title: Towards Transparency in the Selection, Appraisal, and Application of Health State Utility Values in Decision-Making

contributor:
Xie, Feng
Health Research Methodology

abstract:
The identification and selection of health utility inputs for health economic models is an essential yet often overlooked task in the development of useful, context-relevant models. This doctoral thesis was designed to explore existing methodologies and propose novel approaches to improve the comprehensiveness, relevance, and transparency of these processes.
A broadly scoped systematic literature review was designed to identify published health utility estimates in the field of oncology. The objective of this work is to support both researchers and, importantly, reviewers who may not have sufficient resources available to evaluate the available literature and determine whether other viable inputs may have been suitable to inform a model parameter. This review infrastructure will gradually be expanded across the clinical spectrum.
To evaluate the current framing of health utility-relevant concepts in critical appraisal and reporting checklists, a methods-focused literature review was conducted. While several health economic evaluation- and health utility-relevant tools and checklists were identified, this review confirmed that none were designed for the express purpose of systematically critically appraising health utility studies or evaluating context relevance.
Finally, the Health utility Application Tool (HAT) was developed based on the learnings from previous research activities and engagement with knowledge users and doers in the field of health technology assessment. This tool is intended to guide researchers in selecting the most relevant evidence for models, with several questions directed toward clinical and jurisdiction-specific context. Framed primarily as a communication tool, the HAT is intended for researchers to use to document reasoning rather than for critically appraising others’ work.
This body of research has established the groundwork upon which further developments may emerge. The success of these efforts will be realized over time and necessitates a commitment to knowledge translation and dissemination with sustained engagement across the research community.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract: This doctoral thesis was designed to explore existing methodologies and propose novel approaches to improve the comprehensiveness, relevance, and transparency in the development of health economic evaluations. A systematic literature review protocol, as well as a sample of completed work, will support investigators and decision-makers in identifying the available published health utility literature when building or critiquing health economic models. A methods-focused review follows, which highlights an important shortcoming in the tools available to researchers in the evaluation of both the methodological rigour and goodness-of-fit of health utility inputs in their decision contexts. The Health utility Application Tool is then proposed as a solution to the latter issue. It is intended to assist investigators in communicating and defending their reasonings when selecting among the health utility literature. Overall, this body of research is intended as a simple but practical solution to a persistent problem in the health economist’s toolbox.


title: Effects of parental divergence on hybridization and hybrids in the human pathogenic Cryptococcus

contributor:
Xu, Jianping
Biology

subject: The Human Pathogenic fungus Cryptococcus

subject: Hybridization

subject: Genotypes and Phenotypes

abstract: Hybridization refers to mating between species or between genetically differentiated populations of the same species. Although hybrid offspring may exhibit sterility and/or inviability, hybridization can generate novel genotypic and phenotypic diversities, leading to the origin of new traits and new species, the expansion into ecological niches outside of the parental range (e.g., host range), and altered virulence properties in pathogens. However, the relationship between parental genetic divergence and hybrid performance remains largely unknown. The human pathogenic Cryptococcus (HPC) is an ideal model to study the impacts of parental divergence on the genetic and phenotypic consequences of hybridization. HPC consists of a group of divergent lineages with various degrees of interfertility. These yeasts are the etiologic agents of cryptococcosis, a potentially lethal disease in humans and animals. In this thesis, I examined the effects of parental divergence on cryptococcal hybrids from multiple aspects. I conducted genetic crosses between different lineages to evaluate the mating success and the germination of sexual spores (i.e., basidiospores) under various environmental conditions. Then, I investigated the genotypic and phenotypic diversities among the hybrids under different environmental conditions. Furthermore, I examined the genome stability of diploid inter-lineage hybrids through laboratory experimental evolution and the effect of antifungal drug stress on the loss of heterozygosity (LOH) in these hybrids. We found that parental genetic divergence plays an important role in genotypic and phenotypic diversities among hybrid progeny in HPC. However, our results indicate that parental genetic di-vergence alone can’t explain most of the observed variations. Instead, genetic divergence along with specific parental strains, environmental factors, and their interactions all contributed to hybridization success and to hybrid genotypic and phenotypic variations. My findings will broaden the current understanding of the phenotypic and genotypic consequences of hybridization and explore the connection between genetic architecture and hybrid speciation in the human pathogenic Cryptococcus.

abstract: Thesis

abstract: Doctor of Science  (PhD)

abstract: The role of hybridization in evolution can vary widely, giving rise to hybrid vigor and hybrid weakness. Hybridization plays an important role in plants and animals, especially crops, with advantages of increased yield and quality of products. However, the emergence of hybrid vigor in pathogens with increased virulence is an increasing threat to plant, animal, and human healths. My PhD thesis aimed at understanding the effects of parental divergence on hybridization and hybrids in the human pathogenic Cryptococcus. Here, I investigated basidiospore germination rate and hybrid progeny genotypes and phenotypes from diverse genetic crosses in this group of pathogens. My findings contribute towards understanding cryptococcal hybrids and establishing treatment plans against infections by these hybrids.


title: Active Sensor Array for UWB Breast-Cancer Screening

contributor:
Nikolova, Natalia
Chen, James
Electrical and Computer Engineering

subject:
Breast cancer detection
UWB microwave imaging
Active antenna array

abstract:
A microwave imaging system processes scattered electromagnetic fields in the
microwave region to create images. It is an alternative or complementary imaging
tool that can be used in breast cancer imaging. It employs non-ionising radiation
and during measurement, compression of the scanned body part is avoided. These
benefits potentially lead to safer and more comfortable examinations. It also has the
potential to be both sensitive and specific to detect small tumors, whilst being much
lower cost than current methods, such as magnetic resonant imaging, mammography
and ultrasound. This thesis reports a multi-layer active antenna array for breast
imaging using microwaves from 3 GHz to 8 GHz. The proposed structure resolves
the outstanding problem in the design of large active antenna arrays for tissue imaging,
namely, the isolation of the antennas from the electronic circuits. A ground
plane within the multi-layer design separates the antenna array from the electronics
array while providing shielding to the antennas from the back and improved power
coupling into the tissue. The possibility of a high-speed vertical connector to provide
interconnection between the antenna array and the mixer array is investigated
and measurements show that it could be utilized for the frequency range from 3 GHz
to 8 GHz.

abstract: Thesis

abstract: Master of Applied Science (MASc)


title: Toolkit to manage key habitat for amphibians in Ontario forests

title: Toolkit for amphibian habitat monitoring in Ontario

contributor:
Chow-Fraser, Patricia
Biology

subject:
landscape ecology
herpetology
remote sensing
amphibians

abstract:
Forest-dwelling amphibians contribute to diverse ecosystem services in Ontario but are threatened by habitat degradation and fragmentation. My thesis investigated key amphibian habitats in Ontario forests with the goal of providing resource managers with tools and techniques to protect and restore amphibian populations. I primarily focussed on amphibians that breed in temporary forested wetlands known as vernal pools, as these wetlands are overlooked in provincial legislature and particularly sensitive to changes in land-use and climate.
	First, I investigated the distribution and community structure of vernal pools in forests of eastern Georgian Bay, Lake Huron. I developed an accurate remote sensing technique to map vernal pool habitat using readily available spatial data and found that undocumented vernal pools accounted for over half of the wetlands in the region. I documented the importance of the length of pool inundation (hydroperiod) and canopy openness in determining the composition of vernal pool amphibian assemblages. In particular, pools with short hydroperiods and closed canopies tended to support only early breeders and canopy generalists.
	Next, I used two case studies to demonstrate the usefulness of existing amphibian occurrence datasets, specifically for the improvement of habitat mapping and monitoring. For the first case study, I created habitat suitability models using known locations of the endangered Jefferson salamander (Ambystoma jeffersonianum). Models yielded good discriminatory ability between presence and pseudo-absence data and confirmed the importance of deciduous/mixed forests as key habitats. Habitat suitability maps revealed potential undocumented habitat in the Greenbelt region of Ontario. For the second case study, I developed optimizations of time and effort for a salamander monitoring program. I verified the need for at least ten years’ worth of monitoring data for reliable trend detection and demonstrated that the precision and accuracy of occupancy estimates are dependent on the allocation of effort across monitoring sites and repetitions.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract: Amphibian declines represent one of the hallmarks of the current biodiversity crisis. While there are many factors responsible for amphibian declines, the most significant threats are habitat loss and degradation. This Ph.D. thesis describes amphibian habitat use in Ontario forests and provides resource managers with tools and techniques to protect habitat.  Using satellite imagery, I developed a strategy to map small amphibian breeding wetlands (vernal pools) in forests of eastern Georgian Bay. I also identified the importance of pool drying times and forest canopy cover to the amphibians that breed in these wetlands. In the fragmented forest patches of southern Ontario, I mapped suitable habitat for the endangered Jefferson salamander and identified the importance of large deciduous/mixed forests. Lastly, I assessed the effectiveness of a long-term salamander monitoring program in southern Ontario and demonstrated the use of techniques to optimize the allocation of effort and maximize the accuracy of monitoring results.


