Restricted Theses and Dissertations
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Item Embargo Extending ModCP for Change Propagation Analysis in Multilingual Systems(2025-04-09) Mirzaei Malekabad, Mohammadmoein; Walker, Robert James; Reardon, Joel; Maurer, Frank; Walker, Robert JamesIn software engineering, change propagation analysis is a technique that enables developers to identify and manage the ripple effects of software modifications. This process plays an important role in maintaining and evolving complex software systems, as the ripple effects of changes in such systems are often subtle and difficult to notice due to their size, complexity, and interdependencies. Without proper analysis, these hidden impacts can lead to unforeseen issues, such as functionality breakdowns and customer dissatisfaction. ModCP, an existing tool for change propagation analysis, excels in identifying the im-pact of changes within an environment that utilizes a single programming language. How-ever, modern software systems frequently integrate multiple languages for different purposes, which interact with each other, posing challenges that traditional change propagation tools are not equipped to address, particularly in managing cross-language change propagation. This thesis addresses this limitation of ModCP by extending its capabilities to support change propagation across multilingual systems. A general model for interactions among languages is proposed and two realizations of the proposed model are developed, specifi-cally for Java–TSQL and C#–TSQL interactions. These implementations enable ModCP to accurately trace and propagate changes across these language boundaries. The enhanced ModCP is evaluated through a number of examples from official sources and documentation to test its ability to handle inter-language change propagation, particularly in environments involving Java or C# and SQL. These examples compare the performance of the enhanced ModCP against the previous version of ModCP and an industrial tool, Find it EZ Dev Surge, using metrics such as precision, recall, and F1 score. The results demonstrate that the enhanced ModCP consistently outperforms its alternatives, achieving higher scores across all metrics by accurately identifying implicit dependencies and tracing inter-language data flows.Item Embargo After Invention: Engaging with Institutions to Advance Innovation Commercialization and Adoption(2025-04-04) Tsou, Ean; Osiyevskyy, Oleksiy; Osiyevskyy, Oleksiy; Huq, Jo-Louise; Saunders, Chad; Adolph, Roberts; Yuan, Wenlong; Alp, OsmanInteractions between institutions and the actors embedded within them are a key part of understanding how innovations can be commercialized and adopted in complex, heavily institutionalized sectors. My dissertation begins with a cross-sector investigation on institutions before focusing on the healthcare sector, an example of a highly institutionalized sector. It is comprised of three papers investigating the ways actors – such as entrepreneurs and staff in healthcare service providers – work within, around, with and against the institutions that facilitate and hinder innovation commercialization and adoption. The first paper is a meta-analysis on the influence of macro-level factors on the entrepreneurial intention-behavior relationship: a key step to commercializing an innovation. We demonstrated that macro-level factors had little to no influence on the translation of entrepreneurial intention to behavior and proposed that aspiring entrepreneurs can overcome resource barriers at the national-level via interpersonal sources at the meso- and micro-level. In the second paper, a case study was conducted on a healthcare innovation ecosystem with a mandate to support the innovation commercialization of entrepreneurs. It shows how entrepreneurs attempt to change the conditions and institutions of the innovation ecosystem through interactions with innovation ecosystem leaders within their reach, shifting the trajectory of the innovation ecosystem. For the third paper, I developed a qualitative case study on a large healthcare service provider in a public health system to describe how actors engage in institutional work to overcome innovation adoption barriers. I show how agents further embed themselves and their work in existing institutions to legitimize innovations for adoption by end-users. I also depict how agents leverage organizational processes and values to change institutional barriers in the process of facilitating innovation adoption.Item Embargo High performance computing solutions for the study of within-host evolution(2025-03-28) Perera, Duwage Dahampriya Baladeva Deshan; Long, Quan; de Koning, Jason; Gordon, PaulAdvancements in sequencing technologies have driven a big data boom in genomics, advancing studies across evolution, epidemiology, and disease transmission. However, challenges in scalability, accuracy, and modeling complexity persist. This thesis addresses these issues through three projects, each offering innovative solutions to critical problems. The core innovations of my thesis work are the development of a scalable, out-of-core, large-scale parallel processing architecture capable of processing big data. This architecture significantly reduces computational time, enabling the modeling of complex interactions between viral evolution and epidemiology. The first project focuses on understanding the domain of transmission tracing in epidemiology. We developed a pipeline inferring viral transmission networks using Bayesian phylogenetics and TransPhylo. This work revealed a critical gap in the field: the lack of evaluations quantifying the accuracy of inferences across diverse epidemiological scenarios, a limitation rooted in the inability of current tools to scale effectively. To address these shortcomings, through our second project, we developed CATE. Through innovations that include an out-of-core file structure, a novel parallelized value look-up algorithm called Compound Interpolated Search (CIS), and CPU and GPU-based parallelization, CATE achieved speeds over 182 times faster than conventional tools. This breakthrough in computational speed makes evolutionary analyses more accessible for large-scale genomic studies. Building on CATE, the third project, Apollo, models within-host viral evolution and infection dynamics across five epidemiological hierarchies, namely network, host, tissue, cell, and viral genome. By simulating complex dynamics, Apollo can be used to validate computational models and provide a framework for studying the interplay between viral evolution and epidemiology. Collectively, these projects advance the field by providing solutions that address key limitations in scalability, accuracy, and modeling complexity. The tools developed in this thesis pave the way for more efficient analyses, enabling researchers to use big data at scale to tackle fundamental questions in evolutionary biology and public health. Importantly, the proposed infrastructure has potential applications beyond genomics, addressing broader challenges in big data analysis.Item Embargo Gender and Ministerial Appointments in Africa.