VictorJuiz/thesis huggingface dataset:
The Dissociation of Sensory Integration and Associative Learning in Caenorhabditis elegans and the Molecular Mechanisms Leading to Memory Acquisition

The study of associative learning in C. elegans takes advantage of a genetically tractable organism with a fully mapped connectome, and with a simple nervous system compared with that of mammals. A learning deficient mutant found in a mutagenesis screen, lrn-2, was characterized and mapped to the scd-2 gene, which expresses a receptor tyrosine kinase. scd-2 plays role in both sensory integration and associative learning, and was used to dissociate these two processes at the genetic, cellular, and behavioural levels. At the genetic level, it interacts differently with fsn-1, which expresses part of a ubiquitination complex in sensory integration and associative learning. Expression of scd-2 was previously known to be required in AIA interneurons during sensory integration, but I found that during associative learning, NSM expression is required. Not only are sensory integration and associative learning dissociated, but they also occur simultaneously as a C. elegans encounters sensory stimuli in its environment. The expression of scd-2 is necessary for the acquisition of associative memories of pathogenic bacteria, but not memory recall. This was discovered by using a drug (designed to target the mammalian ortholog of SCD-2) to block SCD-2 activity selectively during training or testing to pathogenic bacteria. We also found that SCD-2 acts upstream of two insulin-like peptides during associative learning, and thus facilitating the overall understanding of the neuronal circuit involved in associative learning in C. elegans.

Keywords: Associative Learning
C.elegans
Crizotinib
Memory acquisition
PA14
Sensory Integration
Advisor: van der Kooy, Derek
The Guitar Duo: Interaction and Group Creativity

The aim of this study was to examine the phenomenon of group creativity through the guitar duo, an ensemble which has received little scholarship in the field of music ensemble research. Specifically, this study revealed ways in which professional guitar duos manage non-verbal communication, and how they perceive moments of empathetic creativity during rehearsal and performance. A historical survey of the development of the guitar duo ensemble, along with literature review on specific issues of ensemble performance served as the backdrop for an observational study on the Henderson-Kolk guitar duo. Qualitative data was derived from video recordings of rehearsal and performance in order to examine rehearsal strategies that professional guitar duos utilize in order to promote group synergy and empathetic attunement during performance. A questionnaire was also forwarded to four members of other professional guitar duos which revealed insights into each individual’s own perception of the experience of empathetic attunement and how moments of empathetic creativity are cultivated. Results revealed an overall change in the main mode of communication between rehearsal to performance. Guitar duos utilize different rehearsal strategies to inspire or generate moments of creativity during performance, and the flow of empathetic communication is contingent on a duo’s capacity to listen and respond to each other’s musical intuitions in the moment.

Keywords: Communication
Creativity
Guitar Duo
Interaction
Music Ensemble
Advisor: Mcfadden, Jeffrey
Wear and Friction Modelling of Carbon Fiber Reinforced Epoxy Composites

The wear resistance of unidirectional carbon fiber reinforced epoxy under severe abrasive sliding conditions was studied. It was found that unidirectional laminates tested with the fibers parallel to the sliding direction (UDp) were more wear resistant under the same set of test conditions when compared to the laminates tested with fibers transverse to the sliding direction (UDap). A novel energy-based model was developed to explain the difference in the wear rate of unidirectional laminates. The model predicts that wear volume per sliding distance is proportional to the total frictional energy, the average volume to surface area ratio of the debris, the energy required to generate new surfaces, and a novel k factor that represents the fraction of the total friction energy used for creating wear particles. It was found that while the wear mechanisms of UDp specimens enabled the generation of debris particles with higher volume to surface area ratio, a lower fraction of the frictional energy was used for wear particle generation (a much lower k), which ultimately lead to a lower wear volume per sliding distance compared to UDap specimens. Heterogeneous surface wear models were proposed to predict the specific wear rates of woven carbon fabric reinforced epoxy laminates. Derivation of the models assumed that each fiber orientation was either worn at the same rate due to normal load redistribution (EW model) or worn at different rates but under equal pressure (EP model). Under mild abrasive sliding, the EW model was able to predict the specific wear rates of both laminates well. However, the models grossly under-estimated the specific wear rates of the woven laminates due to wear mechanisms that are specific to woven fabric laminates that involved the out-of-plane fibers at the cross-over points in the carbon weave. Finally, a model was proposed for predicting the coefficient of friction of the woven fabric laminates. This model was derived using the same set of assumptions as the EW model for specific wear rate. The model results matched the experimental data very well in all tested conditions.

