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Quantitative Guidelines for Nanoparticle Targeting
Get PDFNanoparticles are promising vehicles for the precise delivery of molecular therapies to diseased sites. However, less than 1% of administered nanoparticles reach their target sites due to a lack of control over interactions between nanoparticles and their biological environment. To address this challenge, I investigate the nano-bio interactions governing delivery and establish design principles to improve nanoparticle targeting in serum. First, I develop a pharmacokinetic compartment model framework to describe nanoparticle delivery. I represent the biological interactions that help or hinder nanoparticles cross from one compartment to another as intercompartmental transport rates. This model generates a system of equations that predicts nanoparticle delivery to target sites and reveals how these transport rates control the final nanoparticle delivery efficiency. Second, I focus on the effect of serum proteins on nanoparticle binding to target cells. I establish a quantitative scale of serum and target protein binding to nanoparticles and show that serum and targets compete for nanoparticle targeting. I use these scales together to create a quantitative metric that identifies nanoparticle designs that bind effectively to targets in serum with 90% sensitivity and 88% specificity. Finally, I identify a new approach to create targeting nanoparticles that remain functional in serum. I allow proteins to equilibrate on the nanoparticle surface, then conjugate targeting ligands to this equilibrated protein corona. This approach reduces the serum protein binding affinity of the nanoparticles, thereby increasing their target binding ability by 81%. This thesis establishes quantitative tools and strategies to understand and control the effect of serum proteins on nanoparticle targeting.Ph.D
Disentangling the effects of parasite infection and temperature on the aerobic swimming performance of pumpkinseed hosts
Get PDFClimate change is shifting the aerobic capacity of aquatic ectotherms, affecting their ability to move efficiently through their environment. Rising temperatures also alter host-parasite interactions, yet how these stressors interact to impact locomotion remains unclear. This is especially relevant for infections that disrupt streamlining and fin function, with implications for wild fish populations, aquaculture, and fisheries. Pumpkinseed sunfish (Lepomis gibbosus Linnaeus, 1758), a popular recreational fishing species, are naturally co-infected with trematodes, forming rigid cysts on fins and body, and cestode tapeworms, infecting the liver and digestive tract. We tested whether pumpkinseed swimming performance is affected by drag from cysts by measuring critical swimming speed (Ucrit) and aerobic metabolic traits in naturally infected fish and fish treated to remove cestodes. Individuals with more cysts had lower Ucrit, maximum metabolic rate (MMR) and aerobic scope, likely due to increased drag. Next, we acclimated wild-caught, co-infected fish to 20, 25, and 30 °C and measured Ucrit and MMR. Warmer temperatures increased both metrics, and internal parasites were related to reduced MMR and Ucrit. Overall, infections can impair swimming by increasing drag and through physiological effects, but warming does not appear to exacerbate these effects in species not living near their thermal limits.The presentation of the authors' names and (or) special characters in the title of the pdf file of the accepted manuscript may differ slightly from what is displayed on the item page. The information in the pdf file of the accepted manuscript reflects the original submission by the author
Sustainable Recovery of Battery-Grade Nickel and Cobalt Sulfates: From Selective Crystallization to Carbon Sequestration
Get PDFThe shift toward electrified, low-carbon economies has intensified the demand for battery materials such as nickel and cobalt. To meet this demand sustainably, both primary resource extraction and recycling of lithium-ion batteries (LIBs) must be coupled with high-purity recovery processes. This dissertation focuses on selective crystallization and post-crystallization purification to produce battery-grade nickel and cobalt sulfates. Particular emphasis is placed on impurity incorporation pathways and removal mechanisms, while also integrating carbon capture pathways through the valorization of nickel tailings.
A fundamental research gap lies in the lack of understanding of impurity uptake mechanisms during nickel and cobalt crystallization. This is a clear research gap, as even trace-level impurities can jeopardize product quality and fail to meet the stringent purity requirements of battery-grade applications. There is also a broader need to develop integrated hydrometallurgical approaches that consider both impurity control and carbon sequestration potential from the outset of the process design.
The overarching goal of this work is to develop impurity-targeted strategies for the sustainable production of high-purity nickel and cobalt sulfate crystals. The central objective is to recover battery-grade nickel and cobalt sulfates from both primary and secondary process streams with minimal incorporation of impurities. This is achieved through three sub-objectives: (1) Characterizing two-step post-crystallization washing (displacement and repulp) of NiSO4•6H2O and CoSO4•7H2O obtained from synthetic primary (ores) and secondary streams (lithium-ion battery recycling liquors); (2) Investigating the uptake mechanisms of various impurities and establishing a semi-empirical framework that combines theoretical understanding with experimental results to predict the impurity uptake behavior based on the impurity’s physicochemical property; and (3) Developing acid leaching protocols for nickel tailings to extract divalent cations for CO2 mineralization, with evaluation of leaching efficiency, process scalability, and sustainability.
