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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.

On interaction and efficiency : prematch investments with hidden characteristics

Bidner, Christopher 05 1900 (has links)
I develop three models that are designed to aid in the analysis of environments in which agents i) benefit from interacting with others, and ii) optimally choose their characteristics mindful of the fact that such choices will influence the quality of interaction that they can expect. Of central interest is the ways in which a concern for interaction affects the efficiency with which agents choose their characteristics. The first two models contrast with previous work in that each agents' relevant characteristics are both unobserved and endogenously determined. The first model provides an explanation for credentialism in the labour market, and demonstrates how a concern for interaction can lead to over-investment in the relevant characteristic. The second model is motivated by human capital development in the presence of peer effects, and demonstrates how a concern for interaction can exacerbate an inherent under-investment problem. The third model retains the feature of unobserved characteristics, and contrasts with previous work by embedding frictions in the process by which agents compete for partners. The model is set in a labour market and demonstrates that outcomes of interest (equilibrium matching patterns, income, inequality and welfare) are generally not monotonic in the level of frictions. / Arts, Faculty of / Vancouver School of Economics / Graduate

Underlying Mechanism behind Word Responses in Competitive Dynamics

January 2016 (has links)
abstract: The traditional action-response perspective has largely ignored the role of language in competitive dynamics. In this study, I treat language (i.e., word response) as an alternative way to react to rivals when a firm is attacked, in addition to no reaction and action-based reaction. Word response is a specific and public announcement of a focal firm’s potential move in reaction to a competitor’s word or action attack. To explore the underlying mechanism behind word responses, I aim to answer two major questions. The first question is under what situations are responders motivated to use words as competitive responses? For this question I emphasize characteristics of the action, the market, and the actor, using measures such as action type, market dependence of the responder, multimarket contact of the responder in the market, and the competitive aggressiveness of the actor. The second question is what kinds of responders are more likely to use words as competitive responses? For this question, I focus on responder characteristics, such as firm reputation, CEO tenure, and CEO duality. According to Porter’s competitive signaling theory, I argue that responders can use words in reaction to an attack in order to test the waters, deter rivalry, and demonstrate toughness because word responses require few resources, can be accomplished quickly, are reversible, while at the same time still carrying some commitment. Besides incorporating language into the action-response perspective, my dissertation also further integrates the upper-echelons perspective with competitive dynamics research, providing a more realistic and complete understanding of competitive engagement. I test my theory in the consumer electronics (CE) industry with 20 major global CE manufacturers between 2007 and 2014. / Dissertation/Thesis / Doctoral Dissertation Business Administration 2016

The interaction between Hedgehog/Patched and Ras signaling in Rhabdomyosarcoma

Cuvelier, Nicole 07 March 2016 (has links)
No description available.

Molecular tuning of a neural circuit that drives aggregation behaviour in C. elegans

Flynn, Sean January 2018 (has links)
Modulation of network state is a ubiquitous feature of nervous systems. A major challenge in understanding the physiological flexibility of neural circuits is linking molecules that regulate behaviour to changes in the properties of individual neurons. Here, we use a defined neural circuit in C. elegans to frame this universal problem. By genetic dissection of the behavioural state that sustains escape of 21% O2, we identify novel neuronal functions for several highly conserved genes, including a caspase-like molecule, a calcium-sensitive transcription factor, and two translation initiation factors. These molecules have been implicated in diverse forms of human disease, but their role in the nervous system is either unexplored or poorly understood. Using in vivo Ca2+ imaging techniques to investigate neuron physiology in immobilized and behaving animals, we demonstrate their effect on the properties of individual neurons. The activity of RMG hub neurons is associated with the switch in behavioural state induced by 21% O2. Recently it has been shown that the input-output relationship of RMG is controlled by cytokine signaling, an increasingly appreciated form of neuromodulation. Here I present biochemical and genetic evidence that characterize a novel signaling component downstream of IL-17 receptors in RMG. Our data suggest that, reminiscent of its role in the immune system, it performs both scaffolding and enzymatic functions in neurons. Additionally, we show that RMG responsiveness is controlled by widely expressed, putative regulators of gene expression. Our analyses of these proteins elucidate their function within the URX-RMG circuit, but also raise hypotheses that can be tested more generally in the nervous system. We propose that a calmodulin-binding protein regulates adaptation to ambient O2 conditions, which may reflect a widespread requirement for controlling homeostatic plasticity. Two translation factors that have been shown to be dispensable for general translation are important for regulation of the response to stress. Our study raises the possibility that their role in promoting the activity of all, or some subset of, neurons might underlie this contextual requirement. Together, our findings provide mechanistic insight into the regulation of a behavioural state associated with a specific environmental context.

