VictorJuiz/thesis huggingface dataset:
Dissecting Mechanisms of Echinocandin Drug Resistance and Filamentation in the Fungal Pathogen Candida albicans

Invasive fungal infections have a devastating impact on human health worldwide, in part due to the limited repertoire of antifungal drugs available to treat these infections. Candida albicans is a primary cause of systemic mycoses with mortality rates of ~40%, even with current treatment options. Thus, the development of novel therapeutic strategies to combat fungal infections is of utmost importance. My research aims to explore novel therapeutic approaches to treat mycotic infections. This includes strategies to combat antifungal resistance and strategies to target a key C. albicans virulence trait, the ability to transition between yeast and filamentous states. To uncover novel therapies to combat resistance, I explored compounds that potentiate activity of the cell wall-targeting echinocandin antifungal drug caspofungin. A screen of 1,280 pharmacologically active compounds identified 19 that reduced caspofungin resistance. The most potent molecule was a chelator, DTPA, which potentiated echinocandin activity via chelation of magnesium, modulating signaling through the Hog1 stress response pathway. DTPA also induced C. albicans filamentation through zinc chelation, and the combination of caspofungin and DTPA had in vivo therapeutic utility in a murine model of candidiasis. Further, to explore genetic circuitry governing C. albicans morphogenesis, I characterized the role of the transcriptional regulator Mfg1 in mediating filamentous growth. Mfg1 is a core regulator of filamentation in the model yeast Saccharomyces cerevisiae and in C. albicans, and interacts with Flo8 and Mss11 to form a complex important for regulating morphogenesis. Unexpectedly, I identified divergent roles for these complex members in regulating C. albicans filamentation. Experimental evolution exploiting a novel selection strategy revealed triplication of chromosome 6, the genomic location of FLO8, as an adaptive mechanism enabling filamentation in the absence of MFG1. Collectively, this research uncovered new circuitry governing C. albicans drug resistance, evolution, and virulence, suggesting novel therapeutic strategies to treat fungal infections.

Advisor: Cowen, Leah E
Conflict at the Crossroads: Redrawing Global Supply Lines in the Age of Logistics

This dissertation examines the landscapes of logistics, the fast-growing industry responsible for managing the movement of goods, materials, and related information in the global economy. As commodity flows increase in volume, velocity, and distance, they depend on increasingly large-scale transformations of the physical and social environment. How is space being refashioned to accommodate new methods and patterns of circulation? And how do popular forces intervene in these processes? This research employs a multi-sited, relational methodology to investigate how the circulation of commodities is influencing the production of space at multiple scales. Its empirical focus is the recent expansion of the Panama Canal, a logistics megaproject with global reverberations, and the consequent rivalry among North American ports seeking to attract a new generation of oversized container ships. Drawing on a year of mixed-methods fieldwork in Panama City, Los Angeles, and New York, the dissertation analyzes competitive efforts to remake space in the image of smooth, efficient circulation and the struggles that have ensued over land, labour, and the environment. I argue that the landscapes of logistics are contradictory and conflictual spaces: even as global supply chains deliver the material provisions that make possible the reproduction of contemporary life, their development and functioning are undergirded by violent processes of community dispossession, labour exploitation, and environmental degradation. These impacts are disproportionately borne by poor and racialized residents and workers, whose struggles play a fundamental role in shaping corporate production and distribution networks. The research offers a critical reappraisal of the prevailing view that logistics provides a progressive and sustainable path to economic development. It shows that, as logistics has become increasingly vital to the operations of capitalism, the circulation of commodities exacts a heavy toll on those who live and labour in the arteries of global trade.

