VictorJuiz/thesis huggingface dataset:
The Role of Synaptic Activity in Neocortical Seizure State Transitions

Epilepsy is a dynamic disease characterized by seizure state transitions and their underlying phase-amplitude cross frequency coupled oscillations. Where inter-seizure periods show a decreased chance of a transition state with time, seizures are highly likely to self-terminate; however, the underlying synaptic mechanisms of these state transitions remain unclear. Given that presynaptic glutamate release has been implicated in epilepsy-associated oscillations, its regulation could be a critical factor underlying the chance of seizure state transitions. Seizure-like events (SLEs) were recorded from neocortical brain slices obtained from juvenile C57Bl/6 mice and from a knockout model of epilepsy (WWOX). Classification of SLE transitions was performed using PAC-related features applied to an objective state classifier, the hidden Markov model (HMM). Synaptic activity was measured using local field potential and whole cell voltage clamp recordings. The seizure termination sub-state showed an enhanced chance of seizure state transition. This pattern arose only when a 4Hz oscillation was included in the feature set. Antagonizing glutamate receptors inhibited all frequency bands of interest, which led us to hypothesize that glutamate was a critical factor in the occurrence of the SLE state. There was a suppression of presynaptic glutamate release at SLE termination, as demonstrated by electrically and optogenetically-evoked excitatory postsynaptic currents (EPSCs), and focal hypertonic sucrose application, which causes the extrusion of glutamate from the readily releasable pool in the presynaptic terminal. Adenosine A1 receptor blockade interfered with the suppression of this release, increasing the inter-SLE to SLE state transition probability. This finding points to the suppression of activity in human post-ictal generalized EEG suppression, and further application related to the adenosine hypothesis of sudden unexpected death in epilepsy. Furthermore, WWOX epileptic knockouts that exhibit severe seizures and premature death, also demonstrated neocortical bursts resembling polyspike-and-wave complexes with the same delta-gamma PAC features as other SLE models. However, these were dependent on postsynaptic glutamatergic signaling and depressed synaptic inhibition. In summary, the data from the WWOX model demonstrate potential targets for the suppression of seizures, and from other neocortical seizure models, reveal a critical role for presynaptic glutamate release in the transition into and out of the seizure state.

Keywords: epilepsy
glutamate
hidden markov model
seizure
state transition
wwox
Advisor: Carlen, Peter L
Circadian Secretion of Glucagon-like Peptide-1

Circadian rhythms are 24-hour biological rhythms within organisms that have developed over evolutionary time due to pre-defined environmental changes, mainly the light-dark cycle. Interestingly, metabolic tissues, which have been found to express cell-autonomous clocks that are entrained by food intake, are largely responsible for establishing diurnal metabolic homeostasis. The incretin hormone glucagon-like peptide-1 (GLP-1) enhances glucose-stimulated insulin secretion following nutrient ingestion and has recently been shown to follow a circadian rhythm of secretion that parallels the expression of the core clock gene, Bmal1. However, the mechanisms by which the GLP-1 secretory rhythm is established and its role in maintaining diurnal glycemic homeostasis under normal and obesogenic conditions remain largely elusive. Thus, I hypothesized that western diet (WD)-feeding disrupts L cell clock (Bmal1) function thereby impairing rhythmic GLP-1 secretion and diurnal glycemic homeostasis. Use of Bmal1 knockout mice and ex vivo cultures demonstrated the essential role for the clock (Bmal1) in regulating GLP-1 secretion. Mass spectrometry analysis of murine (m) GLUTag L cells identified the SNARE-accessory protein STXBP-1 to be increased at peak GLP-1 secretion, potentially as a result of time-dependent binding of BMAL1 to its promoter region. Metabolic testing in normal and WD-fed mice throughout the 24-hour day demonstrated that insulin secretion is rhythmic and glycemia is normal in response to oral, and not intraperitoneal, glucose administration, implicating an important role for the incretin hormones. Identical injections of the incretin hormones at different timepoints revealed differential insulin responses in normal mice, while WD-fed mice maintained normoglycemia only upon GLP-1, and not glucose-dependent insulinotropic polypeptide, administration, suggesting GLP-1 is the key incretin in WD-conditions. Finally, isolation of primary L cells established time-of-day differences in primary L cell clock gene expression that were dampened by WD-feeding and studies in mGLUTag L cells demonstrated that the saturated fatty acid palmitate, a major component of the WD, impairs L cell BMAL1 expression and mitochondrial function, ultimately resulting in suppression of GLP-1 secretion. In combination, these studies provide novel insight into the regulation and role of circadian GLP-1 secretion that can, ultimately, help in the development of novel therapeutics for the treatment of metabolic disease.

