VictorJuiz/thesis huggingface dataset:
Molecular Mechanisms Regulating Developmental Axon Pruning

The formation of neural connections in the mammalian nervous system is a complex process. During development, axons are initially overproduced and compete for limited quantities of target-derived growth factors. Axons which participate in functional circuits and secure appropriate amounts of growth factors are stabilized, while those axons that are either inappropriately connected or do not obtain sufficient concentrations of growth factors are eliminated in a process termed ‘axon pruning’. In this thesis, I examined the mechanisms that regulate pruning of peripheral, NGF-dependent sympathetic neurons that project to the eye. I determined that pruning of these projections in vivo requires the p75 neurotrophin receptor (p75NTR) and synthesis of brain-derived neurotrophic factor (BDNF) from the activity-dependent exon IV promoter. Furthermore, analysis of an in vitro model of axon competition, which is regulated by the interplay between nerve growth factor (NGF) and neuronal activity, revealed that p75NTR and BDNF are also essential for axon competition in culture. In this model, in the presence of NGF, neural activity confers a competitive growth advantage to stimulated, active axons by enhancing downstream TrkA (NGF receptor) signaling locally in axons. More interestingly, the unstimulated, inactive axons deriving from the same and neighboring neurons acquire a "growth disadvantage" due to secreted BDNF acting through p75NTR, which induces axon degeneration by suppressing TrkA signaling that is essential for axonal integrity. These data support a model where, during developmental axon competition, successful axons secrete BDNF in an activity-dependent fashion which activates p75NTR on unsuccessful neighboring axons, suppressing TrkA signaling, and ultimately promoting pruning by a degenerative mechanism.

Keywords: Neural Development
Neurotrophic Factors
Axon Pruning
Advisor: Miller, Freda
A Novel Asynchronous Access Method for Minimal Interface Users

Current access strategies for minimal interface (e.g., binary switch) users employ time-coded (i.e., synchronous) protocols that map unique sequences of user-generated binary digits (i.e., bits) to each of the available outcomes of a device under control. With such strategies, the user must learn and/or reproduce the timing of the protocol with a certain degree of accuracy. As a result, the number, κ, of device outcomes made accessible to the user is typically bound by the memorization capacity of the latter and by the time required to generate the appropriate bit sequences. Furthermore, synchronous access strategies introduce a minimum time delay that increases with larger κ, precluding access to control applications requiring fast user response. By turning control on its head, this thesis presents an access method that completely eliminates reliance on time-coded protocols. Instead, the proposed asynchronous access method requires users to employ their interfaces only when the behavior of the device under control does not match their intentions. In response to such event, the proposed method may then be used to select, and automatically transmit, a new outcome to the device. Such outcome is informed by historical and contextual assumptions incorporated into a recursive algorithm that provides increasingly accurate estimates of user intention. This novel approach, provides signiﬁcant advantages over traditional synchronous strategies: i) the user is not required to learn any protocol, ii) there is no limit in the number of outcomes that may be made available to the user iii) there is no delay in the response of the device, iv) the expected amount of information required to achieve a particular task may be minimized, and, most importantly, v) the control of previously inaccessible devices may be enabled with minimal interfaces. This thesis presents the full mathematical development of the novel method for asynchronous control summarized above. Rigorous performance evaluations demonstrating the potential of this method in the control of complex devices, by means of minimal interfaces, are also reported.