title: Individual Differences in Reading Proficiency: Investigating Influencing Factors and How They Interact

contributor:
Kuperman, Victor
Cognitive Science of Language

subject:
Reading Proficiency
Individual Differences
Eye-tracking
Linguistic Distance
Statistical Learning
Motivation
Cloze Probability

abstract:
This thesis investigates individual differences and their impact on reading proficiency using different measures of proficiency, a variety of data collection and statistical methods, and different populations. The goal was to examine the impact that individual differences in certain reading-related skills and cognitive abilities have on reading proficiency and how these differences interact.
Through three key studies that make up this thesis, several important discoveries and contributions were made to the field. Chapter 2 introduces an easy-to-use application for measuring cloze probability. ‘ClozApp’, was created and made publicly available, along with a user manual and sample code for programming. Chapter 3 contributed through the development of a novel statistical method used to analyze variance between populations with different linguistic backgrounds. This method was used to demonstrate how an individual’s linguistic background (i.e., whether they were first- or second-language speakers of English) impacted how individual differences in reading skills influence their reading fluency, as indicated through their eye-movements. This statistical prediction method is open source and was made widely available for use along with sample data and code. In Chapter 4, a new connection was found between two important cognitive factors that are well-known in the reading literature: statistical learning and motivation. Using mediation analyses, this project discovered an interaction between these factors that further highlights the ways they impact reading proficiency.
This thesis demonstrates a comprehensive approach to investigating individual differences in reading proficiency in the following ways: (i) both reading fluency and comprehension were investigated as measures of reading proficiency, (ii) data collection included a variety of reading-related skills, cognitive abilities, and group differences, and (iii) unique statistical analysis methods were utilized to investigate both individual and group differences. This thesis highlights important new discoveries and makes significant lasting contributions to the field of reading research.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract: This thesis investigates how individual differences influence reading proficiency. Specifically, it asks how the ways in which people differ on certain reading-related skills and cognitive abilities can determine how well they read. Using different measures of proficiency, a variety of data collection and statistical methods, and looking across different populations, the goal of this thesis was to examine the ways in which people differ in these skills and abilities, how these differences interact, and the resulting impact on reading proficiency. This thesis resulted in three significant contributions to the field. First, it made available a new application for collecting data on an important variable in reading research – cloze probability. In addition, it culminated in the development of a novel statistical method that demonstrates how an individual’s linguistic background can influence their reading fluency. Finally, a new connection was found between two important cognitive factors that interact to influence reading comprehension.


title: EXAMINATION OF PROSTATE CANCER ASSOCIATED FACTORS FOR THEIR CONTRIBUTION TOWARDS THE DEVELOPMENT OF PROSTATE CANCER AND PROGRESSION INTO CASTRATION RESISTANT PROSTATE CANCER

title: PROSTATE CANCER ASSOCIATED FACTORS

contributor:
Tang, Damu
Medical Sciences

subject: Prostate cancer

abstract:
Although early detection and treatment of prostate cancer (PC) shows clinical benefit, advanced PCs that progress despite androgen deprivation therapy almost invariably result in castration resistance. This progression is lethal as castration-resistant prostate cancer (CRPC) are intimately associated with metastasis and remains the predominant cause of PC-related fatalities. Increasing evidence reveal a critical role of prostate cancer stem cells (PCSCs) in facilitatin g PC progression and acquisition of androgen independence. Taking advantage of our putative DU145 cell derived-PCSC population, we examined a number of candidate proteins for their contribution to PC progression and CRPC development.
       We identified three PCSC-specific proteins, BChE, CNTN1 and PCSK9. Butyrylcholinesterase (BChE) is a plasma enzyme known for its role in hydrolyzing ghrelin and bioactive esters, and is associated with altered metabolisms. Serum BChE is reduced in several cancer types. In this thesis we revealed a biphasic alteration of BChE and identified its downregulation at early stage of PC and upregulation at advanced stage PC. In a similar manner, we reported a functional role of CNTN1 in PC advancement. We demonstrate evidence for CNTN1-mediated enhancement of LNCaP cell proliferation in vitro and formation of CRPC in vivo, as well as its oncogenic potency in a prostate-specific CNTN1 transgenic model. Furthermore, we constructed a novel CNTN1-associated gene panel that predicts PC relapse risk with high robustness. IQGAP1 is critical in cytoskeletal dynamics which underlies cancer progression, metastasis, and PCSC biology. We showed IQGAP1 downregulation in both CRPCs and advanced PCs, and constructed a 27-gene signature using differentially expressed genes (DEGs) relative to this downregulation. This IQGAP1-relevant 27-gene panel robustly predicts PC relapse following radical prostatectomy and shows high translational value as a complementary panel to currently available commercial multigene panels. PCSK9 is an important protein in the regulation of cholesterol metabolism but its role in cancer is not known. We provide a comprehensive set of evidence supporting its role in the formation of CRPC, likely via mechanisms involving enhanced intratumoral uptake and sustained AR signalling under androgen-deprived conditions. Importantly, bigenic TRAMP mice deficient in PCSK9 have shown significantly prolonged survival and reduced metastasis.
       Collectively, we identified four factors with pivotal roles in PC development and progression into CRPC, albeit with different mechanisms. The altered expression of these factors in advanced PC and their widespread impact on a diverse range of mechanisms important in cell proliferation and survival underscores the importance of PCSCs in promoting advanced prostate cancer. Taken together, the findings of this thesis will advance our knowledge on PCSC-relevant pathways and their association with prostate cancer progression and metastasis.

abstract: Thesis

abstract: Doctor of Philosophy (Medical Science)


title: Multi-wavelength studies of the interstellar medium and star formation in nearby galaxies

contributor:
Wilson, Christine
Parker, Laura
Physics and Astronomy

subject:
Astronomy
Interstellar Medium
Star Formation
Galaxies

abstract:
In this thesis I investigate three key questions about the interstellar medium (ISM) and star formation in nearby galaxies. The first question is, “how do bars and galaxy interactions affect the distribution of cold gas and the level of central star formation in galaxies?” I use publicly-available spatially-resolved images of CO(1-0) emission in a sample of 126 nearby galaxies from the Extragalactic Database for Galaxy Evolution (EDGE) survey to measure molecular gas concentrations, and I use spatially-resolved optical spectroscopy from the Calar Alto Legacy Integral Field Area (CALIFA) survey to measure the level of central star formation enhancement. I find that gas concentration and the level of central star formation enhancement are positively correlated in barred galaxies but not in unbarred galaxies, and that interacting galaxies show signs of a correlation but not in all cases. These results indicate that central star formation enhancement occurs only in barred galaxies and interacting galaxies with high gas concentrations, which supports theories of bar- and interaction-driven galaxy evolution.

The second question is, “what is the relationship between mid-infrared (MIR) emission and molecular gas at spatially-resolved scales in galaxies?” I extend previous work, which found a tight correlation between global MIR emission in the Wide-field Infrared Survey Explorer (WISE) 12 micron band and CO emission from single-dish radio telescopes, to spatially-resolved scales using EDGE CO data smoothed to WISE 12 micron resolution. I find that these quantities are tightly correlated at ~kiloparsec scales, and that the correlation shows offsets from galaxy to galaxy. I find that these offsets are explained best by differences in the level of global near- and far-ultraviolet emission, and that the 12 micron-CO correlation is the strongest of all the resolved correlations that I considered. These results suggest that there is a tight physical link between WISE 12 micron emission and CO emission on kiloparsec scales, possibly due to a connection between polycyclic aromatic hydrocarbons (PAHs, which dominate the 12 micron emission) and molecular gas. My findings can be used to estimate resolved CO emission based on (easily obtained) WISE 12 micron images and a small number of global multi-wavelength measurements. These results also motivate further work exploring the CO-PAH connection in more diverse conditions and at higher resolution.

Finally, the third question is, “what is the ISM content of red star-forming galaxies?” In comparison to blue star-forming galaxies (“blue actives”) which lie on or above the star-forming main sequence (SFMS), these “red misfits” tend to lie on or slightly below the SFMS. I find that the main property other than colour that differentiates red misfits from blue actives is their low gas mass fractions. The gas depletion times and gas-to-dust ratios are similar between these populations. My results indicate that the star formation of red misfits is in the act of quenching.

The unifying theme of each of these projects is the approach: studying key questions in nearby galaxies based on their molecular gas content along with other multi-wavelength data, at a variety of resolutions. This approach is enabled by large publicly available multi-wavelength data sets at a variety of physical resolutions. Surveys of the global gas content of galaxies with accompanying multi-wavelength data will always be larger, and will continue to be an important reference for smaller resolved surveys. I hope that this thesis serves as a useful comparison between the science that can be done on both global and resolved scales, and will motivate future work on the connection between the ISM and star formation in nearby galaxies.

abstract: Thesis

abstract: Doctor of Science  (PhD)


title: A Dual-Branch Attention Guided Context Aggregation Network for NonHomogeneous Dehazing

contributor:
Jun, Chen
Electrical and Computer Engineering

subject:
image processing
deep learning
dehazing

abstract:
Image degradation arises from various environmental conditions due to the exis tence of aerosols such as fog, haze, and dust. These phenomena mitigate image vis ibility by creating color distortion, reducing contrast, and fainting object surfaces.
Although the end-to-end deep learning approach has made significant progress in
the field of homogeneous dehazing, the image quality of these algorithms in the
context of non-homogeneous real-world images has not yet been satisfactory. We
argue two main reasons that are responsible for the problem: 1) First, due to the
unbalanced information processing of the high-level and low-level information in
conventional dehazing algorithms, 2) due to lack of trainable data pairs. To ad dress the above two problems, we propose a parallel dual-branch design that aims
to balance the processing of high-level and low-level information, and through a
method of transfer learning, utilize the small data sets to their full potential. The
results from the two parallel branches are aggregated in a simple fusion tail, in
which the high-level and low-level information are fused, and the final result is
generated. To demonstrate the effectiveness of our proposed method, we present
extensive experimental results in the thesis.

abstract: Thesis

abstract: Master of Applied Science (MASc)


title: A PILOT PRAGMATIC RANDOMIZED CONTROLLED TRIAL OF A 12-MONTH HEALTHY LIFESTYLES PROGRAM

title: FEASIBILITY STUDY OF THE HEALTHY LIFESTYLES PROGRAM

contributor:
Alvarez, Elizabeth
Health Research Methodology

subject:
Lifestyle Intervention
Behavioural Change
Healthy Lifestyles Program
Feasibility
Pragmatic
Randomized Controlled Trial
Person-centred approach
Goals and action plans

abstract:
Background: The primary objective of this study was to assess the feasibility of the Healthy Lifestyles Program (HLP), a novel 12-month complex intervention based in cognitive behavioural therapy and theories of behavioural change, delivered in a community-based setting in Hamilton, Canada. The secondary objective was to explore implementation factors.

