Thesis (Ph. D.)--University of Missouri-Columbia, 2002. / Typescript. Vita. Includes bibliographical references. Also available on the Internet.

Thesis (Ph. D.)--University of Missouri-Columbia, 2002. / Typescript. Vita. Includes bibliographical references. Also available on the Internet.

The large flashes of radiation that are observed in GRBs are generally believed to arise in a relativistic jetted outflow. This thesis addresses the question of how and where in the jet this radiation is produced. It further explores the jet properties that can be inferred from the observations made by the Fermi GST that regularly observes GRBs in the range 8 keV - 300 GeV.  In my analysis I focus on the observational effects of the emission from the jet photosphere. I show that the photosphere has an important role in shaping the observed radiation spectrum and that its manifestations can significantly vary between bursts. For bursts in which the photospheric  emission component can be identified, the dynamics of the flow can be explored by determining the  jet Lorentz factor and the position of the jet nozzle. I also develop the theory of how to derive the properties of the outflow for general cases. The spectral analysis of the strong burst GRB110721A reveals a two-peaked spectrum, with the peaks evolving differently. I conclude that three main flow quantities can describe the observed spectral behaviour in bursts:  the luminosity, the Lorentz factor, and the nozzle radius. While the photosphere can appear like a pure blackbody it can also be substantially broadened, due to dissipation of the jet energy below the photosphere. I show that Comptonisation of the blackbody can shape the observed spectra and describe its evolution. In particular this model can very well explain GRB110920A which has two prominent breaks in its spectra.  Alternative models including synchrotron emission leads to severe physical constraints, such as the need for very high electron Lorentz factors, which are not expected in internal shocks. Even though different manifestations of the photospheric emission can explain the data, and lead to ambiguous interpretations, I argue that dissipation below the photosphere is the most important process in shaping the observed spectral shapes and evolutions. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 4: In press. Paper 5: Submitted.</p>

Abstract Visceral leishmaniasis is a devastating neglected parasitic disease caused by infection with Leishmania donovani. It life cycle has two stages with promastigote (insect stage) and amastigote (animal stage) morphologies. Miltefosine is currently the only commercially available oral drug available to treat leishmaniasis and recent evidence suggests clinical resistance has emerged. Due to the importance of this drug and the scarcity of new drugs in the pipeline, work has been done on understanding the mechanism(s) of miltefosine, yet the mechanism of action for resistance is still not known. In previous studies investigators generated miltefosine resistance on the insect vector stage (promastigotes), yet there is an important gap in understanding miltefosine resistance in the human infectious stage (amastigotes) of the disease. Before we could accomplish this goal a L. donovani cell line was converted into a stable, continuously cultured axenic amastigote cell line and characterized by disease burden generated in vitro and in vivo. The axenic line of L. donovani (MHOM/SD/75/1246/130) retains characteristics of amastigotes infecting macrophages and proliferated better than metacyclic promastigotes in macrophages in vitro and hamsters. The axenic amastigote line was used to induce miltefosine resistance by using discontinuous stepwise increasing drug pressure. Stable high-grade resistance was established (62-fold) and characterized in vitro and in vivo. Lastly, the fitness of miltefosine resistant versus susceptible parasite was established for the first time. This work adds the first efforts characterizing and understanding the complex problem of miltefosine resistance in amastigotes.

