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Targeting drug resistant lung adenocarcinoma through hyperactivation of oncogenic pathways
No full textERK hyperactivation is a novel vulnerability in lung adenocarcinoma based on killing tumor cells by over activating the ERK/MAPK signaling pathway. While activation of this pathway is typically associated with the malignant phenotype, research has revealed that tumors still depend on tight regulation of ERK/MAPK signaling intensity and are sensitive to both insufficient and excessive signaling. ERK hyperactivation provides a strong negative selection pressure in lung adenocarcinoma, as is evidenced by the mutual exclusivity and synthetic lethality of oncogenic mutations in EGFR and KRAS. However, the signaling vulnerabilities underpinning ERK induced lethality and the clinical relevance remain unclear. To investigate the molecular mechanisms of ERK induced toxicity, I used transcriptional data paired with functional genomics data and identified proteotoxic stress as vulnerability to cells undergoing ERK hyperactivation. Through a limited drug screen, I found that the N-linked glycosylation inhibitor tunicamycin increased sensitivity to ERK hyperactivation. To study ERK hyperactivation in a clinically relevant setting, I generated models of resistance to drugs used for the treatment of lung adenocarcinoma. In a model of trametinib resistance, I found that KRASG12C amplification resulted in a “drug addicted” phenotype, whereby trametinib removal caused ERK hyperactivation lethal to cells. In models of osimertinib resistance, I profiled the potential of multiple genes to induce ERK hyperactivation. I also demonstrated that tunicamycin potentiated ERK hyperactivation induced by overexpression of oncogenes, inhibition of ERK/MAPK negative regulators or drug removal in models of drug resistance. Overall, this thesis explores the molecular mechanisms underpinning ERK induced lethality and demonstrates the potential to harness this dependency in a clinical setting.Medicine, Faculty ofGraduat
Introduction of omics metadata into biobanking ontology
No full textSpecimens and data sharing through biobanking activities has become increasingly important in global biomedical research. These practices offer the potential to accelerate scientific discovery by enabling the reuse of biospecimens and associated data. However, the benefits of data sharing can only be realized when data are findable, accessible, interoperable, and reusable (FAIR). Biobanks remain fragmented—each operating with different standards, data formats, access policies, and query interfaces—making it difficult for researchers to locate and integrate specimen-derived data. This thesis explores the application of semantic web technologies (e.g., RDF, SPARQL, and ontologies) to improve the discovery and integration of biobank data, particularly omics-derived datasets. In Chapter 1, I provide an overview of the evolution and significance of biobanks in biomedical research, highlighting their transition from physical repositories to data-centric infrastructures, and discuss the persistent challenges researchers encounter in locating, accessing, and integrating fragmented and non-standardized specimen-derived data. In Chapter 2, I examine the current challenges in biobank data discovery and integration, including the lack of standardized contextual metadata, inconsistent identifiers, and insufficient support for automated data reuse. I propose semantic web approaches as a viable solution to these problems by enabling machine-readable, interoperable metadata and flexible, federated querying. In Chapter 3, I present the development of the Next-Generation Biobanking Ontology (NGBO), an open-source application ontology designed to represent omics contextual metadata. It provides persistent identifiers and semantically rich metadata to support both human understanding and computational reasoning. Chapter 4 describes a proof-of-concept implementation of a semantic web application that enables federated querying of biobank metadata across multiple SPARQL endpoints. Chapter 5 offers a structured review of how ontologies have been applied in biomedical text mining, with the aim of clarifying the strengths, limitations, and open challenges of ontology-based approaches in this field. The review was undertaken to identify opportunities for leveraging text-mined knowledge in biobank data ecosystems and to inform recommendations for future applications. Chapter 6 presents the discussion, conclusion, and future directions, reflecting on the key contributions of the thesis and outlining recommendations for advancing semantic web technologies in biobank informatics.Science, Faculty ofGraduat
Investigating the role of the anterior cingulate cortex in the production of hyperkatifeia during opioid withdrawal
