title: The Role of Endoplasmic Reticulum Stress in the Development of Essential Hypertension

contributor: Medical Sciences (Division of Physiology/Pharmacology)

subject:
ER Stress
4-PBA
Hypertension
SHR

abstract: Essential hypertension is the leading contributor to premature death worldwide. Endoplasmic reticulum (ER) stress has recently been implicated in diseased blood vessels and hypertension. It is unclear whether ER stress is a cause or a consequence of hypertension. We hypothesized that ER stress inhibition would prevent the development of hypertension in the young spontaneously hypertensive rat (SHR) by improving vascular structure and function. The SHR was used as a genetic model of human essential hypertension, and the Wistar Kyoto (WKY) rat as its normotensive control. The first study conducted involved assessing the levels of ER stress in young SHRs, before they developed hypertension. The second study conducted involved treating rats with 1g/kg/day of the sodium salt of 4-phenylbutyric acid (4-PBA) orally for 8 weeks from 5 weeks of age. Blood pressure was measured weekly, noninvasively via radiotelemetry. Mesenteric arteries were collected at sacrifice. Finally, the third study conducted involved treating rats with 1g/kg/day 4-PBA orally for eight weeks from five weeks of age, and then withdrawing the drug for four weeks to determine if drug treatment created a sustained lowering of blood pressure. In the first study, ER stress markers were observed to be significantly increased in the young SHR when compared to the WKY. In the second study, blood pressure was observed to be significantly lower in the 4-PBA-treated SHR groups than in the untreated SHRs. In addition, mesenteric arteries from the 4-PBA treated SHRs had a significant decrease in media/lumen ratio, ER stress marker expressions, as well as improved vasodilatory response to carbachol and reduced contractile responses to phenylephrine. In the third study, 4-PBA was able to keep the blood pressure low for one week after withdrawal, however, blood pressure returned to similar levels as untreated SHRs by the end of three weeks. Overall, ER stress inhibition, via 4-PBA, blunted the development of hypertension in the SHR.

abstract: Thesis

abstract: Master of Science (MSc)


title: Axisymmetric Jet Impingement onto a Heated Cylinder

contributor: Engineering Physics and Nuclear Engineering

subject:
Thermahydraulics
Jet Impingement
Moderator
CFD

abstract:
The prediction of the flows and temperatures in the moderator system of CANDU reactors is important in the safety evaluation during some potential transients. An experimental program to collect data for CFD validation, including integrated moderator circulation tests has been funded by the CANDU Owners Group. This thesis constitutes a separate effect test within this larger moderator flow study, investigating the behaviour of a jet impinging onto a single heated cylinder.
	A number of experiments were conducted to investigate the behaviour of the jet flow under a variety of scenarios. The inlet Reynolds number and the heater power level were the primary variables considered to assess the impact of the buoyant forces generated by the heated cylinder on the flow. Alongside the experiments, simulations were performed using the experimental geometry to evaluate the performance of some of the most commonly-used turbulence modelling approaches – namely the standard k-ε, realizable k-ε, and standard k-ω RANS models.
	The agreement between the turbulence models and experimental results was determined to be reasonable in the free jet regions, however nearer the cylinder, the simulated results exhibited a wider core region and steeper gradient in the shear layer than the experimental data. At lower Reynolds numbers, over-prediction of velocities both in the axial and lateral direction was also seen. The impact of heating proved minimal in the jet core, however differences were observed in the shear layer at lower Reynolds numbers, and the heated case exhibiting decreased lateral velocities as compared to the isothermal case.

abstract: Thesis

abstract: Master of Applied Science (MASc)


title: THE IMPACT OF NEIGHBOURHOOD TEAM DEVELOPMENT ON RESIDENT QUALITY-OF-LIFE IN LONG-TERM CARE

contributor:
Ploeg, Jenny
Nursing

subject:
long-term care
quality-of-life
culture change
interRAI

abstract: By the year 2024, one in four adults in Canada will be over the age of 65. In Ontario alone, 100,000 residents live in long-term care (LTC). Residents sometimes experience poor quality-of-life (QOL). Culture change has been proposed as an approach to improve residents’ QOL in LTC. One large LTC organization, Schlegel Villages, has developed and implemented an organizational culture change called Neighbourhood Team Development (NTD). This approach focuses on building cross-functional teams to enhance resident-centredness and promote QOL through optimizing residents’ autonomy and dignity. Implementation of NTD started in 2013 in six LTC homes. The aim of this secondary analysis was to evaluate if NTD has an impact on residents’ QOL in LTC. Using a quantitative repeated-measures design, residents from six LTC homes completed QOL assessments. Quantitative data were collected through the Resident Assessment Instrument-Minimum Data Set 2.0 (RAI-MDS) and the interRAI QOL Survey Short Form. QOL data were analyzed using a paired t-test to assess change scores between time point 1 (data collected between August 2011 and December 2012) and time point 2 (data collected between January 2014 and November 2015) for 232 residents. Study results demonstrate that NTD increased residents’ QOL (p = .003). Organizational culture change such as NTD can lead to innovative approaches to improve the QOL of residents in LTC. This study contributes to literature examining culture change in LTC, and helps inform LTC care models, and interventions to increase residents’ QOL in LTC.

abstract: Thesis

abstract: Master of Science (MSc)


title: (Re-)Creating sharing in Agda's GHC backend

contributor:
Kahl, Wolfram
Computing and Software

subject:
Compiler optimizations
Functional programming
Dependent types
Computer science

abstract: Agda is a dependently-typed programming language and theorem prover, supporting proof construction in a functional programming style. Due to its incredibly flexible concrete syntax and support for Unicode identifiers, Agda can be used to construct elegant and expressive proofs in a format that is understandable even to those unfamiliar with the tool. However, the semantics of Agda is lacking resource guarantees of the kind that Haskell programmers are used to with lazy evaluation, where multiple uses of function arguments and let-bound variables still result in the corresponding expressions to be evaluated at most once. With the current compiler backends of Agda, a mathematically-natural way to structure programs therefore frequently results in inefficient compiled programs, where the run-time complexity can be exponentional in cases where corresponding Haskell code executes in linear time. This makes a highly-optimised compiler backend a particularly essential tool for practical development with Agda. The main contributions of this thesis are a series of compiler optimisations that inlines simple projections, removes some expressions with trivial evaluations that can be statically inferred, and reduces the need for repeated evaluations of the same expressions by increasing sharing. We developed transformations that focus on the inherent “loss” of sharing that is frequently the result of compiling Agda programs. Where an Agda developer may imagine that value sharing should exist in the generated Haskell code, it often does not. We present several optimising transformations that re-introduce some of this “lost” sharing without affecting the type-theoretic semantics, then apply these optimisations to several typical Agda applications to examine the memory allocation and execution time effects. In measuring the effects of these optimisations on Agda code we show that overall improvements in runtime on the order of 10-20% are possible. We hope that the development and discussion of these optimisations is useful to the Agda developer community, and may be helpful for future contributors interested in implementing new optimisations for Agda.

abstract: Thesis

abstract: Master of Science (MSc)


title: Three Essays in Behavioral and Corporate Finance

contributor:
Deaves, Richard
Finance

subject:
Behavioral Finance
Corporate Finance

abstract:
This thesis examines topics in corporate finance and behavioral finance. First, I examine the effects of ownership structure on the amount of firm-specific information in stock prices, measured using synchronicity.  With a unique dataset of 6,184 firm-year observations for Canadian companies listed on the Toronto Stock Exchange during 2000-2012, I find evidence of a significant, non-linear relationship between the size of the largest shareholder and synchronicity. Using propensity score matching (PSM) to isolate the effect of family firms on synchronicity, I find no evidence of a significant difference in synchronicity for matched pairs of family and non-family firms. Finally, I find evidence of a negative relationship between firms with multiple large controlling shareholders and synchronicity.
Second, in a co-authored paper with Dr. Richard Deaves (McMaster University) and Dr. Brian Kluger (University of Cincinnati) we investigate the relationship between path-dependent behaviors (i.e., the disposition effect, house money effect and break-even effect) and investor characteristics (e.g., overconfidence and emotional stability) using experimental trading sessions. The majority of our subjects exhibit path-dependent biases and there are significant correlations between these biases. The correlations hint at the possibility that a common underlying factor may be driving all path-dependent behaviors. We also find some evidence that the existence of psychological bias (overconfidence and negative affect) leads to more bias in financial decision-making.
Third, in co-authored work with Dr. Lucy Ackert (Kennesaw State University), Dr. Richard Deaves (McMaster University) and Dr. Quang Nguyen (Middlesex University) we report the results of an experiment designed to explore whether both cognitive ability (IQ) and emotional stability (EQ) impact risk preference and time preference in financial decision-making, finding evidence in support. Specifically, IQ impacts risk preferences and EQ impacts time preferences. Our results are primarily driven by our male participants. Most interestingly, EQ plays a role that is almost as meaningful as IQ when it comes to explaining preferences.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)


title: A Query Structured Model Transformation Approach

contributor:
Maibaum, Tom
Computing and Software

subject:
Model Transformation
Diagrammatic Queries
Model Synchronization Taxonomy
Formal Methods

abstract: Model Driven Engineering (MDE) has gained a considerable attention in the software engineering domain in the past decade. MDE proposes shifting the focus of the engineers from concrete artifacts (e.g., code) to more abstract structures (i.e., models). Such a change allows using the human intelligence more efficiently in engineering software products. Model Transformation (MT) is one of the key operations in MDE and plays a critical role in its successful application. The current MT approaches, however, usually miss either one or both of the two essential features: 1) declarativity in the sense that the MT definitions should be expressed at a sufficiently high level of abstraction, and 2) formality in the sense that the approaches should be based on precise underlying semantics. These two features are both critical in effectively managing the complexity of a network of interrelated models in an MDE process. This thesis tackles these shortcomings by promoting a declarative MT approach that is built on mathematical foundations. The approach is called Query Structured Transformation (QueST) as it proposes a structured orchestration of diagrammatic queries in the MT definitions. The aim of the thesis is to make the QueST approach –that is based on formal foundations– accessible to the MDE community. This thesis first motivates the necessity of having declarative formal approaches by studying the variety of model synchronization scenarios in the networks of interrelated models. Then, it defines a diagrammatic query framework (DQF) that formulates the syntax and the semantics of the QueST collection-level diagrammatic operations. By a detailed comparison of the QueST approach and three rule-based MT approaches (ETL, ATL, and QVT-R), the thesis shows the way QueST contributes to the development of the following aspects of MT definitions: declarativity, modularity, incrementality, and logical analysis of MT definitions.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)


title: Prediction of Mandatory Lane Changing Behavior Using Artificial Neural Network Model

contributor:
Fengjun, Yan
Mechanical Engineering

subject:
Prediction
Mandatory
Lane Changing
Neural Network

abstract: The prediction results demonstrated that the method using six frames of variables as the input vectors for the BPNN model could improve the model prediction accuracy. Also, the number of nodes used in the hidden layer had a significant impact on the performance of the BPNN model. The results indicated that the best prediction accuracies in advance of a driver’s actual driving behavior with a lead time of 1s, 1.5s, and 1.8s were at 89.6%, 84.9%, 78.8% for merge events, and for non-merge events were at 92.2%, 87.5%, 81.1% respectively.

