VictorJuiz/thesis huggingface dataset:
Role of VEGF and VEGF Receptors in the Glomerulus

VEGF is a potent angiogenic and endothelial cell growth factor that is key for the development of the glomerulus, the main filtration unit of the kidney. It is continued to be expressed in the mature glomerulus, with podocytes being the major site of production. VEGF binds to two receptors, VEGFR-1 and VEGFR-2, which are expressed by the adjacent endothelial cells (ECs). VEGFR-2 is the primary mediator of VEGF signaling while VEGFR-1is thought to function as a ‘decoy’ receptor, sequestering VEGF away from VEGFR-2. Gene targeting studies in mice show that VEGF loss from the podocyte results in profound defects of the ECs, consistent with a paracrine signaling loop. However, the identification of VEGF receptors on podocytes in vitro suggests an additional autocrine signaling pathway for VEGF may exist. To further study the role of VEGF in the glomerulus and to address whether a VEGF autocrine loop is functional in vivo, we generated a transgenic mouse model with inducible VEGF upregulation in the podocyte and genetically deleted VEGFR-2 and VEGFR-1 from the podocyte using the Cre-loxP system. Increased VEGF production from the podocyte leads to increased glomerular permeability and ultrastructural changes in the glomerular filtration barrier depending on the time and length of induction. Podocyte-selective deletion of VEGFR-2 did not cause glomerular disease. In contrast, VEGFR-1 loss from the podocyte led to proteinuria and glomerular defects at 6 weeks of age with extensive podocyte foot process effacement. In keeping with the model that VEGFR-1 functions as a VEGF trap, similarities were observed between the glomerular lesions of VEGFR-1 mutant mice and transgenic mice that overexpress VEGF within podocytes. Strikingly, in vitro studies also revealed an increase in podocyte cell adhesion to sVEGFR-1, suggesting additional roles for sVEGFR-1. Together, these data suggest that a tight regulation of VEGF must be maintained in the adult glomerulus. Furthermore, these findings provide the first genetic evidence that VEGF autocrine signaling loop through VEGFR-2 is dispensable in normal glomeruli. In addition, podocytes express sVEGFR-1 and is required in podocytes in vivo to maintain glomerular integrity by regulating VEGF availability and podocyte cell adhesive properties.

Keywords: VEGF
VEGF Receptors
Glomerulus
Podocyte
Advisor: Quaggin, Susan E.
Fantus, George
The Establishment and Stabilization of Anterior-posterior Identity In the Hindbrain: On the Regulation of the Segmentation Gene MafB

In vertebrates, the embryonic hindbrain is transiently subdivided along its anterior-posterior (A-P) axis into 8 well defined segments termed rhombomeres (r1-8). Each rhombomere represents a true cellular compartment in transcriptional profile, lineage restriction and neuronal organization. Thus, the vertebrate hindbrain provides a beautiful model for studying mechanisms of anterior-posterior patterning, signal transduction and interpretation, initiation and maintenance of transcriptional profiles, cell sorting and border formation. The Kreisler/MafB gene, which encodes a basic leucine zipper (bZIP) transcription factor that regulates some Hox genes, is one of the first genes to be expressed segmentally in the hindbrain, and is subject to a dynamic and complex regulatory process. However, unlike the Hox genes, Kreisler/MafB is not located within a large cluster of genes and therefore provides a simple system for dissecting the molecular mechanisms involved in hindbrain compartmentalization. In dissecting the mechanisms that govern Kreisler/MafB regulation, we have identified the S5 regulatory element that directs early MafB expression in the future r5-r6 domain. We have found a binding site within S5 that is specific for the Variant Hepatocyte Nuclear Factor 1 (vHNF1) to be essential, but not sufficient for early induction of r5-r6-specific expression. Thus, early inductive events that initiate MafB expression are clearly distinct from later acting ones that modulate its expression levels. Using mouse mutants, we have shown that MafB is dependent on the M33 polycomb protein and other mechanisms of chromatin remodeling. We then utilized transgenic flies and mice as well as binding assays to identify and validate a PcG/trxG response element (PRE), PRE1 which acts to reorganize the surrounding chromatin, regulating S5-dependent expression. To our knowledge, PRE1 is the first validated vertebrate PcG/trxG response element. Thus, PRE1 provides a springboard for further exploration of the mechanisms governing chromatin remodeling.

