Design and Synthesis of Acridine-Based Macrocyclic G-Quadruplex DNA Ligands

DNA sequences that are rich in the guanine nucleic base possess the ability to fold into higher order structures called G-quadruplexes. These higher level structures are formed as a result of two sets of four guanine bases hydrogen-bonding together in a planar arrangement called a guanine quartet. Guanine quartets subsequently stack upon each other to form quadruplexes. G-quadruplexes are mainly localized in telomeres as well as in oncogene promoters. One unique and promising therapeutic approach against cancer involves targeting and stabilizing G-quadruplexes with small molecules, generally in order to suppress oncogene expression and telomerase enzyme activity; the latter has been found to contribute to “out-of control” cell growth in ca. 80-85% of all cancer cells and primary tumours while being absent in normal somatic cells. In this work, we present efforts towards designing and synthesizing acridine-based macrocycles (Mh) and (Mb) with the purpose of providing potential G4 ligands that are suited for selective binding to G4 vs. duplex DNA, and stabilize G-quadruplex structures. Two ligands described in this study include an acridine core which provides an aromatic surface capable of π-π interactions with the surface of G-quadruplexes. The successful synthesis of 4,5-diaminoacridine is described in chapter 2, as an essential fragment of the macrocycles (Mh) and (Mb). In order to investigate the synthetic method for macrocyclization, model compounds composing almost half of the designed macrocycles were explored. As discussed in chapter 3, the synthesis of the model compound for (Mb) turned out to be challenging. However, as a step towards the synthesis of (Mh), the synthesis of the hydrogen-containing model compound, which is almost half of the desired macrocycle (Mh) was achieved in our group and proved to be promising.

Forging Iconographies and Casting Colonialism: Monuments and Memories in Ontario, 1850-2001

Commemorations are a critical window for exploring the social, political, and cultural trends of a specific time period. Over the past two centuries, the commemorative landscape of Ontario reaffirmed the inclusion/exclusion of particular racial groups. Intended as static markers to the past, monuments in particular visually demonstrated the boundaries of a community and acted as ongoing memorials to existing social structures. Using a specific type of iconography and visual language, the creators of monuments imbued the physical markers of stone and bronze with racialized meanings. As builders were connected with their own time periods and social contexts, the ideas behind these commemorations shifted. Nonetheless, creators were intent on producing a memorial that educated present and future generations on the boundaries of their “imagined communities.” This dissertation considers the carefully chosen iconographies of Ontario’s monuments and how visual symbolism was attached to historical memory. Through the examination of five case studies, this dissertation examines the shifting commemorative landscape of Ontario and how memorials were used to mark the boundaries of communities. By integrating the visual analysis of monuments and related images, it bridges a methodological and theoretical gap between history and art history. This dissertation opens an important dialogue between these fields of study and demonstrates how monuments themselves are critical “documents” of the past.

EXHAUSTING AFFECTS: THE NEGOTIATION OF AFFECTIVE LABOUR, NEOLIBERAL SUBJECTIVITY, AND FEMINIST POLITICS AMONG ANTI-VIOLENCE WORKERS

This thesis explores the affective and political life of anti-violence labour, with particular attention to the ways that neoliberalism comes to bear on subjectivity, embodiment, and relationality among women responding to violence. In fall of 2015, I conducted qualitative interviews with six women engaged in the work of responding to violence. The participants in this project articulated rich descriptions of the affective life of neoliberalism and the demands of neoliberal subjectivity, drawing particular attention to the affective labour involved in navigating the political complexities of anti-violence organizations, negotiating burnout, and affectively self-managing in order to meet norms of professionalism. Bringing participant narratives into conversations with feminist theories of affect, I argue for an account affective labour that centers the specific, materially embodied experiences of that work and for an account of neoliberalism as a system of embodied and affective pressures.