No full textWith the number of opioid-related deaths continuing to rise, the demand for an effective treatment for opioid use disorder is growing. Despite the emotional symptoms of withdrawal, termed hyperkatifeia, being a strong predictor of relapse, there is little understanding as to the mechanisms responsible for producing hyperkatifeia. This thesis examines the role of the anterior cingulate cortex (ACC) in the production of hyperkatifeia. The aim of this thesis was to identify a potential mechanism for producing hyperkatifeia, which could provide a target for future treatments. I first found that electrolytic lesion of the ACC abolished physical and emotional symptoms of withdrawal, measured with the Von Frey test and a conditioned place aversion test, respectively. These results suggest that the ACC is involved in the production of hyperkatifeia, warranting further investigation of this region. Next, I measured dopamine efflux in the ACC using fiber photometry paired with the dopamine sensor GRABDA3h. I found that dopamine in the medial frontal cortex does not encode reward predictor errors. Moreover, our results suggested that instead dopamine functions as an arousal signal and provide support for the dual-state theory. Finally, I found that during opioid withdrawal the dopamine response to emotionally salient events is altered. Specifically, I observed a greater phasic dopamine response to salient events during withdrawal. These elevations in dopamine would affect the ensemble representations which project to downstream regions involved in producing emotional and autonomic responses. We believe hyperkatifeia is the result of these increased phasic dopamine responses.Medicine, Faculty ofGraduat
Audiovisual cues and immersion across gambling and basketball : cognitive, behavioural, and physiological perspectives
No full textImmersion is a psychological state of focused attention, diminished self-awareness, and altered time perception. It is central to understanding engagement in gambling and sport. This dissertation examines how audiovisual cues shape immersion and behaviour across simulated slot machine gambling (Chapters 3–5) and basketball free-throw performance (Chapter 6). Four experimental studies evaluated effects of cue intensity, outcome type (wins, losses, losses-disguised-as-wins; LDWs), and individual differences (gender, psychological distress, ADHD traits) on immersion, gaze behaviour, and task performance.
Findings from Chapter 3 show that moderate (Intermediate), rather than high-intensity (Plus), cues produced the highest immersion, particularly among women, challenging assumptions of a linear cue–immersion relationship. Results in Chapter 4 demonstrates that Spin Initiation Latencies (SILs) were shortest in the Plus cue condition and were further influenced by gender and depressive symptoms. This chapter also replicated the post-reinforcement pause (PRP) effect: SILs were longer following wins compared to LDWs and losses, although unrelated to immersion. Results in Chapter 5 found no preregistered links between immersion and gaze patterns; however, exploratory analyses showed that moderately immersed participants allocated less attention to financial information (credit and win windows) and more to the spinning reels, a pattern more pronounced among men. Chapter 6 revealed no cue-related differences in free-throw performance or immersion, though distress, ADHD symptoms, and physical self-concept correlated with mood and motivation.
Together, these findings support the revised Two-Filter Model of Immersion, which posits that environmental cues are filtered through individual cognitive-affective traits to shape immersive experiences. Across both gambling and basketball, immersion emerged from interactions between audiovisual cues and person-level characteristics, such as gender and psychological distress. These insights may inform future research on the structural design of gambling products, digital game features, and risk mitigation strategies for immersive engagement in digital environments.Medicine, Faculty ofGraduat
Electrostatic charging in gas–solid fluidized beds : effects of gas composition, humidity, and interparticle charging
No full textElectrostatic charging is a pervasive challenge in gas–solid fluidized beds, arising from continuous contacts among fluidizing particles and between particles and the column wall. In commercial operations such as polyolefin polymerization, pharmaceutical manufacturing, and dust handling, uncontrolled electrostatics can lead to wall sheeting, particle agglomeration, and even safety hazards. Despite decades of research, the interplay between particle properties, gas-phase conditions, and boundary effects remains insufficiently understood, limiting the effectiveness of mitigation strategies.
