VictorJuiz/thesis huggingface dataset:
Determination of the Sub-cellular Mechanisms Underlying Neurodegeneration in Parkinson's Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting approximately 1.8% of the population over 65 years of age. It is characterized by three cardinal symptoms: bradykinesia, muscle rigidity and resting tremor. Symptoms are presented following 50% loss of dopaminergic neurons within the substantia nigra pars compacta (SNc). Neurodegeneration is associated with reactive oxygen species (ROS) production, protein aggregation, mitochondrial dysfunction, ubiquitin-proteasome system (UPS) inhibition and lysosomal malfunction; however it is unclear if a single mechanism or multiple mechanisms lead to disease onset. The primary aim of the studies described in this thesis was to elucidate the interactions between various pathological mechanisms underlying PD pathology. An examination of organelle function during exposure of SH-SY5Y neuroblastoma to a variety of toxins which mimic purported pathological processes in PD reveal mitochondrial membrane potential becomes depolarized, not only following mitochondrial impairment, but also after the UPS and lysosome are inhibited. Given that mitochondrial dysfunction appeared to be central to PD pathology, mitochondrial dysfunction was studied in more detail. Mitochondrial fission and fusion maintains mitochondrial integrity, which is critical to neuronal health. Thus, we examined mitochondrial dynamics in a common genetic variant linked with familial PD, known as leucine-rich repeat kinase 2 (LRRK2). Upon the expression of wild-type and mutant LRRK2, mitochondrial fusion was inhibited causing fragmentation of mitochondria. This inhibition of fusion may be the initial step leading to mitochondrial dysfunction, since inhibition of fusion occurs prior to the induction of cell stress. The findings that mitochondrial dysfunction appears to be central to PD pathology, suggest that mitochondria may be an excellent therapeutic target for PD. Thus, the potential neuroprotective function of a regulator of mitochondrial function, known as SIRT3 was examined. In SH-SY5Y cells, over-expression of SIRT3 protected neurons from degeneration associated with LRRK2 over-expression. The studies described in this thesis provide evidence that multiple sub-cellular mechanisms converge to inhibit mitochondrial function. Furthermore, mitochondrial dynamics which regulate mitochondrial function could be a key mediator in the pathology associated with PD. The work herein suggests therapies which target the mitochondria are likely to be successful in the treatment of PD.

Keywords: Parkinson's disease
mitochondria
Advisor: Nash, Joanne
Generalizing Contexts Amenable to Greedy and Greedy-like Algorithms

One central question in theoretical computer science is how to solve problems accurately and quickly. Despite the encouraging development of various algorithmic techniques in the past, we are still at the very beginning of the understanding of these techniques. One particularly interesting paradigm is the greedy algorithm paradigm. Informally, a greedy algorithm builds a solution to a problem incrementally by making locally optimal decisions at each step. Greedy algorithms are important in algorithm design as they are natural, conceptually simple to state and usually efficient. Despite wide applications of greedy algorithms in practice, their behaviour is not well understood. However, we do know that in several specific settings, greedy algorithms can achieve good results. This thesis focuses on examining contexts in which greedy and greedy-like algorithms are successful, and extending them to more general settings. In particular, we investigate structural properties of graphs and set systems, families of special functions, and greedy approximation algorithms for several classic NP-hard problems in those contexts. A natural phenomenon we observe is a trade-off between the approximation ratio and the generality of those contexts.

Keywords: Computer Science
Algorithms
Greedy
Approximation
Advisor: Borodin, Allan
Economic Spillovers and Learning from Others

In chapter 1, I study how spillover effects from competitors' choices affect a firm's decision to open a store. Using panel data from the United Kingdom's fast food industry, I propose and estimate a game of entry under incomplete information that incorporates spillover effects between firms' entry decisions. A positive spillover is identified for Burger King - increasing the stock of existing McDonald's by 1 outlet increases Burger King's estimated equilibrium probability of opening a new store by approximately 18 percentage points. Chapter 2 advances our collective knowledge about the impact of learning from others in industry dynamics, and whether it can generate the clustering of rival retailers. Uncertainty about new markets provides an opportunity for learning from others, where one firm's past entry decisions signal to others the potential profitability of risky markets. The setting is Canada's hamburger fast food industry from its inception in 1970 to 2005, where I introduce a new estimable dynamic oligopoly model of entry/exit with unobserved heterogeneity, common uncertainty about demand, learning through entry, and learning from others. I find that the presence of uncertainty induces retailers to herd into markets that others have previously done well in. Finally, chapter 3 (joint with Feng Chi) studies the early adoption of Twitter in the 111th House of Representatives. Our main objective is to determine whether successes of past adopters have the tendency to speed up Twitter adoption, where past success is defined as the average followers per Tweet - a common measure of "Twitter success" - among all prior adopters. The data suggests that accelerated adoption can be associated with favorable past outcomes: increasing the average number of followers per Tweet among past adopters by a standard deviation (of 8 followers per Tweet) accelerates the adoption time by about 112 days.