SIRT3: Molecular Signaling in Insulin Resistance

Barber, Collin 04 1900 (has links)
A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / Post-translational modification of intracellular proteins through acetylation is recognized as an important regulatory mechanism of cellular energy homeostasis. Specific proteins called sirtuins deacetylate other mitochondrial proteins involved in glucose and lipid metabolism, activating them in metabolic processes. SIRT3 is a sirtuin of particular interest as it is found exclusively in mitochondria and has been shown to affect a variety of cellular metabolic processes. The activity of this enzyme is related to cellular insulin sensitivity. This study attempted to identify the relationship between insulin sensitivity and change in amount of SIRT3 following a bout of exercise in non-diabetic individuals. We find a moderate inverse correlation between insulin sensitivity and increase in SIRT3 abundance following exercise. This suggests that this protein may not be involved directly in cells’ ability to regulate energy homeostasis or that it may act through another mechanism not investigated in this study.

Studium signalizačních molekul imunoreceptorů / Studies on immunoreceptor signaling molecules

Ormsby, Tereza January 2011 (has links)
A delicate balance in the number, specific type and function of leukocytes is required for proper functionality of the mammalian immune system. Innate immunity, which quickly recognizes pathogens, represents the first line of defense. Later, a more specific response is generated via adaptive immunity. Deregulation of the immune system is manifested by the inability to control infection, development of allergic, autoimmune disorders or even cancer, and ultimately can lead to death. To fulfill their functions, cells develop an intricate network of intra- as well as extra-cellular molecules organized into signaling cascades, which allows them to communicate between each other. Better understanding of the molecular mechanisms of signaling pathways in leukocytes is critical for design of efficient therapies. In this thesis, leukocyte signaling was studied in several aspects. First, the role of adhesion molecules in pathogenesis of cervical cancer and the regulation of their expression was investigated. The second publication describes a new transmembrane adaptor protein (TRAP), called prolin rich 7 (PRR7), as a potentially interesting regulator of signaling and apoptosis in activated T cells. The final publication characterized the role of the Btk kinase downstream of the triggering receptor expressed...

Calcium/Calmodulin-Dependent Protein Kinase II Regulation of the Slow Delayed Rectifier Potassium Current, IKs, During Sustained Beta-Adrenergic Receptor Stimulation

