VictorJuiz/thesis huggingface dataset:
Clinically Relevant Models of Cardiac Function using Human Stem Cell-derived Cardiomyocytes

Cardiovascular diseases pose a significant healthcare burden, however, development of effective therapeutics has stagnated, with many recent clinical trials resulting in failure. Moreover, unexpected drug-induced cardiotoxicity contributes to a high attrition rate for all drugs, irrespective of disease indication. These issues largely stem from challenges in modeling the heart’s complex structure and dynamic function in preclinical settings. Emulating key cardiac mechanobiological aspects at a scale sufficient for drug development has been difficult. Human-based preclinical models are needed to reduce the reliance on animals, and mitigate problems arising from cardiological species differences. This research is aimed to broaden our understanding of how human stem cell-derived cardiomyocyte in vitro models can potentially improve downstream clinical translation by incorporating physiologically-relevant high-content study designs. Chapter 2 describes a novel high-throughput testing platform designed to comprehensively evaluate cardiomyocyte contractile function. A machine learning-based classifier to predict drug candidate cardioactivity was developed, illustrating how cardioactivity may be identified earlier in the drug development process to mitigate potential downstream toxicity issues. Using the new analysis platform, cardiac microenvironment biomechanical features were recapitulated in vitro, revealing how mechanical stress present in heart disease may affect drug response. Cardiomyocyte mechanobiology was further explored in Chapter 3 by investigating proteins involved in cardiac force-sensing. Specifically, the integrin-linked kinase adaptor protein beta-parvin was shown to regulate cardiomyocyte structure and function in response to mechanical stress, presenting a potential therapeutic target for cardiac fibrosis and heart failure. Chapter 4 focuses on local anesthetic cardiotoxicity, as a clinically-relevant example of inadvertent drug-induced toxicity. Cardiomyocyte calcium dynamics were found to differentiate the toxicity mechanisms between anesthetics with distinct clinical toxicity profiles, revealing potential anesthetic-specific treatment strategies. These findings were replicated in rodent experiments in vivo, emphasizing the translational utility of stem cell-derived cardiomyocyte models. In summary, the conducted research demonstrates how stem cell-derived cardiomyocyte models can recapitulate key aspects of heart disease pathology and physiologic responses to cardiotropic drugs. The experimental approach described here provides an efficient framework to discover new cardiac therapeutic targets, and investigate cardiotoxicity mechanisms for existing drugs, with the ultimate goal of developing safer and more effective medications.

Keywords: cardiomyocyte
cardiotoxicity
high-throughput
local anesthetic
machine learning
mechanotransduction
Advisor: Maynes, Jason T
Evolutionary Metamorphic Organicism: A Romantic Philosophy of Biology for the Twenty-First Century

The ability of today’s philosophy of biology to meaningfully engage with the diversity of biological subdisciplines is limited because for much of the twentieth century it has not been a philosophy of biology, but rather a philosophy of the Modern Evolutionary Synthesis. My dissertation argues that a turn to Johann Wolfgang von Goethe’s philosophy of biology can help to redress this problem in two ways: First, it offers a compelling alternative philosophy of biology that resonates with contemporary trends in biological theory that emphasize process, organismal dynamics, and agency. Second, it necessitates and integrates a plurality of partial perspectives for understanding organisms, cultivating a “contextual objectivity” that resists universalizing single perspectives on life. By engaging Goethe’s philosophy of biology (which I call metamorphic organicism) in debates about evolution theory today, such as calls for an Extended Evolutionary Synthesis, I make the case that an evolutionary metamorphic organicism can free the philosophy of biology from a pernicious reification of the Modern Evolutionary Synthesis, and show the way to a genuine philosophy of, and for, biology.

Keywords: Developmental Biology
Extended Evolutionary Synthesis
Johann Wolfgang von Goethe
Modern Evolutionary Synthesis
Organicism
Philosophy of Biology
Advisor: Walsh, Denis
Designing Evidence-Informed Microlearning for Graduate-Level Online Courses

Microlearning is a buzzword in eLearning, referring to learning content that is delivered in short bursts or small bites. With no universally accepted definition, it means different things to different people, which further adds to its nebulous nature. This thesis study uses learning theory principles in a graduate education context to explore how students see the benefits or issues with microlearning activities integrated into an online course. Despite its popularity, much is still unknown and unclear about its educational potential especially within the context of formal higher education and how it can be integrated within university-level online courses. By means of a design-based study spanning across three iterations, I explored the role of microlearning in a graduate-level online course from a course design perspective. I achieved this by developing a model called midweek microlesson, under which graduate students enrolled in an online course in Education at a Canadian university were exposed to microlessons on a weekly basis. These microlessons were carefully designed based on theories and evidence-informed practices within the science of learning. The model intended to: a) offer students opportunities for distributed practice; and b) further augment and enrich students’ understanding of the course’s weekly theme. Qualitative and quantitative data was collected and analyzed to understand students’ interaction and experience with the microlessons. The main purpose of this exploratory study is to understand how a specific form of microlearning (i.e., microlessons) can be integrated within a graduate-level online course with the goal to enhance learners’ interaction with the content. Thematic analysis of student commentary led to the emergence of six design themes: content, purpose, timing, length & structure, format and interactivity. I discuss these in light of cognitive learning theories and what they mean for practice. Overall, this study is an attempt to lay a foundation to explore potential educational affordances of microlearning within graduate-level online courses. The study also raises awareness about the lack of theory in current discussions surrounding microlearning and presents an example of exploring and integrating microlearning in course design. Limitations of the study and areas for future exploration are discussed.

