title: Exploring Core-Periphery Subjectivities: Transnational Advocacy Networks  and Environmental Movements in India

contributor: Political Science - International Relations

subject: Transnational Advocacy Networks; Environment; Global South; Environmental Politics; Social Movements; India.

abstract: This dissertation reveals the long-term implications of Transnational Advocacy Networks (TANs) on domestic environmental non-governmental organizations (ENGOs) in India. It asks two questions: i. what opportunities and challenges do Indian NGOs face while addressing environmental issues within a transnational framework? ii.  in what ways can southern domestic activists reduce the challenges of TAN neocolonialism and Indian state repression? It argues that TANs fail to leverage indigenous interests in the global South and that TAN activity increases Indian activists’ exposure to state repression. Existing transnational relations literature downplays the neocolonial side of transnationalism in favour of the short-term benefits of international recognition and material and financial aid. Drawing on over 50 research participant interviews and print documents collected over the course of six-months in New Delhi and Bengaluru, the research teases out the everyday lived experiences and histories of domestic activists in TANs. It analyzes how certain traditional rural-based advocacies that adopt a Gandhi-based approach such as the Narmada Bachao Andolan (NBA) and Pathalgadi movements reject transnational alliances with international NGOs for fear of dominance and oppression, while urban-based advocacies that receive material and financial security from abroad such as Greenpeace India, ActionAid India, and Amnesty International view TANs as a boon for the Indian environmental advocacy sector. The research argues that Indian environmentalists would benefit if they shifted away from TANs towards a ‘global solidarity’ model that incorporates intersectionality between movements and South-South Transnational Advocacy Networks (SSTANs).

abstract: Thesis

abstract: Doctor of Philosophy (PhD)


title: Investigating the intrasession reliability of short and long-afferent inhibition.

contributor:
Nelson, Aimee
Kinesiology

subject:
Transcranial Magnetic Stimulation
Afferent Inhibition
Reliability

abstract: Afferent Inhibition is the reduction in motor output when Transcranial Magnetic Stimulation (TMS) of the motor cortex is preceded by peripheral nerve stimulation. Afferent inhibition can be subdivided into two circuits of Short- (SAI) and Long-Afferent Inhibition (LAI). Reliability reflects the repeatability of a measure and can be measured in terms of both absolute and relative reliability. Relative reliability refers to the ability of a measure to identify individuals on repeated testing, measured through the Intraclass Correlation Coefficient (ICC); absolute reliability is the repeatability of scores through repeated testing, measured through Standard Error of Measurement (SEM) and Smallest Detectable Change (SDC). Current literature has highlighted only the intersession reliability of SAI and LAI, but measures of the intrasession reliability are also needed. This study aims to quantify the intrasession reliability of SAI and LAI, alongside identifying the minimum number of trials needed to obtain a reliable measure. 30 healthy individuals (21.17 ± 2.84 years) took part in one session, with SAI and LAI obtained three times at 30-minute intervals. To identify the minimum number of trials required to reliably elicit SAI and LAI, relative reliability was assessed at running intervals of every 5 trials. Results indicate that SAI had moderate–high, and LAI had high-excellent relative reliability. Both SAI and LAI had high amounts of measurement error. LAI was seen to have high relative reliability when only 5 frames of data were included, whereas for SAI, ~20-30 frames of data resulted in high relative reliability. For LAI, a minimal sample size of 19 is needed to have an SDCGroup < 10, whereas for SAI, a sample size of 22 is needed to achieve the same. These results can be used to inform future work regarding the clinical utility of these measures, particularly in terms of their diagnostic ability.

abstract: Thesis

abstract: Master of Science (MSc)


title: DEVELOPMENT OF MEMBRANE CHROMATOGRAPHIC SEPARATION AND THEIR APPLICATION FOR BIOPHARMACEUTICAL (THERAPEUTIC MONOCLONAL ANTIBODIES AND T7 BACTERIOPHAGE) PURIFICATION

contributor:
Dr. Raja Ghosh, Dr. Robert Pelton
Chemical Engineering

abstract:
Biopharmaceuticals, produced and extracted from living cells and organisms, are targeted treatments for a variety of medical conditions and diseases, some of which have no other available treatments. The manufacturing of biopharmaceuticals consists of upstream and downstream processes. The downstream operation includes several steps, such as purification and quality controls, among others. The purification process is crucial in the production of biopharmaceuticals, as a high impurity rate renders the treatment unusable. The production of therapeutic biopharmaceuticals is bounded by the efficiency of the purification process. Due to its close connection to the purification process, industrial solutions such as Chromatography purification became significantly important, with several qualitative and quantitative techniques for mixture components identification, separation, and purification, was introduced and adopted within this field.
In this thesis, the Trastuzumab purification process is investigated using cation-exchange z2 Laterally-Fed Membrane Chromatography (z2LFMC) purification technique. z2LFMC in a purification device that leverages z2 flow distribution characteristics to enhance the separation efficiency of a laterally-fed membrane chromatography. Exploring the performance discrepancy between z2LFMC and affinity chromatography (Considers as one of the most diverse and powerful chromatographic methods for purification) in the process of Trastuzumab purification. The experimental evaluation highlights that both chromatography methods (z2LFMC and protein A) achieve more than 95% purity efficiency. However, the recovery rate of z2LFMC was noticeably higher (90.4% in comparison with 81.7%).
Bacteriophages were widely used to treat various bacterial diseases in people and animals. Further, the purification of T7 bacteriophage membrane chromatography by anion exchange z2LFMC shows a promising research direction. The results show that following anion exchange z2LFMC enables a recovery rate of up to 89.0%, and a 71.2% endotoxin removal rate.
This thesis further explores the potential enhancements in the separation process. In particular, Computational Fluid Dynamic (CFD) modeling is utilized toward developing several design variations of the z2LFMC. This thesis highlights that the biopharmaceuticals purification process is nowhere optimized, and several state-of-the-art approaches, including z2LFMC, can be used to significantly increase the efficiency of the purification process.

abstract: Thesis

abstract: Master of Applied Science (MASc)


title: Identifying and Characterizing Novel Antithrombin-Inhibiting RNA Aptamers

contributor:
Sheffield, William
Medical Sciences

subject: aptamers antithrombin

abstract:
Antithrombin (AT) is a plasma serine protease inhibitor that regulates thrombin and other activated clotting factors in the intrinsic and common pathways of coagulation. As the most abundant coagulation pathway inhibitor, AT serves to maintain balance in the coagulation system by inducing an anticoagulant effect. The importance of AT is evident in cases where deficiencies of AT lead to increased risk of venous thromboembolic disease. Since an AT antagonist would be considered a procoagulant, inactivating AT could provide a novel approach to restoring hemostasis in patients with inherited or acquired bleeding disorders.
In vitro selection is a powerful tool used to screen large combinatorial oligonucleotide libraries against a target molecule or protein. By employing this technique in combination with high-throughput screening, we identified novel RNA aptamer candidates capable of binding AT with high affinity and inhibiting AT’s inactivation of its main target protease, thrombin.
Kinetic characterization of the most abundant aptamer candidates showed a reduction in AT-mediated thrombin inhibition of 50-60%. The most inhibitory aptamer, R6_15,  mediated a decrease of AT’s second-order rate constant from 2.37 ± 0.06 x 104 to 1.57 ± 0.02 x 104 M-1 s-1 (mean ± SD)  The interaction between the aptamers and AT was also measured in human plasma. In a clotting assay, aptamer R6_15 accelerated clotting time by approximately 7 seconds (from 44.3 ± 0.8 to 37.3 ± 0.7 seconds). This difference in clotting time was the greatest noticed among all the other aptamer candidates. By measuring the change in AT’s fluorescence intensity, we were able to determine the aptamers’ binding capacity. The binding affinities (kd) of aptamers R6_15 and R6_19 were 65.3 ± 8.7 and 67.5 ± 14.5 nM, respectively. Truncation of R6_15 on either its 5’ or 3’ end did not increase its inhibitory activity or binding affinity towards AT. By pairing the selection data with dynamic molecular modelling, the interface of aptamer R6_15 to AT was predicted to be at the site of heparin binding, specifically at residue K114. Although these computer-generated results are not conclusive, they provide a testable hypothesis for future experimentation.
Ultimately, this work provides evidence that the application of in vitro evolution has yielded a novel anti-serpin aptamer. With some modifications, the selection protocol employed in this study could be revisited to identify tighter binders and more potent inhibitors of AT. Either aptamer R6_15 or a future higher affinity AT-binding aptamer could be tested for its efficacy in reducing bleeding in vivo using mouse models of acquired hemophilia or traumatic bleeding.

abstract: Thesis

abstract: Master of Science (MSc)


title: Control of Nanowire Growth by Droplet Dynamics with Optical Applications

contributor:
LaPierre, Ray
Engineering Physics

subject:
nanowires
optics
semiconductors
molecular beam epitaxy
photovoltaics
III-V

abstract:
Self-catalyzed GaAs nanowires (NWs) are grown epitaxially on Si(111) substrates using molecular beam epitaxy (MBE). The dynamics of the droplet are examined to improve NW yield and to control NW morphology. Control and understanding of the NW diameter via droplet dynamics is applied to NW photovoltaics and to novel corrugated NW distributed Bragg reflectors (DBRs). At the beginning of the MBE growth, a Ga pre-deposition step, between 0 s and 500 s in duration, is introduced to improve the yield of the NW arrays. The effect of the pre-deposition time was examined for five different hole diameters and yield was increased to nearly 100% for the appropriate combination of hole diameter and pre-deposition time.
Two models were used to model the NW growth progression under different atomic flux ratios. The first model considers the contributions from direct and diffusion fluxes to the droplet and solves coupled equations for the droplet contact angle and the NW radius. The second model treats the contact angle as constant. Both models explained the accompanying experimental observations. Both models could be used to model future NW growths and the choice between the two would depend on the availability of contact angle data and whether the crystal phase must be considered.
Absorption in NWs is determined by the diameter and the HE1n modes. The effectiveness of a linearly tapered inverted conical NW is demonstrated using finite element simulations. The photocurrent of an optimized inverted conical NW array is found and shown to be similar to that achieved by optical nanocones and nanowires. Diameter modulations can also be introduced into NW structures periodically to produce corrugated NW distributed Bragg reflectors (DBRs). The tunability of the reflectance peaks is demonstrated and explained by changes to the effective refractive index of the structure.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract: This thesis seeks to understand the growth processes behind self-catalyzed nanowire growth. Nanowires (NWs) are very thin, vertical columns of semiconducting material. Self-catalyzed growth is a method of producing these structures that uses a droplet at the top of the structure to add material to the structure over time. These structures have numerous applications. This thesis focuses on solar cells and distributed Bragg reflectors (DBRs). Experiments show how control over the droplet can improve NW yield and give significant control of the NW diameter. These experiments are supported by mathematical models. Control over the diameter is important for the applications discussed. Using numerical simulations, it is shown how control over the diameter of the structure can lead to improvements in light absorption in NW solar cells. Additionally, periodic changes to the diameter can be used to create novel NW structures such as DBRs, which is a promising new application.