Tyler A. Shugg (5930273) 02 January 2019 (has links)
<b>Background:</b> Sustained elevations in catecholaminergic signaling, mediated primarily through β-adrenergic receptor (β-AR) stimulation, are a hallmark neurohormonal alteration in heart failure (HF) that contribute to pathophysiologic cardiac remodeling. An important pathophysiological change during sustained β-AR stimulation is functional inhibition of the slow delayed rectifier potassium current, IKs, which has been demonstrated to prolong action potential duration (APD) and increase ventricular arrhythmogenesis in HF. Though functional inhibition of IKs has been consistently reproduced in cellular, animal, and limited human studies of HF, the mechanisms that mediate IKs inhibition during HF remain poorly understood.<div><br></div><div>In addition, HF results in aberrant calcium handling that is known to contribute to the disease. HF has been demonstrated to increase the expression and function of calcium/calmodulin-dependent protein kinase II (CaMKII), a key regulator of calcium homeostasis and excitation-contraction coupling in cardiomyocytes. Enhanced CaMKII signaling has been consistently demonstrated to contribute to increased arrhythmogenesis in a number of cardiac diseases, including HF. CaMKII is a known pathological regulator of many cardiac ion channels resulting in APD prolongation and the development of arrhythmias.<br></div><div><br></div><div><b>Objective:</b> This investigation aims to assesses the potential for CaMKII regulation of KCNQ1 (pore-forming subunit of IKs) during sustained β-AR stimulation and to characterize the potential functional implications on IKs. Furthermore, this investigation seeks to elucidate the mechanism underlying CaMKII-mediated IKs inhibition during sustained β-AR stimulation.<br></div><div><br></div><div><b>Methods: </b>Phosphorylation of KCNQ1 was assessed using a tandem liquid chromatography- mass spectrometry/ mass spectrometry (LCMS/MS) approach during sustained β-AR stimulation via treatment with 100 nM isoproterenol (ISO) for 4-24 hours and during co-expression with KCNE1. Whole-cell, voltage-clamp patch clamp electrophysiology experiments were performed in HEK 293 cells transiently co-expressing wild-type (WT) or mutant KCNQ1 (mutations conferring mimics of dephosphorylation and phosphorylation were introduced at phosphorylation sites identified by LCMS/MS) and KCNE1 (auxiliary subunit) during ISO treatment, treatment with CaMKII or protein kinase A (PKA) inhibitors, or during lentiviral δCaMKII overexpression. A robotic peptide synthesizer was used to create fifteen residue peptide fragments on a nitrocellulose membrane corresponding to KCNQ1 intracellular domains and the KCNQ1 residues identified via LCMS/MS; membranes were incubated with activated CaMKII or PKA in the presence of radiolabeled ATP to identify potential sites of phosphorylation. Bimolecular fluorescence complementation (BiFC) experiments were performed in HEK 293 cells to assess the impact of CaMKII-mediated KCNQ1 phosphorylation on the interaction of KCNQ1 and KCNE1 subunits. Protein immunoblot experiments were performed to (1) assess CaMKII activation during ISO treatment and (2) to assess plasma membrane expression of KCNQ1 and KCNE1 subunits with mimics of differential KCNQ1 phosphorylation following a membrane protein biotinylation procedure.<br></div><div><br></div><div><b>Results:</b> In Aim 1, we investigated the regulation of the KCNQ1 carboxyl terminus during sustained β-AR stimulation and assessed the associated functional implications on IKs. An LCMS/MS approach identified five novel KCNQ1 carboxyl terminal sites that demonstrated basal phosphorylation, with T482 and S484 having enhanced phosphorylation during treatment with 100 nM ISO for 24 hours (p<0.01 at both sites). Using patch clamp electrophysiology, we demonstrated that treatment with 100 nM ISO for 12-24 hours reduced IKs current density (p=0.01) and produced a depolarizing shift in the voltage dependence of activation (p<0.01) relative to vehicle. Mimics of phosphorylation (mutations to aspartic acid; Triple-D KCNQ1) at S457, T482, and S484 in combination, meanwhile, reduced IKs activation current density relative to dephosphorylation (mutations to alanine; Triple-A KCNQ1) mimics (p=0.02) but did not affect the voltage dependence of activation (p=0.66). Functional assessment of these sites individually revealed that phosphorylation mimics at S457 (p=0.02) and S484 (p=0.04), but not at T482 (p=0.53), reduced IKs current density relative to mimics of dephosphorylation. Similarly, the voltage dependence of activation was right-shifted with phosphorylation mimics at S457 (p=0.03) and S484 (p=0.02), but not at T482 (p=0.99), relative to mimics of dephosphorylation.