VictorJuiz/thesis huggingface dataset:
Applications of Digital Microfluidics for the Extraction and Analysis of Small Molecules from Solid Samples
Keywords: Digital Microfluidics
Dried Blood Spot
Hormones
Sample Preparation
Solid Phase Extraction
Urine Analysis

Digital microfluidics (DMF) has emerged as a valuable technology that may be useful in the goal of realizing true lab-on-a-chip (LOC) or total micro analysis systems (µTAS). DMF is a relatively new microscale liquid-handling technique in which droplets of fluid are manipulated on a flat, two-dimensional array of electrodes coated with a hydrophobic insulator. Droplet movement is driven by the application of electric potentials to successive electrodes, enabling a droplet to be dispensed from a reservoir, merged, mixed and split. One of the strengths of DMF when compared to channel microfluidics is the ease with which DMF can process solid samples, and incorporate solid materials into sample preparation work-flows without the risk of clogging.This thesis describes the exploration of digital microfluidics as a tool for working with solid samples and matrices. Chapter two describes the first method useful for analyzing multiple hormones in dried blood. This method broadens the scope and breadth of information available from the analysis of dried blood spotted directly onto device. Chapter three describes the first method for applying digital microfluidics towards the analysis of pharmaceuticals from blood spotted onto filter paper - dried blood spots (DBS). The DMF method is compared to the traditional macroscale method employed by collaborators at GlaxoSmithKline. Chapter four describes the first combination of DMF and miniature mass spectrometry (MS). This newly developed, automated, multiplexed, and portable platform was designed for the extraction of illicit drugs from dried urine, and is designed to replace the traditional two-tiered urine analysis system with a one-tiered total analysis system. Chapter five describes a new method for on-chip solvent optimization using a design of experiment. Using this system, C18-coated magnetic beads were incorporated onto device, enabling the first instance of fractionation on a DMF device. Finally, chapter six summarizes the principles and concepts derived from this work, and concludes with a look forward to future applications of digital microfluidics as a tool to handle solid samples and matrices.
Decentralized Coordination Control for Dynamic Multiagent Systems
Keywords: Consensus Optimization
Control Theory
Cooperative Systems
Coordination Control
Decentralized Optimization
Multiagent Systems

Engineered networks such as power grids, communication networks and logistics operations are becoming increasingly interdependent and comprised of intelligent components that are capable of autonomously processing and influencing their local environment, as well as interacting with other such components. These emerging capabilities are poised to enable unprecedented efficiency gains across previously disparate application domains. Fully harnessing this potential is contingent in part on our ability to effect coordinated local interactions among such components, ensuring their optimal collective behavior. In this thesis we formulate several Decentralized Coordination Control Problems (DCCPs) for networked multiagent systems involving either static or dynamic agents. We propose that Consensus Optimization (CO) methods constitute a viable foundation for the synthesis of coordination control strategies that address large classes of DCCPs. In order to understand both the potential and the limitations of such strategies, we develop a new framework for the convergence analysis of general CO schemes. In contrast with existing analytic approaches, our framework is based on powerful system-theoretic techniques enabling the study of DCCP scenarios in which the agent dynamics interact with those of the CO algorithm itself, thereby affecting its performance. Aside from fulfilling its intended purpose, our analytic viewpoint also leads to the relaxation of several standard assumptions imposed on numerical CO algorithms, and suggests a methodical approach to deriving conditions under which existing centralized optimization methods can be decentralized. In addition, we propose the Reduced Consensus Optimization (RCO) algorithm -- a streamlined variant of CO which is more innately suited to the DCCP context. Agents implementing RCO generally need not be aware of the network size and topology, and the overall processing and communication overhead associated with agent coordination may be substantially reduced relative to CO. On the basis of RCO, we propose a methodology for the design of decentralized content caching strategies in information-centric networks.
Development of Helper-dependent Adenoviral Vectors for Gene Therapy for Inherited Retinal Diseases
Keywords: ABCA4
eye diseases
gene therapy
helper-dependent adenoviral vector
Stargardt's disease
subretinal gene delivery

There have been significant advancements in the field of retinal gene therapy in the past decade. In particular, therapeutic efficacy has been achieved in three separate human clinical trials using adeno-associated viruses (AAV) to treat a type of Leber's congenital amaurosis caused by
Development of an Energy Harvesting Device using Piezoceramic Materials
Keywords: energy harvesting
piezoceramics

