VictorJuiz/thesis huggingface dataset:
Characterization of Mice with Altered Dopamine Transporter and Vesicular Monoamine Transporter 2 Levels
Keywords: Dopamine
Dopamine transporter
Transgenic mice
Vesicular monoamine transporter 2

Dopamine is a key neurotransmitter that regulates motor coordination and dysfunction of the dopamine system gives rise to Parkinsonâ s disease. Nigrostriatal dopamine neurons are vulnerable to various genetic and environmental insults, suggesting that these cells are inherently at-risk. A cell-specific risk factor for these neurons is the neurotransmitter, dopamine itself. If intracellular dopamine is not appropriately sequestered into vesicles, it can accumulate in the cytosol. Cytosolic dopamine is highly reactive and can trigger oxidative stress, leading to cellular toxicity. Cytosolic dopamine levels are modulated by the plasma membrane dopamine transporter (DAT) that takes up dopamine from the extracellular space, and the vesicular monoamine transporter 2 (VMAT2) that stores dopamine into vesicles. In this thesis, we altered DAT and VMAT2 levels to investigate the detrimental consequences of potentially amplifying cytosolic dopamine in transgenic mice. Project 1 focused on selective over-expression of DAT in dopaminergic cells of transgenic mice (DAT-tg). DAT-tg mice displayed phenotypes of dopaminergic damage: increased dopamine-specific oxidative stress, L-DOPA-reversible fine motor deficits and enhanced sensitivity to toxicant insult, suggesting that increasing DAT-mediated dopamine uptake is detrimental for dopamine cells. As an extension of Project 1, Project 2 focused on mice that simultaneously over-express DAT and under-express VMAT2 (DAT-tg/VMAT2-kd mice). These animals were hypothesized to demonstrate exacerbated dopaminergic toxicity due to buildup of cytosolic dopamine caused by increased uptake and decreased packaging. While DAT-tg/VMAT2-kd mice displayed detrimental phenotypes (poor survival, decreased body weight, reduced dopamine tissue content and release) and compensatory changes (increased dopamine receptors and metabolism), they did not show dopamine cell loss. This is due to unexpected loss of phenotypes in DAT-tg mice from a new colony that no longer displayed dopaminergic neurodegeneration. Thus, instead of Parkinsonian behavior, DAT-tg/VMAT2-kd mice showed novel phenotypes such as hyperactivity and improved fine-motor and cognitive skills compared to other genotypes. DAT-tg/VMAT2-kd mice were also highly sensitive to amphetamine-induced locomotion. Hence, in the absence of neurodegeneration, altered DAT and VMAT2 levels produced unique behavioral changes in DAT-tg/VMAT2-kd mice, shedding light on the complex function of the dopamine system. Collectively, these studies demonstrate how perturbations in dopamine compartmentalization can impact dopamine homeostasis and behavior.
Novel Nation: Victorian Realism and the Fiction(s) of England
Keywords: Critical Reception
England
Imagined Geographies
National Identity
Realism
Victorian Novel

The idea that the Victorian novel—in particular, the Victorian realist novel—became an integral and transformational part of both individual and national identity in England during the nineteenth century provides the broad framework of my dissertation project. In “Novel Nation: Victorian Realism and the Fiction(s) of England,” I examine the careers, works, and public reception of four of the most celebrated authors—then and now—from the second half of the nineteenth century: Elizabeth Gaskell, Anthony Trollope, George Eliot, and Thomas Hardy. These authors, I suggest, saw themselves and were themselves seen as writing within a newly emergent, specifically English literary tradition that placed the novel as a genre, and their novels in particular, at the centre of a living national literature that was actively shaping the contours and character of the nation in very real and lasting ways. More specifically, I argue the representational claims to (and in some cases, denials of) “the real” that these authors made—particularly in relation to place—along with the critical constructions by reviewers and readers of these authors as cultural authorities and national icons, worked to shape a powerful new vision of the English nation as a fundamentally literary entity. By taking into account how the immediate reception of an author’s works influenced their subsequent writings, as well as how their writings influenced their readers, I examine the reciprocal, even porous relationship that existed between the Victorian novel and its readers—a relationship that reveals the seepage between fiction and reality that is at the core of this dissertation project. Thus, while my project examines the specific and varied ways in which these authors and their works imagined, engaged with, and challenged ideas of English national identity and the English nation, it is equally interested in exploring how they and their novels became (willingly or not) symbols and repositories of Englishness—how, that is, they became England’s national culture—and, more broadly, how the English nation became rooted in, realized through, and reimagined by such fictions so that England itself became a “Novel Nation.”
The Modulation of Endothelial Progenitor Cell Function by the Liver X Receptors
Keywords: Atherosclerosis
Cholesterol
Endothelial progenitor cell
Hematopoietic stem cell
Liver x receptor