abstract:
Recently, the applications of some driver assistance systems on vehicles have reduced vehicle accidents. However, studies have shown that the number of vehicle accidents caused by improper lane-changing behavior remains at a high level. Therefore, research has been focusing on developing a lane-changing assistance system to increase the safety level of driving in traffic. Many researchers have attempted to predict lane-changing behavior, and a general trend in the study of predicting driving behavior is the greater application of computational artificial intelligence.
      Artificial Neural Network (ANN) is one of the artificial intelligence methods, and it is well-known for its high reliability in a variety of applications. An ANN model can mimic human thinking and behavior due to its ability to capture the complex relationship among different variables in an environment of uncertainty. In this thesis, a BP (back-propagation) Neural Network model established by two methods was developed to predict a driver’s mandatory lane-changing decisions (merge or non-merge) at an early stage by considering driving environment features as the input vectors. Vehicle trajectory data from the Next Generation Simulation (NGSIM) dataset was used for training and testing the model. The results of the proposed model indicated that the prediction accuracies in advance of a driver’s actual driving behavior with a lead time of 1s, 1.5s, and 1.8s were at 89.6%, 84.9%, 78.8% for merge events, and for non-merge events were at 92.2%, 87.5%, 81.1% respectively.

abstract: Thesis

abstract: Master of Applied Science (MASc)

abstract: Lane-changing behavior at freeway on-ramps has a significant effect on driving safety and the stability of traffic flow. During the lane-changing process, the information processed by drivers is more complicated than that processed while remaining in a lane. If drivers fail to accurately judge the appropriate lane-changing time or the relative movement characteristics of related vehicles, vehicles accidents may occur. Thus, accurate prediction of lane-changing behavior is essential for a driving assistance system to ensure driver safety.


title: Where the Blue Stragglers Roam: The Link Between Formation and Environment in Globular Clusters

contributor:
Sills, Alison
Physics and Astronomy

subject: blue stragglers, formation, environment, globular clusters, stars, red giant, central velocity dispersion

abstract:
 The conditions ideally suited for blue straggler star formation are for the most part unknown, though there is mounting evidence to suggest that the preferred blue straggler formation pathway, whether it be via the coalescence of a primordial binary system or through the collision of two single main-sequence stars, depends largely on the cluster environment. In this thesis we are trying to isolate the preferred blue straggler formation mechanism(s)
operating in various globular cluster environments by comparing relative blue straggler frequencies to global cluster properties.

 We define a series of selection rules to isolate the blue stragglers from main-sequence turn-off and extended horizontal branch stars in the colour-magnitude diagrams of 57 globular clusters taken from HST images of their
central cores. The boundary conditions were defined using only the main-sequence turn-off as a point of reference, and are hence applied consistently from cluster to cluster. We chose to count only those stars found within one core radius of the cluster center in an effort to obtain a sample that is approximately representative of a uniform cluster environment where, ideally, a single blue straggler formation mechanism is predominantly operating. Relative frequencies
of blue straggler stars are then found using the red giant branch for normalization and are subsequently analyzed. We confirm the anticorrelation between relative blue straggler frequency and total integrated cluster luminosity previously observed by Piotto et al. (2004), and find a new anticorrelation between relative blue straggler frequency and the central velocity dispersion, as well as a weak anticorrelation with the half-mass relaxation time. We find no other statistically significant trends. Observational implications pertaining to blue straggler formation mechanisms are then discussed.

 We present a very simple, semi-analytic model designed in an attempt to reproduce the observed trends in the core. Using estimates for the collisional timescales, we find that only a small percentage of the blue stragglers produced are a direct result of collisions. The majority of the blue stragglers created
in our model are thus products of mass-transfer in tight, low-mass binary systems. We were surprised to find a reasonably good agreement between the data and our predictions, given the simplicity of our model. Our results suggest that the binary fraction could be a crucial parameter in shaping blue straggler populations, and hence better and more abundant observations of binary systems and their numbers could prove an important step in gaining a
better understanding of blue straggler formation mechanisms.

abstract: Thesis

abstract: Master of Science (MSc)


title: Fundamental and Applied Aspects of Sol-Gel Based Affinity Assays for Membrane Receptors Using Mass Spectrometry Detection

contributor:
Brennan, John
Biochemistry

subject: fundamental, applied aspects, Sol-Gel based, affinity assays, membrane receptors, mass spectrometry detection, polycationic polymers

abstract:
 This thesis focuses on fundamental and applied aspects of sol-gel based affinity assays for screening membrane receptor targets. Fundamental studies investigate the role of non-specific interactions between polycationic polymers and sol-gel derived monoliths prepared from sodium silicate precursors. Previous studies from our group using time-resolved
fluorescence anisotropy (TRFA) have shown that both the sidechain motion (Φ1) and backbone motion (Φ2) of polycationic polymers, such as poly-D-lysine, can be measured by fitting anisotropy decays of fluorescein labeled polymers to a two component hindered rotor model. These studies demonstrated that polycationic polymers remain fairly mobile in sol-gel derived materials made from sodium silicate precursors, despite the strong electrostatic interactions between the cationic polymers and the anionic silica materials. The first objective of my work was to assess the nature of the electrostatic interactions between several polycationic polymers and a silica material made from sodium silicate using a novel two-point labeling technique with a pyranine dye to determine if previous studies were indeed correct. Our results show that the two-point labeling technique with pyranine provides a more rigid interaction between the polymer and the dye compared to the previous labeling method using fluorescein, allowing for more accurate monitoring of dynamic motions of cationic polymers in sol-gel derived materials. The dynamics of poly-D-lysine entrapped in sol-gel derived materials was indeed seen to be highly restricted, contrary to results obtained in previous studies.

 While the first project provided a framework for understanding the effect of electrostatic interactions on the dynamics of biomolecules, it also provide valuable insight into the effect of non-specific interactions between cationic species and sol-gel derived materials in general. These considerations are important when using sol-gel based affinity columns for small molecule screening. The second study outlines a competitive affinity-based screening method using mass spectrometry (MS) detection that can help reduce the effect of non-specific interactions between test compounds and the column matrix in small molecule screening applications. This technique relies on the use of a high-affinity indicator compound pre-equilibrated on column to identify weak affinity ligands in mixtures through transient spikes in the indicator signal that result from the competition between the indicator and test compounds. The results of this study demonstrate the ability to identify weak affinity ligands for the nicotinic acetylcholine receptor (nAChR) using low to sub-picomole amount of active receptor on column. The technique results in a reproducible signal output that can potentially be used to obtain quantitative data on the binding affinities of target-ligand interactions. The assay is amenable to automation and can be performed at high speeds, thereby demonstrating the potential of this technique as a high-throughput screening tool for screening membrane receptors.

abstract: Thesis

abstract: Master of Science (MSc)


title: Compounds and Methods to Study O-GlcNAc Modification of Proteins

contributor:
McGibbon, Graham A.
Chemistry

subject: compounds, methods, modification of proteins, cytoplasmic, glycosylation, hydrolysis, peptides

abstract:
 A variety of important cell functions rely on O-GlcNAcylation of proteins, a kind of post-translational glycosylation that modifies nuclear and cytoplasmic proteins on serine or threonine residues by the addition of the single sugar moiety β-N-acetylglucosamine (O-GlcNAc). Generally, two enzymes can catalyze the formation and cleavage of the O-GlcNAc O-glycosidic linkage. The O-GlcNAc transferase (OGT) catalyzes the transfer of N-acetylglucosamine from uridine diphosphate N-acetylglucosamine to the hydroxyl group of specific Thr and Ser residues. On the other hand, hydrolysis of the sugar moiety from proteins is achieved via the bi-functional nuclear cytoplasmic O-GlcNAcase and acetyltransferase (NCOAT). Since O-GlcNAcylation plays very important roles in many cell processes such as transcription, translation and protein-protein interaction, my research mainly focused on preparing compounds and developing methods to study the O-GlcNAcylation process and discover the structural information of OGT and NCOAT.

