VictorJuiz/thesis huggingface dataset:
Novel Regulatory Mechanisms of D1 Dopamine Receptor Maturation and Internalization
Keywords: pharmacology
molecular

Novel Regulatory Mechanisms of D1 Dopamine Receptor Maturation and Internalization Michael Ming Chuen Kong Degree of Doctor of Philosophy, 2008 Department of Pharmacology University of Toronto ABSTRACT Dopamine is the most abundant catecholamine neurotransmitter in the mammalian brain and controls various physiological processes. The D1 dopamine receptor (D1DR) is the predominant dopamine receptor in the brain and traditionally couples to stimulatory G proteins, such as Gs, to activate adenylyl cyclase and generate cAMP. Although the trafficking itinerary of ER/Golgi maturation, agonist-induced internalization, and recycling/degradation are features common to many G protein-coupled receptors (GPCRs), the molecular regulation of these individual processes for the D1DR is not fully elucidated. Many GPCRs have been shown to form homo-oligomers; the work presented in this thesis explores how multimerization of D1DR has a role in regulating how these receptors are trafficked to the plasma membrane. In addition, the regulation of D1DR internalization is investigated in the context of emerging evidence highlighting the importance of lipid rafts. Using strategically designed point mutations of the D1DR, specific receptor mutants were found to intracellularly sequester the wild-type receptor by oligomerization. This level of scrutiny by the quality control machinery in the cell could be circumvented by treatment with cell permeable dopaminergic agonists, but not antagonists or inverse agonists. This finding suggests that specific conformational requirements must be achieved before full maturation and anterograde trafficking of the D1DR can proceed. Furthermore, it was determined that cell surface bound D1DRs could internalize through a novel clathrin independent pathway that required binding to the scaffolding protein, caveolin-1. This interaction with caveolin-1 was identified in whole rat brain and was found to require a putative caveolin binding motif in transmembrane domain 7. Palmitoylation of D1DR was found to regulate the rate of agonist-induced caveolae mediated internalization. Finally, we determined that the integrity of caveolae was important in regulating cAMP signaling through D1DR. These findings provide novel insight into the trafficking requirements of newly synthesized D1DRs as well as alternative mechanisms of regulation of receptors after agonist activation. The oligomerization of GPCRs and the localization of GPCRs in lipid rafts represent two emerging concepts important to many aspects of GPCR function. Future work aimed at integrating these overlapping processes will further our understanding of this important group of cell surface receptors.
Mechanism Design with Partial Revelation
Keywords: Mechanism Design
Auctions

With the emergence of the Internet as a global structure for communication and interaction, many “business to consumer” and “business to business” applications have migrated online, thus increasing the need for software agents that can act on behalf of people, institutions or companies with private and often conflicting interests. The design of such agents, and the protocols (i.e., mechanisms) through which they interact, has therefore naturally become an important research theme. Classical mechanism design techniques from the economics literature do not account for the costs entailed with the full revelation of preferences that they require. The aim of this thesis is to investigate how to design mechanisms that only require the revelation of partial preference information and are applicable in any mechanism design context. We call this partial revelation mechanism design. Reducing revelation costs is thus our main concern. With only partial revelation, the designer has some remaining uncertainty over the agents’ types, even after the mechanism has been executed. Thus, in general, the outcome chosen will not be optimal with respect to the designer’s objective function. This alone raises interesting questions about which (part of the) information should be elicited in order to minimize the degree of sub-optimality incurred by the mechanism. But this sub-optimality of the mechanism’s outcome choice function has additional important consequences: most of the results in classical mechanism design which guarantee that agents will reveal their type truthfully to the mechanism rely on the fact that the optimal outcome is chosen. We must therefore also investigate if, and how, appropriate incentives can be maintained in partial revelation mechanisms. We start by presenting our own model for partial revelation mechanism design. Our second contribution is a negative one regarding the quasi-impossibility of implementing partial revelation mechanisms with exact incentive properties. The rest of the thesis shows, in different settings, how this negative result can be bypassed in various settings, depending on the designer's objective (e.g., social welfare, revenue...) and the interaction type (sequential or one shot). Finally, we study how the approximation of the incentive properties can be further improved when necessary, and in the process, introduce and proves the existence of a new equilibrium concept.
Knowledge Provenance: An Approach to Modeling and Maintaining The Evolution and Validity of Knowledge
Keywords: Knowledge Provenance
Trust Formalization