title: Creating Dark Matter Cosmological Simulations to Investigate the Cusp/Core Debate

subject:
Galaxy
Dark Matter
N-Body Simulation

abstract:
Simulations involving only dark matter predict central density profiles that are cusps:
asymptotically peaked negative power-laws. However observational data shows that the
dark matter distribution in smaller galaxies, such as dwarf galaxy satellites of the Milky
Way, are not cusped. Instead, observations of the orbits of stars in dwarf galaxies indicate a
relatively constant density dark matter profile in the central 2 kpc, implying considerably
less matter in those regions than expected for a cuspy profile. Simulations have shown
that highly dynamic motions of baryons such as those created from stellar feedback can
gravitationally transfer energy to collisionless components, like dark matter, and move it
to larger orbits. The net effect is to lower the central density and create a core.
Here, we present the creation of a high-resolution zoom simulation involving only dark
matter. The steps involved in the creation of initial conditions is described and can be easily
extended to include baryonic matter. Simulation analysis shows high-resolution (M_DM ∼
8 × 10^3 M_⊙) dwarf galaxies presenting cuspy density profiles. Future work recreating the
presented simulation with the addition of baryonic matter and feedback can compare with
the results presented here and further explore cusp vs core formation.


title: Novel Colloidal Methods for Fabrication of Composite Coatings

contributor:
Zhitomirsky, Igor
Veldhuis, Stephen C.
Materials Science and Engineering

subject:
colloidal processing
electrophoretic deposition
dip coating
polymer coating
composite coating
charging dispersant

abstract:
Polymer coatings are thin films of polymer deposited on different substrates for various applications. Such surface coatings can serve a functional purpose (adhesives, photographic films), protective purpose (anticorrosion), or decorative purpose (paint). Additionally, their composite coatings containing ceramic, or metal particles are often used to enhance durability, functionality, or aesthetics. Electrophoretic deposition (EPD) and dip coating are two promising methods for the fabrication of polymer and composite coatings due to the ease of fabrication, low cost, and high-volume production.
EPD involves the electrophoresis of charged particles and their deposition on the electrode surface, which requires the colloidal particles to be charged in a stable suspension as a precursor solution for deposition. Many polymers cannot be deposited by EPD directly because of their charge neutrality and poor dispersion. Therefore, it is critical to develop efficient charging dispersants to modify electrically neutral polymers for their EPD. The approach was inspired by the strong solubilization power of bile acids in the human body. Two types of bile salts, cholic acid sodium salt and sodium chenodeoxycholate, and three types of biosurfactants, carbenoxolone sodium salt, glycyrrhizic acid, and 18β-glycyrrhetinic acid, which share similar structures with bile salts, were discovered for charging, dispersion, and EPD of different materials. The electrically neutral polymers (PTFE and PVDF), chemically inert materials (diamond, nanodiamond, graphene, carbon dots, carbon nanotubes and Zr-doped hydrotalcite (MHT)), and their composites can be well dispersed in suspension and deposited using these bio-surfactants as dispersants. It was found that the unique chemical structures of these biomolecules play vital roles in the surface modification and EPD of different materials. Moreover, the deposited polymer (PVDF, PTFE) and composite (PTFE-MHT) coatings can provide outstanding corrosion protection for stainless steel. The biomimetic and versatile strategy opens a way for the deposition of other electrically neutral materials through EPD. These findings also provide a promising strategy for selecting new dispersants for EPD.
The deposition of high molecular weight (MW) polymers such as poly(ethyl methacrylate) (PEMA) at high concentrations in non-toxic solvents continues to be a challenge for dip coating. In this work, we firstly proposed using water-isopropanol as a co-solvent to dissolve high MW PEMA at high concentrations. It was found that water molecules can solvate carbonyl groups of PEMA and facilitate their dissolution. This method avoided the usage of toxic solvents and a long-time heating procedure for their removal. Moreover, it allows the fabrication of high-quality PEMA and composite coatings containing different flame retardant materials (FRMs), including double hydroxide LiAl2(OH)7.2H2O (LiAlDH), huntite, halloysite and hydrotalcite, through the dip coating method. A novel solid state synthesis method was proposed to fabricate LiAlDH, which is promising for the fabrication of other advanced DHs. Such composite coatings combined advanced properties of PEMA and functional properties of FRMs, such as corrosion inhibition and FR properties.

abstract: Thesis

abstract: Doctor of Engineering (DEng)

abstract:
Polymer and composite coatings have been utilized for a wide range of applications due to their barrier properties, scratch and abrasion resistance, chemical resistance, and biocompatibility. Various techniques have been developed to fabricate polymer and composite coatings, such as electrophoretic deposition (EPD) and the dip coating method.
However, limitations remain. EPD unitizes an electrical field to drive charged particles in a suspension toward conductive substrates to achieve film deposition. This process requires a stable suspension with charged particles, therefore, the electroneutral polymers present difficulties in their EPD. In addition, dissolving high molecular weight polymers at high concentrations in a non-toxic solvent is currently challenging, which is vital to utilize dip coating technique.
The objective of this work was to develop advanced charging dispersants for EPD of electroneutral polymers and non-toxic solvents for dip coating of high molecular weight polymers. New biomimetic and versatile approaches have been developed for EPD of different electrically neutral polymers, chemically inert materials, and their composite coatings. A non-toxic co-solvent was proposed to dissolve high molecular weight polymer at high concentration for dip coating of the polymer and its composite coatings containing flame retardant materials. The results presented in this work showed the formation of high-quality films with multifunctionality and paved new strategies for further developments.


title: Hybrid and data-driven modeling and control approaches to batch and continuous processes

contributor:
Mhaskar, Prashant
Chemical Engineering

subject:
Hybrid modeling
Advanced Process Control
Batch Processes

abstract:
The focus of this thesis is on building models by utilizing process information: from data, from our knowledge of physics, or both. The closer the model approximates reality, the better is the expected performance in forecasting, soft-sensing, process monitoring, optimization and advanced process control. In the domain of batch and continuous manufacturing, quality models can help in ensuring tightly controlled product quality, having safe and reliable operating conditions and reducing production/operation costs.

To this end, first a parallel grey box model was built which makes use of a mechanistic model, and a subspace identification model for modeling a batch poly methyl methacrylate (PMMA) polymerisation process. The efficacy of such a parallel hybrid model in the context of a control problem was illustrated thereafter for reducing the volume of fines. Real-time implementation of models in many cases demand the model to be tractable and simple enough, and thus the parallel hybrid model was next adapted to have a linear representation, and then used for control computations. While the parallel hybrid modelling strategy shows great advantages in many applications, there can be other avenues of using fundamental process knowledge in conjunction with historical data. In one such approach, a unique way of adding mechanistic knowledge to improve the estimation ability of PLS models was proposed. The predictor matrix of PLS was augmented with additional trajectory information coming strategically from a mechanistic model. This augmented model was used as a soft-sensor to estimate batch end quality for a seeded batch crystallizer process. In a collaborative work with an industrial partner focusing on estimating important variables of a hydroprocessing unit, an operational data based input-output model was chosen as the right fit in the absence of available mechanistic knowledge. The usefulness of linear dynamic modeling tools for such applications was demonstrated.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)


title: From Reconciliation to Responsiveness: Applying the Relativity Condition to Crown-Indigenous Relations in Canada

contributor:
Sciaraffa, Stefan
Philosophy

subject: Philosophy

abstract: A philosophical examination of the legal relationship between the Canadian government and Indigenous peoples. The author makes the argument here that the current legal relationship is, according to criteria developed by legal scholar Nicole Roughan, illegitimate and must be changed if the Canadian government is to achieve legitimacy.

abstract: Thesis

abstract: Master of Arts (MA)


title: Revolving Scales: Exploring Locality During the Late Formative Period on the Taraco Peninsula, Bolivia

contributor:
Roddick, Andrew
Anthropology

subject:
Archaeology
Andean Archaeology
Ceramics
GIS
Locality
Late Formative
Titicaca Basin
Bolivia

abstract: This study aims to identify processes of localization-moments when material practices become shared or diverge and become individualized- and to clarify spatial organization within Late Formative (250 BC – 590 AD) sites on the Taraco Peninsula, Bolivia. The word local is a term that can embody many meanings as a noun, an adjective, and a process of transformation, but its meaning is assumed in many archaeological investigations. Its usage, however, heavily influences how archaeologists interpret the material record, from archaeological constructions of boundaries of space, to how we conceptualize the ways in which people lived day-to-day. Pottery has also been used extensively to interpret identities, practices, and geographical boundaries through decoration and production elements. Definitions of locality are dependent on perspective and position, and “local” is dynamic in nature. I seek to open the discussion on understanding different scales of locality may intersect and how this influences the interpretations of the past. I study the distribution of ceramics from three sites, Kala Uyuni, Kumi Kipa, and Sonaji. My research explores the differences between the production of locality at these sites, and whether this is visible through ceramic production and deposition. I accomplish this using GIS to visualize and analyze the distribution of paste, surface treatment, sherd carbonization, fragmentation, and paleoethnobotanical data. The results show that ceramic production practices generally constituted one localized community of practice. When it came to depositional practices, I identified two separate localized practices in terms of the treatment of ceramic waste and where inhabitants chose to start fire-related activities. The contributions of this thesis include the creation of GIS ceramic point data, opening further discussion on the concept of locality at other relational scales, a better understanding of the daily motions of past peoples on the Taraco Peninsula, and a method for re-examining and incorporating legacy data.