 In this thesis, the important enzyme substrates (YSDSPSTST for OGT and YSDSP(O-GlcNAc-Ser)TST for NCOAT) were prepared by solid phase synthesis and purified by preparative reverse phase HPLC. Their structure and sequence were confirmed by ESI-MS and tandem MS (MS/MS). The building block S-GlcNAc-Ac3-Ser-COOBn for preparing S-GlcNAcylated peptides was prepared by a multistep procedure. Two potent photoaffinity labeled probes for mapping the active site of sOGT were designed and synthesized, and their IC50 values for sOGT were measured by CapLC and a beta-elimination method. Also, many analytical methods were developed for studying the O-glcNAcylation, including discovering the O-Glycosylation site of peptides by MS/MS and beta-elimination methods, sequencing peptides by MS/MS, analyzing the protein digests by CapLC-MALDI MS and studying the ion mobility of peptides and glycopeptides
using ion mobility spectrometry.

abstract: Thesis

abstract: Master of Science (MSc)


title: Sex dependent associations between microbiome disruption in infancy and the prevalence of behavioural disorders at 81 months

contributor:
Boyland, Khrista
Health Research Methodology

subject:
microbiome
mental health
ALSPAC
SDQ
antibiotics

abstract: The current findings support the hypothesis that disruption of the microbiome in infancy results in measurable, sex specific changes in behavioural characteristics associated with psychopathology. These early exploratory findings support further study into the mechanisms of potential behavioural effects of disruption of the human microbiome in infancy through exposure to antibiotics or birth by caesarean section. If a causal relationship is determined between early life microbiome disruptors and the development of psychopathology, the relative effect of these disruptors in relation to other developmental processes needs further consideration, given the potential impact these findings may have on the utilization of these intervention in infancy and early life.

abstract: Thesis

abstract: Master of Science (MSc)


title: Diversity of TETX-Like Proteins

contributor:
Wright, G. D.
Biochemistry

subject: tetracycline resistance, diversity, protein, TetX, cloned, inactivator

abstract:
 The most uncommon form of tetracycline resistance is enzymatic inactivation of the drug. The first protein characterized that was shown to have this ability was TetX, a 44-kDa cytoplasmic protein responsible for inactivating tetracycline in E. coli. The associated gene, tetX, was found on a transposon in the bacterium Bacteroides fragilis, and encodes an NADP-requiring, FAD-dependent monooxygenase. TetX modifies the structure of tetracycline by the addition of a hydroxyl to the C-11a position, altering the β-diketone system of the tetracycline that is responsible for antibiotic activity. This project was designed to search for novel tetracycline inactivators, and to determine the origin of the tetX. Initially, the search for TetX-like proteins in S. coelicolor and C. hutchinsonii was performed using homologous protein sequences found using BLAST searches. Each of the genes encoding the homologous protein sequences was cloned, over-expressed and purified, then analyzed using HPLC and LC/MS methods to determine their tetracycline inactivating ability. Next, the published tetracycline inactivators Tet34 and Tet37 were tested for their ability to inactivate the drug using HPLC and LC/MS methods, after being cloned, over-expressed and purified. Finally, a search of the Actinomycete library belonging to the Wright Laboratory was conducted looking for novel
tetracycline inactivators. Bioassays were the first step in a series of experiments done, with HPLC and LC/MS assays eventually being used to determine if an inactivation event was occurring. The homologous sequences from S. coelicolor and C. hutchinsonii did not inactivate
tetracycline as determined by HPLC and LC/MS data. The potential inactivators, Tet34 and Tet37, were also found to be void of tetracycline inactivating activity. Finally, one isolate in the actinomycete library was thought to be inactivating the drug, however, upon further inspection via HPLC and LC/MS methods this inactivation event was dismissed. Future research should focus on the search for novel enzymes capable of modifying the structure of tetracycline, as well as the origin of the only known tetracycline inactivator, tetX.

abstract: Thesis

abstract: Master of Science (MSc)


title: Structural and Functional Studies of Non-Homologous End-Joining Regulator 1 (NEJ1)

contributor:
Junop, Murray
Biochemistry and Biomedical Sciences

subject: structural, functional studies, non-homologous, end-joining regulator 1 (NEJ1)

abstract:
 Repair of double-strand breaks is critical for the preservation of genomic integrity and cellular viability. A predominant pathway implicated in the repair of such lesions is the evolutionarily conserved non-homologous end-joining (NHEJ) pathway. Among the major constituents of this pathway in Saccharomyces cerevisiae is Nej1, for which a clear biochemical function has not been determined. The results presented in this work demonstrate that Nej1 exhibits a DNA binding activity comparable to Lif1, with an apparent dissociation constant of 1.8 μM. Characterization of the DNA binding activity revealed that although short ~20 bp substrates can suffice, binding is enhanced with longer substrates (>300). This DNA binding activity supports the hypothesis that Nej1 plays a direct role in the repair of DNA double-strand breaks. Structure-function studies indicated that the C-terminus of Nej1 is not only required, but is sufficient, for mediating DNA interactions. Structural characterization revealed that Nej1 exists as a dimer, and that residues 1-244 are sufficient for dimer formation. Examining the ability of this truncated Nej1 (aa 1-244) to perform NHEJ, revealed a defect in end-joining as measured by an in vivo plasmid repair assay. Preliminary functional and structural studies on the Nej1-Lif1 complex suggest that the proteins stably co-purify and the complex binds DNA with a higher affinity than each independent component. The significance of these results is discussed with reference to current literature on Nej1 and other end-joining factors (mammalian and yeast), specifically the recently identified putative mammalian
homologue of Nej1, XLF. Collectively, these results demonstrate that although there are several functional similarities, there also appear to be important differences in the structure-function relationships of Nej1 and XLF, and Nej1/XLF and Lif1/Xrcc4.

abstract: Thesis

abstract: Master of Science (MSc)


title: On Landau–de Gennes Energy Minimizers Surrounding Generalized Colloid Particles

contributor:
Bronsard, Lia
Mathematics and Statistics

abstract: We consider the interaction between a single colloid particle of generalized shape and nematic liquid crystal in the framework of Landau–de Gennes theory. At the particle surface, general strong or weak uniaxial anchoring conditions are applied as well as uniform uniaxial forcing at infinity. In this context, it is found that the field-free Landau–de Gennes functional with surface energy admits uniformly continuous minimizers. We then study two examples of non-spherical colloids in a limiting regime known as the ‘small particle limit’. Explicit solutions to the small particle limit are found in the case of a prolate and oblate spheroidal colloid with ‘almost homeotropic’ strong anchoring. From there, a Saturn ring defect is numerically observed in both cases.

abstract: Thesis

abstract: Master of Science (MSc)


title: Listening Backward: Queer Time & Rhythm in Popular Music Performance

contributor:
Fast, Susan
English and Cultural Studies

abstract: Listening to music has the capacity to connect us with others. In a society structured by the stultifying logic of heteronormativity, patriarchy, white supremacy, and neoliberalism —ideals that usher all of us into normative and limiting modes of relations—musical listening serves as a bastion of collective queer potential. Music can enhance queer collectivity particularly when it offers us experiences of non-normative temporality. In this dissertation, I argue for a form of music participation that I call listening backward: the act of listening closely and collectively to past musical moments in which alternative worlds were once possible. This form of listening, I argue, encourages resistance to normative signifiers of progressive linear temporality and interrogates notions of progress in both musical sound and society more broadly. Listening backward is important for building queer collectives—in the present and for the future—that can develop and sustain coalitions and resist homonormative impulses and neoliberal claims of individuality and competition. In this dissertation I analyze a variety of music performances that vary in their genre markers, the historical moments from which they come, and the forms of participation they encourage. These disparate performances are bound together by the ways that they that render audible a collective participatory ethos and challenge musical and broader social notions of progress and normative temporality. Listening backward is informed by a history of popular music participation in the late twentieth century and encourages an ear toward liberatory and revolutionary politics—it is attuned to hope in the face of limiting and conservative politics of the present. Past musical moments remain rife for the potential for collective experience—we just need to listen backward.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)


title: Multi-Factorial Exercise and Nutrition Strategies to Improve Strength and Other Measures of Muscle Function and Health in Older Adults

contributor:
Phillips, Stuart
Kinesiology

subject:
nutrition
aging
muscle
isotopes
exercise
protein
creatine
vitamin D
calcium
fish oil

abstract:
Resistance exercise training (RET) and protein supplementation are potent nonpharmacological countermeasures against sarcopenic muscle and strength loss, however
other exercise modalities and isolated nutritional supplements are effective in combating
additional deleterious age-related changes, such as reduced cardiometabolic health.
Accordingly, in Study 1 we assessed the 48-hour integrated muscle protein synthesis
(MPS) response to a single session of RE, aerobic exercise, or high-intensity interval
exercise (HIIE) in a group of healthy older men using the novel heavy water method. The
results of Study 1 indicated that both RE and HIIE were capable of significantly elevating
myofibrillar MPS above resting rates, with the most substantial effect observed following
RE. In Studies 2 and 3 we evaluated whether daily consumption of a nutritional
supplement which comprised whey protein, creatine, vitamin D/calcium, and omega-3
polyunsaturated fatty acids could: augment strength, physical function, and lean tissue
mass (Study 2), and also improve glycemic control, lipidemia, and systemic inflammation
(Study 3) in healthy older men following 6 weeks of supplementation in the absence of
exercise; and enhance exercise training-induced improvements in the same outcomes
following a 12-week RET + HIIT program. Six weeks of multi-ingredient nutritional
supplementation stimulated gains in strength (~6%) and lean mass (~1%), roughly
equivalent to one year's worth of age-related decline, as well as reduced circulating
concentrations of lipids and inflammatory markers. Twelve weeks of combined RET +
HIIT simultaneously improved strength, aerobic fitness, and glucose handling in the same
group of older men. Further improvements in systemic inflammation and glucose
handling were observed when multi-ingredient nutritional supplementation was combined
with exercise training. Collectively, these studies demonstrate that multiple exercise
modalities and nutritional supplements can be employed concurrently to alleviate various
aspects age-related physiological decline.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract:
Aging is associated with a variety of deleterious physiological changes including loss of
skeletal muscle mass and strength, reduced aerobic fitness, dyslipidemia, impaired
glycemic control, and increased systemic inflammation. Broadly, this thesis explores how
multiple exercise modalities and nutritional supplements can be used in combination to
simultaneously alleviate several of these negative aspects of aging. This series of studies
demonstrates that, in older men, consumption of a multi-ingredient nutritional supplement
containing whey protein, creatine, vitamin D, calcium, and fish oil: A) stimulates
significant improvements in lean mass, strength, plasma lipids, and systemic
inflammation over a relatively short period of time (6 weeks) in the absence of exercise
training; and B) enhances exercise training-induced gains in strength and glycemic
control, as well as reductions in systemic inflammation. The findings of this thesis
challenge the relatively common practice of targeting individual facets of aging with
singular exercise or nutrition interventions.


title: Optimal Temperature and Catalyst Renewal Policies in a Tubular Reactor with Catalyst Decay

subject: optimal temperature, catalyst renewal policies, tubular reactor, decay, Maximum Principle

abstract:
 The optimal temperature and catalyst renewal policies which maximize the average profit over a free time period in a tubular reactor with uniform temperature and decaying catalyst for a single irreversible reaction, are sought.

 In addition, the optimal initial catalyst activity and the optimal total time have been studied.

 A numerical procedure together with theoretical developments is used to solve the problem for a more general performance index (average profit function) which takes into account the value of the desired product, the cost for the regeneration of the catalyst and the cost of the fresh catalyst.