The Web has become an open decentralized global information / knowledge repository, a platform for distributed computing and global electronic markets, where people are confronted with information of unknown sources, and need to interact with “strangers”. This makes trust and the validity of information in cyberspace arise as crucial issues. This thesis proposes knowledge provenance (KP) as a formal approach to determining the origin and validity of information / knowledge on the Web, by means of modeling and maintaining the information sources, information dependencies, and trust structures. We conceptualize and axiomatize KP ontology including static KP and dynamic KP. The proposed KP ontology, provides a formal representation of linking trust in information creators and belief in the information created; lays a foundation for further study of knowledge provenance; provides logical systems for provenance reasoning by machines. The web ontology of KP can be used to annotate web information; and KP reasoner can be used as a tool to trace the origin and to determine the validity of Web information. Since knowledge provenance is based on trust in information sources, this thesis also proposes a logical theory of trust in epistemic logic and situation calculus. In particular, we formally define the semantics of trust; from it, we identify two types of trust: trust in belief and trust in performance; reveal and prove that trust in belief is transitive; trust in performance is not, but by trust in belief, trust in performance can propagate in social networks; by using situation calculus in trust formalization, the context of trust is formally represented by reified fluents; we also propose a distributed logical model for trust reasoning using social networks, by which each agent’s private data about trust relationships can be protected. This study provides a formal theoretical analysis on the transitivity of trust, which supports trust propagation in social networks. This study of trust supports not only knowledge provenance but also the general trust modeling in cyberspace.
External Entry and the Evolution of Clusters: A Study of the Biotechnology Industry in Canada
Keywords: industry clusters
innovation
evolutionary economics
entrepreneurship
international business
economic geography

Building on recent work in economic geography, evolutionary economics, and international business, I examine how firms that enter from outside a region alter the knowledge and opportunity structure for potential entrepreneurial entrants and indigenous incumbents in that region. In particular, I examine the short and long run effects of both greenfield and acquisition entry on entrepreneurial entry, as well as on the exit and growth of indigenous incumbents in industry clusters. A comprehensive dataset of all firms in the Canadian biotech industry between 1976 and 2003 is used to study the dynamic effects within all regions that have experienced an external entry. The results show a complex set of processes at work. Newer greenfield and acquisition entrants have consistently opposing effects, with newer greenfields enhancing entrepreneurial entry, but dampening growth and survival of indigenous incumbents in the longer run. Older greenfields, those that have a long presence in a given region and are primarily traditional pharmaceutical firms, have a similar effect to that of acquisitions. Moreover, the level of agglomeration moderates the influence of ‘outsiders’ on the indigenous industry, especially in the case of acquisitions. The results suggest that legal constraints on labor mobility barriers have an important influence on the observed patterns. The overall patterns suggest that the search and site selection of outsiders is an important mechanism driving local industry evolution, complementary to other traditional mechanisms.
Power and Process: The Politics of Electricity Sector Reform in Uganda
Keywords: Uganda
policy
energy
governance
East Africa
public sector reform

In 2007, Uganda had one of the lowest levels of access to electricity in the world. Given the influence of multilateral and bilateral agencies in Uganda; the strong international reputation and domestic influence of its President; the country’s historic achievements in public sector and economic reform; and the intimate connection between economic performance, social well-being and access to electricity, the problems with Uganda’s electricity sector have proven deeply frustrating and, indeed, puzzling. Following increased scholarly attention to the relationship between political change, policymaking, and public sector reform in sub-Saharan Africa and the developing world generally, this thesis examines the multilevel politics of Uganda’s electricity sector reform process. This study contends that explanations for Uganda’s electricity sector reform problems generally, and hydroelectric dam construction efforts specifically, must move beyond technical and financial factors. Problems in this sector have also been the result of a model of reform (promoted by the World Bank) that failed adequately to account for the character of political change. Indeed, the model of reform that was promoted and implemented was risky and it was deeply antagonistic to domestic and international civil society organizations. In addition, it was presented as a linear, technical, apolitical exercise. Finally the model was inconsistent with key principles the Bank itself, and public policy literature generally, suggest are needed for success. Based on this analysis, the thesis contends that policymaking and reform must be understood as deeply political processes, which not only define access to services, but also participation in, and exclusion from, national debates. Future approaches to reform and policymaking must anticipate the complex, multilevel, non-linear character of ‘second-generation’ policy issues like electricity, and the political and institutional capacity needed to increase the potential for success. At the heart of this approach is a need to carefully consider how the character of state-society relations in the country – “governance” – will influence reform processes and outcomes.
On the Scaling and Ordering of Columnar Joints
Keywords: Pattern formation
Nonlinear dynamics
Geophysics
Fracture
Basalt