Piezoelectric energy harvesters are increasingly being pursued for their potential to replace finite-life batteries in wireless sensor modules and for their potential to create self-powered devices. This work presents the development of a novel piezoelectric harvester that attempts to improve upon the power output limitations of current piezoelectric harvesting technology. This novel harvester uses the concept of torsion on a tube to produce shear stresses and hence uses improved piezoelectric properties of the shear mode of piezoceramics to generate higher power outputs. This concept is first presented in this work and a proof-of-concept prototype is utilized to experimentally demonstrate the validity of this novel device. After this, the behaviour of the novel harvester is explored through an investigation into three cross-section geometries of the torsion tube and varying geometries of the eccentric mass using three different comparison metrics. Through this, it is observed that configurations with higher torsional compliance and high eccentric mass inertias have the potential for the highest power output and highest harvester effectiveness. However, the mechanical damping in the system is also found to significantly impact the harvester output resulting in prototypes of the various configurations not performing as expected. As a result of this discrepancy, the factors affecting the performance of the harvester are analyzed in greater detail through the development of a mathematical model that is then used to develop a set of guidelines to direct the design of a torsion harvester for a desired application. These guidelines are then used to develop an improved torsion harvester with a demonstrated ability to produce 1.2 mW of output power at its resonant frequency to power a wireless sensor module. Finally, the use of alternative materials such as single crystals of PMN-PT in the torsion harvester is also examined. Through finite element simulations and with material properties reported in the literature, the torsion harvester used with the sensor module is found to significantly benefit with the addition of the single crystal materials and ultimately generate 300% improvements in average output power while converting 11% of the input energy into usable electrical energy.
Alkene, Ketone, and Polyol Functionalization by Stereoselective Rhodium(I) and Copper(II) Catalysis
Keywords: atom-economy
carbohydrates
copper
hydroacylation
rhodium
transition-metal catalysis

Developing transition metal catalysis for organic synthesis can have a profound impact on the manufacturing of polymers, agricultural agents, and pharmaceuticals. Over the last two to three decades, organic and organometallic chemists have discovered extraordinary reactivity with transition metals, applying it to important problems in biology, medicine, and materials. This thesis will describe the use of transition metals as catalysts for new synthetic reactions that transform simple starting materials into valuable enantioenriched products.Chapters 1 and 2 describe the concepts of `chelation-control' and strain for the development of novel rhodium(I) catalyzed intermolecular alkene hydroacylations. The analogous reaction of ketones is less well-understood and is thus rare in the chemical literature. Chapters 3 and 4 discuss new advances in the field as well as the design and execution of the first enantioselective intermolecular aldehyde-ketone cross-coupling. Mechanistic studies point to a unique mechanism involving homobimetallic activation of the aldehyde. The first dynamic kinetic resolution (DKR) of allylic sulfoxides via rhodium(I) catalyzed hydrogenation is presented in chapter 5. Experimental and theoretical studies reveal that rhodium catalyzes both the racemization of the allylic sulfoxide starting material, as well as the alkene hydrogenation. Preliminary studies toward a DKR hydroacylation are briefly discussed. While there are many examples of alkene hydrogenations and hydroacylations, the related carboacylation reaction is underexplored due to difficulties in activating a C--C bond. Through insights gained from mechanistic studies in hydroacylation, preliminary studies on exploiting C--H activation for enantioselective carboacylation are described in chapter 6. Finally, the use of copper(II) catalysts to activate and acylate carbohydrate derivatives in a regioselective manner is included in Chapter 7.
Developing Individual and Population-level Models of Hospital-acquired Clostridium difficile infection (CDI) to Enable the Timely Identification of High-Risk Patients, to Facilitate Inter-Institution Comparisons of Incidence, and to Promote Quality Improvement
Keywords: Antibiotics
Clostridium difficile
Epidemiology
Infectious disease
Seasonality
Transmission modeling

Clostridium difficile infection (CDI) is a health-care associated disease that causes diarrhea and, in more severe cases, colitis and death. It is the most common of hospital-acquired infections in North America. In this thesis, I present 3 studies elucidating individual and population-level risk factors for CDI. In a meta-analysis of antibiotic effects on community-associated CDI risk, I found that Clindamycin, fluoroquinolones, and cephalosporins, monobactams and carbapenems (CMCs) had the largest effects on CDI risk, while macrolides, sulfonamides and trimethoprim and penicillins had lesser associations with CDI risk. I noted no effect of tetracyclines on CDI risk. A retrospective case-cohort analysis of 2,067 adults hospitalized at a tertiary hospital in Ontario, Canada, between June 2010 and May 2012 was conducted to assess the magnitude and duration of antibiotic effects on CDI risk. I found that risks due to antibiotic exposure begin two days after the initiation of antibiotics and are most elevated for a period of 5 days after antibiotic cessation. In this cohort study, exposure to symptomatic CDI cases was not associated with increased risk of infection. I carried out a time-series analysis on 16 years of monthly CDI incidence rate data in the United States to describe the relationship between CDI incidence and hospital pneumonia and influenza (P) prevalence at a hospital network level. Peak P prevalence preceded peak CDI incidence by 9 weeks and I found that surges in hospital P prevalence were associated with disproportionately large impacts on CDI incidence that lasted for 13 months. These findings suggest that control of CDI must involve a strengthening of antimicrobial stewardship initiatives in order to diminish inappropriate antibiotic exposures. Initiatives that would lessen the impacts of seasonal respiratory infections on hospital admissions, including influenza vaccination and programs to reduce pneumonia-associated hospitalizations, could also help stem the increasing incidence of CDI in the North American health care system.
The Downstream Targets of Complex I Dysfunction in Bipolar Disorder
Keywords: Bipolar Disorder
Dopamine
FRET
inflammation
NLRP3 inflammasome
Oxidative stress

