VictorJuiz/thesis huggingface dataset:
Dopaminergic Modulation of Ionotropic Transmission in the Anterior Cingulate Cortex in Naïve and Inflammatory Pain States

Pain modulation of dopamine (DA) producing nuclei is known to contribute to the affective component of chronic pain. The anterior cingulate cortex (ACC) is a brain region critical for processing acute and chronic pain. Anatomical studies have established bidirectional connectivity between the ACC and ventral tegmental area (VTA) as nodes within the mesocortical pathway with function in regulating motivation. DA modulates behaviour and synaptic transmission by signalling through D1- and D2-like receptors in target areas. I initially sought to characterize the function of the D1R subtype, a receptor imperative for learning and synaptic plasticity. In this regard, I characterized behaviour in a CRISPR/Cas9 mediated somatic knockout of the D1Rs in all neuronal subtypes of the ACC and found enhanced mechanical sensitivity of the hindpaws. Further, patch-clamp electrophysiology on ACC slices from mice revealed that D1R agonists inhibit basal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) currents in the ACC., while co-application of D1R antagonists with D1R agonists paradoxically produced robust synergistic depression of AMPAR currents in the ACC. At a fundamental level, DA release in the ACC would modulate behaviour by modulating ionotropic synaptic transmission. Thus, I explored the role of ACC dopaminergic modulation of excitatory and inhibitory ionotropic transmission in naïve mice and mice with inflammatory pain. With slice electrophysiology, I demonstrated that DA inhibits both glutamatergic and GABAergic transmission in ACC neurons through a postsynaptic G-protein mechanism. In naïve mice, DA induced synaptic inhibition in majority of the ACC neurons by shifting the E/I balance towards inhibition via exerting greater inhibition of excitatory over inhibitory transmission. However, in mice with inflammatory pain, I observed decreased dopaminergic-mediated inhibition of AMPAR-mediated currents. ACC dopaminergic function was also examined by quantifying the expression of DA receptor proteins and neurotransmitter concentrations in the ACC. In mice with CFA treament, DA receptor expression was enhanced three- and four-days post-CFA treatment in the ACC. In addition, onset of inflammation upregulated DA neurotransmitter concentraion in the ACC. These results demonstrate that acute phase of inflammation may upregulate DA activity in the ACC and persistent inflammation may induce activity-dependent changes in DA receptor expression and signalling in the ACC.

Keywords: ACC
CRISPR/Cas9
Dopamine
Electrophysiology
Inflammation
Pain
Advisor: Martin, Loren LM
Banking on Equity: Bay Street and Black Women's Leadership in Banks©

This qualitative research study examines Black women’s leadership experiences in Canadian banks and their perceptions about opportunities for mobility and advancement to executive management positions. The purpose of this research study is to explore and contextualize the epistemic complexities of Black women’s leadership experiences in the Toronto banking sector. The study’s data are collected through in-depth interviews and focus groups with Black women working in leadership positions. Further, this study seeks to examine: (1) the lived experience of Black women’s leadership in Canadian banks; (2) the perceived incongruity between Black women as leaders and those who are seen as possessing characteristics, qualities, and social capital for leadership roles; and (3) how the discourse of multiculturalism, employment equity policies, and corporate climate has impacted Black women’s mobility and advancement opportunities to executive management positions. This study utilizes theoretical frameworks of Critical Race Theory, Black Canadian Feminist Thought, and Intersectionality Theory to explore and examine Black women’s leadership experiences. My analysis engages with discussions of race, gender, class, sexism, and how the construction of whiteness is manifest in institutional power, and how that construction is written and read upon Black women’s leadership to understand the absence of Black women in executive management positions. The findings indicate that being Black and a woman in banking sector negatively impacts their career mobility and advancement. Black women remain locked out of leadership opportunities as they encounter institutional climate of anti-Black racism and sexism, which deems them unfit and incompetent for senior and executive roles based on negative racial stereotypes and lack of sponsorship. Ultimately, these findings relate to the factors and conditions that make Black women’s executive leadership in the Toronto banking sector so exceedingly rare. This study is one of the few Canadian examinations of Black women’s leadership experience in the banking sector.