Advisor: Brubaker, Patricia L
Digital Control for Switched Mode Power Supplies with Improved Power Device Behaviour and Reconfigurable Functionalities

A segmented gate driver IC for mitigating the unwanted current overshoot during the turn-on of Insulated Gate Bipolar Transistors (IGBTs) is presented. The proposed IC is fabricated using TSMCs 0.18μm BCD Gen-2 process. Unlike existing collector current (IC) over-shoot reduction techniques, the proposed technique does not require significant additional external components or any increase in turn-on energy (EON ). A 37% reduction in IC overshoot (2.1 A to 1.3 A) is achieved while maintaining the same EON . A 54% reduction in EON (405 nJ to 185 nJ) is achieved for the same IC overshoot. A 15.5 dBm reduction in Conducted Electro-Magnetic Interference (CEMI), is observed when compared to operation with a constant ROU T and similar EON . In order to reduce the complexity of implementing the proposed gate drive technique (and other intelligent power module control techniques), an embedded stack based processor is developed. This processor is implemented in TSMCs 0.18 μm BCD Gen-2 process on the same die as a segmented gate driver. The compact design of the SPRUCE (Stack Processing Unit For Controlling Energy) processor allows reprogrammable functionality to be easily added to Intelligent IGBT Power Modules. A power consumption of 120 μA/MHz is achieved for SPRUCE. SPRUCE is used to develop a novel duty cycle correction technique. The proposed technique is shown to reduce the harmonic distortion in the output current of an IGBT based Intelligent Power Module by 13.1 dB. SPRUCE enables the logic of the proposed technique to be fully integrated within the Intelligent Power Module with no external controller needed. This completely integrated approach drastically improves the practicality of the proposed technique. Finally, SPRUCE is used to develop a programmable over current protection circuit for a boost converter. Further applications of SPRUCE as well as potential future enhancements to the design are presented in the final chapter.

Keywords: BCD
Gate-Driver
IGBT
IPM
SMPS
Advisor: Ng, Wai Tung
Transsaccadic Memory: Working Memory in Action

Transsaccadic memory is the process by which visual information is maintained and spatially updated across eye movements. Transsaccadic memory resembles general visuospatial working memory in many ways, but it is unclear whether the two functions do share common faculties, or if the transsaccadic functions are underpinned by specialized mechanisms given the unique demands of maintaining spatial constancy across eye movements. Six experiments are presented in this thesis to address this question. In Chapter 2, I found that transsaccadic memory performance is predicted by performance on a 2-Back task, demonstrating commonalities with general visuospatial working memory. I also found, however, that performance on a change detection task did not predict transsaccadic memory performance, indicating a dissociation between a well-established contemporary measure of visuospatial working memory and transsaccadic memory. Change detection performance also failed to predict performance on the 2-Back task, so in Chapter 3, four variants of the change detection task were created to test possible explanations for the dissociations. All change detection tasks correlated strongly with the standard change detection task, but a correlation with the 2-Back task was seen only with a change detection variant where the availability of contextual spatial information during the test phase was minimized. This version of the change detection task was then tested against the transsaccadic task in Chapter 4, along with 2-Back and a no-saccade baseline for the transsaccadic task to isolate saccade-related performance components. Doing so, two saccade-related components were found that predicted performance on the working memory measures, though only one of these components explained variance across all tasks. I conclude that transsaccadic memory does appear to share faculties with general visuospatial working memory, but that like visuospatial working memory itself, it is a multifaceted construct.

