell AMPAR currents were stable during normoxia, but anoxia or pharmacological activation of mKATP channels resulted in a 50% decrease in AMPAR currents. Conversely, mKATP antagonists blocked the anoxia-mediated decrease. Mitochondrial KCa channel modulators responded similarly. Blocking the Ca2+-uniporter also reduced normoxic AMPAR currents by 40%, and including BAPTA in the recording abolished the anoxia or agonist-mediated decrease. Therefore, the mKATP channel is involved in the anoxia-mediated down-regulation of AMPAR activity and is a common mechanism to reduce glutamatergic excitability.
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Application of Vertical-cavity Surface-emitting Lasers for Simultaneous Laser Speckle Contrast and Intrinsic Optical Signal Imaging: Toward Chronic Portable Cortical Hemodynamic ImagingRinguette, Dene 15 August 2012 (has links)
We demonstrated simultaneous intrinsic optical signal imaging (IOSI) and laser speckle contrast imaging (LSCI) using coherence modulation of vertical-cavity surface-emitting laser (VCSEL) diodes. The unique properties of VCSELs were exploited to deliver rapidly switched coherent and non-coherent illumination suitable for high resolution LSCI and IOSI, respectively. Utilizing three near-infrared VCSELs we were able to map changes in cortical blood oxygenation and flow during ischemia. Additionally, the subtle reflectance changes associated with cortical spreading depression were imaged using non-coherent VCSEL illumination. We are currently using two-photon laser-scanning microscopy to quantify the accuracy of LSCI and IOSI implementations.
The small size and efficiency of VCSELs and modern photo diodes, makes the development of implantable dual-mode imaging devices feasible. Devices capable of chronic imaging of cortical hemodynamics could significantly enhance the range of studies available to neuroscientists and significantly aid clinicians postoperatively. The research presented in this thesis significantly furthers this objective.
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The Effect of Alpha 1-Antitrypsin on Ischemia-Reperfusion Injury in Lung TransplantationGao, Wenxi 20 November 2012 (has links)
Ischemia-reperfusion (IR) injury is a severe complication in lung transplantation characterized by inflammation, alveolar damage, and hypoxemia. Alpha 1-antitrypsin (A1AT), a protease inhibitor, is currently used clinically for the treatment of A1AT deficiency emphysema. A1AT has been shown to have the potential to reduce IR injury through its anti-inflammatory and anti-apoptotic effects. We hypothesized that A1AT will ameliorate IR injury through these effects. We tested A1AT in two models of IR: a cell culture model of simulated lung transplantation and a rat in situ pulmonary ligation model. In cell culture, we found that A1AT exerts its protective effects by inhibiting cell death and inflammatory cytokine release in a dose-dependent manner. In the rat pulmonary ischemia-reperfusion model, we found that A1AT improved lung function by inhibiting apoptosis and inflammation. There is potential for future application of A1AT in the treatment of IR injury in lung transplantation.
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Regulation of AMPA Receptor Currents by Mitochondrial ATP Sensitive K+ Channels in Anoxic Turtle NeuronsZivkovic, George 31 December 2010 (has links)
Mammalian neurons rapidly undergo excitotoxic cell death during anoxia, while neurons from the anoxia-tolerant painted turtle can survive without oxygen for hours without apparent damage. An anoxia-mediated decrease in AMPA receptor currents are an important part of the turtle’s natural defence however the mechanism underlying it is unknown. Here I investigate a mechanism that involves activation of a mitochondrial KATP channel that subsequently signals a decrease in AMPAR currents. Whole-cell AMPAR currents were stable during normoxia, but anoxia or pharmacological activation of mKATP channels resulted in a 50% decrease in AMPAR currents. Conversely, mKATP antagonists blocked the anoxia-mediated decrease. Mitochondrial KCa channel modulators responded similarly. Blocking the Ca2+-uniporter also reduced normoxic AMPAR currents by 40%, and including BAPTA in the recording abolished the anoxia or agonist-mediated decrease. Therefore, the mKATP channel is involved in the anoxia-mediated down-regulation of AMPAR activity and is a common mechanism to reduce glutamatergic excitability.