Methods/ design: A pragmatic pilot randomised controlled trial using quantitative and qualitative evaluation methods. Participants were randomly allocated to either intervention group (n=15) or comparator group (n=15). The intervention group attended weekly group education sessions and met in-person with a healthcare team monthly to create personalized health goals and action plans. The comparator group met with a research assistant every three months to develop health goals and action plans. We assessed feasibility of the program by measuring recruitment, participation and retention rates, missing data, and attendance. All participant-directed and clinical outcome measures were analyzed for between and within group changes using Generalized Estimating Equations (GEE). Content analysis was conducted for qualitative data.

Results: We recruited and randomized 30 participants to each group (n=15) within 3 months.  Retention rate was 60% (9/15) for the intervention group and 47% (7/15) for the comparator group. Less than 1% of participant-directed and clinical outcomes were missing. Participants attended an average of 29 of 43 educational sessions and 100% of one-to-one sessions. The healthcare team valued the program’s holistic approach to care, increased time and interaction with participants, professional collaboration, and the ability to provide counselling and health supports. Location accessibility was an important factor facilitating implementation. Reducing the number of psycho-social education sessions and having access to a gym could improve retention and delivery of the program.

Conclusion: This study has demonstrated the feasibility of the HLP with minor modifications recommended for a larger trial and for the intervention.

abstract: Thesis

abstract: Master of Public Health (MPH)

abstract: Rates of chronic physical and mental health illness are rising in Canada. Lifestyle or behavioural changes can prevent or manage chronic diseases. The aim of this pilot study is to test the feasibility of delivering a 12-month Healthy Lifestyles Program to participants in Hamilton, Canada. The Healthy Lifestyles Program is a complex intervention designed to help participants identify health goals and action plans to achieve those goals with the guidance of healthcare professionals. We observed that the program was successfully delivered, accepted by participants and staff and required minor changes to the study design for a scaled-up study. The program showed positive trends for improving goal attainment, depression, and loneliness scores. The results of this study will help inform the design and scale-up of a larger study.


title: In Originalism's Stead: Old Constitutions and Originalism's Normative Foundations

contributor:
Waluchow, Wil
Philosophy

subject: Originalism, Living Constitutionalism, Constitutional Jurisprudence, Legal Philosophy

abstract: This thesis concerns a philosophical analysis of originalism in a context that has not yet received sufficient attention: in the context of old constitutional regimes. Through this lens, I argue that originalism becomes something lesser in that both the normative justification and legitimacy originalism once held begins to withdraw from the theory’s principled commitments. In other words, the nature of old constitutions begins to reject a normative argument for an originalist approach. The thesis bases this analysis on one originalist theory in particular for the sake of brevity: Lawrence Solum’s public meaning originalism. It proceeds through two avenues of argument: originalism as it relates to 1) historical analysis and the interpretation-construction distinction and 2) stare decisis and democratic legitimacy. Taken together, these avenues point to originalism’s fading normative justification and legitimacy in light of the challenges that old constitutions and their characteristics pose for the judicial philosophy.

abstract: Thesis

abstract: Master of Arts (MA)


title: MICROPLASTICS IN BIOTIC AND ENVIRONMENTAL SAMPLES TAKEN NEAR TWO MUNICIPAL WASTEWATER TREATMENTS PLANTS IN THE GRAND RIVER, ONTARIO

contributor:
Kidd, Karen
Biology

subject:
Microplastics
Grand River
Municipal Wastewater Effluent
Environmental Contaminants
Ecotoxicology
Environmental Pollution

abstract: Microplastics are present in municipal wastewater treatment plant (WWTP) effluents; however, it is unclear whether these contaminants are ingested by biota living downstream of these outfalls. This study examined whether microplastic levels in caged biota, resident fish, and environmental samples were elevated near the Waterloo and Kitchener WWTP outfalls along the Grand River in the fall of 2019. Amphipods (Hyalella azteca), fluted-shell mussels (Lasmigona costata), and rainbow trout (Oncorhynchus mykiss) were caged at one upstream reference site and two impacted sites downstream of the Kitchener WWTP for 14 (amphipods and trout) or 28 (mussels) days. Rainbow darter (Etheostoma caeruleum) were collected using a backpack electrofisher from 10 sites up and downstream of both the Kitchener and Waterloo WWTPs, along with surface water and sediment samples. Whole body Hyalella, fish digestive tracts, and fluted-shell mussel tissues (hemolymph, digestive glands, and gills) were digested in 20% potassium hydroxide. Environmental samples were processed using filtration and density separation, then visual identification of microplastics was done. Elevated particle counts were found in rainbow trout digestive tracts at the Kitchener outfall site, compared to the upstream reference and downstream farfield sites. Additionally, particle concentrations in sediment were significantly higher at the Waterloo outfall, compared to all other sites (except for one upstream location). However, whole Hyalella, fluted-shell mussel tissues (hemolymph, digestive glands, and gills), digestive tracts of rainbow darter, and surface waters did not show elevated counts downstream of these discharges. Across all samples, fibers were the most common morphology, and blue and clear particles were prevalent in samples collected near WWTPs. Overall, these findings suggest that the Kitchener and Waterloo WWTPs could be important sources of particles to the Grand River, adding to our understanding of the fate of this contaminant in freshwater ecosystems.

abstract: Thesis

abstract: Master of Science (MSc)


title: The Regulation of Autophagy in YAP Mechanotransduction and Breast Cancer Metastasis

contributor:
Geng, Fei
Mechanical Engineering

subject:
Mechanobiology
YAP
Cancer Metastasis
Breast Cancer
Autophagy
Mechanotransduction
Matrix Stiffness

abstract: Breast cancer metastasis of a variety of vital organs is a major cause of breast cancer mortality. Autophagy has a crucial role in the metastatic breast cancer progression. As a critical mechanotransducer in the Hippo signalling pathway, YAP regulates cell proliferation and promotes autophagy. Previous publications also demonstrated extracellular matrix could regulate the nucleo-cytoplasmic transport of YAP. However, how YAP signalling connects to the interplay of autophagy and mechanotransduction in breast cancer metastasis remains entirely unknown. Through rapamycin-induced autophagy on the metastatic triple negative breast cancer (TNBC) cells, we observed upregulated YAP transcriptional activity and YAP nuclear localization in TNBC. Thus, we reported that YAP nuclear localization regulates autophagy to promote TNBC metastasis. Culturing TNBC cells on PDMS plates with various matrix stiffness demonstrated that stiff matrix promoted the migration of metastatic breast cancer cells in a YAP-dependent mechanism. Therefore, we proposed that YAP mechanotransduction promotes the migration of metastatic breast cancer cells. Then, we advance in these directions by reporting autophagy-mediated YAP nuclear localization is regulated by the response to stiff matrix when TNBC cells were cultured on different matrix stiffness upon autophagy. In conclusion, we suggest autophagy and mechanotransduction mediates YAP nuclear localization together. These findings expand the unknown gap in the convergence of YAP mechanotransduction and autophagy in metastatic breast cancer. They suggest that metastatic breast cancer cells have the potential to exhibit different YAP signalling when they colonize on a secondary location with a distinct matrix stiffness from primary location. Our study further helped to understand YAP biology and the mechanism of breast cancer metastasis that will shed light on future YAP-targeting therapeutics for metastatic breast cancer.

abstract: Thesis

abstract: Master of Applied Science (MASc)


title: Punishment in Canada: Extending Gladue-Like Procedures to Non-Indigenous Offenders

contributor:
Waluchow, Wilfred
Philosophy

subject: Punishment; Criminal Sentencing; legal philosophy

abstract: In the Canadian criminal justice system, there is a procedure which provides additional protections to Indigenous offenders during sentencing and its related events. This procedure is commonly referred to as the Gladue process. This thesis defends the plausibility of extending Gladue-like procedures to non-Indigenous offenders on the grounds that failing to do so would be a failure of consistency of the law. The law must be consistent in the sense that it must treat like cases alike. It will be argued in this thesis that there are other individuals and groups who may be similarly deserving of additional protections during sentencing because of their significant circumstances of vulnerability. This includes black individuals, LGBTQIA+, and mentally ill persons, but this is by no means an exhaustive list. This thesis does not aim to diminish the unique experience of Indigenous persons, but rather, it suggests that extending Gladue-like processes to particular non-Indigenous persons and groups may be required based on consistency of the law and attention to intersectionality. It is my hope that this thesis brings about greater awareness to the sentencing procedures pertaining to both Indigenous and non-Indigenous offenders alike, and that it may spark discussion on the subject of extending additional legal protections to vulnerable persons. This thesis relies heavily on the hybrid theory of punishment, as presented by H.L.A. Hart, which combines both utilitarian and retributivist elements in justifying the act of punishment. Hart’s theory aligns with the Canadian legislation on sentencing and provides a convincing justification for punishment while allowing the inclusion of restorative punishment practices for vulnerable persons. It will be argued that extending restorative practices to non-Indigenous offenders is, in some cases, plausible, and at times, necessary.

abstract: Thesis

abstract: Master of Arts (MA)

abstract:
Within Canadian legislation Indigenous offenders are provided an additional
procedure during sentencing and its related events. This system is commonly known as
the Gladue process. Gladue provides a good model for how the sentencing of vulnerable
individuals and groups should be handled. However, this process or something similar to
it is not provided to other offenders who may also experience vulnerability or should be
comparably deserving of additional protections or mitigating factors during sentencing.
This thesis argues for the plausibility of extending Gladue-like procedures to other,
similarly situated, non-Indigenous offenders based on arguments for consistency of the
law and respect for intersectionality. The law must treat like cases alike, and in doing so,
must pay particular attention to the intersections between layers of vulnerability. The
main contribution of this thesis is to make suggestions for change in Canada’s sentencing
procedures of vulnerable individuals and groups.