abstract: Thesis

abstract: Master of Arts (MA)


title: Finite Element Modelling and High-Level Statistical Analysis for Bridge Condition Prediction and Management

contributor:
Balomenos, Georgios
Becker, Tracy
Civil Engineering

abstract:
Efficient management strategies are essential to ensure bridge safety and functionality while accommodating budget limitations. For such purpose, bridge management systems (BMSs) developed policies to predict the global bridge conditions and any performance deficiencies in the individual components. However, the current policies have some shortcomings that may limit their efficiencies. To address these shortcomings, this thesis proposes several enhancements to three major BMS policies covering inspection and maintenance planning, bearing performance assessment, and seismic screening.
Inspection and maintenance are often planned using Markov Chains deterioration models derived from past inspection records. However, Markov Chains models employ impractical assumptions and neglect the subjectivity of inspections. Alternatively, parameterized fuzzy-logistic deterioration models are proposed to predict future conditions given easy-to-track parameters, such as age and last maintenance date. The proposed models can yield better maintenance predictions compared to Markov Chains and can reduce inspection costs by 30%.
Bearing performance assessment policies are limited to testing bearing material or its behaviour at design displacements. In practice, bearings experience fatigue with repeated displacement cycles even if at low magnitudes, leading to bearing degradation and long-term increase in demands. Thus, a parameterized loading protocol is proposed to guide laboratory testing in assessing the fatigue life. The protocol is derived from the bearing demands attributes observed from a 3D nonlinear analysis in OpenSees for various bridge configurations and loading conditions.
Seismic screening policies were developed to identify the most vulnerable bridges, giving them the highest priorities. The current policies are qualitative, relying on identifying vulnerable details, rather than quantifying the actual performance. Furthermore, the vulnerability estimates are not updated with deterioration. Thus, new risk-based screening procedures are proposed via fragility analysis of the critical components, bearings and columns, while considering their deterioration. Given the components’ fragilities, a seismic vulnerability index is computed to rank the bridge’s priority.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract: Regular inspection and maintenance of bridges are vital to the integrity of transportation networks. The planning and scheduling of such activities have become known as bridge management. Given the limitations of budget and resources, there is a high demand for optimized bridge management. The fundamental goal of this thesis is to explore potential improvements for the current practices of bridge management. Towards this goal, this thesis proposes enhanced methodologies for a more accurate prediction of future bridge conditions and maintenance needs, a better understanding of the lifespan of various bridge components, and early detection of any vulnerabilities that may be detrimental to the functionality of bridges and the safety of bridge users.


title: Development of Human Brain Sodium Magnetic Resonance Imaging (23Na MRI) Methods

contributor:
Noseworthy, Michael D
Biomedical Engineering

subject: MRI, sodium, point-spread function, brain imaging

abstract: Sodium (23Na) plays a critical role in all organisms – it is crucial in cellular homeostasis, pH regulation and action potential propagation in muscle and neuronal fibres. Healthy cells have a low intracellular 23Na and high extracellular concentration, with the sodium-potassium pump maintaining this sodium gradient. In the human brain approximately 50% of its total energy consumption is occupied by maintenance of this gradient, demonstrating the pump’s importance in health. A failure of the sodium-potassium pump leads to cellular apoptosis and ultimately necrosis, with potentially disastrous results for neurological function. Magnetic resonance imaging (MRI) of 23Na is of great interest because of the ubiquity of sodium in cellular processes. However, it is hampered by many technical challenges. Among these are a low gyromagnetic ratio, short T2∗ relaxation times, and low concentrations all of which lead to long acquisitions in order to account for the poor inherent signal. In addition, 23Na MRI requires specialized hardware, non-standard pulse sequences and reconstruction methods in order to create images. These have all contributed to render clinical applications for 23Na MRI virtually non-existent, despite research indicating sodium’s role in various neurological disorders, including multiple sclerosis, Alzheimer’s, stroke, cancer, and traumatic brain injury. This work is motivated by a desire to use 23Na MRI in clinical settings. To that end, hardware and software methods were initially developed to process sodium images. In order to quantify the imaging system the point-spread function (PSF) and the related modulation transfer function (MTF) were calculated with the aid of a 3D-printed resolution phantom with different 23Na concentrations in gelatin. Two pulse sequences, density-adapted projection reconstruction (DA-3DPR) and Fermat looped orthogonally encoded trajectories (FLORET), with similar acquisition times were tested. Reconstructions were performed with the non-uniform fast Fourier transform. Results indicated a full-width, half-maximum (FWHM) value of 1.8 for DA-3DPR and 2.3 for FLORET. In a follow-up study, simulation experiments were added to various sodium phantom concentrations in 3% agar. The simulations indicated high potential variability in the MTF calculations depending on the methodology, while the phantom experiments found a FWHMs of 2.0 (DA-3DPR), and 2.5 (FLORET). Diffusion tensor imaging (DTI) is an MRI technique with wide adoption for the assessment of a variety of neurological disorders. Combining DTI with 23Na MRI could provide novel insight into brain pathology; however, a study with a healthy population is warranted before examinations with other populations. Fifteen subjects were scanned with DTI and sodium MRI, and the latter was used to derive voxel-wise tissue sodium concentration (TSC). Regional grey and white matter (WM) TSC was analyzed and compared to fractional anisotropy (FA) and cerebrospinal fluid (CSF) proximity. Results indicated that WM voxels proximal to CSF regions (i.e. corpus callosum) could have lower than expected FA values and higher measured TSC, with an inverse correlation between TSC and distance to CSF. This is likely the result of the broad PSF of 23Na MRI, as regions distal to CSF did not exhibit this phenomenon. This potentially represents a confounding effect when interpreting sodium concentrations, especially in regions proximal to the high 23Na content in CSF.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)


title: SYSTEM-LEVEL INTERACTIONS BETWEEN ROCKING WALLS AND HOLLOW-CORE SLABS

contributor:
Wiebe, Lydell Andree
Ezzeldin, Mohamed
Civil Engineering

subject: System-level Interactions, Rocking walls, Hollow Core Slabs, Incompatibility of Displacements, Wall-diaphragm interaction

abstract:
Conventional fixed base walls are typically characterized by yielding that results in permanent damage, residual drifts and costly losses due to the service shutdown for structural repairs. Controlled rocking masonry walls have been developed as a solution to prevent structural damage when seismic events take place. These systems purposely allow the wall to rock from its foundation and have an uplift at the base, thus replacing the typical yielding at the base of conventional fixed-base walls. Controlled rocking masonry walls have traditionally been controlled by using unbonded post-tensioning strands to provide the self-centering behaviour. Although post-tensioning has shown favourable results, its implementation is difficult in practical applications, and post-tensioning losses due to yielding of the strands at large deformations can reduce their self-centering ability. In order to overcome such issues, an alternative controlled rocking system for masonry walls was developed recently, which is designed to self-center through vertical gravity loads only, instead of the post-tensioning tendons. The rocking response of this alternative system is controlled by using energy dissipation devices, so the system is referred to as Energy Dissipation-Controlled Rocking Masonry Walls (ED-CRMWs). The vertical gravity loads are primarily transferred to the ED-CRMWs from the floor slab at each level. Therefore, the wall-slab interaction should be investigated in order to ensure a fully resilient system.
In this regard, the current study identifies and categorizes the potential issues that are expected to occur due to the interaction between the wall rocking mechanism and the floor slab, and then investigates the most common of these issues using a parametric study. The parametric study focuses on the vertical incompatibility of displacements that a hollow- core slab suffers when its supporting walls uplift by different displacements during seismic events. Three different spans, four different cross-sections and two different alternatives of prestress configurations are considered in this study. The models were developed using ABAQUS 6.18 commercial software. The results show the cracking/yielding behaviour of the slabs and their displacement capacities at five different stages. The obtained results are promising for the usage of hollow-core slabs on ED-CRMWs or similar systems that require this interaction, as the range of displacement capacities can accommodate many of the vertical displacement incompatibilities expected in many potential situations.

abstract: Thesis

abstract: Master of Applied Science (MASc)


title: Investigating Immune Responses and Pathology During HIV/Mtb Co-Infection Within Humanized Mice

contributor: Medical Sciences (Molecular Virology and Immunology Program)

subject:
HIV
TB
humanized mouse models
co-infection
granuloma
TB vaccine
HIV/TB co-infection pre-clinical model
in vivo HIV/TB co-infection

abstract: There are an estimated 2 billion individuals infected with Mtb, and 37.7 million people living with HIV (PLWH) worldwide. HIV/Mtb co-infection increases the risk of developing active tuberculosis by over 20-fold, and 210,000 of 1.5 million deaths from TB were among co-infected PLWH in 2020. Therefore, development of effective TB vaccination, particularly within the vulnerable PLWH population, is an urgent global issue. With limited in vivo models to study co-infection, humanized NRG (huNRG) mice and humanized DRAG-A2 mice (a next-generation of huNRG mice expressing HLA class I and II transgenes with improved human immune reconstitution, huDRAG-A2) are promising tools for HIV and TB reserach as they develop robust human immune cell populations and recapitulate many aspects of HIV or TB clinical disease. HIV/Mtb co-infection was investigated using huNRG and hu-DRAG-A2 mice in separate experiments where intravaginal (with DMPA pre-treatment) or intraperitoneal HIV-1 infection was administered, respectively, and intranasal infection of Mtb was administered 3.5 weeks later. Both huNRG and huDRAG-A2 mice recapitulated hallmark features of HIV/Mtb co-infection such as severe granuloma pathology, hCD4+ T cell depletion in lung and spleen tissue, and human like lung pathology such as Mtb-infected foamy macrophages in the granuloma. Co-infected huDRAG-A2 mice also displayed significantly higher bacterial burden in the lungs, increased extrapulmonary dissemination into spleen and liver, and significantly lower hCD4+ T cells in the peripheral blood post-Mtb infection when compared to the Mtb-only infected group. To investigate TB vaccine immunogenicity, huNRG and huDRAG-A2 mice were immunized with a novel trivalent vaccine, AdCh68MV. Upon intranasal immunization, both models showed trends of developing higher Mtb antigen-specific hCD4+ T cell responses in the lung and spleen. Overall, this project sets the initial stages of a pre-clinical HIV/Mtb co-infection model in huNRG and huDRAG-A2 mice appropriate for immune investigations, therapeutic and vaccination development.

