VictorJuiz/thesis huggingface dataset:
Synergistic Nanoparticle Formulations against Multi-drug Resistant Breast Cancers
Keywords: Cancer
chemotherapeutics
Mitochondria
Multi-drug resistance
Nanoparticles
Synergistic

Current breast cancer treatments lack specificity, leading to dose-limiting cardiotoxicity, which is often coupled with multi-drug resistance (MDR), and thus severely impedes efficacious cancer treatment. Current efforts to utilize chemotherapeutics and MDR inhibitors have failed in the clinic due to low efficacy, off-target toxicities, and altered pharmacokinetics. Synergistic nanoparticles (NPs) offer spatiotemporal control of therapeutics from the injection site to the tumor site. Synergistic NPs co-encapsulate two or more drugs, whereby the co-encapsulated drugs exhibit anti-cancer activity greater than the sum of the anti-cancer activity exhibited by the single-drug loaded NPs. This thesis demonstrates that doubly-loaded NPs are more efficacious against multi-drug resistant (MDR) breast cancer cells in vitro, relative to each drug alone or combined, singly-loaded drug NPs. The NPs, comprising poly(D,L-lactide-co-2-methyl-2-carboxytrimethylene carbonate)-graft-poly(ethylene glycol)-azide (P(LA-co-TMCC)-g-PEG-N3), were used to co-encapsulate two therapeutics and evaluate their synergistic cytotoxicity of MDR cancer cells: vitamin E succinate modified with octahistidine-octaarginine (VES-H8R8) and a pH-responsive prodrug of doxorubicin (pDox). The mechanism of the anti-cancer activity of VES-H8R8 comprised MDR efflux inhibition, mitochondria depolarization with inhibited bioenergetics, and induction of reactive oxygen species, apoptosis and G1 cell cycle arrest. When VES-H8R8 was co-encapsulated with pDox in NPs, synergistic anti-cancer activity against MDR breast cancer cells was observed, but only when co-encapsulated NPs were administered. Work towards NP-mediated delivery of siRNA targeted against an essential protein, eukaryotic translation initiation factor 3 subunit B (eIF3B), is also presented; however, limitations associated with endo/lysosomal accumulation terminated the use of NPs comprising P(LA-co-TMCC)-g-PEG-N3. This thesis provides the groundwork to study synergistic anti-cancer activity against MDR breast cancer in vivo.
Design of Human Pluripotent Stem Cell-derived Cardiac Microtissue-based Platforms for Functional Screening
Keywords: Bioengineering
Cardiac tissue engineering
Drug screening
Microfabrication/3D printing
Stem cell biology

The improved ability to study heart development, disease, and drug response using high-content engineered heart tissue models would expedite the advancement of strategies to overcome heart disease. To meet this challenge, we created microfabricated platforms to guide the design of aligned and functional 3-D human pluripotent stem cell (hPSC)-derived cardiac microtissues. Tissue properties could be tuned using input cell composition, specifically, screening a range of hPSC-derived cardiac cells to stromal cells ratios identified an optimized formulation that yielded enhanced structural and functional properties. We demonstrate the utility of the optimized platform in a tachycardic model of arrhythmogenesis, an aspect of cardiac electrophysiology not previously recapitulated in 3D in vitro hPSC-derived cardiac microtissue models. We then used the identified design variables to innovate a next-generation platform capable of measuring contractile force, a function parameter that is an important assessor of cardiac function and health. We employed a high-resolution 3D printer to construct custom next-generation 96-well tissue culture plates featuring deflectable elastomeric microcantilevers which can be used to formulate, culture, and assay microtissues. We show the utility of our platform by conducting a central composite design experiment to determine an optimal formulation of cardiac microtissues based upon new input cell identities. We then conduct a cardiotoxicity screen of a selection of cardiotropic compounds that demonstrates both adverse and positive effects on contractile force. Finally, we construct mixed tissues with hPSC-derived epicardial cells and hPSC-derived CM to test the combined effect on contractile force. We aim to have this platform set a new gold-standard in the functional screening and validation of cardiac-associated drugs.
Robotic Manipulation and Selection of Single Sperm for In Vitro Fertilization
Keywords: Automation
Biomedical Engineering
In Vitro Fertilization
Robotics
Sperm