Keywords: Cognitive Science
Design-based Research
Educational Technology
Evidence-Informed Instruction
Microlearning
Online Learning
Advisor: Brett, Clare
Contract Life: A Rhetoric on Law, Tech and Power in Everyday Consumer, Work and User Agreements

Contract has come to structure everyday life. It does this rhetorically, through a set of concepts, narratives, and rhetorical resources that pervade both contract law and contract practice. This dissertation begins by introducing a rhetorical approach to contract law and contract practice, focussing on the concepts of contractual choice and contractual fairness that run through both. I then explore the mechanisms through which contract uses these concepts to give words particular forms of power, through three chapters. First, I elaborate the forms of rhetorical power that contract constructs, both bargaining power and a broader conventionalizing power that tends to reproduce existing structures of relations. Through this power, contract can turn moments of choice into moments of resignation. Second, I consider areas of law that have been designed to contest contractual power: consumer and work law. Through a close reading of the discursive ecosystems that constitute these areas of law, I argue that they have also been structured by contract to a substantial extent, curtailing their ability to limit contractual power. Third, I consider the material context in which contract rhetoric operates, the shifting terrain of new tech. Contract practices, including the making and distribution of offers, performance, and enforcement, are increasingly digitized and automated. For better and worse, new tech spreads contract power further, leaving no part of the everyday untouched. Implications for digital markets policy and contract doctrine are considered. I close by suggesting that contract’s rhetorical potency is what has allowed it to grow and spread through discursive domains, with a glimpse at the utopic and dystopic futures suggested by contract life.

Keywords: Consumer Protection
Contract
Employment and Labour Law
Law and Technology
Power
Rhetoric
Advisor: Radin, Margaret J
Hadfield, Gillian
A Multi-Frequency Perspective on Galactic Magnetism and Dust Extinction

The interstellar medium (ISM) of our Galaxy is a complex environment that is filled with dust and permeated by magnetic fields. The multiphase nature of the ISM makes comparisons of magnetic field tracers notoriously difficult, significantly hampering our ability to reconstruct a three-dimensional model of this field. While interstellar dust impacts astronomical observations across the infrared to ultraviolet frequencies through the effects of attenuation and reddening, the varying size distribution and chemical composition of dust grains render a global extinction model to be nearly impossible. This thesis takes a multi-frequency approach to exploring the multiphase magnetic field in the diffuse ISM and dust extinction in the dense molecular medium. To search for evidence of a common magnetic field that is shared between different ISM phases, we compare spatial gradients of synchrotron continuum polarization data to velocity-resolved HI structures. While the polarization gradient is sensitive to abrupt changes in the thermal electron density and line-of-sight magnetic field strength in warm ionized gas, narrow HI structures highlight the plane-of-sky magnetic field orientation in cold neutral gas. We present multi-frequency observations of a unique high-latitude region in which these tracers exhibit an alignment, demonstrating that the magnetic field is likely connected between the warm ionized and cold neutral phases. We discuss the lack of widespread magnetic field alignments observed in the Galaxy and the associated challenges of interpreting low-frequency polarization data. We examine red stellar populations toward the W3 giant molecular cloud in the Perseus spiral arm to explore dust extinction in the molecular medium. Taking advantage of the relative universality of the near-infrared extinction law and precise Gaia parallax measurements, we develop a method for obtaining spectral classifications of stars and identifying massive OB star candidates that are confidently within the cloud. We obtain parameterized fits of the interstellar extinction curve and establish an empirical correlation between infrared color excess and thermal dust optical depth, finding evidence of a temperature-dependent slope.