Keywords: Globalization
Logistics
Urbanization
Advisor: Cowen, Deborah
Struggles between Rural and Urban Ways: A Qualitative Study of Informal Learning amongst Female Migrant Domestic Workers in China

There are existing researches regarding the subject matter of Chinese rural migrant workers, mainly focusing on economic and social effects of migrant workers, instead of regarding their thoughts, feels and needs. To fill these gaps, this dissertation conducted in-depth interviews involving 30 interviewees as a kind of primary research. It answers three research questions on barriers women migrant domestic workers face, with solutions, informal learning they obtain in workplace, and suggestions to governments, agencies and communities in facilitating their migration process. The thesis presents findings which shed lights to the related researches on the Chinese female rural migrant domestic workers, including the changing requirements as the globalization and urbanization deepen in China, the rural migrants’ active participation into urban life and their enhancing themselves for social upward mobility. The primary focus of analysis in this research is on women’s informal learning that stems from their economic migration between rural and urban areas as well as their work as domestics in the latter. Therefore, this informal learning takes place across a number of locations: within their workplaces (i.e. the homes of employers) but also extends beyond the workplaces (e.g. in discussions with family members or the community). Since this informal learning stems from the relationship of economic migration and domestic work specifically, the learning content is quite diverse. It involves content directly related to work tasks, skills and knowledge as well as relationships with employers (and their families), but it also includes learning content implicated by the context of rural-urban economic migration, such as effects on a worker’s children, husband or parents, aspects of urban living as well as the pendulum swings between their rural and urban lives, and much more. In keeping the type of observations that Malcolm, Hodkinson and Colley (2003) that aspects of informality and formality are likely part of all learning, we will also see how certain aspects of training and even educational attainment of these workers does shape how informal learning occurs, and vice versa learning done informally shapes interest and activity related to training interests, goals and practices as well.

Advisor: Sawchuk, Peter
Virgil in the Northern Renaissance: Spenser, Milton, and Humanist Philology

My dissertation examines how advances in sixteenth-century classical scholarship shaped the Virgilianism of Edmund Spenser and John Milton. Critical studies on the Virgilian commentary tradition have focused on commentaries written no later than the early decades of the sixteenth century, and hence have detected little development in the Renaissance interpretation of Virgil. I argue that, if we are to understand Spenser’s and Milton’s Virgil, we must appreciate the revolutionary advances achieved by mid-sixteenth-century humanists. What made the latter possible was a much-improved knowledge of Greek literature, which gave humanists newfound insight into Virgil’s engagement with both Hellenistic poetry and Attic tragedy. I focus mainly on the French school of humanists including Jean Dorat and his circle of philologists and poets. Their Greek studies allowed these humanists to innovate upon Servius, who lacked firsthand knowledge of Virgil’s Hellenistic models, and to recover the Alexandrian dimension of Virgilian poetics. A new Virgilianism then emerged in the poetry of the Pléiade, one that accounts for the richness and complexity of Spenser’s Virgilian imitations in The Shepheardes Calender and The Faerie Queene more comprehensively than the Virgil of modern career criticism. I also examine how the study of Aristotle’s Poetics helped humanists to recover the dramatic dimension of the Aeneid, and hence to read Dido’s tragedy mimetically rather than allegorically. This approach led, first, to a more sympathetic reading of Dido’s character, and second, to an interest in the theological questions raised by her death. Milton’s imitations of Aeneid 4 in Paradise Lost illustrate how this interpretation shaped the legacy of Dido and the attitude toward eros in English epic. The dissertation thus aims to capture the dynamic nature of Renaissance Virgilianism by exploring how poetic practice kept pace with philological discovery. The first chapter focuses on French philology and the recovery of Virgil’s Alexandrianism; the second, on Spenser’s March and the reception of Hellenistic pastoral; the third, on Book 3 of Spenser’s Faerie Queene and Joseph Scaliger’s scholarship on the Ciris; and the fourth, on Milton’s Paradise Lost and the influence of the Poetics on humanist interpretations of Dido’s tragedy.

