VictorJuiz/thesis huggingface dataset:
Controlled Delivery of Therapeutic Proteins to the Injured Spinal Cord

Spinal cord injury (SCI) results in severe disability and currently lacks effective clinical treatments. Pre-clinical and clinical research have demonstrated the potential for both cell and protein therapeutic strategies; however, a critical challenge is the lack of localized, sustained delivery of bioactive therapeutics. A composite drug delivery system (DDS) consisting of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (np) dispersed in a hyaluronan/methyl cellulose (HAMC) hydrogel was previously found to provide sustained protein release in vitro and compatibility in vivo. This np/hydrogel DDS was further developed for the localized, sustained, and bioactive delivery of platelet-derived growth factor-AA (PDGF-AA), neurotrophin-3 (NT-3), and anti-NogoA. The release of PDGF-AA was sustained over 21 d and the PDGF-AA DDS induced the oligodendrocyte differentiation of neural stem/progenitor cells in vitro. The release of PDGF-AA was affected by the excipient poly(ethylene glycol) (PEG400), which had variable effects on protein stability. The delivery of NT-3 was sustained for up to 49 d in vitro and at least 28 d in vivo, and the NT-3 DDS induced axon growth and modest recovery of function in a model of compressive SCI. Surprisingly, electrostatic interactions occurred between soluble NT-3 and the DDS that delayed release. This discovery led to the development of an encapsulation-free np/hydrogel DDS that provides sustained, tunable release of NT-3 as well as stromal cell-derived factor (SDF) and brain-derived neurotrophic factor (BDNF) and is applicable to many other proteins. Finally, the np/hydrogel DDS was adapted for the combined, bioactive delivery of NT-3 and anti-NogoA. Combined delivery of NT-3 and anti-NogoA increased axon density, reduced the inhibitory environment, and promoted functional recovery after delivery to the injured spinal cord. This work demonstrates that the np/hydrogel DDS is effective for the delivery of growth/differentiation factors as well as therapeutic proteins for the treatment of spinal cord injury.

Keywords: drug delivery
hydrogel
nanoparticle
PLGA
protein
spinal cord injury
Advisor: Shoichet, Molly S
MCMC Methods for Non-linear State Space Models

This thesis is concerned with developing efficient MCMC (Markov Chain Monte Carlo) techniques for non-linear, non-Gaussian state space models. These models are widely applicable in many fields, such as population ecology and economics. However, Bayesian inference in such models remains challenging, since sampling the latent variables and parameters in them can be difficult. We begin by showing how an efficient MCMC method can be developed for a queueing model, inference for which has previously been done with ABC (Approximate Bayesian Computation). This example is an illustration of how we can do inference with MCMC in a model in which inference is considered difficult and for which ABC was used. We do this by expanding the state to include variables involved in the process used to generate the observed data. We then proceed to the main contributions of the thesis, which are developing general MCMC methods for non-linear, non-Gaussian state space models based on the ensemble MCMC and embedded HMM MCMC frameworks. The embedded HMM and ensemble MCMC methods we introduce provide a unified framework that is sufficiently flexible to often address difficult issues in MCMC sampling for non-linear, non-Gaussian state space models, without having to resort to specialized methods for different cases. We start with the basic embedded HMM method of Neal (2003), and Neal, Beal and Roweis (2004), designed for sampling latent state sequences given known parameter values, and develop an efficient ensemble MCMC method for sampling parameters when the parameters and the latent sequence are strongly dependent. This method is tested on a non-linear model of population dynamics. We then show how ensembles can be used to make parameter sampling more efficient in a stochastic volatility model by making use of a caching technique (Neal (2006)). Finally, we develop an ensemble MCMC method for sampling sequences in non-linear, non-Gaussian state space models when the state space is high-dimensional and test it on two sample models with high-dimensional state spaces, one of which is multimodal, and compare the performance of this method to a particle MCMC method.

