Doctor of Philosophy

dissertationSudden Cardiac Arrest (SCA) remains one of the leading causes of death in the United States. During SCA, the inability of the heart to pump blood causes progressive metabolic and functional derangements in the heart itself. In the majority of SCA cases, the defining event of death is the failure of defibrillation shocks and cardio-pulmonary resuscitation (CPR) procedures to restore circulation within the first 10 minutes. Resuscitation failure is often due to either asystole (the lack of activation in the heart) or recurrent ventricular fibrillation following defibrillation. The exact physiological mechanisms determining the occurrence of these phenomena within the clinically relevant time frame remain largely unknown. One postulated mechanism linking metabolic stress and electrical abnormalities during SCA is the loss of mitochondrial inner membrane potential (delta epsilon m) and the consequent activation of the adenosine triphosphate (ATP)-sensitive potassium channel (KATP) when cellular ATP is critically depleted. The goal of this dissertation was to investigate the relationship between delta epsilon m depolarization, electrical failure, and arrhythmias in a model of SCA. The work consisted of three projects. In the first, I characterized the spatiotemporal dynamics of electrical failure in a whole-heart model of VF-induced SCA. I demonstrated that the electrical depression develops in a heterogeneous fashion across the heart and is partially dependent on KATP activation. In the second project, I developed a method to detect delta epsilon m depolarization during global ischemia using spectral analysis of confocally recorded delta epsilon m-sensitive fluorescence. The method is based on the spatial periodicity of mitochondrial packaging in ventricular myocytes and the preferential accumulation of cationic fluorophores in well-polarized mitochondria and addresses the limitations of the traditional mean fluorescence approach during ischemia. Using this method, in the third project, I determined the temporal relationship between ischemic delta epsilon m depolarization and myocardial inexcitability. Additionally, I modulated the energy balance in ischemic hearts using rapid pacing, the inhibitor of myosin II ATPase, blebbistatin, and the inhibitor of anaerobic glycolysis, sodium iodoacetate. This study showed a strong correlation between the onset of asystole and the time of delta epsilon m loss under all tested conditions, and revealed a strong protective effect of Blebbistatin against asystole, delta epsilon m loss, and postreperfusion arrhythmias

SANS From Tetradecylpyridinium Bromide Based Microemulsions

Small-angle neutron scattering is used to investigate tetradecyl pyridinium bromide/pentanol/heptane/heavy water microemulsions in the water-in-oil (W/O) microemulsion phase diagram region. The heavy water content is increased while the other components (surfactant, cosurfactant, hydrocarbon) are kept constant. With use of a simple model assuming spherical micelles interacting with a hard-sphere potential (Percus-Yevick model), aggregate sizes and packing fractions have been extracted and found to agree with values determined from the mixing conditions. These experiments clearly show the transition from the single-particle (heavy water + Stern layer droplet) scattering regime at low water concentration to the mixed single/interdroplet scattering regime when the intermicellar distance becomes comparable to the size of the micelles. © 1990 American Chemical Society

Constraint-based Temporal Reasoning with Preferences

Often we need to work in scenarios where events happen over time and preferences are associated to event distances and durations. Soft temporal constraints allow one to describe in a natural way problems arising in such scenarios. In general, solving soft temporal problems require exponential time in the worst case, but there are interesting subclasses of problems which are polynomially solvable. In this paper we identify one of such subclasses giving tractability results. Moreover, we describe two solvers for this class of soft temporal problems, and we show some experimental results. The random generator used to build the problems on which tests are performed is also described. We also compare the two solvers highlighting the tradeoff between performance and robustness. Sometimes, however, temporal local preferences are difficult to set, and it may be easier instead to associate preferences to some complete solutions of the problem. To model everything in a uniform way via local preferences only, and also to take advantage of the existing constraint solvers which exploit only local preferences, we show that machine learning techniques can be useful in this respect. In particular, we present a learning module based on a gradient descent technique which induces local temporal preferences from global ones. We also show the behavior of the learning module on randomly-generated examples

Herpes Simplex Virus Dances with Amyloid Precursor Protein while Exiting the Cell

Herpes simplex type 1 (HSV1) replicates in epithelial cells and secondarily enters local sensory neuronal processes, traveling retrograde to the neuronal nucleus to enter latency. Upon reawakening newly synthesized viral particles travel anterograde back to the epithelial cells of the lip, causing the recurrent cold sore. HSV1 co-purifies with amyloid precursor protein (APP), a cellular transmembrane glycoprotein and receptor for anterograde transport machinery that when proteolyzed produces A-beta, the major component of senile plaques. Here we focus on transport inside epithelial cells of newly synthesized virus during its transit to the cell surface. We hypothesize that HSV1 recruits cellular APP during transport. We explore this with quantitative immuno-fluorescence, immuno-gold electron-microscopy and live cell confocal imaging. After synchronous infection most nascent VP26-GFP-labeled viral particles in the cytoplasm co-localize with APP (72.8+/−6.7%) and travel together with APP inside living cells (81.1+/−28.9%). This interaction has functional consequences: HSV1 infection decreases the average velocity of APP particles (from 1.1+/−0.2 to 0.3+/−0.1 µm/s) and results in APP mal-distribution in infected cells, while interplay with APP-particles increases the frequency (from 10% to 81% motile) and velocity (from 0.3+/−0.1 to 0.4+/−0.1 µm/s) of VP26-GFP transport. In cells infected with HSV1 lacking the viral Fc receptor, gE, an envelope glycoprotein also involved in viral axonal transport, APP-capsid interactions are preserved while the distribution and dynamics of dual-label particles differ from wild-type by both immuno-fluorescence and live imaging. Knock-down of APP with siRNA eliminates APP staining, confirming specificity. Our results indicate that most intracellular HSV1 particles undergo frequent dynamic interplay with APP in a manner that facilitates viral transport and interferes with normal APP transport and distribution. Such dynamic interactions between APP and HSV1 suggest a mechanistic basis for the observed clinical relationship between HSV1 seropositivity and risk of Alzheimer's disease

Campus : An American Planning Tradition

New Yorkxii, 337 p.: illus.; 25 c

An Investigation of the Managerial Practices and Attitudes toward Organisational Culture Management in Western Australia

Various studies have confirmed the widespread influence of Organisational Culture (OC) on success and failure in organisations. Researchers have confirmed the relationship between OC and specific outcomes like organisational performance and productivity, technology adoption, and organisational growth. Appropriately managing OC is therefore seen as a way to facilitate organisational change and improvement. Despite the importance of OC in supporting the overall success of organisations, relatively few studies have been undertaken on OC Management (OCM) in Australia. In this exploratory investigation the practices and attitudes of managers toward OCM in the context of Western Australia (WA) are surveyed to determine the importance of OCM, which aspects are most important to managers, and the practices in managing OC