Keywords: Milton
Renaissance
Spenser
Virgil
Advisor: Galbraith, David
Generation of induced progenitor-like (iPL) cells using interrupted reprogramming

Regenerative medicine is constrained by suboptimal cell sources with either limited or uncontrolled proliferation and/or incompletely restricted differentiation. We developed a novel "interrupted reprogramming" strategy without traversing the pluripotent state, to generate "induced Progenitor-Like (iPL) cells" using carefully timed transient expression of induced Pluripotent Stem (iPS) cell reprogramming factors (Oct4, Sox2, Klf4 and c-Myc; OSKM). Interrupted reprogramming is not only able to achieve controlled expansion of the selected cell type, but results in the "de-differentiation" of the cells to a progenitor-like state while preserving the parental lineage commitment to generate a limited range of functional progeny. Lineage-specific iPL cells can be derived from distinct airway epithelial populations and function as region-specific progenitor cells. For example, bronchiolar progenitor-like iPL cells can be derived from mature Club cells (Club-iPL cells) and give rise to Club cells, goblet cells and functional CFTR-expressing ciliated epithelium. Embryonic bipotent progenitor-like iPL cells can be derived from adult alveolar type II cells (AEC-II-iPL cells) and the iPL process results in the rescue of the in vitro limited clonogenic capacity of AEC-II cells. These highly specified iPL populations are functional and therapeutic that are capable of directly contributing to lung regeneration through engraftment and differentiation. In vivo, Club-iPL cells were able to repopulate CFTR-deficient bronchiolar epithelium and AEC-II-iPL cells showed utility in ameliorating bleomycin-induced pulmonary fibrosis. This interrupted reprogramming process could be metronomically applied both in vitro and in vivo, to achieve controlled progenitor-like proliferation. Furthermore, harnessing the residual epigenetic “memory” and the plasticity existing in the early stage of the reprogramming process, interrupted reprogramming is able to rejuvenate aged endogenous progenitor AEC-II cells to a youthful state by ameliorating multiple hallmarks of aging, including impaired self-renewal, declined telomerase activity, mitochondrial DNA damages and the epigenome histone alteration. Importantly, cellular identity and function of parental AEC-II cells were maintained, thereby generating large numbers of younger AEC-II cells. In summary, this novel interrupted reprogramming strategy will allow the production of highly specified functional therapeutic populations which can potentially have significant implications for regenerative medicine, specifically for, cell replacement therapy, biohybrid devices, disease modelling, and drug screening for human diseases.

Advisor: Waddell, Thomas
Functional Analysis of the Motor Circuit of Juvenile Caenorhabditis elegans

Caenorhabditis elegans generates alternating dorsal-ventral bending waves across developmental stages. The overall level of dorsal and ventral muscle output is symmetric. In adults, this behavioral symmetry correlates with anatomy symmetry: distinct pools of cholinergic motor neurons activate dorsal and ventral body wall muscles, whereas distinct pools of GABAergic motor neurons contra-laterally inhibit dorsal and ventral muscles, respectively. However, in the first stage larva (L1), cholinergic motor neurons only make neuromuscular junctions to the dorsal muscle, and GABAergic motor neurons to the ventral muscle. How does an asymmetric motor circuit produce symmetric motor output? In the past five years, my colleagues and I undertook anatomical and functional analyses of the L1 larva motor circuit to address this question. First, my colleagues fully reconstructed the connectivity of a complete L1 larva, from which we identified all candidate cellular components for muscle activity. Next, to elucidate the functional contribution of these candidates, I developed a novel all-optical manipulation methodology that allows fast and systemic probing of functional connections of neural circuits. Third, I led the effort to combine free-moving calcium imaging, cellular ablation, chemogenetics, optogenetics, and all-optical interrogation to pinpoint mechanisms for the symmetric L1 muscle output. Collectively, results from these studies show that all cells that make anatomic synaptic connections are insufficient to explain the symmetry of body wall muscle excitability in L1 C. elegans; instead, extra-synaptic transmissions play a crucial role in underling muscle activity regulation. In the L1 motor circuit, the anatomically asymmetric circuit is functionally compensated by extra-synaptic transmissions from both excitatory premotor interneurons and inhibitory motor neurons to operate as a symmetric circuit. Excitatory premotor interneurons can bypass the motor neurons layer to directly regulate excitability of muscle cells, thus assuming dual roles. Animals with distinct wirings can produce similar motor patterns. Our findings in the juvenile C. elegans motor circuit show that structurally divergent neural circuits can functionally converge on the functional output, and that neurons can multiplex. This study further demonstrates a larger role of functional communications devoid of ultrastructural features in a developing neural circuit.