(2025-04-01) Saaka, Saaka Sulemana; Franceschet, Susan; Thomas, Melanee; Rice, Roberta; Lucas, Jack; Bauer, GretchenThis dissertation examines the gendered dynamics of ministerial appointments in Africa, focusing on the vetting process, patterns of portfolio allocations, and cabinet shuffles. The process of appointing cabinet ministers is shaped by both formal and informal rules (Annesley, Beckwith, and Franceschet 2019). While formal rules grant presidents the authority to select ministers, informal norms often constrain their choices (Franceschet 2016). In some contexts, formal rules include confirmation hearings, which enable legislative oversight and public scrutiny (Heitshusen 2015). Despite extensive research on confirmation hearings in Western democracies (Canes-Wrone and De Marchi 2002; Krutz, Fleisher, and Bond 1998), little attention has been paid to how these processes operate in African contexts or whether they are gendered. To address this gap, Chapter One analyzes ministerial confirmation hearings in Ghana and Kenya. The findings reveal that women nominees face greater scrutiny concerning personal appearance and ethical standards than their male counterparts. Building on vetting process, Chapter Two shifts focus to patterns of portfolio allocation across 25 African countries. Recent data shows women hold 23.8% of cabinet positions in Africa, slightly above the global average of 22.8% (Inter-Parliamentary Union 2024; UN Women 2024). However, the criteria for being considered ministrable often include educational and professional backgrounds and political experience (Annesley, Beckwith, and Franceschet 2019). I find that, contrary to expectations, among the women ministers appointed, a higher proportion are assigned to high-prestige portfolios compared to men. Having established the vetting process of minister and portfolio allocations, Chapter Three focuses on cabinet shuffles to address what happens once they are in office. These intra-term changes, made to manage coalitions, consolidate power, or respond to political and economic shocks (Grotz, Kroeber, and Kukec 2022; Helms and Vercesi 2022), often produce gendered outcomes. The findings show that women in Africa serve shorter terms and are more likely to be replaced by men during shuffles. In sum, this dissertation uses a mixed methods approach to study the gender dynamics of ministerial appointments across Africa. By examining confirmation hearings, portfolio allocation, and cabinet shuffles, it advances our understanding of how gender influences political appointments in Africa.Item Embargo N-Heterocyclic Carbene-Derived Diradicaloids Featuring Nitrogen-containing and pi-Extended Aromatic Spacers(2025-03-31) Harrison, Alexander; Roesler, Roland; Welch, Gregory; Love, Jennifer; Heyne, Belinda; Tykwinski, RikThe idea of isolating an organic molecule with two radical centers has intrigued synthetic chemists since the first diradical was reported in 1904. In recent years, there has been a renewed interest in such systems, driven by the desire to understand their unique electronic and magnetic properties and to explore their potential applications. This surge of interest has been made possible by advancements in synthetic strategies and modern spectroscopic techniques, which allow for detailed characterization of these unusual compounds. Despite the progress in discovering new diradical frameworks, efforts to systematically modify existing scaffolds to fine-tune their properties remain limited, which offers an exciting opportunity for further exploration. This dissertation details the investigation into the aspects of structural design that affect the physicochemical properties of diradicaloids, using an efficient and simple synthetic strategy. Chapter One introduces key concepts essential for the design and characterization of diradicals. Topics include the nomenclature and classification of diradicals, synthetic methodologies to tune their properties, and techniques for their characterization. Additionally, this chapter presents my initial exploration into the field of organic diradicals. Chapter Two investigates the impact of functionalizing a 2,2’-bipyridine core at the 5,5’- and 4,4’-positions with spin-bearing imidazolyl substituents. These modifications result in diradicals exhibiting singlet closed-shell and triplet electronic structures, respectively. In Chapter Three, the effects of nitrogen incorporation into the diaryl core on the electronic properties of diradicaloids are studied, with increasing the number of nitrogen atoms yielding increasingly electron-deficient systems. It is determined that a more electron-deficient spacer produced a diamagnetic diradical and a less electron-deficient spacer. Chapter Four examines the influence of expanding π-conjugation in the aromatic spacer through the incorporation of a benzo[ghi]perylene unit. Structural and computational analysis reveal effective spin delocalization across the π-expanded arylene system, stabilizing both the closed-shell singlet ground state and excited open-shell singlet electronic states. A major achievement of this work was the isolation and structural characterization of radical cations derived from these species. This breakthrough, which is outlined in Chapter 2-4, resolved a century-long debate regarding the identity of the persistent monoradical impurity observed in spectroscopic studies of diradicals.Item Embargo Optimization of Well Stimulation Design Based on Detailed Characterization of Particle Movement in Formations: from Theory to Field(2025-03-18) Liu, Huifeng; Chen, Zhangxing (John); Azaiez, Jalel; Hu, Jinguang; Hassanzadeh, Hassan; Tan, ZhongchaoParticle migration in formations