title: MACHINABILITY ANALYSIS OF ALUMINUM-CAST IRON (AlSi-GCI) BIMETALLIC COMPONENTS THROUGH EXPERIMENTAL AND NUMERICAL STUDIES

contributor:
Veldhuis, Stephen
Mechanical Engineering

abstract: This thesis includes experimental and numerical investigations to study the machinability of the dry finish turning of an AlSi-GCI (JIS ADC 12- ASTM A48 class 40) bimetallic workpiece with CBN cutting tools by studying tool life, wear behaviour, cutting forces, and workpiece surface roughness.  This involved the development of a novel experimental setup that captured the fluctuating cutting forces associated with bimetal parts on the cutting tool. In addition, a numerical finite element method (FEM) model was also developed to investigate the thermo-mechanical behaviour of the CBN cutting tool and simulate the bimetal turning process under different cutting conditions. Finally, a study to reduce the cutting forces was conducted using Taguchi’s design of experiment (DOE) approach, which was studied numerically with FEM and validated experimentally. This was done to serve as a model approach that can be applied to study unique machining conditions in the future. The findings of the machinability study comparing two different tool geometries are presented along with the results of the machinability improvement study.

abstract: Dissertation

abstract: Master of Applied Science (MASc)


title: Running Amuq with Obsidian

title: A study on supra-regional socio-economic relationships in the Near East as seen through obsidian consumption practices in the Amuq Valley (S.E. Turkey) (ca. 6000-2400 B.C.E.)

contributor:
Carter, Tristan
Anthropology

subject: The Amuq Valley, Near East, obsidian consumption, XRF, chemical characterization, techno-typological analysis, supra-regional connectivity, socio-economic relationships, long distance trade, Northern Levant, deep-time chronology.

abstract: Southern Turkey’s Amuq Valley has been described as a point of convergence bridging distant regions within the ancient Near East. Through an in depth techno-typological and chemical characterization study of 290 obsidian artefacts, this research details changes in deep-time patterns of obsidian use from the Late Neolithic to Early Bronze Age (6000 BCE – 2400 BCE), arguing that shifting traditions of consumption reflect socio-economic developments both within and beyond the Northern Levant. These artefacts come from the three sites of Tell al-Judaidah, Tell Dhahab and Tell Kurdu, the material excavated during the 1930’s by the University of Chicago’s Oriental Institute. Methodologically raw material sourcing was achieved using energy dispersive X-ray fluorescence spectroscopy (EDXRF) in the well-established McMaster XRF Lab [MAX Lab]. With these artefacts’ raw materials all being exotic to the Amuq Valley, originating from various outcrops in Cappadocia, the Lake Van region and Transcaucasia (Turkey and Armenia), over 1000km away, this study not only offers new insight into how Amuq Valley communities engaged in long-distance  relations, but also contributes to a larger, deep-time regional study of obsidian consumption as a proxy for understanding significant shifts in Near Eastern socio-economics, from hunter-gatherers to the earliest states. In turn, this study, by employing an Annales school framework to consider practice over deep time at the local and supra-regional level further contributes to an ‘archaeology of the long-term’.

abstract: Thesis

abstract: Master of Arts (MA)

abstract: This research involved the chemical analysis of 290 artefacts of archaeological obsidian – a naturally occurring substance made of crystallized lava - as a means of studying ancient exchange systems in the Near East. More specifically, this study covers archaeological periods from 6000 B.C.E. (Late Neolithic) to 2400 B.C.E. (Early Bronze Age) in the Amuq Valley region of southern Turkey. These artefacts were procured during excavations under the Oriental Institute Museum (University of Chicago) beginning in the 1930s. All artefacts are exotic to the Amuq Valley from several known obsidian outcrops in Anatolia (Turkey), some over 1000km away. Analysis was conducted using X-ray fluorescence (XRF) to match each artefact to its geological origin thereby identifying the range of exotic materials were exchanged across long-distances. The goal of this research was to uncover social and/or economic dynamics of the Amuq Valley through deep-time with regards to the greater obsidian trade network of the Near East.


title: The role of resting mast cells in the survival of myenteric neurons in a primary longitudinal muscle-myenteric plexus & bone marrow-derived mast cell co-culture system

contributor:
Forsythe, Paul
Medical Sciences

subject:
Enteric nervous system
Mast cells
Myenteric plexus
BMMC
Excitotoxicity
Kynurenine Pathway

abstract:
The enteric nervous system (ENS) is an incredibly complex neural network that is extensively integrated within the neuroimmunoendocrine system through countless signalling pathways that have yet to be fully characterized. In the last decade we have discovered that many more neurotransmitters are at work in the ENS than was originally thought. This opens up new avenues of research into physiological phenomena traditionally thought to be associated only with the central nervous system, such as NMDA receptor-induced excitotoxicity, and how these may influence immune interactions. In particular, the kynurenine pathway of the tryptophan catabolism produces many neuro-active and immuno-active constituents whose effects are unknown in the ENS but are of great consequence in many neurodegenerative disorders of the CNS. Our study hypothesized that co-culture of the enteric neurons with mast cells would increase neuronal survival through kynurenic acid production in quinolinic acid (QUIN)-induced excitotoxic conditions.

This study developed a novel in vitro co-culture system of enteric neurons and glia grown from murine longitudinal muscle-myenteric plexus tissue and bone marrow-derived mast cells. In addition, a pipeline in image analysis software CellProfiler was designed and optimized in order to reduce human bias and error in subsequent immunocytochemical image analysis. Furthermore, we identified the genetic expression of subunits of the NMDA glutamate receptor in cultured enteric neurons via PCR, which suggests that these cultured neurons may be susceptible to excitotoxicity. PCR analysis of cultured mast cells seemed to indicate that our cultured mast cells do not express KAT-III, the enzyme needed to produce the neuroprotective KYNA. Overall, co-culture with mast cells seemed to decrease neuronal survival. This project developed a novel methodology for the in vivo study of mast cell-nerve interactions, and lays the groundwork for future studies in excitotoxicity in the ENS.

abstract: Thesis

abstract: Master of Science (MSc)

abstract: The enteric nervous system is a vast web of nerves and immune cells that innervates the gut and interacts with the central nervous system through the gut-brain axis. An important mediator in this system is the mast cell, a type of immune cell often involved in protective responses to venoms and allergens. Intriguingly, in normal physiological conditions these cells are in close contact with nerves in the periphery, despite their potential to release damaging constituents. While mast cells are well-known for inciting inflammation and releasing toxic granules, they can also synthesize and release potentially beneficial neuroactive compounds, such as neurotransmitters or growth factors. The aim of this study was to characterize mast cell-nerve interactions in neurotoxic conditions, to see if the proximity of mast cells to nerves might serve a neuroprotective purpose.


title: Detrital Zircon Signal Inversion in the Cretaceous Southwestern U.S. Interior Seaway - A Case Study from the Gallup System New Mexico

contributor:
Bhattacharya, Janok
Earth Sciences

abstract:
Sedimentary provenance analysis has been revolutionized by U-Pb age dating of detrital zircons. This geochronological technique allows researchers the ability to track sediment dispersal from its source to its ultimate sink. A compilation of 13,165 U-Pb zircon ages from 131 samples from the Late Jurassic to Late Cretaceous of the southwestern interior U.S. has shown a distinct change in sedimentary provenance. This study utilizes zircon ages from both sources and sinks to reconstruct the sediment routing systems throughout this period. The uplift of the Mogollon Highlands rift terrane in the Early Cretaceous caused a spike in Yavapai-Mazatzal (1.8-1.6 Ga) zircons in the Late Cretaceous once the sedimentary cover had been exhumed. This spike in Precambrian grains is found as far north as the Ferron Notom delta in south-central Utah, with a more pronounced increase in the nearby San Juan Basin.
A total of 4 new samples were collected from the San Juan Basin in northwestern New Mexico to test changes in sediment provenance across a hypothesized sequence boundary determined by recent high-resolution sequence stratigraphy. A statistically significant shift in zircon signal was found between the Gallup Sandstone Formation and the overlying Torrivio Sandstone Member of the Crevasse Canyon Formation. This data, combined with petrographic analysis, has identified a major sediment provenance change, which is attributed to tectonic forcing and a subsequent increase in sediment supply occurring contemporaneously with a eustatic drop in sea level. Changes in sediment provenance across this sequence boundary between these two units resolves the decades-long debate of whether or not the Torrivio and Gallup are associated units and has implications for future sequence stratigraphic correlations of fluvial sediments which are notoriously difficult to correlate.

abstract: Thesis

abstract: Master of Science (MSc)


title: Theoretical investigation of the instability of hybrid halide perovskites

contributor:
Rubel, Oleg
Materials Science and Engineering

subject:
hybrid halide perovskites
density functional theory
molecular dynamics
metadynamics
thermodynamics

abstract:
It has been 10 years since the first hybrid halide perovskite photovoltaics was fabricated. Power conversion efficiency increases from the initial 3.8% to the current 25.2%. Fabrication method envolves from spin-coating to printable technology, and we deeply experience the drastic development of hybrid halide perovskite photovoltaics.
Although hybrid halide photovoltaics render a variety of advantages over traditional photovoltaics, we still cannot find any practical application of these hybrid halide photovoltaics. There exist a few issues which hinder the commercialization of this type of solar cell. Among these issues, the long-term instability of hybrid halide perovskite is the main concern for the next development. This thesis expands on investigating the instability of hybrid halide perovskites from first principles.
In Chapter 1, two computational methods employed in the thesis: density functional theory and Ab initio molecular dynamics are introduced.
Theoretical investigations of the instability of CH3NH3PbI3 using density functional theory method are mainly conducted at 0 K. The finite temperature effect on this instability of CH3NH3PbI3 is usually neglected. In Chapter 2 of this thesis, we combined density functional calculations and additional thermodynamic data to explain the intrinsic instability of CH3NH3PbI3 under finite temperature conditions. We also analyzed the stability under humid conditions. It is shown that the aqueous solubilities of reactants play an important role in the products’ stabilities. The Born–Haber cycle of NaCl splits the enthalpy change into several components which will give a better understanding of the origin of the corresponding enthalpy change. In Chapter 3, with the extension of the Born–Haber cycle to the hybrid halide perovskites, the reaction enthalpies which govern the intrinsic instability of ionic compounds were analyzed. We proposed a criterion that helps to filter the hybrid halide perovskites with improved stability aimed for photovoltaics.
Since the instability of CH3NH3PbI3 is intrinsic. The long-term instability can be settled by discovering alternative perovskite absorber. In Chapter 4, based on literature research, we propose a three-membered ring cation which has a suitable size to fit into the Pb-I framework, leading to optimal band gap for photovoltaics. Besides, the cation has a good ionization energy which will potentially render better stability. Whereas, a comprehensive study of this cyclic ring based perovskite indicates that the instability of the three-membered ring cation will make it impossible to synthesize this theoretical structure.
Moisture degradation mechanisms of CH3NH3PbI3 are investigated intensively. More importantly, for practical photovoltaics, we have to imagine different situations the modules will encounter, e.g. after a couple of years, cracks appearing on the modules are inevitable, at this stage, understanding of the degradation mechanism of CH3NH3PbI3 according to liquid water becomes important. Chapter 6 elaborately describes a comprehensive degradation mechanism of CH3NH3PbI3 under liquid water. We investigate the energy barrier for the first dissolution event of CH3NH3PbI3 in water. Furthermore, thermodynamic analyses of CH3NH3PbI3 dissolution in water clearly explain the spontaneity of CH3NH3PbI3 degradation in water. Besides, different mechanisms of CH3NH3PbI3 and CsPbI3 dissolution in water are discussed.