Cartesian space path planning involves generating the position and orientation trajectories for a manipulator end-effector. Currently, much of the literature in motion planning for robotics concentrates on topics such as obstacle avoidance, dynamic optimizations, or high-level task planning. The focus of this research is on operator-generated motions. This will involve analytically studying the effects of higher-order properties (such as curvature and torsion) on the shape of spatial Cartesian curves. A particular emphasis will be placed on developing physical meanings and graphical visualization for these properties to aid the operator in generating geometrically complex motions. This research begins with a brief introduction to the domain of robotics and manipulator motion planning. An overview of work in the area of manipulator motion planning will demonstrate a lack of research on generating geometrically complex spatial paths. To pursue this goal, this report will then provide a review of the theory of algrebraic curves and their higher-order properties. This involves an evaluation of several different representations for both planar and spatial curves. Then, a survey of interactive curve generation techniques will be performed, which will draw from fields outside of robotics such as Computer Graphics and Computer-Aided Design (CAD). In addition to the reviewed methods, a new method for describing and generating spatial curves is proposed and demonstrated. This method begins with the study of a finite set of local geometric motion shapes (circular arcs, cusps, helices, etc). The local geometric shapes are studied in terms of their geometric parameters (curvature and torsion), analyzed to give physical meaning to these parameters, and displayed graphically as a family of curves based on these controlling parameters. This leads to the development of path constraints with well-defined physical meaning. Then, a curve generation method is developed that can convert these geometric constraints into parametric constraints and blend between them to form a complete motion program (cycle) of smooth paths connecting several carefully developed local curve properties. Up to ten distinct local curve shapes were developed in detail and one curve cycle demonstrated how all this could be combined into a full path planning scenario. Finally, the developed methods are packaged together into existing software and applied to an example demonstration. / text

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<p>The development of cancer is a process by which an accumulation of genetic changes leads to uncontrolled replication of cells. Since the process of mutation is random, the set of alterations that occur and accumulate during tumorigenesis in one individual is different from that of another. These genetic differences drive tumor heterogeneity. One of the first technologies used to explore genome-wide heterogeneity was the microarray, which can be used to measure the expression of tens of thousands of genes. By exploring differences in expression of not just single genes, but groups of genes that may be altered in one set of tumors compared to another, researchers were able to classify subtypes of cancer that had relevance in disease aggressiveness, treatment, and prognosis. Furthermore, by looking at genome-wide patterns of expression, it is possible to identify specific oncogenic pathways that are activated and critical in driving tumor cell survival, growth, or metastasis. My research utilizes the patterns of expression derived from microarray analyses to study tumor heterogeneity, particularly in response to targeted cancer therapy, and mechanisms of cell death following oncogenic deregulation.</p><p>One of the cancer types that has been explored through expression array analysis is B-cell lymphoma. Human aggressive B-cell non-Hodgkin lymphomas (NHL) encompass the continuum between Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), and display considerable clinical and biologic heterogeneity, most notably related to therapy response. We previously showed that lymphomas arising in the E&mu-Myc transgenic mouse are heterogeneous, mirroring genomic differences between BL and DLBCL. Given the clinical heterogeneity in NHL and the need to develop strategies to match therapeutics with discrete forms of disease, we investigated the extent to which genomic variation in the E&mu-Myc model predicts response to therapy. We used genomic analyses to classify E&mu-Myc lymphomas, link E&mu-Myc lymphomas with NHL subtypes, and identify lymphomas with predicted resistance to conventional and NF-&kappaB targeted therapies. Experimental evaluation of these predictions links genomic profiles with distinct outcomes to conventional and targeted therapies in the E&mu-Myc model, and establishes a framework to test novel targeted therapies or combination therapies in specific genomically-defined lymphoma subgroups. In turn, this will rationally inform the design of new treatment options for aggressive human NHL.</p><p>The second aspect of my thesis looks at the mechanisms of apoptosis following oncogene deregulation. The Rb-E2F pathway is a critical oncogenic pathway that is frequently mutated in cancers. Alterations in the pathway affect genome-wide expression in the cell, which in turn lead to deregulation of the cell cycle. The E2F1 transcription factor regulates cell proliferation and apoptosis through the control of a considerable variety of target genes. Previous work has detailed the role of other transcription factors that cooperate with E2F to mediate the specificity of E2F function. In this work, we identify the NF-YB transcription factor as a novel direct E2F1 target. Genome-wide expression analysis of the effects of NFYB knockdown on E2F1-mediated transcription identified a large group of genes that are co-regulated by E2F1 and NFYB. We also provide evidence that knockdown of NFYB enhances E2F1-induced apoptosis, suggesting a pro-survival function of the NFYB/E2F1 joint transcriptional program. Bioinformatic analysis suggests that deregulation of these NFY-dependent E2F1 target genes might play a role in sarcomagenesis as well as drug resistance. </p><p>Taken together, these studies highlight the importance and power of analyzing genome-wide patterns of expression in investigating cancer heterogeneity, its ability to help predict treatment response, and its role in discovering the mechanisms behind the consequences of gene deregulation.</p> / Dissertation