Keywords: Hindbrain patterning
MafB regulation
Chromatin Remodeling
Polycomb Response Elements
Advisor: Cordes, Sabine
Qur'anic Exegesis in Later Islamic Philosophy: Mulla Sadra's Tafsir Surat al-Fatiha

The work of one of Islam’s most celebrated philosophers, Mulla Sadra Shirazi(d. 1045/1635 or 1050/1640), is characterized by a unique synthesis of the main strands of Islamic thought. Yet Sadra’s role as a philosopher was not simply to synthesize. His penetrating intellect and ability to cast new light on some of the fundamental problems of Islamic thought ensured that all of his books would be landmarks of intellectual achievement in their own right. Amongst his most significant but seriously neglected writings are his compositions on the Qur’an and its sciences. Broadly speaking, the present study investigates the manner in which scriptural exegesis, philosophy, and mysticism came together in Sadra’s writings on the Qur’an. More specifically, this study aims to examine the sophistication of the discussions to be found in Sadra’s Qur’anic works by focusing on his last complete and most mature tafsir, the Tafsir Surat al-fatiha. After surveying the history, reception, and content of Sadra’s writings on the Qur’an and presenting a coherent picture of the theoretical dimensions of his scriptural hermeneutics, we will go on to examine the Tafsir Surat al-fatiha’s structure and sources. This will set the stage for a careful analysis of the problems in cosmology, metaphysics, anthropology, theology, and soteriology addressed by Sadra in the work. Not only will our study demonstrate the manner in which Sadra reads scripture, but it will also afford us a window into the development of his religious thought, since the Fatiha provides him with the opportunity to recast many of his philosophical concerns within the Qur’an’s universe of discourse.

Keywords: Islamic Philosophy
Qur'anic Exegesis
Advisor: Lawson, Todd
Molecular Characterization of the von Hippel-Lindau Tumour Suppressor Protein

Inheritance of one mutant von Hippel-Lindau (VHL) allele gives rise to the development of the autosomal dominant VHL disease, which affects approximately 1 in 36 000 individuals. The VHL tumour suppressor protein plays a critical role in the E3 ubiquitin ligase-mediated destruction of hypoxia-inducible factor (HIF) and the promotion of fibronectin extracellular matrix assembly. A failure in either process is associated with oncogenic progression. Work included in this thesis provides evidence that these tumour suppressor functions are mutually exclusive. Additionally, post-translational modification of VHL by NEDD8 is shown to act as a ‘molecular switch’, altering VHL protein associations and providing a mechanism of pathway segregation. As a result of HIF stabilization, the expression of a homophilic adhesion molecule E-cadherin is significantly down-regulated in primary renal clear-cell carcinoma (RCC) upon VHL loss. E-cadherin down-regulation is shown to increase the invasive potential and is of prognostic value in RCC. Finally, VHL and SOCS1 are shown to dimerize and negatively regulate the JAK2-STAT5 signalling cascade. Defects in this dimerization are shown to underlie Chuvash polycythemia and provide a molecular understanding of the phenotypic observations associated with VHL-related polycythemias.