abstract: Dissertation

abstract: Doctor of Philosophy (PhD)


title: The effect of atherosclerosis progression and exacerbation by diabetes on fibrinolysis

contributor: Medical Sciences (Thrombosis & Haemostasis & Atherosclerosis)

subject: atherosclerosis diabetes fibrinolysis

abstract: Atherosclerosis is a chronic inflammatory disease characterized by plaque or clot build-up in the arterial vessel wall, which leads to blood vessel occlusion and consequently heart attack and stroke. Diabetes is a metabolic disorder characterized by elevated sugar (hyperglycemia), which is a known risk factor for the development and exacerbation of atherosclerosis. Recent studies identified fibrinolytic factors (e.g. plasminogen activator inhibitor 1 (PAI-1), thrombin-activatable fibrinolysis inhibitor (TAFI)) that are linked with worsening of atherosclerosis and diabetes. In addition, since activated TAFI (TAFIa), possesses both antifibrinolytic and anti-inflammatory properties, it is a molecule of interest within the context of atherosclerosis progression. Therefore, we hypothesize that fibrinolysis is influenced by atherosclerosis and diabetes. To test this, we used mice that are prone to developing atherosclerosis (ApoE-/-) and hyperglycemia (Ins2+/Akita) from which the heart and plasma samples were collected at 15- or 25-weeks of age. Overall, no differences in plasma clot lysis times were observed between male (hyperglycemic) and female (normal glycemic) ApoE-/-:Ins2+/Akita mice. Quantitation of plaque volume showed a significant increase at 25-weeks compared with 15-weeks, consistent with previous reports. Closer examination revealed that in 15-week-old mice, plaque volume and PAI-1 levels displayed a trend with lysis time, but not in 25-week-old mice. The lysis times showed no difference with hyperglycemia or age. When TAFIa was inhibited, 15-week-old mice had longer lysis times compared with 25-week-old mice independent of hyperglycemia. In addition, elevation of cholesterol and triglyceride levels from hyperglycemia were only observed at 15-weeks. Total PAI-1 levels appeared to decrease with age. TAFI zymogen levels did not change with hyperglycemia or age. Fragment 1.2 levels, which indicate coagulation activation/thrombin generation increase with age but were not correlated with hyperglycemia. Overall, hyperglycemia does not appear to impact fibrinolysis directly, but rather indirectly through atherosclerosis in ApoE-/-:Ins2+/Akita mice.

abstract: Thesis

abstract: Master of Science (MSc)

abstract: Atherosclerosis is a disease of the large arteries that leads to unwanted blood clot formation that restrict blood flow to the heart and the brain causing heart attack and stroke, respectively. Diabetes mellitus is a metabolic disorder characterized by elevated blood sugar levels (hyperglycemia). Hyperglycemia directly alters protein and cellular structure, and indirectly influences cardiovascular complications (e.g. exacerbation of atherosclerosis progression). Although fibrinolysis, the process of removing clots, has also been linked with hyperglycemia, the mechanism remains unclear. To study the effect of hyperglycemia- mediated atherosclerosis exacerbation on fibrinolysis, we used mice that are prone to atherosclerosis with and without hyperglycemia and quantified: (a) atherosclerosis (lesion size, lipids), (b) blood sugar, and (c) fibrinolysis (lysis times, coagulation/fibrinolytic factors). We found strong correlation between lesion size and lysis time but not with other fibrinolytic markers. Hyperglycemia also did not affect fibrinolysis directly. Therefore, hyperglycemia may indirectly influence fibrinolysis through atherosclerosis.


title: Progression of retinal ganglion cell loss observed as a result of anterior segment dysgenesis following conditional deletion of activating protein-2 in cranial neural crest cells

contributor:
West-Mays, Judy
Medical Sciences

subject:
Eye
Glaucoma
Anterior segment dysgenesis
Experimental model
Activating protein-2beta
Müller cells
Intraocular pressure
Aqueous humor

abstract:
Our lab has shown that conditionally disrupting the tcfap2beta gene, responsible for the activating protein-2beta (AP-2beta) transcription factor, exclusively in the craniofacial neural crest cells, leads to anterior segment dysgenesis. Subsequent loss of the corneal endothelium results in the adherence of the iris to the corneal stroma, causing closure of the iridocorneal angle. The activating protein-2beta neural crest cell knockout (AP-2beta NCC KO) model involves a complete blockage of the both the conventional (through the trabecular meshwork) and non-conventional (uveoscleral) pathways for aqueous humor drainage, and therefore it could be used as a powerful experimental model for glaucoma. As shown by our previous work, elevated intraocular pressure (IOP) and a 35% decrease in the number of cells in the retinal ganglion cell (RGC) layer was observed in AP-2beta NCC KO mice by 2 months; 6 to 11 months sooner than other reported mouse models of glaucoma. These observations suggested that the AP-2beta NCC KO mouse could be a novel and cost-effective experimental model for glaucoma if the RGC loss occurred progressively rather than due to a congenital defect.
The purpose of this research project was to investigate how the retinal ganglion cell layer and macroglial activity changes with respect to age in the AP-2beta NCC KO mutant through immunofluorescence. Specifically, it was investigated whether the loss of RGCs was progressive and due to the increased IOP caused by the blockage of the uveoscleral drainage pathway.
	A significant decrease in the number of RGCs was observed between P4 and P10 in the retinal periphery of both WT and AP-2beta NCC KO mice (p<0.05), which is indicative of the programmed cell death that occurs due to retinal pruning during development. No statistical difference between WT and AP-2beta NCC KO mice phenotypes was observed at postnatal day 4 (P4), suggesting that no developmental defect resulted in the significant loss of RGCs at 2 months. In all other time points investigated, while no statistical difference was found between WT and the AP-2 NCC KO mutant, a clear downward trend was present in the AP-2 NCC KO mutant retinal ganglion cell layer from P10 to P40. There was also an expression of glial fibrillary acidic protein (GFAP) by Müller cells, indicating the presence of neuroinflammation at P35 and P40. This substantiates the potential P42 starting point of neurodegeneration our lab previously observed. This was further corroborated with Müller cell-associated expression of GFAP at P35 and P40 exclusively in the AP-2beta NCC KO mouse.
	Overall, we have shown that the retinal damage observed in our AP-2beta NCC KO mouse is not due to a developmental defect, but rather occurs over time. Thus, this mouse model, which appears to block both the conventional and unconventional uveoscleral pathways, has a profound effect on aqueous humor drainage. As a result, the model requires relatively little time to observe an increase in IOP and subsequent RGC loss. Our findings suggest that the AP-2beta NCC KO mouse can be a novel, powerful, and extremely cost-effective experimental model for glaucoma.

abstract: Thesis

abstract: Master of Science (MSc)


title: Perceptual Cue Weighting of Intervocalic Velar Plosives in English

contributor:
Pape, Daniel
Cognitive Science of Language

abstract: When producing speech, the acoustic signals contain several extractable parameters (cues) about the intended sound which are reliably mapped to achieve robust phoneme identification in speech perception, despite large acoustic variation in speech signals between and within individuals. This thesis presents findings on the perceptual cue weighting of intervocalic velar stop consonants /k/ and /g/ for English listeners, through use of biomechanical stimuli. Four acoustic cues were systematically manipulated to create the experimental stimuli: voicing maintenance throughout consonantal closure (VM), voice onset time (VOT), the duration of consonantal closure (CL) and the duration of the previous vowel segment (VL). This thesis presents the findings of three experiments. Experiment 1 investigates the cue weighting of three acoustic cues (VM, VL, CL) in the absence of a perceptual VOT cue. Experiment 2 defines a perceptually ambiguous VOT value [for the given biomechanical stimuli] and compares the influences of VOT and VM. Experiment 3 analyses how the perceptual cue weighting of the three acoustic cues (VM, VL, CL) is affected when a perceptually ambiguous VOT value is added to stimuli. The results from the three experiments reveal that VM has a significantly higher influence on voicing perception than the other cues, and only at low VM levels do other cues increase their influence. The cues interacted significantly with each other. The effect of VOT – known in literature as the main cue for consonantal voicing distinctions – was apparent at high VM values but significantly increased at low VM values. Experiment 2 gave additional evidence that individual listeners utilized very different strategies in determining voicing perception. Ultimately the results show that the perceptual cue weighting process is highly complex and cannot be attributed to only one or two perceptual cues (e.g. VOT).

