VictorJuiz/thesis huggingface dataset:
Hypoxia, invasion and metastasis in pancreatic cancer

Hypoxia and tumour-stroma cross-talk are implicated in the aggressive pathophysiology of pancreatic ductal adenocarcinoma (PDAC). This thesis explores the heterogeneity in response of targeting hypoxia-related invasive and metastatic pathways in PDAC. The first focus is an exploration of focal adhesion kinase (FAK) targeting supported by prior observations of hypoxic-upregulation of FAK activity in PDAC. The second focus includes preliminary observations from PIMO-PANC, a trial characterizing hypoxia (using the hypoxia tracer PIMOnidazole) in patients with PANCreatic adenocarcinoma. To explore the phenotype of FAK inhibition, the dominant negative acting construct FRNK (FAK-related non-kinase) was stably overexpressed in human PANC1 and BxPC3 PDAC cell lines. Anti-cancer activity was observed in PANC1, a cell line demonstrating features of epithelial-to-mesenchymal transition (EMT), with impaired adhesion to collagen and serum-induced chemotaxis. Orthotopic Panc1-FRNK xenograft tumours were smaller, and tumour-bearing animals had reduced metastatic burden and prolonged survival. Similar effects were not apparent in the more epithelial BxPC3-FRNK tumors. In a patient-derived xenograft model OCIP5I, which demonstrates nuclear Snail expression with loss of cytokeratin, there was a trend to modest anti-invasive and anti-metastatic activity of the FAK/Pyk2 inhibitor PF-562271 (Pfizer). This differential activity in Panc1 and OCIP51 suggests that activity of FAK kinase inhibition might be most relevant to tumours with features of EMT. PIMO-PANC has a primary objective of evaluating the prognostic and biological relevance of severe hypoxia in PDAC through administration of the hypoxia marker pimonidazole to patients prior to resection. Bioactive reduction of pimonidazole yields immune-detectable adducts indicative of severe hypoxia. Although a well-established technique for studying tumour hypoxia, methods of analysis are not standardized. A semi-automated image analysis platform was used to differentiate epithelial and stromal tumour elements and quantify pimonidazole positivity in 10 patient tumours, analyzing multiple sections per individual tumour. This is the first analysis to describe tumoral hypoxia using quantitative immunohistochemistry while exploring the heterogeneity of hypoxia and related sampling error in surgical samples. These findings, including the minimal levels of nitroimidazole-detectable hypoxia observed in a subset of patients, have important implications for the development of hypoxia-targeting strategies in PDAC.

Keywords: focal adhesion kinase
hypoxia
invasion
metastases
nitroimidazole
pancreatic cancer
Advisor: Hedley, David W
Design, Modelling and Analysis of Triboelectric Nanogenerators

In today’s world, energy storage has become a critical issue in energy generation and harvesting technologies. As a result, research efforts in the sustainable energy discipline have consistently focused on the generation of energy from environmentally-friendly sources. Recently, a fundamentally new technology, triboelectric nanogenerator (TENG), has been demonstrated for its unique merits that include considerable output power, high efficiency, and cost-effective materials. There is a significant body of research focusing on designing TENG; however, there are no guidelines for developing improved TENG designs and structures. To address this challenge, this work introduces TENG design guidelines experimental and computational designs. Furthermore, this dissertation has two primary objectives: (1) to develop accurate 3D multi-physics finite element model (FEA) and (2) to perform a detailed techno-economic life cycle assessment. The developed FEA is used to determine appropriate TENG geometries offering an optimal efficiency for such a design. Experimentally, different case studies are developed for water wave, and wind energy harvesting. Regarding water wave energy, a duck-shaped TENG is proposed to achieve an instantaneous output power up to 1.366 W.m-2. As for wind energy, TENG and Darrieus conventional turbines are compared, with results predicting the unique advantages offered by TENG at low rotation speed. Moreover, inspired by the hummingbird-wing structure, we proposed a TENG design that attained 1.5 W m-2 peak electrical output. In addition, an 11 life cycle environmental metrics are determined. The environmental impact of the selected TENGs is lower compared to traditional photovoltaics technologies. Moreover, The Levelized Cost of Electricity of selected TENGs is also very sensitive to the module efficiency and is expected to be lower than that of other energy technologies if the modules’ efficiencies and lifetimes exceed 25% and 15 years, respectively.