 The problem is treated in the format of Pontryagin's Maximum Principle.

abstract: Thesis

abstract: Master of Engineering (MEngr)


title: Geological and Geochemical Analysis of Quaternary Aquifers and Aquitards, Clarington Ontario

title: Assessing Aquifer Vulnerability of Private Wells through Geological and Geochemical Analysis near the Clarington Transformer Station

contributor:
Smith, James
Geography and Earth Sciences

subject: Geochemcial, Quaternary sediments, Aquifers, Aquitard, vulnerability

abstract: Groundwater conditions beneath 11 hectares property owned by HydroOne near the southeastern edge of the Oak Ridges Moraine were assessed for contamination susceptibility using groundwater and geological information from HydroOne monitoring on-site and within one kilometre. Geological information was obtained from preexisting well records and a deep cored hole through dense glacial deposits (Newmarket Till) and through two deep regional sand aquifers (Thorncliffe and Scarborough Aquifers) into shale at 130 mbgs. The multiple data types included water levels, Tritium-Helium groundwater dating, oxygen-18 and deuterium, and major and minor ions. The water table is close to surface (<3m) and wells above 22 m depth in the highly active shallow zone show chemicals and Coliform Bacteria from human activities including roads, septics and agriculture. Shallow groundwater flows downward towards the Thorncliffe aquifer; the bottom of this most active zone is unknown due to insufficient data from deeper wells. Two private wells (100 mbgs) thought to be in the Thorncliffe aquifer contain constituents indicative of human influence. Seven of eight homeowner wells show tritium from nuclear power stations, one at detection limit. Three hypotheses are proposed to explain the susceptibility of wells in the Thorncliffe Aquifer to contamination: 1) the Newmarket aquitard is contains preferential pathways due to fractures connected to sand layers allowing deep penetration of contamination, 2) recharge can occur directly into the Thorncliffe aquifer in areas where Newmarket Till is non-existent, and 3) wells have faulty construction allowing short-circuiting to depth of contaminated shallow water down and along well casings. Based on the current data preferential pathways through the Newmarket is the most plausible hypothesis.  However, additional work to define groundwater flow paths both on and off-site as well as additional geochemical and isotopic analyses from existing and new deep wells is needed to better determine risk to residential wells.

abstract: Thesis

abstract: Master of Science (MSc)

abstract: A groundwater study was conducted in an eight square kilometre area at the southeast edge of the Oak Ridges Moraine near Oshawa, ON. It included: geology from a 130m hole through overburden (including Newmarket Till) to bedrock, groundwater age determinations and water chemistry obtained by Hydro One from 16 monitoring wells on HydroOne property (11 hectares) and 25 nearby homeowner wells, most less than 22m deep. Wells above 22m show salt and other constituents from roads, septics or agriculture and show young groundwater age. Two deep wells (100m) in the Thorncliffe Aquifer beneath the Newmarket Till also show these chemicals; one of them sampled for tritium-helium showed young age, as do some intermediate -depth wells. The pathways for young water migrating so deep are undetermined.


title: Community Paramedicine: Key descriptions of programs and training

contributor: Clinical Epidemiology/Clinical Epidemiology & Biostatistics

subject:
Community paramedicine
Community paramedic
Mobile integrated healthcare
Program
Training

abstract:
Background: Community paramedicine (CP) is an emerging form of health services delivery with the potential to reduce emergency department (ED) visits and to improve access to care.

Rationale: There is growing global interest towards CP. Studies have focused on health outcomes and cost-effectiveness, but there is no comprehensive understanding about the types of CP programs and training; this knowledge may support the development of CP programs, training, and policy.

Objectives: To describe CP programs and the skills for each program type, and to inform recommendations for CP programming and growth.

Methods: A systematic review of MEDLINE and Embase was completed in duplicate by two independent reviewers. The Mixed Methods Appraisal Tool (MMAT) was used to assess studies’ methodological quality. A full methodology is available on PROSPERO (CRD42017051774).

Results: The yield of 47 studies captured 44 unique CP programs. CP programs most often served emergency callers and individuals at risk for ED admission or readmission or hospitalization. The most common services provided were physical assessment; and assessment, referral and/or transport to community services. Training was not described by 43% of CP programs, and the mean MMAT score was three out of four criteria met. Study heterogeneity prevented meta-analysis of health outcomes.

Discussion: CP programs have adapted to various populations by providing different services and training. CP training is centred on technical skills and knowledge. Since CP often involves more client interactions and inter-professional collaboration than traditional paramedicine, CP training should also include communication and teamwork skills. Challenges to CP growth include unclear role definition, introducing new healthcare roles, and competing services.

Conclusion: Of the 44 unique CP programs, common services provided included physical assessments and assessing clients for community services. CP training was centred on technical skills and knowledge, but there should be more training on communication and teamwork skills.

abstract: Thesis

abstract: Master of Public Health (MPH)

abstract: Community paramedicine (CP) is an emerging form of health services delivery with programs established internationally. Community paramedics take on expanded paramedicine roles, including community-based health promotion and prevention activities. Studies on CP have focused on health outcomes and cost-effectiveness, but there is no comprehensive understanding about the types of CP programs and training. Through a systematic review of the literature, the goals of this thesis are to describe CP programs and the skills required for each program type, and to use findings to inform recommendations for CP program development and growth. No other literature review provides information on the components of CP programs and their training. Communities interested in CP can use the findings of this thesis to inform the development of their CP programs and training. By discussing challenges facing continued CP growth, this thesis also identifies areas for change at the program and policy levels.


title: ROBUST PATH FOLLOWING CONTROL FOR INDEPENDENTLY ACTUATED AUTONOMOUS GROUND VEHICLES WITH TRANSIENT PERFORMANCE IMPROVEMENT

contributor:
Yan, Fengjun
Mechanical Engineering

abstract: This thesis addresses the path following control of independently actuated (IA) autonomous ground vehicles (AGVs), and focuses on the constraint control and transient performance improvement. The control aim is to inhibit overshoots and eliminate steady-state errors in path following manoeuvres, and thus to reduce the possibilities of AGVs to surpass safe driving bounds. Centering on this focus, this thesis proposes a novel path-following modeling method, a novel output constraint control approach, and two novel nonlinear control strategies for transient performance improvement. The contributions of this study lie on the following five aspects: 1) A novel definition for the desired heading is proposed using the sideslip-angle compensation, to reduce the steady-state errors in path following caused by the non-zero sideslip-angle and the large/changing path curvature; 2) A novel output constraint control approach using hyperbolic projection technique is proposed to compactly restrain the lateral offset, and thus to prevent the vehicle from surpassing safe lanes; 3) A novel integral sliding mode (ISM)-based composite nonlinear feedback (CNF) technique is proposed to improve the transient performance of path following, considering the system uncertainties, disturbances and actuator saturations; 4) A novel disturbance observer-based CNF technique is proposed to improve the transient performance for path following with differential drive assisted steering (DDAS) when the active steering system is in complete failure. Corresponding comparative simulations based on CarSim-Simulink were conducted to verify the proposed modeling and control strategies in 1)-4); 5) Experiments have been conducted to verify the existence and effectiveness of the DDAS mechanism.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract: This thesis focuses on the constraint control in the path following of autonomous ground vehicles with transient performance improvement, where the system uncertainties, external disturbances and input saturations have been considered. The constraint control is used to constrain the path following errors in the safety regions, and the transient control is used to improve the transient performance. The ultimate control objective is to increase the path following accuracy and convergence speed, and thus to improve the vehicle stability, safety and ride comfort. This thesis proposed a novel desired-heading amendment to modify the traditional path following model to reduce the system overshoot, a novel output constraint strategy to constrain the lateral offset in reasonable bound, and two novel nonlinear control strategies to improve the transient performance. Also, experiments were conducted to verify the effectiveness of the differential drive assisted steering.


title: TARGET FORTIFICATION OF BREAST MILK WITH PROTEIN, CARBOHYDRATE, AND  FAT FOR PRETERM INFANTS IMPROVES GROWTH OUTCOMES: A DOUBLE-BLIND RANDOMIZED CONTROLLED TRIAL

title: TARGET FORTIFICATION FOR PRETERM INFANTS

contributor:
Fusch, Christoph
Medical Sciences

subject:
breast milk
fortification
preterm
growth
target fortification

abstract:
Background: Breast milk is an ideal source of nutrition for newborns as it provides nutrients required for growth in addition to numerous bioactive factors which help to develop an infant’s immune system. However, the macronutrient content of breast milk alone is not able to support preterm infant’s rapid growth needs and requires supplementation with fortifiers. There is strong evidence that the current practice of standard fortification (SF) may lead to nutritional deficits and consequently increases an infant’s risk of inadequate postnatal growth. Furthermore, the natural variation of breast milk composition makes it increasingly difficult to provide recommended macronutrient intakes with the SF. Individualized approaches, like adjustable fortification or target fortification (TFO), have been proposed to improve growth during hospitalization. A recent pilot trial demonstrated that TFO, which individually adjusts deficient macronutrient content after SF by analyzing the breast milk for native protein, carbohydrate and fat, is feasible in clinical practice and significantly reduces variation of macronutrient intakes.
Objectives: To compare the response of preterm infants to feedings of breast milk with either SF or SF+TFO with respect to: 1) weight at 36 weeks’ post-menstrual age and growth velocity during hospitalization; 2) head circumference, length and body composition; and 3) the relationship between preterm infant’s weight or growth velocity and their macronutrient intake factors including protein intake and protein:energy (P:E) ratio.
Methods: This was a single-center, double-blind randomized controlled trial completed at McMaster Children’s Hospital’s Level III NICU with a study period of at least 21 days. Preterm infants (n=103) born at <30 weeks of gestation and tolerating full enteral intakes of breast milk were enrolled and randomized to the Control (SF only) or Intervention (SF+TFO) groups. Native breast milk samples were collected for all infants on each study day and were analyzed for protein, carbohydrate and fat content. In the Control group, SF was provided using Enfamil (Mead Johnson, IL) human milk fortifier at the recommended dosage. In the Intervention group, after the addition of SF, modular macronutrient fortifiers were added based on analysis of the mother’s milk to reach target values based on ESPGHAN recommendations. Adjustment of the modular fortifiers was done three times per week. The primary outcomes were weight at 36 weeks’ PMA and growth velocity during the study period. Head circumference, length and body composition were also assessed at term-equivalent age. Subgroup analysis, stratified around the median protein levels after SF, also compared the growth outcomes between Control and Intervention groups. Multiple regression analysis models examined the effect of macronutrient intake factors and infant characteristics on weight, average growth velocity and daily weight gain.
Results: Infants fed with SF+TFO had significantly higher protein (p<0.001), carbohydrate (p<0.001) and fat intakes (p<0.01) in addition to higher protein:energy and carbohydrate:non-protein energy (CHO:NPE) ratios (p<0.001) compared to those fed with SF alone. The average weight at 36 weeks’ PMA and growth velocity during the 21-day study period were higher for infants in the Intervention group (p<0.001). The Intervention group had significantly higher fat-mass (p<0.05) as well as more fat-free mass than the Control group at term-equivalent age (TEA), but were still within normal limits when compared to normative data from our NICU. At TEA, infants fed with TFO also showed significantly higher change in z-scores from birth for length when compared to infants fed SF with low-protein intakes (p<0.05). Change in head circumference z-scores were not statistically significant between groups. Higher average protein intakes and P:E ratios were each positively associated with higher weight at 36 weeks’ PMA (p<0.05). Moreover, higher daily weight gain was positively associated with higher daily protein intake from the previous study day (p<0.05). The absolute difference in day-to-day macronutrient intakes, however, were not significant predictors of daily weight gain.
Conclusions: This study shows that target fortification of breast milk is promising as an individualized approach to improve the quality of nutrition for preterm infants. By addressing the variation and deficits of macronutrients that occur after standard fortification, infants were able to achieve higher body weight and faster weight gain. In the short term, target fortification may reduce the preterm infant’s risk for sub-optimal postnatal growth. These improved growth outcomes also have positive clinical implications on infant’s long-term health and development. Protein intake and the P:E ratio were identified as important factors for growth and should be considered in nutritional management and future fortification strategies for breast milk fed preterm infants.