IMMUNE-ANGIOGENESIS MECHANISMS ASSOCIATED WITH PORCINE PREGNANCY SUCCESS AND FAILURE

Spontaneous fetal loss (25-40%) leading to decrease in litter size is a significant concern to the pork industry. A deficit in the placental vasculature has emerged as one of the important factors associated with fetal loss. During early pig pregnancy, the endometrium becomes enriched with immune cells recruited by conceptus-derived signals including specific chemokine stimuli. These immune cells assist in various aspects of placental development and angiogenesis. Recent evidence suggests that microRNAs (miRNAs: small non-coding RNAs that regulate gene expression) regulate immune cell development and their functions. In addition, intercellular communication including exchange of biomolecules (e.g. miRNAs) between the conceptus and endometrium regulate key developmental processes during pregnancy. To understand the biological significance of immune cell enrichment, regulation of their functions by miRNAs and transfer of miRNAs across the maternal fetal-interface, we screened specific sets of chemokines and pro- and anti-angiogenic miRNAs in endometrial lymphocytes (ENDO LY), endometrium, and chorioallantoic membrane (CAM) isolated from conceptus attachment sites (CAS) during early, gestation day (gd)20 and mid-pregnancy (gd50). We report increased expression of selected chemokines including CXCR3 and CCR5 in ENDO LY and CXCL10, CXCR3, CCL5, CCR5 in endometrium associated with arresting CAS at gd20. Some of these differences were also noted at the protein level (CXCL10, CXCR3, CCL5, and CCR5) in endometrium and CAM. We report for the first time significant differences for miRNAs involved in immune cell-derived angiogenesis (miR-296-5P, miR-150, miR-17P-5P, miR-18a, and miR-19a) between ENDO LY associated with healthy and arresting CAS. Significant differences were also found in endometrium and CAM for some miRNAs (miR-17-5P, miR-18a, miR-15b-5P, and miR-222). Finally, we confirm that placenta specific-exosomes contain proteins and 14 select miRNAs including miR-126-5P, miR-296-5P, miR-16, and miR-17-5P that are of relevance to early implantation events. We further demonstrated the bidirectional exosome shuttling between porcine trophectoderm cells (PTr2) and porcine aortic endothelial cells (PAOEC). PTr2-derived exosomes were able to modulate the endothelial cell proliferation that is crucial for the establishment of pregnancy. Our data unravels the selected chemokines and miRNAs associated with immune cell-regulated angiogenesis and reconfirm that exosome mediated cell-cell communication opens-up new avenues to understand porcine pregnancy.

A cloud-based system for measuring radiation treatment plan similarity

PURPOSE: Radiation therapy is used to treat cancer using carefully designed plans that maximize the radiation dose delivered to the target and minimize damage to healthy tissue, with the dose administered over multiple occasions. Creating treatment plans is a laborious process and presents an obstacle to more frequent replanning, which remains an unsolved problem. However, in between new plans being created, the patient's anatomy can change due to multiple factors including reduction in tumor size and loss of weight, which results in poorer patient outcomes. Cloud computing is a newer technology that is slowly being used for medical applications with promising results. The objective of this work was to design and build a system that could analyze a database of previously created treatment plans, which are stored with their associated anatomical information in studies, to find the one with the most similar anatomy to a new patient. The analyses would be performed in parallel on the cloud to decrease the computation time of finding this plan. METHODS: The system used SlicerRT, a radiation therapy toolkit for the open-source platform 3D Slicer, for its tools to perform the similarity analysis algorithm. Amazon Web Services was used for the cloud instances on which the analyses were performed, as well as for storage of the radiation therapy studies and messaging between the instances and a master local computer. A module was built in SlicerRT to provide the user with an interface to direct the system on the cloud, as well as to perform other related tasks. RESULTS: The cloud-based system out-performed previous methods of conducting the similarity analyses in terms of time, as it analyzed 100 studies in approximately 13 minutes, and produced the same similarity values as those methods. It also scaled up to larger numbers of studies to analyze in the database with a small increase in computation time of just over 2 minutes. CONCLUSION: This system successfully analyzes a large database of radiation therapy studies and finds the one that is most similar to a new patient, which represents a potential step forward in achieving feasible adaptive radiation therapy replanning.