abstract: Thesis

abstract: Master of Science in Medical Sciences (MSMS)

abstract: There are over 2 billion individuals infected with TB and 37.7 million people living with HIV (PLWH) worldwide. When someone is co-infected with both diseases, the risk of death is greatly increased. Research in co-infection and developing effective TB vaccination for PLWH are urgent global issues. Animal studies are currently limited because studying HIV requires human immune cells. Our lab has established humanized mice (hu-mice) that develop many different human immune cells and are useful for HIV/Mtb co-infection research. When hu-mice were co-infected, they showed more dying lung tissue, immune cell loss, and bacteria in the lungs. Hu-mice were also used to study human immune responses to a novel TB vaccine delivered to the lungs. Trends of higher immune responses towards TB were observed in the lung and spleen of immunized hu-mice. Overall, this project shows the utility of hu-mice as pre-clinical models of HIV/Mtb co-infection and Mtb vaccine studies.


title: CIRCULATORY AND METABOLIC ADAPTATIONS TO HIGH ALTITUDE IN DEER MICE (PEROMYSCUS MANICULATUS)

contributor:
Scott, Graham R.
Biology

abstract: High-altitude deer mice (Peromyscus maniculatus) have evolved to thrive in a persistently cold, low-O2 (i.e., hypoxic) environment that many low-altitude natives find inhospitable. As a result of strong directional selection on the aerobic capacity for heat generation (i.e., thermogenesis), these small endotherms have evolved an enhanced aerobic capacity in hypoxia. However, the physiological modifications regulating tissue O2 supply that might underlie this evolved change in aerobic capacity remain unresolved. Furthermore, very little attention has been paid to mechanisms that possibly reduce routine metabolic demands as a means of coping with cold hypoxia. The overarching goals of my Ph.D. thesis were: A) to understand the integration and mechanistic underpinnings of changes in circulatory physiology that underlie evolved increases in aerobic capacity in high-altitude deer mice; B) to elucidate the effects of chronic exposure to hypoxia or cold hypoxia on cardiovascular physiology, and C) to uncover potential strategies for reducing metabolic demands in high-altitude deer mice. I showed that (i) evolved increases in haemoglobin-O2 affinity and tissue O2 diffusing capacity likely interact to enhance aerobic capacity in hypoxia, and (ii) that evolved changes in adrenergic control of the heart likely contribute to increase cardiac output and thus help enhance aerobic capacity. I also showed that hypoxia alone has relatively modest but sex specific effects on routine metabolism, body temperature, and cardiovascular function in mice. However, cold hypoxia leads to energy-saving reductions in body temperature setpoint that curb the metabolic costs of endothermy, and high-altitude deer mice have evolved a lower body temperature than their low-altitude counterparts. My thesis shows that both environmentally-induced plasticity and evolutionary adaptations in circulatory physiology and metabolism help improve O2 supply and reduce O2 demands in high-altitude deer mice, to help them cope with the unremitting cold and hypoxic conditions at high altitude.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract: Deer mice that live at high altitude have developed genetic adaptations to survive in challenging environments. These mammals must maintain high metabolism to generate body heat and stay warm in the cold temperatures at high altitude, despite the air around them being thinner with less oxygen than at sea level. Previous research has shown that high-altitude deer mice have evolved several physiological adaptations that help them transport oxygen from their environment to the tissues that generate body heat. Less is known about how these adaptations interact at a systems level, the regulatory processes that contribute to these adaptations, and whether high-altitude deer mice also possess adaptations to reduce energetic demands in the cold. In my Ph.D. thesis, I aimed to address these gaps in knowledge. Together, my findings demonstrate that both improvements in oxygen supply by the circulatory system and reductions in body temperature help high-altitude deer mice cope with their extreme environment.


title: The Synthesis and Characterization of Some N-Hydroxyaminopyrenes

title: N-Hydroxyaminopyrenes

contributor:
McCarry, B. E.
Chemistry

subject: N-Hydroxyaminopyrenes, synthesis, nitropyrene, nitro-PAH, dinitropyrenes

abstract:
Nitrated polycyclic aromatic hydrocarbons (nitro-PAH) are
environmental contaminants that have been identified in
extracts of particulates obtained from automobile exhaust,
diesel exhaust, and power plant emissions. One of the most
abundant nitro-PAH, 1-nitropyrene, has been found to be a
powerful bacterial mutagen and a carcinogen in animal tests.
In a bacterial strain (Salmonella tvphimurium TA98) 1-
nitropyrene undergoes reduction and concomitant covalent
binding to DNA, presumably via the N-hydroxy-l-aminopyrene.
This labile compound was prepared by the ascorbic acid
reduction of 1-nitrosopyrene and was characterized by high
performance liquid chromatography (HPLC), combined liquid
chromatography-mass spectrometry (LC-MS), ultraviolet-visible
(UV-VIS), fluorescence and nuclear magnetic resonance (NMR)
spectroscopy (1H and 15N) . In addition the pH stability and
some reactions of this compound were studied. The 1,6- and
1,8-hydroxylaminonitropyrenes derived from the very potent
mutagens 1,6- and 1,8 dinitropyrene were also synthesized and
characterized by high performance liquid chromatography,
ultraviolet-visible and nuclear magnetic resonance
spectroscopy (1H and 15N) .

abstract: Thesis

abstract: Master of Science (MSc)


title: Utilizing Micro-Thermal Networks for Energy Demand Response

contributor:
Cotton, James
Lightstone, Marilyn
Mechanical Engineering

subject:
Micro-Thermal Network
Community Energy Solution
District Heating
Demand Response

abstract:
In recent years, the electrification of technology that is traditionally powered by fossil fuels has become a popular means to reduce greenhouse gases (GHG). Although the intentions are well founded, the strain on the electrical grid is seldom taken into consideration. When there is increased load on the grid, it is typically met by fossil fuel peaking power plants or additional fossil fuel infrastructure. Depending on the electrical generation technology deployed and the power plant efficiency, electrification can result in an increase in GHG emissions. To make better informed decisions for GHG reductions, policy makers and engineers are in need of smart energy systems, such as the Integrated Community Energy and Harvesting (ICE-Harvest) system. ICE-Harvest systems work with and can respond to changes on the electrical grid, providing demand response. The system creates electrical demand when renewable generation sources are available, reduces demand when fossil fuel generation is present, and can offset centralized generation using distributed combined heat and power resources.
In this thesis, steps to design a micro-thermal network (MTN) for the ICE-Harvest system are outlined and different operational strategies are explored that respond to grid behaviour in real time. How fast the thermal network reacts to grid level variations is defined as the response time. The physical response of the thermal network is a temperature set point change. A design map was developed presenting multiple parameters that contribute to the response time, the trade-offs between them, and the corresponding temperature difference achievable.
Through developing models in the equation-based object-oriented software Dymola, the viability for real time temperature set point changes in micro-thermal networks was explored. The MTN and the energy transfer stations (ETSs) that transfer energy between the thermal network and the buildings have been modeled. Yearly system simulations were conducted to analyze the corresponding performance of the MTN in terms of electrical requirements and overall GHG emissions. An operational range of the system was presented demonstrating the flexibility of the ICE-Harvest system.
The simulation results have identified the ICE-Harvest system as a viable means to provide demand response to the grid and to reduce GHG emissions. Future work and recommendations will be made to improve the response of the system and further reduce electrical consumption and GHG emissions.

abstract: Thesis

abstract: Master of Science in Mechanical Engineering (MSME)


title: Aging at the intersection of race and gender: Investigating the health and wellbeing of aging Black women in Canada

contributor:
Kapiriri, Lydia
Grignon, Michel
McKenzie, Kwame
Health and Aging

subject:
Health
Aging
Race
Intersectionality
Life Course
Policy
Mixed Methods

abstract: Inequities in health systematically put groups of people who are socially disadvantaged due to being poor, female, a particular age and/or a member of a disenfranchised racial group at further disadvantage. Black people comprise 3% of Canada’s population and are more likely to be exposed to risk but less likely to seek preventative care. Older Black women face further disadvantages because of multiple intersecting factors related to their race, gender, and age. This dissertation presents findings from a sequential mixed methods study conducted to understand the health, wellbeing, and aging experiences of older Black women aged 55 and older in Canada. The study design and data analysis were informed by two theoretical frameworks: intersectionality and the life course perspective. First, using data from the Canadian Community Health Survey (CCHS), several multilevel logistic regression models were used to establish and compare association between racial identity and inequalities in hypertension, diabetes, cancer, chronic obstructive pulmonary disease (COPD), asthma, self-rated health, and self-rated mental health between Black and White men and women aged 55 and older. Second, qualitative phenomenological interviews were conducted simultaneously to gain a deeper understanding of the health and wellbeing of older Black women and factors that have influenced their health and wellbeing across their life course. These were factors that could not be deeply explored through the CCHS. Twenty-seven semi-structured interviews were conducted with Black women aged 55 and older living in the Greater Toronto Area. Following the conclusion of the first two phases, a thematic content analysis was completed for eight policy documents to determine whether and how the need for adequate housing among older Black women was addressed. These needs were identified in the semi-structured interviews conducted in the previous qualitative phase of the study. Overall, this study demonstrated that there are opportunities for additional research to understand the diverse aging experiences of women across their life course. It also demonstrated the opportunities for the use of intersectionality in mixed methods studies. Doing so will bridge an evidence gap as well as contribute to addressing health and social programming needs among understudied populations.

abstract: Dissertation

abstract: Doctor of Philosophy (PhD)


title: Analyzing the Morphology of Three-Dimensional Tissue Models using Deep Learning

contributor:
Zhang, Boyang
Biomedical Engineering

abstract: Three-dimensional (3D) tissue models, like organoids and spheroids, have been used to recapitulate many characteristics of human tissues. In particular, 3D tissue models can mimic key structural features of the native tissue. However, analyzing the morphology of 3D tissue models is limited by current image analysis tools that extract features like size, contours and texture which cannot fully describe the exhibited morphologies. Instead, deep learning techniques, which can identify objects from images directly can be used to make this type of analysis possible. In this work, we focus on applying deep learning to analyze the 3D tissue morphologies in brightfield images for the first time. Specifically, we developed and validated deep learning models to analyze important structures exhibited by lung spheroids or colon organoids. Deep-LUMEN is a custom deep learning model that can analyze the polarization of lung spheroids. We validated Deep-LUMEN by assessing how the extracellular matrix affects spheroid polarization and how the drug cyclosporin disrupts spheroid assembly. By analyzing the morphological features of lung spheroids, we found that cyclosporin can induce toxic effects at much lower concentrations than expected. This work also presents D-CryptO, a deep learning-based tool that can be used to analyze the structural maturity of colon organoids. D-CryptO analyzes the opacity and the presence of budding structures to assess tissue maturation. We validated D-CryptO by analyzing colon organoid morphology during prolonged culture and short-term perturbation with external stimuli. Additionally, we further applied it to assess organoid morphology following treatment with several chemotherapeutic drugs. Using D-CryptO, we gained insights into potential mechanisms of drug-induced toxicity. Together, these models demonstrate that deep learning is a viable technique to analyze 3D tissue morphology and it can be applied in a broad range of biological studies to gain useful insights into tissue physiology.