abstract: Thesis

abstract: Master of Science (MSc)


title: Synthesis and Reactivity of Functionalised Triarylphosphines in Organic Synthesis

contributor:
McNulty, James
Chemistry

subject: synthesis, reactivity, functionalised triarylphosphines, organic, catalysts ligands, olefins

abstract:
The goal of this research was to develop alternate economic routes for the synthesis of functionalised triarylphosphines. Such species are employed as catalysts ligands in chemical synthesis and can be incorporated into designed-ylides for olefination reactions. The synthesis of the SHOP ligand, the key constituent of the Shell Higher Olefins Process for making linear alpha olefins via ethylene oligomerisation and olefin metathesis, is described using four totally new approaches. These include a Directed Ortho Metalation (DOM) approach, Copper iodide catalyzed cross-coupling, Halogen-Magnesium Exchange reaction and Diazonium salt approaches. The efficiency, in terms of overall yield and mild process conditions, make some of the routes potentially commercialisable. Additionally, a series of ortho-substitued triarylphosphines were derived to probe and modulate the reactivity of the Wittig reaction. We report that non-stabilized ortho-P-alkoxy-substituted ylides react with aromatic and aliphatic aldehydes providing (E)-olefins with high stereocontrol employing an intramolecular phenoxy and alkoxy substituent to promote (E)-olefination through betaine interconversion. In one
particular case; removal of phosphoine oxide was also achieved. Extension of this methodology was also carried out on semi-stabilized benzylic ylides, which are known for producing 1:1 mixtures of (E):(Z) olefins under classical condition. Potential applications of the methodology are also described.

abstract: Thesis

abstract: Master of Science (MSc)


title: Understanding the Inhibition of the Amyloid-β Peptide Oligomerization by Transferrin Utilizing NMR Spectroscopy

contributor:
Melacini, Giuseppe
Chemistry

subject: inhibition, amyloid-β peptide oligomerization, transferrin, NMR spectroscopy, Alzheimer's disease, senile plaques

abstract:
A hallmark of Alzheimer's disease (AD) is the accumulation of insoluble senile plaques in the brain.[1] The major component of the insoluble plaques is the amyloid-β peptide (Aβ) that is produced through cleavage of the amyloid-β precursor protein (APP).[2] It is well understood that once the monomeric Aβ is generated, it has the potential to aggregate into soluble oligomers and further into insoluble fibrils. Recently it has been proposed that early oligomers are the main toxic species in the aggregation cascade.[3] However, it has been shown that the formation of toxic early oligomers is inhibited by several endogenous plasma proteins, including albumin and transferrin (Tf). In this investigation we are focusing on the mechanism of inhibition of the Aβ early oligomerization by Tf. Specifically, we have targeted the early stages of Aβ aggregation using a deletion mutant of the Aβ peptide, i.e. the Aβ12-28 fragment, which selectively stabilizes the early Aβ oligomers. Self-association of this peptide was controlled by adding-NaCl to filtered monomeric Aβ samples and the effect of Tf inhibition on these aggregates was probed by 1H relaxation NMR experiments.[4-7] Our data shows that Tf directly targets intermediary Aβ oligomers via a coating mechanism.
1. Kirkitadze, M.D., Condron, M.M. and Teplow, D.B, JMB 2001 312;1103-1119.
2. Stefan F. Lichtenthaler and Christian Haass, JCI 2004 113(10);1384-1387.
3. Necula M., Kayed R., Milton, S. and Glabe C.G, JBC 2007 282(14);10311-10324.
4. Klement K., Wieligmann K., Meinhardt J., Hortschansky P., Richter W., and Fändrich M., JMB 2007 373;1321-1333.
5. Huang H, Milojevic J, Melacini G. J Phys Chem B. 2008 112(18):5795-802.
6. Milojevic J, Esposito V, Das R, Melacini G. JACS. 2007 129(14):4282-90.
7. Milojevic J, Esposito V, Das R, Melacini G. J Phys Chem B. 2006 110(41):20664-70.

abstract: Thesis

abstract: Master of Science (MSc)


title: Sri Lankan Discourses of Ethno-Nationalism and Religious Fundamentalism

contributor:
Rowe, Mark
Religious Studies

subject:
Sri Lanka
Discourse
Buddhism
Theravada Buddhism
Bodu Bala Sena
Siva Senai
Anthropology
Religious Studies
Religion
Mahavamsa
Ravana
Ravana Balaya
Sinhalese
Tamil
LTTE
Tamil Tigers
Xenophobia
Islamophobia
Religious fundamentalism
Nationalism
Victimhood
Victory
Transitional justice
Memorialization

abstract:
In this thesis, I argue that discourses of victimhood, victory, and xenophobia underpin both Sinhalese and Tamil nationalist and religious fundamentalist movements. Ethnic discourse has allowed citizens to affirm collective ideals in the face of disparate experiences, reclaim power and autonomy in contexts of fundamental instability, but has also deepened ethnic divides in the post-war era.
In the first chapter, I argue that mutually exclusive narratives of victimhood lie at the root of ethnic solitudes, and provide barriers to mechanisms of transitional justice and memorialization. The second chapter includes an analysis of the politicization of mythic figures and events from the Rāmāyaṇa and Mahāvaṃsa in nationalist discourses of victory, supremacy, and legacy. Finally, in the third chapter, I explore the Liberation Tiger of Tamil Eelam’s (LTTE) rhetoric and symbolism, and contend that a xenophobic discourse of terrorism has been imposed and transferred from Tamil to Muslim minorities. Ultimately, these discourses prevent Sri Lankans from embracing a multi-ethnic and multi-religious nationality, and hinder efforts at transitional justice. By shedding light on the discourses underlying popular nationalist movements, I hope to promote understanding and further post-war reconciliation between ethnic groups in Sri Lanka.

abstract: Thesis

abstract: Master of Arts (MA)


title: The Role of Toll-Like Receptor Agonist Treatment on Salmonella Infection in Macrophages

contributor:
Coombes, Brian K.
Biochemistry and Biomedical Sciences

subject: Salmonella, bacterial pathogenesis, macrophage, toll-like receptor, innate immunity, infection

abstract:
Salmonella is a Gram-negative intracellular pathogen that causes gastroenteritis and
typhoid fever in humans. Salmonella can survive and replicate within host cells and has adapted several mechanisms to evade host immune defenses. The innate immune system plays an important role as a first-line of defense against pathogens such as Salmonella,
and is mediated in part by toll-like receptors (TLRs). TLRs recognize fundamental components of pathogenic microorganisms and activation of TLRs leads to downstream signaling cascades eventually resulting in the expression of pro-inflammatory cytokines (4) and also has a role in activating adaptive immunity through presentation of antigens to lymphocytes (86). There are several lines of evidence that suggest that TLR activation may have therapeutic potential in therapies against infectious disease and several TLR agonists have been shown to protect against both bacterial and viral infection in mice (7; 8; 38; 66; 75; 84; 89; 121). To understand how TLR-agonist treatment of host cells affects Salmonella pathogenesis, RAW 264.7 murine macrophages were treated with the TLR agonists liposaccharide (LPS), poly(I:C), peptidoglycan, and CpG-ODN. Treatment of macrophages with all TLR-agonists results in increased phagocytosis of Salmonella compared to control-treated macrophages. These increases in phagocytic activity, however, do not enhance macrophage anti-microbial activity, since Salmonella infection of TLR-treated macrophages results in increased intracellular replication compared to control-treated cells. Infection with Salmonella mutants indicates that increased intracellular replication of Salmonella in TLR-treated macrophages is dependent on a functional SPI-2 type III secretion system. This also indicates that there
was not a generalized defect in macrophage anti-bacterial function. These data exemplify
how interactions between macrophage defense mechanisms and bacterial virulence factors can result in evasion of the innate immune response. Studying how TLR-agonist treatment affects Salmonella pathogenesis will give us a better understanding of the host-pathogen relationship and may provide insight into novel strategies to fight intracellular microorganisms.

abstract: Thesis

abstract: Master of Science (MSc)


title: Investigation of the BldB Homologues of Streptomyces Coelicolor: Regulators of Development and Antibiotic Production

contributor:
Nodwell, Justin R.
Biochemistry and Biomedical Sciences

subject: BldB homologues, Streptomyces Coelicolor, regulators, development, antibiotic production, bioactive compounds

abstract:
The Streptomyces are invaluable as a natural source of antibiotics and other bioactive compounds used in medicine and agriculture. S. coelicolor is the model streptomycete, and is studied for its complex secondary metabolism and multicellular life cycle. The subject of this work is bldB, a gene essential for development and antibiotic production in S. coelicolor, and one of its many homologues, located in the abaA antibiotic regulatory locus. The aim was to study the transcriptional regulation of bldB using a luminescent reporter, and investigate the role of each of the genes in the abaA cluster in regulation of antibiotic production, in order to understand the function and mechanism of action of bldB and its homologues. Individual deletion of each of the four genes in the abaA cluster resulted in varying effects on production of the antibiotic CDA. The bldB homologue, SCO0703, was shown to be a positive regulator of CDA, as the null mutant was severely defective in CDA production. It was found that bldB is expressed in most other bld developmental mutants, with the exception of bldD. There was no direct interaction observed between BldD and the bldB promoter, and possible mechanisms of
indirect regulation are proposed.