Autonomy-Oriented Social Movements and the Politics of Affect

Abstract This dissertation explores damaging tendencies that exist within autonomy-oriented activism in the West. I examine how affect shapes the way that internal conflict is approached and internal strife is dealt with in radical communities. I adopt Sara Ahmed’s proposition “that our emotions are bound up with the securing of the social hierarchy” (Ahmed, 2004b: 4) and given that autonomy-oriented practices are committed to dismantling existing hierarchies, it follows that the less oppressive social configurations sought by autonomous social movements must have different emotional underpinnings. My thesis involves applying critical theory on affect and emotion in social movements to interview data gathered from activists both currently and historically involved in autonomy-oriented social movement communities in Kingston, Ontario. I ask whether anglophone, western-based, autonomy-oriented social movements reproduced understandings of affect/emotions/feelings that underwrite the social order they are working against? I also ask, “how are our emotions conditioned by capitalism?”. The research that I engage with provides responses to these questions by pointing out how the dominant discourse on emotions in the West encourages and informs certain modes of identity production that affect the diminishing and sad practices of autonomy-oriented communities and the (re)production of oppressive practices found in the dominant order. My work critically places this psychologizing view of emotions, and its damaging effects on resistance, within the context of neoliberal capitalism. I argue that the way we understand the politics of affect is an important dimension of radical struggle, and will inform and impact upon our individual and collective capacities to respond to, and refuse to reproduce relations of control and domination. I look for an understanding of “why” and to “what extent” these determinations exists, and look for hope in a politics of affect which supports an autonomy-oriented ethic.

CRISPR/Cas9-Mediated Gene Editing of ARG1 in Cell Lines and Primary Cells

Arginase 1 deficiency, a urea cycle disorder resulting from an inability of the body to convert arginine into urea, results in hyperargininemia and sporadic episodes of hyperammonemia. Arginase 1 deficiency can lead to a range of developmental disorders and progressive spastic diplegia in children, and current therapeutic options are limited. Clustered regularly interspaced short palindromic repeat (CRISPR) /CRISPR associated protein (Cas) 9 gene editing systems serve as a novel means of treating genetic disorders such as Arginase 1 (ARG1) deficiency, and must be thoroughly examined to determine their curative capabilities. In these experiments numerous guide RNAs and CRISPR/Cas9 systems targeting the ARG1 gene were designed and observed by heteroduplex assay for their targeting capabilities and cleavage efficiencies in multiple cell lines. The CRISPR/Cas9 system utilized in these experiments, along with a panel of guide RNAs targeting various locations in the arginase 1 gene, successfully produced targeted cleavage in HEK293, MCF7, A549, K562, HeLa, and HepG2 cells; however, targeted cleavage in human dermal fibroblasts, blood outgrowth endothelial cells, and induced pluripotent stem cells was not observed. Additionally, a CRISPR/Cas system involving partially inactivated Cas9 was capable of producing targeted DNA cleavage in intron 1 of ARG1, while a Cas protein termed Cpf1 was incapable of producing targeted cleavage. These results indicate a complex set of variables determining the CRISPR/Cas9 systems’ capabilities in the cell lines and primary cells tested. By examining epigenetic factors and alternative CRISPR/Cas9 gene targeting systems, the CRISPR/Cas9 system can be more thoroughly considered in its ability to act as a means towards editing the genome of arginase 1-deficient individuals.

EDUCATING THE PUBLIC THROUGH NEWS MEDIA: CASE STUDIES OF NEWS LITERACY IN THE NEW MEDIA LANDSCAPE

Two decades of unprecedented changes in the media landscape have increased the complexity of informing the public through news media. With significant changes to the way the news industry does business and the way news consumers access this information, a new set of skills is being proposed as essential for today’s news consumer. News literacy is the use of critical thinking skills to assess the reliability and source of the information that people consume on a daily basis, as well as fostering self-awareness of personal news consumption habits and how it can create audience bias. The purpose of this study was to examine how adults experience the news in their everyday lives and to describe the nature of the news literacy skills people employ in their daily news consumption. This study purposefully selected four adults who have completed high school, and who regularly consume news information across a number of platforms, both traditional and digital. Two of the participants, one man and one woman, were over 50 years old. One other male participant was in his 30’s and the final participant, a young woman, was in her 20’s. They all utilized both traditional and digital media on a regular basis and all had differing skill levels when using social media for information. Their news experiences were documented by in-depth interviews and the completion of seven daily news logs. In their daily logs the participants differentiated news information from other information available on-line but the interviews revealed a contradiction between their intentions and their news consumption practices. All four participants had trouble distinguishing between news and opinion pieces in the news information realm. In addition all but one seemed unaware of their personal bias and any possible effect it was having on their news consumption. Further research should explore the benefits of an adult-centered news literacy curriculum on news consumers similar to the participants, and should examine the development of audience bias and its relationship to the daily exposure people have to the torrent of information that is available to them on a daily basis.