title: The Wolf Creek Research Basin, Yukon Territory: 26-years of hydrologic change

subject: Hydrology Northern Climate Watershed

abstract: Increasing temperatures and changing precipitation patterns are global consequences of climate change, which are amplified in northern environments. Cold environments are particularly sensitive to warming due to the importance of sub-zero temperatures, which influence frozen ground status and precipitation type. The objective of this research is to evaluate the controls on the timing, rate, and volume of the major hydrological fluxes within the Wolf Creek Research Basin (WCRB), Yukon Territory and to identify any long-term changes. WCRB is a long-term hydrological observatory established in 1993 to evaluate cold region hydrological processes. Within WCRB, three long-term meteorological stations at different elevations with total precipitation measurements and several stream gauges allow a long-term (26 year) evaluation of water balance components. Increases in temperature and precipitation magnitude are consistent with climate models including CIMP6 models. There has also been a significant increase in the number of high intensity precipitation days (primarily in June, July, and August). Fall and winter discharge increased and there was an increase in mean annual baseflows. The proportion of discharge output during freshet (April 1st – July 1st) has not changed, but the timing of peak flow has shifted from late-May to mid-June. This research provides a unique opportunity to study long-term change while recognizing short-term natural variability in hydrologic data. Understanding the mechanisms within catchments will allow for a stronger interpretation of the response of catchments to changing climate regimes which can have diverse impacts on local ecosystems and prevailing geohazards in northern environments.

abstract: Thesis

abstract: Master of Science (MSc)

abstract: Increasing temperatures and changing precipitation patterns are global consequences of climate change, which are amplified in northern environments. This research looks at a long-term hydrologic dataset of the Wolf Creek Research Basin (WCRB), located near Whitehorse, Yukon. Three hydrologic variables were evaluated: air temperature, precipitation, and discharge. Each variable plays a critical role in a watershed’s response to climate change. From 1993 to 2019, there was a significant increase in winter precipitation across the basin. Mean annual temperature also increased at the two lower elevation sites at a rate comparable to the rest of Yukon. Mean annual discharge has also increased, most notably in fall and winter which is reflective of an increase in groundwater contributions to the stream. This research increases our understanding of the relationships and drivers behind hydrometric changes which allows for a stronger interpretation of the response of catchments to climate change.


title: EMERGENCE AND MECHANISMS OF MULTI-DRUG RESISTANT MICROORGANISMS IN PATIENTS AT HIGH RISK FOR ANTIMICROBIAL RESISTANCE

contributor:
Surette, Michael
Biochemistry and Biomedical Sciences

subject:
Antimicrobial Resistance
Multi-Drug Resistance
Resistance Evolution

abstract:
Antimicrobial resistance (AMR) poses a substantial threat to public health and clinical medicine. By 2050, it’s predicted that AMR will be responsible for a yearly mortality rate of 10 million people, surpassing the mortality of cancer. Despite this daunting future we face, there are many efforts currently employed to combat the growth of AMR. One significant effort involves surveillance and early identification of novel resistant bacteria circulating in high antibiotic exposure environments. The second chapter of this thesis focuses on sampling 25 patients from a hospital environment, rich with antibiotics, to build a collection of AMR bacteria that will be tested and added to surveillance efforts/future study. This chapter allowed for the identification of several worrying AMR bacteria that provide greater insights into circulating AMR in Canadian hospitals and their patients. From the AMR collection created in chapter 2, we are also able to advance our scientific understanding of how antibiotic resistance develops within us and causes issues with treatment. In chapter 3, we looked at the effects of antibiotic administration routes on the level of AMR observed in our patient sample. We saw that current approaches to limit selection for AMR in the gut still resulted in clinically significant and concerning increases in AMR. Furthermore, this chapter allowed greater understanding of contributors to increased AMR in patients. AMR
increases are not fully explained by exposure/colonization in hospital settings, but also by
evolution of AMR originating from non-resistant bacteria in the gut. Additionally, analysis of
these bacteria will inform expected AMR evolutionary trajectories and help us plan against them. During analysis of patient data, we also came across evolution of a less understood resistance phenotype, hetero-resistance, to a very important antibiotic, colistin. We investigated a commonly prescribed antifungal, fluconazole, for its ability to promote this resistance phenotype; however, it appeared that fluconazole did not promote this phenotype.
Ultimately, this thesis serves as a valuable reservoir of AMR bacteria for future study and
contributes to a greater understanding of AMR development in patients, one day leading to more informed clinical decision making.

abstract: Thesis

abstract: Master of Science (MSc)


title: Surface modification of additively manufactured metallic components

contributor:
Elbestawi, MA
Koshy, Philip
Mechanical Engineering

subject:
Additive Texturing
Laser Peening
Wettability
Tribology
Residual Stress
Additive Manufacturing
Selective Laser Melting
Dry sliding
Wear rate
Coefficient of Friction

abstract:
Additive Manufacturing (AM) has revolutionized manufacturing processes by enabling the realization of custom products with intricate geometric features that were either too complex or even intractable for subtractive manufacturing processes. Yet, functional surfaces generated in AM have to be often finish machined because of their relatively inferior roughness. The first phase of this research worked around this limitation by tailoring the topography of an AM surface in-process to entail textures that further enhance certain functionalities in a process called Additive Texturing (AT).
In this context, the Selective Laser Melting (SLM) process ability to realize intricate surface microfeatures was explored experimentally, evaluating its geometrical limitations. Utilizing such limitations, various patterns comprising pillars, channels, and re-entrant structures were printed to control the wetting behaviour of SLM stainless steel. AT's efficacy is demonstrated in its capability to generate hydrophobic AM surfaces with water contact angles exceeding 140°. Similarly, other texturing patterns comprising dimples, linear, V-shaped, and X-shaped grooves were investigated to tailor the tribological response of textured surfaces under dry sliding conditions. Evidently, a specific wear rate and coefficient of friction reduction of 80% and 60%, respectively, demonstrated another potential for AT.
The undesirable tensile Residual Stresses (RS) that inevitably accumulate during the SLM process's rapid heating and cooling cycles were investigated in the second phase of this research. Laser Peening (LP) was utilized to post-process the printed samples to eliminate the initial tensile RS and induce near 500 Mpa compressive RS. Moreover, the LP parameters were explored and optimized to enhance RS, surface roughness, hardness, and wear resistance.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)


title: Genome-Wide In Vivo CRISPR Activation Screen to Identify Genetic Drivers of Non-Small Cell Lung Cancer Brain Metastasis

contributor:
Singh, Sheila
Biochemistry and Biomedical Sciences

subject:
CRISPRa
brain metastasis
animal models
functional genomics
genome-wide screens
genetic drivers
non-small cell lung cancer

abstract:
Brain metastasis (BM), the most common tumor of the central nervous system, occurs in 20-36% of primary cancers. In particular, 20-40% of patients with non-small cell lung cancer (NSCLC) develop brain metastases, with a dismal survival of approximately 4-11 weeks without treatment, and 16 months with treatment. This highlights a large unmet need to develop novel targeted therapies for the treatment of lung-to-brain metastases (LBM). Genomic interrogation of LBM using CRISPR technology can inform preventative therapies targeting genetic vulnerabilities in both primary and metastatic tumors. Loss-of-function studies present limitations in metastasis research, as knocking out genes essential for survival in the primary tumor cells can thwart the metastatic cascade prematurely. However, transcriptional overexpression of genes using CRISPR activation (CRISPRa) has the potential for overcoming dependencies of gene essentiality.
	In this thesis, we created and utilized an in vivo genome-wide CRISPRa screening platform to identify novel genes, that when overexpressed, drive LBM. We have developed a patient-derived orthotopic murine xenograft model of LBM using a patient-derived NSCLC cell line (termed CRUK cells) from the Swanton Lab TRACERx study. We introduced a human genome-wide CRISPRa single guide RNA (sgRNA) library into non-metastatic and pro-metastatic lung cancer CRUK cells to achieve 500X representation of each sgRNA in the activation library. We then injected the cells into the lungs of immunocompromised mice and tracked lung tumor development and BM formation. Upon sequencing primary lung tumors and subsequent BM, we will identify enriched sgRNAs which may represent novel drivers of primary lung tumor formation and LBM.
	To the best of our knowledge, this study is the first in vivo genome-wide CRISPR activation screen using patient-derived NSCLC cells to help elucidate drivers of LBM. This work serves to provide a framework to gain a deeper understanding of the regulators of BM formation which will hopefully lead to targeted drug discovery that will ultimately be used in clinical trials to help eradicate brain metastasis in NSCLC patients.

abstract: Thesis

abstract: Master of Science (MSc)

abstract:
Brain metastasis, or the spread of a primary cancer from another organ to the brain, is the most common adult brain tumor. Brain metastases can arise after the treatment of primary tumors and are only detected in the clinic at a highly malignant stage. Current treatments for brain metastasis consist of surgical removal and palliative chemoradiotherapy, which fail to fully eliminate the brain tumor. Over 20% of cancer patients develop brain metastases, with lung, breast, and skin cancers leading as the top three sources of metastasis. In particular, 40% of patients with non-small cell lung cancer develop brain metastasis, with survival of only 4-11 weeks once diagnosed without treatment, and 16 months with treatment. As systemic therapies for the treatment of non-small cell lung cancer are becoming increasingly effective at controlling primary disease, patients are ironically succumbing to their brain tumors. This highlights a large unmet need to develop novel targeted therapies for the treatment of lung-to-brain metastases (LBM). Functional genomic tools provide the opportunity to investigate the genetic underpinnings of LBM. With the advent of gene editing technologies, we are able to overexpress various genes and observe the impact genetic perturbations have on tumor initiation, growth, and metastasis.
	In this thesis, we devised a pre-clinical animal model of LBM that could be used to study genetic drivers of LBM using a gene overexpression tool such that one gene per tumor cell gets activated. We are then able to model the disease trajectory from a lung tumor to brain metastasis development using patient samples in our animal model and identify genes that, upon overexpression, drive LBM. This platform will lead to potential therapeutic targets to prevent the formation of LBM and prolong the survival of patients with non-small cell lung cancer.


