VictorJuiz/thesis huggingface dataset:
Noradrenergic Deficits Contribute to Impairment in the TgCRND8 Mouse Model of Alzheimer's Disease

Autosomal-dominant mutations in the amyloid precursor protein (APP) gene increase the production and aggregation of toxic amyloid-β (Aβ) peptides and cause early-onset Alzheimer’s disease (AD). Noradrenergic cell loss is well documented in AD and has been posited to play a role in cognitive symptoms as well as disease progression. We investigated memory and affect, tissue levels of catecholamines, brain-derived neurotrophic factor (BDNF) mRNA and bioenergetic homeostasis in TgCRND8 mice that express a double mutant (K670N/M671L + V717F) human APP695 transgene. We found that TgCRND8 mice develop object memory impairment and behavioural despair, as well as reductions in noradrenaline and BDNF expression in the hippocampus and cortex, before the appearance of Aβ plaques. Animals with more advanced Aβ pathology exhibit disruptions in energetic status, along with diminished complex I+III activity in the electron transport chain. To test whether the AD-like phenotypes of TgCRND8 mice might be due to altered noradrenergic tone, pre-plaque mice were treated with dexefaroxan, an antagonist of presynaptic inhibitory α2-adrenoceptors that are highly expressed on both noradrenergic and cholinergic terminals. Effects of dexefaroxan were compared to those of rivastigmine, a cholinesterase inhibitor. Both dexefaroxan and rivastigmine improved behavioural phenotypes and BDNF expression without affecting tissue Aβ load. Drug treatments also restored complex I+III mitochondrial activity and increased ATP levels. Reductions in noradrenergic tone appear to underlie Aβ-induced functional impairment in TgCRND8 mice, in addition to BDNF deficits and bioenergetic stress. These studies suggest that α2-adrenoceptor targeting may warrant consideration as a therapeutic strategy in AD.

Keywords: Alzheimer's Disease
Memory
Neurotransmission
Transgenic Mice
Advisor: Mount, Howard
Delineation of Vascular Disruption and Investigation of a Bioengineered ZFP-VEGF Gene Therapy Following Traumatic Spinal Cord Injury

Background: Traumatic spinal cord injury (SCI) results in vascular disruption which appears to contribute to the pathobiology of SCI. Vascular endothelial growth factor (VEGF) is known for vascular development and repair, and more recently for its neuroprotective properties. Given this, I investigated the temporal-spatial changes to the spinal vasculature, as well as examined the role of VEGF as a therapeutic approach for SCI. Hypothesis: It is hypothesized that clip-compression injury will result in significant vascular changes, and that ZFP-VEGF gene therapy will enhance molecular and functional recovery following spinal cord injury. Methods: Briefly, female Wistar rats received a two-level laminectomy and a 35g clip-compression injury at T6-T7 for 1 minute. Control animals received a laminectomy only. AdV-ZFP-VEGF or AdV-eGFP was administered 24 hour post-injury by intraspinal injection. For molecular and vascular analysis, tissues were extracted at various time points between 1 hour and 14 days post-SCI. For behavioural experiments animals were studied for 8 consecutive weeks. Results: I have shown that vasculature undergoes structural and functional changes, which occur as early as 1 hour following SCI. Although endogenous improvement is observed, SCI results in permanent vascular damage. Animals receiving AdV-ZFP-VEGF treatment had increased levels of VEGF mRNA and protein. AdV-ZFP-VEGF resulted in neuroprotection, as observed by increased NF200 protein and NeuN counts, and decreased TUNEL staining. Animals treated with AdV-ZFP-VEGF also showed an increased number of newly formed vessels (angiogenesis), as well as an increase in total number of vessels. Moreover, animals treated with AdV-ZFP-VEGF showed significant increases in hindlimb weight support and reduction neuropathic pain. Conclusions: I have characterized the dramatic temporal-spatial changes which occur in the spinal vasculature following SCI. Additionally, I have demonstrated that AdV-ZFP-VEGF administration results in beneficial molecular and functional outcomes. Overall, the results of this study indicate that AdV-ZFP-VEGF administration can be delivered in a clinically relevant time-window following SCI (24 hours) and provide significant molecular and neurobehavioural benefits, by acting through angiogenic and neuroprotective mechanisms.