Keywords: Perception
Remapping
Saccades
Transsaccadic memory
Visual working memory
Visuomotor systems
Advisor: Frost, Adam L
Vowel Elision, Epenthesis and Metrical Systems in Bedouin Arabic Dialects

This dissertation is a contribution to the understanding of the synchronic metrical phonology and related segmental processes in two Bedouin Arabic dialects of the Arabian Peninsula that have received little attention in the literature, Ruwaili and Hofuf Bedouin. Presented within a lexical phonology and morphology framework, the major goals of the dissertation are to provide a unified prosodic account of structures that result from the processes of syncope (High Vowel Deletion, Trisyllabic Elision, low vowel deletion) and epenthesis, to understand the strategies that are used in each of the dialects to account for unsyllabified segments, and to account for the major metrical patterns. The two varieties, while similar in many ways, also show some significant differences, with Ruwaili closely resembling other Bedouin varieties and Hofuf Bedouin being distinct in many ways and showing types of variation not reported in other Bedouin dialects. Differences between them can be expressed in terms of where various processes occur, most notably that epenthesis is found at different morphological levels in the two dialects. The dissertation examines the history of migration of the various Bedouin varieties and concludes that the differences can be accounted for due to contact with Hofuf Sedentary, a non-Bedouin dialect neighbouring Hofuf Bedouin. Thus, the dissertation both provides extensive data on two understudied Bedouin varieties and considers the similarities and differences between the Bedouin dialects of the Arabian Peninsula, extending earlier studies which focus on individual dialects.

Keywords: Bedouin Arabic Dialects
epenthesis
iambic stress
prosodic representation
vowel deletion
vowel raising
Advisor: Rice, Keren
Exploring Students’ Perspectives on Critical Thinking Integration in College Pre-health Science Education

Educators and healthcare practitioners increasingly recognize the importance of critical thinking (CT) in health sciences education. CT encompasses knowledge, its evaluation/synthesis, and habits of mind. Perspectives from scholars emphasize features that inform a range of theories on CT integration. This research foregrounded the perspectives of college pre-health science students. A case study was conducted to address three research questions: What are the students’ perspectives on 1) what constitutes CT; 2) its role as integrated in pre-health science courses; and 3) the challenges experienced with CT integration? Quantitative/qualitative data was gathered from survey questionnaires at the start of the program. Qualitative data was collected from classroom observations during CT-integrative activities, and individual semi-structured interviews. Inductive-deductive content analysis revealed several themes. Students collectively characterized CT as habits of mind, content and processes aimed at comprehensively, objectively, rationally and normatively ascertaining “truth”. During integrative science activities, students applied CT to learn science content intuitively or consciously depending on their prior science knowledge. CT’s amenability for integration within subjects depended on the students’ prior subject knowledge and perceptions of the comparative nature of subjects to that of CT. Furthermore, how students anticipated CT in healthcare framed their beliefs on CT integration into science curriculum. Challenges with CT integration stemmed from incongruencies between its expected manifestations in healthcare versus its portrayal in education. In education, formalized CT and subject-specific incompatibility felt inauthentic, and risked undermining the learning of science content. A lack of socialization to ambiguity due to CT integration begged more guidance from professors to provide definitiveness over scientific claims. Therefore, authentic CT integration that resonates with students hinges upon a threshold of prior knowledge in individual subjects and CT. Acclimation to CT that is simultaneous with building foundational scientific knowledge might reveal opportunities for conscious and complex integration. Sustained opportunistic integration leveraging natural intersections might acclimate students to CT as part of their education, and further reveal its relevance in healthcare. This thesis concludes with recommendations for theory and practice.