Keywords: MCMC
Advisor: Neal, Radford M
Solvation and Conformational Stability of Proteins and DNA

The work performed in this dissertation is devoted to understanding and quantifying solute-solvent interactions in the folded and unfolded states of proteins and DNA G-quadruplexes using volumetric techniques. We characterized the interactions of the protein stabilizer, glycine betaine (GB), with proteins and their functional groups through a combination of partial molar volume and adiabatic compressibility measurements of N-acetyl amino acid amides, oligoglycines, cytochrome c, ribonuclease A, lysozyme, and ovalbumin at GB concentrations ranging from 0 to 4 M. We evaluated the equilibrium (binding) constant, k, for the reaction in which a GB molecule binds each of the functionalities under study replacing four water molecules. We found that GB forms direct interactions with all protein groups studied here. In addition, the differential free energy of solute-solvent interactions in a concentrated GB solution and water, ΔΔGI, is negative for all the proteins studied and ΔΔGI becomes more favourable as the concentration of GB increases. We also employed volumetric measurements of lysozyme, apocytochrome c, ribonuclease A, and α-chymotrypsinogen A in the solutions at 0 to 8 M urea to quantify the urea-induced solvation changes in the native and unfolded states of proteins. An increase in the concentration of urea to 8 M leads to a ~20% increase in the solvent accessible surface area of apocytochrome c. The urea-induced unfolding of ribonuclease A and α-chymotrypsinogen A is accompanied by increases in solvent accessible surface area of 1.9 ± 0.4 and 2.0 ± 0.6 times that of the native states, respectively. Furthermore, we characterized the volumetric properties of the folded and unfolded states of the Na+-stabilized antiparallel G-quadruplex conformation of Tel22, d[A(GGGTTA)3GGG], and the K+-stabilized hybrid-1 conformation of Tel26, d[AAAGGG(TTAGGG)3AA]. The coil-to-G-quadruplex transition of Tel26 accompanies a release of 434 ± 19 water molecules from its hydration shell to the bulk, which is more than four times the number of waters released compared to Tel22 (103 ± 44). We proposed that this extensive DNA dehydration originates from both the waters in direct contact with the domains that become buried in G-quadruplex formation and a general decrease in solute-solvent interactions all over the surface of the folded structure.

Keywords: Calorimetry (DSC and PPC)
DNA G-Quadruplex
Folded and Unfolded Protein States
Glycine Betaine
Urea
Volume and Compressibility
Advisor: Chalikian, Tigran V.
Assisting Converter Based Topologies for Low-volume High-efficiency Battery Management Systems

Conventional battery management systems (BMSs) for applications that require voltage stepping-up, such as automotive and portable systems, usually consist of a battery pack, a battery charger, and a step-up dc-dc converter. In those applications, a balancing circuit which compensates for different states of charge (SOC) of individual cells is a highly desirable feature. The SOC difference occurs due to aging and differences in the manufacturing process. Through cell balancing the effective capacity and lifetime of the battery pack can be significantly increased. Even though the benefits of cell balancing circuits have been recognized, their use is relatively sparse in the targeted applications, due to overly large extra cost, weight, and volume they add to the system. In this work, a novel battery management architecture (BMA) that integrates voltage stepping-up and cells balancing functionalities in a single converter topology is introduced, offering a solution for a cost-effective implementation of the balancing feature. Moreover, the new architecture has a smaller overall size and better power processing efficiency than the conventional solutions not incorporating the balancing feature. In the new BMA, named the assisting converter architecture, the output of the converter is placed on top of the battery pack and is therefore processing only a portion of the output power. Two assisting converters utilizing the new BMA are introduced in this dissertation namely, the assisting dual active bridge (DAB) converter and the assisting flyback converter. The assisting DAB converter represents the battery power management system for automotive applications and the assisting flyback converter is designed for portable electronics applications.