is a common phenomenon during reservoir development. These particles may originate either from a formation itself or from artificially injected fluids, influencing reservoir performance. Understanding the laws and processes of these migrations is essential for quantifying their impact. This thesis investigates particle movement under two typical conditions associated with well stimulations: acidizing an injector with formation damage caused by retained solid particles brought in by injected water and fracturing a producer in unconventional reservoirs by examining the movement of micro-sized proppants. To characterize particle retention during water injection, the Langmuirian pore-blocking mechanism is employed to describe the evolution of a retained particle distribution over time and distance. An asymptotic analytical solution and an approximate analytical solution are derived to enable predictions of a formation damage factor and a damage zone radius. Water injection cases from the Tarim Basin are analyzed to demonstrate applications of these mathematical models. To address a common condition of horizontal wells with open-hole completion in the Middle East, both chemical and mechanical approaches are designed to uniformize an acid distribution to remove formation damage in long horizontal sections. To characterize the movement of micro-sized proppant particles during hydraulic fracturing, the size exclusion mechanism is applied to describe particle capture, while the linear elastic deformation mechanism quantifies proppant embedment and deformation. An analytical model is derived to determine an optimal proppant packing ratio. Experimental setups are developed to measure the optimal packing ratio and investigate the movement of micro-sized proppant particles under various conditions, including fracturing fluids with different salinities, varying micro-fracture openings, particle entry into competing fractures, and placement in multiple branch fractures. Graded proppant injection schedules are designed for direct stimulation of naturally fractured formations and for stimulating micro-fractures surrounding a hydraulic fracture. A “dust-free” onsite injection method for micro-sized proppants is also formulated to enhance operational efficiency. The significance of this research lies not only in optimizing well stimulation design through detailed characterization of particle movement but also in bridging the gap between theoretical studies and field applications. The proposed methods and schedules provide field engineers with practical tools to directly implement effective well stimulation scenarios.Item Embargo Development of assessment tools for the identification of pain in Angus beef calves (Bos taurus)(2025-03-18) Farghal Abdelnaser, Mostafa Mohamed; Ceballos Betancourt, Maria Camila; Pajor, Ed; Windeyer, Claire; De Boyer des Roches, Alice; Schwartzkopf-Genswein, Karen; Loureiro Luna, Stelio Pacca; Pang, DanielPain assessment in cattle is challenging due to limited pain assessment tools. This thesis aimed to develop a calf grimace scale (CGS) and adapt the qualitative behaviour assessment (QBA) to assess pain in Angus beef calves after surgical castration. Four studies were conducted in this thesis. In the first study, the CGS was developed, and its responsiveness to pain and stress caused by external factors was evaluated. In the second study, the impact of targeted training sessions on the reliability of the CGS was explored. In the third study, the validity of the CGS following COSMIN (Consensus-based standards for the selection of health measurement instruments) guidelines was assessed. In the last study, the use of QBA for assessing emotional states related to acute pain was investigated, and its validity was evaluated. The CGS was developed for front and side views, including 6 facial action units: ear position, orbital tightening, tension above the eye, nostril dilation, straining of chewing muscle (only side view), and mouth opening. The CGS was responsive to pain and stress factors such as changes in environment and dam separation. The CGS was a multidimensional scale with excellent intra- (ICC > 0.87) and inter-observer reliability (ICC = 0.92), robust construct validity, and moderate criterion validity (rs = 0.49 and 0.42 for front and side views, respectively). The side view of the CGS presented the best performance under unrestrained conditions with specificity, sensitivity, and accuracy above 70% when using a threshold score of 0.5/1. Observers’ training improved their reliability and helped achieve scoring consistency using the CGS. In addition, results highlighted that multiple training sessions improved observer reliability compared to one training session. The QBA was able to identify emotional states related to acute pain in beef calves with robust construct validity, strong inter- and intra-observer reliability for some dimensions, and moderate criterion validity for some dimensions (rs = 0.18–0.77). In conclusion, this thesis proposed two measures, the CGS and QBA, as reliable and valid tools for assessing pain and emotional states related to acute pain in Angus calves, respectively.Item Embargo Decision-Making About Screening Mammography: Exploring Perceptions of Family Physicians and Patients(2025-03-26) Orenstein, Sara; Dickinson, James; Kelly, Martina; Nixon, LaraBackground: Mammography screening discussions are assumed by family physicians to be an integral part of the process of deciding whether to begin screening, with women attending their family medicine clinic to discuss screening and receiving a radiology requisition if agreed. For decisions such as screening, shared decision-making (SDM) can help promote informed choice. Little research has been conducted to understand SDM for screening mammography from the perspectives of both patients and physicians. Research Question: Among Albertan family physicians and women of recommended screening age, what does each group understand of the benefits and harms of mammograms and how does communicating this knowledge and various external factors affect screening decisions? Methods: Convenience sampling was used to recruit family physicians, and women between 50-59 years of age in their practices, from Calgary family medicine clinics. Semi-structured interviews were conducted. The transcribed interviews were analyzed with reflexive thematic analysis. Results: Interviews were conducted