Keywords: Anti-Black Racism
Sexism and work
Black Canadian Feminist Thought
Black Women and Leadership
Diversity
Equity
Inclusion
Mentors
Sponsorship
and Networks
Race
Gender
and Leadership
Advisor: w, Njoki
Exploring the Boundaries of Emotion and Language: Elementary School Newcomers with Emerging Print Literacy as Co-researchers

The participants in this study are students in Grades 4 to 6 who arrived in Canadian elementary schools with emerging print literacy not having had the right to learn to read and write before migrating to Canada. The research questions that guide this study are: Who are newcomers with emerging print literacy in elementary schools? What emotions are associated with and shape the students’ identities and literacy practices? And how do the students understand the relationship between these emotions and their identities and literacy practices? To answer these questions, this research combines the theories of translanguaging, which views language as being socially constructed and complex (García & Wei, 2014); identity as social positions through which the self is developed (Hall, 1996; Moje, Luke, Davies & Street, 2009); and the sociality of emotion where emotions create the boundaries of what a person or idea is (Ahmed, 2004). Employing a humanizing methodological design (Paris, 2011), I utilized qualitative critical case studies to work with the students in co-creating oral and written texts as well as co-researching with the students to identify and analyze themes of emotions found in each-other’s texts. Each of the three case studies took place at a different school site and included four to six students and their teachers. Key components of the students’ identities are plurilingualism, racialization, low socio-economic status, English-only writers, avid video-game players and social media users, regional migrators and sophisticated consumers of various cultural experiences. The student identified themes include love of family and friends, safety in religion, anger with writing and shyness about videos, which were interwoven with other themes from the data including trauma, print literacy humiliation and safety in Canada. This research shows how plurilingual children who are in the process of learning to read and write can participate meaningfully in the research process. Emotions and translanguaging combine to take us deeper into understanding how the pedagogical incorporation of the students’ plurilingualism and previous experiences, especially with family, are essential to a classroom without humiliation that is truly culturally sustaining and trauma-informed.

Keywords: Emotion
Identity
Limited prior schooling
Literacy
Refugees
Translanguaging
Advisor: Bale, Jeff
Design Principles for Engineering Dynamic Control of Metabolism in Microbes for Chemical Production

Microbial production of chemicals through metabolic engineering has garnered significant interest in recent years due to growing concerns over the sustainability of conventional chemical production processes. Biochemical production offers an environmentally benign alternative through the use of renewable substrates and the ability to catalyze reactions at mild reactor conditions. While advances in bioengineering and systems biology have enhanced our understanding of microbial metabolism and led to the development of tools and techniques for strain design, several rounds of the design-build-test-learn cycle of strain engineering are necessary before a strain with commercial viability can be realized. Bioprocesses with decoupled growth and chemical production stages – where metabolic states are dynamically controlled, have been proposed as a solution to low chemical productivity. In this work, we explore the design principles that govern the effective implementation of such dynamic control strategies and two-stage chemical production processes to develop bioprocesses that offer optimal Titer, Rate, and Yield (TRY) values. To this end, we first build a computational framework that predicts novel two-stage chemical production processes that use a growth-coupled chemical production stage to outperform one-stage alternatives over a wide range of substrate uptake concentrations. Further, this algorithm also predicts optimal operating points that result in enhanced chemical production characteristics and reveals some common features of ideal production stage flux distributions. Next, in order to facilitate the characterization of large strain and genetic circuit libraries required to validate our experimental hypotheses, we develop an eco-friendly automation platform that effectively characterizes cellular phenotypes. Then, we used a model-based design strategy to improve the switching characteristics of a genetic toggle switch – a gene regulatory device that allows the experimental implementation of dynamic control strategies. Specifically, we were able to improve switching speeds and show a trade-off between the speed and the robustness of the switch. Finally, we validated our model findings by building a large library of toggle switch variants that offer a wide range of switching speeds. We anticipate that these design principles along with the switch library will facilitate the widespread implementation of two-stage chemical production processes.

Keywords: Computational Biology
Dynamic Control
Lab Automation
Metabolic Engineering
Synthetic Biology
Toggle Switch
Advisor: Mahadevan, Radhakrishnan
Towards Reliably Handling Inputs Not From the Training Distribution