This thesis systematically investigates the mechanisms and controlling factors of electrostatic charging in gas–solid fluidized beds. Fluidization experiments were conducted with high-density polyethylene (HDPE) and glass particles under different fluidizing gases and varying relative humidity levels. The results demonstrate that gas composition regulates the saturation charge via its dielectric breakdown strength, with argon in particular shown to effectively suppress charge accumulation of HDPE particles and the associated wall fouling and agglomeration. Humidity, in turn, critically influences both charge generation and dissipation. Its effectiveness is strongly material-dependent and is especially pronounced for glass beads, which are more hydrophilic and possess relatively lower electrical resistivity. Additional studies highlight the role of wall material and grounding in determining charge polarity and accumulation within the bed.
To isolate interparticle charging, a custom-designed acoustic levitation platform was developed to enable controlled collisions between particles of the same or different sizes and materials. These experiments confirmed that for HDPE particles, collisions between dissimilar-sized particles consistently led to size-dependent bipolar charging, while collisions between similar-sized particles produced random polarity outcomes. In contrast, material pairings with large effective work function differences exhibit strongly directional charge transfer, consistent with observations in the fluidized bed system. Pre-charging experiments further revealed that when one particle carried a substantial initial charge, the size-dependent tendency was suppressed, and charge was redistributed to reduce the initial imbalance.
A case study on wood dust handling provides additional insights into charge generation and dissipation mechanisms in practical industrial contexts, highlighting materials commonly encountered in wood processing. These findings help explain electrostatic hazards in dust-handling operations and provide guidance for reducing the risks of fires and explosions in industrial environments.Applied Science, Faculty ofChemical and Biological Engineering, Department ofGraduat
An AI-augmented cross-platform application for enhanced operator training and process optimization in thermoforming
No full textThermoforming is a manufacturing process in which thermoplastic sheets are heated and shaped
over a mould to produce desired geometries. Traditionally, given a mould shape, determining the
optimal heaters configurations to achieve accurate temperature distributions has relied heavily
on trial-and-error methods, resulting in inefficiencies in both time and resource usage. This thesis
presents an interactive operator training application that integrates predictive neural networks with
a series of feedback-providing tools in order to assist in determining an optimal heaters setting in
thermoforming based on the expert-specified temperature distribution target. Users and learners
can interactively sketch their desired thermal distribution on a virtual canvas, and the application
computes and visualizes both the corresponding heater configuration and the resulting temperature profile in real-time. This system combines two neural network architectures: a Backward Convolutional Neural Network (CNN) that determines proper heater power settings based on the thermal targets (R² up to 0.9650) and a Forward Fully Connected Neural Network (FCNN) that predicts temperature distributions from power input configurations with high predictive accuracy (R² > 0.97). Both models were trained on synthetic datasets generated from a calibrated lab-scale simulation environment. These models are embedded within a user-friendly, Unity-based application that runs across multiple platforms, such as tablet or mobile, enabling continuous, interactive exploration of heat transfer behaviour in a digital twin environment.