with nine family physicians and eleven women from their practices. Interviews identified varying perspectives on screening mammography. Physicians emphasized individualized risk assessment, resource availability, and technological support, viewing screening as a collaborative decision based on evidence and tailored guidance. In contrast, patients focused on perceived risk, the importance of screening, personal experiences, and time limitations, often seeing screening as a necessary health measure with only one “correct” choice to be made. Four intersecting themes are developed: Consultation Complexity, The Influence and Impact of Technology on Decisions, Navigating Perceptions of Screening: A Routine or Choice, and Enhancing Informed Decisions. These various factors shaped the perceptions and behaviours around screening. Discussion: Discussions on screening mammography are influenced by a variety of factors including external sources of information, competing organizational messages, and technical challenges such as time available. Women receive information outside of the clinic, adding complexity to patient-provider interactions. When having screening discussions, family physicians must navigate these dynamics, addressing diverse perceptions and providing tailored communication to support informed decision-making.Item Embargo A Parallel Thermal Simulator for Large-Scale Numerical Simulations of Geological Carbon Dioxide Utilization and Storage(2025-03-25) Di, Chaojie; Chen, Zhangxing; Hu, Jinguang; Nourozieh, Hossein; Chen, Shengnan; Xue, LiangThe intensifying global climate crisis, driven by rising greenhouse gas emissions, has underscored the urgent need for effective carbon management strategies. Among these, Carbon Capture, Utilization, and Storage (CCUS) has emerged as a critical technology for achieving carbon neutrality by mitigating anthropogenic CO₂ emissions. The success of these approaches depends on an in-depth understanding of subsurface processes, where numerical reservoir simulation plays a pivotal role in predicting fluid flow in formations, evaluating storage efficiency, and optimizing operational strategies for large-scale deployment. However, current commercial software and academic codes have limitations in simulating the above processes, with many aspects requiring further improvement. To address these challenges, this research focuses on the development of a parallel reservoir simulator tailored for geological CO₂ utilization and sequestration (GCUS). This simulator is an extension and improvement of a compositional reservoir simulator developed by our research group, with parallelization calculation implemented through our Parallel Reservoir Simulation Infrastructure (PRSI). This simulator integrates advanced fluid phase equilibrium and rock wettability models to enhance the accuracy of multiphase flow simulations in geological formations. This study is structured into several key areas. It begins with the development of a fluid phase equilibrium model and a rock wettability modeling framework tailored for CO₂-related fluid systems. These fundamental models are then applied to investigate different CO₂ storage and utilization scenarios, including CO₂ sequestration in deep saline aquifers, where trapping mechanisms and storage efficiency under various geological conditions are evaluated. The research further extends the simulations to CO₂-plume geothermal systems, analyzing the thermal and hydrodynamic behavior of CO₂ for geothermal energy extraction. Additionally, it explores CO₂-enhanced oil recovery, assessing the impact of CO₂ injection on reservoir performance and hydrocarbon production. The findings of this study highlight the influence of gas impurities on carbon sequestration, demonstrating that small amounts of SO₂ have minimal impact on CO₂ solubility but enhance stable storage by increasing the proportion of dissolved and immobile CO₂, while O₂ and H₂ reduce storage stability and increase injection pressure requirements when their concentration exceeds 10%. A novel Adaptive Saturated Composition (ASC) algorithm was developed to improve computational efficiency by selectively bypassing unnecessary stability analyses while maintaining high accuracy, significantly reducing the computational cost of phase equilibrium calculations. Simulations of CO₂ Plume Geothermal (CPG) systems confirmed that CO₂ serves as an effective heat transfer medium, sustaining substantial enthalpy and production rates during operation; however, post-operation thermal expansion increased reservoir pressure, leading to CO₂ leakage exacerbated by temperature-induced wettability alteration. Additionally, a phase labeling method was introduced to enhance the stability and accuracy of CO₂-enhanced oil recovery (EOR) simulations, preventing arbitrary phase transitions and improving numerical robustness. These advancements contribute to a more reliable and computationally efficient framework for modeling geological CO₂ storage and utilization, providing insights into optimizing storage efficiency, mitigating leakage risks, and ensuring the long-term security of CCUS applications.Item Embargo Impact of Lifestyle on the Gut Microbiota of Middle-Aged Adults: Insights from Alberta’s Tomorrow Project(2025-03-14) Shah, Shrushti; Shearer, Jane; Reimer, Raylene; Buzatto, Adriana ZardiniBackground: The escalating prevalence of obesity and its related comorbidities emphasizes a significant need for novel studies to address this growing health crisis. Recognizing the pivotal role of gut microbiota in shaping metabolic health, it is crucial to understand how lifestyle affects the composition and function of the gut microbiota. Objectives: This dissertation investigates the connections between lifestyle and host-microbiota-metabolic axes in mediating the effects of physical activity, Mediterranean diet, and high blood pressure (BP) in middle-aged adults enrolled in Alberta’s Tomorrow Project. Objectives were to: 1) investigate the association between physical activity and hand grip strength on the gut microbiota, 2) examine the influence of healthy dietary patterns on the gut microbiota and its functions, and 3) determine how hypertension-induced alterations in gut microbiota contribute to low-grade chronic systemic inflammation in middle-aged women. Methods: A total of 443 participants aged 38-64 years were recruited from Alberta’s Tomorrow Project. Fecal and serum