Atherosclerosis is a chronic disease that predisposes patients to myocardial infarction and is characterized by deposition of lipid-laden plaques in the aorta. These plaques arise after macrophages uptake modified cholesterol-rich lipoproteins. Bone marrow (BM) transplant experiments highlight the important anti-atherogenic effects of liver x receptors (LXRs) in promoting macrophage cholesterol efflux. However, transplantation of whole BM contains other cells, aside from monocytes/macrophages, including endothelial progenitor cells (EPCs), which facilitate endothelial repair through the release of vasoreparative factors. We hypothesized EPCs may also be involved in the anti-atherogenic response of LXRs by reducing endothelial defects during atherosclerosis. We first investigated the effects of Western diet (WD) feeding on disrupting hematopoietic balance in LXR-knockout (Lxr-/-) mice. Despite increased plasma cholesterol in both WT and Lxr-/- mice after WD feeding, myeloid progenitor and mature populations were increased only in the WD-fed Lxr-/- mice, whereas EPC numbers were significantly decreased. We demonstrated that increased cholesterol content of culture-derived EPCs from WD-fed Lxr-/- mice correlated with increased expression of endothelial markers, Cd144 and Vegfr2, and altered the release of factors that increased in vitro adhesion of monocytes to endothelial cells. We next evaluated the therapeutic potential of LXR activation in EPCs during atherosclerosis. Pharmacologic activation of LXRs during differentiation decreased the expression of Cd144 and Vegfr2 in WT EPCs. Analysis of the secretome by mass spectrometry revealed qualitative changes which resulted in decreased in vitro monocyte-endothelial adhesion. Tail vein administration of conditioned media from agonist-treated EPCs to Ldlr-knockout mice resulted in decreased adhesion molecule expression (VCAM-1), leukocytes (CD45), and lesion area in the aortic sinus. Together, these data support important roles for LXRs in i) regulating the numbers and function of EPCs; ii) preserving the balance of EPCs relative to pro-atherogenic myeloid populations; and iii) producing a secretome from culture-derived EPCs that elicits anti-atherogenic effects.
On the Matter of the Digital in Contemporary Media Art
Keywords: Arts-Based
Digital
Materiality
Media Art
Mediat Theory

This dissertation brings together aesthesis, media art and theory to explore how contemporary media artists are aestheticizing, conceptualizing and grappling with “digital materiality” through their artworks and practices of making. It stems from a series of process-oriented interviews conducted with thirty-three contemporary media artists from across North America and Europe. Responding to prominent themes that emerged through a triangulated analysis of the interviews, corresponding artworks and media theory, the dissertation offers grounded accounts of five coinciding strategies that artists are enacting in an effort to make sense of the materiality of the digital. Developed over five substantive chapters, these key areas of material analysis include: the materiality of glitch; the indexical materialism of digital surfaces; the treatment of digital materiality as a matter of “resolutions”; the transpositional concretization of “formal materialism” in Post-Internet Art; and the deployment of “synesthetic catachresis” as a means of grasping at modes of materialism that remain definitionally evasive. While each chapter maps out a different perspective on materiality, the driving intention of the dissertation is to advance an overarching aesthetic approach that moves beyond hardware/software distinctions to provide needed perspective on the material dynamism of contemporary digital processes.
The role of FAK and related signalling in adipocytes and the pathogenesis of obesity and diabetes
Keywords: adipose tissue
caspase
diabetes
focal adhesion kinase
obesity