title: The Association of the Frequency of Community Paramedicine Sessions and 9-1-1 Calls in Ontario Subsidized Housing: A Multilevel Analysis

contributor:
Agarwal, Gina
Health Research Methodology

subject:
Emergency medical services
Community paramedicine
Health services research
Community-based research

abstract: Older adults, especially those who are of low socioeconomic status, experience higher rates of mortality and chronic disease. As a result, older adults are frequent users of emergency medical service (EMS), comprising approximately 38-48% of all EMS calls. In response to higher EMS demands, community paramedicine has recently emerged as a non-traditional model whereby paramedics provide care in a community- based setting. CP@clinic is a community paramedicine programme that focuses on disease prevention and health promotion with the goal of reducing EMS demand. Given the knowledge that older adults who live in subsidized housing have poorer health outcomes, CP@clinic has been implemented in several subsidized housing building across Ontario. A program evaluation of CP@clinic is currently underway to make recommendations to paramedic partner stakeholders regarding program delivery. As part of this evaluation, I sought to understand the association of the number of CP@clinic sessions held per month and EMS calls per apartment unit. De-identified EMS call data were collated from 9 paramedic services across Ontario from February 2015 to December 2019. I conducted a three-level multilevel regression analysis, with EMS calls per apartment unit as the outcome. The primary analysis found that a one-session increase in the number of sessions held per month was associated with an average 2.4% higher incident rate of EMS calls, adjusted for building size. A secondary analysis, with the number of sessions per month as a categorical variable, revealed that two CP@clinic sessions per month had the smallest association with EMS calls, adjusted for building size. Based on these results, it is recommended that paramedic services offer two or more CP@clinic sessions per month. Future research should investigate the factors that impact each services’ ability to offer the CP@clinic programme.

abstract: Thesis

abstract: Master of Science (MSc)

abstract: Older adults experience high rates of chronic diseases, especially older adults living in subsidized housing. Community paramedicine has recently emerged as a way of addressing the healthcare needs of older adults living in subsidized housing, while simultaneously decreasing the burden on EMS. CP@clinic is a community paramedicine programme aimed at improving the health of older adults and reducing the demand on EMS. To make recommendations to the paramedic services operating CP@clinic, I sought to understand the association between the frequency of CP@clinic sessions and the number of EMS calls per apartment unit in Ontario. Based on the results, CP@clinic sessions were associated with higher incident rate of EMS calls, after accounting for building size, reflecting the trend of rising EMS calls in Ontario. Overall, paramedic services may see improved EMS call outcomes with two or more CP@clinic sessions per month but should offer the programme according to their organizational capacity.


title: IDENTIFYING CIRCULATING MEDIATORS OF CEREBROVASCULAR DISEASE

contributor:
Pare, Guillaume
Biochemistry

subject:
Cerebrovascular disease
Stroke
Genetics
Genomics
Mitochondria
Mendelian Randomization

abstract: Many current drugs for stroke act by targeting circulating molecules, yet these have not been exhaustively evaluated for therapeutic potential. A central challenge is that while many molecules correlate with stroke risk, only a subset cause stroke. To disentangle causality from association, a statistical genetics framework called “Mendelian Randomization” can be used by integrating genetic, biomarker, and phenotypic information. In Study 1, we screened 653 circulating proteins using this technique and found evidence supporting causal roles for seven proteins, two of which (SCARA5 and TNFSF12) were not previously implicated in stroke pathogenesis. We also characterized potential side-effects of targeting these molecules for stroke prevention and did not identify any adverse effects for SCARA5. The remaining two studies focused on investigating the role of an emerging marker of mitochondrial activity, leukocyte mitochondrial DNA copy number (mtDNA-CN). Mitochondria have long been known to play a protective role in stroke recovery; however, a mitochondrial basis for stroke protection has not been extensively studied in humans. In Study 2, we first sought to better understand the genetic basis of mtDNA-CN in a series of genetic association studies involving 395,781 UK residents. We identified 71 loci which represents a 40% increase in our knowledge. In Study 3, epidemiological analyses of 3,498 acute stroke demonstrated that low mtDNA-CN was associated with higher risk of subsequent mortality and worse functional outcome 1-month after stroke. Furthermore, Mendelian Randomization analyses corroborated a causative relationship for the first time, implying that interventions that increase mtDNA-CN levels in stroke patients may represent a novel strategy for mitigating post-stroke complications. Ultimately, this work uncovered several novel therapeutic leads for preventing stroke onset and ameliorating its progression. Future investigations are necessary to better understand the underlying biological mechanisms connecting these molecules to stroke and to further interrogate their validity as potential drug targets.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract: Current stroke medications work by targeting circulating molecules. Our aim was to discover new drug candidates by combining genetic and circulating biomarker data using a technique called “Mendelian Randomization”. In Study 1, we screened 653 circulating proteins and found evidence supporting causal roles for two novel candidates, SCARA5 and TNFSF12. Prior experimental studies suggest an important role for mitochondria in stroke recovery. Accordingly, in Study 2, we characterized the genetic basis of an emerging biomarker, mitochondrial DNA copy number (mtDNA-CN). Analyses of 395,781 participants revealed 71 associated genetic regions, representing a 40% increase in our knowledge. In Study 3, we measured mtDNA-CN in 3,498 acute patients and observed that lower levels predicted elevated risk of worse post-stroke functional outcomes. Furthermore, Mendelian Randomization analysis suggested a likely causal relationship. Overall, this work uncovered several novel therapeutic leads for preventing stroke onset and progression that warrant further investigation to verify therapeutic utility.


title: CHARACTERIZATION OF INTESTINALLY EXPRESSED shc-3 (K11E4.2) IN CAENORHABDITIS ELEGANS

contributor:
MacNeil, Lesley T
Biochemistry and Biomedical Sciences

abstract: SHC proteins are a family of adaptor proteins that play an important role in signal transduction, they are characterized by three crucial domains: the phosphotyrosine binding (PTB) domain, a Src2 homology (SH2) domain and a less conserved collagen homolog (CH1) domain. Two Caenorhabditis elegans SHC proteins have been described: SHC-1 and SHC-2. We have identified a third SHC protein, K11E4.2, that is intestinally expressed. Our analysis revealed that K11E4.2 null mutant animals suffer from a diet-dependent change in fat accumulation and increased sensitivity to starvation and oxidative stress. C. elegans shc-1 plays a role in stress response and lifespan regulation through the insulin signaling pathway. Our data suggest that shc-1 and K11E4.2 do not act redundantly to regulate stress or starvation response, but rather each plays a distinct role in these processes. This project proposes a model where K11E4.2 could have a role as positive insulin signaling regulator in C. elegans.

abstract: Thesis

abstract: Master of Science (MSc)


title: Scaling up eHealth applications in low- and middle- income countries: An example that succeeded

contributor:
Gombay, Christy
Global Health

subject: eHealth

abstract:
Background: Despite barriers such as financial and infrastructural challenges, there are many successfully implemented eHealth projects in Low- and Middle-Income Countries (LMICs). However, project scale-up and sustainability remains a pressing issue. This study analyses in detail an example of one such successful eHealth project: cStock in Malawi, an eHealth tool used to improve child health. This study aims to identify lessons that can be derived from our study of cStock, with support from the literature.
Methods: In this research, a literature review was first conducted to scope existing literature on LMIC eHealth projects. Secondly, a qualitative study was conducted using five Key Informant interviews of individuals directly involved in the cStock case. Thematic content analysis of these interviews was conducted to identify themes.
Findings: Six major themes were identified from my view: (1) facilitators and barriers to cStock implementation; (2) facilitators and barriers related to the scale-up and sustainability of cStock; (3) the impact of the COVID-19 pandemic on cStock operations; (4) the continuing role of paper records in cStock; (5) the transition of cStock and other health systems to full electronic systems in Malawi; and (6) a related set of recommendations for improving cStock operations and future LMIC eHealth projects.
Conclusions and Implications: Despite the strong commitment of the Malawi government to the cStock project, it is widely recognized in Malawi public health system that cStock does not, at this time, have a sustainable financial model. Similar practices of financial precariousness may apply to most LMIC eHealth projects with reliance on external international finance. This study contributes to the growing literature on eHealth and focuses on enabling characteristics and barriers to LMIC eHealth project implementations, scale-ups, and sustainability. Further research is needed to investigate sustainable financial models that are more likely to achieve success for future LMIC eHealth projects.

abstract: Thesis

abstract: Master of Science (MSc)

abstract: This study explored eHealth project implementation and scale-up in Low-and Middle- Income Countries (LMICs), with a specific focus on the cStock eHealth project in Malawi. The intention was to identify key lessons learned from the successful national-level scale- up of cStock in Malawi and its implications for eHealth projects in LMICs. This study contributes to the literature by examining barriers and facilitators to eHealth project implementations, scale-ups, and sustainability; in addition, evaluating the impact of the COVID-19 pandemic on eHealth projects in LMICs; and the role that paper records continue to play in LMICs. Amongst other conclusions, it was found that financial constraints in public health systems in many LMICs lead to a heavy reliance on foreign aid to finance eHealth projects which all-too-frequently lead to financially unsustainable projects; and strong national government commitment at policy, regulatory, human resource, and administrative levels are facilitators to achieving eHealth project success.