Keywords: Battery management architectures
Battery management systems
Cells balancing
Dc-dc converters
Dual active bridge converter
Flyback converter
Advisor: Prodic, Aleksandar
Prevalence of and Risk Factors for Anxiety, Depression, and Post-traumatic Stress in Substitute Decision-makers of Patients in the Intensive Care Unit

Background: Most intensive care units (ICU) patients are incapable of participating in decision-making. Substitute decision-makers (SDMs) generally assume decision-making responsibility yet may vary in preferred level of involvement. Role incongruence refers to discordance between preferred and actual role in decision-making. Role preferences and incongruence may be associated with psychological symptoms (anxiety, depression, and post-traumatic stress) after ICU. Purpose: The primary objective was to explore prevalence and risk factors for symptoms of psychological distress in SDMs after an ICU experience. Methods: Cross-sectional, multi-centre, interviewer-administered survey of SDMs of critically ill adults requiring mechanical ventilation (MV) for greater than 48 hours. Psychological distress was defined as any symptoms of anxiety, depression, or post-traumatic stress using pre-defined cut-points on the Hospital Anxiety and Depression Scale (HADS) and the Impact of Events Scale (IES). The Control Preferences Scale (CPS) was used to evaluate decision-making role preferences and incongruence. Results: 180 SDMs were recruited; response rate was 64%. Active, shared, or passive roles were preferred by 24% (n=43), 44% (n=79), and 31% (n=56) respectively. Almost half (n=85/174; 49%) reported incongruence. Using high thresholds, symptom prevalence was 50% (n=88/176), 32% (n=57/177), and 16% (n=29/177), for post-traumatic stress, anxiety, and depression respectively. The composite outcome of any psychological distress symptom was associated with patient death [OR 2.95 (CI 1.08-8.02); p=0.03], female sex of the SDM [OR 2.96 (95% CI 1.49-5.89); p = 0.002], and role incongruence [OR 3.26 (95% CI 1.67-6.36); p = 0.0005] when high thresholds were considered. High threshold depressive symptoms were associated with spousal relationships [OR 3.01; 95% CI 2.93-3.09; p=0.01] and high threshold post-traumatic stress symptoms were associated with spousal relationships [OR 2.29 (95% CI 1.18-3.26); p=0.01], female sex [OR 2.56 (95% CI 1.28-5.12); p=0.008], role incongruence [OR 2.57 (95% CI 1.33-4.97); p=0.005], and patient death [OR 3.36 (95% CI 1.27-8.86); p=0.01]. Conclusions: High rates of adverse psychological symptoms in this study highlight the need to identify and implement preventative and management strategies for SDMs. Strategies to prepare proxies to engage in decision-making, to enhance shared decision-making, and to mitigate psychological distress symptoms, should be considered before, during, and after the ICU experience.

Keywords: Anxiety
Critical care
Decision-makers
Depression
Intensive care unit
Post-traumatic stress
Advisor: Metcalfe, Kelly
Towards Active Image Guidance in X-ray Fluoroscopy-guided Radiotherapeutic and Surgical Interventions

There is growing concern regarding the ionizing dose delivered during x-ray fluoroscopy-guided minimally invasive clinical procedures, particularly in interventional cardiology and neuroradiology, and in real-time tumor tracking radiotherapy and radiosurgery. As these image-guided procedures advance and become more complex, the associated radiation-related risks are of concern owing to the duration of treatment. The objective of image guidance is to localize and track objects of interest. An insufficient dose may convey less geometric information which may lead to inaccuracy and imprecision in intervention placement. In this study, a method for achieving the required tracking uncertainty for a given x-ray fluoroscopy-guided interventional procedure using minimal dose is investigated. A simple model is used to demonstrate that a relationship exists between imaging dose and tracking uncertainty. A feedback framework for active image guidance (AIG) is introduced that exploits this relationship to modulate the tube current in order to maintain the required uncertainty for a given interventional procedure. This framework is evaluated in the context of a fiducial tracking problem associated with image-guided radiotherapy in the lung by simulating respiratory motion. A particle filter algorithm is used to robustly track the fiducial as it traverses through regions of high and low quantum noise. Published motion models are incorporated in a tracking test suite to evaluate the dose-localization performance tradeoffs. Additionally, the AIG framework is embodied in a physical prototype and validated in a practical setting. With feedback engaged, the tracking error was found to correlate well with the specified targeting uncertainty. Comparison of the feedback framework with a comparable system employing fixed exposure demonstrated dose savings of up to 29%. The analysis reveals a potentially powerful technique for dynamic optimization of fluoroscopic imaging parameters to control the applied dose by exploiting the tradeoff between tracking uncertainty and x-ray exposure per frame.