Keywords: dust extinction
interstellar medium
magnetism
stars
Advisor: Martin, Peter G
Gaensler, Bryan M
Wide-field Polarimetric Second Harmonic Generation Microscopy for Histology Imaging

Nonlinear optical microscopy provides several contrast mechanisms including second harmonic generation (SHG), third harmonic generation (THG) and multiphoton excitation fluorescence (MPEF) that can contribute with additional information to hematoxylin and eosin (H&E) stained tissue histopathology, which is used as a gold standard for cancer diagnostics. Large area imaging is required for practical applications of nonlinear microscopy in whole-slide digital pathology. Nonlinear optical histopathology encompasses multiscale imaging starting from the ultrastructural (nanoscopic) scale, where polarization of SHG is applied to deduce the structural changes of extracellular matrix (ECM) collagen. The distribution of ultrastructural parameters on the microscopic scale provides the information, for example, about the tissue changes at the tumor margins. The hundreds of microns to millimeters scale allows to investigate the spread of induced changes in the tissue providing information about the tumor invasiveness and advancement that can aid in tumor staging and prognostics of the disease. In this thesis, we developed a novel polarimetric wide-field SHG microscopy technique that allows for whole-slide imaging of histopathology samples. We optimized imaging conditions of wide-field microscopy by investigating photobleaching effects of SHG and MPEF signals induced with wide-field illumination in unstained and H&E stained histology tissue sections. A theoretical and experimental description of MPEF and SHG bleaching in H\&E stained samples is performed, providing the basis for choosing optimal laser settings for wide-field microscopy. Moreover, we developed the SHG Stokes polarimetry method (SP-SHG) for quick calculation of ultrastructural parameters required for large area imaging. Generation of polarization states is achieved using liquid crystal variable retarders. SP-SHG is performed on large area images (700 um x 700 um) and ultrastructural parameters are calculated from the polarimetric parameters without data fitting, that shortens the post-processing time of polarimetric data by more than an order of magnitude. Wide-field polarimetric SHG microscopy was used for imaging tendon tissue, as well as histopathology samples from kidney, liver, lung and breast tissue. Changes in the collagen structure are demonstrated for normal and breast tumor tissue. The thesis demonstrates that the novel wide-field polarimetric SHG microscopy imaging method can be readily applied for nonlinear whole-slide digital pathology investigations.

Advisor: Barzda, Virginijus V
Smart Maintenance Management of Highway Bridges Subject to Inspections

Bridge maintenance management aims to balance life-cycle costs and bridge safety based on inspection data and by predicting the time-dependent bridge deterioration using physics-based models or Markov-based models. Through four independent projects, this dissertation develops maintenance optimization frameworks based on the two approaches, contributing to intelligent infrastructure asset management and sustainable societies.Existing research focused on physics-based models has not explored the use of non-destructive inspection data in predicting the deterioration of pre-stressed concrete highway bridges. Based on a real bridge example, we predict the loss of structural capacity resulting from chloride-induced corrosion, simplified by gamma processes. To make the model more realistic, we consider random vehicle arrivals and varying loads, ensuring failure probabilities are not underestimated. Bayesian inference updates are used to select model parameters and determine the associated temporal structural resistances. Current bridge management systems (BMS) adopt Markov chains to simulate the temporal bridge condition rating drops, which ignore the time effect on bridge deterioration rates and underestimate the failure risks of aging bridges. Current fixed-interval inspection policies may also over-inspect new bridges and under-inspect old bridges. Furthermore, existing BMS fail to consider the effects and costs associated with carbon emissions due to maintenance activities. We propose multi-dimensional Markov models to describe temporal bridge deteriorations, the states of which are translated by the Weibull-baseline proportional hazard model into a single hazard indicator for decision-making. Markov decision processes (MDP) are employed to determine optimal repair schemes with the objective to minimize the expected long-term annual maintenance-associated and detouring-related costs. As an alternative to MDP, we also explore the use of Q-learning for single-bridge maintenance optimization. The decision-making procedure implemented in this thesis resembles a quality control chart with time-variant decision thresholds. Integer programming is used to optimize budget allocation processes for bridge networks. For demonstration purposes, we apply the proposed methodologies to bridges in New York state. Comparative evaluations indicate that the proposed methods outperform existing BMS in terms of information richness and total cost savings. Sensitivity analyses reveal the effects of inspection intervals and budget levels on maintenance policies and network carbon emissions, respectively.

Keywords: Bridge asset management
Maintenance budget allocation
Markov decision process
National bridge inventory
Reinforcement learning
Sustainable transportation infrastructure
Advisor: Azhari, Fae
The Social and Economic Integration of Highly Skilled Muslim Immigrants in the Canadian Knowledge Economy