Keywords: neuroscience
gene therapy
spinal cord injury
vascular endothelial growth factor
Advisor: Fehlings, Michael G.
Representing and Reasoning about Skills and Competencies over Time

To stay competitive within the market, organizations need to accurately understand the skills and competencies of their human resources to better utilize them and more effectively respond to internal and external demands for expertise. This is particularly important for most services organizations which provide a variety of products and services to multiple and changing clients. The ability to accurately locate experts is also important to knowledge workers. From this perspective, finding individuals with appropriate knowledge and skills is important for accomplishing knowledge intensive tasks and solving complex problems. This thesis focuses on the problem of representing and reasoning about skills and competencies over time for more effective human resources management and expert finding. Proper modeling of skills and competencies provides, among other things, a common language for assessments, a foundation for consistent interviewing, a linkage between performance management and learning, and a means for aligning business strategy and skills for driving organizational performance. It also improves knowledge management by making explicit what the organization knows and can perform. In this thesis, we present a framework for profiling human resources over time. In particular, we use first-order logic to represent and reason about expertise, skills and competencies and capture information about sources of skill and competency information. The framework provides: - a formal ontology for skill and competency management which specifies how individuals should be represented and evaluated against a skill, - a technique for inferring and validating skills and competencies over time using different sources of information, - a systematic way of evaluating human resources in order to provide a more efficient, structured, and consistent assessment process, and - techniques for identifying unreliable sources of information and revising trust in these sources. This work enhances the ability of organizations to better utilize their human assets and improves the task of expert finding required for accomplishing knowledge intensive tasks and solving complex problems.

Keywords: expert profiling
skills and competency management
human resource management
skills ontology
Advisor: Fox, Mark
“It’s like there’s a string between us”: Transnationalism and the (Re)Creation of Home among Southern Sudanese Canadians

This dissertation is an exploration of the creative spaces often opened up by exile and forced migration, where Southern Sudanese negotiate and perform new forms of belonging and affiliation, while simultaneously (re)producing, ‘local’ practices in order to reaffirm and solidify existing relationships and identity categories. Through my examination of the creative spaces opened up by migration and exile, I also raise questions related to broader concerns in the field of forced migration and refugee studies regarding the need to problematize the often binary distinction between forced and voluntary migrants, which often places refugees in a category stripped of agency and choice. Based on 20 months of multi-sited field work in Calgary, Canada and Juba, South Sudan and exploring issues related community organization and shifting forms of affiliation, long distance nation building, transnational marriage and return migration, this dissertation demonstrates how settling-in and place-making involve both material and moral aspects of practice, and that refugees, regardless of the “forced” nature of their migration, are active agents in this process.

Keywords: Southern Sudanese refugees
Transnationalism
Advisor: Boddy, Janice
Spectral Methods in Extremal Combinatorics

Extremal combinatorics studies how large a collection of objects can be if it satisfies a given set of restrictions. Inspired by a classical theorem due to Erdos, Ko and Rado, Simonovits and Sos posed the following problem: determine how large a collection of graphs on the vertex set {1,...,n} can be, if the intersection of any two of them contains a triangle. They conjectured that the largest possible collection, containing 1/8 of all graphs, consists of all graphs containing a fixed triangle (a triangle-star). The first major contribution of this thesis is a confirmation of this conjecture. We prove the Simonovits–Sos conjecture in the following strong form: the only triangle-intersecting families of measure at least 1/8 are triangle-stars (uniqueness), and every triangle-intersecting family of measure 1/8−e is O(e)-close to a triangle-star (stability). In order to prove the stability part of our theorem, we utilize a structure theorem for Boolean functions on {0,1}^m whose Fourier expansion is concentrated on the first t+1 levels, due to Kindler and Safra. The second major contribution of this thesis consists of two analogs of this theorem for Boolean functions on S_m whose Fourier expansion is concentrated on the first two levels. In the same way that the Kindler–Safra theorem is useful for studying triangle-intersecting families, our structure theorems are useful for studying intersecting families of permutations, which are families in which any two permutations agree on the image of at least one point. Using one of our theorems, we give a simple proof of the following result of Ellis, Friedgut and Pilpel: an intersecting family of permutations on S_m of size (1−e)(m−1)! is O(e)-close to a double coset, a family which consists of all permutations sending some point i to some point j.