samples were collected for microbiota and metabolome analyses. For Study 1, participants with normal and overweight body mass index (BMI) were classified into low (<150 min/week), moderate (150-500 min/week) and high (>500 min/week) physical activity groups. Study 2 involved classifying individuals into four quartiles based on a modified Mediterranean Diet Score ranging from 0 (least healthy) to 9 (most healthy). In Study 3, women diagnosed with hypertension (systolic BP >120 mmHg, diastolic BP >80 mmHg) were compared to those with normal BP (<120/80 mmHg). Comprehensive, multi-omics analyses were performed to investigate the connections between gut microbiota and associated variables. Results: 1) Physical activity-induced alterations in gut microbiota were found to be BMI-dependent, with the most significant benefits observed in individuals with normal BMI. 2) Increased consumption of plant-based foods augmented the composition of microbiota associated with carbohydrate metabolism and microbial-derived dietary metabolites. 3) Hypertension in middle-aged women altered tryptophan metabolism and lowered indole-producing bacteria. Conclusion: This dissertation highlights the intricate connections between lifestyle factors and the gut microbiota in shaping metabolic health. It emphasizes that physical activity, Mediterranean diet, and hypertension all influence gut microbiota composition and function, with significant implications for managing obesity-related comorbidities in middle-aged adults.Item Embargo Performance Enhancement of Cement Paste Using Biosilica Nanoparticles Derived from Agricultural Crop Residues(2025-03-14) Alhalsa, Sohaib; Khoshnazar, Rahil; Nassar, Nashaat; Mwesigye, Aggrey; Hassanzadeh, HassanCommon disposal practices of agricultural crop residues can pose significant environmental challenges, including greenhouse gas (GHG) emissions and hazardous leachate generation. Incorporating these residues into concrete can reduce the landfill volume of residues and enhance the performance of concrete. Most of the existing studies to incorporate crop residues into concrete employed biosilica extracted at high temperatures, leading to substantial energy consumption and GHG emissions. This study, to the best of our knowledge, utilized biosilica nanoparticles obtained from wheat and rice husks using an advanced extraction technique at temperatures below 200 °C for the first time. The extracted biosilica was fully characterized and used in as-extracted and acid-treated forms in cement paste at 1, 3, and 5% by weight of cement. The pastes were tested for compressive strength, heat evolution, microstructure, and rheological behavior. The results showed that all cement pastes incorporating biosilica nanoparticles exhibited higher compressive strength than that of the reference paste at all the testing ages ranging from 3 to 91 days. The highest improvement in the compressive strength (48% compared to the reference sample) was observed for cement paste incorporating 3 wt% acid-treated biosilica from rice husk. This paste exhibited the highest hydration peak intensity and cumulative heat over the 7-day testing period. Moreover, all pastes containing biosilica nanoparticles had less alite and belite and more amorphous content the reference paste beyond 3 days. These pastes also contained low portlandite and high bound water contents at all ages. These findings highlight the cement hydration acceleration and pozzolanic reactivity of the biosilica nanoparticles in cement paste, which contributed to the enhanced compressive strength of the paste. Adding biosilica nanoparticles also increased the viscosity and yield stress of the cement paste although these effects varied based on the characteristics and content of the biosilica nanoparticles.Item Embargo Single-cell level interactions between tumor immune microenvironment and cancer cells influence immunotherapy and metastasis(2025-03-14) Asad, Mohammad Imam Hasan Bin; Wang, Edwin; Riabowol, Karl; Anderson, David; Eszlinger, Markus; Koning, Jason; Hu, PingzhaoRecent advancements in single-cell omics and spatial transcriptomics have allowed detailed profiling of the tumor microenvironment (TME) at high resolution. In this research, we employed single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and single-nucleus ATAC sequencing (snATAC-seq) to explore TME heterogeneity and its consequences across multiple cancer types. To examine the cellular origins of glioma and their effects on patient outcomes, we performed scRNA-seq on samples from 26 glioma patients. We identified two distinct subtypes—RG-like and pri-OPC-like—based on their cellular lineage. These subtypes demonstrated unique strategies to modify their TME to avoid immune detection. To investigate interactions among tumor-infiltrating lymphocyte (TIL) subsets, we analyzed scRNA-seq data from 19 cancer types, defining 20 natural killer (NK) cell and 23 dendritic cell (DC) subsets. In lung cancer, specific TIL subsets were linked to higher T cell infiltration, improved immunotherapy outcomes, and enhanced survival. Notably, interactions involving NK_5_TXNIP, DC_5_CCL5, and CD8_0_GZMK were positively associated with T cell recruitment. Genes such as SELL, CD74, CD33, and CCR1 were found to mediate interactions between tumor-infiltrating NK cells, DCs, and T cells, potentially driving T cell accumulation in tumors and impacting immunotherapy success and survival in lung cancer. Additionally, we explored spatial heterogeneity within the TME using the Visium Spatial Gene Expression (10x Genomics), proposing a new model of spatially distinct tumor immune microenvironments (sTIMEs). In 6 melanoma samples, we identified 15 sTIMEs, each characterized by unique TIL profiles. Four sTIMEs, enriched with subsets like CD8T_5_GZMH and DC_11_CCL3, were associated with positive immunotherapy responses. Within these sTIMEs, cancer cells activated pathways tied to immune cell activation and intercellular signaling, suggesting that cancer cells actively educate the TME to form these spatial niches. Finally, to identify metastasis-like subsets within primary tumors, we constructed a deep neural network model leveraging snATAC-seq. This approach lays the groundwork for studying regulatory transitions from primary to metastatic states. Collectively, our work illuminates the intricate nature of the TME, uncovering interactions among TIL subsets and their connections to