<br></div><div><br></div><div>The focus of Aim 2 was to assess the potential for CaMKII signaling to regulate increased KCNQ1 phosphorylation and reduced IKs function during sustained β-AR stimulation. Peptide fragments corresponding to the KCNQ1 carboxyl terminal sites demonstrating basal phosphorylation via LCMS/MS analysis were synthesized on a nitrocellulose membrane and exposed to activated δCaMKII. Only peptide fragments corresponding to S484 demonstrated CaMKII phosphorylation. Patch clamp experiments demonstrated that CaMKII inhibition via the chemical inhibitor KN-93 (p=0.02) and the peptide inhibitor CN21 (p<0.01) reversed ISO-treatment associated inhibition of IKs activation current density relative to appropriate controls (KN-92 and CN21-Alanine, respectively). Inhibition with KN-93 and CN21 (p<0.01 for both) also reversed ISO-treatment associated right shifts in the voltage dependence of activation relative to appropriate controls. The ability of ISO treatment to activate CaMKII in HEK 293 cells was confirmed via protein immunoblot wherein T287 phosphorylation (CaMKII residue conferring constitutive activity) was increased during ISO treatment (p<0.05). Lentiviral overexpression of δCaMKII inhibited IKs activation current density with WT IKs (p=0.01) but not with Triple-A IKs (p=0.20) relative to lentiviral control. Inhibition of IKs activation current density during δCaMKII overexpression was attenuated with S484A IKs (p=0.04) but not with S457A (p=0.99) relative to WT IKs during δCaMKII overexpression. The voltage dependence of activation was also right-shifted during δCaMKII overexpression relative to lentiviral control (p=0.03). PKA inhibition with the peptide inhibitor PKI did not reverse ISO-treatment associated inhibition of IKs activation current density (p=0.51), and PKA did not phosphorylate peptide fragments corresponding to any of residues identified via LCMS/MS.<br></div><div><br></div><div>Aim 3 investigated the mechanism through which CaMKII-mediated phosphorylation at KCNQ1 S484 inhibits IKs function. To assess whether interaction with KCNE1 affects KCNQ1 phosphorylation, we performed LCMS/MS experiments during expression of KCNQ1 alone and during co-expression with KCNE1. Phosphorylation at S484 was reduced during co-expression with KCNE1 relative to expression of KCNQ1 alone (p<0.01). In addition, mimics of phosphorylation at S484 (S484D) did not affect activation current density (p=0.96) or the voltage dependence of activation (p=0.51) relative to dephosphorylation mimics (S484A). Based on these results, we hypothesized that S484 phosphorylation affected the interaction between KCNQ1 and KCNE1 subunits; accordingly, we assessed the KCNQ1-KCNE1 interaction using BiFC experiments in HEK 293 cells. In accordance with our hypothesis, Venus fluorescent intensity (corresponding to KCNQ1-KCNE1 interaction) was reduced during ISO treatment relative to vehicle (p<0.05) and with S484D KCNQ1 relative to S484A (p<0.01). The role of CaMKII in mediating this disruption of KCNQ1-KCNE1 interaction was demonstrated BiFC experiments that showed co-treatment with ISO and KN-93 attenuated reduced Venus intensity during co-treatment with ISO and KN-92 (p<0.01). These results were corroborated by BiFC experiments with Long QT Syndrome Phenotype 1 (LQT1) mutations that demonstrated that an LQT1 mutation predicted to disrupt CaMKII phosphorylation at S484 (R481I) attenuated reduced Venus intensity during ISO treatment relative to an LQT1 mutations predicted to not affect CaMKII regulation of S484 (S484T; p<0.01). The ability of S484 phosphorylation to affect KCNQ1 and/or KCNE1 trafficking was assessed via protein immunoblot experiments to detect KCNQ1 and KCNE1 following a biotinylation procedure to isolate plasma membrane-bound proteins. Biotinylation experiments demonstrated that KCNQ1 and KCNE1 plasma membrane expression were reduced by ~15% and ~33%, respectively, with S484D KCNQ1 relative to S484A (p<0.05 for both).<br></div><div><b><br></b></div><div><b>Conclusion: </b>CaMKII phosphorylates KCNQ1 S484 during sustained β-AR stimulation to inhibit IKs function. S484 phosphorylation inhibits IKs function by disrupting the interaction between KCNQ1 and KCNE1 subunits and by reducing the plasma membrane expression of KCNQ1 and KCNE1. Pathological regulation of KCNQ1 by CaMKII (and subsequent inhibition of IKs) during sustained β-AR stimulation may contribute to increased arrhythmogenesis during physiologic states of chronically increased catecholaminergic tone, such as during HF.<br></div>