Keywords: combinatorics
Advisor: Pitassi, Toniann
Identification of Candidate Causal Variants and Estimation of Genetic Associations in GWAS and Post-GWAS Studies

Genome-wide association studies (GWAS) and next generation sequencing (NGS) studies are powerful high-throughput methods of scanning the human genome that have dramatically increased our ability to identify disease-causing genetic variants and estimate the magnitude of their effects. Leveraging the power of these technologies requires statistical methods tailored to the real world complexities of the data from these studies. Statistical methods developed during the era of small candidate gene studies fail to account for the extended scope of genome-wide studies, which encompasses: (1) discovery of disease-associated regions; (2) localization of associations to individual risk variants; and (3) estimation of effect size. In addition, high-throughput sequencing used for large samples differs from traditional Sanger sequencing in that genotyping error varies substantially over a region, which can distort evidence used to identify the disease-associated variant. In this thesis, I model these factors in order to increase accuracy of genetic effect estimation and accuracy of identification of disease-causing variants within disease-associated regions. I address these factors in three related settings: (1) GWAS study used alone to both discover and estimate the size of genetic effect at disease-associated variants; (2) GWAS study followed with sequencing to both discover an associated region via GWAS SNPs and estimate the size of genetic effect using the sequencing data; and (3) GWAS study with sequencing or imputation used jointly to identify candidate causal variants and estimate the corresponding effect sizes within an associated region. I develop novel statistical methods to address the specific localization and estimation problems encountered in each setting. Extensive simulation studies are used to explore the nature of these problems and to compare the performance of the new methods with the standard methods. Application to the Welcome Trust Case Control Consortium Type 1 Diabetes dataset and National Cancer Institute BPC3 aggressive prostate cancer study demonstrates the difference the methods make in the interpretation of evidence in these high-throughput studies.

Keywords: statistical genetics
Advisor: Bull, Shelley B.
Sun, Lei
Visual Attention among Patients with Schizophrenia: A Study of Visual Span and Selectivity in Visual Search

Attention is one of the most impaired cognitive functions in schizophrenia; however, the precise mechanisms underlying schizophrenia-related attention impairment are unclear. Progress in identifying these mechanisms has been hampered by using methods that are not designed to isolate specific cognitive processes. The purpose of the present dissertation was to investigate visual attention among patients with schizophrenia using the visual search paradigm — the dominant paradigm for studying attention in the cognitive sciences. Moreover, the current study used eye-tracking methodology to more finely examine the mechanisms underlying impaired visual search in this clinical population. This dissertation had three main objectives: (1) to investigate whether patients with schizophrenia have smaller and/or less dynamic visual spans, (2) to examine whether certain mechanisms guiding the visual selection of objects are impaired in schizophrenia, and (3) to determine the contribution of visual search performance to substitution test performance. Results indicated that patients’ visual spans are both smaller and less dynamic compared to healthy controls. On the other hand, selectivity for more informative distractors is intact in schizophrenia; however, impaired motion perception results in impaired target discrimination in the context of intact target selection. Results also indicated that visual search performance is a primary determinant of substitution test performance. Collectively, these data demonstrate, on one hand, an impairment among patients with schizophrenia in the distribution and flexible modulation of visual attention and, on the other hand, intact visual selective attention in the presence of strong bottom-up cues. The current data also demonstrate the important contribution of visual attention to a highly sensitive neuropsychological test and, by inference, to patients’ cognitive and real-world functioning.

Keywords: Visual Selective Attention
Schizophrenia
Visual Search
Visual Span
Perceptual Span
Spotlight of Attention
Attentional Guidance
Motion Perception
Distractor Ratio
Symbol Digit Substitution
Cognitive Impairment
Advisor: Christensen, Bruce
Temporal Change in Crayfish Communities and Links to a Changing Environment

Community ecology and conservation are complementary disciplines under the umbrella of ecology, providing insight into the factors that determine where and how communities exist, and informing efforts aimed at sustaining the diversity and persistence of the organisms that comprise them. Conservation ecologists apply the principles of ecology and other disciplines, to the maintenance of biodiversity. This thesis uses this approach to assess the status of freshwater crayfish in south-central Ontario and investigate potential anthropogenic drivers of crayfish community change. I start with a temporal analysis of crayfish relative abundance over a period of 18 years and find that all species have experienced significant population declines across the sampled range, resulting in reduced species distributions and crayfish community diversity. Next I employ multivariate statistical techniques to relate changes in crayfish communities between the two time periods to ecological and anthropogenic changes. I identify a number of threats in the region that are correlated with crayfish decline and are likely to pose a threat to aquatic ecosystems more broadly in the region, including calcium (Ca) decline, metal pollution, human development, and species introductions. In the latter two chapters I look more closely at Ca decline as a mechanism driving crayfish declines. First, laboratory analysis of the effect of Ca availability on juvenile Orconectes virilis (a Shield native) reveals that survival is significantly reduced below 0.5-0.9 mg·L-1, which is one of the lowest ever reported Ca requirement thresholds for a crustacean. Second, a correlative study using adult inter-moult crayfish collected from lakes that range broadly in their Ca concentrations, indicates that for O. virilis, carapace Ca content is significantly related to lake Ca concentration, and is under-saturating below 8 mg·L-1. This collective body of work identifies significant anthropogenic threats to crayfish and their aquatic ecosystems in south-central Ontario.