Keywords: asynchronous access
control
accessibility
disabled
disability
physical impairment
access
binary interface
single-switch
human-machine interface
Advisor: Mihailidis, Alex
Age Differences in the Vulnerability to Nicotine Addiction: Evidence from a Rat Model of Adolescent Nicotine Taking

Rationale: Peak initiation of smoking occurs during adolescence and early onset of smoking is associated with a reduced probability of quitting and greater risk of relapse compared to later onset. Considering the epidemiological evidence, adolescents may exhibit a unique biological susceptibility to nicotine taking, in addition to the behavioural and psychosocial factors known to influence adolescent smoking. Objectives: The current series of experiments, using a rat model of adolescent nicotine taking, was designed to investigate age differences in the processes involved in the acquisition and maintenance of nicotine taking that might account for the elevated initiation rates of smoking during adolescence. Methods: We first investigated age differences in the neural response to acute nicotine administration using c-fos mRNA expression. We then examined age differences in the rewarding and aversive effects of nicotine in the conditioned place preference (CPP) and conditioned taste avoidance (CTA) paradigms, respectively. The direct reinforcing effects of nicotine were tested in adolescent and adult rats under a variety of reinforcement schedules in the operant intravenous self-administration paradigm; extinction and nicotine priming-induced reinstatement were also examined. Finally, age differences in nicotine withdrawal precipitated by mecamylamine were assessed. Results: Nicotine had greater activational effects on c-fos mRNA expression in reward-related neural substrates of adolescent compared to adult brain. Adolescent rats were also more sensitive to the rewarding effects of nicotine (CPP) yet less sensitive to its aversive effects (CTA) compared to adult rats. Nicotine was equally reinforcing in adolescents and adults self-administering under simple reinforcement schedules, but adults were more motivated to obtain nicotine under higher reinforcement schedules. Adults were more resistant to extinction, yet both age groups demonstrated similar priming-induced reinstatement of nicotine seeking. Under spontaneous acquisition conditions, adults were more sensitive to the reinforcing effects of a low nicotine infusion dose. The aversive effects of nicotine withdrawal were also more prominent in adults compared to adolescents. Conclusions: These findings have important implications since they demonstrate a unique susceptibility to the conditioned rewarding effects of nicotine that would promote acquisition of smoking behaviour during adolescence, whereas adults may be more vulnerable to processes involved in its maintenance.

Keywords: adolescent
nicotine
rat
reinforcement
reward
self-administration
withdrawal
c-fos mRNA
acquisition of drug taking
maintenance of drug taking
motivation
mecamylamine
behaviour
extinction
reinstatement
conditioned place preference
conditioned taste avoidance
Advisor: Le, Anh Dzung
Economic Analysis of the North American Softwood Lumber Markets

Markets have an important role to play in advancing an improved understanding of international trading relationships. Two most important economic issues, which contribute to improved national welfare and ensure long-run competitive market equilibrium in international markets, are market integration and market efficiency. To provide softwood lumber markets related information to the policy makers, economic analyses relating market integration and market efficiency of the combined markets of Canada and the US have been conducted. The economic analyses include: (i) testing cointegration of prices among North American softwood lumber markets; (ii) identifying price leading markets in long-run price structure of these cointegrated markets; (iii) examining the degree of market integration among these markets; and (iv) testing the efficiency of spatial arbitrage among these markets. First, the price linkages in the North American softwood lumber markets have been explored over different trade regimes. The results indicate that market integration is affected by product aggregation of data. Further investigations of market integration are, therefore, limited to homogeneous softwood lumber product markets. Second, oligopsonistic pricing behavior of traders is identified as the possible reason for imperfect competition among Douglas Fir product markets, while imperfect competition among the markets of Spruce-Pine-Fir and Hem Fir products can not be explained by this behavior. Third, a comprehensive picture of the adherence to price parity is formulated by evaluating the magnitude and persistence of deviations from equilibrium relation of prices. It is found that large volumes of trade, product substitutability, lower prices, and certainty of trade are the factors which contribute to higher degree of market integration among North American softwood lumber product markets. Finally, the inter-temporal shifts in regime probabilities of competitive market equilibrium are assessed over different trade regimes. It is found that lower transaction costs, large volumes of trade, short distances between markets, and certainty of trade contribute to high market efficiency among softwood lumber product markets of North America.