abstract: Thesis

abstract: Master of Applied Science (MASc)


title: Three Essays in Applied Micro-Econometrics

contributor:
Racine, Jeffrey
Economics

abstract:
This thesis, comprised of three chapters, demonstrates how econometric methods can be used to inform policy-relevant questions relating to two international epidemics: the prescription opioid epidemic and the COVID-19 pandemic.
Over the past two decades, Canada has experienced rapid growth in the consumption of prescription opioids. The increase in the consumption of these medications has brought pain relief to many people suffering from chronic and acute pain. Unfortunately, it has also led to a parallel increase in prescription opioid abuse, dependence, and overdose. To develop evidence-based policies that curtail prescription opioid morbidity and mortality without hindering access to necessary pain treatment, it is imperative to use statistical modelling techniques to identify the critical predictors of prescription opioid use and abuse. Chapter 1 illustrates how the existing literature on prescription opioid use consists primarily of analyses that use multivariate logistic regression to model prescription opioid use. Then we demonstrate how nonparametric kernel methods can be used to model prescription opioid use and significantly outperform the logistic regression models from the perspective of correctly classifying prescription opioid users, both in-sample and out-of-sample. Chapter 2 utilizes a natural experiment and exploits robust nonparametric estimation methods to examine the impact of mandatory universal pharmaceutical insurance on prescription opioid use. The results show that, among the general population, the policy led to a significant increase in pharmaceutical insurance coverage and a small in magnitude but statistically significant decrease in prescription opioid use. Additionally, the analysis does not find evidence that the increase in pharmaceutical insurance coverage led to a substitution effect away from over-the-counter pain medications and towards prescription opioids for pain treatment.
Moving from one crisis to another, i.e., from the Canadian prescription opioid epidemic to the global COVID-19 pandemic, we refocus attention on the labour market impacts of the latter. As the Corona Virus (SAR-CoV2) spread across the globe in 2020, many government bodies were forced to implement restrictions to slow down the spread of the virus; this included the shutdown of non-essential businesses and services, the cancellation of in-person events and entertainment, school closures, and the start of work-from-home orders. Many sectors saw a drastic drop-in economic activity, resulting in job losses and reductions in hours worked. Chapter 3 uses Canadian microdata to analyze the labour market effects of the COVID-19 pandemic on Canadian immigrants. Trends in employment status and aggregate hours worked are examined by gender and immigrant status and we find evidence that the labour supply of immigrants, especially immigrant women, was more affected than the labour supply of their non-immigrant counterparts.

abstract: Thesis

abstract: Candidate in Philosophy

abstract: This thesis demonstrates how econometric methods can be used to inform policy- relevant questions relating to two international epidemics: the prescription opioid epidemic and the COVID-19 pandemic. This thesis consists of three chapters. Chapters 1 and 2 demonstrate how nonparametric estimation methods can serve as flexible and data-driven alternatives to conventional parametric estimation methods and provide insight into the determinants of prescription opioid use. Chapter 3 uses Canadian microdata to analyze the labour market effects of the COVID-19 pandemic on Canadian immigrants.


title: EXPLORING THE ROLE OF THE SYNTHETIC FOOD COLOURANT ALLURA RED AC IN THE DEVELOPMENT OF COLITIS

subject:
Inflammatory bowel disease
Colitis
Enterochromaffin cell
Serotonin
Synthetic food colourant
Allura Red AC
Myosin light chain kinase
Intestinal organoids

abstract: Environmental factors such as diet contribute to the pathogenesis of inflammatory bowel disease (IBD). Epidemiological evidence suggests a robust linkage between IBD and the Western diet, which is often characterized by a high intake of food additives. These additives, including synthetic colourants, are widely used, leading to significant human exposure. Allura Red AC (AR) is one of the most popular synthetic colourants, yet little is known about its impact on human health and the role of AR in the pathogenesis of colitis remains elusive. Serotonin (5-hydroxytryptamine; 5-HT), which regulates various gut physiological processes, has been shown to modulate the gut microbiota and enhance susceptibility to colitis. In this thesis, it was discovered that chronic exposure to AR, at a dose found in commonly consumed dietary products, exacerbated dextran sulfate sodium (DSS)-induced colitis and triggered early onset of disease in the CD4+CD45RBhigh T cell-induced colitis model. AR also induced low grade colonic inflammation in naïve C57BL/6 mice. Exposure to AR was associated with increased colonic 5-HT levels and impaired intestinal barrier function via activation of the myosin light chain kinase (MLCK) pathway. However, AR did not promote colitis in mice lacking tryptophan hydroxylase 1 (Tph1), the rate-limiting enzyme responsible for colonic 5-HT synthesis. Further, AR increased colonic 5-HT levels in germ-free (GF) mice and perturbed the gut microbiota composition in specific pathogen-free (SPF) mice. Transfer of this altered microbiota from the dye-exposed SPF mice to GF mice conferred enhanced susceptibility to DSS-induced colitis. Mechanistically, AR induced reactive oxygen species (ROS) generation and promoted 5-HT secretion via the NF-κB pathway in BON cells. Data in this thesis indicate that the widely used synthetic colourant, AR, promotes colitis via colonic 5-HT in microbiota-dependent and -independent pathways. Collectively, these findings provide important information on enhancing public awareness of its detrimental effects on human health.

abstract: Thesis

abstract: Candidate in Philosophy

abstract: Epidemiological and experimental studies suggest a potential link between inflammatory bowel disease (IBD) and diet. The Western diet, often characterized by a high intake of processed foods, is associated with the growing incidence of IBD. Allura Red AC (AR) is a popular artificial food dye found in highly common processed foods, yet little is known about its impact on human health and disease. Serotonin, a key molecule in the gut, has been implicated in large bowel inflammation. Herein, the potential role of AR in the development of colitis was examined. Across multiple models, AR exposure heightened vulnerability to colitis in mice, an effect attenuated by reduced serotonin production in the gut. The effect of AR in enhancing colitis vulnerability occurred via gut microbiota-dependent and -independent pathways. These studies have identified how AR promotes colitis, findings that may advance public health awareness and impact the health of patients with IBD.


title: SOLUBLE MEDIATORS RELEASED BY CD4+ T CELLS ACTIVATE BASOPHILS AND NEUTROPHILS IN THE CONTEXT OF IGE-MEDIATED ALLERGIC DISEASES

contributor:
Larché, Mark
Medical Sciences

abstract: The current paradigm in allergic diseases is that it is driven by Th2 responses, causing the influx of cells including eosinophils, basophils, neutrophils, and Th2 cells, giving rise to the late-phase response. Our lab previously showed that peptide immunotherapy can reduce allergic symptoms – this relief of symptoms coincides with a reduction of IL-8 in allergen-specific T cells. We hypothesized that T cell-derived soluble mediators such as IL-8 contributes to allergic inflammation by stimulating basophils and neutrophils to release histamine. In this study, we determined that IL-8 alone was unable to stimulate basophils to release histamine; however, in the presence of IL-3, IL-3 and IL-8 acted synergistically with subsequent anti-IgE stimulation to release histamine (observed fractional response: 0.807, compared to predicted fractional response if the effects were additive: 0.453). Supernatants derived from CD4+ T cells stimulated with anti-CD3/28 and Immunocult acted synergistically with subsequent anti-IgE stimulation to release histamine (observed fractional response: 0.636 [anti-CD3/28 at 1.0x106 cells/ml] and 0.754 [Immunocult at 2.5x106 cells/ml], compared to predicted fractional response if the effects were additive: 0.364 and 0.434, respectively). Basophils primed with anti-CD3/28 and Immunocult-stimulated T cell supernatants plus anti-IgE did not statistically increase the amount of histamine released, compared to media-stimulated T cell supernatant plus anti-IgE. Basophils were activated by T cell supernatants alone and when used for priming with anti-IgE, by upregulating CD63/CD203c markers (anti-CD3/28 alone, anti-CD3/28+anti-IgE, Immunocult alone, and Immunocult+anti-IgE: 60.7%, 85.3%, 87.7%, and 93.7% CD63/CD203c+, respectively, compared to media+anti-IgE (46.36% CD63/CD203c+). Neutrophils contained histamine (63.71nM per 106 neutrophils) and released significant amounts in response to stimulation by fMLP. Neutrophils did not release histamine in response to stimulation by supernatants derived from T cells. Neutrophils significantly downregulated CD62L when stimulated with supernatants derived from anti-CD3/28 and Immunocult-stimulated CD4+ T cells, and significantly up-regulated CD11b, compared to media-stimulated CD4+ T cells.

abstract: Thesis

abstract: Allergies occur when the immune system overreacts to otherwise harmless substances in our environment. When this happens, innate immune cells, such as basophils, release histamine, causing allergic symptoms. Some people develop symptoms that can last several days, where other immune cells, such as T cells, get involved and contribute to inflammation. We looked at how basophils and neutrophils interacted with T cells, and whether T cells could directly activate basophils and neutrophils. We found that T cells produced substances that activated basophils and neutrophils, but this activation did not result in an increase in histamine. However, we saw that T cells produced substances that interacted with another component involved in allergies (a protein called IgE), which resulted in a supra-additive histamine response.