Keywords: crayfish ecology and conservation
environmental change
calcium declines
south-central Ontario
Advisor: Jackson, Donald Andrew
Characterization of Genetically Modified HUCPVCs as an Osteogenic Cell Source.

Tissue engineering and ex vivo gene therapy can be used synergically as tool to regenerate bone, which overcome the problems of currently available bone replacements. Recently, a new source of mesenchymal stromal cells (MSCs) has been found in the umbilical cord; human umbilical cord perivascular cells (HUCPVCs) provide an alternative to bone marrow derived MSCs and due to their easy harvest, fast expansion, and non-immunogeneic and immunomodulatory phenotype we hypothesized that HUCPVCs are a putative candidate cell source for osteogenic ex vivo gene therapy. This work proposes the generation of cocktails of genetically modified HUCPVCs and their cryopreservation as an “off the shelf” therapeutic. This approach involves the engineering of osteogenic cell populations, by genetically modifying HUCPVCs using recombinant adenoviruses to deliver four fundamental genes for bone formation: bone morphogenetic protein 2 (BMP-2), runt-related transcription factor 2 (Runx2), Osterix (OSX/SP7) transcription factor and vascular endothelial growth factor (VEGF). Our results show that HUCPVCs can be efficiently modified by adenoviruses and can be cryopreserved without affecting the production efficiency and bioactivity of proteins of interest produced by the cells. Moreover, overexpression of BMP2, Runx2 and SP7 enhances ALP activity levels in HUCPVCs and upregulates ALP, OPN, COL1A1 and OCN gene expression; data that provides the first evidence of the effects of combinational expression of BMP2, Runx2 and SP7. Furthermore, we report for the first time the genetic modification of human BMSCs to express SP7 and Runx2, which enhances their ALP activity and matrix mineralization capacity.

Keywords: Runx2
Osterix
BMP-2
VEGF
Ex vivo gene therapy
Osteogenic
Mesenchymal stromal cells
HUCPVCs
Advisor: Davies, John Edward
Canon Law Collections in England ca 600-1066: The Manuscript Evidence

This dissertation summarizes the evidence for the use of canon law collections in England during the Christian Anglo-Saxon period, that is ca 600-1066. The method is text-historical, the focus being firstly on the scientific description of the primary evidence, and secondly on the evaluation of that evidence to determine which canon law collections were in circulation in Anglo-Saxon England, and exactly when, where and (in some cases) to whom they may have been available. An attempt is also made (in Chapter 2) to find a place for future discussion of canon law collections within the field of Anglo-Saxon Studies, a field traditionally resistant to this particular aspect of early medieval legal culture. This dissertation has been envisioned as primarily descriptive. Here and there, however, attempts are made to venture beyond mere description of the evidence and explore the broader significance of canon law collections to Anglo-Saxon legal culture as a whole; however, given the still nascent state of the study of Anglo-Saxon canon law, such explorations are very often speculative and can only be considered preliminary to a more detailed investigation into the social, political and institutional significance of the evidence that is herein presented. This is simply to say that the goals of the present study are more humble than might be hoped. A solid foundation, rather than a consummate edifice of historical analysis, is sought after. Indeed, it bears advertising up front that not only has the definitive treatment of Anglo-Saxon canon law yet to be written; in all likelihood, it will still be many years before it is even prudent to attempt such a thing. The appendices contain a number of transcriptions of canon law collections from Anglo-Saxon manuscripts, including the first ever transcriptions of the Collectio Sanblasiana and Collectio Turonensis, as well as transcriptions of Book 4 of the Collectio quadripartita and of the Collectio Wigorniensis (or 'Excerptiones pseudo-Ecgberhti') in four of its five redactions. The appendices also contain a review of the complex historiography surrounding the latter two collections, as well as case studies of three texts that appear to have been crucial to the development of canon law in the Anglo-Saxon church, namely the Libellus responsionum, the Constitutum Silvestri, and Ecgberht of York's Dialogus. While the appendixed material is intended primarily as support for the broader arguments developed in the dissertation proper, it is also hoped that scholars will find some of that material useful in its own right, and that it will serve to promote further discussion of the importance of canon law collections, especially Continental canon law collections, within the context of Anglo-Saxon history.

Keywords: Medieval Canon Law
Anglo-Saxon England
Advisor: Orchard, Andy