Advisor: Zu, Jean
Optimizing the Molecular Design of Triarylamines, Phthalocyanines, Subphthalocyanines, and Their Derivatives using Organic Light Emitting Diodes

Organic semiconductors are a family of carbon based molecules that possess the ability to conduct electricity. As these materials transition from niche applications to consumer products, compounds with special mechanical, electrical, and optical properties will become increasingly sought after. Since no a-priori rational design process yet exists to design organic semiconductor materials, screening studies are necessary in order to rank and sort promising motifs and derivatives. This rationale forms the basis for the experimental portion of this thesis, in which organic light emitting diodes (OLEDs) are used as a test platform to screen novel compositions of matter from a range of structural families. Based on these experiments, and others, we have determined that the modification of triarylamines using silicone oligomers does not significantly reduce their charge carrier mobility, and that their performance in solution processed hole transport layers show promise compared to their vapour deposited equivalents. We have also shown that the axial substitution of pentafluorphenoxy fragments to Pc rings containing group 13/14 core atoms results in a two order of magnitude improvement in their performance as an HTL in OLEDs. Chloro boron-subphthalocyanine (Cl-BsubPc) was shown to work as an emissive hole transport layer, and as an emissive interlayer in warm-white emitting OLEDs. Key to this functionality are its dual emission peaks, which contribute strongly in the both orange and red portions of the visible spectrum. The importance of this finding in the context of indoor lighting research is discussed. The potential of Cl-BsubNc as a red fluorescent emitter in white emitting OLEDs is also investigated, and found to be relatively poor. Overall, the results presented herein show how simple bi-layer OLEDs can be used as a screening tool to guide ongoing synthetic research into organic semiconductors, and the potential application of some of these materials in white emitting OLEDs are highlighted

Keywords: Aggregate Emission
Fluorescence
Materials Screening
Organic Light Emitting Diodes
Organic Semiconductors
Subphthalocyanines
Advisor: Bender, Timothy P
Quantifying the Resistance and Resilience of Freshwater Ecosystems to Anthropogenic Disturbance

As many as 2 million lakes are estimated to be in Canada that provide beneficial ecosystem services to society such as clean drinking water and freshwater fisheries. However, anthropogenic disturbances on the landscape threaten the delivery of these services and pose questions regarding the maintenance of lake systems to future change. Understanding and quantifying the resistance and resilience of lake systems to disturbance is therefore a priority. The objectives of this thesis are to: 1) develop a quantitative framework for characterizing the resistance and resilience of ecosystems to disturbance; and, 2) quantify the relative resistance and resilience of freshwater lakes in Ontario to anthropogenic disturbance. I begin with a simulation study to demonstrate how distance-based measures in ordination space can provide a framework for characterizing the relative resistance and resilience of systems to disturbance. I then apply the distance-based approach to long-term monitoring data of crustacean zooplankton communities and associated water chemistry data from 19 lakes in Ontario subjected to varying levels of acidification. I show that most zooplankton communities lack resistance to change over time, whether affected by acidification or not, and that water chemistry is changing among all the lakes studied. Finally, I approach resilience from a functional diversity perspective and quantify the functional redundancy of Ontario lake fish communities across the province and relate these patterns to biogeographic and environmental variables. My results demonstrate patterns of redundancy among freshwater fish communities provincially, however, these patterns varied regionally. Overall, this body of work provides a multidimensional approach for characterizing the resistance and resilience of freshwater ecosystems to anthropogenic disturbance that can be applied across systems (e.g., terrestrial, marine, freshwater) and scales (e.g., species, community, ecosystem).