abstract: Thesis

abstract: Master of Science (MSc)


title: THE ASSOCIATION BETWEEN CANMEDS ROLE-SPECIFIC IMPLICIT THEORIES OF INTELLIGENCE AND PLANNING FOR RESIDENT REMEDIATION

contributor:
Monteiro, Sandra
Health Science Education

abstract:
This thesis explores two components of motivational theory that have been unexplored in the context of medical education. First, we applied the notion of motivational dimensionality to physician competence. Previous research on implicit theories of intelligence demonstrated that people hold different beliefs regarding different aspects of intelligence/ability, instead of a global mindset. We applied this to the CanMEDS Framework and showed that respondents held different theories of intelligence regarding the Professional and Medical Expert Role. Second, we aimed to determine if one’s implicit theories are related to their decisions around remediation planning. We hypothesized that respondents would view remediation as either an opportunity for a resident to develop competence or as an opportunity for them to demonstrate their fundamental lack of ability. Here, we showed that one’s own beliefs, or theories of intelligence, not only mediate how they behave in the training environment, but also mediate how they manage others.
In the first of two studies, we measured implicit theories amongst residents, faculty, and experts in medical education at McMaster University regarding both the Professional and Medical Expert CanMEDS Roles and asked them how much effort would be required for a resident to remediate performance deficits in either Role. The second study took place at University of Toronto and involved a similar design. Residents and faculty in the Department of Obstetrics and Gynaecology were invited to participate in a study that measured implicit theories of intelligence and then asked respondents to develop remediation plans for residents described in case vignettes. Drawing on experience in the Board of Examiners, 6 cases were developed, 3 that represented Medical Expert deficits, and 3 that described Professional deficits. The results showed that respondents viewed the Professional Role as relatively more “fixed” than the Medical Expert Role. Those views corresponded to stricter remediation planning, characterized by a short duration of remediation, stricter consequences of failure, and a lower perceived likelihood of success paired with a higher perceived likelihood of Professional deficits in the future.
These results supported the hypotheses that the implicit theories of intelligence differ according to the dimension of physician competence in question. Professional was considered to be more fixed, relative to Medical Expert, and in keeping with the theorization, the resultant remediation plans appeared more as an opportunity to demonstrate a fundamental lack of ability than an opportunity for the resident to develop competence. These findings are consistent with those in other studies, where a fixed theory of intelligence was associated with a “helpless” behaviour pattern, characterized by low persistence, and challenge avoidance. We were able to show that one’s implicit theories extend beyond the self and can influence how an individual manages the education of another. This work sheds light on some of the factors that man influence remediation decision-making and adds to the conversation surrounding professionalism as competency versus an attribute.

abstract: Thesis

abstract: Master of Science (MSc)


title: INFLUENCE OF MATERNAL SELECTIVE SEROTONIN REUPTAKE INHIBITOR EXPOSURE ON THE DEVELOPMENT OF THE GASTROINTESTINAL TRACT OF THE OFFSPRING

subject: Serotonin

subject: Selective Serotonin Reuptake Inhibitors (SSRIs)

subject: Enteric Nervous System

subject: Enterochromaffin Cells

subject: Development

abstract:
10-15% of women take antidepressants during pregnancy. Selective serotonin reuptake inhibitors (SSRIs) are most commonly used for perinatal depression. Perinatal exposure to SSRIs has been shown to disrupt the development of serotonergic signaling pathways in the central nervous system (CNS); however, the effects on the developing enteric nervous system (ENS) remain relatively unexplored. We hypothesized that early life exposure to SSRIs would influence the structural development of the gastrointestinal (GI) tract.  We further hypothesized that these structural changes could lead to clinically relevant functional outcomes, such as modifications in susceptibility to inflammation and altered GI motility.
Female Wistar rats were given the SSRI, fluoxetine, or vehicle from 2 weeks prior to mating through gestation until weaning. At postnatal day 1 (P1), postnatal day 21 (P21; weaning) and 6 months of age (P6 months) intestines were harvested to assess for structural changes. At P6M, intestines were collected to assess motility in vitro and subsets of the offspring were treated with dextran sulfate sodium (DSS) to assess susceptibility to colitis.
At P1, there was a significant decrease in serotonergic neurons in the female colon. At P21, there was a significant increase in serotonergic neurons of both sexes in the colon. At P6M, there was a significant increase in the frequency and velocity of long-distance contractions in the colon when both sexes were combined and an increase in ZO-1 in male colon.
In conclusion, SSRI exposure in utero appears to have structural and functional consequences on the developing ENS in the SSRI exposed offspring. The structural consequences are seen in both sexes at P21 and although the structural changes to the ENS resolve by 6 months, motility in the colon continues to be significantly altered. There were no significant differences in chemical colitis, however, we did see difference of quantitative mRNA cytokines, chemokines and extracellular matrix components which may suggest differences in mucosal immune response. The mechanisms by which these changes occur remain to be explored.

abstract: Thesis

abstract: Master of Science (MSc)


title: STRATIGRAPHY, PROVENANCE, TIMING AND CONTROL OF INCISED VALLEYS IN THE FERRON SANDSTONE

title: INCISED VALLEYS IN THE FERRON SANDSTONE

contributor:
Bhattacharya, Janok P.
Earth and Environmental Sciences

subject:
incised valleys
backwater
tributary valleys
detrital zircons
paleogeography
Turonian
Ferron Sandstone
Notom Delta

abstract:
This thesis evaluates the nature, provenance, geometry and morphology of incised valley fills to test assumptions made by valley models using ancient examples from well exposed outcrops, in the late Turonian Ferron Sandstone Member of the Mancos Shale Formation in southeastern Utah. The relevance of this work will have particular significance to long wavelength cycles of fluvial landscapes and valley morphology, non-marine reservoir characterization and significant implications for non-marine response to high frequency allogenic cycles such as climate change and changes in relative sea-level.
	This study illustrates the stratigraphic complexity of valley fill deposits at three levels of spatial resolution. At channel scale within the lower backwater, facies architecture and paleohydraulic analysis are used to predict the degree of shale drape coverage of point bars in a tidally-influenced incised channel. At channel belt scale the study documents a tidally incised, mudstone prone trunk-tributary valley fill and overlying highstand fluvial succession within a stratigraphic framework of fluvial aggragation cycles. 3D photogrammetry models and a high resolution GPS survey are used to restore the morphology of a trunk-tributary valley floor, revealing a surface of tidal ravinement and tidal drainage morphology. At a regional scale, this study radically revises the paleogeographic mapping of the Ferron trunk system, spanning over 1,600 km2. Provenance analysis reveals Ferron Notom trunk valleys were filled at times by sediment from the Mogollon Highlands of Arizona to the southwest, and alternately by sediment from the Sevier Thrust Front to the northwest. Evidence shows the Ferron trunk rivers, previously hypothesized to be an avulsive axial drainage, to be more analogous to Quaternary examples.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)


title: THE CHARACTERIZATION OF KAISO TRANSGENIC MICE

contributor:
Daniel, Juliet
Biology

subject: Kaiso mice zbtb33 inflammation IBD CRC CAC colitis associated cancer

abstract: The characterization of Kaiso transgenic mice, a potential model for the IBD-to-CAC transition.

abstract:
Colitis-associated cancer (CAC) is a poorly characterized subgroup of colorectal cancers (CRC) that afflicts ~20% patients suffering from inflammatory bowel disease (IBD). The limited understanding of CAC stems from the lack of suitable mammalian model systems, as well as a general gap in knowledge regarding the molecular mechanisms of this disease. Currently, colitis is modelled by the use of the detergent dextran sodium sulfate (DSS) to induce inflammation in the intestines of mice. Studies have shown that increased expression of the transcription factor Kaiso causes intestinal inflammation and early-stage tumorigenesis in mice, even without additional intestinal insult. This inflammatory progression mimics the beginnings of CAC in humans, and we postulate that with a “second-hit” caused by a carcinogen such as azoxymethane (AOM), the mice will cross the threshold from inflammation to carcinogenesis.
Wildtype (WT), KaisoTg mice, and APCmin/+/KaisoTg crossed mice were exposed to various combinations of the pro-inflammatory detergent DSS, the carcinogen AOM and the general anti-inflammatory, aspirin. Intestinal tissues were collected for gross morphological assessment, polyp quantification and Immunohistochemistry (IHC) analysis, in order to determine the relative expression level and localization of pro-inflammatory and tumorigenic proteins. We hypothesized that exposure to DSS or AOM will exacerbate Kaiso-mediated intestinal inflammation and lead to colitis-associated cancer (i.e. polyp formation), while aspirin will rescue the APCmin/+/KaisoTg accelerated tumour forming phenotype. KaisoTg treated with AOM or DSS exhibited an impeded weight gain phenotype, extensive intestinal hyperplasia and altered gene expression. IHC analysis revealed that two key adhesion proteins, p120ctn and E-Cadherin exhibit aberrant expression and localization in KaisoTg, independent of treatment. Additionally, it was observed that AOM treatment and Kaiso overexpression work synergistically to produce an ectopic expression profile for the proliferation marker, Ki67. Together these finding suggest a role for Kaiso in intestinal inflammation, cancer initiation via altered proliferation, and the destabilization of adherens junctions, leading to a compromised intestinal epithelial barrier.

abstract: Thesis

abstract: Master of Science (MSc)


title: Exploring Physician Assistant Role Integration in the Ontario Healthcare System

contributor:
Vanstone, Meredith
Health Research Methodology

subject:
Physician Assistants
Health Services Research
Qualitative
Case study
Collaborative care
Ontario healthcare
Family practice
General surgery
Emergency medicine
Inpatient medicine
Interprofessional
Person-centered care

abstract: Qualitative case study research on Physician Assistants

abstract:
Background: The Ministry of Health and Long Term Care (MOHLTC) introduced Physician Assistants (PAs) into the Ontario health care system in 2006 to help increase patient access to care, decrease wait times, and improve continuity of care. As a new addition to Ontario, little research exists to describe the roles and contributions of PAs. The aim of this dissertation is to explore PA role integration through an in-depth analysis of setting and role descriptions, barriers and facilitators of role integration, and healthcare provider perceptions.

Methods: An exploratory, multiple-case study was used to examine PA role integration in four clinical settings: family medicine, emergency medicine, general surgery, and inpatient medicine. Inductive thematic analysis was used within each of the four cases and for the cross-case thematic analysis.

Results: Forty-six health care providers and administrators were interviewed across 19 different healthcare sites. Support for PA contributions across various health care settings, the importance of role awareness, supervisory relationship attributes, and role vulnerability (in relation to sustainability and funding) are interconnected and dynamic in general surgery, inpatient medicine, emergency department and family medicine settings. These findings demonstrate how the flexible and adaptable nature of the PA role and the PAs ability to build relationships allows for the establishment of interprofessional, collaborative, and person-centered care.