abstract: Thesis

abstract: Master of Science (MSc)


title: THE DEVELOPMENT OF SHYNESS FROM CHILDHOOD TO ADULTHOOD:  SUBTYPES, BIOLOGICAL MECHANISMS, CORRELATES, AND OUTCOMES

contributor:
Schmidt, Louis
Psychology

subject:
Shyness
EEG
Development
Theta
ERP
P3
Social exclusion
Sociability

abstract: Shyness is a personality trait that is stable across time and situations in some individuals.  While childhood shyness is a risk factor for later mental health and emotional problems, not all shy children grow up to have these problems. This thesis examined subtypes of shyness identified based on the temporal stability of shyness and based on levels of sociability and their corresponding outcomes, as well as the roles of social and biological contextual factors.  Chapters 2-4 comprise the empirical studies.  In Chapter 2, I report three shyness trajectories from middle childhood to adulthood (ages 8 to 30-35). Relative to a low-stable non-shy trajectory, children with an increasing, but not a decreasing, shy trajectory were at higher risk for clinically significant social anxiety, depression, and substance use, and were hypervigilant to angry faces in adulthood.  Chapters 3 and 4 then report electrocortical correlates and mechanisms during the processing of non-social auditory novelty and social exclusion across children, adolescents, and adults with varying levels of shyness and sociability.  Chapter 3 established that shyness, but not sociability, was related to the P300 ERP in processing non-social auditory stimuli in both 10-year-old children and adults, in support of the notion that shyness and sociability are independent personality dimensions.  Findings on subtypes of shyness also showed that children characterized by conflicted shyness (with high levels of both shyness and sociability) reported higher neuroticism, but this relation was mediated by increased P300 amplitudes to processing background stimuli.  Finally, Chapter 4 reports that individuals characterized by conflicted shyness who exhibited high theta EEG spectral power to social exclusion were most fearful of negative evaluation, irrespective of age.  Also, conflicted shy adolescents who showed high theta spectral power to social exclusion were most likely to engage in substance-use.  These findings highlight that there is much heterogeneity in shyness, and that shyness is not directly related to adverse mental health outcomes.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract: Shyness is a personality trait that is stable across time and situations in some individuals.  Past research suggests that shy children exhibit more internalizing problems, including anxiety and depression, compared to their non-shy counterparts.  However, the development of shyness has not been studied beyond adolescence, and the biological and social factors that contribute to adverse developmental pathways and outcomes related to shyness are not well understood.   The goal of this thesis was to understand the mental health outcomes of shy individuals by examining different subtypes of shy individuals.  To this end, this thesis first demonstrated how shyness unfolds across the first four decades of life to shape adult mental health outcomes in a cohort of individuals. Second, this thesis examined how neural responses to threatening social and non-social contexts related to the socioemotional outcomes across children, adolescents and adults with varying levels of shyness.


title: Hardenability Improvements and Rate-Limiting Reactions During Hot-Dip Galvanizing of High-Mn Dual-Phase Steels

contributor:
McDermid, Joseph R.
Materials Science and Engineering

subject: hardenability improvements, rate-limiting reactions, hot-dip galvanizing, high-Mn, dual-phase steels, reduction, oxide

abstract:
 Intercritically annealed steels, such as dual-phase steels, have found widespread use in automotive structural components due to their high strength and ductility. Elements such as Mn, Al and Si, added to improve the mechanical properties are selectively oxidized during heat treatment and limit the ability of the alloy to be reactively wet during continuous hot-dip galvanizing. Subsequently, a limit has been placed on the amount of alloy which can be used if the steel is to be subsequently galvanized. The specifics of this limit have not been explored in detail, nor has the mechanism of decreased wettability been well demonstrated in the literature other than to say that the galvanizing reaction is limited by oxides on the surface.

 Using a force balance, it is shown that the presence of MnO on the surface of
steels greatly reduces the wettability with a typical galvanizing bath (Zn-0.2wt%Al, Fe-saturated, 460°C). Furthermore, it was determined that this is caused by the additional and rate-limiting step of aluminothermic reduction of the oxide layer with the bath Al, required for subsequent inhibition layer formation. By using a low pO2 during annealing, the wettability was improved by reducing the thickness of the MnO layer when compared to intermediate and industrially common values of pO2. Using a high pO2 also resulted in improved wettability since the internal oxide which was formed did not reduce the wettability since it was not exposed to the bath alloy.

 Improvements in hardenability were also explored via dilatometry showing that the formation of bainite is delayed with increasing Mn content, as well as a decrease in transformation temperatures from γ during cooling (i.e. Ms and Bs). At ~5wt% Mn, only the the transformation to αM could be observed. This opens the door to
higher strength, galvanized steels - as well as possibly galvanized martensitic steels.

abstract: Thesis

abstract: Master of Applied Science (MASc)


title: Examining microbial carbon source cycling in arsenic contaminated Bangladesh aquifers through lipid and isotopic analyses

contributor:
Slater, Greg
Geography and Earth Sciences

abstract:
Understanding how organic matter is microbially cycled through Bangladesh aquifers is a key component in understanding the spatial and temporal patterns of arsenic release into groundwater occurring on wide regional scales. There is a current gap in the literature for how overall microbial carbon cycles are functioning in Bangladesh aquifers, how these microbial metabolisms factor into arsenic release, including methodology as to approach these questions in situ. This research aimed to provide insight into carbon sources and cycling of the microbial communities in Bangladesh aquifers through a complimentary applied suite of lipidomic, isotopic and inorganic analytical approaches on in situ sediments and groundwater from Bangladesh aquifers.
Through radiocarbon analyses of phospholipid fatty acids (PLFA's), bacterial populations in a shallow Holocene-aged and high arsenic aquifer were found to be predominantly utilizing younger organic matter as their carbon source rather than older sedimentary carbon. At the sites studied, the sources of younger organic matter that coincide with zones where increased reductive dissolution of iron and arsenic release is occurring were consistent with human and livestock waste identified through sedimentary sterol distributions (phytosterols and coprstonaol) and Cl/Br mass ratios in groundwater.  Since poor sanitation is widespread across Bangladesh, sewage-derived waste should be considered a prevalent potential microbial carbon source is these systems. An examination of sediment- versus groundwater-associated microbial communities in Bangladesh aquifers (through PLFA analysis) suggested that the former is 5-6 orders of magnitude more abundant than the latter. Archaeal communities, examined through both groundwater methane and sedimentary archaeal lipid (archaeol and glycerol dialkyl glycerol tetraether (GDGT)) analysis, are suggested to be highly active (depths 5-240 m) but to varying degrees in Bangladesh aquifers. Methanogenesis, dominantly being carried out through CO2 reduction, appears to be spatially associated at some sites with zones of iron/arsenic reductive dissolution in the Bangladesh aquifers.  The analytical approaches and conceptual frameworks applied throughout this dissertation have been demonstrated to be effective strategies to understand how microbial carbon cycling is occurring at a community level and intimately involved in arsenic release.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)


title: PURE Frailty - Prognostic Importance of Frailty and Multi-Morbidity in Low-, Middle-, and High-Income Countries

title: Global Patterns of Frailty and Multi-Morbidity

contributor:
Leong, Darryl
Global Health

subject:
Frailty
Multi-morbidity
PURE
Socioeconomic status
Index
Indices
Country Income

abstract: BACKGROUND. Frailty is a syndrome characterized by a decreased resistance to stressors, leading to increased vulnerability to adverse outcomes, including mortality. Multi-morbidity refers to the presence of two or more chronic diseases, and is associated with increased risk of adverse health outcomes. Most of the literature in frailty is based on older people (65+ years) living in high income countries. OBJECTIVE. To compare the predictive ability of three frailty indices for all-cause and one-year mortality among high- (HIC), middle- (MIC), and low- income country (LIC) participants; and to assess the mortality risk associated with multi-morbidity. METHODS. Using data from the Prospective Urban and Rural Epidemiological (PURE) study, we developed three indices using different definitions of frailty (one phenotypic frailty index; two cumulative deficit indices). All indices were tested for predictive ability for mortality both individually and with multi-morbidity. RESULTS. Prevalence of phenotypic frailty was greatest in LIC (8%), intermediate in MIC (7%), and lowest in HIC (4%). Multi-morbidity was most prevalent in HIC (20%), intermediate in MIC (15%), and lowest in LIC (13%). Increased frailty was associated with greater mortality risk using all frailty indices (e.g. HR (95% CI) of 2.63 (2.35-2.95) for the phenotypically frail relative to the robust). At each frailty level, mortality risk was higher within one year of baseline measurement than afterwards, and increased if it was accompanied by concurrent multi-morbidity (e.g. HR of phenotypic frailty increases from 2.27 (1.96-2.62) to 5.08 (4.34-5.95) if accompanied by multi-morbidity). CONCLUSION. All frailty indices predicted mortality. This study is unique in evaluating the prognostic ability of frailty indices in middle-aged adults across HIC, MIC, and LICs.