Keywords: Market integration
Market efficiency
Softwood Lumber
International trade
Long-run competitive equilibrium
Cointegration
Advisor: Kant, Shashi
Harm from Home Care: A Patient Safety Study Examining Adverse Events in Home Care

Research into adverse events in home care is at a very early stage worldwide. Adverse event research in other health care sectors has demonstrated that patients can and do suffer harm, much of which is preventable, during the receipt of health care services. A stratified, random sample of patients who had received home care nursing service and were discharged in 2004/05 from three Ontario home care programs was studied to develop basic exploratory and descriptive evidence to advance the understanding of AEs in home care. The outcome is an estimate of the incidence of adverse events among patients, description of adverse event types and factors associated with adverse events, and the development of models predictive of home care patients with higher and lower potential for adverse events, and of the location of patients with adverse events. Positive critical indicators were identified in 66.5% of 430 cases. Sixty-one adverse events were identified in 55 (19.2%) of these 286 cases. When adjusted for sampling methodology, the adverse event rate was 13.2 per 100 patients (95%, CI 10.4% - 16.6%, SE 1.6%). Thirty-three percent of the adverse events were rated as having more than a 50% probability of preventability; 1.4% of all patients experienced an adverse event related death. Eight of the 45 factors significantly associated with adverse events formed a single factor model predictive of adverse events. Six two-factor interactions and the absence of one factor were also predictive of the occurrence of adverse events. Five of the 12 critical indicators significantly related to adverse events, as well as 7 critical indicator combinations formed models that reliably located about two-thirds of patients who had, and almost all patients who had not, experienced an adverse event. This study suggests that a significant number of home care patients experience adverse events, two-thirds of which are preventable. Use of adverse event sensitive factors as a screening tool for patients that may benefit from enhanced case management and clinical vigilance, and those unlikely to be placed at increased adverse event risk by maintaining current levels of vigilance, presents an opportunity to improve patient safety. Retrospective critical indicator models identifying home care patients who have experienced an adverse event can be used to estimate adverse event incidence rates and changes in rates over time.

Keywords: patient safety
adverse events
error
home care
qualitly
Advisor: Baker, G. Ross
A Self-renewing Multi-potent Population of Cells and their Progeny Maintain Homeostasis of the Mesenchymal Compartment

Recent evidence suggests that “mesenchymal stem cells” (MSCs) are resident in the perivascular compartment of connective tissues. However, since the definition of a stem cell assumes that these progenitors have clonal self-renewal and multi-lineage differentiation potential, the term “MSC” has been criticised, as it has been impossible to isolate definitive clonally derived “MSCs.” To test for this most basic definition of a stem cell, here it is shown that human umbilical cord perivascular cells (HUCPVCs) are capable of multilineage differentiation in vitro and, more importantly, in vivo, displaying the ability to differentiate into functionally synthetic cells that direct and contribute to rapid connective tissue healing by producing bone, cartilage and fibrous stroma in a mouse injury model. Uniquely, these cells can be enriched to >1:3 clonogenic frequency in early passage culture, making it possible to isolate clones and daughter sub-clones from mixed gender suspensions, determined to be definitively single-cell-derived by Y-chromosome fluorescent in situ hybridization (FISH) analysis. Each clone was assayed for multi-lineage differentiation capacity into the five mesenchymal lineages: myogenic, adipogenic, chondrogenic, osteogenic and fibroblastic (stroma). The observation that daughter sub-clones possess equal or lesser differentiative potential to their respective parent clones demonstrated the two intrinsic properties of stem cells in vitro: clonal self-renewal and multi-lineage differentiation. This evidence provides a new hierarchical structure of robust MSCs self-renewing to produce more restricted progenitors that gradually lose differentiation potential until a state of complete restriction to the fibroblast is reached. The methods described herein combined with recognition of this lineage hierarchy provides a significant advance to the understanding of MSC biology, and will enable interrogation of the properties of robust self-renewal and differentiation of MSCs in serially transplanted living recipients.