Conclusions: This dissertation provides a rich understanding of the role of PAs in the Ontario healthcare system through an exploration of role definition, impact on patient care, and professional perceptions. The findings from this dissertation are important from a broad systems perspective as the results help fill existing knowledge and practice gaps regarding the role of PAs, and will help inform the design of human health resource research in order to optimize health care system efficiencies.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract: Physician Assistants (PAs) are a new health care profession in Ontario, and were introduced by the Ministry of Health and Long Term Care (MOHLTC) in 2006 to help increase access to care and decrease wait times for patients. PAs are trained to work with physicians to extend healthcare services. This research study was undertaken to explore how the PA role has been integrated into number of health care settings, including family practices, emergency departments, general surgery and inpatient medicine settings. The research design is a qualitative case study, which allows for an in-depth exploration of the PA role. Findings revealed that PAs are flexible, collaborative, and adaptable members of healthcare teams in Ontario, who have an interest in enhancing patient care.  Despite these benefits, role optimization is often limited by factors such as lack of funding and resistance from other healthcare providers. The findings from this study help fill research gaps around the PA profession in Ontario, and will help inform stakeholders interested in optimizing the impact of PAs in the Ontario healthcare system.


title: Fundamentals of micro-particle removal by liquid oxide

contributor:
Dogan, Neslihan
Materials Science and Engineering

subject: dissolution mechanism, aluminium titanate inclusion, confocal scanning laser microscope, mass transfer control

abstract:
The grades of steel used for automotive bodies are interstitial free steel grades and titanium stabilized ultra-low carbon steel grades. During the manufacturing of these grades, the addition of titanium in liquid steel is achieved in the steel refining units and may cause processing problems. Titanium reacts with the dissolved aluminum and oxygen to form complex solid aluminum titanate type micro-particles (inclusions). During the flow of titanium alloyed steel grades containing solid inclusions (such as aluminum titanate and alumina type inclusions), the clog accompanied by steel skull can be formed at the submerged entry nozzle between the tundish and the mold. To reduce the effects of aluminum titanate type inclusions, they can be either modified or removed.
The current study focused on the removal of Al2O3, TiO2, and Al2TiO5 inclusions by dissolving them in slag in the temperature range of 1430 – 1600 °C using a high-temperature confocal scanning laser microscope. In this technique, a single particle (inclusion) is placed on the surface of a solid slag, and the inclusion-slag system is heated to steelmaking temperatures. The dynamic changes in inclusion size are measured to determine dissolution kinetics and mechanism.
This work has developed a complex oxide particle synthesis technique and provides the first-ever kinetic data for removal of aluminum titanate inclusions into steelmaking slags. It is found that Al2O3 inclusions have a slower dissolution rate than that of Al2TiO5 inclusions followed by TiO2 inclusions. The rate-controlling steps are investigated using a shrinking core model. It is shown that the rate-controlling step for dissolution of both Al2O3 and Al2TiO5 inclusion types is the mass transfer of alumina. Evidence in support of this finding is the particle-slag interface characterization by line scan analysis and calculated diffusivity values being inversely proportional to the viscosity of slag.
The dissolution path of aluminum titanate is proposed in the following steps. First, aluminum titanate dissociates into alumina, titanium oxide and oxygen while slag penetrates through the particle. In the next step, the alumina and titanium oxide dissolves in slag, and the oxygen leaves the system. The existence of gas bubbles enhances the overall rate of Al2TiO5 dissolution.
The current work establishes a detailed understanding of the dissolution of Al-Ti-O type inclusions in steelmaking slags. This knowledge will inform steelmakers on which inclusions of different chemistry can be removed preferably and develop strategies on better slag design to produce superior quality steel with reduced operational downtime.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)


title: Development of A Multi-channel RGB Laser Diode Driver for  Laser Projection Applications

contributor:
Xu, Chang-qing
Engineering Physics

subject:
RGB laser projector
laser diode driver
iC-HTG
laser diode protection

abstract:
In this thesis, a red green and blue (RGB) laser diode driver (LDD) is designed, assembled and tested, which can work as a standalone device or an internal component fully controlled by a laser projector. In particular, the thesis explores a multi-channel RGB LDD for a retrofitted laser projector, targeting projectors for home, business and education.
If laser diodes (LDs) with the same color are connected in series, a higher forward voltage is required, making most commercial LDDs unsuitable for this application due to their insufficient compliance voltages. If the connections of all the LDs are in parallel, issues on size and cost arise since many LDs are used in this case. Another problem to use the commercial LDDs for RGB laser projection is that there are no proper communication interfaces to link the LDDs to the laser projector. In order to solve these problems by taking advantage of all the features of iC-HTG, an integrated circuit with automatic current control functionality, both the hardware circuits and the software for an eight-channel LDD are designed. Experimental results show that all the RGB channels can achieve compliance voltage of 23 V within the required working current range, which can drive up to 5 blue, 4 green or 10 red LDs in series in each single channel. It is confirmed experimentally that the designed LDD can fulfill the requirements on driving current (i.e. 1% accuracy and 1% stability). The protection functions of the developed LDD are also explored and verified experimentally. It can detect the open laser connection before the LDD channels are enabled. Fast over-current protection can be achieved within 1.5 µs. Circuit interfaces and protocols of the communications enable the multi-channel RGB LDD to work as a standalone device or an internal component of the laser projector.

abstract: Thesis

abstract: Master of Applied Science (MASc)


title: Point-of-need biosensors for the detection of respiratory biomarkers

contributor:
Brennan, John D.
Chemical Biology

subject: Biosensors, Point-of-Need, Point-of-care, Asthma, Aptamer, SELEX, Antibody, Lateral Flow

abstract: Asthma is a chronic disease affecting over 300 million people worldwide. Airway inflammation is a central feature of asthma. Quantitative sputum cytometry is the most validated method to assess this and to adjust anti-inflammatory therapy, yet it is underutilized due to rigorous processing that requires expensive specialized technicians. To address these limitations, this thesis focuses on the development of several point of need biosensors that rapidly quantify respiratory biomarkers as alternatives to traditional laboratory tests. The project began by developing a paper based sensor for detection of myeloperoxidase (MPO), a neutrophil biomarker. A test was developed using commercially available antibodies, showing direct correlation between the test line colour intensity and total neutrophils. This work was expanded to include a second protein target, eosinophil peroxidase (EPX), for identification of eosinophils. Although the test performed well using neat samples, it failed to identify EPX in clinical sputum samples. Analyzing pre-treatment methods identified that a quick immunoprecipitation technique using protein A/G beads followed by syringe filtration allowed for the device to successfully quantify EPX, eliminating the need for a centrifuge. However, the limited supply of commercial anti-EPX antibodies combined with the need for sample pre-treatment prompted investigation into alternative detection avenues. Nucleic acid aptamers were explored, with aptamer selection for EPX producing several aptamer candidates. Binding affinity and specificity tests were performed, with the T1-5 aptamer emerging. T1-5 was capable of selectively binding EPX over MPO with high affinity. This aptamer was integrated into a simple pull-down assay, capable of detecting EPX with an order of magnitude lower limit of detection than the antibody test. Overall this work has developed multiple sensors with the potential to overcome the limitations of accessibility to sputum cytometry, rapidly identify the presence and type of airway inflammation, and deliver personalized treatment strategies that not only reduce the global healthcare burden, but also greatly improve a patient’s quality of life.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)


title: Intermittent hypoxia elicits a unique physiological coping strategy in Fundulus killifish

contributor:
Scott, Graham R.
Biology

subject:
hypoxia tolerance
respiration
metabolism
haematology
gill morphology
muscle histology
respirometry
metabolic depression
glycolysis
excess post-hypoxic oxygen consumption
reoxygenation
reactive oxygen species
oxidative stress
antioxidants
diel cycles
diurnal hypoxia
hypoxia resistance
evolutionary physiology
phylogenetically independent contrasts
aerobic scope
fish
hypoxia
physiology
zoology
enzyme activity
metabolites
critical oxygen tension
loss of equilibrium

abstract:
Fish encounter daily cycles of hypoxia in the wild, but the physiological strategies for coping with repeated cycles of normoxia and hypoxia (intermittent hypoxia) are poorly understood. Contrastingly, the physiological strategies for coping with continuous (constant) exposure to hypoxia have been studied extensively in fish. The main objective of this thesis was to understand how Fundulus killifish cope with a diurnal cycle of intermittent hypoxia, an ecologically relevant pattern of aquatic hypoxia in the natural environment. To do this, I characterized the effects of intermittent hypoxia on hypoxia tolerance, oxygen transport, metabolism, and the oxidative stress defense system of killifish, and compared these effects to fish exposed to normoxia, a single cycle of hypoxia-normoxia, and constant hypoxia.

Specifically, I studied the following topics: (i) how acclimation to intermittent hypoxia modifies hypoxia tolerance, and the hypoxia acclimation response of Fundulus heteroclitus (Chapter 2), (ii) metabolic adjustments occurring during a hypoxia-reoxygenation cycle (Chapter 3), (iii) how acclimation to intermittent hypoxia alters O2 transport capacity and maximal aerobic metabolic rate (Chapter 4), (iv) the effects of hypoxia and reoxygenation on reactive oxygen species and oxidative stress (Chapter 5), and (v) variation in hypoxia tolerance and in the hypoxia acclimation responses across Fundulus fishes (Chapter 6).

Killifish rely on a unique and effective physiological strategy to cope with intermittent hypoxia, and that this strategy is distinct from both the response to a single bout of acute hypoxia-reoxygenation (12 h hypoxia followed by 6 h reoxygenation) and to chronic exposure to constant hypoxia (24 h hypoxia per day for 28 d). Key features of the acclimation response to intermittent hypoxia include (i) maintenance of resting O2 consumption rate in hypoxia followed by a substantial increase in O2 consumption rate during recovery in normoxia, (ii) reversible increases in blood O2 carrying capacity during hypoxia bouts, (iii) minimal recruitment of anaerobic metabolism during hypoxia bouts, and (iv) protection of tissues from oxidative damage despite alterations in the homeostasis of reactive oxygen species and cellular redox status. Of these features, (i) is unique to intermittent hypoxia, (ii) also occurs in fish exposed to acute hypoxia-reoxygenation, and (iii) and (iv) are observed in both fish acclimated to intermittent hypoxia as well as those acclimated to constant hypoxia.

