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.

Queen's College Journal (1889-1890)

The Journal has been Queen's main student newspaper since it was founded in 1873. It appears twice a week on campus with a mix of news, sports, and entertainment stories, editorials, letters to the editor, and photographs. The paper is students' most important source of news and general information and has been a training ground for scores of Canadian journalists.

Queen's College Journal (1890-1891)

The Journal has been Queen's main student newspaper since it was founded in 1873. It appears twice a week on campus with a mix of news, sports, and entertainment stories, editorials, letters to the editor, and photographs. The paper is students' most important source of news and general information and has been a training ground for scores of Canadian journalists.

Queen's College Journal (1891-1892)

The Journal has been Queen's main student newspaper since it was founded in 1873. It appears twice a week on campus with a mix of news, sports, and entertainment stories, editorials, letters to the editor, and photographs. The paper is students' most important source of news and general information and has been a training ground for scores of Canadian journalists.

Queen's College Journal (1892-1893)

The Journal has been Queen's main student newspaper since it was founded in 1873. It appears twice a week on campus with a mix of news, sports, and entertainment stories, editorials, letters to the editor, and photographs. The paper is students' most important source of news and general information and has been a training ground for scores of Canadian journalists.

Queen's College Journal (1893-1894)

The Journal has been Queen's main student newspaper since it was founded in 1873. It appears twice a week on campus with a mix of news, sports, and entertainment stories, editorials, letters to the editor, and photographs. The paper is students' most important source of news and general information and has been a training ground for scores of Canadian journalists.

Queen's University Journal (1894-1895)

The Journal has been Queen's main student newspaper since it was founded in 1873. It appears twice a week on campus with a mix of news, sports, and entertainment stories, editorials, letters to the editor, and photographs. The paper is students' most important source of news and general information and has been a training ground for scores of Canadian journalists.

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.

Queen's University Journal (1895-1896)

The Journal has been Queen's main student newspaper since it was founded in 1873. It appears twice a week on campus with a mix of news, sports, and entertainment stories, editorials, letters to the editor, and photographs. The paper is students' most important source of news and general information and has been a training ground for scores of Canadian journalists.

Queen's University Journal (1896-1897)

The Journal has been Queen's main student newspaper since it was founded in 1873. It appears twice a week on campus with a mix of news, sports, and entertainment stories, editorials, letters to the editor, and photographs. The paper is students' most important source of news and general information and has been a training ground for scores of Canadian journalists.

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.