Obesity and diabetes, key elements of the metabolic syndrome, are fast expanding global epidemics. While obesity is the strongest risk factor for type 2 diabetes, most obese people do not develop diabetes, and many people with diabetes are not obese. This suggests a complex relationship between excess body weight, primarily adipose tissue, and diabetes, characterized by insulin resistance. Adipocyte cell death has been hypothesized to be an initiating factor in chronic, obesity-associated inflammation thought to lead to insulin resistance and diabetes, but the mechanisms regulating this process remain poorly understood. Thus, in this work, I sought to better understand the cell survival pathways regulating adipose tissue and its role in glucose and energy homeostasis. Focal adhesion kinase (FAK) plays a central role in integrin signaling which regulates growth and survival of tumors, but its role in growth in other contexts is less well known. In Chapter IV, I find that FAK is increased in adipose tissue of mice and humans with obesity and insulin resistance. Using adipose tissue-specific FAK knockout mice I report that FAK in adipose tissue is required to maintain insulin sensitivity, particularly in the setting of metabolic stress induced by high fat diet feeding or genetic models of obesity. In Chapter V, I demonstrate that disruption of FAK impairs adipocyte survival both in vitro in 3T3-L1 adipocytes and in vivo, contributing to inflammation and insulin resistance, which can be attenuated by pharmacologic or genetic inhibition of apoptosis. In Chapter VI, I further identify the specific role of apoptotic protein caspase 8 in adipose tissue regulation of glucose and energy homeostasis. I show that disruption of caspase 8 improves glucose tolerance and protects from weight gain in mouse models of obesity and insulin resistance. Our results identify novel roles for FAK in promoting adipocyte survival and insulin sensitivity with metabolic stress, whereas caspase 8 promotes cell death and inflammation contributing to insulin resistance with metabolic stress. Characterizing the interplay of specific signaling pathways helps us to better understand the complex interaction between obesity and diabetes. These findings improve our knowledge of the signaling pathways regulating adipose tissue and their role in obesity, diabetes and metabolic syndrome.
Comparing Patient Engagement and Patient Advocacy Activities and Measuring Preferred Roles in Medical Decision Making among Cystic Fibrosis Patients, Caregivers, Family Members and Patient Advocates
Keywords: cystic fibrosis
medical decision making
patient advocacy
patient engagement

Background: Patient engagement has become a priority for healthcare organizations, yet remains inconsistently defined. Patient engagement has also become a priority for healthcare providers. Current discourse suggests that patients today desire more control over medical decision making than ever before, and that the proliferation of online health information is empowering patients to make autonomous medical decisions. Yet, prior research indicates that patients typically prefer to share decisions with their physician, raising questions about what patient engagement is and whether preferences have changed over time. Methods: This study addresses multiple research questions using three phases of data collection. Phase one asked: how are ‘patient engagement’ and ‘patient advocacy’ defined and perceived by individuals who are involved in engagement and advocacy activities? This question was addressed by conducting semi-structured key informant interviews (N=11). Phases two and three examined preferred roles in medical decision making among cystic fibrosis (CF) patients, caregivers, family members and patient advocates, and whether these roles were related to: trust in the physician, self-assessed health information literacy and demographics. Phase two involved conducting a quantitative cross-sectional survey (N=165), which included three scales: the Problem-Solving Decision-Making Scale (PSDM), the Trust in Physician Scale (TPS), and the electronic Health Information Literacy Scale (eHEALS). T-tests and logistic regressions were computed to determine the relationships between variables. Phase three involved interviewing a subgroup of survey participants to help to explain survey results (N=19). Thematic analysis was used to identify common themes. Results: Our findings suggest that patient engagement and advocacy have multiple meanings, that most survey participants preferred to share medical decisions with their physician (>80%), and that self-assessed health information literacy was associated with preferred roles; as eHealth literacy went down, so did desire for participation in making medical decisions. Follow-up interviews supported these results; participants mentioned how they assessed the credibility of online health information and how they preferred to direct questions to their physician. Conclusion: This research highlights the need for clear language regarding patient engagement activities. This study also suggests that eHealth literacy may influence decision making preferences, and that preference for autonomous decision making should not be assumed.
Actomyosin Dynamics During Coordinated Cell Movements in Embryonic Wound Repair
Keywords: actomyosin contractility
collective migration
FRAP
fruit fly
Laser ablation
wound repair