This is the most extensive investigation to date on how fish cope with the energetic and oxidative stress challenges of intermittent hypoxia, and how these responses differ from constant hypoxia. This thesis adds substantial insight into the general mechanisms by which animals can respond to an ecologically important but poorly understood feature of the aquatic environment.

abstract: Dissertation

abstract: Doctor of Philosophy (PhD)

abstract: Oxygen levels in the aquatic environment are dynamic. Many fishes routinely encounter changes in oxygen content in their environment. However, we have very little understanding of how cycles between periods of low oxygen (hypoxia) and periods of high oxygen (normoxia) affect the physiology of fish. This thesis investigated how Fundulus killifish cope with daily cycles between hypoxia and normoxia (intermittent hypoxia) by modifying oxygen transport, metabolism, and oxidative stress defense systems. I found that killifish rely on a unique and effective physiological strategy to cope with intermittent hypoxia, and that this strategy is distinct from how they respond to a single bout of hypoxia (followed by normoxia) and to a constant pattern of only hypoxia. This is the most extensive investigation to date on how fish respond to the challenges of intermittent hypoxia, an understudied but ecologically important type of aquatic hypoxia.


title: MULTIMATERIAL MULTILAYER FABRICATION OF MICROFLUIDIC DEVICES

contributor:
Selvaganapathy, P. Ravi
Mechanical Engineering

abstract:
Microﬂuidics technology enables miniaturization, integration and automation of chemical and
biochemical assays. Compared to conventional analytical tools, a microﬂuidic device requires
small volume of samples and performs assays faster making it a suitable candidate for point-
of-care diagnostic devices. Various fabrication techniques for microﬂuidic systems have been
developed over past three decades to construct microchannels and microﬂuidics components
such as valves, pumps and electrodes. However, most of these methods are either expensive
and requiring cleanroom environment or limited to use of single or a few materials primarily
due to diﬀerences in process conditions of various materials. Therefore, an easy and robust
fabrication technique that is able to integrate diﬀerent microﬂuidic components into a single
device is highly sought. Xurography as a rapid prototyping tool was introduced over a decade
ago for construction of microchannel. Although this technique has signiﬁcant capability to
pattern variety of materials, it has not been applied for important microﬂuidic components
such as valves and electrodes. In this thesis, combination of xurography with lamination
has been developed to integrate microﬂuidic components. Use of commercially available ﬁlm
in variety of materials such as thermoplastics, elastomers and metals signiﬁcantly reduces
the cost of fabrication. Also, these materials have diﬀerent properties such as insulating,
conductive, elastic, hard, soft, hydrophobic and hydrophilic providing unique functionality
in microﬂuidic devices. Therefore, various applications such as ﬂuid ﬂow controll by active
and passive valves, DNA electrophoresis, electrochemical sensing, electrokinetic mixing and
heating are presented.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)


title: DNA Methylation and the Developmental Origins of Health and Disease: Epigenome-Wide Associations in Canadian Birth Cohorts

contributor:
Pare, Guillaume
Medical Sciences

abstract: In recent years the developmental origins or health and disease (DOHaD) has been a crucial area of study in the etiology, prevention, and treatment of non-communicable diseases (NCDs). Prenatal exposures such as gestational diabetes (GDM), diet, or smoking may affect fetal development in ways that persist to have a long-term impact on offspring health and disease. Epigenetic modifications such as alterations to DNA methylation may be one of the mechanisms by which these prenatal exposures effect long-term changes to adult health. The Epigenome-Wide Association Study (EWAS) has become a prominent method to study the association between changes in DNA methylation with a variety of outcomes. To assess the body of evidence available for prenatal exposures, we reviewed EWAS papers in the PubMed database that found significant associations between cord blood DNA methylation and: smoking, GDM, maternal diet, BMI, or gestational age. Smoking and gestational age demonstrated consistent changes in DNA methylation across studies, while the other exposures had either inconsistent results or minimal investigation. Sites reported as significant in our literature review were assessed for replication in the START and CHILD birth cohorts. A total of 8/94 sites were significantly associated with smoking in CHILD, while 81/279 gestational age sites were significant in each of START and CHILD (54 were significant in both). We also conducted an EWAS examining the relationship between infant cord blood methylation and the glucose-to-insulin ration (GIR), a metric of fetal insulin sensitivity. 13 significant sites were initially identified, and further pathway and risk score analysis demonstrated that differences in underlying cellular composition, specifically natural kill (NK) cells, were likely driving the results. Our results indicate that both DNA methylation alterations and modifications to the underlying tissue composition may be related to prenatal exposures and influence the long-term health implications of these environments.

abstract: Thesis

abstract: Master of Science in Medical Sciences (MSMS)


title: Population-based studies in sarcoma research

contributor:
Ghert, Michelle
Health Research Methodology

subject: Sarcoma, cancer, orthopedic surgery

abstract:
Many study designs are used to provide the answers needed to further the care of orthopedic oncology patients. Underlying these differing study designs, are different data sets. The data sets vary in their size and scope, from single center to population-based, and from provincial to international. They vary in their follow-up time, from years to decades. They vary in the variables included, the fidelity and precision of each variable, and the granularity of detail. This thesis explores the use of population-based studies as a source of data on orthopedic oncology patients, and provides two studies as an example.
	We make use of the large administrative data collected from every soft tissue sarcoma (STS) patient in Ontario over 23 years by the Institute of Clinical Evaluative Sciences (ICES) to answer two questions only possible with population-based studies. Using this large cohort (n=8,896) we provide for the first-time answers to 1) Given the multidisciplinary treatment of sarcoma patients, how are Ontario sarcoma patients being treated in our universal healthcare system, and, have treatment strategies changed over the past 10 years? 2) What are the long-term survival outcomes of Ontario sarcoma patients? Do these outcomes differ for rural or low-income patients?
These studies have engendered international collaborations which are also described. Overall, this thesis explores research questions that are possible to address with population-based data. Through two studies, we aim to provide accurate and clinically useful information that can hopefully be used to better the outcomes of sarcoma patients, both in Ontario and internationally.

abstract: Thesis

abstract: Master of Science (MSc)


title: Queer Archives in Zhang Yuan's East Palace and Ang Lee's Eat Drink Man Woman

contributor:
Attewell, Nadine
English and Cultural Studies

subject:
Queer
Archive
Ang Lee
Zhang Yuan
Food

abstract: If one can come out as queer, how does one come out as queer in the Chinese context? More importantly, how exactly does one come out as “Chinese,” especially given the increasingly complex construction and remaking of “Chineseness” across the Taiwan Strait? Building on Hongwei Bao’s concept of the “queer comrade” as an analytical framework that acknowledges the temporal coevality of its circulation across postsocialist China and Taiwan, this comparative study of Zhang Yuan’s East Palace, West Palace and Ang Lee’s Eat Drink Man Woman explores archives of Chineseness and queerness in a transnational context. At the same time, through examining representations of cruising, traditional opera form, tables, kitchens, and food -- I argue that queer identities are not only about private sexual practices, but also about new family formations, political tensions, and intercultural exchanges. I take cues from archival studies to see them as alternative archival practices and subjectivities which channel new pathways to reimagine Queer Sinophone futurities.

abstract: Thesis

abstract: Master of Arts (MA)


title: From Sanctity to Invulnerability: Disgust as a Function for Avoiding the Cognition of Limits

contributor:
Allen, Barry
Johnstone, Mark
Philosophy

subject: Psychodynamics, Evolutionary theory, Disgust

abstract: I defended the view that one of the notable symbolic functions of disgust is to the avoid the limitations inherent in our unconscious desire to be invulnerable to life. Via the plasticity of disgust's gene-cultural evolution throughout enduring norms on human sanctity, we inherited an unconscious, instinctive desire to be invulnerable, whose characteristic emotion is disgust. My framework on disgust can explain a wider variety of instances of disgust than the contemporary literature, such as the nausea we feel before a theatrical performance, the allure of disgust in humour and storytelling, and disgust where core-disgust elicitors are not operative.

abstract: Thesis

abstract: Master of Arts (MA)

abstract: One of disgust's function is to avoid the reminder that we are not invulnerable to life. We want to be invulnerable to life, but we also recognize that life doesn't work like that. One of disgust's functions is to avoid being reminded that we are vulnerable.


title: DEVELOPMENTAL AND MATERNAL THERMOREGULATORY ADAPTATIONS TO HIGH ALTITUDE IN THE NORTH AMERICAN DEER MOUSE, PEROMYSCUS MANICULATUS

contributor:
McClelland, Grant B.
Biology

abstract: Altricial mammals develop the capacity to independently thermoregulate during the first few weeks of postnatal development. This shift in performance is driven by the maturation of the two primary thermo-effector organs, brown adipose tissue (BAT) and skeletal muscle which are non-functional at birth. In wild rodent populations this is also a time of high mortality (50-95%), making the physiological systems that develop during this period potential targets for natural selection. High altitude is a particularly challenging environments for small endotherms due to unremitting low O2 availability and consistently low ambient temperatures. As a result, some high-altitude taxa have evolved a superior adult thermogenic capacity. However, it is unclear if selection has occurred to survive these unique challenges early in development. The goal of my thesis is to address this gap in knowledge and assess developmental thermoregulatory adaptations in an altricial high altitude endotherm. I used deer mice (P. maniculatus) native to high and low altitude population, and a strictly low altitude species (P. leucopus), all raised under common garden conditions to assess how high altitude adaptation has altered the onset of endothermy, developmental plasticity of thermogenic capacity and maternal care. I have shown that selection has fundamentally delayed the maturation of the BAT and skeletal muscle in high altitude natives and has altered their capacity for developmental plasticity. High altitude pups are able to maintain growth rates and body composition under cold hypoxic conditions despite receiving less maternal care than their low altitude counterparts. These data suggest that high altitude adapted mice have evolved to suppress energetically costly thermogenesis during development.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract: Cold temperatures and less available oxygen make mountain ranges challenging places for small mammals to live. We know very little about how young high-altitude animals overcome these challenges. I have shown that young deer mice adapted to high altitude receive substantially less parental care than their low altitude counterparts, yet they are able to grow at the same rate. They also do to not attempt to burn fuel and oxygen to produce heat until they much older than low altitude mice. Suppressing energetically costly heat production may allow them to save energy, and ultimately survive in their extreme environment.