Columnar jointing is a fracture pattern, best known from locations such as the Giant's Causeway, or Fingal's Cave, in which cracks self-organize into a nearly hexagonal arrangement, leaving behind an ordered colonnade. In this thesis observations of columnar jointing are reported from both a controlled laboratory setting, and in cooled lava flows. Experiments were performed in slurries of corn starch and water, which form columnar joints when dried. This drying process is examined in detail, and it is shown how desiccation leads to the propagation of a sharp shrinkage front. In general, but with some significant exceptions, the size of columnar joints is inversely dependent on the speed of this shrinkage front during their formation. The exceptions, which include sudden jumps in column scale, show that hysteresis is also important in choosing the column scale. Novel observations of the 3D structure of joints in starch show that columnar joints do not settle down to a perfect hexagonal pattern, but rather mature into a continuously evolving dynamic pattern. This pattern is scale invariant, and the same statistical distribution of column shapes applies equally to joints in both starch and lava. Field work was performed to study columnar jointing in the basalts of the Columbia River Basalt Group and the island of Staffa, and the more heterogeneous lava flows of Southwestern British Columbia. The widths of columns and the heights of striae (chisel-like markings that record details of cooling) were examined in detail, and these length scales are shown to be inversely proportional to each other. An additional length scale, that of wavy columns, is also first reported here. Based on these measurements, empirical advective-diffusive models are developed to describe the transport of water in a drying starch-cake, and the transport of heat in a cooling lava flow. These models have only a single scaling parameter, the Péclet number, which relates the fracture front velocity times the column size to the (thermal or hydraulic) diffusivity. In both cases, the formation of columnar joints occurs at a Péclet number of about 0.2. This model explains the hundred-fold differences in scale between columnar joints in starches and lavas, and can be used as a tool for the interpretation of joint patterns in the field.
Genetic Variation at the Insulin-like Growth Factor 1 Gene and Association with Breast Cancer, Breast Density and Anthropometric Measures
Keywords: Epidemiology
Genetics
Breast cancer
Mammographic density
insulin-like growth factor 1

Background and objectives Evidence suggests that circulating IGF-I levels increase mammographic density (a breast cancer risk factor) and breast cancer risk in premenopausal women. The objective of this thesis was to examine the association of genetic variation at the IGF1 gene with IGF-I concentration, mammographic density, breast cancer risk, and related anthropometric measures in premenopausal women. Methods Three IGF1 CA repeat polymorphisms (at the 5′ and 3′ ends, and in intron 2) were genotyped. A cross-sectional design was used to investigate their associations with IGF-I levels, mammographic density, BMI, weight, and height. Families from registries in Ontario and Australia were used to investigate associations with breast cancer risk and also BMI, weight and height. Results In the cross-sectional study, greater number of copies of the 5′ 19 allele were associated with lower circulating IGF-I levels. Greater number of 3′ 185 alleles were associated with greater percentage breast density, smaller amount of non-dense tissue, and lower BMI. Including BMI in regression models removed the association of the 3′ 185 allele with percentage breast density. In the family based study, nominally significant associations (5′ 21 allele, intron 2 212 allele, intron 2 216 allele) with breast cancer risk were observed, but significance was lost after multiple comparison adjustment. There was a stronger association between the intron 2 216 allele and risk under a recessive model, and 5′ allele groupings of length 18 to 20 and 20 or more repeats produced significant positive and negative associations respectively. These associations were not strongly supported in analyses stratified by registry. Results from the family based study did not support an association between genetic variation at IGF1 with BMI, weight or height. Conclusions No specific IGF1 variant influenced each of circulating IGF-I levels, mammographic density, and breast cancer risk. The failure to replicate the association of the 3′ 185 allele with BMI in the family based study suggests that the association of the 3′ 185 allele with percentage breast density is spurious, since this association was mediated through the relationship with BMI (suggesting IGF-I action on body fat). Evidence for an association between IGF1 and breast cancer risk was limited.
The Timecourse of Neurogenic Inflammation and the Effect of Modulatory Agents
Keywords: Inflammation
Pain