Keywords: All-optical interrogation
C. elegans
Extrasynaptic transmission
Motor circuit
Symmetry
Advisor: Zhen, Mei
Exit Music: The Experience of Music Therapy within Medical Assistance in Dying

Since the 2015 legalization of medical assistance in dying (MAiD), healthcare professionals across the interdisciplinary spectrum have been exploring their roles within this practice, and a number of professions have created guidelines and policies to define their role(s). Many Canadian music therapists also found themselves implicated in care for those requesting MAiD. No prior research has been done to gain insight into the role of music therapy within the context of MAiD. This qualitative hermeneutic phenomenological study, the first of its kind, examines the experience of music therapy within medically assisted dying from three perspectives: the patient, their primary caregiver, and the music therapist/researcher. Ten cases that vary in duration of involvement of the music therapist, demographic, characteristics, and nature of the music therapy are presented through a hermeneutic phenomenological methodology lens. A total of 24 music therapy sessions and seven caregiver interviews were transcribed and analyzed. A total 28 researcher reflections were analyzed. The analysis of data revealed thematic trends of life reflection activated by the musical interaction (wherein the music functioned as a narrator and a trigger), control (over musical and ritualistic choices), communication and connectedness (with the self and others through music), and aesthetic pleasure (as a catalyst for therapeutic outcomes such as pain and symptom management). Caregiver participant results revealed trends of immediacy of access to emotion through music, reflection (on personal narratives within music), witnessing (of patients’ emotional and narrative expressions), and unexpected opportunities (for life review through music). Researcher reflection data analyses revealed thematic trends of trusting (in the midst of uncertainty), witnessing (of the unfolding of narratives through music), therapeutic relationship creation (with a sense of immediacy), and support for patients and caregivers in their navigation of their MAiD processes. These results may have implications as to how music therapy is offered, standardized, and implemented in settings where MAiD is provided, as the overarching thematic findings show therapeutically beneficial outcomes in terms of quality of life, life review, and symptom management. Further research is merited to continue to explore the role of music therapy in the context of assisted dying.

Keywords: End of life
MAiD
Music Therapy
Palliative care
Phenomenology
Qualitative
Advisor: Bartel, Lee R
Rodin, Gary M
Toward Feminist Geographies of Cycling

Transport cycling uptake is on the rise in many cities; in Toronto, Canada, cycling is the fastest growing mode of transportation. In many of these cities there is evidence that cycling participation rates are not distributed equally across the population. Notably, a gender-gap in cycling has been observed in many cities with low cycling rates, including Toronto, whereby approximately two thirds of commuter cyclists identify as men and one third identify as women. This thesis is concerned with gender and cycling. Drawing from perspectives from feminist geography, this research examines how the embodied experience of cycling shapes, and how is it shaped by, intersecting axes of identity. A critical literature review of articles concerned with gender and cycling finds that two hypotheses are commonly explored to explain the gender-gap in cycling: (1) that women cycle less than men due to greater concerns over safety and (2) due to their tendency to complete more household-serving travel, a type of travel said to be more challenging to do by bike because it often involves carrying goods and/or children. The social factors underpinning these trends, as well as the ways in which other axes of identity intersect with gender to shape cycling behaviours is lacking from the current literature. This research aims to address this research gap by providing a feminist geography of cycling. To do so, a research project was completed in collaboration with Bike Host, a cycling mentorship program targeting immigrants and refugees in Toronto, Canada. Amongst other research activities, semi-structured interviews were completed with participants to explore the embodied experience of cycling. Key results from this study are presented in three chapters. The first examines the gendered and classed embodied practices that shape and are shaped by cycling. Then, the social, temporal, and spatial dimensions of many different types of fear of cycling are explored. Finally, the ways in which participants used bicycles to complete household-serving travel, a gendered mobility, are reported. Taken together, this dissertation demonstrates the role patriarchal and classist power relations play in shaping who cycles.