Keywords: Empirical industrial organization
Urban economics
Advisor: Aguirregabiria, Victor
Efficient Workload and Resource Management in Datacenters

This dissertation focuses on developing algorithms and systems to improve the efficiency of operating mega datacenters with hundreds of thousands of servers. In particular, it seeks to address two challenges: First, how to distribute the workload among the set of datacenters geographically deployed across the wide area? Second, how to manage the server resources of datacenters using virtualization technology? In the first part, we consider the workload management problem in geo-distributed datacenters. We first present a novel distributed workload management algorithm that jointly considers request mapping, which determines how to direct user requests to an appropriate datacenter for processing, and response routing, which decides how to select a path among the set of ISP links of a datacenter to route the response packets back to a user. In the next chapter, we study some key aspects of cost and workload in geo-distributed datacenters that have not been fully understood before. Through extensive empirical studies of climate data and cooling systems, we make a case for temperature aware workload management, where the geographical diversity of temperature and its impact on cooling energy efficiency can be used to reduce the overall cooling energy. Moreover, we advocate for holistic workload management for both interactive and batch jobs, where the delay-tolerant elastic nature of batch jobs can be exploited to further reduce the energy cost. A consistent 15% to 20% cooling energy reduction, and a 5% to 20% overall cost reduction are observed from extensive trace-driven simulations. In the second part of the thesis, we consider the resource management problem in virtualized datacenters. We design Anchor, a scalable and flexible architecture that efficiently supports a variety of resource management policies. We implement a prototype of Anchor on a small-scale in-house datacenter with 20 servers. Experimental results and trace-driven simulations show that Anchor is effective in realizing various resource management policies, and its simple algorithms are practical to solve virtual machine allocation with thousands of VMs and servers in just ten seconds.

Keywords: Data centers
Cloud computing
Request mapping
Optimization
VM placement
ADMM
Cooling efficiency
Stable matching
Advisor: Li, Baochun
A Quantum Light Source for Light-matter Interaction

I present in this thesis the design, implementation and measurement results of a narrowband quantum light source based on cavity-enhanced Parametric Down-Conversion (PDC). Spontaneous Parametric Down-Conversion (SPDC) is the workhorse in the field of optical quantum information and quantum computation, yet it is not suitable for applications where deterministic nonlinearities are required due to its low spectral brightness. By placing the nonlinear crystal inside a cavity, the spectrum of down-conversion is actively modified, such that all the non-resonant modes of down-conversion experience destructive interference, while the resonant mode sees constructive interference, resulting in great enhancement in spectral brightness. I design and construct such a cavity-enhanced down-conversion source with record high spectral brightness, making it possible to use cold atoms as the interaction medium to achieve large nonlinearity between photons. The frequency of the photons is tunable and their coherence time is measured to be on the order of 10 nanoseconds, matching the lifetime of the excited state of typical alkali atoms. I characterize extensively the output of the source by measuring the second-order correlation function, quantifying two-photon indistinguishability, performing quantum state tomography of entangled states, and showing different statistics of the source. The unprecedented long coherence time of the photon pairs has also made possible the encoding of quantum information in the time domain of the photons. I present a theoretical proposal of multi-dimensional quantum information with such long-coherence-time photons and analyze its performance with realistic parameter settings. I implement this proposal with the quantum light source I have built, and show for the first time that a qutrit can be encoded in the time domain of the single photons. I demonstrate the coherence is preserved for the qutrit state, thus ruling out any classical probabilistic explanation of the experimental data. Such an encoding scheme provides an easy access to multi-dimensional systems and can be used as a versatile platform for many quantum information and quantum computation tasks.