title: Optical Biopsy Instrument Design and Parameter Extraction from Hyperspectral Time-Resolved Fluorescence Data

contributor:
Fang, Qiyin
Biomedical Engineering

subject:
Optical Biopsy
Fluorescence Lifetime
Diffuse Reflectance
Phasor Analysis

abstract:
Complete resection is correlated to better patient outcome in aggressive cancers such as glioblastoma. Optical biopsy refers to a family of techniques utilizing optical properties of living targets to make diagnoses where a biopsy would conventionally be used. Such a technology can potentially guide neurosurgeons in removing glioblastomas.
Diffuse reflectance (DR) and Time-resolved fluorescence (TRF) have previously been investigated for their ability to measure biomarkers indicative of cancer. One of the difficulties faced in using TRF as a diagnostic tool is that multiple endogenous fluorophores will simultaneously contribute to the signal. This makes it difficult to attribute fluorescence lifetimes or spectral changes to one type of molecule in the tissue.
This thesis focuses on the challenge of separating the components in a TRF measurement and their fractional contributions. A DR-TRF instrument was designed and built and characterized using fluorescent dyes. An orthonormal basis deconvolution method combined with a Fourier-domain method were tested for their ability to unmix fluorescent components in a hyperspectral TRF measurement. This method was tested on dye mixtures and retrieved fluorescence lifetimes of 4.6±0.4 ns and 2.7±0.2 ns in a mixture of Fluorescein and Coumarin-6 at concentrations of 5 μM each. It was also tested on an ex-vivo brain tissue where the fluorescence was approximated as a sum of 2 components.

abstract: Thesis

abstract: Master of Applied Science (MASc)


title: Reproducing Pregnancy: Risk and Responsibility in Research During Pregnancy

contributor:
Gedge, Elisabeth
Philosophy

subject:
Bioethics
Research
Pharmaceutical Research
Pregnancy
History of medicine
Risk
Feminist Philosophy

abstract:
This dissertation explores the bioethical construction of pregnancy as site of risk and argues that pregnancy is best characterised as sitting in a constant state of tension, as simultaneously healthy-normal-natural and risky. This tension and how it is acknowledged or ignored is a significant factor in many ethical issues centered upon pregnancy. Using a genealogical analysis, this study identifies features of the social discourse around pregnancy that impede clinical research during pregnancy despite both policy changes and educational campaigns emphasising the benefits and importance of such research.
 The first major finding of the project is the identification of stigma about pregnancy and pharmaceuticals arising out of the mid twentieth century pharmaceutical scandals.  This stigma continues to distort the perception of risk during pregnancy, such that the risk of inaction during pregnancy is significantly undervalued and the risk of actions—particularly pharmaceutical interventions—is overestimated. This is related to both the exclusion of pregnant women from pharmaceutical research, and an accompanying tendency towards medical over-intervention in childbirth. The second major finding is how narratives of health and risk construct pregnancy as women’s initiation into ‘responsible motherhood’ and the corresponding surveillance, pressures and expectations that align with the narrative. Pregnant women’s desire to act in their child’s best interest and the knowledge that not only acting or choosing ‘wrong’ may harm their child, make women less inclined to both take risks and/or act outside of conventional norm.
 This thesis recommends that successful, stakeholder education needs to widen to include a broader range of issues including the effect of stigma upon risk perception, the broader bias towards inaction, and the normative strength of social narratives of good mothering and maternal responsibility.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract: This dissertation explores the idea of pregnancy as site of risk. It argues that pregnancy is best characterised as a state that is simultaneously healthy and at risk. The tension between these two ways of understanding pregnancy is central to many ethical issues related to pregnancy. This study identifies ideas about pregnancy that impede clinical research during pregnancy. The first major finding of the project is the identification of stigma about pregnancy and pharmaceuticals arising out of the mid twentieth century pharmaceutical scandals. The second major finding is how ideas of health and risk construct pregnancy as women’s initiation into ‘responsible motherhood’ and the corresponding surveillance, pressures and expectations that align with the narrative. This thesis recommends that stakeholder education needs to include a broader range of issues including the effect of stigma, the bias towards inaction, and the role of social narratives of good mothering and maternal responsibility.


title: Physics-based and data-driven strategies for simulating colloid behavior in fractured aquifer systems

contributor:
Dickson, Sarah
El-Dakhakhni, Wael
Civil Engineering

subject:
Colloids
Fractures
Data driven
Aquifer system

abstract: The design of effective quality management strategies in groundwater systems is crucial, as clean water is essential for livelihood, health, and development. Colloids represent a class of contaminants that might be pathogenic or benign. Colloids can also enhance or inhibit the transport of dissolved contaminants in groundwater, which has inspired the use of benign colloids in the remediation of contaminated aquifers. Reliable modelling of colloid behavior is therefore essential for the design of effective remediation strategies, both those employing benign colloids and those aiming at the removal of pathogenic colloids. While colloid transport is controlled by groundwater velocity, colloid retention is governed by the physical and chemical properties of the aquifer together with those of the colloid. The present study aims at enhancing the reliability of modelling colloid behavior in fractured aquifers through: i) developing a synchronization-based framework that can effectively identify hydraulic connections within the aquifer; ii) developing a mathematical model for the relationship between the fraction of colloids retained along a fracture (Fr) and the parameters describing the aquifer’s physical and chemical properties; iii) developing an analytical model for the relationship between Fr and the coefficient describing irreversible colloid deposition in single fractures; and, iv) developing a numerical technique that can efficiently simulate colloid behavior in single fractures and fracture networks under different physical, chemical, and matrix conditions. The performance of the synchronization-based framework, mathematical and analytical models, and the numerical technique was assessed separately for different verification cases, and the corresponding efficacy was confirmed. Coupling the tools developed in the present study enables the reliable prediction of colloid behavior in response to changes in the groundwater-colloid-fracture system’s physical and chemical properties, which can aid in understanding how to manipulate the system’s properties for the effective design of groundwater quality management and remediation strategies.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract: Microorganisms, microplastics, clay, and fine silt are classified as colloids within the spectrum of contaminants that might exist in groundwater. Although some colloids are benign (e.g., clay and fine silt), they can still affect the groundwater quality and aquifer porosity. Colloids can also enhance or inhibit the migration of other contaminants in groundwater because of their high adsorption capacity. Several remediation strategies are being envisioned to remove pathogenic colloids and eliminate other contaminants adsorbed onto benign colloids, where effective design of such strategies requires reliable models of colloid behavior. The present study aims at enhancing the reliability of simulating colloid behavior in fractured aquifers through: i) developing models that capture the effects of the aquifer’s physical and chemical properties on colloid behavior; and, ii) designing a framework that improves the reliability of aquifer conceptualization. Effective remediation strategies can then be designed for contaminated fractured aquifers based on the developed tools.


title: A Qualitative Study on Perceived Barriers and Facilitators of Implementing an Antimicrobial Stewardship Intervention in the Management of Urinary Tract Infections in a Long-Term Care Setting

contributor:
Dolovich, Lisa
Health Research Methodology

subject:
antimicrobial stewardship
long-term care
barrier
facilitator
urinary tract infection

abstract:
Background
50% of antibiotic courses in long-term care facilities (LTCFs) are unnecessary, leading to increased risk of harm such as Clostridiodes difficile infection and antibiotic-resistant organisms. Antimicrobial Stewardship (AS) interventions plays an important role in optimizing antibiotic use. Most studies to improve antibiotic prescribing in LTCFs showed modest and unsustained results. We aimed to identify facilitators, barriers and strategies in implementing a urinary tract infection (UTI)-focused AS intervention at a LTCF with the secondary objective of exploring the pharmacist’s potential role(s) in this intervention.

Methods
A qualitative approach using conventional content analysis was used. Through purposeful sampling, we recruited different healthcare providers and administrators at Kensington Gardens. Interviewees attended focus groups or one-on-one interviews. Data were collected using a semi-structured interview guide. Data were analyzed inductively using a codebook modified in an iterative analytic process. Barrier and facilitator themes were identified from the transcripts and mapped using the COM-B (capability, opportunity, motivation and behaviour) model (Michie et al). Similarly, themes were identified from the transcripts regarding the pharmacist’s roles in this intervention.

Results
Sixteen participants were interviewed. Most barriers and facilitators mapped to the opportunities domain of the COM-B model. The main barrier themes were lack of access, lack of knowledge, ineffective communication, lack of resources and external factors while the main facilitator themes were education, effective collaboration, good communication, sufficient resources and access. For the pharmacist’s role, the barrier themes were ineffective collaboration and communication. Furthermore, the pharmacist can play a role in education and antibiotic selection.