Keywords: Carbon Fiber
Composites
Friction
Wear
Advisor: Kortschot, Mark T
The Development of Pragmatic Competence in Request Speech Acts of Thai Learners of English in Study Abroad Contexts

This mixed-methods study examines the effect of study abroad on the development of pragmatic competence by Thai learners of English. Drawing on Brown and Levinson’s (1987) politeness theory as a theoretical framework, this study focuses on the production of speech acts of request. Data were collected using an enhanced discourse completion test (EDCT), a bio-data questionnaire, and semi-structured interviews. The four study groups used in this study include two groups of Thai learners of English: one with study abroad experience and another without. Two additional groups were used to represent the learners’ native language (L1), Thai, and target language (L2), English. Request data were coded based on the coding system developed by Blum-Kulka et al. (1989). Quantitative methods were employed to analyze six aspects of requests: request perspectives, request strategies, internal modifications, request structures, alerters, and supportive moves. Follow-up questionnaires included in the EDCT and semi-structured interviews provided insights into the participants’ perceptions regarding their request production and L2 development. The results reveal linguistic and cultural differences between the learners’ L1 and L2 communities. Although, in general, the linguistic features analyzed in the requests of both learner groups tended to conform more closely to L2 norms than to the norms of their L1, the study abroad group showed greater development toward L2 norms in terms of the variety and frequencies of various linguistic features, suggesting a positive effect of study abroad. Data controlling for the social variables of social distance and relative power revealed only minimal differences between the two learner groups, suggesting study abroad did not impact the learners’ sensitivity to these variables. Interview data showed that study abroad learners generally held a very positive view of the impact of study abroad on their pragmatic development, citing confidence gains resulting from the greater number of real-world interactions as a catalyst for this development. These findings support previous research that has demonstrated a positive effect of study abroad on L2 learners’ pragmatic competence. Moreover, from these findings come implications for instruction of L2 pragmatic skills as well as recommendations for future research.

Keywords: interlanguage
pragmatics
requests
speech act
study abroad
Thai learners of English
Advisor: Rehner, Katherine
Bioconjugate Strategies for Antisense Therapeutic Delivery to Glioblastoma Stem Cells

Antisense therapeutics, including antisense oligonucleotides (AONs) and small interfering ribonucleic acids (siRNAs), are powerful tools for regulating genes, making them a promising therapy for diseases such as cancer where oncogenic genes are over-expressed. The delivery of antisense therapeutics to target cells presents a significant challenge due to the many barriers a nucleic acid must face in order to reach the cytoplasm where it exerts its effects. In this thesis, I explored multiple strategies for delivery of AONs and siRNAs, focusing on targeting the desired cell population, inducing endocytosis, and facilitating endosomal escape. This was done within the context of glioblastoma (GBM), and specifically the glioblastoma stem cells (GSCs), an aggressive subpopulation of GBM cells that are involved in resistance, migration, and recurrence. Antisense oligonucleotides against a relevant GBM gene were conjugated to an antibody engineered to target CD44, a cell surface receptor which is highly expressed on GSCs. Using this system, we demonstrated functional targeting, endocytosis, and gene knockdown in the GSCs, leading to a morphological change in the cells. This represented the first time an antibody-oligonucleotide conjugate was used to target the GSC population. We were challenged with a lack of endosomal escape when using the antibody delivery platform, so we next looked at using a protein with a native endosomal escape mechanism to facilitate oligonucleotide delivery. For the second strategy, I conjugated attenuated diphtheria toxin (aDT), a protein which escapes the endolysosomal pathway, to siRNAs against relevant gene targets involved in GSC proliferation and invasion. Using this aDT-siRNA conjugate, we could downregulate genes of interest in the glioblastoma stem cells, leading to significant changes in cell viability and the invasive capacity of these cells. This is the first diphtheria toxin-based siRNA delivery vehicle and represents a platform technology for siRNA- and AON-based therapies.

Keywords: Drug Delivery
Glioblastoma
Nucleic Acids
Advisor: Shoichet, Molly S
Molecular Dissection of Centrosome Biogenesis and its Implication in Human Disease

Centrosomes function as the primary microtubule-organizing centers in animal cells and play instrumental roles in the control of cell signaling, motility, division and polarity. A typical centrosome consists of a centriole pair that recruits the microtubule-nucleating pericentriolar material, organizes mitotic spindle assembly, and templates the formation of cilia/flagella. In cycling cells, centriole number is tightly controlled and aberrations in this process are associated with a set of human disorders including cancer, microcephaly and ciliopathies. Although factors essential for centriole assembly, such as STIL and PLK4, have been identified, the underlying molecular mechanisms that drive this process are incompletely understood. Herein, I characterize ANK2 and CEP85 as novel proteins that are essential for centriole formation. Firstly, I show that ANK2 localizes to centrosomes and interacts with CEP120. Functionally, ANK2 is required for CEP120 centrosomal localization and centriole duplication. ANK2 also plays a role in regulating microtubule stability and the distribution of centriolar satellites. Using protein proximity mapping and high-resolution structural methods, I identify CEP85 as a novel centriole duplication factor that directly interacts with STIL. Structure-guided mutational analyses indicate that this interaction is critical for centriole loading of STIL, robust PLK4 activation and efficient centriole assembly. In addition, I also find that CEP85 and STIL play important roles in cancer cell migration, probably through the ARP2/3 mediated actin organization. Taken together, my PhD research advances the mechanistic understanding of centriole duplication and thus paves the way for new therapeutic approaches to treat human diseases with abnormal centrosomes.