Dividend Signaling and Sustainability

Hobbs, Jeffrey 05 January 2007 (has links)
Since the 1970s, dividends have not only become less common (Fama and French, 2001), they have become less sticky, too. Today, it is not uncommon for a firm to cease dividend payments within three years of initiation. I examine the differences between firms that continue to pay dividends for a long period of time after initiation and those that do not. Although investors do not distinguish between the two groups at the time of the dividend initiation announcement, the firms that pay over a long period of time experience superior operating performance in subsequent years. I construct a model that predicts, at the time of the initiation announcement, whether a firm is likely to pay dividends well into the future. My predictions also extend to performance; the firms that I predict to pay for a long period of time also outperform those whose payments I predict to be temporary. Thus, it appears that the relationship between dividend stickiness and long-run performance is not fully reflected in stock returns surrounding the announcements of dividend initiations. / Ph. D.

G Protein-Coupled Receptor Expression and Signaling in Yeast: Design and Optimization of Host/Protein Platform for Therapeutic Development

January 2019 (has links)
archives@tulane.edu / G protein-coupled receptors (GPCRs) constitute the largest family of human proteins with approximately around 800 genes and, are therapeutic targets for more than 35% of the FDA-approved drugs with around 180 billion dollars in sales. The therapeutic potential of GPCRs is still not completely utilized. Structure-guided drug discovery will definitely aid in identifying novel compounds with therapeutic responses while minimizing adverse effects in patients. Multiple protein engineering strategies including deletions, truncations, insertion of stable soluble protein or thermostabilizing mutations have been utilized to obtain the structural information of these membrane proteins. Yet to date, the high-resolution structure of only 63 GPCRs have been determined, with only a few of these structures being of active protein. Heterologous expression of most GPCRs results in low yields of active receptors and additional strategies are required to improve active receptor yields for these “hard-to-express” GPCRs. Yeast provides a unique heterologous expression platform to produce mammalian GPCRs, as it also allows us to measure downstream signaling activity with an easy and inexpensive high-throughput assay via its MAPK response pathway. The adenosine A2A receptor (A2AR) shows exceptional expression and trafficking to the plasma membrane in yeast; however, this is not the case for other adenosine receptors. A2AR has a longer C-terminus than the other adenosine receptor subtypes, which may contribute to its exceptional trafficking to the plasma membrane. To test the possibility to improve trafficking of the adenosine A1 receptor (A1R), chimeric receptors containing the seven transmembrane domains of A1R and the full-length or truncated A2AR C-terminus were constructed. The chimeric receptor showed improved localization to the plasma membrane and was capable of binding radioligand with native-like A1R affinity. Functionally active A1R receptor variants were produced at a theoretical yield of 95 pmol/mg total membrane protein, estimated using radioligand binding data, which is greater than three-fold higher than previously reported yields from other heterologous expression systems, and should facilitate biophysical characterization and drug discovery efforts. Recent efforts to determine the high-resolution crystal structures for the adenosine A1 and A2A receptors have utilized modifications to the native receptors in order to facilitate receptor crystallization and structure determination. One common modification is a truncation of the unstructured C-terminus, which has been employed for all the adenosine crystal structures obtained to date. Here, the presence of the full-length C-terminus is shown to affect downstream signaling using a yeast MAPK response-based fluorescence assay. Upon ligand binding, the A1d291R or A2Ad316R variants were unable to couple to human-yeast chimeric G-protein chimeras to generate a downstream signal in yeast, though full-length receptors showed native-like G-protein coupling. Further, constructs transfected into HEK-293 cells showed similar behavior – i.e. the variants with C-terminal truncations lacked cAMP-linked signaling compared to the full-length receptors. Although the C-terminus was essential for Ga protein- associated signaling, chimeras of A1R with a C-terminus of A2AR coupled to the A1R-specific Ga (i.e. Gai1 versus Gas). This surprising result suggests that the C-terminus is important in signaling, but not specificity, for the interaction with Ga protein. Based on these results for chimeric A1R variants, chimeric variants for adenosine A3R and tachykinin 2 receptor (NK2R) were constructed. The A3/A2AR variant was constructed using an approach similar to that for A1/A2AR; the resulting construct showed a two-fold increased expression as compared to the wild-type A3R. This chimeric variant showed native-like signaling activity in engineered yeast strains with a modified MAPK pathway, whereas the wild-type receptor showed no activity. In order to improve the functional expression of human NK2R required for high-resolution structural studies, NK2R chimeras utilizing sequences from rat NK2R previously shown to have a higher functional expression in yeast than human NK2R were utilized. Herein, we show that NK2R chimeras incorporating the rat NK2R C-terminus demonstrated improved expression, ligand binding, and downstream signaling in engineered yeast strains. Taken together, these results highlight the utility of the chimeric receptor engineering strategy to facilitate the expression of active receptors. / 0 / Abhinav Rabindra Jain

The Role of Calcium Flux in the Regulation of Filopodia Dynamics

Ademuyiwa, Omolade Mary 12 August 2019 (has links)
No description available.

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