Deep learning methods today are exceptional at handling test inputs coming from the training distribution. This makes them effective for automating processes in a controlled and closed environment, like in a lab or a factory. To broaden their applicability, we need to develop systems that can act safely in open environments, where they may face ``unexpected’’ inputs. One strategy to handle unexpected inputs is to abstain from making a decision. For example, an image classifier trained to recognize animals in photographs should abstain from assigning a label when the input image contains a building. Bayesian neural networks are promising candidates to make deep classifiers better at detecting such unexpected inputs. The first part of the thesis presents a new variant of Bayesian neural networks that provides computational savings while performing well on benchmark tasks that simulate detecting unexpected inputs. Another strategy to handle unexpected inputs is to estimate how likely an input is from the training distribution. This view decouples the capability of a classifier from how unexpected a test input is. An ideal method can identify whether an input comes from the training distribution and only pass down inputs from the training distribution, effectively creating a closed environment. Deep generative models are good surrogates to the training distribution, hence are promising methods to enable this strategy. We study different types of generative models, identify one practical issue with a popular class of density models built on invertible neural networks, and show promising results for using unnormalized density models for detecting unexpected inputs. The last strategy to cope with inputs not from the training distribution is to adapt to them, using transfer learning and few-shot learning. We first demonstrate that modern generative models are capable of generating images of concepts not present in the training set using auxiliary information. Then, we show two novel applications of few-shot learning. Finally, we propose a benchmark and a baseline method for anomaly detection in the few-shot classification setting. The goal of this last study is to facilitate research on improving the reliability of machine learning models in the increasingly popular few-shot setting.

Keywords: Deep Learning
Generative Models
Machine Learning
Outlier Detection
Advisor: Zemel, Richard
Uncovering Outdoor Mobility Behaviours of Older Adults With and Without Dementia from GPS Data

One of the greatest health challenges of the growing ageing population is dementia. Currently, there is no way to stop the progression of dementia or reverse its physiologic changes, and thus, there is an acute need for (1) supporting people with dementia to maintain a healthy lifestyle, and (2) making early diagnosis of the disease. A key determinant of a healthy and active lifestyle is outdoor mobility. However, dementia affects complex activities such as navigation by impairing cognitive and functional abilities, making outdoor mobility particularly challenging for individuals. In addition, with certain dementias such as Alzheimer’s disease, navigational impairment is considered to be one of the earliest signs of the disease process. In this context, characterizing and supporting outdoor mobility for older adults with dementia is of great significance. Global positioning system (GPS) provides an avenue for addressing outdoor mobility challenges in dementia, and its application in dementia detection has become an area of increased interest. Therefore, the overarching aim of this thesis is to provide means to better understand and support outdoor mobility of people with dementia by using passively collected data from GPS. To operationalize this goal, Chapter 2 and 3 of this work present a new outlook on outdoor mobility patterns in dementia by developing a framework for classifying higher complexity mobility behaviours, ranging from temporal characteristics such as the timing of the user’s trips to semantic characteristics such as the user’s transportation modes and activity types. Chapter 4, then, evaluates the extent to which one can predict the future whereabouts of people with dementia by learning from their past mobility behaviours captured by the GPS-based framework. Finally, Chapter 5 explores driving behaviours, the most common form of transportation among older adults, by modelling older adults’ driving behaviours in naturalistic settings using GPS. In summary, this thesis is an attempt toward developing a comprehensive GPS Mobility Construct for understanding and supporting the complex and interconnected relationship between older adults with dementia and their environment.

Keywords: Automobile Driving
Dementia
Global Positioning System
Machine Learning
Outdoor Mobility
Spatial Analytics
Advisor: Mihailidis, Alex AM
Deciphering the Pro-apoptotic Mechanism of PUMA and its Role in Neuronal Cell Death and Axon Degeneration

The regulation of programmed cell death (apoptosis) coordinates organismal development, while its dysregulation in the adult drives the pathology of disease. At the level of the individual cell, the functional interactions among pro- and anti-apoptotic BCL-2 family proteins regulates the committing step for a cell to die. The abnormal overexpression of anti-apoptotic proteins drives cancer progression by preventing tumour cell death, while in contrast, atypical activation of pro-apoptotic proteins can drive neurodegeneration with the premature death of post-mitotic neurons. PUMA is just one member of the BCL-2 family of proteins, with a known importance in the death and degeneration of mouse neurons, but unknown role in human neuron destruction. Moreover, newly developed small-molecule inhibitors designed to displace pro-apoptotic proteins and kill tumour cells fail to displace PUMA. As a result, a better understanding of PUMA’s pro-apoptotic mechanism is needed to better kill tumour cells, while conversely preventing neuronal cell death and degeneration. Here, the measurement of interaction between PUMA and anti-apoptotic proteins reveals a novel binding site on the carboxyl-terminal sequence of PUMA. This site prevents small-molecule displacement of PUMA by promoting a high affinity protein interaction with globular anti-apoptotic proteins, independent of its known membrane binding function. This novel binding site is also important for the interaction and activation of the pore-forming protein BAX. PUMA knockout human neurons, derived from CRISPR-modified induced pluripotent stem cells, are resistant to a plethora of apoptotic stimuli. Low expression of PUMA results in little BAX activation and axon degeneration, but does result in apoptosis. As a result, neurons require PUMA to die, but can control its expression to regulate apoptosis versus axon degeneration based on the rheostat activation of BAX.