In vitro fertilization (IVF) is the standard clinical treatment for infertility, which is a growing global health issue with psychological, social, and economic implications. DNA fragmentation of the sperm used in IVF treatments deterministically lowers the fertilization rate, causes embryo arrest in development, increases the miscarriage rate, and results in genetic disorders in the offspring. Current clinical practice of sperm selection either destroys the sperm for invasive DNA assessment or assumes that sperm motility and morphology are correlated with sperm DNA integrity. However, this correlation has never been proved due to the lack of single-cell manipulation and characterization techniques. Targeting non-invasive selection of high DNA integrity sperm, this thesis focuses on (1) developing enabling robotic manipulation techniques for pick-place of single sperm for subsequent DNA analysis, and (2) establishing, for the first time, the correlation between sperm motility and morphology parameters and the same sperm's DNA integrity. Closed-loop visual servo control algorithms were developed to adjust sperm position and orientation, based on which robotic immobilization of motile sperm were achieved via two approaches: tapping the sperm tail with a micropipette or firing laser pulses to ablate the motor proteins on the sperm tail. Computer vision algorithms were also developed to non-invasively measure sperm motility and morphology parameters in real-time. The same sperm, with its motility and morphology characteristics recorded, was transferred for DNA integrity analysis. These robotic techniques not only free human from tedious labor operation, but also bring state of the art population-based sperm analysis to the single-cell level. Experimental results confirmed the long-hypothesized correlation that sperm with normal motility and normal morphology have low DNA fragmentation. Finally, based on the established correlation, a set of quantitative criteria was formulated for automated, objective, and non-invasive selection of sperm with high DNA integrity.
Listening to the State: Radio and the Technopolitics of Sound in Mao’s China
Keywords: China
Politics
Radio
Socialism
Technology

My dissertation argues that radio played vital roles in state building and social integration in the 1950s and 1960s China. Radio as a technological infrastructure brought about a series of radical changes that fundamentally affected the state’s self-perception as well as its agenda in transforming everyday life. My dissertation demonstrates that the acoustic state heavily utilized the senses and techniques of hearing and listening. The state incorporated listening techniques into government bodies during the management of everyday life to inform, educate and mobilize the masses and to modernize the country. The techniques of speaking and their institutionalization in return signaled the state’s efforts to search for and naturalize a voice for its presence in daily life. The dissemination of the voice further gave birth to a new type of state-agents, the radio operators, who carried radio sets with them to areas beyond the reach of electricity. As radio became integral to listeners’ work and life, it triggered further political and social changes, one of which was that listeners learned to circumvent local authorities and contact the higher-level radio stations for solving their concerns. Listeners also became not only selective in listening to state-sanctioned programs but also curious enough to transgress the state’s acoustic boundary to listen to radio programs from abroad. Radio also played a crucial role in drawing the boundaries between enemies and people, which was crucial to the creation and maintenance of the socialist regime. Such transgressive listeners prompted the state to perceive sound as sovereign territory and consequently led it to territorialize sound to defend itself from the sonic invasion of capitalist countries. To conclude, radio not only equipped the state with new techniques of governance but also fundamentally changed the way the state interacted with the masses, reshaping socialist modernity and subjectivity.
Punishment and Necessity: On the Problem of the Mastery of Nature in the First and Second Treatises of Friedrich Nietzsche’s On the Genealogy of Morality
Keywords: Genealogy
Mastery of Nature
Nietzsche
Punishment
Revenge