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Application of Vertical-cavity Surface-emitting Lasers for Simultaneous Laser Speckle Contrast and Intrinsic Optical Signal Imaging: Toward Chronic Portable Cortical Hemodynamic ImagingRinguette, Dene 15 August 2012 (has links)
We demonstrated simultaneous intrinsic optical signal imaging (IOSI) and laser speckle contrast imaging (LSCI) using coherence modulation of vertical-cavity surface-emitting laser (VCSEL) diodes. The unique properties of VCSELs were exploited to deliver rapidly switched coherent and non-coherent illumination suitable for high resolution LSCI and IOSI, respectively. Utilizing three near-infrared VCSELs we were able to map changes in cortical blood oxygenation and flow during ischemia. Additionally, the subtle reflectance changes associated with cortical spreading depression were imaged using non-coherent VCSEL illumination. We are currently using two-photon laser-scanning microscopy to quantify the accuracy of LSCI and IOSI implementations.
The small size and efficiency of VCSELs and modern photo diodes, makes the development of implantable dual-mode imaging devices feasible. Devices capable of chronic imaging of cortical hemodynamics could significantly enhance the range of studies available to neuroscientists and significantly aid clinicians postoperatively. The research presented in this thesis significantly furthers this objective.
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The Effect of Alpha 1-Antitrypsin on Ischemia-Reperfusion Injury in Lung TransplantationGao, Wenxi 20 November 2012 (has links)
Ischemia-reperfusion (IR) injury is a severe complication in lung transplantation characterized by inflammation, alveolar damage, and hypoxemia. Alpha 1-antitrypsin (A1AT), a protease inhibitor, is currently used clinically for the treatment of A1AT deficiency emphysema. A1AT has been shown to have the potential to reduce IR injury through its anti-inflammatory and anti-apoptotic effects. We hypothesized that A1AT will ameliorate IR injury through these effects. We tested A1AT in two models of IR: a cell culture model of simulated lung transplantation and a rat in situ pulmonary ligation model. In cell culture, we found that A1AT exerts its protective effects by inhibiting cell death and inflammatory cytokine release in a dose-dependent manner. In the rat pulmonary ischemia-reperfusion model, we found that A1AT improved lung function by inhibiting apoptosis and inflammation. There is potential for future application of A1AT in the treatment of IR injury in lung transplantation.
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Regulation of Connexin40 Gap JunctionsSheela, Thomas Vinaya 31 August 2008 (has links)
Gap junctions provide direct electrical and biochemical communication between cardiomyocytes in the heart. Connexin40 (Cx40) is the major connexin in the atria of the heart and little is known regarding its regulation. Thus, the goal was to investigate the regulation of Cx40 in both physiological and pathophysiological conditions. The first objective of this thesis was to determine whether Cx40 gap junctions were regulated by â-adrenergic receptor activation. Cx40 has previously been shown to be acutely activated by cAMP, this cAMP-induced increase in Cx40-mediated cell-to-cell dye transfer has been shown to be effected through the â-adrenergic receptor-adenylyl cyclase- Protein Kinase A (PKA) pathway in Cx40-transfected HeLa cells. The second objective of this thesis was to determine whether Cx40 gap junctions were regulated by intracellular Ca2+ concentration ([Ca2+]i ). [Ca2+]i was increased by addition of the ionophore ionomycin and elevating extracellular calcium [Ca2+]o from 1.8 mM to 21.8 mM. This resulted in an elevation of [Ca2+]i and effected an inhibition of Cx40-mediated cell-to-cell dye transfer (IC50 of 500 ± 0.72 nM) which was Calmodulin-dependent. The third objective of this thesis was to determine whether Cx40 gap junctions were regulated by ischemia. Inducing ischemia chemically by inhibiting the electron transport chain with sodium cyanide and glycolysis with iodoacetate and 2-deoxyglucose effected an inhibition of Cx40-mediated cell-to-cell dye transfer that was shown to be Calmodulin dependent. The main conclusions of this thesis were: (1) â-adrenergic receptor activation increases Cx40-mediated cell-to-cell dye transfer which requires the activation of PKA; (2) A sustained elevation in [Ca2+]i causes a partial inhibition of Cx40 gap junction-mediated cell-to-cell dye transfer which was Ca2+-and Calmodulin dependent; (3) Chemical ischemia causes a partial inhibition of Cx40 gap junction-mediated cell-to-cell dye transfer which was shown to be Calmodulin-dependent.