Keywords: quantum information
quantum optics
narrowband
light source
light-matter interaction
multidimensional
quantum computation
Advisor: Steinberg, Aephraim
Expanding the uses of Split-inteins through Protein Engineering

Split-protein systems are invaluable tools used for the discovery and investigations of the complexities of protein functions and interactions. Split-protein systems rely on the non-covalent interactions of two fragments of a split protein to restore protein function. Because of this, they have the ability to restore protein functions post-translationally, thus allowing for quick and efficient responses to a milieu of cellular mechanisms. Despite this, split-protein systems have been largely limited as a reporting tool for protein-protein interactions. The recent discovery of inteins has the potential of broadening the scope of split-protein systems. Inteins are protein elements that possess the unique ability of post-translationally ligating protein fragments together with a native peptide bond, a process termed protein splicing. This allows split-proteins to reassemble in a more natural state. Exploiting this property and utilizing protein engineering techniques and methodologies, several approaches are described here for restoring and controlling split-protein functions using inteins. First, the protein splicing behaviour was demonstrated with the development of a simple in vitro visual fluorescence assay that relies on examining the subcellular localization of different fluorescent proteins. Inteins were then used to reassemble and restore function to artificially split genetically encoded Ca2+ indicators. Second, inteins were shown to be able to simultaneously restore protein function to two target proteins. The first target protein was restored through the normal protein splicing pathway while the second was restored through non-covalent interactions of the split-protein fragments. This is a previous unknown property of inteins. Lastly, an intein was engineered to respond to an external light-stimulus that triggered protein splicing to restore split-protein function. The photoactivatable intein, coupled with the versatility of light, allows exquisite control in both space and time for the restoration of protein function within cells. The modularity of the photoactivatable intein can be simply attached to a variety of split-proteins. This was demonstrated with the restoration of various split-protein functions.

Keywords: Intein
Protein Engineering
Advisor: Truong, Kevin
Teaching Versatility to Post-secondary Violin Students

In this dissertation I examine arguments for teaching post-secondary violin students to be versatile musicians rather than specialists in one genre or area of music. In order to do this, I assess the professional and educational opportunities in Toronto based on interviews with nine professional violinists as well as teachers and administrators at four institutions that offer post-secondary instruction in violin performance. To supplement information gathered through interviews, violinists and violists performing with the National Ballet of Canada and the Esprit Orchestra were asked to respond to a questionnaire regarding their training and work experiences. Data collected through fieldwork is contextualized by an analysis of scholarly writing, periodicals and websites on the topic of current post-secondary music curriculum and pedagogy methods. Throughout the dissertation, I build the case that, despite strong opinions and many years of pedagogy that emphasize the contrary, versatility provides many advantages to professional violinists when compared to specialization. In order to maximize the benefits of versatility in a professional career, I draw on Benjamin Brinner&rsquo;s notion of core competences (Brinner 1995) to posit the skills necessary for professional musicians to pursue successful, enduring careers in Toronto. Applying these core competences to an analysis of violinists&rsquo; training, I explore the violin curriculum of post-secondary music schools in Toronto: The University of Toronto, the Glenn Gould School, Humber College, and York University to examine how students are being trained. In particular, I query how students are being prepared to be profession violinists with a focus on whetherthey are being prepared to be versatile musicians or specialists in one style. I conclude by offering recommendations as to how to better teach versatility based on the findings of the previous chapters. I explain that versatility can be nurtured in the school environment through teacher training and curricular changes that emphasize informal learning approaches, shifts in conventionally held assumptions about musical value and career success, and by encouraging exploration and improvisation as a basis of developing creativity.

Keywords: Violin
Versatility
Specialization
music
non-classical
post-secondary
glenn gould school
humber college
york university
university of toronto
strings
performance
curriculum
education
creativity
Advisor: Elliott, Robin
Exploring an HIstorical Transition in Early Childhood Education in Ontario

This predominantly qualitative study looks at the current changes in early childhood education in Ontario, Canada from an early childhood education leadership perspective. The analysis and recommendations resulting from my dissertation adds to the growing body of work examining the rapidly changing landscape of the early years. My dissertation utilizes a constructivist lens to reconstruct perspectives surrounding matters of importance in a field that is on the cusp of obtaining true professional recognition. With the advent of a self-regulating body (College of Early Childhood Educators) and a shift in management from the Ministry of Children and Youth Services to the Ministry of Education, the study highlights some of the changes occurring in the early years sector, both institutionally and professionally. The ensuing data was collected through 35 interviews of early years champions and 167 surveys from various early years teacher-educators and practitioners, revealing strong topics of discussion that add to the cacophony of voices heralding demands that the early childhood educator be perceived and treated as an equal participant in the education system. Of the 8 themes that emerged from the data analyzed, 3 were the focus of this study. The first theme focused on leadership, including characteristics of leaders and themes of emerging leadership; the second on professionalization of the early years sector (Feeney, 2012): for example, consistency in terminology, pay equity, universality, and issues regarding the current infrastructure; and the third theme investigated was intellectualization as part of the professional process: for instance, current curriculum focus, higher-learning demands, ongoing learning, the value of lab schools, faculty responsibilities, and specialization as a means of differentiated staffing (Zigler, Gilliam, & Barnett, 2011). This study also includes miniature profiles of the early years leaders interviewed, and a synopsis of their personal journeys to leadership. In the concluding chapter, the recommendations presented suggest various ways that current and emerging early years leaders can make positive impact within this transforming sector. Empowerment of self, recognition of professional status, and a view to the long-term visioning of education provides the impetus for change.