Keywords: Community ecology
Diversity
Freshwater
Resilience
Resistance
Advisor: Jackson, Donald A
Somers, Keith M
Natures of Alterity in British Romanticism

This dissertation explores intersections between naturalist debates and formulations of human otherness in the Romantic period. Alterity, which in this study denotes a range of incongruities in experience and being, furnishes the writers I consider with means to interrogate the meanings generated in aesthetic, scientific, and sociological representations of the human. The long eighteenth century witnessed the advent of new scientific approaches to the study of human nature, and with this line of experimentalism came initiatives to transform modernizing European societies in accordance with new objective knowledge. The view that politics, jurisprudence, civil society, and other social organizations could be approached alongside new revelations about the laws of our nature found adherents from a range of political, scientific, and aesthetic orientations well into the nineteenth century. Exploring writings by William Blake, William Wordsworth, Mary Shelley, and James Hogg, I claim that some of the major categories of otherness explored in the Romantic period – mental illness, the non-human, and various forms of cultural difference – achieve meaning directly in relation to these discourses. As I illustrate, the social ostracism afflicting Wordsworth’s mentally ill, Frankenstein’s indeterminate lifeform, Hogg’s fanatics, and Blake’s outlaws stems partly from the category problems these figures illustrate within the emergent human sciences. The writings I examine offer at least two lines of rejoinder to dominant long eighteenth-century constructions of human nature: the first ontological, interrogating the viability of a category like human nature; and the second social, exploring the concrete problems attending recent initiatives to rethink social organizations as extensions of what Wordsworth labels “the primary laws of our nature.” By exploring how Romantics use certain forms of otherness to critique the discourses by which difference could be measured in nature and society, my study offers a corrective to what continues to remain a truism for many commentators: that for most Romantics, understanding our nature is of undisputed importance to our imaginative, emotional, and interpersonal life. I show that otherness can provide Romantic writers with a unique foundation for confronting the problems involved in nature thinking, especially when its categories become mobilized in the nascent sciences of society.

Keywords: alterity studies
British Romanticism
history of science
intellectual history
Advisor: Bewell, Alan
The Role and Regulation of Insulin-Like Growth Factor Binding Protein-4 in the Rodent Intestinal Mucosa

Insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF) and glucagon-like peptide-2 (GLP-2) are all hormones that induce intestinal mucosal proliferation and growth. They are also interdependent as GLP-2 relies on IGF-1 and EGF to act as intermediary factors, which in turn act synergistically on the intestinal epithelium to stimulate proliferation. IGF binding protein-4 (IGFBP-4) regulates the activity of IGF-1 and is expressed highly in the intestine. IGFBP-4 can inhibit IGF-1 activity, but also promotes IGF-1-induced growth in a protease-dependent manner in whole body and bone. However, the role of IGFBP-4 within the intestine is not well defined. Thus, I hypothesized that IGFBP-4 is required for the growth promoting effects of GLP-2, which require the actions of IGF-1, but inhibits basal intestinal epithelial proliferation. Because the intestinal growth factors stimulate Sox9 expression, a transcriptional promoter for IGFBP-4, I also hypothesized that mucosal IGFBP-4 expression is stimulated by GLP-2, IGF-1, and EGF. GLP-2-treated control mice displayed increased intestinal weight per body weight, crypt-villus height and epithelial proliferation while the IGFBP-4 knockout (KO) mice had impaired increases in all of these parameters. In contrast, vehicle-treated IGFBP-4 KO mice had elevated intestinal weight per body weight, crypt-villus height, and epithelial proliferation compared to vehicle-treated control mice. Consistently, IGFBP-4 dose-dependently decreased IEC-6 cell proliferation in an IGF-1 receptor (IGF-1R)- and MEK1/2-dependent manner. Finally, chronic GLP-2 treatment in vivo increased mucosal IGFBP-4 mRNA expression. However, chronic inhibition of EGFR and/or intestinal epithelial IGF-1R KO in vivo did not alter mucosal IGFBP-4 expression. Altogether, the results demonstrate that IGFBP-4 is integral for promoting GLP-2-induced mucosal growth and inhibiting growth under basal conditions and that mucosal IGFBP-4 expression is regulated in a GLP-2-dependent but not IGF-1/EGF-dependent manner.