Keywords: Cell migration
Centriole duplication
Centriole elongation
Centrosomes
CEP85
STIL
Advisor: Pelletier, Laurence
The Role of FHL2 in Mechanically Regulated Valve Interstitial Cell Osteogenic Differentiation and Aortic Valve Disease

Calcific aortic valve disease (CAVD) is the most common valvular heart disease and lacks effective pharmacological treatment in large part because the molecular mechanisms underlying the disease are not well understood. CAVD lesions often include osteoblasts and form preferentially in the natively stiffer fibrosa side of the leaflet, suggesting roles for valve interstitial cell (VIC) osteogenesis and matrix biomechanics in valve disease. In other cell types, osteogenic differentiation is mediated by four and a half LIM domains protein 2 (FHL2) and modulated by matrix stiffness via RhoA, however their roles in mechanically regulated VIC osteogenesis and valve disease are unknown. This thesis provides the first examination of FHL2 expression in human aortic valves from CAVD patients and found upregulated FHL2 expression in diseased regions co-localized with elevated levels of the osteogenic marker Runx2 suggesting FHL2 could play a role in disease. In vitro experiments utilizing substrates of different stiffness found RhoA activation and FHL2 nuclear localization were mechanoresponsive in VICs, increasing as matrix stiffness increased. Increased matrix stiffness and RhoA activation also promoted VIC osteogenic aggregation. Notably, FHL2 knockdown inhibited aggregate formation downstream of RhoA highlighting FHL2 as an important mediator of mechanically regulated VIC osteogenesis. The role of this mechanosensitive FHL2 pathway was examined in vivo with Ldlr-/-;Apob100/100 mice that had mild CAVD as determined by elevated transvalvular velocities and aortic velocity ratios. FHL2 and Runx2 expression in the murine aortic valves were co-localized consistent with the human results. A protocol was developed that optimized sectioning technique, tissue rehydration, and probe diameter to allow the measurement of physiologically relevant stiffness in murine aortic valves by atomic force microscopy (AFM) at cellular length-scales and increased FHL2 expression in cells correlated with increased local matrix stiffness supporting the in vitro results. The work in this thesis provides additional characterization of the Ldlr-/-;Apob100/100 mouse model of CAVD, presents a refined AFM technique to spatially correlate local matrix stiffness measures with cellular protein expression to enable ex vivo mechanotransduction studies, and identifies a mechanically regulated FHL2 signaling pathway that directs VIC osteogenesis in vitro providing insight into CAVD development and potential therapeutic targets.

Keywords: Atomic Force Microscopy
Calcific Aortic Valve Disease
FHL2
Mechanotransduction
RhoA
Valve Interstitial Cells
Advisor: Simmons, Craig A
Design and Evaluation of a Soft Robotic Hand Orthosis with People with Severe Hand Impairment after Stroke

Fifteen million individuals worldwide experience a stroke each year with 50,000 of these cases occurring in Canada. Approximately one-third never fully recover the hand function required to perform activities of daily living independently. The goal of this thesis was to design a usable and accessible robot that provides the necessary assistive forces to move the affected hand after stroke into functional extension and grasp postures. The robot was iteratively designed with occupational therapists and people after stroke to create and update the design specifications and mechanical, electrical and software design choices. Successive design and evaluation cycles of the Hand Extension Robot Orthosis (HERO) are discussed. The successive design iterations were evaluated by a total of 30 participants with severe hand impairment after stroke. The iterations were increasingly effective in assisting flaccid and clenched finger extension, range of motion and grip force. With the final iteration, My-HERO, established criteria for clinically meaningful important difference thresholds were surpassed by all participants for the Fugl-Meyer Assessment-Hand and the majority of participants for the Chedoke Arm and Hand Activity Inventory-13. The majority of participants were satisfied with My-HERO and desired to use it in the clinic and at home for rehabilitation and assistance during their therapy and daily routines. This work presents novel robotic hand orthoses and novel methods for controlling them. This work shows how well robotic hand orthoses extend flaccid and clenched fingers, increase range of motion and grip strength, and enhance hand function and performance on daily living tasks. Therapists and people after stroke should use this information when planning how to incorporate these devices into therapy and daily routines. This work shows it is feasible to use a user-centred design process to develop usable adaptive and rehabilitation technology.