Keywords: Case Study
Critical Thinking
Curriculum Integration
Post-Secondary Education
Pre-Health Science Education
Qualitative Research
Advisor: Pedretti, Erminia
Multiphysics Modelling and Characterisation of the Survivability of Encapsulated Microelectronics in Precision Guided Projectiles

Precision-guided projectiles (PGPs) are subjected to severe shock loads that often lead to the failure of highly essential embedded microelectronic systems (EMES) responsible for guidance and control. In this research program, we seek to identify and better understand the parameters affecting the survivability of the embedded electronics over their entire lifespan and to develop an effective shock attenuation system (SAS) to protect them. Accordingly, three aspects of the work were considered: (i) conduct comprehensive multiphysics simulations of a PGP containing EMES subjected to propellant induced shock loads accounting for fluid-structure and solid-solid interactions, (ii) evaluate the survivability of microelectronic components and assess the effectiveness of various encapsulation designs to attenuate both short duration impulses and long duration launch loads, and (iii) examine the long term aging degradation of the mechanical and physical properties of the polymeric encapsulant through extensive experimental testing. The outcomes of this work reveal that the flight state transition at muzzle exit is characterized by high oscillatory pressure and acceleration profiles. Additionally, this work determined that the intensity of both propellant- and precursor- induced shock waves diminish rapidly due to the rapid expansion of the shock wave front at muzzle exit. Meanwhile, the frictional forces resulting from contact with the inside of the barrel significantly increase the amplitude of the projectile’s oscillatory acceleration profile following muzzle exit. In regards to the EMES survivability, it was determined that soft and hard single-layered encapsulant arrangements are ineffective as SAS because these arrangements allow for either excessive deformation of the encapsulant or excessive rigidity that is incapable of damping the fluctuations after muzzle exit. In contrast, the proposed trilayer encapsulant arrangements reduce the induced stress field, while also dampening the oscillations following muzzle exit. Finally, significant reductions in the physical and mechanical properties of epoxy encapsulant were demonstrated when they were subjected to thermal, hygrothermal and UV radiation aging conditions.

Keywords: Embedded microelectronic systems
Finite Element
Multiphysics
Precision-guided projectiles
Propellant
Survivability
Advisor: Meguid, Shaker A
Advance Care Planning in Advanced Heart Failure: A Relational Exploration of Autonomy

Advance care planning (ACP) is the process of understanding and sharing personal values and goals to ensure people with serious illnesses receive healthcare and treatment that is consistent with their goals and preferences. With the increasing number of treatment options available to patients living with advanced heart failure (HF), ACP is regarded as a means of preserving individual autonomy throughout the illness trajectory. Despite significant public awareness campaigns, research and interventions developed to increase participation in ACP, this practice remains severely under-utilized by those who are chronically ill. This gap in practice highlights the need for further exploration of how patients, families and healthcare providers (HCP) engage with ACP as a practice that is intended to promote patient autonomy. Therefore, the aim of this research was to gain an understanding of how patients, families and healthcare providers (HCP) understand and express their autonomy within the process of ACP. Critical qualitative multiple case study methodology, guided feminist ethics and relational autonomy, was used. Patients with advanced HF were purposefully recruited from two sites; cases were constructed using data from 19 interviews with seven patients, eight caregivers, and nine HCPs. Constructions of autonomy were developed using within and across-case analysis, guided by relational conceptualizations of autonomy. There were three key findings that resulted from this study. First, ACP is understood as external to treatment decision making within the current biomedical landscape, with a specific focus on the power of the legal model. Second, the experience of autonomy in advanced HF is incongruent with the dominant individualistic approach and instead, is a relational experience that is based on relationships of trust. Finally, ACP is influenced by interpersonal relationships and responsibilities as well as interpersonal and social power dynamics. Although ACP is considered a practice that preserves individual autonomy, interpersonal, institutional and societal level relationships were all heavily influential in this practice. Future research and practice endeavors should consider the advancement of ACP (and the enactment of autonomy) using a relational framework that acknowledges autonomy is experienced within the context of institutional, social, and interpersonal relationships.