This dissertation investigates Nietzsche’s critique of punishment in the first two treatises of his On the Genealogy of Morality. It argues that the critique of punishment clarifies Nietzsche’s understanding of the relationship between nature and human will. Central to this project is a reconstruction of a uniquely Nietzschean understanding of punishment as the attempt to transform or eradicate both nature and human nature. While punishment has been most recently viewed as the attempt to discipline or control nature, Nietzsche views the antagonism between punishment and nature even more radically: punishment is the attempt to replace the order of nature with an order of will. Consequently, this study argues that attending to Nietzsche’s more comprehensive view of punishment reveals the true scope of his critique of morality. For it reveals punishment as the chief instrument of morality, which aims to change and therefore correct that which it finds defective in the world. This project is situated in ongoing debates in the fields of political theory and philosophy about the role that mastery of nature plays in Nietzsche’s thought. The critique of punishment provides a novel resource for understanding this role, clarifying Nietzsche’s attitude towards mastery of nature in at least four ways. First, and contrary to the standard interpretation, it shows that Nietzsche is a critic of projects, both moral and scientific, that attempt to master nature. Second, by highlighting the relationship between morality and change, the critique of punishment encourages a critical reexamination of Nietzsche’s own call for a new noble morality. Third, it clarifies Nietzsche’s critical attitude toward the will to power. By highlighting the will to power’s drive to fit the world to its own needs and desires, Nietzsche shows the will to power to be far from an unmitigated good, but instead a potential barrier to knowledge. Finally, Nietzsche’s critique of punishment points to his view of the supremacy of the contemplative life. Nietzsche seeks to understand nature not in order to transform the world, but rather to understand it and, most importantly, himself.
Who Decides and Why it Matters: Institutions, Differentiation and Northern Rural Higher Education
Keywords: Canadian Provincial Norths
Differentiation
Higher Education Policy
New Institutional Theory
Power
Strategic Reaction Theory

The purpose of this research was to study the impact of institutional forces on higher education policy processes. The project involved a case study analysis of the alignment between intention and perceived impact, focused specifically on the implementation of higher education differentiation policy within two of Canada’s provincial norths (Northern Alberta and Northern Ontario). These provinces were chosen because they represent two of the largest jurisdictions in Canada by population, and because they have both implemented differentiation policy frameworks within the last decade and a half. The research was undertaken within a theoretical framework that combined elements of new institutionalism (North, 1990; DiMaggio Powell, 1991; Thelen, 1999; Peters, 2012; Lowndes Roberts, 2013; Scott, 2014), strategic reaction theory (Oliver 1991), pragmatism (Allison Pomeroy, 2000; Duemer Zebidi, 2009; Anderson Shattuck, 2012; Kaye, 2013), and power (Foucault, 1980; Mills, 2003). Through examination of the ways in which similar policy goals were implemented in Northern and Rural Central Alberta, and in Northern Ontario, it was possible to identify institutional forces that impacted the policy process in each jurisdiction. The central argument of this study was that, in order to improve alignment between policy intentions and policy outcomes, policy makers (political decision makers) and policy implementers (organizational decision makers) must take these institutional forces into account at every stage in the higher education policy process.
Developing Combined Optical Spectroscopy and Mass Spectrometry Tools to Probe the Conformation of Double-Stranded DNA in the Gas Phase
Keywords: DNA
Ethidium
FRET
Laser-induced fluorescence
Mass Spectrometry
turn-on fluorophore

Mass spectrometry (MS) has long been a popular analytical technique for the characterization of gas-phase molecules. Beginning in the late 20th century, the coupling of MS with soft ionization techniques such as electrospray ionization (ESI) and the development of various gas-phase methodologies facilitated the structural analysis of intact biomolecules. To that end, this dissertation describes the coupling of MS with optical spectroscopy for the characterization of isolated DNA-binding dyes and non-covalent double-stranded DNA (dsDNA) complexes in the gas phase. MS and optical spectroscopy analysis is performed using a quadrupole ion trap (QIT) that has been modified to perform photodissociation (PD) and laser-induced fluorescence (LIF) on mass-selected ions. First, fluorescence measurements on trapped rhodamine 640 ions are performed to visualize the cloud of trapped ions inside the QIT. Second, the intrinsic photophysical properties of the classic dsDNA intercalator, ethidium bromide, is presented via photodissociation action spectroscopy, dispersed emission spectra, and time-resolved measurements. Finally, latter chapters describe the use of non-covalent DNA-binders that exhibit “turn-on” fluorescence responses in solution and Förster Resonance Energy Transfer (FRET) methodologies to probe the conformation of dsDNA ions in the gas phase. The work described in this dissertation serves to develop methodologies that use MS and optical spectroscopy techniques to investigate the intrinsic intra- and intermolecular interactions present in biomolecules, without competing solvent effects.
Targeting Acetyl-CoA Metabolism in Bacteria - Structural Characterization of Pantothenate Kinases and Lipoate-Protein Ligases
Keywords: Antimicrobial
Lipoate-protein ligase
Pantothenate kinase
Structure-based drug design
X-ray crystallography