Keywords: EGF
Epithelium
GLP-2
IGF-1
IGFBP-4
Intestine
Advisor: Brubaker, Patricia L
Therapeutic Potential of Surfactant Protein D (SP-D): Regulation of Apoptosis, Efferocytosis and Lung Inflammation

Apoptosis is a process by which cells die in a silent and non-inflammatory way. This process is usually followed by efferocytosis, the uptake of apoptotic bodies by alveolar macrophages. Apoptosis and efferocytosis are important for maintaining baseline tissues homeostasis. Accumulation of dying cells is damaging in many ways for the tissues and is the cause of many inflammatory lung diseases. Surfactant protein D (SP-D) is a soluble innate immune protein present on the airway surface and other mucosal surfaces. SP-D has been shown to bind to dying cells and improve the phagocytosis of apoptotic cells and bodies. Dead cells have been shown to accumulate in the lung of SP-D knockout mice. However, the effect of SP-D on apoptotic pathways, apoptotic microparticle (MP) generation and MP-mediated inflammatory response are unknown. For my PhD project, I hypothesize that SP-D modulates the extrinsic pathway of apoptosis and enhances MP formation and uptake by alveolar macrophages while suppressing their inflammatory response. The studies conducted for this thesis uncovered that SP-D binds to T cells and delays the progression of Fas:Fas ligand (FasL) and TNF-α related apoptosis inducing ligand (TRAIL):TRAIL receptor-induced, but not TNF-α:TNF-α receptor-mediated apoptosis. SP-D does this by reducing caspase-8 and -3 activation, and the exposure of phosphatidylserine (PS) to the surface of apoptotic cells. The effect of SP-D is related to the extrinsic pathway with no effect on caspase-9 activation in the presence of caspase-8 inhibitor. Furthermore, when the caspase-9-mediated branch of intrinsic pathway is inhibited, SP-D shows the same caspase-8 reduction. Importantly, SP-D accelerates the release of apoptotic MPs and concomitantly increases their clearance by alveolar macrophages. Notably, SP-D indirectly enhances the clearance of MPs by increasing MP number, but not by increasing the uptake of MPs by alveolar macrophages. Also, SP-D suppresses MP-mediated IL-6 and TNF-α expression by alveolar macrophages after efferocytosis. Therefore, SP-D regulates baseline immune cell homeostasis and lung inflammation, and has a therapeutic potential in regulating apoptosis, MP generation, efferocytosis and airway inflammation.

Keywords: Clearance
Efferocytosis
Inflammation
Microparticle
Surfactant protein D (SP-D)
T cell Apoptosis
Advisor: Kotra, Lakshmi P
Multi-Objective Optimization of Unidirectional Non-Isolated DC/DC Converters

Engineers have to fulfill multiple requirements and strive towards often competing goals while designing power electronic systems. This can be an analytically complex and computationally intensive task since the relationship between the parameters of a system's design space is not always obvious. Furthermore, a number of possible solutions to a particular problem may exist. To find an optimal system, many different possible designs must be evaluated. Literature on power electronics optimization focuses on the modeling and design of particular converters, with little thought given to the mathematical formulation of the optimization problem. Therefore, converter optimization has generally been a slow process, with exhaustive search, the execution time of which is exponential in the number of design variables, the prevalent approach. In this thesis, geometric programming (GP), a type of convex optimization, the execution time of which is polynomial in the number of design variables, is proposed and demonstrated as an efficient and comprehensive framework for the multi-objective optimization of non-isolated unidirectional DC/DC converters. A GP model of multilevel flying capacitor step-down converters is developed and experimentally verified on a 15-to-3.3~V, 9.9~W discrete prototype, with sets of loss-volume Pareto optimal designs generated in under one minute. It is also demonstrated how the GP model can be used to determine the sensitivity of the optimized designs to the design parameters. Furthermore, a general procedure for deriving GP models is presented and demonstrated on the example of inductors for higher power applications. Finally, using the example of the seven-switch flying capacitor converter, it is shown how in cases where a converter-level GP model is not possible, component-level GP models can be coupled with a circuit simulator to perform efficiency optimization quickly. This hybrid approach is used to design a wide input and output voltage range, 2~A output current converter IC. The results show that GP is of great value to both researchers and practicing engineers. The methods demonstrated for deriving GP models of power converters are extendable to other converter topologies, allowing for the creation of a rigorous mathematical framework for the optimization of power electronics that guarantees globally optimum designs generated quickly.