immunotherapy efficacy and survival, thus deepening the molecular understanding of cancer immunity.Item Embargo Thermophoresis in Aqueous Systems(2025-03-04) Pu, Di; Benneker, Anne; Natale, Giovanniantonio; Hejazi, Hossein; Husein, Maen; Marriott, Robert; Hill, ReghanThermophoretic transport of colloidal particles in aqueous media, driven by temperature gradients, plays a crucial role in applications such as separation, enrichment, and biochemical sensing. The interplay between colloid size, surface chemistry, electrolyte composition, and background temperature govern thermophoretic behavior, though inconsistencies remain in both theoretical and experimental studies. This work addresses unresolved aspects of colloid thermophoresis, focusing on the size, temperature, and surface chemistry dependencies of the Soret coefficient in aqueous solutions. A mode-coupling model within the Fokker-Planck framework was developed to describe colloid thermophoresis, capturing the contributions of both bulk and interfacial effects. The analysis indicates that, while bulk effects are independent of colloid size, interfacial effects such as electrostatic, hydration entropy, and depletion interactions exhibit distinct size dependencies. For silica microspheres, the ionic shielding effect negatively impacts the Soret coefficient because of the dissociation of terminal silanol groups at the silica-water interfaces, whereas the hydration entropy effect provides a positive contribution. In contrast, polystyrene nanoparticles show positive ionic shielding contributions driven by temperature-dependent variations in Bjerrum length, with hydration entropy interactions exerting a negative influence on the overall Soret coefficient. For protein suspensions of T4 lysozymes, it was shown that the interplay between bulk viscosity effect and interfacial interactions determined the overall Soret coefficient. Surface chemistry effects were further explored in surfactant solutions below the critical micelle concentration (CMC). Silica microspheres in non-ionic surfactants, such as Tween 20 and Triton X-100, exhibited enhanced hydration entropy interactions due to surfactant-assisted silanol dissociation. In anionic surfactant solutions, the adsorption of DS- at the solid-liquid interface governed thermophoretic behavior. For soft surfactant-laden micro-droplets, increasing droplet size with temperature amplified ionic shielding contributions but led to negative hydration entropy effects, driven by charge regulation at the liquid-liquid interface. The findings provide insight into the fundamental mechanisms driving thermophoresis in aqueous colloidal systems, offering pathways for improved separation, enrichment, and biochemical sensing in microfluidic environments.Item Embargo The RAD51C-XRCC3 Homologous Recombination Repair Complex: Structural Basis for its Interactions and Cancer Associated Mutations(2025-02-19) Pepper, Jordan Tan; Williams, Gareth; Schriemer, David C.; Lees-Miller, SusanThe RAD51 paralogs are crucial proteins involved in the repair of double-stranded DNA breaks (DSBs) via homologous recombination repair (HRR). There are six human RAD51 paralogs, RAD51B, RAD51C, RAD51D, XRCC2, XRCC3, and SWSAP1, and mutations in these genes are associated with cancer and other diseases. The RAD51 paralogs operate as discrete multi-protein complexes whose functional roles and structures are not fully understood. A key RAD51 paralog complex is the RAD51C-XRCC3 heterodimer (CX3), which is the focus of this thesis. I used biochemical, structural, and computational approaches to 1) profile disease and cancer-linked missense mutations found in RAD51C in the context of CX3, 2) determine the structural details of human CX3, and 3) identify and characterize potential CX3 protein interaction partners. I used the Alvinella pompejana ortholog of CX3 to investigate the impact of 5 different cancer associated missense mutations of human RAD51C on protein stability and biochemistry using heterologous expression and purification, mass photometry, fluorescence polarization assays, molecular dynamics simulations, and in silico mutation stability calculators. To investigate human CX3, I used a combination of small-angle X-ray scattering, cross-linking mass-spectrometry, structural prediction models and analysis to uncover features of how RAD51 family members interact with one another. Finally, I used affinity-purification and mass-spectrometry proteomics to detect possible CX3 protein-protein interaction partners, which I then attempted to verify using fluorescence-detection size-exclusion chromatography, with post-hoc analysis of candidate interaction partners using AlphaFold 3 and in silico calculation of interprotein energetics and affinity. From this work, I uncover insights in the structure of the CX3 complex, its possible roles in HRR, and a pathway towards characterizing it in association with interaction partners.Item Embargo Cellular Network Interactions Comprising the Pancreatic Ductal Adenocarcinoma (PDAC) Microenvironment(2025-02-05) Torabian, Pedram; Bathe, Oliver; Minoo, Parham; Wang, Edwin; Schaeffer, David; Bose, PinakiBackground: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, marked by complex interactions between tumor and stromal cells and significant resistance to treatment. Understanding the cellular and molecular heterogeneity within the PDAC tumor microenvironment is crucial for developing more targeted therapeutic strategies. Spatial transcriptomics offers a powerful approach to capture cell-to-cell interactions within the tumor microenvironment, revealing tissue architecture and providing insights into the spatial organization of cellular populations. Methods: Spatial transcriptomics was performed on three PDAC samples from a single patient to explore cellular and genetic complexities within the tumor microenvironment. Cells were manually annotated; however, some cells remained unclassified based on stringent criteria. To address this, an XGBoost machine learning classifier was developed, utilizing differentially expressed genes from tumor cells and fibroblasts as classification features. After sample integration, the number of clusters for tumor cells and fibroblasts was calculated, resulting in the identification of three tumor clusters (T1, T2, T3) and three fibroblast clusters (F1, F2, F3). The spatial organization of these clusters was further investigated using the