Together, these findings contribute to the fundamental understanding of impurity behavior in crystallization and enable improved design of integrated recovery systems. Beyond scientific insights, this work presents applied solutions for critical material supply, reduced chemical input, and alignment with carbon sequestration goals—advancing a more sustainable battery value chain.Ph.D
Predicting LRR-RLK functions at scale in Arabidopsis thaliana using network biology and evolutionary tools
Get PDFPlants are sessile organisms and thus cannot move to avoid pathogenic attack or search for improved environmental conditions. Therefore, in order to survive plants must respond to numerous extracellular signals which guide both development and immunity. To aid in discriminating between these signals, plants have developed a large suite of cell surface receptors. My research focuses on a subset of cell surface receptors called leucine-rich repeat receptor-like kinases (LRR-RLKs), of which there are approximately 230 members present in the model organism Arabidopsis thaliana. Despite increased research, the functions of many of these LRR-RLKs remain unknown. My research uses network biology and evolutionary tools to make functional predictions about LRR-RLKs at scale and subsequently confirms the function of one LRR-RLK using classical genetic techniques. I used network analysis via various algorithms to create subnetworks of receptors which can then be used to predict functions for various unknown receptors. Through network analysis, I identified a robust 38-member immunity subnetwork which was predicted to contain immune related LRR-RLKs. Within this immunity subnetwork, I identified members of the LRR-V subfamily including SRF9, SRF7 and SRF6. In parallel, I also performed a large-scale evolutionary analysis to identify LRR-RLK subfamilies that are likely to contain novel immune related receptors. My findings demonstrated a lineage specific expansion of LRR-I within the Brassicales that had high rates of gene expansion. These characteristics are suggestive of families containing stress-related receptors and are likely to contain novel immune-related receptors. While LRR-V does not show these expected features, if they are damage associated molecular pattern (DAMP) receptors as predicted they would be expected to resemble LRR-RLKs involved in growth and development as they recognize self-derived molecules. Based on these results, I chose to focus on the SRF family and demonstrated a role for SRF6 in the DAMP pathway. My results demonstrated that SRF6 is necessary for proper response to trigalacturonic acid (TGA) elicitation including activation of defense genes and bacterial resistance. Overall, I demonstrated that both network and evolutionary analyses can be used to make accurate predictions about LRR-RLK function with more candidates waiting to be tested.Ph.D
Private Motives, Public Benefits: The role of Conservation Easements in Canadian Biodiversity Conservation
Get PDFAmid increasing urban sprawl, global temperatures, a growing population, and shrinking habitat, there are calls to expand and transform biodiversity conservation strategies. In response, I present four cases focused on the role of Conservation Easements (CEs) in Canadian private land conservation (PLC), examining how they support, impact, and transform individuals, institutions, and broader socio-ecological contexts. I use qualitative studies to a) examine their theoretical relationship with private property logics, relational connections between individuals and communities, and their place within settler-colonial logics of racism, access, and control; b) how their subnational legislation was developed and influenced across the provinces and territories of Canada; c) what motivates landowners and land trusts in Alberta to rely primarily on CEs for PLC; and why a unique grazing co-operative in southwestern Alberta has used CEs as both a means to support sustainable livelihoods and biodiversity, while rapidly expanding their landholdings via PLC payments. I employ political ecology to analyze policy documents, grey literature, existing literature, survey data, and semi-structured interviews. Considering questions of access, private rights, and public responsibilities, I argue that CEs unevenly fit within existing private-public property binaries but provide a unique PLC tool that can support conservation objectives by cultivating a constellation of diverse relationships within and beyond fence lines. This research is foundational as it presents the first in-depth qualitative analysis of the multifaceted nature of CEs in a purely Canadian context.Ph.D
Avoidance and Approach Learning in Uncertain Environments: A Computational Study of Pain and Reward Learning