title: Effects of the Next Generation Probiotic, Akkermansia muciniphila, on Intestinal Inflammation and Barrier Function

contributor:
Khan, Waliul
Medical Sciences

subject: Gut Barrier Function, Inflammation, Gut Microbiota

abstract:
Inflammatory bowel disease (IBD), characterised by chronic intestinal inflammation, is hypothesised to arise from the interplay between susceptibility genes, the immune system, environmental factors, and gut microbiota.
Akkermansia muciniphila is a symbiotic bacterium that accounts for 1-5% of the human fecal microbiota. This microbe has been hailed as a next-generation probiotic, principally with regards to its plethora of beneficial host interactions, including the ability to influence mucin secretion and strengthen the intestinal barrier. Though a clear-cut role and mechanism by which A. muciniphila influences inflammatory conditions is unknown, evidence indicates this microbe is depleted in IBD, suggesting it may have protective effects that are lost in these conditions.
Here, we investigate the role and mechanism of A. muciniphila in intestinal inflammation and its influence on intestinal barrier function by utilizing barrier-disrupting models of colitis, including dextran sulphate sodium (DSS) and Trichuris muris. Though only minor benefits were derived from this microbe in germ-free mice, in specific pathogen-free (SPF) mice, administration of pasteurized A. muciniphila in a DSS recovery model ameliorated inflammation severity and promoted recovery compared to controls. When gavaged prior to DSS administration, both live and pasteurized A. muciniphila failed to diminish inflammatory markers indicating minimal preventative effects. T. muris-infected SPF mice treated with live A. muciniphila showed increased levels of Th2 and anti-inflammatory cytokines, decreased worm burden, and enhanced levels of the mucin, Muc5ac, compared with those receiving control broth or pasteurized bacteria. Further, both live and pasteurized A. muciniphila ameliorated the severity of inflammation in mucin 2 deficient (Muc2-/-) mouse model of spontaneous colitis, indicating that these protective effects are Muc2-independent.
These observations provide us not only with an enhanced understanding of the role A. muciniphila plays in the pathogenesis of intestinal inflammatory conditions but also may fuel novel avenues of treatment for those with IBD.

abstract: Thesis

abstract: Master of Science (MSc)

abstract: Akkermansia muciniphila is a bacterium that accounts for 1-5% of the human fecal microbiota and has been shown to stimulate intestinal mucus production and strengthen the gut barrier. Though several studies have linked inflammatory bowel disease (IBD) with decreased levels of A. muciniphila, the precise role of this microbe in gut inflammation is unknown. In this research, we investigate the role of A. muciniphila in gut barrier function and inflammation. Across several experimental models, we find that supplementation with live, and in some cases, pasteurized A. muciniphila, can help curb established inflammation and promote a more anti-inflammatory gut environment. We also identify that these changes are independent of this bacteria’s ability to influence mucin 2, the main building block of intestinal mucus. This study has the potential to both enhance our understanding of microbial influence in intestinal inflammation and may also lead to the development of future treatments for IBD.


title: Coins in the Archaeological Context: The Villa of Titus Case Study

contributor:
Beckmann, Martin
Classics

subject:
Classics
Archaeology
Numismatics
Roman Villas

abstract: In 2019, three coins were found in the same stratum in a large Roman villa called the Villa of Titus, which was constructed between the late first century BC to the early first century AD. Two of the coins are bronze asses and one is a copper quadrans, all of which were struck under the emperor Claudius and range in date from AD 41-54. This thesis, through the use of methodologies, determines as much information as possible about the coins and the stratum within which they were found in order to learn more about the villa’s past. In the first chapter, the main methodologies that are used to examine the coins and context will be examined in detail, which include iconographic, epigraphic and archaeological analyses. The second chapter uses iconographic analysis, along with epigraphic analysis, to examine the coins found at the Villa of Titus. First, there is an overview of the Roman mint and imperial coinage with a focus on Claudius’ coinage; since, all three coins are struck under Claudius. Then, a synopsis of Claudius’ iconography on all of his coinage is used to determine where the villa coins fit in his iconography. The historical context is also surveyed in order to determine why certain images were chosen for the coins. In the third chapter, the archaeological context in which the coins were found is examined. First, two case studies on coins in the archaeological context are studied to determine how coins are interpreted differently depending on the context in which they are found. Then, the methodologies from these examples are used to analyse the Villa of Titus context, which includes taking a detailed look at the materials found in the stratum, determining the function, determining the depositional process and finally describing the interpretation of the stratum.

abstract: Thesis

abstract: Master of Arts (MA)


title: The adaptive response of ribosome content to aerobic and resistance exercise training

contributor:
Parise, Gianni
Kinesiology

subject:
Ribosome
Aerobic exercise training
Resistance exercise training
Mitochondria
Skeletal muscle
Exercise physiology
Muscle physiology

abstract: Ribosomes are the essential machinery for cellular protein synthesis. Ribosome content is hypothesized to support muscle growth and is suggested that those with more ribosomes may better respond to resistance training. Aerobic training also elicits distinct physiological adaptations; however, no direct measures of ribosome content following aerobic training have been measured. Ribosomes interact with mitochondria for mitochondrial protein synthesis and import. Mitochondria may also provide cellular energy to ribosomes. We hypothesized that aerobic and resistance training would increase ribosome content and that ribosome content following aerobic training would correspond to changes in mitochondrial-related protein content and gene expression. Fourteen young men and women performed 6 weeks of single-legged aerobic followed by 10 weeks of bilateral resistance training. Muscle biopsies were taken following aerobic (Pre RT) and resistance training (Post RT) in the aerobically trained (EX) and control (CTL) legs. Pre RT, EX had greater COXIV staining intensity in Type 1 (1.17-fold; p=0.020) and Type 2 (1.22-fold; p=0.015) fibres compared to CTL; however, no differences in whole-muscle mitochondrial-related protein content or gene expression were observed (p>0.05). No differences in regulatory (UBF, Cyclin D1, TIF-1A, POLR-1B), cytosolic (45S, 5.8S, 18S, 28S rRNAs) or mitochondrial (12S rRNA) ribosome-related gene expression were observed (p>0.05), except for c-Myc (CTL>EX; p=0.034) and 5S rRNA (Pre RT CTL<Pre RT EX; p=0.076). When stratified for leg-lean soft tissue mass (LLSTM), legs with greater LLSTM had lower expression in 3/13 ribosome-related genes (p<0.10). When stratified for ΔLLSTM following resistance training, legs with the greatest ΔLLSTM had lower expression in 11/13 ribosome-related genes prior to (p<0.10) and less change or decrease in expression in 9/13 genes following resistance training (p<0.05). These results indicate that baseline ribosome content was sufficient to support aerobic adaptations (capillarization, VO2 peak) that were previously observed and that ribosome’s efficiency, rather than content, is likely more important to support increases in muscle hypertrophy following resistance training.

abstract: Thesis

abstract: Master of Science in Kinesiology

abstract: Ribosomes are essential in making proteins within the cell, and their content has been hypothesized to support the adaptive responses observed with exercise training. Ribosome content has previously been shown to increase following resistance training likely to support skeletal muscle growth. However as aerobic training also influences cellular adaptations, it is plausible that ribosome content also supports these training adaptations. We hypothesized that both aerobic and resistance training would increase ribosome content. Contrary to our hypotheses, no changes in ribosome content were observed following aerobic or resistance training despite previously observing adaptations characteristic of each respective training stimulus. However, those with the greatest increases in muscle mass had lower baseline ribosome content and less change in content following resistance training. These results suggest that baseline ribosome content is sufficient for aerobic adaptations and that ribosome’s efficiency is likely more important than content to elicit resistance training adaptations.


title: Delineating the impact of tobacco smoke on antimicrobial immunity in the upper and lower respiratory tract