Keywords: Early Childhood
Leadership
Training and Education
Advisor: Cameron, Linda
Formal Caregivers Assisting Residents with Moderate and Severe Alzheimer’s Disease: Investigating the use of Communication Strategies during Activities of Daily Living

The prevalence of Alzheimer’s disease (AD) in Canada is on the rise, creating the need for evidence-based care practices designed to support individuals with AD and their care providers. Declines in memory, language, visual-spatial, executive abilities, and functional capacity associated with AD create the need for caregiver assistance during the completion of activities of daily living (ADLs). Unfortunately, assisting individuals with more advanced stages of AD is further complicated by communication breakdowns that occur in the dyad (i.e., caregiver and the individual with AD) established to meet a common goal: to complete ADLs. Clinically recommended communication strategies are the current solution used to support caregivers interacting with individuals with AD. However, there are limitations to these recommendations, including that the majority are based on caregiver experience, few are supported by empirical research, and little is known about which strategies are effective when assisting individuals with moderate to severe AD specifically during the context of completing ADLs. This dissertation presents novel research studies that systematically examined formal caregivers’ use of communication strategies while successfully assisting residents with moderate and severe AD during the completion of a representative ADL. Two observational studies and one focus group interview study were conducted to address our hypotheses and research objectives. Key findings from the studies comprising this dissertation were: (1) caregivers used a variety of verbal and nonverbal task-focused communication strategies when successfully assisting residents with AD during the completion of a representative ADL; (2) the task-focused communication strategies caregivers most frequently used were supported by empirical literature and included the use of one direction or idea (i.e., proposition) at a time, closed-ended questions, and paraphrased repetition; (3) when assisting residents with severe AD, caregivers used the resident’s name, one proposition, and paraphrased repetition significantly more than when assisting residents with moderate AD; and (4) the communication strategies that caregivers perceived to use in their care practice indicate that person-centered dementia care is a central aspect to facilitating the completion of ADLs. This research is an important step towards the development of evidence-based communication strategies for caregivers assisting individuals with AD during ADLs.

Keywords: Alzheimer's disease
Caregivers
Communication
Activities of daily living
Advisor: Rochon, Elizabeth
Technological Change in the Early Middle Pleistocene: The Onset of the Middle Stone Age at Kathu Pan 1, Northern Cape, South Africa

This dissertation describes the technological behaviors represented by the ~500-thousand-year-old stratum 4a lithic assemblage from Kathu Pan 1 (KP1), Northern Cape, South Africa, and situates new evidence from this site into evolutionary context. The findings highlight the significance of the early Middle Pleistocene in Africa for understanding behavioral evolution in later Homo. The stratum 4a assemblage at KP1 represents a mainly flake and blade-based industry that employed multiple strategies to produce blanks that were retouched into a variety of forms, including unifacially retouched points. Diverse core reduction strategies at KP1 suggests that KP1 hominins were flexible to the demands of local raw materials, consistent with increased degrees of ‘behavioral variability’ and adaptability. Several lines of evidence indicate that the KP1 points were used as spear tips. Points from sites ~300 thousand years ago (ka) and younger were often used as weapon tips, and evidence for this behavior can now be pushed back to ~500 ka, with important implications for cognition and social behavior among early Middle Pleistocene hominins. Raw materials in the KP1 assemblage were acquired from multiple local sources. Based on comparisons with a sample from the underlying stratum 4b Acheulean assemblage, the stratum 4a assemblage does not exhibit major changes in the kinds or quality of raw material exploited; thus, the technological changes represented by the stratum 4a assemblage are not explained by changes in raw material. New evidence from KP1 poses problems for current models that link the appearance of Middle Stone Age technologies to speciation and dispersion ~300 ka. Middle Stone Age technologies appear in the African archaeological record by ~500 ka. The new timing for the origins of Middle Stone Age technologies provides a parsimonious explanation for technological similarities between the lithic assemblages of Neanderthals and modern Homo sapiens, who share a common ancestor in the early Middle Pleistocene. Limits imposed by the nature of the African archaeological record and chronometric analyses may explain why the antiquity of these technological changes was not previously recognized.

Keywords: Middle Stone Age
South Africa
Lithic Analysis
Human Evolution
Advisor: Michael, Chazan