Keywords: efficiency
geometric programming
optimization
power density
power electronics
switching converters
Advisor: Prodic, Aleksandar
Taylor, Joshua A
Rearrangements of 7q11.23: disorders of the epigenome

Rearrangements of a 1.5 Mb region on chromosome 7q11.23 produce two distinct multisystem developmental disorders. Deletion of this region causes Williams-Beuren syndrome (WS; MIM 194050) and the reciprocal duplication causes 7q11.23 duplication syndrome (Dup7; MIM 609757). Individuals with WS and Dup7 show an array of contrasting and overlapping phenotypes, including variable intellectual disability, Attention Deficit Hyperactivity Disorder, social disinhibition and anxiety. Rearrangements at 7q11.23 provide an excellent model for studying gene dosage sensitivity in neurodevelopment and the molecular mechanism of related neuropsychiatric disorders. Little is known about how rearrangements at 7q11.23 contribute to the manifestation of specific phenotypes in these disorders. Several genes at this locus have been associated with epigenetic mechanisms and parent-of-origin dependent expression of specific phenotypes have been noted. To understand the impact of rearrangements at 7q11.23 on the epigenome, I have studied parent-of-origin dependent expression of individual genes at this locus, as well as genome-wide DNA methylation. Here I provide the first evidence to show that rearrangements of 7q11.23 result in dose-dependent changes to DNA methylation in peripheral blood from children with WS and Dup7. Aberrant DNA methylation was also identified in cortical neurons from a mouse model of WS, suggesting that DNA methylation is likely disrupted in neural tissue from individuals with 7q11.23 rearrangements. Using a combination of rare atypical deletions and duplications of 7q11.23 and mice with hemizygous deletions of Gtf2i and Gtf2ird1, I provide the first evidence that the TFII-I family of transcription factors contribute to aberrant DNA methylation when deleted or duplicated. Lastly, I identified monoallelic expression of Fkbp6, a gene involved in meiosis and piRNA biogenesis, in mouse and human cortical tissue, which may contribute to parent-of-origin dependent expression of phenotypes in WS. These data suggest WS and Dup7 are disorders of the epigenome, and that DNA methylation may be an important mechanism in the pathogenesis of these disorders.

Keywords: 7q11.23
DNA methylation
Imprinting
Advisor: Osborne, Lucy R
Untimely Research: Making time as existential post-qualitative research practice

This thesis presents six exemplars of posthuman theorizing that enact qualitative research in untimely ways. In order to move through the text in an untimely way, each chapter will act as an exemplar (Massumi, 2002). The connectibility of each chapter hinges on the details that each chapter activates. As a unity of self-relation, each new detail introduces the possibility of the chapter falling apart, shifting the course of the writing. The text moves through these sites of vulnerability of connectibility, providing the writing a space to “pass,” entering into new blocs of experience where and when time matters. Writing in this way, the thesis responds to the paradoxes and contradictions of adhering to chronological representations of qualitative research. In accounting for the paradoxes and contradictions of academic writing, the aim of this thesis is to interfere with the normativities of thinking and doing that renders research “recognizable” and “examinable” in order to move beyond a “system of acculturation and anticreativity” (Deleuze, 1995, p. 27), while at the same time write within and about this gridlocking system. Each chapter wrestles with these tensions in their own peculiar way, developing untimely methodologies for reviewing, reflecting, translating, mediating and researching. Concerned with experiences of posthuman anguish, the thesis emphasizes an affirmative potential of the humanities facing the “post.” Tracing the immediacy of lived experience, the thesis draws from critical moments of theorizing in the humanities, and reads them through a posthuman framework of memory. Posthuman memory is a creative and affirmative process of anchoring the self in the midst of anguish. As a process that is capable of “transmuting negative passions into productive and sustainable praxis” (Braidotti 2013, p. 122), the thesis demonstrates the untimely potential of this framework for pedagogical events of remembering where we slide on the precipice of time towards generational ethics of relating. As such, normative and traditional notions of audience and implications are disrupted in unexpected ways in order to make space for untimely research practices, when and where who we are when and where we meet cannot be known in advance.

Keywords: existentialism
posthumanism
postqualitative
research-creation
Advisor: Springgay, Stephanie