Keywords: VHL
Hypoxia
Advisor: Ohh, Michael
Linear-time invariant Positive Systems: Stabilization and the Servomechanism Problem

Positive systems, which carry the well known property of confining the state, output, and/or input variables to the nonnegative orphant, are of great practical importance, as the nonnegative property occurs quite frequently in numerous applications and in nature. These type of systems frequently occur in hydrology where they are used to model natural and artificial networks of reservoirs; in biology where they are used to describe the transportation, accumulation, and drainage processes of elements and compounds like hormones, glucose, insulin, and metals; and in stocking, industrial, and engineering systems where chemical reactions, heat exchanges, and distillation processes take place. The interest of this dissertation is in two key problems: positive stabilization and the positive servomechanism problem. In particular, this thesis outlines the necessary and sufficient conditions for the stabilization of positive linear time-invariant (LTI) systems using state feedback control, along with providing an algorithm for constructing such a stabilizing regulator. Moreover, the results on stabilization also encompass the two problems of the positive separation principle and stabilization via observer design. The second, and most emphasized, problem of this dissertation considers the positive servomechanism problem for both single-input single-output (SISO) and multi-input multi-output (MIMO) stable positive LTI systems. The study of the positive servomechanism problem focuses on the tracking problem of nonnegative constant reference signals for unknown/known stable SISO/MIMO positive LTI systems with nonnegative unmeasurable/measurable constant disturbances via switching tuning clamping regulators (TcR), linear quadratic clamping regulators (LTQcR), and ending with MPC control. Finally, all theoretical results on the positive servomechanism problem are justified via numerous experimental results on a waterworks system.

Keywords: positive systems
positive stabilization
positive servomechanism problem
tracking and disturbance rejection
tuning clamping regulators
LQR and MPC optimal control
Advisor: Davison, Edward J.
Bibliofictions: Ovidian Heroines and the Tudor Book

This dissertation explores how the mythological heroines from Ovid‘s Heroides and Metamorphoses were cataloged, conflated, reconceived, and recontextualized in vernacular literature; in so doing, it joins considerations of voice, authority, and gender with reflections on Tudor technologies of textual reproduction and ideas about the book. In the late medieval and Renaissance eras, Ovid‘s poetry stimulated the imaginations of authors ranging from Geoffrey Chaucer and John Gower to Isabella Whitney, William Shakespeare, and Michael Drayton. Ovid‘s characteristic bookishness—his interest in textual revision and his thematization of the physicality and malleability of art in its physical environments—was not lost upon these postclassical interpreters who engaged with his polysemous cast of female characters. His numerous English protégés replicated and expanded Ovid‘s metatextual concerns by reading and rewriting his metamorphic poetry in light of the metaphors through which they understood both established networks of scribal dissemination and emergent modes of printed book production. My study of Greco-Roman tradition and English bibliofictions (or fictive representations of books, their life cycles, and the communication circuits in which they operate) melds literary analysis with the theoretical concerns of book history by focusing on intersections and interactions between physical, metaphorical, and imaginary books. I posit the Tudor book as a site of complex cultural and literary negotiations between real and inscribed, historical and fictional readers, editors, commentators, and authors, and, as my discussion unfolds, I combine bibliographical, historical, and literary perspectives as a means to understanding both the reception of Ovidian poetry in English literature and Ovid‘s place in the history of books. This dissertation thus contributes to a growing body of book history criticism while also modeling a bibliographically enriched approach to the study of late medieval and Renaissance intertextuality.

Keywords: Ovid
Tudor
Early Modern
Renaissance
Late Medieval
Print Culture
Book History
querelle des femmes
epistolary
Elizabethan
Henrician
metamorphosis
Classical Tradition
De Worde, Wynkyn
Caxton, William
Daniel, Samuel
Chaucer, Geoffrey
Shakespeare, William
Drayton, Michael
Whitney, Isabella
Skelton, John
Advisor: Harvey, Elizabeth D.
Greater Toronto Area Urban Heat Island: Analysis of Temperature and Extremes