Keywords: advance care planning
autonomy
bioethics
end of life
heart failure
qualitative research
Advisor: Peter, Elizabeth
Pardoning Profit: Neoliberal Transitional Justice in Côte d’Ivoire

This dissertation builds on an emerging critical literature that contends transitional justice aligns with neoliberal governance by overlooking socioeconomic harms and by protecting elite interests. Using Côte d’Ivoire as a case study, the dissertation argues that contemporary transitional justice does not merely align with neoliberalism in postwar contexts; it advances this reordering of governing and social order by limiting the moral obligation on government and society to respond to structural injustices. By restricting the moral obligation to address the suffering of others to a limited set of human rights violations, transitional justice establishes a new moral order where harms caused by individual rights violations are recognised as intolerable and demands justice, but the suffering caused by grave inequality, deprivation and other forms of structural injustice are implicitly tolerated and hence more easily overlooked by the state and by fellow citizens. Transitional justice institutions thus shape post-conflict justice into a process that protects elite interests and excludes transformative reforms or more radical demands such as wealth or land redistribution. The national reconstruction process that followed Côte d’Ivoire’s decade long civil war combined neoliberalisation and transitional justice as core priorities of the post-conflict regime. This dissertation shows that transitional justice in Côte d’Ivoire had the dual function of reinforcing neoliberal reforms while also legitimizing this reordering of governance as just and democratic. As such, it served as the ideological foundation for President Alassane Ouattara’s expansive and market-oriented governance reform agenda while simultaneously advancing a discourse domestically and abroad about the rights-respecting and liberal democratic nature of the new government.

Keywords: Côte d'Ivoire
Peacebuilding
Transitional Justice
Truth Commissions
Advisor: Jung, Courtney
Generating Isogenic Models of Li-Fraumeni Syndrome and Restoring p53 using CRISPR

Li-Fraumeni syndrome (LFS) is a highly penetrant familial cancer predisposition disorder characterized by a spectrum of multiple early-onset primary cancers in first- and second-degree relatives, usually caused by a germline mutation in the TP53 tumor suppressor gene. The discovery of CRISPR has led to precision gene editing strategies which provides new opportunities to model and treat genetic disorders. By applying CRISPR gene editing strategies to correct germline TP53 mutations in patient derived LFS fibroblast models and in a mouse LFS osteosarcoma model, this thesis demonstrates the feasibility and explores the limitations of mutant TP53 allele specific targeting. First, to understand the role of heterozygous germline TP53 mutations (H193P and S240G) in the context of normal cell function and the development of cancer, we used a CRISPR gene editing approach to specifically target mutant TP53 alleles in LFS patient-derived fibroblast lines and restore two functional wild-type TP53 alleles. Our approach was highly specific (no detectable editing in wild-type alleles); surprisingly, repaired TP53 fibroblast lines exhibited a reduced response to DNA damage (low p53 and p21 expression) when compared to unedited fibroblast lines harbouring either mutant or wild-type TP53. Repaired fibroblast lines were significantly more susceptible to senescence, suggesting that the restoration of a homozygous wild-type TP53 genotype in heterozygous mutant TP53 LFS fibroblast lines disrupts the balance of p53 signaling and prevents the escape of LFS fibroblasts from replicative senescence. In a second study, we designed a CRISPR-mediated approach to target mutant Trp53 and restore p53 function as a therapeutic in tumour cell lines derived from a p53R172H/+ LFS mouse model. After generating double-strand breaks with sgRNAs targeting the R172H Trp53 mutation in an osteosarcoma cell line, single-cell clonal populations were generated and examined. 76% of clonal lines had multiple short indels, indicating a high preference for NHEJ repair. sgRNA efficiency for generating targeted double stranded breaks approached 100% in generated clones, but none had observed p53 restoration. Overall, these results highlight the feasibility of precision gene editing in mutant p53 systems and shed light on the complexities of germline p53 mutant signaling in both normal and cancer cells.

Keywords: cancer
crispr
li-fraumeni syndrome
p53
Advisor: Malkin, David