contributor:
Stampfli, Martin
Medical Sciences

subject:
Cigarette smoke
Influenza
IgA
Antibody

abstract:
Cigarette smoke is the leading cause of preventable mortality worldwide. This excess death is attributable to an increased risk of acquiring a variety of conditions, including chronic respiratory/cardiovascular diseases and various types of cancer. Smokers are additionally predisposed to develop infectious diseases, notably including pneumonia caused by the influenza virus, one of the most prevalent and burdensome pathogens in existence today. Although cigarette smoke is well known to modulate many aspects of the immune system, the specific mechanisms by which this predisposition is mediated are incompletely understood. Also unclear is the effect of cigarette smoke on responses to intranasal immunization strategies aimed at eliciting immunity against pathogens such as influenza in the upper airways, where protection may substantially contribute to sterilizing immunity.
	This PhD thesis focused primarily on addressing these knowledge gaps. In the first study, we assessed the effect of cigarette smoke on antibody induction following intranasal immunization in the upper airways of mice, finding that smoke exposure attenuated antigen-specific IgA induction in the upper respiratory tract, reproductive tract, and systemic circulation. In addition, we found that these nasal IgA demonstrated a reduced antigen-binding avidity in the acute post-immunization period. Mechanistically, deficits in nasal IgA were associated with a reduced accumulation of antigen-specific IgA antibody-secreting cells (ASCs) in the nasal mucosa, induction of these cells in nasal-draining lymphoid tissues, and upregulation of molecules critical to ASC homing (vascular cell adhesion molecule-1; VCAM-1) and IgA transepithelial transport (polymeric immunoglobulin receptor; pIgR) in the nasal mucosa. Ultimately, in tandem with recent clinical work published by others, our study strongly suggests that cigarette smoke can attenuate IgA induction in the upper airways, which may have implications for aspects of intranasal vaccine efficacy. Thus, smoking status should be more consistently considered in the design of clinical trials for IgA-oriented intranasal vaccines.
	The second study did not assess smoking and host defense directly, but rather served to optimize protocols for assessing immunoglobulins in human mucoid respiratory samples as a precursor to future studies in smoking-related disease. In this regard we found that, relative to phosphate-buffered saline (PBS), dithiothreitol (DTT)-based processing of human sputum samples increased total IgA yields, decreased IgE yield, and improved the detection of a specific IgG autoantibody. These findings suggest that processing choices for human mucoid respiratory samples should be made with specific goals in mind as they pertain to antibody isotype(s) of interest.
	Finally, in the third study we investigated potential mechanisms by which cigarette smoke exposure promotes influenza, given that smokers are at increased risk of acquiring the pathogen, progressing to severe disease, and being admitted to hospital/ICU following infection. In doing so, we found that concurrent smoke exposure increased morbidity, hypoxemia, pulmonary edema, neutrophilia, and ultimately mortality in a mouse model of H1N1 infection. These changes were associated with an increased accumulation of viral (v)RNA in cells independent of any change in the shedding of replication-competent viral particles. Using a novel dysregulation score approach, we found that interleukin (IL)-6 and colony-stimulating factor (CSF)3 expression was highly exacerbated in the lungs and circulation of smoke-exposed, infected mice relative to controls. Supplementation of recombinant (r)CSF3 increased morbidity, hypothermia and edema, while blockade of the cognate receptor (CSF3R) improved alveolar-capillary barrier function. On the cellular level, single cell RNA-sequencing revealed a shift in the distribution of Csf3+ cells towards neutrophils. Finally, deep transcriptional analysis of neutrophils revealed a gene signature that was largely indicative of an exacerbated form of typical disease with select unique regulatory elements. Ultimately, this work identifies potential therapeutic targets (CSF3R signaling, excess vRNA accumulation) for the treatment of cigarette smoke-augmented influenza, and warns against clinical rCSF3 therapy to treat neutropenia during viral infectious disease.
	In conclusion, the work presented in this PhD dissertation expands our understanding of the relationship between cigarette smoke and antimicrobial host defense as it pertains to both IgA immunity in the upper airways, and the pathogenesis of cigarette smoke-augmented influenza.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract:
Cigarette smoke exposure is well known to have many harmful effects on human health, including through its ability to promote various infectious diseases such as influenza. However, the mechanisms by which it promotes infection are not fully known. This is an important knowledge gap given that over 1.1 billion individuals continue to smoke worldwide, and a large number of people are exposed to the harmful effects of second-hand smoke, both with fatal consequence. The central goal of this thesis was to gain a better understanding of this relationship between cigarette smoke and infectious disease, specifically by assessing how smoke exposure impacts immune responses in the upper and lower airways.
	 In the first study, we found that smoke exposure interferes with the ability to activate immunoglobulin (Ig)A antibody responses in the nasal passages of mice, which may have important implications for human nasal vaccination strategies. The second study investigated different methods with which to best measure antibodies in human respiratory samples. Finally, in the third study we defined a role for a specific molecule, CSF3, in worsening health in a mouse model of concurrent cigarette smoke and influenza infection. Overall, this work provides new insights into the ways in which smoking can increase the risk of respiratory infection, thereby informing the future design and testing of vaccines and treatments for use in our highly smoke-exposed global population.


title: Methodologic Considerations in the Evaluation of Opioids and Medical Cannabis for Chronic Pain

contributor: Clinical Epidemiology/Clinical Epidemiology & Biostatistics

abstract:
Opioids are commonly prescribed for chronic pain, particularly in North America; however, growing awareness of their modest benefits and risk of serious harms has raised concerns whether their wide-spread use is evidence-based. Moreover, there are multiple opioids available for use, including both short-acting and sustained-release formulations, and their comparative effectiveness for chronic pain has not been established. It remains possible that some types of opioids may be associated with greater net benefits than others. The first chapter of my thesis presents the results of a network meta-analysis that explores the relative effectiveness of opioids available for the management of chronic non-cancer pain.
The strength of inferences from the results of network meta-analyses depends on the certainty of the evidence, and different approaches are available to make this appraisal. The second chapter of my thesis explores the concordance of two approaches for assessing the certainty of evidence from network meta-analyses, the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) working group system, and the Confidence in Network Meta-Analysis (CINeMA) approach.
Concerns over increasing rates of opioid-related overdose and death have generated enthusiasm for reducing opioid dose among chronic pain patients managed with long-term opioid therapy. My third chapter presents a systematic review of the impact of medical cannabis on opioid use among people living with chronic pain.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)


title: Development and Benchmarking of RAVEN with TRACE for use in Dynamic Probabilistic Risk Assessment

contributor:
Novog, David
Engineering Physics

subject: probabilistic risk assessment

abstract:
The identification of potential accident conditions for a nuclear power plant requires a systematic evaluation of postulated hazards, and accurate methods for predicting the behaviour of the system if these hazards were to occur. It is particularly important to identify scenarios which carry severe consequences (e.g., large radioactive releases to the environment), even if the conditions have a low probability of occurrence, so that preventative measures can be implemented.
Dynamic probabilistic risk assessment (DPRA) is a field of analysis that aims to determine the failure pathways of complex systems while simultaneously analyzing the time-evolution of the proposed accident. By studying the dynamics of the system, DPRA methods are capable of analyzing the impact of impaired or late equipment response, human actions during the transient, and the inter relationship between different systems and failures. This approach promotes realistic predictions of the complex response of the system under accident conditions, and for the dynamics of the accident progression to unfold with timing that is not pre-determined by an analyst, thereby removing potential user bias from the results.
The work that is outlined in this thesis was undertaken in order to demonstrate the DPRA software platform called RAVEN, and to leverage its application in the near-future probabilistic assessment of accident conditions applied to CANDU reactor simulation models. Features of the work include:
•	Demonstration of the capability of RAVEN to produce predictable results using the dynamic event tree (DET) approach;
•	The development of a code interface to allow RAVEN to drive DET simulations of TRACE simulation models; and
•	Demonstration of the capability of the developed RAVEN-TRACE interface to produce predictable results for systems that are well-understood.

abstract: Thesis

abstract: Master of Applied Science (MASc)


title: Methods to Simulate Correlated Binomial Random Variables

contributor:
Canty, Angelo
Davies, Katherine
Mathematics and Statistics

subject: Statistics Binomial Correlation Simulation Multivariate

abstract:
Single nucleotide polymorphisms (SNPs) have been involved in describing the risk a
person is at for developing diseases. Simulating a collection of d correlated autosomal
biallelic SNPs is useful to acquire empirical results for statistical tests in settings such
as having a low sample size. A collection of d correlated autosomal biallelic SNPs can
be modeled as a random vector X = (X1,...,Xd) where Xi ∼ binomial(2, pi) and
pi is the minor allele frequency for the ith SNP. The pairwise correlations between
components of X can be specified by a d ×d symmetric positive definite correlation
matrix having all diagonal entries equal to one. Two versions of a novel method to
simulate X are developed in this thesis; one version is based on generating correlated
binomials directly and the other is based on generating correlated Bernoulli random
vectors and summing them component wise. Two existing methods to simulate X are
also discussed and implemented. In particular, a method involving the multivariate
normal by Madsen and Birkes (2013) is compared to our novel methods for d ≥ 3.
Our novel binomial method has a different variance for the Fisher transformed sample
correlation than the other two methods. Overall, if the target pairwise correlations
are smaller than the lowest upper bound possible and the number of SNPs is low,
then our novel Bernoulli method works the best since it is faster than the Madsen
and Birkes method and has comparable variability and bias for sample correlation.

abstract: Thesis

abstract: Master of Science (MSc)


title: SD Draw: A State Diagram Tool including Elm Code Generation for Interactive Applications

contributor:
Anand, Christopher Dr
Computer Science

subject:
State Diagram
Model Driven Development tool

abstract:
To make computational thinking appealing to young learners, initial programming instruction looks very different now than a decade ago, with the increasing use of graphics and robots both real and virtual.  After the first steps, children want to create interactive programs, and they need a model for this.  State diagrams provide such a model, as observed previously by other researchers.

This thesis documents the design and implementation of a Model-Driven Engineering tool, SD~Draw, that allows even primary-aged children to draw and understand state diagrams,
and create modifiable app templates. We have tested this with grade 4 and 5 students. In our initial test, we discovered that children very quickly understand the motivation and use of state diagrams using this tool, and will independently discover abstract states even if they are only taught to model using concrete states. To determine whether this approach is appropriate for children of this age we asked three questions: do children understand state diagrams, do they understand the role of reachability, and are they engaged by them. We found that they are able to translate between different representations of the state diagrams,  strongly indicating that they do understand them. We found with confidence p=0.001 that they do understand reachability by refuting the null hypothesis that they are creating diagrams randomly. And we found that they were engaged by the concept, with many students continuing to develop their diagrams on their own time after school and on the weekend.