Get PDFThe ability to learn from experience and update beliefs about the environment is essential for adaptive behaviour—a process often modelled as reinforcement learning. Pain and reward are fundamental drivers of learning, yet how they independently or jointly shape behaviour under varying levels of environmental uncertainty remains unclear. Using a hierarchical Bayesian model, we investigated how pain, monetary reward, and their combination shaped learning across stable and volatile contexts. Uncertainty modulated learning across all conditions. Pain increased response time, suggesting heightened vigilance—particularly in the pain-avoidance group, where response times were correlated with fear of pain. Despite differences in behavioural adaptations, learning rates remained comparable across motivational contexts, suggesting that motivational influence on learning engaged mechanisms beyond belief-updating speed. By leveraging a biologically plausible model, we show that vigilance is a key factor underlying motivational differences in learning, providing insight into adaptive behaviours in aversive and rewarding environments.M.Sc
Strengthening Reconstructive Urology with an Aim for Capacity-Building in a Low-Middle-Income Country: A Multi-Institutional Global Surgery Collaboration Initial Report
Get PDF<b>Background/Objectives:</b> Reconstructive urology is critically underrepresented in global surgery initiatives, despite its essential role in managing congenital and acquired urogenital conditions. In response, a multinational Global Surgery Collaborative was launched in 2022 by a faculty from the University of Toronto, aiming to enhance reconstructive urology capacity in the Philippines, among other low- to low-middle-income countries through longitudinal mentorship and skills transfer. This report presents early experience from 2022 to 2024. <b>Methods:</b> This collaboration delivered annual in-person surgical missions from 2022 to 2024 at two major Philippine healthcare institutions. Training focused on pediatric and adult reconstructive urologic procedures. Local mentees participated in structured preoperative planning, intraoperative teaching, and postoperative debriefing. We conducted a prospective service evaluation comprising a prospective registry of consecutive cases and paired pre/post trainee surveys. Data were collected on patient demographics and surgical metrics. Primary clinical endpoints included operative time, length of stay, and complications (Clavien&ndash;Dindo), with standardized follow-up windows. Mentee educational outcomes were assessed through pre- and post-training trainee-reported (Likert) measures, evaluating comfort and technical understanding. Statistical analysis used the Wilcoxon signed-rank test to assess changes. <b>Results:</b> Over three years, 33 surgical cases were performed with 45 surgical resident mentees (Post-graduate year (PGY)4&ndash;PGY6) engaged. The median patient age was 23 (inter-quartile range [IQR] 12.5&ndash;41.5) years, with 33.3% pediatric and 84.8% of cases classified as major. The complication rate was 15.1%, with only one major event (3%). Across 45 mentees, comfort increased from a median 4.0 (IQR 2.5&ndash;5.0) to 7.0 (5.5&ndash;8.0) and technique understanding from 5.0 (4.0&ndash;6.5) to 9.0 (8.0&ndash;10.0), with large Wilcoxon effects (r = 0.877 and r = 0.875; both <i>p</i> &lt; 0.001). Year-by-year analyses showed the same pattern with large effects. <b>Conclusions:</b> In this early three-year experience (33 cases, 84.8% major), this multi-institutional collaboration longitudinal mentorship model was feasible and safe, and was associated with significant trainee-reported improvements in comfort and technical understanding. This demonstrates a replicable model for global surgery in reconstructive urology, successfully enhancing surgical skills and fostering sustainable capacity in low- and middle-income countries (LMIC) settings
The Toxicity and Chemical Characterization of Thiol-Reactive Disinfection By-Products and Related Electrophiles
Get PDFThis thesis explores the role of thiol reactivity in driving the toxicity of disinfection by-products (DBPs) and related electrophiles in the environment. Over multiple studies, thiol reactivity is shown to be a crucial mechanism in inducing electrophilic oxidative stress. The identification of unknown thiol-reactive environmental electrophiles is essential to protect water quality and public health. The Thiol Reactome method introduced in Chapter 2 describes a reactivity-directed approach to detect and prioritize thiol-reactive DBPs in treated water. Using a thiol probe, the Thiol Reactome identifies 181 DBP-probe adducts, including nitrogenous DBPs (NDBPs) and α,β-unsaturated carbonyls. This chapter further confirms that thiol-reactive DBPs drive in vitro oxidative stress, emphasizing the importance of the detection of thiol-reactive DBPs for water quality.
Chapter 3 expands the Thiol Reactome to potable water reuse, revealing that wastewater treatments dramatically reduce oxidative stress. Targeted DBPs only accounted for negligible toxicity, suggesting that unknown DBPs drive oxidative stress of potable reuse. The Thiol Reactome identified 26 thiol-reactive DBPs in a water reuse source which correlated strongly with oxidative stress. The thiol-reactive DBP profiles of potable water reuse were found to be low in NDBPs and high molecular weight DBPs when compared to treated raw surface water.
The structure-mediated toxic mechanism of haloacetonitriles (HANs), a class of thiol-reactive DBPs, to induce oxidative stress was elucidated in Chapter 4. Dibromoacetonitrile was demonstrated to exhibit the greatest toxicity out of the tested HAN cohort due to a unique radical-mediated reaction with glutathione, forming glutathione disulfide and completely debrominated glutathione-acetonitrile adducts.