Keywords: Mesenchymal
Stem Cells
Advisor: Stanford, William L.
Davies, John Edward
A New Conceptualization of Occupational Outcome

This thesis presents a new conceptual model of occupational outcome based on the results of input from 5 key stakeholder groups in the field of occupational health including patients, healthcare providers, employers, unions, and insurers. Data from 77 participants who took part in one of either 18 individual interviews or 11 focus groups were qualitatively content analyzed. The goals were to: 1) compare the range of meanings given to the concepts of health, occupational health, and occupational outcome, 2) understand the range of opinions among stakeholders and identify areas of agreement or disagreement and, 3) to develop a framework of occupational outcome incorporating the views of all key stakeholders. Health, occupational health, and occupational outcome were found to have different and complex meanings that extended beyond those in existing research, and that related to the role a variable is hypothesized to have in a larger framework. Stakeholders differed in the depth, breadth, and qualitative nature of the themes discussed. Natural alignments among some stakeholder groups emerged which varied depending on the context, however a specific focus could be identified for each group. No single stakeholder group alone expressed all the themes and the complexity of the relationships among them; the whole could only be understood in terms of the sum of the stakeholder parts. A new model emerges in which occupational outcome is encompassed by the interactions of 3 key factors: Function and Ability, Individual Behaviours, and Environmental Factors. These are embedded within larger models of both occupational health that includes both individual health and workplace health, and of quality which is comprised of the interactions between structure variables, system participant factors, and outcome. The new model and the process undertaken to develop it meet two important needs for occupational health; enhancing understanding and conceptualization of occupational outcome, and enhancing understanding of the perspectives of stakeholders in the occupational healthcare system. The findings have implications for research, and delivery of quality care to patients with occupational disease or injuries. Some next steps include model validation and testing, measurement scale development, clarifying new variables through ongoing stakeholder discussion, and model application.

Keywords: outcome
occupational health
stakeholders
quality
Advisor: Holness, Dorothy Linn
GLI2 Transcriptional Cascade During Mouse Fetal Lung Development

The lung is an organ that contains a vast system of airways carefully constructed to achieve maximal surface area in a confined space, requiring guidance from a multitude of developmental factors. The Shh pathway is one such signaling mechanism that is critical to proper lung formation, guiding branching morphogenesis and cellular proliferation through its downstream Gli transcription factors. Additionally, Foxf1 has been shown to be a key developmental factor required for proper lung formation during embryogenesis. Although theorized that the Gli transcription factors are responsible for regulating foxf1 levels, their exact relationship has yet to be revealed. Using five different models for Shh signaling (gli2 null, gli2 over-expressor [hVER-Gli2], gli3 null, Gli3 constitutive repressor [Gli3Δ699] and cyclopamine treated lung explants), I compared and contrasted the role of Gli2 and Gli3 in terms of their effect on cell cycle regulation, and on the expression levels of foxf1 and its potential downstream target genes tbx4, tbx5 and fgf10. I found that ectopic over-expression of gli2 resulted in increased Shh pathway activation, and increased expression of G1/S phase cyclins, which was associated with increased cellular proliferation and lung growth. However, no change in the levels of G1/S phase cyclins due to altered Gli3 signaling was observed. Foxf1 levels positively correlate with the levels of gli2, and appear to be independent of Gli3 activity. The amount of tbx4, tbx5, and fgf10 transcripts were observed to follow the levels of gli2 in the different gli2 mouse models, however, there was no significant change in gli3 null or Gli3Δ699 mice. Finally, by analyzing gene expression at different time points during gestation, I found that while gli2 levels affect foxf1 throughout gestation, the relationship to tbx4, tbx5 and fgf10, occurs only during the latter stages of lung development. I conclude, that Gli2 and not Gli3 appears to be the primary transducer of Shh signaling influencing cyclin regulation, leading to changes in embryonic lung growth. Furthermore, that Gli2 and not Gli3 appears to regulate foxf1 expression levels, and that this may extend downstream to influence tbx4, tbx5 and fgf10 expression.