Advisor: Jaffray, David A
Fiume, Eugene
Studies of Mitochondrial Dysfunction in Models of Rett Syndrome

Rett syndrome (RTT) is a neurodevelopmental disorder affecting primarily females that is predominantly caused by mutations in the MECP2 gene. RTT is characterized by a loss of previously acquired skills, ambulatory deficits, respiratory problems and overall retarded growth. Mitochondrial dysfunction and oxidative stress identified in MeCP2-deficient tissues raised the possibility that mitochondrial impairments may play role in the pathogenesis of RTT. To further investigate the role of mitochondrial dysfunction in the absence of MeCP2, I analyzed mitochondrial function and morphology in Mecp2-deficient mouse adult skin fibroblasts (ASF) and in Mecp2-null mouse ESC derived neurons using an array of fluorescent dyes coupled with flow cytometry and confocal microscopy. The heterogeneity of cellular responses in ASF prevented identification of consistent changes in mitochondrial function, making them an unsuitable model for studying mitochondrial dysfunctions. Mecp2-null mouse ESC were differentiated into enriched population of neurons. Mecp2-null neurons displayed hyperpolarized mitochondria, high levels of ROS, low ATP and impaired mitochondrial trafficking. Resveratrol and mitochondrial cocktail that target expression of mitochondrial genes and mitochondrial metabolism, but not simple ROS scavengers, were successful at ameliorating ROS levels and normalizing mitochondrial membrane potential. Since oxidative stress was reported in RTT mice, I tested whether resveratrol and mitochondrial cocktail could reverse or improve behavioral phenotype in RTT mice. Mitochondrial cocktail but not resveratrol improved exploratory, locomotor and social behavior deficits in RTT mice. Taken together these results suggest that both mitochondrial deficits and oxidative stress are not only the consequences of dysfunctional MeCP2, but are likely the causes of the RTT phenotype. Further, I determined that over-expression of mitochondrial Sirt3, known for its multifaceted effects on mitochondrial metabolism, is sufficient to protect neurons form various cytotoxic insults including oxidative stress. Overall, this study paves the way for potential new therapeutic strategies aimed at improving quality of life in RTT patients.

Keywords: Antioxidants
MeCP2
Mitochondrial cocktail
Mitochondrial dysfunction
Oxidative stress
Rett syndrome
Advisor: Eubanks, James H
Mills, Linda R
Urban District Reform for Equity: The Case of the Model Schools for Inner Cities Program in the Toronto District School Board

Urban districts have failed to change the schooling and life outcomes of marginalized and racialized students, resulting in persistent achievement and opportunity gaps. This study explores urban district reform for equity through the lens of critical pedagogy, by exploring the case of the Model Schools for Inner Cities (MSIC) Program in the Toronto District School Board (TDSB) from 2004-2014. TDSB is Canada's largest school district and is situated in a highly centralized and Neoliberal, provincial education system. The MSIC Program serves 150 elementary schools (over 1/4 of the schools in the TDSB), whose students face the greatest external barriers to success. Using the conceptual argument, Districts as Institutional Actors (Rorrer, Skrla Scheurich, 2008), this study explores how the MSIC Program implemented practices and pedagogies aimed at increasing student success, access and opportunities, with considerations for how the reform was initiated and sustained over time, and how participants understood and measured district reforms for equity. This study aims to explain, rather than evaluate the MSIC Program, and describes the tensions in implementing this reform in an era of accountability. Data was triangulated using two sets of interviews with 15 participants and 12 key documents using discourse analysis. Participants have been actively connected to the Program for a minimum of 2 years and include 3 from each of the following stakeholder groups: district leaders, MSIC Program staff, key principals, community partners and elected officials. Documents are publicly available in print and/or online, and include: program documents, district-level policy documents, professional articles, and program data. Findings suggest two main ideological approaches to closing opportunity gaps (charitable and transformative) that significantly influenced the direction of reform efforts. Reforms were further influenced by politics within and outside of the reform, and mediated by the leadership of key decision-makers. Ideological, political and leadership influences impacted three major tensions: accountability and responsibility; centralization and decentralization; and when and how to scale up reforms for equity. Key findings from this study highlight the need for a focus on transformative, social justice approaches to education, critical democracy in engagement and training in social justice leadership. This study informs future research and/or implementation for similar district reforms for equity.