This study analyzes the trends in temperature, and their extremes, in the Greater Toronto Area (GTA) in the context of urban heat island. The trends in annual and seasonal temperature changes were investigated in the GTA over the past century and a half with special focus on 1970-2000. The Mann-Kendall test is used to assess the significance of the trends and the Theil-Sen slope estimator is used to identify their magnitude. Statistically significant increasing trends for mean and minimum temperatures are observed mainly at the urban and suburban stations. The sequential Mann-Kendall test is used to identify any abrupt change in the time series of temperature (31 -161 years), and the results indicate that increasing trend for annual mean temperature has started after 1920 at Toronto downtown, after the 1960s at the suburban stations, and has increased significantly during the 1980s at all stations, which is consistent with the pace of urbanization during these periods in the GTA. The observed urban heat island (UHI) in Toronto is quantified and characterized by considering three different rural stations. The UHI intensity (∆Tu-r) in Toronto is categorized as winter dominating or summer dominating depending on the choice of a rural station. The results from the trend analysis of annual and seasonal ∆Tu-r suggest that the choice of the rural station is crucial in the estimation of ∆Tu-r, and thus can overestimate or underestimate its prediction depending on the location and topographical characteristics of a rural station relative to the urban station. The trends in extreme temperature indices are also investigated and the results indicate that indices based on daily maximum temperature are more pronounced at the urban and suburban stations compared to that at the rural stations. The changes in the trends for extreme indices based on daily minimum temperature are consistent at all stations for the period of 1971-2000. With the decrease in the percentage of cold nights and the increase in the percentage of warm nights, the diurnal temperature range has decreased throughout the GTA region. The analysis of heating degree days and cooling degree days revealed that the former is associated with decreasing trends and the latter exhibited increasing trends at almost all stations in the GTA. Finally, it is evident from the results that urban heat island phenomenon exerts warmer influence on the climate in cities, and with the current pace of urbanization in the GTA, it is imperative to understand the potential impact of the emerging UHI on humans and society.

Keywords: Urban heat island
Climate change in cities
Trend analysis
Greater Toronto Area
Advisor: Gough, William A.
Characterization of Peripherin Isoforms in Amyotrophic Lateral Sclerosis

Peripherin is a type III intermediate filament protein that is predominately expressed in the peripheral nervous system and in subsets of efferent projections in the central nervous systems. While the exact role of peripherin remains unclear, it is found upregulated after traumatic neuronal injury and in the devastating neurodegenerative disease amyotrophic lateral sclerosis (ALS). Interestingly, peripherin overexpressing transgenic mice succumb to motor neuron disease with pathological hallmarks reminiscent of those found in ALS. Pathological peripherin abnormalities occur with high frequency in both familial and sporadic forms of ALS, with peripherin found associated with the majority intracellular inclusions present within degenerating motor neuron populations. The findings of peripherin mutations in sporadic ALS have reinforced the importance of peripherin as a prospective etiological or propagative factor of disease pathogenesis. Surprisingly, inherited peripherin gene mutations have not been identified; as such, understanding the post-transcriptional mechanism at which peripherin imparts its effect(s) is considered a key goal and represents a pathological point-of-convergence for an otherwise complex, multifaceted disease. Prior to the commencement of this work, our group identified the presence of an abnormal peripherin alternative splice variant upregulated in ALS. In doing so, we consistently observed the presence of a second peripherin species of ~45 kDa on immunoblots of cell lysates derived from full-length peripherin transfections. Here, we identified this protein as a constitutively expressed isoform, termed Per-45, that arises from alternative translation and that is required for normal filament assembly: changes to the normal isoform expression pattern are associated with malformed filaments and intracellular inclusions. In lieu of the possibility of distinct peripherin intra-isoform associations, we identified isoform-specific expression and ratio changes in traumatic neuronal injury, in mouse models of motor neuron disease, and in ALS. Finally, we explored the interrelationships between peripherin isoform expression, protein aggregation, and neuritic outgrowth by linking these phenotypes with major pathogenic features associated with ALS, including in vitro models of oxidation, glutamate excitotoxicity, and neuroinflammation. Overall, this thesis provides exciting new insight into our knowledge of basic IF biology and the role of peripherin isoforms in injury and in motor neuron disease.