abstract: Thesis

abstract: Master of Science (MSc)


title: The effects of high-intensity interval training on mental health and the acute inflammatory response

contributor:
Heisz, Jennifer
Kinesiology

abstract: Mental illness is on the rise in university students, with approximately one third of all students experiencing depression. One way that depression can arise is through chronic stress, a common experience for university students. Exercise has been shown to buffer the effects of chronic stress and improve depression. One hypothesis suggests that exercise improves depression by decreasing pro-inflammatory cytokines at rest; however, it is unclear what role exercise intensity plays. Prior work has shown that over 6 weeks of training, HIIT buffered the development of depressive symptoms, but increased stress, anxiety, and resting-state pro-inflammatory cytokines IL-6 and TNF-a. However, it is unknown how HIIT influenced the acute inflammatory response, and if adaptations in this response can improve mood. The aim of this study was to examine the effect of HIIT on mood and both resting state and acute inflammation over a training period of 9 weeks. Fifty-two sedentary university students (63% females), aged 18-30 (M±SD: 19.9±2.2 years) were randomized into one of two groups: 1) high-intensity interval training (HIIT), consisting of exercise three times per week, or 2) sham-exercise (controls), who were instructed to remain sedentary during the intervention. The sham-exercise group was given a cover story that they were part of an “acute” exercise group, and thus believed they were also assigned to an exercise condition. Mood was tracked weekly using surveys for depression (BDI-II), anxiety (BAI), and stress (PSS). Levels of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β) were measured using serum draws at rest and immediately after the completion of a peak power output test at the beginning, middle, and end of the training period. Both groups decreased in depression and anxiety across the nine-week training period (p < 0.001), and decreased in stress during the first three weeks of training (p =0.07), suggesting that HIIT exercise does not improve mood to a greater extent than a sham-exercise condition. Interestingly, at the end of training, HIIT had higher levels of IL-6 compared to controls (p = 0.03), and this may be why one reason why the HIIT group did not improve mood over controls.  Despite an increase in overall IL-6 levels at rest, nine weeks of HIIT attenuated the acute pro-inflammatory response to exercise compared to controls, who experienced an elevated IL-6 response (p = 0.04) and TNF-α response (p = 0.003). Taken together, these results suggest that HIIT exercise impacts the inflammatory response both at rest and in response to maximal exercise, but it may not be an effective intensity of exercise for improving mental health outcomes in sedentary individuals.

abstract: Thesis

abstract: Master of Science in Kinesiology


title: ESTABLISHING THE ROLE OF MESENCEPHALIC ASTROCYTE-DERIVED NEUROTROPHIC FACTOR (MANF) AND CEREBRAL DOPAMINE NEUROTROPHIC FACTOR (CDNF) AS THERAPEUTIC TARGETS FOR BIPOLAR DISORDER

title: MANF AND CDNF AS THERAPEUTIC TARGETS FOR BIPOLAR DISORDER

contributor:
Mishra, Ram K
Neuroscience

subject:
Neuroscience
Bipolar Disorder
SH-SY5Y
Lithium
Valproic acid

abstract: Bipolar disorder (BD) is a chronic mood disorder affecting ~1-2% of the global population, characterized by cycling moods of mania and depression. The exact pathogenesis of BD is unknown; however, it has been established that endoplasmic reticulum (ER) stress plays an important role. It is known that BD patients have abnormal activity and expression of ER stress proteins in several brain regions. There exists a need for a definitive diagnostic test for the early detection of BD as it is often misdiagnosed for other conditions including unipolar depression and schizophrenia. Understanding the underlying mechanisms and therapeutic targets being used by BD treatments will be helpful in establishing a diagnostic test. The current gold standard for BD treatment includes Lithium (LiCl) prescription, along with other mood stabilizers such as Valproic acid (VPA) and antipsychotics such as Olanzapine. Current therapies only relieve symptoms and are unable to stop disease progression. Neurotrophic factors (NTFs) are naturally occurring proteins that are responsible for the maintenance, differentiation, and survival of neurons. Cerebral dopamine NTF (CDNF) and Mesencephalic astrocyte-derived NTF (MANF) belong to a novel class of NTFs specific to dopaminergic neurons. This study investigated the role of CDNF and MANF as therapeutic targets for bipolar disorder in SH-SY5Y cells and Sprague Dawley rats, as well as determining the endogenous mRNA levels of CDNF and MANF in BD patients. We demonstrated that common BD mood stabilizers – LiCl and VPA – significantly increased the mRNA expression of MANF and CDNF in vitro. Additionally, we also established that these mood stabilizers alter the NTFs expression in different rat brain regions including pre-frontal cortex (PFC) and cortex. These findings suggest that BD drug treatments potentially act via NTFs in order to relieve symptoms. Thus it highlights the importance of further investigating the interaction between neurotrophic factors and bipolar disorder.

abstract: Thesis

abstract: Master of Science (MSc)


title: The genetic and functional characterization the tumour suppressor ivp-3 in Caenorhabditis briggsae

title: The genetic and functional characterization of ivp-3

contributor:
Gupta, Bhagwati
Biology

subject: Developmental Biology, Evolution, Genetics, Molecular Biology, C. elegans, C. briggsae, Tumour suppressor

abstract: A Thesis Submitted to the School of Graduate Studies in the Partial Fulfillment of the Requirements for the Degree Master of Science

abstract: Caenorhabditis elegans and one of its close relatives, Caenorhabditis briggsae, are animal models that are commonly used for comparative studies to understand the evolution of developmental mechanisms and gene function. Although the two species appear nearly identical morphologically, comparative genomic analyses have revealed interesting differences between the genomes. Whether such differ- ences contribute to changes in developmental mechanisms and signalling pathways is an active area of research. One of the most well studied phenotypes associated with C. elegans signalling pathways are those that affect the specification of vulval tissue. Within the system of vuval development, mutants that exhibit the Mul- tivulva (Muv) phenotype are important as they show inappropriate divisions of vulva cells, which model tumour formation. Comparing gene function in different species genetic backgrounds can lead to an understanding of how genetic differ- ences contribute to different responses in cancer development. Genetic screens, conducted in our laboratory, yielded several genes whose loss of function results in a Muv phenotype and identified a novel regulator of C. briggsae vulval devel- opment, Cbr-ivp-3. Using the nematode C. briggssae as experimental system, we have characterized the tumour suppressor gene, Cbr-ivp-3, which impacts cell sig- nalling and cell division. I have carried out molecular genetic analyses of ivp-3 in both C. briggsae and C. elegans and have begun to characterize the functional role of Cbr-ivp-3. The findings in this thesis suggest that Cbr-ivp-3 is functioning to negatively regulate EGF/Cbr-lin-3.

abstract: Thesis

abstract: Master of Science (MSc)

abstract: The nematodes Caenorhabditis elegans and Caenorhabditis briggsae, are commonly used for comparative studies to understand the evolution of developmental mechanisms and gene function. Although both species appear morphologically similar, comparative genomic analyses reveal differences between genomes. Comparing gene function in different genetic backgrounds can lead to an understanding of how genetic differences contribute to different responses in cancer development. Genetic screens have yielded several genes whose loss of function results in a Multivulva phenotype, showing inappropriate division of vulva cells, modeling tumor formation. We have carried out molecular genetic analyses of ivp-3, a novel regulator of C. briggsae vulval development, in both species and have found that Cbr-ivp-3 is regulating vulva development by negatively regulating EGF/Cbr-lin-3.


title: SINGLE VERSUS MULTIPLE RED BLOOD CELL UNIT TRANSFUSION STRATEGIES

contributor:
Heddle, Nancy
Crowther, Mark
Cook, Richard
Hsia, Cyrus
Health Research Methodology

abstract:
Historical practice supported the transfusion of multiple units of red blood cells (RBCs) successively.  Recent recommendations from transfusion medicine experts now support transfusion of single units of RBCs with reassessment before transfusing successive units.  Two systematic reviews of the literature were performed to determine if A) transfusion guidelines and review articles recommended either strategy and B) if studies directly support the benefit of transfusion.  A lack of concordance in recommendations in the published literature was found and in addition to a lack of evidence supporting single unit transfusion strategies.
A survey of transfusion medicine experts demonstrated that while most agreed on single unit transfusion strategies for stable inpatients, variability in practice was seen in outpatients and patients with comorbidities.  Common elements were seen in what constitutes reassessment which may be useful to practicing clinicians.
A conceptual flow diagram was developed to outline the factors that might influence the decision to use a single or multiple unit transfusion strategy and outcomes important to assess.  The flow diagram was then used to guide an exploratory analysis to determine if defining single and multiple unit cohorts retrospectively, baseline characteristics could be collected, and to determine what outcomes could be assessed.  This then led to the design of a retrospective study that would assess: In adult (age ≥18) inpatients at tertiary care hospitals in HHS and SJHH between January 1, 2010 to December 31, 2016 who were transfused RBCs during their first hospitalization, is there a difference in the gap time between the first and second transfusion episode depending on whether the patient was transfused a single unit or multiple units during their first transfusion episode?
The findings from this study may be hypothesis generating to develop future prospective studies to determine if single unit transfusion strategies have benefit.

abstract: Thesis

abstract: Master of Health Sciences (MSc)


title: The Molecular Structure of Human Red Blood Cell Membranes from Highly Oriented, Solid Supported Multi-Lamellar Membranes

subject:
membrane biophysics
red blood cell membrane
X-ray diffraction
molecular structure

abstract: There are various techniques that are used to study the interactions between drugs and cells. However, the interaction between a drug and the cell membrane – the barrier between inter- and intracellular medium - is difficult to determine and is the focus of current research. Various common drugs, such as aspirin and cortisone, have been shown to have a significant effect on the membrane structure. While those investigations study the interaction between drugs and artificial membranes, i.e. simple lipid bilayers, their impact on native cell membranes is challenging. Due to the complex structure of a cell membrane and the cell itself, it is difficult to separate cellular lipid bilayers from other cell compartments and the cytoskeleton. This thesis presents a new protocol that allows to extract the membranes from red blood cells (RBCs) and to prepare highly ordered multi-lamellar stacks of these membranes on silicon wafers. Human RBC ghosts were prepared by hemolysis. The name of these empty RBC vesicles originates from their appearance under the microscope. Although the original preparation protocol by Dodge, Mitchell and Hanahan was a remarkable step in the development of membrane proteomics and lipidomics, modifications were necessary. The morphology of the vesicles, the hemoglobin concentration and the presence of the cytoskeleton were analyzed using fluorescence microscopy and Ultraviolet spectroscopy. Due to the observed complex structure and the present actin filaments, the ghost solution was sonicated before applied onto silicon wafers and slowly dried and annealed over several days. The vesicles fuse on the silicon substrate, resulting in highly ordered multi-lamellar stacks of RBC membranes. X-ray diffraction was used to analyze the structure of these membranes. Multiple series of well-developed Bragg peaks were observed indicating a high degree of orientation of the membranes. These series can be identified as signals from liquid ordered (lo), liquid disordered (ld) lipids and coiled-coils peptide domains. There was evidence that the lipids form nanometer sized domains and the collected data allows presenting a detailed picture of the domain- and membrane structure. The RBC ghosts allows to analyze the effect of drugs on the structure of a native membrane. The effect of aspirin, which is one of the most common drugs from the class of non-steroidal anti-inflammatory drugs (NSAID's), was investigated. NSAID's are known to interact with cell membranes. However, the data presented in this thesis indicates that aspirin incorporates preferably into the head group region of the liquid ordered lipid domains leading to a fluidification of these membrane domains.

abstract: Canada Foundation for Innovation (CFI),  Natural Sciences and Engineering Research Council of Canada (NSERC), McMaster University


title: Clay-Coated Polyurea Microcapsules for Controlled Release

contributor:
Stöver, Harald D. H.
Chemistry

subject: clay coated polyurea, microcapsules, controlled release, membrane diffusion systems, polymer

abstract:
 Polyurea microcapsules are micron-scale, hollow polymer spheres commonly used in agriculture to encapsulate pesticides for controlled diffusive release onto target crops. Diffusion of these active materials through a protective polymer wall offers a safer and more effective method of delivery compared to the direct spraying of crops with toxicants. The approach we are taking to control the release rate is to coat pre-formed porous polyurea capsules with a separate release-controlling outer layer. This allows us to separately optimize the load-bearing capsule wall and the release control layer, an approach commonly used in other membrane diffusion systems.