Keywords: achievement gaps
district
equity
opportunity gaps
reform
urban
Advisor: Flessa, Joseph
The Form of the Firm: A Critical and Normative Theory of the Corporation

This dissertation explores the corporation from the perspective of normative political theory. As I argue, the corporation is not easily located within the theoretical matrix of liberal democracy. Because of this, a political theory of the corporation is required in order to evaluate whether our corporate institutions are consonant with the liberal democratic values we affirm. The first half of the dissertation explores the Chicago School’s political theory of the corporation. In this view corporations are taken to be the result of market-like individual voluntary initiatives, and therefore should be left alone for the sake of efficiency and liberty. The Chicago School argues for this, however, at the expense of coherence and sociological rigor. The better way to approach the corporation, I argue, is by seeing it as enabling what I call “norm-governed production.” On my account, firms overcome market inefficiencies by drawing on social and cooperative scripts that allow for cooperative activity that the market under-produces or does not produce at all. This analysis opens up an avenue for prescription and critique that does not deny the economic aspects of the corporation; if we admit that the efficiencies produced by the corporation entail normative scripts, and not merely voluntary contracts, then we can ask whether or not such scripts are compatible with our notions of fairness and justice. We can also ask whether changing scripts in the direction of fair or just relationships can be done without sacrificing too much in the way of corporate efficiency. In the second half of my dissertation I leverage this account of corporate efficiency into an alternative political theory of the corporation. I argue that our legal and political institutions ought to be restricted so as to protect corporations’ vulnerable parties and to encourage ownership patterns that empower those who make the most personal investments. I further argue that, from the perspective of business ethics, the corporation ought to be reconceived as an agent in maximizing efficiency while also being an agent for mitigating social injustice.

Keywords: Business Ethics
Corporate Governance
Normative Political Theory
Theory of the Firm
Transaction Costs
Worker Democracy
Advisor: Carens, Joseph
Heath, Joseph
Teaching and Learning about Zoos and Biodiversity Conservation: Student, Teacher, and Zoo Staff Perspectives and Experiences

This study is situated at the intersection of school science and zoo education programs. It seeks to contribute to the literature by focusing on the perspectives and experiences of students, teachers, and zoo staff. The research moves beyond focusing on a visit to the zoo to include a complementary unit of study in a science classroom. Using a case study research design (Yin, 1994), I engaged in a unit of study focusing on zoos and biodiversity conservation with a teacher and his Grade 11 biology class; conducted interviews with the teacher, 14 students, and 11 zoo staff; administered teacher and student surveys; and collected supporting documentation. The curricular context for this study aligned with STSE education emphases and strategies (Pedretti Nazir, 2011). Significant themes were identified in the data using the constant comparative method (Lincoln Guba, 1985) and formed the basis for six vignettes (Polkinghorne, 1995). It was found that the teacher and most students held mixed views (concurrently for and against zoos), except for one student who held a consistent against-zoos stance. The zoo staff held a predominately for-zoos stance, yet were concerned about poor public perception of zoos. Findings suggest that the complex nature of modern zoos in society (Hyson, 2004; Lindburg, 1999) was reflected in the participants' views. The teacher and zoo staff responded to these views in various ways, but educating the students about zoos was most common. The students stated that views against zoos did not impact their learning, although occasional tension over views occurred amongst students and the variable nature of zoos appeared to affect the students' willingness to learn in zoos. The students revealed that exposure to multiple perspectives influenced how they formed views on zoos, and educator positioning on zoos was noticed by the students. These findings suggest that the teacher and zoo staff faced pedagogical challenges when responding to multiple views on zoos, including positioning on issues and influence over students. Implications from this research are provided for consideration by researchers, teachers, and zoo staff.

Keywords: case study
informal education
participant perspectives
science education
secondary education
zoos
Advisor: Pedretti, Erminia