Antibiotics are regarded as one of the most important medical discoveries of all time. Since their clinical implementation in the early 20th century, countless lives have been saved, rates of infectious disease have plummeted, and medical advancements such as surgical implantation have flourished. However, the rise of antibiotic resistance has mirrored the rise in antibiotic use, and we are now running out of reliable drugs. At a time when there is a negative correlation between the rise of resistance and the approval of new drugs, the future of antibiotic development needs to embrace novel treatment strategies and target pathways to help turn the tide in the arms race against bacterial drug resistance. In the present study, we propose the central axis between coenzyme A (CoA) biosynthesis and acetyl-CoA (AcCoA) production to be a viable target for future antimicrobial development. AcCoA and CoA are central to pyruvate oxidation, the TCA cycle, biofilm
A "Time When Principles Make Best Politics"? The Western Response to "Genocide" in East Pakistan
Keywords: British foreign policy
Canadian foreign policy
East Pakistan
Genocide studies
South Asia
US foreign policy

This study examines the formulation of and interplay between the US, Canadian, and British policies generated in response to the mass atrocities perpetrated by Islamabad authorities in East Pakistan during 1971. It focuses on the reactions of these three closely-connected North Atlantic powers to the gross human rights abuses, analyzing the decision-making processes in Washington, Ottawa, and London during the crucial first few months of the crisis, identifying the forces at play in determining policy, and investigating the nature, development, and resolution of debates over national interests and ethical concerns. The analysis is built primarily upon documentary evidence from the US National Archives, the Nixon Presidential Materials Project, Library and Archives Canada, and the National Archives of the United Kingdom. In Washington, President Richard Nixon and his national security advisor, Henry Kissinger, exerted great personal influence over the determination of policy and favored a strategy of appeasement. Importantly, their secret initiative to secure rapprochement with China, which only sprang into life at the end of April, did not drive their thinking during the vital first month after the clampdown began as Kissinger has previously claimed. In Ottawa, the Canadian government developed a tentative four-strand response, unwilling to hazard bilateral ties with Islamabad or draw attention to its own separatist issue in Quebec. In the UK, notably strong public sympathy for the victims of the clampdown only influenced policy to a limited extent. Nevertheless, Londonâ s response, though similar in form to that of Ottawa, in substance demonstrated a greater willingness to coerce Islamabad into ending its oppressive action. This work considers the limited interplay between the North Atlantic powers in determining their reactions, discussing the collaborative opportunities both accepted and spurned. The overall conclusion compares policies and their determinants, assesses the alternative options available, considers the blinkered nature of government institutional cultures formed around the protection of national interests narrowly construed, and explains the techniques of obfuscation and excuse employed by officials to avoid demands for firmer action.
The Dialogical Element in Machiavelli's Works
Keywords: Dialogue
Marshall McLuhan
NiccolĂ˛ Machiavelli

This dissertation will examine the dialogical element in NiccolĂ˛ Machiavelli's works including his two dialogues Arte della guerra and Discorso intorno alla lingua, as well as those which do not belong to the dialogic genre, namely Il principe and Mandragola, but which display many of the key elements of the genre. This will be accomplished using contemporary theories, with the addition of Marshall McLuhan's work on the medium. By treating the dialogue not only as a genre, but also as a medium, this opens up a new avenue of study with which to analyze and evaluate not only some of Machiavelli's most celebrated works, but also how his legacy is tied to modernity.
Shelter from the Storm: Asylum in American Narratives of Natural Disaster
Keywords: Asylum
Disaster narratives
Hurrican Katrina
Natural disaster
Refuge