Embryos repair epithelial wounds rapidly, in a process driven by collective cell behaviors. Upon wounding, filamentous actin and the motor protein non-muscle myosin II polarize in the cells adjacent to the wound, forming a supracellular cable around the lesion. Contraction at the wound margin coordinates cell movements and drives rapid wound closure. Using FRAP in Drosophila embryos, we found that myosin turnover at the wound margin was slower than in actomyosin networks with reduced contractility. Using laser ablation we showed that tension in the wound margin cable increased as wound closure progressed, which was associated with reduced myosin turnover. Reducing tension resulted in increased turnover and loss of myosin from the wound edge. Finally, myosin motor activity was necessary for its stabilization around the wound and for efficient wound closure. Our results indicate that mechanical forces regulate myosin dynamics during embryonic wound repair, however we could not discount regulation of myosin through its binding partner, actin. To investigate a role for tension in regulating actin during wound repair, we used FRAP to show that actin was stabilized around embryonic wounds. Loss of tension through laser ablation led to loss of actin fluorescence, however, photobleaching experiments after laser severing showed no change in actin turnover. We found no changes in actin dynamics between early and late wound closure, when tension is higher. Together these data suggest that tension may be partially necessary for actin localization, but it is neither necessary nor sufficient to regulate actin turnover. To begin to pick apart the relationship between actin and myosin at the wound margin, we inhibited myosin activity and measured actin turnover. Actin stabilization was independent of myosin activity, suggesting actin may be regulated independently. To understand whether myosin turnover is independent of actin, we stabilized actin networks pharmacologically and monitored for changes in myosin dynamics. Myosin turnover was unaffected by actin stabilization. These results suggest that actin and myosin are independently regulated, and that these networks are more complex than expected. This work provides insights into the mechanisms used by cells to coordinate their behaviour and could have implications for development and disease.
Reconstructing Rural Chengdu: Urbanization as Development in the Post-Quake Context
Keywords: Chengdu
China
development
earthquake
planning
urbanization

On 12 May 2008 Western China was struck by an 8.0-magnitude earthquake (the Wenchuan Earthquake) that left over 87,000 people dead or missing, and destroyed nearly 8 million homes. The epicenter of the quake lay less than 100 km away from Chengdu, the capital city of Sichuan Province. Although the central city itself was not damaged by the quake, many settlements in Chengdu’s rural periphery had to be completely rebuilt. This dissertation examines how the Chengdu government used post-quake reconstruction as an opportunity to urbanize rural areas in the metropolitan region under the policy of “urban-rural integration”. But urban-rural integration was not merely urbanization in the sense of an expansion of the built-up urban core; it was a far more comprehensive project that was framed as a means of developing the rural economy, improving living environments, and bolstering peasants’ rights. I argue that Chengdu’s urbanization is best understood as a developmental project—a form of “development qua urbanization”—and as a form of governmental power in the Foucauldian sense. I further interpret the underlying logics of urban-rural integration—that rural areas are best developed through urbanization—in the context of China’s current historical conjuncture. In doing so, I turn to Polanyi’s description of the transition to a market society, and Lefebvre’s prediction of the transition to an urban society. Drawing on media and policy analysis, academic debates on Chengdu’s urban-rural integration project, and participant observation work and in-depth interviews conducted in peri-urban Chengdu over a period of nearly two years, I examine the multiple forms that post-quake urbanization in Chengdu took, including rationalizing land use throughout the metropolitan region, building concentrated villages, assigning individual titles to rural collective land, developing markets for rural property rights, encouraging large-scale agribusiness, extending social services to rural areas, reforming rural governance institutions, and transforming peasants into self-managing citizens.
Graceful Symmetry: The Politics of Grace in Shakespeare, Spenser, and Milton
Keywords: Early Modern literature
Edmund Spenser
Intellectual History
John Milton
Protestant theology
William Shakespeare