title: Absent Schlemm's Canal With Reduction in Intraocular Pressure Through Uveoscleral Pathway Observed After Conditional Deletion of AP-2β in the Mouse

contributor:
West-Mays, Judith
Medical Sciences

abstract: A unique mouse model recently developed in our laboratory (AP-2β TMR-KO) achieves a conditional deletion of transcription factor AP-2β from the developing periocular mesenchyme and its derivatives using MgpCre/loxP technology. These mutants fail to develop SC and exhibit increased IOP, which temporarily reduces with latanaprost treatment. Here we have shown changes in protein and gene expression of various SC markers. Specifically, Prox1 expression was detected in the wildtype at P4, P10, and P14, but was absent in the AP-2β TMR-KO mice at those stages. Klf4 expression was not present in either wildtype or mutant at P4 but was detected at P10 and P14 in the wildtype only. Additionally, decreased gene expression was observed of Prox1, Klf4, and Tie2 in the SC region at P4 and P10, and of Angpt1 in the trabecular meshwork region, in mutant eyes. Furthermore, dextran tracer studies were performed to assess aqueous outflow in wildtype and AP-2β TMR-KO mice; dextran was detected in regions of both outflow pathways in the wildtype but was clustered in the anterior chamber in the mutant, with the corrected total fluorescence significantly higher in the anterior chamber and significantly lower in regions of outflow for the mutant relative to wildtype. Upon latanaprost treatment, dextran was similarly present in the wildtype, but detected further along the uveoscleral pathway in the mutant with time. The data generated in this project provides more insight into the role of AP-2β in the development and function of the aqueous humor outflow pathways. This information will be critical to elucidating the genetic cascade through which AP-2β regulates anterior segment development. Additionally, this project points to the potential of the AP-2β TMR-KO mice as a model for glaucoma.

abstract: Thesis

abstract: Master of Science (MSc)

abstract: Glaucoma is one of the leading causes of blindness in the world, with an estimated 76 million people affected by it. This number is projected to increase by almost 30% over the next decade. This drastic increase is a threat to healthcare systems and care facilities, as it will put a great strain on the number of resources that can be provided. In addition, age-related visual disability can lead to several other conditions due to increased risk of injury. Irreversible blindness with glaucoma occurs when the retinal ganglion cells in the eye are damaged due to elevated intraocular pressure, which results from a disruption in aqueous humor drainage. Data from this thesis provides important insight into the development of an important aqueous humor drainage structure, Schlemm’s canal, and points to the potential of a mutant mouse model as a model for glaucoma.


title: COMPARING LEARNER EXPERIENCES WITH QUEST- VS XMOOC- FORMAT MODULES IN AN ONLINE TWITTER COURSE FOR HEALTH PROFESSIONALS

contributor:
Chan, Teresa
Bayer, Ilana
Monteiro, Sandra
Health Science Education

subject:
faculty development
online learning
social media
curriculum design
e-learning

abstract:
BACKGROUND: Over the past decade, massive open online courses (MOOCs) have been used by healthcare professionals to develop their knowledge and skills. They are an attractive learning option due to their openness, accessibility, and flexibility regarding time and space, but have notably low completion rates. “Fac.Dev” is a platform for faculty development by McMaster’s Office for CPD offering online courses through a Query-based, Ubiquitous Educator and Scholars Training (QUEST) model. QUEST modules use task-based activities and authentic assessment in their instructional design, in contrast to the traditional MCQ assessment methods in MOOCs.
PURPOSE: This study aimed to compare learner engagement and experiences of health professionals enrolled in a one-month Twitter skills online course delivered on the Fac.Dev platform through QUEST-format modules versus xMOOC-format modules.
METHOD: This study was conducted as a randomized controlled trial. 27 participants were randomized into either learning Twitter skills through a course with QUEST- formatted or xMOOC-formatted modules. Quantitative and qualitative methods were used to analyse the outcome measures, which included completion rates, barriers to completion, self-rated Twitter proficiency, self-perceived achievement of learning outcomes, likelihood of recommending to a peer, and suggestions for module improvement.
RESULTS: Quantitative findings revealed that no significant difference in the completion rates of the course delivered through QUEST or xMOOC format. Lack of time was the primary barrier to course completion. Participants in both arms reported an improvement in their Twitter proficiency and were similarly likely to recommend the course to a peer. Thematic analysis of participant feedback revealed incorporating interactivity, increased use of video and media elements, and providing more time for completion would improve their experience.
CONCLUSION: Participants’ feedback for improving the modules were consistent with best practices for digital learning for faculty recommended in literature, which can be implemented in future Fac.Dev course offerings to support and improve learner engagement.

abstract: Thesis

abstract: Master of Science (MSc)


title: Glycemic control in Children with Type 1 Diabetes During the COVID-19 Pandemic

contributor:
Samaan, M. Constantine
Health Research Methodology

subject:
Type 1 diabetes mellitus
Child
COVID-19
Glycemic Control

abstract:
Background: Since March 2020, health systems around the world shifted to virtual care approaches as social distancing measures were recommended to stem the spread of SARS-COV-2, the virus responsible for the COVID-19 pandemic. For children and families living with type 1 diabetes, virtual consultations in pediatric diabetes care were rare prior to the pandemic but became the norm since the start of the pandemic. Data regarding glycemic outcomes and comorbidities in children living with type 1 diabetes mellitus (T1DM) during the pandemic are limited, and there is a need for these data to drive future care models design and delivery.
Aim & Methods: The aim of this project was to assess the association of the COVID-19 pandemic with measures of glycemic control (HbA1c), hyperglycemia, hypoglycemia, diabetic ketoacidosis (DKA) and hospitalization for the period spanning March 2020-2021 at McMaster Children’s Hospital, a tertiary pediatric academic center in Hamilton, Ontario, Canada. Data from the onset of virtual care were compared with data from two years pre-pandemic.
Results: The COVID-19 pandemic was not associated with changes in HbA1c (MD -0.14, p=0.058), hospitalization (OR 0.57, p=0.068), or hypoglycemia (OR 1.11, p=0.484), but was significantly associated with the increase in reported hyperglycemia (OR 1.38, p=0.003) and reduction in DKA presentation (OR 0.30, p=0.009).
Conclusions: Glycemic control was stable during the early stages of the COVID-19 pandemic, when virtual and hybrid care models prevailed in diabetes care. These results suggest that patients and their families were able to adapt to the uncertain circumstances of the pandemic. Virtual consultations for pediatric diabetes did not hinder glycemic control, and likely aided in the maintenance of diabetes management. Longitudinal studies are necessary before virtual consultations should be recommended to replace in-person clinic visits, but the initial data seem encouraging.

abstract: Thesis

abstract: Master of Science (MSc)

abstract: The COVID-19 pandemic restricted face-to-face healthcare-based interactions to limit the spread of the virus. These restrictions posed as a challenge for children and youth with type 1 diabetes mellitus (T1DM), who relied exclusively on in-person clinic visits as part of their care regimen pre-pandemic. In this retrospective study, we assessed the association of the first year of the COVID-19 pandemic with measures of glycemic control (HbA1c), diabetic ketoacidosis (DKA), hospitalization, hyperglycemia, and hypoglycemia, compared to two years pre-pandemic. We determined that children living with type 1 diabetes had no deterioration of glycemic control measures, apart from an increase in hyperglycemia, during the first 12 months of the pandemic. This study provides insights into health outcomes of children living with T1DM in the early stages of the pandemic and offers a roadmap to guide the further avenues of exploration needed to assess the full impact of the pandemic on this population.


title: The Application of Artificial Intelligence and Elastography to EBUS-TBNA Imaging Technology for the Prediction of Lymph Node Malignancy

contributor: Clinical Health Sciences (Health Research Methodology)

subject:
Lung Cancer
Endoscopy
Lymph Nodes
Elastography
Artificial Intelligence

abstract:
Background: Before making any treatment decisions for patients with non-small cell lung cancer (NSCLC), it is crucial to determine whether the cancer has spread to the mediastinal lymph nodes (LNs). The preferred method for mediastinal staging is Endobronchial Ultrasound Transbronchial Needle Aspiration (EBUS-TBNA). However, EBUS-TBNA has been reported to generate inconclusive results as much as 40% of the time. Since this jeopardizes good patient care, there is near-universal consensus on the need to develop and study a novel method for LN staging. Recent research has shown that AI and deep learning are used to accurately interpret images with comparisons to clinicians in radiology, pathology, and cardiology.  Additionally, EBUS-Elastography is a novel modality which could be used as an adjunct to EBUS-TBNA for LN staging. This technology uses impedance ultrasonography to measure tissue stiffness.

Methods: There are three parts to this thesis. The first part involved the training, validating, and testing NeuralSeg, a deep neural network, to predict LN malignancy based on B-mode EBUS-TBNA images. The second part of this thesis involves EBUS-Elastography, defining the blue colour threshold and the optimal SAR cut-off value based on the blue threshold that most accurately distinguished benign and malignant LN. Finally, this thesis's third part involves validating part II's findings.

Results: Part I resulted in an overall accuracy of 80.63% (76.93% to 83.97%), a sensitivity of 43.23% (35.30% to 51.41%), a specificity of 96.91% (94.54% to 98.45%), a positive predictive value of 85.90% (76.81% to 91.80%), a negative predictive value of 79.68% (77.34% to 81.83%), and an AUC of 0.701 (0.646 to 0.755). Part II Level 60 was chosen as the blue threshold with an AUC of 0.89 (95% CI: 0.77-1.00), and the optimal SAR cut off was found to be 0.4959 with a sensitivity of 92.30% (95% CI: 62.10% to 99.60%) and a specificity of 76.50% (95% CI: 49.80% to 92.20%). Using the blue threshold and SAR cut-off, the results of part III resulted in an overall accuracy of 70.59% (95% (CI) 63.50% to 77.01%), the sensitivity of 43.04% (CI: 31.94% to 54.67%), and a specificity of 90.74% (CI: 83.63% to 95.47%).