America's origin story depicts the nation as sanctuary incarnate. From the Puritans seeking religious refuge to generations of immigrants arriving at Ellis Island, to slaves fleeing north across the Ohio River, in the national imaginary America functions as asylum extant -- as the end of the story. This dissertation interrogates this iconic narrative at a critical historical moment. Reading narratives of natural disaster -- accounts of historical drought, flood, and hurricane -- it produces a nuanced theory of refuge which counters the myth of nationalized sanctuary. In an era of normative catastrophe, narratives of 'natural' disaster problematize the discourse of the nation-state as the exemplary guarantor of refuge. This theory of asylum constitutes a vital prehistory for increasingly urgent current engagement with vulnerable citizenship and the emerging canon of eco-catastrophe narratives. Chapter One examines the Dust Bowl as represented in John Steinbeck's The Grapes of Wrath (1939), Woody Guthrie's folk song 'This Land is Your Land' (1940) and documents of the National Park Service (1936). These disaster narratives demonstrate that asylum is defined both by an inviolable border, and by imaginative expansion beyond that defensible perimeter to borderless, abstracted, and infinite refuge. Chapter Two examines the texts of the Great Mississippi Flood of 1927. Flood Relief Chairman Herbert Hoover's memoir (1952), President Calvin Coolidge's 1927 State of the Union Address as well as 'Saving the Day' (1928) -- a sermon by Rev. Sutton E. Griggs -- constitute a trenchant critique of the nationalized provision of refuge. Delving further into the 1927 flood, Chapter Three considers Richard Wright's short stories 'The Man Who Saw the Flood' (1937) and 'Down by the Riverside' (1938) as well as William Faulkner's novella Old Man (1939). These texts demonstrate how racialized asylum subverts the conventions of the disaster narrative's promise of catastrophic renewal. Concluding with a contemporary disaster, Chapter Four examines Dave Eggers' Zeitoun (2009), James Lee Burke's short story 'Jesus Out to Sea' (2006) and Spike Lee's documentary film When the Levees Broke (2006). In these Hurricane Katrina narratives, refuge's doubled nature is revealed, and asylum is re-configured as perilous as well as sheltering.
Exploring the Role of the School in the Development and Course of Problem Behaviour in Adolescence
Keywords: Adolescence
Developmental trajectories
Problem behaviour
School connectedness

Problem behaviour during adolescence is a pressing societal concern. While extensive work has been conducted to identify relevant risk and protective factors, comparatively little attention has been paid to the role the school may play in protecting against maladaptive outcomes. Employing a socio-ecological framework, this dissertation began by exploring trajectories of problem behaviour and school connectedness across the early to mid-adolescent period in a sample of 2,396 youth drawn from the National Longitudinal Survey of Children and Youth. Three trajectories of problem behaviour were identified, with the large majority of youth showing little to no problem behaviour over time. Two trajectories of school connectedness were also identified as well as a general downward trend in connectedness across the study period. Multivariate analysis was used to explore the impact of risk and protective factors on trajectory group membership. Results were generally consistent with existing literature though importantly this study established a strong association between school connectedness and problem behaviour. Specifically, youth on the decreasing trajectory of school connectedness were between 2.2 and 4.5 times more likely to fall onto either of the concerning problem behaviour trajectories. The second paper followed a sample of 139 youth with matching teacher- and principal-report data to examine factors at the level of student, classroom, and school that predicted change in school connectedness two years later. While much of the variance in connectedness at time two was accounted for by individual-level variables, several classroom and school factors emerged. Specifically, teacher support for managing discipline problems within the classroom was found to predict improved connectedness whereas low school socioeconomic status was associated with worse connectedness by time 2. As well, an interaction was identified between student problem behaviour trajectories and the percentage of low income families within the school such that students attending lower socioeconomic status schools who engaged in delinquent behaviour were significantly less likely to report feeling connected to their school. Taken together, these findings underscore the importance of considering school connectedness as a key protective variable for adolescent problem behaviour. Implications for policy and practice are also discussed.