Keywords: Amyotrophic Lateral Sclerosis (ALS)
Isoforms
alternative translation
aggregation
Advisor: Robertson, Janice
'Just Act Naturally': A Poetics of Documentary Performance

This dissertation formulates a poetics of performance in nonfiction film and television. Building on a large body of converging research that calls for an acknowledgment of: the constructedness of documentary texts; the performative nature of identity; and the significance of screen performance, I illustrate the way in which documentary subjects must finally be seen as creative agents who (consciously or not) play a significant role in determining the meanings, functions, and effects of the films in which they appear. A first chapter lays the groundwork for this discussion, setting out a means of understanding and investigating the documentary performer’s work. It is argued that nonfiction performance is a three-tiered process, wherein everyday performative activity (tier #1) is shaped by and often tailored to the camera (tier #2) within specific nonfiction film frameworks (tier #3). In addition to providing a flexible and generally applicable model of what the nonfiction subject’s work entails, this conceptualization suggests an appropriate means of analysing individual documentary performances, indicating the necessity of attending to the way in which twice modified everyday self-presentational tools serve as signifiers in any given nonfiction text. Subsequent chapters turn from the issue of what nonfiction performance involves to a consideration of what it accomplishes. Drawing from scholarship devoted to each of the three levels of the documentary ‘social actor’s’ work, I posit three major functions for nonfiction performance. Chapter 2 demonstrates the way in which the individuals who appear in documentaries play a significant role in the construction of ‘characters’, which, in turn, exert an indelible influence on the meaning(s) of the texts in which they figure. Chapter 3 argues that nonfiction performance helps to bolster and/or to destabilize normative understandings of identity categories such as gender, sexuality, age, ethnicity, race, class and dis/ability. Finally, the concluding chapter discusses the way in which documentary performers help to invite affective reactions from spectators, and – in so doing – contribute significantly to nonfiction texts’ ability to effectuate social change. Detailed analyses of a wide range of documentaries provide support for these contentions.

Keywords: Documentary Film
Performance
Self-Presentation
Advisor: Keil, Charlie
'Hast Thou Been Tampering?' Adaptive Dramaturgy and Richard III

Shakespeare’s Richard III is the most often performed history play within the western dramatic canon, yet at the end of the seventeenth century it was considered virtually unplayable. The extensive textual alteration undertaken by comedian Colley Cibber in 1700 revived interest in the rarely performed play, and actor David Garrick’s adoption of Cibber’s text in 1744 ensured the work’s popular survival. Regular performance and textual revision throughout the eighteenth century positioned Cibber’s adaptation as one of the most well-known works on the London stages, and by the time Henry Irving permanently restored Shakespeare’s text to the popular repertoire in 1877, Cibber’s adaptation had served as a conduit to restoring Richard III from its “virtually unplayable” position to its lost Elizabethan fame. The adaptive development of Richard III from unplayable to indispensable can be tracked dramaturgically, from Shakespeare’s Quarto (1597) and Folio (1623) to Cibber’s version, eighteenth- and nineteenth-century performative adaptations, and twentieth century film realisations. Through parallel-text analysis of the prompt-scripts of some of the most notorious, iconic, and effective adaptations of the play, this study examines in a practical sense the dramaturgical drive present throughout the play’s varied life-span: often changing, but nevertheless a constant product. The negative stigma attached to adaptation – characterised in Cibber’s words as “tampering” – is examined throughout the performative history of Richard III. Chapter one considers theoretical perspectives on adaptation studies, and adopts Gérard Genette’s evocative “transtextuality” discourse to quantify conclusions to emerge from parallel comparison of texts. Chapter two analyses Cibber’s process of “re-visioning” Shakespeare’s play; Chapter three examines the impact of performative adaptation on six different stage editions of Richard III. Chapter four addresses the transitional process of developing a stage-bound text on film through the screenplay format, and Chapter five demonstrates the use of cinematic visualisation on the text. Finally, Chapter six tracks the impact of adaptation on the survival and perpetuation of texts over successive generations and throughout varied cultures and contexts. Through analysis of fourteen different performance editions, prompt-books, film texts, and unpublished manuscripts, this dissertation considers the validity of “tampering” on the adaptive process.

Keywords: dramaturgy
adaptation
Advisor: Levenson, Jill L.
Astington, John H.
Hutcheon, Linda
Hodgdon, Barbara