 Montmorillonite clay incorporation into polymer matrices can reduce membrane permeability by forcing diffusants to take a tortuous path around the stacked silicate sheets. Effective formation of clay-polyurea composites requires the delamination of clay particles into thin sheets with high aspect ratios, and their incorporation into polyurea microcapsules either during interfacial polymerization, or post-polymerization. The net negative surface charge of the silicate sheets should facilitate their initial binding to the cationic polyurea surfaces, as well as subsequent binding of polycations to the clay-coated polyurea capsules to create layer-by-layer (LbL) capsule assemblies with
decreasing release rates of internal materials.

 The main focus of this project is to gain a fundamental understanding of montmorillonite clay and polyurea microcapsules, and the development of a model polyurea composite capsule for release rate analysis. Emphasis will be placed on the reduced permeability of microcapsules coated with clay by LbL assembly post-polymerization, followed by an exploration of further layering with polycations.

abstract: Thesis

abstract: Master of Science (MSc)


title: FORSAKING PAUL BUNYAN: A GENDERED ANALYSIS OF FORESTRY COMPANY SAFETY POLICY ON VANCOUVER ISLAND IN THE MID-TWENTIETH CENTURY

contributor:
Frager, Ruth
History

subject:
History
Canada
British Columbia
Forestry
Safety
Gender
Masculnity
Postwar

abstract: This thesis examines the safety policies implemented by three British Columbia forestry companies between 1943 and 1968. Companies sought to increase the efficiency of their operations by reducing the number of compensable accidents and fatalities among their workers. These companies, along with other member-companies in the BC Loggers Association and BC Lumber Manufacturers Association, took the lead in creating a safety regime in BC’s coastal forest industry, but were joined in the endeavor by the provincial Workmen’s Compensation Board (WCB) and the forest workers’ union, the International Woodworkers of America. In order to obtain worker consent for new safety programs, companies targeted worker’s masculinity. Workers who had seen themselves as following in the footsteps of the rugged and independent Paul Bunyan were a problem for companies who wanted to create a sense of mutual responsibility for safety across their entire workforce. Safety programs, accordingly, were heavily gendered and promoted a white, hetero-patriarchal masculinity. This masculine ideal was intended to reduce worker’s willingness to take unnecessary risks. In the later years of this study, companies obtained greater control over the work process by introducing tight controls over the work process in the name of safety. Overall, efforts by companies, as well as the union and the WCB, were successful in reducing many of the hazards of working in forestry by the later 1960s. However, many of the dangers in this industry persist into the twenty-first century.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract: This thesis looks at the safety policies implemented by three British Columbia forestry companies between 1943 and 1968. Companies sought to increase the efficiency of their operations by reducing the number of compensable accidents and fatalities among their workers. They took the lead in creating a safety regime in forestry, but were joined in the endeavor by the provincial Workmen’s Compensation Board (WCB) and the forest workers’ union, the International Woodworkers of America. Safety programs were heavily gendered, with companies promoting a hetero-patriarchal masculinity in an attempt to reduce worker’s risk-taking. Efforts by companies, as well as the union and the WCB, were successful in reducing many of the hazards of working in forestry. However, many of the dangers in this industry persist into the twenty-first century.


title: Targeting Glutamate in Prostate Cancer-Induced Depression

contributor: Medical Sciences (Division of Physiology/Pharmacology)

subject:
Prostate Cancer
Depression

abstract: Affecting one in every eight Canadian men, prostate cancer is the most common type of cancer among males. As with other forms of cancer, men with prostate cancer are much more likely to develop comorbid depression than the general population without cancer diagnoses. Depression negatively affects these men’s quality of life and increases mortality rates among cancer patients. Therefore, effective therapies to manage depression in this unique subpopulation are needed. This project sets out to assess the efficacy of glutamate-targeting drugs as antidepressants. The major excitatory neurotransmitter in the central nervous system, glutamate is released in excessive quantities by cancer cells. It is thought that this abundance of glutamate leads to excitotoxicity and neurodegeneration, affecting neurons in important regions of the brain relating to mood and mood regulation. A validated mouse model of depression was established using RM1 murine prostate cancer cells. This model was then used to test the properties of three drugs: sulfasalazine (SSZ), (S)-4-carboxyphenylglycine ((S)-4-CPG), and 2,3-dioxo-6-nitro-1,2,3,4-tetrahydro-benzo[f]quinoxaline-7-sulfonamide (NBQX). Results show that these drugs were able to improve depressive-like behaviours and symptoms to varying degrees, at least partially reversing the negative effects of tumours. This project showed that disrupting glutamate release and/or signaling could be an effective approach for an antidepressant therapy or adjuvant in prostate cancer patients.

abstract: Thesis

abstract: Master of Science (MSc)

abstract: Prostate cancer affects one in every eight Canadian men. Cancer patients are at a much higher risk of developing depression than the rest of the population. Unfortunately, current antidepressants are limited in their ability to improve depressive symptoms in cancer patients. Therefore, this project sets out to identify new options for treating depression in prostate cancer patients. Glutamate is a signalling molecule that is released in abundance by cancer cells and is largely responsible for communication between neurons in the central nervous system. This project showed that limiting the amount of glutamate released by cancer cells and limiting glutamate-based signaling improves depressive-like symptoms in mice with prostate cancer tumours. These results suggest that targeting glutamate could be an effective antidepressant therapy in the cancer population.


title: The Antibacterial Activity of Silicone-Polyether Surfactants

contributor:
Brook, Michael A.
Biomedical Engineering

subject: nonionic silicone polyether surfactants; antibacterial; microbial adhesion; wetting; interfacial chemistry; cytophobic

abstract:
The increase in microbial resistance to antibiotics underscores the need for novel antibacterial surfaces, particularly for silicone-based implants, because the hydrophobicity of silicones has been linked to undesirable microbial adhesion and biofilm formation. Unfortunately, current strategies for mitigation, such as pretreatment of surfaces with antiseptics/antibiotics, are not consistently effective. In fact, they can facilitate the prevalence of resistant pathogens by exposing bacteria to sublethal concentrations of biocides. Therefore, scientific interest has shifted to preventing initial adhesion (prior to surface colonization) by using surfactants as surface modifiers.
Accordingly, Chapter 2 studied the bioactivity of ACR-008 UP (an acrylic-terminated superwetting silicone surfactant) after it was copolymerized in increasing weight percentages with butyl methacrylate (BMA) and/or methyl methacrylate (MMA). Interestingly, copolymers of 20 wt % ACR showed at least 3x less adhesion by Escherichia coli BL21 (E. coli) than any other formulation. This was not a consequence of wettability, which followed a parabolic function with ACR concentration: high contact angles (CA) with sessile water drops were observed at both low (< 20 wt %) and high (> 80 wt %) concentrations of ACR in materials.  The CA at 20 wt % ACR was 66°. The lack of E. coli adhesion was ascribed to surfactant-membrane interactions; hence, the antibacterial potential of compounds related to ACR was further probed.
Chapter 3, therefore, examines the structure-activity relationships of nonionic silicone polyether surfactants in solution. Azide/alkyne click chemistry was used to prepare a series of eight compounds with consistent hydrophilic tails (8- 44 poly(ethylene glycol) units), but variable hydrophobic heads (branched silicones with 3-10 siloxane linkages, and in two cases phenyl substitutions). The compounds were tested for toxicity at 0.001 w/v %, 2.5 w/v % and their critical micelle concentrations (CMCs), against different concentrations of E. coli in a 3-step assay. Surfactants with smaller head groups had as much as 4x the bioactivity of larger analogues, with the smallest hydrophobe exhibiting potency equivalent to SDS. Smaller PEG chains were similarly associated with higher potency. This data suggests that lower micelle stability, and the theoretically enhanced permeability of smaller silicone head groups in membranes, is linked to antibacterial activity. The results further demonstrate that the simple manipulation of nonionic silicone polyether structures, leads to significant changes in antibacterial action.
To ensure similar results were achievable when such surfactants are immobilized on surfaces, 8 compounds with shorter, ethoxysilylpropyl-terminated PEG chains, and branched or linear hydrophobes, were incorporated into a homemade, room temperature vulcanization (RTV) silicone (Chapter 4). The materials, containing 0- 20 wt% surfactants) were then tested for contact killing and cytophobicity against the same E. coli strain. Elastomers modified with 0.5- 1 wt% of (EtO)3Si-PEG- laurate, and separately (EtO)3Si-PEG-tBS, were on average 2x more hydrophilic relative to controls (103°) and differed in their wettability by ~40°, yet both were anti-adhesive; a ~30-fold reduction in adhesion was seen on modified surfaces relative to the control PDMS. Additionally, the (EtO)3Si-PEG-tBS surface demonstrated biocidal behavior, which further highlighted the importance of surfactant chemistry- not just wettability- in observing a specific antibacterial response (if any).
Based on the data collated from each Chapter, silicone surfactants seem to have great potential as bioactive agents and warrant further systematic investigations into their mechanisms of action. In so doing, their chemistry may be optimized against different microbes for a variety of applications. In particular, their potential to create non-toxic, cytophobic silicones is particularly encouraging, given the need for anti-adhesive, biofilm preventing material surfaces.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)