Keywords: Bicycling
Embodiment
Fear
Gender
Household-Serving Travel
Urban
Advisor: Buliung, Ron N.
DNA Damage-inducible Nuclear Microtubules Mobilize Rad52 Liquid Droplets to Mediate Repair

Damaged DNA exhibits increased mobility to promote repair. In Saccharomyces cerevisiae, repair of DNA double-strand breaks (DSBs) is driven by their clustering into nucleoplasmic DNA repair centres or mobilization to the nuclear periphery. This apparently random mobility is paradoxically abrogated upon disruption of microtubules or kinesins, which typically mediate the directional movement of macromolecules. We herein resolve this paradox by characterizing novel DNA damage-inducible intranuclear microtubule filaments (DIMs) that mobilize damaged DNA and promote repair. DNA damage-induced relief of centromeric constraint triggers DIMs that subsequently capture and directionally mobilize DNA lesions. Repressing and hyper-inducing DIMs abrogates and hyper-activates DNA repair, respectively. Accounting for DIM dynamics, by measuring directional changes of DSBs across cell populations, reveals an increased non-linear directional behavior in nuclear space. Abrogation of DIM-dependent processes or repair-promoting factors decreases directional behavior. We further reveal that the DNA repair protein Rad52 forms liquid droplets at different sites of DNA damage. Forces generated by the mechanical motions of short DIMs subsequently promote the coalescence of Rad52 droplets into repair centres. Upon coalescence, the large Rad52 droplet concentrates tubulin to connect the repair centre droplet to elongated DIMs for kinesin motor-dependent targeting of DSBs to the nuclear periphery and repair. Thus, inducible nuclear microtubule filaments cooperate with repair protein liquid droplets to cluster and directionally mobilize damaged DNA for repair.

Advisor: Mekhail, Karim
Model-Predictive Control of HVDC Grid

This thesis introduces, develops and verifies a control strategy for a Voltage-Sourced Converter (VSC)-based High-Voltage Direct-Current (HVDC)-grid. The envisioned control: (1) regulates and retains the HVDC-grid variables within their permissible ranges during transients and steady-state conditions; (2) shares control objectives among all operational converter stations; (3) generates control-command variables without infeasibility problem; and (4) mitigates impacts of communication delay on the HVDC-grid control. The proposed control strategy has a distributed control structure and includes a local outer controller (LOC) for each converter station. Each LOC consists of five building blocks: setpoint calculator SCdc; local estimator LEdc; DC-side local outer controller LOCdc; AC-side local outer controller LOCac; and control-command generator CCG. The proposed LOCdc comprises a two-level control structure. The lower level is based on discrete-time infinite-horizon Linear-Quadratic Regulator (LQR) method. The higher level, which is based on Model-Predictive Control (MPC) method, is formulated such that the MPC optimization problem always possesses one and only one optimal solution. The formulation of the two levels is such that the output of the higher level and the optimal solution of the MPC optimization problem are known, if the output of the lower level satisfies the HVDC-network constraints over the MPC prediction horizon. A cooperative approach is adopted in formulating the MPC optimization problems of all LOCs. As different communication delays affect the receiving time-instants of different measured signals at each LEdc, the proposed LEdc is formulated to mitigate the communication-delay impacts on the HVDC-network state-vector estimation. The SCdc computes setpoint values based on a steady-state model of the HVDC network, considering its variable limits. The LOCac is formulated based on continuous-time infinite-horizon LQR method. The proposed CCG is formulated based on assigning priority levels to the conditions that the CCG aims to satisfy and obtaining a set of control-command vectors restricted by the priority levels. The proposed approach guarantees that the CCG always can generate control-command variables, and the generated control-command variables minimize violations of the conditions. The control system performance is evaluated based on time-domain simulation studies in MATLAB/Simulink environment. The investigations conclude that the proposed control system meets the expectations.

Keywords: communication delay
converter
HVDC grid
Model Predictive Control
partially decentralized
regulation
Advisor: Iravani, Reza
Yazdani, Amirnaser