abstract: Thesis

abstract: Master of Science (MSc)


title: CMOS Single-Photon Avalanche Diodes Towards Positron Emission Tomography Imaging Applications

contributor:
Deen, M. Jamal
Biomedical Engineering

subject:
Single-Photon Avalanche Diode
Positron Emission Tomography
CMOS
Photosensor
Time-to-digital Converter

abstract:
Single-photon avalanche diodes’ (SPADs) capabilities of detecting even a single photon with excellent timing resolution and compatibility with strong magnetic fields make them the most promising sensor for positron emission tomography imaging systems. With the advancements of silicon fabrication techniques, SPADs designed in standard planar complementary metal-oxide-semiconductor (CMOS) processes show competitive performance and a lower manufacturing cost. Additionally, CMOS SPADs have the potential for monolithic integration with other CMOS signal conditioning and processing circuits to achieve simple, low-cost, and high-performance imaging solutions. This work targets the design and optimization of SPAD sensors to improve their performance using low-cost standard CMOS technologies.
Firstly, a detailed review on the SPADs in recent literature is presented. Then, the random telegraph signal (RTS) noise is investigated based on n+/p-well SPADs fabricated in a standard 130 nm CMOS process. Through the measurements and analysis, the RTS noise of a SPAD is found to correlate with its dark count rate and afterpulsing. Next, we design n+/p-well SPADs with field poly gates to improve the noise performance. Furthermore, a SPAD pixel, consisting of a p+/n-well SPAD and a compact and high-speed active quench and reset circuit is designed and fabricated in a standard TSMC 65 nm CMOS process. The post-layout simulations show that this pixel achieves a short 0.1 ns quenching time and a 3.35 ns minimum dead time. The measurement results show that the SPAD pixel has a dark count rate of 21 kHz, a peak photon detection probability of 23.8% at a 420 nm wavelength and a timing jitter of 139 ps using a 405 nm pulsed laser when the excess voltage is set to 0.5 V. Due to the short quenching time, almost no afterpulsing is observed even at a low operating temperature of -35 °C. Finally, a new differential quench and reset (QR) circuit consisting of two QR circuits on both the cathode and anode to quench and reset the SPAD through both terminals is proposed to reduce the reset time, to increase the count rate, to reduce the afterpulsing and to reject the common-mode noise.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract: Positron emission tomography (PET) imaging is a powerful tool for diagnosis and assessment of cancers and tumors in the clinical field. Due to their capabilities of detecting even a single photon, excellent timing resolution, and their compatibility with magnetic fields to build PET/MRI (magnetic resonance imaging) multimodal imaging systems; single-photon avalanche diodes (SPADs) become the most promising sensor technology for PET imaging applications. SPADs fabricated in standard complementary metal-oxide-semiconductor (CMOS) technologies allow for a lower manufacturing cost and present the potential to integrate with other CMOS circuits to form a complete imaging system. In this thesis, random telegraph signal noise in SPADs is investigated first. Then, the poly gate is used in the design of an n+/p-well SPAD to improve the noise performance. In addition, a compact and high-speed SPAD pixel is designed and fabricated using an advanced standard CMOS process. Thanks to the fast quench and reset circuit, the SPAD pixel achieves a very short quenching time and a high-count rate. Finally, a differential quench and reset (QR) circuit consisting of two QR circuits on both the cathode and anode to quench and reset the SPAD through both terminals is proposed and studied.


title: Learning from Inuit perspectives on marine governance

contributor:
Nancy, Doubleday
Global Health

subject:
Indigenous research
Planetary health
Feminist standpoint theory
Critical theory

abstract:
Our ocean is undergoing drastic changes. In the circumpolar north, this reality is highly visible. Social-ecological systems thinking informs that social and ecological systems are intertwined, yet hegemonic governance systems appear unable or unwilling to reorient themselves to promote planetary health amidst the climate crisis. To rethink our relationship with the ocean, I explore the research question, “What can I learn from Inuit perspectives about the ocean and marine governance within Inuit Nunangat, and how does this relate to planetary health?”
This study applies critical theory methodologies. In particular, feminist standpoint theory informs the approach of engaging with knowledge and lived experience of marginalized or oppressed populations. Inuit knowledge in the form of a purposefully sampled collection of publicly available Inuit documents that relate to the marine environment is the primary evidence that informs analysis. Inuit produced declarations, websites, and reports are analysed using thematic analysis. This study does not depend on ethics review or community engagement; research using publicly available information is exempt from these ethical requirements. Nevertheless, the positionality I strive to embody is allyship with Inuit.
Two main themes are interpreted from analysis. First, the meaning of the marine contains the key ideas: Inuit culture relies upon marine ecosystems; rapidly social-ecological systems have cultural implications; and environmental protection focuses on marine areas of significance. A rights-based approach reflects the assertions: Inuit are rightsholders not stakeholders; political equality is still hindered by systems of racism and oppression; and collaborative governance approaches are the path forward.
Governance mechanisms that recognize Indigenous rights have the capacity to promote planetary health. Inuit self-determination is health promotion, supporting marine protection, equitable marine governance, and strengthening Inuit culture. Decision-making systems that are characterized by polycentricity, community collaboration, and a respect for Indigenous knowledge present a path forward.

abstract: Thesis

abstract: Master of Science (MSc)


title: Analyzing Patient-Physician Communication On Lifestyle Medicine To Promote Mental Health

contributor:
Keyna, Bracken
Global Health

subject:
Global Health
Medicine
Communication
Patient-Physician Communication

abstract: Mental illness affects 1.2 million children and youth in Canada. Female adolescents, in particular, suffer significant consequences associated with this. While family physicians are often the first line of contact for a health-related concern, little is known about how the promotion of lifestyle medicine to enhance the mental wellbeing of female adolescents is being communicated. Using a qualitative content analysis approach, a survey about counseling on lifestyle medicine was completed by 126 Hamilton Family Physicians giving a response rate of 25.2%. Key informants discussed with the highest agreement the following three themes: lifestyle medicine factors, barriers, and improvements for communication to female adolescent patients. The global prevalence of female adolescent mental health issues in combination with the use of screening tools was showcased within this study population. Results indicated that Hamilton family physicians integrate global recommendations into their line of care with patient-centered dialogue, awareness of patient needs, and lifestyle medicine education.

abstract: Thesis

abstract: Master of Science (MSc)


title: THE GENETIC AND BEHAVIOURAL UNDERPINNINGS OF NATURAL VARIATION IN SOCIAL BEHAVIOUR

title: THE GENETIC AND BEHAVIOURAL UNDERPINNINGS OF SOCIAL BEHAVIOUR

contributor:
Dukas, Reuven
Psychology

subject:
Social behaviour
Sociability
Fruit flies
Drosophila
Sexual aggression
Aggression
Indirect genetic effects
Artificial selection
Heritability
Social plasticity
RNAseq
Differential expression
Forced copulation
Genetic correlation

abstract: A rich diversity of social behaviours exists in the animal kingdom, and these behaviours have evolved to perform a variety of adaptive functions. Social behaviours show variation both among and within species, however the mechanisms that give rise to this variation are not well understood. Using fruit flies (Drosophila melanogaster), my goal was to uncover the genetic and behavioural mechanisms that underpin natural variation in two different social behaviours: sociability and sexual aggression. First, I showed that sociability, which is the tendency of animals to engage in friendly activities together, is influenced by indirect genetic effects (IGEs), and that encounters among individuals drive these effects (Chapter 2). I then showed that sociability and social plasticity have low-moderate heritability (Chapter 3), and sociability is not correlated between the sexes or with activity. I then generated lineages of flies with high and low sociability using artificial selection (Chapter 4). The evolved lineages had significantly diverged sociability which was not associated with fitness measures or nearest-neighbor distances, but was negatively correlated with intrasexual aggression (Chapter 4). Finally, in sexual aggression, which I quantified as male forced copulation rate, I showed that evolved differences and differences due to social plasticity were both associated with the differential expression of many genes, but only a few of these genes were significant in both (Chapter 5). I also showed that these sets of genes are enriched in neuropeptide hormone and serotonin gene ontology categories, and that 4 of 7 chosen genes were validated for their effects on sexual aggression. Overall, this thesis sheds light on the complex mechanisms that underlie variation in these social behaviours, and it paves the way for future research to further elucidate some of these mechanisms, especially on the genetic basis of sociability using the evolved lineages I generated.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract: Individual animals tend to vary in many traits including social behaviours. Using fruit flies, my goal was to understand what causes individuals to vary in two social behaviours: sociability and sexual aggression. I found that highly sociable flies tended to influence other flies to become more sociable due to a change in how much these flies interacted. I also found that individual differences in sociability are moderately heritable, and the genetic variation contributing to this is different between the sexes. Also, less sociable flies tended to be more aggressive than highly sociable flies. Finally, for sexual aggression, I showed that variation in a male’s success in forcibly mating with a female was associated with changes in the expression of hundreds of genes, but these changes were mostly unique for evolved versus environmentally induced variation. Future work will similarly look to identify genes involved with individual differences in sociability.


title: Investigating the impact of maternal diet on offspring immune function

title: Maternal Diet and Offspring Immune Function

contributor:
Bowdish, Dawn M.E.
Sloboda, Deborah M.
Medical Sciences

subject:
maternal diet
perinatal exposure delayed effects
streptococcus pneumoniae
respiratory tract infection
maternal obesity
offspring health
adult offspring
developmental programming
immunophenotyping

abstract: Maternal obesity has significant consequences on the lifelong health of the developing child and rising global incidences make it one of the most common comorbidities during pregnancy. Offspring of obese mothers are at an increased risk of hospitalization for respiratory infections throughout childhood, which predispose these children to non-communicable respiratory diseases in later life. Animal models of maternal high fat diet (mHFD) feeding have observed common inflammatory outcomes with obesogenic models, but the effect on offspring varies with timing of the nutritional challenge and diet composition across studies. These studies demonstrate significant alterations to circulating and lung specific immune cells but the sequence of events that link maternal diet to these fetal outcomes are unclear, nor have they been tested in the context of a bacterial respiratory infection. Streptococcus pneumonaie is the most common causative pathogen of bacterial pneumonia and meningitis, making it of high clinical relevance. We aimed to investigate the effect of a mHFD (45% kcal from fat) during gestation and lactation, on offspring outcome and recovery from Streptococcus pneumoniae infection. Immunophenotyping, both before and after infection, revealed a hypo-inflammatory phenotype in circulating monocytes of the mHFD offspring with a decreased capacity to both initiate and terminate inflammatory responses. These offspring had significantly higher bacterial counts in lung tissues during infection and sustained cellular inflammation in survivors. In this thesis, we present foundational work on the detrimental influence of excess maternal nutrition on offspring immune function and infection outcomes, which may be involved in susceptibility to inflammatory and chronic disease in later life. A better understanding of this deep and lasting influence of the maternal environment will allow us to target preconception health as a form of harm reduction, informing stake holders and institutions to direct efforts towards DOHaD knowledge translation.

abstract: Thesis

abstract: Master of Science (MSc)