To evaluate the educational effectiveness of the developed application, we conducted a user study
with participants from engineering and computer science backgrounds to evaluate the educational effectiveness of the developed application. The accuracy of task performance increased significantly when interacting with the predictive module (from 80.6% to 92.10%, p < 0.001, Cohen’s d = 1.27), indicating the application’s potential for conceptual learning and skill transfer. Furthermore, no differences in performance were found according to academic background, prior thermoforming skill, or immersive tool experience, indicating that the application ensures equitable learning for a variety of user groups. By equipping operators with intelligent tools that reduce reliance on costly physical prototyping and accelerate decision-making, this work contributes to the goals of Industry 5.0, promoting sustainable, human-centric manufacturing through emerging digital innovations.Applied Science, Faculty ofEngineering, School of (Okanagan)Graduat
Creation and creativity in early Daoism
No full textThe papers in this dissertation provide philosophical interpretations of two early Daoist texts, the Laozi ⽼⼦ or Daodejing 道德經 and the Zhuangzi 莊⼦, on themes related to creation and creativity. The papers utilize conceptual and formal resources from analytic philosophy and empirical science in order to bring the views contained in those texts to bear on contemporary philosophical debates. The first paper, “The Metaphysics of Creation in the Daodejing,” offers an original interpretation of the Daodejing as containing a distinctive account of creation. In my reading, the Daodejing envisions the creation of the cosmos by Dao (1) as a movement from the absence of phenomenal forms to phenomenal forms and (2) as a movement from nothingness to existence. I interpret creation as a unique metaphysical operation that explains how (1) and (2) are possible. The second paper, “A Daoist Theory of Creativity,” interprets the Zhuangzi in order to offer a theory of the creative process. I extract from the text the thesis I call “representational underdetermination,” according to which, given a certain circumstance, there are mutually incompatible but equally good ways of representing it. I utilize representational underdetermination to formulate a notion of a perspective as a total way of mapping representations over a circumstance. Then, I build on such a notion a model of the creative process. The third paper, “The Logic of Ideal Agency in the Zhuangzi,” reconstructs the argumentative logic behind the picture of ideal agency contained in the Zhuangzi. I claim that the text envisions reality as characterized by ubiquitous change. Given such a view of reality, I consider (1) what are the conditions the satisfaction of which makes one an ideal agent, and (2) what are the capacities that realize ideal agency. I answer (1) by interpreting ideal agents as being maximally adaptive and identify a criterion for adaptability. I answer (2) by identifying in the text an agential stance that is purportedly attained by emptying one’s mind of its contents.Arts, Faculty ofPhilosophy, Department ofGraduat
Sensorimotor processing in Huntington's disease : from behavior to circuit
No full textVoluntary movement arises from coordinated computations across cortical and subcortical circuits. Huntington’s disease (HD) perturbs these processes early, yet how cortical dynamics and striatal neurotransmission jointly change during action remains unresolved. This thesis integrates automated home-cage behavior, chronic mesoscale cortical imaging, and subcortical fiber photometry to define circuit mechanisms underlying impaired motor refinement in early-manifest zQ175DN knock-in mice (~6–8 months).
In Chapter 2, I established an automated, forelimb lever-pull task that required maintaining the lever within a goal range for a required hold time that increased with performance. Wild-type (WT) and zQ175 mice showed comparable initial engagement. However, as task demands increased, zQ175 mice exhibited marked difficulty adapting to longer hold times. WT animals progressively refined their strategy, shifting from variable to precise pulls, while zQ175 mice maintained erratic performance. Ex vivo, experience-dependent plasticity in contralateral dorsolateral striatum (DLS), present in WT, was absent in zQ175, indicating early disruption of motor learning-relevant corticostriatal circuits in HD.
Chapter 3 details the development and validation of a chronic, multiscale platform combining widefield Ca²⁺ imaging of dorsal cortex with striatal fiber photometry. The method yielded stable, concurrent measurements over weeks and supported repeated recordings during behavior.
Using this platform, in Chapter 4 I examined motor execution in a lever-pull paradigm with home-cage pretraining and head-fixed recordings. In the home cage, WT mice improved over days, while zQ175 mice maintained lower success with minimal improvement. Under head fixation, primary sensorimotor cortex exhibited robust, lever pull-aligned activity in both genotypes, whereas secondary motor cortex (rostral forelimb area, M2/RFA) was selectively under-recruited in zQ175. In dorsal striatum, glutamate transients (fiber photometry) were time-locked with similar peak amplitude and latency across genotypes but decayed more slowly in zQ175.
Collectively, these findings define an early-manifest phenotype with preserved movement initiation but impaired refinement under higher accuracy demands. Mechanistically, selective M2/RFA under-recruitment together with prolonged striatal glutamate signaling likely degrade feedback-based control and experience-dependent tuning while sparing basic motor drive. These systems-level insights identify concrete targets for mechanistic dissection and for translational strategies to stabilize network function early in HD.Medicine, Faculty ofGraduat
Cougar (Puma concolor) demography and foraging ecology in the southern interior of British Columbia, Canada
No full textLarge carnivores face complex challenges in human-modified landscapes, where mortality risk, resource availability, and habitat structure interact to shape population dynamics and predation patterns. In this dissertation, I examined how environmental and anthropogenic factors influence cougar (Puma concolor) demography, survival, and foraging behaviour in the southern interior of British Columbia, Canada. Using GPS-collared individuals, kill site investigations, remote cameras, and spatial modeling, I integrated demographic, dietary, and spatial ecology approaches to understand how cougars navigate trade-offs between ecological opportunity and risk.