This dissertation consists of three essays on microeconomics. The first essay considers matching markets, markets where buyers and sellers and concerned about who they interact with. It proposes a model to analyze these markets akin to the standard supply and demand framework. The second essay considers mechanism design, the problem of designing rules to make collective decisions in the presence of private information. It proposes the concept of strategyproofness in the large, which is that an agent without too fine information has negligible gains from misreporting her type in a large market. It argues that, for all practical purposes, this concept correctly separates mechanisms where behavior akin to price-taking is observed, and those where participants rampantly manipulate their stated preferences. A Theorem is proven that gives a precise sense in which strategyproofness in the large is not a very restrictive property. The third essay considers the evolutionary origins of the endowment effect bias, where the willingness to pay for a good is smaller than the willingness to accept. It gives evidence that this bias is not present in a modern hunter-gatherer population, questioning standard evolutionary accounts. It shows that cultural shocks in a subpopulation did give rise to the bias. / Economics

The Vasoactive Intestinal Peptide (VIP) is an agonist of the CFTR chloride channel in the human airways. In the genetic disease Cystic Fibrosis, where CFTR is defective or absent from the apical membrane of epithelial cells, VIP innervations are lost. Our group has demonstrated that VIP increases CFTR membrane stability through PKCε. However, the mechanism remained to be determined. Here we found that VIP stimulation increases the interaction of NHERF1 and P-ERMs with CFTR through PKCε phosphorylation. Moreover a reduction of the interaction between intracellular CFTR and the Golgi associated protein, CAL was observed following VIP stimulation. Silencing either ERMs or NHERF1 with siRNA prevented the VIP ability to increase CFTR surface expression and function, confirming that NHERF1 and P-ERMs are necessary for VIP regulation of the sustained activity of membrane CFTR. This study shows the cellular mechanism by which prolonged VIP stimulation of airway epithelial cells regulates CFTR-dependent secretions.

The anodic polarization of Ni electrode in 0.5 M aqueous KOH solution at various polarization potential (Ep), time (tp) and temperature (T) values leads to the formation of β-Ni(OH)2 films. The growth of the hydroxide layers are irreversible and cannot be reduced electrochemically to metallic Ni. The hydroxide layer becomes thicker at higher values of Ep and/or tp and/or T. The thickness of β-Ni(OH)2 hydroxide were determined using ex–situ XPS and depth–profile techniques. Application of the oxide growth theories to our data indicate that the development of the β-Ni(OH)2 layer follows inverse logarithmic growth kinetics. The driving force of the process is the strong electric field that is established across the oxide layer. The strength of electric field is in the range of 0.015 – 0.197 x 109 V m–1. The oxidation mechanism of the Ni(II) surface compound to Ni(III) is electrochemically irreversible and the process is treated according to Randles–Sevcik equation. A linear relation was determined between the peak current density (jp) and the square root of the potential scan rate (v1/2) for the entire range of Ep, tp and T. The diffusion coefficient (D) values calculated for anodic and cathodic processes are 8.1 ± 0.2 x 10–12 and 4.3 ± 0.2 x 10–12 cm2 s–1, respectively. The activation energy (Ea) values for the diffusion process are 23 ± 2 kJ mol–1 (anodic) and 26 ± 2 kJ mol–1 (cathodic). The D and Ea values calculated from chronoamperometry measurements are comparable with those calculated from jp vs. v1/2 plots. The electro–reduction of PtO electrochemically pre–formed on Pt electrode in 0.5 M aqueous H2SO4 solution was also investigated. A well–controlled reduction conditions (Er, tr and T) were applied to determine the amount of the reduced PtO oxide. The reduction of the PtO requires much less time once ca. 1 monolayer (ML) of the oxide has been removed (ca. 1 ML of PtO remains). As expected, the longer tr and/or lower Er values, the greater the amount of the reduced oxide and consequently the smaller the amount of the remaining PtO oxide. / Thesis (Ph.D, Chemistry) -- Queen's University, 2011-02-08 10:58:54.114