DEVELOPMENT OF AN ADJUSTABLE SUTURE TECHNIQUE FOR TRABECULECTOMY

This research presents a new design of an adjustable suture that could provide a better intraocular pressure (IOP) control in the post treatment of trabeculectomy surgery and limit associated complication with the current suturing techniques. A better control in tension suture brings a great deal of advantages to this surgical technique compared with the traditional adjustable suture. A length adjustment can be added in advance to a 10-0 nylon suture which enables suture tension to be released during the postoperative period of trabeculectomy surgery. This adjustment has a D-ring geometry made of 10-0 nylon suture adhered to a 10-0 nylon surgical suture which is used to close the scalar flap. The D ring was adhered with about 180 microdroplet of Loctite 4311that was found to form a strong joint to connect the D ring to the main 10-0 nylon suture and strong enough to carry the added tension instead after cutting the central suture between the two joints of the D ring. The geometry of adjustment is the key factor of maintaining the IOP at the normal range and keeping the scleral flap tight enough and secure so that aqueous humor continues to percolate under the subconjunctiva. It has been found that a 365, and 450 µm length extensions can release suture tension postoperatively and relieve the intraocular pressure within the eye by 33, and 66% respectively. The fabrication process of the new adjustable suture was divided into two steps: fabrication of micro jig and forming microdroplets. A micro jig was fabricated in order to form and bond a precise length extension to the new design of the adjustable suture. In addition, a new liquid separation technique has been followed in this study in order to generate micro adhesive droplets as small as 50µm for bonding the new adjustable suture structure.

SINGLE STAGE LED DRIVER TECHNOLOGY WITH LOW FREQUENCY RIPPLE CANCELLATION

Because of high efficacy, long lifespan, and environment-friendly operation, LED lighting devices become more and more popular in every part of our life, such as ornament/interior lighting, outdoor lightings and flood lighting. The LED driver is the most critical part of the LED lighting fixture. It heavily affects the purchasing cost, operation cost as well as the light quality. Design a high efficiency, low component cost and flicker-free LED driver is the goal. The conventional single-stage LED driver can achieve low cost and high efficiency. However, it inevitably produces significant twice-line-frequency lighting flicker, which adversely affects our health. The conventional two-stage LED driver can achieve flicker-free LED driving at the expenses of significantly adding component cost, design complexity and low the efficiency. The basic ripple cancellation LED driving method has been proposed in chapter three. It achieves a high efficiency and a low component cost as the single-stage LED driver while also obtaining flicker-free LED driving performance. The basic ripple cancellation LED driver is the foundation of the entire thesis. As the research evolving, another two ripple cancellation LED drivers has been developed to improve different aspects of the basic ripple cancellation LED driver design. The primary side controlled ripple cancellation LED driver has been proposed in chapter four to further reduce cost on the control circuit. It eliminates secondary side compensation circuit and an opto-coupler in design while at the same time maintaining flicker-free LED driving. A potential integrated primary side controller can be designed based on the proposed LED driving method. The energy channeling ripple cancellation LED driver has been proposed in chapter five to further reduce cost on the power stage circuit. In previous two ripple cancellation LED drivers, an additional DC-DC converter is needed to achieve ripple cancellation. A power transistor has been used in the energy channeling ripple cancellation LED driving design to successfully replace a separate DC-DC converter and therefore achieved lower cost. The detailed analysis supports the theory of the proposed ripple cancellation LED drivers. Simulation and experiment have also been included to verify the proposed ripple cancellation LED drivers.