Conclusion: It was observed that both AI and AI-powered EBUS-Elastography achieved high specificities on larger sample sizes, indicative that these methods may be helpful in identifying LN malignancy. However, due to the novelty of these technologies, more extensive multi-centre studies must be conducted before these processes can be standardized.

abstract: Thesis

abstract: Master of Health Sciences (MSc)

abstract: Non-Small Cell Lung Cancer (NSCLC) treatment decisions are made using vital information by performing biopsies to collect tissue from the lymph nodes near the lungs. The current method is called Endobronchial Ultrasound Transbronchial Needle Aspiration (EBUS-TBNA), which involves a scope with a fine needle attached to it. This scope is led down the airway and guided by ultrasound to obtain the tissue needed to determine whether the lymph nodes have cancerous tissue. If the lymph nodes contain cancerous tissue, the patient may need chemotherapy; however, lung surgery may be the best treatment option if they do not. Many factors impact how successfully these tissue samples can be obtained, such as the skill and experience of the surgeon. These factors often lead to inconclusive results, making it difficult to make correct treatment decisions. Novel technologies such as Artificial Intelligence and Elastography are being used to diagnose lung cancer by interpreting images and providing information on tissue stiffness. We trained an Artificial Intelligence program to predict malignancy based on EBUS-TBNA images. Additionally, we trained the AI program to analyze Elastography images to aid us in understanding the relationship between the colour pattern of the elastography images and cancerous tissue. This thesis assesses how these novel technologies contribute to lung cancer diagnosis.


title: New Advances in Capillary Electrophoresis for Biomonitoring in Population Health and Newborn Screening of Cystic Fibrosis

contributor:
Britz-McKibbin, Philip
Chemistry and Chemical Biology

subject:
Capillary Electrophoresis
Electrolytes
Iodide
Thiocyanate
Sweat Chloride
Bicarbonate
UV Detection
Mass Spectrometry
Metabolomics
Biomarker Discovery
Epidemiology
Iodine Nutrition
Tobacco Smoke Exposure
Clinical Chemistry
Cystic Fibrosis
Analytical Methods

abstract: Biological markers (i.e., biomarkers) are essential in clinical and epidemiological studies as they may provide mechanistic insights into the developmental origins of disease, as well as improve diagnostic testing and risk assessment for disease prevention. However, major challenges remain due to the lack of rapid yet selective analytical methods for high throughput screening that are also amenable to volume-restricted specimens. This thesis includes two major research themes that take advantage of capillary electrophoresis (CE) separations, including (1) the targeted analysis of urinary iodide and thiocyanate for assessment of nutritional adequacy and tobacco smoke exposures in the population, and (2) the discovery of new biomarkers in sweat specimens that may improve universal newborn screening programs for cystic fibrosis (CF) infants beyond impaired chloride transport. Chapter II examines the prevalence and risk factors associated with iodine deficiency in 24 h urine samples collected from 800 participants across four clinical sites in Canada as part of the Prospective Urban and Rural Epidemiological (PURE) study when using CE with UV detection in conjunction with sample self-stacking. Importantly, regional variations in iodine status were revealed with participants from Quebec City and Vancouver at greater risk for iodine deficiency than Hamilton and Ottawa. Overall, iodine supplement use, thyroxine prescription, urinary sodium excretion, and self-reported dairy intake were found to be protective factors against iodine deficiency. Chapter III applied a validated CE assay to measure urinary thiocyanate as a biomarker of tobacco smoke and dietary exposures in an international cohort of 1000 participants from the PURE study spanning 14 countries with varied income status, smoking habits, and diet quality. Current smokers residing in high-income countries had the highest extent of cyanide exposure indicative of greater harms from tobacco smoke compared to middle- and low-income countries after adjusting for smoking intensity and other covariates. Chapter IV introduces a rapid CE method with indirect UV detection to simultaneously measure sweat chloride and bicarbonate from presumptive CF infants’ residual sweat samples. Although bicarbonate did not provide clinical value in neonatal CF diagnosis, sweat chloride testing by CE may reduce test failure rates due to insufficient volumes from infants in a clinical setting. Lastly, Chapter V applied an untargeted strategy to characterize the sweat metabolome from presumptive CF infants when using multisegment injection-capillary electrophoresis-mass spectrometry (MSI-CE-MS). A panel of sweat metabolites were found to discriminate CF from non-CF (i.e., unaffected carriers) infants, including aspartic acid, glutamine, oxoproline, and pilocarpic acid, which also correlated with sweat chloride. The clinical utility of these sweat metabolites to prognosticate late-onset CF infants from indeterminate sweat chloride test results was also explored. In summary, this thesis contributes innovative separation methods for biomarker screening and discovery in clinical and epidemiological studies for the prevention and early treatment of human diseases that benefit from optimal nutrition.

abstract: Dissertation

abstract: Doctor of Philosophy (PhD)


title: Fractured: A Study of Intraprofessional Paramedic Dynamics on Professionalization in Ontario, Canada

contributor:
Dunn, James
Health and Aging

subject: professionalization, paramedics, sociology

abstract: Despite documented threats and challenges to professional workers, occupations and professions of all kinds remain motivated to pursue professionalization projects aimed at improving their social location. However, to drive professionalization from within an occupation means resisting or adapting to a variety of pressures from other professions, managerial organizations, and neoliberal government agendas. Emerging research has highlighted that some professions can adapt to or resist these pressures, while others falter.  How intraprofessional dynamics impact professionalization in these conditions is less understood. This thesis aims to address this gap through a qualitative case study of paramedic professionalization in Ontario, Canada. Data from interviews with paramedic leaders and a document analysis were used to examine how intraprofessional dynamics have impacted paramedic professionalization. Drawing on various theoretical and conceptual threads from neo-Weberianism and neo-institutional theory, each empirical chapter examines a topic related to professionalization: regulation, higher education, and expansions in work. The findings of each chapter reveal widespread intraprofessional stratification, and at times, conflict. Some paramedic leaders are driven to improve paramedic status, recognition, and autonomy, however, must do so in increasingly flexible, collaborative, and subtle ways. While intentional stratification is at times pursued as an innovative strategy in response to organizational and government pressures and mandates, it comes at a cost to professional unity. Others are resistant or skeptical of professionalization that may change the physical, boots-on-the-ground ethos of frontline paramedics. The finding of this thesis sheds light on the intraprofessional dynamics of an understudied occupation and how they relate to contemporary scholarly debates about the processes and outcomes of contemporary professionalization.

abstract: Thesis

abstract: Candidate in Philosophy

abstract: Professions are a special type of occupation that has high social status. Social scientists have long studied how occupations try to gain status and recognition, a process called professionalization. In recent years, researchers have highlighted that it may be more challenging for occupations to professionalize as they face pressures from governments and their employers. This thesis aims to contribute to this research by presenting three papers examining paramedic professionalization in Ontario, Canada through the eyes of paramedic leaders and documents. Paper 1 found that paramedic leaders are divided on the need for changes to paramedic regulation to professionalize. Papers 2 and 3 found that paramedics are pursuing new roles for paramedics in healthcare and academics as a professionalization strategy. Paramedics face an internal conflict that has limited their ability to pursue a collective professionalization strategy. If differences across the profession cannot be resolved, it may continue to fracture the profession.


title: REDISTRIBUTION OF SYNAPTIC INPUTS IN THE NEONATAL RODENT AUDITORY BRAINSTEM OCCURS IN THE ABSENCE OF ACOUSTICALLY DRIVEN ACTIVITY

contributor:
Gillespie, Deda
Biomedical Engineering

abstract:
Principal neurons in the lateral superior olive (LSO) receive excitatory input from the anteroventral cochlear nucleus (AVCN) and inhibitory inputs from the medial nucleus of the trapezoid body (MNTB). These two phenotypically different inputs arriving at individual neurons in mature LSO are precisely matched for stimulus frequency. However, in the immature LSO, excitatory and inhibitory inputs arriving at individual neurons are crudely matched for stimulus frequency. During postnatal development, both excitatory and inhibitory pathways undergo substantially physiological measurable refinement before hearing onset, presumably under the guidance of spontaneous activity generated in the immature cochlea. In the neighbouring nucleus, MSO, inhibitory synapses are redistributed toward the soma, arguably through an experience-dependent manner. Here, in LSO, I investigate how excitatory and inhibitory synapses are redistributed before hearing onset.
In order to do so, I implemented hardware to label single cells in acute living slices, Matlab scripts to segment synapses in 3D, and Matlab scripts for spike sorting and firing state reconstruction (not reported here). Using the tools that I developed, I investigated the developmental distribution of excitatory and inhibitory synapses in prehearing LSO.
At birth, excitatory synapses surprisingly outnumbered inhibitory synapses at the soma and the proximal dendrite. In the ensuing week, before hearing onset, while excitatory synapses are redistributed away from the soma, inhibitory synapses are redistributed toward the soma, such that by hearing onset inhibitory synapses outnumber excitatory synapses at the soma and the proximal dendrite.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract: How immature neurons coordinately refine their excitatory and inhibitory inputs is a fundamental question in developmental neuroscience. Lateral superior olive (LSO) is a model system for this question. Principal neurons in mature LSO receive excitatory and inhibitory inputs that are precisely matched for stimulus frequency. This sharp frequency alignment of the two phenotypically different inputs is achieved during postnatal refinement, including synapse elimination and strengthening and changes in neuronal morphology. Synapse redistribution may also contribute to the refinement. Here, I investigated the developmental distribution of excitatory and inhibitory synapses in prehearing rats. Before hearing onset, the distribution of excitatory and inhibitory synapses shifted in complementary directions in the absence of acoustic activity.


title: CHARACTERIZING THE CO-OCCURRENCE OF SUBSTANCE USE AND MENTAL HEALTH SYMPTOMS AMONG ADOLESCENTS IN GENERAL POPULATION AND CLINICAL SAMPLES

contributor:
Georgiades, Katholiki
Health Research Methodology

subject:
Substance use
Mental Health
Adolescent

abstract: Background: Despite policy and practice guidelines highlighting the need to identify and treat substance use early and concurrently with other mental health symptoms, efforts remain uncoordinated and guidelines lack specificity. Limited evidence characterizing patterns and correlates of co-occurring substance use and mental health symptoms hinders our ability to effectively address these concerns early during adolescence. This dissertation deepens our understanding of the patterns and correlates of co-occurring substance use and mental health symptoms among adolescents, how to collect relevant data in inpatient settings, and how to rigorously analyze and report findings. Methods: The first paper is a systematic review of 70 cluster-based studies examining patterns of multiple substance use among adolescents. The second examines patterns and correlates of co-occurring substance use and mental health symptoms through multilevel latent profile analysis and multilevel multinomial regression using a large, representative sample of secondary students and schools across Ontario. The third paper is a pilot study examining the feasibility, acceptability, and importance of standardized assessments of substance use and mental health symptoms in an adolescent psychiatric inpatient unit. Results: The substantive findings of this work include: 1) multiple substance use is common; 2) co-occurrence of substance use and mental health symptoms is common, though not universal; 3) substance use may be related to mental health symptom severity, comorbidity, and hospital service use; 4) school climate, belonging, and safety represent important targets for school-based interventions; and 5) adolescent psychiatric inpatient units may represent important contexts for standardized assessments, though more professional training and standardization in assessments and interventions are needed. Methodological recommendations are also presented to improve the collection, analysis, and reporting of similar work in the field. Conclusions: Collectively, this dissertation provides novel, timely, and actionable insight into adolescent substance use patterns, correlates, and potential targets for assessment and intervention efforts.