In Chapter 2, I analyzed population demography and cause-specific mortality of 56 GPS-collared adults and 59 ear-tagged kittens. Human activities were the main source of adult mortality, while predation dominated kitten deaths. Survival varied by sex, season, and landscape features, with higher risk near roads and agricultural areas. Kittens were most vulnerable in early denning stages, particularly when maternal care was reduced or dens were distant from recent cutblocks and roads.
In Chapter 3, I examined prey selection and dietary overlap among 38 cougars using 875 kill sites and prey availability data from 146 remote cameras. Males killed larger prey than females, and prey use varied seasonally. Diet similarity was highest at intermediate spatial overlap, indicating that territorial neighbors balance competition and prey availability in their dietary selection.
In Chapter 4, I assessed habitat drivers of predation across 886 kill sites. Kill sites were concentrated in core home ranges and influenced by terrain and disturbance features. Deer kills were associated with rugged terrain in snow months and with cutblocks and burns 10–20 years post-disturbance in snow-free months, enhancing both prey catchability and abundance. Multi-species clustering was limited, but these habitats increased hunting success for multiple ungulate species.
These chapters illustrate how mortality risk, prey dynamics, and landscape features interact to shape cougar ecology in human-dominated ecosystems. This work advances understanding of carnivore–prey dynamics and provides guidance for mitigating human–wildlife conflict and conserving wide-ranging predators in heterogeneous landscapes.Science, Irving K. Barber Faculty of (Okanagan)Biology, Department of (Okanagan)Graduat
Ethical space of engagement : exploring perspectives and practices of indigenization in post-secondary education as situated in place
No full textThe notion of “Indigenization” within the academy has been taken up by Indigenous scholars and activists for more than two decades, and more recently, it has become a priority in the tertiary sector in Canada with federal and provincial endorsement. Still, Indigenization remains a relatively ambiguous concept within higher education. This doctoral dissertation offers a portrait of Indigenization, providing insight into this process within the academy in Canada. It explores the history of this land we now call Canada and the forces that have gotten us to where we are now, having to re-Indigenize, decolonize, and work towards reconciliation. It considers the contemporary landscape of Indigenization, how it is characterized, envisioned, and practiced in higher education. Using an Indigenous métissage methodology and theories of ethical space and ethical relationality, this study looked at two unidentified public post-secondary institutions as positioned on Indigenous territories in British Columbia, Canada, to catch a glimpse of Indigenization in situ within a snapshot in time. Multiple methods were employed to gather knowledge at each case site including physical and virtual space observations, policy reviews, semi-structured interviews with senior administrators, and a questionnaire offered to other institutional personnel.
Findings revealed the practical, everyday challenges of Indigenization within institutions such as organizational silos, gaps in communication and perspectives, and a lack of Indigenous peoples to guide, support, and direct Indigenization initiatives. Results also showed deeper and more ideological barriers to consequential Indigenization such as an unhealthy institutional culture, the absence of a cohesive, holistic, and living vision for Indigenization as well as a sincere and robust accountability structure to measure goal progress and success. These outcomes indicate that transformational change is required. At the crux, institutions need to focus on the decolonization of attitudes and perceptions, policies and practices and, simultaneously, the adoption or equal inclusion of an Indigenous governance approach. An ethical space of engagement (Ermine, 2007) is suggested to promote transformational change and bring together disparate perspectives within distinct and complex institutions of higher education to realize meaningful Indigenization. Honouring the spirit, intent, and principles of a treaty partnership is recommended to achieve consequential Indigenization.Education, Faculty ofEducational Studies (EDST), Department ofGraduat