Conclusions
A UTI-focused antimicrobial stewardship intervention in LTCF should consider strategies to improve access, knowledge, communication and collaboration in its design, having sufficient resources and addressing external factors in order to optimize the intervention’s success.  Pharmacists can play a role in education and antibiotic selection.

abstract: Thesis

abstract: Master of Science (MSc)

abstract: Half of antibiotics prescribed in long-term care are not needed, leading to increased harm. It is unclear which strategies should be used to improve antibiotic prescribing. This project aims to identify facilitators, barriers and strategies in identifying and managing urinary tract infection in a long-term care facility as well as exploring the role of the pharmacist in this setting. We conducted focus groups and interviews to gather information and analyzed the transcripts to determine barrier and facilitator themes relating to urinary tract infection management and the role of the pharmacist. The main barrier themes were lack of access, lack of knowledge, ineffective communication, lack of resources and external factors while the main facilitator themes were education, effective collaboration, good communication, sufficient resources and access. For the pharmacist’s role, the barrier themes were ineffective collaboration and communication. In addition, the pharmacist can play a role in education and antibiotic selection.


title: EVALUATING ANALGESIC INTERVENTIONS FOR ACUTE SURGICAL PAIN, PREVENTION OF PERSISTING POST-SURGICAL PAIN, AND CHRONIC LOW BACK PAIN

title: Analgesic Interventions in Acute and Chronic Pain

contributor:
Thabane, Lehana
Health Research Methodology

subject: analgesia; pain; chronic pain; pain prevention; opioids; ketamine; steroids; gabapentin; low back pain; pregabalin; systematic review; metaanalysis

abstract: Acute and chronic pain conditions cause significant patient distress, interference with daily activities, and increased health care costs. It is important to evaluate analgesic interventions to improve pain relief, function, quality of life, and also to prevent persisting pain after surgery. This thesis is a combination of studies evaluating analgesic interventions in the setting of acute surgical pain; prevention of persistent post-surgical pain; and chronic low back pain. In part 1, we report our comparison of morphine and hydromorphone in 402 ambulatory surgery patients, for their ability to achieve satisfactory analgesia with minimal emesis using a design of multicentre randomized controlled trial. We observed no differences in their analgesic potential and common side effects and note that appearance of side effects is likely to be idiosyncratic. In part 2, we report our 2×2 factorial feasibility trial to prevent persistent post-surgical pain in patients having elective video-assisted thoracic surgery lobectomies, comparing N-methyl-D-aspartate antagonists versus placebo, and intravenous steroids versus placebo. As our feasibility outcomes were not met, we suggest appropriate considerations for protocol changes before embarking on a definitive larger trial. In part 3, we report on our systematic review and meta-analysis assessing the effectiveness and safety of gabapentinoids (gabapentin and pregabalin) in adult patients with chronic low back pain. We observed that the existing evidence is small and there is minimal improvement in pain and other outcomes with potential for adverse events. We suggest that the use of gabapentinoids for chronic low back pain merits caution and there is need for large high-quality trials.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract: It is important to evaluate analgesic interventions to decrease pain, improve function, and lessen health care costs. In a randomized controlled trial of day surgery patients, we demonstrate that there are no differences between morphine and hydromorphone in achieving pain relief and common side effects. To prevent persistent post-surgical pain in patients having elective video-assisted thoracic surgery lobectomies, we performed a 2×2 factorial, feasibility randomized controlled trial, to compare N-methyl-D-aspartate antagonists versus placebo, and intravenous steroids versus placebo. We observe that appropriate protocol changes must be made before embarking on a larger trial. Finally, we report our systematic review and meta-analysis on the use of gabapentinoids in adult patients with chronic low back pain and observe that the existing evidence is small and not supportive, and the use of gabapentinoids for chronic low back pain merits caution.


title: ELEVATED TEMPERATURE DEFORMATION AND FORMING BEHAVIOUR OF AA7075 ALUMINUM SHEET MATERIAL

contributor:
Jain, Mukesh
Mechanical Engineering

abstract:
Aluminum alloys are considered an attractive candidate in industry for automotive panels
and structural parts for their high strength to weight ratio and consequently their higher
potential for reduced fuel consumption and reduced carbon emission to environment.
Wrought aluminum alloys from AA5xxx and AA6xxx series have been predominantly
used in the manufacturing of automotive panels in the past. However, automotive industry
is looking at aluminum alloys from AA7xxx series for further light weighting of
automotive structural components. Specifically, AA7075 alloy has been of much interest
especially in the context of hot stamping process since its room temperature formability is
quite limited.
This thesis aims at understanding the room and elevated temperature formability of
automotive AA7075 sheet metal in different tempers (F, O and T6). Also, the relationship
between formability, fracture, other mechanical properties, and microstructural and
surface characteristics of this alloy are investigated in the low temperature range, 180°C-
260°C, in isothermal forming of this alloy. SEM-based microstructure studies for voidinduced
damage and fractographic analysis as well as X-Ray diffraction (XRD) studies
for analyzing undeformed and deformed grain orientation distribution (bulk texture) are
carried out for different AA7075 sheet metal tempers. In addition, a study of development
of surface roughness and material flow localization as a function of strain path and
temperature is carried out. Lastly, two different strain rate and temperature dependent
constitutive material models for AA7075 sheet are utilized in conjunction with the welliv
known Marciniak-Kuczynski (or M-K) theory to predict the forming limits in the above
experimental temperature range.

abstract: Thesis

abstract: Candidate in Philosophy


title: Access and Use of Formal Health and Social Services by Caregivers of Stroke Survivors: An Interpretive Description Study

title: Health and Social Service Use: Caregivers of Stroke Survivors

contributor:
Ploeg, Jenny
Nursing

subject:
Stroke
Caregivers
Health and social services
Access
Use

abstract:
Background: Evidence has shown that family and friend caregivers of stroke survivors are significantly and negatively impacted by caregiving.  The negative effects of caregiving may persist over time suggesting the need for ongoing care and support.  However, little is known about caregivers’ use of formally funded health and social services or the factors influencing their access to and use of these services.
Purpose: To increase understanding of: (a) the context of providing care for a stroke survivor; (b) the experiences of stroke caregivers in accessing and using formal health and social services; and (c) the factors that influence stroke caregivers’ use of formal health and social services, from the perspective of stroke caregivers and healthcare providers.
Methods: A qualitative study was conducted using interpretive description.  In-depth interviews were conducted with caregivers of survivors who experienced a stroke between six months to five years ago and healthcare providers who support caregivers and stroke survivors.  Constant comparison was used to identify codes and develop key thematic constructs.
Results: Interviews were conducted with 22 stroke caregivers at an average 30 months post-stroke and 18 health providers.  Key findings include: (a) few caregivers use services, (b) caregivers face challenges accessing services, (c) services used by stroke survivors benefit caregivers, and (d) factors influencing stroke caregivers’ use of services include: adequacy of social support networks, finances and transportation, and trust in leaving the stroke survivor under the care of health providers.
Conclusion: Stroke caregivers experience significant challenges in accessing and using formal health and social services.  These challenges could be addressed by increasing availability of subsidized community-based supports such as respite and counselling tailored to meet the ongoing needs of caregivers.  Systemic change is needed by the health system that readily includes and supports caregivers throughout the stroke recovery continuum, particularly in the community setting.

abstract: Dissertation

abstract: Doctor of Philosophy (PhD)

abstract: Caregivers often experience challenges supporting stroke survivors.  Their caregiving role may negatively affect their health and ability to return to their previous lifestyle.  Little is known about stroke caregivers’ use of funded supportive services.  The purpose of the study was to better understand caregivers’ experience using health and social services as well as the factors that influenced their access to and use of these supportive services.  Findings showed that: (a) few caregivers use services despite expressing a need for these services (e.g. counselling), (b) caregivers struggle to trust the health providers supporting the stroke survivors, (c) caregivers’ social lives are often greatly affected by their caregiving role which in turn impacts their need for services, and (d) caregivers pay many financial costs when using supportive services.  Overall, better ongoing assessment of stroke caregivers is required including using tailored services to meet their needs and help them in their caregiving role.


title: The influence of short-term aerobic training on muscle hypertrophy and satellite cell content following resistance training in healthy young men and women.

contributor:
Parise, Gianni
Kinesiology

subject:
Satellite cells
Hypertrophy
Capillaries

abstract: Resistance exercise training is the most effective and accepted strategy for increasing skeletal muscle mass and strength.  There is tremendous individual variability in the adaptive response to exercise and the source(s) contributing to this variability are largely unknown.  Recent evidence in the literature supports the notion that capillaries may be a potential target for improving outcomes to chronic resistance exercise.  Aerobic exercise training is a proven stimulus for eliciting angiogenesis and increasing capillary content.  Therefore, we hypothesize that completing a period of aerobic training prior to resistance training will result in a greater increase in fibre cross sectional area (CSA) compared to resistance training alone.  Fourteen participants (8M, 6F) completed 6 weeks of unilateral single leg aerobic training prior to undergoing 10 weeks of bilateral lower body resistance exercise training.  Performance and anthropometric measures were completed at baseline, post aerobic training and post resistance training.  Skeletal muscle biopsies were obtained from the vastus lateralis and immunofluorescent staining of muscle cross sections was completed to determine fibre CSA and satellite cell content.  Following unilateral aerobic training, single leg VO2 work peak (Watts) (p<0.001), and oxygen consumption (O2 mL  min-1) (p=.0033) was significantly higher in the aerobically trained limb (EX) versus the control (CTL) limb.  Capillary to perimeter fibre exchange index (CFPE) (p<0.05), a measure of microvascular perfusion, was significantly higher in the EX versus CTL limb following unilateral aerobic training.  Resistance training resulted in increases in 1-repetition maximum of both squat (p<0.0001) and leg press (p<0.0001).  A main effect of time was observed for limb fat free mass (p<0.0001) as determined via DEXA.  Type-II fibre CSA of the EX limb was greater (p<0.05) versus CTL limb following resistance exercise training.  Type-II fibre associated satellite cell content of the CTL limb was elevated (p<0.01) following resistance training.  Results suggest that a period of unilateral aerobic training elevates the aerobic capacity and relative microvascular perfusion of the trained leg significantly in comparison to the non-aerobically conditioned limb.   Subsequent resistance training, bilateral leg strength increased post resistance training while type II CSA increased in the aerobically pre-conditioned limb following resistance training.  Collectively, these results suggest that a period of aerobic preconditioning may augment the muscle’s ability to respond to a hypertrophic stimulus.

abstract: Thesis

abstract: Master of Science (MSc)

abstract: Resistance exercise training is the most effective and accepted strategy for increasing skeletal muscle mass and strength.  Yet, there is tremendous individual variability in the adaptive response to exercise and the source(s) contributing to this variability are largely unknown.  Recently, evidence has emerged suggesting that capillaries may be a potential target for enhancing the adaptive response to chronic resistance exercise training.  Research has only begun to characterize the extent to which microvascular perfusion (capillarization and blood flow to the muscle) plays a role in muscle health and resistance training outcomes.  Currently, it is unknown if elevating microvascular perfusion is enough to facilitate greater accretion (hypertrophy) of muscle mass and strength following resistance training.  Therefore,  the current study hypothesized that increased microvascular perfusion induced by a pre-conditioning period of aerobic training, lasting 6-weeks, would be sufficient to enhance muscle accretion (hypertrophy) and elevate muscle stem cell content following resistance exercise training.  To examine this, a cohort of young men and women performed 6 weeks of unilateral (single-leg) cycling following by 10 weeks of bilateral (both legs) resistance exercise training.  Results demonstrated an increased oxidative capacity and capillary perfusion in the aerobically-trained limb following single-leg cycling, as expected.  Consistent with our initial hypothesis, we observed superior muscle hypertrophy of type-II muscle fibres (increased fibre cross-sectional area), in the aerobically-conditioned limb following resistance training.  The results suggest that muscle capillarization may be a determinant and facilitator of adaptation to resistance training and its outcomes.