CERAMICS IN BRITAIN (1840-90): MEANINGS AND METAPHORS

The intention of this thesis, “Ceramics in Britain (1840–90): Meanings and Metaphors” is to present new approaches for interpreting ceramics in nineteenth-century Britain by situating, problematizing, and contextualizing pottery and porcelain in the popular debates of the day within the methodologies of material culture, design, cultural and art histories. I ask how did ceramics—portable, functional, and often decorative objects—contribute to shaping modes of experiences? Crockery, tableware and blue-white-porcelain, admittedly largely mediated in texts and paintings, are at the centre of this research to examine how they imposed symbolism and influenced the engagement of their subjects beyond their intended meanings and functions. This thesis tracks a common rhetoric shared by writers and artists across genres and understood by readers and viewers: crockery in the cupboard, on the mantel, the table or the floor were popular motifs exemplifying class, gender, character, etiquette, and taste. This thesis also seeks to map ceramics’ relations with other objects and people depicted. Their meanings and metaphors changed, depending on their exchange with other objects in the room and who uses them. The conventions of representing ceramics dictated a particular grammar that writers and artists used, critiqued, discarded or personalized. The examination of ceramics mediated in text and image especially in comparison with extant objects invites a deeper probing of both material culture and artistic practice, which helps to situate the agency of the ceramic objects themselves. Also this thesis, in attempt to explore new methodological approaches for ceramic studies, examines the social life of the mid-Victorian relief-moulded “Minster” Jug in the Gardiner Museum in Toronto. The product originating in Staffordshire in 1843 and exported to the colonies holds significance due to its multiple life histories. Viewing the “Minster” through the lenses of curator, collector, consumer, and critic its layered lives unfold to reveal the protocols of museum praxis as well as important aspects of mid-nineteenth-century British society related to design reform, gender, imperialism and consumption patterns. This thesis contends that the British experienced ceramics in sometimes unexpected ways, unrelated to their original purpose, such as tools of violence or containers of solace, and transformative fantasy.

Nonlinear soil-structure interaction for buried pressure pipes under differential ground motion

Pipelines extend thousands of kilometers across wide geographic areas as a network to provide essential services for modern life. It is inevitable that pipelines must pass through unfavorable ground conditions, which are susceptible to natural disasters. This thesis investigates the behaviour of buried pressure pipelines experiencing ground distortions induced by normal faulting. A recent large database of physical modelling observations on buried pipes of different stiffness relative to the surrounding soil subjected to normal faults provided a unique opportunity to calibrate numerical tools. Three-dimensional finite element models were developed to enable the complex soil-structure interaction phenomena to be further understood, especially on the subjects of gap formation beneath the pipe and the trench effect associated with the interaction between backfill and native soils. Benchmarked numerical tools were then used to perform parametric analysis regarding project geometry, backfill material, relative pipe-soil stiffness and pipe diameter. Seismic loading produces a soil displacement profile that can be expressed by isoil, the distance between the peak curvature and the point of contraflexure. A simplified design framework based on this length scale (i.e., the Kappa method) was developed, which features estimates of longitudinal bending moments of buried pipes using a characteristic length, ipipe, the distance from peak to zero curvature. Recent studies indicated that empirical soil springs that were calibrated against rigid pipes are not suitable for analyzing flexible pipes, since they lead to excessive conservatism (for design). A large-scale split-box normal fault simulator was therefore assembled to produce experimental data for flexible PVC pipe responses to a normal fault. Digital image correlation (DIC) was employed to analyze the soil displacement field, and both optical fibres and conventional strain gauges were used to measure pipe strains. A refinement to the Kappa method was introduced to enable the calculation of axial strains as a function of pipe elongation induced by flexure and an approximation of the longitudinal ground deformations. A closed-form Winkler solution of flexural response was also derived to account for the distributed normal fault pattern. Finally, these two analytical solutions were evaluated against the pipe responses observed in the large-scale laboratory tests.