Keywords: Sonic Hedgehog
Gli2
Foxf1
Lung
Pulmonary
Mouse
Transgenic
Development
Gli3
Shh
Cellular Proliferation
Morphogenesis
Fgf10
Branching Morphogenesis
Embryo
Transgene
Advisor: Post, Martin
Point-based Ionizing Radiation Dosimetry Using Radiochromic Materials and a Fibreoptic Readout System

Real-time feedback of absorbed dose at a point within a patient can help with radiological quality assurance and innovation. Two radiochromic materials from GafChromic MD-55 and EBT films have been investigated for applicability in real-time in vivo dosimetry of ionizing radiation. Both films were able to produce a real-time measurement of optical density from a small volume, allowing positioning onto a tip of an optical fibre in the future. The increase in optical density was linear with absorbed dose for MD-55, and non-linear for EBT. The non-linearity of EBT is associated with its increased sensitivity to ionizing radiation compared to MD-55, thus reaching optical saturation at a much lower dose. The radiochromic material in EBT film was also shown to polymerize and stabilize faster, decreasing dose rate dependence in real-time measurements in comparison to MD-55. The response of the two media was tested over 75 kVp – 18 MV range of x-ray beams. The optical density measured for EBT was constant within 3% throughout the entire range, while MD-55 exhibited a nearly 40% decrease at low energies. Both materials were also shown to be temperature sensitive, with the change in optical density generally decreasing when the temperature increased from ~22°C to ~37°C. This was accompanied by a shift in the peak absorbance wavelength. It was illustrated that some of this decrease can be corrected for by tracking the peak position and then multiplying the optical density by a correction factor based on the predicted temperature. Overall, the radiochromic material in GafChromic EBT film was found to be a better candidate for in vivo real-time dosimetry than the material in GafChromic MD-55. A novel mathematical model was proposed linking absorbance to physical parameters and processes of the radiochromic materials. The absorbance at every wavelength in the spectrum was represented as a sum of absorbances from multiple absorbers, where absorbance is characterized by its absorption coefficient, initiation constant, and polymerization constant. Preliminary fits of this model to experimental data assuming two absorbers suggested that there is a trade-off between EBT’s greater sensitivity and its dose linearity characteristics. This was confirmed by experimental results.

Keywords: radiation dosimetry
radiochromic media
fibre-optic readout
Advisor: Jaffray, David A.
Vitkin, Alex
Graphical Models for Robust Speech Recognition in Adverse Environments

Robust speech recognition in acoustic environments that contain multiple speech sources and/or complex non-stationary noise is a difficult problem, but one of great practical interest. The formalism of probabilistic graphical models constitutes a relatively new and very powerful tool for better understanding and extending existing models, learning, and inference algorithms; and a bedrock for the creative, quasi-systematic development of new ones. In this thesis a collection of new graphical models and inference algorithms for robust speech recognition are presented. The problem of speech separation using multiple microphones is first treated. A family of variational algorithms for tractably combining multiple acoustic models of speech with observed sensor likelihoods is presented. The algorithms recover high quality estimates of the speech sources even when there are more sources than microphones, and have improved upon the state-of-the-art in terms of SNR gain by over 10 dB. Next the problem of background compensation in non-stationary acoustic environments is treated. A new dynamic noise adaptation (DNA) algorithm for robust noise compensation is presented, and shown to outperform several existing state-of-the-art front-end denoising systems on the new DNA + Aurora II and Aurora II-M extensions of the Aurora II task. Finally, the problem of speech recognition in speech using a single microphone is treated. The Iroquois system for multi-talker speech separation and recognition is presented. The system won the 2006 Pascal International Speech Separation Challenge, and amazingly, achieved super-human recognition performance on a majority of test cases in the task. The result marks a significant first in automatic speech recognition, and a milestone in computing.

Keywords: Robust Speech Recognition
Graphical Models
Speech Separation
Dynamic Noise Adaptation
Variational Expectation-Maximization (GEM)
Super-human Automatic Speech Recognition (ASR)
Advisor: Aarabi, Parham
Frey, Brendan J.