This study explores the social and economic integration outcomes and lived experiences of highly skilled Muslim immigrants in Canada. It investigates the effect of race and religion on their experiences of socio-economic integration and examines their strategies of resistance in response to the challenges. An overall aim was to critically understand the human capital-based integration discourse as it relates to their lived realities. Research has shown that Muslim immigrants in Canada experience low economic outcomes compared to non-Muslim Canadians and are the target of a rise in hate crimes due to anti-Muslim sentiment. There is a substantive body of mainly quantitative literature on the integration of highly skilled immigrants in Canada, as it pertains to their successful settlement processes. However, there is limited data and research on the socio-economic integration of highly skilled Muslim immigrants. This study conducted twenty-one qualitative, semi-structured interviews and applied the theoretical perspectives of Anti-colonial Discursive Framework in combination with Muhammad Iqbal’s concept of Khudi (Self). The study found that Muslim immigrants are at a clear and significant disadvantage in the Canadian labour market facing Islamophobia and racism in hiring, retention, and daily social interactions. All participants experienced the non- recognition of their foreign credentials and skills, a demand for Canadian experience, occupational downgrading, and received no resume call backs. Muslim immigrants show a strong sense of Khudi (Self) and identity in the face of these challenges. They invoke resistance and agency through a reliance on indigenous knowledge and faith-based strategies. They also showed a high sense of belonging to Canada and engagement in the community through political participation and volunteering.

Keywords: Canadian Labour Market
High Skilled
Immigration
Integration
Islamophobia
Knowledge economy
Advisor: Dei, George
Next Generation Ultrafast Electron Diffractometers

The emerging field of ultrafast electron diffraction has made incredible progress in the last two decades, paving the way for studying ultrafast structural dynamics with electron probes. Modern ultrafast electron diffractometers now routinely break the sub-picosecond time resolution by either using the compact design principle or via electron pulse compression. This thesis details the development of two distinct UED apparatuses, one that involves the novel implementation of semiconductor photocathodes, and the other is a more conventional compact design electron gun. Semiconductor cathodes have been a staple in photoinjectors technology, providing ultrabright beams for various accelerator applications. The appeal of semiconductor cathodes is their superior quantum efficiency and initial emittance at the source, corresponding to a higher spatial resolution for more complex systems such as proteins and nanoparticles. The design of this electron gun must accommodate the stringent vacuum requirements of semiconductors, adding extra complexity and cost. The compact UED takes a more minimalist approach, aiming to shorten the electrons' transit distance from the cathode to the sample, being the most straightforward approach for achieving ultrashort pulse durations. The lack of beamline elements and pulse compression devices eliminates sources of jitter in electron beam propagation. My last project proposes a novel time-zero determination method for UED that exploits a system with a known response function. Here we used polycrystalline bismuth (Bi) deposited on a home-built silicon nitride (SiN) chip for its ultrafast non-thermal melting time response. The advantage of this time-zero determination method over others is that it closely matches actual UED experimental conditions while determining time-zero with a precision better than the native temporal resolution of our UED instrument. We also investigate the effect of the silicon nitride substrate on the melting dynamics. We found that the coupling of SiN and Bi alters the intrinsic melting rate of Bi. This thesis work explored the next generation of high brightness ultrafast electron sources and provided a robust, simple-to-implement timing tool that greatly facilitates the application of UED.

Keywords: electron diffraction
femtosecond
molecular movie
UED
ultrafast
Advisor: Miller, RJ Dwayne RJDM
Environmental Education Inspired by Critical Literacy, Indigenous Perspectives, and World-ending Texts: A Practitioner Inquiry Study with High School English Students

This practitioner inquiry study took place in a high school English classroom at an alternative social justice-oriented school in a large urban area in Ontario, Canada. Working as a practitioner researcher, I collaboratively taught two units over ten weeks with a classroom teacher in his Grade 11/12 English classroom, seeking opportunities within the existing curricula for youth to engage with environmental issues. The key research question that guided the work is: How do students engage with a critical literacy approach to environmental education? I constructed an ecoliteracies framework which positions the environment as a text that recognizes functional, cultural, and critical aspects of environmental issues. I took up concepts from environmental education and critical literacy to intervene in “business as usual” environmental education in ways that allow for nuance, complexity, and the social experiences of youth. Data for this research emerged from students’ assignments and classroom participation as well as from follow up focus groups where, along with recorded conversation, students made projects that described their understandings of a critical literacy approach to environmental education. Findings from this study suggest that the environment is a social practice. As youth show through their work, taking a critical literacy approach to environmental education allows teachers and students to trouble assumptions, reimagine ways of connecting, dwell in difficulty, and speculate about our experiences with a damaged planet. This research therefore offers ways that critical literacy and environmental education can support and sustain each other while engaging youth in intertwined social and environmental catastrophes currently rocking our world. Rather than a neat, nice package of knowledge about environmental issues, environmental education can be taken up as a cyclical process of world-ending and world-building. The implication for educators is that existing English curricula have space to recognize the creative, theoretical, and conceptual genius of young people to explore and represent their own experiences of their worlds. This dissertation offers teachers and researchers opportunities to take up nuanced and complex relational environmental engagement, along with some examples of how youth might respond if given the leeway to creatively remake their worlds within schools.

Keywords: critical literacy
ecoliteracies
environmental education
maker literacies
practitioner inquiry
teacher researcher
Advisor: Simon, Rob