BuildNicheAssay function, which applies a KNN algorithm to define the local neighborhood of each cell, followed by K-means clustering to categorize cells into three spatial niches based on prior knowledge. Results: Three distinct cell niches were identified: T1F2 (the proliferating hub), T2F3 (the metabolic battery), and T3F1 (the adaptive core). Each niche displayed unique functional properties. The T1F2 niche, containing proliferating tumor cells supported by fibroblasts, was associated with enhanced tumor growth and angiogenesis. The T2F3 niche demonstrated considerable metabolic plasticity, supporting energy demands. The T3F1 niche was characterized by epithelial-mesenchymal transition (EMT)-driven tumor cells interacting with fibroblasts, coupled with WNT/β-catenin and hedgehog signaling pathways, providing insights into PDAC invasion and metastasis mechanisms. Conclusion: Our study reveals a niche-based model of PDAC progression, where specialized microenvironments contribute distinct functionalities to tumor growth and adaptation. This model enhances our understanding of PDAC heterogeneity, offering insights that may guide the development of more targeted and effective therapies.Item Embargo A Feasibility Study of a Culinary Medicine Intervention for Bone Health in Adults Living with Age-Associated Low Bone Mass or Increased Fracture Risk(2025-01-23) MacLaren, Julia Marie; Campbell, David John Thomas; Billington, Emma Olive; Fenton, Tanis Rosemary; Chan, Catherine B.; McWhorter, John WesleyBackground: Dietary intervention is a valuable co-therapy in the primary and secondary prevention of fractures, and food and cooking skills protect against nutrition risk in older adults. Culinary Medicine (CM) interventions have potential to improve dietary quality and health outcomes, but there is a lack of randomized trials in this area. Objective: This pilot trial assessed the feasibility and acceptability of implementing and evaluating dietitian-led virtual CM intervention for bone health as an adjunct to usual care at our specialty osteoporosis center. Methods: Forty adults aged 45 years and older referred for fracture risk assessment were randomized to receive either usual care (group nutrition education) or usual care plus a CM program. The CM program included a 1.5-hour virtual group session with two dietitians, a recipe package, and an optional follow-up session. The usual care group could attend the CM program after study completion (wait-list control). At baseline and 3 months, participants completed surveys on home cooking and confidence in eating well for bone health and were asked to complete 2 dietary recalls. The CM group completed an acceptability survey post-session. Primary feasibility outcomes were recruitment (target: 100% in 6 months), adherence (target: ≥85%), and retention (target: ≥85%). Acceptability was measured using a questionnaire adapted from the Theoretical Framework of Acceptability. Findings: We recruited 40 participants in 6 months, meeting the recruitment target. The adherence target was also met. Most participants (80%, CI 64%-91%) were retained through the 3-month follow-up, indicating feasibility but suggesting this aspect of study design could be improved. Only 5 participants (25%, CI 9%-49%) completed all 4 dietary recalls. The intervention was generally acceptable, with the lowest scores in the ‘burden’ and ‘opportunity cost’ constructs. Conclusion: This pilot RCT suggests CM intervention is a feasible and acceptable adjunct to usual care at our osteoporosis center. However, dietary assessment measures were infeasible as delivered, and further refinement of the intervention may improve acceptability sub-constructs. In future studies, opportunities exist to increasingly tailor CM interventions for older adults, and test the optimal duration and intensity needed to achieve meaningful improvements in behavior change, nutrition status, and bone preservation.Item Embargo Quantifying Naturalistic Driving and Navigation Behaviours: Insights into Early Signs of Alzheimer’s Disease(2025-01-23) Long, Kelly; Bayat, Sayeh; Stefanakis, Emmanuel; Barber, Philip; Saidi, SaeidAlzheimer’s disease (AD) has been associated with changes in driving behaviours and navigational deficits, often emerging in early stages. The ATN framework defines AD pathology through beta-amyloid (A), tau (T), and neurodegeneration (N) biomarkers, which can manifest before clinical symptoms. In this study, we designed and calculated several metrics to quantify navigation and driving behaviours to understand how they relate to ATN biomarkers in individuals without cognitive impairment. Cerebral spinal fluid biomarker (CSF) concentrations and GPS driving data were collected from 125 cognitively normal participants between ages 65 and 85 enrolled in a longitudinal study at Washington University School of Medicine. Participants were categorized as biomarker-negative (-) or biomarker-positive (+) according to CSF concentrations of A, T, and N biomarkers. Several metrics were designed to capture temporal, spatial, and navigational aspects of driving. Temporal metrics included idle time at the start and end of trips to examine driver hesitation. Spatial metrics included distance travelled and life space (distance from home). Navigational metrics included turn counts, route straightness and route complexity, route diversity (proportion of unique routes), most common route concentration (frequency of most travelled route), and comparisons of actual versus time-optimized routes to evaluate navigational decision-making. Exploratory cross-sectional analyses over one and longitudinal analyses assessed trends over two years revealed notable relationships between the metrics and ATN biomarkers. N+ participants may have lower idle time at the start of a trip and lower route diversity than N- participants. Route diversity may also be reduced for T+ participants compared to T- participants. Complexity was higher for A+ participants after accounting for age, though it decreased with age. Idle time at the start of a trip increased with time for T- and N- participants but not T+ or N+ participants. Additionally, both straightness and the ratio of the actual route straightness to the optimized route straightness increased over time for N+ participants but not N- participants. These findings highlight the utility of the metrics in capturing subtle changes in driving and navigation behaviours