A Poetics of Annotation: Alexander Pope's Footnotes

Studies of Alexander Pope's poetry tend to examine only the footnotes to his Dunciads, if they examine his footnotes at all. This dissertation will address this deficit in our understanding of Pope's poetics through an examination of Pope's use of footnotes in support of his verse throughout his career. With Gerard Genette's taxonomy of footnotes as variously paratext and text and Hugh Kenner's idea of the technological space of the printed page as frameworks within which Pope's footnotes operate, this dissertation will show that – over the course of his career – Pope developed a poetics of annotation that deployed footnotes rhetorically as appeals to ethos and pathos that both built up Pope's own authorial ethos for his audience in the literary market place of early eighteenth-century London and for posterity and used that authorial ethos in support of his literary and political friends.

The Flotation of Niobium Oxide Minerals from Carbonatite Ores

Global niobium production is presently dominated by three operations, Araxá and Catalão (Brazil), and Niobec (Canada). Although Brazil accounts for over 90% of the world’s niobium production, a number of high grade niobium deposits exist worldwide. The advancement of these deposits depends largely on the development of operable beneficiation flowsheets. Pyrochlore, as the primary niobium mineral, is typically upgraded by flotation with amine collectors at acidic pH following a complicated flowsheet with significant losses of niobium. This research compares the typical two stage flotation flowsheet to a direct flotation process (i.e. elimination of gangue pre-flotation) with the objective of circuit simplification. In addition, the use of a chelating reagent (benzohydroxamic acid, BHA) was studied as an alternative collector for fine grained, highly disseminated pyrochlore. For the amine based reagent system, results showed that while comparable at the laboratory scale, when scaled up to the pilot level the direct flotation process suffered from circuit instability because of high quantities of dissolved calcium in the process water due to stream recirculation and fine calcite dissolution, which ultimately depressed pyrochlore. This scale up issue was not observed in pilot plant operation of the two stage flotation process as a portion of the highly reactive carbonate minerals was removed prior to acid addition. A statistical model was developed for batch flotation using BHA on carbonatite ore (0.25% Nb2O5) that could not be effectively upgraded using the conventional amine reagent scheme. Results showed that it was possible to produce a concentrate containing 1.54% Nb2O5 with 93% Nb recovery in ~15% of the original mass. Fundamental studies undertaken included FT-IR and XPS, which showed the adsorption of both the protonized amine and the neutral amine onto the surface of the pyrochlore (possibly at niobium sites as indicated by detected shifts in the Nb3d binding energy). The results suggest that the preferential flotation of pyrochlore over quartz with amines at low pH levels can be attributed to a difference in critical hemimicelle concentration (CHC) values for the two minerals. BHA was found to be absorbed on pyrochlore surfaces by a similar mechanism to alkyl hydroxamic acid. It is hoped that this work will assist in improving operability of existing pyrochlore flotation circuits and help promote the development of niobium deposits globally. Future studies should focus on investigation into specific gangue mineral depressants and inadvertent activation phenomenon related to BHA flotation of gangue minerals.

British Romantic Criticism and the Fine Arts: A Study in Philosophical Theories of Literary Unity

This dissertation is an exploration of how a small but important group of Romantic critics, finding fault in the ideal of three unities developed by neoclassical Academicians and wrongly attributed to Aristotle, turned to the terminology and practices of the fine arts to emphasize their conception of organic unity in literature. The Romantic analogy to painting in particular enables a philosophical criticism of literature to present the aesthetic semblance of painting, the comprehension of a multitude of details in a harmonious whole that is a natural unity to its medium, as a paradigm of modern-romantic poetry and its aspirations to similar complexity, particularity, and imaginative colour. Further, in extension of the French Querelle des anciens et des modernes of the seventeenth century, the division of ancient and romantic art by Romantic critics like August Schlegel, Samuel Taylor Coleridge, and William Hazlitt not only establishes an ethnological and historical difference between the artistic productions of these two cultural periods but also allows, unlike the neoclassical unities, a non-anachronistic philosophical vocabulary of whole and parts or of the general and particular in the criticism of poetry, which involution provides a “rule” more consonant with the laws of the imagination rather than with the rhetorical and absolutist dicta that were thither available in the literary canon.