Activation of nociceptors causes them to secrete neuropeptides, such as substance P (SP) and calcitonin-gene related peptide (CGRP). By reacting with receptors on blood vessels these peptides contribute to inflammation by evoking vasodilation and increasing vascular permeability that allows proteins and fluid to leave the blood vessels (plasma extravasation, PE). These substances can also lead to the sensitization of nociceptors and the resulting positive feedback thereby prolongs inflammation and pain. Thus, blocking the release of neuropeptides may have important therapeutic value in pain conditions where neuropeptides have been implicated. Therefore, the aim of this study was to define the time course of changes in vascular permeability and to test the ability of novel agents to modulate this response. PE and vasodilation was evoked by stimulating the saphenous nerve or by injecting the chemical irritant capsaicin into the rat hindpaw. Changes in blood flow were evaluated with a laser Doppler and digitized image analysis was used to measure changes in reflectance of the skin due to accumulation of extravasated (EB) dye. Analysis of the change in pixel intensity in the digitized images revealed that the magnitude of PE was dependent on the stimulus pulse number. Moreover, the time course of enhanced vascular permeability produced by electrical stimulation was a transient event compared to a much longer response with capsaicin. It was also demonstrated that sumatriptan, (a 5-HT1B/D receptor agonist) and botulinum neurotoxin type-A were effective treatments for capsaicin and saphenous nerve induced vasodilation and PE. Neither drug interfered with activation of the SP or CGRP receptor, which may suggest that both drugs work by inhibiting neuropeptide release. Therefore, this study has described the time course of vascular permeability evoked by two different stimuli and has demonstrated the ability of two novel agents to attenuate these responses.
The Disposable Camera: Image, Energy, Environment
Keywords: Cinema
Environment

“The Disposable Camera” theorizes the relationship between the cinematic image and energy resources. Framed by the emergent carbon-neutral cinema, the recent UCLA report on the film industry’s environmental footprint, as well as common perceptions about digital sustainability, “The Disposable Camera” posits that cinema has always been aware of its connection to the environment, the realm from which it sources its power, raw materials and, often enough, subject matter. But because the natural environment is so inextricably embedded within film’s basic means of production, distribution and reception, its effects remain as overlooked as they are complex. “The Disposable Camera” argues that cinematic history and theory can and indeed ought to be reappraised against the emerging ascendancy of environmental politics, all films; as such, all cinema could logically be included within the analytical parameters of this project. Primary focus, however, is given to documentary cinema, as well as notable experimental and narrative films. Selected texts do not overtly represent an environmental issue; rather, they reflexively engage with and theorize themselves as films, thus addressing the technological, industrial, and resource-derived essence of the moving image. Of import here are films that reveal how specific formal or aesthetic choices evidence and critique the ideology attached to resource consumption and/ or abuse. While it composes a distinctly environmental trajectory of the cinematic image, this project likewise historicizes and critiques these same stages and also challenges the utopian and/ or apocalyptical tendencies challenging eco-politics. Additionally, “The Disposable Camera” is committed to mapping out the shift from a distinctly tangible celluloid-based cinematic infrastructure to the ostensibly immaterial form of digital filmmaking. Indeed, the tension that now pits cinema’s material past against its immaterial future corresponds with the decline of natural reality on the one hand and the rise of cyber realities on the other, a parallel condition that fully evidences the increasingly palpable overlap between environmental and cinematic politics.
Oculomotor Biomarkers of Illness and Response to Transcranial Magnetic Stimulation in Major Depression
Keywords: Depression
Eye-Tracking
Neuromodulation
Saccade
Transcranial Magnetic Stimulation

Currently, little rationale exists for treatment selection and staging in depression despite the variety of therapies and frequent occurrence of treatment resistance. In this study, patients experiencing a major depressive episode and healthy controls completed an eye-tracking task, the interleaved pro- and anti-saccade task (IPAST), to assess dorsolateral prefrontal cortex (dlPFC) function at baseline, and again at a follow-up visit. Between visits, patients with depression received 4 weeks of daily transcranial magnetic stimulation (TMS) targeting the dlPFC. Group differences in reaction time (RT), error rates, and speed-accuracy trade-off (SATO) measures, and their association with depressive symptomatology, were tested. At baseline, patients with depression had impaired anti-saccade RT which differed by subsequent treatment response, suggesting both diagnostic and prognostic value. Change in reflexive anti-saccade errors was associated with change in depressive symptoms. Together, this suggests eye-tracking biomarkers may have some utility in selecting candidates for TMS treatment and monitoring treatment response.
The Dynamic Orchestration of Self-Driving Laboratories
Keywords: Bayesian Optimization
Chemistry
Self-Driving Lab

Self-Driving Labs (SDLs) combine automated hardware with computational experiment planning tools to reduce the time between experiments and liberate chemists from routine work, allowing them to focus on bigger, more conceptual problems. SDLs thus have the potential to acceleration of chemical research. However, SDLs are often difficult to implement for existing labs. Barriers include financial cost, lack of accessible Application Programming Interfaces (APIs) for chemical hardware, and modularity. Another one is orchestration: the administration of the plethora of toolsavailable to the laboratory users. Unfortunately, existing frameworks lack one of the following key elements: modularity, data collection strategies, and a comprehensive real-life implementation. To address these concerns, this research presents a framework for orchestrating chemical labs, and the automation of laboratory instruments. In addition, implementations are presented to demonstrate the implementation of this framework: A campaign for the synthesis of organic laser molecules, as well as an electrochemical optimization experiment.