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Einfluss von Geschlechtshormonen auf die Volumenregulation von MüllerzellenNeumann, Florian 21 February 2013 (has links) (PDF)
Osmotic swelling of glial cells may contribute to the development of retinal edema. We investigated whether sex steroids inhibit the swelling of glial somata in acutely isolated retinal slices and glial cells of the rat. Superfusion of retinal slices or cells from control animals with a hypoosmolar solution did not induce glial swelling, whereas glial swelling was observed in slices of postis- chemic and diabetic retinas. Progesterone, testosterone, estriol, and 17ß-estradiol prevented glial swelling with half-maximal effects at approximately 0.3, 0.6, 6, and 20 lM, respectively. The effect of progesterone was apparently mediated by transactivation of metabotropic glutamate receptors, P2Y1, and adenosine A1 receptors. The data suggest that sex steroids may inhibit cytotoxic edema in the retina.
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Diffusion in inhomogenous mediaBandola, Nicolas 30 October 2009 (has links)
This project considers the diffusion of water molecules through a cellular medium
in which the cells are modeled by square compartments placed symmetrically in a
square domain. We assume the diffusion process is governed by the 2D diffusion
equations and the solution is provided by implementing the Crank-Nicolson
scheme. These results are verified and illustrated to agree well with the finite
element method using the Comsol Multiphysics package. The model is used to
compute the values of the apparent diffusion coefficient, (ADC) which is a
measure that is derived from diffusion weighted MRI data and can be used to
identify, e.g., regions of ischemia in the brain. With our model, it is possible to
examine how the value of the apparent diffusion coefficient is affected whenever
the extracellular space is varied. We observe that the average distance that the
water molecules travel in a definite time is highly dependent on the geometrical
properties of the cellular media. / UOIT
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Dietary n-3 fatty acids and cerebral ischemia/reperfusionSlack, Penelope Jean 05 1900 (has links)
Many populations have low intakes of n-3 fatty acids, yet there is substantial evidence that the long chain n-3 fatty acid docosahexaenoic acid (DHA; 22:6n-3), found at high concentrations in the brain, is required for the proper development of the nervous system. However, less is known about requirements of long chain n-3 fatty acids for maintenance and function of the nervous system in later life. Several recent studies have reported that high amounts of long chain n-3 fatty acids reduce the extent of brain damage caused by cerebral ischemia in animals. However, whether or not a dietary deficiency of n-3 fatty acids increases the extent of injury when cerebral ischemia occurs has not been previously reported. The present studies, therefore, sought to determine if a diet deficient in n-3 fatty acids influences the extent of brain injury in the rat following cerebral ischemia. Male rats were fed an n-3 fatty acid adequate (control), an n-3 fatty acid deficient, or a high DHA diet for 5 weeks from weaning. Middle cerebral artery occlusion (MCAO) was induced and infarct volume was measured by 2,3,5,-triphenyltetrazolium chloride staining 24 hours after the procedure. Brain and platelet fatty acids were analyzed by gas liquid chromatography. DHA (22:6n-3) was 21-28% lower in brain phospholipids, and 17% lower in brain total fatty acids in the n-3 fatty acid deficient compared to control group, while 22:6n-3 was 12% higher in total brain fatty acids in the high DHA group than the control group. There was no significant difference in infarct volume (203, 220 and 218 mm³) among the control, n-3 fatty acid deficient, and high DHA groups, respectively. Platelet fatty acids and platelet aggregation were assessed to determine if these were influenced by the high DHA diet, and could possibly explain the observation of an apparent, but not statistically significant, higher number of rats with hemorrhages in the high DHA diet group. Platelet lipid arachidonic acid was not lower and platelet aggregation, assessed ex vivo using whole blood with a platelet function analyzer, was not longer in rats fed the high DHA compared to control or n-3 fatty acid deficient diets. In summary, dietary n-3 fatty acid deficiency did not increase the extent of brain injury following cerebral ischemia. The possibility that high dietary 22:6n-3 might increase susceptibility to cerebral hemorrhage will require further study.
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