Chapter 5 broadens the scope by examining quinones, another class of environmental electrophile. Inconsistencies between a reactive oxygen species (ROS)-based acellular assay and a cellular assay which probes both ROS and protein-alkylation suggest that protein-alkylation is the cellular toxic mechanism for quinones. Additionally, quinone-free thiol reactivity and activity-based-protein-profiling were found to be closely matched.
Thiol-reactivity plays a central role in the oxidative stress and toxicity of environmental electrophiles. The Thiol Reactome is a powerful tool to detect these compounds. This thesis provides the basis for future research of toxic DBPs and thiol-reactive electrophiles to better protect public health.Ph.D
Vascular and Ventricular Properties at Rest and Exercise in Paediatric Marfan and Loeys-Dietz Syndrome
Get PDFMarfan syndrome (MFS) and Loeys-Dietz syndrome (LDS) are genetic ConnectiveTissue Disorders (CTDs) associated with significant cardiovascular complications, including
progressive aortic dilation, altered biomechanical properties, and myocardial dysfunction. While
aortic pathology has been extensively studied, the broader cardiovascular implications of these
syndromes remain incompletely understood. This dissertation provides a comprehensive
evaluation of cardiovascular function in paediatric MFS and LDS patients, integrating genetic,
functional, and physiological assessments to address key gaps in clinical knowledge.
The first study investigates genotype-phenotype interactions in LDS, specificallycomparing cardiovascular phenotypes in patients with TGFBR1 and TGFBR2 mutations. The
findings demonstrate that TGFBR2 mutations are associated with more severe aortic pathology,
including larger dimensions, reduced distensibility, and increased stiffness indices. These results
emphasize the genetic heterogeneity of LDS and suggest the importance of genotype-specific
risk stratification.
The second study evaluates subclinical myocardial dysfunction in paediatric MFS andLDS patients using speckle-tracking echocardiography (STE)-derived left atrial (LA) strain
alongside conventional echocardiographic parameters. MFS and LDS patients exhibit reduced
LA reservoir and conduit strain compared to controls, despite preserved LA pump function.
Additionally, traditional diastolic parameters indicate early relaxation abnormalities in both
syndromes. These findings demonstrate subclinical diastolic function changes in paediatric MFS
and LDS patients prior to clinical manifestations and support LA strain as a sensitive, non-
invasive marker for diastolic dysfunction.
The third study examines cardiovascular responses to physiological stress in paediatricMFS patients using exercise stress echocardiography (ESE). Despite baseline differences in
aortic dimensions, vascular stiffness, and diastolic function, MFS patients demonstrate preserved
systolic and diastolic reserve during incremental exercise, comparable to healthy controls. These
results challenge the assumption that resting abnormalities necessarily translate to impaired
functional capacity and provide evidence supporting the safety of endurance exercises in MFS.
Together, this dissertation provides an integrated perspective on the genetic, functional,and physiological aspects of MFS and LDS pertaining to the cardiovascular system. These
findings have implications for improved risk stratification, early detection of cardiovascular
changes, and long-term management, underscoring the need for ongoing research to refine
clinical care strategies for these at-risk populations.Ph.D
Elucidating Nanoparticle-Protein Interactions for Targeted Delivery
Get PDFNanoparticles are used to deliver medical agents to target cells. The surface of nanoparticles can be engineered to target and recognize cells using ligand-receptor interactions. When nanoparticles are exposed in biological environments, serum proteins immediately adsorb onto the nanoparticle surface. Serum proteins can interfere with nanoparticle-cell binding and compromise their targeting ability depending on nanoparticle design. It is crucial that we understand how proteins interact with nanoparticles and its impact on targeting to improve how we rationally engineer nanoparticles for targeting. This PhD contributes to this goal by investigating the mechanisms that control protein-nanoparticle interactions and their effect on targeting. We found that nanoparticle– target binding in serum depends on the competing interactions between serum proteins and target receptors for the nanoparticle surface. Modelling this competition using a mathematical expression, termed the binding ratio, yielded strong predictive power for nanoparticle–target binding efficiency. We also leveraged the nanoparticle protein corona as a scaffold for conjugating targeting ligands onto. This design strategy led to improved nanoparticle targeting efficiency in serum. Overall, this thesis provides key mechanisms that control nanoparticle-protein interactions and their impact on targeting. Our findings can inform the rational design of future nanomedicines, bringing personalized, targeted medicines closer to reality.Ph.D