abstract: Dissertation

abstract: Doctor of Philosophy (PhD)

abstract: This dissertation deepens our understanding of the patterns of co-occurring substance use and mental health concerns among adolescents. First, a review of all existing studies that explore patterns of multiple substance use among adolescents was conducted. Second, patterns of substance use and mental health symptoms were identified in secondary students and schools across Ontario. Third, the feasibility of assessing substance use and mental health symptoms using standardized approaches on an inpatient adolescent psychiatric unit was evaluated. Overall, this work suggests that substance use and mental health concerns commonly co-occur, and that schools and inpatient psychiatric units are important settings for prevention, assessment, and intervention. This work provides actionable next steps to inform assessment, prevention, and intervention efforts designed to address co-occurring substance use and mental health concerns among adolescents.


title: Consumption of Cannabis Oil During Pregnancy Disrupts Implantation Site Remodelling and Causes Fetal Abnormalities at Term

contributor:
Ashkar, Ali
Medical Sciences

abstract: The use of cannabis during pregnancy has increased dramatically in recent years, as legalization altered the accessibility and acceptability of cannabis use. However, maternal cannabis use has been found to substantially increase the risk of several adverse pregnancy outcomes like stillbirth and low birthweight. Despite the clear risk little is known about how cannabis causes these complications and whether all cannabis consumption methods pose a risk. For a successful pregnancy, the uterus must create a favourable environment to support fetal growth. This process is largely modulated by uterine Natural Killer (uNK) cells which are responsible for promoting tissue remodelling at the maternal-fetal interface. The current project aims to assess whether cannabis oil alters proper uNK cell functioning and in turn causes pregnancy complications. To assess pregnancy outcomes, we administered either CBD oil, THC oil or control oil via gavage from gestation day (GD) 6.5-11.5 in CD57BL/6J mice and assessed fetal outcomes on GD 18.5. Fetuses from pregnant mice receiving THC oil had significantly lower weights, lengths, and head size whereas mice treated with CBD oil had reduced fetal head size and a trend for elevated odds of being small for gestational age. To pinpoint the cause of these abnormal fetal outcomes we examined implantation site remodelling earlier in pregnancy at GD10.5 and 12.5. CBD oil reduced placental area and caused a significant increase in the number of uNK cells within the decidua. Additionally, both CBD and THC oil impaired vascular remodelling. Lastly, we found that both THC and CBD reduced human NK cell production of the angiogenic factors IFN-y and VEGF, which may account for the abnormal vessel remodelling. Thus, the present work highlights that both CBD and THC oil cause fetal abnormalities at term which may be a result of improper implantation site remodelling driven by uNK cell dysfunction.

abstract: Thesis

abstract: Master of Science (MSc)


title: Regulation of Specialized Metabolism in Streptomyces

contributor:
Elliot, Marie
Biology

subject:
Streptomyces
Specialized metabolism
Nucleoid-associated protein
Regulation

abstract:
In Streptomyces bacteria, the expression of many antibiotic biosynthetic clusters is controlled by both cluster-specific regulators and more globally-acting regulators; however, much remains unknown about the factors that govern antibiotic production. In Streptomyces venezuelae, we have discovered that the broadly-conserved nucleoid-associated protein Lsr2, plays a major role in repressing specialized metabolic cluster gene expression.
To understand how Lsr2 exerts its gene silencing effects, we focused our attention on the well-studied, but transcriptionally silent, chloramphenicol cluster in S. venezuelae. We established that Lsr2 represses transcription of the chloramphenicol cluster by binding DNA both within the cluster and at distal positions. CmlR is a known activator of the chloramphenicol cluster, but expression of its associated gene is not under Lsr2 control. We discovered that CmlR functions to ‘counter-silence’ Lsr2 activity, alleviating Lsr2 repression and permitting chloramphenicol production, by recruiting RNA polymerase.
Lsr2 plays a central role in controlling antibiotic production in Streptomyces; however, beyond this counter-silencing activity, little is known about how Lsr2 is regulated. We identified regulators that could control the expression of lsr2, and found that Lsr2 and LsrL, an Lsr2 homologue that is encoded by all streptomycetes, interact directly with each other, and that their respective DNA-binding activities are altered by the presence of the other protein. These data suggest that LsrL may impact Lsr2 activity in regulating antibiotic production in Streptomyces.
		Beyond Lsr2, we wanted to develop a comprehensive understanding of the regulatory proteins that impact biosynthetic gene cluster expression. To define the regulatory protein occupancy of antibiotic clusters, we developed ‘in vivo protein occupancy display-high resolution’ (IPOD-HR) technology for use in Streptomyces. This work will lay the foundation for establishing a comprehensive regulatory network map for biosynthetic clusters in Streptomyces, and guide future work aimed at stimulating the expression of metabolic clusters in any Streptomyces species.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)

abstract: Streptomyces bacteria produce the majority of naturally-derived antibiotics, and they have the genetic potential to produce many more antibiotics and antibiotic-like compounds (‘specialized metabolites’). Specialized metabolism is controlled by multiple regulatory systems. In Streptomyces venezuelae, we have discovered that the nucleoid-associated protein, Lsr2, represses the expression of most specialized metabolic clusters, and manipulating Lsr2 activity can stimulate antibiotic production. To better understand how Lsr2 exerts its repressive effect, we explored how Lsr2 controlled the production of a known antibiotic. We ultimately identified multiple regulators that could impact the expression and/or activity of Lsr2. Building on the regulatory foundation provided by Lsr2, we then set out to establish a comprehensive regulatory network that governs biosynthetic gene cluster expression. Collectively, this work improves our understanding of antibiotic gene regulation in Streptomyces bacteria, and has the potential to guide novel strategies aimed at stimulating the production of new antibiotics in Streptomyces.


title: Effects of wave load models on the uplift risk of ports exposed to hurricanes.

contributor:
Balomenos, Georgios
Civil Engineering

subject:
pile-supported ports
wave models
uplift failure
fragility analysis
Monte Carlo simulation
Parameterized fragility analysis

abstract:
Pile-supported ports allow seawater to run below the deck, and thus may suffer structural
damages during extreme coastal events such as hurricanes. These structural damages, in
turn, may result to port closures that can cause significant economic losses. Risk analysis
can predict the post-hazard functionality of ports though the structural damage assessment
of these structures prior to coastal events. However, assumptions on the selected demand
estimates may affect the estimated probability of structural damage.
This research aims to shed light on the sensitivity of the wave model selection for the risk
assessment of pile-supported ports when subjected to storm surge and waves. The
examined structural damage is the uplift of the deck, and the risk assessment is conducted
through the development of fragility curves for a typical deck-pile connection, for which
fragility curves are developed for different wave models. Uncertainties are also considered
in parameters affecting the demand and capacity of the examined deck-pile connection and
are propagated through the Monte Carlo simulation using the Latin Hypercube Sampling.
The results indicate changes to the uplift probability as a result of the selected wave model.
Thus, wave model selection can alter the uplift failure probability. In addition, the study
proposes parameterized fragility models to enable the uplift risk assessment across a
region. The presented results aim to throw light on the proper model selection to produce
more realistic risk assessment estimates towards the resilience of coastal infrastructure.

abstract: Thesis

abstract: Master of Applied Science (MASc)


title: High throughput exposomic studies for new insights into smoke exposures in occupational and population health

subject: Metabolomics; Exposomics; Urine; Firefighters; Epidemiology; Smoking; Nutrition; Capillary Electrophoresis Mass Spectrometry

abstract: Exposomics aims to characterize the totality of exposures over the lifespan, and their impact on human health. Currently, chronic exposure to harmful chemicals from air pollution and/or tobacco smoke, along with a suboptimal diet, remain leading causes for preventable mortality and morbidity worldwide. As a result, new analytical methods are needed to measure robust biomarkers of smoke exposure and food intake for improved risk assessment of clinical events. This thesis aims to develop high throughput methods to rapidly quantify urinary biomarkers of environmental smoke in high-risk occupations, and diverse global populations using multisegment injection-capillary electrophoresis-mass spectrometry (MSI-CE-MS) technology. Chapter II outlines an inter-laboratory method comparison for the targeted analysis of urinary 1-hydroxypyrene (HP) when using gas chromatography-high resolution mass spectrometry (GC-HRMS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) on urine samples collected from firefighters. This work revealed the critical role of incomplete enzymatic deconjugation on method bias and underreporting of true smoke exposures. Chapter III introduces a high throughput MSI-CE-MS/MS method (< 3 min/sample) to directly analyze the intact glucuronide conjugate of HP (HP-G) in urine without complex pre-column enzyme deconjugation and derivatization procedures. Importantly, firefighters deployed under emergency conditions at the 2016 Fort McMurray wildfire had creatinine normalized HP-G concentrations below the biological exposure index, likely caused by delays in urine collection under emergency conditions, at early stages of firefighting. Chapter IV extends from targeted biomonitoring of occupational smoke exposure, towards elucidating the relative risk of tobacco smoking in an international cohort of participants (n=1000) from the Prospective Urban and Rural Epidemiological (PURE) study. Comprehensive analysis of nicotine metabolites in urine by MSI-CE-MS allowed for reliable determination of the total nicotine equivalent and nicotine metabolic ratio as robust indicators of recent tobacco smoke exposure and nicotine dependence, respectively. This method also offers a more accurate approach for biochemical verification of smoking status in large-scale epidemiological studies that are prone to social desirability and gender bias when relying on standardized questionnaires. Lastly, Chapter V employs a nontargeted metabolomics workflow using MSI-CE-MS to identify urinary metabolites that may serve as objective dietary biomarkers of food intake in participants across 14 countries from the PURE cohort. A panel of robust and generalizable metabolites were validated for biomonitoring of complex dietary exposures, that may further exacerbate the hazards of tobacco smoking. In summary, this thesis contributes high throughput analytical tools for characterizing the human urine exposome to better decipher the roles of smoke exposure, and suboptimal diet on chronic disease burden among diverse populations and regions worldwide.

abstract: Thesis

abstract: Doctor of Philosophy (PhD)