Graceful Symmetry explores the relationship between grace and political agency in the work of William Shakespeare, Edmund Spenser, and John Milton. These writers were part of a Protestant culture that understood grace through the slogan sola gratia, or “grace alone,” which means that God has the prerogative to save or condemn human beings freely. Protestants inherited this vision of salvation from St. Paul, who imagines grace as a form of liberation within submission to God—so that liberty is, paradoxically, the experience of being bound. Shakespeare, Spenser, and Milton explore the political ramifications of these scriptural paradoxes. They suggest that, by magnifying the freedom of God, and by redefining the believer’s agency as a form of submission to the divine, grace challenges existing political obligations between subjects and their human sovereign. Shakespeare and Spenser deploy the rhetoric of religious grace to explore the degree to which monarchical power is compatible with active political participation from Protestant citizens. Taking this approach to a radical extreme, Milton argues that grace regenerates ordinary Christians to the extent that that they become capable of wielding sovereignty as citizens of a free republic, thus making monarchy unnecessary. Shakespeare, Spenser, and Milton ultimately coopt the religious language of grace to reimagine a wide range of political concepts—such as imperialism, absolutism, nationalism, and republicanism—during political crises such as Tyrone’s rebellion in Ireland and the English Civil Wars. I argue that grace is central not only for Protestant theology but also for the political ideals of Renaissance humanism, such as republicanism. The interdisciplinary resonance of grace was ultimately due to the tendency among a wide variety of early modern writers—including the literary writers I explore—to use Paul as an authority on legal and political questions as well as religious ones. By demonstrating how Paul’s writing on grace influenced early modern culture and religion, I argue that politics is inseparable from theology in post-Reformation English literature.
Applications of Piers-Rubinsztajn Chemistry: Synthesis of Materials for Organic Electronics
Keywords: Organic Electronics
Piers-Rubinsztajn
silicon phthalocyanine
siloxane
triarylamine

Since the advent of the age of organic electronics, new materials are being developed regularly for use in these types of devices. Their processing methods have also evolved over the years, resulting in new, commercially-available applications. The application of these materials from solution, also known as solution processing, is lower-cost and less energy intensive with many other added benefits. To that end, this thesis explores the Piers-Rubinsztajn reaction as a tool to enable the solution processing of organic electronic materials. Piers-Rubinsztajn chemistry is a versatile, expedient reaction using an organic Lewis acidic catalyst tris(pentafluorophenyl)borane to couple a Si-H bond with an oxygen based nucleophile. This type of chemistry is underexplored in the field of materiasl development for organic electronics applications. This chemistry can be used to incorporate different types of siloxane oligomers into the structure of an organic electronic material, thus merging the properties of siloxane materials, such as flexibility, with those of the original compound. This methodology is used in this thesis to alter the physical properties of a variety of organic electronic materials to enable and ameliorate their solution processing. Chapters 2 to 5 explore the use of Piers-Rubinsztajn chemistry to cross-link triarylamine derivatives, to allow sequential solution processing for its application in an organic light emitting diode. Chapter 6 involves the synthesis of phenoxylated siloxane polymers, via Piers-Rubinsztajn chemistry, as a new material with improved organic-phase miscibility, for potential application in an organic electronic device. Chapters 7 and 8 follow the scale-up synthesis and application of a liquid triarylamine derivative in a dye-sensitized solar cell. Finally, Chapter 9 will cover the use of Piers-Rubinsztajn chemistry to functionalize insoluble silicon phthalocyanine derivatives to enable their use in bulk-heterojunction organic photovoltaics.