title: CHARACTERIZING THE RELATIONSHIP BETWEEN PCSK9 AND THE ENDOPLASMIC RETICULUM (ER): IMPLICATIONS IN CARDIOMETABOLIC DISEASE

contributor:
Austin, Richard
Medicine

subject:
PCSK9
lipid metabolism
cardiovascular disease
ER stress

abstract:
The proprotein convertase subtilisin/kexin type 9 (PCSK9) was first characterized in 2003 by Seidah and colleagues and marked the beginning of what is now considered by many as the greatest advancement in the field of cardiovascular disease (CVD) research since the discovery of the LDLR nearly half of a century ago. Since its discovery, PCSK9 was shown to enhance the degradation of cell-surface low-density lipoprotein (LDL) receptor (LDLR) and gain-of-function (GOF) mutations were shown to correlate with CVD risk. In contrast, patients carrying loss-of-function (LOF) mutations in PCSK9 highlighted a novel therapeutic approach for LDL lowering as they exhibit a life-long state of hypocholesterolemia and reduced CVD risk.  A decade after the cloning of the PCSK9 gene, pharmaceutical companies have now developed a variety of PCSK9 inhibitors, ranging from monoclonal antibodies (mAbs) to small interfering RNA (siRNA) and vaccines, which have been shown to markedly reduce LDL cholesterol levels in pre-clinical models, as well as in patients at high risk of CVD. Despite these advances, there remained several unanswered questions regarding the mechanisms by which PCSK9 expression and secretion is regulated in the liver; the tissue from which the circulating pool of PCSK9 almost exclusively originates. The thought that further development of our understanding of PCSK9 biology may lead to the discovery of a signaling cascade that could be targeted by small molecules, the only class of inhibitor that has not yet been developed, has now merited additional research attention.
	The focal point of my doctoral studies represents the axis between a cellular process known as endoplasmic reticulum (ER) stress and PCSK9 expression/biosynthesis. ER stress is a deleterious cellular process that is known to occur in secretory cell types, such as liver hepatocytes, and is a well-established causative driver of an array of human diseases ranging from CVD to neurodegenerative diseases. ER stress is prevalent in the livers of patients with metabolic disease and is also known to activate the transcription factor capable of regulating PCSK9 levels, the sterol regulatory element-binding protein 2 (SREBP2). Based on this information, the first aim during the course of my PhD studies was to determine whether ER stress affected the expression and secretory status of PCSK9. In the past several years, I demonstrated that ER stress caused by ER Ca2+ depletion led to a marked increase in PCSK9 protein expression, but blocked its secretion as a result of its retention in the ER. Such a result was also associated with heightened hepatic LDLR expression and reduced LDL cholesterol levels in mice. Additional studies also characterized a variety of agents, including caffeine, as potent inhibitors of PCSK9 expression via increasing ER Ca2+ levels, which antagonized SREBP2 activity.  As our initial studies revealed ER PCSK9 retention as a viable strategy for PCSK9 inhibition and LDL lowering, follow-up studies were also carried out to determine the outcome of such a strategy on liver function and injury. Given that heritable mutations in proteins that transit the ER can accumulate in this compartment and cause ER storage disease (ERSD), it was critical to further evaluate whether ER PCSK9 retention would lead to a similar outcome.
	In a series of experiments with rather surprising outcomes, we observed that the retention of the LOF Q152H PCSK9 mutant in the ER failed to cause ER stress; even in mice overexpressing the protein. Interestingly, tissue culture and mouse models demonstrated that the retention of PCSK9 in this cellular compartment increased the cellular abundance of ER stress response chaperones, such as the glucose-regulated proteins of 78- and 94-kDa (GRP78 and GRP94, respectively), but did not activate transducers of the ER stress signaling cascade. Strikingly, mice expressing the ER-retained PCSK9 Q152H mutant were protected against ER stress, suggesting a novel co-chaperone-like role of intracellular PCSK9. Collectively, the ER environment including secondary messengers like Ca2+ as well as its chaperones, plays a critical regulatory role on PCSK9 expression and secretion. Agents that increase ER Ca2+ levels can be utilized to block PCSK9 expression at the mRNA level to increase hepatic LDL clearance, and ER PCSK9 retention may also represent a safe avenue with a similar LDL lowering outcome. Beyond LDL lowering, hepatic ER PCSK9 retention may also serve as a novel strategy to enhance ER function and protect against ER stress-driven diseases of the liver.

abstract: Thesis

abstract: Doctor of Philosophy (Medical Science)


title: SYNTHESIS OF EDEINE DERIVATIVES AS AN APPROACH TO TACKLE THE ANTIBIOTIC CRISIS

contributor:
Capretta, Alfredo
Chemistry and Chemical Biology

subject:
edeine
organic chemistry
synthesis
antibiotic

abstract:
Abstract
	The current rise in antibiotic resistance and lack of discovery of new antibiotics in recent years has caused an antibiotic crisis. A strategy for overcoming this crisis is to relook at previously discarded antibiotics and with medicinal chemistry, use their structure as a scaffold for the development of a new antibiotic. Edeines are a group of antimicrobials discovered by Kurylo-Borowska in 1959 that were discarded for toxicity and this work aimed to use edeine for the structural basis in the development of a novel antibiotic. Using both solution phase and solid phase peptide synthesis ꞵ-tyrosine-L-isoseryl-diaminopropionic acid was synthesized to develop a synthetic strategy for the peptide synthesis of Edeine A. Solid phase peptide synthesis techniques were used to synthesize two simplified edeine analogues which demonstrated that the amino acid 2,6-diamino-7-hydroxylazaleic acid was necessary for antimicrobial activity. A synthetic strategy for the synthesis of 2,6-diamino-7-hydroxylazaleic acid (DAHAA) using ring closing metathesis and aminohydroxylation was developed and starting materials were synthesized. Using solid phase synthesis and the strategy for synthesizing DAHAA, a library of edeine analogues could be made using parallel synthesis and assayed for specific antimicrobial activity. This could lead to the development of a lead antibiotic which used edeine as a structural scaffold, therefore a novel antibiotic could be clinically used without large scale resistance present in the environment like the currently used antibiotics.

abstract: Thesis

abstract: Master of Science (MSc)


title: DEVELOPMENT OF POLYOLEFIN-BASED MULTIPLE AND REVERSIBLE SHAPE MEMORY POLYMERS

contributor:
Zhu, Shiping
Thompson, Michael
Chemical Engineering

subject:
reversible shape memory polymer
polyolefin

abstract:
A shape memory polymer (SMP) is stimuli-responsive with the fantastic capacity to “memorize” a temporary shape under certain conditions and to recover to its permanent shape upon exposure to certain external stimulus (e.g. heat, light, electromagnetic field). In the past few decades, various SMPs have been investigated and applied in the area of aerospace, biomedicine, and textiles, etc. Recently, a special type of SMP called a ‘two-way reversible shape memory polymer’ or ‘reversible shape memory polymer’ (RSMP) capable of transitioning between two temporary shapes without the need for reprogramming after each change has attracted the attention of many researchers. In this class of polymer, the semicrystalline RSMP was studied considerably due to the various chain structures produced by relatively simple synthesis routes. The crystallization-induced elongation (CIE) and melting-induced contraction (MIC) of the oriented crystal domains has been theorized as the main mechanism of semicrystalline RSMP. However, most RSMPs are predominantly thermosets, which implies significant drawbacks regarding reprocessing and recycling.
This thesis focuses on the development of RSMP based on polyolefin materials, especially novel high-performance polyolefin elastomers, due to the advantages of high crystallizability, varying chain structures, tunable and broad melting transitions, and low cost. The thesis starts off by demonstrating the reversible shape memory effect (RSME) of the thermoplastic ethylene/1-octene diblock copolymer, which contains the ethylene-rich hard segments and the 1-octene-rich soft segments. The delicately designed chain structure exhibited a broad melting transition and strong physical crosslinks, which contributed to the resulting RSME and the CIE/MIC effect at load-free conditions. Furthermore, the commercially available polyolefin elastomer blends demonstrated the RSME. The utilization of commercial products and simple processing method to achieve a thermoplastic RSMP offers easy production in large scale and low costs. The second part of the thesis developed a polyolefin-based RSMP with reconfigurable network by introducing a transesterification catalyst into a crosslinked poly(ethylene-co-vinyl acetate). The network reconfiguration achieved a dynamic covalent polymer network by breaking the ester bonds and reconnecting. The third part of the thesis explored a new RSMP foam material developed by utilizing polyolefins. The polyolefin elastomers of differing compositions were blended and foamed to fabricate the porous structure. The RSME in a load-free condition was then demonstrated successfully. This thesis represents significant progress in the development of polyolefin-based RSMPs, outlining new structural design, processability improvements, and potential applications.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract: Shape memory polymer (SMP) is stimuli-responsive capable of “memorizing” a temporary shape and yet recovering to its permanent shape upon a certain external trigger. SMPs are widely studied and applied in the areas of aerospace, biomedicine, textile, etc. On the other hand, a reversible shape memory polymer (RSMP) is a new type of SMP that can shift back and forth between two different temporary shapes without the need of reprogramming between transitions, and has been applied in soft actuators, microrobotics, and artificial muscles. In this thesis, unique polyolefin-based RSMP were developed with good reprocessability and shown in new application scenarios. Firstly, a thermoplastic semicrystalline polymer was demonstrated to exhibit the reversible shape memory effect (RSME) by using a lab-designed ethylene/1-octene diblock copolymer and commercial polyolefin elastomer blends. Subsequently, the reprocessability of a crosslinked poly(ethylene-co-vinyl acetate) (PEVA) RSMP was improved by introducing a dynamic covalent polymer network. Finally, transitional changes between shapes was amplified by developing a RSMP foam by utilizing polyolefin elastomer blends. This thesis represents significant progress in the study of polyolefin-based RSMPs.