and emphasize their potential as early markers of AD-related changes.Item Embargo Leveraging Solubility of Engineered Polysaccharides for Pickering and High Internal Phase Emulsions(2025-01-29) Firdous, Karim; Trifkovic, Milana; Bryant, Steven; Husein, Maen; Giovanni, NataleEmulsion design using sustainable materials remains a key area of interest in our efforts to move away from the use of inorganic molecules or surfactants that pose environmental risks. Polysaccharide-based stabilizers offer us a route towards sustainable emulsion design. However, their functional performance as emulsion stabilizers is limited and either surface modification or complexation with other molecules is required to enhance their interfacial affinity. In this thesis we demonstrate the use of enzymatically polymerized α-1,3-glucan (NG) and quaternized α-1,3-glucan (QG) for Pickering emulsion stabilization. Analyzing the microstructure and flow behaviour of generated emulsions and dispersions we investigate the network strength and the underlaying mechanisms governing the stability of emulsions. A new strategy to enhance emulsifying performance of polysaccharides that eliminates physiochemical modification and instead utilizes the solubility of polysaccharides with respect to pH to increase effective surface area is presented. The technique resulting in significant microstructural and rheological improvements over “as received” polysaccharide was successfully applied onto two physiochemically different polysaccharides i.e. α-1,3-glucan and β-1,4-chitosan demonstrating the versatility of the approach. Highly stable, gel-like high internal phase emulsions (HIPEs) using single stabilizer (QG) were generated using s single step homogenization approach. It was shown that QG had ability to reduce interfacial tension and provide electrostatic repulsion between droplets to provide stability owing to their permanent surface charge.Item Embargo Oil Sands Tailings Consolidation Employing Capillary Suction or Core-Shell Coagulant(2025-01-31) Lashkari, Reza; Husein, Maen; Salama, Amgad; Husein, Maen; Salama, AmgadThe Canadian oil sands bitumen extraction process produces a huge volume of tailings. Tailings are a mixture of water, fine particles, and residual hydrocarbons. Tailings gradually stratify into layers, with the middle layer being a stable gel-like suspension of fine clay particles, water, and bitumen known as mature fine tailings (MFT). MFT poses a considerable environmental concern, including air pollution, groundwater contamination, potential for tailings pond failure, as well as extensive land footprint. Additionally, the slow settling of MFT particles adversely affects dewatering and land reclamation, raising liability problems for operators. This work attempts to provide options to MFT reclamation using two approaches. The first approach uses the natural phenomenon of capillary action with porous surfaces to increase evaporation. The selective absorption of water into the porous substrate increases the surface area for evaporation. A filter paper substrate enhanced evaporation rates by ~ 35%, leading to a decrease in reclamation time by 33–55% relative to a non-porous surface. A mathematical model was developed to fit the evaporation rates coupling thermodynamic and mass transport principles. In the second approach, a novel core-shell coagulant (CSCC) consisting of 85 wt% Ca(OH)2 core and a 15 wt% CaCO3 shell, was assessed for its efficacy in enhancing the quality of recovered water and improving the geomechanical stability of the reclaimed MFT. At its optimum dose (4330 ppm) CSCC surpassed the performance of the optimum dose of the conventional Ca(OH)2 coagulant (3250 ppm). CSCC achieved 7% and 70% lower Na+ and Ca2+ concentrations, respectively, with 12% lower suspended solids. Therefore, the detrimental effects of these ions and suspended solids on the oil recovery and the processing equipment is reduced. At higher dose (5400 ppm), CSCC exhibited enhanced efficiency, decreasing Na+ and Ca2+ concentrations by 18% and 56%, respectively, and lowering suspended solid content by 60%. Characterization methods, such as SEM, XRD, and TGA, validated the development of pozzolanic products in the solid phase separated from the MFT after 90 days of aging. The controlled release of Ca(OH)2 from the CaCO3 shell promoted prolonged pozzolanic reactions, hence enhancing long-term reclamation stability.Item Embargo A Glutamatergic Circuit Between the Medial Zona Incerta and Cuneiform Nucleus(2025-01-31) Belway, Cole R.; Whelan, Patrick; McGirr, Alexander; Trang, TuanMovement and locomotion are fundamental for goal-directed behaviours in diverse invertebrate and vertebrate organisms. Integrating higher brain centers with evolutionarily conserved descending brainstem locomotor command centers plays a key role in orchestrating context-specific behaviours. The mesencephalic locomotor region (MLR), primarily comprised of the cuneiform nucleus (CnF) and pedunculopontine nucleus (PPN) is one such conserved descending locomotor center in diverse vertebrate species shown to produce locomotion. Excitatory glutamatergic neurons of the CnF have been shown to set both speed and gait for high-speed locomotion implicated in defensive flight when activated. The medial zona incerta (mZI) is an important hub, allowing for rapid responses to sensory inputs. Projections from the mZI to CnF exist, forming a critical inhibitory circuit for the expression of exploratory behaviours. Less is known on the information however evolved around excitatory afferents to the CnF and their functional implications. Using both a retrograde and anterograde viral tracing approach, I identified a glutamatergic circuit between the mZI and CnF. Activation of the mZI-CnF glutamatergic circuit did not provoke an increase in locomotion within an open field. However, an increase in aversive behaviour with less time spent in a conditioned chamber as well as exhibited heightened levels of anxiety with increased grooming and immobility was observed. Mouse grimace scale (MGS) testing did not reveal any significant difference in pain-related facial expressions. Together, these results highlight that glutamatergic afferents from the mZI to CnF elicits aversive behaviour that is independent of locomotion. My thesis provides evidence that activation of this circuit is sex-specific, with females showing significant aversion compared to male mice.