Mitochondrial complex I dysfunction is consistently reported in bipolar disorder (BD), implicating its role in increased oxidative stress. Therefore, the overall aim of my PhD was to examine potential downstream targets of complex I dysfunction in BD. First, microarray studies examining complex I subunits in patients with BD or schizophrenia were re-evaluated to examine if complex I defect was specific to BD. Results revealed that complex I subunits that are involved in the electron transfer process are decreased only in patients with BD, suggesting that oxidative stress from complex I dysfunction may be specific to BD. Next, using post-mortem brain, I confirmed lower levels of complex I and its subunit, NDUFS7, in the frontal cortex of patients with BD, supporting the role of complex I dysfunction in the pathophysiology of BD. As an extension of a post-mortem brain study from our group demonstrating the mitochondria and the synapse as targets of oxidative stress, I first examined downstream targets of complex I dysfunction in the post-mortem brain, focusing on the mitochondria and the synapse. To demonstrate the mitochondria as a target of complex I dysfunction, I measured the activation of the NLRP3-inflammasome, which is a marker of mitochondrial oxidative stress. Results revealed that increased activation of the NLRP3-inflamamsome may be specific to BD, suggesting that mitochondria may be a target of complex I dysfunction. To examine the synapse as a target of complex I defect, I measured oxidative modifications to the dopaminergic synapse as increased dopamine signaling is known to underlie mania. Oxidative modifications to dopaminergic proteins, the dopamine transporter and tyrosine hydroxylase, were altered in the post-mortem prefrontal cortex of patients with BD, demonstrating the synapse as another potential target of complex I dysfunction in BD. Downstream targets of complex I dysfunction were further explored in cell models, allowing us to directly inhibit the electron transfer process of complex I using rotenone. The effect of lithium was also tested as it is uniquely used for the treatment of BD and therefore allows us to assess if the observed alterations may be relevant to BD pathology. Inhibiting complex I with rotenone increased protein oxidation and nitration, and caused an increase in methylation and hydroxymethylation of DNA. Moreover, lithium pre-treatment was able to decrease these alterations, suggesting that they may be downstream targets of complex I defect in BD. Together, these studies suggest that complex I dysfunction may be specific to BD, and that it may play an important role in the pathophysiology of this disease.
A Cities Approach to Sustainability
Keywords: Cities
Infrastructure
Sustainability
Sustainable Development
Urban

A Cities Approach to SustainabilityThis thesis provides a response to the question of how we might achieve greater sustainability, and from that sustainable development. An engineering approach, or applied science (physical and social), integrated within a multi-stakeholder partnership, is proposed. A road map to a partial, or `shadow agreement' is proposed, that would hopefully serve as the start of a global process leading to comprehensive sustainable development.An argument is made why cities are the most likely actors to design and bring about such an agreement. An agreement among the world's larger cities (those urban areas with 5 million or more residents by 2050) is possible, and is likely a necessary, but not sufficient condition to achieve sustainable development. Each city is viewed as a unique system as well as collectively within a `system-of-systems,' and more broadly within local and global ecosystems and economies. Global boundaries and objectives such as the Sustainable Development Goals are down-scaled and applied at a metro-city level.Population projections are provided for the world's larger cities (in 2025, 2050, 2075 and 2100). Along with the hierarchy of sustainable cities, two new tools are developed in this thesis: (i) a cities approach to physical and socio-economic boundaries, and: (ii) sustainability costs curves. These two tools underpin the shadow agreement and are powerful planning and engineering tools in their own right. Case study application of the tools is provided for Dakar, Mumbai, Sao Paulo, Shanghai, and Toronto.
Systemic MSC Transplantation Restores Functional Bone in a Mouse Model of Age-related Osteoporosis
Keywords: Cell Therapy
MSCs
Osteoporosis
Translational Research
Transplant