Keywords: Assistive Technology
Hand Therapy
Open-Source
Rehabilitation
Stroke
Wearable Robotics
Advisor: Mihailidis, Alex
Heparin for the Prevention of Preeclampsia: The Role of Non-anticoagulant Mechanisms

Preeclampsia is a serious disorder of pregnancy characterized by new-onset hypertension with evidence of organ damage. The severe, early-onset form of preeclampsia with fetal growth restriction originates from impaired spiral artery remodeling during early pregnancy, resulting in poor placental function later in pregnancy. Small randomized clinical trials have determined that low molecular weight heparin (LMWH) could effectively prevent preeclampsia, while recent multi-center trials showed no effect. The mechanisms by which LMWH could confer protection against the development of preeclampsia, anticoagulant or non-anticoagulant, have not been thoroughly investigated. Elucidating the mechanisms of LMWH for the prevention of preeclampsia could provide insight into which women may benefit from LWMH therapy. In this thesis, the hypothesis that anticoagulation-independent mechanisms of LMWH mediate the protective effects against features of preeclampsia in the rat reduced uterine perfusion pressure (RUPP) model was tested using a non-anticoagulant derivative of LMWH, termed glycol-split heparin. The non-anticoagulant properties of glycol-split heparin were first validated against dalteparin, a clinically utilized LMWH, through a series of in vitro experiments. Glycol-split heparin demonstrated similar properties to dalteparin, including stimulating the release of placental growth factor from first trimester human placental villous explants; promoting angiogenic tube formation by cultured endothelial cells; and inhibiting complement activation and leukocyte adhesion. Results from rat studies demonstrated that, although dalteparin was unable to suppress the development of hypertension in the RUPP model of preeclampsia, dalteparin significantly improved fetal growth and normalized placental labyrinth structure disrupted by model induction. However, glycol-split heparin did not elicit the same fetoplacental effects as dalteparin, and was comparable to vehicle-treated RUPP rats. The data presented in this thesis provide novel insights into the mechanistic effects of LMWH for the prevention of preeclampsia, suggesting that LMWH may mediate improvements in placental function and fetal growth. LMWH therapy may therefore be most beneficial for the subset of patients at risk of the severe early-onset phenotype of preeclampsia, characterized by placental dysfunction and fetal growth restriction. These findings provide the basis for future experimental and clinical studies to elucidate the role of LMWH as a potential preventative therapy against the development of severe early-onset preeclampsia.

Keywords: Fetal growth restriction
Heparin
Placenta
Preeclampsia
Advisor: Kingdom, John C
Harmonic Function in the Late Nineteenth-Century Chromatic Tonality of Wagner and Strauss: A Study of Extensions to Classical Prolongational Practices

That mid-to-late nineteenth-century chromatic tonality challenges diatonic-based prolongational models of tonality is a well-known assertion. Recently, the field has embraced alternative frameworks, especially neo-Riemannian and transformational approaches, to account for coherence in the works of composers such as Richard Wagner or Richard Strauss. These approaches, however, only occasionally capture the extent to which this repertoire exhibits the prolongational procedures operative in classical tonality despite the unfamiliarity of the chromatic syntax. My dissertation investigates how this chromatic syntax can be approached as an extension of familiar diatonic models. My broader theoretic basis involves recognizing a proliferation of harmonic polysemy, whereby chords that have commonplace sonorities do not function in ways traditionally associated with that sonority. To account for this disjunction, I develop a model of Functional Interval Progressions (FIPs), which proposes dominant function is a product not of sonority, nor an isolated leading tone, but rather a combination of a univalent dissonance (a tritone or diminished seventh) combined with its conventional resolution: in short, I suggest function is a product of motion. I apply this principle in various ways. Firstly, I postulate the possibility of chromatically altered diminished-seventh chords: these chords often have the sonority of commonplace tonal chords, such as dominant or half-diminished sevenths, but their behaviour is more consistent with diminished-seventh chords. The presence and resolution of a diminished-seventh interval, I posit, overwrites the centrifugal nature of the chromatic alteration. I then export this principle to triads, arguing that a similar half-enharmonic reinterpretation can explain what Lorenz (1933) refers to as apparent consonances. Contrary to Cohn (2004/2012), I view these triads then as tonal dissonances, rather than as acoustic consonances. Lastly, I argue for a contextual remodeling of chordal inversion, following Schenker’s (1922) notion of “the roothood-tendency of the lowest tone,” suggesting that in certain cases inverted chords project the function of their bass, rather than their root. I conclude by applying these principles to larger-scale analysis, proposing that through a more thorough understanding of the surface-level harmonic syntax, deeper-level prolongations— and their relationships to one another—can be adduced with greater certainty and clarity in highly chromatic music.

Keywords: Analysis
Chromatic Harmony
Nineteenth Century Music
Richard Strauss
Tonality
Wagner
Advisor: McClelland, Ryan