Keywords: Apoptosis
Axon degeneration
BAX
Neuron
PUMA
Advisor: Andrews, David W
Where Do All The Adjectives Go and What Do They Mean? Adjective Distribution and Interpretation in L1 Spanish

This dissertation investigates what Spanish speaking adults and children know about the distribution and interpretation of DP-internal adjectives in their language. The distribution of DP-internal adjectives in Spanish depends on their lexical subclass. Adults near categorically prefer pre-nominal ordinals (la segunda esquina ‘the second block’) and post-nominal relational adjectives (los animales marinos ‘the marine animals’). Despite more variability in ordering, superlatives (las riquisimas empanadas ‘the delicious empanadas’) and lexical shifts on their non-subsective (los pobres elefantes ‘the poor elephants’) and non-intersective (los buenos amigos ‘the good friends’) readings are also preferred pre-nominally [the former more so than the later]. Finally, epithets (el calido sol / el sol calido Lit. ‘the warm sun / sun warm’) and discourse contextual adjectives (los pequenos arreglos / los arreglos pequenos Lit. ‘the small repairs / repairs small’) occur in both pre- and post-nominal position. The position of the later further depends on restrictivity; pre-nominal discourse contextual adjectives are more acceptable in non-restrictive contexts, whereas post-nominal adjectives are not sensitive to context. There is little evidence for the distribution of Spanish adjectives in child directed speech. A corpus study of María (López Ornat, 1997) and Juan (Linaza, 1981) identifies few pre-nominal adjectives and finds the pre-nominal position is not productive in child speech. However, pre-nominal adjectives in the input share several semantic characteristics that could guide the learner. The results of a preference task and an acceptability judgement task support grammatical conservatism (Snyder, 2007). Children are not using the pre-nominal position in spontaneous speech because they haven’t figured out the lexical distribution of adjectives in their language. This does not result in a categorical preference for post-nominal position based on token frequency in the input, rather guessing performance is followed by the protracted emergence of ordering preferences beginning with ordinals, relational adjectives, and the high frequency lexical item pobre ‘poor’. As expected for children still figuring out the lexical distribution of adjectives in their language, even the oldest children in our sample lack awareness of the effect of restrictivity on discourse contextual adjectives. However, the acceptability of these adjectives in pre-nominal position grows with age.

Keywords: language acquisition
semantics
Spanish
syntax
Advisor: Pérez Leroux, Ana Teresa
Suffering Time: Nietzsche and the Generativity of Suffering

This dissertation explicates and extends Friedrich Wilhelm Nietzsche’s idea that “the ascetic ideal” provides meaning for suffering. I argue that responding to meaningless suffering is the singularly most important feature in the generation of religious, political, and moral narratives that identify, define, and enclose suffering within frameworks that dynamically seek to hold the reality of suffering as meaningful. I take it as given that meaningless suffering is cognitively and morally intolerable and essentially requires a response. The problem of suffering, as I understand it in this dissertation, is a problem of how to understand the dynamic relationship that narratives hold with suffering. Narratives shift and redefine the meaning of suffering as the terrain of suffering itself shifts. This constant movement discloses to us that cultivating better responses to suffering is a practice of critique of inherited ideas about suffering, as well as an ongoing and never-ending practice of relating oneself to the terrible novelty that meaningless suffering brings with it. I argue that interpretations of suffering tell us about the vision of life to which these interpretations belong, and interpretations of suffering are themselves generative of religious, political, and social realities that, in turn, condition the vision of life from which they emerge. Ultimately, the problem of suffering is not a problem that can be solved, but only a problem that can be lived through. Further, I extend Nietzsche’s critique of pessimism and suicidal nihilism to argue that how narratives understand suffering points toward ideas about the value of life itself. A truly “life affirmative” stance is one that can affirm the eternal repetition of our identical lives. Time, as our currency on earth, is limited and the suffering that comes with this recognition is an ever-present feature within Nietzsche’s analysis of the concept of suffering. I argue that in addition to providing a key way of understanding the generation of narratives of existential import, suffering is inherently temporal: both because it is temporary, but also because suffering occurs in time.

Keywords: Ascetic ideal
Eternal return
Meaninglessness
Nietzsche
Overcoming
Suffering
Advisor: DiCenso, James