Osteoporosis affects millions of people, and represents a substantial quality of life and economic burden. In human aging, the decline in the number and function of resident bone marrow mesenchymal stromal cells (MSCs) has been widely reported. This has led to the speculation that MSCs are required for the maintenance of skeletal homeostasis, and their loss is associated with age-related osteoporosis. Supporting this etiology, the Sca-1 deficient mouse model of human age-related (type II) osteoporosis demonstrates both decreased MSC self-renewal and expansion, leading to defective maintenance of bone mineral density and bone quality. Therefore, to test the hypothesis that increasing the pool of MSCs could provide therapeutic benefits to patients with type II osteoporosis, we assessed the capacity of transplanted wild type MSCs to rescue osteoporosis in Sca-1-/- mice. Donor MSCs were highly clonogenic and retained high osteogenic activity. Short-term engraftment of DiR labeled MSCs transplanted by intravenous tail vein injection displayed successful engraftment into hind limbs of Sca-1-/- mice for at least 14 days. To assess long-term engraftment, a single bolus of labeled MSCs from male donor mice was transplanted into individual 10-week-old Sca-1-/- females. A half year later, mice were sacrificed and engraftment was assessed. Transplanted Sca-1-/- mice displayed low-level MSC engraftment in the bone marrow and lungs beyond 34 weeks of age. However, histological analyses of trabecular tissue revealed increased bone formation, higher osteoclast numbers, and heterogeneous mineralization indicative of healthier bone in these animals compared to untreated Sca-1-/- controls. Furthermore, MicroCT revealed improved trabecular bone connectivity and a restoration of trabecular anisotropy in mice transplanted with wild type MSCs versus untreated Sca-1-/- controls. Taken together, these results demonstrate that a single systemic transplanted dose of MSCs can reduce the inherent bone formation deficit observed in osteoporotic mice, protect them from progressive reduction in bone quality, and restore functional bone microarchitecture for at least 24 weeks following treatment.
Productivity of Finnish Vowel Harmony: Experimental Evidence
Keywords: Finnish
language change
language game
phonetics
phonology
vowel harmony

Finnish has a well-studied palatal harmony system whereby front and back vowels cannot co-occur in non-compound words and suffixes alternate according to the stem's harmonic class. Nevertheless, disharmonic forms exist in the language. This thesis examines the phonetic realization of vowels in harmonic and disharmonic loanwords and nonce forms created by a language game in order to establish the productivity of stem and suffix harmony. With respect to stem harmony, when words were borrowed into Finnish in the past, disharmonic stems tended to be repaired, providing evidence for the productivity of stem harmony. If stem harmony is robust, some degree of harmonization is expected in disharmonic loans and language games. While stem harmonization was observed in existent words and novel forms created by the game, the harmonization rates were lower than would be expected of a robust constraint, indicating that stem harmony is no longer fully productive, at least for some speakers. When harmonization did occur, a strength asymmetry was apparent with [+back] functioning as a stronger harmony trigger.The examination of the phonetic suffixes indicated that front suffixes were unexpectedly common with all loanword stem types. While co-articulation was a possible cause of some fronting, certain speakers, especially young females, exhibited substantial overlap in the expected front and back suffix categories. For some, this overlap was not exclusive to loanwords but was also observed with compound words. Even in the speech of speakers with discrete front and back suffix categories, front suffixes were unexpectedly frequent in the language game output and occurred even in certain cases where the stem contained no front harmonic vowels to condition the suffix. The phonetic results indicate that stem and suffix harmony in Finnish appear to be in a state of decline. The change is likely due to internal pressures which occur in Finnish and have been associated with weakening cross-linguistically. These factors include low pitch, stresslessness, and non-modal phonation. This conspiracy of phonetic factors may result in lessened prominence of the suffix vowels. Together, these internal pressures may have conspired to reduce the perceptibility of the harmonic suffix vowels, leading to the weakening of harmony.
Willful Women Creating the World: Life Stories of Feminist and Queer Activists
Keywords: activism
arts-informed
autoethnography
feminism
life history
queer theory

This thesis documents themes from the lives of three women who have been high-profile activists in the women's and LGBTQ communities of Toronto for more than 20 years. There has been no previous major work that documents and examines their lived experiences, their social/historical contexts, and their personal resistance and political strategies. This research explores how these women have responded to multiple oppressions such as homophobia, heterosexism, sexism, racism and poverty, and used collective political action to pursue new visions, structures, and spaces for women and LGBTQ people in the public world.The research draws on multiple methodological and theoretical influences. It is guided by several strands of feminist scholarship broadly informed by the "post" traditions, including intersectionality, the attribution of willfulness, feminist world-building and queer world-making. Particular attention is given to the diverse ethno-cultural, historical and socio-economic contexts of these women's lives, and to the shaping of individual experience through Canada's history as a white-settler nation.The author employs narrative and autoethnographic writing strategies to present life histories, using the metaphor of a tree to tell each life story. Data was gathered through multiple in-depth interviews focused on significant life events, photographs/artifacts and memories. The findings are presented using an arts-informed approach that includes drawings and photographs, and aims to educate and inspire audiences both within and beyond the academy.